problem solving in logy

Problem Solving in

RheumatologyKEVIN PILE MB ChB, MD, FRACPConjoint Professor of Medicine, University of Western Sydney,New South Wales, Australia

LEE KENNEDY BSc, MB ChB, MD, PhD, FRCP, FRCPE, FRACPProfessor of Medicine, School of Medicine, Department of Medicine, James Cook University, Queensland, Australia

C L I N I C A L P U B L I S H I N G

O X F O R D

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Contents

Abbreviations vii

S E C T I O N 1 General Rheumatology and Soft TissueRheumatism

1. New Onset Painful Joints 12. An Acutely Swollen/Hot Joint 63. Painful Shoulders – Rotator Cuff and Frozen Shoulder 114. Tennis Elbow and Golfer’s Elbow 185. Carpal Tunnel Syndrome and Other Entrapment Neuropathies 216. Fibromyalgia Syndrome 277. Plantar Fasciitis 33

S E C T I O N 2 Osteoarthritis8. Causes and Prevention 399. Non-Pharmacological Treatment 45

10. Drug Treatment 5011. NSAIDs – Gastric Side Effects and Protection 5412. NSAIDs – Cardiac Complications 6013. Joint Replacement Surgery 65

S E C T I O N 3 Rheumatoid Arthritis14. Causes 7115. Laboratory and Imaging Investigations 7716. Managing Rheumatoid Arthritis at Onset 8217. Evaluating the Response to Treatment 8718. Pregnancy and Rheumatic Diseases 9219. Diet and Arthritis 9720. Polyarthritis in the Elderly 103

S E C T I O N 4 Systemic Lupus Erythematosus, Sjögren’sSyndrome and Scleroderma

21. Antinuclear Factor 10922. SLE – Risk Factors and Diagnosis 11623. Monitoring and Managing SLE 122

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24. Sjögren’s Syndrome 12925. Raynaud’s Phenomenon 13426. Assessing and Treating Scleroderma 13927. Immunosuppressive Drugs 147

S E C T I O N 5 Vasculitic Syndromes28. Vasculitic Disease 15329. Giant Cell Arteritis and Polymyalgia Rheumatica 15930. Behçet’s Syndrome 165

S E C T I O N 6 Back and Specific Joint Problems31. Acute Back Pain 16932. Chronic Back Pain 17533. Psoriatic Arthritis 17834. Asymptomatic Hyperuricaemia 18435. Gout – Acute Attack and Beyond 18936. Pseudogout – Investigation and Management 19537. Joint and Bone Infections 19938. Viral Arthritis 20539. Rheumatological Complications of Diabetes 211

S E C T I O N 7 Bone Diseases40. Osteoporosis – Prevention and Lifestyle Management 21741. Bisphosphonates for Osteoporosis – Which Agent and When? 22242. Osteoporosis – Drugs Other Than Bisphosphonates 22743. Male Osteoporosis 23344. Glucocorticoid-Induced Osteoporosis 23745. Paget’s Disease of Bone 24146. Bone Complications of Renal Disease 246

S E C T I O N 8 Muscle Diseases47. Steroid myopathy 25348. Inflammatory Myopathies 26049. Muscle Complications of Statin Therapy 265

General index 271

Contentsvi

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ABD adynamic bone diseaseACE angiotensin-converting enzymeACR American College of RheumatologyADAMTS a disintegrin and metalloproteinase

with thrombospondin motifADFR Activate, Decrease osteoclast

activity, Free of treatment andRepeat

ADP adenosine diphosphateADR adverse drug reactionAMP adenosine monophosphate ANA antinuclear antibodyANCA anti-neutrophil cytoplasmic

antibodiesANF antinuclear factorAP alkaline phosphataseAP-1 activator protein-1 APPROVe Adenomatous Polyp Prevention on

Vioxx studyAPS antiphospholipid syndrome AS ankylosing spondylitisASC apoptosis-associated speck-like

proteinATP adenosine triphosphateB19 parvovirus B19 BASMI British Ankylosing Spondylitis

Metrology Index BMD bone mineral density BMI body mass indexBP blood pressureBPs bisphosphonatesC5 fifth cervical segment c-ANCA cytoplasmic anti-neutrophil

cytoplasmic antibody CCB calcium channel blockerCCTG cytosine-cytosine-thymine-guanineCCL2 monocyte chemoattractant protein-

1 (see also MCP-1)CCP cyclic citrullinated peptideCDSN corneodesminCEP circulating endothelial precursorcGMP cyclic guanosine monophosphateCHB congenital heart block CI confidence interval

CIM critical iIlness myopathyCK creatine kinaseCKD chronic kidney disease CKD-MBD CKD-mineral and bone disorder CLASS Celecoxib Long-term Arthritis

Safety Study Clc-l chloride channelCMC carpometacarpophalangealCNS central nervous systemCORE Continuing Outcomes Relevant to

Evista COX cyclooxygenaseCOX-1 cyclooxygenase-1COX-2 cyclooxygenase-2CPEO Chronic Progressive External

OphthalmoplegiaCPPD calcium pyrophosphate dihydrate CREST Calcinosis; Raynaud’s phenomenon;

Esophageal dysmotility;Sclerodactyly, Telangiectasia

CRP C-reactive proteinCSS Churg–Strauss syndromeCT computed tomography CTG cytosine-thymine-guanineCTGF connective tissue growth factor CTS carpal tunnel syndromeCTLA4-Ig cytotoxic lymphocyte-associated

antigen linked to immunoglobulin CVD cardiovascular disease CXR chest X-rayD3 1,25-dihydroxy-vitamin D3

DC dendritic cellDD Dupuytren’s disease DEXA dual-energy X-ray absorptiometryDHA docosahexaenoic acidDHEA dehydroepiandrosterone DIL drug-induced lupusDIP distal interphalangealDISH diffuse idiopathic skeletal

hyperostosisDLCO diffusing capacity for carbon

monoxideDM dermatomyositis DM1 myotonic dystrophy type 1

Abbreviations

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DM2 myotonic dystrophy type 2DMARD disease-modifying antirheumatic

drugDMOAD disease-modifying osteoarthritis

drugDMPK myotonic dystrophy protein kinase dsDNA double-stranded DNAEBV Epstein–Barr virus EDTA ethylenediaminetetraacetic acidEEG electroencephalogramEGF epidermal growth factor eGFR estimated glomerular filtration rateELISA enzyme-linked immunosorbent

assayEMG electromyographyENA extractable nuclear antigeneNOS endothelial nitric oxide synthaseEPA eicosapentaenoic acid ESR erythrocyte sedimentation rateET endothelinFA fatty acidFBC full blood countFDG-PET (18)-F-fluorodeoxyglucose-positron

emission tomographyFGF fibroblast growth factorFKBP-12 12 kDa FK506-binding protein FMS fibromyalgia syndromeFVC forced vital capacity FSH follicle-stimulating hormoneGAIT Glucosamine/chondroitin Arthritis

Intervention TrialGCA giant cell arteritis GDM gestational diabetes GFR glomerular filtration rateGI gastrointestinalGMP guanosine monophosphateGSD glycogen storage diseaseGTP guanosine triphosphateGVHD graft-versus-host disease H2RA histamine H2 receptor antagonist HBA1C glycosylated haemoglobinHBO2 hyperbaric oxygen HDL high-density lipoproteinHELLP Haemolytic anaemia, Elevated Liver

enzymes, Low PlateletsHIV human immunodeficiency virusHLA human leukocyte antigen (genetic

designation for human majorhistocompatibility complex)

HNPP hereditary neuropathy with liabilityto pressure palsies

hnRNP heterogeneous nuclearribonucleoprotein

HPRT hypoxanthinephosphoribosyltransferase

HRCT high-resolution computedtomography

HRT hormone replacement therapyHSP Henoch-Schönlein purpuraHTLV-1 human T-lymphotropic virus type 1IBD inflammatory bowel diseaseIBM inclusion body myositis IFN interferonIg immunoglobulin IGF-1 insulin-like growth factor-1Iκβ inhibitor of kappa-betaIL interleukinIL-1ra interleukin-1 receptor antagonist IMPDH inosine monophosphate

dehydrogenase IMT intima-media thickness INR International Normalized RatioIP inflammatory polyarthritis IU International UnitsJSN joint space narrowing LBP low back painLDL low-density lipoproteinLFA-1 lymphocyte function-associated

antigen-1LFT liver function testLIFE Losartan Intervention for Endpoint

reductionLJM limited joint mobilityLORA late-onset RA LRP-5 LDL receptor-related protein-5 LUMINA Lupus in minorities: nature versus

nurtureLH luteinizing hormoneMCP metacarpophalangealMCP-1 monocyte chemoattractant protein-

1 (see also CCL2)MCTD mixed connective tissue disease MELAS Myopathy, Encephalopathy, Lactic

Acidosis and StrokeMERRF Myoclonic Epilepsy with Ragged

Red FibresMI myocardial infarctionMMF mycophenolate mofetil MMP matrix metalloproteinaseMORE Multiple Outcome of Raloxifene

EvaluationMPA microscopic polyangiitis

Abbreviationsviii

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MRI magnetic resonance imagingMRSA methicillin-resistant Staphylococcus

aureusMSA myositis-specific antibodiesMTOR mammalian target of rapamycin MTP metatarsophalangealMUA manipulation under anaesthesiaNALP pyrin domain-containing proteins

sharing structural homology withNODs

NCS nerve conduction studiesNFAT nuclear factor of activated T

lymphocytesNF-κB nuclear factor-κ-betaNHANES National Health and Nutrition

Examination Survey NIH National Institutes of Health NO nitric oxideNOD nucleotide-binding and

oligomerization domain proteinsNOS nitric oxide synthaseNOS-2 inducible nitric oxide synthaseNOS-3 endothelial nitric oxide synthase

(eNOS)NSAID non-steroidal anti-inflammatory

drugOA osteoarthritis OCP oral contraceptive pill25(OH)D 25-hydroxy-vitamin DOPG osteoprotegerinOR odds ratioPADAM partial androgen deficiency in aging

men PADI peptidylarginine deaminasePAH pulmonary artery hypertension PAN polyarteritis nodosap-ANCA perinuclear anti-neutrophil

cytoplasmic antibody PCR polymerase chain reactionPCT plasma procalcitonin PDGF platelet-derived growth factorPET positron emission tomography PG prostaglandinPGI2 prostacyclinPIP proximal interphalangealPM polymyositis PM/DM polymyositis/dermatomyositis PMR polymyalgia rheumatica PP pyrophosphatePPAR peroxisomal proliferator-activated

receptor

PPI proton pump inhibitorPPRP 5¢phosphoribosyl 1-pyrophosphatePRIMO Prediction of Muscular Risk in

Observational conditionsPsA psoriatic arthritisPTH parathyroid hormonePTNP22 protein tyrosine phosphate non-

receptor type 22PUFAs polyunsaturated fatty acidsQALY quality-adjusted life yearRA rheumatoid arthritisRANK receptor activator of NF-κBRANKL receptor activator of NF-κB ligandRCT randomized controlled trialREM rapid eye movementRF rheumatoid factorRISC RNA-induced silencing complex RNA ribonucleic acidRNP ribonucleoproteinROD renal osteodystrophy ROS reactive oxygen speciesRR relative riskRS3PE remitting seronegative symmetric

synovitis with pitting oedema RUTH Raloxifene Use for The Heart SAPHO Synovitis, Acne, Pustulosis,

Hyperostosis and OsteitisSE shared epitopeSELENA Safety of Estrogens in Lupus

Erythematosus National Assessment SERM selective oestrogen receptor

modulatorSHBG sex hormone binding globulinSI sacroiliacsIL-6R soluble receptor for IL-6 SJC swollen joint countSLC22A4 solute carrier family 22 A4SLE systemic lupus erythematosusSm Smith antigenSOBOE shortness of breath on exertionSOTI Spinal Osteoporosis Therapeutic

Intervention SPARC secreted protein acidic and rich in

cysteineSPECT single photon emission computed

tomographySRP signal recognition particleSRRR sibling recurrence risk ratio SS Sjögren’s syndrome SSc systemic sclerosis ssDNA single-stranded DNA

Abbreviations ix

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STAT1 signal transducer and activator oftranscription-1

sTNFR soluble receptor for TNFSSRI selective serotonin reuptake

inhibitorTB tuberculosisTBF thermal biofeedback TGF-β transforming growth factor-βTh1 T helper 1 cellsTh2 T helper 2 cellsTIMP tissue inhibitor of

metalloproteinaseTJC tender joint countTLR Toll-like receptorTKA total knee arthroplastyTMV turnover, mineralization and

volume TNF tumour necrosis factorTNFR2 TNF-α receptor type 2TRAP tartrate-resistant acid phosphatase

TROPOS Treatment Of PeripheralOsteoporosis Study

TSH thyroid-stimulating hormoneTxA2 thromboxane A2

U1RNP uracil-rich 1 ribonucleoprotein UA uric acidU/E urea and electrolytesUDP uridine diphosphateUK United KingdomUS United StatesUV ultraviolet lightVDR vitamin D receptorVEGF vascular endothelial growth factorVIGOR Vioxx Gastrointestinal Outcomes

Research studyWBC white blood cellWHO World Health Organization WOMAC Western Ontario and McMaster

UniversitiesXO xanthine oxidase

Abbreviationsx

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01 New Onset Painful Joints

General Rheumatology and SoftTissue Rheumatism

S E C T I O N O N E 01

01 New onset painful joints02 An acutely swollen/hot joint03 Painful shoulders – rotator cuff and frozen shoulder04 Tennis elbow and golfer’s elbow05 Carpal tunnel syndrome and other entrapment neuropathies06 Fibromyalgia syndrome07 Plantar fasciitis

P R O B L E M

Case HistoryJune is a 32-year-old tour guide with an eight-week history of painful stiff hands anddifficulty walking in the mornings. The symptoms usually last for 90 minutes. For the lastsix weeks she has been using diclofenac 50 mg bd with moderate benefit. Her mother hasrheumatoid arthritis treated with methotrexate.

What additional history will help to determine a diagnosis?

What is the relevance of her family history?

What aspects of the examination will be particularly relevant?

Which investigations should be performed?

© Atlas Medical Publishing Ltd

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BackgroundHistoryObtaining a clear history of June’s symptoms will assist greatly in narrowing your initialdifferential diagnosis as a prelude to examination and investigations. Open questionsthat encourage the person to start with their initial symptoms provide chronology andthe pattern of progression. Gentle prompting can, towards the end of consultation, besupplemented with specific questions. As you listen to the story, you will be assessing theimpact of the symptoms on the individual’s life and its components of family, work andleisure. Specifically:

� Are symptoms related to a musculoskeletal problem?

� Was there an identified trigger or precipitant?

� What has been the pattern or progression of symptoms?

� Are there features of systemic illness or inflammatory disease?

� Has anything helped the problem?

Pain and loss of function are primary presenting symptoms, but do not always coexist.Individuals differ in their descriptors of pain, its intensity and its impact. You will be toldwhen the problem began and where. Is the pain in a joint; in a related joint structure suchas tendon, ligament or bursa; or in a bone? What is the nature of the pain; when does itoccur; and what is the effect of movement? Malignant pain is usually a dull, deep achewithin a bone, occurring at night or when resting. Similar symptoms may occur withPaget’s disease or with a fracture. Differentiators of inflammatory from non-inflamma-tory/mechanical joint pain are summarized in Table 1.1.

Localization of pain requires clarification as to whether symptoms are recreated bycontact or movement in the area, or whether the pain is referred from another site.Referred pain occurs when sensory perception externalizes nociceptive input from thesclerotome or myotome of an affected structure to the relevant dermatome. Table 1.2shows common referred pain patterns.Onset of symptoms following trauma supports mechanical disruption of a joint, dis-

ruption of a joint’s surrounding capsule and ligaments, or fracture. Less obvious triggersto explore are infections (Table 1.3), vaccinations (Rubella) and recent travel. A tactfulapproach is required when soliciting information on genitourinary symptoms or a

§01 General Rheumatology and Soft Tissue Rheumatism2

Inflammatory pain Non-inflammatory/mechanical pain

• Pain and stiffness predominant in morning and at end of day • Short-lived joint stiffness• Stiffness greater than 30minutes • Pain worsens with activity• Symptoms lessen with activity • Pain improves with rest• Pain does not improve with rest• Localized erythema, swelling, tenderness• Systemic features – fatigue, weight loss

Table 1.1 Differentiators of joint pain


history of a new sexual partner, as it is not obvious to a patient with arthritis as to whyyou would be asking such questions.A comprehensive family history is a key part of every clinical history. A familial pat-

tern of a specific diagnosis such as rheumatoid arthritis (RA), ankylosing spondylitis orsystemic lupus erythematosus (SLE) highlights that diagnosis, and may also raise relateddiagnoses that are particularly relevant for seronegative spondyloarthritides such as pso-riasis or inflammatory bowel disease.

ExaminationExamination identifies the pattern and number of joints involved and extra-articular fea-tures (Table 1.4). Features of inflammation are sought: temperature, pulse and bloodpressure are measured, and an assessment is made of localized erythema and warmth,tenderness, inflammation obscuring the joint margins, and reduced function. Youshould distinguish monoarthritis from oligoarthritis (≤4 joints) and polyarthritis (>4joints), whether these joints are large or small, and whether there is spinal (particularlysacroiliac) involvement. Distal to the wrist and ankle there are at least 56 joints, so that asthe number of joints increases, the greater the probability is of involvement of bothhands and feet and of the pattern becoming increasingly ‘symmetrical’. Fingernails areassessed for pitting or onycholysis suggestive of psoriasis. The scalp, umbilicus, natal cleftand extensor surfaces of knee and elbow should be inspected. The presence of a malarrash or photosensitive rash in a young woman suggests SLE.

InvestigationsInvestigations serve to:

� Confirm or refute a diagnostic possibility

01 New onset painful joints 3

Area pain experienced Origin of pain

Shoulder Cervical spine

Biceps and lateral upper arm Shoulder and rotator cuff

Groin, inner knee Hip

Lateral thigh, buttock Trochanteric bursa

Table 1.2 Common presentations of referred pain

Viral Gastrointestinal Genitourinary

Hepatitis B, C Salmonella typhimurium Chlamydia trachomatis

Rubella Shigella flexneri

Parvovirus Yersinia enterocolitica

Arbovirus * Campylobacter jejuni

* Serology should be tested according to exposure.

Table 1.3 Common infections associated with arthritis


� Monitor for known complications of the disease process or proposed treatment

� Document a parameter that changes with disease activity or treatment

The latter includes the inflammatory markers erythrocyte sedimentation rate (ESR)and C-reactive protein (CRP), which are non-specific markers. Whenever the possibilityof a septic joint is considered, obtaining aspirate and culture from the joint is mandatory.Aspirated fluid is collected into a sterile container and an ethylenediaminetetraacetic acid(EDTA)-containing tube to enable a cell count, and is sent with a request for Gram stain-ing, polarized light microscopy, culture and sensitivity, and cell count and differentialcell count. If there will be a significant delay in the sample reaching the laboratory, fluidcan be inoculated into a blood culture system.The early signs and symptoms of RA are not always typical. RA is characterized as

autoimmune partly on the basis of the presence of rheumatoid factor (RF), an autoanti-body (usually immunoglobulinM [IgM]) targeting the Fc portion of IgG. Its sensitivity islow, ranging from 60%–80%, and specificity is lower, the antibody being frequently pre-sent in other connective tissue diseases, which limits the diagnostic utility.

Recent Developments1 RF is present in 70% of RA cases but is not specific, occurring in 5% of healthy

individuals, and globally is more associated with chronic infection than rheumaticdiseases. Non-RF antibodies were first described in the 1960s, with the target


Pattern Monoarthritis Inflammatory Asymmetrical Symmetrical small DIP handsspinal disease large joint joint arthritisSacroiliitis arthritis (MCP, PIP, MTP)

Differential Trauma Ankylosing Psoriatic arthritis RA Inflammatory OAdiagnosis spondylitis (if involves PIP and

1st CMC)Haemophilia Psoriatic arthritis Reactive arthritis SLE Psoriatic arthritisSeptic IBD IBD Psoriatic arthritisGoutPseudogout

Further X-ray Review personal Review personal Examine X-ray handsinvestigations and family history and family history rheumatoid nodules

Aspirate for HLA-B27 Examine for Skin rashes,crystals and conjunctivitis and serositis orculture urethritis, and scalp mucositis

and buttocks forpsoriasis

X-ray lumbar Infection screen Urinalysisspine and SI joints RF, CCP antibodies,

ANAX-ray handsand feet

ANA, antinuclear antibodies; CCP, cyclic citrullinated peptides; CMC, carpometacarpophalangeal; DIP, distal interphalangeal; IBD, inflammatory boweldisease; MCP, metacarpophalangeal; MTP, metatarsophalangeal; OA, osteoarthritis; PIP, proximal interphalangeal; RA, rheumatoid arthritis; RF,rheumatoid factor; SI, sacroiliac; SLE, systemic lupus erythematosus.

Table 1.4 Patterns of arthritis


epitopes now identified as citrulline residues, which are arginine residuesmodified by peptidylarginine deaminase (PADI). Assays are now available for thedetection of antibodies to cyclic citrullinated peptides (anti-CCP antibodies),which are highly sensitive and specific for RA and are a poor prognostic markerof joint erosion, vasculitis and rheumatoid nodules.1 The specificity of anti-CCPin RA is >90% with sensitivity of 33%–87%. When combined with IgM-RF, anti-CCP has positive predictive value of >90% for RA.2 A study of undifferentiatedpolyarthritis found that 93% of subjects positive for anti-CCP at first clinic visitprogressed to RA compared to 25% who were anti-CCP negative.3

2 Smoking increases the risk of RA 2–4 fold and also influences the manifestationsof the disease – with increased RF positivity and erosive disease, nodularity andvasculitis – similar to the findings noted with anti-CCP antibodies. Smoking maybreak immune tolerance by creating neo-epitopes on IgG and thus leading to RFdevelopment. Recent work has shown that smoking is associated with increasedcitrullination. The subsequent citrullinated antigens bind with more affinity tothe HLA-DR4 shared epitope subtypes, leading to increased risk of RA.4

ConclusionPersistent arthropathy in a younger patient necessitates both accurate diagnosis andeffective management. A working knowledge of local infectious triggers is required, withsupplemental knowledge of the likely pathologies based on age and gender. History andexamination need to include potential exposure to infectious triggers, along with per-sonal and family history. Examination will confirm or exclude significant joint inflam-mation, and provide information on its pattern and severity (number of joints andfunctional impact). Targeted investigations will narrow the diagnosis, with the urgentinvestigation being exclusion of septic arthritis if there is clinical suspicion.

Further Reading1 Mimori T. Clinical significance of anti-CCP antibodies in rheumatoid arthritis. Intern Med

2005; 44: 1122–6.

2 Schellekens GA, Visser H, De Jong BAW et al. The diagnostic properties of rheumatoid arthri-

tis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 2000; 43: 155–63.

3 van Gaalen FA, Linn-Rasker SP, van Venrooij WJ et al. Autoantibodies to cyclic citrullinated

peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis:

a prospective cohort study. Arthritis Rheum 2004; 50: 709–15.

4 Gorman JD. Smoking and rheumatoid arthritis: another reason just to say no. Arthritis Rheum

2006; 54: 10–13.

01 New onset painful joints 5


Case HistoryYou have been asked to see a 28-year-old man who presents with a 36-hour history of ared and very swollen right knee, upon which he is unable to weight bear. He has beenpreviously well and has no relevant family history. The clinic nurse has recorded histemperature as 37.9°C and a random blood glucose is 7.3 mmol/l.

What is your preliminary differential diagnosis?

What additional history and examination is relevant?

What are the key investigations?

How should he be managed?

BackgroundDifferential diagnosisThe knee is one of the most common joints affected by monoarthritis, which is fortunatesince it is so easy to aspirate. The differential diagnosis of monoarthritis is listed in Table2.1.

Trauma conjures images of motor vehicle accidents or dramatic tackles in rugby; how-ever, much more mundane twisting injuries or valgus/varus strains when under load arecommon. A rapidly developing joint swelling within minutes of the injury is suspiciousof an anterior cruciate ligament tear with involvement of the blood vessel running alongits surface. If internal mechanical derangement is considered possible, then imaging or


02 An Acutely Swollen/Hot Joint

P R O B L E M

Trauma –Meniscal or ligamentous tears ± haemarthrosis

Sepsis – Gonococcal arthritis, Staphylococcus aureus, penetrating injury, foreign body

Reactive arthritis – Following gastrointestinal or genitourinary infection

Haemophilia

Crystal arthritis – Gout, pseudogout

Inflammatory – e.g. Rheumatoid, psoriatic

Table 2.1 Differential diagnosis of monoarthritis



orthopaedic review is warranted. Table 2.2 highlights some common errors in diagnosingacute monoarthritis.The presence of fever suggests infection, and the patient should be questioned and

examined to determine the likely source. Septic arthritis is usually exquisitely tender withresistance to joint movement. Staphylococci are the most common cause of muscu-loskeletal sepsis, with the prevalence of both streptococcal and mycobacterial infectionincreasing. For infections with staphylococci, streptococci, Gram-negative bacteria andanaerobes, only one joint is usually involved. Polyarticular involvement is more likely inthe elderly or immunosuppressed, with infection by Haemophilus influenza, meningo-cocci and Neisseria gonorrhoeae. Lyme disease can present with knee involvement,although the diagnosis can be quickly excluded if there has been no exposure to the tickvector of Borrelia burgdorferi.In young patients, gonococcal arthritis is the most common non-traumatic acute

monoarthritis, and questioning regarding sexual partners and genitourinary symptomsis necessary. In addition to arthritis (often polyarticular), tenosynovitis and a pustularrash of the extremities should be sought. Gonococcal arthritis is 3–4 times more com-mon in women, who often develop arthritis in the perimenstrual period. Men oftenexperience a urethritis as dysuria, and may notice a morning discharge, whereas womenmay be asymptomatic.Reactive arthritis is a sterile arthritis, occurring distant in both time and place from an

inciting infection (usually gastrointestinal or genitourinary). Lower limb asymmetricoligoarthritis is most common, with associated enthesitis such as Achilles tendinitis, andmucocutaneous features of conjunctivitis, pustular rash on the hands and feet and sterileurethritis. Common triggers are genitourinary infection with Chlamydia trachomatis andgastrointestinal infection with Salmonella typhimurium, Shigella flexneri, Campylobacterjejuni and Yersinia enterocolitica. Stool culture and collection of early morning urine fordetection of chlamydia DNA by polymerase chain reaction (PCR) should be considered.Crystal arthritis is both dramatic and rapid in onset, with the most commonly impli-

cated crystals being uric acid, calcium pyrophosphate and hydroxyapatite. Gout is

02 An acutely swollen/hot joint 7

Error Reality

The problem is the joint because the patient Surrounding soft tissues, including bursitis, may be thehas ‘joint pain’ source of pain

The presence of intra-articular crystals excludes Crystals can be present in a septic jointinfection

Fever distinguishes infectious causes from Fever may be absent in septic monoarthritis, and in theother causes immunocompromised patient. Acute crystal arthritis may cause

fever

A normal serum urate makes gout unlikely, and a Serum urate is normal for 30% of acute gout attacks, and onlyhigh level confirms gout 5% of those with hyperuricaemia develop gout each year

Gram staining and culture of synovial fluid are Fastidious, slow-growing organisms, or fragile organisms, maysufficient to exclude infection not be identified in early infection. Liaison with the laboratory is

required for specialist media and prolonged incubation

Table 2.2 Common errors in diagnosing acute monarthritis


unusual in the young and is usually preceded bymore distal joint involvement, classicallythe first metatarsophalangeal joint (podagra). Pseudogout or calcium pyrophosphatedihydrate (CPPD) deposition disease is uncommon below the age of 50 years andthe knee is most often involved, followed by wrist and shoulder. Basic calcium phosphate(hydroxyapatite) results in a calcific periarthritis, which most commonly affects theshoulder.

Aspirating a knee jointEvery medical graduate should feel confident to undertake knee aspiration (Figure 2.1).The knee is exposed with the patient lying so that you can obtain access to either themedial or lateral aspect. The knee is generously cleaned with antiseptic and allowed to drywhilst you are preparing the aspiration syringes. The patella is pinched between thumband index finger at its midpoint, which allows you to detect tension in the quadricepsmuscles and also allows you to distract the patella upwards to increase the infrapatellarspace. Local anaesthetic (5–10 ml) is infiltrated via a 21G or 23G needle at a point proxi-mal and inferior to where you are holding the patella, noting that the pain-sensitivestructures are the dermis and the thickened synovium as you enter the joint. When theanaesthetic has been given time to work, the joint is aspirated along the same needle trackwith a fresh 10–20 ml syringe and 18G needle. Afterwards, a dressing is applied firmly forseveral minutes to ensure haemostasis and to prevent synovial fluid leakage.

Only 1–2 ml of fluid is sufficient to complete all investigations; however, the jointshould be aspirated of as much fluid as possible without increasing the trauma of the pro-cedure. Substantial pain relief is achieved by aspirating a tense effusion, and while reac-cumulation will occur, it buys some time while the preliminary investigation results arereceived. As the aspirate is removed, you should note its colour, viscosity and turbidity.Normal synovial fluid is similar to egg white (syn = resembling, ovium = egg) and is bothviscous and acellular. As the degree of inflammation increases – from the negligibleamount found in osteoarthritis to the mid-range of rheumatoid arthritis and the extremeof septic arthritis – the viscosity decreases and the cellularity and turbidity increase.


Figure 2.1 Arthrocentesis of the left knee –medial approach.


Blood-coloured effusions suggest either trauma or CPPD deposition disease. Synovialfluid characteristics are shown in Table 2.3.It is suggested that approximately 2 ml of fluid is collected into a container plus anti-

coagulant, and the remaining fluid collected in a large-volume sterile container. Testsrequested should include an urgent Gram stain, cell count and differential count, crystalexamination using polarized light microscopy and culture. If gonococcal or fungal infec-tions are suspected, this needs to be highlighted as it influences the culture medium andlength of culture required.Analgesics, antipyretics and rest should be employed in the first instance, with the

aspiration itself often affording a considerable pain relief. If septic arthritis is suspected,then intravenous antibiotics covering Staphylococcus aureus and N. gonorrhoeae shouldbe commenced after the synovial fluid aspiration. The presence of bacteria on Gramstaining or subsequent bacterial growth requires specialist medical and orthopaedicreview to combine antibiotic therapy with joint lavage.Gout is confirmed by the presence of intracellular, negatively birefringent urate crys-

tals, with intracellular pyrophosphate crystals confirming pseudogout. Both of these con-ditions are self-limited and spontaneously improve over a few days. Adequate hydrationcombined with analgesia and the introduction of a non-steroidal anti-inflammatorydrug will generally suffice. Colchicine at a dose sufficient to impact on acute gout invari-ably causes diarrhoea. If you have confirmed the joint is sterile, then intra-articular corti-costeroid injection provides excellent resolution.

Recent Developments1 A prospective study of children presenting for investigation of possible septic

arthritis of the hip concluded that oral temperature >38.5°C was the bestpredictor, followed by an elevated serum C-reactive protein (CRP), an elevatederythrocyte sedimentation rate, refusal to weight bear and an elevated white cellcount.2 CRP >20 mg/l was a strong independent risk factor and a valuable toolfor assessing and diagnosing septic arthritis of the hip. As the number of riskfactors increases so does the predicted probability of septic arthritis, such thatthree to five factors present is associated with 83%–98% predictive probability.

02 An acutely swollen/hot joint 9

Normal Non-inflammatory Inflammatory Septic

Colour Clear Straw yellow Yellow Variable

Clarity Transparent Transparent Hazy opaque Opaque

Viscosity High High Low Low–Thick

WBC (¥ 106/l) 0–200 200–2000 2000–75000 >75000

Neutrophils <25% <25% 25%–50% >75%

WBC, white blood cell.

Table 2.3 Synovial fluid characteristics



2 Increased plasma procalcitonin (PCT) may be a useful marker for osteomyelitisbut not septic arthritis. Procalcitonin is cleaved in neuroendocrine tissues – suchas thyroid C cells, lung and pancreatic tissue – to calcitonin. During infection,large amounts of PCT are released. The source is probably monocytes stimulatedby endotoxin, and hepatocytes stimulated by tumour necrosis factor orinterleukin-6. The role of PCT measurement with a rapid immunoassay wasinvestigated in children admitted with suspected osteomyelitis or septic arthritis.3

The authors reported specificity of 100% and sensitivity of 58% for osteomyelitisand the same specificity, but lower 27% sensitivity, in septic arthritis.

3 High-resolution magnetic resonance imaging (MRI) of soft tissues and joints isincreasingly used prior to interventions such as arthroscopy. In a cohort ofchildren, Luhmann and colleagues4 compared radiological interpretation of kneeMRI with that of the surgeon who integrated the history, clinical examination,plain radiographs, MRI scans and radiologist report. The pre-operative diagnosisby the surgeon was better (P <0.05) than the formal radiology interpretation withrespect to anterior cruciate ligament tear, lateral meniscal tear, osteochondritisdissecans and discoid lateral meniscus.

ConclusionAn acutely hot, swollen joint is an urgent presentation. Exclusion of sepsis is mandatory,particularly in children and immunocompromised patients. Joint aspiration remains theinvestigation of choice. Subsequently, treatment will often include antibiotics, pendinglaboratory results, combined with judicious use of analgesia and anti-inflammatorymedications. Analysis of synovial fluid is valuable in establishing the diagnosis of gout,particularly in joints other than the classical podagra of the great toe. Patients often inter-pret the doctor’s ‘it could be gout’ comment about their sore joint as either a definitivediagnosis or as a slur on an indulgent lifestyle, when neither may be intended.

Further Reading1 Siva C, Velazquez C, Mody A, Brasington R. Diagnosing acute monoarthritis in adults: a

practical approach for the family physician. Am Fam Physician 2003; 68: 83–90.

2 Caird MS, Flynn JM, Leung YL, Millman JE, D’Italia JG, Dormans JP. Factors distinguishing

septic arthritis from transient synovitis of the hip in children. A prospective study. J Bone Joint

Surg Am 2006; 88: 1251–7.

3 Butbul-Aviel Y, Koren A, Halevy R, SakranW. Procalcitonin as a diagnostic aid in

osteomyelitis and septic arthritis. Pediatr Emerg Care 2005; 21: 828–32.

4 Luhmann SJ, SchootmanM, Gordon JE, Wright RW. Magnetic resonance imaging of the knee

in children and adolescents. Its role in clinical decision-making. J Bone Joint Surg Am 2005; 87:497–502.


Case HistoryMr Lawrence, a 76-year-old retired driver, is having difficulty living independently afterreturning home following a recent myocardial infarction. On the day of discharge he fellheavily, landing on his left upper arm. His concern is a very painful left shoulder,especially at night and when he tries to move his left arm during the day.

How would you determine whether he has adhesive capsulitis (frozen shoulder)?

Is there a role for medical imaging, and if so, what modality?

What treatment should be initiated?

BackgroundShoulder pain is an almost unavoidable life experience; in one study, 7% of an adult pop-ulation aged 25–75 years reported at least one month’s shoulder pain in the previousyear. The peak annual incidence of shoulder disorders is in the fourth and fifth decades,at a rate of 0.25%. A Dutch study found that 25% of all 85-year-olds in Leiden sufferedfrom chronic shoulder pain and restriction. Community-based surveys concur with thishigh incidence of soft tissue lesions about the shoulder, with roughly equal sex incidence.Up to 20% of patients with chronic symptoms and 65% of all diagnoses relate to lesionsof the rotator cuff. Rotator cuff disease is the most common cause of shoulder pain foundin these studies. An ultrasound study found rotator cuff tears in 13% of 50–59-year-olds,20% of 60–69-year-olds, 31% of 70–79-year-olds and 51% of subjects aged over 80 years,even when they were asymptomatic.Table 3.1 summarizes causes of shoulder pain. The pain-sensitive structures of the

shoulder are mainly innervated by the fifth cervical segment (C5), so that pain from thesestructures is referred to the C5 dermatome creating the sensation of pain over the anter-ior arm, especially the deltoid insertion. The acromioclavicular joint is innervated by theC4 segment – pain arising here is felt at the joint itself and radiates over the top of theshoulder into the trapezius muscle and to the side of the neck.

Clinical assessmentA history of trauma, marked night pain and weakness on resisted abduction strongly sug-gests a rotator cuff tear. The sleeping position that induces night pain is an important clue:

03 Painful shoulders – rotator cuff and frozen shoulder 11

03 Painful Shoulders – Rotator Cuff andFrozen Shoulder

P R O B L E M



shoulder pain that results in awakening when not lying on that shoulder is found in adhe-sive capsulitis and inflammatory arthritis; pain when lying on the affected shoulder is seenin acromioclavicular joint disease and rotator cuff disease. Prior shoulder problems sug-gest rotator cuff disease with chronic impingement, or calcific tendinitis. A history ofmarked shoulder joint swelling suggests inflammatory arthropathy with the presence ofan anterior bulge in the shoulder usually secondary to a subacromial bursa effusion.Glenohumeral osteoarthritis (OA) is characterized bymorning stiffness, pain with use andchronicity of symptoms. OA, however, is less common than rotator cuff dysfunction.Examination of the shoulder is best undertaken with the patient wearing the mini-

mum of upper body clothing. The contours of the shoulder are examined for wasting,asymmetry andmuscle fasciculation. Palpation should proceed from the sternoclavicularjoint along the clavicle to the acromioclavicular joint, to the tip of the acromion and thehumeral head beneath the acromion. The shoulder range of movement should be exam-ined both actively and passively, with muscle strength and pain on resistance assessed.There are essentially three movements to test in the shoulder: abduction due tosupraspinatus contraction; external rotation as a result of infraspinatus and teres minormovement; and internal rotation due to subscapularis movement (Box 3.1).

Complete rotator cuff tears will show no active abduction but near full-rangemovementwhen passively moved. During examination ask about a painful arc during abduction(Figure 3.1). When examining active and passive abduction you should stand behind thepatient and place one hand over the shoulder and scapula. The scapula should not begin to


Category Cause Clinical features

Extracapsular Rotator cuff and subacromial bursa (e.g. impingement Painful arc of abductionlesions syndromes, calcific tendinitis, cuff tears, bursitis) Pain on resisted cuff muscle movements, with intact

passive movement (allowing for pain and guarding)Pain on impingement manoeuvres as the inflamedrotator cuff tendons impinge on the inferior surface ofthe acromion and coracoacromial arch

Intracapsular Glenohumeral joint (inflammatory arthritis – RA, Loss of both active and passive movementlesions spondyloarthritis, pseudogout) Reduced glenohumeral range

Joint capsule (adhesive capsulitis) Night painBone disease (Paget’s disease, metastases) Muscle strength, allowing for pain, is intact

Referred pain Cervical spine (facet joint root impingement, discitis) Arm and hand pain with paraesthesiaBrachial plexus (brachial amyotrophy) Marked muscle weakness and wastingThorax (Pancoast’s tumour) Neck pain and stiffnessThoracic outlet syndrome Herpes zoster rashSuprascapular nerve entrapment Systemic features with weight lossSubdiaphragmatic (abscess, blood, hepatic lesions)

Table 3.1 Causes and clinical characteristics of shoulder pain

Box 3.1 Practice Point

Three positive clinical tests (supraspinatus weakness, weakness of external rotation andimpingement) or two positive results for a patient older than 60 years are highly pre-dictive of a rotator cuff tear.1


elevate or rotate until at least 90 degrees of abduction has been reached. Early scapulotho-racic movement localizes the abnormality to the glenohumeral joint or capsule, as seen infrozen shoulder. You should examine external rotation at 0 degrees abduction, with theelbow beside the chest, and if external rotation is absent then a frozen shoulder is likely.Next re-examine both internal and external rotation at 90 degrees abduction; if both arerestricted, a frozen shoulder is again likely. Bicipital tendinitis is examined by testingresisted flexion at 30 degrees external rotation, and feeling for tenderness in the bicipitalgroove. Shoulder impingement can be reproduced by internally rotating the arm heldflexed at 90 degrees and bringing the inflamed rotator cuff against the anterior acromion.The ‘empty can’ test is suggestive of a rotator cuff tear: it shows pain on resisted elevation ofthe inverted arm held extended at 90 degrees, as if emptying a can of drink.

Rotator cuff diseaseThe glenohumeral joint is, by virtue of its anatomical shape, inherently unstable, relyingon the joint capsule as well as the rotator cuff muscles (supraspinatus, infraspinatus andsubscapularis) for additional stability. Impingement of the rotator cuff between the prox-imal humerus and the acromioclavicular arch may occur from anomalies of the arch(structural impingement) and from instability due to joint hyperlaxity or weak rotatorcuff muscles (functional impingement). Coracoacromial arch anomalies may be congen-ital, dependent on acromial shape. Three shapes have been described – flat, curved and


180°

120°

Painful arc of abductionacromioclavicular joint

Painful arc ofabduction inrotator cuff

70°

Figure 3.1 Painful arc: the patient slowly abducts the arm as high as possible, describing symptoms as thearm rises.


hooked – although there is poor inter-observer agreement on identifying the shape.Acquired impingement occurs secondary to osteophytes growing from the acromioclav-icular joint or calcification of the acromioclavicular ligament. Impingement occurs whenthe cuff becomes compressed in the subacromial space as the arm is elevated. As thehumeral head rotates, the rotator cuff tendons are compressed between the greatertuberosity of the humerus and the anterior edge of the acromion, the coracoacromial lig-ament, the under-surface of the acromioclavicular joint and with the reactive inflamma-tory subacromial bursa.In addition to the impingement theory, a vascular theory has been proposed. With the

arm at the side, it has been suggested that the supraspinatus tendon has a relative avascu-lar area 1 cm proximal to its insertion at the greater tuberosity, directly beneath theimpingement zone. This may be affected by the position of the shoulder and increaseswith age. However, the infraspinatus tendon has a similar vascular watershed area, sug-gesting that factors other than vascularity are important. Chronic irritation in the avascu-lar region produces tendinitis, leading to local inflammation and further compression.Other causes of tendinitis include trauma, instability and possibly infarction of the cuff inpatients with vascular disease. The vascular and impingement theories are not mutuallyexclusive and it is possible that the high incidence of supraspinatus pathology is the resultof impingement in and around a critical zone of vascular supply.With time, wearing and attrition of the cuff leads to impaired action or rupture of the

short rotators stabilizing the humeral head into the glenoid fossa, so that the deltoid pullsthe humerus against the under-surface of the acromion and a vicious impingement cycleis established. Impingement-caused tears are usually incomplete in the supraspinatusand infraspinatus tendons and complete in the long head of biceps. Complications ofimpingement include a frozen shoulder, rupture of the rotator cuff tendons or long headof biceps and, in elderly patients with a long-standing tear, a feared end-stage lesion,‘recurrent haemorrhagic shoulder of the elderly’.Treatment depends on the mechanism of impingement. Patients with functional

impingement are treated with a resting sling for 24–36 hours, pendular exercises and full-dose non-steroidal anti-inflammatory drug (NSAID). Structural impingement is treatedsimilarly but the surgical options of arthroscopic surgery to remove osteophytes or trimthe acromion are available. Corticosteroid injection to the subacromial space can becombined with an initial 4–7 days of pendulum exercises and avoidance of abductionprior to a programme of shoulder-strengthening exercises. Infraspinatus strengtheningmay be important to provide stabilization of the humeral head to prevent superior sub-luxation on abduction.Studies of eccentric loading exercises have shown promising results, particularly in

lesion of the Achilles tendon. Eccentric loading exercises involve a load being applied to amuscle in its contracted position and the muscle is lengthened under the load. In theshoulder, the supraspinatus would be contracted with the arm abducted and under loadthe arm would slowly return to the side. Exercise programmes require highly motivatedpeople and there is concern that exercises can increase symptoms initially.

Frozen shoulder/adhesive capsulitisInitially described in 1872, this condition remains as ‘difficult to treat and difficult toexplain from the point of pathology’ as Codman observed in 1934. This common disor-



der (2% cumulative risk in an at-risk population annually) is frequently misdiagnosedand is characterized by painful restriction of all shoulder movements, both active andpassive, with characteristic restriction in the glenohumeral range. There is marked reduc-tion or absence of shoulder external rotation at 0 degrees abduction, reduction of bothinternal and external rotation at 90 degrees abduction, as well as prominent restriction ofplacing the hand behind the back on internal rotation. Frozen shoulder is characterizedpathologically by fibrosis and retraction affecting predominantly the anterior and infer-ior structures of the glenohumeral joint capsule. Patients usually present in the sixthdecade and onset before the age of 40 years is uncommon. Table 3.2 lists the diseasesassociated with frozen shoulder, diabetes being the most significant. Diabetes, particu-larly long-standing insulin-dependent diabetes, is associated with glycosylation of subcu-taneous collagen and the development of soft tissue contraction – so called diabeticcheiroarthropathy.

Three phases of frozen shoulder are recognized:

1 Painful inflammatory phase. Beginning insidiously, with often only a minor injurybeing recalled, nocturnal awakening pain develops. The pain may be constant andprevents the patient lying on the shoulder. Physiotherapy often aggravates symptomsat this stage and corticosteroid injections are of limited benefit. This phase lasts2–9 months.

2 Frozen shoulder. With time, the night and rest pain eases, but the shoulder remains‘frozen’. Mean duration is 4–12 months.

3 Recovery phase. After a mean delay of 5–26 months, shoulder limitation slowlyrecovers in the majority of patients towards normal range (usually a 10%–30% lossof motion, which is often undetected by the patient). The total duration ofsymptoms lasts 12–42 months, with mean disease duration of 30 months.

In 10%–20% of patients a contralateral frozen shoulder develops, usually milder thanthe first, while the original shoulder is ‘thawing’. It is important to educate patients thatthe condition will spontaneously resolve and the stiffness will greatly reduce. NSAIDsand analgesics are used but there are no randomized controlled trials studying efficacy. Aprospective study in frozen shoulder compared exercise within the limits of pain withintensive physiotherapy. Those who performed exercises within the limits of pain hadbetter results, recorded as near-normal painless shoulder movement (64% of patients at12 months, 89% at 24 months), compared to intensive physiotherapy (63% of patients at


• Acute shoulder trauma and shoulder immobilization• Diabetes mellitus• Thyroid disease (both hyper- and hypothyroidism)• Cardiac disease, particularly after cardiac surgery• Neurological disease with loss of consciousness or hemiplegia• Pulmonary disease – tuberculosis and carcinoma• Rotator cuff disease, especially cuff tear• Acute glenohumeral joint inflammation

Table 3.2 Common disorders associated with frozen shoulder


24 months).2 An early meta-analysis by Hazleman on the use of intra-articular steroidsreported that the outcome depended on the duration of symptoms and hence possiblestage of disease. Patients who receive the injection earlier in the course of the diseaserecover more quickly.3 An extensive meta-analysis by Buchbinder et al. found a benefitfor glenohumeral intra-articular corticosteroid injection for frozen shoulder comparedwith placebo.4

For those unable to tolerate the pain and disability of a frozen shoulder, manipulationunder anaesthesia (MUA) is a reliable way to improve the range of movement. It is par-ticularly indicated when disability persists after six months of non-operative therapy.More recently, arthroscopic release of the capsule has been advocated as a more con-trolled release of the capsule than MUA. Arthroscopic release also avoids the complica-tions of MUA such as fracture of the humerus and iatrogenic intra-articular shoulderlesions.5

ImagingImaging is undertaken primarily when considering referred pain or a malignant process.In the assessment of rotator cuff disease, no imaging may be required initially, and mayonly be undertaken subsequently if the clinical progression is not as expected. A plain X-ray should then be the initial imaging modality, because if there is marked superiormigration of the humeral head, there must be complete rotator cuff disruption. Eithermagnetic resonance imaging or ultrasound can confirm a possible full-thickness rotatorcuff tear, although ultrasound is significantly cheaper and is preferred by patients.Suspected partial-thickness tears are best verified with an ultrasound scan.1

Recent Developments1 Oral steroids may be useful in frozen shoulder, particularly during the early

inflammatory phase. Buchbinder et al.6 undertook a randomized controlled trialon a series of 50 patients and found that oral steroid therapy initially improvedthe frozen shoulder but the effect did not last beyond six weeks. Their subsequentanalysis of five small trials, in which all subjects received physiotherapy or anexercise programme, confirmed that oral prednisolone or cortisone when givenfor 3–4 weeks had a modest benefit on pain and disability and ability to movethe shoulder.7

2 Recently, a neural aetiology for tendinopathy has been considered.8 Tendinopathywas proposed as an appropriate term for a symptomatic primary tendon disorder,as it made no assumption as to the underlying pathological process. Underlyingthe neural theory are four basic observations: tendons are innervated; substance Phas been found in rotator cuff tendinopathy and is a pro-inflammatory mediator;the neurotransmitter glutamate is also present in tendinopathy; and tendon nervecell endings are closely associated with mast cells. It has been tentativelypostulated that neural stimuli secondary to overuse or mechanical irritation leadto mast cell degranulation and release of mediators that begin an inflammatorycascade.



ConclusionFrozen shoulder is a common and painful condition that impacts adversely on an indi-vidual’s activities of daily living. Despite being self-limited, recovery is protracted and ahigh proportion of patients do not regain full function. As a condition, it is largely man-aged in the community by primary physicians, physiotherapists and occupational thera-pists. Treatments that aim to mechanically stretch or disrupt the joint capsule (MUA,arthroscopic release or hydrodilation of the capsule) are reserved for those with severesymptoms who have failed to progress with conservative therapy.

Further Reading1 Diehr S, Ison D, Jamieson B, Oh R. Clinical inquiries. What is the best way to diagnose a

suspected rotator cuff tear? J Fam Pract 2006; 55: 621–4.

2 Diercks RL, Stevens M. Gentle thawing of the frozen shoulder: a prospective study of

supervised neglect versus intensive physical therapy in seventy-seven patients with frozen

shoulder syndrome followed up for two years. J Shoulder Elbow Surg 2004; 13: 499–502.

3 Hazleman BD. The painful stiff shoulder. Rheumatol Phys Med 1972: 11: 413–21.

4 Buchbinder R, Green S, Youd JM. Corticosteroid injections for shoulder pain. Cochrane

Database Syst Rev 2003; CD004016.

5 Dias R, Cutts S, Massoud S. Frozen shoulder. BMJ 2005; 331: 1453–6.

6 Buchbinder R, Hoving JL, Green S, Hall S, Forbes A, Nash P. Short course prednisolone

for adhesive capsulitis (frozen shoulder or stiff painful shoulder): a randomised, double

blind, placebo controlled trial. Ann Rheum Dis 2004; 63: 1460–9.

7 Buchbinder R, Green S, Youd JM, Johnston RV. Oral steroids for adhesive capsulitis.

Cochrane Database Syst Rev 2006; CD006189.

8 Rees JD, Wilson AM, Wolman RL. Current concepts in the management of tendon

disorders. Rheumatology 2006; 45: 508–21.



Case HistorySimon is a 48-year-old labourer. His work has required a large amount of manualscrewdriver use, and he presents with a three-month history of an increasingly painfulelbow. He now has trouble grasping objects such as a cup.

What is the difference between tennis elbow and golfer’s elbow?

What are the characteristics of each condition, and what treatment is indicated?

BackgroundTennis elbowTennis elbow or lateral epicondylitis is an overload injury, which occurs after minor orunrecognized microtrauma to the proximal insertion of the extensor muscles of the fore-arm – particularly extensor carpi radialis brevis. Tennis elbow is the most frequentlydiagnosed elbow condition (Box 4.1); it occurs commonly in middle life (age 35–55years) and has an incidence in general practice of 4–7 cases per 1000. Despite its commonname, most cases occur in non–tennis players and it is frequently a work-related enthe-sopathy affecting up to 15% of workers in at-risk industries. Operative specimens revealtendon glycosaminoglycan infiltration and microtears, as well as new bone formation atthe attachment site. Both traction injury and ischaemia play a role in its development.Flexion deformity is unusual, occurs late and is minimal. Loss of 20 degrees of exten-

sion cannot be attributed to tennis elbow and warrants investigation for arthritis,impingement at the olecranon fossa or a soft tissue mass in the posterior aspect of theelbow. Tennis elbow is usually self-limiting, having an average duration of six months totwo years, with 90% of subjects recovering within one year. Various conservative inter-ventions exist including pain-relieving medications, corticosteroid injections, physio-therapy, elbow supports, acupuncture, surgery and shockwave therapy (Box 4.2).


04 Tennis Elbow and Golfer’s Elbow

P R O B L E M

Box 4.1 Diagnosis of tennis elbow

� Lateral elbow pain with tenderness on palpation just distal to the lateralepicondyle

� Worsening pain localizing to the lateral epicondyle on resisted wrist dorsiflexion

� X-rays excluding calcific tendinitis, exostoses and osteoarthritis of the radio-ulnarjoint



Most important in treatment is activities modification – both frequency and methodof performance. In tennis players, common errors are inadequate conditioning, incorrectgrip size, faulty backhand style and problems with the racquet and its stringing. In thework setting, a review by an occupational therapist is recommended, particularly focus-ing on pronation/supination movements and grip size. A physiotherapy programme thatincludes strengthening exercises for the entire upper limb and a graded resistive pro-gramme for wrist dorsiflexors is recommended.In the setting of localized tenderness it is tempting to inject the lesion. As noted in Box

4.2, the short-term gain may be offset by a poorer long-term outcome. The injectiontechnique is a small volume of corticosteroid and local anaesthetic injected into thetendinous insertion of extensor carpi radialis brevis into the lateral epicondyle. As theinjection is not into a potential space but into an already tender, dense area, the injectionis against resistance and is both uncomfortable and has the risk of steroid tracking super-ficially to the subcutaneous tissues, leading to depigmentation and atrophy. In contrastto other painful overuse syndromes in which total tendon ruptures have been reported(Achilles, biceps, patella), the tendon of the extensor carpi radialis brevis is strongly con-nected and supported by other extensors of the wrist.A small number of patients have recalcitrant lateral epicondylitis and are considered

for operative intervention – open, arthroscopic and percutaneous. Operative interven-tions followed for a minimum of two years demonstrate an improvement compared topre-operative status, with no difference in outcome according to procedure technique.1

Golfer’s elbowGolfer’s elbow or medial epicondylitis is the mirror image of tennis elbow, and is thoughtalso to relate to repetitive traction stress and microtears at the insertion of the forearmflexors (flexor carpi radialis) and pronator teres into the medial epicondyle. It occurs inboth professional and amateur sports players, as well as manual workers such as brick-layers. It is much less common than tennis elbow, with approximately one-twentieth theincidence. Similar to tennis elbow, the diagnosis is clinical, with localized tenderness thatworsens on resisted wrist flexion and forearm pronation (Box 4.3).

04 Tennis elbow and golfer’s elbow 19

Box 4.2 Treatment of tennis elbow

� Structured physiotherapy consisting of elbowmanipulation and exercise, supple-mented with home exercises and self-manipulation

� Practical advice booklet on self-management and ergonomics

� Recommend avoidance of corticosteroid injections, as short-term benefit is offsetby a poorer longer-term outcome

Box 4.3 Golfer‘s elbow

� Elbow pain at the medial epicondyle

� Increasing symptoms on resisted wrist flexion and resisted forearm pronation

� Treatment includes modification of activities, upper limb exercises and analgesics


Recent DevelopmentsA randomized controlled trial compared the effectiveness of physiotherapy, cortico-steroid injections and a ‘wait and see’ approach in 198 patients with tennis elbow whowere randomized to the three treatment arms.2 Physiotherapy was eight sessions ofmobilization with movement and exercises plus home exercises and self-manipulation.Injection therapy with triaminolone acetonide (10 mg) and 1% lidocaine was the secondstudy arm. The ‘wait and see’ approach consisted of ergonomic instruction and use ofanalgesics, heat, cold and braces if needed. At six weeks the main outcome measures(global improvement, pain-free grip strength, assessor’s rating of complaints, severity ofelbow pain and elbow disability) were significantly better in the corticosteroid-treatedgroup than in the other groups. However, all groups were improving and the benefit ofthe steroid injection was short-lived, such that a crossover occurred around twelve weeks,with the one-year results showing physiotherapy superior to corticosteroid injections forall outcome measures. Importantly, at one year, the injection-treated group was signifi-cantly worse on all outcomes compared with the physiotherapy group, and on two out ofthree measures compared with the ‘wait and see’ group. The corticosteroid injectiongroup also had the most reported recurrences. A similar study with only seven weeks offollow-up confirmed the benefits of steroid injections in the short term.3

ConclusionTennis elbow is a common problem in general practice and is best treated with theknowledge that it is a self-limiting condition, with the majority of patients improving inthe medium term. Whilst corticosteroid injections offer short-term benefit, there is thepotential for both short-term adverse effects and the possibility of a worse outcome atone year. Physiotherapy provides benefit that is slower in onset but is more sustained andallows patients to become self-reliant in their own management.

Further Reading1 Szabo SJ, Savoie FH, Field LD, Ramsey JR, Hosemann CD. Tendinosis of the extensor carpi

radialis brevis: an evaluation of three methods of operative treatment. J Shoulder Elbow Surg

2006; 15: 721–7.

2 Bisset L, Beller E, Jull G, Brooks P, Darnell R, Vicenzino B. Mobilisation with movement and

exercise, corticosteroid injection, or wait and see for tennis elbow: randomised trial. BMJ

2007; 333; 939–45.

3 Tonks JH, Pai SK, Murali SR. Steroid injection therapy is the best conservative treatment for

lateral epicondylitis: a prospective randomised controlled trial. Int J Clin Pract 2007; 61:240–6.



Case HistoryBeatrix is a 33-year-old production-line worker. For the last four weeks she has beenawakening with painful pins and needles in her left hand and a dull pain that radiatesfrom her wrist to her elbow. Shaking the arm improves the symptoms and she sometimessleeps with her arm hanging out of the bed.

What are the clinical features of the carpal tunnel syndrome?

What is the role for imaging and nerve conduction studies?

What investigations are appropriate to determine the cause?

How would you manage this problem?

BackgroundEntrapment neuropathies are disorders where peripheral nerves are damaged by com-pression as they pass through a bony or fibrous canal. The disorders may be precipitatedby repetitive motion or strain, and carpal tunnel syndrome (CTS) is by far the common-est entrapment neuropathy and the most common focal peripheral neuropathy. Themedian nerve, along with the flexor tendons, passes through the carpal tunnel, which isbridged by the transverse carpal ligament (Figure 5.1). CTS affects 3% of the populationalthough there is an imperfect correlation between reported symptoms and electrophysi-ological findings. Women are three times more likely than men to be affected with CTS,and a number of predisposing conditions are recognized (Box 5.1).CTS causes pain, numbness and tingling in the distribution of the median nerve: i.e.

anteriorly, in the lateral half of the ring finger to themedian half of the thumb; and poste-riorly, in the distal halves of the ring and middle fingers. If severe, the symptoms mayradiate up the arm and they can often occur at night, thus disturbing sleep. In severe casesthere is a loss of small muscle function, which impairs manual dexterity and can lead towasting of muscles of the thenar eminence. The symptoms of CTS are common and clin-ical signs (Box 5.2) are not always present. Accurate diagnosis is one of the major deter-minants of successful treatment. The diagnosis should be confirmed wherever possibleby nerve conduction studies.

05 Carpal tunnel syndrome and other entrapment neuropathies 21

05 Carpal Tunnel Syndrome and OtherEntrapment Neuropathies

P R O B L E M




Median nerve

Tendon sheath

Carpal ligament

Bundle of tendons

Figure 5.1 Anatomy of the carpal tunnel.

Other common nerve entrapment syndromesThoracic outlet syndromesThese are due to compression of the brachial plexus and brachial vessels in the neck.Costoclavicular syndrome, due to a narrowing of the space between the clavicle and firstrib, may arise from congenital abnormality or because of poor posture. Cervical rib syn-drome is due either to an extra rib or to a fibrous band between the seventh cervical ver-tebra and the sternum. Compression of nerves and vessels occurs as they pass over theadditional structures. Adson’s test may be positive: the patient looks to the affected sideand takes a deep breath while the examiner lifts the arm to 90 degrees. If compression ispresent, the radial pulse may disappear.

Suprascapular neuritisThe suprascapular nerve (cervical segments C5/C6) supplies sensation to the shoulder jointand motor supply to the infraspinatus and supraspinatus muscles. It can become com-pressed as it passes through the suprascapular notch and under the transverse ligament.

Ulnar neuritisCompression of the ulnar nerve usually occurs in the canal, where it is covered by the arcu-ate ligament. It may also occur between the two heads of flexor carpi ulnaris just distal tothe elbow joint. The syndromemay occur as a result of direct trauma or fracture, repetitive


movements or rheumatoid arthritis affecting the elbow joint. It causes pain and tinglingdown the inside of the forearm to the little finger and medial aspect of the ring finger. Thenerve gives rise to a sensory supply to the skin of the hypothenar eminence and a motorsupply tomuscles of the hypothenar eminence and other small muscles in the hand.

Median neuritisThis is a much less common syndrome and is usually due to entrapment of the nerve atthe elbow. Symptoms are similar to those of the carpal tunnel syndrome and may beexacerbated by pronation of the forearm.

Radial neuritisAgain, this is relatively uncommon. Compression usually occurs at the elbow and causessensory symptoms in the forearm bone to the base of the thumb.


Box 5.2 Clinical signs of CTS

Tinel’s sign Tapping over themedian nerve elicits symptoms in the distributionof the nerve

Phalen’s sign Place both hands together palm to palm,with thewrists extended to90 degrees, and forearms horizontal and close to the chest. Theaffected handwill begin to tingle within 1–2minutes

Reverse Phalen’s As above, butwith the hands placed back to back

Box 5.1 Causes of CTS

Overuse Repetitive flexion or extension of thewrist, particularly whilegripping objects firmlyUse of walking stick in patients withmobility disordersOccupational – use of power tools, assembly-linework

Injury Colles fractureSubluxation of the lunate bone

Arthritis Rheumatoid – tendon sheath inflammationOsteoarthritisGout or pseudogout

Wrist ganglion Outpouching of thewrist joint capsuleIncreased canal Pregnancyvolume Obesity

Congestive cardiac failureLipoma

Infections Septic arthritisLyme diseaseTuberculosis

Metabolic DiabetesHypothyroidismAcromegalyAmyloidosis


Meralgia paraestheticaThe lateral cutaneous nerve of the thigh passes through the femoral canal, where it issharply angulated and liable to compression. The syndrome leads to sensory symptomsin the middle and lower part of the lateral aspect of the thigh. It is caused by obesity,direct trauma or by repetitive flexion of the thigh.

Anterior compartment syndromeThis part of the lower leg contains the tibialis anterior and extensor digitorum musclesand the deep peroneal nerve (supplies skin between the first and second toes). The nervemay be injured by unaccustomed running, as a result of tibial or fibular fractures orthrough direct trauma.

Medial compartment syndromeThis is the most common lower-leg nerve entrapment syndrome. The symptoms includepain and tenderness on the medial aspect of the shin (‘shin splints’). It is often precipi-tated by unaccustomed running on a hard surface.

Posterior compartment syndromeThis compartment contains the soleus and gastrocnemius muscles, which join together toform the Achilles tendon and are responsible for plantar flexion. The syndrome is associatedwith calf pain precipitated by exercise and with altered sensation on the sole of the foot.The management of all of these nerve entrapment syndromes is somewhat similar: the

patient should rest wherever possible and avoid movements or actions that exacerbatethe symptoms; local injection with anaesthetic or steroid is indicated in some cases, and aminority of patients require surgical decompression of the affected nerve.

Management of CTS1,2

� General measures include trying to relax the grip, using grip-adapted implementssuch as large pens, taking frequent breaks, keeping the hands warm and consideringposture and position (e.g. if using a keyboard, this should be at elbow height).Conservative management with ultrasound has been advocated but there are limitedtrial data to support this therapy.

� Splinting the wrist in neutral position may alleviate symptoms related to soft tissueswelling and is most effective when used soon after the onset of symptoms. Night-time splinting is often sufficient.

� Non-steroidal anti-inflammatory drugs are effective in some cases, althoughimprovement may be short-lived. Oral corticosteroids are more effective (e.g.prednisolone 20 mg/day for 2–3 weeks, followed by reducing doses). Diuretics arewidely used but are often disappointing in their effect.

� The use of local injection of anaesthetic and steroid into the proximal carpal tunnelis supported by trial data. The outcome is probably comparable to that of systemicsteroids, but the patient is not exposed to the risk of side effects associated with high-dose steroid therapy. The injection may be directly into the carpal tunnel orproximal to the carpal tunnel. Benefit from local injection may last for up to threemonths and is increased by concurrent splinting.

� For patients who have either severe symptoms or do not respond to conservativemeasures, surgery is required. This has traditionally been carried out by an open



procedure, which can be performed without admission to hospital. More recently,endoscopic carpal tunnel release through two small incisions has been used by manysurgeons. This has the advantage of causing less scarring.

Recent Developments1 Not all patients have ready access to nerve conduction studies. Several studies have

shown that high-resolution ultrasound and magnetic resonance imaging (MRI) maybe very accurate in diagnosing CTS.3,4 These methods can demonstrate altered


History and examination to search for underlying causesEnquire about occupation and repetitive strain

Mild symptoms Severe symptomsModerate symptoms with signs

RestRemove precipitating cause

Trial of splintingNCS ± imaging

No further action Confirmed diagnosis

Conservative measures

Local injectionSystemic steroids

Repeat treatmentat 3 months

Consider surgery• Open• Endoscopic

Confirm symptoms are in median nerve distribution

Figure 5.2 Investigation andmanagement of CTS. Imaging is with high-resolution ultrasound or withMRI. NCS, nerve conduction studies.


anatomy and decreased volume of the carpal tunnel, and in patients with CTS showthe median nerve is swollen distal to the compression.

2 Some familial cases of nerve entrapment are due to inherited anatomicalabnormalities. Recently, the condition of hereditary neuropathy with liability to thepressure palsies (HNPP) has been described.5,6 This condition is inherited in an auto-somal dominant manner and is due to a deletion at locus 17p11.2. HNPP is a slowlyprogressive condition, punctuated by episodes of acute peripheral neuropathy at sitesthat are liable to nerve entrapment.

3 Endoscopic surgery has revolutionized treatment of CTS. The two-portal endoscopicapproach to managing CTS has been adopted in many centres. Although thisapproach is attractive, recent trials7,8 suggest that it has very little to offer over tradi-tional open surgery. In general, surgical treatment is more successful than medical orconservative treatment in patients with proven CTS.9

ConclusionCTS is the most common form of entrapment neuropathy. Definitive diagnosis is bynerve conduction studies, but ultrasound andMRI are increasingly being used to confirmthe diagnosis. It is worth routinely excluding hypothyroidism and diabetes as predispos-ing causes but there is not usually a treatable or identifiable underlying cause. A limitedtrial of conservative or medical measures is justified in mild cases but surgery is generallyrequired for severe, progressive or unresponsive cases.

Further Reading1 Viera AJ. Management of carpal tunnel syndrome. Am Family Physician 2003; 68: 265–72.

2 Ashworth N. Carpal tunnel syndrome. Clin Evid 2006; 15: 1–18.

3 Wiesler ER, Chloros GD, Cartwright MS, Smith BP, Rushing J, Walker FO. Use of diagnostic

ultrasound in carpal tunnel syndrome. J Hand Surg 2006; 31: 726–32.

4 de Noordhout AM. Diagnosing entrapment neuropathies: probes and magnets instead of

electrodes and needles? Clin Neurophysiol 2006; 117: 484–5.

5 Sander MD, Abbasi D, Ferguson AL, Steyers CM,Wang K, Morcuende JA. The prevalence of

hereditary neuropathy with liability to pressure palsies in patients with multiple surgically

treated entrapment neuropathies. J Hand Surg 2005; 30: 1236–41.

6 Koc F, Guzel R, Benlidayi IC, Yerdelen D, Guzel I, Sarca Y. A rare genetic disorder in the

differential diagnosis of the entrapment neuropathies: hereditary neuropathy with liability to

pressure palsies. J Clin Rheumatol 2006; 12: 78–82.

7 RabM, Grunbeck M, Beck H et al. Intra-individual comparison between open and 2-portal

endoscopic release in clinically matched bilateral carpal tunnel syndrome. J Plast Reconstr

Aesthet Surg 2006; 59: 730–6.

8 Atroshi I, Larsson G-U, Ornstein E, Hofer M, Johnsson R, Ranstam J. Outcomes of endoscopic

surgery compared with open surgery for carpal tunnel syndrome among employed patients:

randomised controlled trial. BMJ 2006; 332: 1473–6.

9 Hui ACF, Wong S, Leung CH et al. A randomized controlled trial of surgery vs steroid

injection for carpal tunnel syndrome.Neurology 2005; 64: 2074–8.



Case HistorySandra is in her early 40s and is seeing you because she hurts from her scalp to her toes.This has been present for at least eight years and is ruining her life. She tires easily andaches with any activity. Her sleeping is restless, she awakes tired and she has an irritablebowel. There are no abnormalities on physical examination.

What is fibromyalgia and how would you support this diagnosis?

Are there any investigations that might help?

What treatment, if any, would you suggest to Sandra?

BackgroundFibromyalgia syndrome (FMS) is a soft tissue musculoskeletal condition with manyfeatures in common with chronic fatigue syndrome, the major difference being the pre-dominance of musculoskeletal features in FMS. Diagnosis of FMS is based on theAmerican College of Rheumatology (ACR) criteria (1990):

� Pain on both sides of the body

� Pain above and below the waist

� Pain in an axial distribution

� Local tenderness in at least 11 out of 18 defined trigger points (Figure 6.1)

The pain is often defined as ‘aching’ or ‘burning’ and varies in intensity and locationfrom day to day. Other features of FMS are shown in Table 6.1.

06 Fibromyalgia syndrome 27

06 Fibromyalgia Syndrome

P R O B L E M

Symptom % Symptom %

Muscular pain 100 Paraesthesiae 52

Fatigue 96 Memory impairment 46

Insomnia 86 Leg cramps 42

Joint pains 72 Poor concentration 41

Headaches 60 Anxiety 32

Restless legs 56 Major depression 20

Table 6.1 Frequency of FMS symptoms



Musculoskeletal pain is the most consistent feature of FMS. Fatigue can be almost asdebilitating. Disordered sleep is also a very frequent feature and contributes to fatigueand to the mood disturbances. Sleep abnormalities are strongly correlated with thealpha-electroencephalogram (EEG) abnormality and movement disorders including theperiodic jerking of arms and legs, teeth grinding (bruxism) and restless legs. Gastro-oesophageal reflux disease occurs with high frequency, as does irritable bowel syndrome.Headaches may be of the migraine or tension type. Facial pain is also relatively common,including discomfort related to temporomandibular joint dysfunction. Psychologicaland psychiatric morbidity are increased. There is high prevalence of anxiety disordersincluding obsessive-compulsive disorder and post-traumatic stress disorder.2


Figure 6.1 Trigger points for the diagnosis of FMS. There are 18 points in total (nine identical locations oneach side). Anterior: anterior aspects of C5, C6 and C7; second rib; lateral epicondyle; knee (medial fat pad).Posterior: suboccipital muscle insertions; supraspinatus muscle origin; trapezius (midpoint upper border);gluteal (upper outer quadrants); greater trochanter. Adapted with permission from Borg-Stein 2006.1


Epidemiology and aetiologyA number of recent studies2–4 have examined incidence and prevalence of FMS. The esti-mated prevalence is between 1% and 4%. FMS is between two and six times more likelyto occur in women. Incidence in the female population has been estimated at 11.3 per1000 person-years. It can occur at any age but becomes more common with advancingyears. FMS has been associated with other rheumatic disorders including rheumatoidarthritis (RA) and systemic lupus erythematosus (SLE).There is clearly strong interplay between physical and psychological factors in FMS.

The onset of illness may be triggered by physical illness (including viral diseases) or bytrauma (including surgery). There is some suggestion that heredity may play a part, withcomponents of the serotonergic and dopaminergic systems being potential candidatesfor involvement. Some of the symptomatology around the trigger points may be due toincreased acetylcholine at the motor endplate causing contraction and shortening of thesarcomere. This may lead to increased energy consumption and increased local bloodsupply, with resulting local tenderness. A number of local and systemic mediators havebeen implicated. These include bradykinin, calcitonin gene-related peptide, substance P,tumour necrosis factor-a, interleukin-1, noradrenaline and serotonin.

InvestigationsRoutine investigations – including full blood count and biochemistry, plus erythrocytesedimentation rate (ESR), C-reactive protein (CRP) and other inflammatory markers –are within the normal range. Because thyroid disease is common, it is useful to includethyroid function tests. There are no specific endocrine abnormalities. X-ray, computedtomography (CT) and magnetic resonance imaging (MRI) scans are generally normal.There are no specific abnormalities on muscle biopsy, electromyography or nerve con-duction studies. EEG ormore formal sleep studies may be requested in patients who havemarked sleep disturbance. This may reveal abnormalities including periodic limb move-ment disorder, rapid eye movement (REM) sleep disorder or sleep apnoea. The diagnosisof FMS is one of exclusion and is made clinically.

Prognosis, differential diagnosis and treatmentThe outlook for FMS is variable and the condition tends to become chronic. However,more widespread understanding and clearer definition, along with a more highly devel-oped treatment flow, are beginning to streamline management and improve the outlook.There is a danger that over-enthusiastic investigation might contribute to making thecondition more chronic. However, this should not deter the clinician from making a fullinvestigation and the clinical picture warrants it. The major differential diagnosis is otherconnective tissue disorders, including rheumatoid disease, SLE and scleroderma. Majordifferential diagnoses of FMS and investigation of the condition are summarized inFigure 6.2.There is no specific treatment for FMS. Therapeutic measures include the following:

� General: investigation and clear diagnosis; educating the patient as to the nature ofthe diagnosis and reassuring them; attention to psychological and social factors, andencouraging the patient to have a normal sleep pattern as well as to engage inphysical activity consistent with their state of health and preferences.



� Pain relief. This may range from simple analgesics such as paracetamol to morepowerful agents. Inappropriate use of powerful opioid analgesics should be avoided asthis may lead to dependence and seldom alleviates the symptoms in the long term.Non-steroidal anti-inflammatory drugs have marginal benefits over simple analgesics.Tramadol is a weak opioid with some action to inhibit the uptake of serotonin.

� Antidepressants. Either tricyclic antidepressants or selective serotonin reuptakeinhibitors are of benefit in many cases, even when there is not major evidence ofdepression. Dual inhibitors of both noradrenaline and serotonin uptake, such asduloxetine, may be of particular benefit.

� a2-adrenergic agonists, such as clonidine or tizanidine, are of benefit to somepatients and may act by preventing the action of neurotransmitters such asglutamate or substance P within the central nervous system.

� Anticonvulsants may contribute to pain relief. There is increasing experience withnewer agents such as pregabalin or gabapentin, which have proved to be of use inother painful neurological conditions.


Musculoskeletal pain• Affecting the axial skeleton• Both sides of the body• Above and below the waist• At least 11/18 trigger points tender

Associated symptoms ? Referred pain• Visceral• Skeletal

1veImaging• X-rays• CT scan• MRI scan2ve

2ve 1veClassic FMS

(clinical diagnosis)

Consider:• RA• Scleroderma• SLE• Lyme disease

Joint swelling ordeformity

2ve

Limited Ix• FBC 1ESR• CRP• FT4 1TSH

Further Ix• RF• ANF• Viral serology

2ve

Figure 6.2 Investigation of suspected FMS.- ve, negative; + ve, positive; ANF, antinuclear factor ; CRP,C-reactive protein; CT, computed tomography; ESR, erythrocyte sedimentation rate; FBC, full blood count;FMS, fibromyalgia syndrome; FT4, thyroxine; Ix, investigation;MRI, magnetic resonance imaging; RA,rheumatoid arthritis; RF, rheumatoid factor; SLE, systemic lupus erythematosus; TSH, thyroid stimulatinghormone. Adapted from Schneider et al. 2006.5


� Trigger point injection may be undertaken with local anaesthetic, steroid orbotulinum toxin. The latter may be more effective than steroid injection; it may actby diminishing acetylcholine release, thus decreasing muscle activity and localischaemia.

� Postural training, exercise and ergonomic adjustments (particularly in theworkplace) may help a patient to adapt to disability associated with FMS.

� Stress reduction may be achieved by a variety of means including cognitivebehavioural therapy, relaxation techniques and biofeedback methods.

� Physical therapies including acupuncture, massage, transcutaneous electrical nervestimulation and ultrasound may be helpful. These should always be performed by asuitably qualified and reputable practitioner.

Recent Developments1 There is some discordance between the clinical diagnosis of FMS and the diagnosis

using ACR criteria.6 In a survey of 206 patients, FMS was diagnosed in 49.0% whileonly 29.1%met ACR criteria. The authors of the report proposed a survey methodfor diagnosis of FMS that did not require clinical examination.

2 Improved understanding of the pathophysiological basis for the syndrome is not onlylending credence to the diagnosis, but is also giving rise to more logical management.7

Patients are often mislabelled as having a purely psychological diagnosis, leading tothe undertreatment or mismanagement of the physical symptoms. Increased activityof the hypothalamic–pituitary–adrenal axis and the sympathetic nervous system hasbeen proposed to be responsible for some of the clinical features.8

3 More than 90% of patients have tried alternative or complementary treatments.Acupuncture has been widely used but not intensively studied. A recent randomizedcontrolled trial of acupuncture in FMS9 reported greater improvements in thetreatment group compared with the control group. Symptoms of fatigue and anxietywere particularly improved and the treatment is very well tolerated. These patientsalso experienced better pain relief.

4 Being overweight or obese is associated with a variety of physical and psychologicalsymptoms, including many of the symptoms that form part of the FMS complex.Results of the recently published behavioural weight loss programme10 confirm thatmodest weight loss is associated with an improvement in FMS symptoms.

ConclusionAttempts should be made to establish the diagnosis in the above patient. This shouldinclude the exclusion of thyroid disease and connective tissue disorders. Thorough med-ical assessment should be undertaken, with care not to increase the patient’s anxiety.Once the diagnosis is established, this should be carefully explained to the patient and arealistic management plan should be agreed. This should include trying to manage painand sleep disturbance with the minimum of pharmacological intervention. Physicalactivity should be encouraged within the limits imposed by her condition. Weight loss is




important in the overweight patient for future health and may also help to alleviate thesymptoms of FMS.

Further Reading1 Borg-Stein J. Treatment of fibromyalgia, myofascial pain, and related disorders. Phys Med

Rehabil Clin N Am 2006; 17: 491–510.

2 Raphael KG, Janal MN, Nayak S, Schwartz JE, Gallagher RM. Psychiatric comorbidities in a

community sample of women with fibromyalgia. Pain 2006; 124: 117–25.

3 Weir PT, Harlan GA, Nkoy FL et al. The incidence of fibromyalgia and its associated comor-

bidities: a population-based retrospective cohort study based on International Classification

of Diseases 9th Revision codes. J Clin Rheumatol 2006; 12: 124–8.

4 McNally JD, Matheson DA, Bakowsky VS. The epidemiology of self-reported fibromyalgia in

Canada. Chronic Dis Can 2006; 27: 9–16.

5 Schneider MJ, Brady DM, Perle SM. Commentary: differential diagnosis of fibromyalgia

syndrome: proposal of a model and algorithm for patients presenting with the primary

symptom of chronic widespread pain. J Manipulative Physiol Ther 2006; 29: 493–501.

6 Katz RS, Wolfe F, Michaud K. Fibromyalgia diagnosis: a comparison of clinical, survey, and

American College of Rheumatology criteria. Arthritis Rheum 2006; 54: 169–76.

7 Dadabhoy D, Clauw DJ. Fibromyalgia: progress in diagnosis and treatment. Curr Pain

Headache Rep 2005; 9: 399–404.

8 Sarzi-Puttini P, Atzeni F, Diana A, Doria A, Furlan R. Increased neural sympathetic activation

in fibromyalgia syndrome. Ann NY Acad Sci 2006; 1069: 109–17.

9 Martin DP, Sletten CD,Williams BA, Berger IH. Improvement in fibromyalgia symptoms

with acupuncture: results of a randomized controlled trial.Mayo Clin Proc 2006; 81: 749–57.

10 Shapiro JR, Anderson DA, Danoff-Burg S. A pilot study of the effects of behavioural weight

loss treatment on fibromyalgia symptoms. J Psychsom Res 2005; 59: 275–82.


Case HistoryShirley is aged 43 years and presents with exquisite pain beneath her left heel whenwalking. She is moderately obese (body mass index 32 kg/m2) and finds it hard to walkfirst thing in the morning. She prefers to wear open sandals.

Should Shirley have X-rays to determine whether she has a plantar spur?

What effect, if any, does Shirley’s weight have on her condition?

What are the current supported therapies?

BackgroundPlantar fasciitis commonly causes inferior heel pain and occurs in up to 10% of theUnited States population. It affects both active and sedentary adults of all ages, but ismore likely to occur in persons who are obese, who spendmost of the day on their feet orwho have limited ankle dorsiflexion. Plantar fasciitis is a musculoskeletal disorder pri-marily affecting the fascial enthesis. Although poorly understood, development of plan-tar fasciitis is thought to have a mechanical origin. In particular, pes planus foot typesand lower-limb biomechanics that result in a lowered medial longitudinal arch createexcessive tensile strain within the fascia, producing microscopic tears. The roles of bothchronic inflammation and arch mechanics in the aetiology of plantar fasciitis arecontroversial.1

Diagnosis is based on the history and physical examination (Table 7.1); the differentialdiagnosis is listed in Table 7.2. Unaccustomed walking in the sedentary or prolongedrunning in the athlete may induce fatigue tears of the plantar fascia and avulsion fracturemay cause pain at the medial calcaneal tuberosity. The same area is involved in spondy-loarthropathy (ankylosing spondylitis, psoriatic arthritis and reactive arthritis) as plantar

07 Plantar fasciitis 33

07 Plantar Fasciitis

P R O B L E M

• Chronic inferior heel pain on weight bearing: throbbing, searing, piercing in character• Pain worst with the first steps in the morning or after rest• Pain reduces after mobilization, to recur with continued activity• Walking barefoot, on toes or up stairs exacerbates pain• Tenderness aroundmedial calcaneal tuberosity at the plantar aponeurosis• Bilateral plantar fasciitis is highly suggestive of spondyloarthropathy

Table 7.1 Diagnosis of plantar fasciitis2



fascia enthesitis. Insertional plantar fascia pain is typically increased by passive dorsiflex-ion of the big toe and is located centromedially at the medial calcaneal tuberosity. Heelpain may be caused by an entrapment neuropathy of the calcaneal branches of theposterior tibial nerve or the first branch of the lateral plantar nerve. Since encroachmentoccurs between the abductor hallucis fascia and the quadratus plantae muscle, maximaltenderness is in the medial border of the heel. Diagnostic imaging does not contributeunless another diagnosis is strongly suspected, such as calcaneal stress fracture. The lattermay be diagnosed by plain X-ray or by isotope bone scanning for confirmation.Radiography may show calcifications in the soft tissues around the heel, or osteophyteson the anterior calcaneus (i.e. heel spurs). Fifty per cent of patients with plantar fasciitisand 20% of persons without plantar fasciitis have heel spurs.Plantar fasciitis is five times more likely to occur in obese individuals. Although the

link between obesity and plantar heel pain is poorly understood, research to date hasfocused on the impact of adiposity of the subcalcaneal fat pad and the function of themedial longitudinal arch.4 The plantar fascia is the primary structure stabilizing themedial longitudinal arch of the foot. Both abnormal arch structure and movement havebeen implicated in the development of plantar fasciitis. In particular, pes planus or


• Posterior calcaneal pain– Superficial bursitis– Achilles tendonitis– Retrocalcaneal bursitis– Calcaneal epiphysitis (Sever’s disease) in adolescents

• Plantar calcaneal pain– Central: fat pad atrophy (primary, or secondary to corticosteroid infiltration), obesity– Medial: compression neuropathy of nerve to abductor digiti minimi andmedial calcaneal branch of the

posterior tibial nerve; posterior tibialis tendonitis– Medial central: plantar fasciitis, avulsion fractures, fascial microtears– Lateral: calcaneal stress fracture, calcaneal cysts

Table 7.2 Common causes of heel pain2,3

Clinical recommendation Evidence rating

Off-the-shelf (non-magnetic) insoles B

Custom-made insoles are not more effective than fabricated insoles B

Plantar fascia stretching more effective than calf stretching and should be recommended Bto all patients

Corticosteroid iontophoresis should be considered for short-term relief if initial therapy fails B

Custom-made night splints B

Extracorporeal shock therapy is not effective B

Walking casts in those who have failed conservative therapy C

Open or endoscopic surgery for those who have failed all conservative measures B

B, inconsistent or limited quality evidence; C, consensus, usual practice or expert opinion.

Table 7.3 Therapeutic recommendations2


biomechanics that result in a lower longitudinal arch (i.e. foot pronation) increase ten-sion within the plantar fascia and thereby increase the risk of fascial injury. The plantarfat pad is a specially organized and richly innervated adipose tissue that provides cush-ioning to the underlying foot structures of the heel, dampening impulses associated withheel strike. The heel pad is particularly receptive to detecting vibration, suggesting a rolefor detection of gait-induced shock waves. Consequently, changes leading to increasedstiffness and reduced compressibility of the subcalcaneal fat pad have been linked to thedevelopment of plantar fasciitis, presumably by lowering the attenuation of impulse aris-ing from heel strike.Most patients with plantar fasciitis eventually improve, albeit slowly; 80% of patients

treated conservatively are in complete remission at four years. A variety of therapies areused in the treatment of plantar fasciitis and key recommendations, including exercises(Figure 7.1), are summarized in Table 7.3. Limited evidence supports the use of cortico-steroid injections; the benefit is short-lived and may be associated with adverse effectssuch as fascial rupture. Corticosteroid-induced atrophy of the subcalcaneal fat pad mayalso exacerbate the underlying biomechanical predisposition.

Recent Developments1 Foot orthoses are commonly used for plantar fasciitis but, if custom-made, require a

period of weeks between initial consultation and use. Off-the-shelf orthoses arequicker and cheaper, but cost and availability may still be a barrier to use. Short-termtreatments, such as supportive taping, are frequently used to alleviate symptomsinitially. Low-Dye taping is one of the most frequently applied methods, andimproves symptoms by reducing strain in the plantar fascia during standing andwalking. Utilizing taping around both the midfoot and the level of the Achillesinsertion into the calcaneum, comparison was made between individuals whoreceived taping plus sham ultrasound and individuals receiving sham ultrasoundonly.5 The primary outcome was ‘first-step’ pain one week after tape application, andthere was a statistically significant though clinically small reduction in pain withtaping. The 12.3 mm reduction in a visual analogue scale for pain was greater thanthe 9–10 mm difference thought to be clinically meaningful.

2 The sensory nerve supplying the skin of the heel and the medial side of the sole is themedial calcaneal branch of the posterior tibial nerve; researchers have suggested thatentrapment of this nerve might present as an important factor causing heel pain.Nerve conduction tests have confirmed latency in the medial calcaneal nerve insubjects with plantar fasciitis, but these subjects have normal conduction in theirsural, medial and lateral plantar nerves and posterior tibial nerves.6

ConclusionPlantar fasciitis, if not treated, tends to follow a chronic course. Being overweight, thepresence of bilateral symptoms and duration greater than six months are associated withpoorer outcome. Treatment should be directed along biomechanical lines – weight




Figure 7.1 Recommended exercises for plantar fasciitis. (1) Before stepping down, especially aftersleeping or resting, stretch the arch of the foot by stretching your legs out in front of you (do not bend theknee). Place a towel around the ball of the foot. Slowly pull on the ends of the towel, pulling the toes and ballof the foot back as far as is comfortable. Hold the foot in this position for ten seconds. Repeat at least tentimes. You should feel a pull on the bottom of the foot, especially in the arch. This stretches the plantarfascia and reduces its pull on the heel. (2) Stand about two to three feet from a wall. Lean forward with yourhands against the wall. With the painful foot behind, place the other foot forward. Press against the wall,shifting weight over the front foot, while straightening the back leg. Keep the heel of the back foot on thefloor and feel the stretch in the heel, Achilles tendon and calf. Hold this position for ten seconds. Repeat atleast ten times, and try to do this three times a day.


reduction, orthoses and plantar stretching. Since there is limited evidence regarding thevalue of treatments, a reasonable approach is to start with patient-directed, low-risk,minimal-cost interventions, such as regularly stretching the calf muscles and the plantarfascia, avoiding flat shoes and walking barefoot, using over-the-counter arch supportsand heel cushions, and limiting extended physical activities. A trial of non-steroidal anti-inflammatory drugs is reasonable. More costly treatments, such as custom-madeorthotics, night splints and immobilization with casts, may be options when the condi-tion does not improve, although the value of these treatments is uncertain.

Further Reading1 Wearing SC, Smeathers JE, Urry SR, Hennig EM, Hills AP. The pathomechanics of plantar

fasciitis. Sports Med 2006; 36: 585–611.

2 Cole C, Seto C, Gazewood J. Plantar fasciitis: evidence-based review of diagnosis and therapy.

Am Fam Physician 2005; 72: 2237–42.

3 Canoso JJ. Foot pain. In: Rheumatology in Primary Care. WB Saunders, Philadelphia, 1997;

Chapter 29.

4 Wearing SC, Hennig EM, Byrne NM, Steele JR, Hills AP. Musculoskeletal disorders associated

with obesity: a biomechanical perspective.Obes Rev 2006; 7: 239–50.

5 Radford JA, Landorf KB, Buchbinder R, Cook C. Effectiveness of low-Dye taping for the

short-term treatment of plantar heel pain: a randomised trial. BMCMusculoskelet Disord 2006;

7: 64.

6 Chang CW,Wang YC, HouWH, Lee XX, Chang KF. Medial calcaneal neuropathy is

associated with plantar fasciitis. Clin Neurophysiol 2007; 118: 119–23.



08 Causes and Prevention

Osteoarthritis

S E C T I O N T W O 02

08 Causes and prevention09 Non-pharmacological treatment10 Drug treatment11 NSAIDs – gastric side effects and protection12 NSAIDs – cardiac complications13 Joint replacement surgery

P R O B L E M

Case HistoryJohn is a 48-year-old accountant who is overweight (body mass index 32 kg/m2). Hisgeneral health has been good, but he has become concerned recently about twinges ofpain in his knees. He was a keen road runner in his teens and 20s, but no longer takesregular exercise. He smokes and takes no regular medications. Both of his parentssuffered from osteoarthritis, his father requiring knee replacements in his early 60s.

What is the current thinking about the inheritance of osteoarthritis?

Which environmental factors play a part in its progression?

Can the disease be prevented in a predisposed individual?

BackgroundOsteoarthritis (OA) is an increasing public health problem because of the rising preva-lence of obesity and because of the increasing number of older people in the population.1

Currently, in the United States, 350 000 hip and knee replacements are performed eachyear. OA is markedly age related, affecting around 12% of those aged 55 years, 50% of



those aged 65 years and as many as 80% of those aged 75 years and over. Prevalence esti-mates have largely come from population-based X-ray surveys. However, there is a vari-able relationship between radiological features and symptoms. In clinical practice, OA isonly diagnosed when clinical symptoms (pain and stiffness) coexist with evidence ofstructural damage to the joint. With age, the higher prevalence of OA in females becomeseven more exaggerated. The hips, knees and hands are the most commonly affectedjoints, although almost any joint can be affected. Joint failure arises from a combinationof systemic and mechanical factors, including weakness of supporting muscles and liga-ments, growth of new bone, erosion of articular cartilage and loss of joint space. A simplegrading system is presented in Box 8.1. OA may be primary or secondary; secondarycauses are summarized in Box 8.2.

§02 Osteoarthritis40

Box 8.1 Radiological severity scoring of OA

Grade0 None No features1 Possible Minimal osteophytes2 Minimal Osteophytes, normal joint space3 Moderate Diminution of joint space4 Severe Decreased joint space, bony sclerosis

Box 8.2 Secondary causes of OA

AnatomicalLeg length inequality, jointmalalignmentSlipped femoral epiphyses, epiphyseal dysplasiasPerthe diseaseCongenital dislocation of the hipHypermobility syndromes

TraumaticOccupational arthropathiesFracture through or near a jointJoint surgeryMajor external trauma

InflammatoryInflammatory arthropathiesSeptic arthritis

MetabolicCrystal arthropathiesHaemochromatosisAcromegalyOchronosis, chondrodysplasias


The traditional view is that OA is a simple mechanical condition, in which repeated orsustained stresses on the joint lead to articular cartilage damage and loss. The notion thatthe cartilage is the tissue primarily affected in patients prone to OA has been challenged.In fact, cartilage is a relatively inert tissue with no direct blood supply, nerve input orcapacity to become inflamed. Severe OA can occur in rare genetic conditions – ochrono-sis and chondrodysplasias – but generally in OA, predisposed individuals do not appearto have an alteration in their cartilage structure or composition. In the early stages,changes in modelling of adjacent bone and in the collateral ligaments of the joint mayprecede the development of changes in cartilage and symptoms. Aging and post-menopausal changes in bone turnover are almost certainly important in the disease.From post-mortem and other studies, it seems clear that changes in the joint capsule andcollateral ligaments can also precede the classic structural findings of OA. These changesmay affect joint stability and alignment leading to increased mechanical forces on boneand cartilage. Furthermore, weakening of periarticular muscles further compromisesjoint stability and predisposes to malalignment. This is a particular factor in knee OAwhere quadriceps wasting and weakness leads to decreased joint stability. Loss of coordin-ation, vision and proprioception with age contribute to the individual responding lesswell to unexpected stresses on the joint and thus increasing the impact of minor, poten-tially traumatic events.

A genetic predisposition to OA was first suspected in the 1940s when prevalence ofHeberden’s nodes was noted to be three times higher in first-degree relatives of OApatients. Several segments of the human genome have been identified as susceptibilityloci, and at least twelve candidate genes have been studied. Genetic factors account foraround 50% of the variance in susceptibility to OA. Twin studies suggest a concordancerate of around 0.65 for monozygotic twins and 0.4 for dizygotic twins.2 In a UnitedKingdom study,2 first-degree relatives of patients who had total hip replacement carried arelative risk of 1.9 for also requiring the procedure. The comparable figure for total kneereplacement was 4.8. From genome-wide scans, susceptibility loci have been hypothe-sized at chromosomes 2q, 4q, 6p, 11q and 16p. The only candidate genes identified so farin these regions of the genome are the collagen genes COL29A1 and COL11A2. Othergenes are COL2A1, which codes for collagen II (the major protein of cartilage), CRTL1(coding for a cartilage link protein) and CRTM (coding for a cartilage matrix protein).Polymorphisms of the genes for the vitamin D receptor (VDR) and the oestrogen-areceptor have also been related to risk – both are major determinants of bone density.The COL2A1 andVDR genes are located closely together on chromosome 12q. Cartilage-remodelling protein gene expression may also play a role; expression of the gene formatrix metalloproteinase-3 (MMP-3), which degrades collagen, and the gene for a disin-tegrin and metalloproteinase with thrombospondin motif-5 (ADAMTS-5) both increasecartilage breakdown in vitro. Levels of expression of these enzymes may be both geneti-cally determined and increase in response to mechanical stress of cartilage.

Obesity is by far the best-studied environmental factor, particularly with respect toincreasing risk of knee arthritis. Several factors may underlie the association between obe-sity and OA. Mechanical stresses predispose to joint damage, although obesity alsoincreases risk of OA in non-weight-bearing joints, and alterations in gait and predisposi-tion to injury contribute to joint alignment. Hormonal changes are factors, including lowlocal levels of androgens because of increased aromatase activity. Hyperglycaemia appearsto be a risk factor – partly because of its association with obesity, but also because of other

08 Causes and prevention 41


metabolic factors including the inhibitory effect of advanced glycation end products onproteoglycan synthesis. The low-grade inflammation found in obese subjects and otherpro-inflammatory states also predispose. Glucosamine blocks the effect of cytokines onnitric oxide synthesis and also increases glycosaminoglycan production. Other nutritionalfactors have been identified: low vitamin C intake and vitamin E as an antioxidant anddeterminant of collagen turnover have been implicated, as has low vitamin D status.

Numerous studies have confirmed the increased risk of OA with obesity, particularlywhen obesity develops at a younger age.3–5 In the study by Dawson et al.,3 women whosmoked heavily were also at increased risk. Even a modest increase in weight within thenormal healthy range increases risk of developing OA.4 The latter observation was alsoconfirmed in a national Swedish study,5 although a decreased risk of OA of the hip wasreported in smokers. The effect of smoking on OA is therefore uncertain but appearsunlikely to be marked.

Occupational risk factors are well documented,6 with those who undertake manuallabour being at increased risk. Repeated stress on the knee, particularly with the knee


Anatomical

• Strong family history• Joint replacement in first-degree relative• Premature onset

• Lose weight

• Avoid repeated strain• Support knee

Traumatic Metabolic Inflammatory

Age, post-menopausal

Others – Low vitamin C, D or E; neuromuscular weakness; low BMD

Genetic

Secondary OA

Primary OA

Mechanical loading(± occupational)

Overweight or obese

Female gender

Figure 8.1 Risk factors for OA.


bent, increases mechanical stress on the patello-femoral compartment of the joint.Moderate sporting activity does not seem to pose a risk. Elite athletes are at increasedrisk. Having high bone mineral density (BMD) may predispose to development of osteo-phytes, but high bone turnover – as in post-menopausal osteoporosis – leads to micro-architectural deterioration around the joint. The bone in this area consequently becomes‘stiff’ and less able to absorb shock, placing the patient at higher risk of OA. Hormonereplacement therapy (HRT) has been said to be protective. This may relate to its protect-ive effect on BMD, but it should be noted that use of HRT is associated with a variety ofother lifestyle factors. Risk factors for OA are summarized in Figure 8.1. The risk factorsfor progression are similar and appear to operate more markedly on the knee. Theseinclude obesity, injury, crystal arthropathy, neuromuscular dysfunction and poor phys-ical alignment of the joint.

Recent Developments1 Levels of adiponectin, a hormone product of fat cells, are decreased in obesity. Low

levels increase the risk of developing diabetes and vascular disease. High levels ofadiponectin have recently been reported in synovial fluid from patients with OA.7

The hormone is thought to have a protective role by upregulating the tissue inhibitorof metalloproteinase-2 (TIMP-2) and by inhibiting interleukin(IL)-1–inducedincreases in matrix metalloproteinase-13 (MMP-13).

2 The rate of development of OA in women increases markedly after the menopause,suggesting that oestrogen may have a protective effect. In a large study,8 low plasmaoestrogen and low urinary levels of its metabolites were associated with increasedrisk of OA. Measures to preserve exposure to oestrogen may protect the joints.

3 Biomarkers of disease activity could prove to be a considerable asset.9 Candidatesinclude the urinary C-terminal peptide of collagen type II, serum hyaluronan andcartilage oligomeric matrix protein. Measurement of these markers could becombined with other clinical measures (e.g. C-reactive protein), symptom scoresand genetic/molecular markers of risk to help focus programmes of treatment onpatients who are either at high risk or have rapidly progressive disease.

ConclusionOA is a disorder with a strong genetic component. Patients with a first-degree relativewho has a joint replacement, Heberden’s nodes or who has developed premature OAshould be aware that they are at risk of developing OA. The major, modifiable risk factoris being overweight or obese. There is evidence that weight loss in those who are over-weight improves OA symptoms and retards progression. It is important to identify fac-tors that place increased strain on the joints, including occupational risks, repetitiveinjuries and joint malalignment. Simple measures may decrease the risk from physicalfactors. OA is one of the major degenerative diseases of aging. While we can delay theimpact of the disorder on individual patients, we are not at a stage where OA can be rou-tinely prevented.

08 Causes and prevention 43


Further Reading1 Arden N, Nevitt MC. Osteoarthritis: epidemiology. Best Pract Res Clin Rheumatol 2006; 20:

3–25.

2 Loughlin J. Genetic epidemiology of primary osteoarthritis. Curr Opin Rheumatol 2001; 13:111–16.

3 Dawson J, Juszczak E, ThorogoodM, Marks SA, Dodd C, Fitzpatrick R. An investigation of

risk factors for symptomatic osteoarthritis of the knee in women using a life course approach.

J Epidemiol Community Health 2003; 57: 823–30.

4 Holmberg S, Thelin A, Thelin N. Knee osteoarthritis and body mass index: a population-based

case-control study. Scand J Rheumatol 2005; 34: 59–64.

5 Järvholm B, Lewold S, Malchau H, Vingård E. Age, bodyweight, smoking habits and the risk of

severe osteoarthritis in the hip and knee in men. Eur J Epidemiol 2005; 20: 537–42.

6 Rossignol M. Primary osteoarthritis and occupation in the Quebec national health and social

survey.Occup Environ Med 2004; 61: 729–35.

7 Chen TH, Chen L, Hsieh MS, Chang CP, Chou DT, Tsai SH. Evidence for a protective role for

adiponectin in osteoarthritis. Biochim Biophys Acta 2006; 1762: 711–18.

8 Sowers MR, McConnell D, Jannausch M, Buyuktur AG, Hochberg M, Jamadar DA. Estradiol

and its metabolites and their association with knee osteoarthritis. Arthritis Rheum 2006; 54:2481–7.

9 Kraus VB. Do biochemical markers have a role in osteoarthritis diagnosis and treatment? Best

Pract Res Clin Rheumatol 2006; 20: 69–80.



Case HistoryAP is a 58-year-old womanwhose symptoms of osteoarthritis (OA) are beginning to limither activity. She complains that she feels stiff. She takes paracetamol regularly but doesnot want to take other drugs. One of her friends recently suffered gastrointestinalhaemorrhage while taking a non-steroidal anti-inflammatory drug (NSAID).

What non-pharmacological interventions are available?

Are natural treatments effective at decreasing symptoms and protecting joints?

Is cartilage protection a valid treatment goal?

BackgroundEffective analgesia and use of anti-inflammatory drugs can transform the lives of patientswith OA. However, pharmaceuticals are not the sole mode of treatment for OA. Non-pharmacological approaches are often underused. Also many patients resort to naturalproducts. Health practitioners need to understand these products and whether they work.Drug treatment should only be considered when lifestyle and non-pharmacologicalmanagement has failed.

Body weightBeing overweight or obese increases the risk of developing OA and accelerates progres-sion of the disease.1 In the Framingham study, an increase in body mass index (BMI) ofonly 2 kg/m2was associated with a 50% increase in the risk of developing OA in women.2

Studies documenting the benefit of weight loss have generally been short term, lasting nomore than two years. Maintenance of a normal or near-normal body weight is also asso-ciated with other health benefits including prevention of diabetes and cardiovascular dis-ease. While the cornerstone of weight management is diet and exercise, the role of drugs(including orlistat, sibutramine and rimonabant) should be considered.

Weight reduction reduces mechanical stresses on the joints of the axial skeleton. Beingoverweight also increases the risk of joint malalignment. Some of the benefits of a weight-management programme may relate directly to the effects of exercise and to improvedmetabolic factors and lower levels of chronic inflammation. It is important that treat-ment goals are realistic and that the patient receives adequate support. The practitionershould always be alert to the possibility of psychological problems, including eatingdisorders.

09 Non-pharmacological treatment 45

09 Non-Pharmacological Treatment

P R O B L E M



ExercisePhysical exercise contributes to weight loss or at least to weight maintenance.Independently of this, it increases overall function and well-being, and decreases risk offalling. As well as protection from OA,1 exercise also lowers risk of osteoporosis, diabetesand cardiovascular disease. Exercise is of particular benefit in knee protection. Isokineticexercises that utilize either flexion against resistance or extension against resistance areeffective. Both aerobic exercise (low impact) and specific strengthening exercises for peri-articular muscles have been found to be effective. Whichever form of exercise is used,there is benefit from the input of a qualified therapist; undue pain or discomfort shouldbe avoided and the approach should be based on the patient’s ability and motivation,with only gradual increase in the effort required.

Glucosamine and chondroitinGlucosamine, available as sulphate or hydrochloride, is a hexosamine that is a naturalconstituent of keratin sulphate, the glycosaminoglycan of hyaline cartilage. It is fre-quently administered with chondroitin sulphate, another naturally occurring constituentof the cartilage matrix (being a constituent of aggrecan, which is the major proteoglycanof cartilage). Although studies have reported effects comparable with NSAIDs, resultshave been extremely variable. This may be partly because of differences between glu-cosamine hydrochloride and glucosamine sulphate. Studies using the former preparationhave tended to show negative results whereas use of the latter compound tends to bemore effective. This has been attributed by some to the fact that it is a source of sulphate,rather than because of the glucosamine per se. Glucosamine sulphate is given as a single,daily oral dose of 1500 mg and is well absorbed. Some of its effect is mediated throughinhibition of cytokine-induced nitric oxide production and through inhibition of prote-olytic enzymes.

A Cochrane review in 2000 included 16 studies of patients (total 2029) who used glu-cosamine sulphate 1500 mg each day for six weeks.3 Sixty per cent of patients reportedimproved pain and 33% reported improved function. A more recent Cochrane review3

included 20 trials with 2570 patients and, overall, did not confirm improved pain andfunction with glucosamine. However, ten trials using one preparation (RottaPharmaceuticals) did show improvements. A recent study4 randomized 1583 patientswith knee arthritis to glucosamine hydrochloride 1500 mg/day, chondroitin sulphate1200 mg/day, glucosamine and chondroitin together, 200 mg celecoxib or placebo. Up to4 g/day of paracetamol was allowed as rescue analgesia. Neither glucosamine, chon-droitin, nor the combination was successful overall. The combination of the two wassomewhat effective in patients with moderate to severe knee pain. It is noteworthy thatglucosamine hydrochloride was used in this study.

Other nutritional components and supplementsThere is evidence that low vitamin C levels or status is related to the risk of developingOA and to the progression of the disease. The two major essential fatty acids are linoleicacid (18:2 n-6) and a-linolenic acid (18:3 n-3). These two fatty acids form eicosanoidsthrough the action of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and5-lipoxygenase. When cell membranes comprise predominantly n-6 fatty acids (leadingto prostaglandin E2 and leukotriene B4 production) a pro-inflammatory state exists,



while the incorporation of predominantly n-3 fatty acids results in an anti-inflammatorystate. There is considerable evidence for the benefit of n-3 fatty acid supplementation inmanagement of OA.

Patients with OA frequently use complementary and alternative medicines – up to40% of patients were using such products in a recent survey.5 Fish oils, garlic extracts andcelery extract are among the most commonly used products. This high level of usagereflects, to an extent, the fact that patients get incomplete relief frommedical approaches,and also that many patients do not want to be reliant on pharmaceuticals.

ViscosupplementationHyaluronic acid is a high-molecular-weight polysaccharide that contributes to the phys-ical properties of synovial fluid and cartilage. Synovial fluid supplementation, or visco-supplementation, was developed in the 1980s as a treatment proposed to relieve pain inthe short term and to restore the viscoelastic properties associated with hyaluronan insynovial joints. The products used are derivatives of hyaluronan and hylan and are givenby intra-articular injection – sometimes weekly for the first three weeks, but then at inter-vals of at least four weeks for up to six months. A recent Cochrane review6 considered76 controlled trials comparing viscosupplementation products, or examining their usewith intra-articular steroids or NSAIDs. The conclusion was that viscosupplementationtreatment was effective, especially at the 5–13-week period. Firm conclusions about therelative value of different products could not be made.

Two recent studies have confirmed the potential benefits of viscosupplementation.Sun et al.7 administered hyaluronic acid to 75 patients with ankle OA. Patients reportedincreased pain relief and improved function. The effects were apparent both duringtreatment and for up to six months afterwards. In another study,8 intra-articularhyaluronic acid (three injections) was compared with an exercise regimen for patientswith knee OA. Both treatments were effective and there was no statistical differencebetween the two.

Other measuresUse of a walking stick (cane) may help. The stick should be used on the opposite side tothe worst affected joints, with the hand holding the stick at the level of the greatertrochanter, and the foot of the affected leg and the stick striking the ground more or lesssimultaneously. The importance of the joint being as well aligned as possible cannot beoveremphasized. Shoe inserts, braces or taping of the affected joint may minimize theeffect of malalignment including valgus (knees closer together than ankles) and varus(ankles closer together than knees) deformities. Local application of capsaicin cream(0.025%–0.075%), which acts as a counter-irritant, can be useful. Footwear should bechosen according to the following advice:

� Thick, soft soles with maximum shock absorption

� Minimum heel raise

� Broad forefoot, allowing the toes to splay (thus improving balance and decreasingthe likelihood of falls and injuries)

� Soft uppers

� Adequate depth of the shoe



Recent Developments1 Glucosamine has recently been studied in chondral and synovial cultures in vitro.9 In

this study, glucosamine suppressed the secretion of matrix metalloproteinases(MMP-2 andMMP-9), key enzymes involved in cartilage degradation. Urokinaseplasminogen activator has also been implicated in the development of OA, particularlywhere there are joint effusions. Again, levels of this enzyme were suppressed byglucosamine.

2 The hexosamine biosynthetic pathway may be a major cellular nutrient sensor.10 Thefirst step in this pathway is the formation of glucosamine-6-phosphate fromfructose-6-phosphate. The pathway leads to formation of uridine diphosphate(UDP)-N-acetyl-glucosamine, which becomes incorporated into the side chains of


Diet• Suitable calorie intake• Reasonable protein content• ? Vitamin C• ? Essential FA (n-3)

Exercise• Aerobic (general fitness)• Resistance (muscle bulk and function)• Strengthening (periarticular muscles)

Viscosupplementation(hyaluronic acid)

Weight loss(if overweight/obese)

Weight maintenance

General measures• Accident/injury prevention• Sensible footwear• Taping or bracing affected joint• Orthotics (joint alignment)• Walking aids (stick etc.)

Capsaicin for pain relief

Glucosamine sulphate ± chondroitin sulphate

Figure 9.1 Non-pharmacological management of OA. FA, fatty acid.



proteins and lipids. There is concern that increased flux through this pathway(including by glucosamine supplementation) may worsen insulin resistance andincrease susceptibility to diabetes complications.

3 Some of the properties of mature cartilage depend on the charge of sulphate moietiesof chondroitin sulphate. Dietary sulphate largely comes from high-protein foods,and low sulphate intake or low serum levels of sulphate have been associated withincreased risk of OA. Blinn et al.11 have shown that prolonging the overnight fast oringestion of calories without protein leads to lower serum levels of sulphate.

ConclusionNon-pharmacological management should be considered at the outset before drug treat-ments are initiated (Figure 9.1). The most important factors are weight management,exercises to increase general fitness and to increase strength around affected joints,measures to decrease stresses on joints, and improvement of the alignment of joints ifneed be. Current evidence favours the use of glucosamine sulphate (usually withchondroitin sulphate) and viscosupplementation with hyaluronic acid products. Anumber of nutritional factors, including antioxidant vitamins and essential fatty acids,are almost certainly important, but routine supplementation is not currently recommended.

Further Reading1 Roddy E, Doherty M. Changing life-styles and osteoarthritis: what is the evidence? Best Pract

Res Clin Rheumatol 2006; 20: 81–97.

2 Felson DT, Zhang Y, HannanMT et al. Risk factors for incident radiographic knee

osteoarthritis in the elderly: the Framingham Study. Arthritis Rheum 1997; 40: 728–33.

3 Towheed TE, Maxwell L, Anastassiades TP et al. Glucosamine therapy for treating osteoarthri-

tis. Cochrane Database Syst Rev 2005; CD002946.

4 Clegg DO, Reda DJ, Harris CL et al. Glucosamine, chondroitin sulphate, and the two in com-

bination for painful knee osteoarthritis.New Engl J Med 2006; 354: 795–808.

5 Zochling J, March LM, Lapsley H, Cross M, Tribe K, Brooks P. Use of complementary

medicines for osteoarthritis – a prospective study. Ann Rheum Dis 2004; 63: 549–54.

6 Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Viscosupplementation for the

treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2006; CD005321.

7 Sun SF, Chou YJ, Hsu CW et al. Efficacy of intra-articular hyaluronic acid in patients with

osteoarthritis of the ankle: a prospective study.Osteoarthritis Cartilage 2006; 14: 867–74.

8 Karatosun V, Unver B, Gocen Z, Sen A, Gunal I. Intra-articular hyaluranic acid compared

with progressive knee exercises in osteoarthritis of the knee: a prospective randomized trial

with long-term follow-up. Rheumatol Int 2006; 26: 277–84.

9 Chu SC, Yang SF, Lue KH et al. Glucosamine sulfate suppresses the expressions of urokinase

plasminogen activator and inhibitor and gelatinases during the early stage of osteoarthritis.

Clin Chim Acta 2006; 372 : 167–72.


10 Buse MG. Hexosamines, insulin resistance, and the complications of diabetes: current status.

Am J Physiol Endocrinol Metab 2006; 290: E1–8.

11 Blinn CM, Biggee BA, McAlindon TE, Nuite M, Sibert JE. Sulphate and osteoarthritis:

decrease of serum sulphate levels in an additional 3-h fast and a 3-h glucose tolerance test after

an overnight fast. Ann Rheum Dis 2006; 65: 1223–5.


10 Drug Treatment

P R O B L E M

Case HistoryMrs GT is 67 years old. Since she developed osteoarthritis (OA) five years ago she has triedhard to control symptoms with diet, exercise and nutritional supplements. She isincreasingly frequently requiring analgesics. She wants to discuss drug treatments for herOA. Her general health is good and she has no history of dyspepsia.

Do non-steroidal anti-inflammatory drugs (NSAIDs) have an advantage over simpleanalgesia?

How should drug therapy be approached?

What are the prospects for disease-modifying drugs?

BackgroundThe first line of treatment for OA should always be non-pharmacological. When drugtherapy is required, paracetamol in doses of up to 4 g/day is the usual first-line treatment.Zhang et al.1 conducted a meta-analysis of published controlled trials of simple analgesiafor OA. The pain response to paracetamol was assessed along with the Western Ontarioand McMaster Universities (WOMAC) OA index score, a score that focuses largely onfunctional symptoms. Combining data from the four trials identified, the pain responsewas classified as weak, while there was minimal functional improvement. Further trialdata confirm that the effect of paracetamol is modest, while there is clear evidence fromnumerous trials that NSAIDs have at least a modest benefit in alleviating pain and



improving function.2 Paracetamol should be used only with caution in patients with liverdisorders, but it seldom (except in overdose) causes hepatic dysfunction. Compared withaspirin and NSAIDs, paracetamol is relatively safe in patients with renal impairment.

If paracetamol is of limited efficacy, domore potent analgesics have greater effect? Thebest-studied agent is tramadol. In addition to its opioid action, it is a weak centralinhibitor of noradrenaline and serotonin uptake. There is no question from available tri-als that tramadol is moderately effective at decreasing pain and improving function (byWOMAC score) in patients with OA.3 A total daily dose of 200–300 mg is usual (given individed doses), and the drug may be combined with paracetamol either to increase effector to minimize the dose of each agent. Side effects include dizziness, somnolence,headache and constipation, but the drug is generally very safe, as well as being cheap.There is a range of alternatives including dextropropoxyphene and pentazocine. Morepotent opiates do not offer any advantage in terms of symptom relief and are more likelyto cause side effects including dependence. The efficacy of tramadol is comparable to thatof lower doses of NSAIDs or cyclooxygenase-2 (COX-2) inhibitors.

Topical NSAIDs may be as effective as systemic administration.2 Since only up to 5%of the topical dose is absorbed systemically, risk of severe adverse drug reactions is sub-stantially lower than with oral dosing. Side effects are usually limited to the site of admin-istration – localized itching, burning or skin rash. The only concern with topical NSAIDsfrom trials is that their benefit may be relatively short-lived.

OA is not primarily an inflammatory disorder. However, inflammation does con-tribute to symptoms and to disease progression. For knee OA in particular, intra-articular corticosteroid injection can be useful. The agents used are prednisolone,methylprednisolone, betamethasone and triamcinolone. The treatment leads to short-term symptom relief but does not modify the long-term progression of the disease. Fromassessment of nearly 30 trials,4 the treatment is clearly superior to placebo for pain relief.It is comparable in effect to other pharmacological treatments for pain, but varyingeffects on functional improvement have been reported. There is a risk of introducinginfection into the joint, and the treatment is not useful where there is substantial effusionin the joint.

The focus of treatment in OA has been on symptom relief, but there is increasinginterest in development of drugs that may modify the progress of the disease, and inapproaches to reconstructing the cartilage matrix.5,6 Diacerein is an antagonist to inter-leukin (IL)-1b that has already been demonstrated to have some efficacy in controlledclinical trials. Other anti-inflammatory approaches include antagonists to tumour necro-sis factor (TNF)-a. It appears most likely that local administration of disease-modifyingagents may be preferred to avoid the systemic effects of immunosuppression. Localinhibitors of nitric oxide synthase (NOS) have the potential to decrease activation ofcytokines and the COX-2 enzyme system. Colchicine has been proposed as a means ofdecreasing local inflammation within the joint. Both bisphosphonates and oestrogentreatment (in women) may impact favourably on the increased bone turnover thatoccurs around affected joints. Decreasing the turnover of the cartilaginous matrix is oneof the goals of therapy. Twenty-eight matrix metalloproteinase (MMP) enzymes havenow been identified and are key targets for disease-modifying drugs. Of these drugs, thetetracyclines – including doxycycline and minocycline – are the most widely studiedagents. The joint space is a relatively easy target for locally administered gene therapy.

10 Drug treatment 51


Amongst gene targets studied have been the insulin-like growth factor-1 (IGF-1) geneand the gene for the IL-1 receptor antagonist. Experimental tissue-engineeringapproaches include the use of mesenchymal stem cells, autologous cartilage plugs,implantation of autologous chondrocytes and use of artificial cartilage matrix.

Although unlikely to be as potent as pharmaceuticals and tissue-engineeringapproaches, there is considerable interest in the potential role of diets and supplements.These approaches are cheap, safe and popular with patients. Evidence relating to theireffects andmodes of action is accumulating. Various polyphenols, including the catechingroup, have been studied because of their anti-inflammatory and chondroproliferativeproperties. The best-known supplement is green tea (epigallocatechin gallate), which iswidely used as a herbal remedy. There is also considerable interest in ginger extracts andavocado/soybean non-saponifiables.


Figure 10.1 Drug treatments for OA. GI, gastrointestinal; PPI, proton pump inhibitor.

(Glucosamine ± chondroitin)

Local measures• Capsaicin cream• NSAIDs• Methylsalicylate

High GI risk• Add PPI• Misoprostol• COX-2

More potent opioids oranalgesia 1NSAID Intra-articular treatment

• Steroids• Hyaluronan

Consider surgery

DietExercise

Joint support and alignment

Paracetamol

Maximum dose4 g/day

Tramadol Low GI risk• NSAID


Recent Developments1 Doxycycline has been proposed as a disease-modifying drug for OA. Amongst its

actions in the joint, the drug inhibits breakdown of type XI collagen and decreasesactivity of collagenase and NOS. A 30-month trial of doxycycline in women withradiologically proven knee OA7 showed 40% less reduction in the knee joint space intreated patients compared with placebo. While doxycycline appeared to slow theprogression of joint disease in this study, its effects on symptom control were disap-pointing.

2 Nuclear factor-k-beta (NF-kB) is a transcription factor that plays an important partin modulating immunological and inflammatory responses. When the NF-kBpathway is activated, there is increased expression of inflammatory mediators andproteins involved in the regulation of apoptosis.8 The NF-kB pathway is inhibited bycorticosteroids and a number of other immunomodulatory agents. There is a searchfor more specific agents. The pathway is involved in the pathogenesis of OA not onlythrough regulation of inflammation but also through its involvement in regulationof cartilage turnover.

ConclusionA scheme for managing drug therapy in OA is proposed in Figure 10.1. Paracetamol isthe most widely used analgesic and is often effective in alleviating pain without a majorrisk of side effects. The potential benefits of local treatments and more potent analgesics(including tramadol) are often forgotten before proceeding to NSAIDs. Progress is beingmade with disease-modifying drugs on a number of fronts. The most promisingapproaches are those that may downregulate the local increases in inflammation and car-tilage turnover.

Further Reading1 ZhangW, Jones A, Doherty M. Does paracetamol (acetaminophen) reduce the pain of

osteoarthritis? A meta-analysis of randomised controlled trials. Ann Rheum Dis 2004; 63:901–7.

2 Bannwarth B. Acetaminophen or NSAIDs for the treatment of osteoarthritis. Best Pract Res

Clin Rheumatol 2006; 20: 117–29.

3 Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis. Cochrane Database

Syst Rev 2006; 3: CD005522.

4 Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Intraarticular corticosteroid

for treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2006; CD005328.

5 FajardoM, Di Cesare PE. Disease-modifying therapies for osteoarthritis: current status.Drugs

Aging 2005; 22: 141–61.

6 Baker CL, Ferguson CM. Future treatment of osteoarthritis.Orthopedics 2005; 28 (4 Suppl):s227–34.

10 Drug treatment 53


7 Brandt KD, Mazzuca SA, Katz BP et al. Effects of doxycycline on progression of osteoarthritis:

results of a randomized, placebo-

controlled, double-blind trial. Arthritis Rheum 2005; 52: 2015–25.

8 Roman-Blas JA, Jimenez SA. NF-kb as a potential therapeutic target in osteoarthritis andrheumatoid arthritis.Osteoarthritis Cartilage 2006; 14: 839–48.


11 NSAIDs – Gastric Side Effects andProtection

P R O B L E M

Case HistoryMr JS is a 58-year-old carpenter. He was diagnosed as having rheumatoid arthritis at theage of 40 years. He is a smoker and is prone to dyspepsia. He does not currently requiredisease-modifying drugs. However, he does have pain and stiffness and is not able to workcomfortably without symptomatic relief.

To what extent do non-steroidal anti-inflammatory drugs (NSAIDs) causegastrointestinal symptoms?

Does the presence of dyspeptic symptoms influence the choice of agent?

What strategies are available for gastric protection?

BackgroundThe NSAIDs are an important class of drug with analgesic, antipyretic and anti-inflam-matory activities. They are among the most common drugs prescribed. NSAIDs accountfor around 3% of the total United States (US) drugs market, and it is estimated that5%–10% of the population use NSAIDs on a regular basis (Box 11.1). In the US during2001, 70 million prescriptions were issued for NSAIDs and 30 billion doses were boughtover the counter. NSAIDs are weak acids (pKa 3–5) that are highly lipid soluble and read-ily absorbed from the stomach. In the plasma they are highly protein bound (>95%,mainly to albumin). They are metabolized and conjugated in the liver and mainlyexcreted in the urine.



NSAIDs reversibly inhibit the cyclooxygenase (COX) enzyme, which catalyses the firststep in the pathway that converts arachidonic acid to key regulatory prostaglandins. Theenzyme exists in two isoforms: COX-1 is constitutively expressed in most tissues whileCOX-2 is an inducible enzyme, the expression of which is upregulated at sites of inflam-mation (Figure 11.1). The gastric side effects of NSAIDs relate to inhibition of COX-1 inthe gastric mucosa, where prostaglandins increase gastric mucous and bicarbonate secre-tion, decrease gastric acid secretion and stimulate mucosal blood flow. COX-2 is not

11 NSAIDs – gastric side effects & protection 55

Arachidonic acid

COX-1constitutive/inducible

COX-2constitutive/inducible

PGs• Inflammation

− Fever− Pain− Headache

• Carcinogenesis• Kidney, stomach, uterus• CNS and spine• Endothelium

PGs• GI cytoprotection• Platelet aggregation• Renal function

(blood flow)

Membrane phospholipids

Phospholipase A2

Figure 11.1 Prostaglandin generation by COX-1 and COX-2. CNS, central nervous system; GI,gastrointestinal; PG, prostaglandin.

Box 11.1 Uses of NSAIDs

OsteoarthritisRheumatoid arthritisInflammatory spondyloarthropathies (ankylosing spondylitis, reactive arthritis,psoriatic arthritis)Post-operative painAcute goutSoft tissue injuries (including sports injuries)DysmenorrhoeaRenal colic


normally expressed in the gastric mucosa. The beneficial, anti-inflammatory actions ofNSAIDs are mediated through inhibition of COX-2. NSAIDs vary greatly in their relativeCOX-1 and COX-2 inhibitory activity. Aspirin, sulindac and piroxicam have muchgreater selectivity for COX-1. The mechanism of aspirin action differs from that of otherNSAIDs in that it acts by irreversibly acetylating the active site of COX-1. Meloxicam, thefirst of the selective COX-2 inhibitors, is three times more potent on COX-2 comparedwith COX-1. COX-2 is not inhibited by aspirin but is downregulated by glucocorticoids.

NSAIDs are generally very safe and well tolerated. However, because of the number ofpatients using them, adverse reactions are frequently encountered. By far the most com-mon side effects relate to gastric mucosal injury (Box 11.2). Up to 20% of patients takingNSAIDs suffer gastrointestinal symptoms including heartburn, dyspepsia, nausea,vomiting and abdominal pain. In endoscopic studies, haemorrhagic reactions to thepresence of the tablets in the stomach are almost universal, superficial erosions occur in50% of subjects and 20% of regular users have chronic ulceration (i.e. ulcers that pene-trate the muscularis mucosa). There is a variable relationship between symptoms and thechanges in the mucosa visible on endoscopy.

The gastrointestinal side effects of NSAIDs are a major cause for concern.1 Seriousgastric side effects occur in less than 1% of patients. However, this is sufficient to accountfor 100 000 hospital admissions, contribute to 16 000 deaths and cost $1.5 billion in theUS each year. Similarly in the United Kingdom, where there are around four millionusers with osteoarthritis, use of NSAIDs contributes to 2000 deaths each year.

Hooper et al.2 conducted a review comparing gastric protection strategies in subjectsreceiving NSAIDs. In all, 112 trials with 74 666 participants were included; 248 seriousgastrointestinal adverse drug reactions (ADRs) were reported and there were 138 deaths.Histamine H2 receptor antagonists proved to be ineffective at preventing any of the pri-mary outcomes. Proton pump inhibitors significantly reduced symptomatic ulcers (rela-tive risk [RR] 0.09; 95% confidence interval [CI] 0.02–0.47) and serious complications(RR 0.57; 95% CI 0.36–0.91). Misoprostol is a prostaglandin analogue that increasesmucous protection and decreases acid-induced damage. It may be prescribed alone(Cytotec) or in combination with diclofenac (Arthrotec). A dose of 200mg/day is usuallysufficient, while higher doses may cause diarrhoea, abdominal pain and bloating.Misoprostol decreased the rate of symptomatic ulcers (RR 0.36; 95% CI 0.20–0.67) andserious gastrointestinal side effects (RR 0.57; 95% CI 0.36–0.91). Use of COX-2-selectiveagents was associated with lower rates of symptoms (RR 0.49; 95% CI 0.38–0.62) andserious gastrointestinal ADRs (RR 0.55; 95% CI 0.38–0.80). H2 receptor antagonists areeffective at preventing symptoms and duodenal ulcers with NSAIDs but probably do notprevent gastric ulcers. They are probably more cost-effective than COX-2-selective drugsand their routine prescription with non-selective COX inhibitors may be justified.3


Box 11.2 Risk factors for gastric side effects

High dose ofNSAID Use ofmultiple agentsUse of non-selectiveNSAID Concurrent use of aspirin, warfarin or steroidsFirst threemonths of treatment Previous ulcer historyAge>50 years Helicobacter pylori infectionPrevious ulcer history General disability


Helicobacter pylori infection is implicated in the pathogenesis of gastric and duodenalulcers. It is not clear whether there should be routine screening for and eradication of thisagent in patients starting NSAIDs. Screening can be undertaken using breath tests, sero-logical testing for antibodies or endoscopy with gastric biopsy. Serology is cheap andconvenient but a positive result does not necessarily indicate current infection and doesnot change after eradication.

The Celecoxib Long-term Arthritis Safety Study (CLASS) and the VioxxGastrointestinal Outcomes Research (VIGOR) study each enrolled over 8000 patientsand confirmed that COX-2 inhibitors were as effective as non-selective agents forpatients with arthritis.1 Use of COX-2 inhibitors was associated with lower risk of symp-tomatic ulcers and serious gastrointestinal side effects. A number of studies have con-firmed that COX-2-selective agents reduce the incidence of serious gastrointestinal sideeffects by 40%–50%. Their role in preventing dyspeptic symptoms has been less certain.Spiegel et al.4 recently reviewed 26 published studies comparing COX-2-selective withnon-selective agents; the relative risk of dyspeptic symptoms was decreased by 12% andthe absolute risk was decreased by 3.7% with a COX-2-selective agent. By contrast, com-pared with non-selective NSAIDs alone, NSAID plus concurrent proton pump inhibitorled to a relative risk reduction of dyspeptic symptoms of 66% and an absolute risk reduc-tion of 9%. Aspirin andNSAIDsmay be associated with decreased risk of cancers, includ-ing those of the gastrointestinal tract. Studies in vitro have shown that COX-2 inhibitionmay decrease the growth of gastric cancers, and COX-2 inhibitors have been suggestedfor the treatment of pre-cancerous gastric lesions in humans.5

Increased risk of myocardial infarction has been associated with use of high-dose,non-selective NSAIDs and with use of COX-2-selective agents (chapter 12). Renal sideeffects include salt and water retention, hypertension, acute renal failure, interstitialnephritis, nephrotic syndrome and acute tubular necrosis.6 Renal side effects are morelikely when the patient is also taking angiotensin-converting enzyme inhibitors or diuret-ics. COX-2 is constitutively expressed in the kidney, and patients taking COX-2inhibitors are as likely to experience renal side effects as patients taking non-selectiveagents. Other side effects are headache, dizziness, tinnitus and pruritus. Photosensitivitymay occur with piroxicam or diclofenac. NSAIDsmay cause increased liver enzymes and,occasionally, severe hepatitis.

Recent Developments1 The role of COX isoenzymes in ulcer healing has recently been investigated in

COX-1 and COX-2 knockout mice with induced gastric ulcers.7 The COX-1enzyme apparently had no part to play in ulcer healing, while ulcer healing wasimpaired in COX-2 knockout mice or in wild-type mice treated with COX-2inhibitors. Inducible nitric oxide synthase (NOS-2) and endothelial nitric oxidesynthase (NOS-3) were upregulated in healing ulcers, suggesting that theseenzymes might play a part in the healing process. Some of the potential benefit ofselective COX-2 inhibitors in protecting against ulcer formation may be offset bytheir inhibitory effect on ulcer healing.

2 The proton pump inhibitors are widely used in prevention and treatment ofgastric injury induced by NSAIDs and their use is well supported by trial




Pain (e.g. from arthritis)

Simple analgesia (paracetamol)

NSAID indicated

Correct risk factors if possible• Smoking• Alcohol excess• Stress• Use of steroid, warfarin or aspirin

No ulcerPrevious ulcer

H. Pylori (screen and eradicate)Consider endoscopy/barium

Estimate risk of GI side effectsWarn patient of risks

High riskMedium riskLow risk

Lowest possibledose NSAID

COX-2-selectiveNSAID 1H2RA

NSAID 1 PPINSAID 1 misoprostol

Careful follow-up

Figure 11.2 NSAIDs and risk of gastrointestinal side effects. The considerations shown take account of therelative costs of different drugs and combinations as well as their efficacy. COX-2, COX-2-selective agent;H2RA, histamine H2 receptor antagonist (e.g. cimetidine, ranitidine); NSAID, non-steroidal anti-inflammatory drug (non-selective agent); PPI, proton pump inhibitor.



evidence. Several non-acid-dependent mechanisms are also thought to beimportant in promotion of gastric ulcers. In a recent animal study,8 lansoprazoledecreased oxidative stress within the gastric mucosa and this was thought tocontribute to its effect in protecting from mucosal damage induced by NSAIDs.

3 The interaction between NSAIDs and H. pylori infection in the causation ofgastric and duodenal ulcers is controversial. A recent study compared rates ofgastrointestinal symptoms in patients positive and negative for H. pylori andtreated with NSAID.9 Furthermore, the positive group was divided, with halfbeing treated with H. pylori eradication therapy and half with placebo. Overall,there was no relationship between dyspeptic symptoms induced by NSAID andH. pylori status. These data do not favour routine screening for and eradicationof H. pylori in patients who are being started on NSAIDs.

ConclusionNSAIDs represent one of the most commonly prescribed groups of drugs. Their use isfrequently associated with gastrointestinal symptoms, and serious drug reactions occurin up to 1% of patients annually. The anti-inflammatory action of NSAIDs relates toinhibition of the COX-2 isoenzyme, while gastrointestinal side effects are due to inhib-ition of COX-1. Individual agents vary widely in their relative inhibitory activity for thetwo isoenzymes. COX-2-selective agents are much less likely than non-selective agents tocause dyspeptic symptoms. However, combining non-selective NSAIDs with protonpump inhibitors or misoprostol probably provides even greater protection. Recent datashowing that the COX-2-specific agents in particular are associated with increased risk ofmyocardial infarction have limited the use of this class of drug and led to the withdrawalof some agents. Management of risk of gastric problems with NSAIDs is summarized inFigure 11.2.

Further Reading1 Fennerty MB. NSAID-related gastrointestinal injury. Evidence-based approach to a

preventable complication. Postgrad Med 2001; 110: 87–94.

2 Hooper L, Brown TJ, Elliott R, Payne K, Roberts C, Symmons D. The effectiveness of five

strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-

inflammatory drugs: systematic review. BMJ 2004; 329: 948–58.

3 Elliott RA, Hooper L, Payne K, Brown TJ, Roberts C, Symmons D. Preventing non-

steroidal anti-inflammatory drug-induced gastrointestinal toxicity: are older strategies more

cost-effective in the general population? Rheumatology 2006; 45: 606–13.

4 Spiegel BMR, Farid M, Dulai GS, Gralnek IM, Kanwal F. Comparing rates of dyspepsia

with Coxibs vs NSAID+PPI: a meta-analysis. Am J Med 2006; 119: 448.e27–36.

5 Jiang XH, Wong BCY. Cyclooxygenase-2 inhibition and gastric cancer. Curr Pharm Des

2003; 9: 2281–8.


6 Cheng HF, Harris RC. Renal effects of non-steroidal anti-inflammatory drugs and selective

cyclooxygenase-2 inhibitors. Curr Pharm Des 2005; 11: 1795–804.

7 Schmassmann A, Zoidl G, Peskar BM et al. Role of the different isoforms of cyclooxygenase

and nitric oxide synthase during gastric ulcer healing in cyclooxygenase-1 and -2 knockout

mice. Am J Physiol Gastrointest Liver Physiol 2006; 290: G747–56.

8 Blandizzi C, Fornai M, Colucci R et al. Lansoprazole prevents experimental gastric injury

induced by non-steroidal anti-inflammatory drugs through a reduction of mucosal oxidative

damage.World J Gastroenterol 2005; 11: 4052–60.

9 Schaeverbeke T, Broutet N, Zerbib F et al. Should we eradicateHelicobacter pylori before pre-

scribing an NSAID? Result of a placebo-controlled study. Am J Gastroenterol 2005; 100:2637–43.


12 NSAIDs – Cardiac Complications

P R O B L E M

Case HistoryMrs JA is a 64-year-old lady who finds that her osteoarthritis symptoms are no longercontrolled with simple analgesia. She has suffered from angina since the age of 57. Shehas never had a myocardial infarction (MI) and her angina is stable. Her exercise toleranceis not governed by angina and would be better if her arthritic symptoms were improved.

Would you prescribe her a non-steroidal anti-inflammatory drug (NSAID)?

Which agent would you choose?

What is the current thinking about NSAIDs and the risk of cardiac events?

BackgroundThe cyclooxygenase (COX) enzymes catalyse the first stage in the formation ofprostaglandins and thromboxanes from arachidonic acid. The COX-1 isoenzyme is con-stitutively expressed in most tissues, while COX-2 expression is induced at sites ofinflammation. The major side effects of the NSAID group of drugs, including the effectson the stomach, are caused by COX-1 inhibition, while the beneficial effects are almostentirely due to COX-2 inhibition. A classification of drugs with NSAID action is shown



in Box 12.1. Paracetamol has analgesic but no anti-inflammatory properties.Unquestionably, endoscopic studies have shown that COX-2 inhibitors are less likelythan traditional NSAIDs to produce gastric ulceration. In late 2004, emerging data fromthe Vioxx Gastrointestinal Outcomes Research (VIGOR) and Adenomatous PolypPrevention on Vioxx (APPROVe) studies demonstrated that risk of MI was increased upto two-fold in patients treated with rofecoxib (Vioxx). This led to withdrawal of the drugand valdecoxib was withdrawn because of similar considerations.

Activation of COX-1 in platelets leads to increased thromboxane A2 (TxA2) and con-sequent platelet aggregation, vasoconstriction and smooth muscle proliferation.1 Thispathway is irreversibly blocked by aspirin. Recent studies suggest that non-selectiveNSAIDs including naproxen and ibuprofen, when given concurrently with aspirin, mayinterfere with this beneficial effect of aspirin and increase coronary events. COX-2 isexpressed only at very low levels in healthy blood vessels but is abundantly expressed inatherosclerotic vessels. The enzyme is expressed in smooth muscle cells,macrophages/foam cells and in the endothelium. Secretion of prostacyclin (PGI2) byendothelial cells counteracts the effects of TxA2 released from platelets. This intrinsicprotection mechanism is lost when the COX-2 enzyme is inhibited. Figure 12.1 depictsthe proposed model of prothrombotic and antithrombotic balance for low-dose aspirin,traditional NSAIDs and selective COX-2 inhibitors.

Recent data suggest that the adverse effects noted with rofecoxib are a class effect. Atrial with celecoxib2 revealed a dose-dependent increase in fatal and non-fatal cardiovas-cular events. Deaths from cardiovascular events were three times more likely on400 mg/day and six timesmore likely on 800 mg/day. Hazard ratios for any cardiovascular

12 NSAIDs – cardiac complications 61

SalicylatesAspirinBenorilateDiflunisal

2-arylpropionic acids (profens)IbuprofenFenbufenFenoprofenNaproxenKetoprofenFlurbiprofen

CoxibsCelecoxib (Celebrex)Parecoxib (Dynastat)Lumiracoxib (Prexige)Rofecoxib *Valdecoxib *

*Drugwithdrawn from themarket.

Arylalkanoic acidsDiclofenacEtodolacIndomethacinSulindacTolmetin

OxicamsPiroxicamMeloxicamTenoxicam

Pyrazolidine derivativesPhenylbutazoneOxyphenbutazoneAzapropazone

N-arylanthranilic acidsMefenamic acidTolfenamic acid

Box 12.1 The non-steroidal anti-inflammatory drugs (NSAIDs)


event were 1.5 and 1.9, respectively, for the two doses. Other studies with parecoxib (apro-drug for valdecoxib) have confirmed an increased cardiovascular risk, even withshort-term usage. Non-selective NSAIDs also inhibit COX-2 to a variable extent.Increased cardiovascular risk has been noted in patients taking diclofenac, ibuprofen ornaproxen. Comparing COX-2 inhibitors with non-selective NSAIDs is difficult as the lat-ter also have some COX-2-inhibitory activity. It is agreed that naproxen is the preferreddrug to compare with selective COX-2 inhibitors. Some of the conditions for whichNSAIDs are used are themselves associated with increased cardiovascular risk (e.g.rheumatoid arthritis and systemic lupus erythematosus). The low-grade inflammationassociated with arthritic conditions may contribute to cardiovascular risk throughincreasing endothelial dysfunction, decreasing availability of nitric oxide within vesselsand increasing the generation of reactive oxygen species.

Since the withdrawal of the two coxib drugs at the end of 2004, there has been consid-erable activity to clarify whether safety concerns should include all selective COX-2inhibitors and even extend to some non-selective agents. A large Canadian study3

included 113 927 elderly subjects starting COX-2 inhibitors and who did not have a his-tory of MI. Rofecoxib was associated with increased risk of MI. The increased risk withlow-dose rofecoxib was offset by concurrent use of aspirin. There was no increased riskassociated with celecoxib or meloxicam use. Kearney et al.4 conducted a meta-analysis oftrials published between 1966 and April 2005. Patients taking COX-2 inhibitors hadincreased risk of vascular events. The annual rates of serious cardiovascular events were1.2% per year for patients taking COX-2 inhibitors and 0.9% per year for patients receiv-ing placebo. There was no difference in event rate between COX-2-treated patients and


NORMAL

NSAIDSELECTIVE COX-2

ASPIRIN

LOW-DOSEASPIRIN

PGI2

Pro-thrombotic

Anti-thrombotic

Pro-thrombotic

Anti-thrombotic

Pro-thrombotic

Anti-thrombotic

Pro-thrombotic

Anti-thrombotic

PGI2TxA2

TxA2

TxA2

PGI2PGI2

TxA2

Figure 12.1 Dynamic balance of prostacyclin (PGI2) and thromboxane A2 (TxA2) under the influence ofNSAIDs.


those treated with non-selective COX inhibitors. There was, however, considerable het-erogeneity amongst the latter agents: relative risk of an event (compared with placebo)was 0.92 (95% confidence interval 0.67–1.26) for naproxen, 1.51 (0.96–2.37) for ibupro-fen and 1.63 (1.12–2.37) for diclofenac. Another meta-analysis of 114 controlled clinicaltrials5 has reported increased risk of renal toxicity and arrhythmias with rofecoxib but noincrease with other coxib drugs.

Recent Developments1 A Danish study6 has investigated rates of death and re-admission with MI in

58 432 patients discharged following acute MI. There was a trend towardsincreased hospitalization for use of both COX-2-selective and non-selectiveagents. The hazard ratios for death were 2.80 (95% confidence interval 2.41–3.25)for rofecoxib, 2.57 (2.15–3.08) for celecoxib, 1.50 (1.36–1.67) for ibuprofen, 2.40

12 NSAIDs – cardiac complications 63

High gastric riskor symptoms

Or

Analgesia (paracetamol up to 4 g/day)

Low cardiac risk* Angina Previous MI or stroke

NSAID NSAID 1aspirin

Stronger analgesia(e.g. tramadol)

Add PPI ormisoprostol

COX-2

High gastric riskor symptoms

Naproxen 1aspirin

Add PPI ormisoprostol

Review need for NSAID regularly (every 3 months)

Non-pharmacological treatments been fully explored?

Figure 12.2 Use of NSAIDs in patients with cardiovascular risk. * Measure lipids, blood glucose and bloodpressure; it is useful to use a cardiovascular risk calculator. COX-2, COX-2-selective agent; NSAID, non-selective anti-inflammatory drug; PPI, proton pump inhibitor.


(2.09–2.80) for diclofenac and 1.29 (1.16–1.43) for other NSAIDs. The risk ofdeath was related to dose of drug taken.

2 A nationwide Finnish study7 examined the use of NSAIDs in 33 309 patientsadmitted with their first MI. These subjects were age- and gender-matched withcontrols. The apparent risk with NSAIDS for first MI was 1.40 (95% confidenceinterval 1.33–1.48). No difference was noted between non-selective agents, semi-selective COX-2 inhibitors or selective COX-2 inhibitors. There was nosuggestion that any of the drugs was protective against MI.

3 A study to compare etoricoxib with diclofenac is under way.8 This study inpatients with rheumatoid arthritis or osteoarthritis should answer the question ofwhether the risk associated with use of COX-2 inhibitors is any greater than thatfor conventional NSAIDs. The study has enrolled nearly 35 000 patients.

ConclusionOver 30 million people worldwide take NSAIDs regularly. Recent studies have shownthat use of these drugs is associated with increased risk of MI. If non-pharmacologicalmeans and simple analgesia fail to control the above patient’s symptoms, then it is rea-sonable to consider use of NSAIDs. It is probably best, initially, to use one of the conven-tional agents and naproxen is the drug of choice, the dose and duration of exposure beingkept to a minimum. There is an argument for using higher-dose aspirin to overcome theeffects of COX-2 inhibition. A scheme for considering NSAID use is presented in Figure12.2. There is considerable heterogeneity of cardiovascular risk amongst both COX-2-selective and non-selective NSAIDs, although it seems likely that increased risk is relatedto the ability of the individual drug to inhibit the COX-2 isoenzyme.

Further Reading1 HermannM, Ruschitzka F. Coxibs, non-steroidal anti-inflammatory drugs and cardiovascular

risk. Intern Med J 2006; 36: 308–19.

2 Solomon SD, McMurray JJ, Pfeffer MA et al; Adenoma Prevention with Celecoxib (APC)

Study Investigators. Cardiovascular risk associated with celecoxib in a clinical trial for

colorectal adenoma prevention.New Engl J Med 2005; 352: 1071–80.

3 Lévesque L, Brophy J, Zhang B. The risk for myocardial infarction with cyclooxygenase-2

inhibitors: a population study of elderly adults. Ann Intern Med 2005; 142: 481–9.

4 Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-

oxygenase inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk

of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006; 332: 1302–8.

5 Zhang J, Ding EL, Song Y. Adverse effects of cyclooxygenase 2 inhibitors on renal and

arrhythmia events: meta-analysis of randomised trials. JAMA 2006; 296: 1619–32.

6 Gislason GH, Jacobsen S, Rasmussen JN et al. Risk of death or reinfarction associated with the

use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal anti-inflammatory

drugs after acute myocardial infarction. Circulation 2006; 113: 2906–13.



7 Helin-Salmivaara A, Virtanen A, Vesalainen R et al. NSAID use and the risk of hospitalization

for first myocardial infarction in the general population: a nationwide case-control study from

Finland. Eur Heart J 2006; 27: 1657–63.

8 Cannon CP, Curtis SP, Bolognese JA, Laine L. Clinical trial design and patient demographics

of the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) study program:

cardiovascular outcomes with etoricoxib versus diclofenac in patients with osteoarthritis and

rheumatoid arthritis. Am Heart J 2006; 152: 237–45.

13 Joint replacement surgery 65

13 Joint Replacement Surgery

P R O B L E M

Case HistoryMary has been passing on your advice on preventing osteoarthritis (OA) to the membersof the local bowls club. The information may have come a little late for George who hassevere right hip OA. He is now aged 62 years, is moderately overweight at 89 kg (bodymass index 28.7 kg/m2) and has asked about a hip replacement.

Will weight reduction delay George’s need for surgery?

What are the indications for a knee or hip replacement?

What are the options for joint replacement and what is their expected lifespan?

BackgroundIn the United States and United Kingdom (UK), the number and rate has doubled forknee replacements and tripled for hip replacements over the past decade. Future projec-tions are that >750 000 of these procedures will be performed per year by the year 2030. Acritical variable in these estimations is the low proportion of individuals who on the basisof symptoms warrant joint replacement but remain unwilling to consider the procedure.

Weight reductionGiven that obesity is modifiable by conservative treatment such as weight loss, its impor-tance in reducing the incidence of large joint OA is often advocated, yet determining theimpact prospectively of weight reduction is more problematic.1 The effect of adult weightchange on risk for total hip replacement resulting from primary OAwas studied prospect-ively in a large Norwegian cohort whose weight had been recorded over a mean 14-year



period from age mid-30s to late 40s. With an average follow-up of nine years, there wasno association of weight slope, absolute weight change or relative weight change betweenscreenings with later total hip replacement.2

A number of studies have shown that after large joint replacement weight increases,from a small amount in the pre-operatively non-obese patient to an average 4.8 kg gainin the pre-operatively obese.3,4 Post-operative weight gain has been documented for bothhip and knee replacement, with younger hip-replacement patients gaining a significantamount of weight.5 Obesity therefore needs to be treated as an independent disease thatincreases the risk of requiring major joint replacement, and is adversely impacted bysurgery that is aimed at reducing pain and increasing a person’s exercise ability.

ExerciseExercise is beneficial for people with arthritis, and pre-operative functional status is posi-tively related to post-operative functional status. Inclusion of both pre-operative andpost-operative strength training in a total hip replacement programme improves phys-ical function at 12 and 24 weeks post-operatively.6 The optimal type and the amount ofexercise plus the timing of the pre-operative intervention need to be established.

Indications for hip or knee replacementThese indications are summarized in Figure 13.1. Concerns about the timing of surgerysurface for two primary classes of patients: the younger, active candidate and the oldercandidate. For the younger (less than 60 years of age), active patient, the long-term sur-vival of the prosthesis is the major concern. While there are several studies on long-termoutcome, most of these describe prosthesis survival for the more typical older and lessactive individual. Furthermore, as prosthesis design and materials improve, the newerprostheses will have longer survival.

For the less active, older patient in whom long-term prosthesis survival is less of a con-cern, some information may be provided by comparing outcomes in patients with poorpre-operative symptoms versus those with better pre-operative symptoms as proxies forlate versus early surgery. When followed at 6 and 24 months post-operation, those withpoorer pre-operative status had poorer outcomes. Patients need to appreciate the smallbut real risk of perioperative complications and, for younger patients, the potential forrevision surgery. However, they also should be appraised that likelihood of functionalbenefit is higher if they enter into surgery with a better functional status.

Perioperative preparations and complicationsRheumatoid arthritis (RA) patients also benefit from joint replacement, and in theseindividuals their immunosuppressant therapy needs to be considered. Weeklymethotrexate is the mainstay of most RA regimes, and can be continued up to the time ofsurgery and recommenced upon return of baseline fluid balance and renal function. In aprospective, randomized study of post-operative infection and surgical complications in388 RA patients in the UK who underwent elective orthopaedic surgery, one group con-tinued methotrexate and the other group ceased methotrexate two weeks pre-operativelyand recommenced treatment two weeks post-operatively.6 Complication rates werecompared between groups and with 228 RA patients not on methotrexate and under-going elective orthopaedic surgery. No increase in the duration of early post-operative



infections or rate of complications was found. Patients who continued methotrexate hadsignificantly fewer adverse events than either of the other two groups (P <0.003).Additionally, those who did cease methotrexate had a higher incidence of disease flares inthe six weeks following surgery than those who continued the medication.

The risk of death is approximately 1% in the 90 days following hip replacement andslightly less for knee replacement. Pulmonary embolism andmyocardial infarction occurwithin 90 days in 1% of patients. Dislocation occurs in 3% of total hip replacements.Deep joint infection occurs in about 0.4% of total knee replacements and 0.2% of totalhip replacements. While dislocation and infection remain potential complications overthe longer term, the risk is much higher in the first 90 days than subsequently.

How long will it last?Long-term success of total hip arthroplasty is dependent on prosthetic component fix-ation and the amount of wear and debris generated by the bearing surface. Advances in


Indications: Pain limiting function despite conservative therapyNocturnal pain disrupting sleepUnderstanding of potential complications

Contraindications: Severe neurological or cognitive impairment that willimpair rehabilitationVascular disease/unstable angina/anaesthetic riskChronic sepsis

Plain X-ray

Confirms significantjoint pathology

No or mild X-raychanges

Review to excludeperiarticular source of pain

Orthopaedicreferral

Figure 13.1 Hip and knee joint replacement surgery.


both femoral cementing techniques and the design of cemented stems have resulted innear-perfect (98%) survivorship at ten years and good survivorship (93%) at 25 years.7

Comparable survival rates have been reported using cementless techniques for thefemoral component. In the acetabular component, ten-year survival rates are similar forcemented and cementless techniques (approximately 95%–98%); however, at 15 years,cementless technology supersedes cemented (85%–95% versus 70%–95%).

Cemented total knee arthroplasty (TKA) is the current gold standard, with consistentlong-term (10–14 years) survival rates of 94%–98%. Whilst some cementless TKA tech-niques have demonstrated good long-term survival, themajority have not reliably resultedin bone ingrowth. Long-term survival rates and functional abilities are comparable in cru-ciate-retaining and cruciate-substituting prostheses. To improve patient satisfaction andfunction, implants have an increased arc of flexion that may approach 150 degrees of kneeflexion. Recent literature searches andmeta-analyses suggest that resurfacing the patella atTKA likely improves outcomes and long-term, pain-free patella function.

Recent Developments1 Ogonda et al.8 randomized patients to a standard 16 cm incision or a minimal

(≤10 cm) incision for their hip replacement. They found that although thestandard incision group had a higher estimated blood loss, there was nodifference in mean units of transfusion or haematocrit at discharge. There werealso no significant differences found in post-operative pain, timed 10 m walk onthe second post-operative day, length of hospital stay or functional outcome.

2 Although TKA is currently the gold standard for knee joint replacement,unicompartmental arthroplasty has emerged as a suitable option for advancedmedial compartment osteoarthritis, with outcomes comparable with those forTKA. The procedure is generally performed using a minimally invasive approachand leads to more rapid recovery, minimal bone loss, less pain and earlydischarge compared to TKA. The 10–15-year survival rates for unicompartmentalknee arthroplasty are high and range from 95%–98%.9

ConclusionTotal joint replacement should not be regarded as an intervention of last resort andshould be offered to patients when their quality of life is compromised. Pre-operativefunctional status is the most significant predictor of post-operative functional status.Surgery should be considered when symptoms warrant it and when the intervention willcontribute to a person’s post-operative life experience. As procedures, total hip and kneejoint replacements (Figure 13.2) are costly, but total hip replacement is among the mostcost-effective interventions in medicine. Long-term follow-up is available on older pros-theses and relief of pain and restoration of function can be expected in over 90% ofpatients, with a complication rate that is rare and a mortality rate of <1%.




Figure 13.2 Total hip and knee joint replacements. (A) An artificial hip joint with metallic femoral stemand ultra-high-molecular-weight polyethylene acetabular cup. An artificial knee joint in situ, with metallicfemoral component and ultra-high-molecular-weight polyethylene bearing. (Both figures redrawnwithpermission from Fisher 2004.10).

(A)

(B)


Further Reading1 Powell A, Teichtahl AJ, Wluka AE, Cicuttini FM. Obesity: a preventable risk factor for

large joint osteoarthritis which may act through biomechanical factors. Br J Sports Med

2005; 39: 4–5.

2 Flugsrud GB, Nordsletten L, Espehaug B, Havelin LI, Meyer HE. Weight change and the

risk of total hip replacement. Epidemiology 2003; 14: 578–84.

3 Donovan J, Dingwall I, McChesney S. Weight change 1 year following total knee or hip

arthroplasty. ANZ J Surg 2006; 76: 222–5.

4 Aderinto J, Brenkel IJ, Chan P. Weight change following total hip replacement: a

comparison of obese and non-obese patients. Surgeon 2005; 3: 269–72.

5 Heisel C, Silva M, dela Rosa MA, Schmalzried TP. The effects of lower-extremity total

joint replacement for arthritis on obesity. Orthopedics 2005; 28: 157–9.

6 Grennan DM, Gray J, Loudon J, Fear S. Methotrexate and early postoperative

complications in patients with rheumatoid arthritis undergoing elective orthopaedic

surgery. Ann Rheum Dis 2001; 60: 214–17.

7 Jones DL, Westby MD, Greidanus N et al. Update on hip and knee arthroplasty: current

state of evidence. Arthritis Rheum 2005; 53: 772–80.

8 Ogonda L, Wilson R, Archbold P et al. A minimal-incision technique in total hip

arthroplasty does not improve early post-operative outcomes. A prospective, randomized,

controlled trial. J Bone Joint Surg Am 2005; 87: 701–10.

9 Yang KY, Wang MC, Yeo SJ, Lon NN. Minimally invasive unicondylar versus total

condylar knee arthroplasty – early results of a matched pair comparison. Singapore Med J

2003; 416: 559–62.

10 Fisher J. Surgery for arthritis: total hip and knee joint replacement. ARC Topical Reviews

2004, Number 3.



14 Causes

Rheumatoid Arthritis

S E C T I O N T H R E E 03

14 Causes15 Laboratory and imaging investigations16 Managing rheumatoid arthritis at onset17 Evaluating the response to treatment18 Pregnancy and rheumatic diseases19 Diet and arthritis20 Polyarthritis in the elderly

P R O B L E M

Case HistorySteve’s rheumatoid arthritis (RA) has beenmanaged for the past four years with acombination of methotrexate, hydroxychloroquine and sulphasalazine. He is rheumatoidfactor (RF) positive and has significant joint damage. He wishes to explore with you whyhemay have developed RA. His daughter, aged 24 years, has recently been told that she isRF positive.

What genetic factors influence the development or severity of RA?

What environmental factors are known to be involved?

How does being RF positive influence the likelihood of developing RA?

BackgroundRA is a chronic inflammatory disease affecting the synovium and leading to joint damageand absorption of adjacent bone. Peak age of onset is in the fifth decade and females are



two to three times more likely to be affected, although the sex distribution becomes lessapparent with increasing age. Apart from the disability caused by the disease, it also has asignificant impact on life expectancy, with RA patients living on average three to ten yearsless than unaffected individuals. The overall incidence of the condition is 20–50 per100 000 per year. This may have decreased since the 1960s. The prevalence varies in dif-ferent countries:1

� 0.5%–1.1% in Northern Europe and North America

� 0.3%–0.7% in Southern Europe and other warmer countries

� 0.5% in developing countries

In the pre-clinical phase of RA, immunoglobulin G (IgG) may be elevated and RF(polyclonal antibodies directed at the Fc fragment of IgG) and anti-cyclic citrullinatedpeptide (anti-CCP) antibodies may be detected. Citrullination is a post-translationalmodification of arginine by peptidylarginine deaminase enzymes. Specific disease-modifying treatment is not indicated at this early phase of the disease.

Genetics of RAThe importance of genetic factors is clear from family studies: prevalence is 2%–12% infirst-degree relatives of RA sufferers – i.e. approximately ten times that of the back-ground population. Concordance rate is 10%–30% in monozygotic twins and 5%–10%in same-sex dizygotic twins. The genetic component of RA has been studied by genome-wide linkage analyses and by study of individual candidate genes.2 The major sus-ceptibility gene for RA is the DRB1 gene located in the class II histocompatibility regionon chromosome 6p. Risk of RA is associated with the alleles HLA-DRB1*0401,DRB1*0404, DRB1*0405, DRB1*0408, DRB1*0101 and DRB1*0102. These alleles havesimilar or identical sequences at the third hypervariable region in the b chain betweenamino acid positions 70 and 74. According to the shared epitope (SE) hypothesis, thissequence is directly involved in the immunopathogenesis of RA, although the precisemechanism is not clear.The human leukocyte antigen (HLA) component accounts for around 30% of the

genetic risk. The susceptibility alleles linked to RA are present in around 70% of patientsbut also in 40% of the general population. Thus genotyping is not currently useful inclinical practice. Other genes associated with RA include:

� Tumour necrosis factor (TNF)-a located in the class II part of the histocompatibilitycomplex on 6p. Polymorphisms influence the level of TNF-a expression

� The TNF-a receptor type 2 gene (TNFR2) located at 1p36. The 196R allele of thisgene is linked with RA

� Peptidylarginine deaminases (PADIs), also located at 1p36. These enzymes catalysethe citrullination of arginine residues and, therefore, determine the level of citrulli-nated peptides

� SLC22A4 (solute carrier family 22 A4) at chromosome 5q31 – also implicated inCrohn’s disease

� PTNP22 (tyrosine phosphate non-receptor type 22) at 1p13 – also linked with type 1diabetes and autoimmune thyroid disease

§03 Rheumatoid Arthritis72


Environmental factorsThese triggers may begin to operate long before clinically apparent disease develops. Thepre-clinical phase of RA may last for up to 15–20 years. During this phase the prevalenceof autoantibody markers increases amongst susceptible individuals as the onset of clin-ical disease approaches. IgA rheumatoid factors are probably the first markers to appearin most patients. Neither RF nor anti-CCP antibodies are entirely sensitive, but togetherthe markers are reasonably specific – 85% to 90% for RF and 98% for anti-CCP. Markersof inflammation – including total IgG, erythrocyte sedimentation rate (ESR) andC-reactive protein (CRP) – may be increased during the clinical phase. The patient mayexperience symptoms of malaise and fatigue and intermittent joint symptoms (palin-dromic rheumatism).Risk factors for RA are summarized in Figure 14.1. Environmental triggers may be

more important than genetic factors.3 Some studies have shownmuch higher associationthan this in families but it is difficult to disentangle genetic influences from social andother environmental influences.

14 Causes 73

Genetic • Family history• Other autoimmune disease• HLA-DRB1 SE etc.• Female gender

Environmental • Smoking• Infections (EBV etc)• Low UV (vitamin D)

Diet Protective Aggravating

Omega-3MediterraneandietFruitVitamin C

Red meatCaffeine ?

Occupation • Agriculture• Postal and print• Silica• Mineral oil

SmokingAgingOestrogen withdrawalDecreased androgen levelsPeriodontal disease

Susceptibility

Subclinical

Progression

Disease onset

Figure 14.1 Development of rheumatoid arthritis. EBV, Epstein–Barr virus; UV, ultraviolet light.


Smoking is probably the most potent environmental trigger, with smokers at two- tofour-fold increased risk of RA. The risk is dose dependent with heavy smokers being athigher risk than light smokers. A number of mechanisms could account for the linkbetween smoking and RA – these include the immunomodulatory effect of tobacco com-ponents, oxidative stress and oestrogenic effects, and the effect of smoke in promotingpeptide citrullination. Smoking also increases the risk for anti-double-stranded DNA(anti-dsDNA)-positive systemic lupus erythematosus. Smoking is associated with moresevere rheumatoid disease: erosive arthropathy, rheumatoid nodules and vasculitis. TheNurses Health Study was a large cohort study investigating the effect of aspirin and vita-min E in preventing cardiac disease. In a prospective study of 103 818 women from thiscohort followed from 1976 to 2002,4 there were 680 new cases of RA. Women with a his-tory of ten pack-years or more were at increased risk, and the risk of RA was related bothto the intensity and duration of smoking. The increased risk persisted for up to 20 yearsafter cessation of smoking.Oestrogen exposure in women has a protective effect. This is consistent with increased

risk of the disease after the menopause and the slight protective effect of using hormonereplacement therapy. It is not clear why the prevalence of RA is somuch higher in womencompared with men. As with other autoimmune diseases, pregnancy is protective, withthe incidence during pregnancy being 70% lower than that for age- and sex-matchedcontrols. However, there is a rebound increase after pregnancy with risk increased by asmuch as five-fold in the months after delivery. Breast-feeding also appears to increaserisk. This may be due to the low-oestrogen state or to pro-inflammatory actions of pro-lactin. The relationship between sex steroid status and susceptibility to autoimmune dis-ease is complex.5

The influence of social, employment and educational status does not seem to be greatin RA. The disease is more prevalent in urban populations, but this could be partly due tomigration of patients with chronic RA to metropolitan centres. Certain occupations doseem to have increased risk: men who work in agriculture and in the paper and transportindustries, and female printer and postal workers, appear to be at increased risk. Workersexposed to silica dust (e.g. from drilling or crushing rock) are at up to three-foldincreased risk. Mineral oil exposure has been noted to increase risk of a number ofautoimmune diseases including RA.Low intake of fruit and vitamin C relates to increased risk, while high intake of red

meat carries a high risk. Regular consumption of oily fish (a source of omega-3 fattyacids) is protective, as is adherence to a Mediterranean diet. Low vitamin D status isprobably a risk factor for RA, but there is no evidence that vitamin D supplementationprotects against the disease. Some immune-mediated diseases, particularly type 1 dia-betes andmultiple sclerosis, are more common in latitudes where there is lower exposureto ultraviolet light.6 While vitamin D status is the most plausible explanation for thisassociation, other metabolic factors may equally be involved.The notion of an infectious trigger for RA is appealing. Evidence in favour of this

includes the decreasing incidence of the condition and the associations with previousblood transfusion and pet ownership. There is no evidence for a seasonal incidence of thecondition. Amongst candidate organisms are Epstein–Barr virus (EBV), rubella, parvo-virus and Borrelia burgdorferi. Of these, the strongest evidence is with EBV, the glyco-protein of which has cross-reactivity with the HLA-DRB1 SE. Increased incidence and



levels of EBV DNA have been reported in peripheral blood mononuclear cells and syn-ovial fluid of RA patients and the virus is well documented to have immunomodulatoryproperties.

Recent Developments1 Two recent studies7,8 have pooled data from the United Kingdom and United Statesto demonstrate that there are important susceptibility loci at chromosomes 6q and16p. There appears to be an interaction between these loci and HLA determinants.Further study of the genes at these loci may shed more light on the pathogenesis ofRA.

2 In a recent Swedish case–control study,9 positive immunostaining for citrullinatedpeptides was found in the cells from bronchoalveolar lavage of smokers.Furthermore, there was a strong association between smoking status and thepresence of anti-citrulline antibodies. There was a positive interaction between anti-citrulline autoimmunty and the presence of SE in the HLA-DR region. Individualswho smoked and had double copies of theHLA-DR SE had a 21-fold increased riskof RA.

3 In a mouse model of RA, oestrogen deficiency by oophorectomy accelerated thedevelopment of arthritis and increased levels of RF, anti-dsDNA and anti-collagenantibodies.10

4 Periodontal disease is mainly caused by infection with Gram-negative anaerobes.These lead to increased production of cytokines that damage gingival connectivetissue and increase resorption of dental alveolar bone. Marotte et al.11 haveshown that the presence of HLA-DR SE correlates with increased periodontalbone destruction. Furthermore, periodontal bone destruction strongly correlatedwith wrist bone resorption in patients with RA.

ConclusionRA has a significant genetic component but perhaps not as strong as was once thought.The most powerful genetic influence is the HLA-DRB1-related SE. Of known environ-mental triggers, smoking is the most powerful. Women are more prone to the disease butlow oestrogen status appears to increase susceptibility. The presence of RF is notabsolutely specific for the disease but is generally highly predictive. The antibody doesoccur in a proportion of the general population and may occur in other autoimmuneconnective tissue disorders. A long pre-clinical phase with positive RF and anti-CCPantibodies, sometimes with mild and variable symptoms, is common in RA.

Further Reading1 Alamanos Y, Drosos AA. Epidemiology of adult rheumatoid arthritis. Autoimmun Rev 2005; 4:130–6.

14 Causes 75



2 Dieude P, Cornelis F. Genetic basis of rheumatoid arthritis. Joint Bone Spine 2005; 72: 520–6.

3 Oliver JE, Silman AJ. Risk factors for the development of rheumatoid arthritis. Scand JRheumatol 2006; 35: 169–74.

4 Costenbader KH, Feskanich D, Mandl LA, Karlson EW. Smoking intensity, duration, andcessation, and the risk of rheumatoid arthritis in women. Am J Med 2006; 119: 503.e1–9.

5 Cutolo M, Lahita RG. Estrogens and arthritis. Rheum Dis Clin North Am 2005; 31: 19–27.

6 Ponsonby AL, Lucas RM, van der Mei IAF. UVR, vitamin D and three autoimmunediseases – multiple sclerosis, type 1 diabetes, rheumatoid arthritis. Photochem Photobiol

2005; 81: 1267–75.

7 Etzel CJ, Chen WV, Shepard N et al. Genome-wide meta-analysis for rheumatoid arthritis.

Hum Genet 2006; 119: 634–41.

8 John S, Amos C, Shepard N et al. Linkage analysis of rheumatoid arthritis in US and UK

families reveals interactions between HLA-DRB1 and loci on chromosomes 6q and 16p.

Arthritis Rheum 2006; 54: 1482–90.

9 Klareskog L, Stolt P, Lundberg K et al. A new model for an etiology of rheumatoid

arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to

autoantigens modified by citrullination. Arthritis Rheum 2006; 54: 38–46.

10 Yoneda T, Ishimaru N, Arakaki R et al. Estrogen deficiency accelerates murine

autoimmune arthritis associated with receptor activator of nuclear factor-kB ligand-mediated osteoclastogenesis. Endocrinology 2004; 145: 2384–91.

11 Marotte H, Farge P, Gaudin P, Alexandre C, Mougin B, Miossec P. The associationbetween periodontal disease and joint destruction in rheumatoid arthritis extends the link

between the HLA-DR shared epitope and severity of bone destruction. Ann Rheum Dis

2006; 65: 905–9.


Case HistoryJoan is a 52-year-old schoolteacher who you have diagnosed with rheumatoid arthritis(RA). You have discussed a range of treatment options with her and also discussed withher a number of investigations. She is keen to know about the monitoring andinvestigation required for different medications and what information will be gainedfrom other scheduled investigations.

What investigations should be undertaken at the onset of RA?

What investigations help with monitoring the activity of the condition?

How should follow-up be planned?

BackgroundMaking a diagnosis of RAJoan has an inflammatory arthritis; it is established as a chronic problem, havingextended beyond eight to ten weeks, which makes a post-viral arthropathy unlikely. TheAmerican College of Rheumatology classification for RA requires four of seven criteria tobe met, with the clinical features of arthritis being present for at least six weeks:

� Morning stiffness of greater than one hour duration

� Objective evidence of joint inflammation, such as soft tissue swelling or fluid in 3 of 14defined joint areas (right or left proximal interphalangeal [PIP], metacarpophalangeal[MCP], wrist, elbow, knee, ankle andmetatarsophalangeal joints)

� At least one of the joint areas demonstrating inflammation must be in the hands

� Simultaneous involvement of the same joint area bilaterally in at least one pair

� Rheumatoid nodules

� A positive rheumatoid factor (RF) using a method that is positive in <5% of normalsubjects

� Typical changes of RA in hand and wrist X-rays, which must include erosions orunequivocal periarticular osteopenia

RA is one of the most common autoimmune diseases, affecting 1% of the population.Other diagnoses, such as psoriatic arthritis or systemic lupus erythematosus (SLE), couldpresent with the same clinical scenario and the history and examination undertaken willhave considered these in the differential diagnosis.

15 Laboratory and imaging investigations 77

15 Laboratory and Imaging Investigations

P R O B L E M



Investigations for RARF is a polyclonal antibody predominantly of the immunoglobulin M (IgM) and IgGclasses, which targets the Fc region of the IgG.Whilst commonly thought to have diagnos-tic significance by both doctors and patients, it has a very poor predictive value, being pres-ent in only 70% of RA cohorts and also present in 5% of the normal population. RFpositivity increases with age and is positive in any circumstance with prolonged antigenstimulation, so that chronic infections such as malaria and tuberculosis account for thebulk of RF positivity globally. Similarly in individual patients, age and chronic sepsis needto be considered in addition to the pattern of joint disease before attributing a positive RFwith a diagnosis of RA. RF positivity associates with increased joint erosions and vasculitis.Radiographs of the hands and wrists, feet and cervical spine were historically under-

taken at baseline and then one- to two-yearly to monitor for erosive disease. Fortunately,the model of therapy has changed so that the goal is suppression of inflammation as soonas possible after diagnosis is established; this is combined with the knowledge that jointerosions detected by magnetic resonance imaging (MRI) or musculoskeletal ultrasoundoccur up to 18 months before their detection on plain X-ray. In Joan’s case, radiographswill add little, demonstrating the soft tissue swelling that was observed on clinical examin-ation and therefore reinforcing the clinical pattern noted. In later disease, different pat-terns of involvement can be noted for psoriasis, SLE and RA. Psoriasis classically develops‘pencil in cup’ erosions of both PIP and distal interphalangeal joints with the proximalphalanx narrowing to the sharpened pencil, burrowing into the cup-like, widened distalphalanx. SLE is almost always a non-erosive disease. X-ray changes in RA mirror thejoints clinically involved, primarily affecting the hands, the PIP, MCP and wrists. Soft tis-sue swelling occurs early, with periarticular osteopenia noted, and subsequently there issymmetrical joint space narrowing. Erosions when they occur begin at the site of synoviallining of the joint capsule reflecting onto the cartilage/periosteum junctions, so that theyoccur slightly distant from the joint surface.Joan’s erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) will

both be increased and will act as a means to monitor therapy, with the goal being theirnormalization. Both ESR and CRP are measures of acute phase proteins produced in theliver in response tomonocyte-derived cytokines. CRP testing is more expensive than ESRbut is the preferred measurement for monitoring success in suppressing joint inflamma-tion, particularly in RA. The situation is more complex in SLE, with some individualshaving a cytokine pattern resulting in an elevated CRP, and others whose disease patternis not associated with a rise in CRP.1

The blood film commonly shows an inflammatory thrombocytosis, with more estab-lished disease showing a normochromic normocytic anaemia; this can eventually mimicthe hypochromic microcytic picture of iron deficiency, due to the inflammatory processinhibiting the utilization of iron stores. Concomitant therapies such as non-steroidalanti-inflammatory drugs (NSAIDs) may cause genuine iron deficiency through gastro-intestinal blood loss. Corticosteroids induce a neutrophil leukocytosis. The presence oflymphopenia in Joan would have caused a reconsideration of the diagnosis of SLE.Clinical examination should include urinalysis, with the presence of proteinuria or

leukocytes warranting further microscopy and evaluation. Proteinuria would suggestglomerular inflammation. If SLE remains part of the differential diagnosis, an antinu-clear antibody (ANA) test can be requested. A significant positive result is a titre of 1:160



or greater, and again in itself has poor diagnostic or prognostic value unless interpretedas part of the clinical presentation. Evaluation of electrolytes, renal function and liverfunction should be undertaken. NSAIDsmay exacerbate hyperkalaemia and impair renalfunction, with several of the disease-modifying agents notable for their potential to causehepatitis with elevation of transaminases.

Safety monitoring of RA medicationsA guide to the safety monitoring for the agents used for treatment of RA is shown inTable 15.1. Methotrexate, alone or in combination with other agents, is the basis of mostRA regimes. Biological agents that target specific cytokines such as tumour necrosis fac-tor (TNF) and interleukin-1, or that block cell-to-cell signalling (such as cytotoxic lym-phocyte-associated antigen linked to immunoglobulin [CTLA4-Ig; abatacept]) arebecoming increasingly used in those who do not respond quickly to ‘standard’ therapy.Screening for hepatitis B and C is recommended, although a positive result is not anabsolute contraindication to therapy. Recent studies have suggested an enhanced hepa-titis C antiviral effect of interferon and ribavirin in the setting of concomitant etanercept.

Liaison between specialist and primary care practitionerA close collaboration and correspondence flow is required. The management plan will bedeveloped between Joan and her specialist, but much of its implementation will be withher general practitioner. They will need to consider the impact that any new illness willhave on her RAmanagement, and also the impact of her RAmanagement on intercurrentillness as well as preventative activities such as vaccinations. Common points of ambiguityare who will undertake prescribing and who will monitor and communicate with Joanabout any abnormalities detected on periodic screening. Joan should be encouraged toattend her general practitioner regularly and this eventually should allow alternating visitsbetween the two physicians, with specialist attendance four- to six-monthly.

Recent Developments1 Detection of antibodies to cyclic citrullinated peptides (CCP) has a sensitivity similarto RF, but specificity is much higher in the range of 95%–99%.2,3 In patients withearly undifferentiated arthritis, the presence of anti-CCP antibodies has an odds


NSAIDs Methotrexate Sulphasalazine Leflunomide Anti-TNF therapy

Baseline BP, oedema, K+, Chest X-ray, FBC, LFT Chest X-ray, Chest X-ray, hepatitis Bcreatinine hepatitis B & C serology, hepatitis B & C & C serology; screen for

FBC, LFT, chest serology, FBC, LFT, latent TB as per localauscultation chest auscultation guidelines

Periodic K+ and creatinine at FBC, LFT at four- to six- FBC, LFT monthly ¥3, FBC, LFT at four- to As clinically indicatedone week; BP and weekly intervals; then three-monthly six-weekly intervals;oedema at each chest auscultation at chest auscultation atclinical visit each clinical visit each clinical visit

BP, blood pressure; FBC, full blood count/screen; K+, serum potassium; LFT, liver function tests; TB, tuberculosis.

Table 15.1 Guide to safety monitoring of commonly used antirheumatic medications


ratio of 38 for subsequent development of RA, and is an adverse prognostic markerfor both clinical disease and radiological progression. Repeated measurementcurrently has no clinical utility, with therapeutic intervention leading to only modestreduction in levels that do not correlate with clinical indicators.

2 Anti-TNF therapy appears to protect against joint damage but may have littleinfluence on systemic inflammatory markers such as ESR and CRP.4High-sensitivityCRPmeasurement can generate specific values lower than the previous threshold inRA subjects with a normal CRP; subjects with high-sensitivity CRP values 2–8 mg/lhad higher disease activity scores, less remission rates and greater depression andhelplessness than those with values <2 mg/l. High-sensitivity CRP also performsconsistently better than ESR at predicting other disease activity variables.5 A patient’sjoint count is, not surprisingly, a good marker of activity and subsequent prognosis.In subjects with early arthritis of less than one year’s duration, a joint count ofgreater than seven actively diseased joints accurately predicted subsequentperformance and function.6

3 Detailed radiological imaging and scoring has been undertaken in trials of biologicaltherapy, which suggest that progression can be halted and that joint erosions canmature with regrowth of cortical bone and infilling. Plain radiographs of the handsand feet remain quick and affordable imaging modalities, but erosions can bedetected by more sensitive imaging techniques around 18 months before they aredetected on plain films. Imaging modalities that can be used include ultrasound,MRI and computed tomography (CT). Most erosions at the wrist will be detected byboth CT andMRI, although CT will detect more erosions particularly at themetacarpal bases, possibly because of its ability to delineate cortical bony margins.7

High-resolution ultrasound requires good apposition of the probe and an ability toaccess the bone surface. As a consequence, wrist examination is suboptimal, withMCP joints 2 and 5 exhibiting better correlation with MRI than ultrasound ofMCP 3 and 4, which can only be accessed in two planes.8

ConclusionA clear and positive approach is needed as you discuss the investigations that will assist inconfirming the diagnosis, and in determining disease activity and its current impact onfunction. The shared care between specialist and primary care physician is aimed at inhib-ition of the inflammatory process and therefore halting the local and systemic impact ofthe disease. Involving the patient in the goal setting at the start is helpful in gaining theirunderstanding of the strategies you are using to bring the disease under control. A cleargoal of the absolute minimum number of tender and swollen joints, lowering of inflam-matory markers and improvement in a patient’s quality of life is critical. Antirheumaticmedications are highly effective in bringing disease under control, and that should alwaysbe the opening when discussing any new medications: to clearly put the benefits so thatthis can be weighed against the potential adverse events, which themselves are discussedin the context of how to minimize them and how to detect them early. RA remains achronic disorder that, while not curable, is eminently treatable with an increasing rangeof options and flexible delivery systems to maintain a high quality of life in nearly allpatients.



Further Reading1 Liou LB. Different monocyte reaction patterns in newly diagnosed, untreated rheumatoid

arthritis and lupus patients probably confer disparate C-reactive protein levels. Clin Exp

Rheumatol 2003; 21: 437–44.

2 Riedemann JP, Muñoz S, Kavanaugh A. The use of second generation anti-CCP antibody

(anti-CCP2) testing in rheumatoid arthritis – a systematic review. Clin Exp Rheumatol

2005; 23 (5 Suppl 39): S69–76.

3 Zendman AJW, van Venrooij WJ, Pruijn GJM. Use and significance of anti-CCP

autoantibodies in rheumatoid arthritis. Rheumatology 2006; 45: 20–5.

4 Smolen JS, van der Heijde DM, St Clair EW et al. Predictors of joint damage in patients

with early rheumatoid arthritis treated with high-dose methotrexate with or without

concomitant infliximab: results from the ASPIRE trial. Arthritis Rheum 2006; 54: 702–10.

5 Dessein PH, Joffe BI, Stanwix AE. High sensitivity C-reactive protein as a disease activity

marker in rheumatoid arthritis. J Rheumatol 2004; 31: 1095–7.

6 Gerber LH, Furst G, Yarboro C, el-Gabalawy H. Number of active joints, not diagnosis, is

the primary determinant of function and performance in early synovitis. Clin Exp

Rheumatol 2003; 21 (5 Suppl 31): S65-70.

7 Perry D, Stewart N, Benton N et al. Detection of erosions in the rheumatoid hand; a compara-

tive study of multidetector computerized tomography versus magnetic resonance scanning. J

Rheumatol 2005; 32: 256–67.

8 Szkudlarek M, KlarlundM, Narvestad E et al. Ultrasonography of the metacarpophalangeal

and proximal interphalangeal joints in rheumatoid arthritis: a comparison with magnetic res-

onance imaging, conventional radiography and clinical examination. Arthritis Res Ther 2006;

8; R52.



Case HistoryJason, aged 48 years, has returned for his second visit with suspected rheumatoid arthritis(RA). He has a three-month history of increasing pain involving his hands, wrists and feet.He is a non-smoker. You note active synovitis affecting most of his proximalinterphalangeal joints andmetacarpophalangeal joints, both wrists and hismetatarsophalangeal joints. Erythrocyte sedimentation rate (ESR) is 63 mm/h, serumC-reactive protein (CRP) 26 mg/l. He has strongly positive rheumatoid factor (RF) andelevated anti-cyclic citrullinated peptide (anti-CCP) antibodies.

What medications would you recommend to Jason?

Will providing Jason with educational material and support impact on his RA?

BackgroundTo impact on the morbidity of RA, long-term management of patients is required, basednot only on drug treatment, but also on non-pharmacological approaches such as phys-iotherapy and psychosocial support. The pharmacological treatment of RA is still prob-lematical and as yet there are no reliably curative or disease-remitting therapies, althoughconsiderable gains have been made recently with the advent of biological therapies.However, RA often progresses to disability. It is hoped that the full application of theolder disease-modifying antirheumatic drugs (DMARDs) together with the newerDMARDs and biological agents can improve this outlook. First-line pharmacologicaltherapy for all of the inflammatory arthritic diseases includes the non-steroidal anti-inflammatory drugs (NSAIDs). These are useful symptomatically but have no clear effecton the progression of RA, with virtually all patients requiring additional treatment with aDMARD.

Omega-3 oil supplementationInflammation contributes to a range of acute and chronic human diseases and is charac-terized by the production of inflammatory cytokines, arachidonic acid-derivedeicosanoids (prostaglandins, thromboxanes, leukotrienes), reactive oxygen species andadhesion molecules. Long-chain omega-3 fatty acids – eicosapentaenoic acid and


16 Managing Rheumatoid Arthritis atOnset

P R O B L E M



docosahexaenoic acid – have anti-inflammatory properties when taken in doses greaterthan 2.7 g daily and are of proven benefit in RA, providing reduced morning stiffness,decreased tender joint count and a lessened need for NSAIDs.At sufficiently high intakes, long-chain n-3 polyunsaturated fatty acids (PUFAs), as

found in oily fish and fish oils, decrease production of inflammatory eicosanoids,cytokines and reactive oxygen species and decrease the expression of adhesionmolecules.Long-chain n-3 PUFAs act both directly (e.g. by replacing arachidonic acid as aneicosanoid substrate and inhibiting arachidonic acid metabolism) and indirectly (e.g. byaltering the expression of inflammatory genes through effects on transcription factoractivation). Long-chain n-3 PUFAs also give rise to a family of anti-inflammatory medi-ators termed resolvins. The required dose of omega-3 fish oil can be taken using a largenumber of fish oil capsules (more than nine standard fish oil capsules containing oil fromeviscerated fish bodies [30% omega-3] daily); however, the cost can be prohibitive. A lessexpensive alternative is to take about 10–15 ml of bottled fish body oil daily. The palata-bility and hence long-term acceptance of fish oil can be improved by using a ‘two-glasstechnique’. This involves ‘floating’ the dose of fish oil on 30 ml of fruit or vegetable juicein a small glass. The contents are swallowed without contact with the lips, avoiding thefish oil taste. This is followed by slowly sipping a further 40 ml of juice (from a separateglass) to rinse the mouth. Reflux of the fish oil can be avoided by taking it immediatelybefore a solid meal – and without any extra fluid – to encourage mixing of the fish oilwith the food and its transport from the stomach into the small intestine. Passage of theoil from the stomach can also be facilitated by lying on the left side for 15 minutes afterthe dose, or by dividing the daily dose and having each half immediately before themorning and evening meals.1

DMARDsA recent change in the use of DMARDs is that they are generally commenced as soon as adiagnosis of an inflammatory arthritis is made, in order to have the maximal effect onslowing the progress of the disease.2 The rationale for early initiation of therapy is thedemonstration of rapid functional decline, and evidence that many of the deleteriouseffects of RA, such as erosions of bone, occur within the first one to two years of disease.This approach contrasts to the older disease-management regimens in which DMARDswere only commenced on the appearance of bony erosions on joint X-rays.Many patients with RA and other inflammatory arthritic diseases are also adminis-

tered intra-articular and/or low-dose oral corticosteroids. They are frequently adminis-tered as bridging therapy until the effect of a DMARD is fully established. In somepatients they are used long term with a DMARD, in order to satisfactorily suppress thedisease. Corticosteroids may also be used alone for disease control in the elderly if thiscan be achieved with a daily dose equivalent of 7.5 mg prednisolone or less.

Biological agentsThese are inhibitors of either tumour necrosis factor (TNF) or interleukin-1. These drugsproduce rapid control of RA in a high percentage of cases, and joint destruction may behalted and even reversed in some patients. There are, however, potential problems withthe biological agents, particularly the activation of infections, as well as very high finan-cial costs.

16 Managing rheumatoid arthritis at onset 83


Themost recent strategy to optimize treatment of RA has been the introduction of ini-tial combination therapy. This approach is based on the experience of oncologists, withthe combination of different mechanisms of action leading to additive or synergisticeffects without significantly increasing toxicity. Studies in which one arm receives inter-mediate- to high-dose corticosteroids have demonstrated a clinical superiority thatbecomes less noticeable, however, as the steroid dose reduces or is withdrawn.Interestingly, in these studies a radiographic benefit does continue to be seen for severalyears, suggesting that the initial, rapid clinical and laboratory improvement does retardor halt the structural damage that is otherwise occurring.3

The first-line choices of a single agent in RA consist of methotrexate, leflunomide andsulphasalazine. Methotrexate is currently the gold standard DMARD, with doses acceler-ated to achieve 20 mg/week within 6–8 weeks of commencement, with folic acid supple-mentation of 5 mg/week. Objective outcomes need to be recorded including swollen andtender joint counts, inflammatory markers (ESR, CRP) and a quality of life/functionalindex. Failure to achieve remission of disease activity after a maximum of 3–4 months oftherapy should result in an escalation or switching of therapy. An algorithm of treatmentis suggested in Figure 16.1.

Patient educationPatient education is thought to be beneficial in helping patients cope with their diseaseand cooperate with its complex management. The focus is to teach patients to adjusttheir daily activities as dictated by disease symptoms. In addition to teaching patientswhat they should do, patients are also instructed on how to approach situations and tomake adjustments that are appropriate for each individual and their needs. However, it isnot clear which educational interventions are most effective in improving health statusfor patients with chronic disease. A systematic review of randomized controlled trialsfocused on the effects of patient education on pain, functional disability, joint counts,patient and physician global assessment, affect scores and measures of acute phase reac-tants.4 The quality of studies identified was not very high, with issues of randomizationand concealment impacting adversely on their quality. At first follow-up there is a smallbut significant beneficial effect, particularly for functional disability. The magnitude ofthe effect is small, however, similar to that gained from the use of the weaker DMARDs.The duration of effect is also brief, being lost at follow-up 3–14 months later. Thereforestrategies to preserve and extend the initial beneficial effects of education over a longertime need to be explored.

Recent Developments1 The clinical response to treatment of RA can be assessed by the proportion ofpatients who have a 70% or greater improvement according to seven clinical andlaboratory measures of disease activity; this is designated as having an AmericanCollege of Rheumatology (ACR)-70 response. ACR-70 responses were found in19%–21% of patients receiving methotrexate monotherapy in trials in early RAbut in 33%–40% of those receiving TNF inhibitors with methotrexate. Inestablished RA, ACR-70 responses occurred in fewer than 5% of patientsreceiving methotrexate monotherapy but in 10%–27% of those receiving the



combination. TNF inhibitors substantially reduce the erosive damage assessed onX-ray and magnetic resonance imaging. They also decrease the self-assesseddisability measured using the Health Assessment Questionnaire and improve thequality of life assessed using SF-36.7

2 Cigarette smoking remains the most important lifestyle risk factor and one that ismodifiable. Males are three times more likely to develop RA if they smoke, with therisk increasing 13-fold in both sexes for heavy smokers (41–50 pack-years). Theinfluence of smoking is substantially greater in those with a backgroundHLA-DRB1

16 Managing rheumatoid arthritis at onset 85

Establish RA diagnosisor

• RF 1 unclassified oligoarthritis/polyarthritisor

• RF 2 unclassified oligoarthritis/polyarthritis .3 monthsduration

Document baseline disease activity

• Patient education on disease and its therapy• Commence analgesia, NSAID as needed• Omega–3 oil supplementation• Consider low-dose steroid• Start DMARD and safety monitoring

Methotrexate 20–25 mg/wkplus folate

Evaluate at 10–12 weeks

Adequate response Inadequate response

• Combination therapy• Biological agents

Periodic review

Figure 16.1 Antirheumatic therapy in early RA. (Adapted with permission from the American College ofRheumatology Subcommittee on Rheumatoid Arthritis Guidelines 20025 and Smolen et al. 2005.6)


shared epitope genetic susceptibility. Stopping smoking can reduce this risk,although the benefit is not seen until at least ten years after quitting, when theincreased risk halves.8

ConclusionEarly recognition of RA and prompt disease suppression with DMARDs and pred-nisolone is the key to the initial improvement of patients’ quality of life and to minimiz-ing subsequent progressive joint damage. Methotrexate retains its key role in the earlytreatment of RA, and whilst there remains controversy over unequivocal demonstrationof the superiority of combination therapy, several studies do support the concept. Someof the best evidence in support of combination therapy is that of TNF blockers whencombined withmethotrexate, in which the combination is superior tomonotherapy witheither agent with respect to clinical, functional and radiographic outcome. The strategyof aiming for tight disease control with rapid switching of regimens if patients do notimprove when assessed against measurable and recorded outcome is also a key advance.The literature also suggests that the addition of intermediate- to high-dose prednisoloneto DMARDs, whether as monotherapy or combination therapy, is beneficial if intro-duced early in the course of RA.

Further Reading1 Cleland LG, James MJ, Proudman SM. Fish oil: what the prescriber needs to know.

Arthritis Res Ther 2006; 8: 202–10.

2 Nell VP, Machold KP, Eberl G, Stamm TA, Uffmann M, Smolen JS. Benefit of very early

referral and very early therapy with disease-modifying anti-rheumatic drugs in patients

with early rheumatoid arthritis. Rheumatology 2004; 43: 906–14.

3 Smolen JS, Aletaha D, Keystone E. Superior efficacy of combination therapy for

rheumatoid arthritis: fact or fiction? Arthritis Rheum 2005; 52: 2975–83.

4 Riemsma RP, Taal E, Kirwan JR, Rasker JJ. Systematic review of rheumatoid arthritis

patient education. Arthritis Rheum 2004; 51: 1045–59.

5 American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines.

Guidelines for the management of rheumatoid arthritis. Arthritis Rheum 2002; 46: 328–46.

6 Smolen JS, Aletaha D, Machold KP. Therapeutic strategies in early rheumatoid arthritis.

Best Pract Res Clin Rheumatol 2005; 19: 163–77.

7 Scott DL, Kingsley GH. Tumor necrosis factor inhibitors for rheumatoid arthritis. N Engl J

Med 2006; 355: 704–12.

8 Oliver JE, Silman AJ. Risk factors for the development of rheumatoid arthritis. Scand J

Rheumatol 2006; 35: 169–74.



Case HistoryCharles and Dianna are a married couple who have been under your care for some years.Charles is aged 43 years with a 20-year history of ankylosing spondylitis (AS), and Diannais aged 48 years and has had rheumatoid arthritis (RA) for eight years. You have notedthat they are increasingly restricted in their activities. As part of your ongoingcommitment to care, you want to implement a method of recording the impact of yourtreatment.

What measures are available for monitoring disease activity?

How can function and quality of life be quantified?

BackgroundThe benefit of any therapeutic intervention must outweigh the cost, with cost most easilymeasured in monetary terms. More difficult to measure is the cost to the individual interms of convenience of use, monitoring and adverse effects – both actual and potential.Similarly it can often be difficult to measure benefit, and this particularly applies torheumatic disease, where a hard end-point such as mortality is rarely the outcome mea-sure. Patients with rheumatic disease experience pain and impaired function, but overtime they adapt to these circumstances and symptom-reporting alters, so that quietly andwithout complaint function is lost. RA and AS are contrasting diseases. In Table 17.1 thedemographic and clinical characteristics are compared, providing insight into the differ-ent outcome measures that need to be evaluated for each disease process.

17 Evaluating the response to treatment 87

17 Evaluating the Response to Treatment

P R O B L E M

Rheumatoid arthritis Ankylosing spondylitis

Gender F >M M> F

Age Middle age onwards Late teens onwards

Peripheral Predominant with involvement of hand Unusual, with occasional involvement of hip anddisease and feet shoulder

Spinal disease Cervical inflammation Ascending spinal restriction with impaired posture

F, female; M, male.

Table 17.1 Characteristics of RA and AS



Outcome measures vary according to the situation and purpose for which they arebeing evaluated, often differing significantly when being used in routine clinical practiceand research trials. A pragmatic approach is required if they are to be utilized by the aver-age practitioner who either does not have specialist knowledge or lacks specialist equip-ment. In broad terms, the outcomes of interest in rheumatic disease are:

� Laboratory evidence of inflammation recorded as erythrocyte sedimentation rate orserum C-reactive protein

� Clinical joint inflammation recorded as the number of tender or swollen joints onexamination

� Clinical examination of spinal function

� Patient’s self-reported experience of pain, fatigue or functional consequence of theirdisease

� Radiological progression

Laboratory markers of disease activityLaboratory investigations, by themselves, can be misleading. It is not unusual for a per-son to have normal inflammatorymarkers despite a small number of inflamed peripheraljoints; similarly, elevated markers may be caused by incidental illness such as urinarytract infection. RA, with its distinct synovial inflammation, often leads to elevatedinflammatory markers, whereas the spondyloarthropathies (in which enthesial inflam-mation at the tendon–periosteal interface predominates) have much lower and oftennormal values.

Physical evaluation of disease activityCounting a patient’s tender and swollen joints is a quick and easy way of both examiningthe patient and evaluating the extent of their disease activity. While you could examineevery joint, examining the easy-to-access 18 joints of upper limbs and knees has beenshown to be a valid measure of disease activity (Figure 17.1). The joints examined are theinterphalangeal joint of the thumb, proximal interphalangeal joint of the fingers, themetacarpophalangeal joints, wrists, elbows, shoulders and knees – totalling 18 joints. Themethod of examination is to palpate the joint in two directions – applying sufficient pres-sure to blanch the distal third of the nail bed of your thumb – to determine separately thepresence of swelling and tenderness. The tender joint count (TJC) and swollen jointcount (SJC) can be recorded both within the clinical record and in correspondence toother practitioners (i.e. SJC = 4/18, TJC = 6/18). This allows a quick analysis for trendsover time and also provides an indicator of absolute disease severity. A count of six toeight indicates moderate severity, sufficient for entry into many trials of new therapeuticagents.Assessing spinal function requires a fuller examination and exposure of the patient but

does allow serial evaluations, which are valid in detecting progressive loss of function andpotentially act as patient motivation for their ongoing exercise programme. An index ofspinal movement – the British Ankylosing Spondylitis Metrology Index (BASMI) – pro-vides a score of relative severity for any outcome and allows serial comparison. Tables17.2 and 17.3 describe both the scoring system and method of measurement relating to




Figure 17.1 Mannequin showing the 28 easily accessible joints for evaluation in routine practice(highlighted).

Score 0 1 2

Tragus to wall (cm) <15 15–30 >30

Lumbar flexion (cm) >4 2–4 <2

Cervical rotation (degrees) >70 20–70 <20

Lumbar side flexion (cm) >10 5–10 <5

Intermalleolar distance (cm) >100 70–100 <70

Adapted with permission from Irons and Jeffries 2004.1

Table 17.2 BASMI scoring system


AS. The ability to comment to a patient on the progress of their disease is important, andcan also be a motivating force for compliance with interventions, particularly exerciseand physiotherapy.

Evaluating quality of lifeAs medical practitioners, it is readily acknowledged that for many patients physicians arenot able to cure them of their disease but aim instead to improve their ‘quality of life’.The latter has many domains, and in practice physicians are primarily aiming to influ-ence those areas related to a person’s health that impact on their global well-being – so-called health-related quality of life. Even within this more circumscribed area there areinstruments that measure this in a generic way, thus allowing the same instrument to beused in different disease states providing comparisons that may be used to support healthresource distribution decisions. Disease-specific instruments also exist and often providegreater insights into an individual disease and may respond quicker to interventions forthat illness. Some self-reported questionnaires available for RA and AS are listed in Table17.4, and can be accessed via internet search.


Measure Starting position Method

Tragus to wall Standing with back to wall, outer edges of Patient draws chin in as far as possible. Examinerfeet 30 cm apart measures distance between tragus and the wall with a

rigid ruler

Lumbar flexion Outer edges of feet 30 cm apart. Examiner Patient flexes forward fromwaist with knees fully(modified Schober) marks midpoint of line level with iliac crests; extended. Distance between upper and lower marks is

a second point is marked 10 cm above and a measured, and then 15 cm is subtractedthird 5 cm below

Cervical rotation Patient supine on bed Patient rotates head as far as possible. Angle between(performed for neutral position and rotation is measured witheach side) goniometry

Lumbar side flexion As for tragus to wall Measure from tip of middle finger to floor with rigid 1 m(performed for ruler. Patient side-flexes without forward flexion oreach side) knee flexion. Remeasure from tip of middle finger to floor.

Calculate difference between twomeasurements

Intermalleolar distance Patient lies supine on floor Keeping knees straight, patient moves legs as far apartas possible. Distance betweenmedial malleoli ismeasured

Modified with permission from Irons and Jeffries 2004.1

Table 17.3 Obtaining BASMI measurements

RA AS

Health Assessment Questionnaire (HAQ) AS Quality of Life (ASQOL)

RA Quality of Life (RAQOL) BAS Disease Activity Index (BASDAI)

BAS Functional Index (BASFI)

BAS, British Ankylosing Spondylitis.

Table 17.4 Self-reported health-related quality of life questionnaires


An important domain to consider in patients with RA and AS is that of fatigue. Unlikenormal tiredness, fatigue is chronic and typically is not related to over-exertion and is notrelieved by rest. Fatigue is a frequent complaint in many chronic diseases and can beassessed via visual analogue scales and also by dedicated questionnaires. As an outcome ithas a strong relationship with the other joint symptoms in RA and AS, and is negativelyinfluenced by sleep disorders. Regular physical activity helps alleviate fatigue andimproves quality of life.

Recent Developments1 There are conflicting data regarding survival in patients with AS. A broadpopulation-based study from Rochester, Minnesota, showed no difference inmortality between men with AS and the general population. Other studiesindicate that mortality amongst AS patients seen in specialist referral centres ishigher – standardized mortality ratio of 1.7 – with a linear relationship betweenmortality and disease severity. Furthermore, mortality in AS may be related todisease duration. Mortality risk ratios relative to the general male population are4.0 for gastrointestinal disease, 1.3 for circulatory diseases and 1.2 forcerebrovascular disease. Smoking is a dose-dependent risk factor for thedevelopment of atherosclerosis, but it is unknown whether or not AS patientssmoke more than the general population. However, smoking is associated withworse clinical, functional and radiological outcomes in AS.2

2 The inflammatory processes in AS may affect various structures of the heart; themost characteristic conditions are conduction defects and aortic insufficiency and,less commonly, pericarditis, cardiomyopathy and mitral valve disease. Conductiondisturbances may occur in AS due to inflammation and fibrosis of theinterventricular septum thereby affecting the atrioventricular node. Aorticinsufficiency develops because the inflammatory process affects the aortic walldirectly behind and above the sinuses of Valsalva. This leads to scarred, fibrotic,thickened and shortened aortic valve cusps and to a dilated aortic root, resulting inaortic regurgitation. The occurrence of conduction disturbances in patients with ASvaries from 1% to 33%, and of aortic insufficiency from 1% to 10%, and increaseswith age, disease duration and the presence of peripheral arthritis. Impairedventricular relaxation leading to diastolic dysfunction is being increasinglyrecognized in AS, even in subjects with clinically mild disease. Yildirir and colleaguesexamined 88 AS patients and 31 healthy controls and found that diastolic functionof the left ventricle was significantly disturbed in AS patients compared to controls. 3

3 It is now recommended that three domains be assessed in the clinic fortherapeutic responses in RA: patient-reported measures of physical functionand/or global disease activity; physician-reported measures of physical functionand/or global disease activity; and imaging of the hands and/or feet on a biannualbasis.4 In practice, a 10 cm visual analogue scale can be used by both patient andphysician for the global disease activity. Radiographic images should be comparedover time, and may require the assistance of your local radiologist. Measures ofimprovement for individually relevant physical activities need to be defined foreach patient.




18 Pregnancy and Rheumatic Diseases

P R O B L E M

Case HistoryJane is a 32-year-old lawyer who has been treated for rheumatoid arthritis (RA) for thepast four years. Her symptoms are well controlled onmethotrexate 20 mg/week anddiclofenac 50 mg bd as needed. She and her partner would like to start a family. Shewishes to discuss the effect a pregnancy would have on her arthritis and vice versa.

What are the beneficial and adverse effects of pregnancy on RA?

Does she need to change her treatment?

Will RA affect her chances of becoming pregnant?

ConclusionA range of practical and relevant measures exists for measuring meaningful outcomes inpatients with arthritis – particularly AS and RA. These neatly combine laboratory, objec-tive clinical and subjective physician and patients’ measurements to provide a multido-main assessment that provides information on current disease activity and its impact onthe person’s quality of life, and allows you to evaluate the utility of interventions that thepatient is receiving.

Further Reading1 Irons K, Jeffries C. The Bath Indices. Outcome Measures for use with Ankylosing Spondylitis

Patients.National Ankylosing Spondylitis Society, East Sussex, United Kingdom, 2004.

http://www.nass.co.uk/bath_indices.htm [Accessed November 2007]

2 DoranMF, Brophy S, MacKay K, Taylor G, Calin A. Predictors of longterm outcome in

ankylosing spondylitis. J Rheumatol 2003; 30: 316–20.

3 Yildirir A, Aksoyek S, Calguneri M, Oto A, Kes S. Echocardiographic evidence of cardiac

involvement in ankylosing spondylitis. Clin Rheumatol 2002; 21: 129–34.

4 Zatarain E, Strand V. Monitoring disease activity of rheumatoid arthritis in clinical practice:

contributions from clinical trials.Nat Clin Pract Rheumatol 2006; 2: 611–18.



BackgroundRA tends to improve in pregnancy, with 80% of patients enjoying virtually completeremission. The disease remains active in the remainder but only worsens in a smallminority. Most causes of inflammatory polyarthritis (IP) follow this pattern. A smallproportion of patients with systemic lupus erythematosus (SLE) experience flares duringpregnancy. These are now less common with more effective therapy before pregnancyand with planning of pregnancy. Previously, pregnancy flares of SLE may have beenlargely due to withdrawal of drugs in patients with disease that was still quite active.Prolactin is a pro-inflammatory hormone and may contribute to some cases of IP wors-ening in pregnancy and in the post-partum.RA is an autoimmune inflammatory disease in which CD4+ T lymphocytes have a

prominent role in the underlying pathological process. CD4+ T cells can be divided intotwo subsets: T helper 1 cells (Th1) and T helper 2 cells (Th2). Th1 cells produce inter-feron-g, interleukin (IL)-2, tumour necrosis factor (TNF)-b and IL-12. Activation of thiscell type and dominance of the Th1 cytokine pattern facilitates cell-mediated immunity.The Th2 cell pattern leads to secretion of IL-4, IL-10 and IL-13, which facilitates humoralimmunity. Of the two T-cell patterns, the Th1 cell-mediated immunity pattern is moreconsistent with active autoimmune diseases. In general terms, pregnancy is associatedwith a shift towards a Th2 humoral pattern of immunity.1,2 Furthermore, circulatingantagonists to Th1-type cytokines are increased, both during normal pregnancy and inpregnancies of patients with autoimmune diseases. These antagonists include interleukin-1 receptor antagonist (IL-1ra) and the soluble receptors for TNF and IL-6 (sTNFR andsIL-6R). The cytokine pattern in pregnant patients with rheumatic diseases does not differmarkedly from that of normal pregnant women. Increased levels of oestrogen, androgensand progesterone may all contribute to the shift away from the pre-pregnant Th1 pattern,and this leads to decreased cell-mediated immunity. Impairment of antigen-presentingfunction and neutrophil activity may also be relevant, as these are the initial steps that leadto normal activation of lymphocytes. It is noteworthy that remission of inflammatoryconditions is more likely if the mother and foetus are dissimilar in HLA determinants,suggesting that the more active pregnancy-related immunosuppression occurs in womenwhere there is the most marked HLA disparity between themselves and their foetus.

Fertility in rheumatic diseasesWomen with RA are more likely to be nulliparous or to have a smaller family than theirnon-RA counterparts. There is, however, no evidence of a general decrease in fertilityamong patients with RA.3 Their general debility and drug treatment (including steroids)may decrease sexual desire and the frequency of intercourse. They may also be concernedabout potential effects of disease-modifying antirheumatic drugs (DMARDs) on theirbaby, and about their ability to deal with pregnancy and to care for a young child.Concerns about worsening symptoms during pregnancy and afterwards may also play apart. Paradoxically, while normal women often experience marked decrease in physicalfunction and increase in symptoms (including pain) during pregnancy, many womenwith RA feel better and experience less pain. There is an increased rate of fetal loss relatedeither to the underlying disease states or to drug treatments, including non-steroidalanti-inflammatory drugs (NSAIDs).

18 Pregnancy and rheumatic diseases 93


Cyclophosphamide is rarely needed in the management of RA but is used in the man-agement of severe SLE, particularly for nephritis or vasculitis. Its use in women over theage of 35 years generally renders them infertile, with its effects on younger women beingmore variable. The effects of cyclophosphamide on the ovary can be diminished by use ofa high-oestrogen oral contraceptive preparation or with gonadotrophin-releasing hor-mone agonists or antagonists. Alternatively, oocyte recovery with cryopreservation canbe used. In men, sperm count is decreased with methotrexate, cyclophosphamide or sul-phasalazine. The count usually recovers when the drug is stopped but, if there is concern,sperm can be stored. Fertility treatment is possible for women with RA and SLE – careshould be taken with SLE as hormone treatments may increase disease activity.

Disease during pregnancyThe risk of increased activity of SLE may be less than was once thought. With moderntreatment, more women start pregnancy with the disease in remission. Also, we havebecome comfortable with using some of the disease-modifying drugs in pregnancy sothat the disease can be effectively treated throughout. Flares of lupus during pregnancyare generally mild. However, disease activity in pregnancy increases risk of intrauterinedeath, fetal growth retardation, pre-eclampsia and premature rupture of membranesleading to early delivery. Lupus flares in pregnancy are less likely if the disease is well con-trolled at conception. Unplanned pregnancies, however, can lead to worsening of skinrash, increased joint symptoms, mucosal ulceration, anaemia and thrombocytopenia,hypertension and proteinuria, renal casts and increasing levels of anti-double-strandedDNA (anti-dsDNA) antibodies with decreased complement (C3 and C4).The risk of thromboses, particularly venous thromboses, is increased two- to four-

fold during normal pregnancy and in the six weeks post-partum, and is particularly highafter Caesarean section. The risk of both venous and arterial thrombosis is increased inwomen with antiphospholipid syndrome (APS), and all women with lupus or a history ofpregnancy loss should be screened by testing for lupus anticoagulant and anti-cardiolipinantibodies. APS is present in 37% of patients with SLE, but can occur in other auto-immune disease and in the absence of autoimmune disease.4 APS also increases the riskof pre-eclampsia, premature labour and HELLP (Haemolytic anaemia, Elevated Liverenzymes, Low Platelets).The effect of pregnancy on the spondyloarthropathies is more variable – the periph-

eral manifestations (arthropathy and uveitis) tend to improve, while spinal symptomsoften worsen. Vasculitides are relatively rare and there are few systematic studies duringpregnancy. Like SLE, these conditions may flare up (particularly in the first and secondtrimesters). Patients with Behçet’s disease are at increased risk of thrombosis in preg-nancy. Lupus nephritis and renal vasculitis can be difficult to distinguish from pre-eclampsia. The latter is more likely to be associated with hypertension and improvesrapidly following delivery. Systemic sclerosis does not appear to be at particular risk ofprogressing during pregnancy.

Effect on the foetusTransplacental passage of immunoglobulin G (IgG) antibodies, including anti-SSA/Roand anti-SSB/La, can lead to neonatal lupus syndrome and congenital heart block (CHB).The former can cause a transient photosensitive rash, hepatic dysfunction and bone



marrow depression. CHB occurs in the offspring of mothers who are anti-SSA/Ropositive, andmost infants born with this complication require a pacemaker before the ageof one year. It is rare, occurring in only 2% of infants of such mothers, and in 1 in 22 000of the general population. Ideally, all young women with an inflammatory arthropathysuch as SLE or RA should be screened for lupus anticoagulant, anti-cardiolipin antibodiesand anti-SSA/Ro prior to them considering a family, or they should be tested early in theirpregnancy. The rash of neonatal lupus resolves over the first three to five months of life, asthe maternally derived IgG is cleared from the baby’s circulation.SLE disease activity at conception and the presence of antiphospholipid antibodies are

the major determinants of fetal outcome. Fetal loss occurs in up to 30% of patients withactive lupus. All inflammatory arthropathies increase the risk of premature delivery.However, with modern obstetric monitoring and neonatal management, the risk to thechild has been markedly decreased in recent years.

DrugsNone of the drugs used in IP (except simple analgesics) is entirely safe during pregnancy.Methotrexate, cyclophosphamide, azathioprine, gold and cyclosporine should all bestopped at least three and preferably six months before pregnancy. Leflunomide has avery prolonged functional half-life (several months) due to its enterohepatic recircula-tion and is also very teratogenic. Prior to its prescription to a young woman, it is advis-able to discuss the time frame of possible pregnancies and to clearly state that pregnancyshould not occur within two years of ceasing the medication, unless the drug has beenwashed out using cholestyramine and a plasma drug level obtained that confirmselimination.NSAIDs should be stopped if possible before pregnancy as they may increase risk of

early pregnancy loss. Later adverse effects on the infant include premature closure of theductus arteriosus with resulting pulmonary hypertension, cutaneous and intracranialbleeding and impaired renal function leading to oligohydramnios. If NSAIDs arerequired in pregnancy, older agents with a short half-life are best – indomethacin,ibuprofen and diclofenac. Corticosteroids are relatively safe in pregnancy if the dose iskept below the equivalent of 20 mg/day prednisolone. If it is considered necessary to treatmother and foetus, then dexamethasone or betamethasone should be used. Otherwise,hydrocortisone, cortisone or prednisolone should be used; less than 10% of these aredelivered to the foetus (the remainder that crosses the placenta is inactivated by 11b-hydroxysteroid dehydrogenase). Side effects of steroid therapy mainly affect the motherand include hypertension, oedema, pre-eclampsia and gestational diabetes.The most extensively documented teratogenic effect is with methotrexate, which can

also induce miscarriage even with normal foetuses. The drug may cause a range of con-genital abnormalities including limb anomalies, craniofacial anomalies and a range ofnervous system anomalies including anencephaly and hydrocephalus.Sulphasalazine has been extensively used throughout pregnancy in patients with both

RA and inflammatory bowel disease and is considered safe. Where immunosuppressionis required, azathioprine is a reasonable choice. The foetus cannot convert it to its activemetabolite, 6-mercaptopurine, and it is therefore relatively free of teratogenic effect. Ithas, however, been associated with growth retardation and premature rupture ofmembranes.

18 Pregnancy and rheumatic diseases 95



Recent Developments1 In a national (United States) study with access to data from over four milliondeliveries, Chakravarty and colleagues5 showed that, compared with the backgroundpregnant population, women with RA or SLE were more likely to develop ahypertensive disorder, spend more time in hospital and to have a Caesarean delivery.The prevalence of hypertensive disorders was highest in patients with SLE and wascomparable in these patients to the prevalence of hypertensive disorders ingestational diabetes (GDM). There was increased risk of premature rupture ofmembranes and of intrauterine growth retardation in both RA and SLE. TheCaesarean section rate was not as high as in patients with GDM.

2 There are fewer data available on Sjögren’s syndrome (SS) in pregnancy than for RAor SLE. A recent case–control study6 investigated reproductive problems in patientswith SS. Complaints of vaginal dryness were found twice as commonly as in controlsand affected over 50% of SS patients. The previously documented associationbetween SS and endometriosis was confirmed. Fertility was not decreased in SS, butwomen chose to have fewer children because of their disease.

ConclusionThe patient should stop methotrexate at least three months before pregnancy, whichshould be carefully planned wherever possible. Careful monitoring of the condition inthe months before pregnancy should be achieved, which will determine the level of ther-apy required. Clearly the latter should be kept to a minimum before and during preg-nancy. One would not expect a major reduction in fertility in the above patient.

Further Reading1 Gordon C. Pregnancy and autoimmune diseases. Best Pract Res Clin Rheumatol 2004; 18:

359–79.

2 Østensen M, Förger F, Villiger PM. Cytokines and pregnancy in rheumatic disease. Ann NY

Acad Sci 2006; 1069: 353–63.

3 Katz PP. Childbearing decisions and family size among women with rheumatoid arthritis.


4 Tincani A, Bompane D, Danieli E, Doria A. Pregnancy, lupus and antiphospholipid syndrome

(Hughes syndrome). Lupus 2006; 15: 156–60.

5 Chakravarty EF, Nelson L, Krishnan E. Obstetric hospitalizations in the United States for

women with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 2006;

54: 899–907.

6 Haga HJ, Gjesdal CG, Irgens LM, ØstensenM. Reproduction and gynaecological

manifestations in women with primary Sjögren’s syndrome: a case– control study. Scand J

Rheumatol 2005; 34: 45–8.


Case HistoryMichelle is 37 years old and has had rheumatoid arthritis (RA) for four years. She iscompliant with her medication and has achieved near-remission but does not like takingtablets. She has a body mass index of 27.6 kg/m2 and is seeking advice on whether thereare any effective diets or supplements.

What is the effect of being overweight or obese on rheumatic diseases?

Are there pro- or anti-inflammatory components of the diet?

What simple, risk-free advice might she be given?

Is there a place for food supplements?

BackgroundPharmacological measures to improve symptoms and drugs to modify disease activityhave transformed the management of rheumatic diseases. Dietary measures have a muchless certain place but emerging evidence is beginning to point to a role in disease preven-tion in patients who are at high risk of developing the diseases, and in controlling symp-toms or preventing relapse in patients who have diagnosed disease. There is increasingpressure on health professionals to be knowledgeable about dietary factors as patients areincreasingly informed. The increased predisposition to osteoarthritis amongst patientswho are either overweight or obese is now well documented, as is the importance of vari-ous dietary components in RA.

Diet as a susceptibility factor for RAThe cause of RA is unknown but is likely to involve both genetic susceptibility and envir-onmental factors such as diet, and may involve interplay of both factors. Available datasuggest that at least one-third of RA susceptibility is explained by environmental vari-ation. The possibility that diet may play a role in both the onset and persistence of RA is afrequently reported experience and there is a growing literature in support of thishypothesis.1 A large prospective study was performed in the United Kingdom using RAcases registered from the Norfolk Arthritis Register. A number of dietary factors emergedas being of possible relevance.2 Low fruit and vitamin C intake was associated with a doub-ling in the risk for RA, with the highest daily intake of the antioxidants b-cryptoxanthinand zeaxanthin having the lowest risk for RA. It was suggested that one glass of freshly

19 Diet and arthritis 97

19 Diet and Arthritis

P R O B L E M



squeezed orange juice per day would be sufficient to offer protection. A high intake of redmeat had a modest risk for RA, which is independent of any lowering of fruit and vege-table intake, and may be explained by red meat providing a dietary source of omega-6oils. The reported effects of decaffeinated/caffeinated coffee, tea or total caffeine con-sumption are internally inconsistent and conflicting, making a real effect unlikely.2

Alcohol consumption and the risk of developing RA has only been studied in women.The results are conflicting, at best suggesting a modest protective effect in women con-suming the most alcohol.1

Fruit, vegetables and antioxidantsMonocytes, macrophages and granulocytes at the site of an inflammatory process gener-ate reactive oxygen species. These, in turn, lead to increased production of inflammatorymediators. This process, which is partly mediated by increased local nitric oxide produc-tion, can potentially be inhibited by antioxidants, which scavenge reactive oxygenspecies.3 Interestingly, in patients with RA, blood markers of antioxidant nutritionalstatus are lower than in normal controls. Fruit and vegetables are the main source of anti-oxidants in the diet, including retinoids, vitamins C and E, carotenoids, selenium andlutein. Lower intake of vitamin C is associated with increased risk of inflammatorypolyarthritis.4

Essential fatty acids and the Mediterranean dietThe Mediterranean diet is characterized by less red meat and more fish, with olive oil asthe primary fat source, an abundance of plant food and moderate wine consumption.High levels of omega-3 fatty acids may protect against inflammation by substituting foromega-6 fatty acids. Polyunsaturated fatty acids contain two or more double bonds, withthe omega-3 or omega-6 classification according to the site of the double bond proximalto the methyl terminus. Mammals do not possess the enzyme necessary to introducedouble bonds at the 3 or 6 positions – they are therefore essential fatty acids and must beobtained from the diet. The Western diet is abundant in omega-6 fatty acids due to theabundance of linoleic acid in soybean, safflower, sunflower and corn oil.5 Fish oil con-tains the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid(DHA). These compete with arachidonic acid for cyclooxygenase (COX)-1, COX-2 andlipoxygenase enzymes, and their metabolism leads to incorporation of anti-inflamma-tory prostanoids and leukotrienes in cell membranes. Olive oil is rich in oleic acid, whichcan be metabolized to eicosatrienoic acid, similar to omega-3 polyunsaturated fatty acidfrom fish oil. Stamp et al.5 have extensively reviewed the role of dietary oils in RA. Incombination with non-steroidal anti-inflammatory drugs (NSAIDs)/aspirin, omega-3oil produced a novel family of bioactive lipids known as resolvins, named for their anti-inflammatory effect and tendency to resolve inflammation at the site of study. Fish oilsupplementation reduced expression of the antigen-presenting class II HLA-DR mol-ecule on human monocytes, with a reduced ability to present antigen after culture withEPA and DHA. The risk of RA has been documented to be lower in those who consumehigher amounts of olive oil or oily fish.6 These observations are consistent with severalrandomized controlled trials showing modest antirheumatic benefit of omega-3 fattyacid supplementation, including reduced early morning stiffness, tender joint count anduse of NSAIDs (Box 19.1).



Dietary supplements and RAIn all studies of fish oils, the benefits were observed against a background of standardtherapy of NSAIDs, disease-modifying agents and immunomodulators. Collectively,these studies have established that fish oil supplementation that delivers 2.6 g or more perday of the long-chain fatty acids EPA plus DHA reduces symptoms after a latent period ofthree months. The latency can be reduced with higher doses of fish oil. For anti-inflammatory effect it is recommended to take 2.6–4.0 g of EPA and DHA per day. Therequired dose of fish oil can be taken either as fish oil capsules or from bottled fish bodyoil, with patient preference relating to cost and palatability. In addition to oil supple-ments, patients should be encouraged to review their background diet so as to minimizeomega-6 oil intake and maximize omega-3 intake (Box 19.2).Elemental diets provide food in the most basic forms – i.e. free amino acids, medium

chain triglycerides and small sugars – and are proposed as being hypoallergenic. Generalbenefit has not been evident in several trials. Vegetarian and vegan diets have beenreported to improve symptoms. Many of the studies commence with a fast with resultantimprovement in clinical and biochemical parameters, which is not always sustained inthe longer term when caloric intake in its modified form is reintroduced. Fasting hasbeen shown to reduce both clinical and laboratory markers of inflammation, possibly byredirecting scarce resources away from inflammatory pathways and reducing diseaseactivity but compromising immune defences. It is important to ensure that sufficientcalories and nutrients are being provided to ensure well-being. Elimination diets seek toremove foods that are putatively allergenic from the diet. Studies demonstrate that a pro-portion of patients improve when putative allergenic foods are eliminated, with worsen-ing of symptoms at some point when foods are sequentially reintroduced.


Box 19.2 Diet in rheumatoid arthritis

� Diet as a risk factor– Low fruit, vitaminC, b-cryptoxanthin, zeaxanthin– Highmeat

� Diet as a protective or therapeutic factor– High consumption of oily fish, olive oil, cooked vegetables

� Conflicting data– Caffeine, decaffeinated coffee, tea– VitaminD and dairy products

� Doubtful benefit– Elemental diet

Box 19.1 Effects of omega-3 oils on the manifestations of RA

� Modest clinical improvementwhen usedwith standard pharmacotherapy� Deterioration in symptoms after discontinuation� Ability to decrease or ceaseNSAIDs and hence reduce associated gastrointestinal

and cardiovascular risk� Reduce sudden cardiac death


Recent Developments1 Turmeric has been used for centuries in Ayurvedic medicine as a treatment forinflammatory disorders including arthritis. In an animal model of arthritis, acurcuminoid-containing turmeric extract demonstrated efficacy in preventing jointswelling and destruction as determined clinically, histologically and by measurementof bone mineral density.7 The putative mechanism of action was further elucidatedby analysis of turmeric’s effect on articular transcription factor activation andmicroarray analysis of articular gene expression. Treatment in vivo prevented localactivation of nuclear factor-k-beta (NF-kB) and the subsequent expression ofNF-kB-regulated genes mediating joint inflammation and destruction, includingchemokines, COX-2 and receptor activator of NF-kB ligand (RANKL). Consistentwith these findings, inflammatory cell influx, joint levels of prostaglandin E2 andperiarticular osteoclast formation were all inhibited by turmeric extract. Otherresearchers using curcumin have documented antiproliferative, anti-inflammatoryand immunosuppressive activities, as identified by inhibition of neutrophilactivation, synoviocyte proliferation and angiogenesis.8

2 Polyphenols are secondary metabolites of plants and are generally involved in thedefence mechanism against ultraviolet radiation and insects, but have anti-inflammatory activity when consumed. Classified into four groups – flavonoids,stillbenes, lignas and phenolic acids – these naturally occurring plant compoundscan have potent effects on reducing chronic disease in animal models.9 Flavanols(one of the flavonoids) have been extensively studied, and there is an estimated dailyconsumption of 20–25 mg/day in the United States. The potential mechanisms oftheir anti-inflammatory activities include inhibition of COX and lipoxygenaseenzymes, as well as nitric oxide synthase, and inhibition of the transcription factorsNF-kB and PPARs (peroxisomal proliferator-activated receptors). In collagen-induced arthritis (a mouse model of RA, which is triggered by tumour necrosisfactor [TNF]-a) the oral administration of flavonoids improves the arthritis evenwhen the disease has become established.10 Dietary sources of flavonoids include tea,red wine, fruits, vegetables and legumes. Flavanones are in citrus, isoflavones in soyproducts, anthocyanidins in wine and bilberry, and flavans are in apples and tea.Citrus flavonoids are found in citrus fruits, rutin in buckwheat, epigallocatechingallate in green tea and naringenin in grapefruit. Oligomeric proanthocyanidins arefound in grape seeds and skins. Quercetin is found in onions, tea and apples.Polyphenols are the most abundant group of compounds in fresh tea leaves and arefound in green and black tea beverages as 30%–42% and 3%–10% of the total drymatter, respectively. Many medicinal plants contain bioflavonoids, such as ginkgobiloba, hawthorn and Chinese skullcap.

Conclusion‘Does my diet affect my arthritis?’ is a question familiar to all rheumatologists and pri-mary care practitioners. One-third to three-quarters of RA patients believe that foodplays an important role in their symptom severity, and up to half will have tried dietarymanipulation to improve their quality of life. The most consistent link between diet and



arthritis to date remains that of polyunsaturated omega-3 oils. Additional potentialmechanisms are under exploration, and it is prudent advice to any patient with inflam-matory polyarthritis that they aim to alter their omega-3/omega-6 balance (Table 19.1).This should occur in parallel with the use of single and preferably combination disease-modifying agents. There is limited evidence for benefit of restrictive or elimination dietsand any benefits are likely to be individual and not transferable to the next patient.


FATS AND OILSUse either canola, sunola or olive oil spread, mayonnaise and salad dressing instead of your usual oil productsFlaxseed oil can be used in salad dressings or mixed with sunola or olive oil and used in baking

BREADS AND CEREALSChoose breads, crispbreads and cereals that have added linseed

NUTSMacadamias, hazelnuts, cashews and almonds can be enjoyed every day in limited amounts (one handful)Peanuts (and peanut paste) and pistachios – one handful 2–3 times a week

MEATUse lean cuts of meat

FISHChoose oily fish, i.e. mullet, flathead, snook, trevally, fresh tuna, canned pink salmon, canned sardines

FRUITS AND VEGETABLESEat freely

CONVENIENCE FOODSFrozen chips (these are pre-cooked in canola oil)McCain – Healthy Choice; Straight Cut or Country StyleBirds Eye – Steak House, Crinkle Cut, Home Style, French Fries, Flavour Crisp (Seasoned CrunchyWedges only)

SNACK FOODS & CONFECTIONERYMost potato crisps are cooked in omega-6 fats, which may prevent the omega-3 fats going into your bodyKettle Chip Company chips are cooked in sunola oil

FAST FOODSPizza Haven and Fasta Pasta use canola oil

Based on a pamphlet developed by Dr EMantzioris, Dr MJ James and Prof LG Cleland, Royal Adelaide Hospital, Australia.

Table 19.1A Omega-3 friendly foods

FATS AND OILSAvoid all other oils, cooking sprays, dressings, mayonnaise, lards, dairy blends, drippings, cooking margarines and spreads

NUTS & LEGUMESBrazil nuts, pecan nuts, pine nuts, walnuts, sesame seeds (tahini paste, houmous), sunflower seeds

FISHPackaged frozen fish such as fish fingers

CONVENIENCE FOODSAll other varieties of frozen chips. Avoid those fruits or vegetables that are canned in dressings (e.g. potato salad)

SNACK FOODS & CONFECTIONERYHealth food bars – sesame bars, nut bars, muesli bars

Table 19.1B Foods to avoid



Research into the dietary polyphenols may open up new areas of dietary manipulation inthe treatment of chronic inflammatory disease.

Further Reading1 Pattison DJ, Harrison RA, Symmons DPM. The role of diet in susceptibility to rheumatoidarthritis: a systematic review. J Rheumatol 2004; 31: 1310–19.

2 Oliver JE, Silman AJ. Risk factors for the development of rheumatoid arthritis. Scand JRheumatol 2006; 35: 169–74.

3 Pattison DJ, Symmons DPM, Young A. Does diet have a role in the aetiology of rheumatoidarthritis? Proc Nutr Soc 2004; 63: 137–43.

4 Pattison DJ, Silman AJ, Goodson NJ et al. Vitamin C and the risk of developing inflammatorypolyarthritis: prospective nested case–control study. Ann Rheum Dis 2004; 63: 843–7.

5 Stamp LK, James MJ, Cleland LG. Diet and rheumatoid arthritis: a review of the literature.Semin Arthritis Rheum 2005; 35: 77–94.

6 Choi HK. Dietary risk factors for rheumatic diseases. Curr Opin Rheumatol 2005; 17: 141–6.

7 Funk JL, Frye JB, Oyarzo JN et al. Efficacy and mechanism of action of turmeric supplements

in the treatment of experimental arthritis. Arthritis Rheum 2006; 54: 3452–64.

8 Jackson JK, Higo T, Hunter WL, Burt HM. The antioxidants curcumin and quercetin inhibitinflammatory processes associated with arthritis. Inflamm Res 2006; 55: 168–75.

9 Yoon J-H, Baek SJ. Molecular targets of dietary polyphenols with anti-inflammatoryproperties. Yonsei Med J 2005; 46: 585–96.

10 Kumazawa Y, Kawaguchi K, Takimoto H. Immunomodulating effects of flavonoids on acuteand chronic inflammatory responses caused by tumor necrosis factor alpha. Curr Pharm Des

2006; 12: 4271–9.


Case HistoryJohn is 69 years old and presents because of pain in his shoulders and hands. He is unableto get out of bed with ease or dress himself. His symptoms started suddenly five weeksago and he thought they would get better with tablets he bought from the chemist.

What are the common forms of polyarthritis in the elderly?

Is there evidence that osteoarthritis can be modified by the use of medication?

What factors should be considered in the treatment of arthritis in the elderly?

BackgroundArthritis and rheumatism are major physical and psychological burdens in the elderlypopulation. As most forms of arthritis are chronic, the combination of increasing life-span, cumulative arthritis incidence and concomitant disease and treatments creates thealmost inevitable experience of arthritis. Approximately two-thirds of elderly peopleexperience sufficient symptoms each day to warrant regular use of non-steroidal anti-inflammatory drugs (NSAIDs). Symptoms are sufficient to disrupt the sleep or leisureactivities of one-third of the elderly population, with nearly all these people using at leastone medical, complementary or self-care strategy. Arthritis is the most prevalent chroniccondition among adults over the age of 65 years (48.9 per 100 adults), followed by hyper-tension (40.3 per 100 adults) and heart disease (28.6 per 100 adults). The psychologicalburden of arthritis is often underestimated.

OsteoarthritisOsteoarthritis (OA) is the commonest condition to affect synovial joints and the singlemost important cause of locomotor disability. Although not an inevitable consequenceof aging, OA is strongly related to age, whichmay represent cumulative insult to the joint,possibly aggravated by decline in neuromuscular function or senescence of homeostaticrepair mechanisms. OA is uncommon and multiple joint OA is rare in persons aged lessthan 45 years. Prevalence of OA varies in different populations, but on average affects60%–70% of those aged over 45 years. The prevalence of radiographic OA exceeds that ofclinical OA, and is almost universal in the elderly population in distal interphalangealjoints and knees. The prevalence of symptomatic OA also increases with age, 15% ofthose aged 55 years having symptomatic knee OA. There is a pronounced female prepon-derance after the age of 55 years for severe radiographic OA. This has suggested that

20 Polyarthritis in the elderly 103

20 Polyarthritis in the Elderly

P R O B L E M



oestrogen deficiency may play a role in aetiology. Occupation predisposes to OA of spe-cific joints (e.g. hip of farmers). The best-characterized OA risk factor is obesity, with OAin the knee and to a lesser extent in the hip correlating with higher body weights.OA is a condition of synovial joints characterized by focal cartilage loss and an accom-

panying reparative bone response. It is a slowly progressing inflammatory process and notsimply ‘wear and tear’. The final common pathway of OA is cartilage degradation. Brandtand Mazzuca1 reviewed nine clinical trials purporting to demonstrate disease modifica-tion in OA, with their focus on placebo-controlled randomized clinical trials in whichjoint space narrowing (JSN) was used as an outcome. They also examined the effects of thepurported disease-modifying osteoarthritis drugs (DMOADs) on joint pain (Table 20.1).Whilst some agents have shown possible efficacy, trial design has been poor with heteroge-neous populations and insufficiently sensitive outcomemeasures. No therapy has yet beenapproved as having either chondroprotective or structure-modifying properties in OA.

The Glucosamine/chondroitin Arthritis Intervention Trial (GAIT)2 involving 1500overweight subjects with symptomatic and radiographic knee OA, found that neitherglucosamine nor chondroitin – alone or in combination – were better than placebo forsymptom control. The internal active control in this study was celecoxib and this was sig-nificantly better than placebo for symptom control. A potential explanation for this lackof clinical effect of glucosamine is the differences between the serum levels obtained invivo after standard doses of glucosamine and the doses used in the precursor loading ofcultured human chondrocytes studied in vitro. In clinical studies, a single dose of glu-cosamine sulphate was detected in 17 of 18 subjects at 30–45 minutes after administra-tion, with peak concentrations occurring at 90–180 minutes. The detected serumconcentration range of 2–11mmol/l would contribute only 2% of galactosamine incorpor-ation into chondroitin sulphate in the in vitro experiments in human chondrocytes.3

Rheumatoid arthritisThe onset of rheumatoid arthritis (RA) is often abrupt in the elderly, and although theclassical peripheral symmetrical small joint polyarthritis develops, shoulder symptoms


Intervention Joint Study duration (months) JSN Sx control

GI. Sulp 1500 mg K 36 � ?

GI. Sulp 1500 mg K 36 � �

Ch. Sulp 800 mg K 24 ? �

Ch. Sulp 800 mg K 12 ? �

Doxycycline 200 mg K 30 � �

Risedronate 5/15 mg K 12 � �

IA Hyaluronan K 12 ? ?

Diacerein 100 mg H 36 � �

Ch. Sulp, chondroitin sulphate; GI. Sulp, glucosamine sulphate; H, hip; IA, intra-articular; JSN, joint space narrowing; K, knee; Sx, symptom.

Table 20.1 Effect of disease-modifying osteoarthritis drugs (DMOADs)


may predominate initially and prominent hand oedemamay obscure the diagnosis. Late-onset RA (LORA) has been reported to have a more equal gender distribution, an acuteonset and prominent elevation of erythrocyte sedimentation rate (ESR). It is also charac-terized by disabling morning stiffness and marked pain, predominantly in the upperextremities. The physical examination is of pronounced synovitis of the shoulders andthe wrists as well as the metacarpophalangeal joints and proximal interphalangeal joints,with marked limitation of motion and severe soft tissue swelling. Conditions that maymimic and cause diagnostic confusion with LORA are remitting seronegative symmetricsynovitis with pitting oedema (RS3PE) and polymyalgia rheumatica (PMR) (Table 20.2).A diagnosis of PMR or LORA can be made in the same patient at different stages of thesame illness depending on the predominant clinical manifestation at the time. RS3PE isan acute onset, bilateral symmetrical synovitis predominantly of the wrist, carpus, smallhand joints and flexor digitorum sheaths, associated with marked oedema of the dorsumof the hand. Patients are persistently rheumatoid factor (RF) negative and respondrapidly to low-dose steroids. Cantini et al.,4 in their prospective five-year study of PMRand RS3PE, found no demographic, clinical or immunogenetic differences. No patientdeveloped RA, and they concluded that PMR and RS3PE constitute a spectrum withinthe same disease.

In general, the therapeutic approach in LORA is similar to that for younger patients.Consideration needs to be given, however, to concomitant illnesses and the elderlypatient’s reduced physiological reserve, and the ability of the liver and kidneys to metab-olize medications. NSAIDs increase the risk of gastrointestinal bleeding and can impairrenal function, with the resultant salt and water retention impacting on hypertension andcardiac function. Themortality for gastrointestinal bleeding increases rapidly in later life,with risk factors for bleeding being age over 65 years, past history of peptic ulcers or


LORA PMR RS3PE

Age of onset Over 60 years Over 55 years Over 60 years

Sex ratio F:M 1:1 5:1 1:4

Mode of onset Acute or subtle Acute Acute

Predominant Peripheral joints in upper Shoulders, lower back, hips, Hands, wrists, shoulders, kneesjoint pattern limbs and shoulders knees

Distal oedema May be present May be present Present

RF positivity 50% Negative Negative

HLA association DR4 ? B7

Course Severe in RF+ Long-term steroids 2–4 years Self-limited 1–2 yearsMild in RF– Giant cell arteritis in 10%–15%

Response to Poor in RF+ Good Goodlow-dose steroid Good in RF–

Modified with permission from Canoso JJ. Rheumatology in Primary Care. WB Saunders Co., Philadelphia, 1997.

Table 20.2 Differences and similarities between LORA, PMR and RS3PE


bleeds, concomitant steroids/anticoagulants/antiplatelet agents and general frailty. Riskfactors for renal failure include age over 65 years, hypertension, cardiac failure and con-comitant diuretics or angiotensin-converting enzyme inhibitors. The evidence that select-ive cyclooxygenase-2 inhibitors offer meaningful gastroprotection in an elderly cohort isdoubtful, and any positives are outweighed by adverse impact on renal and cardiacfunction.In the past, low-dose corticosteroids have been promoted for use in the elderly due to

their rapid onset of action. This strategy is acceptable if the goal is rapid suppression ofthe inflammatory process with the steroids acting as a bridge to a longer-term alternativeagent allowing the withdrawal of steroids. The danger is if the alternative agent is notintroduced and/or the patients continue to receive steroids in the long term. Even low-dose steroids (<7.5 mg prednisolone per day) are associated with reduction in bone min-eral density, hyperglycaemia, weight gain and hypertension.

GoutProlonged hyperuricaemia is a necessary prerequisite for clinical gout, but fortunatelygout only develops in a small percentage of patients with chronic hyperuricaemia. Inmen, uric acid accumulation begins after puberty, with the first attacks usually occurringafter the age of 35–40 years. In women, oestrogen facilitates renal excretion of urate, suchthat the age at which clinical gout occurs is older; occurrence is often the combination ofpost-menopausal status and, frequently, thiazide diuretic use, andmore recently the con-comitant use of low-dose aspirin. In the elderly, joints previously damaged (mostly byOA) facilitate seeding of uric acid crystals through exposed collagen and glycosaminogly-cans. Age-related and concomitant illness impacts on renal function to further enhanceuric acid retention, leading to more frequent andmore severe attacks of gout. Eventually,the patient may have chronic polyarticular gout, which no longer resembles the acute,self-limited illness, and is easily confused with a polyarthritis such as RA.Colchicine is related to the cytotoxic agents vincristine and vinblastine, and is renally

excreted. Its use in the elderly is often associated with diarrhoea and risk of bone marrowsuppression. Oral, intramuscular and intra-articular steroids are well suited to suppress-ing an acute attack of gout. In the longer term, allopurinol remains the agent of choice inthe elderly, as it does not rely on preserved renal function and does not increase the riskof renal calculi. It is, however, renally excreted, with any dosage reduction either basedempirically on renal function, or more specifically based on the serum measurement ofthe active allopurinol metabolite, oxypurinol.

ConclusionOA, gout, pseudogout, RA and PMR are commonly encountered in the elderly popula-tion. Diagnostic confusion may occur because of age-related effects on diagnostic testssuch as ESR, RF and antinuclear antibodies. The onset of scleroderma, systemic lupuserythematosus or idiopathic polymyositis is uncommon in the elderly. Increasing life-span is impacting both on overall prevalence and incidence of the rheumatic diseases inthe elderly community. The combination of aging, cumulative morbidities andpolypharmacy makes the elderly particularly susceptible to drug-related adverse events.



This, however, should not detract from the same overall goal of improving an individ-ual’s quality of life and functioning.

Further Reading1 Brandt KD, Mazzuca SA. Lessons learned from nine clinical trials of disease-modifying

osteoarthritis drugs. Arthritis Rheum 2005; 52: 3349–59.

2 Clegg DO, Reda DJ, Harris CL et al. Glucosamine, chondroitin sulfate, and the two in combi-

nation for painful knee osteoarthritis.N Engl J Med 2006; 354: 795–808.

3 Biggee BA, Blinn CM, McAlindon TE, Nuite M, Silbert JE. Low levels of human serum

glucosamine after ingestion of glucosamine sulphate relative to capability for peripheral

effectiveness. Ann Rheum Dis 2006; 65: 222–6.

4 Cantini F, Salvarini C, Olivieri I et al. Remitting seronegative symmetrical synovitis with pit-

ting oedema (RS3PE) syndrome: a prospective follow up and magnetic resonance imaging

study. Ann Rheum Dis 1999; 58: 230–6.



21 Antinuclear Factor

Systemic Lupus Erythematosus,Sjögren’s Syndrome andScleroderma

S E C T I O N F O U R 04

21 Antinuclear factor22 SLE – risk factors and diagnosis23 Monitoring and managing SLE24 Sjögren’s syndrome25 Raynaud’s phenomenon26 Assessing and treating scleroderma27 Immunosuppressive drugs

P R O B L E M

Case HistoryMary is 32 years old and presents with chronic fatigue and general malaise. She has twoyoung children aged two and five years. Her pregnancies were uncomplicated. Her mothersuffers from autoimmune thyroid disease. Her erythrocyte sedimentation rate (ESR) isslightly elevated at 25 mm/h and the immunology laboratory reports that her serum isantinuclear antibody (ANA) positive at a titre of 1:320.

What is the clinical significance of the positive ANA?

What factors will aid the interpretation of this result?

Are there other tests that should be requested?


04-PS Rheumatology-cpp :04-PS Rheumatology-ppp.QXD 18/3/08 14:30 Page 109

BackgroundANA is detected by indirect immunofluorescence on fixed and permeabilized Hep2 cellsderived from a human laryngeal carcinoma. ANA is positive in the majority of patientswith systemic lupus erythematosus (SLE) but is not specific for SLE, frequently beingpositive in other connective tissue diseases. ANA may also be detected in autoimmunethyroid and liver diseases. It may become positive in patients with infections and inflam-matory disorders including inflammatory bowel disease. A small proportion of the nor-mal population, particularly the elderly, are also ANA positive. ANA results are reportedas titres – the maximum dilution at which the antibody can be detected by immunofluor-escence.1 Beginning at 1:40 dilution, serial doubling dilutions are analysed until theobserver no longer detects the presence of antinuclear fluorescence (i.e. 1:40, 1:80, 1:160,1:320, 1:640 dilutions and so on). Often reported as positive at a titre of 1:40, clinicallymeaningful positives begin at 1:160. Although higher titres are more likely to indicate thepresence of an underlying disease, repeated measurements are generally not useful intracking the activity of underlying diseases. Different patterns of staining, indicatingwhich antibody may be present, have long been recognized but are now of less clinicalsignificance as specific markers for connective tissue diseases have been described:

Homogeneous: Due to anti-double-stranded DNA (anti-dsDNA), anti-histone (seen indrug-induced lupus) or anti-nucleosome (histone–DNA complex).

Membranous: Antibodies to membrane components including lamins A, B and C.

Speckled: Antibodies directed at non-histone antigens. Coarse speckles – anti-Sm (Smithantigen) and anti-uracil-rich 1 ribonucleoprotein (anti-U1RNP); fine speckles – anti-SSA/Ro or anti-SSB/La.

Anti-centromere: Characteristic of limited form of systemic sclerosis (CREST syndrome).

Nucleolar: Anti-DNA topoisomerase I (Scl-70), a marker for systemic sclerosis.

The Hep2000 cell line is increasingly used for ANA testing as it contains a proportionof Ro antigen-transfected cells and identifies both ANA and anti-Ro antibodies.Sensitivities and specificities for various disease states are shown in Table 21.1. PositiveANA should always be interpreted in the light of the clinical picture. Extractable nuclearantigens are antibodies directed against small ribonuclear proteins and include anti-Sm,anti-U1RNP, anti-SSA/Ro and anti-SSB/La. With modern diagnostic techniques, it isdebatable whether SLE can be diagnosed in the absence of antinuclear antigens althougholder literature suggests that up to 5%–10% of cases may be autoantibody negative. Of263 patients referred with a presumptive diagnosis of SLE, 29% were ANA positive butdid not have autoimmune disease, and half of these had received treatment with cortico-steroids at dosages as high as 60 mg/day.2

Anti-dsDNADNA was the first of the nuclear antigens to be identified (in 1957). High avidityimmunoglobulin G (IgG) antibodies directed at double-stranded DNA are highlyspecific for SLE. The antigenicity of DNA is increased when it is complexed to histones orother nucleosome proteins. The level of anti-dsDNA is a reasonable marker of diseaseactivity, particularly where there is renal involvement. Antibodies against the comple-

§04 Systemic Lupus Erythematosus, Sjögren’s Syndrome and Scleroderma110


ment component C1q may also be useful. The antibodies are not only markers for thedisease but directly participate in the disease process through immune complex depos-ition, cross reactivity with other antigens and promotion of immune reactions within tis-sues. A variety of methods have been described for detection including the Farr assay,Crithidia luciliae immunofluorescence and a range of enzyme-linked immunosorbentassays (ELISAs).

Anti-SSA/Ro and anti-SSB/LaThese were first described as antibodies against determinants in salivary glands ofpatients with Sjögren’s syndrome. They are directed against 52 kDa and 60 kDa Ro pro-teins, La or to one of a number of RNA particles. Anti-Ro occurs in some patients withSLE, mixed systemic sclerosis (SSc)/SLE syndrome, primary biliary cirrhosis and in15%–20% of patients with polymyositis/dermatomyositis (PM/DM). In SLE, it has beenassociated with non-erosive (Jaccoud’s) arthropathy and with late onset of the disease (atage >50 years). Anti-La is most commonly found in Sjögren’s syndrome. In SLE, it gener-ally occurs with anti-Ro and together they are a marker for low risk of renal disease. Anti-La is also found in patients with hypergammaglobulinaemia or cryoglobulinaemia.Anti-Ro is found in patients with complement C2 or C4 deficiency. Anti-Ro IgG crossesthe placenta and is responsible for congenital heart block in the offspring of mothers withSLE. Heart block and tachyarrhythmias occur with increased frequency inmixed connect-ive tissue disease (MCTD), SSc and PM/DM, where they are often associated with thepresence of anti-Ro.4

Anti-Sm and anti-RNPAnti-Sm shows high specificity for SLE but is only found in 5%–30%of patients, with fewerCaucasian patients and up to 30% of black patients being positive. Anti-RNP is positive in25%–47% of SLE patients, and is a particularly good marker for MCTD. Although the twoautoantibodies are highly associated, they may have different clinical associations: anti-RNP in patients with SLE and Raynaud’s phenomenon and typically with milder renalinvolvement; anti-Sm, along with high anti-dsDNA, is a marker for more severe renalinvolvement. Anti-Sm is directed at seven proteins that form the core of U1, U2, U4 andU5small nuclear ribonucleoprotein particles. Anti-RNP is directed at 70 kDa, A and C pro-teins in the core of U1RNA particles. Detection is by counterimmunoelectrophoresis,

21 Antinuclear factor 111

Disease Sensitivity (%) Specificity (%)

Systemic lupus erythematosus 96 57

Scleroderma 85 54

Secondary Raynaud’s 64 41

Polymyositis/dermatomyositis 61 63

Sjögren’s syndrome 48 52

Rheumatoid arthritis 41 56

Adapted with permission from Habash-Bseiso et al. 2005.3

Table 21.1 ANA in connective tissue diseases


immunoblotting or ELISA. Anti-Sm is technically difficult to detect and more than onemethod may be required. Anti-Sm may arise by molecular mimicry with an Epstein–Barrvirus, while cross-reactivity with influenza B has been suggested for anti-RNP.

Anti-Jo-1Initially described in 1980 in a patient with interstitial pulmonary fibrosis (John P), theseantibodies are highly specific for inflammatory myopathies. Anti-Jo-1 is directed at thehistidyl-tRNA synthetase. Autoantibodies against six of the 20 aminoacyl-tRNA syn-thetases have now been described. The antibody occurs in 20%–30% of patients withPM, but in 60%–70% where there is concurrent pulmonary fibrosis. DM is more fre-quently associated with malignancy than PM, but anti-Jo-1 is present in 5%–10% ofcases. Anti-Jo-1 often occurs along with anti-Ro52. The association of inflammatorymyositis, interstitial pulmonary fibrosis and Raynaud’s phenomenon has been called‘antisynthetase syndrome’. Detection of anti-Jo-1 is by counterimmunoelectrophoresis,immunoblotting or ELISA.

Anti-Scl-70These are antibodies against the enzyme topoisomerase I. They are rarely found inhealthy individuals and are reasonably specific for SSc, particularly where there is diffusecutaneous involvement or interstitial pulmonary fibrosis. They are detectable in about40% of patients with SSc, and have also been described in patients with localized sclero-derma, eosinophilia myalgia syndrome and graft-versus-host disease.

Anti-hnRNPAntibodies to heterogeneous nuclear ribonucleoproteins (hnRNPs) have only relativelyrecently come to prominence and are positive in 35% of rheumatoid arthritis patients,20%–30% of patients with SLE and in 40% with MCTD. The hnRNPs are abundantnuclear proteins involved in RNA processing in association with RNA polymerase II. Themost common anti-hnRNPs are antibodies against the A1 protein (a marker forRaynaud’s phenomenon associated with SLE), the A2/B complex (associated with erosivearthritis in SLE) and K protein. Anti-RA33 is thought to be a relatively specificmarker forrheumatoid disease.

The above autoantibodies should only be sought if ANA is positive and there is a strongclinical suspicion of the related disease. The associations between autoantibodies and thevarious disease states is summarized in Table 21.2.

Recent Developments1 Environmental factors including drugs and infections are important triggers for the

development of ANA. In a recent study,5 ANA (measured by ELISA) was found in10.9% of men and 12.2% of women. Records of infectious diseases in early life wereavailable. Participants who had mumps, rubella or a diarrhoeal illness later in lifewere more likely to be ANA positive.

2 Smoking is another environmental trigger for rheumatoid arthritis, SLE,autoimmune thyroid disease and multiple sclerosis. Generation of reactive oxygen



species in smokers may lead to exposure of potential autoantigens or may alterantigens rendering themmore immunogenic. In the study by Freemer et al.,6 currentsmokers had a higher risk for anti-dsDNA positivity than never smokers (odds ratio[OR] 4.0; 95% confidence interval [CI] 1.6–10.4). Current smokers had a higher riskthan previous smokers (OR 3.0; 95% CI 1.3–7.1).

3 Recent technical advances both in immunofluorescence techniques7 and inmultiplex technologies8 are not only allowing for more standardized testing but areincreasing throughput and decreasing cost. Multiplex technologies include pre-coating nitrocellulose strips with multiple antigens or using polystyrene beads coatedwith antigen. In the latter case, the presence of autoantibodies to specific antigenscan be quantified by fluorescence-activated cell sorting. A line blot immunoassay hasbeen developed for the simultaneous detection of multiple antibodies to extractablenuclear antigens.9

4 Endometriosis affects 5%–15% of women and is characterized by growth ofendometrial tissue in extrauterine sites. An association with autoimmunity has longbeen postulated. In a recent study, circulating ANA was found in 46 out of112 women with laparoscopically proven endometriosis.10 Laminin-1 is a majorcomponent of basement membranes. Autoantibodies to laminin-1 determinantshave been associated with infertility and recurrent abortion, and the incidence ofsuch antibodies is increased in endometriosis.11

ConclusionANA positivity does not necessarily signify that the patient has an underlying connectivetissue disorder. However, the above patient has a high titre of ANA and some symptomsthat would be consistent with an autoimmune disorder. History and examination shouldfocus on the presence or otherwise of joint symptoms, skin lesions, renal involvement


SLE MCTD SS SSc RA PM/DN Raynaud’s

ANA +++ ++ ++ +++ + ++ ++

dsDNA ++++ ++ – – – – +

Ro ++ ++ – – – ++ –

La + – ++ – – – –

Sm ++ + + – – – –

RNP ++ +++ + – – – ++

Jo-1 + + + – – +++ +

Scl-70 – – – ++ – – +

hnRNP ++ ++ + – ++ – –

The higher number of + signs, the greater utility in diagnosis for each syndrome. This does not imply that the markers are useful for monitoring diseaseactivity. ANA, antinuclear antibody; dsDNA, double-stranded DNA;MCTD, mixed connective tissue disease; PM/DM, polymyositis/dermatomyositis; RA,rheumatoid arthritis; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus; SS, Sjögren’s syndrome; SSc, systemic sclerosis.

Table 21.2 Autoantibodies in connective tissue diseases



Positive ANA

Signs and symptoms of• Arthropathy• Skin lesion• Lung involvement (fibrosis)• Nervous system involvement

Check renal and hepatic function

Titre ,1:80 Titre 1:80–1:320

Possible clinicalsignificance

? Clinicalsignificance

Ix further only ifstrong clinical

suspicion

Likely to besignificant

dsDNAC3 and C4 levelsSLE unlikely

Screen for ENA

Measure specific autoantibodies

Interpret results with clinical picture

Specific diagnosis and treatment

Titre .1:320

If normal

? Increased inflammatory markers (ESR and CRP)? Normocytic anaemia

Figure 21.1 Investigation of a patient with positive ANA. ENA, extractable nuclear antigen; Ix,investigation.



and central nervous system problems. Increased levels of inflammatory markers (ESRand serum C-reactive protein [CRP]) would be consistent with an active autoimmunecondition. SLE should be excluded by measurement of anti-dsDNA and complement C3and C4. Levels of the latter would be lower than normal in a patient with active SLE.Management of the patient with positive ANA is summarized in Figure 21.1.

Further Reading1 Muro Y. Antinuclear antibodies. Autoimmunity 2005; 38: 3–9.

2 Narain S, Richards HB, Satoh M et al. Diagnostic accuracy for lupus and other systemic

autoimmune diseases in the community setting. Arch Int Med 2004; 164: 2435–41.

3 Habash-Bseiso DE, Yale SH, Glurich I, Goldberg JW. Serologic testing in connective tissue

diseases. Clin Med Res 2005; 3: 190–3.

4 Lazzerini PE, Capecchi PL, Guideri F, Acampa M, Galeazzi M, Laghi Pasini F. Connective

tissue diseases and cardiac rhythm disorders: an overview. Autoimm Rev 2006; 5: 306–13.

5 Edwards CJ, Syddall H, Goswami R, Dennison EM, Cooper C. Infections in infancy and

the presence of antinuclear antibodies in adult life. Lupus 2006; 15: 213–17.

6 Freemer MM, King TE, Criswell LA. Association of smoking with dsDNA autoantibody

production in systemic lupus erythematosus. Ann Rheum Dis 2006; 65: 581–4.

7 Tsiakalou V, Tsangaridou E, Polioudaki H et al. Optimized detection of circulating anti-

nuclear envelope autoantibodies by immunofluorescence. BMC Immunol 2006; 7: 20–9.

8 Binder SR. Autoantibody detection using multiplex technologies. Lupus 2006; 15: 412–21.

9 Damoiseaux J, Boesten K, Giesen J, Austen J, Tervaert JWC. Evaluation of a novel line-

blot immunoassay for the detection of antibodies to extractable nuclear antigens. Ann NY

Acad Sci 2005; 1050: 340–7.

10 Dias JA, de Oliveira RM, Abrao MS. Antinuclear antibodies and endometriosis. Int J

Gynaecol Obstet 2006; 93: 262–3.

11 Inagaki J, Kondo A, Lopez LR, Shoenfeld Y, Matsuura E. Pregnancy loss andendometriosis. Pathogenic role of anti-laminin-1 autoantibodies. Ann NY Acad Sci 2005;

1051: 174–84.


Case HistoryJenny, aged 21 years, presented with fatigue, a photosensitive rash on her arms and face,recurrent mouth ulcers and sore joints. She smokes 20 cigarettes per day and consumesvery little alcohol. Her medications are the oral contraceptive andminocycline for acne.

On what basis could you make a diagnosis of systemic lupus erythematosus (SLE)?

What further investigations should be undertaken?

What environmental or inherited risk factors predispose to SLE?

BackgroundDiagnosis of SLESLE is a disease characterized by the production of a variety of antibodies against nuclearcomponents that causes inflammation and injury to multiple organs. It primarily affectswomen from the late teens onwards with a peak incidence between the ages of 15 and45 years. In European populations the prevalence is 12–64 cases per 100 000, and it isthree to five times more prevalent in African-American and Afro-Caribbean women.Recent studies in human populations and animal models have associated elements of theinnate immune system and abnormalities in the immature B lymphocyte receptor reper-toires with disease initiation. A variety of cytokines, most notably type 1 interferons(IFN-a, IFN-b), play an important role in pathogenesis.The American College of Rheumatology (ACR) criteria for the classification of SLE

(Table 22.1) act as an aide-memoire to the multisystem nature of SLE and to the investiga-tions that should be undertaken. Patients with SLE almost always suffer from debilitatingfatigue, with the majority having associated weight loss and fever. Three-quarters ofpatients with SLE have mucocutaneous disease in the form of butterfly rash, oral ulcers,alopecia and Raynaud’s phenomenon; purpura, vasculitis or urticaria occur less often. Themajority (60%) experience arthralgia or arthritis in a pattern that may mimic rheumatoidarthritis (RA). Renal disease and haematological problems occur in approximately one-third of patients; cardiac, neuropsychiatric and gastrointestinal problems occur in 20%.Lack of antinuclear antibody (ANA) at a titre of 1:160 or higher makes SLE very unlike-

ly. Remaining patients are often positive for anti-Ro antibodies. False-positive ANAresults increase with age, and up to 5% of healthy individuals may be ANA positive.Specific ANA immunofluorescence patterns – such as anti-centromere, anti-nucleolar orproliferating cell nuclear antigen – may be reported and require no further characteriza-


22 SLE – Risk Factors and Diagnosis

P R O B L E M



tion. Sera with either a homogeneous or rim pattern on ANA testing should undergo anti-double-strandedDNA (anti-dsDNA) testing, and a speckled ANApattern should undergotesting for antibodies to extractable nuclear antigens. Anti-dsDNA antibodies are themostspecific autoantibody; however, they are not very sensitive, occurring in only one-half oflupus patients during the course of their disease. Anti-dsDNA antibodies may also befound in autoimmune hepatitis and chronic infections such as syphilis, subacute bacterialendocarditis and parasitic infection.2 The presence of anti-Sm antibodies is specificallyidentified in the ACR criteria, even though low titres have been reported in other diseases.Anti-Sm is very rare in normal individuals and is virtually pathognomonic for SLE. It isfound in 5%–30% of SLE patients and is more prevalent in black Americans.

Environmental and genetic interaction in the aetiologySeveral genetic loci have been associated to SLE in multiplex families using genome-widelinkage studies. Alleles within the major histocompatibility complex (Fcg receptors,immunoglobulin receptor homologues, cell signalling molecules, cytokines/chemokines, complement, opsonins etc.) have been found to be associated with SLE.Concordance rate in monozygotic twins is <60%, invoking a significant environmentalcontribution to the disease.SLE, as already noted, is characterized by a wide range of autoantibodies that target

intracellular, cytoplasmic, cell-surface and plasma antigens. Autoantibodies to DNA andhistones – individually and together (as the nucleosome complex) – have been found inserum of individuals years before the onset of disease, and progressive accumulation ofthe autoantibodies precedes the onset of disease. An understanding of the mechanismthat allows B cells to be exposed to and subsequently to develop antibodies to nuclearantigens that are shielded from immune surveillance is critical to our understanding ofthe pathogenesis of SLE. A common link between many of the antigens that are targetedin SLE is that they are translocated to the cell surface as nuclear blebs during apoptosis.The current dogma is that clearance of intact dying cells prevents secondary necrosis ofapoptotic cells and hence release of nuclear blebs containing potential autoantigens.

22 SLE – risk factors and diagnosis 117

1. Malar rash� Fixed erythema over the malar eminences, sparing the nasolabial folds

2. Discoid rash� Erythematous patch with keratotic scaling and follicular plugging

3. Photosensitive skin rash4. Oral ulcers5. Arthritis

� Non-erosive joint inflammation in 2+ peripheral joints6. Pleuritis or pericarditis7. Renal disorder

� Proteinuria >0.5 g/24 h, or cellular casts8. Neurological disorder

� Seizures or psychosis (not explained by drugs or metabolic changes)9. Haematological disorder

� Haemolytic anaemia, leukopenia, lymphopenia, thrombocytopenia10. Immunological disorder

� Anti-DNA antibody, anti-Sm antibody, antiphospholipid antibody11. Antinuclear antibody

Table 22.1 American College of Rheumatology (ACR) classification criteria for SLE1


However, under special circumstances, apoptotic cells may trigger an immune response,which may activate T and B cells and the formation of autoantibodies.

Drug-induced lupusThere are various kinds of lupus: (a) SLE; (b) discoid lupus (inflammatory scarring skinlesions); (c) subacute cutaneous lupus (non-scarring, non-atrophy producing photo-sensitive dermatosis); and (d) drug-induced lupus (DIL). Drugs responsible for develop-ing DIL can be divided into three groups (Table 22.2).3

There are no symptoms pathognomonic for DIL; however, some features are com-mon. Patients often present with mild lupus-like symptoms, which can develop as earlyas one month after initiation of treatment or can be delayed as long as a decade. Men areas frequently affected as women, and Caucasians are affected up to six times more fre-quently than black patients and may have a more severe illness. Features common in DILare fever, arthralgia, pleuritis, pericarditis, mild cytopenia, anaemia and elevated erythro-cyte sedimentation rate. Hypocomplementaemia and clinical features of malar or discoidrash, photosensitivity, oral ulcers, alopecia and renal or neurological disorder are veryuncommon. Anti-histone antibodies, especially IgG anti-([H2A-H2B]-DNA) are posi-tive in 75%–95% of DIL patients, but also occur in 75% of SLE patients. There is usuallyan absence of anti-dsDNA and anti-extractable nuclear antigen (anti-ENA) antibodies,with a high frequency of anti-single-stranded DNA (anti-ssDNA) antibodies. Amongstthe medications definitely capable of inducing lupus, procainamide is currently the drugmost frequently associated with DIL. Between 2% and 21% of patients receivinghydralazine also develop the disease, the greatest risk being with doses >200 mg/day.The link betweenminocycline and DIL became evident whenminocycline became used

for the treatment of acne and RA. A case–control prospective study found an eight-foldincreased risk for current users, and DIL has been individually confirmed by rechallenge.Developing any time between three months and six years after initiation, minocycline DIL(in contrast to classical DIL) has a female preponderance. Typical is a symmetrical poly-arthritis with early morning stiffness, often with fever and myalgia. A wide range of cuta-neous manifestations are reported: vasculitis, livedo reticularis, erythema nodosum andsubcutaneous nodules. Positive ANA is found in >80%of patients. Hepatic damage is oftenassociated but prognosis of minocycline DIL is generally good, with rapid resolution of allaspects including chronic active hepatitis on withdrawal of the drug.The high incidence of SLE in females during their reproductively capable years has

prompted the association with female sex hormones. However, it remains controversialas to whether the addition of exogenous oestrogens on a background of endogenous


Definitely capable of DIL� Hydralazine, procainamide, isoniazid, methyldopa, chlorpromazine, quinidine, minocycline

Possibly inducing lupus� Sulphasalazine, anticonvulsants, antithyroid drugs, statins, b-blockers, interferon-a, penicillamine, fluorouracil,

thiazide diuretics

Suggested to induce lupus� Multiple antibiotics, oestrogens and oral contraceptives, captopril, calcium channel blockers, etanercept,

infliximab

Table 22.2 Drugs implicated in drug-induced lupus3


hormones can induce or worsen lupus. It had been suggested that both oral contraceptivepills (OCPs) and hormone replacement therapy (HRT) could be used without changingdisease activity if patients were normotensive, non-smoking, with only stable to moder-ate disease and were antiphospholipid antibody negative.4 The Safety of Estrogens inLupus Erythematosus National Assessment (SELENA) trials comprised two separate ran-domized controlled trials of low-dose synthetic oestrogen and progestin OCPs,5 andHRT6 in women with inactive or stable SLE disease activity. The twelve-month rates ofsevere flares and for mild or moderate flares were almost identical for the group receivingOCPs and for the placebo group, demonstrating safe use of low-dose OCPs in SLEpatients with stable disease. In the HRT trial severe flares were rare, with a twelve-monthsevere flare rate of 0.081 for the HRT group and 0.049 for the placebo group. Mild tomoderate flares were significantly increased in the HRT group: 1.14 flares/person-yearfor HRT vs 0.86 flare/person-year for placebo (P <0.01), with an increased probability ofany type of flare by twelve months in the HRT group (P <0.01). Adding a short course ofHRT is associated with a small risk for increasing the natural flare rate of lupus.

Recent Developments1 Whereas genetic information (with the exception of somatic mutations) is

homogeneous in an organism regardless of cell type, epigenetic modifications arecharacteristic of different cell types and play a role in defining the transcriptome,which determines the identity of each cell type.7 The epigenetic framework couldexplain several disease characteristics, including age dependence and quantitativenature, and the mechanism by which environment modulates geneticpredisposition to disease. Abnormalities in the DNA methylation system aberrantlyincrease or decrease gene expression, which has been implicated in SLE. Supportfor this concept is the global hypomethylation of T cells from patients with activeSLE and the hypomethylating effect of drugs used to induce SLE such asprocainamide, hydralazine and 5-azacytidine (Table 22.3). In the case of histonemodification, histone-deacetylating drugs skew gene expression of CD40L,interleukin (IL)-10 and interferon-g. Alteration of T cell–B cell interactions hasbeen proposed as the common pathogenic mechanism that leads to disease.However, the recognition of dendritic cells (DCs) as efficient stimulators of B andT cell lymphocytes, as well as key controllers of immunity and tolerance, has ledto the hypothesis that SLE may be driven by inappropriate DC activation. Twomechanisms have been described: elevated functional levels of interferon,8 anddefective complement-mediated clearance of apoptotic cells (Figure 22.1).9

2 Monocytes from SLE patients have enhanced antigen-presenting ability and act likemyeloid dendritic cells; serum from SLE patients rapidly differentiates normalmonocytes into cells with DCmorphology and function. A candidate serum cytokinethat may be responsible for this maturation is type 1 interferon (IFN-1). Elevatedlevels of IFN-1 have been found in the serum of SLE patients. Administration ofexogenous IFN-1 as therapy for chronic viral infection or malignancy is associatedwith autoantibody production in up to 34% of recipients and autoimmunecomplications in 4%–19%.10Mature DCs activate cytotoxic T cells, leading to celldeath and the generation of nucleosomes that can be captured and presented by DCs



generated in the presence of IFN-1. Together with IL-6, IFN-1 promotes thedifferentiation of mature B cells into plasma cells, which are long-lived autoantibodyproducers. Thus, the effect of IFN-1 on DCs, B cells and T cells could explain thebreakdown of tolerance to nuclear antigens, and the subsequent autoantibodysecretion and immune complex formation characteristic of SLE.

3 In humans there is a very strong association between deficiencies of the complementcomponents C1 and C4 and the presence of SLE. It has been hypothesized9 thatcomplement deficiency leads to impaired clearance of dying cells and allowsprolonged exposure of nuclear blebs (the putative source of autoantigens). The sameauthors expanded the theory to include any mechanism that impairs clearance ofapoptotic cells, with evidence for C1q, C4, IgM, macrophage phagocytosis and tissuetransglutaminase. In the presence of adequate complement levels, apoptotic cells arerapidly taken up by immature DCs before the release of intracellular material can


Epigenetic change Consequence Disease association

Methylation of cytosine in Repression of transcription Autoreactivity via T cell response to sub-thresholdCpG dinucleotides promoters antigenic stimuli, and overexpression of adhesion

receptor LFA-1Altered nuclear architecture CD70 overexpression leading to excess B cell

stimulation in SLEHistone modification Repression of tumour suppressor genes leading to� Lysine acetylation Transcriptional activity malignant transformation� Lysine methylation, Variable transcriptional effect Hypomethylation causing chromosomal instabilityserine phosphorylation Altered nuclear architecture Failed transcriptional regulation of imprinted genes

(e.g. Prader–Willi syndrome)

Table 22.3 Epigenetic changes in SLE

Loss of tolerance andautoantibody production

Complementdeficiency

↑ Type 1interferon

↑ Apoptosis andnuclear blebs

Viral infection IFN mutations

Monocyte

Myeloid DC

↓ Clearance ofapoptotic cells

Figure 22.1 Decreased complement and increased interferon (IFN) predispose to autoantibodyproduction. DC, dendritic cell.



activate them, yet at the same time allowing for the nuclear material to be processedby the DC in its immature form leading to tolerance.

ConclusionSLE is one of the great masqueraders in medicine, with multiple varied presentations.Despite its potential to be a devastating illness, in the majority of cases the presentation isoften a poorly defined illness with subjective complaints greater than any observedabnormalities. Many of the classification criteria listed in Table 22.1 develop over timeand are not cumulative, such that a detailed previous history needs to be undertaken,particularly as many of the features such as mouth ulcers or photosensitivity may notsubsequently be recalled spontaneously. It is in this setting that the clinical challenge is toconsider the diagnosis of SLE, to investigate appropriately, but then not to over-rely onthe presence of an antinuclear antibody to make the diagnosis.

Further Reading1 Hochberg MC. Updating the American College of Rheumatology revised criteria for the

classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725.

2 Kurien BT, Scofield RH. Autoantibody determination in the diagnosis of systemic lupus

erythematosus. Scand J Immunol 2006; 64: 227–35.

3 Sarzi-Puttini P, Atzeni F, Capsoni F, Lubrano E, Doria A. Drug-induced lupus erythematosus.

Autoimmunity 2005; 38: 507–18.

4 Kreidstein S, Urowitz MB, Gladman DD, Gough J. Hormone replacement therapy in systemic

lupus erythematosus. J Rheumatol 1997; 24: 2149–52.

5 Petri M, KimMY, Kalunian KC et al. Combined oral contraceptives in women with systemic

lupus erythematosus.N Engl J Med 2005; 353: 2550–8.

6 Buyon JP, Petri MA, KimMY et al. The effect of combined estrogen and progesterone

hormone replacement therapy on disease activity in systemic lupus erythematosus: a random-

ized trial. Ann Intern Med 2005; 142: 953–62.

7 Ballestar E, Esteller M, Richardson BC. The epigenetic face of systemic lupus erythematosus. J

Immunol 2006; 176: 7143–7.

8 Pascual V, Farkas L, Banchereau J. Systemic lupus erythematosus: all roads lead to type 1

interferons. Curr Opin Immunol 2006; 18: 676–82.

9 Cook HT, Botto M. Mechanisms of disease: the complement system and the pathogenesis of

systemic lupus erythematosus.Nat Clin Pract Rheumatol 2006; 2: 330–7.

10 Borg FAY, Isenberg DA. Syndromes and complications of interferon therapy. Curr Opin

Rheumatol 2007; 19: 61–6.


Case HistoryJane, having contacted the Arthritis Foundation and looked on the internet, realises thatsystemic lupus erythematosus (SLE) is a multisystem disorder. She wishes to discuss thepotential problems that she may face in the future.

What are the most frequent manifestations of SLE?

What monitoring should she undergo?

What are the current treatments for SLE?

BackgroundThe term lupus was first used in the early 1800s, and is derived from the Latin term for wolf(Canis lupus). It was applied to the skin condition lupus vulgaris to imply an appearance ofthe skin that looked to be torn off as a wolf might have done. Subsequently, the Latin termfor redness – erythematosus – was appended. The clinical features are represented in Figure23.1. Almost ubiquitous is the presence of fatigue, weight loss and intermittent fevers. Afterconstitutional symptoms, arthralgia andmucocutaneousmanifestations are themost com-mon, and in various forms account for five of the eleven American College ofRheumatology (ACR) criteria for the classification of SLE. Joint painwith or without object-ive inflammation is the most common reason for patients to present to their doctor. Mostcommonly, this presents as a small joint peripheral arthritis, which also involves wrists andknees and in many respects resembles rheumatoid arthritis. Both can be multisystem inmanifestation, and nodules similar to rheumatoid nodules may be present in up to 10% ofpatients. It is unusual for patients with SLE to develop any erosive changes.The butterfly rash in a malar distribution with sparing of the nasolabial folds is the

pathognomonic rash of SLE. Photosensitivity occurs in around one-half of SLE patients,and warrants reminding of the importance of sun avoidance and sunblock, with light inthe 360–400 nm spectrum inducing both rash and systemic exacerbations. Other rashesare less common. Alopecia varies in its pattern from ‘more hair in my brush or showerplug hole’ to distinct patches of hair loss, particularly if there have been scarring discoidlesions of the scalp. Immunosuppressive agents may lead to hair thinning.Progressive renal disease in SLE is often asymptomatic and should be sought by urin-

alysis for blood and protein and serial serum creatinine measurements. Any abnormalitywarrants further evaluation including 24-hour urine collection, microscopy of urinarysediment and a low threshold for review by a renal physician.


23 Monitoring and Managing SLE

P R O B L E M



Pleural manifestations have been reported in 30%–60% of patients, and includesymptomatic pleurisy, effusions and pleural rubs. Pleurisy is usually not associated withpleural rub, and the differential diagnosis includes primary pleural serositis and sec-ondary serositis due to underlying infection, or pulmonary infarct (particularly in thosewith thrombophilia). Pleural effusions may be found incidentally on chest X-ray and areusually small. When sufficiently large to drain, an exudate is present with a normal glu-cose level.

Monitoring SLESLE afflicts African-Americans three times more frequently than their European-American counterparts, and they are considered to have a poorer prognosis. Some of the

23 Monitoring and managing SLE 123

DepressionPsychosis12%–20%

AlopeciaRash

Oral ulcer75%

PleurisyLung disease15%–30%

Gastrointestinal15%–25%

PericarditisCardiac disease

5%–20%

Renal40%–70%

Arthritis5%–75% Raynaud’s

35%–50%

Figure 23.1 Clinical features of SLE.


different socioeconomic, demographic, psychological and behavioural variables arehighly correlated. The LUMINA (Lupus in minorities: nature versus nurture) cohortstudy resulted in a series of papers, with a recent report on predictors of disease activityover time.1 The cohort of 554 subjects included 18% Texan Hispanics, 17% Puerto RicanHispanics, 36% African-Americans and 29% Caucasians. Univariate analysis confirmedan odds ratio of 3 between Texan Hispanic or African-American ethnicity andCaucasian, and higher disease activity over time. These characteristics remained signifi-cant in a multivariate model. High disease activity was independently associated withlack of health insurance, abnormal illness-related behaviour and poor social support, andwas negatively associated with age.

Laboratory monitoringEarly detection of renal disease is a major goal (Table 23.1), as the survival curves arevastly different for those with and without renal disease. Specific symptoms are notobserved by the individual until there is advanced nephrotic syndrome or renal failure.Urinalysis is an extremely cheap and highly sensitive approach to detect haematuria andproteinuria, and can then be followed by a 24-hour urine collection and quantitativemicroscopy. Regular serum creatinine measurement is recommended.Routine haematology is undertaken for the detection of anaemia, leukopenia and

thrombocytopenia. Interpretation of results should take into account the effect of treat-ment, with steroids elevating neutrophil counts and decreasing lymphocyte counts, andimmunosuppressants exerting cytotoxic effects.In the LUMINA study, the immunological variable identified as being independently

associated with high levels of disease activity was the presence of anti-double-strandedDNA (anti-dsDNA) antibodies.1 Previously these antibodies had been associated withdisease activity and with lupus nephritis but not concomitantly with flares, as it is pro-posed that as the immune complexes are deposited in tissues their circulating levelsdecrease. Increasing levels of anti-dsDNA antibodies, which then fall, may herald exacer-bations of lupus nephritis or other organ involvement. Whilst this remains controversial,


History Examination Laboratory investigations

Fatigue Vitals – BP, pulse, temperature Urinalysis for proteinuria, haematuriaMucocutaneous features (oral Cardiorespiratory – rubs, effusions Urine microscopy for castsulcers, photosensitive rash) and fibrosis Full blood screenChest pain, SOBOE Arthritis – number and severity Renal functionArthritis Skin rash C-reactive proteinUrinary features

Preventative screeningSmoking cessation; body mass index goal <25 kg/m2

Monitor BP (target of <130/80 mmHg). Treat if >140/90 mmHgFasting lipids (target LDL-cholesterol <2.6 mmol/l. Treat if >3–4 mmol/lFasting glucose, and homocysteineAnti-Ro, anticardiolipin and lupus anticoagulant prior to planned pregnancyAnti-dsDNA antibodies

BP, blood pressure; LDL, low-density lipoprotein; SOBOE, shortness of breath on exertion.

Table 23.1 Monitoring of SLE patients


some authors have recommended corticosteroid therapy to prevent flares in SLE patientsmanifesting this pattern. If an increasing titre of anti-dsDNA antibody is detected, carefulexamination should be undertaken.

Preventative monitoringWith modern drugs, the survival rate for SLE has dramatically improved, as has survivalfrom acute disease flares. This has, however, revealed a later mortality due to cardiovas-cular disease (CVD). The predisposition of younger women to SLE results in pre-menopausal women with SLE having a 50-fold increased risk of myocardial infarction.Autopsy and angiographic studies demonstrate increased prevalence of atheroscleroticlesions in SLE patients. Measurements of intima–media thickness (IMT) of the carotidartery can be used as a surrogate measure of atherosclerosis; it is not clear from studies ofIMT in patients with SLE whether this marker is increased in the condition. Cross-sectional studies reveal carotid plaques in one-third of women with lupus. There remainsuncertainty as to whether atherosclerosis in SLE is increased in a general distribution orwhether it is primarily an increased risk of localized plaque. Traditional risk factors forCVD should be sought andmonitored in patients with SLE, but research is highlighting anumber of other risk factors (Figure 23.2).2

The suppression of inflammation is the aim of SLE therapy, and this can be assessed byboth the erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP). In


Cardiovascular diseasein SLE

Hypertension

Hyperhomocysteinemia Hyperlipidaemia

DiabetesInflammation

CRP, TNFa

Lipid oxidationProthrombosis

(anticardiolipin antibodies)

? SLE treatment(steroid therapy)

Smoking

Figure 23.2 Potential factors for cardiovascular disease in SLE. Adapted with permission from Frostegård2005.2


SLE the profound hypergammaglobulinaemic response leads to chronic elevation of theESR, leaving CRP to be the better marker of inflammation. Systemic inflammation accel-erates the atherosclerotic process. In the general population, increased levels of CRP areassociated with increased risk of CVD. In one of the LUMINA reports, CRP was a specificrisk factor for CVD: the median serum CRP in all patients with vascular events wasapproximately three times that in those without vascular events. This finding, however,also raises the conundrum of corticosteroids, which on the one hand are very potentinhibitors of inflammation, yet in long-term high doses do contribute to adverse cardio-vascular outcomes. It is possible that low doses of corticosteroids that optimize suppres-sion of inflammation may have a net beneficial cardiovascular effect.3

Guidance and support in the cessation of smoking is advised, as smoking promotesboth atheroma and flares of lupus. A recent meta-analysis showed that smokingincreased the likelihood of SLE (odds ratio 1.5), most notably with antibodies todsDNA.4,5 The risk–benefit ratio of low-dose aspirin (60–100 mg/day) favours its use inall patients with SLE.6 All SLE patients who have defined risk for CVD should receivelow-dose aspirin, as should those patients with both SLE and either a positiveimmunoglobulin G anticardiolipin antibody or lupus anticoagulant.

Treatment of SLEModifiable lifestyle factors include sun avoidance, stopping smoking, exercise, diet (withemphasis on altering the omega-3:omega-6 balance and reducing salt intake if hyperten-sive) and weight management. Specific interventions may be required for the treatmentof dyslipidaemia, diabetes and hypertension. The threshold for intervention is lower dueto the adverse effect of SLE itself.In practice, sun avoidance needs to be constantly reinforced – wide-brimmed hats,

clothing that provides sun protection and the regular application of quality sunblock.The availability of a range of cosmetic-grade moisturisers and make-up containing sun-block has aided the acceptability of this advice.Non-steroidal anti-inflammatory drugs and selective cyclooxygenase-2 (COX-2)

inhibitors are frequently used for soft tissue symptoms and control of arthralgia andarthritis in the general population, and have been used in SLE, although they are not usu-ally specifically registered for this population group. They should, however, be used withcaution due to risks of induction of hypertension, peripheral oedema and reduced renalfunction. Most regulatory agencies have stated that COX-2 inhibitors should not be usedin patients who have, or are at major risk of, CVD.Hydroxychloroquine (200–400 mg/day) is useful for skin rashes, joint pain and oral

ulcers. It also has a weak antithrombotic action. Doses of <6 mg/kg/day are associatedwith a very low risk of retinopathy, and physicians are advised to discuss with a local oph-thalmologist as to a monitoring regime. Higher doses can be used in the short term forpatients with ongoing photosensitivity. While its mechanism of action remains uncer-tain, it does alter antigen processing by affecting the pH of the phagolysosome, and mayalso regulate innate immunity via Toll-like receptors. A teratogenic effect was suspectedbut seems to have been ruled out,7 and its use is safe and effective in pregnancy.Dehydroepiandrosterone (DHEA) has been advocated for the treatment of SLE, pro-

viding a reduction in fatigue. DHEA is a sex-hormone precursor produced by the adren-al glands and is converted to either oestrogen or androgen in different peripheral tissues.



Randomized placebo-controlled trials support a modest beneficial effect when doses of200 mg daily are used, but this is outweighed by side effects of hirsutism, acne, hyperten-sion and adverse lipid profile.8

It is tempting to prescribe oral corticosteroids to the patient who is miserable withsymptoms of SLE. However, once commenced, it is very hard to keep good control on thedose and to cease therapy. Corticosteroid toxicity includes hyperglycaemia, hypercholes-terolaemia, hypertension, osteoporosis, glaucoma, weight gain, skin fragility, myopathyand avascular necrosis. As an adjunct and steroid-sparing agent, azathioprine is one ofthe immunosuppressants most commonly used in SLE (chapter 27). A purine analogue,its effect is to inhibit DNA synthesis, and in doses of 1.5–2.5 mg/kg/day it has benefit inpreventing serious lupus complications. Drug hypersensitivity occurs in a small percent-age of patients, resulting in systemic illness, rash, acute hepatitis and abdominal pain.Monitoring of bone marrow, liver function and lipase is recommended at four- to six-weekly intervals. As a cytotoxic agent it has been generally recommended that azathio-prine not be used in pregnancy although the evidence for teratogenicity is limited and thebeneficial effects of disease control on fertility, fetal outcome and the health of themother may warrant its continuation during pregnancy.

Recent Developments1 SLE nephritis is characterized by immune complex-mediated glomerular and

tubulointerstitial inflammation, which leads to chronic renal insufficiency in up to30% of affected patients. Cyclophosphamide is the principal treatment of diffuseglomerulonephritis (World Health Organization [WHO] class IV).Cyclophosphamide given as 6 ¥ 500 mg infusions followed by oral azathioprine wasas effective as the initial high-dose cyclophosphamide National Institutes of Health(NIH) regime.9 The evolution of mycophenolate mofetil (MMF) from a transplantrejection modifier to a broader immunosuppressant application has shown that2–3 g/day is as effective as cyclophosphamide in inducing and maintaining remissionin those with mild to moderate renal disease. MMF has a better safety profile thancyclophosphamide, avoiding haemorrhagic cystitis, ovarian failure and the longer-term cancer risks. A systematic review and meta-analysis found that a complete orpartial (66%–80%) response was more frequent with MMF than withcyclophosphamide, with one additional complete or partial response for every eightpatients treated.10

2 Central nervous system involvement has been described in up to 50% of lupuspatients. Cognitive dysfunction and headaches are the most common features,affecting 60%–80% of patients. Aseptic meningitis, demyelination, myelopathy,acute confusional states or psychosis are rare. The prevalence of depression is nohigher in SLE than in other chronic debilitating diseases.11 Psychosis in lupus ischaracterized by delusions or hallucinations; it is uncommon in SLE and occurs inonly 2%–5% of patients receiving high-dose (1 mg/kg/day) corticosteroids.Secondary causes such as drug use or drug withdrawal, metabolic and electrolytederangements and sepsis should always be excluded before concluding that it islupus psychosis.




ConclusionSLE is challenging both to diagnose and to treat successfully. With its protean manifest-ations, milder forms are being increasingly recognized or suspected due to the increasingavailability of autoantibody testing. There have been major advances in therapy.Immunosuppressants such as MMF have led to significant gains in the treatment ofnephritis. Even newer therapies are on the horizon, with the monoclonal antibody rituxi-mab providing dramatic and long-lasting remissions in patients who were previouslyunresponsive. The remaining challenges are in improving overall quality of life, reducingthe impact of fatigue and protecting patients from cardiovascular deaths as they survivethe initial insult of SLE.

Further Reading1 Alarcón GS, Calvo-Alén J, McGwin G et al; LUMINA study group. Systemic lupus

erythematosus in a multiethnic cohort: LUMINA XXXV. Predictive factors of high disease

activity over time. Ann Rheum Dis 2006; 65: 1168–74.

2 Frostegård J. SLE, atherosclerosis and cardiovascular disease. J Intern Med 2005; 257: 485–95.

3 Hall FC, Dalbeth N. Disease modification and cardiovascular risk reduction: two sides of the

same coin? Rheumatology 2005; 44: 1473–82.

4 Costenbader KH, Kim DJ, Peerzada J et al. Cigarette smoking and the risk of systemic lupus

erythematosus: a meta-analysis. Arthritis Rheum 2004; 50: 849–57.

5 Freemer MM, King TE, Crisswell LA. Association of smoking with dsDNA autoantibody

production in systemic lupus erythematosus. Ann Rheum Dis 2006; 65: 581–4.

6 Wahl DG, Bounameaux H, de Moerloose P, Sarasin FP. Prophylactic antithrombotic therapy

for patients with systemic lupus erythematosus with or without antiphospholipid antibodies:

do the benefits outweigh the risks? Arch Int Med 2000; 160: 2042–8.

7 Costedoat-Chalumeau N, Amoura Z, Duhaut P et al. Safety of hydroxychloroquine in preg-

nant patients with connective tissue diseases: a study of one hundred thirty-three cases com-

pared with a control group. Arthritis Rheum 2003; 48: 3207–11.

8 Sibilia J. Treatment of systemic lupus erythematosus in 2006. Joint Bone Spine 2006; 73: 591–8.

9 Houssiau FA, Vasconcelos C, D’Cruz D et al. Early response to immunosuppressive therapy

predicts good renal outcome in lupus nephritis: lessons from long-term followup of patients

in the Euro-Lupus Nephritis Trial. Arthritis Rheum 2004; 50: 3934–40.

10 Moore RA, Derry S. Systematic review and meta-analysis of randomised trials and cohortstudies of mycophenolate mofetil in lupus nephritis. Arthritis Res Ther 2006; 8: R182.

11 Bruns A, Meyer O. Neuropsychiatric manifestations of systemic lupus erythematosus. Joint

Bone Spine 2006; 73: 639–45.


Case HistoryYou have been asked to seeWilma, aged 52 years, because she may have Sjögren’ssyndrome (SS). Wilma has a teenage family of three and works part-time in the family drycleaning business. Recently she has become fatigued. Her optician recommended dropsfor dry eyes and she complains of mouth dryness. Investigations have been normal apartfrom a 1:160 positive antinuclear antibody (ANA).

What are the potential causes of sicca syndrome?

How would you investigate?

Assuming she has SS, how should she be followed-up and managed?

BackgroundAfter rheumatoid arthritis (RA), SS is the second most common autoimmune rheumaticdisease.1–3 It is named after Henrik Sjögren, who described a series of cases in 1933. SSaffects 0.5% of the population and is nine times more common in women. SS may affectup to two million people in the United States. There are two peaks of onset – one aftermenarche and a second following menopause. The cardinal symptoms are dryness of theeyes (keratoconjunctivitis sicca) and mouth (xerostomia) secondary to autoimmune dis-ease of the exocrine glands (lacrimal and salivary). The international consensus criteriafor diagnosis of primary SS are summarized in Box 24.1. Diagnosis of secondary SS canbe made when there is an established connective tissue disease, at least one symptom ofsicca syndrome and at least two objective tests to confirm the diagnosis. SS associatedwith RAmay produce more lacrimal than oral symptoms. Secondary SS may occur in upto 40%–50% of patients with RA, 10%–30% of those with SLE andmay also occur in sys-temic sclerosis, polymyositis and polychondritis. Tests to measure tear and saliva pro-duction should be carried out when the patient is not taking anticholinergic drugs. Atleast 50% of glandular tissue needs to be lost before patients begin to experience symp-toms. The following should be considered in a differential diagnosis: radiation to thehead and neck, sarcoidosis, infection (human immunodeficiency virus [HIV], humanT-lymphotropic virus type 1 and hepatitis C) and graft-versus-host disease.In SS, the exocrine glands are infiltrated by CD4+ helper T lymphocytes, which trigger

activation of cytotoxic T cells and B cells with consequent production of autoantibodyand destruction of glandular tissue. Anti-SSA/Ro or anti-SSB/La are present in a highproportion of patients and may have a diagnostic sensitivity comparable with that of

24 Sjögren’s syndrome 129

24 Sjögren’s Syndrome

P R O B L E M



salivary gland biopsy.4 ANA is positive in the majority, but is not detectable in up to 25%of patients. Other autoantibodies may also be detected, particularly in secondary SS.

Dry eyesOver 85% of patients with SS present with sicca syndrome. Decreased tear production canbe demonstrated using Schirmer’s test, where a strip of filter paper is placed under thelower eyelid. The degree of wetting of the paper over five minutes is measured. There is anage-related decrease in tear formation, probably contributed to by androgen or oestrogendeficiency. Subjects who habitually use computer screens may complain of dry eyesbecause of decreased blinking, particularly if they work in a low-humidity environment.Not only is the volume of tears decreased in sicca syndrome, but there is also decreasedtear content of lysozyme and lactoferrin. Management may include use of artificial tears,topical immunosuppressives (corticosteroid, cyclosporin) and punctal occlusion.

Dry mouthPatients with dry mouth are at risk of oral candidiasis, dental caries and fissuring of thetongue and gums. Decreased saliva flow is easily demonstrated using sialometry – the


Box 24.1 International consensus criteria for diagnosis of SS

Ocular symptoms (at least one)Persistent dry eyes every day for at least threemonthsRecurrent sensation of sand or gravel in the eyesUse of a tear substitutemore than three times per day

Oral symptoms (at least one)Persistent drymouth every day for at least threemonthsRecurrent feeling of swollen salivary glandsNeed to drink liquid in order to swallowdry food

Objective evidence of dry eyes (at least one)Schirmer’s testRose-BengalLacrimal gland biopsywith focus score >1 (at least 50 lymphocytes per lobulewithfour lobules assessed)

Objective evidence of salivary gland involvement (at least one)Salivary gland scintigraphyParotid sialographyUnstimualtedwhole sialometry (≤1.5 ml per 15minutes)

Laboratory abnormality (at least one)Anti-SSA or anti-SSBANAImmunoglobulinM (IgM) rheumatoid factor

Positive biopsy of a minor salivary glandFocus score >1 (see above)

At least four of the above six criteria should be satisfied for a positive diagnosis ofprimary SS


patient discharges his/her saliva into a vessel for 15 minutes and the amount of saliva isweighed. Flow rates of <0.1ml/min are abnormal. Differential diagnosis of dry mouth ispresented in Box 24.2. Salivary flow is stimulated by acetylcholine acting through mus-carinicM1 andM2 receptors. Drugs with anticholinergic action (e.g. tricyclic antidepres-sants) should be avoided where possible. Muscarinic secretagogues (pilocarpine orcevimiline) may improve salivary flow. Patients should avoid alcohol and smoking if pos-sible, and not use alcohol-containing mouthwashes. Careful attention should be paid tooral and dental hygiene. Antibacterial mouthwashes (e.g. chlorhexidine) may be useful.Chewing sugar-free gum or use of artificial salivamay provide temporary relief. Fluoride-releasing preparations including dental varnishes are often used. A topical preparation ofinterferon is being tried although, as with decreased lacrimation, the glands are largelydestroyed by the time symptoms develop and immunomodulatory treatment is likely tobe of limited use.

Extraglandular manifestationsThese are extremely variable but can pose a considerable threat to health. Skin lesionsinclude palpable and non-palpable purpura, alopecia, vitiligo and an increased incidenceof cutaneous lymphoma. Arthralgia is typically symmetrical and non-erosive, althougherosive arthralgia can occur. Muscular pains can produce a picture like fibromyalgia orpolymyalgia, but inflammatory polymyositis can occur. Gastrointestinal manifestationsinclude swallowing problems related to decreased saliva, atrophic gastritis, abnormalliver tests and autoimmune liver disease. The lungs may be affected by interstitial pneu-monitis and there is an increased risk of pulmonary lymphoma. Pericarditis and pul-monary hypertension can occur. Renal problems, including interstitial nephritis, mayoccur with SS or as a result of immunosuppressives. Cranial and peripheral neuropathies


Sjögren’s syndrome� primary� secondary

Salivary duct aplasia or atresiaSalivary duct stonesSialadenitis� bacterial (staphylococcal,

streptococcal)� viral (e.g.mumps)

Irradiation or chemotherapy

Dehydration,mouth breathing

Diabetes (mellitus or insipidus)HypercalcaemiaHyperlipoproteinaemia

Autonomic neuropathyLambert–Eaton syndrome

DrugsAnticholinergicsTricyclic antidepressantsAntihistaminesBenzhexol, benztropineEntacaponeLoperamideDiuretics

SmokingAlcoholMarijuana

Taste disturbancesHead/neck trauma

SarcoidosisAmyloidosisCirrhosis

Box 24.2 Differential diagnosis of xerostomia


are described. Autoimmune thyroiditis is very common. The chronic and disablingsymptoms may lead to anxiety, depression or other psychological problems. There is a40-fold increase in the risk of lymphoma in SS. Manifestations may include enlargingparotids, hypergammaglobulinaemia and hepatosplenomegaly.The presence of systemic features may necessitate the prescription of disease-

modifying drugs. Hydroxychloroquine (6–8 mg/kg/day) is useful where there is myalgiaor arthralgia. Visceral manifestations may respond to low-dose corticosteroids (pred-nisolone <15 mg/day). Other immunosuppressives used include azathioprine (1–2 mg/kg/day), methotrexate (7.5–25 mg/week) and cyclophosphamide (0.5–1 g/m2/day).Leflunomide or cyclosporin are useful in refractory cases.

Recent Developments1 Both sarcoidosis and SS affect salivary and lacrimal glands and they share many

systemic features. The presence of autoantibodies obviously favours SS, while hilarlymphadenopathy or hypercalcaemia would point towards sarcoidosis. A number ofcases have now been identified where the two conditions coexist.5While this may becoincidence, it could point to the presence of common aetiological factors.

2 Geographical distribution and seasonality of onset suggest that there could be aninfectious trigger. Amongst the leading candidates are Coxsackie viruses, whichappear to have a predilection for exocrine glands. Recently, Coxsackie virus B4sequences have been identified in the salivary glands of SS patients.6 Subclinicalinfection may trigger localization of helper lymphocytes in the salivary glandsleading to lymphocytic and dendritic cell activation.

3 Anti-centromere antibodies are characteristic of limited forms of scleroderma butcan also be detected in some patients with SS. The molecular determinants are agroup of centromere proteins (CENP-A, -B, -C, -D, -E, -F, -G and -H). Antibodiesto CENP-B or CENP-C have been described in about one-half of patients withlimited scleroderma and one-fifth of those with SS.7 By contrast, antibodies toCENP-Hmay be more specific for SS, and may identify a distinct group separatefrom those who are positive for anti-Ro and anti-La.8

4 The difficulty in defining SS as a clinical entity has led to a quest for more specificserological markers. Antibodies to the protein a-fodrin were described about tenyears ago. a-fodrin is an intrinsic membrane protein that binds to calmodulin, actinand microtubules, and is involved in regulation of exocytosis. A recent study9 hasconfirmed that these antibodies are present in a small proportion of a large series ofSS patients, and may be positive in some who are negative for anti-Ro and anti-La.

ConclusionNormally, up to 500 ml of saliva is produced daily. SS is an autoimmune condition, andinvestigations should confirm diminished lacrimal and salivary secretion. Ideally,autoimmune markers should be positive, and evidence of lymphocytic infiltrationshould be demonstrated on a biopsy of lacrimal or salivary gland. SS may be primary oroccur in association with an underlying connective tissue disease. If the disease is thoughtto be primary, careful inquiry should be made about systemic symptoms and involve-



ment of organs other than the exocrine glands. Treatment is mainly symptomatic andtopical (Figure 24.1), with immunosuppressive treatment being reserved for patientswith involvement of other organs including the lung and kidney.

Further Reading1 Derk CT, Vivino FB. A primary care approach to Sjögren’s syndrome. Postgrad Med 2004; 116:

49–59.


Dry eyes Decreased lacrimation (test)Dry mouthDecreased saliva (test)Autoantibody (Ro, La, ANA)Positive salivary/lacrimal biopsy

4 out of 6 positive Underlying CT disease

Primary SS Secondary SS

Dry eyes• Artificial tears• Punctal closure• Local immunosuppressives

Exclude other causes

Dry mouth• Dental/oral hygiene• Pilocarpine, cevimiline• Artificial saliva

Systemic/visceral involvement

Low-dose prednisolone

Azathioprine, cyclophosphamide or methotrexate

Leflunomide or cyclophosphamide

Figure 24.1 Investigation andmanagement of SS. CT, connective tissue.



25 Raynaud’s Phenomenon

P R O B L E M

Case HistoryRachel is aged 14 years and presents because she has poor circulation. Her motherdescribes Rachel’s fingers as going white, blue and then red when the weather is cold orwhen Rachel has been exercising. Her mother is concerned about this and wants to knowwhat it may mean for Rachel’s future health.

What is Raynaud’s phenomenon?

How would you determine whether it is a marker for future disease?

What treatment options exist for management?

BackgroundIn 1862, a medical student Maurice Raynaud described the phenomenon that bears hisname; it is characterized by transient cessation of blood flow to the digits of the hands or

2 Fox RI. Sjögren’s syndrome. Lancet 2005; 366: 321–31.

3 Fox RI, Liu AY. Sjögren’s syndrome in dermatology. Clin Dermatol 2006; 24: 393–413.

4 Kessel A, Toubi E, RozenbaumM, Zisman D, Sabo E, Rosner I. Sjögren’s syndrome in the

community: can serology replace salivary gland biopsy? Rheumatol Int 2006; 26: 337–9.

5 Ramos-Casals M, Brito-Zeron P, Garcia-Carrasco M, Font J. Sarcoidosis or Sjögren

syndrome? Clues to defining mimicry or coexistence in 59 cases.Medicine 2004; 83: 85–95.

6 Triantafyllopoulou A, Moutsopoulos HM. Autoimmunity and coxsackievirus infection in

primary Sjögren’s syndrome. Ann NY Acad Sci 2005; 1050: 389–96.

7 Gelber AC, Pillemer SR, Baum BJ et al. Distinct recognition of antibodies to centromere pro-

teins in primary Sjögren’s syndrome compared with limited scleroderma. Ann Rheum Dis

2006; 65: 1028–32.

8 Hsu TC, Chang CH, Lin MC, Liu ST, Yen TJ, Tsay GJ. Anti-CENP-H antibodies in patients

with Sjögren’s syndrome. Rheumatol Int 2006; 26: 298–303.

9 Ruiz-Tíscar JL, López-Longo FJ, Sánchez-Ramón S et al. Prevalence of IgG anti-a-fodrin anti-bodies in Sjögren’s syndrome. Ann NY Acad Sci 2005; 1050: 210–16.



feet (Box 25.1). Occasionally other structures are involved such as the tip of the nose, anearlobe, nipple or even tongue.Raynaud’s phenomenon occurs in 3%–5% of the population, although symptoms have

been reported in 10% of women and 8% of men. The prevalence is higher in women, withonset generally between menarche and menopause, and the severity is greater over thisperiod. Between 80% and 90% of Raynaud’s phenomenon is termed primary and has noidentifiable cause or associated disease. Secondary Raynaud’s phenomenon is most oftenfound in association with an underlying rheumatic disease (Box 25.2). There is some evi-dence for a genetic predisposition, especially in those with early onset (age <40 years).

The Practice Points (Box 25.3) identify a number of factors that can be evaluated inpredicting the likelihood of the Raynaud’s presentation being the first indicator of a moreserious disease. Of the four points listed, the absence of distorted nailfold capillaries is themost predictive of a benign outcome. Even patients with isolated Raynaud’s with nailfoldcapillaroscopy abnormalities and/or antinuclear antibody have only a 10%–15% likeli-hood of developing a connective tissue disease during long-term follow-up.

25 Raynaud’s phenomenon 135

Box 25.1 Triphasic colour changes of Raynaud’s phenomenon

White: excessive vasoconstriction and cessation of regional blood flowBlue: cyanosis due to residual blood desaturationRed: hyperaemia as the attack subsides and blood flow is restored

Box 25.2 Primary and secondary Raynaud’s phenomenon

Primary Raynaud’s phenomenon –Anuncomplicated and usually benign condition,oftenwith a long-standing history, beginning in adolescence, with no orminimal tissuedamage.

Secondary Raynaud’s phenomenon –Associatedwith underlying connective tissuedisease (systemic sclerosis ormixed connective tissue disease), with potentiallydisabling ulceration or tissue necrosis. Onset is usually after age 30–40 years. Lesscommon causes are use of vibrating tools, paraproteinaemias, cryoglobulinaemia, largeblood vessel disease and drugs (b-blockers, bleomycin, cisplatin, fentanyl, nicotine).

Box 25.3 Practice Points

Raynaud’s phenomenon as a precursor of an underlying connective tissue disease suchas scleroderma or systemic lupus erythematosus is very unlikelywith:

� Absence of tissue damage such as pulp scarring or atrophy

� Normal erythrocyte sedimentation rate

� Negative antinuclear antibody

� Absence of distortion of nailfold capillaries observed with an ophthalmoscope setat 40+ dioptre


PathogenesisThe association with female gender suggests a hormonal influence. Increased vascularreactivity also occurs in the pre-ovulatory part of the menstrual cycle. A large epidemio-logical study found no association between Raynaud’s phenomenon and smoking,although severity may be worse in smokers. The pathogenesis of Raynaud’s phenomenonhas been reviewed by Herrick1 and by Boin andWigley.2 The overall model of aetiology isan imbalance of vasoconstriction over vasodilation. This results from changes in the vas-cular endothelium and smoothmuscle, neural mediators of vascular tone and circulatingplatelet-derived mediators. These factors are in turn moderated by the level of physicalactivity, ambient temperature, emotional state and direct trauma or inflammation of thevessels. Table 25.1 summarizes the multiple influences that underlie the pathogenesis.

Non-pharmacological therapyEducation and introduction of conservative management are needed for all patients(Table 25.2). Avoidance of cold exposure is advocated, including frozen food sections ofsupermarkets. Patients should maintain or try and increase the temperature of the chestand abdomen to enhance peripheral vasodilation as a heat dissipation measure.Thermal biofeedback (TBF) is a psychophysiological technique in which subjects are

trained to control peripheral vasoconstrictor responses and to acquire voluntary hand-warm-ing skills. Initially taught with feedback such as peripheral temperature or blood flow, it is


Increased vasoconstriction Reduced vasodilation

Vascular factors ≠ Endothelin-1 ØNO and prostacyclin≠Angiotensin II≠Thromboxane A2

Neural factors Activation ofa2-adrenoreceptors ØCalcitonin gene-related peptide

Circulating factors ≠Platelet-derived thromboxane and serotoninOxidative stress damaging endothelium

Flow factors Reduced fibrinolysis predisposing to fibrin deposition and vascular obstructionIncreased viscosity and reduced red cell deformability

NO, nitric oxide.

Table 25.1 Pathogenetic factors

Non-pharmacological therapy Pharmacological therapy

Avoid cold, emotional stress, smoking Antiplatelet agentsBiofeedback

≠Vasodilation ØVasoconstriction

Calcium channel blockers Angiotensin II receptor antagonistsSildenafil/tadalafil ACE inhibitorsIntravenous/oral prostanoids BosentanL-arginine supplementation Serotonin reuptake inhibitors

a1/a2-adrenergic blockers

ACE, angiotensin-converting enzyme.

Table 25.2 Treatment strategies


hypothesized that subsequent hand-warming can occur without the feedback instrument. Asystematic review of eight randomized controlled trials (RCTs) highlightedmajor shortcom-ings in study design, particularly in the teaching of TBF and taking account of environmentalfactors.3However, the authors concluded that TBF treatment was efficacious.Cervical spinal cord stimulation has been proposed for severe Raynaud’s phenom-

enon, but remains controversial and is not yet supported by good clinical trials. Low-level laser therapy, applied to the fingers and dorsum of the hand for 30 minutes in fivesessions over three weeks, significantly decreased the frequency and severity of attacks ina sham-controlled double-blind trial. The mechanism of action remains unexplained.

Pharmacological treatmentThe sympathetic nervous systemmediates a tonic vasoconstrictive effect on the vascular wall,with noradrenaline-induced vasoconstriction mediated by a1 and a2 adrenoreceptors. Thea2 receptors are more important in the regulation of digital vascular tone. Trials of non-selective sympathetic blockers have not been successful. Prazosin, an a1 receptor antagonist,showed amodest benefit over placebo, but probably insufficient to balance side effects. Ana2receptor antagonist has been developed, and in an RCT reduced the frequency of Raynaud’sattacks in scleroderma-associated Raynaud’s, but not in primary Raynaud’s patients.Calcium channel blockers (CCBs), particularly of the dihydropyridine class, are wide-

ly prescribed for Raynaud’s phenomenon. A meta-analysis evaluated the effectiveness ofCCBs in primary Raynaud’s and noted an average reduction of three to five attacks perweek and a one-third reduction in severity.4Nifedipine is the most studied and has bene-fits over placebo and nicardipine. Adverse effects of CCBs include flushing, headache,oedema and tachycardia.Prostacyclin is a potent, short-lived vasodilator that also has antiproliferative effects

on smooth muscle and reduces platelet aggregation. Intravenous iloprost decreases thenumber and duration of vasospastic episodes, but its use usually requires central-lineadministration and is complicated by cost, hypotension and parotid and menstrual pain.Serotonin is a potent platelet-derived vasoconstrictor, and it is therefore counter-

intuitive to use selective serotonin reuptake inhibitors (SSRIs) as they would be expectedto increase the plasma concentration of serotonin. Despite this, several case reportsdescribe the use of SSRIs in Raynaud’s phenomenon, with both beneficial and worseningoutcomes. Fluoxetine decreases the frequency and severity of vasospastic episodes andincreases the rate of rewarming after a cold challenge.Angiotensin II receptor antagonists and angiotensin-converting enzyme inhibitors

have both shown effects on endothelial function and remodelling. On this basis, their usein Raynaud’s phenomenon is being explored. The frequent findings of microthrombin insecondary Raynaud’s and evidence of platelet activation suggest a potential benefit fromantiplatelet therapy or anticoagulation. Two controlled trials that studied aspirin anddipyridamole in patients who had scleroderma failed to show a benefit; however, manyclinicians recommend low-dose aspirin unless there is a contraindication.

Recent Developments1 Sildenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific

phosphodiesterase type V; its use leads to an increase in cGMP and thus it

25 Raynaud’s phenomenon 137


potentiates the effect of nitric oxide-mediated activation of guanylate cyclase. cGMPcauses a decrease in intracellular calcium, resulting in vascular smooth musclerelaxation and dilatation. Lichtenstein was the first to successfully use sildenafil forRaynaud’s phenomenon in a group of ten patients.5 Fries et al.6 reported a crossoverstudy of 16 patients with secondary Raynaud’s who had failed to respond to at leasttwo conventional vasodilatory agents. Active treatment was sildenafil 50 mg bd andthe frequency and duration of symptoms of Raynaud’s phenomenon decreasedsignificantly, leading to improved well-being of the patients. In this study, capillaryblood flow was severely impaired and sometimes hardly detectable, with sildenafilleading to a >400% increase in flow velocity. Despite its short half-life (four hours),the data on capillary flow and symptom control suggest a longer functional effect ofsildenafil. Further refinements in phosphodiesterase inhibition are on the horizon,with the longer-acting tadalafil (half-life 17 hours) having been used in a patient withsecondary Raynaud’s who was resistant to sildenafil.7

2 Cilostazol (100 mg bd) is a phosphodiesterase type III inhibitor that in a crossovertrial showed no change in symptoms and only a very modest increase in flow-mediated dilation of the brachial artery in patients with primary and scleroderma-related Raynaud’s.8

3 Bosentan is a non-selective endothelin A/B antagonist. In a trial of sclerodermapatients with digital ulcers, bosentan almost halved the development of new ulcerscompared to placebo during the four-month trial.9However, there was no benefit onhealing of existing ulcers, and self-assessed Raynaud’s severity was similar betweenactive and placebo therapy. In a case report of severe Raynaud’s phenomenon,beneficial effects of bosentan in healing of gangrenous digits were observed. Areduction of CD146 cells – a population of mainly endothelial cells – was noted,suggestive of reduced vascular injury. A concomitant increase in CD34 cells – whichare stem cells containing endothelial progenitors – suggested increased vascularrepair.10

ConclusionCold-induced vasospasm is common in the teenage years and for the majority of patientsdoes not require medical review. For those patients presenting to a doctor, it is helpful tohave a scheme to identify those at risk of developing a connective tissue disease. Themajor-ity of patients will fulfil the criteria for primary Raynaud’s phenomenon and require no fur-ther investigation. Avoidance of cold and emotional triggers is important, as oncevasospasm has occurred its resolution can be protracted and painful. A range of treatmentsis under investigation, although at this time the benefit:risk ratio is marginal for most.

Further Reading1 Herrick AL. Pathogenesis of Raynaud’s phenomenon. Rheumatology 2005; 44: 587–96.

2 Boin F, Wigley FM. Understanding, assessing and treating Raynaud’s phenomenon. Curr Opin

Rheumatol 2005; 17: 752–60.

3 Karavidas MK, Tsai P-S, Yucha C, McGrady A, Lehrer PM. Thermal biofeedback for primary

Raynaud’s phenomenon: a review of the literature. Appl Psychophysiol Biofeedback 2006; 31:203–16.



26 Assessing and treating scleroderma 139

26 Assessing and Treating Scleroderma

P R O B L E M

Case HistoryMary is 42 years old and presents with increasing stiffness of her hands. Since her mid-thirties she had noted painful blanching of her fingers in cold water or when handlingcold objects. Last winter she had ulcers on her fingertips and she had indigestion most ofthis year. She has bilateral sclerodactyly. Her blood pressure (BP) is 145/93 mmHg and sheis easily fatigued.

What clinical and laboratory features will assist you in the diagnosis?

What treatments should be used for scleroderma?

4 Thompson AE, Pope JE. Calcium channel blockers for primary Raynaud’s phenomenon: a

meta-analysis. Rheumatology 2005; 44: 145–50.

5 Lichtenstein JR. Use of sildenafil citrate in Raynaud’s phenomenon: comment on the article by

Thomson et al. Arthritis Rheum 2003; 48: 282–3.

6 Fries R, Shariat K, vonWilmowsky H, BöhmM. Sildenafil in the treatment of Raynaud’s

phenomenon resistant to vasodilatory therapy. Circulation 2005; 112: 2980–5.

7 Baumhaekel M, Scheffler P, BoehmM. Use of tadalafil in a patient with secondary Raynaud’s

phenomenon not responding to sildenafil.Microvasc Res 2005; 69: 178–9.

8 Rajagopalan S, Pfenninger D, Somers E et al. Effects of cilostazol in patients with Raynaud’s

syndrome. Am J Cardiol 2003; 92: 1310–15.

9 Korn JH, Mayes M, Matucci Cerinic M et al. Digital ulcers in systemic sclerosis: prevention by

treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 2004; 50:3985–93.

10 Dunne J, Dutz J, Shojania K, Ng B, van Eeden S. Treatment of severe Raynaud’s phenomenonwith bosentan in a patient with systemic sclerosis. Rheumatology 2006; 45: 911–12.



BackgroundScleroderma is a rare condition with a prevalence of approximately 1 in 5000, and anannual incidence of 1 in 50 000 to 1 in 300 000. Strictly, scleroderma denotes disease lim-ited to the skin and subcutaneous tissues (localized scleroderma, or morphea), and dis-ease involving the internal organs is systemic sclerosis (SSc). Morphea is characterized byfibrosis of the skin and adjacent structures. Morphea can be differentiated from SSc bythe distribution of lesions (no sclerodactyly or perioral involvement), absence ofRaynaud’s phenomenon and/or periungual telangiectasia.1

The generalized form of disease can be divided into limited cutaneous SSc/sclero-derma and diffuse cutaneous SSc/scleroderma; limited cutaneous disease does not extendbeyond the elbow and knee, although the face may be involved. In diffuse cutaneous dis-ease, the skin lesions involve the more proximal limb and trunk. Diffuse scleroderma ismore common in African-Americans, black patients in Africa and the Choctaw Indian.Genome-wide scanning has identified susceptibility loci on three different non-HLAchromosomes: fibrillin on chromosome 15, SPARC (secreted protein acidic and rich incysteine) on chromosome 5 and topoisomerase 1 on chromosome 20.The characteristics of diffuse and limited cutaneous scleroderma are presented in

Table 26.1. CREST is often but not always used as a synonym for limited cutaneous scle-roderma, and dates from the early 1960s. CREST patients have three or more of the fivesyndromic features:

� Calcinosis

� Raynaud’s phenomenon

� oEsophageal dysmotility

� Sclerodactyly

� Telangiectasia

CREST can be considered with limited cutaneous SSc. Wollheim proposed that thefive CREST components were not meant to serve as criteria of a special subset ofscleroderma, and features of CREST occur with time irrespective of other diseasecharacteristics.2


Diffuse cutaneous scleroderma Limited cutaneous scleroderma

History of Raynaud’s phenomenon with onset within one year Skin involvement restricted to hands, face, forearm, feetSkin sclerosis proximal to the elbow, andmay involve trunk Prominence of calcinosis and telangiectasiaTendon friction rubs may occur

Nailfold capillary dilation, aneurysm and dropout Nailfold capillary dilation, aneurysm and dropout

Early onset of pulmonary, renal and diffuse gastrointestinal Delayed but often severe pulmonary hypertensioninvolvement

Often anti-topoisomerase 1 antibodies (anti-Scl-70); rarely Anti-centromere antibodies common especially withanti-centromere antibodies calcinosis and telangiectasiaAnti-RNA polymerase III

Ten-year survival: 54%–62% Ten-year survival: 69%–89%

Table 26.1 Characteristics of diffuse and limited scleroderma


Ninety-five per cent of patients with scleroderma have a positive antinuclear antibody(ANA) test, but specific patterns are not reliably diagnostic. Both anti-centromere andanti-topoisomerase 1 (anti-Scl-70) have a low sensitivity, and a diagnosis of sclerodermais not excluded by a negative result. Anti-centromere antibodies favour a diagnosis oflimited cutaneous scleroderma. Anti-topoisomerase 1 antibodies are only 30% sensitive,but are highly specific for SSc and correlate with interstitial lung disease.The skin capillaries can be visualized at the nailfold using an ophthalmoscope or a der-

moscope, or in the research situation using video capture. A range of abnormalities havebeen described including dilatation and aneurysm formation, dropout, haemorrhageand budding. Three-quarters of scleroderma patients have abnormalities of their nailfoldcapillaries, and the presence of normal capillaries is the strongest negative predictor ofscleroderma in patients with Raynaud’s phenomenon. There appears to be no nailfoldcapillary difference between limited cutaneous and diffuse cutaneous scleroderma.The initial complaint of limited cutaneous scleroderma is Raynaud’s phenomenon,

whereas patients with diffuse cutaneous scleroderma often present with generalized handswelling, skin thickening or arthralgias with or without Raynaud’s phenomenon. Theymay initially complain of tight, puffy fingers that occurs in the morning but then lasts allday. This is the oedematous stage, with oedema usually non-pitting and painless. Thisusually progresses to a thickened, tight indurative stage over months to years, with theskin becoming shiny and adherent to the underlying subcutis. Dermal thickening andepidermal thinning lead to loss of dermal appendages, with hair loss and absent sweating.Mottled hyper- and hypopigmentation may be noted. Facial involvement may lead to apinched nose, tightened lips and a ‘mouse-like’ appearance. Finally, there is an atrophicstage in which the dermis softens and thins but remains firmly bound down to the subcu-taneous fat. With limited cutaneous scleroderma, clusters of dilated tortuous capillariesand venules are noted. Joint pain, immobility and contractures are the result of fibrosisaround tendons and other periarticular structures. Contractures of the hand are mostcommon, but large joint contractures may occur. Some patients have palpable and/oraudible deep tendon friction rubs due to fibrinous tenosynovitis.Skin ulcers are of two forms: digital tip ulcers secondary to ischaemia, and ulceration

over bony prominences where the skin is contracted and tight and susceptible to trauma.Reduced vascularity perpetuates poor healing. Both limited and late diffuse cutaneousscleroderma may develop calcinosis at areas of pressure such as the finger pads, olecra-non bursa, extensor surface of forearm, buttocks and around the patella.The gastrointestinal (GI) tract is the second most commonly affected organ, with

involvement in 75%–90% of cases. The hallmark effect is smoothmuscle fibrosis, leadingto dysmotility, with 80% of patients developing oesophageal dysfunction. Impaired gas-tric emptying and decreased lower oesophageal sphincter tone allow reflux with heart-burn and dysphagia. In the longer term, Barrett’s oesophagus and strictures may develop,and the risk of adenocarcinoma of the oesophagus is increased. Dysmotility occursthroughout the GI tract and can cause gastroparesis, small bowel bacterial overgrowthand malabsorption, pseudo-obstruction, severe constipation and megacolon.Pulmonary involvement occurs in more than 70% of cases and is the most common

cause of SSc-related death. Pulmonary fibrosis is common and can cause severe restrict-ive lung disease. Chest X-ray shows lower lobe interstitial thickening in a reticular–nodular pattern. High-resolution computed tomography (HRCT) may show ground-glass



appearance, representing alveolitis, or fibrotic honeycombing with traction bronchiecta-sis. Pulmonary function testing can serially document changes in lung volumes withrestriction and increasing impairment of gas transfer. Readily detected by right heartcatheterization and echocardiograph, pulmonary artery hypertension (PAH) occurs in20%–40% of patients with SSc. The five-year cumulative survival is 10% in those withPAH compared with 80% in those without. PAH can develop early, particularly in limit-ed cutaneous SSc, and can occur without pulmonary fibrosis. In diffuse cutaneous SSc,development of pulmonary fibrosis may lead to secondary PAH. The patient developsdyspnoea disproportionate to any lung findings, and may have accentuation of the pul-monary component of the second heart sound. A clue to PAH is disproportionate reduc-tion in the carbon monoxide diffusion capacity relative to the forced vital capacity(FVC).Renal disease occurs almost only in those with diffuse cutaneous disease. Scleroderma

renal crisis, which could result in rapid death or dialysis, is essentially a thing of the pastdue to the use of angiotensin-converting enzyme (ACE) inhibitors. The crisis occursmost often in patients with early diffuse cutaneous SSc in the context of rapid skin pro-gression. It is characterized by accelerated hypertension presenting as headache, short-ness of breath, seizures, retinal haemorrhage, left heart failure and renal failure.

PrognosisItalian and French-Canadian studies report increasing mortality with increasing skininvolvement using a diffuse, intermediate and limited classification. A five-year studyfrom the United Kingdom (UK) identified advanced age, diffuse cutaneous disease, high-er skin score, elevated erythrocyte sedimentation rate (ESR) and signs of organ involve-ment as poor prognostic factors in univariate analysis. However, logistic regressionanalysis identified proteinuria, elevated ESR and reduced carbon monoxide diffusioncapacity as the most important factors.3,4 PAH has a devastating impact on survival andoutcome, because the progressive elevation of pulmonary artery pressure leads to rightventricular failure, arrhythmias and death. The mean survival of untreated patients withprimary PAH is 2.8 years from diagnosis. In untreated and treated patients with SSc-associated PAH, mean survival is less than one year in those with severe disease.Several manifestations are associated with specific antibodies: interstitial lung disease

with anti-topoisomerase 1 (Scl-70), and anti-centromere antibodies with digital necrosisand delayed pulmonary hypertension independent of pulmonary fibrosis. Anti-RNApolymerase III antibodies in limited cutaneous scleroderma correlate with severe skinand renal involvement. U3-RNP antibodies, including fibrillarin, occur in both limitedand diffuse disease and correlate with pulmonary hypertension, cardiac involvement andmyositis. In a multicentre study of 1012 Italian patients, ten-year actuarial survival was72% in patients with and 81% in those without anti-centromere antibody, and 73% inpatients with ANA.5Overall, ANA is of limited help in predicting prognosis.

Pathophysiology and treatmentThree abnormalities have been identified:

1 Fibroblast dysfunction leading to increased production and deposition of extracellu-lar matrix, particularly collagen



2 Vascular abnormality leading to tissue hypoxia

3 An immune response manifest as altered T- and B-lymphocyte function and produc-tion of autoantibodies

Endothelial damage and vascular dysfunction occur early, with activated lymphocytessecreting transforming growth factor-b (TGF-b) causing endothelial injury and upregu-lation of the major histocompatibility complex, adhesion molecules and connective tis-sue growth factor (CTGF). TGF-b maintains fibroblasts in an activated state, promotescollagen and matrix protein production and decreases synthesis of collagen-degradingmatrix metalloproteinases. CTGF is an important growth factor in fibrosis, triggeringangiogenesis and the structural organization of connective tissue. Endothelial damageresults in the increased production of endothelin (ET)-1 and impaired prostacyclinrelease, resulting in imbalance between vasodilators and vasoconstrictors. ET combinedwith platelet-derived factors changes the vascular smooth muscle cell into a myofibro-blast, with proliferation of these narrowing the vessel lumen. Later in the disease processthe inflammatory vasculopathy subsides and fibrosis dominates, with skin thickening,interstitial lung fibrosis, and GI and renal disease.

Skin: The natural history of skin involvement is quite variable, with striking improve-ment occurring without intervention. Cyclophosphamide, mycophenolate mofetil andmethotrexate are all used, but only methotrexate has shown a statistical benefit in con-trolled trials.

Kidney: Renal crises are treated with ACE inhibitors titrated to achieve a systolic BPreduction of 10–20 mmHg over 24 hours. Continuous low-dose prostacyclin improvesBP control and renal blood flow. Creatinine clearance is monitored and ACE inhibitorsmaintained even during dialysis. There is a prolonged period of potential renal recovery.Refractory hypertension may require calcium channel blockers or a-adrenergic blockers.

Pulmonary fibrosis: The greatest evidence of efficacy is available for cyclophos-phamide. Recent trials include:

1 A UK study of 45 SSc patients who received low-dose prednisolone and six infusionsof cyclophosphamide monthly, followed by oral azathioprine or placebo. At one yearthis did not demonstrate improvement in the primary endpoints (FVC and diffusingcapacity for carbon monoxide [DLCO]) or secondary endpoints (HRCT appearanceand dyspnoea scores).6

2 A United States study of 158 SSc patients with interstitial lung disease who receivedoral cyclophosphamide (≤2 mg/kg/day) or placebo for one year and were followedfor one additional year.7 The mean difference in FVC at 12 months was 2.5% favour-ing cyclophosphamide, which was maintained at 24 months. The clinical benefit wasmodest, aiding skin scores, dyspnoea and health-related quality of life.

Pulmonary hypertension: Early diagnosis is essential to optimize outcome. Mortalityand morbidity of PAH has been improved by the use of long-term oxygen therapy,diuretics and digoxin for symptom relief, and anticoagulation. Intravenous prostacyclinleads to a rapid improvement in cardiac output, exercise capacity and survival but isexpensive and associated with adverse effects.

Gastrointestinal: Oesophageal dysmotility occurs in the majority and requires regularuse of proton pump inhibitors, sometimes with prokinetic agents. Monitoring for



Barrett’s oesophagus is indicated. Broad-spectrum antibiotic and prokinetic agents mayaid midgut disease. Stool frequency can be improved with frequent, small, low-fibremeals, with alternating aperients and antidiarrhoeals.

Recent Developments1 ET is a key mediator in the pathology of PAH and also SSc, participating in

fibrotic, hypertrophic and inflammatory processes. The oral dual ET-A/ET-Breceptor antagonist bosentan has proven benefit in patients with severe PAH. In asix-month open-label prospective study, eight patients with PAH and pulmonaryfibrosis related to SSc received bosentan 62.5 mg bd for four weeks followed bymaintenance dosing of 125 mg daily.8 Mean six-minute walking distanceincreased from 72 m at baseline to 192 m after three months, and to 203 m aftersix months. Six of eight patients responded with improvement in functional class.

2 The two pivotal trials of bosentan included 52 patients with SSc and other connectivetissue diseases. During a four-month trial, mean treatment effect on six-minutewalking distance was 37 m. In the long-term extension, survival was 82% after oneyear and 67% after two years.9 Bosentan has also been used in connective tissuedisease patients with PAH who were non-responsive to prostanoid therapy.10

Thirteen patients (primarily with SSc) were treated for one year. A progressiveimprovement in exercise capacity was noted, with half improving their six-minutewalking distance.

3 Scleroderma/SSc and chronic graft-versus-host disease (GVHD) resemble eachother in tissue distribution (skin, lung, oesophagus), lymphocytic infiltration inaffected tissues and tissue fibrosis. It has also been suggested that SSc may be aform of GVHD.11 GVHD occurs when foreign immunocompetent cells in graftedor transfused tissue react with the recipient’s cell-surface antigens. To induceGVHD, the graft must contain immunocompetent cells, the host must appearforeign to these cells and the host must be incapable of mounting an effectiveresponse and destroying them. The hypothesis of microchimaerism underlying SScwas postulated in 1989. As an aetiological factor, microchimaeric cells could befrom previous pregnancies, or from maternal origin in the case of nulliparouswomen or male patients. The mere presence of these cells in peripheral blood istherefore not sufficient to cause SSc and a second, unknown activation step ispostulated. Microchimaeric cells are absent from the skin of normal subjects, andare present in higher numbers in the normal skin of SSc subjects compared withinvolved skin.12

4 Statins have more widespread effects than just lowering cholesterol (Figure 26.1).There appear to be substantial differences amongst the statins as to their impact onthese alternate pathways.13 The potential of this approach has been trialled in anopen-label study of atorvastatin 10 mg/day for twelve weeks.14 Raynaud’sphenomenon improved, indicated by reduced subjective scoring. A two- to eight-fold increase in circulating endothelial precursors was noted, although not to normallevels. A reduction in the angiogenic factors vascular endothelial growth factor andbasic fibroblast growth factor was observed.




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26.1

Beneficialeffectsofstatinsinscleroderma.CEP,circulatingendothelialprecursors;eNOS,endothelialnitricoxidesynthase;HMG-CoA,3-hydroxy-3-

methylglutarylcoenzymeA;LDL,low-densitylipoprotein;PP,pyrophosphate;ROS,reactiveoxygenspecies;TGF-

b,transforminggrowthfactor-b;VEGF,vascular

endothelialgrowthfactor.



ConclusionScleroderma is a rare disease of unknown cause, which is diagnosed essentially on clinicalgrounds. To date, most interventions have been of little clinical utility, except protonpump inhibitors for reflux disease and ACE inhibitors for renal crisis. The challenges forthe future are in the early diagnosis of and effective intervention for pulmonary fibrosisand pulmonary hypertension. Use of ET receptor antagonists has shown it is possible tointervene with an oral medication, but the gains in either morbidity or mortality aremodest. A holistic approach is required, which includes a broad treatment strategy aimedat reducing vascular complications of this disorder.

Further Reading1 Chung L, Lin J, Furst DE, Fiorentino D. Systemic and localized scleroderma. Clin Dermatol

2006; 24: 374–92.

2 Wollheim FA. Classification of systemic sclerosis. Visions and reality. Rheumatology 2005; 44:1212–16.

3 Bryan C, Knight C, Black CM, Silman AJ. Prediction of five-year survival following

presentation with scleroderma: development of a simple model using three disease factors at

first visit. Arthritis Rheum 1999; 42: 2660–5.

4 Meyer O. Prognostic markers for systemic sclerosis. Joint Bone Spine 2006; 73: 490–4.

5 Ferri C, Valentini G, Cozzi F et al. Systemic sclerosis: demographic, clinical, and serologic fea-

tures and survival in 1,012 Italian patients.Medicine 2002; 81: 139–53.

6 Hoyles RK, Ellis RW,Wellsbury J et al. A multicentre, prospective, randomized, double-blind,

placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by

oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum

2006; 54: 3962–70.

7 Tashkin DP, Elashoff R, Clements PJ et al. Cyclophosphamide versus placebo in scleroderma

lung disease.N Engl J Med 2006; 354: 2655–66.

8 Ahmadi-Simab K, Hellmich B, Gross WL. Bosentan for severe pulmonary arterial

hypertension related to systemic sclerosis with interstitial lung disease. Eur J Clin Invest 2006;

36 (Suppl 3): 44–8.

9 Denton C, Humbert M, Rubin L, Coghlan J, Black C. Dual endothelin receptor antagonism in

pulmonary arterial hypertension related to systemic sclerosis. Eur J Clin Invest 2005; 35 : I72.

10 Cozzi F, Montisci R, Marotta H et al. Bosentan therapy of pulmonary arterial hypertension in

connective tissue disease. Eur J Clin Invest 2006; 36 (Suppl 3): 49–53.

11 Jimenez SA, Artlett CM. Mirochimerism and systemic sclerosis. Curr Opin Rheumatol 2005;

17: 86–90.

12 Sawaya HHB, Jimenez SA, Artlett CM. Quantification of fetal microchimeric cells in clinicallyaffected and unaffected skin of patients with systemic sclerosis. Rheumatology 2004; 43: 965–8.

13 KuwanaM. Potential benefits of statins for vascular disease in systemic sclerosis. Curr Opin

Rheumatol 2006; 18: 594–600.


14 KuwanaM, Kaburaki J, Okazaki Y, Yasuoka H, Kawakami Y, Ikeda Y. Increases in circulatingendothelial precursors by atorvastatin in patients with systemic sclerosis. Arthritis Rheum

2006; 54: 1946–51.

27 Immunosuppressive drugs 147

27 Immunosuppressive Drugs

P R O B L E M

Case HistoryMrs TJ is 55 years old and developed sicca syndrome after the menopause at age 51 years.Her serum is positive for antinuclear antibody (ANA), anti-Ro and anti-La. She hassymptoms of general malaise, arthralgia andmyalgia, and a recent chest X-ray suggeststhat she is developing pulmonary infiltrates. Inflammatory markers (erythrocytesedimentation rate and serum C-reactive protein) are elevated. She has been takingprednisolone for the past six months but this has only partly relieved her symptoms.

What factors influence the choice of immunosuppressive agent?

How should she be monitored?

Is immunosuppression becoming safer and more effective?

BackgroundImmunosuppressive treatment is a large part of rheumatological practice. It is the cor-nerstone for many of the immune-mediated connective tissue disorders includingrheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis, vas-culitides and Sjögren’s syndrome. Because of the widespread use of immunosuppressiveagents, the generalist and the general practitioner should understand current usage ofthese drugs and how they are monitored.

GlucocorticoidsThese bind to glucocorticoid response elements in the genome, thus regulating activity ofa broad range of genes. They downregulate expression of pro-inflammatory cytokinesincluding interleukin (IL)-1 and IL-6. Decreased IL-2 production from T cells is associ-ated with decreased lymphocyte proliferation. Cytotoxic and phagocytic cells areinhibited. Increased activity of the inhibitor of k-beta (Ikb) decreases activity of the key



regulatory pathway involving nuclear factor-k-beta (NF-kb) with consequent down-regulation of components of the immune response and increased lymphocyte apoptosis.Between 1 in 400 and 1 in 200 of the population (higher in the elderly) is taking chron-

ic steroid medication, usually prednisolone. One of the major indications for use of otherimmunosuppressive drugs is to minimize exposure to steroids and to protect the patientfrom long-term side effects. The latter include hypertension, hyperglycaemia, osteo-penia, cataracts, gastric ulceration, impaired wound healing and susceptibility toinfection. Topical agents (inhaled, rectal or skin) should be used where possible.

Antiproliferative and antimetabolic drugsAzathioprine (Imuran) is a purine derivative that has been used as an antimetabolitesince the early 1960s. It is used in transplant patients and in treatment of RA. Side effectsinclude bone marrow suppression, susceptibility to infections (especially varicella andherpes simplex viruses), hepatotoxicity, alopecia and increased risk of malignancies.Methotrexate is used for psoriasis and RA as well as in treatment of malignancies. It

inhibits dihydrofolate reductase, therefore decreasing purine synthesis and progressionthrough the G1 and S phases of the cell cycle. This may explain its cytotoxic effects, withits anti-inflammatory effects related to increasing adenosine levels. Side effects includebone marrow suppression, interstitial pneumonitis and increased liver enzymes withoccasionally more severe hepatic impairment. A full blood count (FBC) and liver func-tion tests (LFTs) should be monitored monthly and adequate contraception used.Cyclophosphamide is used particularly in SLE and in vasculitic conditions including

Wegener’s granulomatosis. Side effects include leukopenia, haemorrhagic cystitis andincreased risk of transitional cell carcinoma, infertility, alopecia and increased risk oflymphoma.Leflunomide is used in active RA, particularly in those unresponsive to methotrexate,

for whom leflunomide can be used alone or in combination with methotrexate. Sideeffects are diarrhoea, alopecia, severe skin reactions, pneumonitis, hypertension and neu-rological toxicity. FBC and LFTs should be monitored monthly for the first six monthsand then two-monthly. Blood pressure should be monitored. Adequate contraception isessential, with leflunomide having a long practical half-life due to enterohepaticcirculation.Mycophenolate mofetil is hydrolysed to mycophenolic acid in the body, and inhibits

T- and B-cell proliferation through its inhibitory effect on the enzyme inosinemonophosphate dehydrogenase (IMPDH). It may cause bone marrow suppression,pneumonitis and severe diarrhoea.Sirolimus (Rapamune) binds to the 12 kDa FK506-binding protein (FKBP-12) and

inhibits the protein kinase mammalian target of rapamycin (MTOR), a key protein incellular proliferation. The drug is mainly used in transplant patients and in drug-elutingstents for patients with coronary artery disease.

Calcineurin inhibitorsCalcineurin is a Ca2+/calmodulin-dependent protein phosphatase involved in T-cell dif-ferentiation and proliferation. The enzyme catalyses dephosphorylation of the nuclearfactor of activated T lymphocytes (NFAT), which is subsequently translocated to thenucleus and increases expression of pro-inflammatory cytokines including IL-2.



Cyclosporin (by interacting with cyclophilin) and tacrolimus (by interacting with FKBP-12) inhibit the phosphatase activity of calcineurin.Cyclosporin is a cyclic peptide of eleven amino acids, which is secreted by the fungus

Beauveria nivea. Its predominant effect is inhibiting T-cell responses. It can be givenintravenously (Sandimmune) or orally (Neoral). Its main uses are in transplant, RA andpsoriasis. For transplant patients, it is usually combined with steroids and either azathio-prine or mycophenolate mofetil. In RA, it is usually reserved for patients who do notrespond to first- or second-line disease-modifying antirheumatic drugs (DMARDs)including methotrexate. With the introduction of anti-tumour necrosis factor (anti-TNF) agents, cyclosporin is being used less. Nephrotoxicity is the most common severeside effect. The drug may also worsen hypertension, hyperglycaemia and hyperuri-caemia. Side effects also include tremor, hirsutism and gum hyperplasia. Monitoring tokeep the plasma concentration of the drug in the range 50–100 ng/ml should be under-taken.Tacrolimus (Prograf) is a macrolide antibiotic secreted by Streptomyces tsukubaensis.

It can be given orally or systemically, and is mainly used for transplant patients.Nephrotoxicity and neurotoxicity are relatively common with its use.

Antibody treatmentsLymphocyte immune globulin and antithymocyte globulin have been used in immuno-suppression since the 1960s. To avoid the potential problems of using polyclonal sera,monoclonal or monospecific antibody treatments have been developed. These include:

Anti-CD3 Directed at the e chain of the T-cell receptor

Anti-CD25 Daclizumab and basiliximab, directed at the IL-2 receptor

Anti-CD52 Alemtuzumab

Anti-TNF-a Infliximab, etanercept, used in refractory RA

Anti-lymphocyte function-associated antigen-1 (anti-LFA-1) Efalizumab

Anti-CD20 Rituximab, B-cell depleting antibody

Other drugsHydroxychloroquine (Plaquenil, 200–400 mg/day) is an antimalarial drug used in RAand SLE. It may be particularly useful for skin lesions in the latter. It is usually well toler-ated but can cause macular damage. Patients should have an ophthalmological assess-ment at baseline and six-monthly.Sulphasalazine is used in RA and in seronegative spondyloarthropathies. It may cause

gastrointestinal symptoms, headache, rash (including photosensitivity) and discolour-ation of soft contact lenses. Because of potential bone marrow toxicity, a FBC should bemeasured every two weeks for the first three months, then three-monthly. LFTs shouldbe monitored monthly for the first three months then six-monthly.Use of immunosuppressive drugs has transformed management of many non-

malignant diseases. They should only be used where they are clearly indicated (Box 27.1)and with an appropriate programme of drug monitoring. An algorithm for monitoringof the most commonly prescribed drugs is presented in Figure 27.1. Increasingly with



newer drugs – including cyclosporine, mycophenolate mofetil, sirolimus and tacrolimus– therapeutic monitoring of drug levels is being undertaken.1

Recent Developments1 The field of pharmacogenomics is developing rapidly. Expression of levels of key

enzymes varies considerably between individuals, and this may explain why somepatients fail to respond to drugs while others are very sensitive and more susceptibleto side effects. Levels of thiopurine methyltransferase may be useful in predictingresponse to azathioprine.2 Those with high levels of the enzyme are at risk of beingunderdosed, and patients with low enzyme levels may be more susceptible to sideeffects including bone marrow suppression. In a similar fashion, variations in theexpression of methylene tetrahydrofolate reductase may be important determinantsof the response to methotrexate.3

2 It is not clear whether elderly onset RA behaves differently from that which has anearlier onset. In the recent study by Tutuncu et al.,4 elderly patients with RA hadcomparable duration and comparable indices of severity compared with youngerpatients. They were, however, less likely to receive as aggressive treatment; this maybe partly due to under-recognition of the severity of the disease – particularly if thereare comorbidities – or to concern about potential side effects.

3 Much of the stimulus for development and clinical trials with newer agents has comefrom the transplant field. Examples of the way practice is changing are the increasinguse of mycophenolate mofetil for lupus nephritis5 (where previouslycyclophosphamide was the drug of choice) and the increasing use of cyclosporin forautoimmune diseases.6 Renal toxicity may limit the use of this drug by rheumatologistsbut it certainly may prove very useful in life-threatening situations where other drugshave failed. Amongst biological therapies, the TNF-a antagonists have found thewidest use in RA. Themaximum effect of biological therapies in RA is likely to be seenwhen they are combined with cytotoxic treatments such as methotrexate.7

ConclusionThe range of immunosuppressive drugs is increasing, as is trial evidence relating totheir use in individual diseases. The choice of agents depends on the clinical picture


Box 27.1 Use of immunosuppressive drugs

� Underlying diagnosis well established� Less toxic alternatives have failed� The disease poses a severe threat to health� Patient is informed of the risks and benefits� Infection andmalignancy excluded� Nopossibility that the patient will become pregnant� Arrangements formonitoring and treating complications in place


and diagnosis, along with an assessment of the likely benefits and potential risks.Corticosteroids are often used in the first instance but the tendency now is to uselower doses, and thus they are often combined with other drugs. Methotrexate, aza-thioprine and cyclophosphamide have been used for many years but still have a majorplace in management. Monitoring of FBC, hepatic function and renal function is themost important aspect generally. Use of newer drugs and biological agents is increas-ing, although this is still limited by cost and clinical experience. With appropriatemonitoring and choice of regimens, the treatment of autoimmune connective tissuedisease with agents that suppress the immune system is becoming safer and moreeffective.

Further Reading1 Holt DW, Armstrong VW, Griesmacher A, Morris RG, Napoli KL, Shaw LM. International

Federation of Clinical Chemistry/International Association of Therapeutic Drug Monitoring


Baseline FBC, LFTs, U/E and CXR

FBC

Weekly – C*, A, M

Monthly – M

3-monthly – A

? StopWBC ,1.5 3 109/lPl ,100 3 109/l

LFTs

2-weekly – C, A, M

Monthly – C*, A, M

3-monthly – A, M

? StopTransaminases3 3 upper limit

of normal

U/E

Weekly – C, A, M

Monthly – C*, A, M

2-monthly – A, M

? StopCreatinine

>30% abovebaseline

Figure 27.1 Therapeutic monitoring of common immunosuppressives. Lowwhite blood cell (WBC) count,increased liver enzymes or increasing creatinine may necessitate temporarily or permanently stopping thetreatment – a decision best made by the specialist responsible for starting it. * monitor at this frequency forthe duration of treatment; A, azathioprine; C, cyclophosphamide; CXR, chest X-ray; FBC, full blood count;LFT, liver function text; M, methotrexate; Pl, platelet; U/E, urea and electrolytes.


and Clinical Toxicology working group on immunosuppressive drug monitoring. Ther Drug

Monit 2002; 24: 59–67.

2 Patel AA, Swerlick RA, McCall CO. Azathioprine in dermatology: the past, the present, and

the future. J Am Acad Dermatol 2006; 55: 369–89.

3 Hughes LB, Beasley TM, Patel H et al. Racial or ethnic differences in allele frequencies of sin-

gle-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their

influence on response to methotrexate in rheumatoid arthritis. Ann Rheum Dis 2006; 65:1213–18.

4 Tutuncu Z, Reed G, Kremer J, Kavanaugh A. Do patients with older-onset rheumatoid

arthritis receive less aggressive treatment? Ann Rheum Dis 2006; 65: 1226–9.

5 Dooley MA. Mycophenolate mofetil: what role in the treatment of lupus? Lupus 2006; 15:179–82.

6 Ponticelli C. Cyclosporine: from renal transplantation to autoimmune diseases. Ann N Y Acad

Sci 2005; 1051: 551–8.

7 Heiberg MS, Rødevand E, Mikkelsen K et al. Adalimumab and methotrexate is more effective

than adalimumab alone in patients with established rheumatoid arthritis: results from a

6-month longitudinal, observational, multicentre study. Ann Rheum Dis 2006; 65: 1379–83.



28 Vasculitic Disease

Vasculitic Syndromes

S E C T I O N F I V E 05

28 Vasculitic disease29 Giant cell arteritis and polymyalgia rheumatica30 Behçet’s syndrome

P R O B L E M

Case HistoryMrs SR attends your clinic with a rash over her legs. She is aged 32 years and for the lastsix months has been unwell, with intermittent fevers, loss of appetite and fatigue. Recentblood tests show elevated erythrocyte sedimentation rate (ESR; 83 mm/h) and C-reactiveprotein (CRP; 46 mg/dl). Today she has palpable purpura on her lower legs. Urinalysis ispositive for blood and protein.

What are the clinical clues to vasculitis?

What investigations will assist with a precise diagnosis?

How should the condition be treated and monitored?

BackgroundThe vasculitides are an important group of disorders in which an immune reactionaffects the walls of the blood vessels.1,2 The immune dysfunction may be triggered bydrugs or by an underlying autoimmune disease, but often an underlying cause is notidentified. Manifestations vary between diseases and from person to person. The follow-ing are common: general malaise, arthralgia, normocytic anaemia, skin lesions (palpablepurpura or necrotic ulcers), renal dysfunction and neurological dysfunction (particularlywrist drop and ankle drop). Differential diagnosis includes drug reactions (antibiotics,amphetamines, ergot derivatives), infections (human immunodeficiency virus [HIV],



subacute bacterial endocarditis), malignant disease and antiphospholipid syndrome.Classification of vasculitides, shown in Box 28.1, is based on the size of blood vesselsaffected.Individually, the diagnoses, with the exception of giant cell arteritis (GCA), are rela-

tively rare. Collectively (excepting GCA), there is an incidence of 20–40 per million of thepopulation per year. There is considerable geographical variation and also a seasonalvariation in incidence. The latter suggests an infectious trigger and exposure toMycoplasma pneumoniae has been linked with risk of GCA. The latter is more commonin Caucasians than all the other diagnoses put together (around 170 per million of thepopulation per year). Cutaneous vasculitis may occur in isolation or as part of an under-lying systemic disorder.3 In each case of suspected vasculitis, a careful search for multi-organ involvement should be undertaken.

Small vessel vasculitisThe vessels involved are the venules, capillaries and arterioles of the skin, kidney and gas-trointestinal (GI) tract. The hallmark lesion is palpable purpura, which is a slightly raised,non-blanching lesion that typically affects the lower legs. Gut involvement causes colickyabdominal pain and may lead to melaena.Henoch–Schönlein purpura is common in children after viral or streptococcal infec-

tion. The blood vessels are affected by immunoglobulin A (IgA)-containing immunecomplex deposition. Apart from the purpura, abdominal pain and arthralgia, renalinvolvement develops in up to 40%, with progression to chronic nephritis in 10% ofcases. The condition is generally self-limiting and immunosuppressive treatment is notusually required.Cryoglobulins are antigen–antibody complexes that precipitate in the cold. In add-

ition to the other common manifestations of small vessel vasculitis, they may be associ-ated with serious liver and pulmonary disease. Cryoglobulinaemia occurs in one-third ofpatients with hepatitis C infection. Cryoglobulins should be sought in all patients with aclinical picture of small vessel vasculitis, and all positive patients should be tested forhepatitis C.

Small to medium vessel vasculitisThese diseases generally affect the skin, upper respiratory tract, lungs and kidneys.Wegener’s granulomatosis often begins with apparently innocent symptoms including

§05 Vasculitic Syndromes154

Box 28.1 Classification of vasculitis

Small vessels Medium vessels� Henoch–Schönlein purpura � Polyarteritis nodosa� Mixed cryoglobulinaemia � Kawasaki syndrome

Small tomedium vessels Large vessels� Wegener’s granulomatosis � Giant cell arteritis� Churg–Strauss syndrome � Takayasu’s arteritis� Microscopic polyangiitis


sinusitis, nasal ulcers, otitis media and hearing loss (70% of cases). Pulmonary infiltratesor nodules develop in 85% of cases, and 80% of patients have renal involvement with afocal necrotizing glomerulonephritis that frequently progresses to renal failure.Histologically, there is necrotizing vasculitis of medium-sized vessels with extravasculargranulomata. Cytoplasmic anti-neutrophil cytoplasmic antibody (c-ANCA) is present in80% of patients and perinuclear ANCA (p-ANCA) in 20%, with at least 90% of patientsoverall being ANCA positive. The disease is usually treated with prednisolone andcyclophosphamide.Microscopic polyangiitis is a variant of polyarteritis where patients present with pul-

monary haemorrhage and glomerulonephritis. Churg–Strauss syndrome presents withallergic rhinitis and asthma. Eosinophilia, and infiltrates of the lungs and GI tractaccount for the features of the disease. Up to 75% of patients have palpable purpura orskin nodules. It affects the kidneys in up to 50% of cases. Immunosuppressives are fre-quently required.

Medium vessel vasculitisPatients with polyarteritis nodosa typically present with fever, myalgia and arthralgia.Renal disease develops in up to 60% of cases, with cardiac and GI involvement in 40%(may lead to bowel infarction), and central or peripheral nervous system involvement in20%. Angiography reveals multiple microaneurysms of vessels, with beading and taper-ing of the vessel lumen. Biopsy of affected tissues reveals focal necrosis of vessel walls.p-ANCA is positive in 20% of cases and c-ANCA in 10%. The disease is associated withhepatitis B and carries a worse prognosis in this circumstance. Treatment is with pred-nisolone and cytotoxic agents, with plasma exchange used for extreme cases. Vidarabineand interferon are useful where there is concurrent hepatitis B infection.Kawasaki syndrome typically affects children presenting with fever, conjunctival

infection, red tongue, arthralgia and lymphadenopathy. Fatal coronary arteritis candevelop if the syndrome is untreated. Aspirin and intravenous immunoglobulin is themainstay of treatment.

Large vessel vasculitisGCA almost exclusively occurs in patients over the age of 50 years and is frequentlyaccompanied by polymyalgia rheumatica. Visual loss may arise from central retinalartery occlusion, anterior ischaemic optic retinitis or occipital cortex infarction.Claudication or ischaemia of the tongue is a frequently overlooked but fairly commonsymptom. Temporal artery biopsy should be carried out where possible and will reveallymphocytic and giant cell infiltration with fragmentation of the internal elastic lamina.Treatment with prednisolone usually suffices, with doses tailored according to the ESR.Occasionally, other immunosuppressive agents are required.Takayasu’s arteritis (pulseless disease) usually affects young women who present with

fever, arthralgia and myalgia and have high ESR. Treatment is with prednisolone andother immunosuppressive agents. Transluminal angioplasty or other mechanical revas-cularization may be required where there is risk of infarction.Patient demographics and the pattern of organ involvement provide clues to the

underlying diagnosis (Figure 28.1). A full blood count will often show a normocytic

28 Vasculitic disease 155


anaemia, particularly where there is systemic disease. Urea and creatinine should be care-fully monitored in all cases so that renal involvement can be identified early. ESR andCRP will almost invariably be elevated and are useful to monitor disease activity andresponse to treatment. Liver tests should be monitored, not only because of potentialhepatic involvement in vasculitis, but also because of potential side effects of treatment.Detection of antinuclear antibody and rheumatoid factor (RF) may indicate the presenceof an underlying connective tissue disorder. Apart from rheumatoid disease, RF may alsobe positive in patients with Sjögren’s syndrome, and is more likely to be positive inpatients with hepatitis B infection. Patients with both vasculitis and antiphospholipidantibodies are recognized. Anti-neutrophil cytoplasmic antibodies (ANCA) are morespecific markers for certain vasculitic disorders (Table 28.1). c-ANCA are antibodies pri-marily directed at the enzyme proteinase-3. The perinuclear pattern (p-ANCA) is much


Child: (Any – HSP; Asian – Kawasaki)

Young adult: (Middle Eastern – Behçet’s; Asian – Takayasu’s)

Elderly: (GCA – mainly Caucasian)

Palpable purpura: Small- to medium-sized vessels involved

Ulcers or ischaemia: PAN, CSS, Wegener’s

Pain 1 stiffness: GCA

Swollen/inflamed: PAN, CSS, Wegener’s

PAN, CSS, Wegener’s, cryoglobulinaemia

Ischaemia: PAN, Takayasu’s

Glomerulonephritis: MPA, Wegener’s, cryoglobulinaemia, CSS, HSP

Renal

Demographics

Skin

Muscle

Joints

Neuropathy

Figure 28.1 Clinical pointers as to underlying disease state. The pattern and nature of organ involvementgive clues as to the likely underlying diagnosis. CSS, Churg–Strauss syndrome; GCA, giant cell arteritis; HSP,Henoch–Schönlein purpura; MPA, microscopic polyangiitis; PAN, polyarteritis nodosa.


less disease specific, and antibodies are directed at a number of determinants includingmyeloperoxidase, lactoferrin, elastase, cathepsin G and lysozyme. c-ANCA is also posi-tive in many patients with crescentic or necrotizing glomerulonephritis. ANCA (pre-dominantly p-ANCA) is positive in a proportion of patients with antiglomerularbasement membrane disease, inflammatory bowel disease, autoimmune hepatitis, scler-osing cholangitis and Felty syndrome. ANCA has traditionally been detected by indirectimmunofluorescence techniques but modern enzyme-linked immunosorbent assays(ELISAs) with specific antigens provide a more sensitive test. Cryoglobulins should besought. Patients should be screened for hepatitis B and C, as well as HIV. Low levels of thecomplement components C3 and C4 are consistent with systemic lupus erythematosus,and may be increased in other inflammatory conditions. Chest X-ray will reveal the pres-ence of pulmonary nodules or infiltrates. Biopsy of affected tissue may be required.Punch biopsy is suitable for most skin lesions, but excision biopsy is required where largevessel vasculitis is suspected. The characteristic change of leukocytoclastic angiitis is seenin small to medium vessel disease.Treatment depends on the diagnosis and severity of the disease. Simple measures for

skin lesions include avoiding contact with lesions (loose clothing, bedding etc.), elevatingthe affected part, analgesia and non-steroidal anti-inflammatory drugs. The mainstay isimmunosuppression, usually initially with high-dose steroids with the later addition ofother immunosuppressive agents including cyclophosphamide, azathioprine andmethotrexate. Cyclosporine and mycophenolate mofetil may be used in more seriouscases, while plasmapheresis and intravenous immunoglobulinmay also be useful in resist-ant cases. Induction and maintenance phases of treatment require different approaches.For some patients, colchicine or dapsone are useful to maintain remission. Finally, bio-logical therapies may be required for the most serious cases.4 These include the anti-CD20 (anti-B cell) antibody rituximab, and the anti–tumour necrosis factor (TNF)-aagents: infliximab, adalimumab and etanercept.

Recent Developments1 Recent evidence5 suggests that ANCA antibodies are directly involved in thevasculitic disease process. Their action helps promote neutrophil activation andadhesion, facilitating interaction with cytokine-primed vascular endothelium. Theymay arise frommolecular complementarity – the antibodies being directed againstpeptides encoded by the antisense strands of key epitopes. This phenomenon has

28 Vasculitic disease 157

Proteinase-3 (c-ANCA) Myeloperoxidase (p-ANCA)

Wegener’s granulomatosis 80% 10%

Microscopic polyangiitis 30% 60%

Churg–Strauss syndrome 30% 30%

Figures show percentage of cases with each condition that has the ANCA subtype.

Table 28.1 Major diseases associated with ANCA


been invoked to explain the relationship between ANCA positivity and exposure toinfectious agents. Possible genetic determinants of ANCA-positive vasculiticsyndromes have also been identified: these include increased carrier frequency of theZ allele of a1-antitrypsin (SERPINA1) and certain alleles of Fc receptors.Environmental triggers include exposure to silica, solvents, asbestos and pesticides.Drug triggers include the antithyroid drugs propylthiouracil and carbimazole,phenytoin, cocaine and allopurinol.

2 Data to support the use of the antibody therapies (rituximab, infliximab andetanercept) in vasculitic conditions, particularly Wegener’s granulomatosis, areaccumulating.6 The role of TNF-a in many of these disease processes means thatinfliximab and etanercept may find broader usage. Even in GCA, which is generallyvery responsive to steroids, biological therapies may find a use where the individualis susceptible to side effects of steroids. Interferon (a and b) has shown promise fortreatment of Churg–Strauss syndrome.

3 The recent interest in atherosclerosis as an inflammatory disease may give rise tonovel therapies for common vascular disorders including coronary heart disease andstroke.7 Vascular inflammation is known to play a prominent role in thedevelopment of atherosclerotic plaques and their subsequent rupture, giving rise toacute vascular events. Therapeutic strategies to decrease this vascular inflammationinclude use of statins, cyclooxygenase inhibition, blockade of the renin–angiotensinsystem and inhibition of pro-inflammatory cytokines. Proposed biologicalapproaches include immunization against the protein component of low-densitylipoproteins (apoB-100).

ConclusionVasculitic disease is extremely variable in its presentation. The most common cutaneousmanifestation is palpable purpura. The pattern of organ distribution and the nature ofthe lesions give clues to the underlying disease process. In all cases, the potential forinvolvement of major organ systems (lung, liver, heart, kidneys and nervous system)should be considered. The lesions are accompanied by symptoms of systemic inflamma-tion and inflammatory markers are increased. Once diagnosis is established, or before insevere cases, treatment should be started. This is mainly with immunosuppressive agents.The acute and maintenance phases of treatment require different approaches. Biologicaltreatments, including antibodies to B cells and TNF-a, are making a major impact on themanagement of difficult and refractory cases.

Further Reading1 Roane DW, Griger DR. An approach to diagnosis and initial management of systemic

vasculitis. Am Fam Physician 1999; 60: 1421–30.

2 Scott DGI, Watts RA. Systemic vasculitis: epidemiology, classification and environmental

factors. Ann Rheum Dis 2000; 59: 161–3.

3 Carlson JA, Cavaliere LF, Grant-Kels JM. Cutaneous vasculitis: diagnosis and management.

Clin Dermatol 2006; 24: 414–29.



4 Foster R, Rosenthal E, Marques S, Vounotrypidis P, Sangle S, D’Cruz D. Primary systemic

vasculitis: treatment of difficult cases. Lupus 2006; 15: 143–7.

5 Bosch X, Guilabert A, Font J. Antineutrophil cytoplasmic antibodies. Lancet 2006; 368:4004–18.

6 Chan AT, Flossmann O, Mukhtyar C, Jayne DRW, Luqmani RA. The role of biologic therapies

in the management of systemic vasculitis. Autoimm Rev 2006; 5: 273–8.

7 Stoll G, Bendszus M. Inflammation and atherosclerosis: novel insights into plaque formation

and destabilization. Stroke 2006; 37: 1923–32.

29 Giant cell arteritis and polymyalgia rheumatica 159

29 Giant Cell Arteritis and PolymyalgiaRheumatica

P R O B L E M

Case HistoryMrs FM is a 74-year-old womanwho complains of headaches, general malaise andstiffness of the upper arms and shoulders. The symptoms have gradually increased overfour weeks. She is generally healthy and takes nomedication apart from paracetamol forher mild osteoarthritis.

Is temporal artery biopsy required to diagnose giant cell arteritis (GCA)?

What is current thinking on the aetiology of GCA and polymyalgia rheumatica(PMR)?

For how long is she likely to require steroid treatment?

How should the condition be monitored?

BackgroundGCA is the most common vasculitic disease and affects medium- to large-sized arteries.GCA presents with headache, tenderness over the temporal artery or scalp, jaw claudica-tion and sometimes visual loss. The latter develops quickly and is frequently permanent,making urgent diagnosis and treatment mandatory. PMR is a closely related conditionthat usually presents with pain and stiffness of the shoulder muscles, often accompaniedby general malaise, fever and weight loss. PMR occurs in about 50% of patients with



GCA; of patients with PMR, around 10% will have GCA. The prevalence of PMR isaround 10–15 per 1000 and women are affected twice as often as men. GCA is more com-mon in colder climates, is less common than PMR and has an incidence of about 20 per100 000 per year. Both GCA and PMR are very uncommon under the age of 50 years.1,2

GCA and PMR are much more common in Caucasians, particularly those ofScandinavian descent. The fact that there is a racial predisposition and that familial clus-tering has been described points to a genetic component to the aetiology. Alleles ofHLA-DRB1*04 have been commonly implicated. Amongst infectious triggers that have beenconsidered areMycoplasma pneumoniae, parvovirus B19 and parainfluenza virus type 1.3

In GCA, inflammation in the vascular wall leads to structural changes including intimalhyperplasia, fragmentation of the internal elastic laminae and luminal occlusion. Thedisorder in the vessel wall is driven by activated T cells andmacrophages. T cells enter thevessel wall through the vasa vasorum, become activated through contact with antigenand produce a range of pro-inflammatory cytokines including interferon-g. Thesecytokines lead to macrophage homing and activation.Shoulder pain and stiffness are the most common symptoms of PMR. Systemic symp-

toms include fever, mood changes, sweating, anorexia and weight loss. Erythrocyte sedi-mentation rate (ESR) is usually greater than 50 mm/h and there is often mildnormochromic anaemia. Muscles are not strikingly tender. There is often some limita-tion of movement due to muscle stiffness, and secondary increase in joint pains is com-mon. Differential diagnosis includes fibromylagia, rheumatoid arthritis, polymyositisand osteoarthritis. Some patients develop swelling of the distal digits, carpal tunnel syn-drome and tenosynovitis.GCA can affect any medium- to large-sized artery but most commonly affects the

internal and external carotid arteries. Headache has often been present for several weeks


Frequency (%)

Headache 85

Temporal artery thickened, pulseless or tender 73

Malaise, anorexia or weight loss 61

Jaw claudication 41

Polymyalgia rheumatica 40

Scalp tenderness 33

Retinal ischaemia 23

Visual loss 13

Fever 10

Dysphagia 5

Cerebrovascular accident 2

Recent onset of peripheral arterial disease 2

Adapted from Gonzalez-Gay et al. 2006.1

Table 29.1 Features of GCA


before the patient presents. Depression, malaise, weight loss and fever often accompanythe diagnosis, even in the absence of clinically apparent PMR. GCA is unusual when theESR is less than 50 mm/h. The temporal artery may be thickened, tender and lack pulsa-tion. Eyes should be examined, looking for loss of vision, an afferent papillary defect andocular movement disorders (diplopia). Fundoscopy should be carried out to look forsigns of ischaemic retinopathy. Table 29.1 lists the common features of GCA.The initial investigation should be ESR, which is seldom normal and frequently

greater than 100 mm/h. The normal upper limit for ESR is estimated as:

Men: Age (years)� 2Women: Age (years) + 10)� 2

Up to 20% of patients with PMR have normal ESR. SerumC-reactive protein (CRP) isalso usually elevated. CRP and ESR values are generally very strongly correlated. Otherlaboratory findings include normochromic anaemia, thrombocytopenia and elevatedliver enzymes. There may be a mild leukocytosis, and thrombocytosis is recognized.Temporal artery biopsy is the cornerstone of diagnosis and should be considered evenwhere symptoms appear to strongly support the diagnosis. Before embarking on pro-longed steroid therapy, a precise diagnosis is highly desirable. If the initial biopsy is nega-tive, and symptoms are highly suggestive, biopsy of the contralateral temporal arteryshould be considered. Positive biopsy shows inflammatory infiltrate with disruption ofthe internal elastic lamina. The inflammation is focal and segmental and granulomatouswith multinucleate giant cells. The biopsy should be performed at the most symptomaticsite and should ideally be at least 2.5 cm long. Temporal artery biopsy is not usually car-ried out in patients with what appears to be uncomplicated PMR. Newer diagnostic tech-niques are colour-coded duplex ultrasonography and positron emission tomography(PET). Both have a high sensitivity for detecting vascular disease, but changes are oftennot specific. Magnetic resonance imaging (MRI) angiography is also emerging as a usefultool. There are no documented associations with circulating autoantibodies.Prednisolone is the first-line treatment. An initial dose of 10–20 mg/day is usually suf-

ficient for patients with PMR. Response is usual within two weeks, and after one monththe dose can begin to be tapered down. The usual duration of therapy is two to threeyears. GCA usually requires prednisolone 40–60 mg/day. Initiation should not bedelayed while the results of investigations, including temporal artery biopsy, are awaited.Visual symptoms seldom develop after steroid therapy has been commenced. If present,or allowed to develop, visual symptoms usually do not recover. Severe, refractory or vis-ual symptoms can be treated with intravenous methylprednisolone (1 g daily for threeconsecutive days). Symptoms respond to prednisolone within days and the dose can betapered after a month. At six months, a dose in the range 7.5–10 mg/day is usual.Treatment for two to three years is generally required. Alternate day steroid regimens oradjuvant methotrexate are of uncertain benefit. Flare-up of disease activity may occurwith both PMR and GCA as the steroid dose is reduced below 7.5 mg/day. These flarescan be managed by temporarily increasing the steroid dose. Safely decreasing and stop-ping prednisolone requires clinical judgement supported by the patient’s account ofsymptoms and measurement of inflammatory markers. For refractory cases or those athigh risk from corticosteroid side effects, methotrexate, azathioprine and infliximab arethe agents with the best evidence for benefit.



As well as anti-inflammatory therapy, antiplatelet therapy (e.g. low-dose aspirin)should be considered. As steroid treatment is likely to be ongoing for at least two years,baseline bone mineral density measurements should be carried out. Those with osteo-penia or who are otherwise at high risk of osteoporosis should have prophylactic calcium(1000 mg/day) and vitamin D (800 Units/day) supplements. Those with osteoporosisshould be considered for bisphosphonate treatment (chapter 44). Patients should bescreened periodically for impaired glucose tolerance/diabetes, and their blood pressureshould be monitored for the duration of treatment.

Recent Developments1 Epidemiological studies are difficult because PMR and GCA are generally managedin primary care. A recent study4 documented the incidence in the United Kingdombetween 1990 and 2001. During this period, the incidence of PMR increased from6.9 to 9.3 per 10 000 person-years. There was no parallel increase in GCA, whichremained static at 2.2 per 10 000 person-years.

2 Beyond its association withHLA-DRB1*04, remarkably little is known about thegenetic basis of GCA. An association with alleles of the Fcg receptors has beenproposed.5 These are important in immune regulation. Improved knowledge of thegenetic factors in pathogenesis may help to identify susceptible individuals.

3 Study of the genes expressed in temporal artery biopsies may also give clues to diseasepathogenesis and help to identify likely responders to treatment. Cid et al.6 reportedincreased expression of the chemokine monocyte chemoattractant protein-1 (MCP-1;also called CCL2) in temporal artery biopsies of patients with GCA. Furthermore,expression of CCL2 correlated with systemic measures of inflammation, and thehighest level of expression was seen in those with relapsing disease.

4 While ESR and CRP are highly correlated with each other and with a positivetemporal artery biopsy, this is not invariable.7 The sensitivity of ESR alone may be nomore than 76%, while positive CRP has a sensitivity of 97.5% alone and 99% whencombined with ESR. Neither is specific and values of ESR and CRP should beinterpreted in the light of the clinical picture and other investigations.

5 Lee et al.8 conducted a retrospective chart review and demonstrated that 16.2% ofGCA patients in the study who were taking antiplatelet drugs suffered an ischaemicevent compared with 48% of those who were not taking antiplatelet therapy. There isno compelling evidence to start all GCA patients on aspirin or clopidogrel at presentbut these interventions appear to pose little risk and may have considerable benefit.

6 Pulsed intravenousmethylprednisolone is used for initial therapy in those at high riskfrom an ischaemic event. Using this treatment initiallymay actually decrease steroidrequirements subsequently. In a recent small study,9 10 of 14 patients treated initiallywith intravenousmethylprednisolone were taking £5 mg/day prednisolone at 36 weeks,compared with only 2 out of 13 patients treated conventionally (P= 0.003). Evenwithout intravenous steroid, most agree that high-dose steroid to bring the conditionunder control quickly allows a decrease in steroid exposure over succeedingmonths.

7 It is not known why older people are uniquely susceptible to PMR and GCA.Dehydroepiandrosterone (DHEA) is the most abundant circulating steroid hormoneand levels decline with age. This decline has been associated with a range of



involutional changes including decreased cognitive function, decreased muscle bulkand a decline in bone health. Low levels of DHEA have been reported in patientswith PMR or GCA plus PMR.10 There is currently no evidence to support routinetreatment with DHEA in PMR or GCA.

ConclusionAs the number of elderly people is increasing, it is likely that GCA and PMR will beencountered more commonly in practice. Prompt diagnosis and effective treatment are


Consider other causes:Statin treatmentInflammatory myopathyOsteoarthritisRheumatoid arthritis

High ESR and CRP

Headache or temporal artery symptoms/signsESR .80 mm/hourConstitutional symptomsPoor response to low-dose steroids

Temporal artery biopsy

? Contralateral biopsy? Another diagnosis

Prednisolone 40–60 mg/day*

Monitor for: HyperglycaemiaHypertensionOsteoporosis (consider prophylaxis)

* Taper dose of prednisolone down after one month if there is satisfactory response

Prednisolone 10–20 mg/day*

Negative Positive

Muscle pain and stiffness

Figure 29.1 Diagnosis andmanagement of PMR and GCA.


essential not only to alleviate symptoms but also to prevent permanent disability fromblindness and other serious vasculitic complications. Many clinicians diagnose andman-age GCA without recourse to temporal artery biopsy. However, most experts agree thatbiopsy is indicated where there is a high suspicion of GCA. Given that the conditionrequires prolonged steroid treatment, it seems prudent to make a definitive diagnosiswherever possible. Diagnosis and management of PMR and GCA are summarized inFigure 29.1. The aetiology remains unknown but there appears to be some genetic influ-ence, and amongst environmental factors a variety of infectious triggers have been pro-posed. Steroid treatment is usually required for at least two years. Careful monitoring ofthe clinical response and inflammatory markers is required to minimize exposure tosteroids. Low-dose aspirin and osteoporosis prophylaxis should be considered, and allpatients should be monitored for potential side effects of corticosteroids.

Further Reading1 Gonzalez-Gay MA, Garcia-Porrua C, Miranda-Filloy JA, Martin J. Giant cell arteritis and

polymyalgia rheumatica: pathophysiology and management.Drugs Aging 2006; 23: 627–49.

2 Carroll SC, Gaskin BJ, Danesh-Meyer HV. Giant cell arteritis. Clin Experiment Ophthalmol

2006; 34: 159–73.

3 Nordborg E, Nordborg C. Giant cell arteritis: epidemiological clues to its pathogenesis and an

update on its treatment. Rheumatology 2003; 42: 413–21.

4 Smeeth L, Cook C, Hall AJ. Incidence of diagnosed polymyalgia rheumatica and temporal

arteritis in the United Kingdom, 1990–2001. Ann Rheum Dis 2006; 65: 1093–8.

5 Morgan AW, Robinson JI, Barrett JH et al. Association of FCGR2A and FCGR2A-FCGR3A

haplotypes with susceptibility to giant cell arteritis. Arthritis Res Ther 2006; 8: R109.

6 CidMC, HoffmanMP, Hernandez-Rodriguez J et al. Association between increased CCL2

(MCP-1) expression in lesions and persistence of disease activity in giant-cell arteritis.

Rheumatology 2006; 45: 1356–63.

7 Parikh M, Miller NR, Lee AG et al. Prevalence of a normal C-reactive protein with an elevated

erythrocyte sedimentation rate in biopsy-proven giant cell arteritis.Ophthalmology 2006; 113:1842–5.

8 Lee MS, Smith SD, Galor A, Hoffman GS. Antiplatelet and anticoagulant therapy in patients

with giant cell arteritis. Arthritis Rheum 2006; 54: 3306–9.

9 MazlumzadehM, Hunder GG, Easley KA et al. Treatment of giant cell arteritis using

induction therapy with high-dose glucocorticoids: a double-blind, placebo-controlled,

randomized prospective clinical trial. Arthritis Rheum 2006; 54: 3310–18.

10 Narváez J, Bernad B, Díaz Torné C et al. Low serum levels of DHEAS in untreated polymyalgia

rheumatica/giant cell arteritis. J Rheumatol 2006; 33: 1293–8.



Case HistoryA 26-year-old woman presents with subacute onset of fever and arthralgia and hasdeveloped oral and genital ulceration within the past two weeks. There is no familyhistory of note. She has recently returned from a holiday in a subtropical region but thereis no evidence of an infectious disease. Her previous health has been excellent and shetakes nomedications apart from the oral contraceptive pill.

How can the diagnosis of Behçet’s syndrome be established?

What treatment options are available?

What is her likely prognosis?

BackgroundBehçet’s syndrome (Adamantiades–Behçet’s disease) is a relapsing and remitting vas-culitic condition of unknown aetiology, the manifestations and severity of which varywidely from patient to patient. The condition typically runs a more severe course in menand in those of either gender who develop it at an earlier age (<25 years). The conditionwas first described by Hulusi Behçet in 1937, and is most common in patients ofMediterranean or Asian origin. The common features are summarized in Table 30.1.1,2

30 Behçet’s syndrome 165

30 Behçet’s Syndrome

P R O B L E M

Oral aphthous ulceration 98%Genital ulceration 80%Anterior uveitis 50%

Acne Retinal vasculitisErythema nodosumSkin ulceration

Arthralgia Non-destructive arthritis

Vasculitis: Arteritis Cerebral lesionsThrombophlebitis Pulmonary lesionsAneurysm formation

Gastrointestinal ulceration

Epididymitis

Table 30.1 Features of Behçet’s syndrome



The most common feature is oral ulceration. The ulcers vary in size but are typicallysmall and occur in crops on the gums, inside of the mouth and on the tongue. Genitalulcers also occur in the majority, and frequently leave residual scarring when they havehealed. Uveitis causes blurred vision, discomfort (particularly when looking at brightlights) and redness. Retinal vasculitis may lead to blindness if left untreated. Joint symp-toms most commonly affect the knees, wrists, ankles and knees. Central nervous systeminvolvement may cause headache, neck stiffness (if the meninges are involved), featuresof encephalitis (including fever, confusion, impaired consciousness, fits and coma) andfocal neurological signs and symptoms. The disease usually starts in the 20s and 30s. It ismore common in men in prevalent areas but in other countries, such as the UnitedStates, it occurs slightly more commonly in women.The aetiology appears to involve both genetic and environmental factors. The most

prominent pathological feature is involvement of the small blood vessels with either vas-culitis or thrombosis. Abnormalities at the vascular endothelium appear to be responsiblefor initiating the disease. Immunoglobulin M (IgM) anti-endothelial antibodies have beendescribed. These may be, in part, directed at the endothelial enzyme a-enolase, a compo-nent of the glycolytic pathway. Cross-reaction of these antibodies with proteins of otherorganisms has been proposed to account for some of the environmental component of theaetiology. These organisms include Saccharomyces cerevisiae, Streptococcus pneumoniae andCandida albicans. There is markedly increased expression of cytokines and their receptorsin affected tissues. The role of autoimmunity is uncertain – there are no specific immunemarkers. Diagnosis is made clinically andmay be confirmed by biopsy of affected tissue.Treatment depends on the severity and manifestations of the disease. There is no spe-

cific treatment. Milder cases only require symptomatic therapy (e.g. mouthwashes fororal ulceration or non-steroidal anti-inflammatory drugs for arthralgia). Genital ulcer-ation can be treated with azathioprine, cyclosporine, colchicine or thalidomide. The lat-ter has to be used with care in female patients because of its teratogenicity. Biologicalagents may be required in severe cases of orogenital ulceration. Agents with proven effectinclude interferon-a, etanercept and infliximab. Uveitis or retinal vasculitis can be sight-threatening and require prompt treatment. The usual first-line approach is cortico-steroids plus one of the cytotoxic agents (azathioprine or cyclophosphamide).Cyclosporine or interferon-a may be used for refractory cases. Anticoagulation shouldbe considered in those with severe thrombophlebitis. There is a risk of haemorrhage fromaneurismal or vasculitic lesions (particularly in the lungs).

Recent Developments1 Behçet’s syndrome sufferers have a high prevalence of psychological disorders andquality of life is impaired. The latter particularly relates to fatigue, arthralgia andmucocutaneous lesions.3,4 Effective management of the disorder requires thatpsychological and psychosocial factors are taken into account.

2 The genetic contribution is not at all well understood. The best-characterized markeris HLA-B51, but a wide variety of other genetic polymorphisms have been studied.Recently, the tumour necrosis factor (TNF)-a-1031C allele has been linked withsusceptibility to Behçet’s syndrome.5Other workers have found no relationship with



polymorphisms of the TNF-a gene.6Other candidate genes that have been studiedinclude those for the solute carrier SLC11A1 and the interleukin-18 gene. Noassociation with polymorphisms of these genes was found, although levels of IL-18are particularly high in patients with Behçet’s syndrome. The disease may be adisorder of the interaction between the innate immune system and bacterialcommensals or pathogens. A recent study found no link with polymorphisms for thegenes for Toll-like receptors and no link with leptin gene polymorphism.7,8Highlevels of leptin have been described in Behçet’s syndrome. One positive linkdescribed recently has been a relationship with the Val16 allele for the superoxidedismutase gene in Japanese patients.9

3 Erdem et al.10 have reported increased insulin resistance in Behçet’s syndromepatients. This is not surprising since systemic inflammation and endothelialdysfunction are both forerunners of insulin resistance. Other vascular risk factors inBehçet’s patients include impaired endothelium-dependent vasodilatation andincreased circulating levels of homocysteine.11 Recently, increased platelet activationhas been described and may contribute to the prothrombotic state.12

ConclusionThe aetiology of Behçet’s syndrome is still relatively poorly understood. The diagnosis ismade on clinical grounds. There is no specific serological marker. Measures of systemicinflammation including serum C-reactive protein and cytokine levels may be useful inmonitoring disease activity. Biopsy of affected tissue may help to establish the diagnosis.There is no specific treatment. The cornerstone of its management is symptomatic mea-sures along with judicious use of corticosteroids and other immunosuppressive agents.The typical course is a relapsing and remitting one, but the disease does not usually leadto premature mortality. Vascular disorders and neurological involvement are the majorthreats but only occur in a minority of patients.

Further Reading1 Kalayciyan A, Zouboulis C. An update on Behçet’s disease. J Eur Acad Dermatol Venereol 2007;

21: 1–10.

2 Yazici H, Fresko I, Yurdakul S. Behçet’s syndrome: disease manifestations, management, and

advances in treatment.Nat Clin Pract Rheumatol 2007; 3: 148–55.

3 Bodur H, Borman P, Ozdemir Y, Atan C, Kural G. Quality of life and life satisfaction in

patients with Behçet’s disease: relationship with disease activity. Clin Rheumatol 2006; 25:329–33.

4 Mumcu G, Inanc N, Ergun T et al. Oral health related quality of life is affected by disease activ-

ity in Behçet’s disease.Oral Dis 2006; 12: 145–51. [Erratum appears inOral Dis 2006; 12: 356]

5 Akman A, Sallakci N, CoskunM et al. TNF-alpha gene 1031 T/C polymorphism in Turkish

patients with Behçet’s disease. Br J Dermatol 2006; 155: 350–6.

30 Behçet’s syndrome 167



6 Ates A, Kinikli G, Düzgün N, DumanM. Lack of association of tumor necrosis factor-alpha

gene polymorphisms with disease susceptibility and severity in Behçet’s disease. Rheumatol Int

2006; 26: 348–53.

7 Bacanli A, Sallakci N, Yavuzer U, Alpsoy E, Yegin O. Toll-like receptor 2 Arg753Gln gene

polymorphism in Turkish patients with Behçet’s disease. Clin Exp Dermatol 2006; 31:699–701.

8 Aydin F, Kara N, Senturk N et al. Lack of association between leptin G2548A gene polymor-

phism and Behçet’s disease. J Eur Acad Dermatol Venereol 2007; 21: 68–71.

9 Nakao K, Isashiki Y, Sonoda S, Uchino E, Shimonagano Y, Sakamoto T. Nitric oxide synthase

and superoxide dismutase gene polymorphisms in Behçet disease. Arch Ophthalmol 2007; 125:246–51.

10 ErdemH, Dinc A, Pay S, Simsek I, TuranM. Peripheral insulin resistance in patients withBehçet’s disease. J Eur Acad Dermatol Venereol 2006; 20: 391–5.

11 Kayikçioglu M, Aksu K, Hasdemir C et al. Endothelial functions in Behçet’s disease.

Rheumatol Int 2006; 26: 304–8.

12 Akar S, OzcanMA, Ates H et al. Circulated activated platelets and increased platelet reactivity

in patients with Behçet’s disease. Clin Appl Thromb Hemost 2006; 12: 451–7.


31 Acute Back Pain

Back and Specific Joint Problems

S E C T I O N S I X 06

31 Acute back pain32 Chronic back pain33 Psoriatic arthritis34 Asymptomatic hyperuricaemia35 Gout – acute attack and beyond36 Pseudogout – investigation and management37 Joint and bone infections38 Viral arthritis39 Rheumatological complications of diabetes

P R O B L E M

Case HistoryYou have been asked to do a home visit to see Bob. He is a 46-year-old storeman who ismoderately overweight (body mass index 32 kg/m2) and who had a sudden onset of lowback pain yesterday whenmoving a box of parts in the storeroom.

What features enable you to plan investigation and management?

What are the important prognostic features?

BackgroundLow back pain (LBP) is common, with an annual incidence of 2%–5%, and 70%–90% ofthe population will experience an episode of LBP at some point. Prevalence increaseswith age until 65 years and decreases thereafter. LBP is the most common work-related‘injury’ and is second only to the common cold as a cause of absence from work (Table



31.1). Fortunately, 90% of individuals with acute LBP improve within four to eightweeks, and only 5% of patients develop persistent or chronic LBP lasting longer thanthree months. For practical purposes, LBP is bounded by the level of the 12th thoracicvertebra and the gluteal folds, and pain may radiate into the leg.

The cause of LBP is unknown in at least 80% of cases (Table 31.2) LBP is classified asnon-specific LBP or simple backache, nerve-root (Box 31.1) or spinal nerve compromise,or potentially serious spinal pathology (including infection, cancer, fracture, inflamma-tory back pain and cauda equina syndrome). In the retrospective study of Deyo et al.,1 of

§06 Back and Specific Joint Problems170

Strongest: Previous history of back pain

Strong: Poor job satisfactionEmotional distressManual labourer involving heavy liftingProlonged sitting or standing

Moderate: Vibration tool useSmokingObesityPoor physical fitness

Table 31.1 Risk factors for LBP

97% Mechanical LBP80% Idiopathic20% Prolapsed intervertebral disc

Lumbar spondylosisSpondylolisthesisSpinal stenosisFractureScheuermann’s disease

1% Non-mechanical spinal painInflammatory spondyloarthritis

1%–2% Visceral diseaseInfectionNeoplasia

Table 31.2 Causes of LBP

� Weight loss, fever, night sweats� Nocturnal pain� History of malignancy� Recent or current infection� Acute onset <20 or >55 years� Constant or progressive pain� Bilateral or alternating symptoms� Neurological or sphincter disturbance� Morning stiffness� Claudication or peripheral ischaemia

Table 31.3 ‘Red flags’ of LBP


subjects presenting with acute LBP, 4% had compression fractures and 1% had cancer,infection, inflammatory disorders or cauda equina syndrome. Another cohort of patientswith acute LBP had an even smaller percentage of serious pathology.2 Sinister causes ofback pain are relatively rare and suspicious features are listed in Table 31.3.

Investigations are not usually indicated in simple backache. Where investigation isrequired, it should be aimed at confirming a specific pathological process. Cauda equinasyndrome should be suspected when leg pain that includes several spinal nerve levels isaccompanied by widespread motor and/or sensory weakness, and when there is associ-ated bladder or bowel dysfunction.

Specific pathology leading to acute LBPThe spine is commonly described as a three-joint complex, consisting of the interverte-bral disc anteriorly and the two facet joints posterolaterally. These border the triangular-shaped spinal canal (Figure 31.1). Deformity of the three-joint complex, anterior orposterior subluxation (spondylolisthesis) of a vertebral body, as well as deformity of theposterior longitudinal ligament and ligamentum flavum can lead to nerve-root impinge-ment in the lower spine or spinal cord compression at higher levels. The spinal cord endsat approximately the level of lumbar vertebrae L1/L2 so that neurological manifestationsin LBP syndromes are lower motor neurone lesions affecting peripheral nerve roots. Themost common site of disc prolapse is the L4/L5 disc where a posterolateral protrusionimpinges on the L5 nerve root. A centrally placed bulge may affect multiple lower nerveroots bilaterally, causing a cauda equina syndrome. The combined pathologies of facetjoint hypertrophy/osteophyte formation, disc bulges and deformity of the long ligamentsstenoses the spinal canal and presents with pseudoclaudication, sciatica and dysfunctionof the cauda equina.

31 Acute back pain 171

Box 31.1 Indicators for nerve root problems3

� Unilateral leg pain > lowback pain� Radiates to foot or toes� Numbness and paraesthesia in same distribution� Straight leg-raising inducesmore leg pain� Localized neurology in one nerve root

Intervertebraldisc

Normal intervertebraldisc, facet joints and

exiting nerve root

Central disc bulge and posterolateral bulgewith ligamentum flavum hypertrophy

Facet joint hypertrophy

Figure 31.1 Nerve root pain.


Prolapsed intervertebral discThe intervertebral disc comprises the inner nucleus pulposus and the outer annulusfibrosus. The nucleus is a proteoglycan matrix that must remain hydrated to act as ashock absorber. The overlapping zig-zag alignment of the layers of collagen fibres withinthe annulus provides resistance to bulging when load is applied. The outer third of theannulus is innervated such that mechanoreceptors respond to distortion.

Spinal fractureIn the older patient, particularly female, presenting with sudden-onset localized backpain after minor trauma, osteoporotic compression fracture should be suspected.Fracture in younger people without major trauma is a rare cause of LBP. Lateral spinalviews for compression fractures, or oblique views, will identify established or majorchanges on X-ray. Isotope bone scan or single photon emission computed tomography(SPECT) imaging may be more sensitive.

CancerFour clinical features have been proposed to be most predictive of malignancy as a causeof LBP:

1 Previous history of cancer2 Aged 50 years or older3 Failure of conservative therapy4 Weight loss

An erythrocyte sedimentation rate of >50 mm/h also leads to magnetic resonanceimaging (MRI) investigation.

InfectionA history of immunosuppression or risk factors for breaches in the normal barriers tobacteraemia should be elicited, coupled with an examination looking for septic foci.Culture and microbial analysis of relevant tissue should be undertaken. In 40% of casesof spinal osteomyelitis there is haematogenous spread from an identifiable extraosseoussource, most commonly genitourinary, skin or respiratory. The most common organismis Staphylococcus aureus, with Gram-negative organisms in the elderly or intravenousdrug users being common.

Inflammatory LBPIt has been proposed that amongst patients with chronic LBP, up to 5% have inflamma-tory back pain due to spondyloarthropathy (i.e. ankylosing spondylitis, reactive arthritis,psoriatic arthritis or inflammatory bowel disease).

Management of acute LBPPatients benefit from non-steroidal anti-inflammatory drugs (NSAIDs) to relieve pain,and should be encouraged to remain active (Box 31.2). Medications such as muscle relax-ants may help but can cause drowsiness.

Although the contribution of psychosocial factors to chronic LBP is appreciated,successful interventions aimed at patients with increased risk are yet to be identified. A



general practitioner-implemented intervention focused on the identification of psy-chosocial prognostic factors and discussing these with the patient, setting specific goalsfor reactivation and providing an educational booklet had no effect on any outcomemeasure.4

Outcome of LBPThe prognosis of chronic LBP is poorly documented, with cohorts varying as to theircomposition and adequacy for defining an underlying aetiology of pain. Socioeconomicfactors including litigation, unemployment benefits and educational opportunities alsoimpact on outcome. Poor prognostic factors include fear avoidance behaviour, leg painand low job satisfaction. However, it is consistently reported that over 90% of patientsimprove by six to twelve weeks. Refshauge and Maher5 have explored this further; thefindings are a reminder that not all patients with LBP present for medical care (and thatthis may not be influenced by severity of pain), and that others return to work despiteongoing pain. Recurrences of LBP are common, with an estimated three-quarters ofpatients having a recurrence within one year. The severity, however, is usually less anddoes not always lead to a new visit to the doctor.

Recent Developments1 In the majority of patients with ankylosing spondylitis there is a ten-year delay

between onset of symptoms and diagnosis. In about 95% of patients, the firstsymptoms of spondyloarthritis develop before the age of 45 years and this should bethe target group for screening. To help reduce the delay between symptom onset anddiagnosis, it has been proposed that patients with LBP of duration greater than threemonths should be screened for the presence of inflammatory back pain, the presenceof HLA-B27 and for evidence of sacroiliitis.6 If one or more of these parameters isconfirmed, patients should be referred to a rheumatologist.

2 New criteria have been proposed by Rudwaleit et al.7 to assist in defininginflammatory LBP. The four parameters are (a) morning stiffness duration >30 min,(b) improvement with exercise but not with rest, (c) awakening during the secondhalf of the night and (d) alternating buttock pain. For classification purposes, two ormore criteria have a sensitivity of 70% and specificity of 81%. As the number ofparameters increases, the likelihood ratio also increases, from 0.25 for no parametersto 2.3 for two parameters and to 12.0 for three or more parameters.7

31 Acute back pain 173

Box 31.2 Summary of treatment guidelines for acute LBP3

� Reassure patient of favourable prognosis� Advise to remain active, and discourage bed rest� Donot prescribe specific back exercises� Prescribe regularmedication consisting of:

� Paracetamol� NSAIDs

� Consider benefit ofmuscle relaxants



ConclusionThe majority of patients with LBP require either no medical intervention or only conser-vative therapies consisting of advice, simple analgesics and continuation of daily activi-ties. Considering, however, its prevalence and impact on health economy there are still alarge number of therapies offered but not of proven benefit. Critical appraisal of featuresidentified in history-taking and examination is required to provide a more accurate andspecific diagnosis, and hence provide guidance on investigation, treatment and prog-nosis.

Further Reading1 Deyo R, Rainville J, Kent D. What can the history and physical examination tell us about low

back pain? JAMA 1992; 268: 760–5.

2 McGuirk B, KingW, Govind J, Lowry J, Bogduk N. Safety, efficacy, and cost effectiveness of

evidence-based guidelines for the management of acute low back pain in primary care. Spine

2001; 26: 2615–22.

3 Koes BW, van Tulder MW, Thomas S. Diagnosis and treatment of low back pain. BMJ 2006;

332: 1430–4.

4 Jellema P, van der Windt DAWM, van der Horst HE, Twisk JWR, StalmanWAB, Bouter LM.

Should treatment of (sub)acute low back pain be aimed at psychosocial prognostic factors?

Cluster randomised clinical trial in general practice. BMJ 2005; 331: 84–90.

5 Refshauge KM, Maher CG. Low back pain investigations and prognosis: a review. Br J Sports

Med 2006; 40: 494–8.

6 Sieper J, Rudwaleit M. Early referral recommendations for ankylosing spondylitis (including

pre-radiographic and radiographic forms) in primary care. Ann Rheum Dis 2005; 64: 659–63.

7 Rudwaleit M, Metter A, Listing J, Sieper J, Braun J. Inflammatory back pain in ankylosing

spondylitis: a reassessment of the clinical history for application as classification and

diagnostic criteria. Arthritis Rheum 2006; 54: 569–78.


Case HistoryJolene is a 43-year-old womanwho has become rather depressed and angry about herpainful back, which has been present for two years. She was a typist until her chair slippedout from under her and she landed heavily on her sacrum. Despite the best efforts ofhealth practitioners she still experiences severe pain that no one can explain. She isfrustrated at the number of doctors who have seen her and left her with the impression‘there is nothing abnormal to find’.

Are there strategies for successful management of chronic low back pain (LBP)?

When should we investigate further?

BackgroundIn patients with chronic LBP the terms non-specific or mechanical LBP are used with animplication that an anatomical or pathological basis is understood. In reality, the aetiologyremains unknown for the majority of cases. Observation is used to determine alteration inposture, muscle wasting, changes in the physiological lordosis and the effects of move-ment on spinal alignment. Palpation can be undertaken to assist in evaluating movementat a segmental level, and also to identify local tenderness. Dynamic procedures are used toelicit alteration in symptoms to a manoeuvre that is aimed at identifying the cause ofsymptoms. A systematic review analysed examination procedures used in the assessment

32 Chronic back pain 175

32 Chronic Back Pain

P R O B L E M

ObservationJudging lordosis: two quality studies indicating reliability, two againstDetecting lateral spinal shift: low reliabilityEvaluating abnormal posture or movement: low reliabilityTimed endurance testing: high reliability in low-quality studies

PalpationEvaluating muscle tension or spasm: conflicting evidenceExistence of a fixation or ‘manipulative lesion’: low reliabilityIdentifying spinal level: low reliabilityInstability testing: conflicting evidence

Symptom responsePain response to repeated movement: conflicting to low reliabilityPain on palpation and trigger points: low reliability

Table 32.1 Reliability of clinical examination



of LBP.1 Methodological flaws were identified in the majority of studies, but the resultsremain interesting. Palpation-based assessment was of low reliability, with moderate reli-ability of some examination procedures based on symptom response (Table 32.1).

Abnormalities on X-ray and magnetic resonance imaging (MRI) are poorly associatedwith the occurrence of non-specific LBP. Abnormalities foundwhen imaging people with-out back pain are just as prevalent as those found in patients with LBP, and it needs to beremembered that radiological abnormalities of degeneration and spondylolysis have beenreported in 40%–50% of people without LBP.With a prevalence of suchmagnitude, it hasbeen suggested that this background prevalence of abnormalities be included in radiologi-cal reports.2 Computed tomography and MRI are equally effective in diagnosing lumbardisc herniation and stenosis, but only have meaning if the presentation had suggested thisas the likely diagnosis and the imaging findings remain compatible with clinical findings.

Conservative treatmentExercise and intensive multidisciplinary pain-treatment programmes are effective (Box32.1). Evidence supports use of cognitive behaviour therapy, analgesics, antidepressants,non-steroidal anti-inflammatory drugs (NSAIDs), back schools and spinal manipula-tion. However, the effects are usually only small and short term. Unfortunately, manycommonly used interventions lack sufficient evidence of benefit. No evidence supportsusing interventions such as steroid injections, lumbar supports and traction.

Invasive treatmentA review of the efficacy of surgery and invasive interventions for the treatment of LBPand sciatica indicated that facet joint, epidural, trigger point and sclerosant injectionhave not clearly been shown to be effective.3 No sound evidence is available for the effi-cacy of spinal stenosis surgery, although surgical discectomy may be considered in thosewith sciatica due to lumbar disc prolapse who have failed to respond to conservativemanagement. Randomized controlled trials (RCTs) comparing fusion surgery with con-servative treatment show conflicting results.

Recent Developments1 Sciatica resulting from disc herniation resolves in the majority of patients within four

weeks. Of fifteen RCTs of epidural steroid injection, nine showed no benefit, with six


Box 32.1 Guidelines for the treatment of chronic LBP4,5

� Recommend cognitive behavioural therapy, supervised exercise, brief educationalinterventions andmultidisciplinary (biopsychosocial) treatments

� Advise patient to remain active� Short-termuse ofNSAIDs andweak opioids� Consider net benefit ofmuscle relaxants, back schools, antidepressants and

manipulation� Avoid passive treatment such as ultrasound and shortwave diathermy� Invasive treatments such as facet joint injections generally not recommended


showing short-term benefit that did not last longer than one month. Valat hasreviewed an additional three studies,6 in which patients received three epiduralinjections at between two-daily (one study) and three-weekly (two studies) intervals.Three-weekly methylprednisolone (80 mg) did not alter the primary outcomemeasure (the Oswestry Disability Questionnaire). Alternate daily prednisolone(50 mg) also had no effect. Three-weekly triamcinolone (80 mg) plus 10 mlbupivacaine led to significant improvement in leg pain and self-reported function atthree weeks, which was not sustained to six weeks or at one year.

2 Martell and colleagues reviewed the prevalence of opioid use in chronic LBP, itseffectiveness and the prevalence of substance use disorders.7 Meta-analysis of fourstudies assessing the efficacy of opioids compared with placebo or a non-opioidcontrol did not show reduced pain with opioids. Meta-analysis of five studies directlycomparing efficacy of different opioids showed there was no reduction in pain. Onthe important end-point of substance use disorders, there was a lifetime prevalenceof substance use disorders of 1:2 to 1:3, with the estimate of the prevalence of currentsubstance use disorder as high as 43%. It has to be noted that none of the trialsextended beyond four months. While short-term use of opioids may be beneficial,the value beyond four months is unclear, with substance use disorders common andaberrant medication-taking behaviours documented in a quarter of cases.

3 In another recent meta-analysis, the efficacy of psychological interventions wasevaluated in patients with non-malignant chronic LBP.8 Outcomes included painintensity, emotional functioning, physical functioning, participant rating of globalimprovement, healthcare use, pain medication and compensation status. Positiveeffects of psychological interventions, contrasted with various control groups, werenoted for pain intensity, pain-related interference, health-related quality of life anddepression. Cognitive behavioural and self-regulatory treatments were found to beefficacious. Multidisciplinary approaches that included a psychological componentwere also noted to have short-term effects on pain interference and positive long-term effects on return to work.

ConclusionChronic LBP is common and produces a significant burden on healthcare resources, theindividual and their caring practitioners. Treatment guidelines provide much-neededinformation on what works and what does not, but the meta-analyses underpinningthese recommendations also identify the weaknesses in our studies to date. The apparentbenefit of psychological interventions should be borne inmind, and should be invoked inthe maintenance of an ongoing supportive and empathetic relationship with the patientwho has chronic LBP.

Further Reading1 May S, Littlewood C, Bishop A. Reliability of procedures used in the physical examination of

non-specific low back pain: a systematic review. Aust J Physiother 2006; 52: 91–102.

32 Chronic back pain 177



33 Psoriatic Arthritis

P R O B L E M

Case HistoryAlice is 26 years old and has had psoriasis since age 18. This has been treated with topicalpreparations and she currently has only mild skin disease. She presents with pain andswelling in the small joints of her hands and reports pains in her back and right knee overthe past fewmonths. Her mother, aged 56, has psoriasis with associated arthritis.

Is it likely that she is developing psoriatic arthritis (PsA)?

How relevant is the positive family history?

What steps should be taken to diagnose psoriatic arthritis?

What is the treatment and prognosis?

2 RolandM, van Tulder M. Should radiologists change the way they report plain radiography of

the spine? Lancet 1998; 352: 229–30.

3 van Tulder MW, Koes B, Seitsalo S, Malmivaara A. Outcome of invasive treatment modalities

on back pain and sciatica: an evidence-based review. Eur Spine J 2006; 15: s82–92.

4 Koes BW, van Tulder MW, Thomas S. Diagnosis and treatment of low back pain. BMJ 2006;

332: 1430–4.

5 Airaksinen O, Brox JI, Cedrashi C et al. European guidelines for the management of chronic

nonspecific low back pain. Eur Spine J 2006; 15 (Suppl 2): S192–300.

6 Valat J-P. Epidural corticosteroid injections for sciatica: placebo effect, injection effect or anti-

inflammatory effect?Nat Clin Pract Rheumatol 2006; 2: 518–19.

7 Martell BA, O’Connor PG, Kerns RD et al. Systematic review: opioid treatment for chronic

back pain: prevalence, efficacy, and association with addiction. Ann Intern Med 2007; 146:116–27.

8 Hoffman BM, Papas RK, Chatkoff DK, Kerns RD. Meta-analysis of psychological

interventions for chronic low back pain.Health Psychol 2007; 26: 1–9.



BackgroundPsoriasis is a common disorder of keratinocyte growth and differentiation affecting up to2% of the population. The skin lesions are red, scaly, raised plaques typically found onthe scalp, elbows and knees. Onset is usually in adolescence or early adulthood although alate-onset form is recognized. Prevalence estimates for psoriatic arthritis range from 10%to 40% of all cases of psoriasis. Clinically significant arthritis affects about one in sixpatients with psoriasis.1,2 There is a decrease in the granular layer of keratinocytes, whichare not fully differentiated and do not stack normally. Psoriasis is considered to be anorgan-specific autoimmune disease that is predominantly T-cell mediated. The lesionsare heavily infiltrated with lymphocytes, monocytes and neutrophils. There is activationof antigen-presenting cells and endothelial cells, and blood vessels at the base of thelesions are hyperplastic. The T-cell response is a type 1 reaction with interleukin (IL)-12and IL-23 production leading to increased interferon-g and tumour necrosis factor(TNF)-a, with consequent activation of inflammatory pathways through signal trans-ducer and activator of transcription-1 (STAT1). There is decreased local expression ofthe anti-inflammatory cytokine IL-10. Platelet-derived growth factor (PDGF) and vascu-lar endothelial growth factor (VEGF) contribute to the intense inflammatory and vascu-lar reaction. The normal keratinocyte maturation cycle spans 30 days, and this istruncated to only four days in psoriatic lesions.

There is a strong genetic component in the aetiology of psoriasis. It is common inCaucasians, much less common in those of Asian descent (prevalence 0.1%) and veryrare in individuals of African descent. Up to one-third of patients have a family history ofthe condition and 8% have an affected first-degree relative. Concordance rate in dizy-gotic twins is 15%–30% and in monozygotic twins is around 65%. At least five suscepti-bility loci have been identified for psoriasis by genome-wide scanning studies.3 The moststudied locus (PSORS1) is in the HLA region of chromosome 6p. Susceptibility is linkedwith a haplotype that includes theHLA-Cw0602 allele. However, non-HLA determinantsin this region are also thought to be important (including polymorphisms of TNF-a),and there has been particular interest in the gene for corneodesmin (CDSN), which codesfor a protein involved in keratinocyte maturation. The PSORS2 locus at chromosome17q25 contains several candidate genes including SLC9A3R1, NAT9 and RAPTOR (thep150 target of rapamycin). Other loci are PSORS3 (4q35), PSORS4 (1q21) and PSORS5(3q21). PSORS2 and PSORS4 contain genes that are also involved in susceptibility toatopic dermatitis. There is relatively little known about the genetics of PsA. The CARD15gene at chromosome 16q has been suggested as a candidate, and is also involved in sus-ceptibility to Crohn’s disease.

PsA characteristically begins after five to ten years of psoriasis, but may present at thesame time as the skin lesions or even precede them. PsA is an important determinant ofquality of life and disease burden associated with psoriasis. Studies have been hamperedby lack of a specific biomarker, thus placing reliance on clinical scoring systems. The sim-plest of these is presented in Box 33.1. It should not be assumed that all arthritis inpatients with psoriasis is PsA – other conditions should be carefully excluded. At onset,there is pain, redness and stiffness which usually only affects a few joints in the firstinstance, with development of the typical symmetrical polyarthropathy over time.Involvement of the distal interphalangeal (DIP) joints is usual, and helps to distinguish

33 Psoriatic arthritis 179


PsA from rheumatoid arthritis (RA) (Box 33.2). PsA is classified with the spondyloarthri-tides and spine involvement occurs in up to 40% of cases. One important characteristicof PsA is the involvement of entheses – the points at which tendons, ligaments and jointcapsules insert into bone. Enthesitis most frequently affects the plantar fascia, Achillestendon and the ribs and pelvis. Another feature is dactylitis, where a whole digit isinflamed because of a combination of enthesitis and synovitis. These changes are bestdiagnosed on a fat-suppressed magnetic resonance imaging scan.

Five different forms of PsA are recognized (often reflecting the stage to which the dis-ease has progressed): asymmetrical; symmetrical; predominantly DIP joint involvement;spondylitis; and arthritis mutilans. The latter is the most severe form, affecting mainlythe small joints of the hands and feet and causing considerable deformity. It affects lessthan 5% of patients with PsA. Spondylodiscitis is another serious, though fortunatelyrare, complication. SAPHO syndrome (Synovitis, Acne, Pustulosis, Hyperostosis andOsteitis) is an unusual overlapping syndrome. PsA is a serious diagnosis with the minor-ity of cases running an entirely benign course.


Box 33.1 Scoring system for diagnosis of PsA

PsA can be diagnosedwhen the patient has an inflammatory arthropathy (articular,spine enthesis) plus ≥3 from the following:

1 Active psoriasis, a personal or family history of psoriasis; current active psoriasisscores 2

2 Nail dystrophy – pitting, onycholysis, hyperkeratosis3 Rheumatoid factor (RF) negative4 Active or previous dactylitis5 Juxta-articular newbone formation onX-ray of the hands and feet (not osteophytes)

All features score 1 if present, except active psoriasis, which scores 2. Adapted from Taylor et al. 2006.4

Box 33.2 Comparison between PsA and RA

PsA RA

Small joint involvement ++ +++DIP involvement +++ +Spine, sacroiliac joint involvement ++ +Enthesitis +++ -Synovitis ++ +++Subcutaneous nodules - ++Skin lesions +++ +RFpositive + +++Anti-cyclic citrullinated peptide (anti-CCP) antibodies ± +++Inflammatorymarkers ++ +++Family history +++ +When fully expressed, both diseases can cause a symmetrical, deforming polyarthropathy, which predominantly affects small joints of the handsand feet.


Diagnosis and treatment is summarized in Figure 33.1. Management of PsA overlapswith that of the skin condition, particularly where systemic disease-modifying drugs areused. For mild cases, physical treatments (exercises, splinting etc.) along with non-steroidal anti-inflammatory drugs where needed suffice. Intra-articular steroid is usefulfor large joint inflammation. Systemic steroids are generally avoided because of the riskof flare-up of skin lesions when the steroid is stopped. Methotrexate is the most com-monly used disease-modifying drug for the skin condition and is also useful for jointinvolvement. As for RA, sulphasalazine, chloroquine, hydroxychloroquine, azathioprineand leflunomide may be useful. Mycophenolate mofetil has also been used. The involve-ment of T cells in the pathogenesis of PsA has stimulated the use of cyclosporine andtacrolimus (both anti-T-cell agents), although their use is often limited by renal toxicity.Finally, biological agents are increasingly used for patients with severe disease. These


NodulesRF*Anti-CCP

Inflammatory polyarthritis

Active psoriasis Exclude RAPrevious psoriasisF/H psoriasis

Predominantly DIP**Spinal, SI jointDactylitisNail dystrophy

PsA

Symptomatic• Physiotherapy• NSAIDs

DMARDs

Biological therapies

Figure 33.1 Diagnosis andmanagement of PsA. * RF and anti-CCP are positive in a proportion of patientswith PsA. ** One of these is sufficient to make a diagnosis of PsA in the presence of active psoriasis; twoshould be present to make the diagnosis when there is a previous or family history (F/H) of psoriasis.anti-CCP, antibodies to cyclic citrullinated peptides; DIP, distal interphalangeal; DMARDs, disease-modifying antirheumatic drugs; NSAID, non-steroidal anti-inflammatory drug; PsA, psoriatic arthritis; RF,rheumatoid factor; SI, sacroiliac.


include IL-2 receptor antagonists, anti-T-cell agents (alefacept and efalizumab) andTNF-a antagonists (etanercept, infliximab and adalimumab).

Recent Developments1 Disturbed angiogenesis is a key feature of psoriasis, with increased local

production of angiogenic peptides. Butt et al.5 have investigated polymorphismsin the genes for VEGF, fibroblast growth factor (FGF)-1 and FGF-2, andepidermal growth factor (EGF). Increased prevalence of a polymorphism of theVEGF gene was demonstrated in patients with PsA.

2 High levels of RF in a patient with symmetrical polyarthritis supports thediagnosis of RA. However, RF positivity is not uncommon in inflammatory orimmune disorders other than RA, and does occur in a minority of patients withPsA. Anti-CCP antibodies are more specific for RA, but have also been describedin 5%–10% of patients with clinical PsA.6

3 Self-assessed quality of life and health status are directly linked to disease activityin PsA.7 The number of joints either involved or deformed has a direct bearing.Morning stiffness, level of inflammatory markers and duration of disease are alsoimportant. With increasing duration of disease, the activity of the diseasebecomes a less important determinant of health status.

4 Evidence is accumulating that disease-modifying drugs for PsA, including thenewer biological agents, are not only clinically effective but that their use alsobrings cost benefits.8 This is leading to earlier and more aggressive treatment. PsAis a progressive condition and evidence of radiological joint damage begins toappear as the number of joints involved increases.9 There are strong argumentsfor making the diagnosis early and limiting the progression of a disease that canbe devastating and disabling.

5 Psoriasis and PsA are associated with deterioration in cardiovascular risk profile.10

This is probably due to the widespread inflammation that accompanies thesedisorders. Thus dyslipidaemia, hyperglycaemia, endothelial dysfunction andoxidative stress are all increased, as may be the impact of other conventionalcardiovascular risk factors such as smoking and obesity. Recently, patients withPsA have been shown to have increased carotid intima–media thickness – a directcorrelate with increased risk of vascular disease.11

ConclusionPsA is a fairly common accompaniment to the skin lesions of psoriasis. It appears likelythat the above patient is developing PsA, but other causes of arthritis should be consid-ered. The family history is highly relevant. Several genetic determinants of psoriasis havenow been identified. Environmental triggers for the disease are relatively poorly under-stood at present. It is not clear to what extent the genetic predisposition for PsA is separ-ate to that of the skin disease. Diagnosis of PsA is largely clinical. There is no specificbiological marker. Initial treatment is usually symptomatic, including the use of anti-inflammatory drugs. Systemic corticosteroids are not usually administered. There is



increasing evidence favouring the early use of disease-modifying drugs, including thenewer biological agents. PsA is a serious disease, often progressive, and associated withimpaired function and quality of life as well as with increased cardiovascular risk.

Further Reading1 Myers WA, Gottlieb AB, Mease P. Psoriasis and psoriatic arthritis: clinical features and

disease mechanisms. Clin Dermatol 2006; 24: 438–47.

2 Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature 2007;

445: 866–73.

3 Bowcock AM, Cookson WOCM. The genetics of psoriasis, psoriatic arthritis and atopic

dermatitis. Hum Mol Genet 2004; 13: R43–55.

4 Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H. Classification

criteria for psoriatic arthritis: development of new criteria from a large international study.


5 Butt C, Lim S, Greenwood C, Rahman P. VEGF, FGF1, FGF2 and EGF gene

polymorphisms and psoriatic arthritis. BMC Musculoskelet Disord 2007; 8: 1–7.

6 Inanc N, Dalkilic E, Kamali S et al. Anti-CCP antibodies in rheumatoid arthritis and

psoriatic arthritis. Clin Rheumatol 2007; 26: 17–23.

7 Husted JA, Tom BD, Farewell VT, Schentang CT, Gladman DD. A longitudinal study of

the effect of disease activity and clinical damage on physical function over the course of

psoriatic arthritis. Arthritis Rheum 2007; 56: 840–9.

8 Bansback NJ, Ara R, Barkham N et al. Estimating the cost and health status consequences

of treatment with TNF antagonists in patients with psoriatic arthritis. Rheumatology 2006;

45: 1029–38.

9 Bond SJ, Farewell VT, Schentag CT, Gladman DD. Predictors for radiological damage in

psoriatic arthritis: results from a single centre. Ann Rheum Dis 2007; 66: 370–6.

10 Wakkee M, Thio HB, Prens EP, Sijbrands EJG, Neumann HAM. Unfavorable

cardiovascular risk profiles in untreated and treated psoriasis patients. Atherosclerosis 2007;

190: 1–9.

11 Kimhi O, Caspi D, Bornstein NM et al. Prevalence and risk factors of atherosclerosis in

patients with psoriatic arthritis. Semin Arthritis Rheum 2007; 36: 203–9.



Case HistoryGeoffrey is a 43-year-old man who recently applied for life insurance. As part of theapplication, a biochemical profile was undertaken which, from your pathology service,includes a serum uric acid level. Geoffrey’s result was 0.62 mmol/l (normal range0.15–0.50 mmol/l). He has neither gout nor renal stones and is generally very healthy.

Should his hyperuricaemia be treated?

Should he be worried about vascular disease or renal impairment?

What lifestyle measures should be recommended?

BackgroundUric acid (UA) is the final breakdown product of purine nucleotides (adenine and gua-nine) in the body. The final metabolic steps are hypoxanthine to xanthine, which in turnforms UA. Both these steps are catalysed by the enzyme xanthine oxidase (XO). In mostanimals, UA is further metabolized to allantoin by urate oxidase (uricase). Allantoin is5–10 times more soluble that UA and is readily eliminated by the kidneys. Humans andother primates have a non-sense mutation that results in defective uricase activity andthus higher concentrations of serum urate are reached.

UA is a weak acid and in the extracellular fluid is predominantly ionized – 98% asmonosodium urate. Plasma is saturated with UA at a concentration of 0.415 mmol/l(6.8 mg/dl) and above. When the plasma is saturated, UA crystals are liable to form. Theprecise threshold for this varies slightly because of other physicochemical and environ-mental influences. Excretion of UA is almost entirely by the kidney, with urine at pH 5being virtually saturated with UA. At higher pH, the solubility of UA increases exponen-tially and urine can contain more UA without risk of crystallization. It is for this reasonthat urinary alkalinization is used with uricosuric agents.

UA can only be formed in tissues that contain XO (liver and the small intestine).About two-thirds of the daily purine load is generated endogenously from turnover ofcells, while one-third is derived from diet. Levels are generally higher in men, andincrease substantially at puberty. In women, plasma UA increases after the menopause tolevels comparable to that of men. Women are at lower risk of gout but, when the satur-ation threshold for UA is reached, crystallization is equally likely to occur. Increased UAis present in 5%–8% of males in the United States, and is higher in some racial groupswith particular predisposition to obesity and vascular disease.


34 Asymptomatic Hyperuricaemia

P R O B L E M



A detailed knowledge of UA metabolism1 is not required by the practising clinician. Asimplified scheme is presented in Figure 34.1. This also serves as a reminder of howclosely interrelated UAmetabolism is with other aspects of intermediarymetabolism. UAis almost entirely secreted by the kidneys. The UA transporter URAT1 (SLC22A12) isexpressed in the proximal tubule and is a target for drug treatment. In most individualswith high UA, no underlying cause will be found. The clinician, however, should beaware of the large number of clinical associations. When there is an underlying cause,90% are due to disorders of UA excretion while the remaining 10% relate to increasedUA production. The causes of hyperuricaemia are summarized in Box 34.1.

The most common contributor to UA overproduction is excessive dietary intake,including foods high in purines. Also, obesity and metabolic syndrome are associatedwith a marked tendency to increased UA synthesis. Fructose intake increases UA: follow-ing cellular uptake, fructose is phosphorylated, consuming adenosine triphosphate(ATP) and generating adenosine diphosphate (ADP). As shown in Figure 34.1, ADPfeeds into the UA synthetic pathway, and this is favoured by intracellular phosphatedepletion, which can also accompany fructose ingestion. Alcohol ingestion also leads tointracellular ATP depletion and consequent increases in both ADP and adenosine

34 Asymptomatic hyperuricaemia 185

XO

Ribose-5-P 1 ATP

Inosine monophosphate

Hypoxanthine

XO

Adenosine

ATP

AMP

Adenine

Urate

Xanthine Guanine

Guanosine

GMP

GTPPRPP

Inosine

Figure 34.1 Purine metabolism. Ethanol, fructose feeding, glycogen storage diseases and severe hypoxialead to ATP depletion and thus increased influx of AMP and adenosine into the UA synthetic pathway. Thelast two steps in the above, simplified pathway are catalysed by xanthine oxidase (XO). AMP, adenosinemonophosphate; ATP, adenosine triphosphate; GMP, guanosine monophosphate; GTP, guanosinetriphosphate; PRPP, 5’ phosphoribosyl 1-pyrophosphate; Ribose-5-P, ribose-5-phosphate.


monophosphate (AMP). Beer and spirits are more likely to provoke increased UA thanwine. A number of rare inborn errors of metabolism increase UA synthesis. The mostcommon of these is deficiency of hypoxanthine phosphoribosyltransferase (HPRT),complete deficiency of which causes Lesch–Nyhan syndrome (self-mutilation, choreoa-thetosis andmental retardation). The disorder is X-linked and carrier females are asymp-tomatic. A partial deficiency of the enzyme causes Kelley–Seegmiller syndrome with themetabolic consequences of increased UA but without central nervous system manifesta-tions. Other inborn errors include activating mutations of the phosphoribosylpyrophos-phate synthetase gene and deficiencies of adenine phosphoribosyltransferase,adenylsuccinate lyase, myoadenylate deaminase, adenosine deaminase and purine nucle-oside phosphorylase.

The association of high UA with metabolic syndrome and cardiovascular risk hasattracted a great deal of attention.2,3 Increased UA may be a useful marker for insulinresistance. Even in subjects who have not yet developed metabolic syndrome there is acorrelation between UA levels and body mass, total and high-density lipoprotein (HDL)cholesterol and triglycerides. As overweight individuals lose weight, UA levels decrease inparallel with serum leptin. Twenty to forty per cent of patients with untreated hyperten-sion have high UA, and this is increased where there is also renal impairment. UA levelsalmost always increase in evolving renal failure. However, although increased UA is amarker for cardiovascular risk, it is not certain that it is an independent risk factor andone that we should be attempting to modify. To date, there is no direct evidence to sug-gest that drug treatment to decrease UA protects against cardiovascular events. There issuggestive evidence from the Greek Atorvastatin and Coronary Heart Disease Evaluation


Box 34.1 Causes of hyperuricaemia

A: IncreasedUAproduction (10%)

Obesity Myeloproliferative disease Paget’s diseaseAlcohol Polycythaemia vera Psoriasis

Haemolysis Rhabdomyolysis

Glycogen storage diseases (type III, V andVII)Inborn errors ofmetabolism (includingHPRTdeficiency)

B:DecreasedUA excretion (90%)

Renal impairment StarvationPolycystic kidney disease Acidosis (ketoacidosis, lactic acidosis)

Toxaemia of pregnancyHypothyroidismHyperparathyroidism Bartter’s syndromeDiabetes insipidus Down’s syndrome

Sarcoidosis Lead poisoning

Drugs: Aspirin DiureticsCyclosporine EthambutolL-dopa Pyrazinamide


study4 and from the Losartan Intervention for Endpoint Reduction (LIFE) study withlosartan that decreasing UAmay parallel decreasing vascular risk in intervention studies.5

The vast majority of patients with hyperuricaemia do not require treatment. Thisshould be reserved for patients who are either symptomatic or who are perceived to be atparticularly high risk. The only widely used drug is allopurinol, which is an inhibitor ofXO. All patients with high UA should have the benefit of dietary advice (Box 34.2). Apurine-free diet may also be used to investigate the underlying cause of hyperuricaemia.On such a diet, normal individuals will excrete less than 3.6 mmol/day (600 mg) of UA inthe urine. Those who continue to excrete greater than 4.2 mmol/day almost certainlyhave a condition that leads to UA overproduction. Uric acid excretion can be increasedby alkalinizing the urine with either sodium bicarbonate or acetazolamide.

Recent Developments1 Fructose feeding of rats leads to development of the metabolic syndrome and also

increases circulating UA. In a recent animal study,6 the XO inhibitor allopurinoland the uricosuric agent benzbromarone decreased the effect of fructose feedingon increasing insulin levels, systolic blood pressure and triglycerides, and alsoprevented weight gain. Furthermore, direct effects of UA-lowering agents onendothelial function were demonstrated by studying the response of isolatedaortic rings to acetylcholine.

2 The recommended adult daily allowance for protein is 0.8 g per kilogram ideal bodyweight. High protein intake is associated with higher UA, which may contribute to

34 Asymptomatic hyperuricaemia 187

Box 34.2 Dietary recommendations for hyperuricaemia and gout

� Reduce bodyweight if overweight� Avoid extremes of food intake – both large, richmeals and fasting can increaseUA.

Eat small, regularmeals� Maintain fluid (water) intake – aim for 2–3 litres per day, particularly during flare-

ups of gout� Limit alcohol intake to nomore than one drink per day� Avoid fatty food – fried foods, fattymeats and excessive use of butter ormargarine� Limit protein intake and focus on proteins that are low in purines (dairy produce)� The ideal diet is relatively high in carbohydrate but some high-fibre andwholegrain

foods are relatively high in purines

The following are high in purines and best avoided:Gamemeats and birds; liver; kidney; small oil fish (sardines, anchovies,mackerel);seafood (mussels, scallops, prawns);meat extract; yeast supplements

The following are relatively high in purines and intake should be limited:Oatmeal (<2⁄3 cup per day); wheat bran andwheat germ (<1⁄4 cup per day); peas, beans,spinach, asparagus, cauliflower andmushrooms (<1⁄2 cup per day); poultry,meat, fishand shellfish (1–2 servings per day); dried beans, lentils and other pulses (maximum1cup per day cooked)


decline in renal function in patients with chronic kidney disease.7 There is debateabout the benefit of restricted protein diets in patients with declining renal function.The balance of evidence slightly favours protein restriction as a measure for patientswith chronic kidney disease.

3 At present, allopurinol is the only agent in common use for lowering UA. The drug iswell tolerated and generally quite effective. Febuxostat is a non-purine XO inhibitor.A recent trial8 with this drug in patients with gout demonstrated that the drug waswell tolerated and was more effective than allopurinol in lowering serum UA.

ConclusionIncreased UA predisposes to gout, nephrolithiasis and renal impairment. Current evi-dence does not favour routinely treating hyperuricaemia in asymptomatic individuals.The exception is for patients that were treated with cytolytic chemotherapy for malignantdisease. Increased cellular breakdown in these patients can cause marked hyperuri-caemia. Most patients with increased UA do not develop gouty arthritis, and the lattercan be effectively treated when it arises. A causative role for UA in the genesis of vascularand renal disease remains to be established. The above patient should be encouraged tomaintain a healthy body weight and may consider restricting foods that are known to behigh in purines.

Further Reading1 Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med 2005; 143:

499–516.

2 Baker JF, Krishnan E, Chen L, Schumacher HR. Serum uric acid and cardiovascular disease:

recent developments, and where do they leave us? Am JMed 2005; 118: 816–26.

3 Becker MA, Jolly M. Hyperuricaemia and associated diseases. Rheum Dis Clin North Am 2006;

32: 275–93.

4 Athyros VG, Elisaf M, Papageorgiou AA et al. Effect of statins versus untreated dyslipidaemia

on serum uric acid in patients with coronary heart disease: a subgroup analysis of the GREek

Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Am J Kidney Dis 2004;

43: 589–99.

5 AldermanM, Aiyer KJV. Uric acid: role in cardiovascular disease and effects of losartan. Curr

Med Res Opin 2004; 20: 369–79.

6 Nakagawa T, Hu H, Zharikov S et al. A causal role for uric acid in fructose-induced metabolic

syndrome. Am J Physiol Renal Physiol 2005; 290: F625–31.

7 Mandayam S, MitchWE. Dietary protein restriction benefits patients with chronic kidney

disease.Nephrology 2006; 11: 53–7.

8 Becker MA, Schumacher HR, Wortmann RL et al. Febuxostat compared with allopurinol in

patients with hyperuricaemia and gout.N Engl J Med 2005; 353: 2450–61.



Case HistorySamuel is a 38-year-old mine worker who had an episode of pain and swelling in his leftgreat toe six months ago. He now presents with a one-week history of right ankleswelling. His serum uric acid (UA) is elevated and aspiration of his right ankle jointconfirms that he has acute gout. His general health is good and he takes nomedications.

What features of the clinical history are important?

What aspects of examination may help determine if there is an underlying cause?

How should he be treated and followed up?

BackgroundGout is the most common inflammatory arthritis and usually presents with single jointinvolvement, with the first metatarsophalangeal joint affected in over 70% of cases.1 Ithas been recognized for centuries,2 affects about 1% of the population in developedcountries and is becoming more common because of the increasing prevalence of obesityand metabolic syndrome. The prevalence increases with age and is around 4% in thoseaged 65 years and over. Males are two to three times more commonly affected. Gout isalmost unique in being a disease state precipitated by a physicochemical reaction – i.e.crystallization of UA when the plasma and synovial fluid become saturated with UA at aconcentration of around 0.42 mmol/l. Dietary factors are extremely important and fre-quently neglected. High-purine vegetable foods do not appear to affect UA levels somuch as meat-based foodstuffs.

The typical attack begins in the early hours of the morning and affects the great toe(podagra), ankle, fingers, elbow or, occasionally, knee. The distribution of joints affectedrelates to the prevailing temperature in the joints, with UA precipitation more likely tooccur in cool joints. A variety of nucleating agents in the joint space – including collagen,chondroitin sulphate and proteoglycans – may initiate crystallization of UA. Gout istherefore more likely to occur in joints that are already damaged, for example byosteoarthritis. The pain is typically very severe and the affected joint is swollen, red andtender. Differential diagnosis includes septic arthritis, pseudogout and reactive arthritis.An acute attack usually resolves within 7–10 days, even without specific treatment.However, there will be a recurrence within three years in at least 80% of cases. Tophi arecrystal deposits of UA in soft tissue and do not elicit an inflammatory response compar-able to that found in joints. They typically occur on the ears, hands, feet or elbow.

35 Gout – acute attack and beyond 189

35 Gout – Acute Attack and Beyond

P R O B L E M



The gold-standard investigation is the finding of UA crystals in a joint aspirate in asso-ciation with elevated plasma UA. In practice, joint aspiration is frequently not under-taken. Plasma UA may increase during an acute attack of gout, but one-third of patientswith acute gout have normal plasma UA levels. White cell count may be modestly ele-vated, while a very high count might suggest septic arthritis. If the full blood count isotherwise normal, a myeloproliferative disorder is unlikely (Box 35.1). Renal functionmay be impaired in patients with chronic hyperuricaemia, and should be checked in allcases. It may be useful to measure urinary urate concentration, since high levels wouldpreclude the use of uricosuric agents. Hyperglycaemia and dyslipidaemia are frequentamongst patients with increased UA. Hypothyroidism is quite common, andmay precip-itate gout. X-ray of the affected joint usually only demonstrates the associated soft tissueswelling, but may show erosions around the joint in patients with chronic gout.

Management of the acute attack is usually straightforward.3–5 Conservative measuresinclude rest, elevation of the affected joint and cooling of the joint. It is important toensure that the patient has adequate analgesia. Non-steroidal anti-inflammatory drugs(NSAIDs) are widely used and may be the only treatment required. Colchicine has beenused for many years, but should be regarded as a second-line drug. It acts by decreasingphagocytosis of UA crystals by neutrophils, and thus limits the inflammatory response.The drug has a narrow therapeutic window and toxic effects include diarrhoea, nauseaand vomiting. A dose of 0.5 mg tds is often sufficient. Some would precede this with aloading dose of 1 mg. Up to 6 mg/day can be given, although side effects are almost uni-versal at this dose. It can be given intravenously, but there is a high risk of toxicity. Thethird line of therapy is corticosteroids, given either systemically or intra-articularly. Forthe latter, methylprednisolone or triamcinolone are most commonly used. Systemicsteroids may be particularly useful where there is multiple joint involvement. A singledose of 80–120 mgmethylprednisolonemay be used, or a course of prednisolone startingwith 30–60 mg/day. UA-lowering therapy should not be used during the acute attack.

Planning of chronic treatment for a patient with high UA is summarized inFigure 35.1. The patient should be given appropriate dietary advice (chapter 34) and, ifoverweight, advised to lose weight. The two major approaches to pharmacological ther-apy are decreasing UA production by inhibiting xanthine oxidase (XO), or increasing UAexcretion using uricosuric agents. A third approach, not currently widely available, is to


Box 35.1 Common risk factors for gout

Age Male gender

Race (black >white) Acute illness with dehydration

Increased uric acid Overweight or obese

Diet – high calorie and high purine Alcohol

Proliferative lesions – psoriasis, haemolysis, trauma/burns,myeloproliferative disease

Drugs –most commonly diuretics

Initiation ofUA-lowering therapy



Failed

Successful

If not increased

UA .0.42 mmol/lConfirmed gout (clinically or by joint aspiration)

Treat acute attackWait for 4 weeks

? Overweight – decrease weightDietary advice (low purine, low fat)

Limit alcohol intakeWater intake 2–3 litres/day

Renal functionThyroid function

Plasma lipidsBlood glucose

First attack or#2 attacks per year

.2 attacks per yearUA .0.6 mmol/l

Allopurinol

Check urinary urateUA ,0.36 mmol/lDecreased attacks

Consider uricosuric agent (e.g. sulphinpyrazone)• Losartan if hypertensive• Fenofibrate if dyslipidaemic

Continue treatmentMonitor UA 1 renal function

Lifestyle managementMonitor UA at 3 months

Figure 35.1 Prophylaxis of gout.


use uricase preparations (bacterial or fungal) to increase UA breakdown in vivo. Humanslack the enzyme uricase and cannot degrade UA.

AllopurinolThe mainstay of drug treatment for the past 50 years has been the XO inhibitor allopuri-nol, itself a purine derivative. Generally, it should be reserved for patients who have twoor more attacks per year. Unless the UA level is very high, there is no justification forusing drug therapy in patients with asymptomatic hyperuricaemia. The drug is well toler-ated but reactions may occur in up to 2% of patients. These range from mild urticariaand pruritus to severe hypersensitivity. The latter causes severe (often ulcerating) skinlesions, fever, neutrophilia and often renal impairment. Other rare side effects includeleukopenia, thrombocytopenia, peripheral neuropathy and Guillain–Barré syndrome. Intrials, only as few as 20% of patients treated with allopurinol reach the target serum UAvalue of 0.36 mmol/l. There are a number of potential drug interactions. Allopurinolinhibits the breakdown of the purine drugs azathioprine and mercaptopurine, and willincrease risk of bone marrow toxicity from these drugs. Allopurinol may increase circu-lating levels of theophylline and increase International Normalized Ratio (INR) inpatients taking warfarin. The dose of allopurinol should generally be kept to 300 mg/dayor less, and should be decreased in patients with renal impairment (Box 35.2).Allopurinol is the pro-drug for the active metabolite oxypurinol, and many laboratoriesare able to provide oxypurinol levels as a guide to compliance or for titration of a lowerdose in those with renal impairment.

Most rheumatologists concur with a cost–benefit analysis indicating that allopurinolonly be commenced if >2 attacks of gout are occurring per year. After the acute attack, itmay be useful to commence prophylactic treatment with either a low-dose NSAID (e.g.indomethacin 25 mg bd or diclofenac 25 mg bd) or colchicine 0.5 mg bd. This is contin-ued throughout the introduction and adjustment of allopurinol and for three monthsafterwards. After one month of prophylaxis and quiet joints, allopurinol 100 mg is com-menced in addition to the colchicine/NSAID. At one month the serum UA is measured,and if greater than 0.36 mmol/l, the dose of allopurinol is increased to 200 mg/day whilstcontinuing on the colchicine/NSAID. This continues monthly until the serum UA isbelow 0.36 mmol/l or 400 mg/day of allopurinol is reached. Patients are strongly advisedthat in the event of an acute attack of gout, they must not discontinue or alter their allop-urinol dose but rather reinstitute their acute management plan with either an NSAID or


Box 35.2 Allopurinol dose vs glomerular filtration rate

Estimated creatinine clearance (ml/min) Dose

>100 300 mg/day60 200 mg/day40 150 mg/day20 100 mg/day10 100 mg every other day<10 100 mg every third day


colchicine and seek medical review. If the aim is tophi dissolution, then the plasma UAlevel needs to be lowered towards the lower limit of normal. The current recommenda-tion is for lifelong therapy.

UricosuricsFor patients who either do not respond to allopurinol or are intolerant of the drug,options are fairly limited.6 Currently, the second-line approach is to use uricosuricagents. In order to work, uricosurics require near-normal renal function, a sufficienturine volume and a suitable pH to prevent UA stone formation, and are contraindicatedin anyone with renal stones or in those with a high urinary excretion of UA. Uricosuricswill not work with concomitant salicylates. Probenecid and sulphinpyrazone are old-fashioned drugs that are still available. Themore potent uricosuric benzbromarone is notlicensed in most countries because of hepatic toxicity, but can be used on a namedpatient basis in some countries. Losartan should be considered if the patient is hyperten-sive, and fenofibrate if there is dyslipidaemia. Both of these drugs have uricosuric action,as does the NSAID azapropazone. For patients with frequent attacks, or rebound attacks,low-dose colchicine can be used to help prevent recurrences.

Recent Developments1 Becker et al.7 studied 762 patients with gout and hyperuricaemia randomly

assigned to receive 300 mg/day of allopurinol or febuxostat at a dose of 80 mg or120 mg. Of the latter two groups, 53% and 62%, respectively, reached theprimary endpoint – a serum UA concentration of 0.36 mmol/l. No difference wasnoted in the rate of flare-up of gout during the 52 weeks of the study. Decreasein the size of gouty tophi was also demonstrated.

2 Martinon et al.8 have provided insight into the molecular basis for the intenseinflammation that arises as a consequence of UA crystal deposition in joints.Activation of inflammatory cascades in phagocytic cells involves the formation ofa unit called an inflammasome. This is formed on activation of the cells by thecomplexing of a member of the NALP family of proteins (pyrin domain-containing proteins sharing structural homology with NODs [nucleotide-bindingand oligomerization domain proteins]) with the linking protein ASC (apoptosis-associated speck-like protein) and the enzyme caspase-1. In this study, UAcrystals activated NALP3-containing inflammasomes. Colchicine, acting upstreamfrom inflammasome formation, decreased activation of the pro-inflammatorycytokine interleukin-1b.

ConclusionIn the vast majority of patients with gout, there is no single underlying cause. A positivefamily history could favour an underlying metabolic disturbance. Splenomegaly mightsuggest an underlying myeloproliferative disorder. Associated conditions are muchmorefrequent than underlying causes. These include renal impairment, obesity, hypertension



and themetabolic syndrome.Management of the acute attack is with hydration and anal-gesia, often with the addition of colchicine. In planning ongoing management, carefulattention should be paid to lifestyle factors. Allopurinol is the first-line agent to lowerUA, but does not need to be prescribed to all patients who either have high UA or havehad an attack of gout.

Further Reading1 Choi H. Epidemiology of crystal arthropathy. Rheum Dis Clin North Am 2006; 32: 255–73.

2 Nuki G. Treatment of crystal arthropathy – history and advances. Rheum Dis Clin North Am

2006; 32: 333–57.

3 Suresh E. Diagnosis and management of gout: a rational approach. Postgrad Med J 2005; 81:572–9.

4 UnderwoodM. Diagnosis and management of gout. BMJ 2006; 332: 1315–19.

5 ZhangW, Doherty M, Bardin T et al. EULAR evidence based recommendations for gout. Part

II: Management. Report of a task force of the EULAR Standing Committee for International

Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2006; 65: 1312–24.

6 Bardin T. Current management of gout in patients unresponsive or allergic to allopurinol.

Joint Bone Spine 2004; 71: 481–5.

7 Becker MA, Schumacher HR, Wortmann RL et al. Febuxostat compared with allopurinol in

patients with hyperuricaemia and gout.N Engl J Med 2005; 353: 2450–61.

8 Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals

activate the NALP3 inflammasome.Nature 2006; 440: 237–41.



Case HistoryReg is aged 53 years and presented last week with a four-day history of an acutelyswollen and very painful left knee that had occurred without trauma. He was afebrile buthad a large knee effusion and Baker’s cyst. Aspiration yielded 45 ml of non-viscousblood-stained fluid that appeared turbid. The laboratory confirmed sterile synovial fluidand amoderate presence of red cells, plus elevation of white cells (of which 60% areneutrophils) and abundant intracellular calcium pyrophosphate crystals.

What are the known factors predisposing to pseudogout?

How should these be investigated?

What management strategies will you employ?

BackgroundThe most frequent manifestation of calcium pyrophosphate dihydrate (CPPD) depos-ition disease is chondrocalcinosis, the asymptomatic radiographic finding of calcificationof articular cartilage or fibrocartilage. Up to 5% of the population show radiographic evi-dence of chondrocalcinosis, with the incidence rising with age to 15%–40% of those over60 years of age, and 30%–60% of those >85 years old. Because over three-quarters of pre-senting patients are >60 years old, and most have pre-existing joint damage, it is likelythat biochemical changes in aging cartilage favour crystal nucleation.

The acute symptomatic presentation of chondrocalcinosis is termed pseudogout. Whileusually mild, it can lead to quite severe and rapidly destructive arthritis. The presentation isof an inflammatory arthropathy with loss of function, earlymorning stiffness and improve-ment with activity. Other manifestations include atypical forms of osteoarthritis (OA),severe destruction mimicking neuropathic arthropathy, a symmetrical synovitis similar torheumatoid arthritis, and calcification of the intervertebral discs and longitudinal spinalligaments leading to restricted spinal mobility and hence resembling ankylosing spondylitisbut without sacroiliitis. Disordered calcification of cartilage and other skeletal tissuesoccurs commonly among the elderly, yet the reasons for this are poorly understood.1

CPPD deposition is associated with acute attacks of pseudogout, characterized byjoint effusions with marked neutrophilia. The release of CPPD crystals into a joint space

36 Pseudogout – investigation and management 195

36 Pseudogout – Investigation andManagement

P R O B L E M



is followed by neutrophilic phagocytosis and subsequent release of potent chemoattrac-tant and inflammatory mediators. Pseudogout most commonly involves the knee fol-lowed by the wrists, metacarpophalangeal joints, hips, shoulders, elbows and ankles. Thejoint distribution may provide a clue to CPPD deposition disease, as primary OA rarelyinvolves the metacarpophalangeal joint, wrist, elbow, shoulder or ankle. CPPD crystals,however, may also be found in the synovial fluids of patients with primary OA, eitheralone or in association with basic calcium phosphate crystals. Acute attacks of pseudo-gout may be precipitated by local events that induce crystal shedding from cartilage intothe synovial fluid, such as trauma, arthroscopy or intra-articular injection of high-molecular-weight hyaluronic acid as a viscosupplement. Systemic changes affectingcalcium concentration – such as rapid changes in fluid balance, medical illness, com-mencement of thyroxine or parathyroid surgery – can also induce an acute attack. A sys-temic response to pseudogout is noted in half of patients, with fever, neutrophilleukocytosis and raised inflammatory markers.

Definitive diagnosis of CPPD deposition disease would require unequivocal identifi-cation of weakly positive birefringent rhomboid or rod-shaped CPPD crystals in jointfluid or articular cartilage. Aspirated fluid is often turbid or blood-stained, with reducedviscosity and a marked neutrophil leukocytosis. Articular cartilage at any site maydemonstrate chondrocalcinosis; the classical sites are the triangular ligament of the wrist,the pubic symphysis and the menisci of the knee. It has been proposed that the presenceof CPPD crystals in synovial fluid combined with radiographic evidence of calcificationof the cartilage would make a definitive diagnosis, and either one would make a probablediagnosis. Because joint aspiration or biopsy is impractical in population studies, pres-ence of radiographic chondrocalcinosis is often used in epidemiological and clinicalstudies.2 There are no population epidemiological studies of pseudogout, although mostcase series suggest that the mean age at presentation is between the seventh and eighthdecades, with a female predominance of 2–3:1. The prevalence of radiographic chondro-calcinosis increases with age, with the reported prevalence of radiographic chondrocal-cinosis in the knee joints of elderly males increasing from <4% in those less than 70 yearsof age to 27% in those aged over 85 years.3

Only a minority of patients with CPPD arthritis have metabolic or hereditary abnor-malities. These include hyperparathyroidism, haemochromatosis, hypophosphatasia and


Secondary to underlying medical condition� Hyperparathyroidism� Hypophosphatasia� Haemochromatosis� Hypomagnesaemia� Familial hypocalciuric hypercalcaemia� Possibly hypothyroidism� Chronic gout

Secondary to underlying cartilage alterations� Aging and OA� Post-meniscectomy� Epiphyseal dysplasia

Table 36.1 Conditions associated with CPPD


hypomagnesaemia (Table 36.1 and Figure 36.1). Hypothyroidism is probably associatedwith chondrocalcinosis, but not necessarily pseudogout. The presence of a CPPDarthropathy in a patient younger than 50 years, or in those with florid polyarticular chon-drocalcinosis, should lead to investigation for an underlying metabolic disorder.

Hereditary CPPD deposition disease has been reported in several ethnic populations,usually with autosomal dominant inheritance, and has early onset and varying pene-trance. Whether genetic risk factors are involved in later-life chondrocalcinosis has notbeen established. Small studies suggest an increased recurrence risk in first-degree rela-tives of 11%–28%, and while this is likely to be greater than the prevalence in matched,unrelated individuals, this has not formally been established. A comparison of the recur-rence rate of chondrocalcinosis of the knee in siblings of index cases and unrelated com-munity members found significantly increased familiarity for chondrocalcinosis (siblingrecurrence risk ratio [SRRR] 2.0); for pyrophosphate arthropathy (chondrocalcinosisand OA combined), SRRR was 2.3.4 This showed that the familiarity of knee chondrocal-cinosis in elderly patients is low, as would be expected for a common disease, and thatseverely affected young cases may provide a more rewarding genetic focus.1

TreatmentThe therapeutic options for pseudogout are more limited and less based on an under-standing of the underlying metabolic derangement than is the treatment for gout.Symptomatic therapy with non-steroidal anti-inflammatory drugs, colchicine, jointaspirations, intra-articular steroids and non-pharmacologic support are the main

36 Pseudogout – investigation and management 197

HypophosphatasiaAlkaline phosphatase

Hypomagnesaemia Iron

Human ANKHmutation

↑ Extracellularpyrophosphate

AMPATP

↑ Iron, Fe31. Fe21

Hypomagnesaemia

CPPD Disease

↓ Pyrophosphataseactivity

Hypercalcaemia↑ Crystal nucleation

Figure 36.1 Metabolic factors predisposing to CPPD disease.


approaches to acute management of the acutely inflamed joint and are applied topseudogout. There are, however, few controlled trials.

There is currently no specific treatment to slow or prevent the gradual joint deterior-ation due to chondrocalcinosis, or the progression of the crystal deposition, other thantreatment of any underlying biochemical or metabolic disorders.

Recent Developments1 Toll-like receptors (TLRs) are a family of receptors with roles in host defence and

inflammation. They provide a critical step in the innate immune response andare particularly adapted to recognize microbial components; for example,lipopolysaccharide is recognized by TLR4, and peptidoglycan by TLR2. The TLRsshare a cytosolic Toll/interleukin-1 receptor domain that transduces upregulationof pro-inflammatory genes through activation of nuclear factor-k-beta (NF-kB).TLR2 is expressed constitutively in chondrocytes and is upregulated in cartilageas a consequence of OA. Liu-Bryan et al. demonstrated that CPPD crystals couldfunction as a ligand for TLR2 and mediate signalling to initiate nitric oxideproduction in chondrocytes.5

2 Two chromosome regions (on chromosomes 5 and 8) have been linked tochondrocalcinosis. The chondrocalcinosis gene on chromosome 5p at theCCAL2locus has been demonstrated to be theANKH gene.ANKH is a transmembranepyrophosphate transporter and dysfunction of the gene causes elevation ofintracellular, and reduction in extracellular, pyrophosphates.Mutations of theANKHgene altering the amino terminal of the protein cause familial autosomal dominantchondrocalcinosis; changes towards the carboxy terminal cause cranialmetaphysealdysplasia.6,7Cells transfectedwithANKH variants have not shown significant effectson pyrophosphate levels, leaving open the possibility thatANKHmutations causechondrocalcinosis through effects other than on pyrophosphate transport.7

ConclusionChondrocalcinosis and pseudogout remain enigmatic diseases. Currently, the vastmajority of cases are termed primary or idiopathic, reflecting our lack of knowledgerather than providing a useful classification. Human genome mapping and lessons fromanimal models have provided genetic clues in our understanding of pyrophosphatemetabolism and transport. It is hoped that further analysis of both populations and fam-ilies with the various forms of CPPD deposition disease will identify both the basis of thedisease and effective therapies.

Further Reading1 Zhang Y, BrownMA. Genetic studies of chondrocalcinosis. Curr Opin Rheumatol 2005; 17:

330–5.

2 Choi H. Epidemiology of crystal arthropathy. Rheum Dis Clin North Am 2006; 32: 255–73.



3 Felson DT, Anderson JJ, Naimark A, Kannel W, Meenan RF. The prevalence of

chondrocalcinosis in the elderly and its association with knee osteoarthritis: the Framingham

Study. J Rheumatol 1989; 16: 1241–5.

4 ZhangW, Neame R, Doherty S, Doherty M. Relative risk of knee chondrocalcinosis in siblings

of index cases with pyrophosphate arthropathy. Ann Rheum Dis 2004; 63: 969–73.

5 Liu-Bryan R, Pritzker K, Firestein GS, Terkeltaub R. TLR2 signaling in chondrocytes drives

calcium pyrophosphate dihydrate and monosodium urate crystal-induced nitric oxide

generation. J Immunol 2005; 174: 5016–23.

6 Williams CJ, Zhang Y, Timms A et al. Autosomal dominant familial calcium pyrophosphate

dehydrate deposition disease is caused by mutation in the transmembrane protein ANKH. Am

J Hum Genet 2002; 71: 985–91.

7 Pendleton A, JohnsonMD, Hughes A et al. Mutations in ANKH cause chondrocalcinosis. Am

J Hum Genet 2002; 71: 933–40.

37 Joint and bone infections 199

37 Joint and Bone Infections

P R O B L E M

Case HistoryMr DH is 32 years old and was diagnosed with type 1 diabetes at the age of 8. He presentswith a hot, swollen right knee with marked overlying cellulitis. The symptoms developedrapidly over 24 hours. He had been working on his garden the day before. He is febrile(38.3°C) with tender lymphadenopathy in his right groin. He has maintained satisfactoryglycaemic control by increasing his insulin. His knee is aspirated and the aspirate ispurulent with large numbers of Gram-positive cocci.

What is the likely organism?

Is he likely to have a bone infection (osteomyelitis)?

What investigations and treatment are indicated?



BackgroundSeptic arthritisThe diagnosis of joint infection is usually easy. The patient typically presents with a singlehot, swollen and tender joint with fever, rigors and systemic upset. The knee is affected inaround 50% of cases, the hip and ankle each in 15%, the elbow in 10% and the wrist andshoulders each in 5%. Around 10% of cases are polyarticular, particularly where theunderlying infection is gonorrhoea, group B streptococcus, pneumococcus or Gram-negative organisms. Risk factors are summarized in Box 37.1.

The incidence of septic arthritis is increasing, partly because of the aging populationstructure and partly because of antibiotic resistance. Much of the increase is due to methi-cillin-resistant Staphylococcus aureus (MRSA) and group B streptococci. The average age


Box 37.1 Risk factors for septic arthritis

Prior joint problems (osteoarthritis, rheumatoid arthritis, gout)Joint surgery, prosthetic joints, injection or arthroscopyLoss of skin integrity (ulcer, psoriasis, eczema)DiabetesRenal failureCirrhosisImmunosuppression (including use of anti-tumour necrosisfactor [TNF]-a therapy)Intravenous drug abuseNounderlying risk factor in 20%of cases

Box 37.2 Organisms responsible for septic arthritis

Organism % of cases

Staphylococcus aureus 44.3Streptococcus pyogenes 7.6Streptococcus pneumoniae 6.5Haemophilus influenzae 4.3Mycobacterium tuberculosis 4.2Escherichia coli 3.8Coagulase-negative staphylococci 3.5Neisseria gonorrhoeae 3.2Streptococcus agalactiae 2.9Pseudomonas aeruginosa 1.5Neisseriameningitidis 1.2Salmonella 1.0OtherGram-negative organism 4.6Other b-haemolytic streptococci 4.3Polymicrobial 1.4Other (including fungi) 5.9

Adapted from Ross et al. 2003.1


at onset is 50 years. The elderly, those with comorbidities (including diabetes) and thoseinfected with b-haemolytic streptococci are at increased risk.2 S. aureus is by far the mostcommon organism and joint infection often follows a transient bacteraemia. The range oforganisms implicated is very wide (Box 37.2).

Unusual infections and at-risk groups include:

� Brucellosis related to consumption of unpasteurised milk products. Presents withmono- or oligoarthropathy, often affecting the sacroiliac joint. Diagnosed by bloodculture or serology and treated with doxycycline or streptomycin

� Human and animal bites may present with mixed organisms (usually includingstreptococci and staphylococci) or unusual organisms. Rat-bite fever is caused byStreptococcus moniliformis and presents with arthralgia, systemic upset and rash ofthe palms and soles

� Melioidosis, caused by Burkholderia pseudomallei, is an endemic infection in ruralSouth-East Asia and tropical Australia. Prolonged treatment with Bactrim, doxy-cycline or cephalosporin is required to prevent reactivation

� Intravenous drug users. The most prominent organism (60% of cases) in this groupis Pseudomonas aeruginosa. The infection may affect joints not usually involved inseptic arthritis including the sternoclavicular joint, sacroiliac joints or the pubicsymphysis

Investigation and management is summarized in Figure 37.1. The patient is usuallyfebrile but peripheral white blood cell count is not always elevated. Inflammatory mark-ers (erythrocyte sedimentation rate and, particularly, C-reactive protein [CRP]) arealmost always increased. Where possible, the joint should be aspirated; for hip infections,this should be done in theatre. It is not clear whether arthroscopy with joint washout isroutinely superior to simple aspiration. Arthroscopy should be carried out if there is apossibility of a foreign body in the joint and where there has been injury to the joint. Thewhite cell count on aspiration of a septic joint is usually greater than 50000 cells/ml. Thislevel of white cell count can also be seen with crystal arthritis. Blood cultures can also betaken, and the chances of a positive culture from a joint aspirate may be increased if asample of the aspirate is incubated in a blood-culture bottle. The choice of antibioticdepends on the organism. An initial choice, unless Gram stain of the aspirate suggestsotherwise, should include cover against S. aureus. A combination of flucloxacillin 500 mgqds and clindamycin 300 mg qds, both intravenously, is suitable. Generally, the patientshould stay on antibiotics for a total of six weeks.

OsteomyelitisBone infection is either blood-borne or arises from contiguous spread from a focus ofinfection.3 Osteomyelitis may be further classified as acute or chronic. An anatomic clas-sification is also used: medullary osteomyelitis is infection limited to medullary contentand endosteal surface (equivalent to early haematogenous spread); superficial impliesearly change from local spread, and necrosis is limited to the exposed surface of bone;localized implies full cortical thickness, but which could be removed without comprom-ising the stability of the bone; diffuse implies a segment of bone is involved and debride-ment would affect bone stability.




Gram 1ve cocci e.g. Gram 2ve bacilli

Hot, swollen, tender joint

FBCBlood culturesESR 1 CRP

Arthroscopy 1irrigation

Aspirate

Aspirate WBC .50 000 per mlNo crystals

Gram stainCulture aspirate

Flucloxacillin 1clindamycin

Other antibioticse.g. vancomycin

Rest 1 elevation of jointAnalgesia

IV antibiotics until swelling subsided and CRP near normal

Oral antibiotics (6 weeks total antibiotics treatment)

Figure 37.1 Management of septic arthritis. +ve, positive; –ve, negative; CRP, C-reactive protein; ESR,erythrocyte sedimentation rate; FBC, full blood count; WBC, white blood cell count.


Haematogenous spread is the source of infection in about 20% of cases and S. aureus isby far the most common organism. It usually presents with local pain but with relativelylittle constitutional upset. The vertebral column is a common site, and the lumbar spineis affected in 45% of cases, thoracic spine in 35% and cervical spine in 20%. Patients withdiabetes, renal failure or other chronic disease associated with a compromised immunesystem are at particular risk, with men twice as likely to be affected.

Contiguous-focus osteomyelitis without vascular insufficiency may follow trauma orsurgical procedure (typically one month afterwards). Procedures include internal fix-ation of fracture or insertion of a joint prosthesis. S. aureus is commonly implicated butinfections are often mixed and include Gram-negative bacilli and anaerobes.Contiguous-focus osteomyelitis with vascular insufficiency is most commonly seen indiabetic patients with poor vasculature, neuropathy and foot ulcers. It typically affectsthe small bones of the foot and generally requires amputation.

The earliest X-ray signs of osteomyelitis in the long bones are periosteal thickening orelevation. Lytic areas may not be apparent for some weeks, when up to 75% of the bonematrix has been lost. Radionuclide scanning with technetium 99m is frequently helpfulin localizing osteomyelitis, although the presence of an area of increased uptake does notnecessarily equate with bone infection. A gallium scan may be helpful in difficult cases.Indium-labelled leukocyte scans are seldom used in clinical practice and have little tooffer over other modalities. Magnetic resonance imaging (MRI) is very helpful, withareas of infection showing as increased intensity on the T2-weighted image.

Management should include wound toilet and debridement where appropriate.Antibiotics should be continued for at least six weeks. The antibiotic regimen will dependon the clinical scenario and whether an organism has been isolated. Ciprofloxacin,clindamycin, levofloxacin and cephalexin are frequently useful. Two separate anti-staphylococcal agents are usually prescribed. Outpatient intravenous treatment using aperipherally inserted central catheter is frequently used to avoid a prolonged hospitaladmission. Hyperbaric oxygen (HBO2) therapy, though not universally available, is auseful adjunct. The oxygen tension in infected bone is very effectively increased withHBO2. Low oxygen tension decreases migration of cells involved in wound healing,including fibroblasts, and also impairs the bacterial killing ability of phagocytic cells.4

Recent Developments1 Culture-negative septic arthritis (5%–20% of cases) may occur because of organisms

that are difficult to detect or because the patient has been partially treated withantibiotics. A variety of markers in serum or synovial fluid have been proposed.These include TNF-a, lactic acid, lactate dehydrogenase and procalcitonin. Recentstudies, both with children5 and adults,6 confirm that procalcitonin is a highlyspecific marker for bone and joint infections. Sensitivity is improved by combiningthe results with CRP level. An alternative is polymerase chain reaction (PCR)screening for bacterial products. Availability of high-throughput techniques shouldmake this method of diagnosis a viable option in the very near future.

2 Gavet et al.7 have compared joint infections in elderly patients with those that occurat a younger age. The range of causative organisms, the distribution of jointinvolvement and the incidence of polyarticular disease were similar. There was a



marked increase in mortality with age: death occurred in 0.7% of patients aged under60 years, in 4.8% of those aged between 60 and 79 and in 9.5% of those aged 80 andolder.

3 Spinal infections account for only between 2% and 4% of cases of osteomyelitis.8

Diagnosis is frequently delayed and should be suspected in patients who present withback pain that is not clearly of mechanical origin. Inflammatory markers are usuallyelevated and are extremely useful in following the response to treatment. Imaging isextremely important in making the diagnosis and a combination of plain X-rays,radionuclide scanning andMRI is frequently required. Definitive diagnosissometimes requires either open or percutaneous biopsy.

4 (18)-F-fluorodeoxyglucose-positron emission tomography (FDG-PET) is emergingas a potentially useful tool in the diagnosis of musculoskeletal infections.9 It may beeven more accurate than conventional radionuclide scanning for the diagnosis ofosteomyelitis, and may be particularly useful where there are metal implants orprostheses.

5 The increasing use of invasive radiological techniques for angiography and lesionbiopsy is placing an increasing number of patients at risk of staphylococcalbacteraemia.10 Risk factors for bacteraemia include general debility, being on ahaemodialysis programme, having an indwelling vascular catheter and acquiring thebacteraemia outside a hospital setting. The duration of symptoms is also important.When undergoing a procedure, patients should be made aware of the need to reportsymptoms suggestive of infection promptly.

ConclusionBy far the most likely causative organism in the above case is S. aureus. However, a widerange of other organisms commonly causes septic arthritis. The diagnosis should be con-firmed by joint aspiration where possible. The patient’s history of diabetes is highly rele-vant and represents a major risk factor. It is unlikely that the patient has osteomyelitis.Treatment should begin with intravenous antibiotics, which should be continued untilthe infection is fully subsided and inflammatory markers have returned virtually to nor-mal. In total, antibiotics should be given for at least four to six weeks. The risk of boneand joint infections increases with age, and they are still associated with considerablemortality, some of which is related to delayed diagnosis and inadequate antibiotictherapy.

Further Reading1 Ross JJ, Saltzman CL, Carling P, Shapiro DS. Pneumococcal septic arthritis: review of 190

cases. Clin Infect Dis 2003; 36: 319–27.

2 Ross JJ. Septic arthritis. Infect Dis Clin North Am 2005;19: 799–817.

3 Calhoun JH, Manring MM. Adult osteomyelitis. Infect Dis Clin North Am 2005; 19: 765–86.

4 KawashimaM, Tamura H, Nagayoshi I, Takao K, Yoshida K, Yamaguchi T. Hyperbaric

oxygen therapy in orthopaedic conditions.Undersea Hyperb Med 2004; 31: 155–62.



5 Butbul-Aviel Y, Koren A, Halevy R, SakranW. Procalcitonin as a diagnostic aid in

osteomyelitis and septic arthritis. Paediatr Emerg Care 2005; 21: 828–32.

6 Martinot M, Sordet C, Soubrier M et al. Diagnostic value of serum and synovial procalcitonin

in acute arthritis: a prospective study of 42 patients. Clin Exp Rheumatol 2005; 23: 303–10.

7 Gavet F, Tournadre A, Soubrier M, Ristori JM, Dubost JJ. Septic arthritis in patients aged 80

and older: a comparison with younger adults. J Am Geriatr Soc 2005; 53: 1210–13.

8 An HS, Seldomridge JA. Spinal infections: diagnostic tests and imaging studies. Clin Orthop

Relat Res 2006; 444: 27–33.

9 Stumpe KDM, Strobel K. 18F FDG-PET imaging in musculoskeletal infection.Q J Nucl Med

Mol Imaging 2006; 50: 131–42.

10 Fowler VG, Justice A, Moore C et al. Risk factors for hematogenous complications of intravas-

cular catheter-associated Staphylococcus aureus bacteremia. Clin Infect Dis 2005; 40: 695–703.

38 Viral arthritis 205

38 Viral Arthritis

P R O B L E M

Case HistoryJG is a 45-year-old womanwho presents with three days of pain and stiffness in herknees, ankles and hands. She reports fever, mild upper respiratory tract symptoms andaccompanying myalgia. There is no past medical history of note. Her white blood cellcount is normal but erythrocyte sedimentation rate is elevated at 56 mm/h andC-reactive protein is elevated at 80 mg/l.

What other clinical features should be sought?

Which viruses commonly give rise to this clinical picture?

How should she be investigated and managed?

BackgroundViral arthritis is relatively uncommon, accounting for only around 3% of acute poly-arthropathies.1,2 It is usually self-limiting. Persistent joint symptoms can occur, particu-larly in patients who are immunocompromised or have persistent infection. In practice,it is often difficult to be certain of a diagnosis of viral arthritis initially: evidence of recentor past viral infection is very common; the range of viruses that can cause joint symptoms



is broad; joint tissue is very vascular, especially when inflamed, and even the finding ofviral particles or DNA in joint tissue cannot alone be taken as evidence for a viral aeti-ology for the arthropathy. Joint inflammation following viral infection can occur bydirect damage due to viral replication in the joint (as in rubella) or alteration of thehumoral and cell-mediated immune systems (as with hepatitis B and C), and manyviruses can predispose to low-level autoimmunity. The latter can lead to autoantibodiesincluding those to double-stranded DNA (dsDNA), rheumatoid factor (RF), SSA (Ro),SSB (La), neutrophil cytoplasmic antigen and cardiolipin. The appearance of low titres ofautoantibodies does not necessarily signify that an autoimmune disease has developed.Conversely, many patients with autoimmune diseases have antiviral antibodies, but thisdoes not necessarily signify previous viral infection. An example is the frequency of anti-bodies to human immunodeficiency virus (HIV) p24 core in patients with systemic lupuserythematosus or Sjögren’s syndrome (SS). The viruses that most commonly cause viralarthritis are summarized in Table 38.1.

Parvovirus B19 (B19)Until recently, B19 was thought to be a single species and the only parvovirus to infecthumans. In fact, three closely related genotypes (differing by less than 10%) have beenidentified. Parvovirus is a single-stranded DNA virus encoding two capsid proteins – VP1and VP2 – the latter being the major capsid protein. The virus replicates in erythroid pre-cursors. Epidemics of infection occur in late winter and early spring. The virus is spreadby respiratory secretions. Symptoms develop after 7–18 days incubation and includeupper respiratory tract symptoms, fever, arthralgia, myalgia and skin lesions. The charac-teristic skin lesion, erythema infectiosum (‘slapped cheek’), occurs in most children butis characteristically absent in adults. Joint symptoms develop in only 8% of infected chil-dren but in 80% of adults. It typically causes symmetrical polyarthopathy, with affected


Parvovirus B19

Rubella

Hepatitis C

Alphaviruses� Chikungunya� O’nyong-nyong� Ross River Virus� Barmah Forest Virus� Sindbis Virus, Pogosta Disease

Flaviviruses� Kunjin� Dengue� Kokobera

Retroviruses

Others – Hepatitis B, Epstein–Barr, Varicella Zoster,Coxsackie B4 (Bornholm Disease), Cytomegalovirus

Table 38.1 Causes of viral arthritis


joints being tender and swollen but usually not erythematous and not deformed. Othermanifestations include a transient aplastic anaemia, which can also occur in developingfoetuses due to transplacental passage of the virus. Infection of a pregnant woman canlead to spontaneous miscarriage or hydrops fetalis.

Development of immunoglobulin M (IgM) antibodies, followed by IgG antibodies, ischaracteristic of acute infection. Isolation of viral DNAmay be achieved by hybridizationor with polymerase chain reaction. As the pattern of joint involvement resembles that inrheumatoid arthritis (RA), and B19 infection is frequently accompanied by low titre RF,the virus has been considered as a potential aetiological agent for RA. Persistent jointinvolvement following B19 infection may occur in patients who fail to develop neutraliz-ing titres of antibody, and this may be difficult to distinguish from RA. Intravenousimmunoglobulin treatment should be considered for patients with evidence of contin-ued infection.

RubellaThis is the only member of the Rubivirus genus of the Togaviridae family, and is anenveloped, single-stranded, positive-sense RNA virus. Sporadic cases are now typical,with the advent of vaccination programmes, while previously late-winter epidemics werecharacteristic. After an incubation of 7–9 days, the patient develops fever, cervical andsuboccipital lymphadenopathy and a characteristic maculopapular rash that lasts up tofive days. Petechiae on the soft palate (Forchheimer’s spots) are characteristic. The vac-cines used are live attenuated vaccines andmay also cause joint symptoms. The arthralgiaof rubella has a typical ‘rheumatoid’ distribution. Low-level titres of RF are quite com-mon, and RF positivity may conversely give a false positive for rubella IgM. Joint mani-festations are much more common in adults, and more likely in females.

Hepatitis CThis is an enveloped, single-stranded RNA flavivirus. More than 170 million peopleworldwide have now been exposed to hepatitis C. The prevalence is increasing, largelyamongst intravenous drug users and prison populations. The infection now affects up to3% of the United States population. Joint symptoms occur in up to 40% of hepatitis C-infected patients, but arthritis occurs in only 2%. Again the distribution is usually likethat found in RA, but erosive changes are absent. Around 20% of patients have mixedcryoglobulinaemia, and this is associated with an asymmetrical, pauciarticular, medium-large joint arthritis. The virus has been associated with a range of autoimmune diseasesincluding RA, autoimmune hepatitis, glomerulonephritis and SS. Between 15% and 20%of SS patients show evidence of hepatitis C, often with absent SSA or SSB antibodies. Theprevalence of RF positivity is greatly increased in hepatitis C-infected patients, but anti-bodies to cyclic citrullinated peptides (anti-CCP; a more specific marker for RA) are usu-ally not detected. The presence of severe joint involvement should lead to antiviraltherapy being considered. Up to 75% of patients with hepatitis C infection have extra-hepatic manifestations, which usually improve with antiviral therapy. The usual treat-ment is with weekly subcutaneous peginterferon-a for 48 months and twice-dailyribavarin for 24 weeks. Corticosteroids may also be used for arthropathy, as may hydroxy-chloroquine, and there is some evidence of benefit with anti-tumour necrosis factor



therapy. Hepatitis B infection is not commonly complicated by arthritis unless poly-arteritis nodosa develops.

AlphavirusesThere are around 26 members of this genus of the Togaviridae family. The central RNA-containing nucleoplasmid is surrounded by a lipid bilayer, into which is embeddedmultiple copies of the two encoded glycoproteins. The viruses are transmitted by mos-quitoes, and reservoirs include birds, mammals andmarsupials. A careful travel history isessential. Some of the common viruses of this group are listed in Table 38.1.Chikungunya occurs in central Africa, South and East Asia and the West Pacific;O’nyong-nyong occurs in central East Africa; Ross River Virus is found in Australia andthe West Pacific; Barmah Forest Virus occurs only in Australia; Sindbis Virus occurs inScandinavia, Northern Russia, Africa and Australia; Pogosta Disease is largely confinedto Finland.

Symptoms are variable. After 7–12 days incubation, the patient may develop anorexia,nausea and vomiting, abdominal pain, pharyngitis, headache and photophobia. Facialflushing may give rise to a more generalized maculopapular rash. Joint symptoms – asymmetrical, non-deforming polyarthropathy – may precede the rash and other symp-toms. Diagnosis is made on paired sera 10–14 days apart, with increased IgM antibodyindicating recent infection. Viral DNA can be persistent in synovial tissue, whiledetection of viral DNA in blood indicates ongoing or chronic infection. Treatment issymptomatic. Salicylates should be avoided if there is a possibility of dengue infectionbecause of the increased risk of haemorrhagic complications.

RetrovirusesArticular manifestations are common and include arthralgia, spondyloarthropathy, SS(with CD8+ lymphocytic infiltration of salivary and lachrymal glands), myopathy, sys-temic vasculitis and increased risk of septic arthritis. The latter may be caused by a varietyof organisms including Staphylococcus aureus, streptococcus, salmonella and atypicalmycobacteria. The presentation is often like reactive arthritis with uveitis and skinlesions. Psoriasis is also more common, frequently with joint manifestations. With theadvent of highly active antiretroviral therapy in the 1990s, the risk of death from HIVinfection decreased, while improved prognosis has been associated with a higher inci-dence of chronic complications, including those affecting the joints.

Recent Developments1 A recent serological survey3 in the United Kingdom showed that 25% of young

children had been exposed to parvovirus B19, compared with up to 75% of the adultpopulation. Maternal infection could affect up to one in 500 pregnancies, and thusbe a significant contributor to fetal loss. Recent studies4–6 confirm increased B19seropositivity in patients with RA. While this does not prove a causative relationship,the finding that viral DNA is present in synovial tissue from a proportion of patients,and that the presence of B19 DNAmay precede the onset of clinical RA, adds weightto the hypothesis that B19 infection may contribute to the risk of RA. Furthermore,



cross-reactivity to the VP1 unique region has also been implicated in thedevelopment of antiphospholipid antibodies.7

2 There has been recent interest in the RNA-induced silencing complex (RISC).8 It isstriking that the viruses that cause arthritis are RNA viruses, and that many of theautoantibodies involved in connective tissue diseases are directed at proteinsinvolved in regulation of RNA replication and expression. RNA interference is animportant post-transcriptional regulatory mechanism whereby small RNA species ofup to 25 nucleotides direct the interaction between proteins and RNA. Nucleolyticenzymes (Dicer and the Argonaute proteins) are responsible for the generation of thesmall RNA species, which clearly could be of viral as well as of host origin.

3 Arthritis related to hepatitis C infection could become an increasing problem.9

Recent data confirm that the joint manifestations are not directly due to viralreplication, and that less-direct, immune-activating mechanisms must beresponsible.10 Understanding of the mechanism of hepatitis C-induced arthritis isimportant since it may not be influenced by antiviral treatment but may be amenableto other forms of immune modulation.


Travel historySexual historyDrug usage

Other symptoms and signsCRP, ESR

1st serum sample

2nd serum sample (10–14 days)

NSAIDsRange of motionexercises

Serology negativePersistent or worsening symptoms

Consider steroid treatment Reconsider diagnosis• Rheumatoid etc.• Lyme disease• Reactive arthritis

IgM positive4-fold increase in Ab titre

Viral arthritis

Figure 38.1 Diagnosis and treatment of viral arthritis. CRP, C-reactive protein; ESR, erythrocytesedimentation rate; NSAID, non-steroidal anti-inflammatory drug.



ConclusionGiven the range of viruses that cause clinically significant human infections, it is surpris-ing how few have been associated with viral arthritis. Diagnosis and treatment are sum-marized in Figure 38.1. The mainstay of diagnosis is paired serological tests with anincrease in antibody titre of four-fold above baseline or development of IgM antibodiesindicating recent infection. Treatment is symptomatic, and usually confined to non-steroidal anti-inflammatory drugs and a range of motion exercises. Steroids may be use-ful for patients who have a confirmed diagnosis and who have mounted a serologicalresponse to the infecting agent.11 Prolonged arthritis may occur with parvovirus B19 andwith the alphaviruses. For patients with severe, atypical or persistent symptoms, otherdiagnoses should be considered.

Further Reading1 Calabrese LH, Naides SJ. Viral arthritis. Infect Dis Clin North Am 2005; 19: 963–80.

2 Franssila R, Hedman K. Viral causes of arthritis. Best PractRes Clin Rheumatol 2006; 20:1139–57.

3 Vyse AJ, Andrews NJ, Hesketh LM, Pebody R. The burden of parvovirus B19 infection in

women of childbearing age in England andWales. Epidemiol Infect 2007; 135: 1354–62.

4 Caliskan R, Masatlioglu S, Aslan M et al. The relationship between arthritis and human par-

vovirus B19 infection. Rheumatol Int 2005; 26: 7–11.

5 Chen YS, Chou PH, Li SN et al. Parvovirus B19 infection in patients with rheumatoid

arthritis in Taiwan. J Rheumatol 2006; 33: 887–91.

6 Baskan EB, Yilmaz E, Saricaoglu H et al. Detection of parvovirus B19 DNA in the lesional

skin of patients with Behçet’s disease. Clin Exp Dermatol 2007; 32: 186–90.

7 Tzang BS, Tsay GJ, Lee YJ, Li C, Sun YS, Hsu TC. The association of VP1 unique region

protein in acute parvovirus B19 infection and anti-phospholipid antibody production. Clin

Chim Acta 2007; 378: 59–65.

8 Jakymiw A, Ikeda K, Fritzler MJ, Reeves WH, SatohM, Chan EKL. Autoimmune targeting of

key components of RNA interference. Arthritis Res Ther 2006; 8: R87–95.

9 Sanzone AM, Bégué RE. Hepatitis C and arthritis: an update. Infect Dis Clin North Am 2006;

20: 877–89.

10 Tarantino G, Riccio A, Spanò A et al. HCV infection and chronic arthritis: Does viral replica-

tion matter?Hepatol Res 2006; 35: 238–41.

11 Mylonas AD, Harley D, Purdie DM et al. Corticosteroid therapy in an alphaviral aarthritis.

J Clin Rheumatol 2004; 10: 326–30.


Case HistoryMr JT is a 62-year-old man who has had type 2 diabetes for ten years. Glycaemic control isnot perfect (glycosylated haemoglobin [HBA1C] 8.2%) on a combination of sulphonylureaandmetformin. He presents with stiffness and some pain around his left shoulder.Shoulder movement is limited and he cannot place his hand behind his head.

Is his problem likely to be related to diabetes?

What might be the underlying mechanism?

Are musculoskeletal symptoms increased in patients with diabetes?

BackgroundThe prevalence of diabetes is increasing globally. Currently, around 7% of the adult pop-ulation is affected, and by 2025 the number of patients in the world with diabetes willhave increased to over 300million. This increase is largely attributed to the aging popula-tion structure and the rising prevalence of obesity. It is well established that the presenceof diabetes relates to impaired quality of life and functional ability. Much of this is due tothe direct metabolic consequences of diabetes, and also to its associated vascular compli-cations. The development of diabetes also predisposes to a variety of musculoskeletalcomplications. These are often under-recognized in clinical practice.

Rheumatological complications of diabetes have been classified according to whetherthey are due to the metabolic consequences of the condition, to microvascular compli-cations or to underlying aetiological mechanisms.1,2 The problems encountered will beconsidered according to the affected tissue. Increased uric acid is frequent as part of themetabolic syndrome, possibly making gout more common in patients with diabetes.Osteoarthritis is much more common in obese individuals, who are also more likely todevelop diabetes. Nerve entrapment syndromes may also be more common amongstpatients with diabetes.

Muscle complicationsStatin drugs are increasingly prescribed for the dyslipidaemia of diabetes. Muscle symp-toms are relatively common with statin treatment, and severe muscle complications

39 Rheumatological complications of diabetes 211

39 Rheumatological Complications ofDiabetes

P R O B L E M



including myalgia, myositis and rhabdomyolysis occur in around 1% of treated patients.Diabetic muscular infarction is a rare disorder that usually occurs in patients with type 1or type 2 diabetes of long standing and is associated with the presence of vascular compli-cations. It presents as pain and swelling, most commonly in the thigh, but can occur inthe calf or other muscle groups and may cause symptoms in multiple muscle groups.Conditions that should be excluded are venous thrombosis, abscess, haematoma, trau-matic muscle tear and inflammatory myositis. The aetiology is not clear but may includepoor muscle perfusion from vascular disease, increased thrombotic tendency, metabolicalterations in skeletal muscle and the mechanical demands made on large muscle groupssuch as those in the thigh.

Ligament, tendon and capsular problemsLower limb complications of diabetes – osteomyelitis, foot ulceration and Charcot’sarthropathy – are more likely to be serious and life-threatening. However, upper limbcomplications are more common and contribute considerably to the functional disabilityassociated with diabetes. The most common of these are adhesive capsulitis of the shoul-der, Dupuytren’s disease, limited joint mobility syndrome (cheiroarthropathy) and pal-mar flexor tenosynovitis (trigger finger). These may occur in isolation or associated witheach other. They are more common in patients with long-standing diabetes, with poorglycaemic control and with microvascular complications. Increased collagen glycosyla-tion and cross-linking has been implicated in the pathogenesis of these complications.

Adhesive capsulitis causes pain and stiffness and limits the range of movement. Itoccurs in 2%–3% of the non-diabetic population but is up to five times more common inpatients with diabetes, who are also more likely to have bilateral involvement. Treatmentis with exercises, non-steroidal anti-inflammatory drugs (NSAIDs), injected steroids orsurgery. In a Finnish study,3 the prevalence of rotator cuff tendonitis and non-specificshoulder pain was 2% and 12%, respectively, in the general population. The risk of symp-toms was much higher amongst patients with insulin-requiring diabetes (odds ratio =8.8). There was a strong association between shoulder symptoms and psychological dis-turbances.

Dupuytren’s disease (DD), due to fibrosis and nodules in the palmar fascia, leads toflexion contractures of the digits and occurs particularly in patients with long-standingand poorly controlled diabetes. DD primarily affects the middle and ring fingers. Thereported prevalence amongst patients with diabetes varies between 3% and 30%. It isequally common in type 1 and type 2 diabetes. There is no strong relationship betweenrisk of DD and the level of glycaemic control. Generally DD is more common in men butin diabetes the two genders are almost equally affected. Patients with diabetes are lesslikely to require, or have, surgical treatment.

Cheiroarthropathy is usually manifest as an inability to extend the metacarpopha-langeal joints fully. The prayer sign is usually positive – the patient is unable to flatten thehands together. The relationship between limited joint mobility (LJM) and poor diabetescontrol is not established. LJM may contribute to the development of the diabetic foot,including altering plantar pressures and predisposing to ulceration. The prevalence ofLJM may have decreased in recent years, perhaps because of improvements in manage-ment.4 Nonetheless it still may occur in up to one in five patients, and is associated withlonger duration of diabetes.



Bone complicationsHyperostosis may present as spondylosis, hyperostosis frontalis interna or calcification ofthe joints and ligaments. All are much more common in patients with diabetes. Diffuseidiopathic skeletal hyperostosis (DISH) is a condition with excessive new bone forma-tion, particularly in the enthesal region. There is considerable interest in this conditioncurrently as it is associated not only with diabetes but also with other components of themetabolic syndrome including hyperinsulinaemia and increased growth hormone.

The relationship between diabetes and low bone mineral density (BMD) has beenuncertain. Patients with type 1 diabetes may have decreased BMD from an early stage.Low levels of vitamin D have been documented as a risk factor of diabetes, and this maypartly explain the association. Insulin is a growth factor for bone. Insulin deficiency intype 1 diabetes has been suggested as a contributor, although patients with type 1 dia-betes are generally not insulin deficient for long. Patients with type 2 diabetes are gener-ally somewhat protected because of the associated obesity.

Joint disordersNeuropathic arthropathy (Charcot joints) occurs in 0.1%–2.0% of patients with dia-betes. It most commonly affects the metatarsophalangeal, tarsometatarsal, ankle andinterphalangeal joints, and occurs when sensation is lost but motor function is preserved.Initially affected joints are often swollen, red and tender. Charcot arthropathy isdescribed in a wide range of neurological conditions but diabetes is by far the most com-mon disorder in which it occurs. It frequently occurs alongside diabetic foot ulcerationbecause of the altered foot pressure distribution, which occurs when the joints of the footare misaligned. The affected bones are usually osteoporotic. The major differential diag-nosis is with osteomyelitis. Inflammatory markers (higher in bone infection) and mag-netic resonance imaging help to distinguish the diagnoses. Treatment is with rest andpressure relief. Bisphosphonate drugs are widely used – most commonly a course ofintravenous pamidronate. Intranasal calcitonin is also used to decrease bone turnover.Preliminary evidence supports the use of this treatment in patients with neuropathicarthropathy.5

Recent Developments1 Expression profiling of genes potentially involved in the pathogenesis of DD reveals

significant changes in the matrix-degrading matrix metalloproteinases (MMPs).6

These enzymes are also involved in vascular remodelling and in the pathogenesis ofthe vascular complications. Expression ofMMP1,MMP13 andMMP14 were allincreased in DD tissue. Another recent study has reported increased activity ofMMP2 in DD tissue.7 DD is due to increased fibroblast activity in affected tissue. As aconsequence, there is increased production of matrix and remodelling ofextracellular tissues.

2 It now seems certain that risk of osteoporotic fracture is increased amongst patientswith insulin-requiring diabetes. In the Tromsø study,8 over 27 000 patients werefollowed up for six years. The relative risk (RR) of all non-vertebral fractures was 3.1for men with type 1 diabetes and the RR for hip fracture was 17.8. For women, the



RR of hip fracture was 8.9 and 2.0 for type 1 and type 2 diabetes, respectively. TheWomen’s Health Initiative study9 followed more than 93000 women for seven years.Women with type 2 diabetes were at increased risk of fracture in spite of the fact thatBMDwas at least as high in diabetic patients as in those without diabetes. There isconcern that thiazolidinedione drugs (rosiglitazone and pioglitazone), used intreatment of type 2 diabetes, accelerate bone loss and thus predispose to fracture.10


Statin-induced myopathy Diabetic muscle infarction

Shoulder• Capsulitis• Tendonitis

Cheiroarthropathy(Limited Joint Mobility)

Dupuytren’s disease Trigger finger

LIGAMENTTENDONCAPSULE

JOINT

Osteoporosis Hyperostosis• Local• Diffuse

Neuropathic arthropathy(Charcot’s)

Association*• Rheumatoid• Psoriatic

MUSCLE

BONE

Figure 39.1 Musculoskeletal complications of diabetes. * Rheumatoid disease and type 1 diabetes sharesome genetic predisposition but it is uncertain whether the two are associated. There is emerging evidencethat psoriasis and its arthropathy are associated with diabetes, but the mechanism for this is not known.


ConclusionMusculoskeletal complications are common in patients with diabetes mellitus (Figure39.1). Attention has focused on foot complications, including neuropathic arthropathy.This is not unreasonable since these cause considerable disability and contribute greatlyto the cost of managing diabetes. However, diabetes is associated with a wide range ofmusculoskeletal problems, the commonest of which involve the hand.11 Musculoskeletalcomplications are not strongly related to the level of glycaemic control, or even to theduration of diabetes. They do correlate with the presence of microvascular complications(retinopathy and neuropathy) and it may well be that microvascular changes in connect-ive tissue are important in their pathogenesis.

Further Reading1 Crispin JC, Alcocer-Varela J. Rheumatologic manifestations of diabetes mellitus. Am JMed

2003; 114: 753–7.

2 Arkkila PE, Gautier JF. Musculoskeletal disorders in diabetes mellitus: an update. Best Pract

Res Clin Rheumatol 2003; 17: 945–70.

3 Miranda H, Viikari-Juntura E, Heistaro S, Heliövaara M, Riihmäki H. A population study on

differences in the determinants of a specific shoulder disorder versus nonspecific shoulder

pain without clinical findings. Am J Epidemiol 2005; 161: 847–55.

4 Lindsay JR, Kennedy L, Atkinson AB et al. Reduced prevalence of limited joint mobility in

type 1 diabetes in a UK clinic population over a 20-year period.Diabetes Care 2005; 28:658–61.

5 Bem R, Jirkovská A, Fejfarová V, Skibová J, Jude EB. Intranasal calcitonin in the treatment of

acute Charcot neuroosteoarthropathy: a randomized controlled trial.Diabetes Care 2006; 29:1392–4.

6 Johnston P, Chojnowski AJ, Davidson RK, Riley GP, Donell ST, Clark IM. A complete

expression profile of matrix-degrading metalloproteinases in Dupuytren’s disease. J Hand

Surg 2007; 32: 343–51.

7 Augoff K, Ratajczak K, Gosk J, Tabola R, Rutowski R. Gelatinase A activity in Dupuytren’s

disease. J Hand Surg 2006; 31: 1635–9.

8 Ahmed LA, Joakimsen RM, Berntsen GK, Fønnebø V, Schirmer H. Diabetes mellitus and the

risk of non-vertebral fractures: the Tromsø study.Osteoporos Int 2006; 17: 495–500.

9 Bonds DE, Larson JC, Schwartz AV et al. Risk of fracture in women with type 2 diabetes: the

Women’s Health Initiative observational study. J Clin Endocrinol Metab 2006; 91: 3404–10.

10 Schwartz AV, Sellmeyer DE, Vittinghoff E et al. Thiazolidinedione use and bone loss in older

diabetic adults. J Clin Endocrinol Metab 2006; 91: 3349–54.

11 Ardic F, Soyupek F, Kahraman Y, Yorgancioglu R. The musculoskeletal complications seen in

type II diabetics: predominance of hand involvement. Clin Rheumatol 2003; 22: 229–33.



40 Osteoporosis – Prevention andLifestyle Management

Bone Diseases

S E C T I O N S E V E N 07

40 Osteoporosis – prevention and lifestyle management41 Bisphosphonates for osteoporosis – which agent and when?42 Osteoporosis – drugs other than bisphosphonates43 Male osteoporosis44 Glucocorticoid-induced osteoporosis45 Paget’s disease of bone46 Bone complications of renal disease

P R O B L E M

Case HistoryJane is a fit 51-year-old woman whose periods are becoming infrequent. She is concernedabout developing osteoporosis as she approaches the menopause. Her mother hasrecently fractured her hip. Jane has recently had her bone mineral density (BMD)measured, and was told that she has osteopenia.

What are the risk factors for osteoporosis?

What advice would you give her on preventing osteoporosis?

What is the role for calcium and vitamin D supplementation?

BackgroundOsteoporosis arises from loss of BMD with consequent disruption of bony microarchi-tecture and increased fracture risk. Osteoporosis is, by definition, present when theT score is –2.5 or less – i.e. bone density is 2.5 standard deviations below the estimated



§07 Bone Diseases218

peak BMD for the population. Osteopenia is defined as a T score between –1 and –2.5.While both males and females are at risk of fracture in later life, the dramatic decrease inoestrogen at menopause in women means that they are generally at greater risk from anearlier age. BMD is most conveniently measured by dual-energy X-ray absorptiometry(DEXA). Screening of the population with DEXA is not generally recommended but maybe justified in women aged over 65 years. Low BMD should always be interpreted in thelight of the overall clinical picture and estimated fracture risk. All patients with fragilityfractures should be screened for osteoporosis, and treatment should be considered whereindicated.Fifty per cent of women and 20% of men will suffer a fragility fracture during their

lifetime. Osteoporotic fracture is uncommon below the age of 60 years, and 85% of frac-tures occur in subjects over the age of 65. Peak bone density is attained in early adult life(around age 30 years); there is a steady decline in BMD thereafter, and this acceleratesmarkedly after the menopause. Individuals with higher peak BMD are better able towithstand the later decline in BMD. At least 50% of variance in peak BMD is geneticallydetermined. Polymorphisms in genes for the vitamin D receptor, collagen 1A1, low-density lipoprotein (LDL) receptor-related protein-5 (LRP-5) and the oestrogen receptormay all be determinants of peak BMD. The remainder of the variance in peak BMD is dueto environmental factors including nutrition in early life, calcium and vitamin D statusand exercise habits. These factors also determine the maintenance of BMD during mid-dle life. At menopause, loss of oestrogen leads to activation of bone-resorbing cytokinesincluding interleukin-1 (IL-1) and tumour necrosis factor (TNF)-a. Osteoclasts are acti-vated through the receptor activator of nuclear factor-k-beta (RANK). The ligand forRANK (RANKL) is expressed on osteoblasts. Osteoprotegerin (OPG) – a matrix proteinproduced by osteoblasts and stromal cells – functions as an orphan receptor for RANKL,decreasing its ability to activate RANK on osteoclasts. Declining with age, OPG expres-sion may contribute to development of osteoporosis.Increasing availability of drug treatments over the past 20 years has revolutionized

management of patients with osteoporosis. Vitamin D and its analogues, oestrogen,selective oestrogen receptor modulators (SERMs, e.g. raloxifene), bisphosphonates, teri-paratide and strontium all increase both trabecular and cortical bone. Data with vitaminD treatment suggest that it may reduce risk of fracture by up to 25%.1 Subclinical vitaminD deficiency is common and the major impact of treatment is in patients with subopti-mal vitamin D status. The place of oestrogen therapy has also altered, mainly as a result ofthe Nurses Health Initiative.2 In this large group of healthy post-menopausal women,oestrogen had the predicted benefits on bone health but risk of cardiovascular events inwomen taking combined hormone replacement therapy (HRT) actually increased.Stroke risk increased by 8 per 100 000 person-years; risk of breast cancer increased by asimilar amount. HRT is now only recommended for relatively short-term use in womenwith vasomotor and other menopausal symptoms.3 Bisphosphonates are the first line oftreatment for patients with established osteoporosis. There is some doubt, however,about how long they should be used for, and the typical three to five years of treatmentrepresents only a fraction of the time that many patients are exposed to risk of osteo-porotic fracture.Lifestyle factors and secondary causes of osteoporosis are summarized in Box 40.1.

Higher levels of activity, particularly weight-bearing exercise, are well documented to pro-


tect against loss of BMD. Furthermore, exercise leads to improved muscle tone and func-tion, and thus to lower risk of fall. Lock et al.4 have reviewed the literature on short- tomedium-term exercise interventions for patients at high risk. Studies were difficult to com-pare because of differences in patient cohort, type of intervention and study design. At pres-ent, the evidence that short-term exercise interventions protect against fracture is limited.Up to 15% of the adult population, and up to 90% of very elderly subjects, have sub-

optimal vitamin D status.5,6 This can be checked by measuring plasma 25-hydroxy-vitamin D (25[OH]D). A target range of 50–100 nmol/l (20–40 ng/ml) is generallyagreed, and 75 nmol/l (30 ng/ml) is a reasonable threshold below which supplementsshould be considered. Toxicity is unlikely at levels below 250 nmol/l. The recommendeddaily allowance of vitamin D is 400 International Units (IU) per day, increasing to 800IU/day in those at high risk of osteoporosis. Cholecalciferol (vitamin D3) is produced inthe skin by the action of ultraviolet-B light in the wavelength range 290–315 nm on theprecursor 7-dehydrocholesterol. Vitamin D3 is transported in the bloodmainly bound tovitamin D-binding protein. Sequential 25- and 1-hydroxylation in the liver and kidney,respectively, lead to formation of active 1,25-dihydroxy-vitamin D. The actions of thishormone include increasing intestinal and renal calcium absorption, as well as skeletalactions. Maintaining plasma calcium in the optimal range suppresses parathyroid hor-mone (PTH) secretion, therefore decreasing bone turnover. Low levels of vitamin D havealso been implicated in autoimmune diseases such as type 1 diabetes and multiple scler-osis, and in malignancies including colon and breast cancers. For routine replacement,cholecalciferol (vitamin D3) should be used. Activated vitamin D analogues (calcitrioland alfacalcidol) should be reserved for use where there is a 1-hydroxylation defect – i.e.patients with hypoparathyroidism or renal impairment.

Recent Developments1 Bisphosphonate treatment decreases the risk of fracture by up to 50% in high-risk

groups but only by around 20% in the age group 50–59 years, which is at relativelylow risk of fracture. A recent cost–benefit analysis7 confirms that it is not cost-effective to routinely treat the younger age group by pharmacological means.

40 Osteoporosis – prevention and lifestyle management 219

Box 40.1 Risk factors for osteoporosis

Age Number of years sincemenopause

Family history Lowbodyweight

Smoking Low calcium intakeExcessive alcohol intake Inadequate vitaminD

Prolonged immobility Prolonged amenorrhoeaLack of exerciseGlucocorticoid exposure Hyperthyroidism

Previous fragility fractureHyperparathyroidism


2 In trials of bisphosphonates, patients are routinely supplemented with calcium andvitamin D. Unfortunately, less attention is paid to nutritional factors in routineclinical practice. The recent launch of a combination once-weekly treatment of70 mg alendronate with 2800 IU (70mg) cholecalciferol should streamline thetreatment of many patients with established osteoporosis.8


Normal BMD Osteopenia or osteoporosis

Further decrease in BMD or fracture

Perimenopausal and patient concernedFamily history of osteoporosis

Other risk factors

Avoid smokingLimit alcohol intake

Exercise – high intensity if possibleDietary advice – calcium and vitamin D intake

Measure BMD

Thyroid functioncalcium, phosphate, PTH

Reassure

Consider repeat DEXAin 3–5 years

Consider HRT if post menopauseand has menopausal symptoms

Check 25(OH)D

<50 nmol/l

Repeat DEXA at 18–24 months

>75 nmol/l50–75 nmmol/l

Recheck at 6 months No supplement800 IU D3/day

Consider drug treatment

Figure 40.1 Managing osteoporotic risk. 25(OH)D, 25-hydroxy-vitamin D; BMD, bone mineral density;DEXA, dual-energy X-ray absorptiometry; HRT, hormone replacement therapy; IU, International Units; PTH,parathyroid hormone.


3 In a recent study,9 subclinical vitamin D deficiency was present in 75.4% of a cohortof elderly women selected from acute hospital admissions. Of those with vitamin Ddeficiency, 36.7% had secondary hyperparathyroidism. Even after supplementation,35.3% of the cohort still had suboptimal vitamin D status, partly because ofimperfect compliance. This argues for more robust means of supplementation – i.e.larger doses given as infrequent boluses.

4 A better understanding of the relationship between physical activity and bonephysiology may lead to more effective exercise interventions. In a recent study ofpre-menopausal women,10 only relatively high-intensity exercise was associated withfavourable changes in BMD. Lower levels of exercise may, of course, be beneficial forother aspects of health.

ConclusionOsteoporosis will affect one in three women and one in eight men. Increasing numbers ofelderly people mean that the condition will become more prevalent over the next fewdecades. An algorithm for management of osteoporotic risk in perimenopausal women isshown in Figure 40.1. Adequate calcium and vitamin D status should be ensured. Thepatient should receive advice on smoking, alcohol consumption and maintaining bodyweight in a desirable range. There is a relatively limited role for drug treatment in the agegroup of the above patient. HRT should be reserved for patients with menopausal symp-toms, and the duration of therapy kept to a minimum.

Further Reading1 Sambrook P, Cooper C. Osteporosis. Lancet 2006; 367: 2010–18.

2 Rossouw JE, Anderson GL, Prentice RL et al. Risks and benefits of estrogen plus progestin in

healthy postmenopausal women: principal results from theWomen’s Health Initiative

randomized controlled trial. JAMA 2002; 288: 321–33.

3 Ettinger B, Harris ST, Kendler D, Kessel B, McClung MR. Management of osteoporosis in

postmenopausal women.Menopause 2006; 13: 340–67.

4 Lock CA, Lecouturier J, Mason JM, Dickinson HO. Lifestyle interventions to prevent

osteoporotic fractures: a systematic review.Osteoporos Int 2006; 17: 20–28.

5 Boonen S, Vanderschueren D, Haentjens P, Lips P. Calcium and vitamin D in the prevention

and treatment of osteoporosis – a clinical update. J Intern Med 2006; 259: 539–52.

6 Souberbielle JC, Friedlander G, Kahan A, Cormier C. Evaluating vitamin D status.

Implications for preventing and managing osteoporosis and other chronic diseases. Joint Bone

Spine 2006; 73: 249–53.

7 Sanders KM, Nicholson GC, Watts JJ et al. Half the burden of fragility fractures in the

community occur in women without osteoporosis. When is fracture prevention cost-effective?

Bone 2006; 38: 694–700.

8 Epstein S. The problem of low levels of vitamin D and osteoporosis: use of combination

therapy with alendronic acid and colecalciferol (vitamin D3).Drugs Aging 2006; 23: 617–25.

40 Osteoporosis – prevention and lifestyle management 221



41 Bisphosphonates for Osteoporosis –Which Agent and When?

P R O B L E M

Case HistoryMrs RC is a 66-year-old woman who has lost 3 cm in height over the past three years. Shehas not had any other fractures. Her only medication is a diuretic that she takes forhypertension. X-ray reveals a wedge fracture of the T12 vertebra and generalizedosteoporosis. A subsequent dual-energy X-ray absorptiometry scan shows the T score forher lumbar vertebrae to be –2.8, and that for her hip to be –2.1.

Would you carry out any further investigations?

Should she have treatment with a bisphosphonate?

If so, which one would you choose and for how long should it be used?

BackgroundBisphosphonates (BPs) have found wide usage in patients with metastatic bone disease,myeloma, Paget’s disease and osteoporosis. They are stable analogues of inorganicpyrophosphate and bind to hydroxyapatite bone surfaces with high affinity, decreasingbone turnover by inhibiting osteoclastic activity.1 The general structure of BPs is shownin Figure 41.1. The R1 moiety is generally a hydroxyl group (except clodronate, where itis a chloride), while the structure of the R2 side-chain moiety varies. Two classes of BPshave been developed. The older group, which includes etidronate, tiludronate and clo-dronate, has an R2 group that does not contain nitrogen. Within the osteoclast, BPs

9 DeLappe E, McGreevy C, ni-Chadhain N, Grimes H, O’Brien T, Mulkerrin E. Vitamin D

insufficiency in older female community-dwelling acute hospital admissions and the response

to supplementation. Eur J Clin Nutr 2006; 60: 1009–15.

10 Vainionpää A, Korpelainen R, Vihriälä E, Rinta-Paavola A, Leppäluoto J, Jämsä T. Intensity of

exercise is associated with bone density change in premenopausal women.Osteopor Int 2006;

17: 455–63.



become incorporated into non-hydrolysable adenosine triphosphate (ATP) analoguesand thus inhibit a number of intracellular processes. The second group of BPs have anitrogen-containing R2 group and include the more potent, modern drugs such as alen-dronate, risedronate, pamidronate, ibandronate and zoledronate. These modify the syn-thesis of isoprenoid compounds by inhibiting the enzyme farnesyl pyrophosphatesynthase. They thus modify activity of several guanosine triphosphate (GTP)-bindingproteins, inhibiting activity and promoting apoptosis of osteoclasts.The first clinical use of BPs was in imaging because of the affinity of the drugs for areas of

bone with high turnover. BPs are now the mainstay of treatment for established osteopor-osis. Over a typical three-year course of treatment, BPs increase spine bonemineral density(BMD) by 40%–50% and BMD at the hip by 20%–40%. There is clear evidence from trialsthat this increase in BMD translates into decreased fracture risk, both spinal and at othersites including the hip.2 BPs are indicated for patients in the following categories:

� Osteoporosis (T score <–2.5) plus fracture(s)

� Osteopenia (T score –1 to –2.5) plus fracture(s)

� Osteoporosis without fracture but at high risk

At present, they are not indicated for patients with uncomplicated osteopenia. One ofthe theoretical risks of bisphosphonate treatment was that, with prolonged use, theymight inhibit bone mineralization. The window between doses that inhibit osteoclastactivity and decrease mineralization is relatively narrow for etidronate but much widerfor more modern agents. It is also possible that the drugs could increase brittleness ofbone by progressively increasing bone mineral content. Patients from the major alen-dronate trials have now been followed for up to ten years and there is no evidence oflong-term side effects or a rebound increase in fractures after the initial three years oftreatment. The agents currently recommended for treatment of patients with establishedosteoporosis are:

� Alendronate (Fosamax) – can be given in a daily dose of 10 mg or in a weekly dose of70 mg. The recent availability of a 70 mg/week preparation with 70mg of cholecalcif-erol (2800 International Units vitamin D; Fosamax Plus) should proveadvantageous, especially for older patients

� Risedronate (Actonel) – given in a daily dose of 5 mg or in a weekly dose of 35 mg

� Ibandronate (Bonviva) – given as a single dose of 150 mg once a month

BPs should all be taken on an empty stomach. The patient should swallow the tabletwith a full glass of water and remain upright for at least 30 minutes. The less frequent

41 Bisphosphonates for osteoporosis – which agent and when? 223

OH

P P OCO

OHR1

OH OHR2

Figure 41.1 General structure of bisphosphonates.


dosing schedules (weekly or monthly) have improved compliance since many patientshad difficulty adhering to the above routine on a daily basis. Intravenous infusion ofpamidronate or ibandronate can be used in patients who cannot tolerate oral BPs. Potentdrugs such as zoledronate may need to be given as infrequently as once a year.The major uncertainty with bisphosphonate treatment is the optimal duration.

Following a three-year course of treatment, markers of bone turnover may be suppressedfor up to five years. Available evidence3 suggests that the drugs continue to be safe andbeneficial beyond three years. Long-term follow-up data with ibandronate are not avail-able. Two non-placebo-controlled studies with alendronate following patients for up toten years, and two similar studies with risedronate, have been published. These are continu-ation studies from the original three-year placebo-controlled trials. In these studies, con-tinued fracture-prevention benefit was apparent. There was no evidence of majorgastrointestinal toxicity. Osteonecrosis is a very rare side effect and is often related to otherfactors such as poor dentition, high doses of bisphosphonate or concurrent chemotherapy.Alendronate, risedronate, ibandronate, raloxifine, calcitonin, strontium ranelate and

teriparatide have all been conclusively shown to prevent vertebral fracture. For non-vertebral fracture, the available evidence shows that alendronate, risedronate, strontiumranelate and teriparatide are effective. Based on currently available data, alendronate andrisedronate are the drugs of first choice for treatment of established osteoporosis in post-menopausal women.4 The drugs are probably entirely comparable in terms of their effi-cacy, and the safety profile of both is excellent.The efficacy and safety of oral ibandronate given as a single monthly dose has been

established in animal, pre-clinical and clinical studies.5,6 The BONE study7 was a three-year, randomized, double-blind, placebo-controlled trial involving 2946 post-menopausal women with osteoporosis and at least one vertebral fracture. Daily (2.5 mg)and alternate day (20 mg) doses were compared. The rate of new vertebral fractures inthe placebo group was 9.6% compared with 4.7% in the daily ibandronate group and4.9% in the alternate day group. In a post hoc analysis, there was also a reduction in risk ofnon-vertebral fracture. The MOBILE study8 was a two-year, randomized, parallel groupstudy, and was the first to examine the efficacy of a monthly dosing regimen. A total of1609 women with post-menopausal osteoporosis were enrolled. The study confirmedthat monthly dosing regimens were superior to daily dosing schedules. The 150 mgsingle-dose regimen gave the best results in terms of increased BMD.

Recent Developments1 Osteonecrosis affecting either the mandible or maxilla is a recently described

complication of bisphosphonate therapy.9 It occurs particularly in patients who havebeen exposed to high doses or multiple agents – as used in metastatic disease. Itpresents with swelling, tenderness and pain. Treatment is with analgesia,withdrawing the bisphosphonate and using hyperbaric oxygen. It is thought thatexposure of bone in the periodontal space and rapid turnover of bone in patientswith dental problems or periodontal disease may predispose to osteonecrosis.Patients starting BPs should have any anticipated dental work carried out beforestarting bisphosphonate treatment, and be careful about dental hygiene while ontreatment.



2 Siris et al.10 have examined compliance issues in a database of 35 537 women in theUnited States who were prescribed BPs. Only 43% of patients were completely refill-compliant and only 20% persisted with bisphosphonate therapy for the entire24 months of the study. There was a decreased fracture rate in women who compliedwith, and persisted with, bisphosphonate treatment.

41 Bisphosphonates for osteoporosis – which agent and when? 225

No response

Response

If osteoporosisprogressing

BMD measured by DEXAX-ray spine and other affected areas

Thyroid function, 25(OH)DDeoxypyridinoline

Osteopenia 1fracture

Osteoporosis Normal orosteopenia

Raloxifene if osteoporosis predominantlyspinal; HRT if menopausal symptoms

Alendronate or risedronate

Deoxypyridinoline 3 monthsRepeat DEXA 12–18 months

Continue for 3–5 years

Stop if BMD restored and no further fractureMonitor deoxypyridinoline 6 monthly

Check PTH*DEXA every 18–24 months

Oral ibandronate orIV bisphosphonate or

teriparatide

LifestyletreatmentVitamin D

Figure 41.2 Bisphosphonate treatment of post-menopausal osteoporosis. * Increased parathyroidhormone (PTH) may be a sign that bone turnover is increased and that further treatment is warranted.25(OH)D, 25-hydroxy-vitamin D; DEXA, dual-energy X-ray absorptiometry; HRT, hormone replacementtherapy.



ConclusionThe above patient has osteoporosis by definition. Baseline investigations might includethyroid function, renal function, erythrocyte sedimentation rate and protein electro-phoresis to exclude myeloma, and measurement of plasma 25-hydroxy-vitamin D, cal-cium and parathyroid hormone. Calcium and vitamin D supplementation should beconsidered if there are grounds for suspecting that the patient may be deficient. The firstline of treatment for this woman would be either alendronate or risedronate in a weeklydosing regimen. Progress can be monitored as shown in Figure 41.2. If there is noprogress (determined by bonemarkers or BMD), changing to an alternative bisphosphon-ate is suggested (e.g. monthly oral ibandronate). Teriparatide is useful in refractory cases.There is considerable uncertainty about the optimal duration of bisphosphonate therapy.Typically, three to five years is recommended but this may depend on demonstrated ben-efit and perceived risk of stopping the treatment.

Further Reading1 Russell RGR. Bisphosphonates: from bench to bedside. Ann N Y Acad Sci 2006; 1068: 367–401.

2 Sambrook P, Cooper C. Osteoporosis. Lancet 2006; 367: 2010–18.

3 Liberman UA. Long-term safety of bisphosphonate therapy for osteoporosis: a review of the

evidence.Drugs Aging 2006; 23: 289–98.

4 Iwamoto J, Takeda T, Sato Y. Efficacy and safety of alendronate and risedronate for

postmenopausal osteoporosis. Curr Med Res Opin 2006; 22: 919–28.

5 Epstein S. Ibandronate treatment for osteoporosis: rationale, preclinical, and clinical develop-

ment of extended dosing regimens. Curr Osteoporos Rep 2006; 4: 14–20.

6 Reginster J-Y, Felsenberg D, Cooper C et al. A new concept for bisphosphonate therapy: a

rationale for the development of monthly oral dosing of ibandronate.Osteoporos Int 2006; 17:159–66.

7 Chesnut CH, Skag A, Christiansen C et al. Effects of oral ibandronate administered daily or

intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 2004; 19:1241–9.

8 Miller PD, McClungMR, Macovei L et al. Monthly oral ibandronate therapy in

postmenopausal osteoporosis: 1-year results from the MOBILE study. J Bone Miner Res 2005;

20: 1315–22.

9 Farrugia MC, Summerlin DJ, Krowiak E et al. Osteonecrosis of the mandible or maxilla associ-

ated with the use of new generation bisphosphonates. Laryngoscope 2006; 116: 115–20.

10 Siris ES, Harris ST, Rosen CJ et al. Adherence to bisphosphonate therapy and fracture rates in

osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims

databases.Mayo Clin Proc 2006; 81: 1013–22.


Case HistoryMrs JM is a 60-year-old woman who developed a wedge fracture of her L1 vertebra twoyears ago. She had low bone mineral density (BMD) (T score –2.6 for lumbar spine, –1.6 forhip). At a recent follow-up dual-energy X-ray absorptiometry (DEXA) scan, her BMD haddeteriorated further (lumbar spine T score –2.9, hip –2.1). She insists that she has beentaking her bisphosphonate, and continues to suffer back pain.

Should she persist with bisphosphonate treatment?

What other treatments should be considered?

Is combination therapy an option?

BackgroundBisphosphonate drugs have been the cornerstone of osteoporosis treatment in recentyears. However, a small proportion of patients do not appear to respond.While changingto another, sometimes more potent, bisphosphonate may be the answer for somepatients, other treatment options are now available.

RaloxifeneRaloxifene is a benzothiophene derivative that acts as a selective oestrogen receptor mod-ulator (SERM). It has protective, oestrogen-like effects on bone and breast. The MultipleOutcome of Raloxifene Evaluation (MORE) trial, published in 1999, included 7705women and confirmed that raloxifene increased spine and hip BMD. There wasdecreased risk of vertebral fracture but no definite effect on non-vertebral fracture. Arecent meta-analysis1 has analysed seven studies in total, including the MORE trial.Raloxifene consistently decreased risk of vertebral fracture – by 40%–49% in those withprevious vertebral fracture, and by 35% in those without. There is a suggestion ofdecreased risk of non-vertebral fracture in patients who are at particularly high risk. Theissue of non-vertebral fracture is addressed in the Continuing Outcomes Relevant toEvista (CORE) study, in which 4001 women from theMORE trial were followed for up toeight years.2 Those originally taking placebo continued to take placebo. Those originallyrandomized to 60 mg or 120 mg raloxifene continued with 60 mg. There was no signifi-cant benefit of raloxifene in terms of non-vertebral fracture prevention.

42 Osteoporosis – drugs other than bisphosphonates 227

42 Osteoporosis – Drugs Other ThanBisphosphonates

P R O B L E M



Tamoxifen is a first-generation SERM and is widely used in the treatment of breast can-cer. It may also decrease the incidence of oestrogen receptor-positive breast cancer by upto 48%. The MORE study also demonstrated that raloxifene prevented the developmentof aggressive breast cancer. Tamoxifen slightly increases the risk of uterine cancer, whileraloxifene may be neutral in this regard. Oestrogen (in hormone replacement therapy[HRT]) has beneficial effects on lipid profile. Recent trials, however, have not confirmedthat this translates into a decreased risk of cardiovascular disease. One of the hopes forraloxifene, a second-generation SERM, has been that improved lipid profile may lead tobetter cardiovascular outcomes. The Raloxifene Use for The Heart (RUTH) studyenrolled over 10 000 post-menopausal women who had, or were at high risk of, cardiovas-cular disease. Prior to the results being published, the manufacturers disclosed anincreased risk of stroke. A more recent analysis3 of the patients enrolled in MORE andCORE has shown neither benefit nor increased risk for cardiovascular disease. Raloxifeneis not recommended for cardiovascular protection and should not be administered towomen at high risk of stroke. Studies suggest that raloxifene may help protect against cog-nitive decline with aging, but it remains to be established whether this is clinically relevant.Raloxifene causesmenopausal-type vasomotor symptoms in 10%–25%of patients and legcramps in 7%, and increases the risk of venous thromboembolic disease by up to two-fold.

Strontium ranelateStrontium is an alkaline earth metal with atomic number 38. For pharmacological use, itis administered in a stable complex with an organic moiety (ranelate). Early in vitro stud-ies confirmed that strontium ranelate had beneficial effects on bone formation (stimulat-ing production of collagen and non-collagen proteins of the matrix) and on boneabsorption (inhibiting both differentiation and activation of osteoclasts). There is nowadequate clinical evidence to support the use of the drug in post-menopausal osteopor-osis. It is well tolerated, but causes diarrhoea in up to 6% of patients. This usually disap-pears within three months. Increases in muscle creatine kinase may also occur, butseldom necessitate stopping the drug.The Spinal Osteoporosis Therapeutic Intervention (SOTI) trial4 recruited 1649 post-

menopausal women with osteoporosis. Strontium ranelate (2 g/day) was associated witha risk reduction of new vertebral fractures of 49% during the first year, and 41% overthree years. Vertebral BMD increased by 14.4% and hip BMD by 8.3%. The TreatmentOf Peripheral Osteoporosis Study (TROPOS)5 recruited 5091 women. Overall, stron-tium treatment decreased risk of non-vertebral fracture by 16% (relative risk = 0.84),while risk of hip fracture was decreased by 36% in high-risk individuals. A recentCochrane review has examined evidence from four trials6 and confirms that strontiumincreases BMD (see Box 42.1) and prevents both vertebral and non-vertebral fracture.


Box 42.1 Strontium ranelate and BMD

Strontiumhas a higher atomicweight than calcium and thus has a disproportionateeffect on bonemineral content andBMD,which are therefore overestimated. A 1%increase in strontium can increase BMDby asmuch as 10%. In patients treatedwith thedrug there is a relatively weak correlation between increases in BMDand fractureprotection.


There was a suggestion of increased venous thrombosis and pulmonary embolism, and ofnervous system problems including headache, seizures and memory loss.

TeriparatideTeriparatide (recombinant human parathyroid hormone [PTH] 1–34) differs from otheravailable agents in that it predominantly stimulates bone formation. Evidence supportsits use in both men and women with osteoporosis, in patients with corticosteroid-induced osteoporosis and, particularly, in those at very high risk of fracture.7

Hyperparathyroidism classically causes increased bone turnover with hypercalcaemia.The reasons why intermittent dosing with PTH stimulates net bone formation areincompletely understood. There is evidence that intermittent PTH dosing stimulatesexpression of a range of genes in the osteoblast including growth factors (transforminggrowth factor [TGF]-b, epidermal growth factor [EGF], amphiregulin), cell-signallingmolecules andMCP-1 (monocyte chemoattractant protein-1).Teriparatide increases osteoblast number and activity, increases the rate of bone

remodelling and increases both trabecular thickness and connectivity. The increase inbone turnover is more marked in the first twelve months of treatment and tails off there-after. The effect is more marked on trabecular bone than cortical bone. Typically, verte-bral BMD increases by about 10% over 12–18 months, while femoral neck BMDincreases by about 5%. Use of teriparatide decreases vertebral fracture rate by around65% and non-vertebral fracture rate by 50%. Its effect on fracture reduction is clearlyrelated to increased BMD, although the two are imperfectly correlated.The drug is given subcutaneously at a daily dose of 20mg and is licensed to be given for

up to two years. Antibodies to themolecule develop in about 3% of cases but do not appearto be clinically significant. Most patients have an increase in plasma calcium, usually withinthe normal range, but hypercalcaemia has been noted in up to 3% of patients. Plasma cal-cium, 25-hydroxy-vitamin D, PTH and renal function should be checked at baseline.Calcium and renal function should be checked after a month of treatment. Teriparatideincreases uric acid levels and should only be givenwith caution in patients who are at risk ofgout. Themost worrying potential side effect is the development of osteosarcoma. This hasbeen described with prolonged usage in animals, and occasional human cases have beenrecognized. Teriparatide should not, therefore, be given to patients with an unexplainedhigh level of bone alkaline phosphatase, patients who have had previous bone irradiation orto patients with Paget’s disease. Recommended practice is to warn patients starting thedrug about this potential adverse reaction. There is now reasonable evidence that prior orconcurrent exposure to bisphosphonates blunts the effect of teriparatide. Since teriparatideis often given to patients whose osteoporosis continues to progress in spite of treatmentwith first-line drugs, many patients will have been exposed to bisphosphonates. It is sug-gested to stop the latter drugs before treatment with teriparatide. It is justified to restart thebisphosphonate once teriparatide treatment is complete. During treatment, calcium intake(including supplements) should be kept to 1500 mg or less per day and vitamin D intakeshould be nomore than 100 International Units per day. Teriparatide is safe and effective inthe elderly and its benefits do not depend on baseline BMD.

Combination treatmentsWhether combinations of the currently available treatments are useful or desirable is con-troversial. There is considerable concern that a very marked decrease in bone turnover



may lead to increased brittleness of bone. Short-term data (twelve months) show thatraloxifene combined with alendronate increases hip and spine BMD and decreases boneturnover markers. It is not known whether these changes translate into decreased fracturerisk. It is clear that bisphosphonates should not be combined with teriparatide. Recentdata suggest that combination of raloxifene and teriparatidemay increase BMD gain at thehip,8while teriparatide withHRT has also been reported to be synergistic.9 In general, dataon combination treatments have proved disappointing, in spite of the fact that combiningan anabolic agent with an inhibitor of bone turnover appears attractive. Sequential treat-ments appear to be a much more viable option. One approach is to use teriparatide rela-tively early to increase bone formation. The next phase is to use a bisphosphonate todecrease bone turnover, following which the patient is left treatment-free for a period, andthen the process is repeated. This approach has been called ADFR (Activate, Decreaseosteoclast activity, Free of treatment and Repeat). Osteoporosis is a lifelong condition andwe need effective strategies for its long-termmanagement.

Recent Developments1 Third-generation SERMs are being developed. The ideal drug would protect bone

and the cardiovascular system without risk of thromboembolism. Amongst thedrugs being developed are lasofoxifene, arzofoxifene and bazedoxifene. Lasofoxifeneshows promise as a bone-protective agent, increasing bone density and bonestrength in animal studies.10

2 An analysis of patients treated with strontium ranelate in two previous multinationalstudies has confirmed that the drug was effective in preventing fracturesindependently of the baseline characteristics of the patient.11Neither the baselineBMD nor the presence or number of fractures appeared to influence the subsequentresponse to strontium.

3 A cost–benefit model has been used to assess the benefit of teriparatide.12 Thegreatest cost–benefit ratio was when the drug was used in more recent-onset disease.The cost per quality-adjusted life year (QALY) gained was 20 000 Euros in patientswith a recent vertebral fracture, and 64000 Euros in patients with previous vertebralfracture. This study emphasizes the fact that many treatments for osteoporosis, andother chronic diseases, are often used too late in the course of the disease.

ConclusionThe majority of osteoporotic patients respond well to bisphosphonates, but a significantproportion shows no or little response. Other options for treating osteoporosis includeSERMs, strontium ranelate and teriparatide. These should be considered for patientswho do not tolerate or respond to bisphosphonates, and also for patients already treatedwith bisphosphonate but who require ongoing treatment. The available options are sum-marized in Figure 42.1. In general, combination treatments are often of limited benefit.Bisphosphonates and teriparatide should not be given together. There is some limitedevidence favouring a combination of bisphosphonates with oestrogen or SERMs.



Further Reading1 Seeman E, Crans GG, Diez-Perez A, Pinette KV, Delmas PD. Anti-vertebral fracture efficacy of

raloxifene: a meta-analysis.Osteoporos Int 2006; 17: 313–16.

2 Siris ES, Harris ST, Eastell R et al. Skeletal effects of raloxifene after 8 years: results from the

continuing outcomes relevant to Evista (CORE) study. J Bone Miner Res 2005; 20: 1514–24.


Calcium and vitamin D• Perimenopausal to prevent OP• Elderly (many are vitamin D deficient)• No limit to duration• Can be used with other agents

Strontium• Anabolic and antiresorptive• Established general OP (with or without fracture)• Use for 3 years (based on available trials)

Bisphosphonate• Established OP (especially with fracture)• Use up to 5 years• All ages

Oestrogen• Only if menopausal symptoms• Early years after menopause• Maximum 5 years

Raloxifene• Generally ,65 years• Especially for vertebral OP

Teriparatide• Anabolic (± antiresorptive)• Use if high risk of fracture• Limit use to 18 months• Caution with other agents• ? Use before bisphosphonate because of anabolic action

Figure 42.1 Drugs for the treatment of post-menopausal osteoporosis (OP).


3 Ensrud K, Genazzani AR, Geiger MJ et al. Effect of raloxifene on cardiovascular adverse

events in postmenopausal women with osteoporosis. Am J Cardiol 2006; 97: 520–7.

4 Meunier PJ, Roux C, Seeman E et al. The effects of strontium ranelate on the risk of

vertebral fracture in women with postmenopausal osteoporosis. New Engl J Med 2004; 350:459–68.

5 Reginster JY, Seeman E, De Vernejoul MC et al. Strontium ranelate reduces the risk of

nonvertebral fractures in postmenopausal women with osteoporosis: treatment of

peripheral osteoporosis (TROPOS) study. J Clin Endocrinol Metab 2005; 90: 2816–22.

6 O’Donnell S, Cranney A, Wells GA, Adachi JD, Reginster JY. Strontium ranelate for

preventing and treating postmenopausal osteoporosis. Cochrane Database Syst Rev 2006;

CD005326.

7 Hodsman AB, Bauer DC, Dempster DW et al. Parathyroid hormone and teriparatide for

the treatment of osteoporosis: a review of the evidence and suggested clinical guidelines for

its use. Endocr Rev 2005; 26: 688–703.

8 Deal C, Omizo M, Schwartz EN et al. Combination teriparatide and raloxifene therapy for

postmenopausal osteoporosis: results from a 6-month double-blind placebo-controlled

trial. J Bone Miner Res 2005; 20: 1905–11.

9 Ste-Marie LG, Schwartz SL, Hossain A, Desaiah D, Gaich GA. Effect of teriparatide

(rhPTH(1-34)) on BMD when given to postmenopausal women receiving hormone

replacement therapy. J Bone Miner Res 2006; 21: 283–91.

10 Ke HZ, Foley GR, Simmons HA, Shen V, Thompson DD. Long-term treatment of

lasofoxifene preserves bone mass and bone strength and does not adversely affect the

uterus in ovariectomized rats. Endocrinology 2004; 145: 1996–2005.

11 Roux C, Reginster JY, Fechtenbaum J et al. Vertebral fracture risk reduction with

strontium ranelate in women with postmenopausal osteoporosis is independent of baseline

risk factors. J Bone Miner Res 2006; 21: 536–42.

12 Lundkvist J, Johnell O, Cooper C, Sykes D. Economic evaluation of parathyroid hormone

(PTH) in the treatment of osteoporosis in postmenopausal women. Osteoporos Int 2006;

17: 201–11.



Case HistoryA 60-year-old man presents with back pain. X-ray of his spine shows a crush fracture ofL2 and a generalized decrease in bone mineral density (BMD). A subsequent dual-energyX-ray absorptiometry (DEXA) scan confirms that he has osteoporosis with T scores of –3.2for the lumbar spine and –2.6 for the hip. His serum testosterone is 7.2 nmol/l (normalrange 9–30 nmol/l).

What are the causative factors in male osteoporosis?

What investigations should routinely be carried out?

What treatment options are proven to work?

BackgroundAlthough osteoporosis is predominantly a disease affecting females, it should be remem-bered that 20% of fractures, and 30% of hip fractures, occur in males. One in three menover the age of 60 years will suffer a fracture. Osteoporosis in men is more likely to pre-sent with a fragility fracture, while many cases in women are diagnosed from screening.Morbidity and mortality following fracture is poorer in men than in women. For exam-ple, 80% of men do not return to their pre-fracture physical function after hip fractureand as many as 50% will not return to an independent existence. Underlying causes aremore commonly discovered in men, with glucocorticoid excess (mostly iatrogenic)occurring in 20% of cases, heavy alcohol intake in 15%–20% and hypogonadism in15%–20%. Other secondary causes such as hyperthyroidism, hyperparathyroidism, mal-absorption, antiepileptic treatment and multiple myeloma should be considered as forfemale osteoporosis (Box 43.1). Biological determinants of bone density in men includeactivity of the growth hormone/insulin-like growth factor (IGF)-1 axis, decreasingtestosterone with age and local oestrogen production and action. With regard to the

43 Male osteoporosis 233

43 Male Osteoporosis

P R O B L E M

Box 43.1 Indications for DEXA scanning in men

� Low trauma fracture � Undernutrition� Hypogonadism � Hyperparathyroidism� Glucocorticoid treatment or excess � Prolonged immobilization� Osteopenia onX-ray



latter, polymorphisms of both the aromatase gene (responsible for peripheral conversionof androgens to oestrogen) and the oestrogen receptor may be important. Vitamin D sta-tus and parathyroid hormone (PTH) activity are also important, and change with age.The data on benefits of calcium and vitamin D supplementation are variable, and may

relate to the background status of the population being studied.1 Patients who are defi-cient in calcium and vitamin D are more likely to respond to supplementation. Theprevalence of vitamin D deficiency increases with age, partly because of decreased dietaryintake and reduced sunlight exposure. The recommended daily intake of calcium formen under 65 years is 1000 mg, while for men over 65 years it is 1500 mg. Calorie intakegenerally decreases with age, and the average diet contains less than 400 mg calcium per1000 kcal. The recommendedminimum vitamin D intake is 400 International Units (IU)per day for men under 70 years and 600 IU/day for men over 70. Supplementation isindicated for individuals whose calcium or vitamin D intakes fall below, or are in dangerof falling below, these thresholds. This will not necessarily recover lost bone density inpatients with established osteoporosis.The mainstay of treatment for patients with established disease is bisphosphonates

(BPs). BPs should be used with calcium and vitamin D supplementation where neces-sary. Currently, three oral BPs are used for male osteoporosis. Alendronate was the firstof the newer generation BPs to be studied. For example, in the study by Gonnelli et al.,2

alendronate treatment of osteoporotic men increased spine BMD by 4.2% at one year,6.3% at two years and 8.8% at three years. Corresponding increases at the hip were 1.6%,2.9% and 3.9%, respectively. There was a parallel increase in bone quality as assessed byquantitative ultrasound at the heel. The drug protects against fractures at both vertebraland non-vertebral sites. There is every reason to believe that two other BPs – risedronateand ibandronate – are equally safe and effective. Alendronate (Fosamax) can be given indaily (10 mg) or weekly (70 mg) dosing schedules and should, like the other bisphosphon-ate drugs, be taken on an empty stomach with the patient upright, and the tablet shouldbe swallowed with a full glass of water. Alendronate has not only been shown to be clinic-ally effective, but the cost-effectiveness of treatment has also been demonstrated.3

Risedronate (Actonel) may also be given daily (5 mg) or weekly (35 mg) and haseffects comparable to alendronate. The newer agent ibandronate (Bonviva) can be givenas a single monthly dose of 150 mg. For patients who have gastrointestinal side effectsfrom BPs, pamidronate or ibandronate can be administered parenterally. For patientswho either cannot tolerate or do not respond to BPs, treatment with PTH (teriparatide;Forteo) may be indicated. This is given for up to 18months as a daily subcutaneous injec-tion. Patients should be monitored for hypercalcaemia. The long-term benefit and safetyof teriparatide have yet to be established. From animal studies there is a theoretical risk ofosteosarcoma.Administration of testosterone to hypogonadal men with osteoporosis increases BMD

and protects against fracture. Testosterone can be administered orally, transdermally(with either gel or patches), by depot intramuscular injection (every 2–4 weeks) or usingimplants that are usually inserted every six months. Testosterone treatment of hypo-gonadal men also improves muscle bulk and function, improves cardiovascular functionand protects against coronary artery disease, as well as generally improving quality of life.Sex-steroid levels tend to decrease with age in normal men. This decrease is more markedin some men than in others. The term partial androgen deficiency in aging men



(PADAM) has been proposed, and it is not clear whether this physiological change withaging merits treatment, particularly in the face of markers of lower androgen status suchas decreasing BMD. There is certainly now some evidence that, in the short to mediumterm, androgen replacement can reverse some of the biological changes that accompanydeclining androgen status. Risks of androgen therapy include changes in liver function,polycythaemia and predisposition to prostate and breast cancer. In the study by Gennariet al.,4 bone density and sex-steroid status were monitored over four years in 200 agingmen. Androgen and oestrogen status both decreased with time, and those with the great-est decrease also had the greatest loss of BMD. The ratio of testosterone to oestradiol, ameasure of aromatase activity, varied widely and patients with the lowest estimated levelsof aromatase lost bone faster. The role of oestrogen status in regulating bone loss in agingmen is controversial; Lormeau et al.5 found no relationship between oestrogen levels andbone loss in aging men. They did, however, report that sex hormone binding globulin(SHBG) levels were related to bone loss, with the highest levels being associated with thefastest bone loss. SHBG tends to increase with age, and by binding free androgen andoestrogen may decrease free, bioavailable levels of sex steroids.

Recent Developments1 Assessment of vitamin D status is usually by measurement of total circulating

25-hydroxy-vitamin D3 (25[OH]D3). Levels of vitamin D-binding protein are vari-able and may increase with age. This increase may effectively decrease the amount offree and bioavailable vitamin D. In a recent study,6 25(OH)D3 levels were no differ-ent in men with osteoporosis compared with controls. However, levels of vitaminD-binding protein were increased in osteoporotic men and the concentration of1,25-dihydroxy-vitamin D3 (1,25[OH]D3) was decreased.

2 Androgen deprivation therapy for patients with prostate cancer is now a leadingcause of osteoporosis in men.7,8 In recent years, this therapy has become much moreeffective at decreasing prostatic exposure to androgen, but therefore places men atrisk of osteoporosis. BMD loss of up to 8% per year at the spine and 6% per year atthe hip is common, and up to 20% of men who survive five years or more will suffera fracture. Bone loss can be prevented with BPs but it is not clear whether thistranslates into decreased fracture risk.

ConclusionOsteoporosis in males is more likely to have an underlying cause. The most common ofthese are excessive alcohol intake, use of glucocorticoids and hypogonadism. The diag-nostic workup (Figure 43.1) should always include measurement of calcium and vitaminD, serum testosterone, SHBG, luteinizing hormone (LH) and follicle-stimulating hor-mone (FSH). Even mild calcium and vitamin D deficiency should be corrected. At pres-ent, testosterone replacement should be reserved for patients with proven hypogonadismand a precise diagnosis should be established in all cases. The mainstay of treatment isbisphosphonate therapy. Alendronate, risedronate and ibandronate are widely used andare probably of comparable efficacy and safety. Teriparatide should be considered forpatients with severe or unresponsive disease.

43 Male osteoporosis 235


Further Reading1 Kamel HK. Male osteoporosis: new trends in diagnosis and therapy.Drugs Aging 2005; 22:

741–8.

2 Gonnelli S, Cepollaro C, Montagnani A et al. Alendronate treatment in men with primary

osteoporosis: a three-year longitudinal study. Calcif Tissue Int 2003; 73: 133–9.

3 Borgström F, Johnell O, Jönsson B, Zethraeus N, Sen SS. Cost effectiveness of alendronate for

the treatment of male osteoporosis in Sweden. Bone 2004; 34: 1064–71.


Osteoporosis confirmed

Good response Poor response

Bisphosphonate treatment

Alternative bisphosphonateor teriparatide

Fragility factureOsteopenia on X-ray

High clinical risk

Measure BMD

Measure calcium, 25(OH)D3, PTHUrinary deoxypyridinolone*

Testosterone, SHBG, LH and FSH

Exclude secondary causes• Excessive alcohol• Glucocorticoids• Hypogonadism

Assess calcium and vitamin D statusUse supplements if necessary

Follow-up includingannual BMD

Figure 43.1 Diagnosis and management of male osteoporosis. * Measurement of markers of bone turnovermay help to predict response to treatment, as they respond quicker than BMD. BMD, bone mineral density;FSH, follicle-stimulating hormone; LH, luteinizing hormone; PTH, parathyroid hormone; SHBG, sex hormonebinding globulin.


44 Glucocorticoid-induced osteoporosis 237

44 Glucocorticoid-Induced Osteoporosis

P R O B L E M

Case HistoryMrs SP is a 45-year-old woman who has suffered asthma since childhood. The asthma isnow stable, but she is concerned about osteoporosis since she has had an average of threecourses of steroids each year for the past ten years. She has regular periods but she isapproaching the menopause. Her mother developed osteoporosis in later life. A dual-energy X-ray absorptiometry (DEXA) scan confirms that she has low bone mineral density(BMD).

What are the causes of steroid-induced osteoporosis?

How might the condition be prevented?

What treatment options are available?

BackgroundOverall, 0.5%–0.9% of the population requires intermittent or continuous treatmentwith steroids. Up to 2.5% of the elderly population (age >70 years) take corticosteroids.In addition to the risks imposed by steroids, some of the underlying conditions requiringsteroids also predispose to osteoporosis (e.g. rheumatoid arthritis and multiple

4 Gennari L, Merlotti D, Martini G et al. Longitudinal association between sex hormone levels,

bone loss, and bone turnover in elderly men. J Clin Endocrinol Metab 2003; 88: 5327–33.

5 Lormeau C, Soudan B, d’Herbomez M, Pigny P, Duquesnoy B, Cortet B. Sex hormone-

binding globulin, estradiol, and bone turnover markers in male osteoporosis. Bone 2004; 34:933–9.

6 Al-oanzi ZH, Tuck SP, Raj N et al. Assessment of vitamin D status in male osteoporosis. Clin

Chem 2006; 52: 248–54.

7 Gilbert SM, McKiernan JM. Epidemiology of male osteoporosis and prostate cancer. Curr

Opin Urol 2005; 15: 23–7.

8 Holmes-Walker DJ, Woo H, Gurney H, Do VT, Chipps DR. Maintaining bone health in

patients with prostate cancer.Med J Aust 2006; 184: 176–9.



myeloma). The pathogenesis of glucocorticoid-induced osteoporosis is complex,1,2

occurring in two phases with rapid bone loss of up to 12% of total BMD within the firstyear followed by a slower rate of bone loss of typically up to 3% per year. Corticosteroidsdecrease the formation of osteoblasts and markedly increase (by up to three-fold) apop-tosis of osteoblasts. The early phase with increased bone loss is also characterized byincreased osteoclastic activity. Decreased osteoprotegerin (OPG) may be partly respon-sible for this effect. OPG acts as a soluble decoy receptor for the receptor activator ofnuclear factor-k-beta ligand (RANKL), and decreased activity of OPG allows increasedinteraction between RANKL and its native receptor (RANK) leading to activation of thepathway that includes nuclear factor-k-beta (NF-kB). Other mechanisms involvedinclude decreased expression of bone morphogenetic proteins and a diversion of bonemarrow precursor cells into the adipocyte lineage.Use of glucocorticoids is the most prevalent cause of secondary osteoporosis. In spite

of the widely known detrimental effect of steroids, perhaps only as few as 15% of patientscommencing steroids have investigations to exclude osteoporosis or treatment to preventloss of BMD. Patients with glucocorticoid-induced osteoporosis have a greater risk offracture than other subjects with comparable BMD. It has, therefore, been suggested thatthe threshold for intervention should be lower and a T score of –1.5 is widely used.Between 30% and 50% of patients taking long-term steroids will suffer a fragility frac-ture. The equivalent of prednisolone 10 mg/day for six months or more increases the riskof hip fracture seven-fold and the risk of vertebral fracture 17-fold. Investigation andmanagement is summarized in Figure 44.1. As with all osteoporosis patients, attentionshould be paid to lifestyle factors, including calcium and vitamin D status, and otherpotential secondary causes. The patient should be taking 1500 mg of calcium per day and800 International Units (IU) per day of vitamin D. If it does not seem that these levels ofintake are being achieved, supplements should be prescribed. At all times efforts shouldbe made to minimize the exposure to glucocorticoids and to withdraw them completelywhere possible. There is evidence for recovery of bone density when steroid treatment iswithdrawn.Of the available treatments,3,4 the greatest evidence by far is with use of bisphosphon-

ates (BPs). Glucocorticoids impair calcium absorption from the gut and reabsorption inthe kidney. Calcium supplementation is therefore indicated in many cases but will notprevent the rapid loss of BMD in the months after steroid therapy is initiated. Vitamin Dis more effective and may be particularly indicated in older people. Cholecalciferol atdoses between 300 IU/day and 100 000 IU/week helps to minimize the effect of glucocor-ticoids; vitamin D analogues such as dihydrotachysterol, calcitriol and alfacalcidol are atleast as effective. However, no vitamin D analogue or dose is as effective as BPs. Sex-steroid replacement is controversial and relatively short-term use only is recommendedfor women with menopausal symptoms. Testosterone replacement should be prescribedfor men with proven hypogonadism. Current evidence does not favour the use of calci-tonin for treatment of glucocorticoid-induced osteoporosis.Alendronate and risedronate are now the most commonly used drugs for prevention

and treatment of osteoporosis caused by steroids. Both appear to be effective in at leastpreserving hip and spine BMD, and there are reasonable data showing that they protectagainst vertebral and non-vertebral fracture. Intravenous pamidronate may be usedwhere oral drugs are not tolerated or where compliance is poor. Etidronate is now sel-



dom used and is much less potent than second-generation BPs. Teriparatide (para-thyroid hormone) increases BMD both at vertebral and other sites, but it is not knownwhether it is effective in treatment of glucocorticoid-induced osteoporosis.

44 Glucocorticoid-induced osteoporosis 239

Repeat DEXA in 12 months

Repeat DEXA in 12 months

Is dose $5 mg prednisolone or equivalent?Is treatment of 3 months or more likely?

Patient at risk

Check calcium and vitamin D status(supplement if necessary)

DEXA scan

T score ,–1.5 T score .–1.5

Alendronate orrisedronate

Lifestyle measures• Stop smoking• Weight-bearing exercise• Limit alcohol intake

Minimize steroid• Lowest possible dose• Topical steroids• Other immunosuppressives• Alternate day dose regimen

Figure 44.1 Investigation and management of glucocorticoid-induced osteoporosis. DEXA, dual-energyX-ray absorptiometry.



Recent Developments1 A number of new, potential therapeutic targets have been identified for primary and

glucocorticoid-induced osteoporosis.5 These include sclerostin, a bonemorphogenetic protein produced by osteocytes. Deficiency of this protein isassociated with high BMD. The RANK–RANKL–OPG pathway is central to osteoclastrecruitment. Attempts to manipulate activity of this pathway in animal modelsinclude use of a monoclonal antibody to RANKL. CD40 and its ligand belong to thetumour necrosis factor (TNF) superfamily and are involved in apoptosis of bone cells.Inhibition of osteoblast apoptosis may increase bone formation.

2 Agents with improved anti-inflammatory and immunosuppressive activity withoutsteroid side effects would offer a major advantage.6,7 The anti-inflammatory effectsof steroids are mediated through inhibition of the NF-kB and activator protein-1(AP-1) pathways, while side effects occur through transcriptional modification of avariety of genes. The search for new drugs includes agents with selectiveglucocorticoid receptor-modulator activity.

3 In a recent study,8 201 patients who were about to start steroids at doses equivalentto prednisolone 7.5 mg/day or greater were randomly assigned to receivealendronate 10 mg/day with an alfacalcidol placebo or alfacalcidol at a dose of1mg/day. Patients were followed for 18 months. BMD of the lumbar spine increasedby 2.1% in those treated with alendronate, while it decreased by 1.9% in thealfacalcidol-treated group. There was a similar disparity in bone density at the hip.

ConclusionUse of glucocorticoids is associated with a phase of rapid bone loss due to excessive boneabsorption over formation. This is followed by a slower phase of bone loss due mainly todecreased bone formation resulting from decreased recruitment and increased apoptosisof osteoblasts. Prevention should be by minimizing other risk factors for osteoporosisand, where possible, eliminating other secondary causes. Exposure to steroids should beminimized, and combination with other immunosuppressive agents should be consid-ered where prolonged therapy is needed. Adequate calcium and vitamin D status shouldbe ensured. The bisphosphonates alendronate and risedronate are currently the mainstayof treatment but are grossly underused in clinical practice.

Further Reading1 Weinstein RS. Glucocorticoid-induced osteoporosis. Rev Endocr Metab Disord 2001; 2: 65–73.

2 Canalis E, Bilezikian JP, Angeli A, Giustina A. Perspectives on glucocorticoid-induced osteo-

porosis. Bone 2004; 34: 593–8.

3 Orcel P. Prevention and treatment of glucocorticoid-induced osteoporosis in 2005. Joint Bone

Spine 2005; 72: 461–5.

4 Devogelaer J-P, Goemaere S, Boonen S et al. Evidence-based guidelines for the prevention of

glucocorticoid-induced osteoporosis: a consensus document of the Belgian Bone Club.

Osteoporos Int 2006; 17: 8–19.


5 Mazziotti G, Angeli A, Bilezikian JP, Canalis E, Giustina A. Glucocorticoid-induced

osteoporosis: an update. Trends Endocrinol Metab 2006; 17: 144–9.

6 Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids – newmechanisms for old

drugs.New Engl J Med 2005; 353: 1711–23.

7 Rosen J, Miner JN. The search for safer glucocorticoid receptor ligands. Endocr Rev 2005; 26:452–64.

8 de Nijs RNJ, Jacobs JWG, LemsWF et al. Alendronate or alfacalcidol in glucocorticoid-

induced osteporosis.New Engl J Med 2006; 355: 675–84.

45 Paget’s disease of bone 241

45 Paget’s Disease of Bone

P R O B L E M

Case HistoryMr JS is a generally fit 74-year-old man. He complains of increasing pain in his back andin his left shin. The latter feels warm but is not deformed. A scintigraphic bone scan showsincreased uptake at several areas in the spine and in his left shin. There is no evidence ofmalignant disease. His plasma calcium and phosphate levels are normal, but alkalinephosphatase is increased at 420 units/l (normal = up to 120 units/l).

How should he be investigated and followed up?

What is the current thinking on the aetiology of Paget’s disease?

When should treatment be considered, and what is the best treatment?

BackgroundFirst described as osteitis deformans by Sir James Paget in 1877, Paget’s disease is achronic, focal disorder of bone where increased areas of marked bone turnover lead topain, local bone expansion, deformity and risk of fracture.1,2 It most commonly affectsthe skull, clavicles, vertebrae, pelvis, femur and tibia. Paget’s disease is relatively commonand may affect up to 1.5% of the population aged 40 years and over, 5% of those aged 55years and over and as many as 20% of 85-year-olds. It is particularly common in subjectsof Northern European descent and thus relatively common in the United Kingdom,



North America, Western Europe and Australia. The prevalence may have decreased byup to 50% in the past 20 years. The vast majority of cases are asymptomatic.The cause of Paget’s disease is not known, but it is likely that both genetic and envir-

onmental factors are important. Up to 20% of patients have a history of Paget’s disease inone or more first-degree relatives. A high proportion of families with Paget’s disease andup to 15% of sporadic cases have mutations in the sequestosome 1/p62 gene, which isinvolved in the activation of osteoclasts. Infectious agents have been implicated andcould account for some of the geographical variation in prevalence. Amongst candidateagents are paramyxoviruses, measles, respiratory syncytial virus and canine distempervirus. The disease typically presents with aching bone pain, which may be worse onweight bearing. Occasionally it presents with deformity or pathological fracture. Manycases are discovered incidentally because of radiological features or increased serum alka-line phosphatase. Complications of Paget’s disease are relatively uncommon but impor-tant to recognize (Box 45.1). The most common complication is deafness due toinvolvement of the petrous temporal bone.

X-ray of painful or deformed sites should be undertaken, but systematic skeletal sur-vey is not usually indicated. The initial changes are of focal lysis leading to areas withmixed lysis and sclerosis, trabecular expansion, thickening of cortical bone and deform-ity. Cortical fissure fractures may be identified and may coincide with sites of pain.Metastatic disease may be considered in the differential diagnosis but it is unusual forbone biopsy to be required. Skeletal scintigraphy is much more sensitive than plain radi-ology but it is also less specific. Widespread disease may be apparent, even in patientswho are relatively asymptomatic. The most useful biochemical marker is serum alkalinephosphatase, although it is only increased in 85% of patients. The level of alkaline phos-phatase is directly related to activity and to extent of the disease. It is frequently normal inpatients with monostotic disease. Measurement of bone-specific alkaline phosphatasemay be useful where total alkaline phosphatase is normal or in the presence of liver dis-ease. Other markers of bone turnover may also be useful, particularly in monitoring theearly response to therapy. Measurement of urinary deoxypyridinoline or the cross-linkedN-telopeptide of type 1 collagen is widely used.Investigation and treatment are summarized in Figure 45.1. Often, supportive mea-

sures such as physiotherapy and use of aids such as a walking stick may suffice. For thosewho require specific treatment, bisphosphonates (BPs) are the mainstay. Indications fortreatment include severe pain, extensive disease (particularly if major neurological or


Box 45.1 Complications of Paget’s disease

� Hearing loss – involvement of petrous temporal bone� Osteogenic sarcoma –<1%of cases� Pathological fracture� Cranial neuropathies� Entrapment neuropathies and radiculopathies� Spinal stenosis� Cardiac failure – very rare� Hypercalcaemia –with prolonged immobility


vascular structures are at risk), neurological complications, hypercalcaemia resultingfrom prolonged immobility and where the disease is affecting the site of proposedsurgery (such as a hip or knee replacement). Available BPs are summarized in Box 45.2.Etidronate and tiludronate are now seldom used. Alendronate at doses up to 40 mg/dayfor up to six months or risedronate 30 mg/day for two to six months are equally effective.Intravenous pamidronate can be given for patients who are at risk of gastrointestinal sideeffects from BPs. A variety of regimens have been used, ranging from a single dose of30–60 mg, to three doses of 30 mg given on consecutive days, or 30–60 mg given once perweek for up to six weeks. Serum alkaline phosphatase decreases with modern bisphos-phonate treatment in the vast majority of cases. Patients are usually followed up at three-monthly intervals and treatment is repeated after six months if there is recurrence ofsymptoms or if the alkaline phosphatase increases again. BPs are contraindicated whenthe glomerular filtration rate is less than 35 ml/min/1.73 m2. The newer BPs zoledronicacid and ibandronate may be used. Salmon calcitonin is still useful in some cases,particularly when BPs are either contraindicated or poorly tolerated, or as an add-ontherapy when there is severe pain. Calcitonin can be given subcutaneously at doses of50–100 IU/day or on alternate days for up to 18 months. The chemotherapeutic agentplicamycin is now seldom used.

Recent Developments1 Osteoclast differentiation is known to be regulated by members of the tumour

necrosis factor superfamily, including the receptor activator of nuclear factor-k-betaligand (RANKL) and osteoprotegerin (OPG). Deactivating mutations to the lattergene (TNFRSF11B) are known to be responsible for most cases of juvenile Paget’sdisease.3Mutation of the sequestosome 1 (SQSTM1) gene on the long arm ofchromosome 5 is the most consistently identified genetic abnormality in adultPaget’s disease. An argument for genetic screening of patients who have or are at riskof Paget’s disease has been advanced.4

2 There appears to be very little to choose between the currently available potent BPsin terms of efficacy.5,6 Alendronate, risedronate and pamidronate have very similareffects in inducing remission, although use of a different agent may be justified ifthere is no response or limited response to the first agent.

3 Zoledronic acid, a third-generation bisphosphonate, is widely used in the treatmentof hypercalcaemia of malignancy. Recent evidence suggests that a single infusion ofthis agent is superior to current bisphosphonate regimens.7,8However, as might beexpected, side effects may also be more common with more potent agents. These side


Box 45.2 Bisphosphonates for Paget’s disease

Etidronate 200–400 mg/day 6monthsTiludronate 400 mg/day 6monthsAlendronate 10–40 mg/day 3–6monthsRisedronate 30 mg/day 2–6monthsPamidronate 30–60 mg 1–6 doses



Bone painDeformity

Increased AP

X-ray site of symptoms

Measure AP

Bone scintigraphy

Consider need for treatment

Analgesia (NSAIDs)Aids (physiotherapy)

Alendronate or risedronate(IV pamidronate if poorly compliant or GI intolerance)

Review with AP or other bone markers 3 monthly

Repeat treatment if recurrent symptomsor increasing AP

Calcitonin if no response to or does not tolerate bisphosphonate

Provisional diagnosis of Paget’sPTH – exclude hyperparathyroidism

25(OH)D – exclude deficiency

Bone-specific APUrinary deoxypyridinoline

Figure 45.1 Investigation and management of Paget’s disease. 25(OH)D, 25-hydroxy-vitamin D;AP, alkaline phosphatase; GI, gastrointestinal; NSAIDs, non-steroidal anti-inflammatory drugs; PTH,parathyroid hormone.



effects include hypocalcaemia (often transient) and increases in serum creatinine.Apart from potency in inducing remission, use of potent agents such as zoledronicacid may increase compliance and decrease the cost of administering and monitoringtherapy.

4 Patients with Paget’s disease have a higher rate of comorbidities thanmatched controlsand the disease is costly, with increased costs particularly relating to physician visitsand diagnostic tests.9Compared withmatched controls, patients with Paget’s diseasehad increased rates of pathological fracture (4.9% vs 0.4%), heart murmurs (3.3% vs0.4%), low back pain (19.7% vs 8.6%) and hearing loss (13.5% vs 5.7%).

ConclusionThe diagnosis of Paget’s disease generally relies on the finding of increased serum alkalinephosphatase, along with radiological features and focal areas of increased uptake on iso-tope bone scan. Other markers of bone turnover can be helpful. Bone biopsy is seldomrequired. Environmental factors are poorly characterized at present, while genetic mark-ers are recognized for both juvenile and adult forms of Paget’s disease. Treatment is gen-erally not required. The most common indication for treatment is bone pain.Bisphosphonates are the mainstay of treatment and alkaline phosphatase is the most use-ful marker for success of treatment.

Further Reading1 Whyte MP. Paget’s disease of bone.New Engl J Med 2006; 355: 593–600.

2 Selby PL, Davie MWJ, Ralston SH, Stone MD. Guidelines on the management of Paget’s

disease of bone. Bone 2002; 31: 366–73.

3 Whyte MP. Paget’s disease of bone and genetic disorders of RANKL/OPG/RANK/NF-kBsignaling. Ann N Y Acad Sci 2006; 1068: 143–64.

4 Michou L, Collet C, Laplanche J-L, Orcel P, Cornélis F. Genetics of Paget’s disease of bone.

Joint Bone Spine 2006; 73: 243–8.

5 Walsh JP, Ward LC, Stewart GO et al. A randomized clinical trial comparing oral alendronate

and intravenous pamidronate for the treatment of Paget’s disease of bone. Bone 2004; 34:747–54.

6 Rendina D, Mossetti G, Viceconti R, Sorrentino M, Nunziata V. Risedronate and pamidronate

in the clinical management of patients with severe Paget’s disease of bone and acquired

resistance to bisphosphonates. Calcif Tissue Int 2004; 75: 189–96.

7 Hosking D. Pharmacological therapy of Paget’s and other metabolic bone diseases. Bone 2006;

38 (2 Suppl 2): S3–7.

8 Maricic M. The use of zoledronic acid for Paget’s disease of bone. Curr Osteoporos Rep 2006; 4:40–4.

9 Briesacher BA, Orwig D, SetonM, Omar M, Kahler KH. Medical care costs of Paget’s disease

of bone in a privately insured population. Bone 2006; 38: 731–7.


Case HistoryJR is a 64-year-old man with type 2 diabetes. His glycaemic control is reasonable withoral hypoglycaemic agents but blood pressure has been difficult to control. He currentlytakes an angiotensin-converting enzyme inhibitor, a diuretic and a calcium channelblocker for blood pressure control. Plasma creatinine is increased at 342 mmol/l. Hisparathyroid hormone (PTH) is marginally high and bone mineral density (BMD), measuredusing a dual-energy X-ray absorptiometry (DEXA) scan, is low (T score –2.4 for lumbarspine, –1.8 for hip).

What other investigations would be useful?

Can we be certain that he is developing osteoporosis?

Is he a candidate for bisphosphonate therapy?

BackgroundBone complications are common in chronic kidney disease (CKD). The bone complica-tions of CKD are underdiagnosed and under-recognized. One of the reasons is that pre-cise diagnosis has been based on bone biopsy findings. Bone biopsy is not carried outfrequently, except in specialist centres. The morphological changes in bone that occurwith renal failure have been known as renal osteodystrophy (ROD). The syndrome isimportant because of the increasing prevalence of CKD, increasing recruitment ofpatients into dialysis programmes with consequent increase in lifespan for CKD patients,and also because it is accompanied by increased morbidity and premature mortality. Thelatter relates to vascular changes including ectopic calcification. A broader term – CKD-mineral and bone disorder (CKD-MBD) – has been proposed and encompasses themany facets of this complication of CKD (Box 46.1).ROD can be classified according to whether bone turnover is low, normal or high;

whether mineralization is normal or decreased; and whether bone volume is low, normal


46 Bone Complications of Renal Disease

P R O B L E M


Box 46.1 Definition of CKD-MBD

‘A constellation of bone disorders present or exacerbated by chronic kidney disease thatlead to bone fragility and fractures, abnormalmineralmetabolism and extraskeletalmanifestations.’


or high. Apart from the cellular component, bone comprises mainly organic matrix(osteoid) and inorganic matrix (mineral). Around 15% of bone turns over each year.Osteoid, secreted by the osteoblasts, consists mainly of type 1 collagen with proteogly-cans and other, quantitatively, relatively minor proteins including fibronectin andosteonectin. The inorganic component is mainly hydroxyapatite crystals. Apart from theamount of mineralized bone (which determines BMD) and intact microarchitecture ofthe bone, the correct balance of organic and inorganic components is essential for nor-mal mechanical properties (strength, ability to absorb shock and deformability). PTHand levels of active vitamin D (1,25-dihydroxy-vitamin D3 [D3]; calcitriol) are the mostimportant determinants of bone structure and calcium metabolism. PTH maintainsplasma calcium by increasing intestinal absorption, increasing renal reabsorption andmobilizing calcium from bone. Excess PTH results in increased bone turnover. Thisaffects both trabecular and cortical bone. More than 98% of active D3 is synthesized inthe cells of the proximal renal tubule, and synthesis is decreased in patients with renalimpairment. Synthesis is normally increased by PTH, and there is a negative feedbackloop whereby D3 decreases PTH secretion. D3 increases calcium absorption from the gutand calcium mobilization from bone. The key measurements made on bone biopsy arebone volume, bone turnover (using double tetracycline labelling), osteoid tissuemineral-ization and metal deposition (particularly aluminium). This allows for diagnosis of theseveral forms of renal failure-related bone disease.1,2

1. High turnover bone disease (osteitis fibrosa cystica)This is characteristic of PTH excess with increased osteoblast and osteoclastactivity. The balance may be tipped towards either excess bone formation or excessbreakdown. The former leads to excess osteoid and peritrabecular fibrosis, which mayimpair bone marrow formation. Excess bone breakdown may lead to the characteristiccystic change. Increased cortical porosity contributes to increased risk of fracture. Thedisorder is usually asymptomatic, and routine biochemistry is normal apart fromincreased PTH levels. Increased vitamin D (acting through the vitamin D receptor) andincreased calcium (acting through the calcium-sensing receptor) are both powerfulstimuli to decrease PTH secretion. Both responses are downregulated in secondaryhyperparathyroidism and PTH secretion is inappropriately high. The trigger for thisincrease in PTH is probably low calcitriol levels. High levels of phosphate lead to cal-cium binding, with a consequent decrease in ionized calcium and thus increased PTHsecretion. In addition, phosphate may directly increase PTH secretion and inhibitsrenal 1a-hydroxylase.

2. Defective mineralization (osteomalacia)This is a direct consequence of suboptimal vitamin D status, although it is not usuallysevere enough to warrant a clinical diagnosis of osteomalacia. In the past, aluminiumexposure was a major risk factor, and because this is less prevalent, pure osteomalacia isbecoming less common in CKD.

3. Mixed RODFeatures of PTH excess are combined with defective mineralization due to the relativedeficiency of vitamin D.

46 Bone complications of renal disease 247


4. Adynamic bone disease (ABD; low turnover state)This is the opposite end of the spectrum from the state that exists with PTH excess, and isparticularly common in the elderly and in those with diabetes. It occurs in up to 50% ofbiopsy specimens. ABD is most common where calcium and vitamin D therapy is exces-sive, following parathyroidectomy or with aluminium toxicity. There is decreasedosteoid and very little evidence of either osteoblast or osteoclast activity, and no tetracy-cline labelling. ABD is associated with increased fracture risk, bone pain and ectopic cal-cification. Bone mineralization is normal in ABD.The relative rates of the different forms of bone disease are shown in Table 46.1.

Evaluation should include measurement of serum PTH, calcium (corrected for albu-min concentration or ionized), phosphate, alkaline phosphatase and plasma bicarbonate,as well as imaging for soft tissue calcification. While precise diagnosis of ROD requiresbone biopsy, there is probably limited justification for more widespread use of this test asit is invasive, ideally requires prolonged preparation of the patient with double tetracy-cline labelling and can only be interpreted in specialized centres. PTH is the single mostuseful biomarker and is increased where there is increased bone turnover. The place ofmarkers of bone turnover in diagnosis is not established, although they may be useful tohelp follow the effects of treatment. Markers of bone formation include osteoprotegerin,total and bone-specific alkaline phosphatase, osteocalcin and procollagen type 1 carboxy-terminal extension peptide. Markers of bone resorption include pyridinoline anddeoxypyridinoline, tartrate-resistant acid phosphatase (TRAP) and procollagen type 1cross-linked carboxy-terminal peptide.BMD measurements do not correlate perfectly with fracture risk. Distal radius is the

preferred site for BMD measurement in CKD. The major concern is that low BMD doesnot necessarily indicate osteoporosis and therefore the need for antiresorptive therapy.Bone biopsy is indicated when biochemical features are difficult to interpret, when frac-ture or bone pain are prominent and cannot be explained by non-invasive investigations,where aluminium toxicity is suspected and where there is severe and progressive vascularcalcification. Bone histomorphometry uses measures of turnover, mineralization andvolume to classify ROD – the TMV classification. Biopsy is usually undertaken at the iliaccrest. Use of two doses of tetracycline given four weeks apart prior to biopsy allows forassessment of bone formation and mineralization rate.


Pre-dialysis (%) Dialysis (%)

High turnover 10 0

Mixed 20 65

Low turnover (osteomalacia + ABD) 30 35

Normal histology 40 0

Figures show the relative distribution of different types of ROD in pre-dialysis patients and in those undergoingdialysis. Normal histology very rarely occurs in the dialysis population. Adapted from Schwarz et al. 2006.1

Table 46.1 Distribution of ROD subtypes


In general, the metabolic abnormalities that lead to altered bone morphology and vas-cular calcification do not occur until glomerular filtration rate (GFR) has decreasedbelow 60 ml/min/1.73 m2. However, these bone and vascular changes occur in childrenand young adults with more modest decreases in GFR (to <90 ml/min/1.73 m2). Cautionshould be exercised in diagnosing pure osteoporosis in a patient who has renal impair-ment. For routine screening, vascular calcification is best detected on lateral abdominalplain X-rays looking for aortic calcification. Computed tomography (CT) scans give


Low GFR

Measure:• Calcium (corrected total and ionized)• Phosphate• Vitamin D (25[OH]D and 1,25[OH]2D)• PTH

Assess vascular risk (BP, lipids)Screen for glucose intolerance/diabetes

Lateral abdominal X-ray (vascular calcification)

Bone biopsy if:• Biochemistry does not explain clinical findings• Bone pain or fracture• Risk of aluminium toxicity

Vitamin D replacementDecrease phosphate:• Diet• Phosphate binders

Persistent high PTH:• Calcimimetic• Parathyroidectomy

Vigorous CV risk reduction

Figure 46.1 Diagnosis and management of bone complications of renal disease. 25(OH)D, 25-hydroxy-vitamin D; 1,25(OH)2D, 1,25-dihydroxy-vitamin D; BP, blood pressure; CV, cardiovascular.


more precise information and quantitative methods are described for research purposes,but routine CT scanning is not currently justified.High phosphate levels can be improved by effective renal replacement therapy (dialy-

sis or transplant), although response to dialysis is often incomplete. Dietary phosphateshould be restricted. For many patients, treatment with phosphate binders is required.Alu-Caps swallowed whole before meals are very effective but, in the long term, there is arisk of bone and brain toxicity. Calcichew, Titralac and Phos-Ex (calcium acetate) arecalcium-containing phosphate binders which, again, are taken 15 minutes before meals.Sevelamer has been introduced recently and is a non-aluminium and non-calcium-containing phosphate binder. Careful replacement of vitamin D should be undertaken.As the problem is with renal generation of active 1,25-dihydroxy-vitamin D3, an activeanalogue of vitamin D such as alfacalcidol is usually required. Cinacalcet is a cal-cimimetic drug that acts at the calcium-sensing receptor on parathyroid gland cells andleads to decreased PTH secretion. The drug is relatively expensive but effective. Surgeryto remove the parathyroid glands is required for patients with very high PTH levels.Investigation and treatment are summarized in Figure 46.1.

Recent Developments1 There is emerging evidence that many patients may harbour subtle abnormalities

from an early stage of renal decline, and that these abnormalities contribute toprognosis. Levin et al.3 studied 1814 patients with varying degrees of renal function.Suboptimal vitamin D status (<22 pg/ml) was present in 13% of patients withestimated glomerular filtration rate (eGFR) of >80 ml/min and in over 60% of thosewith eGFR <30 ml/min. High PTH was common in patients with even modest renalimpairment (eGFR >80 ml/min).

2 In patients with renal disease, vascular calcification leads to structural changes in thevascular wall and accelerated atherogenesis. However, patients with asymptomatichyperparathyroidismmay have subtle abnormalities in vascular function thatcontribute to the development of macrovascular disorders. These abnormalitiesinclude insulin resistance, endothelial activation and increased arterial stiffness. Inasymptomatic patients, the changes in glucose tolerance do not appear to progressrapidly.4 Fallo et al.5 have demonstrated increased soluble E-selectin and vonWillebrand factor in patients with hyperparathyroidism. These markers provideevidence of endothelial activation and may help to assess cardiovascular risk prior toand following treatment of hyperparathyroidism.

3 Mineral abnormalities contribute to development of insulin resistance and type 2diabetes. On the other hand, treatment of diabetesmay influence bone andmineralstatus. Thiazolidinediones (rosiglitazone and pioglitazone) are widely used in treatmentof type 2 diabetes. In bone, these drugs enhance adipogenesis while decreasingosteoblast differentiation. There is concern, therefore, that theymay predispose users toosteoporosis. Certainly recent evidence suggests that use of glitazone drugs can decreaseBMD.6 It remains to be seen whether this translates into increased fracture risk.

4 Data from the third National Health and Nutrition Evaluation Survey (NHANES III)confirmed that low vitamin D status was a risk factor for type 2 diabetes.7 This is notonly confirmed by recent data,8 but it also appears that patients with type 2 diabetes



and low vitamin D status are at greater risk of requiring insulin and are more likelyto develop microvascular complications. Consideration should be given to screeningfor abnormalities of calcium and vitamin D status in patients with insulin-resistantstates, and studies are required to evaluate whether vitamin D supplementationimproves prognosis for patients with metabolic syndrome and type 2 diabetes.

ConclusionThe term ‘renal osteodystrophy’ is of limited use in routine clinical practice as it can onlybe diagnosed and classified with bone biopsy. At present, markers of bone turnover arenot able to specifically diagnose bone complications of CKD. Vascular calcification is animportant risk marker for patients with renal disease and is part of the metabolic disturb-ance that also leads to bone disease. Biochemical changes in calcium, phosphate, vitaminD and PTH metabolism appear when eGFR falls below 40 ml/min, but subtle changescan occur with mild degrees of renal impairment. The above patient should have assess-ment of his calcium and vitamin D status. His renal impairment means that bisphospho-nate therapy is not indicated without more detailed knowledge of his underlying bonestatus. Vitamin D supplements may decrease PTH levels and thus bone turnover. LowBMD in this case confirms decreased bone mineral content but may reflect decreased vit-amin D and increased PTH status and not simply primary osteoporosis.

Further Reading1 Schwarz C, Sulzbacher I, Oberbauer R. Diagnosis of renal osteodystrophy. Eur J Clin Invest

2006; 36 (Suppl 2): 13–22.

2 Ferreira A. Development of renal bone disease. Eur J Clin Invest 2006; 36 (Suppl 2): 2–12.

3 Levin A, Bakris GL, Molitch M et al. Prevalence of abnormal serum vitamin D, PTH, calcium,

and phosphorus in patients with chronic kidney disease: results of the study to evaluate early

kidney disease. Kidney Int 2007; 71: 31–8.

4 Ayturk S, Gursoy A, Bascil Tutuncu N, Ertugrul DT, Guvener Demirag N. Changes in insulin

sensitivity and glucose and bone metabolism over time in patients with asymptomatic primary

hyperparathyroidism. J Clin Endocrinol Metab 2006; 91: 4260–3.

5 Fallo F, Cella G, Casonato A et al. Biochemical markers of endothelial activation in primary

hyperparathyroidism.Horm Metab Res 2006; 38: 125–9.

6 Schwartz AV, Sellmeyer DE, Vittinghoff E et al. Thiazolidinedione use and bone loss in older

diabetic adults. J Clin Endocrinol Metab 2006; 91: 3349–54.

7 Scragg R, Sowers M, Bell C; Third National Health and Nutrition Examination Survey. Serum

25-hydroxyvitamin D, diabetes, and ethnicity in the Third National Health and Nutrition

Examination Survey.Diabetes Care 2004; 27: 2813–18.

8 Suzuki A, Kotake M, Ono Y et al. Hypovitaminosis D in type 2 diabetes mellitus: Association

with microvascular complications and type of treatment. Endocr J 2006; 53: 503–10.



47 Steroid Myopathy

Muscle Diseases

S E C T I O N E I G H T 08

47 Steroid myopathy48 Inflammatory myopathies49 Muscle complications of statin therapy

P R O B L E M

Case HistoryJG is a 62-year-old man with severe obstructive pulmonary disease. He has been takingsteroids continuously for ten years – generally 5–10 mg of prednisolone per day but morewith exacerbations. He complains of progressive weakness andmuscle wasting, and notesparticular difficulty climbing stairs. He is a moderately heavy drinker. There is no historyof diabetes and no family history of muscle disease.

How can steroid myopathy be diagnosed?

What is his prognosis?

What treatment options are available for him?

BackgroundThis chapter is a general background to muscle disease, with specific emphasis onsteroid-induced myopathy. While muscle symptoms are common, diseases of muscle arerelatively uncommon and many of the specific diagnoses are rare. Table 47.1 is a sum-mary classification of disorders of muscle.

Congenital myopathies usually present in infancy with a floppy baby that has poormuscular effort. Plasma creatine kinase (CK) is normal, and electromyography (EMG)shows a myopathic pattern. Central core disease usually presents with mild, non-progressive weakness in infancy leading to delay in walking and other physical develop-ment milestones. It is inherited as an autosomal dominant condition. Nemaline rod



myopathy is more serious, presenting with weakness and hypotonia. The consequencesare feeding difficulties, delay in walking and sometimes respiratory muscle weakness. It isslowly progressive and older children or adults with the condition characteristically havedecreased muscle bulk and an abnormally long face with protruding jaw. It can be inher-ited in either a dominant or a recessive fashion. Centronuclear (myotubular) myopathyagain presents in infancy and is relentlessly progressive, usually leading to death at anearly age. Involvement of the eye muscles is common.

Muscular dystrophies. Onset and severity varies. Specific genetic tests are now availablefor many of these conditions and all patients/families should receive genetic counselling.Onset is usually in childhood, although some forms typically present later. The mostcommon forms are:

� Myotonic dystrophy. This is the most common inherited disease of muscle.Myotonic dystrophy type 1 (DM1) is inherited as an autosomal dominant disorderand is due to an expanded cytosine-thymine-guanine (CTG) trinucleotide repeat inthe 3¢ untranslated region of the myotonic dystrophy protein kinase (DMPK) geneon chromosome 19q13.3. In addition to myopathy, patients suffer cognitiveimpairment, subcapsular cataracts, cardiac conduction abnormalities, sensorineural

§08 Muscle Diseases254

A: Congenital

Congenital myopathies – Central core disease– Nemaline rod myopathy– Centronuclear (myotubular)

Muscular dystrophies

Channelopathies

Inherited metabolic diseases

Mitochondial myopathy syndromes

B: Acquired

Inflammatory – Dermatomyositis– Inclusion body myositis– Polymyositis

Metabolic – Hypothyroidism and hyperthyroidism– Vitamin D deficiency– Cushing’s syndrome– Conn’s syndrome and Addison’s disease– Hypokalaemia– Critical care myopathy

Drugs and toxins – Alcohol– Organophosphates– Snake venoms– Corticosteroids– Statins, clofibrate– Vincristine, cyclosporine– Amiodarone– Zidovudine

Paraneoplastic – Carcinomas– Dermatomyositis

Table 47.1 Diseases of muscle


deafness, frontal balding and hypogonadism. Myotonic dystrophy type 2 (DM2) isalso an autosomal dominant condition and is due to expansion of a cytosine-cytosine-thymine-guanine (CCTG) repeat in intron 1 of the ZNF9 gene onchromosome 3q. It causes a proximal muscle pattern of myopathy, sometimes withpain and hypertrophy, but no cognitive impairment. Both DM1 and DM2 lead toalternative splicing of the voltage-gated chloride channel (ClC-1) and are thereforeconsidered along with the channelopathies.

� Duchenne muscular dystrophy. An X-linked condition, which therefore affects boys,that is due to deletion in the dystrophin gene. It usually presents between the ages oftwo and six years. The patient is usually wheelchair-bound by their early teens, andsurvival beyond late teens or early adulthood is the exception. Weakness is proximaland limb girdle and there may be pseudohypertrophy of the calves, cardiacconduction abnormalities and scoliosis.

� Becker muscular dystrophy. This is also X-linked, with a similar distribution ofmuscle weakness to Duchenne muscular dystrophy. It is usually milder thanDuchenne, but is variable in severity. Symptoms may not begin until age ten years orlater, and patients can have a long lifespan, albeit with varying degrees of disability.

� Emery–Dreifuss muscular dystrophy. An X-linked disorder that is due to a mutationin the emerin gene. Symptoms start around five years of age with upper arm andlower leg weakness. Proximal muscle weakness develops later. Contractures and jointproblems may develop, and patients are at risk of sudden cardiac death because ofconduction abnormalities.

� Limb girdle muscular dystrophy. There can be dominant (type 1) or recessive (type2) inheritance. A number of gene abnormalities may cause the syndrome andprognosis is, therefore, variable. Cardiac abnormalities may be present. Boys andgirls are equally affected, and symptoms typically begin in late childhood.

� Facioscapulohumeral muscular dystrophy. This is an autosomal dominant conditionaffecting males and females. Onset is usually in late childhood or early adulthood.The symptoms can be quite mild, although may become more generalized, affectingthe lower limbs later.

Channelopathies are a recently recognized group of conditions where there is a geneticdefect in one of the ion channels involved in regulating normal muscle.1 A summary ispresented in Table 47.2. Myotonia arises from repetitive bursts of action potential whenmuscle contraction is voluntarily activated. The result is inability to relax the muscle.Symptoms usually improve during activity. By contrast, paramyotonia worsens with coldand after exercise. Becker myotonia is the most common form while Thomsen’s disease,although less common, usually presents with milder symptoms. Hyperkalaemic periodicparalysis may be triggered by potassium intake and symptoms are ameliorated by glu-cose. The reverse applies to hypokalaemic periodic paralysis. Andersen syndrome is anautosomal dominant disorder where episodes of paralysis are provoked by prolongedinactivity (including sleep), calorie deprivation and cold. It is associated with long QTinterval on the electrocardiogram, making patients prone to tachycardias. Malignanthyperthermia can be provoked by volatile anaesthetics, depolarizing muscle relaxants orextreme physical activity. A sustained increase in cellular calcium in skeletal muscle leads

47 Steroid myopathy 255


to intense muscle contraction with hyperthermia, metabolic acidosis, hypoxia andhyperkalaemia.

Mitochondrial myopathies are being increasingly recognized in clinical practice,although they remain rare:

� MELAS (Myopathy, Encephalopathy, Lactic Acidosis and Stroke) – episodicencephalopathy, stroke-like episodes; a progressive neurodegenerative disorder oftenalso causing diabetes

� MERRF (Myoclonic Epilepsy with Ragged Red Fibres) – optic atrophy, peripheralneuropathy, dementia, myoclonic epilepsy, cerebellar ataxia and sensorineuraldeafness

� Kearns–Sayre syndrome – progressive oculomotor symptoms including ptosis,pigmentary retinal degeneration, sensorineural deafness, proximal myopathy andcardiac conduction defects

� CPEO (Chronic Progressive External Ophthalmoplegia) – like Kearns–Sayresyndrome but later onset and not associated with retinal degeneration

Congenital metabolic disorders should be considered in the differential diagnosis ofmuscle disorders, particularly where they occur early in life or where there is a relevantfamily history. Differential diagnosis includes the glycogen storage diseases (GSDs).Disorders that lead to prominent muscle symptoms in adult patients include:

� Pompe disease (Type II GSD) due to deficiency of the lysosomal enzyme alpha-1,4-glucosidase (acid maltase) leading to unregulated accumulation of glycogen withdisruption of muscle structure and function

� Cori disease (Type III GSD; limit dextrinosis) due to deficiency of the debrancherenzyme leading to accumulation of abnormal glycogen, which cannot be brokendown to release glucose


Channel Disease Heritance

Sodium(SCN4A, Ch 17q23.1) Paramyotonia congenita Dominant

Hypokalaemic periodic paralysis (type 2) DominantHyperkalaemic periodic paralysis Dominant

Potassium(KCNJ2, Ch 17q23–24) Andersen syndrome Dominant

Calcium(CACNA1S, Ch 1q31–32) Hypokalaemic periodic paralysis (type 1) Dominant

Malignant hyperthermia Dominant(RyR1, Ch 19q13.1) * Malignant hyperthermia Dominant

Chloride(CLCN1, Ch 7q32) Becker myotonia Recessive

Thomsen’s disease DominantAcetylcholine receptor † Congenital myasthenia Dom/Rec

* RyR1, calcium release channel. † One of five genes affected, each encoding different subunits of the nicotinic acetylcholine receptor. Dom/Rec,inheritance may be dominant or recessive.

Table 47.2 Channelopathies


� McArdle disease (Type V GSD) due to deficiency of myophosphorylase which, again,leads to defective glycogen breakdown. Muscle swelling and tenderness occurs, CKlevels are generally very high and there may be episodes of rhabdomyolysis

� Tarui disease (Type VII GSD) leads to a clinical presentation similar to that ofMcArdle disease and is due to deficiency of muscle phosphofructokinase

� Carnitine-palmitoyl transferase deficiency causes episodes of muscle pain andweakness, intermittent CK elevation and myoglobinuria

In adult practice, except in highly specialized centres, acquired muscle diseases aremuch more common than congenital disorders. Amongst these, myopathy caused byalcohol or drugs, including corticosteroids, is encountered not uncommonly.2

Acute alcoholic myopathy is relatively rare and leads to muscle necrosis, with variableinflammatory infiltrate causing muscle weakness and pain. Plasma CK is markedlyincreased, and there may be myoglobinuria and rhabdomyolysis with accompanyingrenal impairment. Recovery generally occurs following alcohol withdrawal and support-ive measures. Chronic alcoholic myopathy principally affects type II (fast twitch, anaero-bic, glycolytic) fibres. It typically occurs after ten years of consuming greater than100 grams (10–12 units) of alcohol per day. The aetiology is not precisely known. Factorsinclude ethanol-induced impaired mitochondrial function, leading to defective adeno-sine triphosphate generation and fatty acid utilization, acetaldehyde accumulationinhibiting protein synthesis, defective protein synthesis because of decreased amino acidavailability and decreased activity of the growth hormone/insulin-like growth factor-1(IGF-1) axis, and free radicals causing cell membrane damage.Steroid myopathy does not always occur with either prolonged exposure or high

doses. It is more common with potent fluorinated steroids (dexamethasone, betametha-sone and triamcinolone). As with alcoholic myopathy, acute and chronic forms are rec-ognized. Acute steroidmyopathy usually occurs after acute exposure to high-dose steroidand can take many months to recover. A subacute, necrotizing form of myopathy withsteroids is described, and leads to severe symptoms with CK levels more than ten timesnormal.3 Exposure of myocytes to steroid impairs protein synthesis and leads to loss ofthe protective effects of IGF-I. Furthermore, increased cellular protease activity increasesmuscle protein breakdown. Biopsy reveals variation in fibre diameters, loss of type IIfibres and necrotic and basophilic fibres throughout the muscle. As with other metabolicmyopathies, symptoms characteristically affect the proximal muscles althoughmore gen-eral involvement, including respiratory muscles, may occur in severe cases. In patientsexposed to steroids long-term, there are usually other clinical features of steroid excesspresent by the time myopathy develops. Treatment (Figure 47.1) consists of minimizingexposure by decreasing the dose, using topical preparations, using alternate day regimensand avoiding fluorinated steroids. Progressive resistance-training exercises are useful inrestoring normal function and muscle bulk. Recovery is slow in chronic cases, and com-plete recovery may not be achieved.Critical illness myopathy (CIM), or acute quadriplegic myopathy, in its full-blown

form is a rare entity with acute onset of generalized weakness. Plasma CK levels are nor-mal. It is similar to steroid myopathy – indeed many patients have been treated withsteroids – but is more severe and more generalized. Neuromuscular blocking drugs havealso been implicated in the aetiology. EMG shows low or normal action potentials.



Biopsy may show type II fibre atrophy or necrosis similar to that seen in steroid myo-pathy. There is no specific treatment. Recovery is usually complete but can be slow.

Recent Developments1 CIM is associated with increased hospital stay, increased risk of requiring mechanicalventilation and increased mortality.4,5 Patients are at increased risk of developingCIM if they have sepsis, are hyperglycaemic or require steroid treatment. Amongst


Young age1ve Family history

Increased CK

Steroidmyopathydiagnosed

? Congenital cause ? Inflammatory cause

Review steroid dose and duration

Muscle biopsy EMG

Resistance exercises? Nutritional supplements

Muscle weaknessMuscle wasting

Alcohol historyother drugs

Minimize exposure to steroids• Avoid fluorinated steroids• Use topical agents• Use other immunosuppressive drugs• Minimize dose• Alternate day dose regimens

Markedly ↑ CK1ve Inflammatory markers

Autoantibodies

Figure 47.1 Diagnosis andmanagement of steroid myopathy. +ve, positive.


causative factors are systemic inflammation (particularly with sepsis), increasedproteolysis and oxidative and metabolic stresses. There are often neuropathicfeatures, and there is impairment of excitation–contraction coupling. Intensiveinsulin therapy has been considered as a means of protecting patients from theconsequences of CIM.

2 Muscle loss with inactivity is exacerbated if it is accompanied by stress and this isthought to be due to hypercortisolaemia. Essential amino acids formulated toreplicate the proportion found in muscle are a potent anabolic stimulus in themyopathies of inactivity and steroid exposure.6 Attention should be paid to nutritionin patients exposed to steroids, those who are critically ill and those who are likely tosuffer prolonged immobility.

3 Creatine supplementation diminishes the impaired exercise capacity that occurswhen experimental animals are administered supraphysiological doses of steroids.7,8

The supplement attenuates loss of muscle mass with steroids. Clinical trials inpatients taking steroids or admitted to critical care facilities are required to evaluatethis intervention, which may prove a safe prophylactic measure.

ConclusionSteroid myopathy is diagnosed by excluding other causes of muscle weakness and wast-ing. Except in the acute necrotizing form of steroid myopathy, there is not usually sys-temic inflammatory activation or increased circulating muscle markers. Steroid dosedoes not have to be high nor the duration of treatment long for the patient to developmyopathy. Muscle biopsy may be required for definitive diagnosis. Prognosis is variableand relates to severity. Improvement is usual if steroids can be decreased or withdrawn.Other risk factors for muscle loss should be eliminated where possible. These include cer-tain drugs and high intake of alcohol. There is no specific treatment. Resistance exercisesto rebuild muscle mass and nutritional supplements have been advocated but there is noevidence to support this from randomized clinical trials.

Further Reading1 Jurkat-Rott K, Lehmann-Horn F. Muscle channelopathies and critical points in functional

and genetic studies. J Clin Invest 2005; 115: 2000–9.

2 Owczarek J, Jasinska M, Orszulak-Michalak D. Drug-induced myopathies. An overview of the

possible mechanisms. Pharmacol Rep 2005; 57: 23–34.

3 Bronner IM, Hoogendijk JE, Wintzen AR et al. Necrotising myopathy, an unusual presenta-

tion of a steroid-responsive myopathy. J Neurol 2003; 250: 480–5.

4 Deem S. Intensive-care-unit-acquired muscle weakness. Respir Care 2006; 51: 1042–52;discussion 1052–3.

5 Friedrich O. Critical illness myopathy: what is happening? Curr Opin Clin Nutr Metab Care

2006; 9: 403–9.



6 Paddon-Jones D, Wolfe RR, Ferrando AA. Amino acid supplementation for reversing bed rest

and steroid myopathies. J Nutr 2005; 135: 1809S–12S.

7 Campos AR, Serafini LN, Sobreira C, Menezes LG, Martinez JAB. Creatine intake attenuates

corticosteroid-induced impairment of voluntary running in hamsters. Appl Physiol Nutr

Metab 2006; 31: 490–4.

8 Menezes LG, Sobreira C, Neder L, Rodrigues-Júnior AL, Martinez JAB. Creatine

supplementation attenuates corticosteroid-induced muscle wasting and impairment of

exercise performance in rats. J Appl Physiol 2007; 102: 698–703.


48 Inflammatory Myopathies

P R O B L E M

Case HistoryA 56-year-old woman complains of difficulty in rising from a chair and climbing stairs.She has an erythematous rash on the back of her hand. Symptoms have increased over thepast four weeks. Her previous health has been very good and she is not taking anymedications.

What other clinical features should be considered?

How should she be investigated?

What treatment is available and what is the prognosis?

BackgroundThis group of disorders (Box 48.1) is quite rare but not infrequently needs to be consid-ered in practice. This chapter considers only the primary inflammatory myopathies, ofwhich dermatomyositis (DM) and inclusion bodymyositis (IBM) are the most common.Together, their incidence is 2–8 per million per year. They present classically with muscleweakness. Pain and stiffness are less prominent symptoms.DM and polymyositis (PM) present with similar distribution of involvement.

Proximal muscle weakness predominates over distal weakness. Pelvic girdle involvementusually precedes and is more marked than shoulder girdle involvement. The typical ini-tial symptoms are difficulty rising from a chair or climbing stairs. DM is a disorder ofhumoral immunity where antibody binding/deposition or immune complexes lead tocapillary damage, resulting in localized atrophy or infarction. It may present at any age.



Twenty per cent of cases in later life occur with an underlying malignancy. There is noassociation with any particular malignancy. In children, DM does not usually give rise toprofound weakness, but is more frequently associated with subcutaneous calcificationand facial flushing. However, the characteristic rash is usually absent and the condition isseldom associated with malignancy. Presentation of DM is usually subacute but it maydevelop very rapidly and present with severe symptoms. The characteristic rash, whichoccurs in most patients, is a photosensitivity reaction on the cheeks, exposed anteriorchest or the knuckles. It can be similar to the rash of systemic lupus erythematosus (SLE).The eyelids may show a purple discolouration and there may be a scaly eruption(Gottron’s sign). Interstitial lung disease occurs in up to 30% of cases and in over 60% ofthose who have antibodies against aminoacyl-tRNA synthetases. Increased mortality inDM relates to lung disease, underlying malignancy and, occasionally, associatedmyocarditis. The serum of patients with lung disease is usually positive for anti-aminoacyl-tRNA synthetase antibodies (particularly anti-Jo).PM is much less common than the other two idiopathic inflammatory myopathies. Its

onset is usually more insidious than that of DM. It is not associated with skin lesions orwith underlying malignancy. Histologically, it is distinct from the other two disorders,but muscle biopsy may not reveal characteristic changes in a patient with apparent PM.PM is predominantly a disorder of cell-mediated immunity where CD8+ cells home tomuscle that is aberrantly expressing class I major histocompatibility antigens.IBM classically involves the quadriceps and the long finger flexors, leading respectively

to unexplained falling or knees giving way and compromised hand grip.2,3 Unlike the

48 Inflammatory myopathies 261

Box 48.1 Inflammatory myopathies

1. PrimaryDermatomyositisInclusion bodymyositisPolymyositis

2. Connective tissue diseasesMixed connective tissue disease (MCTD)Systemic lupus erythematosusSclerodermaSjögren’s syndromeRheumatoid arthritis

3. InfectionsViral (Coxsackie,HIV etc.)BacterialParasitic

4. MiscellaneousGraft-versus-host diseaseEosinophilicmyositisMacrophagicmyofasciitisSarcoidosisAssociatedwith systemic vasculitis

HIV, human immunodeficiency virus. Adaptedwith permission fromHilton-Jones 2003.1


other two conditions, symptoms may be asymmetric with facial involvement or dyspha-gia from an early stage. Foot drop is common. Microscopic features resemble those ofPM, and overlap with the immunocytochemical features of Alzheimer’s disease in thebrain has been suggested. The latter include vacuolar formation with foci of amyloid andphosphorylated tau. The extent to which autoimmunity is involved in the pathogenesis isuncertain. Hereditary forms are well described and, not surprisingly, may present at anearly age. IBM typically occurs in the sixth decade or beyond and is now the primaryinflammatory myopathy most commonly diagnosed in this age group. An associationwith human immunodeficiency virus (HIV) and human T-lymphotropic virus type 1(HTLV-1) has been described and it is associated with other autoimmune diseases inabout one-third of cases. IBM is often relentlessly progressive and response to treatmentsis disappointing. There is emerging anecdotal evidence to support the use of anti-T-celltherapies and stem-cell therapy has been considered.Diagnosis and management of inflammatory myopathies is summarized in Figure

48.1. Measurement of serum creatine kinase (CK) is the simplest screening tool. Mild ele-vations outside the normal range are common and may be due to exercise, trauma orintramuscular injections. Men have higher values than women and values are higher inpatients of Afro-Caribbean origin. Electromyography characteristically shows fibrillationpatterns with sharp waves.Ninety per cent of patients with inflammatory myopathy have autoantibodies to nuclear

or cytoplasmic antigens. Myositis-specific antibodies (MSA) are directed against cytoplas-mic ribonucleoproteins and are present in 30% of cases. Antibodies against aminoacyl-tRNA synthetases are particularly present in those with rapid onset, skin rash and interstitiallung disease. Antibodies against six of the 20 aminoacyl-tRNA synthetases have beendescribed. The commonest of these, anti-Jo (directed against the histidyl-tRNA synthetase),is present in around 10%of cases. Antibodies to signal recognition particle (SRP; involved inendoplasmic reticulum transport of polypeptides) are found particularly in African-American women, and are associated with acute onset, widespread features (including car-diac) and poor prognosis.M1-2 is a nuclear antigen, antibodies to which are found inDM.Muscle biopsy should be carried out where possible given the potential gravity of the

conditions and that there may be a need for immunosuppressive treatment. The deltoidor quadriceps muscles are usually used. The best choice is an affected muscle but not onethat is severely affected, as the biopsy may then only show severe atrophy. Open biopsy orneedle biopsymay be used, andmagnetic resonance imaging (MRI) or computed tomog-raphy scanning may be used to guide the site of biopsy. MRI studies may be useful diag-nostically and in following progress. Ultrasound may also be useful.Exercise is important to ensure that residual muscle capacity is maximized. Also, pas-

sive exercises help to minimize the risk of contractures. All patients should have the helpof a qualified physiotherapist. Adequate calorie and protein intake should be ensured tominimize muscle catabolism, particularly if the patient has dysphagia. The mainstay ofdrug treatment is corticosteroids. Initially, intravenous methylprednisolone at a dose of500 mg for five days may induce remission. This is followed by prednisolone 1 mg/kgbody weight/day, gradually reduced as the plasma CK decreases. Other immunosuppres-sive drugs are also useful – e.g. methotrexate (up to 30 mg/week) or azathioprine(2.5 mg/kg/day). Cyclosporine and cyclophosphamide are also widely used. Intravenousimmunoglobulin is effective for DM or PM. IBM is much more refractory to steroids orother immunosuppressive therapies.



48 Inflammatory myopathies 263

Proximal muscleinvolvement

QuadricepsHand muscles

Muscle weakness1 stiffness1 pain

Increased• CK• ESR and CRP

? Skin lesions – Face, chest, hands? Lung involvement – CXR, pulmonary function tests? Internal malignancy – CXR, CT scan, tumour markers

Possible inflammatory myopathy

? DM or PM ? IBM

EMG MRI or U/S

Corticosteroid

Muscle biopsyAutoantibodies

Maintenance dose

Biological agent

Second-line immunosuppressive

Diagnosis of DM or PM

Figure 48.1 Diagnosis andmanagement of inflammatory myopathies. CK, creatine kinase; CRP, C-reactiveprotein; CT, computed tomography; CXR, chest X-ray; DM, dermatomyositis; EMG, electromyography; ESR,erythrocyte sedimentation rate; IBM, inclusion body myositis; MRI, magnetic resonance imaging; PM,polymyositis; U/S, ultrasound.


Recent Developments1 There is increasing experience with use of biological agents,4,5 although the rarity ofthe conditions means that controlled trials are not available. Rapamycin ormonoclonal antibodies have been used as anti-T-cell agents. There is someexperience with tumour necrosis factor (TNF)-a blockers (etanercept andinfliximab). The anti-B-cell (CD20) antibody rituximab has been used, as it has inother connective tissue diseases. Eculizumab, a monoclonal antibody that inhibitscleavage of the complement component C5, has also been used.

2 The pathogenesis of IBM is becoming more clearly understood. Although it isfrequently associated with immune disturbance, it may primarily be a degenerativedisease.2,6 Accumulation of amyloid-beta protein and its precursor, evidence ofoxidative stress, abnormal protein folding and disturbed proteasomal degradation ofproteins may all contribute to the pathological features.

3 Identification of further antigenic targets and other immune disturbances mayimprove our understanding of pathogenesis but it is not clear whether these willcontribute to streamlining diagnosis and management. Recently, increasedinterleukin-18 (IL-18) has been described in DM and PM, in keeping with a T helper1 (Th1)-dominated immune response.7 Two novel nuclear antigens with molecularmasses of 140 kDa and 155 kDa have been described in Japanese patients.8 Thepresence of antibodies to these antigens may be strongly associated with coexistingmalignancy.

ConclusionAlthough rare, inflammatory myopathies are important to diagnose. They carry a signifi-cant mortality but prognosis has been improved by use of modern diagnostic techniquesand immunosuppressive therapy.9 Patients with suspected myopathy should be carefullyand fully investigated and precise diagnosis relies on muscle biopsy. There should beenquiry and investigation for cutaneous, pulmonary and cardiac involvement and asearch for malignancy in DM. The latter may not be apparent at diagnosis but typicallymanifests itself within one year of diagnosis. Corticosteroids are the first line of treatmentand should be commenced in sufficiently high doses to control disease activity quickly.Doses should also be decreased rapidly as the condition becomes less active. If this doesnot occur, addition or substitution of other immunosuppressive agents should be con-sidered. The outlook for patients with inflammatory myopathies has improved in recentyears because of more effective diagnosis and availability of a wider range of treatments.

Further Reading1 Hilton-Jones D. Diagnosis and treatment of inflammatory muscle diseases. J Neurol Neurosurg

Psychiatry 2003; 74 (Suppl 2): ii25–ii31.

2 Engel WK, Askanas V. Inclusion-body myositis: clinical, diagnostic, and pathologic aspects.

Neurology 2006; 66 (2 Suppl 1): S20–9.



3 Dalakas MC. Inflammatory, immune, and viral aspects of inclusion-body myositis.Neurology

2006; 66 (2 Suppl 1): S33–8.

4 Cordeiro AC, Isenberg DA. Treatment of inflammatory myopathies. Postgrad Med J 2006; 82:417–24.

5 Dalakas MC. Therapeutic targets in patients with inflammatory myopathies: present

approaches and a look to the future.Neuromuscul Disord 2006; 16: 223–36.

6 Askanas V, Engel WK. Inclusion-body myositis: a myodegenerative conformational disorder

associated with Abeta, protein misfolding, and proteasome inhibition.Neurology 2006; 66(2 Suppl 1): S39–48.

7 Tucci M, Quatraro C, Dammacco F, Silvestris F. Interleukin-18 overexpression as a hallmark

of the activity of autoimmune inflammatory myopathies. Clin Exp Immunol 2006; 146: 21–31.

8 Kaji K, Fujimoto M, HasegawaM et al. Identification of a novel autoantibody reactive with

155 and 140 kDa nuclear proteins in patients with dermatomyositis: an association with

malignancy. Rheumatology 2007; 46: 25–8.

9 Briani C, Doria A, Sarzi-Puttini P, Dalakas MC. Update on idiopathic inflammatory

myopathies. Autoimmunity 2006; 39: 161–70.

49 Muscle complications of statin therapy 265

49 Muscle Complications of Statin Therapy

P R O B L E M

Case HistoryMO is a 52-year-old man with type 2 diabetes. Glycaemic control is reasonable with dietalone. Six months ago, he was started on a statin because of his cholesterol level. Over thepast three months, he has noted muscle aches and pains. These have becomemuchmoresevere in the past two weeks and his calves are tender bilaterally.

What is the risk of muscle complications in patients treated with statins?

Does the risk differ with different agents?

How should statin-induced muscle problems be prevented, diagnosed and treated?



BackgroundStatins – 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors – decrease endogenouscholesterol synthesis. Statins are now the most commonly prescribed group of drugs.They lower total and low-density lipoprotein (LDL) cholesterol, as well as slightly lower-ing triglycerides and increasing high-density lipoprotein (HDL) cholesterol. For sec-ondary prevention of cardiovascular disease, total and LDL cholesterol levels of4.0 mmol/l and 2.0 mmol/l, respectively, are now recommended. Statins typicallydecrease LDL cholesterol by 30%–40%, while combination treatments or high-dosestatins can decrease LDL by up to 55%. Lipid-lowering therapy is also recommended forprimary prevention where the estimated risk of a cardiovascular event is greater than20% in ten years. This includes many patients with type 2 diabetes. While statins are veryeffective and safe, the number of patients receiving these drugs means that even unusualside effects are encountered routinely in practice. Setting tighter cholesterol targets hasled to higher doses being prescribed and increasing use of more potent agents, which alsoincreases the risk of side effects. For similar cholesterol-lowering activity, different dosesand drugs are comparable in their fringe benefits (levels of triglycerides and HDL choles-terol, anti-inflammatory effects) and their risk of side effects.The risk of muscle disorders became widely recognized when cerivastatin (Baycol) was

withdrawn five years ago.1 Muscle problems occurred particularly following high dosesand when the drug was combined with the fibrate gemfibrozil. Increased hepatictransaminases occurs in 0.5%–2.0% of cases, although progression to liver failure is rare.Muscle side effects are now commonly reported but it is not clear to what extent these aregreater than in non-treated patients. ‘Myopathy’ usually implies a condition that leads tomuscle weakness. However, the term is used in the statin literature to represent any mus-cle disorder. Myalgia is defined as muscle symptoms without elevation of serum creatinekinase (CK); myositis signifies muscle aches and weakness with CK elevation; rhabdomy-olysis is muscle necrosis usually associated with severe symptoms and CK greater thanten times normal. Rhabdomyolysis with renal impairment can be fatal but occurs in lessthan one per million patients prescribed statins. Available statins appear to have similarlikelihood of causing myopathy (0.2%–0.5%). Rhabdomyolysis occurs in 0.02%–0.04%of patients. Fibrate treatment alone carries a similar risk of muscle side effects. Whenfibrates and statins are used together, risk of myopathy increases to around 1%. Patientsshould be warned to report muscle side effects. There is no role for routine monitoring ofCK. The benefits of statin therapy are clear. Muscle symptoms are common in the generalpopulation. If muscle symptoms occur with normal or less than three times normal CK,it is usually reasonable to follow the symptoms and CK levels at one- to two-weekly inter-vals without discontinuing the drug. For patients with mild symptoms and modest or noCK elevation, the drug should be discontinued for a few weeks and cautiously reintro-duced with careful monitoring. Risk of statin-induced myopathy is increased in the fol-lowing situations:

� Advanced age (>80 years), especially in women

� Low body weight

� Strenuous exercise

� Hypothyroidism



� Multisystem disease, particularly renal failure

� Perioperative or other catabolic states

� With other medications:– Nicotinic acid– Fibrates– Cyclosporine– Macrolide antibiotics– Antifungal agents– Verapamil– Amiodarone– Protease inhibitors for human immunodeficiency virus (HIV) infection– Alcohol abuse

The prevalence of muscle side effects may have been underestimated in the majorstatin trials since high-risk individuals were excluded (e.g. the elderly, those with renalimpairment). Muscle symptoms are often overlooked in routine clinical practice. ThePRIMO (Prediction of Muscular Risk in Observational conditions) survey2 investigatedthe prevalence of muscular symptoms in patients receiving high-dose statins. Of the 7924patients surveyed, muscular symptoms developed in 10.5%. Amongst patients whoreported symptoms, 38% stated that the exertion required for everyday activities was pre-vented, while 4% described themselves as being severely limited. Fluvastatin XL had arate of muscular symptoms (5.1%) that was only half of that with other statins. Drugsthat inhibit the cytochrome P450 enzyme CYP3A4 increase risk of statin-inducedmyopathy since most statins are metabolized by this enzyme. Fluvastatin is metabolizedby CYP2C9, and this may explain the lower incidence of muscle symptoms. While thePRIMO study was only observational, it does underline the fact that muscular side effectsare common, particularly when the patient is taking higher doses of statins.Rhabdomyolysis is the most severe muscular complication.3 It is important to appre-

ciate that it is more likely to occur with a fibrate alone than with a statin alone. Adding afibrate to statin therapy leads to a twelve-fold increase in risk of muscle complications.These are most common within a month of starting or escalating therapy.Rhabdomyolysis causes myoglobinaemia, myoglobinuria and renal impairment. It maypresent with back pain or proximal muscle pain, but many cases have a non-specific pre-sentation (e.g. fatigue or flu-like symptoms). Risk of rhabdomyolysis does not appear torelate to serum levels of the drugs. However, high serum levels of rosuvastatin have beennoted in Asian patients, for whom a lower dose of the drug is recommended.Rhabdomyolysis is diagnosed when muscle symptoms are accompanied by a CK rise togreater than ten times normal. Enquiry should be made about agents that may provokestatin toxicity (including alcohol), and for other causes of CK increase such as exercise,fall and intramuscular injections. If there is doubt as to whether symptoms are related tostatin treatment, it is reasonable to stop the statin for two weeks to see whether symptomsimprove and CK levels decrease. Plasma levels of thyroid-stimulating hormone (TSH),antinuclear factor (ANF) and anti-Jo antibodies should be checked. One of the postu-lated mechanisms for muscle toxicity is depletion of coenzyme Q10. Supplementation atdoses of up to 1200 mg/day has been advocated. Acute management includes carefulmonitoring of renal function, rehydration, alkalinizing the urine to prevent myoglobin



precipitation and discontinuing the statin. The optimal approach to ongoing lipid-low-ering therapy is unclear. Changing to a more hydrophilic statin (pravastatin or rosuvas-tatin) should be considered. Fluvastatin has been associated with lower risk of muscleproblems. The risk of recurrence is high if the statin is reinstituted. Ezetimibe may beused alone or with a decreased dose of statin but, in either case, there appears to be somerisk of recurrent muscle symptoms. Niacin and fibrates may cause muscle symptoms inpatients who have previously had problems with statins. Resins such as cholestyramine


Muscle pain or weaknessFatigue

Decreased exercise tolerance

Review drug and alcohol history*

CK, TSH, ANF, Anti-Jo

Toxicity possible

Lower dose of statinLess toxic statin• Pravastatin• Rosuvastatin• Fluvastatin• Ezetimibe

Regular follow-up• Muscle symptoms• Lipid control• Renal function and CK

• Stop the statin• Rehydrate• Alkalinize urine• Muscle biopsy

Diet 1 resinEzetimibe

Toxicity probable

Drug holidayDrug holiday U/E, myoglobin†

Rhabdomyolysis

Figure 49.1 Management of statin-inducedmuscle disease. * Check for drugs that may precipitate muscletoxicity. † Plasma and urine myoglobin should be measured. ANF, antinuclear factor; CK, creatine kinase;TSH, thyroid-stimulating hormone; U/E, urea and electrolytes.


have a low risk of toxicity but patients may not reach current cholesterol targets.Management of statin-induced muscle disease is summarized in Figure 49.1.

Recent Developments1 Kaufmann et al.4 have demonstrated mitochondrial toxicity whereby exposure tostatins dissipated the mitochondrial membrane potential with consequent decreasedbeta oxidation and disruption in mitochondrial structure. The latter effect may beimportant in promoting apoptosis of myocytes.5 Effects were seen with the lipophilicstatins (cerivastatin, fluvastatin, simvastatin and atorvastatin) but not with thehydrophilic pravastatin. Another recent study6 has reported inhibition of the humanmonocarboxylate transporter 4, which is responsible for lactate efflux from themyocyte. Again, inhibition was seen to a major degree only with the lipophilic statins.

2 Potential benefits of statins beyond their ability to lower cholesterol include anti-inflammatory properties and favourable effects on bone remodelling.7Annual sales ofstatins are worth over $12.5 billion (United States). Their increasing use includes manyelderly patients. It is reassuring that elderly patients do not appear to be particularlysusceptible to side effects.8Ameta-analysis of 119 trials including a total of 86 000patients9 concluded that statins were very safe with an odds ratio for rhabdomyolysis of1.59 andmyositis of 2.56. There was a very low withdrawal rate because of adverseevents. It must be borne inmind, however, that high-risk individuals are excludedfrom clinical trials but frequently require treatment in routine practice.

3 Ezetimibe inhibits intestinal absorption of cholesterol. It is useful in patients who donot achieve target cholesterol values with statins alone, or in patients who are at riskof adverse effects of statins and where it is, therefore, desirable to keep the dose ofstatin to a minimum. Vytorin is a combination of ezetimibe and simvastatin atrespective doses of 10/10, 10/20, 10/40 and 10/80 mg. An analysis of 17 trials withthis drug combination10 reports that the incidence of muscle side effects is no greaterthan with the statin used alone.

4 Rosuvastatin (Crestor) is the first of a new generation of potent statins. In view oftheir increased potency, the safety of these newer drugs is obviously a matter ofconcern. Recent studies are reassuring. Using a database of over two million Dutchpatients, more than 45 000 statin users were identified.11Overall, the incidence ofadverse events was less than 1 per 3000 person-years and there was no difference inadverse events comparing rosuvastatin with other available drugs of this class.Shepherd et al.,12 using a large database of nearly 17 000 patients taking statins, againshowed a side-effect profile that was very little different to that of patients takingplacebo. Rosuvastatin was similar to other statins in the incidence of side effects,including those affecting muscle.

ConclusionMuscle side effects occur in a minority of patients taking statins but can, at worst, lead tofatality. The risk of clinically apparent muscle side effects has been estimated at around1 per 3000 patient-years. This may be minimized by avoiding the drugs in very high-risk



patients, by minimizing the dose and being aware of potential drug interactions. Theavailable statins appear to be similar in terms of risk of muscle complications. In vitrostudies suggest that the more hydrophilic compounds may be safer, as may fluvastatinbecause its route of metabolism differs from that of other statins. Management of musclecomplications depends on the severity. The drug should be withdrawn, but may be cau-tiously reintroduced after symptoms have abated if the adverse event is mild. Otherwise,management of hydration and renal impairment are usually the most important aspects.For patients whose CK reaches greater than ten times the upper limit of normal, statinshould not be reintroduced and management of hyperlipidaemia in this scenario pre-sents a challenge.

Further Reading1 Pasternak RC, Smith SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C.

ACC/AHA/NHLBI Clinical Advisory on the use and safety of statins. J Am Coll Cardiol 2002;

40: 567–72.

2 Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B. Mild to moderate muscular symptoms

with high-dosage statin therapy in hyperlipidemic patients – the PRIMO study. Cardiovasc

Drugs Ther 2005; 19: 403–14.

3 Antons KA, Williams CD, Baker SK, Phillips PS. Clinical perspectives of statin-induced

rhabdomyolysis. Am J Med 2006; 119: 400–9.

4 Kaufmann P, TörökM, Zahno A, Waldhauser KM, Brecht K, Krähenbühl S. Toxicity of statins

on rat skeletal muscle mitochondria. Cell Mol Life Sci 2006; 63: 2415–25.

5 Dirks AJ, Jones KM. Statin-induced apoptosis and skeletal myopathy. Am J Physiol Cell Physiol

2006; 291: C1208–12.

6 Kobayashi M, Otsuka Y, Itagaki S, Hirano T, Iseki K. Inhibitory effects of statins on human

monocarboxylate transporter 4. Int J Pharm 2006; 317: 19–25.

7 Almuti K, Rimawi R, Spevack D, Ostfeld RJ. Effects of stains beyond lipid lowering: potential

for clinical benefits. Int J Cardiol 2006; 109: 7–15.

8 Agostini JV, Tinetti ME, Han L, McAvay G, Foody JM, Concato J. Effects of statin use on

muscle strength, cognition, and depressive symptoms in older adults. J Am Geriatr Soc 2007;

55: 420–5.

9 McClure DL, Valuck RJ, Glanz M, Hokanson JE. Systemic review and meta-analysis of

clinically relevant adverse events fromHMGCoA reductase inhibitor trials worldwide from

1982 to present. Pharmacoepidemiol Drug Saf 2007; 16: 132–43.

10 DavidsonMH, Maccubbin D, Stepanavage M, Strony J, Musliner T. Striated muscle safety ofezetimibe/simvastatin (Vytorin). Am J Cardiol 2006; 97: 223–8.

11 GoettschWG, Heintjes EM, Kastelein JJP, Rabelink TJ, Johansson S, Herings RMC. Results ofa rosuvastatin historical cohort study in more than 45,000 Dutch statin users, a PHARMO

study. Pharmacoepidemiol Drug Saf 2006; 15: 435–43.

12 Shepherd J, Vidt DG, Miller E, Harris S, Blasetto J. Safety of rosuvastatin: update on 16,876rosuvastatin-treated patients in a multinational clinical trial program. Cardiology 2007; 107:433–43.



ACR-70 response, rheumatoid arthritis 84activator protein-1 (AP-1) pathway 240acupuncture, value in fibromyalgia syndrome 31acute quadriplegic myopathy 257–9adalimumabuse in psoriatic arthritis 182use in vasculitides 157

Adamantiades–Behçet’s disease see Behçet’ssyndrome

ADAMTS-5 gene 41adenine phosphoribosyltransferase deficiency 186adenosine deaminase deficiency 186adenylsuccinate lyase deficiency 186ADFR (Activate, Decrease osteoclast activity, Free

of treatment and Repeat) 230adhesive capsulitis (frozen shoulder) 14–16, 212adiponectin 43Adson’s test 22adynamic bone disease 248alcohol consumptionas cause of male osteoporosis 233effect on uric acid synthesis 185–6relationship to RA risk 98

alcoholic myopathy 257alefacept, use in psoriatic arthritis 182alemtuzumab 149alendronate 223combination with cholecalciferol 220combination with raloxifene 230fracture prevention 224long-term use 224use during corticosteroid therapy 238, 240use in male osteoporosis 234use in Paget’s disease 243

alfacalcidol 219, 240, 250alkaline phosphatase, levels in Paget’s disease 242allantoin 184allopurinol 106, 187, 188, 192–3, 194alopecia, in SLE 122alpha2-adrenergic agonists, use in fibromyalgia

syndrome 30alpha-adrenergic antagonists, value in Raynaud’s

phenomenon 137alphaviruses 208Alu-Caps 250Alzheimer’s disease, similarity to inclusion body

myositis 262

American College of Rheumatology (ACR),classification criteria for SLE 117

aminoacyl-tRNA synthetase antibodies 261, 262Andersen syndrome 255androgen deprivation therapy, osteoporosis risk

235androgen therapy, male osteoporosis 234–5angiogenesis, abnormalities in psoriasis 182angiotensin II receptor antagonists, use in

Raynaud’s phenomenon 137angiotensin-converting enzyme (ACE) inhibitorsuse in Raynaud’s phenomenon 137use in scleroderma renal disease 142, 143

animal bites 201ANKH gene 198ankylosing spondylitis 4, 87BASMI 88–90diagnosis 173effects on heart 91mortality risk 91

anterior compartment syndrome 24anterior cruciate ligament tears 6antibiotic treatmentof osteomyelitis 203of septic arthritis 201, 204

antibody treatments 149use in Behçet’s syndrome 166use in inflammatory myopathies 264use in psoriatic arthritis 181–2use in vasculitides 157, 158see also anti-TNF therapy

anti-CCP antibodies 5, 72, 73, 79–80association with smoking 75in psoriatic arthritis 182

anti-centromere antibodies 110scleroderma 141, 142Sjögren’s syndrome 132

anticonvulsants, use in fibromyalgia syndrome 30antidepressants, use in fibromyalgia syndrome 30anti-dsDNA antibodies 110–11, 117in monitoring of SLE 124–5

anti-histone antibodies 117, 118anti-hnRNP antibodies 112anti-inflammatory properties, statins 269anti-Jo-1 antibodies 112, 261, 262anti-neutrophil cytoplasmic antibodies (ANCA)

155, 156–7, 157–8

Index

09-PS Rheumatology-Index-ppp:Index 18/3/08 14:33 Page 271

anti-nuclear antibodies (ANAs) 78–9, 110,113–15

anti-dsDNA 110–11anti-hnRNP 112anti-Jo-1 112, 261, 262anti-Scl-70 112, 141, 142anti-Sm and anti-RNP 111–12anti-SSA/Ro and anti-SSB/La 111, 116, 129in endometriosis 113environmental factors 112in scleroderma 141, 142in Sjögren’s syndrome 130in SLE 116–18

antioxidant intake, relationship to RA risk 97,98

antiphospholipid antibodies 209antiphospholipid syndrome (APS), risks during

pregnancy 94antiplatelet therapyin giant cell arteritis 162use in Raynaud’s phenomenon 137

anti-RA33 antibodies 112anti-RNA polymerase III antibodies, scleroderma

142anti-RNP antibodies 111–12anti-Scl-70 antibodies 112, 141, 142anti-Sm antibodies 111–12, 117anti-SSA/Ro antibodies 111, 116, 129anti-SSB/La antibodies 111, 129antisynthetase syndrome 112anti-TNF therapy 51, 80, 83, 85in hepatitis C 207in inflammatory myopathies 264in psoriatic arthritis 182safety monitoring 79in vasculitides 157see also etanercept; infliximab

anti-topoisomerase (anti-Scl-70) antibodies 112,141, 142

antiviral antibodies 206anxiety disorders, in fibromyalgia syndrome 28aortic calcification 249–50aortic insufficiency, AS 91aplastic anaemia, parvovirus B19 as cause 207apoB-100 immunization 158APPROVe (Adenomatous Polyp Prevention on

Vioxx) study 61aromatase activity, relationship to bone loss 235arthritisacute monoarthritis, differential diagnosis 6–8new onsetexamination 3history-taking 2–3investigations 3–4

patterns of 4

in SLE 122see also osteoarthritis; psoriatic arthritis;

rheumatoid arthritis; septic arthritis; viralarthritis

arthritis mutilans 180arthroscopic release, frozen shoulder 16arthroscopy, in septic arthritis 201arylalkanoic acids 612-arylpropionic acids (profens) 61arzofoxifene 230ASC protein, role in gout 193aspiration of joints 4diagnosis of septic arthritis 7, 201in gout 190knee 8–9in pseudogout 196

aspirin, low doseconcurrent non-selective NSAID therapy 61use in Raynaud’s phenomenon 137use in SLE 126

atherosclerosis, therapeutic strategies 158athletes, risk of osteoarthritis 43atrophic stage, scleroderma 141autoantibodies, viral infection as trigger 206azapropazone 193azathioprine 148, 151interaction with allopurinol 192prediction of response 150use in Behçet’s syndrome 166use in GCA and PMR 161use in inflammatory myopathies 262use during pregnancy 95, 127use in psoriatic arthritis 181use in Sjögren’s syndrome 132use in SLE 127use in vasculitides 157

B19 (parvovirus) 206–7back pain see low back painbacteraemia, risk factors 204Barmah Forest Virus 208basiliximab 149bazedoxifene 230Becker muscular dystrophy 255Becker myotonia 255Behçet’s syndrome 165–6effect of pregnancy 94genetic factors 166–7insulin resistance 167

benzbromarone 193betamethasone, intra-articular injection 51bicipital tendinitis 13biological agentsuse in Behçet’s syndrome 166

Index272


use in inflammatory myopathies 264use in psoriatic arthritis 181–2use in vasculitides 157, 158see also anti-TNF therapy

biomarkers of osteoarthritis 43biopsy, in vasculitis 157

see also bone biopsy; muscle biopsybisphosphonates 218, 219–20, 223–4, 226, 231in combination treatment 230interaction with teriparatide 229osteonecrosis risk 224patient compliance 225structure and function 222–3use during corticosteroid therapy 238–9, 240use in male osteoporosis 234use in neuropathic arthropathy 213use in osteoarthritis 51use in Paget’s disease 242–3, 245use in post-menopausal osteoporosis 225

blood cultures, septic arthritis 201blood film appearance, rheumatoid arthritis 78body mass index (BMI), relationship to

osteoarthritis risk 45bone biopsy 247, 248bone histomorphometry 248bone mineral density (BMD) 217–18in diabetes 213effect of strontium ranelate 228effect of teriparatide 229relationship to osteophyte formation 43in renal osteodystrophy 248

bone mineralization, effect of bisphosphonates223

bone remodelling, effects of statins 269BONE study 224bone turnover 247bone turnover markers, Paget’s disease 242bosentan 144value in Raynaud’s phenomenon 138

botulinum toxin injection, fibromyalgiasyndrome 31

breast cancer risk, effect of SERMS 228breast-feeding, effect on rheumatoid arthritis risk

74British Ankylosing Spondylitis Metrology Index

(BASMI) 88–90brucellosis 201Burkholderia pseudomallei 201butterfly rash 122

c-ANCA 156, 157C-reactive protein (CRP) 4, 161in giant cell arteritis 162in rheumatoid arthritis 78, 80

in septic arthritis 9, 201in SLE 125–6

caffeine intake, relationship to RA risk 98Calcichew 250calcineurin inhibitors 148–9calcinosis, in scleroderma 141calcitoninfracture prevention 224use in neuropathic arthropathy 213use in Paget’s disease 243

calcitriol (1, 25-dihydroxy-vitamin D3) 219,247

calcium channel blockers, value in Raynaud’sphenomenon 137

calcium levels, in teriparatide therapy 229calcium pyrophosphate dihydrate (CPPD)

deposition disease (pseudogout) 8, 9, 195–6associated conditions 196–7diagnosis 196hereditary 197role of ANKH mutations 198toll-like receptors 198treatment 197–8

calcium supplementation 231in corticosteroid therapy 238men 234

cancersassociation with dermatomyositis 260–1breast cancer risk, effect of SERMS 228as cause of lower back pain 172vitamin D levels 219

capsaicin cream, value in osteoarthritis 47carbon monoxide diffusion capacity, scleroderma

142CARD15 gene 179cardiac complications, ankylosing spondylitis 91cardiovascular disease riskeffect of NSAIDs 61–4effect of raloxifene 228in hyperuricaemia 186–7in psoriasis 182in SLE 125–6

carnitine-palmitoyl transferase deficiency 257carpal tunnel, anatomy 22carpal tunnel release 24–5endoscopic 26

carpal tunnel syndrome (CTS) 21causes 23clinical signs 23imaging techniques 25–6management 24–5

cartilage, in osteoarthritis 41cartilage oligomeric matrix protein 43caspase-1 role in gout 193cauda equina syndrome 171

Index 273


CCL2 162CD4* T lymphocytes 93in Sjögren’s syndrome 129

celecoxib, cardiovascular risk 61–2, 63CENP antibodies 132central core disease 253central nervous system involvementBehçet’s syndrome 166SLE 127

centronuclear (myotubular) myopathy 254cerivastatin 266cervical rib syndrome 22cervical rotation measurement 89, 90cervical spinal cord stimulation, Raynaud’s

phenomenon 137channelopathies 255–6Charcot joints (neuropathic arthropathy) 213cheiroarthropathy 15, 212Chikungunya 208children, investigation of acute monoarthritis

9–10chloroquine, value in psoriatic arthritis 181cholecalciferol 219combination with alendronate 220

cholestyramine 268–9chondrocalcinosis 195

see also pseudogoutchondroitin, value in osteoarthritis 46, 49, 104chronic kidney diseaseprotein restriction 187–8use of allopurinol 192

chronic kidney disease-mineral and bonedisorder (CKD-MBD) 246–7, 251

adynamic bone disease 248diagnosis and management 248–50in early renal disease 250high turnover bone disease (osteitis fibrosa

cystica) 247mixed 247osteomalacia 247

Churg–Strauss syndrome 155ANCA 157interferon therapy 158

cilostazol, value in Raynaud’s phenomenon 138Cinacalcet 250citrullination 72citrulline residues 5CLASS (Celecoxib Long-term Arthritis Safety

Study) 57clodronate, structure and function 222–3clonidine, use in fibromyalgia syndrome 30coenzyme Q10 depletion 267cognitive behavioural therapy, chronic low back

pain 177cognitive decline, effect of raloxifene 228

cognitive dysfunction, in SLE 127colchicine 9, 106use in Behçet’s syndrome 166use in gout 190, 192–3use in osteoarthritis 51use in pseudogout 197use in vasculitides 157

collagen genes 41combination therapyin osteoporosis 229–30in rheumatoid arthritis 84

compartment syndromes 24complement deficienciesantinuclear antibodies 111association with SLE 120, 157

compliance, bisphosphonate treatment 225computer use, dry eyes 130conduction disturbances, AS 91congenital heart block 94, 95, 111congenital myopathies 253–4connective tissue growth factor (CTGF), role in

scleroderma 143continuous-focus osteomyelitis 203contractures, in scleroderma 141coracoacromial arch anomalies 13–14CORE (Continuing Outcomes Relevant to Evista)

study 227Cori disease 256corticosteroid-induced osteoporosis, investigation

and management 238–9corticosteroid therapy 147–8, 151as cause of male osteoporosis 233in carpal tunnel syndrome 24in frozen shoulder 16in GCA and PMR 161in gout 106in hepatitis C 207in inflammatory myopathies 262injection 9in carpal tunnel syndrome 24epidural 176–7in fibromyalgia syndrome 31in frozen shoulder 16intravenous, in giant cell arteritis 161, 162in osteoarthritis 51in pseudogout 197in psoriatic arthritis 181in rotator cuff disease 14in tennis elbow 19, 20

long-term 162during pregnancy 95in rheumatoid arthritis 83, 84, 106in Sjögren’s syndrome 132in SLE 126, 127steroid myopathy 257, 258, 259

Index274


in vasculitides 157in viral arthritis 210

costoclavicular syndrome 22COX isoenzymes, role in ulcer healing 57COX-2 inhibitors 56, 57cardiovascular risk 61–4use in SLE 126

coxibs 61cardiovascular side effects 61–3

Coxsackie virus, as trigger for Sjögren’ssyndrome 132

CPEO (Chronic Progressive ExternalOphthalmoplegia) 256

creatine kinase (CK) 262monitoring in statin therapy 266, 270

creatinine supplementation, value during steroidtherapy 259

CREST syndrome 110, 140critical illness myopathy (CIM) 257–9Crohn’s disease 179CRTL1 gene 41CRTM gene 41cryoglobulinaemia 154antinuclear antibodies 111

crystal arthritis 7–8, 9see also gout; pseudogout

crystals, intra-articular 7culture-negative septic arthritis 203curcumin, effect on inflammation 100cyclooxygenase (COX) inhibitors 56–7COX-2 selective drugs 56, 57cardiovascular risk 61–4use in SLE 126

cyclooxygenase (COX) isoenzymes, role in ulcerhealing 57

cyclophosphamide 148, 151effect on fertility 94use in inflammatory myopathies 262use in scleroderma 143use in Sjögren’s syndrome 132use in SLE nephritis 127use in vasculitides 157

cyclosporin 149use in Behçet’s syndrome 166use in inflammatory myopathies 262use in psoriatic arthritis 181use in vasculitides 157

cytokine patterns in pregnancy 93

daclizumab 149dactylitis, in psoriatic arthritis 180dapsone, use in vasculitides 157dehydroepiandrosterone (DHEA)levels in GCA and PMR 162–3

use in SLE 126–7dental hygiene, Sjögren’s syndrome 131depressionin Sjögren’s syndrome 132in SLE 127

dermatomyositis (DM) 260–1antinuclear antibodies 111, 112, 113pathogenesis 264

dextropropoxyphene 51diabetesbone complications 213cheiroarthropathy 15, 212joint disorders 213ligament, tendon and capsular problems 212musculoskeletal complications 211–12, 214–15osteoporosis risk 213–14type 2, risk from low vitamin D status 250–1vitamin D levels 219

diacerein 51value in osteoarthritis 104

diastolic dysfunction, AS 91diclofenaccardiovascular risk 64side effects 57

diet 100–2in inflammatory myopathies 262recommendations in hyperuricaemia and gout

187dietary risk factors, rheumatoid arthritis 74,

97–8dietary supplements 99–100

see also vitamin D treatmentdiffuse cutaneous scleroderma 140diffuse idiopathic skeletal hyperostosis (DISH)

213diffuse osteomyelitis 201disc prolapse 171, 172discectomy 176discoid lupus 118disease-modifying antirheumatic drugs

(DMARDs) 83–4effect on fertility 93–4use during pregnancy 95

disease-modifying drugs, benefits in psoriaticarthritis 182

disease-modifying osteoarthritis drugs(DMOADs) 51–2, 104

dislocation, risk after hip replacement surgery 67diuretics, use in carpal tunnel syndrome 24DNA methylation abnormalities 119docosahexaenoic acid 98benefit in RA 82–3

doxycycline, value in osteoarthritis 51, 53, 104DRB1 gene 72drug abuse, septic arthritis 201

Index 275


drug-induced lupus 118–19drug interactions, with allopurinol 192dry eyes, Sjögren’s syndrome 130dry mouth, Sjögren’s syndrome 130–1dual-energy X-ray absorptiometry (DEXA) 218indications in men 233

Duchenne muscular dystrophy 255duloxetine, use in fibromyalgia syndrome 30Dupuytren’s disease (DD) 212matrix metalloproteinases 213

eccentric loading exercises, rotator cuff disease14

eculizumab, use in inflammatory myopathies264

efalizumab 149use in psoriatic arthritis 182

eicosapentaenoic acid 98benefit in RA 82–3

elbow paingolfer’s elbow 19tennis elbow 18–19, 20

elderly peoplepolyarthritis 103gout 106osteoarthritis 103–4rheumatoid arthritis 104–6, 150

recurrent haemorrhagic shoulder 14elemental diets 99elimination diets 99Emery–Dreifuss muscular dystrophy 255endometriosis 113endoscopic carpal tunnel surgery 26endothelial dysfunction, scleroderma 143endothelin (ET), role in scleroderma 143, 144enthesitis, in psoriatic arthritis 180entrapment neuropathies 21–4, 25–6association with diabetes 211carpal tunnel syndrome 24–5as cause of heel pain 35

eosinophilia myalgia syndrome 112epidermal growth factor (EGF), polymorphisms

in psoriasis 182epidural steroid injections, value in low back

pain 176–7epigenetic modifications, SLE 119, 120Epstein–Barr virus (EBV), as trigger for

rheumatoid arthritis 74–5erythema infectiosum (‘slapped cheek’) 206erythrocyte sedimentation rate (ESR) 4, 161in giant cell arteritis 162in polymyalgia rheumatica 160in rheumatoid arthritis 78in scleroderma 142

in septic arthritis 201in SLE 125–6

etanercept 149use in Behçet’s syndrome 166use in inflammatory myopathies 264use in psoriatic arthritis 182use in vasculitides 157, 158

ethnic differencesin GCA and PMR 160in gout 184in psoriasis 179in scleroderma 140in SLE 123–4in use of statins 267

etidronate 238–9structure and function 222–3use in Paget’s disease 243

etoricoxib, risk comparison with diclofenac 64exerciseprotection against fractures 218–19, 221value in inflammatory myopathies 262value in osteoarthritis 46

exercise programmesin frozen shoulder 15–16in joint replacement surgery 66in plantar fasciitis 36in rotator cuff disease 14

extractable nuclear antigens 110ezetimibe 268, 269

facet joint hypertrophy 171facet joint injections 176facial pain, in fibromyalgia syndrome 28facioscapulohumeral muscular dystrophy 255family history, in new-onset joint pain 3fasting, effect on inflammation 99fatigue 91in fibromyalgia syndrome 28

FDG-PET, in diagnosis of infections 204febuxostat 188, 193fenofibrate, use in gout 191, 193fertility 93–4in Sjögren’s syndrome 96

fetus, effects of maternal rheumatic disease 94–5fever, significance in monoarthritis 7fibrates, muscle side effects 266, 267, 268fibrillin 140fibroblast dysfunction, scleroderma 142, 143fibroblast growth factors, polymorphisms in

psoriasis 182fibromyalgia syndrome (FMS) 27–8epidemiology and aetiology 29investigation 29, 30outlook and management 29–31

Index276


fingernails, in psoriasis 3fish oil, benefit in RA 82–3, 98–9flavonoids 100fluorinated steroids, risk of myopathy 257fluoxetine, value in Raynaud’s phenomenon 137fluvastatin, risk of muscle side effects 267, 268a-fodrin antibodies 132footwear choice, osteoarthritis 47fracture preventionraloxifene 227strontium ranelate 228, 230teriparatide 229

fractures, osteoporotic 218in men 233–5risk in glucocorticoid-induced osteoporosis

238see also osteoporosis

frozen shoulder 13, 14–16, 17fructose, effect on uric acid synthesis 185, 187fruit intake, relationship to RA risk 97, 98

gabapentin, use in fibromyalgia syndrome 30GAIT (Glucosamine/chondroitin Arthritis

Intervention Trial) 104gastric side effects, NSAIDs 55, 56, 59, 61protection strategies 56–7risk evaluation 58

gastro-oesophageal reflux, in fibromyalgiasyndrome 28

gastrointestinal problemsin scleroderma 141, 143–4Sjögren’s syndrome 131

gemfibrozil, combination with cerivastatin 266gender differencesin gout 184in osteoarthritis 103in osteoporosis risk 218in Raynaud’s phenomenon 135in Sjögren’s syndrome 129in SLE 118–19

gene therapy, osteoarthritis 51–2genetic factorsin Behçet’s syndrome 166–7in osteoarthritis 41, 43in pseudogout 197, 198in psoriasis 179in rheumatoid arthritis 72, 75in systemic lupus erythematosus 117

genetic screening, Paget’s disease 243giant cell arteritis (GCA) 154, 155, 159–60,

163–4antiplatelet therapy 162biological therapies 158clinical features 160–1

DHEA levels 162–3epidemiology 162genetic basis 162investigation 161, 163treatment 161–2, 163

ginger extracts, value in osteoarthritis 52glenohumoral osteoarthritis 12glitazones, osteoporosis risk 214, 250glucocorticoid-induced osteoporosis 237–8, 240investigation and management 238–9

glucocorticoid therapy see corticosteroid therapyglucosamine, value in osteoarthritis 46, 48–9,

104glycogen storage diseases 256–7golfer’s elbow 19gonococcal arthritis 7Gottron’s sign 261gout 7–8, 9, 10, 106, 189, 193–4acute management 190association with diabetes 211dietary recommendations 187gender and ethnic differences 184investigations 190molecular basis for inflammation 193prophylaxis 190–3risk factors 190serum urate levels 7see also hyperuricaemia; uric acid

graft-versus-host disease 112similarity to scleroderma 144

Greek Atorvastatin and Coronary Heart DiseaseEvaluation study 186–7

green tea, value in osteoarthritis 52

headachesin fibromyalgia syndrome 28in SLE 127

health status, in psoriatic arthritis 182heart, effects of ankylosing spondylitis 91Heberden’s nodes, genetic predisposition 41heel paincommon causes 34plantar fasciitis 33–7

heel spurs 34Helicobacter pylori infection, interaction with

NSAID therapy 57, 59Henoch–Schönlein purpura 154Hep2000 cell line 110hepatitis, viral arthritis 206hepatitis B 208hepatitis C 207–8, 209cryoglobulinaemia 154

hereditary neuropathy with liability to thepressure palsies (HNPP) 2

Index 277


hexosamine biosynthetic pathway 48–9high turnover bone disease (osteitis fibrosa

cystica) 247hip, septic arthritis 9hip fracture, morbidity 233hip fracture prevention, strontium ranelate 228hip replacement surgery 65, 69complications 67exercise programmes 66indications 66, 67minimal incision 68prosthesis survival 67–8value of weight reduction 65–6

histamine H2 receptor antagonists, use withNSAIDs 56

histone modification 119HIV infection 208association with inclusion body myositis 262

HLA-B51 166HLA-Cw0602 allele 179HLA-DRB1*04 160, 162homocysteine levels, Behçet’s syndrome 167homogeneous staining, ANA 110, 117hormone replacement therapy (HRT) 218, 231combination with teriparatide 230in osteoarthritis 43, 51use in SLE 119

HTLV (human T-lymphotropic virus)-1infection, association with inclusion bodymyositis 262

human bites 201hyaluronan, serum levels 43hyaluronic acid, intra-articular injection 47, 49,

104hydralazine, association with DIL 118hydroxychloroquine 149use in hepatitis C 207use in psoriatic arthritis 181use in Sjögren’s syndrome 132use in SLE 126

hyperbaric oxygen therapy, osteomyelitis 203hypergammaglobulinaemia, antinuclear

antibodies 111hyperglycaemia, association with osteoarthritis

41–2hyperkalaemic periodic paralysis 255hyperostosis 213hyperparathyroidism, vascular dysfunction 250hypertensive disorders of pregnancy 96hyperuricaemia 188cardiovascular disease risk 186–7causes 185–6dietary recommendations 187treatment 187see also gout

hypogonadism 233testosterone treatment 234–5

hypokalaemic periodic paralysis 255hypomethylation, association with SLE 119hypothyroidismchondrocalcinosis 197gout 190

hypoxanthine phosphoribosyltransferase (HPRT)deficiency 186

ibandronate 223, 224use in male osteoporosis 234use in Paget’s disease 243

ibuprofencardiovascular risk 63interaction with aspirin 61

imagingchronic low back pain 176rheumatoid arthritis 78see also magnetic resonance imaging; positron

emission tomography (PET);radiographyimmobility, muscle loss 259immunoglobulin, use in inflammatory

myopathies 262immunosuppressive drugs 147antibody treatments 149antiproliferative and antimetabolic drugs 148

see also azathioprine; cyclophosphamide;leflunomide; methotrexate;mycophenolate mofetil

calcineurin inhibitors 148–9glucocorticoids 147–8

see also corticosteroid therapyhydroxychloroquine 149indications for use 150sulphasalazine 149therapeutic monitoring 149–50, 151use in vasculitides 157

impingement theory, rotator cuff disease 13–14incision length, hip replacement 68inclusion body myositis (IBM) 261–2pathogenesis 264

indurative stage, scleroderma 141infection, risk after joint replacement surgery 67infectionsassociation with arthritis 3as cause of lower back pain 172as cause of Paget’s disease 242as trigger for giant cell arteritis 154, 160as trigger for rheumatoid arthritis 74–5as trigger for Sjögren’s syndrome 132see also septic arthritis

inflammation assessment, SLE 125–6

Index278


inflammatory lower back pain 172, 173inflammatory markers, as outcome measures 88inflammatory myopathies 260–2diagnosis and management 262–3use of biological agents 264

infliximab 149use in Behçet’s syndrome 166use in GCA and PMR 161use in inflammatory myopathies 264use in psoriatic arthritis 182use in vasculitides 157, 158

insulin resistancein Behçet’s syndrome 167possible effect of glucosamine supplementation

49interferon therapyin Behçet’s syndrome 166in Churg–Strauss syndrome 158interferon 1, possible role in SLE 119–20topical use in Sjögren’s syndrome 131

interleukin-1 inhibitors 83interleukin-18association with Behçet’s syndrome 167levels in DM and PM 164

intermalleolar distance measurement 89, 90interstitial pulmonary fibrosis 112intervertebral disc prolapse 171, 172discectomy 176

intravenous drug users, septic arthritis 201intravenous immunoglobulin, use in vasculitides

157irritable bowel syndrome, in fibromyalgia

syndrome 28

joint aspiration 4diagnosis of septic arthritis 7, 201in gout 190knee 8–9in pseudogout 196

joint count 88, 89prognostic value in RA 80

joint painacute monoarthritis, differential diagnosis 6–8new onsetexamination 3history-taking 2–3investigations 3–4

joint replacement surgery 65, 69complications 67exercise programmes 66indications 66, 67minimal incision 68perioperative methotrexate therapy 66–7prosthesis survival 67–8

unicompartmental knee arthroplasty 68value of weight reduction 65–6

juvenile Paget’s disease 243

Kawasaki syndrome 155Kearns–Sayre syndrome 256Kelley–Seegmiller syndrome 186knee jointaspiration 8–9magnetic resonance imaging 10monoarthritis, differential diagnosis 6–8osteoarthritis, corticosteroid injection 51

knee replacement surgery 65, 69complications 67indications 66, 67post-operative weight gain 66prosthesis survival 68unicompartmental 68

laminin-1 113lansoprazole, gastric protection in NSAID

therapy 59large vessel vasculitis 155laser therapy, Raynaud’s phenomenon 137lasofoxifene 230late-onset RA (LORA) 105–6, 150lateral cutaneous nerve of the thigh, meralgia

paraesthetica 24lateral epicondylitis (tennis elbow) 18–19RCT of treatments 20

leflunomide 148avoidance during pregnancy 95safety monitoring 79use in psoriatic arthritis 181use in Sjögren’s syndrome 132

leptin levels, Behçet’s syndrome 167Lesch–Nyhan syndrome 186LIFE (Losartan Intervention for Endpoint

Reduction) study 187lifestyle modification, SLE 126ligamentum flavum hypertrophy 171limb girdle muscular dystrophy 255limited cutaneous scleroderma 140limited joint mobility (LJM), diabetes 212linoleic acid 46a-linolenic acid 46local anaesthetic injection, fibromyalgia

syndrome 31losartan, use in gout 191, 193low back painacute 169–70, 174ankylosing spondylitis 173causes 170–1

Index 279


low back pain – contdacute – contdmanagement 172–3outcome 173specific pathology 171–2

chronicclinical examination 175–6imaging 176opioid use 177treatment 176–7

indicators for nerve root problems 171inflammatory 172, 173‘red flags’ 170risk factors 170

Low-Dye taping, plantar fasciitis 35lumbar flexion measurement 89, 90LUMINA (lupus in minorities: nature versus

nurture) study 124, 126lupus nephritis 122, 124, 127, 150Lyme disease 7lymphoma, risk in Sjögren’s syndrome 132

M1-2 antibodies 262McArdle disease 257magnetic resonance imaging (MRI)in carpal tunnel syndrome 24–5in giant cell arteritis 161in inflammatory myopathies 262of knee joint 10in low back pain 176in osteomyelitis 203in psoriatic arthritis 180

male osteoporosis 233–5diagnosis and management 236

malignancyassociation with dermatomyositis 260–1breast cancer risk, effect of SERMS 228as cause of lower back pain 172vitamin D levels 219

malignant bone pain 2malignant hyperthermia 255–6mammalian target of rapamycin (MTOR) 148manipulation under anaesthesia (MUA), value in

frozen shoulder 16matrix metalloproteinases (MMPs)in Dupuytren’s disease 213as therapeutic targetes 51

medial calcaneal nerve entrapment 35medial compartment syndrome 24medial epicondylitis (golfer’s elbow) 19median neuritis 23Mediterranean diet 98medium vessel vasculitis 154–5medullary osteomyelitis 201

MELAS (Myopathy, Encephalopathy, LacticAcidosis and Stroke) 256

melioidosis 201meloxicam, cardiovascular risk 62membranous staining, ANA 110menopauseeffect on BMD 218effect on osteoarthritis risk 43

meralgia paraesthetica 24mercaptopurine, interaction with allopurinol 192MERRF (Myoclonic Epilepsy with Ragged Red

Fibres) 256metabolic syndrome, association with

hyperuricaemia 186methotrexate therapy 148, 151effect on fertility 94in GCA and PMR 161in inflammatory myopathies 262joint replacement surgery 66–7prediction of response 150in psoriasis 181teratogenicity 95in rheumatoid arthritis 84, 86safety monitoring 79in scleroderma 143in Sjögren’s syndrome 132in vasculitides 157

methylene tetrahydrofolate reductase levels 150methylprednisoloneepidural injection 177intra-articular injection 51intravenous, in inflammatory myopathies 262use in GCA 161, 162

microchimaerism hypothesis, scleroderma 144microscopic polyangiitis 155ANCA 157

minimal incision, hip replacement surgery 68minocycline 51association with DIL 118

misoprostol 56mitochondrial myopathies 256mitochondrial toxicity, statins 269mixed connective tissue disease (MCTD),

antinuclear antibodies 111, 112, 113MMP-3 gene 41MOBILE study 224monitoringof immunosuppressive treatment 149–50, 151of systemic lupus erythematosus (SLE) 123–5

monoarthritis 4diagnostic errors 7differential diagnosis 6–8see also gout; septic arthritis

monocarboxylate transporter 4 inhibition, statins269

Index280


monoclonal antibodies 149monocyte chemoattractant protein-1 (MCP-1)

162MORE (Multiple Outcome of Raloxifene

Evaluation) trial 227, 228morphea 140

see also sclerodermamovement disorders, in fibromyalgia syndrome

28multidisciplinary management, low back pain

177multiple sclerosis, vitamin D levels 219multiplex technologies 113muscle biopsy 262muscle complications of statins 211–12, 266–7,

269–70diagnosis and management 267–9pathogenesis 269rhabdomyolysis 267

muscular dystrophies 254–5muscular infarction, diabetic 212muscular pains, Sjögren’s syndrome 131myalgia 266mycophenolate mofetil (MMF) 148, 150use in psoriatic arthritis 181use in scleroderma 143use in SLE nephritis 127use in vasculitides 157

Mycoplasma pneumoniae, as trigger for giant cellarteritis 154, 160

myoadenylate deaminase deficiency 186myocardial infarction riskafter joint replacement surgery 67NSAIDs 57, 61–4

myopathiesacquiredalcoholic myopathy 257critical illness myopathy 257–9steroid myopathy 258, 259

channelopathies 255–6classification 254congenital 253–4in congenital metabolic disorders 256–7inflammatory 260–2diagnosis and management 262–4

mitochondrial 256muscular dystrophies 254–5

myositis-specific antibodies (MSA) 262myotonia 255myotonic dystrophy 254–5myotubular (centronuclear) myopathy 254

n-3 fatty acid supplementation, value inosteoarthritis 46–7

N-arylanthranilic acids 61nailfold capillaries, Raynaud’s phenomenon 135,

140, 141NALP proteins, role in gout 193naproxen, interaction with aspirin 61NAT9 gene 179nemaline rod myopathy 253–4neonatal lupus syndrome 94–5Neoral see cyclosporinnerve root problems 171neural theory of tendinopathy 16neuropathic arthropathy (Charcot joints) 213neuropathies, Sjögren’s syndrome 131–2niacin, muscle symptoms 268nifedipine, value in Raynaud’s phenomenon 137night pain, shoulder 11–12nitric oxide synthase inhibitors, value in

osteoarthritis 51nitric oxide synthases, role in ulcer healing 57non-steroidal anti-inflammatory drugs (NSAIDs)

54-5classification 61gastric side effects 56–9mechanism of action 55–6safety monitoring 79use in carpal tunnel syndrome 24use in elderly people 105–6use in gout 190, 192use in osteoarthritis 50–1use in patients with cardiovascular risk 63use during pregnancy 95use in pseudogout 197use in SLE 126

nuclear factor-k-beta (NF-kB) pathway 53, 240nucleolar staining, ANA 110Nurses Health Initiative 218Nurses’ Health Study, smoking, relationship to

RA risk 74nutritional supplements, value in osteoarthritis

46–7, 52

obesityassociation with osteoarthritis 41–2, 43, 45association with plantar fasciitis 34and joint replacement surgery 65–6as risk factor for osteoarthritis 104

occupational risk factorsosteoarthritis 43rheumatoid arthritis 74

oedematous stage, scleroderma 141oesophageal dysfunction, scleroderma 141,

143–4oestrogeneffect on osteoarthritis risk 43

Index 281


oestrogen – contdeffect on rheumatoid arthritis risk 74, 75

oestrogen therapyin osteoarthritis 51in osteoporosis 218, 231see also hormone replacement therapy (HRT)

oligoarthritis 3olive oil 98omega-3 friendly foods 101omega-3 oil 98benefits in rheumatoid arthritis 82–3, 99

O’nyong-nyong 208opioids, use in chronic low back pain 177oral contraceptive pills, use in SLE 119orlistat 45orthosesvalue in osteoarthritis 47value in plantar fasciitis 35

osteitis fibrosa cystica (high turnover bonedisease) 247

osteoarthritis 39–40, 103–4aetiology 41association with diabetes 211comparison with pseudogout 196drug treatment 50–3non-pharmacological treatment 45–9radiological severity scoring 40risk factors 41–3secondary causes 40

osteoblast apoptosis inhibition 240osteoblasts, effect of corticosteroids 238osteoclast differentiation 243osteoclasts, activation at menopause 218osteoid 247osteomalacia 247osteomyelitis 201, 203plasma procalcitonin 10spinal 172, 204

osteonecrosis, as side effect of bisphosphonates224

osteopenia, indications for bisphosphonates 223osteoporosis 217–18, 221drug treatments 218, 231, 234bisphosphonates 219–20, 223–4combination treatment 229–30raloxifene 227–8sequential treatments 230strontium ranelate 228–9, 230teriparatide 229, 230third generation SERMS 230

glucocorticoid-induced 238–9investigations 226male 133–5diagnosis and management 236

management 225, 226

prevention in long-term steroid therapy 162risk factors 218–19risk in insulin-requiring diabetes 213–14risk from thiazolidinediones 250risk management 220spinal fracture 172

osteoprotegerin (OPG) 218, 238, 243, 248osteosarcoma, as side effect of teriparatide 229outcome measures, RA and AS 88–92oxicams 61

p-ANCA 156–7Paget’s disease 241–2avoidance of teriparatide 229comorbidities 245complications 242genetic factors 243investigation and management 242–3, 244pain 2

pain managementin fibomyalgia syndrome 30in low back pain 176

painful arc 13painful jointsacute monoarthritis, differential diagnosis 6–8new onsetexamination 3history-taking 2–3investigations 3–4

pamidronate 224structure and function 223use during corticosteroid therapy 238use in male osteoporosis 234use in neuropathic arthropathy 213

paracetamol 61value in osteoarthritis 50–1

parainfluenza virus 160paramyotonia 255parathyroid hormone (PTH) 247in evaluation of renal osteodystrophy 248recombinant see teriparatide

parathyroidectomy, in renal osteodystrophy 249,250

parecoxib, cardiovascular side effects 62partial androgen deficiency in aging men

(PADAM) 234–5parvovirus B19 160, 206–7, 208–9patient education, rheumatoid arthritis 84peak bone mineral density 218peginterferon-a therapy, hepatitis C 207pentazocine 51peptidylarginine deaminases (PADIs) 72periodontal disease, effect on rheumatoid

arthritis 75

Index282


Phalen’s sign 23pharmocogenomics 150Phos-Ex (calcium acetate) 250phosphate binders, use in chronic kidney disease

250phosphoribosylpyrophosphate synthetase gene

mutations 186photosensitivity, SLE 122, 126pioglitazone, osteoporosis risk 214, 250piroxicam, side effects 57plantar fascia stretching 36plantar fasciitis 33–5management 35–7

plasmapheresis, use in vasculitides 157pleural disease, SLE 123Pogosta Disease 208polyarteritis nodosa 155polyarthritis 3in elderly people 103gout 106osteoarthritis 103–4rheumatoid arthritis 104–6

polymerase chain reaction (PCR) screening, indiagnosis of infection 203

polymyalgia rheumatica (PMR) 105, 155,159–60, 163–4

DHEA levels 162–3epidemiology 162investigation 161, 163treatment 161–2, 163

polymyositis (PM) 260, 261antinuclear antibodies 111, 112, 113pathogenesis 264

polyphenols 100value in osteoarthritis 52

Pompe disease 256positron emission tomography (PET)in diagnosis of giant cell arteritis 161in diagnosis of infections 204

posterior compartment syndrome 24prayer sign 212prazosin, value in Raynaud’s phenomenon 137prednisolonein GCA and PMR 161in inflammatory myopathies 262intra-articular injection 51risk of fracture 238see also corticosteroid therapy

pregabalin, use in fibromyalgia syndrome 30pregnancyeffect on rheumatoid arthritis risk 74effect on rheumatoid diseases 93, 94parvovirus B19 infection 208use of azathioprine 127use of hydroxychloroquine 126

preventive screening, SLE 124, 125–6primary biliary cirrhosis, antinuclear antibodies

111primary Raynaud’s phenomenon 135PRIMO (Prediction of Muscle Risk in

Observational conditions) survey 267probenecid 193procainamide, association with DIL 118procalcitonin (PCT) 10as marker for infection 203

prolactin 93prolapsed intervertebral discs 171, 172discectomy 176

prostacyclineffect of NSAIDs 61–2value in Raynaud’s phenomenon 137value in scleroderma 143

prostaglandin generation, COX-1 and COX-2 55prostate cancer, androgen deprivation therapy 235prosthesis survival, joint replacement 66, 67–8protein restriction, chronic kidney disease 187–8proteinuriain rheumatoid arthritis 78–9in scleroderma 142

proton pump inhibitors, use with NSAIDs 56,57, 59

pseudoclaudication 171pseudogout 8, 9, 195–6associated conditions 196–7diagnosis 196hereditary 197role of ANKH mutations 198toll-like receptors 198treatment 197–8

Pseudomonas aeruginosa joint infections 201psoriasis 3, 179cardiovascular disease risk 182in retrovirus infection 208

psoriatic arthritis 4, 179–80, 182–3comparison with rheumatoid arthritis 180diagnosis 180, 181management 181–2X-ray changes 78

PSORS loci 179psychological disordersin Behçet’s syndrome 166in fibromyalgia syndrome 28in Sjögren’s syndrome 132

psychological interventions, value in low backpain 177

psychosis, in SLE 127PTNP22 gene 72pulmonary artery hypertension (PAH)bosentan therapy 144scleroderma 142, 143

Index 283


pulmonary embolism, risk after joint replacementsurgery 67

pulmonary fibrosis, scleroderma 141–2, 143pulmonary manifestationsdermatomyositis 261Sjögren’s syndrome 131

pulseless disease (Takayasu’s arteritis) 155purine metabolism 184–5purine nucleoside phosphorylase deficiency 186purine-rich foods 187purpura 154, 158pyrazolidine derivatives 61

quality of life, in psoriatic arthritis 182quality of life evaluation 90–1quercetin 100

radial neuritis 23radiographyin gout 190in low back pain 176in osteomyelitis 203in Paget’s disease 242in pseudogout 196in rheumatoid arthritis 78vascular calcification 249

radionuclide scanning, in osteomyelitis 203raloxifene 227–8, 231in combination treatment 230fracture prevention 224

RANK-RANKL pathway 218, 238, 240, 243rapamycin, use in inflammatory myopathies 264RAPTOR gene 179rashesbutterfly 122in dermatomyositis 261

rat-bite fever 201Raynaud’s phenomenon 134–5autoantibodies 111, 113benefits of statins 144pathogenesis 136in scleroderma 141treatment 136–8

reactive arthritis 4, 7recurrent haemorrhagic shoulder of the elderly

14red meat intake, relationship to RA risk 98referred pain 3around shoulder 11, 12

remitting seronegative symmetric synovitis withpitting oedema (RS3PE) 105

renal diseasein scleroderma 142, 143

Sjögren’s syndrome 131in SLE 122, 124, 127, 150

renal osteodystrophy (ROD) 246–7, 251adynamic bone disease 248diagnosis and management 248in early stage disease 250high turnover bone disease (osteitis fibrosa

cystica) 247mixed 247osteomalacia 247

renal side effects, NSAIDs 57rofecoxib 63

resolvins 98retinal vasculitis, Behçet’s syndrome 166retroviruses 208reverse Phalen’s sign 23rhabdomyolysis, statin therapy 266, 267rheumatoid arthritis 71–2anti-CCP antibodies 79–80antinuclear antibodies 111, 113comparison with psoriatic arthritis 180diagnosis 4–5, 77investigations 78–9

diet, susceptibility factors 97–8dietary supplements 99–100disease-modifying antirheumatic drugs 83–4,

86effect on fetus 94–5effect of pregnancy 93effect on pregnancy 96effect of smoking 5, 85–6in elderly people 104–6, 150environmental factors 73–5fertility 93–4genetic factors 72, 75omega-3 oil supplementation 82–3parvovirus B19 seropositivity 208–9patient education 84primary care and specialist liaison 79prognostic markers 80safety monitoring of medications 79treatment algorithm 85treatment response 84–5treatment response evaluation 87–8, 90–2

rheumatoid factor (RF) 4, 72, 73, 77, 78, 156in hepatitis C 207in parvovirus B19 infection 207in psoriatic arthritis 182in rubella 207

ribavarin therapy, hepatitis C 207rimonabant 45risedronate 223fracture prevention 224long-term use 224use during corticosteroid therapy 238

Index284


use in male osteoporosis 234use in osteoarthritis 104use in Paget’s disease 243

rituximab 149use in inflammatory myopathies 264use in SLE 128use in vasculitides 157

RNA-induced silencing complex (RISC) 209rofecoxibcardiovascular risk 61, 62, 63renal toxicity 63

rosiglitazone, osteoporosis risk 214, 250Ross River Virus 208rosuvastatin 269dosage in Asian patients 267

rotator cuff disease 11, 13–14, 212clinical assessment 11–13imaging 16

rubella 206, 207RUTH (Raloxifene Use for The Heart) study

228

sacroiliitis 4salicylates 61

see also aspirin, low doseSandimmune (cyclosporin) 149SAPHO (Synovitis, Acne, Pustulosis,

Hyperostosis and Osteitis) syndrome 180sarcoidosis 132Schirmer’s test 130sciatica, value of epidural steroid injection 176–7scleroderma 140–2, 146antinuclear antibodies 111, 112pathophysiology 142–3prognosis 142similarity to graft-versus-host disease 144treatment 143–4

sclerosant injections, low back pain 176sclerostin 240secondary Raynaud’s phenomenon 135selective oestrogen receptor modulators (SERMS)

227third generation 230see also raloxifene

selective serotonin reuptake inhibitorsuse in fibromyalgia syndrome 30use in Raynaud’s phenomenon 137

SELENA (Safety of Estrogens in LupusErythematosus National Assessment) trials119

septic arthritis 200–1, 204culture-negative 203of hip, diagnosis 9investigation 4, 7

investigation and management 201, 202mortality, relationship to age 204plasma procalcitonin 10in retrovirus infection 208treatment 9

sequential treatments, osteoporosis 230sequestosome 1 (SQSTM1) gene mutations 243Sevelamer 250sex hormone binding globulin (SHBG),

relationship to bone loss 235shoulder pain 11, 212causes and characteristics 12clinical assessment 11–13frozen shoulder 14–16, 17imaging 16rotator cuff disease 13–14

sialometry 130–1sibutramine 45sicca syndrome 130side effectsof allopurinol 192of androgen therapy 235of azathioprine 148of bisphosphonates 224of colchicine 190of corticosteroids 106, 127, 148of cyclophosphamide 148of cyclosporin 149of hydroxychloroquine 149of leflunomide 148of methotrexate 148of mycophenolate mofetil 148of NSAIDs 57cardiac 61–4gastrointestinal 55, 56–9

of raloxifene 228of statins 211–12, 266–70of strontium ranelate 228of sulphasalazine 149of teriparatide 229

signal recognition particle (SRP) antibodies 262sildenafil, value in Raynaud’s phenomenon

137–8simvastatin, combination with ezetimibe 269Sindbis Virus 208sirolimus (Rapamune) 148Sjögren’s syndrome 129–30anti-centromere antibodies 132antiviral antibodies 206association with hepatitis C 207autoantibodies 111, 113dry eyes 130dry mouth 130–1extraglandular manifestations 131–2fertility 96

Index 285


Sjögren’s syndrome – contdinfections as trigger 132international consensus criteria for diagnosis

130investigation and management algorithm 133

skin lesions, Sjögren’s syndrome 131‘slapped cheek’ disease (erythema infectiosum)

206SLC9A3R1 gene 179SLC11A1 gene 167SLC22A4 gene 72SLC22A12 (URAT1) 185sleep abnormalities, in fibromyalgia syndrome

28, 29small vessel vasculitis 154–5smoking 112–13effect on ankylosing spondylitis 91effect on osteoarthritis 42effect on Raynaud’s phenomenon 136effect on rheumatoid arthritis 5, 74, 75, 85–6effect on SLE 126

SOTI (Spinal Osteoporosis TherapeuticIntervention) trial 228

SPARC 140speckled staining, ANA 110, 117spinal canal stenosis 171surgery 176

spinal cord stimulation, Raynaud’s phenomenon137

spinal fracture 172spinal function assessment 88–90spinal fusion surgery 176spinal infections 172, 203, 204spondyloarthropathies, effect of pregnancy 94spondylodiscitis 180spondylolisthesis 171statinsbenefits in scleroderma 144–5cholesterol-lowering activity 266muscle symptoms 212, 266–7, 269–70diagnosis and management 267–9pathogenesis 269rhabdomyolysis 267

steroid myopathy 257, 258, 259steroids see corticosteroid therapyStreptococcus moniliformis 201stress reduction, fibromyalgia syndrome 31stroke risk, raloxifene 228strontium ranelate 228–9, 230, 231fracture prevention 224

subacute cutaneous lupus 118sulphasalazine 149effect on fertility 94safety monitoring 79use during pregnancy 95

use in psoriatic arthritis 181sulphate intake, relationship to osteoarthritis risk

49sulphinpyrazone 191, 193superficial osteomyelitis 201superoxide dismutase gene, Val16 allele 167suprascapsular neuritis 22swollen joint count (SJC) 88synovial fluid characteristics 8–9systemic lupus erythematosus (SLE) 3, 4, 78,

121, 128ACR classification criteria 117aetiology 117–18, 119–20antiviral antibodies 206autoantibodies 110, 111, 113cardiovascular disease risk 125–6central nervous system involvement 127clinical features 122–3diagnosis 116–17drug-induced 118effect on fetus 94–5effect of pregnancy 93effect on pregnancy 94, 96fertility 94monitoring 123–5nephritis 127preventive screening 124, 125–6risk from smoking 74SELENA trials 119treatment 126–7

systemic sclerosis 140autoantibodies 111, 112, 113effect of pregnancy 94

T score, definition of osteoporosis 217–18tacrolimus 149use in psoriatic arthritis 181

Takayasu’s arteritis (pulseless disease) 155tamoxifen 228tapingvalue in osteoarthritis 47value in plantar fasciitis 35

Tarui disease 257temporal artery biopsy 155, 161, 162, 164tender joint count (TJC) 88tendinopathy, neural aetiology 16tennis elbow 18–19RCT of treatments 20

teriparatide 224, 226, 229, 231in combination treatment 230cost-benefit analysis 230use during corticosteroid therapy 239use in male osteoporosis 234

testosterone, use in male osteoporosis 234–5

Index286


tetracycline labelling, bone biopsy 248tetracyclines, value in osteoarthritis 51, 53, 104Th1 and Th2 cell patterns 93thalidomide, use in Behçet’s syndrome 166therapeutic monitoring, immunosuppressives

149–50, 151thermal biofeedback (TBF) 136–7thiazolidinediones, osteoporosis risk 214, 250thiopurine methyltransferase levels 150Thomsen’s disease 255thoracic outlet syndromes 22three-joint complex, spine 171thrombosis, risk during pregnancy 94thromboxane A2, effect of NSAIDs 61–2thyroiditis, in Sjögren’s syndrome 132tiludronatestructure and function 222–3use in Paget’s disease 243

Tinel’s sign 23tissue-engineering, osteoarthritis 52Titralac 250tizanidine, use in fibromyalgia syndrome 30TNFR2 gene 72TNFRSF11B mutations 243toll-like receptors (TLRs) 198tongue, claudication 155tophi 189dissolution 193

topical NSAIDs, value in osteoarthritis 51topoisomerase 1 140tragus to wall measurement 89, 90tramadol 30use in osteoarthritis 51

transforming growth factor-b (TGF-b), role inscleroderma 143

transplant patients, cyclosporin therapy 149treatment response evaluation, AS and RA

87–92triamcinoloneepidural injection 177intra-articular injection 51

tricyclic antidepressants, use in fibromyalgiasyndrome 30

trigger point injectionsfibromyalgia syndrome 31low back pain 176

trigger points, fibromyalgia syndrome 28, 29triphasic colour changes, Raynaud’s 135TROPOS (Treatment of Peripheral Osteoporosis

Study) 228tumour necrosis factor (TNF)-a-1031C allele

166tumour necrosis factor (TNF)-a antagonists 51,

80, 83, 85, 149, 150safety monitoring 79

tumour necrosis factor (TNF)-a polymorphisms,association with RA 72

turmeric, effect on inflammation 100twin studiesosteoarthritis 41rheumatoid arthritis 72

U3-RNP antibodies, scleroderma 142ulcer healing, role of COX isoenzymes 57ulcersin Behcet’s syndrome 166in scleroderma 141

ulnar neuritis 22–3ultrasoundin carpal tunnel syndrome 24–5in giant cell arteritis 161

unicompartmental knee arthroplasty 68URAT1 (SLC22A12) 185urate levels, in diagnosis of gout 7uric acid metabolism 184–5

see also gout; hyperuricaemiauricase 184uricase preparations, use in gout prophylaxis

192uricosuric agents 190, 191, 193urinary C-terminal peptide of collagen type II

43urine alkalinization 184, 187uveitis, Behçet’s syndrome 166

vascular calcification, in renal disease 249–50,251

vascular dysfunctionin hyperparathyroidism 250in scleroderma 143

vascular endothelial growth factor (VEGF)polymorphisms, psoriasis 182

vascular theory, rotator cuff disease 14vasculitides 153–4ANCA 157–8antibody therapies 158classification 154diagnosis 155–7effect of pregnancy 94large vessel 155medium vessel 155small vessel 154treatment 157, 158see also Behçet’s syndrome; giant cell arteritis

(GCA)VDR gene 41vegetarian/ vegan diets 99vertebral fracture prevention 224

Index 287


vertebral fracture prevention – contdraloxifene 227strontium ranelate 228teriparatide 229

VIGOR (Vioxx Gastrointestinal OutcomesResearch) 57, 61

viral arthritis 205–6alphaviruses 208causes 206diagnosis and treatment 209–10hepatitis C 207–8, 209parvovirus B19 206–7, 208–9retroviruses 208rubella 207

viscosupplementation 47, 49visual symptoms, GCA 161vitamin C intake, relationship to RA risk 97, 98vitamin C status, relationship to risk of

osteoarthritis 46vitamin D 219calcitriol (1, 25-dihydroxy-vitamin D3) 247

vitamin D deficiency 221vitamin D receptor gene 41vitamin D statusin male osteoporosis 235relationship to rheumatoid arthritis risk 74relationship to risk of type 2 diabetes 250–1

vitamin D treatment 218, 231in chronic kidney disease 250

in corticosteroid therapy 238men 234

Vytorin 269

walking sticks, use in osteoarthritis 47warfarin, interaction with allopurinol 192Wegener’s granulomatosis 154–5ANCA 157

weight reductionvalue before joint replacement surgery 65–6value in fibromyalgia syndrome 31women, rheumatoid arthritis risk 74

wrist splints, carpal tunnel syndrome 24

X-rays see radiographyxanthine oxidase (XO) 184xanthine oxidase inhibitors 188

see also allopurinolxerostomiadifferential diagnosis 131Sjögren’s syndrome 130–1

zoledronatedosage 224structure and function 223use in Paget’s disease 243, 245

Index288


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