Repurposing leflunomide and hydroxychloroquine to treat Sjögren's disease (RepurpSS-II): a randomised, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND

Sjögren's disease is a systemic autoimmune disease characterised by secretory gland dysfunction that lacks effective systemic treatment. We aimed to replicate the findings of the RepurpSS-I trial and determine the efficacy and safety of leflunomide and hydroxychloroquine combination therapy as a first conventional treatment for Sjögren's disease.

METHODS

This randomised, placebo-controlled, double-blind, phase 2b trial (RepurpSS-II) was done at University Medical Center Utrecht, The Netherlands. Eligible patients were adults aged 18-75 years with an European Alliance of Associations for Rheumatology Sjögren's Syndrome Disease Activity Index (ESSDAI) of at least 5. Exclusion criteria included an active wish to conceive within 2 years or use of leflunomide or hydroxychloroquine in the past 6 months. Patients were randomly assigned (1:1) to receive placebo or leflunomide (20 mg) and hydroxychloroquine (400 mg) orally, once a day. Investigators, patients, and laboratory staff were masked to treatment until 24 weeks. The primary endpoint was the between-group difference in change in ESSDAI from baseline to 24 weeks. Primary and secondary analyses were done in the intention-to-treat population using mixed-effect analysis, accounting for repeated outcome assessment and controlling for baseline ESSDAI. This study was registered with the European Union Clinical Trials Register (EudraCT 2020-001933-11) and is completed. Patients from the RepurpSS-I trial and Sjögren's disease patient representatives contributed to the study design.

FINDINGS: Between Oct 12, 2021, and July 5, 2024, 243 patients were approached for inclusion. 158 were excluded before screening and 39 were excluded following screening. 46 patients were enrolled and randomly assigned to receive leflunomide-hydroxychloroquine (n=21) or placebo (n=25). Median age was 55·00 years (IQR 51·00-60·50). 43 (93%) of 46 patients were female and three (7%) were male. The mean difference in ESSDAI between the leflunomide-hydroxychloroquine group and placebo group at 24 weeks was -4·135 (95% CI -6·558 to -1·709, p=0·0012). One serious adverse event occurred in the treatment group; probably unrelated to study medication (hospital admission for myocardial infarction). Adverse events were similar between groups; gastrointestinal discomfort was most common (six [29%] of 21 patients in the leflunomide-hydroxychloroquine group and four [16%] of 25 in the placebo group). There were no deaths during the study.

INTERPRETATION: This study supports previous findings that leflunomide in combination with hydroxychloroquine is an effective treatment for systemically active Sjögren's disease and was generally well tolerated. This therapy might be an affordable and widely available option for patients with active systemic Sjögren's disease. Future studies should investigate whether this combination is effective in other patient populations, such as those with low systemic disease activity but high patient-reported outcomes.

FUNDING: ZonMW and ReumaNederland.