Scleroderma and Inflammatory Myositis Kathryn Dao, MD Arthritis Center February 16, 2006

SclerodermaScleroderma n “Skleros-” = hard “-derma” = skin n Incidence 1-2/100,000 in USA n Peak age of onset y.o. n Female:male 7-12: 1 n Disease manifestation is a result of host factors + environment (concordance is similar in monozygotic and dizygotic twins)

SclerodermaScleroderma Three major disease subsets: based on extent of skin dz n Localized Scleroderma ] Morphea: manifests as focal patches ] Linear scleroderma: band-like (linear) areas of thickening. (Coup de Sabre) n Limited disease AKA "CREST" syndrome ] Calcinosis, Raynauds, Esophageal dysmotility Sclerodactyly, Telangiectasias n Diffuse disease - skin abnormalities extending to the proximal extremities (AKA - PSS) n (Scleroderma sine scleroderma)

DDX of Tight Skin n Pseudosclerodactyly ] IDDM, Hypothyroidism n Drugs: Tryptophan, bleomycin, pentazocine, vinyl chloride, solvents n Eosinophilic fasciitis n Overlap syndromes n Scleredema

DDX of Tight Skin n Scleromyxedema (popular mucinosis) n Scleroderma-like conditions ] Eosinophil myalgia syndrome (tryptophan) ] Porphyria cutanea tarda ] Toxic oil syndrome ] Nephrogenic fibrosing dermopathy

ACR Systemic Sclerosis Preliminary Classification Criteria* n Major Criterion ] Proximal Scleroderma n Minor Criteria ] Sclerodactyly ] Digital pitting or scars or loss of finger pad ] Bibasilar pulmonary fibrosis * One major and two minor required for diagnosis

Scleroderma: Onset n Raynauds n Swollen or puffy digits n Loss of skin folds, no hair growth n Digital pulp sores/scars n Arthralgias >> Arthritis

Scleroderma A disorder of Collagen, Vessels n Etiology: unknown? n Autoimmune disorder suggested by the presence of characteristic autoantibodies such as ANA, anti-centromere and anti-SCL-70 antibodies. n Pathology: ] Early dermal changes lymphocytic infiltrates primarily of T cells ] Major abnormality is collagen accumulation with fibrosis.

Scleroderma A 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. n Microvascular disease Normal PSS Cold

PSS - Clinical n Skin: ] Skin thickening is most noticeable in the hands, looking swollen, puffy, waxy. ] Thickening extends to proximal extremity, truncal and facial skin thickening is seen. ] Raynaud's phenomenon is present. ] Digital pits or scarring of the distal digital pulp n Musculoskeletal: Arthralgias and joint stiffness are common. ] Palpable tendon friction rubs associated with an increased incidence of organ involvement. ] Muscle weakness or frank myositis can be seen.

Skin Scores Extent of skin involvment predictive of survival: % Survival at 5 yr 10 yr Sclerodactyly Truncal J Rheumatol 1988;15:

n Gastrointestinal: Esophageal dysmotility, dysphagia, malabsorptive or blind loop syndrome, constipation. PSS - Clinical

Renal: 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.

Scleroderma Renal Crisis n 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 äpericardial effusion äheart insufficiency ] preceded high-dose corticoid therapy ] pregnancy Am J Med 1984;76:

Scleroderma Renal Crisis n Microangiopathic hemolytic anemia +Microscopic hematuria n Fatal before the introduction of ACE-I, CCB ] Survival without ACE-I 1 year, with ACE-I 45% at 5 years n Continue use of ACE-I even if dialysis appears imminent Ann Int Med 1990;113:

Pulmonary Manifestations of PSS n Dyspnea n Pulmonary HTN primarily in CREST n Ground glass (alveolitis) n Interstitial fibrosis (bibasilar) n High resolution CT vs Gallium Scan ] Major cause of death n RARE: ] Pulmonary embolism ] Pulmonary vasculitis

n Decreased DLCO is the Earliest Marker n Increased A-a Gradient with Exercise n Restrictive Pattern ]  VC,  FEV1/FVC n Pulmonary Vascular Disease ]  DLCO with Normal Volumes PFT’s in Systemic Sclerosis

Cardiac Findings in PSS n Myocardial fibrosis n Dilated cardiomyopathy n Cor pulmonale n Arrhythmias n Pericarditis n Myocarditis n Congestive heart failure n Myocardial infarction (Raynaud’s)

Comparison CREST v. PSS FeatureLimited CRESTDiffuse PSS Calcinosis+++ Arthralgia/Arthritis Pulmonary fibrosis Pulmonary HTN ++ + Tend friction rubs 0+++ Renal crisis0 + Centromere Ab ++++/0 Anti-Scl 70 Ab+++ + Relative percentages: %; %; %; %; % Raynaud’s+++++ Telangiectasia Esophageal dysmotility yr Survival

Treatment of Scleroderma n Localized: none n Raynauds: warmth, skin protection, vasodilator therapy n CREST: same as Raynauds n PSS: none proven ] No Value: Steroids, Penicillamine, MTX ] Cytoxan: for lung disease? ] Experimental: stem cell transplant, TNF-I –Epoprostenol (Flolan): Prostacyclin –Bosentan (Tracleer): Endothelin receptor antagonist ] Finger ulcers: difficult; vasodilators, Abx

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

Proposed Criteria for Myositis 1. Symmetric proximal muscle weakness 2. Elevated Muscle Enzymes (CPK, aldolase, AST, ALT, LDH) 3. Myopathic EMG abnormalities 4. Typical changes on muscle biopsy 5. Typical rash of dermatomyositis n PM Dx is Definite with 4/5 criteria and Probable with 3/5 criteria n DM Dx Definite with rash and 3/4 criteria and Probable w/ rash and 2/4 criteria

Polymyositis Classification Bohan & Peter 1. Primary idiopathic dermatomyositis 2. Primary idiopathic polymyositis 3. Adult PM/DM associated with neoplasia 4. Childhood Dermatomyositis (or PM) ä often associated with vasculitis and calcinosis 5. Myositis associated with collagen vascular disease

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

DDX MYOPATHIIES n Toxic/Drugs ] Etoh, Cocaine, Steroids, Plaquenil, Penicillamine, Colchicine, AZT, Statins, Clofibrate, Tryptophan, Taxol, Emetine n Infectious ] Coxsackie, HBV, HIV, Stept, Staph, Clostridium, Toxoplasma, Trichinella n Inflammatory Myopathies n Congenital/metabolic myopathies n Neuropathic/Motor Neuron Disorders-MG, MD n Endocrine/Metabolic-hypothyroidism n Inclusion body myositis

NONMYOPATHIC CONSIDERATIONS n Fibromyalgia/Fibrositis/Myofascial Pain disorder n Polymyalgia Rheumatica ] Caucasians, > 55 yrs, M=F ] ESR > 100, normal strength, no synovitis n CTD (SLE, RA, SSc) n Vasculitis n Adult Still's Disease

INFLAMMATORY MYOSITIS Immunopathogenesis n Infiltrates - T cells (HLA-DR+) & monocytes n Muscle fibers express class I & II MHC Ags n T cells are cytotoxic to muscle fibers n t-RNA antibodies: role? FOUND IN <50% OF PTS n Infectious etiology? Viral implicated n HLA-B8/DR3 in childhood DM n DR3 and DRW52 with t-RNA synthetase Ab

DERMATOMYOSITIS 5 Skin Features 1. Heliotrope Rash: over eyelids nSeldom 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

Why is it called a heliotropic rash?

CalcinosisCalcinosis

DIAGNOSTIC TESTING n Physical Examiniation: Motor Strength (Gowers sign), Neurologic Exam n Acute phase reactants unreliable n Muscle Enzymes ] CPK: elevated >65%; >10% MB fraction is possible ] Muscle specific- Aldolase, Troponin, Carb. anhydraseIII ] AST > LDH > ALT ] Beware of incr. creatinine (ATN) and myoglobinuria n EMG: increased insertional activity, amplitude, polyphasics, neuropathic changes, incremental/decremental MU changes

DIAGNOSTIC TESTING n 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 n Magnetic Resonance Imaging - detects incr. water signal, fibrous tissue, infiltration, calcification n Investigational: Tc-99m Scans, PET Scans n Serologic Tests: ANA (+) 60%, Abs against t-RNA synthetases

INFLAMMATORY MYOSITIS Biopsy Findings n Inflammatory cells n Edema and/or fibrosis n Atrophy/ necrosis/ degeneration n Centralization of nuclei n Variation in muscle fiber size n Rarely, calcification

Polymyositis: CD8+Tcells, endomysial infiltration Dermatomyositis: Humoral response B cells, CD4+ T cells; perifascicular/perivascular infiltration

Anti-synthetase syndrome: ILD, fever, arthritis, Raynauds, Mechanics hands

Autoantibodies in PM/DM AbFreq (%)Clinical Syndrome ANA50Myositis U1-RNP15SLE + myositis Ku<5PSS + myositis Mi230Dermatomyositis PM115PSS – PM overlap Jo-125Arthritis+ ILD+ Raynaud SS-B (La)<5SLE,Sjogrens, ILD, PM PL-12,7<5ILD + PM

Anti-synthetase syndrome: ILD, fever, arthritis, Raynauds, Mechanics hands– association with Jo-1

INFLAMMATORY MYOSITIS n NORMAL/NOT INVOLVED: ] Face Uncommon ] Renal ] RES: LN, spleen, liver (enzymes from muscle) n NOT UNCOMMON ] RA-like arthritis ] Fever/chills/night sweats ] Myalgias

MALIGNANCY & MYOSITIS n Higher association with DM, less common with polymyositis n Common tumors: Breast, lung, ovary, stomach, uterus, colon, NHL n 60% the myositis appears 1st, 30% neoplasm 1st, and 10% contemporaneously n Studies found 20-32% with DM developed CA Lancet 2001 Ann Int Med 2001.

Dermatomyositis and Malignancy n 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 Complications PULMONARY n Aspiration pneumonitis n Infectious pneumonitis n Drug induced pneumonitis n Intercostal, diaphragm involvement n Fibrosing alveolitis n RARE: ] Pulmonary vasculitis ] Pulmonary neoplasia CARDIAC n Elev. CPK-MB n Mitral Valve prolapse n AV conduction disturbances n Cardiomyopathy n Myocarditis

Recap: PM/DM Diagnosis n Symmetric progressive proximal weakness n Elevated muscle enzymes (CPK, LFTs) n Muscle biopsy evidence of myositis n EMG: inflammatory myositis n Characteristic dermatologic findings

INFLAMMATORY MYOSITIS Treatment n Early Dx, physical therapy, respiratory Rx n Corticosteroids : mg/day ] 80% respond within 12 weeks n Steroid resistant ] Methotrexate ] Azathioprine n IVIG, Cyclosporin, Chlorambucil: unproven n No response to apheresis

PROGNOSISPROGNOSIS n Poor in pts. with delayed Dx, low CPK, early lung or cardiac findings, malignancy n PT for muscle atrophy, contractures, disability n Kids:50% remission, 35% chronic active disease n Adult 55 yrs. n Adults: Mortality rates between 7 yrs. n Relapses & functional disability are common n Death: due to malignancy, sepsis, pulm. or cardiac failure, and complications of therapy

RHABDOMYOLYSISRHABDOMYOLYSIS n Injury to the sarcolemma of skeletal muscle with systemic release of muscle macromolecules such as CPK, aldolase, actin, myoglobin, etc n Maybe LIFE-THREATENING: from hyperkalemia, met. acidosis, ATN from myoglobinuria n Common causes: EtOH, Cocaine, K+ deficiency, infection, PM/DM, infection (clostridial, staph, strept), medications, exertion/exercise, cytokines

INCLUSION BODY MYOSITIS n Bimodal age distribution, maybe hereditary n Males > females n Slow onset, progressive weakness n Painless, distal and proximal weakness n Normal or mildly elevated CPK n Poor response to corticosteroids n Dx: light microscopy may be normal or show CD8+ lymphs and vacuoles with amyloid. Tubulofilamentous inclusion bodies on electron microscopy

Inflammatory Myositis n Polymyositis (PM) and dermatomyositis (DM) are types of idiopathic inflammatory myopathy (IIM). IIM are characterized clinically by proximal muscle weakness n Etiology: There is now known etiology. n Demographics: PM is more common than DM in adults. Peak incidence occurs between 40 and 60 yrs. F:M 2:1 n Muscles: Proximal muscle weakness, dysphagia, aspiration. respiratory failure or death. n Skin: Gottron's papules, heliotrope rash, "V" neck rash, periungual erythema, "Mechanic's hands", calcinosis n Dx: Muscle enzymes (CPK, aldolase), EMG, Biopsy n Rx: Steroids, MTX, Azathioprine, IVIG