Clinical trials in systemic sclerosis: lessons learned and outcomes

Abstract

The pathogenesis of systemic sclerosis (SSc) is complex and largely unclear. The clinical heterogeneity of the disease and its progression over a number of years makes the choice of endpoints in the design of clinical trials difficult. The overwhelming need in this disease is to diagnose it early and identify those patients who will benefit most from early, aggressive treatment that potentially can alter the clinical disease course. To achieve this, innumerable challenges must be overcome. This article reviews data from recent clinical trials and the lessons derived from retrospective observational studies, databases, and patient registries. Taken together, these observations will help to improve our understanding of the diverse clinical course of SSc and permit refinement of existing outcome measures for the design of future clinical trials, in which the likelihood of observing a positive treatment effect with the drugs at our disposal will be maximized.

Figure 1

Key outcomes for the BUILD-2 study of bosentan versus placebo in SSc-ILD. BUILD, Bosentan in Interstitial Lung Disease in Systemic Sclerosis; DLCO, carbon dioxide diffusing capacity; EOS, end of study; FVC, forced vital capacity; ILD, interstitial lung disease; 6 MWD, 6 min walk distance; Rx, treatment; SSc, systemic sclerosis.

Figure 2

Cyclophosphamide versus placebo: effect on FVC. CYC, cyclophosphamide; FVC, forced vital capacity. Reproduced with permission from Tashkin et al. N Engl J Med 2006 Copyright © 2006 Massachusetts Medical Society [4].

Figure 3

Pilot study showing mRss over time following immunoablation therapy. mRss, Modified Rodnan Skin Score. This research was originally published in Blood Online. Nash RA et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the U.S. multicenter pilot study. Blood. Prepublished online April 23, 2007; DOI 10.1182/blood-2007-02-072389 [24].

Figure 4

Time to development of severe disease in patients with diffuse SSc. SSc, systemic sclerosis.

Figure 5

Association between severity of PF and survival in patients with SSc. FVC, forced vital capacity; PF, pulmonary fibrosis; SSc, systemic sclerosis. Reproduced with permission from Steen et al. Arthritis Rheum 1994 © John Wiley & Sons/American College of Rheumatology [28].