Systemic Sclerosis SCLERODERMA

ראיורב ש לאירבג ר " ד היגולוטמוארל הדיחיה קדצ ירעש יאופרה זכרמה

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SCLERODERMA- systemic sclerosis Definition

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

Epidemiology

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

Classification of systemic sclerosis

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

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 c alcinosis, R aynaud's phenomenon, e sophageal dysmotility, s clerodactyly, t elangiectasia

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Pathogenesis

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

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Pathogenesis

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

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 (?)

Pathogenesis of SSc Endothelial injury (? oxidation products, immune factors) genetic background, microchimerism, environmental stimuli,?infection

adhesion molecules endothelin growth factors T cell recruitment, activation ?autoantigens

TGFß, PDGF, IL-4, IL-1, IL-13 Mast cells hypoxia

Organ Damage

VASCULAR DISEASE FIBROSIS Fibroblast autocrine factors, signaling, matrix, selection, imprinting FIBROSIS

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

Clinical features

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

Raynaud’s phenomenon

Raynaud’s phenomenon

Terminal digit resorption

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

Edematous phase

Skin Induration

Acrosclerosis

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

Acrolysis

Digital pitting scars

CREST syndrome: calcinosis cutis

Calcinosis and acrolysis

Facial changes

Telangiectasia

 Face / mucous membrane  blanched by pressure

Calcinosis

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

Abnormal motility

Diverticula

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

Diverticula

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)

האיר תוברועמ המרדורלקס

 Limited cutaneous  Diffuse cutaneous  Pulmonary Hypertension Fibrosing alveolitis

Screening for PAH-SSc: ESC/ERS Guidelines 2009

Symptomatic patients (breathlessness, fatigue, weakness, angina, syncope, abdominal distension) Asymptomatic patients Yearly echo is recommended Yearly echo may be considered Confirmation of PAH requires RHC

Galiè et al; Eur Heart J (2009)

Interstitial lung Disease (fibrosing alveolitis)

 Diagnosis  PFT- DLCO  HRCT  (BAL -Differential(

Interstitial lung Disease (fibrosing alveolitis)

Treatment: Cyclophosphamide + Prednisone Micophenolate mofetyl

Clinical features

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

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

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

Diagnosis

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

Prognosis

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

דיתעל טבמ המרדורלקס

interferon gamma הזנגורביפלו סיזורביפל ענומ לופיט םינוש םינדגנ ןכו הזנגלוק  TGF beta ןוגכ םיניקוטיצ ימסוח  םייטנג םילופיט  םייתביבס םיעגפמ תעינמ 