Safety and efficacy of rituximab in systemic sclerosis (DESIRES): a double-blind, investigator-initiated, randomised, placebo-controlled trial

Abstract

Background: Systemic sclerosis is a connective tissue disease characterised by multiorgan fibrosis with an autoimmune background and poor prognosis. Although a few drugs have shown some efficacy in treating the disease, there remains a great unmet medical need. We aimed to investigate the efficacy and safety of rituximab in patients with systemic sclerosis.

Methods: We did a double-blind, investigator-initiated, randomised, placebo-controlled trial at four hospitals in Japan. Patients aged 20-79 years, who fulfilled the 2013 American College of Rheumatology and European League Against Rheumatism classification criteria for systemic sclerosis, with a modified Rodnan Skin Score (mRSS) of 10 or greater, and an expected survival of at least 6 months were randomly assigned (1:1) to receive intravenous rituximab (375 mg/m²) or placebo once per week for 4 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was the absolute change in mRSS 24 weeks after initiation of study treatment, measured in all patients who received at least one dose of study treatment and had one endpoint assessment. This study is registered with ClinicalTrials.gov, NCT04274257, and UMIN-CTR, UMIN000030139.

Findings: Between Nov 28, 2017, and Nov 6, 2018, 80 individuals were screened and 56 (70%) were enrolled and randomly assigned; 51 (91%) were women and five (9%) were men. 27 (96%) of 28 patients in the rituximab group and 22 (79%) of 28 patients in the placebo group received at least one dose of their allocated treatment and completed 24 weeks of follow-up. The absolute change in mRSS 24 weeks after initiation of study treatment was lower in the rituximab group than in the placebo group (-6·30 in the rituximab group vs 2·14 in the placebo group; difference -8·44 [95% CI -11·00 to -5·88]; p<0·0001). Adverse events were similar in both groups and occurred in 28 (100%) of 28 patients in the rituximab group and 23 (88%) of 26 patients in the placebo group. One serious adverse event leading to treatment discontinuation occurred in one patient in each group (decreased serum albumin in the rituximab group and biliary enzyme increase in the placebo group). The most common adverse event was upper respiratory infection, which occurred in 11 patients (39%) in the rituximab group and ten patients (38%) in the placebo group. There were no deaths during follow-up.

Interpretation: Rituximab appears to be an effective and safe treatment for systemic sclerosis. Although this study has some limitations, this is the first clinical trial to show efficacy of rituximab with skin sclerosis as the primary endpoint.

Funding: Japan Agency for Medical Research and Development (AMED), Zenyaku Kogyo.

Translation: For the Japanese translation of the abstract see Supplementary Materials section.