Background Systemic sclerosis (SSc) is characterized by fibrosis and widespread vascular pathology. Initial events involve endothelial cell damage, loss of normal vasodilatory mediators and excessive vasoconstriction. Previous studies have demonstrated that angiotensin II is involved in the synthesis of type I collagen.
Objectives To evaluate the effects of blockade of angiotensin II receptor by irbesartan on lung, peripheral circulation and skin involvement in SSc patients.
Methods Forty-two SSc patients, mean age 47.9 years and mean disease duration of 5.7 years with symptoms despite ongoing therapy were recruited. All patients fulfilled the ACR criteria for the classification of SSc. None were on ERA or PG analogues. Patients were randomized into 2 groups, the first group(n = 21) received 75mg/d of irbesartan and the second group(n = 21) received placebo for 4 months. Patients were allowed to continue their ongoing therapies provided the dosages were kept constant. The patients were matched for age, sex, SSc classification and concomitant medications. The outcome measures assessed included changes in exercise capacity (six minute walk distance (6MWD), Borg’s dyspnoea scale), cardiopulmonary haemodynamics, Raynaud’s phenomenon (RP) severity and frequency and dermal sclerosis. Lung involvement was assessed by pulmonary function tests (PFTs) and chest high resolution computed tomography (HRCT). Dermal involvement was assessed both clinically by the modified Rodnan skin score (MRSS) and histologically by skin biopsies (for changes in collagen deposition). The markers of endothelial damage: ICAM-1, thrombomodulin, vWF, endothelin-1 and nitric oxide were assessed by specific ELISA assay kits. All parameters were assessed at baseline and at the end of the study. Safety and tolerability was also assessed.
Results Irbesartan improved exercise capacity, had a positive effect on haemodynamic parameters and was well tolerated. There was a significant increase in forced vital capacity (FVC) in the irbesartan group compared to baseline (mean ±SD 66.8±16.86 vs 74.9±16.9). The median percentage of improvement of FVC in the irbesartan group was 8.8% whereas the worsening in the placebo group was 3.9%, p = 0.001. HRCT scores improved but did not reach statistical significance versus placebo. After 4 months of therapy, MRSS decreased from 22.0±6.0 to 16.7±5.7 in diffuse cutaneous SSc and from 16.0±5.9 to 10.3±5.7 in limited cutaneous SSc reaching significance. In the irbesartan group there was a significant reduction of collagen deposition in the dermis at 4 months compared to baseline. The median percentage improvement of dermal fibrosis in the irbesartan group was 31% whereas in the placebo group skin fibrosis worsened. There was a statistically significant improvement in SHAQ-DI score in the treatment group versus the placebo group, p< 0.001. Endothelial markers of activation showed statistically significant improvement from baseline values in the irbesartan group versus the placebo group.
Conclusions The results of the present study demonstrated that irbesartan improved vascular dysfunction, skin fibrosis, lung capacity and patient function. The good patient tolerance and safety of the drug, may prove angiotensin receptor blockers, a welcome and invaluable addition to the therapeutic armamentarium of SSc. However, larger scale longitudinal studies are needed.
Disclosure of Interest None Declared