Digital ulcers in systemic sclerosis: Prevention by treatment with bosentan, an oral endothelin receptor antagonist

Abstract

Objective. Recurrent digital ulcers are a manifestation of vascular disease in patients with systemic sclerosis (SSc; scleroderma) and lead to pain, impaired function, and tissue loss. We investigated whether treatment with the endothelin receptor antagonist, bosentan, decreased the development of new digital ulcers in patients with SSc.Methods. This was a randomized, prospective, placebo-controlled, double-blind study of 122 patients at 17 centers in Europe and North America, evaluating the effect of treatment on prevention of digital ulcers. The primary outcome variable was the number of new digital ulcers developing during the 16-week study period. Secondary assessments included healing of existing digital ulcers and evaluation of hand function using the Scleroderma Health Assessment Questionnaire.Results. Patients receiving bosentan had a 48% reduction in the mean number of new ulcers during the treatment period (1.4 versus 2.7 new ulcers; P ‫؍‬ 0.0083). Patients who had digital ulcers at the time of entry in the study were at higher risk for the development of new ulcers; in this subgroup the mean number of new ulcers was reduced from 3.6 to 1.8 (P ‫؍‬ 0.0075). In patients receiving bosentan, a statistically significant improvement in hand function was observed. There was no difference between treatment groups in the healing of existing ulcers. Serum transaminase levels were elevated to >3-fold the upper limit of normal in bosentantreated patients; this elevation is comparable with that observed in previous studies of this agent. Other side effects were similar in the 2 treatment groups.Conclusion. Endothelins may play an important role in the pathogenesis of vascular disease in patients with SSc. Treatment with the endothelin receptor antagonist bosentan may be effective in preventing new digital ulcers and improving hand function in patients with SSc.

Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: A twenty‐year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis

“…Taken together, these data suggest that a sustained and cumulative burden of microvascular damage has already occurred when definite SSc is diagnosed. Since new therapeutic agents are being evaluated in patients with SSc (45,46), awareness of this sequence of microvascular damage has potential implications for future trials. For example, in trials of novel angiogenic, vasculogenic, or fibrosis-modulating agents, it would appear logical to select patients at a uniform stage of microvascular damage and with similar SScspecific autoantibodies and to evaluate such damage longitudinally by NCM to assess response to therapy.…”

ESVM guidelines – the diagnosis and management of Raynaud’s phenomenon

“…Bosentan has been evaluated as a treatment of digital ulceration secondary to SSc and conferred benefi t in two multicentre RCTs [38,39] in terms of prevention of new ulcers, although it had no effect on healing of existing ulcers. However its use for pure (uncomplicated) RP has as yet no evidence base and cannot be recommended.…”

Raynaud’s phenomenon and digital ischaemia - pharmacologic approach and alternative treatment options

“…The eff ects of the non-selective ET1-R antagonist bosentan in patients with severe SSc-related RP and digital ulcers were investigated in two placebo-controlled RCTs (RAP-IDS-1 and RAPIDS-2) [59,60]. In both studies, bosentan reduced the development of new digital ulcers in SSc patients, and it has therefore received the European Medicines Agency's (EMA) approval for the secondary prevention of SSc-related digital skin ulcers.…”