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Systemic sclerosis 

Systemic sclerosis

Chapter:
Systemic sclerosis
Author(s):

Christopher P. Denton

and Carol M. Black

DOI:
10.1093/med/9780199204854.003.191103

November 30, 2011: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

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date: 26 March 2017

The scleroderma spectrum of disorders includes a number of diseases that have Raynaud’s phenomenon or skin sclerosis in common, comprising (1) limited cutaneous scleroderma; (2) systemic sclerosis (SSc)—the most important form of scleroderma—limited cutaneous SSc, diffuse cutaneous SSc, and overlap syndromes (with features of another autoimmune rheumatic disease, e.g. systemic lupus erythematosus); (3) Raynaud’s phenomenon—autoimmune (with antinuclear or other SSc-associated antibodies) or primary. These conditions affect women four times as often as men, most often beginning in the fifth decade.

The cause of SSc is not known: current models suggest that (unknown) initiating events involve changes in the vasculature and immune system, with subsequent interplay between genetic, vascular, inflammatory, and fibrotic processes. Most patients carry a hallmark autoantibody: three generally (although not always) mutually exclusive reactivities are seen—anticentromere; antitopoisomerase-1 (anti-Scl 70); and anti-RNA polymerase III.

Clinical features

Limited cutaneous SSc—formerly termed ‘CREST’ (calcinosis circumscripta, Raynaud’s, (o)esophagus, sclerodactyly, and telangiectasia), this condition accounts for 60% of cases of SSc. The onset of skin changes is gradual and often preceded by several years of worsening Raynaud’s phenomenon; skin sclerosis is limited to the face, neck, and hands distal to the wrists. Telangiectasia and intracutaneous/subcutaneous calcification are common. Significant visceral disease is less frequent than in diffuse cutaneous SSc, affecting oesophagus (74%), lungs (pulmonary fibrosis 26%, pulmonary hypertension 21%), kidneys (8%), and heart (9%).

Diffuse cutaneous SSc—patients typically present over 1 to 3 years with widespread changes in skin texture, puffy oedematous extremities, generalized pruritus, and profound constitutional and inflammatory symptoms. Vasospastic symptoms are not usually prominent during the early stages. Presentation with headache, blurring of vision, and significant hypertension is a medical emergency, portending scleroderma renal crisis and requiring immediate action. Significant visceral disease is common, affecting oesophagus (60% of cases), lungs (pulmonary fibrosis 41%, pulmonary hypertension 17%), kidneys (18%), and heart (12%).

Management

Gastrointestinal symptoms—most patients with SSc have at least one gastrointestinal manifestation, usually oesophageal dysmotility and associated reflux oesophagitis that often responds dramatically to treatment with proton pump inhibitors.

Raynaud’s phenomenon—is helped by hand warmers, protective clothing, and evening primrose oil, and may be helped by vasodilator drugs (e.g. oral calcium channel blockers, topical glyceryl trinitrate, and parenteral prostacyclin in severe cases).

Immunosuppressive and other treatments—it is believed that immunomodulatory strategies are most appropriate in the earlier stages of diffuse disease (1–3 years from onset). The most commonly used agents are steroids (particularly for fibrosing alveolitis), cyclophosphamide and (increasingly) mycophenolate mofetil, and intensive immunosuppression combined with autologous peripheral stem cell transplantation has been performed. Antifibrotic approaches might in theory be more appropriate in established cases, but none are proven effective.

Prognosis and complications

The most frequent cause of death related to systemic sclerosis is pulmonary disease, either fibrosing alveolitis (interstitial fibrosis) or pulmonary vascular disease.

Fibrosing alveolitis—serial lung function tests, including carbon monoxide diffusing capacity, are probably the most sensitive screening tools for this condition, with any abnormality pursued by high-resolution CT of the lungs, the appearances of which help predict response (or lack of it) to immunosuppressive treatment.

Pulmonary arterial hypertension—this is typically discovered during regular monitoring with pulmonary function tests (isolated reduction in carbon monoxide transfer factor, with preservation of lung volumes, is suggestive of the problem), ECG, and Doppler echocardiography. Milder cases are treated supportively with diuretics, oral anticoagulation, and (in some cases) digoxin. Patients with more severe disease are treated with oral endothelin receptor antagonists (e.g. bosentan, sitaxentan), switching to a phosphodiesterase V inhibitor (e.g. sildenafil) if there is no response. Advanced disease is treated with both of these agents in combination and/or inhaled or parenteral prostacyclin therapy, with lung transplantation appropriate for a very few cases.

Scleroderma renal crisis—this may be the first manifestation of SSc and typically presents with accelerated phase hypertension, acute renal impairment, and microangiopathic haemolysis. Treatment is with angiotensin converting enzyme (ACE) inhibitors, which have reduced mortality from over 75% to around 10%.

Prognosis—survival in SSc has improved to more than 80% at 5 years, even in the diffuse cutaneous subset. The therapeutic nihilism that was once prevalent is no longer appropriate—the disease should be regarded as often treatable, if not curable.

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