Understanding inflammatory arthritis

Evaluation and Management principles

CDC: Census Bureau 2004

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What is inflammation?

Normal body defence mechanism Increased blood flow Blood cells produce chemical messengers to

continue the process Heat, swelling, redness, pain, loss of function

Acute vs Chronic Inflammatory Arthritis

Acute ArthritisRapid onset (hours or days)Severe symptomsMediated by components of innate immune response, especially neutrophils (proteases, leukotrienes, prostaglandinsCan result in rapid joint destruction Can also evolve into chronic diseaseExamples: Gout and Infectious Arthritis

Chronic ArthritisMore gradual onset (days to weeks)Symptoms are more moderate, AM stiffness is a prominent symptomMediated by the adaptive immune response, especially T cells

and macrophages - a Th1 diseaseCytokines and chronic inflammation lead to joint remodeling and destruction via erosionsExamples: Rheumatoid Arthritis, Ankylosing Spondylitis, SLE, Lyme Disease

Diversity of Rheumatologic Diseases:Inflammatory and Immune Responses

Inflammatory Diseases (innate immunity)OsteoarthritisGoutPseudogout

Immunologically-Mediated Diseases (adaptive immunity)Rheumatoid Arthritis*Systemic Lupus ErythematosusSpondyloarthropathies*

Ankylosing spondylitis *Reactive Arthritis (Reiter’s Syndrome)Psoriatic Arthritis *Spondylitis associated with IBD

Sjogren’s SyndromePolymositis/DematomyositisLyme DiseaseRheumatic FeverBehcet’s SyndromeSystemic Sclerosis (Scleroderma)Wegener’s GranulomatosisGiant Cell Arteritis

* Diseases that will be covered in depth later in lecture of this course.

Pattern of Joint Involvement is Distinct in Different Diseases

Monoarticular vs PolyarticularMono PolyGout RAInfection SLEReactive

Joint distributionPIPs and MCPs: RA, SLEDIPs: Osteoarthritis, PsoriaticMTP: Gout

Symmetrical vs AsymmetricalSymmetrical: RA, SLEAsymmetrical: Psoriatic, Reactive

Multiple Factors Contribute to the Development of Arthritis

Nature Reviews Immunology, 2007

Genetic Basis of Rheumatic Diseases:

Genotype contributes to rheumatic disease susceptibility

________ Twin Studies____________ Monozygotic Dizygotic Genetic Component

Disease Concordance (%) Concordance (%) Explained by HLA (%)

Rheumatoid Arthritis 15-34 0-6 35

SLE 25-57 0-3

Ankylosing Spondylitis 50-75 13-18 37______________________________________________________________________________

Most often rheumatic diseases are polygenic. A certaingenotype predisposes an individual to a disease, but does not make disease development a certainty.

October 2009: >30 RA Risk Loci

Plenge RM, ACR Annual Meeting Presentation, October 2009

Together explain ~35% of the genetic burden of disease

HLA DR4

“Shared epitope” hypothesis PADI4 PTPN22 CTLA

4

TNFAIP4

STAT4

TRAF1-C5

IL2-IL21

CD40

CCL21

CD244

IL2RB

TNFRSF14

PRKCQ

PIP4K2C

IL2RA

AFF3

REL

BLK

TAGAP

CD28

TRAF0

PTPRC

FCGR2A

PRDM1

CD2-CD58

1978 1987 2003 20072004 2005 2008 2009

Oral Health and RA Periodontal disease more common in people with

RA than controls Oral bacterium, Porphyromonas gingivalis, may

be the connectionu Associated with autoantibodies (CCP)u Could be part of causal pathwayu Many ongoing studies of role in RA

Rosenstein ED et al. Inflammation 2004;28:311-8

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Symptoms

Joint pain Joint swelling Morning stiffness Fatigue Weight loss Flu-like symptoms

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Rheumatoid Arthritis: PIP Swelling Swelling is confined to

the area of the joint capsule

Synovial thickening feels like a firm sponge

Rheumatoid Arthritis: Ulnar Deviation and MCP Swelling

An across-the-room diagnosis

Prominent ulnar deviation in the right hand

MCP and PIP swelling in both hands

Synovitis of left wrist

Rheumatoid Arthritis

Early erosion at the tip of the ulnar styloid

2010 ACR/EULARClassification Criteria for RA

JOINT DISTRIBUTION (0-5)1 large joint 0

2-10 large joints 1

1-3 small joints (large joints not counted) 2

4-10 small joints (large joints not counted) 3

>10 joints (at least one small joint) 5

SEROLOGY (0-3)Negative RF AND negative ACPA 0

Low positive RF OR low positive ACPA 2

High positive RF OR high positive ACPA 3

SYMPTOM DURATION (0-1)<6 weeks 0

≥6 weeks 1

ACUTE PHASE REACTANTS (0-1)Normal CRP AND normal ESR 0

Abnormal CRP OR abnormal ESR 1

≥6 = definite RA

What if the score is <6?

Patient might fulfill the criteria…

Prospectively over time (cumulatively)

Retrospectively if data on all four domains have been adequately recorded in the past

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Extraarticular ?

Eyes: dryness, inflammation, uveitis Lungs: fluid, inflammation, nodules Skin: nodules, ulcers, psoriasis,

balanitis, keratoderma blenorhagia Heart: fluid, inflammation, ischaemic

heart disease Blood: anaemia, low counts

Spondyloarthritis, Psoriasis and PsA

Spondyloarthritis (SpA) The prevalence of SpA is comparable to that of RA (0.5–1.9%)1,2

Psoriasis (Pso) Psoriasis affects 2% of population 7% to 42% of patients with Pso will develop arthritis3

Psoriatic Arthritis A chronic and inflammatory arthritis in association with skin psoriasis4

Usually rheumatoid factor (RF) negative and ACPA negative5

u Distinct from RA Psoriatic Arthritis is classified as one of the subtypes of spondyloarthropathies

u Characterized by synovitis, enthesitis, dactylitis, spondylitis, skin and nail psoriasis4

1Rudwaleit M et al. Ann Rheum Dis 2004;63:535-543; 2Braun J et al. Scand J Rheumatol 2005;34:178-90;3 Fitzgerald “Psoriatic Arthritis” in Kelley’s Textbook of Rheumatology, 2009;

4Mease et al. Ann Rheum Dis 2011;70(Suppl 1):i77–i84. doi:10.1136/ard.2010.140582;5Pasquetti et al. Rheumatology 2009;48:315–325

Juvenile SpA

Reactivearthritis

Arthritis associated with

IBD

PsA

UndifferentiatedSpA (uSpA)

Ankylosingspondylitis (AS)

RA: Rheumatoid arthritis

AS: A Debilitating Rheumatic DiseaseAS: A Debilitating Rheumatic Disease

1Linden VD et al. Chapter 10. In: Firestein, Budd, Harris, McInnes, Ruddy and Sergent, eds. Kelley’s Textbook of Rheumatology: Spondyloarthropathies. 8th ed. Saunders Elsevier;2009:p.1171

2 Braun J & Sieper. J Rheumatology 2008;47:1738-40

Ankylosing Spondylitis

“Bamboo Spine”

Repeated process of healing and bone formation leads to

formation of syndesmophytes ‘bone bridges’

ACR Slide Collection on the Rheumatic Diseases; 3rd edition. 1994.

• Mortality figures parallel RAMortality figures parallel RA6,7,86,7,8

““Rare”Rare”

““Not” a serious disease, functional limitation is Not” a serious disease, functional limitation is mildmild

““Rarely shortens life”Rarely shortens life”

AS (“Mis-”) Perceptions

• Burden of disease significant in pain, sick leave, early Burden of disease significant in pain, sick leave, early retirementretirement3,4,53,4,5

• 0.1-0.9%0.1-0.9%1,21,2

11 Sieper J et al. Sieper J et al. Ann Rheum Dis. Ann Rheum Dis. 2002; 61 (suppl 3);iii8-18. 2002; 61 (suppl 3);iii8-18.2 2 Lawrence RC., Arthritis Rheum 1998; 41:778-99. Lawrence RC., Arthritis Rheum 1998; 41:778-99. 33 Zink A., et al., Zink A., et al., J RheumatolJ Rheumatol 2000; 27:613-22. 2000; 27:613-22.4 4 Boonen A. Boonen A. Clin Exp RheumatolClin Exp Rheumatol. 2002;20(suppl 28):S23-S26.. 2002;20(suppl 28):S23-S26.55 Gran JT, et al. Gran JT, et al. Br J RheumatolBr J Rheumatol. 1997;36:766-771.. 1997;36:766-771.

66 Wolfe F., et al. Arthritis Rheum. 1994 Apr;37(4):481-94. Wolfe F., et al. Arthritis Rheum. 1994 Apr;37(4):481-94. 77 Myllykangas-Luosujarvi R, et al. Myllykangas-Luosujarvi R, et al. Br J Rheumatol.Br J Rheumatol. 1998;37:688-690. 1998;37:688-690.

88 Khan MA, et al. Khan MA, et al. J Rheumatol.J Rheumatol. 1981;8:86-90. 1981;8:86-90.99 Braun J., Pincus T., Clin Exp Rheumatol. 2002; 20(6 Suppl 28):S16-22. Braun J., Pincus T., Clin Exp Rheumatol. 2002; 20(6 Suppl 28):S16-22.

AS: Signs and SymptomsAS: Signs and Symptoms

Axial manifestations:

• Chronic low back pain

• With or without buttock pain

• Inflammatory characteristics:

– Occurs at night (second part)

– Sleep disturbance

– Morning stiffness

• Limited lumbar motion

• Onset before age of 40 yearsSengupta R & Stone MA. Nat Clin Pract Rheumatol 2007;3:496-503

Hultgren S et al. Scand J Rheumatol 2000;29:365-369Linden VD et al. Chapter 10. In: Firestein, Budd, Harris, McInnes, Ruddy and Sergent, eds. Kelley’s

Textbook of Rheumatology: Spondyloarthropathies. 8th ed. Saunders Elsevier;2009:p.1175

Inflammatory back pain (IBP) = Characteristic symptom

MRI sacro-iliac joint

Peripheral manifestations

Enthesitis Peripheral arthritis Dactylitis

AS: Signs and SymptomsAS: Signs and Symptoms

50% patients with enthesitis1

1Cruyssen BV et al. Ann Rheum Dis 2007;66:1072-10772Sidiropoulos PI et al. Rheumatology 2008;47:355-361

Up to 58% patients ever had arthritis1

Much smaller number of patients2

Why are Dactylitis and Enthesitis Important?

The first abnormality to appear in swollen joints associated with

spondyloarthropathies is an enthesitis2

Likelihood of erosions is higher for digits with dactylitis than

those without1

1Brockbank. Ann Rheum Dis 2005;62:188-90; 2McGonagle et al. The Lancet 1998;352.

AS: Extra-skeletal Signs and SymptomsAS: Extra-skeletal Signs and SymptomsOther common symptoms seen during the early stages of disease include:

• Anorexia

• Malaise

• Low grade fever

• Weight loss

• Fatigue

1Missaoui B. et al. Ann Readapt Med Phys 2006;49:305-8, 389-391Linden VD et al. Chapter 10. In: Firestein, Budd, Harris, McInnes, Ruddy and Sergent, eds. Kelley’s

Textbook of Rheumatology: Spondyloarthropathies. 8th ed. Saunders Elsevier;2009:p.1176

Fatigue is a frequent complaint of patients with AS1

AS: AS: Extra-articular Manifestations (EAM)Extra-articular Manifestations (EAM)

EAM Prevalence in AS Patients (%)

Anterior uveitis 30-50

IBD 5-10

Subclinical inflammation of the gut 25-49

Cardiac abnormalitiesConduction disturbancesAortic insufficiency

1-33 1-10

Psoriasis 10-20

Renal abnormalities 10-35

Lung abnormalitiesAirways diseaseInterstitial abnormalitiesEmphysema

40-88 82

47-65 9-35

Bone abnormalitiesOsteoporosisOsteopenia

11-18 39-59

Elewaut D & Matucci MC. Rheumatology 2009;48:1029-1035

Terminal ileitis

Anterior uveitis

Cardiac abnormalities

Spondyloarthritis and Classification Criteria

SpondyloarthropathiesAxial and Peripheral AMOR criteria (1990) ESSG criteria (1991)

Axial Spondyloarthritis ASAS classification 2009

Ankylosing spondylitisPrototype of axial spondylitidis Modified New York criteria 1984

Peripheral Spondyloarthritis ASAS classification 2010

Psoriatic arthritis From Moll & Wright 1973 to CASPAR criteria 2006

Sieper et al. Ann Rheum Dis 2009;68:ii1-ii44Taylor et al. Arthritis & Rheum 2006;54:2665-73

Van der Heijde et al. Ann Rheum Dis 2011;70:905-8

ESSG: European Spondyloarthropathy Study GroupASAS: Assessment of Spondyloarthritis International SocietyCASPAR: Classification criteria for psoriatic arthritis

Infliximab (IFX) and Golimumab (GLM)indications

ASAS Classification Criteria for Axial SpAASAS Classification Criteria for Axial SpAIn patients with back pain ≥3 months and age at onset <45 years

Sacroiliitis* on imaging

plus

≥1SpA feature**

HLA-B27

plus

≥2 other SpA features**

**SpA features:•Inflammatory back pain•Arthritis•Enthesitis (heel)•Uveitis•Dactylitis•Psoriasis•Crohn’s disease/ulcerative colitis•Good response to NSAIDs•Family history for SpA•HLA-B27•Elevated CRP

*Sacroiliitis on imaging:•Active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with SpA

or•Definite radiographic sacroiliitis according to modified New York criteria

Rudwaleit M et al. Ann Rheum Dis 2009;68(6):770-6

OR

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Psoriatic Arthritis

Psoriatic Arthritis

ACR Slide Collection on the Rheumatic Diseases; 3rd edition. 1994.Data on file, Centocor, Inc.

Pso patients6-8

• Psychosocial burden• Reactive depression • Higher suicidal ideation• Alcoholism

Metabolic Syndrome3-5

• Hyperlipidemia• Hypertension• Insulin resistent • Diabetes • Obesity Higher risk of Cardiovascular disease (CVD)

Ocular inflammation1

(Iritis/Uveitis/ Episcleritis)

IBD2

Comorbidities in PsA Patients

1Qieiro et al. Semin Arth Rheum 2002;31:264; 2Scarpa et al. J Rheum 2000;27:1241; 3Mallbris et al. Curr Rheum Rep 2006;8:355; 4Neimann et al. J Am Acad Derm 2006;55:829; 5Tam et al. 2008;47:718; 6Kimball et al. Am J Clin Dermatol 2005;6:383-392;

7Naldi et al. Br J Dermatol 1992;127:212-217; 8Mrowietz U et al. Arch Dermatol Res 2006;298(7):309-319

Classical Description of PsA Using the Diagnostic Criteria of Moll and Wright

Including 5 clinical patterns:u Asymmetric mono-/oligoarthritis (~30% [range 12-70%])1-4

u Symmetric polyarthritis (~45% [range 15-65%])1-4

u Distal interphalangeal (DIP) joint involvement (~5%)1

u Axial (spondylitis and Sacroiliitis) (HLA-B27) (~5%)1,3

u Arthritis Mutilans (<5%)1,3

References see notes

• However patterns may change over time and are therefore not useful for classification 5

HLA: Human leucocytes antigen

Paradigm shift in the treatment of inflammatory arthritis

Rationale for Treatmentu Large body of evidence which shows joint damage

is an early phenomenon of rheumatoid arthritisu Joint erosions occur in up to 93% of patients with

less than 2 years of disease activityu The rate of radiographic progression is greatest in

the first two yearsu Disability occurs early – 50% of patients with RA

will be work disabled at 10 yearsu Severe disease is associated with increased

mortality!

It’s like an Iceberg

It’s what you don’t see!

Approach to Inflammatory Arthritis “Window of Opportunity”

u Early and aggressive treatment may have long-term benefits

Principles of Treatmentu Treat Earlyu Treat Appropriately

A Fire in the Joints

If there’s a fire in the kitchen do you wait until it spreads to the living room or do you try and put it out?

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Principles of Treatment

Early diagnosis Early initiation of treatment Regular assessment (Disease Activity Scores) “Treat to Target” Annual review

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Reduction of Joint Damage

Disease-modifying Anti-Rheumatic Drugs

MethotrexateSulfasalazineLeflunomideHydroxychloroquineAzathioprineCiclosporinGoldPenicillamine

Biologic drugs

Anti-TNF therapy: Infliximab Etanercept Adalimumab Certolizumab Golimumab

Rituximab Abatacept Tocilizumab

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