1. Scleroderma and Inflammatory Myositis Kathryn Dao, MD Arthritis Consultation Center January 22, 2010

2. ObjectivesObjectives n Define scleroderma n Identify the inflammatory myopathies n Describe the subsets of these diseases n Recognize their clinical features and disease that may mimic them n Understand possible complications that may occur in these diseases

3. What 1996 movie put scleroderma on the map and why?

4. SclerodermaScleroderma n “Skleros-” = hard “-derma” = skin n Incidence 1-2/100,000 in USA n Peak age of onset 30-50 y.o. n Female:male 3: 1 n Disease manifestation is a result of host factors + environment (concordance is similar in monozygotic and dizygotic twins)

5. Scleroderma A disorder of Collagen, Vessels n Etiology: unknown? acquired? n Autoimmune disorder suggested by the presence of characteristic autoantibodies such as ANA, anti-centromere and anti- SCL-70 antibodies.

6. Scleroderma Pathogenesis Hallmarks: 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

7. How do you categorize Scleroderma?

8. Scleroderma Classification Three major disease subsets: based on extent of skin involvement: nLnLocalized Scleroderma nSnSystemic Sclerosis (SSc) ]D]Diffuse SSc ]L]Limited SSc AKA "CREST" syndrome nSnScleroderma sine scleroderma

9. Localized Scleroderma: Morphea

10. Linear scleroderma

11. What is this condition called? “En Coup de Sabre”

12. Scleroderma Classification Three major disease subsets: based on extent of skin involvement: n Localized Scleroderma n 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 n Scleroderma sine scleroderma

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

14. Diffuse SSc - Clinical n 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 Normal SSc

17. Skin Scores Extent 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.

19. 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?

21. 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

24. ??? TRUE OR FALSE ??? INFLAMMATORY ARTHRITIS IS THE MOST COMMON MUSCULOSKELETAL MANIFESTATION OF SYSTEMIC SCLEROSIS FALSE

25. Systemic 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.

26. Where in the GI tract does SSc affect? Anywhere from the mouth to the anus

27. n Small oral aperture, dry mucosal membranes with periodontal disease n Esophageal dysmotility, reflux, esophagitis, stricture, dysphagia n Delayed stomach emptying, n Pseudoobstruction of the small intestines, bacterial overgrowth, malabsorption n Wide mouth diverticuli n Fecal incontinence due rectal sphincter fibrosis Systemic Sclerosis: GI

28. 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: Renal

30. 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 ] high-dose corticoid therapy ] pregnancy Am J Med 1984;76:779-786.

31. Scleroderma Renal Crisis n Microangiopathic hemolytic anemia +Microscopic hematuria n 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.

32. ???TRUE or FALSE??? ACE inhibitors should be continued in patients with renal crisis despite rising creatinine and potassium TRUE

33. Systemic Sclerosis: Renal n Some patients will require dialysis despite ACE-I and good blood pressure control n As long as the ACE-I are continued during dialysis, approximately 50% will have enough improvement to stop dialysis in 6-18 months. n Inconsistent data with ARBs n Some patients will require dialysis despite ACE-I and good blood pressure control n As long as the ACE-I are continued during dialysis, approximately 50% will have enough improvement to stop dialysis in 6-18 months. n Inconsistent data with ARBs Rheum Dis Clin North Am. 1996 Nov;22(4):861-78

34. Systemic Sclerosis: Pulmonary **** LEADING CAUSE OF MORTALITY *** n Interstitial fibrosis +/- pulmonary hypertension n Dyspnea, cough, chest pain n Other manifestations: ] Pulmonary embolism ] Pulmonary vasculitis ] Pulmonary hemorrhage ] Lung cancer ] Aspiration ] Respiratory distress from muscle disease

36. n Decreased DLCO is the earliest marker (especially with normal lung volumes) n Increased A-a Gradient with Exercise n Restrictive Pattern ]  VC,  FEV1/FVC PFT’s in Systemic Sclerosis

39. Systemic Sclerosis: Cardiac n Symptoms are subtle n 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)

41. Comparison CREST v. Diffuse SSc FeatureLimited CRESTDiffuse SSc Calcinosis+++ Arthralgias ++ ++++ Pulmonary fibrosis ++ +++ Pulmonary HTN ++ + Tend friction rubs0+++ Renal crisis0 + 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+++++++++

42. Treatment of SSc n Morphea: none n Treat the manifestations of the disease: n Raynauds: warmth, skin protection, vasodilator therapy (e.g., NTG, CCB, ARB, Niacin, anti- adrenergics, prostacyclin, endothelin antagonists, nerve blocks) n Systemic therapy: ] Unproven benefits--Steroids, Penicillamine, MTX ] CYP: for alveolitis ] Experimental: stem cell transplant ] Finger ulcers: difficult; vasodilators, Abx

43. DDX of Tight Skin n Pseudosclerodactyly ] IDDM, Hypothyroidism n Drugs: Tryptophan, bleomycin, pentazocine, vinyl chloride, solvents n Eosinophilic fasciitis n Overlap syndromes n Scleredema n Scleromyxedema (papular mucinosis)

44. DDX of Tight Skin n Scleroderma-like conditions ] Porphyria cutanea tarda ] Nephrogenic fibrosing dermopathy

45. Inflammatory Myositis: Polymyositis/Dermatomyositis n F:M = 2:1 n Acute onset n Weakness: 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

46. What percentage of patient with DM/PM will have pain? Less than 50%

47. 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

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

50. 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 HISTORICAL CONSIDERATIONS

51. n Toxic/Drugs ] EtOH, Cocaine, Hydroxychloroquine, Penicillamine, Clofibrate, Taxol Colchicine, AZT, Statins, Steroids, Hydralazine, Gemfibrozil, CYA, L-dopa, Phenytoin, Cimetidine, Sulfonamides, PCN n Infectious ] Coxsackie, HBV, HIV, Strep, Staph, Clostridium, Toxoplasma, Trichinella n Congenital/metabolic myopathies n Neuropathic/Motor Neuron Disorders (MG, MD) n Endocrine/Metabolic-hypothyroidism n Inclusion body myositis DDX: Myopathies

52. n Fibromyalgia n Polymyalgia Rheumatica ] Caucasians, > 55 yrs, M=F ] Elevated ESR/CRP, normal strength, no synovitis n CTD (SLE, RA, SSc) n Vasculitis n Adult Onset Still's Disease Nonmyopathic DDx

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

54. 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 Dermatomyositis: Skin features

55. Why is it called a heliotropic rash?

60. CalcinosisCalcinosis

62. 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 rising creatinine (ATN) and myoglobinuria n EMG: increased insertional activity, amplitude, polyphasics, neuropathic changes, incremental/decremental MU changes Diagnostic Testing

63. 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 Diagnostic Testing

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

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

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

67. Autoantibodies in PM/DM AbFreq (%)Clinical Syndrome ANA50Myositis U1-RNP15SLE + myositis (MCTD) Ku<5SSc + myositis Mi230Dermatomyositis PM115SSc + PM overlap Jo-125Arthritis+ ILD+ Raynaud SS-B (La)<5SLE,Sjogrens, ILD, PM PL-12,7<5ILD + PM

68. What is an anti-synthetase syndrome? It is a subcategory of the inflammatory myositis defined 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.

69. Mechanics hands– association with Jo-1

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

72. 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

73. 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

74. 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

75. n Early Dx, physical therapy, respiratory Rx n High dose steroids (e.g., prednisone 1-2 mg/kg/day) ] 80% respond within 12 weeks n Steroid resistant ] Methotrexate ] Azathioprine ] Rituximab ] CYP n IVIG, Cyclosporin, Chlorambucil, TNFi: unproven n No response to apheresis TreatmentTreatment

76. 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 28-47% @ 7 yrs. n Relapses & functional disability are common n Death: due to malignancy, sepsis, pulm. or cardiac failure, and complications of therapy PrognosisPrognosis

77. 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

78. 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 therapy n Dx: light microscopy may be normal or show CD8+ lymphs and vacuoles with amyloid. Tubulofilamentous inclusion bodies on electron microscopy Inclusion Body Myositis

79. 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

80. ConclusionConclusion n Scleroderma and the inflammatory myopathies are diseases that require prompt recognition n Early intervention may decrease morbidity/mortality