In systemic sclerosis patients, Bosentan is safe and effective for digital ulcer prevention and it seems to attenuate the development of pulmonary arterial hypertension

Sir, SSc is a chronic connective tissue disease characterized by endothelial dysfunction and fibrosis of the skin and internal organs. Vascular dysfunction is one of the hallmarks of SSc and involves both the macro- and microvasculature. Many of the severe internal organ complications of SSc are vascular, including pulmonary arterial hypertension (PAH) and scleroderma renal crisis [1]. Patients with SSc are at high risk for the development of ischaemic digital ulcers (DUs), which occur in 35–60% of SSc patients. Bosentan 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 [2]. According to various series, PAH occurs in about 5–9% of SSc patients [3]. Fifty-four patients fulfilling the ACR preliminary criteria for the classification of SSc were enrolled in this study [4]. Twenty-eight patients had dcSSc and 26 had lcSSc. All patients have a history of DUs and Bosentan therapy was started for DU prevention. Bosentan was administered at a dose of 125 mg/day for the first month and 250 mg/day for the resting observational period. Patients with known manifest PAH, hemodynamically significant valvular disease, a history of uncontrolled systemic hypertension, hyperlipidaemia, cardiac failure, hepatic failure, diabetes, cerebrovascular diseases, peripheral vascular diseases, coagulopathy, smokers and pregnant or breastfeeding women were excluded. Written consent was obtained from the subjects according to the Declaration of Helsinki and the study was approved by the ethics committee of Sapienza University of Rome. Doppler echocardiography was performed by a senior cardiologist at the baseline and every 12 months of the Bosentan therapy. According to the European Society of Cardiology recommendations, systolic pulmonary arterial pressure (sPAP) was based on tricuspid regurgitation. Pulmonary hypertension was defined as sPAP >45 mmHg on cardiac echocardiography and confirmed at right cardiac catheterization (RHC) by a mean pulmonary arterial pressure (mPAP) ≥25 mmHg with a pulmonary capillary wedge pressure ≤15 mmHg [5]. The mean duration of Bosentan therapy was 41.4 months (s.d. 18.5). The DU episodes were 3.9 per year (s.d. 2.2). During the treatment period the DU episodes significantly (P < 0.001) decreased from 3.9 (s.d. 2.2) to 1.6 (s.d. 1.7). At baseline no patient presented with echocardiographic indirect signs of PAH and no one was in New York Heart Association (NYHA) functional class III or IV (44 patients were in class I and 10 patients were in class II). At baseline the mean value of sPAP was 29 mmHg (s.d. 6.3). Twenty patients had an early capillaroscopic pattern, 15 an active pattern and 19 a late pattern according to Cutolo et al. [6]. The baseline mean value of sPAP was 28 mmHg (s.d. 5.4) in patients with an early capillaroscopic pattern, 28.8 mmHg (s.d. 8.2) in those with an active capillaroscopic pattern and 30.2 mmHg (s.d. 5.9) in those with a late capillaroscopic pattern. No significant differences of sPAP (P > 0.05) were observed in the three capillaroscopic groups. The mean value of sPAP did not show significant (P > 0.05) differences from baseline [29 mmHg (s.d. 6.3) vs 30 (s.d. 7.9)] (Fig. 1). After 56 months of Bosentan therapy, one patient (1.8%) showed a significant increase in sPAP (51 mmHg) and PAH was confirmed by RHC. Throughout the treatment period, transaminase levels were not significantly elevated (>3 times the upper limit of normal) in any of the patients. Bosentan treatment was stopped after 9 months in one patient because of hepatotoxicity. Mean value of systolic pulmonary arterial pressure pre- and post-therapy with Bosentan. The results of this study demonstrate that resting sPAP did not increase within 41.4 months (s.d. 22.5) of follow-up in SSc patients who underwent Bosentan therapy for DU prophylaxis. In our selected cohort of SSc patients the prevalence (1.8%) and yearly incidence (0.52%) are lower than those reported by larger randomized studies. In fact, the ItinérAIR-Sclérodermie programme, conducted in a large cohort of patients with SSc from specialized scleroderma centres in France, demonstrated that the prevalence of SSc-PAH and the yearly incidence were 7.85% and 0.61%, respectively [7]. Endothelin-1 (ET-1) showed a key role in the pathogenesis of SSc-associated DUs, digital microvascular damage and PAH. Plasma ET-1 concentrations are increased early in patients with SSc. Previous double-blind, randomized, placebo-controlled trials demonstrated that Bosentan, an oral ET receptor antagonist, reduces the occurrence of new DU [2]. In addition, Bosentan improved skin perfusion in SSc patients with PAH, although it did not ameliorate symptoms of RP [8]. Since SSc-PAH is a vascular disease, we can suppose that an early start of Bosentan therapy can reduce the progression of pulmonary vascular impairment. Therefore large randomized controlled trials are needed to confirm our preliminary data. Systolic pulmonary arterial pressure did not increase in SSc patients who underwent Bosentan therapy for digital ulcer prophylaxis. Disclosure statement: The authors have declared no conflicts of interest.