A combination of two widely available anti-rheumatic drugs offers the first effective and affordable treatment for patients with Sjögren's disease with systemic disease activity, according to new results from a clinical trial that was coordinated by UMC Utrecht. The study showed that treatment with leflunomide and hydroxychloroquine reduced disease activity in patients with moderate-to-severe disease, while maintaining a favorable safety profile.
Sjögren's disease is a chronic autoimmune disease, characterized by lymphocytic infiltration and functional impairment of exocrine glands . It affects approximately 0.5 percent of the population, mainly women. Patients experience severe dryness of eyes and mouth, which is treated with artificial tears and saliva substitutes. In addition to these local symptoms, patients may develop systemic disease, with involvement of other organs. This includes the skin, lungs or the kidneys. Furthermore, patients are at increased risk of developing non-Hodgkin lymphoma. Currently, a treatment to suppress systemic disease activity is lacking.
Clear treatment effect without background immunosuppressive therapy
In the RepurpSS-II trial (which was financed by ZonMw and ReumaNederland and coordinated by UMC Utrecht), 46 patients from 12 Dutch clinical centers were randomly assigned to receive either placebo or daily oral treatment with leflunomide and hydroxychloroquine . Patients treated with the drug combination experienced a significantly greater reduction in disease activity, measured with the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), compared with placebo. The average difference between groups was more than four points (-4.135, 95% CI -6.558 – -1.709, p=0.0012) after 24 weeks of treatment. This is a clinically meaningful improvement that closely mirrors the positive findings from the earlier RepurpSS-I proof-of-concept study. In addition, using newer assessment methods for Sjögren's syndrome research, the STAR and CRESS scores which include objective dryness and patient-reported outcomes next to disease activity, the researchers also observed that more patients on active treatment responded positively to treatment. No clear significant improvement was found in secondary endpoints such as dryness, fatigue, and pain.
Researchers say the results are particularly important because the study was conducted without background immunomodulatory therapy, allowing the effect of the drug combination to be assessed more accurately. According to the investigators, this makes RepurpSS-II the first trial to show positive results of conventional disease-modifying anti-rheumatic drugs (DMARDs) in Sjögren's disease, replicating the RepurpSS-I data. The treatment was generally well tolerated. Gastrointestinal complaints were the most common adverse events, occurring in both treatment groups. One serious adverse event, a myocardial infarction, occurred in the treatment arm but was probably unrelated to the study medication based on cardiac analysis.
"Our study confirms earlier proof-of-concept findings and represents the first successful conventional DMARD therapy in Sjögren's syndrome in a randomized, placebo-controlled setting without background immunosuppressive medication. As such, RepurpSS-II not only offers the prospect of a readily applicable treatment but also provides an important foundation for future mechanistic research", concludes immunologist and principal investigator of the study Joel van Roon, PhD (Center for Translational Immunology and Department of Rheumatology & Clinical Immunology, UMC Utrecht).
Growing understanding of disease mechanisms
Beyond the clinical improvements, the findings also strengthen the growing understanding that Sjögren's disease is driven by multiple interacting immune pathways. Earlier mechanistic analyses from the RepurpSS program showed that the drug combination suppresses B-cell activity, interferon signaling, and inflammatory chemokines associated with systemic disease activity. The researchers believe that these biological effects may have implications beyond symptom control alone. Persistent immune activation in Sjögren's disease has been linked to complications such as development of non-Hodgkin lymphoma , suggesting that more effective immune suppression could potentially improve also long-term outcomes.
Affordable and globally accessible treatment option
The authors note that further studies are needed to determine whether the treatment is equally effective in patients with lower systemic disease activity but high symptom burden, a group that represents a large proportion of Sjögren's patients. In addition, long-term tolerability will also require further evaluation. Still, the investigators say that drug repurposing (in this case combination therapy with leflunomide and hydroxychloroquine in Sjögren's disease) stands out because both drugs are already widely available, affordable, and orally administered, advantages that could make the treatment accessible worldwide, including in lower-resource healthcare settings.
Publication
Wong W-Y, Rijnenberg D, Baloche VMD, Blokland SLM, Welsing PMJ, Bonte-Mineur F, Bekker CPJ, Hamkour S, Bogers C, Groot N, Leavis HL, van Roon JAG. Repurposing leflunomide and hydroxychloroquine to treat Sjögren's disease (RepurpSS-II): a randomized, double-blind, placebo-controlled, phase 2b trial. Lancet Rheumatology, published May 20, 2026
