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Sjögren’s disease is a chronic autoimmune condition characterized by lymphocytic infiltration and functional impairment of exocrine glands. While it primarily presents with severe dryness of the eyes and mouth, patients can develop systemic involvement affecting organs such as the skin, lungs, or kidneys. Furthermore, individuals with this disorder face an increased risk of developing non-Hodgkin lymphoma. Currently, effective treatments to suppress systemic disease activity are limited.
According to Eurekalert, a clinical trial coordinated by UMC Utrecht investigated whether two widely available anti-rheumatic drugs could provide the first effective and affordable treatment for patients with moderate-to-severe Sjögren’s disease. The RepurpSS-II trial enrolled 46 patients across 12 Dutch clinical centers who were randomly assigned to receive either placebo or a daily oral combination of leflunomide and hydroxychloroquine.
Significant Reduction in Disease Activity
The study measured treatment effectiveness using the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI). After 24 weeks of intervention, patients treated with the drug combination showed a significantly greater reduction in disease activity when compared to those receiving placebo. The average difference between the two groups exceeded four points (-4.135, p=0.0012), representing a clinically meaningful improvement.
Researchers emphasized that this finding is particularly noteworthy because the trial was conducted without background immunomodulatory therapy. This design allowed investigators to assess the true effect of the drug combination more accurately. The results replicate positive findings from an earlier proof-of-concept study (RepurpSS-I) and represent a major milestone in conventional disease-modifying anti-rheumatic drugs (DMARDs).
Safety Profile and Tolerability
The treatment regimen was generally well tolerated by the participants. Gastrointestinal complaints were identified as the most common adverse events, occurring in both the treatment group and the placebo group. One serious adverse event, a myocardial infarction, occurred within the treatment arm; however, cardiac analysis suggested it was likely unrelated to the study medication.
Using advanced assessment methods, including STAR and CRESS scores—which incorporate objective dryness measurements alongside patient-reported outcomes—the researchers also observed that more patients on active treatment responded positively. While no clear significant improvement was found in secondary endpoints such as fatigue or pain, the primary outcome regarding disease activity remains robust.
As immunologist and principal investigator Joel v concluded, "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."
The data suggests that leflunomide and hydroxychloroquine provide a powerful, accessible therapeutic option for managing systemic Sjögren’s disease activity.