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Scleroderma and Inflammatory Myositis Kathryn Dao, MD Arthritis Center February 16, 2006 Scleroderma “Skleros-” = hard “-derma” = skin Incidence 1-2/100,000 in USA Peak age of onset 30-50 y.o. Female:male 7-12: 1 Disease manifestation is a result of host factors + environment (concordance is similar in monozygotic and dizygotic twins) Scleroderma Three major disease subsets: based on extent of skin dz Localized Scleroderma Morphea: manifests as focal patches Linear scleroderma: band-like (linear) areas of thickening. (Coup de Sabre) Limited disease AKA "CREST" syndrome Calcinosis, Raynauds, Esophageal dysmotility Sclerodactyly, Telangiectasias Diffuse disease - skin abnormalities extending to the proximal extremities (AKA - PSS) (Scleroderma sine scleroderma) DDX of Tight Skin Pseudosclerodactyly IDDM, Hypothyroidism Drugs: Tryptophan, bleomycin, pentazocine, vinyl chloride, solvents Eosinophilic fasciitis Overlap syndromes Scleredema DDX of Tight Skin Scleromyxedema (popular mucinosis) Scleroderma-like conditions Eosinophil myalgia syndrome (tryptophan) Porphyria cutanea tarda Toxic oil syndrome Nephrogenic fibrosing dermopathy ACR Systemic Sclerosis Preliminary Classification Criteria* Major Criterion Proximal Scleroderma 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 Raynauds Swollen or puffy digits Loss of skin folds, no hair growth Digital pulp sores/scars Arthralgias >> Arthritis Scleroderma A disorder of Collagen, Vessels Etiology: unknown? Autoimmune disorder suggested by the presence of characteristic autoantibodies such as ANA, anti-centromere and anti-SCL-70 antibodies. 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. Microvascular disease Cold Cold Normal PSS PSS - Clinical 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 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 Sclerodactyly 79-84 Truncal J Rheumatol 1988;15:276-83. 10 yr 47-75 48-50 22-26 PSS - Clinical Gastrointestinal: Esophageal dysmotility, dysphagia, malabsorptive or blind loop syndrome, constipation. 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 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 pericardial effusion heart insufficiency preceded high-dose corticoid therapy pregnancy Am J Med 1984;76:779-786. Scleroderma Renal Crisis Microangiopathic hemolytic anemia +Microscopic hematuria Fatal before the introduction of ACE-I, CCB Survival without ACE-I 16% @ 1 year, with ACE-I 45% at 5 years Continue use of ACE-I even if dialysis appears imminent Ann Int Med 1990;113:352-357. Pulmonary Manifestations of PSS Dyspnea Pulmonary HTN primarily in CREST Ground glass (alveolitis) Interstitial fibrosis (bibasilar) High resolution CT vs Gallium Scan Major cause of death RARE: Pulmonary embolism Pulmonary vasculitis PFT’s in Systemic Sclerosis Decreased DLCO is the Earliest Marker Increased A-a Gradient with Exercise Restrictive Pattern VC, FEV1/FVC Pulmonary Vascular Disease DLCO with Normal Volumes Cardiac Findings in PSS Myocardial fibrosis Dilated cardiomyopathy Cor pulmonale Arrhythmias Pericarditis Myocarditis Congestive heart failure Myocardial infarction (Raynaud’s) Comparison CREST v. PSS Feature Calcinosis Arthralgia/Arthritis Pulmonary fibrosis Pulmonary HTN Tend friction rubs Renal crisis Centromere Ab Anti-Scl 70 Ab Raynaud’s Limited CREST ++ ++ ++ ++ 0 0 +++ + +++++ Diffuse PSS + ++++ +++ + +++ + +/0 ++ +++++ Telangiectasia +++++ ++++ Esophageal dysmotility +++++ +++++ 5 yr Survival +++++ ++++ + Relative percentages: +++++ 81-100%; ++++ 61-80%; +++ 41-60%; ++ 21-40%; + 1-20% Treatment of Scleroderma Localized: none Raynauds: warmth, skin protection, vasodilator therapy CREST: same as Raynauds 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 F:M = 2:1 Acute onset Weakness (+ myalgia): Proximal > Distal Skeletal muscle: dysphagia, dysphonia Sx: Rash, Raynauds, dyspnea 65% elevated CPK, aldolase 50% ANA (+) 90% +EMG 85% + muscle biopsy Proposed Criteria for Myositis 1. 2. 3. 4. 5. Symmetric proximal muscle weakness Elevated Muscle Enzymes (CPK, aldolase, AST, ALT, LDH) Myopathic EMG abnormalities Typical changes on muscle biopsy 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 Polymyositis Classification Bohan & Peter 1. 2. 3. 4. Primary idiopathic dermatomyositis Primary idiopathic polymyositis Adult PM/DM associated with neoplasia Childhood Dermatomyositis (or PM) often associated with vasculitis and calcinosis 5. Myositis associated with collagen vascular disease MYOPATHY: HISTORICAL CONSIDERATIONS Age/Sex/Race Acute vs. Insidious Onset Distribution: Proximal vs. Distal Pain? Drugs/Pre-existing Conditions Neuropathy Systemic Features DDX MYOPATHIIES Toxic/Drugs Infectious Etoh, Cocaine, Steroids, Plaquenil, Penicillamine, Colchicine, AZT, Statins, Clofibrate, Tryptophan, Taxol, Emetine Coxsackie, HBV, HIV, Stept, Staph, Clostridium, Toxoplasma, Trichinella Inflammatory Myopathies Congenital/metabolic myopathies Neuropathic/Motor Neuron Disorders-MG, MD Endocrine/Metabolic-hypothyroidism Inclusion body myositis NONMYOPATHIC CONSIDERATIONS Fibromyalgia/Fibrositis/Myofascial Pain disorder Polymyalgia Rheumatica Caucasians, > 55 yrs, M=F ESR > 100, normal strength, no synovitis CTD (SLE, RA, SSc) Vasculitis Adult Still's Disease INFLAMMATORY MYOSITIS Immunopathogenesis Infiltrates - T cells (HLA-DR+) & monocytes Muscle fibers express class I & II MHC Ags T cells are cytotoxic to muscle fibers t-RNA antibodies: role? FOUND IN <50% OF PTS Infectious etiology? Viral implicated HLA-B8/DR3 in childhood DM DR3 and DRW52 with t-RNA synthetase Ab DERMATOMYOSITIS 5 Skin Features 1. Heliotrope Rash: over eyelids 2. 3. 4. 5. Seldom seen in adults Gottrons Sign/Papules (pathognomonic): MCPs, PIPs, MTPs, knees, elbows V-Neck Rash: violaceous/erythema anterior chest w/ telangiectasias Periungual erythema, digital ulcerations Calcinosis Why is it called a heliotropic rash? Calcinosis DIAGNOSTIC TESTING 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 incr. creatinine (ATN) and myoglobinuria EMG: increased insertional activity, amplitude, polyphasics, neuropathic changes, incremental/decremental MU changes DIAGNOSTIC 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 INFLAMMATORY MYOSITIS Biopsy Findings Inflammatory cells Edema and/or fibrosis Atrophy/ necrosis/ degeneration Centralization of nuclei Variation in muscle fiber size Rarely, calcification Polymyositis: CD8+Tcells, endomysial infiltration Dermatomyositis: Humoral response B cells, CD4+ T cells; perifascicular/perivascular infiltration Autoantibodies in PM/DM Ab ANA U1-RNP Ku Mi2 PM1 Jo-1 SS-B (La) PL-12,7 Freq (%) 50 15 <5 30 15 25 <5 <5 Clinical Syndrome Myositis SLE + myositis PSS + myositis Dermatomyositis PSS – PM overlap Arthritis+ ILD+ Raynaud SLE,Sjogrens, ILD, PM ILD + PM Anti-synthetase syndrome: ILD, fever, arthritis, Raynauds, Mechanics hands– association with Jo-1 MALIGNANCY & MYOSITIS Higher association with DM, less common with polymyositis Common tumors: Breast, lung, ovary, stomach, uterus, colon, NHL 60% the myositis appears 1st, 30% neoplasm 1st, and 10% contemporaneously Studies found 20-32% with DM developed CA Lancet 2001 Ann Int Med 2001. Dermatomyositis and Malignancy All adults with DM should have ageappropriate 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 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 Recap: PM/DM Diagnosis Symmetric progressive proximal weakness Elevated muscle enzymes (CPK, LFTs) Muscle biopsy evidence of myositis EMG: inflammatory myositis Characteristic dermatologic findings INFLAMMATORY MYOSITIS Treatment Early Dx, physical therapy, respiratory Rx Corticosteroids : 60-80 mg/day 80% respond within 12 weeks Steroid resistant Methotrexate Azathioprine IVIG, Cyclosporin, Chlorambucil: unproven No response to apheresis PROGNOSIS 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 RHABDOMYOLYSIS Injury to the sarcolemma of skeletal muscle with systemic release of muscle macromolecules such as CPK, aldolase, actin, myoglobin, etc Maybe LIFE-THREATENING: from hyperkalemia, met. acidosis, ATN from myoglobinuria Common causes: EtOH, Cocaine, K+ deficiency, infection, PM/DM, infection (clostridial, staph, strept), medications, exertion/exercise, cytokines INCLUSION BODY MYOSITIS Bimodal age distribution, maybe hereditary Males > females Slow onset, progressive weakness Painless, distal and proximal weakness Normal or mildly elevated CPK Poor response to corticosteroids Dx: light microscopy may be normal or show CD8+ lymphs and vacuoles with amyloid. Tubulofilamentous inclusion bodies on electron microscopy