Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial

Abstract

ObjectivesIschaemic digital ulcers (DUs) are common in patients with systemic sclerosis (SSc) and are a cause of disease-related morbidity. In an earlier trial, treatment with bosentan, an oral endothelin receptor antagonist, reduced the occurrence of new DUs by 48%. The present study (RAPIDS-2, for ‘RAndomized, double-blind, Placebo-controlled study with bosentan on healing and prevention of Ischemic Digital ulcers in patients with systemic Sclerosis’) was conducted to more fully evaluate the effects of bosentan treatment on DUs associated with SSc.MethodsThis double-blind, placebo-controlled trial conducted at 41 centres in Europe and North America randomised 188 patients with SSc with at least 1 active DU (‘cardinal ulcer’) to bosentan 62.5 mg twice daily for 4 weeks and 125 mg twice daily thereafter for 20 weeks (n=98) or matching placebo (n=90; total 24 weeks). The two primary end points were the number of new DUs and the time to healing of the cardinal ulcer. Secondary end points included pain, disability and safety.ResultsOver 24 weeks, bosentan treatment was associated with a 30% reduction in the number of new DUs compared with placebo (mean±standard error: 1.9±0.2 vs 2.7±0.3 new ulcers; p=0.04). This effect was greater in patients who entered the trial with more DUs. There was no difference between treatments in healing rate of the cardinal ulcer or secondary end points of pain and disability. Peripheral oedema and elevated aminotransferases were associated with bosentan treatment.ConclusionsBosentan treatment reduced the occurrence of new DUs in patients with SSc but had no effect on DU healing. Bosentan was well tolerated and may be a useful adjunct in the management of patients with SSc with recurrent DUs.

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

“…However, there were no reductions in the frequency or intensity of attacks of RP and no improvement in ulcer healing in patients with digital ulcers at baseline [59]. In RAPIDS-2, 188 SSc patients with digital ulcers at trial entry demonstrated a signifi cant 30 % reduction in new digital ulcers compared with placebo (1.9 % vs. 2.7 %), but again, no diff erences in the healing rate of the cardinal ulcer or RP attacks were observed [60]. In a recently published study, Cutolo et al demonstrated the benefi cial eff ects of bosentan in addition to cyclic intravenous iloprost in patients with severe SSc-related RP [ ESM 2,9].…”

“…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.…”

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.…”

Successful Treatment with Bosentan for Pulmonary Hypertension and Reduced Peripheral Circulation in Juvenile Systemic Sclerosis

“…Bosentan has been shown to be effective for the treatment of patients with SSc-PAH [2,7]. Recently, it has been shown that bosentan also ameliorates decreased skin perfusion and digital ulceration secondary to SSc [5,6]. These effects may be mediated through vasodilatory and antifibrotic effects, indicating that these agents may be attractive potential disease modifying agents for SSc.…”

“…The ET receptor antagonist named bosentan has been shown to be effective in the treatment of adult patients with SSc-PAH [2,7]. Furthermore, it has been shown that bosentan ameliorates decreased skin perfusion and digital ulceration secondary to SSc [5,6]. A previous report showed that bosentan was effective for treatment of children with primary and secondary PAH [3].…”