Treatment with leflunomide in combination with hydroxychloroquine has been proven to be beneficial, helping reduce disease activity in patients with systemically active Sjögren’s disease, in the phase 2b RepurpSS-II trial.
“RepurpSS-II met its primary endpoint and validated the efficacy and safety of a 24-week leflunomide– hydroxychloroquine treatment in patients with Sjögren’s disease who had moderate-to-severe disease activity and were not using any concomitant disease-modifying antirheumatic drugs (DMARDs) alongside the investigational drugs,” noted first study author Dr Wing-Yi Wong from the University Medical Center Utrecht, Utrecht, Netherlands, and colleagues.
At week 24, the mean difference in the European Alliance of Associations for Rheumatology Sjögren’s Syndrome Disease Activity Index (ESSDAI) score—the primary endpoint—between leflunomide–hydroxychloroquine and placebo was –4.135 points (95 percent confidence interval [CI], –6.558 to –1.709; p=0.0012). [Lancet Rheumatol 2026;doi:10.1016/S2665-9913(26)00075-5]
Notably, the ESSDAI score decreased significantly from baseline to week 24 with leflunomide–hydroxychloroquine (p=0.016), whereas no substantial changes were observed with placebo (p=0.66).
Compared with placebo, leflunomide–hydroxychloroquine was also associated with more favourable changes in serum IgG concentration (mean difference, −1.600 g/L; p=0.016), rheumatoid factor concentration (mean difference, −8.715 IU/mL; p=0.013), and complement component 4 concentration (mean difference, 0.021g/L; p=0.031).
No significant safety concerns
In terms of safety, “leflunomide–hydroxychloroquine therapy was generally well tolerated,” said Wong and colleagues.
Adverse events (AEs) occurred in 95 percent of patients in the leflunomide–hydroxychloroquine group and 84 percent in the placebo group, with gastrointestinal discomfort being the most common. One patient who received the combination had a serious AE (ie, non-ST-segment elevation myocardial infarction that required short hospital admission) that was deemed unrelated to the study drugs. There were no deaths during the study.
This DMARD combination therapy shows potential to be the first affordable and widely available oral treatment for at least a subset of patients with Sjögren’s disease.
These findings replicate those of the preceding phase 2a RepurpSS-I study, which showed a significant improvement in Sjögren’s disease activity for patients who received leflunomide–hydroxychloroquine vs placebo (mean ESSDAI score between-group difference at 24 weeks, –4.35 points, 95 percent CI, –7.45 to –1.25; p=0.0078). [Lancet Rheumatol 2020;2:e260-e269]
An important milestone
“The RepurpSS-II trial represents an important milestone: the first replication of a positive randomized controlled trial of conventional synthetic DMARDs in Sjögren’s disease,” wrote Prof Gaetane Nocturne from Université Paris-Saclay in Le Kremlin-Bicêtre, France, in an accompanying editorial. [Lancet Rheumatol 2026;doi:10.1016/S2665-9913(26)00143-8]
Nocturne highlighted the clinical implication of the findings, noting that there is no disease-modifying treatment currently approved for systemic disease activity in Sjögren’s disease patients despite its burden.
“RepurpSS-II brings encouraging news for patients with active systemic Sjögren’s disease. An accessible, oral, safe, and affordable treatment with replicated efficacy now exists,” Nocturne said. “The challenge ahead is to identify who will benefit most, to develop outcome measures that capture the full burden of the disease, and to build the collaborative networks that will make the next generation of trials possible.”
RepurpSS-II population
RepurpSS-II included 46 adult patients (median age 55 years, 93 percent female) who had an ESSDAI score of ≥5 points at baseline. These patients were randomly assigned to treatment with either leflunomide 20 mg plus hydroxychloroquine 400 mg (n=21) or placebo (n=25) without concomitant DMARDs or glucocorticoids. Treatment was administered orally for 24 weeks.
Wong and colleagues performed a post hoc analysis to assess the newer composite endpoints, Sjögren’s Tool for Assessing Response (STAR) and Composite of Relevant Endpoints for Sjögren’s Syndrome (CRESS), which incorporated patient-reported outcomes and objective dryness assessments in addition to systemic disease involvement.
At week 24, response rates were significantly higher in the leflunomide–hydroxychloroquine group than in the placebo group for both the STAR (64 percent vs 19 percent; p=0.0067) and the CRESS (57 percent vs 24 percent; p=0.046).
These post hoc data, according to Nocturne, “are particularly reassuring,” given that scoring ESSDAI, which remains the reference standard for systemic disease activity in clinical trials, “is not easy for non-experts… These new tools need to be considered in future trials.”