Leflunomide–Hydroxychloroquine Combination Shows Efficacy in Systemic Sjögren's Disease in Phase 2b Trial
Key Insights
The RepurpSS-II phase 2b trial demonstrated that leflunomide combined with hydroxychloroquine significantly reduced systemic disease activity in patients with moderate-to-severe Sjögren's disease (search) compared to placebo.
At 24 weeks, the ESSDAI score was 4.135 points lower in the treatment arm, replicating the earlier phase 2a RepurpSS-I results and validating the combination's efficacy.
Both drugs are existing, inexpensive oral tablets, making this a potentially accessible treatment option worldwide, including in low-income countries.
For the first time, researchers have identified an effective treatment for the systemic inflammation caused by Sjögren's disease (search) — and the solution involves two existing, inexpensive rheumatology drugs already available worldwide. The phase 2b RepurpSS-II trial, led by University Medical Center Utrecht and published in The Lancet Rheumatology, found that a daily combination of leflunomide and hydroxychloroquine significantly reduced disease activity in patients with moderate-to-severe systemic Sjögren's disease.
Sjögren's disease (search) is a chronic autoimmune condition in which the immune system attacks the body's own tissues, primarily damaging the salivary and tear glands and causing dry eyes, dry mouth, and tooth decay. In more severe cases, inflammation can spread to the joints, lungs, skin, and kidneys — known as systemic disease — for which no effective treatment has existed until now. The condition predominantly affects women and, by 2027, is expected to affect 2.7 million people worldwide.
Trial Design and Patient Population
The RepurpSS-II trial enrolled 46 patients across twelve Dutch hospitals between October 2021 and July 2025. Participants had a median age of 55 years, and 93% were women. All had moderate-to-severe Sjögren's disease (search), defined as a European Alliance of Associations for Rheumatology (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) score of 5 points or higher.
In a double-blind design, patients were randomly assigned to receive once-daily oral leflunomide 20 mg and hydroxychloroquine 400 mg (n=21) or placebo (n=25) for 24 weeks. Notably, no oral glucocorticoids were used during the study, and other immunosuppressive drugs were discontinued three months before inclusion — making this, as the authors note, "the only positive trial done in the absence of background immunomodulatory therapy beyond the investigational treatment."
Efficacy Results
The results were clear-cut. At baseline, the mean ESSDAI was 9.52 points in the leflunomide–hydroxychloroquine group and 9.88 points in the placebo group. During the treatment period, ESSDAI decreased significantly in participants receiving the combination therapy but did not change significantly in those given placebo. By week 24, the score was a significant 4.135 points lower in the treatment arm than in the placebo arm.
This finding aligns closely with the earlier RepurpSS-I trial, where the difference between groups was a significant 4.35 points at week 24. Lead researcher and immunologist Dr. Joël van Roon emphasized that this replication validates the efficacy of the combination and highlights its potential as a treatment for moderate-to-severe Sjögren's disease (search).
Among secondary outcomes, both serum immunoglobulin G and rheumatoid factor concentrations were significantly lower in the treatment arm compared with placebo at week 24, while complement component 4 concentration was significantly higher. However, no significant differences were observed between groups in complement component 3 concentration, measures of oral and ocular dryness, or the EULAR Sjögren's Syndrome Patient Reported Index.
Post-hoc analysis using the novel responder endpoints of the Sjögren's Tool for Assessing Response (STAR) and Composite of Relevant Endpoints for Sjögren's Syndrome (CRESS) showed significantly more responders in the leflunomide–hydroxychloroquine group than in the placebo group.
Safety Profile
The investigators observed "no clinically significant safety concerns" and noted that the safety profile was consistent with that reported in the RepurpSS-I study. Gastrointestinal events were the most common adverse events, affecting 29% of patients in the leflunomide–hydroxychloroquine group and 16% of those in the placebo group.
Clinical Significance and Global Access
Dr. van Roon called the findings significant, noting it is the first time an existing rheumatology treatment has been successfully tested in Sjögren's without additional immunosuppressive drugs. "This study not only offers the prospect of a practical treatment, but also helps us better understand the disease," he said.
A key advantage is that both leflunomide and hydroxychloroquine have been available for years, are relatively inexpensive, and can be taken as tablets — potentially making the therapy accessible worldwide, including in countries with limited healthcare infrastructure. As the authors state, "The affordability and wide availability of this treatment make it a promising option, even in low-income countries."
The researchers stress that further studies are needed to assess long-term safety and to identify which patients benefit most. The trial also provides, in the authors' words, "a robust foundation for future mechanistic analyses to further elucidate the unresolved underlying pathophysiology of Sjögren's disease (search), disease activity, and treatment effects."