1. Systemic Sclerosis SCLERODERMA ד"ר גבריאל ש ברויאר היחידה לראומטולוגיה המרכז הרפואי שערי צדק

2. SCLERODERMA- systemic sclerosis Definition 1. Systemic sclerosis (scleroderma) 1. Systemic sclerosis (scleroderma) - a multisystem disorder characterized by - a multisystem disorder characterized by 1) functional and structural abnormalities of blood vessels 1) functional and structural abnormalities of blood vessels 2) fibrosis of the skin and internal organs 2) fibrosis of the skin and internal organs 3) immune system activation 3) immune system activation 4) autoimmunity 4) autoimmunity 2. Localized scleroderma 2. Localized scleroderma - morphea, linear scleroderma - morphea, linear scleroderma

3. Epidemiology 1. Prevalence: 19-75 cases per 100,000 1. Prevalence: 19-75 cases per 100,000 2. Susceptibility: host factor 2. Susceptibility: host factor 1) age - peak occurrence: age 35-65 years 1) age - peak occurrence: age 35-65 years 2) gender - female : male = 7-12 : 1 2) gender - female : male = 7-12 : 1 3) genetic background 3) genetic background - Choctaw native Americans in Oklahoma (469 per 100,000) - Choctaw native Americans in Oklahoma (469 per 100,000) 3. Environmental factors 3. Environmental factors 1) infection 1) infection 2) occupational exposures: silica dust 2) occupational exposures: silica dust

4. Classification of systemic sclerosis 1. Diffuse cutaneous systemic sclerosis 1. Diffuse cutaneous systemic sclerosis 1) proximal skin thickening 1) proximal skin thickening - distal and proximal extremity and often the trunk and face - distal and proximal extremity and often the trunk and face 2) tendency to rapid progression of skin change 2) tendency to rapid progression of skin change 3) rapid onset of disease following Raynaud’s phenomenon 3) rapid onset of disease following Raynaud’s phenomenon 4) early appearance of visceral involvement 4) early appearance of visceral involvement 5) poor prognosis 5) poor prognosis

5. Classification of systemic sclerosis 2. Limited cutaneous systemic sclerosis 1) symmetric restricted fibrosis - affecting the distal extremities and face/neck 2) prolonged delay in appearance of distinctive internal manifestation 3) prominence of calcinosis and telangiectasia 4) good prognosis * CREST syndrome - calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia 2. Limited cutaneous systemic sclerosis 1) symmetric restricted fibrosis - affecting the distal extremities and face/neck 2) prolonged delay in appearance of distinctive internal manifestation 3) prominence of calcinosis and telangiectasia 4) good prognosis * CREST syndrome - calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia

6. Pathogenesis 1. Vasculopathy of small artery and capillary 1. Vasculopathy of small artery and capillary - endothelial cell injury - endothelial cell injury - adhesion and activation of platelet - adhesion and activation of platelet - PDGF, thromboxane A2 release - PDGF, thromboxane A2 release - vasoconstriction & growth of endothelial cell and fibroblast - vasoconstriction & growth of endothelial cell and fibroblast - narrowing or obliteration, increased permeability - narrowing or obliteration, increased permeability 2. Fibrosis 2. Fibrosis - aberrant regulation of fibroblast cell growth - aberrant regulation of fibroblast cell growth - increased production of extracellular matrix - increased production of extracellular matrix (collagen, fibronectin, and glycosaminoglycan) (collagen, fibronectin, and glycosaminoglycan) - thickening of the skin & fibrosis of internal organs - thickening of the skin & fibrosis of internal organs

7. Pathogenesis 3. Immunologic mechanism 3. Immunologic mechanism 1) cell mediated immunity 1) cell mediated immunity - skin: cellular infiltrates in perivascular region and dermis - skin: cellular infiltrates in perivascular region and dermis (T cell, Langerhans cell, plasma cell, macrophage) (T cell, Langerhans cell, plasma cell, macrophage) 2) humoral immunity 2) humoral immunity - hypergammaglobulinemia - hypergammaglobulinemia - autoantibody production - autoantibody production antinuclear antibody (+) > 95% antinuclear antibody (+) > 95%

8. Pathogenesis 4. Environmental factors 1) silica dust 2) organic solvents 3) biogenic amines 4) urea formaldehyde 5) polyvinyl chloride 6) rapeseed oil 7) bleomycin 8) L-tryptophan 9) silicone implant (?) 4. Environmental factors 1) silica dust 2) organic solvents 3) biogenic amines 4) urea formaldehyde 5) polyvinyl chloride 6) rapeseed oil 7) bleomycin 8) L-tryptophan 9) silicone implant (?)

9. FIBROSIS TGFß, PDGF, IL-4, IL-1, IL-13 adhesion molecules T cell recruitment, activation ?autoantigens endothelin growth factors hypoxia FIBROSIS genetic background, microchimerism, environmental stimuli,?infection Endothelial injury (? oxidation products, immune factors) Fibroblast autocrine factors, signaling, matrix, selection, imprinting Mast cells VASCULAR DISEASE Pathogenesis of SSc OrganDamage

10. Review: Evidence That Systemic Sclerosis Is a Vascular Disease Arthritis & Rheumatism Volume 65, Issue 8, pages 1953-1962, 26 JUL 2013 DOI: 10.1002/art.37988 http://onlinelibrary.wiley.com/doi/10.1002/art.37988/full#art37988-fig-0002 Volume 65, Issue 8, http://onlinelibrary.wiley.com/doi/10.1002/art.37988/full#art37988-fig-0002

11. Clinical features 1. Vascular abnormalities 1. Vascular abnormalities 1) Raynaud's phenomenon 1) Raynaud's phenomenon - cold hands and feet - cold hands and feet with reversible skin color change (white to blue to red) with reversible skin color change (white to blue to red) - induced by cold temperature or emotional stress - induced by cold temperature or emotional stress - initial complaint in 3/4 of patients - initial complaint in 3/4 of patients - 90% in patients with skin change - 90% in patients with skin change (prevalence in the general population: 4-15%) (prevalence in the general population: 4-15%) 2) digital ischemic injury 2) digital ischemic injury

12. Raynaud’s phenomenon

14. Terminal digit resorption

15. Clinical features 2. Skin involvement (1) 1) stage - edematous phase - indurative phase - atrophic phase 2) firm, thickened bound to underlying soft tissue 3) decrease in range of motion, loss of facial expression, inability to open mouth fully 2. Skin involvement (1) 1) stage - edematous phase - indurative phase - atrophic phase 2) firm, thickened bound to underlying soft tissue 3) decrease in range of motion, loss of facial expression, inability to open mouth fully

16. Edematous phase

17. Skin Induration

18. Acrosclerosis

19. Clinical features 2. Skin involvement (2) 4) ulceration, loss of soft tissue of finger tip, pigmentation, calcific deposit, capillary change 5) pathology - atrophy of dermal appendages - loss of rete pegs - compact bundles of collagen 3. Polyarthritis and flexion contracture 2. Skin involvement (2) 4) ulceration, loss of soft tissue of finger tip, pigmentation, calcific deposit, capillary change 5) pathology - atrophy of dermal appendages - loss of rete pegs - compact bundles of collagen 3. Polyarthritis and flexion contracture

20. Acrolysis

21. Digital pitting scars

22. CREST syndrome: calcinosis cutis

23. Calcinosis and acrolysis

24. Facial changes

25. Telangiectasia Face / mucous membrane Face / mucous membrane blanched by pressure blanched by pressure

26. Calcinosis

27. Clinical features 4. intestinal involvement 1) esophagus: hypomotility and retrosternal pain, reflux esophagitis, stricture 2) stomach: delayed emptying 3) small intestine: pseudo-obstruction, paralytic ileus, malabsorption 4) large intestine: chronic constipation and fecal impaction diverticula 4. intestinal involvement 1) esophagus: hypomotility and retrosternal pain, reflux esophagitis, stricture 2) stomach: delayed emptying 3) small intestine: pseudo-obstruction, paralytic ileus, malabsorption 4) large intestine: chronic constipation and fecal impaction diverticula

28. Abnormal motility

29. Diverticula Barium enema study Barium enema study - multiple wide-mouthed - multiple wide-mouthed diverticula of colon diverticula of colon - broad base and neck - broad base and neck - usually asymptomatic - usually asymptomatic

30. Diverticula

31. Clinical features 5. lungs 1) 2/3 of patients affected - leading cause of mortality and morbidity in later stage of systemic sclerosis 2) pathology - interstitial fibrosis - intimal thickening of pulmonary arterioles (pulmonary hypertension) 5. lungs 1) 2/3 of patients affected - leading cause of mortality and morbidity in later stage of systemic sclerosis 2) pathology - interstitial fibrosis - intimal thickening of pulmonary arterioles (pulmonary hypertension)

32. סקלרודרמה מעורבות ריאה Limited cutaneous Limited cutaneous Pulmonary Hypertension Pulmonary Hypertension Diffuse cutaneous Fibrosing alveolitis

33. Yearly echo may be considered Asymptomatic patients Screening for PAH-SSc: ESC/ERS Guidelines 2009 Symptomatic patients (breathlessness, fatigue, weakness, angina, syncope, abdominal distension) Yearly echo is recommended Confirmation of PAH requires RHC Galiè et al; Eur Heart J (2009)

35. Interstitial lung Disease (fibrosing alveolitis) Diagnosis Diagnosis PFT -DLCO PFT -DLCO HRCT HRCT (BAL -Differential ( (BAL -Differential (

36. Interstitial lung Disease (fibrosing alveolitis) Treatment: Cyclophosphamide + Prednisone Micophenolate mofetyl

37. Clinical features 6. heart (10%) 1) pericarditis 2) heart failure 3) arrhythmia 4) myocardial fibrosis 6. heart (10%) 1) pericarditis 2) heart failure 3) arrhythmia 4) myocardial fibrosis

38. Clinical features 7. kidney 1) diffuse scleroderma in association with rapid progression of skin involvement 2) pathology - intimal hyperplasia of the interlobular artery - fibrinoid necrosis of afferent arterioles - glomerulosclerosis 3) proteinuria, abnormal sediment, azotemia, microangiopathic hemolytic anemia, renal failure 7. kidney 1) diffuse scleroderma in association with rapid progression of skin involvement 2) pathology - intimal hyperplasia of the interlobular artery - fibrinoid necrosis of afferent arterioles - glomerulosclerosis 3) proteinuria, abnormal sediment, azotemia, microangiopathic hemolytic anemia, renal failure

39. Review: Evidence That Systemic Sclerosis Is a Vascular Disease Arthritis & Rheumatism Volume 65, Issue 8, pages 1953-1962, 26 JUL 2013 DOI: 10.1002/art.37988 http://onlinelibrary.wiley.com/doi/10.1002/art.37988/full#art37988-fig-0003 Volume 65, Issue 8, http://onlinelibrary.wiley.com/doi/10.1002/art.37988/full#art37988-fig-0003

40. Diagnosis 1. major criteria: proximal scleroderma 1. major criteria: proximal scleroderma 2. minor criteria: 2. minor criteria: 1) sclerodactyly 1) sclerodactyly 2) digital pitting scar or 2) digital pitting scar or loss of substance from the finger pads loss of substance from the finger pads 3) bibasilar pulmonary fibrosis 3) bibasilar pulmonary fibrosis * one major or 2 or more minor criteria for diagnosis * one major or 2 or more minor criteria for diagnosis

41. Prognosis 1. quite variable and difficult to predict 1. quite variable and difficult to predict 2. cumulative survival 2. cumulative survival diffuse limited diffuse limited 5 yr 70% 90% 5 yr 70% 90% 10 yr 50% 70% 10 yr 50% 70% 3. major cause of death 3. major cause of death 1) renal involvement 1) renal involvement 2) cardiac involvement 2) cardiac involvement 3) pulmonary involvement 3) pulmonary involvement

42. סקלרודרמה - מבט לעתיד טיפול מונע לפיברוזיס ולפיברוגנזה interferon gamma קולגנזה וכן נגדנים שונים טיפול מונע לפיברוזיס ולפיברוגנזה interferon gamma קולגנזה וכן נגדנים שונים חוסמי ציטוקינים כגון TGF beta חוסמי ציטוקינים כגון TGF beta טיפולים גנטיים טיפולים גנטיים מניעת מפגעים סביבתיים מניעת מפגעים סביבתיים