Scleroderma Systemic Sclerosis Definition Systemic sclerosis scleroderma a

Scleroderma (Systemic Sclerosis)

Definition 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 Sclero=thickened, derma=skin

Epidemiology 1. Prevalence: 20 new cases per million per year 2. Susceptibility: host factor 1) age - peak occurrence: age 35 -65 years 2) gender - female : male = 4 : 1 3) genetic background 4) enviromental factors Occurs at a younger age and has a worse prognosis in African American women

Classification 1. Systemic sclerosis 2. – Diffuse cutaneous systemic sclerosis – – Limited cutaneous systemic sclerosis Overlap syndromes Localized scleroderma – Morphoea – Linear scleroderma • En coup de sabre

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) the pacients usually have Raynaud’s phenomenon for years 4) prominence of calcinosis and telangiectasia 5) good prognosis * CREST syndrome - calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia

Classification of systemic sclerosis 3. Overlap syndromes – Features of systemic sclerosis together with those of at least one other autoimmune rheumatic disease, e. g. SLE, RA, or polymyositis

Etiology Environmental factors Genetic predisposition 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 (? ) Defective immunoregulation 1) cell mediated immunity CD 4/CD 8 , cytokines 2) humoral immunity – hypergammaglobulinemia – autoantibody production – antinuclear antibody (+) > 95%

Pathogenesis Susceptible host Exogenous events Immune system activation Fibroblast activation Endothelial cell activation/damage End stage pathology Obliterative vasculopathy Fibrosis

Pathogenesis

Pathogenesis 1. Vasculopathy of small artery and capillary - endothelial cell injury - adhesion and activation of platelet - PG F, thromboxane A 2 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

Pathogenesis 3. Immune system activation producing autoantibodies: -anti-topoisomerase I (anti Scl 70) -anti-centromere -anti RNA polymerases -anti U 1 RNP -anti B 23

Clinical features 1. Vascular abnormalities 1) Raynaud's phenomenon - cold hands and feet or ears/ nose/ tongue -with reversible skin color change (white to blue to red) - induced by cold temperature or emotional stress - initial complaint in 3/4 of patients 2) digital ischemic injury

Raynaud’s phenomenon-pallor phase

Raynaud’s phenomenon-cyanotic phase

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, contractures

Edematous phase

Skin Induration

Acrosclerosis

Facial changes Tight, thin lips with vertical perioral furrows

Salt and pepper pigmentation

Clinical features 2. Skin involvement (2) ulceration, loss of soft tissue of finger tip, pigmentation, calcific deposit, capillary change 3. Musculoskeletal system • Polyarthritis and flexion contracture • Muscle weakness and atrophy (primary /secondary)

Terminal digit resorption

Acrolysis

Digital pitting scars

CREST syndrome: C is for calcinosis

CREST : R is for Raynaud

CREST : E is for esophageal dysmotility. . . actually, you have to imagine this one CREST : S is for Sclerodactyly

CREST: T is for telangiectasia

RODNAN score

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, weight loss, cachexia 4) large intestine: chronic constipation and fecal impaction diverticula

Abnormal motility Diverticula

Clinical features 4. exocrine glands –Xerostomia –xerophthalmia 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)

Pulmonary fibrosis

Clinical features 6. heart (10%): pericarditis, heart failure, arrhythmia, myocardial fibrosis 7. kidney-scleroderm renal crisis Features: HTN, microangiopathic hemolytic anemia and oliguric renal failure. Risk Factors: • Diffuse disease within the first five years • Anti-RNA polymerase III antibody • Pericardial effusion • > 15 mg prednisone daily or • Cyclosporin therapy

Laboratory findings 1. ANA, RF 2. anti-Scl-70 (DNA topoisomerase I) antibody 1) 20 -30% in diffuse scleroderma 2) 10 -15% in limited scleroderma 3. anticentromere antibody 1) 50 -90% in limited scleroderma 2) 5% in diffuse scleroderma 4. Anti RNA polymerase III Ab: 10 - 25% in Diffuse SSc, Renal Disease.

Subsets of systemic sclerosis

Diagnosis- ACR criteries 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 *the major or 2 or more minor criteria for diagnosis

Scoring Systems for Severity (? !? ) • Disease burden: The Systemic Sclerosis Severity Scale Includes nine organ systems. • Functional Assessment: Scleroderma Health Assessment Questionnaire Disability Index (SHAQ) and Scleroderma Functional Score. • Quality of Life: Short Form Health Survey (SF-36) for psychological and mental functioning

Differential dignosis • Raynaud phenomenon: primary Raynaud’s syndrome, SLE, systemic vasculitis, medicationinduced. • Skin thickening: scleredema, scleromyxedema, POEMS syndrome, diabetic cheiroarthropathy, morphea • Overlapping clinical features: SLE, Sjogren syndrome, RA, inflammatory myopathies.

Treatment A wide spectrum of clinical manifestations and severity - spontaneous improvement occurs frequently • Disease modifying interventions (? ) - methotrexate - immunosuppressive agent: cyclosporin, cyclophosphamide, mycophenolate mophetil - recombinant human relaxin • Symptomatic (organ-specific) treatment

Treatment Raynaud’s phenomenon and ischemia 1) avoid cold exposure layers of warm, loose-fitting clothing 2) quit smoking 3) vasodilator therapy - calcium channel blocker (nifedipine), prazosin, ACE-i 4) finger / toe necrosis - intravenous prostaglandin (PGE 1, PGI 2) - amputation

Treatment Gastrointestinal 1) reflux esophagitis and dysphagia - elevation of head of bed - small frequent meal - avoid lying down within 3 -4 hours of eating - abstaining from caffeine-containing beverages, cigarette smoking - H 2 blocker, proton-pump inhibitor 2) gastroparesis: promotility agent (metoclopramide) 3) malabsorption syndrome: broad spectrum antibiotics

Treatment Pulmonary 1) Interstitial fibrosis - corticosteroid - cyclophosphamide, azathioprine 2) pulmonary artery hypertension - calcium channel blocker - prostacyclin -sildenafil - transplantation Renal renal crisis: -early detection and ACE inhibitor 1 year survival without captopril 15% 1 year survival with captopril 76% - dialysis

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