Background: Two pivotal studies, RAPIDS-1 and RAPIDS-2 revealed that bosentan reduces the development of new digital ulcers (DUs) in patients with systemic sclerosis (SSc). However data regarding the long-term use of this dual endothelin antagonist receptor in the treatment of DUs is scarce.

Objectives: The aim of the present study was to evaluate long term efficacy and safety profile of bosentan in patients with DUs related to SSc.

Methods: A prospective observational case-control study, conducted between 2014 and 2020 enrolled 65 SSc patients with ≥1 active DUs at baseline, who received bosentan therapy. Demographic and clinical features, including DUs incidence and patients subjective perception of DU pain and/or Raynaud’s Phenomenon, were collected. Nailfold videocapillaroscopy was performed in all patients.

Results: The study included 51 females and 14 males, with a mean age of 52.6 years, 30 with diffuse subset, most of them with late scleroderma pattern (46/65). Number of DUs at baseline was 4.55 (±2.8), median duration of treatment was 25.95 (±19.4) months. Microangiopathy evolution score (MES) was 5.1 (2.19), visual analog scale (VAS) for DU was 77.9, VAS for Raynaud was 73.4.

Patients receiving bosentan had clinically significant reduction in the mean number of DU (p<0.001). The effect was most powerful for the first 6 months of treatment, but the improvement was sustained until 24 months’ follow-up, when the mean DU number reached a plateau that was kept until end of study. 6 month and 24 month evaluations also revealed significant decrease in the VAS for DU (p<0.05) and in the VAS for Raynaud (p<0.01). Statistically significant difference was noted between bosentan-treated and the control group with respect to the decrease in the mean number of digital ulcers. (p=0.005).

There was a clear trend towards an improvement in MES score, between baseline and the next follow-up assessments (p=0.003). The difference was statistically significant when compared to control group, but only for the first 18 months of treatment (p<0.001).

14 patients (28.75%) discontinued bosentan therapy for administrative reasons. The median time among patients who interrupted the treatment was 6.9 months. An accelerated development of new DU was described 6 months after (p=0.02). Following recommencement of bosentan, the mean number of DU has rapidly decreased (p=0.008). There was no significant difference between patients who temporarily discontinued bosentan for 6 or 12 months.

Bosentan was stopped due to lack of efficacy in 2 cases and due to side effects in 7 cases: 4 elevated liver enzymes, 1 severe trombocytopenia, 1 dyspneea agravation and low blood pressure.

Conclusion: The present data suggest that treatment with endothelin receptor antagonist bosentan was associated with a significant reduction in the mean number of DU in patients with SSc. The beneficial effect of bosentan persisted throughout the study but was most evident in the first 6 months of treatment. Statistical analysis showed a significant improvement of the microangiopathy evolution score from baseline to end of therapy. 14 patients had a high relapse rate due to potential rebound effect, 6 months after bosentan withdrawal.The drug was reintroduced succesfully for 10 (70%) patients with a significant decrease in the number of DU.

REFERENCES:

[1]UK Scleroderma Study Group: digital vasculopathy in systemic sclerosis, Rheumatology, Volume 54, Issue 11, November 2015, Pages 2015

[2]Groseanu L, Berghea F, Bojinca V, et al AB0779 Long term follow-up of a systemic sclerosis group treated with bosentan, Annals of the Rheumatic Diseases 2018;77:1523-1524.

Disclosure of Interests: None declared