Beneficial treatment with leflunomide and hydroxychloroquine combination in Sjögren’s Disease

A significant reduction in the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score at week 24 was the successful primary outcome of the combination of leflunomide and hydroxychloroquine compared with placebo. Significant improvements were also seen in IgG, rheumatoid factor, and complement C4 levels.

After positive results in a previous study (EudraCt2014-003140-12), the combination of leflunomide and hydroxychloroquine was now tested in the phase 2b, placebo-controlled RepurpSS-II trial (EudraCt: 2020-001933-11) over 24 weeks [1]. This 24-week trial included a subsequent single-arm crossover and 24-week open-label extension.

Dr Wing-Yi Wong (University Medical Center Utrecht, the Netherlands) presented the results of the randomised phase involving 46 adult participants. The primary endpoint was defined as the difference in ESSDAI score at week 24.

Participants had a median age of 55 and were over 90% female. Baseline ESSDAI scores averaged 9.52 in the leflunomide plus hydroxychloroquine arm versus 9.88 in the placebo arm. Median serum IgG levels were 12.7 g/L and 14.1 g/L, respectively.

“We found a statistically significant improvement in the ESSDAI score (P=0.001) with an effect size of -4.135 points in the treatment group,” Dr Wong reported. Further significant benefits of the combination treatment were established for serum IgG (P=0.016), rheumatoid factor (P=0.013), and C4 levels (P=0.031).

Exploratory endpoints, including the Composite of Relevant Endpoints for Sjögren's Syndrome (CRESS) and the Sjögren’s Tool for Assessing Response (STAR), also favoured the combination treatment (P=0.046 and P=0.007 in Pearson’s chi-square test)

“The total number and severity distribution of adverse events (AE) were comparable between the 2 groups,” Dr Wong stated regarding safety. However, 3 patients from the active group discontinued due to AEs versus none in the placebo group. The most frequent AEs were gastrointestinal discomfort, COVID-19, and common cold.

“The RepurpSS-2 study confirmed the safety and efficacy of 24 weeks of leflunomide and hydroxychloroquine therapy in patients with primary Sjögren’s disease with moderate to high disease activity,” Dr Wong concluded.

1. Wong WY, et al. RepurpSS-II: Validation of leflunomide-hydroxychloroquine combination therapy in patients with primary Sjögren’s Disease: A double-blinded, placebo-controlled, randomized trial. LB0005, EULAR 2025, 11–14 June, Barcelona, Spain.

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Posted on 18 June 2025