Elsevier

The Lancet

Volume 367, Issue 9523, 20–26 May 2006, Pages 1683-1691
The Lancet

Seminar
Systemic sclerosis: hypothesis-driven treatment strategies

https://doi.org/10.1016/S0140-6736(06)68737-0Get rights and content

Summary

We review data from controlled trials and randomised controlled trials to examine the hypothesis for the pathogenesis of systemic sclerosis. Strategies used to treat the vascular complications in systemic sclerosis have so far shown the biggest successes, especially in the management of renal crisis and pulmonary arterial hypertension. Because these drugs have improved function and quality of life and have increased survival rates, they can truly be classified as disease-modifying compounds. Immunosuppressive therapy with cyclophosphamide in particular has also shown evidence of efficacy, and randomised controlled trials of autologous stem-cell transplantation are underway. So far, strategies to reduce or control fibrosis directly (bosentan, interferon gamma, and relaxin) have been disappointing but new strategies against fibrosis based on advanced understanding of the molecular biology of systemic sclerosis hold promise. Treatments against several cardinal features of the disorder simultaneously have not yet been examined but are being considered for future trials.

Section snippets

Limited cutaneous scleroderma

Calcinosis and telangiectases, seen in the classic CREST variant, could take years or even decades to develop into limited cutaneous systemic sclerosis.7 Patients with the limited disorder generally have more favourable outcomes than patients with the diffuse form, and the 5-year survival rate has been reported to be as high as 86%.10 However, substantial morbidity and mortality can occur from occlusive digital vascular disease, gastrointestinal effects, interstitial lung fibrosis, and

Diffuse cutaneous scleroderma

Patients with diffuse cutaneous systemic sclerosis typically have a much more aggressive early disease course than those with the limited form.5, 7 Raynaud's phenomenon might not be present initially and could, in fact, follow the onset of skin swelling. Initial presentation can include diffusely swollen, oedematous, pruritic skin; fatigue; and non-specific joint and muscle pain. Skin thickening is typically rapid, extending proximally on the arms and legs, with or without truncal effects,

Pathogenesis

The clinical presentation of systemic sclerosis is typified by three cardinal features: excessive collagen production and deposition, vascular damage, and inflammation or autoimmunity (figure 1).6, 13 Although the causes of the disorder are not yet understood, a plausible hypothesis has been forwarded to explain the inter-relations and interactions among these three features (figure 1). The three major clinical features and their interactions can be seen as a pathophysiological triangle of

Evolution of trial design, study conduct, and outcome measures

Although drugs such as methotrexate, sulfasalazine, gold, and even cyclophosphamide have existed for decades to treat rheumatoid arthritis, the recent introduction of four new disease-modifying anti-rheumatic drugs (DMARDs; eg, leflunomide, etaneracept, inflixamab, and adalimamab) has given physicians and patients new alternatives to treat the symptoms of rheumatoid arthritis and to decrease the rate of joint destruction, deformity, and disability. These recent advances were made possible by

Search strategy and selection criteria

We searched PubMed using the key word “scleroderma” with the relevant topics—eg, “pathogenesis”, “CREST”, “genetic predisposition”, “transforming growth factor beta”, “autoimmunity”, “vascular damage”. Fields were restricted to publications in English. We also searched the citations from obtained papers. References were chosen based on the best evidence from clinical or laboratory studies. Review articles of scleroderma published in the past 5 years were also examined to ensure minimum

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