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scleroderma (diffuse cutaneous systemic sclerosis)

A systemic disorder of unknown etiology characterized by thickening & hardening of the skin & visceral organs, risk of hypertensive renal crisis, & shortened survival. The CREST syndrome represents a limited form of scleroderma. Etiology: 1) unknown 2) autoimmune 3) agents which may induce some manifestations of scleroderma a) exposure to polyvinyl chloride (PVC) b) exposure to silica (coal miners) c) bleomycin Pathology: 1) microangiopathy & fibrosis of skin & visceral organs 2) arterial vasospasm of small arteries, arterioles - repeated episodes of ischemia-reperfusion injury - fibrosis - Raynaud's phenomenon [4] 3) gastrointestinal a) atrophy & fibrosis of smooth muscle from pharynx to colon b) lower esophageal sphincter incompetence c) esophageal dysmotility, esophageal hypomotility d) esophageal strictures e) enteric telangiectasias f) gastric antral venous ectasia 4) myocardial fibrosis 5) microangiopathic hemolytic anemia 6) skin: a) thickening of reticular dermis with excessive collagen deposition b) atrophy of papillar dermis & epidermal rete pegs c) cutaneous vessels show intimal proliferation, collagen deposition in the vessel wall & mild perivascular inflammation 7) pulmonary: - diffuse interstitial fibrosis (75% at autopsy) - progressive restrictive lung disease * histopathology images [25] Clinical manifestations: 1) skin (also see vascular) a) skin thickening, tightening (induration) b) millet size calcifications may develop c) pruritus & ulceration may occur d) distribution: 1] fingers (sclerodactyly), digital ulceration - nailfold capillary changes, pitting [4] 2] dorsum of hand proximal to MCP joints 3] forearms, face, legs, trunk 4] limited disease involves face & skin distal to elbows & knees [4] 5] diffuse disease involves skin proximal to elbows & knees [4] e) nail fold capillary changes f) edema & erythema of the hands & forearms may precede induration in early scleroderma [4] g) salt & pepper skin changes described [29] - areas of depigmentation with relative sparing ofvperifollicular areas & preservation of pigmentation overveins 2) joints a) joint contractures b) synovitis (arthritis) c) tendon sheath inflammation (tendonitis) 3) vascular a) most manifestations have a vascular basis b) vasculitis is rare c) Raynaud's phenomenon (95%) 1] initial presentation in 70% of patients [4] 2] absence of Raynaud's phenomenon should prompt consideration of another diagnosis [4] d) telangiectasias on hands, cheeks & lips are common e) nail fold capillary changes f) microangiopathic hemolytic anemia 4) cardiac a) conduction disturbances & arrhythmias b) congestive heart failure c) coronary vasospasm d) accentuated P2 heart sound e) may be asymptomatic (for heart disease) f) myocardial fibrosis g) pericardial disease 5) pulmonary (80%) a) pulmonary basilar crackles b) diffuse interstitial fibrosis (75% at autopsy) c) pulmonary hypertension (50%) d) cor pulmonale e) pulmonary complications are more severe in the CREST syndrome f) aspiration pneumonia secondary to esophageal dysfunction & gastroesophageal reflux g) pleural involvement (pleurisy, pleural effusion) is rare 6) renal a) nephrosclerosis b) hypertension, including hypertensive crisis c) renal insufficiency d) scleroderma renal crisis occurs almost exclusively in patients with early cutaneous disease 1] severe hypertension 2] renal failure 3] microangiopathic hemolytic anemia 7) gastrointestinal (50-90%) [4,21] a) may precede skin manifestations of scleroderma b) esophageal dysfunction is the most common visceral organ manifestation 1] reflux esophagitis (GERD) 2] esophageal strictures 3] esophageal dysmotility, dysphagia c) upper GI bleed - gastric antral ectasia (also see complications) d) decreased bowel motility - altered peristalsis due to fibrosis e) bacterial overgrowth syndrome - blind loop syndrome f) malabsorption g) bloating h) abdominal distension i) diverticulosis j) pseudotoxic megacolon 8) myositis 9) CREST syndrome * images [25,27] Diagnostic criteria: - sclerodermatous skin changes that extend proximal to the MCP joints or - 2 of the following a) sclerodactyly b) digital pitting c) basilar fibrosis visible of chest X-ray Laboratory: 1) serology for autoantibodies a) antinuclear antibodies (ANA) 1] present in about 95% of patients 2] usually speckled or homogenous pattern 3] nucleolar & centromere patterns, less common, but more specific for systemic sclerosis 4] centromere pattern most common with limited cutaneous scleroderma b) anti Scl-70 Ab 1] speckled pattern 2] 20-50% in diffuse scleroderma 3] associated with diffuse cutaneous disease & interstitial lung disease [4,28] 4] associated with pulmonary fibrosis, cadiac fibrosis & poor prognosis [35] c) anti-centromere Ab (70-80% in CREST) 1] centromere pattern 2] Ab against kinetichore proteins 3] associated with diffuse cutaneous disease & pulmonary hypertension [4] d) anti RNA polymerase I (4-20%) e) anti RNA polymerase II (4%) f) anti RNA polymerase III (23%) - anti-POLR3C g) fibrillarin Ab in serum (U3-snRNP Ab) 1] speckled pattern 2] associated with diffuse cutaneous disease, pulmonary hypertension & myositis [4] h) anti PM-ScL (PMSCL1, PMSCL2) 1] nucleolar pattern 2] associated with myositis [4] i) anti To 1] nucleolar pattern 2] associated with diffuse cutaneous disease & pulmonary hypertension [4] j) anti NOR-90 k) Sjogren's syndrome/scleroderma autoantigen 1 l) RPP38 2) other autoantigens associated with scleroderma - SPOP, TEX101, EXOSC9, EXOSC10, RPP30, UBF1, SSSCA1, 3) hypergammaglobulinemia (50%) 4) complete blood count (CBC) a) mild eosinophilia (5-10%) b) anemia is generally mild 1] iron studies 2] serum folate, serum vitamin B12 5) serum creatinine is generally normal in the absence of hypertension & renal crisis 6) see ARUP consult [6] Special laboratory: 1) pulmonary function testing (every 6 months) a) progressive restrictive lung disease b) low diffusion capacity (DLCO) is earliest manifestation 2) echocardiogram to evaluate pulmonary artery pressure & to assess septal fibrosis or pericardial effusions [4,11] (30% of patients have asymptomatic pericardial effusions) - annual monitoring for pulmonary hypertension in patients without interstitial lung disease [4] 3) right heart catheterization if further evaluation of pulmonary hypertension if needed [4] 4) upper gastrointestinal endoscopy if iron-deficiency anemia [4,12] 5) nailfold capillarioscopy can distinguish Raynaud's phenomenon secondary to systemic sclerosis from primary Raynaud's phenomenon [4] Radiology: 1) chest X-ray may show a) interstitial lung disease b) basilar fibrosis 2) high-resolution CT to evaluate a) interstitial lung disease [4] b) alveolitis (may precede interstitial lung disease) c) pulmonary fibrosis [4] 3) barium swallow if dysphagia [4] * images [26,27] Differential diagnosis: 1) eosinophilic fasciitis 2) eosinophilia myalgia syndrome 3) scleroderma variants a) morphea (localized cutaneous scleroderma) b) limited cutaneous systemic sclerosis c) systemic sclerosis sine scleroderma d) CREST 4) graft versus host disease 5) mycosis fungoides 6) primary biliary cirrhosis 7) pulmonary hypertension, primary - idiopathic pulmonary fibrosis 8) reflex sympathetic dystrophy 9) mixed connective tissue disease 10) nephrogenic systemic fibrosis 11) Buschke scleredema 12) scleromyxedema [4] Complications: - patients with limited cutaneous scleroderma confined to the face & distal extremities are at increased risk for pulmonary hypertension [4] - patients with diffuse cutaneous scleroderma are at increased risk for interstitial lung disease, serositis, & scleroderma renal crisis [4] - progressive diffuse parenchymal lung disease - interstitial pneumonitis - pulmonary fibrosis: 35% of scleroderma-related deaths [20] - major cause of death in scleroderma [4] - cardiovascular & renal - systemic hypertension - sclerodermal renal crisis (glucocorticoids a risk factor) - do not use glucocorticoids to treat scleroderma - pulmonary hypertension: 26% of scleroderma-related deaths [20] - cardiomyopathy due to coronary vasospasm, myocardial fibrosis - 5 year mortality 75% [4] - 26% of scleroderma-related deaths [20] - pericardial disease - gastrointestinal - gastric antral ectasia -> GI bleed -> iron deficiency [4,21] - intestinal bacterial overgrowth -> malabsorption -> vitamin B12 deficiency (serum folate is increased) - pregnancy is associated with increased risk of miscarriage, preterm birth & intrauterine growth retardation [4] Management: 1) No curative therapy - myeloablative autologous stem-cell transplantation for severe scleroderma with renal or pulmonary involvement may improve long-term event-free survival [30] 2) problem-oriented (organ-specific) approach - do not use glucocorticoids to treat scleroderma 3) Raynaud's phenomenon a) cessation of smoking b) cold avoidance, central warmth c) calcium channel blockers [4] d) anti-platelet agents, low-dose aspirin e) prazosin losartan, sildenafil, topical nitrates [4] f) phenoxybenzamine, reserpine, guanethidine g) bosentan may be useful for preventing recurrences of digital ulcers [4,16] h) intravenous epoprostenol for acutely ischemic digit(s) [4] i) sympathetic ganglion blockade for patients with digital ulceration that have failed conservative management 4) skin a) physical therapy b) methotrexate, mycophenolate, cyclophosphamide [4,15,17] c) rituximab appears to be beneficial for both skin fibrosis & pulmonary function [17] d) antihistamines, low-dose prednisone for pruritus e) penicillamine f) laser therapy for telangiectasias g) adipocyte transplantation (CPT) 5) gastrointestinal a) reflux esophagitis (GERD) 1] proton pump inhibitor (omeprazole, lansoprazole) 2] H2 receptor antagonists 3] sucralfate 4] promotility agent for diminished esophageal peristalsis: metoclopramide 5] Ca+2-channel antagonists may worsen reflux 6] lifestyle changes 7] fundoplication for patulous lower esophageal sphincter contraindicated b) esophageal strictures - dilation c) gastric antral vascular ectasia: laser ablation d) gut motility, bloating & abdominal distension - metoclopramide, erythromycin - long-term therapy can cause tardive dyskinesia, limit therapy to 12 weeks - octreotide for ileus e) bacterial overgrowth - rotating antibiotics: tetracycline, metronidazole - cholestyramine for fat malabsorption f) correct iron deficiency g) correct folate deficiency, vitamin B12 deficiency h) fiber, polyethylene glycol, &/or senna for constipation 6) renal a) aggressive blood pressure control with ACE inhibitor b) high-dose glucocorticoids increase risk of renal crisis c) ACE inhibitor for renal crisis regardless of serum creatinine [4] d) ACE inhibitor for renal insufficiency [4] e) hemodialysis as needed 7) cardiovascular a) standard therapies for specific problems b) ACE inhibitor for hypertension [4] c) vasodilators for pulmonary artery hypertension 1] phosphodiesterase-5 inhibitors 2] prostacyclin analogues 3] endothelin receptor antagonists [4] 8) pulmonary a) standard therapies for specific problems b) treatment of pulmonary alveolitis with mycophenolate or cyclophosphamide may improve symptoms & delay progression of interstitial lung disease c) rituximab appears to be beneficial for both skin fibrosis & pulmonary function [17] d) pulmonary hypertension - supplemental oxygen - treat right-sided heart failure - prostanoids, endothelin receptor antagonists, PDE5 inhibitors, soluble guanylate cyclase inhibitors (nitric oxide inhibitors) e) lung transplantation [4] 9) arthritis, tendonitis & myositis a) weekly methotrexate [4] b) prednisone 10) pregnancy is high risk a) increased risk of small full-term infants b) increased risk of premature births [4] c) avoid pregnancy in women with pulmonary hypertension or severe restrictive lung disease [4] 11) prognosis: a) progressive disease b) 45% 10 year survival for diffuse form

Related

CREST syndrome morphea; localized cutaneous scleroderma; linear scleroderma scleredema (Buschke disease) scleromyxedema; lichen myxedematosus; papular mucinosis systemic sclerosis sine scleroderma

Specific

scleroderma in pregnancy scleroderma renal crisis

General

systemic sclerosis

References

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