SclerodermaSclerodermaand and

Inflammatory MyositisInflammatory Myositis

SclerodermaSclerodermaand and

Inflammatory MyositisInflammatory Myositis

Kathryn Dao, MD

Arthritis Consultation Center

January 22, 2010

ObjectivesObjectivesObjectivesObjectives

Define scleroderma Identify the inflammatory myopathies Describe the subsets of these diseases Recognize their clinical features and

disease that may mimic them Understand possible complications that

may occur in these diseases

What 1996 movie put What 1996 movie put scleroderma on the map and scleroderma on the map and

why?why?

What 1996 movie put What 1996 movie put scleroderma on the map and scleroderma on the map and

why?why?

SclerodermaSclerodermaSclerodermaScleroderma

“Skleros-” = hard “-derma” = skin Incidence 1-2/100,000 in USA Peak age of onset 30-50 y.o. Female:male 3: 1 Disease manifestation is a result of host

factors + environment (concordance is similar in monozygotic and dizygotic twins)

SclerodermaSclerodermaA disorder of Collagen, VesselsA disorder of Collagen, Vessels

SclerodermaSclerodermaA disorder of Collagen, VesselsA disorder of Collagen, Vessels

Etiology: unknown? acquired? Autoimmune disorder suggested by the

presence of characteristic autoantibodies such as ANA, anti-centromere and anti-SCL-70 antibodies.

Scleroderma PathogenesisScleroderma PathogenesisScleroderma PathogenesisScleroderma PathogenesisHallmarks: Vasculopathy (not vasculitis) and fibrosis

Early dermal changes lymphocytic infiltrates primarily of T cells Hypersensitive 2 receptors resulting in heightened

vasoconstriction Tissue ischemia/ reperfusion

Susceptible Host

Exogenous event

Immune System Activation

Endothelial Cell Activation/Damage

Fibroblast Activation

Obliterative Vasculopathy & Fibrosis

Klippel JH, ed. Primer on the Rheumatic Disease. 2001

How do you categorize How do you categorize Scleroderma?Scleroderma?

How do you categorize How do you categorize Scleroderma?Scleroderma?

Scleroderma ClassificationScleroderma ClassificationScleroderma ClassificationScleroderma Classification

Three major disease subsets: based on extent of skin involvement:

Localized Scleroderma Systemic Sclerosis (SSc)

Diffuse SSc Limited SSc AKA "CREST" syndrome

Scleroderma sine scleroderma

Localized Scleroderma: Morphea

Linear scleroderma

What is this condition called?

“En Coup de Sabre”

Scleroderma ClassificationScleroderma ClassificationScleroderma ClassificationScleroderma ClassificationThree major disease subsets: based on extent of skin

involvement: Localized Scleroderma Systemic Sclerosis (SSc)

Diffuse SSc - skin abnormalities extending to the elbows/knees, often include the face, neck, & trunk

Limited SSc AKA "CREST" syndrome Calcinosis, Raynauds, Esophageal dysmotility

Sclerodactyly, Telangiectasias Scleroderma sine scleroderma

ACR Systemic Sclerosis ACR Systemic Sclerosis Preliminary Classification Criteria*Preliminary Classification Criteria*

ACR Systemic Sclerosis ACR Systemic Sclerosis Preliminary Classification Criteria*Preliminary Classification Criteria*

Major Criterion Scleroderma proximal to the MCP or MTP

Minor Criteria Sclerodactyly Digital pitting or scars or loss of finger pad Bibasilar pulmonary fibrosis

* One major and two minor required for diagnosis

Diffuse SSc - ClinicalDiffuse SSc - ClinicalDiffuse SSc - ClinicalDiffuse SSc - Clinical

Skin: Skin thickening: most noticeable in the hands --

swollen, puffy, waxy. Thickening extends to proximal extremity, truncal

and facial skin thickening is seen. Loss of skin folds, no hair growth Digital pits or scarring of the distal digital pulp Calcinosis, telangiectasias Raynaud's phenomenon

Cold

Cold

Normal

SSc

Skin ScoresExtent of skin involvment predictive of survival:

% Survival at 5 yr 10 yr

Sclerodactyly 79-84 47-75

Truncal 48-50 22-26

J Rheumatol 1988;15:276-83.

What are the typical colors of Raynaud’s?In what order do they occur?

Why?

White, Blue, Red pallor cyanosis reperfusion erythema

Flag of the Russian Federation

BONUS: What country’s flag is this?

SclerodermaSclerodermaA disorder of Collagen, VesselsA disorder of Collagen, Vessels

SclerodermaSclerodermaA disorder of Collagen, VesselsA disorder of Collagen, Vessels

Small to medium-sized blood vessels, which show bland fibrotic change Vasculopathy, NOT vasculitis!

Small thrombi may form on the altered intimal surfaces.

Microvascular disease Normal

PSS

Cold

Cold

??? TRUE OR FALSE ???

INFLAMMATORY ARTHRITIS IS THE MOST COMMON

MUSCULOSKELETAL MANIFESTATION OF

SYSTEMIC SCLEROSIS

FALSE

Systemic SclerosisSystemic SclerosisSystemic SclerosisSystemic Sclerosis

Musculoskeletal: Arthralgias >>> Arthritis Palpable tendon

friction rubs associated with an increased incidence of organ involvement.

Muscle weakness or frank myositis can be seen—can be associated with medications.

Where in the GI tract does SSc affect?

Anywhere from the mouth to the anus

Small oral aperture, dry mucosal membranes with periodontal disease

Esophageal dysmotility, reflux, esophagitis, stricture, dysphagia

Delayed stomach emptying, Pseudoobstruction of the small intestines, bacterial

overgrowth, malabsorption Wide mouth diverticuli Fecal incontinence due rectal sphincter fibrosis

Systemic Sclerosis: GISystemic Sclerosis: GISystemic Sclerosis: GISystemic Sclerosis: GI

Kidney involvement is an ominous finding and important cause of death in diffuse scleroderma. A hypertensive crisis (AKA renal crisis) may herald the onset of rapidly progressive renal failure.

Systemic Sclerosis: RenalSystemic Sclerosis: Renal

Scleroderma Renal CrisisScleroderma Renal CrisisScleroderma Renal CrisisScleroderma Renal Crisis

Risk Factors diffuse skin involvement rapid progression of skin thickening disease course < 4 years anti-RNA-polymerase III-antibodies newly manifested anemia newly manifested cardiac involvement high-dose corticoid therapy pregnancy

Am J Med 1984;76:779-786.

Scleroderma Renal CrisisScleroderma Renal CrisisScleroderma Renal CrisisScleroderma Renal Crisis

Microangiopathic hemolytic anemia +Microscopic hematuria

Fatal before the introduction of ACE-I Survival without ACE-I 16% @ 1 year, with

ACE-I 45% at 5 years ACE-I increases levels of two potent renal

vasodilators: bradykinin and angiotensin 1-7

Ann Int Med 1990;113:352-357.

???TRUE or FALSE???

ACE inhibitors should be continued in patients with renal crisis despite rising

creatinine and potassium

TRUE

Systemic Sclerosis: RenalSystemic Sclerosis: RenalSystemic Sclerosis: RenalSystemic Sclerosis: Renal

Some patients will require dialysis despite ACE-I and good blood pressure control

As long as the ACE-I are continued during dialysis, approximately 50% will have enough improvement to stop dialysis in 6-18 months.

Inconsistent data with ARBs

Some patients will require dialysis despite ACE-I and good blood pressure control

As long as the ACE-I are continued during dialysis, approximately 50% will have enough improvement to stop dialysis in 6-18 months.

Inconsistent data with ARBs

Rheum Dis Clin North Am. 1996 Nov;22(4):861-78

Systemic Sclerosis: PulmonarySystemic Sclerosis: PulmonarySystemic Sclerosis: PulmonarySystemic Sclerosis: Pulmonary

**** LEADING CAUSE OF MORTALITY ***

Interstitial fibrosis +/- pulmonary hypertension Dyspnea, cough, chest pain Other manifestations:

Pulmonary embolism Pulmonary vasculitis Pulmonary hemorrhage Lung cancer Aspiration Respiratory distress from muscle disease

Decreased DLCO is the earliest marker (especially with normal lung volumes)

Increased A-a Gradient with Exercise Restrictive Pattern

VC, FEV1/FVC

PFT’s in Systemic SclerosisPFT’s in Systemic SclerosisPFT’s in Systemic SclerosisPFT’s in Systemic Sclerosis

Systemic Sclerosis: CardiacSystemic Sclerosis: CardiacSystemic Sclerosis: CardiacSystemic Sclerosis: Cardiac

Symptoms are subtle Myocardium, myocardial blood vessels, pericardium

can all be involved: Myocardial fibrosis Dilated cardiomyopathy Cor pulmonale Arrhythmias Pericarditis (30-40%) Myocarditis Congestive heart failure (diastolic dysfunction) Myocardial infarction (Raynaud’s)

Comparison CREST v. Diffuse SScComparison CREST v. Diffuse SScComparison CREST v. Diffuse SScComparison CREST v. Diffuse SSc Feature Limited CREST Diffuse SSc

 Calcinosis ++ +

 Arthralgias  ++  ++++

 Pulmonary fibrosis

 ++  +++

 Pulmonary HTN  ++  +

 Tend friction rubs

0 +++

 Renal crisis 0  +

 Centromere Ab  +++ +/0

 Anti-Scl 70 Ab + ++

+ Relative percentages: +++++ 81-100%; ++++ 61-80%; +++ 41-60%; ++ 21-40%; + 1-20%

Raynaud’s +++++ +++++

Telangiectasia +++++ ++++

Esophageal dysmotility

+++++ +++++

5 yr Survival +++++ ++++

Treatment of SScTreatment of SScTreatment of SScTreatment of SSc

Morphea: none Treat the manifestations of the disease: Raynauds: warmth, skin protection, vasodilator

therapy (e.g., NTG, CCB, ARB, Niacin, anti-adrenergics, prostacyclin, endothelin antagonists, nerve blocks)

Systemic therapy: Unproven benefits--Steroids, Penicillamine, MTX CYP: for alveolitis Experimental: stem cell transplant Finger ulcers: difficult; vasodilators, Abx

DDX of Tight SkinDDX of Tight SkinDDX of Tight SkinDDX of Tight Skin

Pseudosclerodactyly IDDM, Hypothyroidism

Drugs: Tryptophan, bleomycin, pentazocine, vinyl chloride, solvents

Eosinophilic fasciitis Overlap syndromes Scleredema Scleromyxedema

(papular mucinosis)

DDX of Tight SkinDDX of Tight SkinDDX of Tight SkinDDX of Tight Skin Scleroderma-like conditions

Porphyria cutanea tarda Nephrogenic fibrosing dermopathy

Inflammatory Myositis:Inflammatory Myositis: Polymyositis/DermatomyositisPolymyositis/Dermatomyositis

Inflammatory Myositis:Inflammatory Myositis: Polymyositis/DermatomyositisPolymyositis/Dermatomyositis

F:M = 2:1 Acute onset Weakness: Proximal > Distal Skeletal muscle: dysphagia, dysphonia Sx: Rash, Raynauds, dyspnea 65% elevated CPK, aldolase 50% ANA (+) 90% +EMG 85% + muscle biopsy

What percentage of patient What percentage of patient with DM/PM will have pain?with DM/PM will have pain?What percentage of patient What percentage of patient with DM/PM will have pain?with DM/PM will have pain?

Less than 50%

Proposed Criteria for MyositisProposed Criteria for MyositisProposed Criteria for MyositisProposed Criteria for Myositis1. Symmetric proximal muscle weakness2. Elevated Muscle Enzymes (CPK, aldolase,

AST, ALT, LDH)3. Myopathic EMG abnormalities4. Typical changes on muscle biopsy5. Typical rash of dermatomyositis

PM Dx is Definite with 4/5 criteria and Probable with 3/5 criteria

DM Dx Definite with rash and 3/4 criteria and Probable w/ rash and 2/4 criteria

Myositis ClassificationMyositis ClassificationBohan & PeterBohan & Peter

Myositis ClassificationMyositis ClassificationBohan & PeterBohan & Peter

1. Primary idiopathic dermatomyositis2. Primary idiopathic polymyositis3. Adult PM/DM associated with

neoplasia4. Childhood Dermatomyositis (or PM)

*often associated with vasculitis and calcinosis

5. Myositis associated with collagen vascular disease

Age/Sex/Race Acute vs. Insidious Onset Distribution: Proximal vs. Distal Pain? Drugs/Pre-existing Conditions Neuropathy Systemic Features

HISTORICAL CONSIDERATIONS

Toxic/Drugs EtOH, Cocaine, Hydroxychloroquine, Penicillamine,

Clofibrate, Taxol Colchicine, AZT, Statins, Steroids, Hydralazine, Gemfibrozil, CYA, L-dopa, Phenytoin, Cimetidine, Sulfonamides, PCN

Infectious Coxsackie, HBV, HIV, Strep, Staph, Clostridium,

Toxoplasma, Trichinella Congenital/metabolic myopathies Neuropathic/Motor Neuron Disorders (MG, MD) Endocrine/Metabolic-hypothyroidism Inclusion body myositis

DDX: MyopathiesDDX: MyopathiesDDX: MyopathiesDDX: Myopathies

Fibromyalgia Polymyalgia Rheumatica

Caucasians, > 55 yrs, M=F Elevated ESR/CRP, normal strength,

no synovitis CTD (SLE, RA, SSc) Vasculitis Adult Onset Still's Disease

Nonmyopathic DDxNonmyopathic DDxNonmyopathic DDxNonmyopathic DDx

Infiltrates - T cells (HLA-DR+) & monocytes Muscle fibers express MHC class I & II Ags T cells are cytotoxic to muscle fibers Infectious etiology? Viral implicated HLA-B8/DR3 in childhood DM DR3 and DRW52 with t-RNA synthetase Ab

Inflammatory myositis: Inflammatory myositis: pathogenesispathogenesis

Inflammatory myositis: Inflammatory myositis: pathogenesispathogenesis

1. Heliotrope Rash: over eyelids Seldom seen in adults

2. Gottrons Sign/Papules (pathognomonic): MCPs, PIPs, MTPs, knees, elbows

3. V-Neck Rash: violaceous/erythema anterior chest w/ telangiectasias

4. Periungual erythema, digital ulcerations

5. Calcinosis

Dermatomyositis: Skin featuresDermatomyositis: Skin featuresDermatomyositis: Skin featuresDermatomyositis: Skin features

Why is it called a heliotropic rash?

CalcinosisCalcinosisCalcinosisCalcinosis

Physical Examiniation: Motor Strength (Gowers sign), Neurologic Exam

Acute phase reactants unreliable Muscle Enzymes

CPK: elevated >65%; >10% MB fraction is possible Muscle specific- Aldolase, Troponin, Carb. anhydraseIII AST > LDH > ALT Beware of rising creatinine (ATN) and myoglobinuria

EMG: increased insertional activity, amplitude, polyphasics, neuropathic changes, incremental/decremental MU changes

Diagnostic TestingDiagnostic TestingDiagnostic TestingDiagnostic Testing

Muscle Biopsy (an URGENT not elective procedure) Call the neuropathologist! 85% Sensitive. Biopsy involved muscle (MRI guided) Avoid EMG/injection sites or sites of trauma

Magnetic Resonance Imaging - detects incr. water signal, fibrous tissue, infiltration, calcification

Investigational: Tc-99m Scans, PET Scans Serologic Tests: ANA (+) 60%, Abs against t-

RNA synthetases

Diagnostic TestingDiagnostic TestingDiagnostic TestingDiagnostic Testing

Inflammatory cells Edema and/or fibrosis Atrophy/ necrosis/ degeneration Centralization of nuclei Variation in muscle fiber size hydroxyapatite crystals (rare)

HistopathologyHistopathologyHistopathologyHistopathology

Polymyositis: CD8+Tcells, endomysial infiltration

Dermatomyositis: Humoral response B cells, CD4+ T cells; perifascicular/perivascular infiltration

Autoantibodies in PM/DMAutoantibodies in PM/DMAutoantibodies in PM/DMAutoantibodies in PM/DM

Ab Freq (%) Clinical Syndrome

ANA 50 Myositis

U1-RNP 15 SLE + myositis (MCTD)

Ku <5 SSc + myositis

Mi2 30 Dermatomyositis

PM1 15 SSc + PM overlap

Jo-1 25 Arthritis+ ILD+ Raynaud

SS-B (La) <5 SLE,Sjogrens, ILD, PM

PL-12,7 <5 ILD + PM

What is an anti-synthetase What is an anti-synthetase syndrome?syndrome?

What is an anti-synthetase What is an anti-synthetase syndrome?syndrome?

•It is a subcategory of the inflammatory myositisdefined by the presence of autoantibodies to aminoacyl-tRNA synthetases. •Specific clinical manifestations :ILD, arthritis, Raynaud's phenomenon, fever, and mechanics hands. •Examples: Antibodies to Jo-1, PL-12, OJ, EJ, PL-7, KS, and Zo are some that have been reported.

Mechanics hands– association with Jo-1

Higher association with DM, less common with polymyositis

Studies found 20-32% with DM developed CA

Common tumors: Breast, lung, ovary, stomach, uterus, colon, NHL

60% the myositis appears 1st, 30% neoplasm 1st, and 10% simultaneously

Lancet 2001

Ann Int Med 2001.

Malignancy and myositisMalignancy and myositisMalignancy and myositisMalignancy and myositis

Dermatomyositis and MalignancyDermatomyositis and MalignancyDermatomyositis and MalignancyDermatomyositis and Malignancy

All adults with DM should have age-appropriate screening annually during first several years after presentation: CXR Colonoscopy or sigmoidoscopy PSA/prostate exam in men Mammogram, CA-125, pelvic exam,

transvaginal ultrasonography in women

PM/DM ComplicationsPM/DM ComplicationsPM/DM ComplicationsPM/DM Complications

PULMONARY Aspiration pneumonitis Infectious pneumonitis Drug induced

pneumonitis Intercostal, diaphragm

involvement Fibrosing alveolitis RARE:

Pulmonary vasculitis Pulmonary neoplasia

CARDIAC Elev. CPK-MB Mitral Valve prolapse AV conduction

disturbances Cardiomyopathy Myocarditis

Early Dx, physical therapy, respiratory Rx High dose steroids (e.g., prednisone 1-2 mg/kg/day)

80% respond within 12 weeks Steroid resistant

Methotrexate Azathioprine Rituximab CYP

IVIG, Cyclosporin, Chlorambucil, TNFi: unproven No response to apheresis

TreatmentTreatmentTreatmentTreatment

Poor in pts. with delayed Dx, low CPK, early lung or cardiac findings, malignancy

PT for muscle atrophy, contractures, disability Kids:50% remission, 35% chronic active

disease Adult < 20 yrs. do better than >55 yrs. Adults: Mortality rates between 28-47% @

7 yrs. Relapses & functional disability are common Death: due to malignancy, sepsis, pulm. or

cardiac failure, and complications of therapy

PrognosisPrognosisPrognosisPrognosis

Bimodal age distribution, maybe hereditary Males > females Slow onset, progressive weakness Painless, distal and proximal weakness Normal or mildly elevated CPK Poor response to therapy Dx: light microscopy may be normal or show

CD8+ lymphs and vacuoles with amyloid. Tubulofilamentous inclusion bodies on electron microscopy

Inclusion Body MyositisInclusion Body MyositisInclusion Body MyositisInclusion Body Myositis

ConclusionConclusionConclusionConclusion

Scleroderma and the inflammatory myopathies are diseases that require prompt recognition

Early intervention may decrease morbidity/mortality