Meta-Analysis of Healing and Prevention of Digital Ulcers in Systemic Sclerosis


Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada. E-mail:



To assess the efficacy of therapies in healing and preventing digital ulcers (DUs) in systemic sclerosis (SSc; scleroderma).


Medline and EMBASE databases, and American College of Rheumatology and European League Against Rheumatism abstracts, were searched. Randomized controlled trials (RCTs) with outcomes investigating healing or prevention of DUs in SSc and comparing a pharmacologic therapy with placebo or an active agent were included. The pooled risk ratios (RRs) using the fixed-effects model were calculated and heterogeneity was tested using the I2 statistic.


Sixty studies were found; 19 were not randomized, and 10 did not give DU quantitative data or no comparison of a different drug, leaving 31 RCTs with a total of 1,989 patients. Quality was 3 of 5 or less for 11 trials. DUs were not the primary outcome in many RCTs. Phosphodiesterase type 5 (PDE-5) inhibitors were significant for DU healing (RR 3.28 [95% confidence interval (95% CI) 1.32, 8.13], P = 0.01). Two large bosentan trials were significant for mean number of new DUs (standardized mean difference [SMD] −0.34 [95% CI −0.57, −0.11], P = 0.004). Oral prostacyclins were not statistically different from placebo, but intravenous (IV) iloprost prevented new DUs (SMD 0.77 [95% CI −1.46, −0.08], P = 0.03). Single trials for atorvastatin and vitamin E were positive in the prevention and healing of DU, respectively. There were many negative trials: antiplatelet therapy, oral N-acetylcysteine, heparin, dimethyl sulfoxide, ketanserin, prazosin, prostaglandin E1, cyclofenil, quinapril, and topical nitroglycerin formulation.


Small sample sizes, few comparative trials, and heterogeneity limits the conclusions. The results suggest a role for PDE-5 inhibitors in the healing of DUs; bosentan and IV iloprost may prevent new DUs.