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Leflunomide, HCQ Combo Effects Validated in Sjögren Disease
BARCELONA, Spain — In the treatment of primary Sjögren disease, the use of leflunomide (LEF) and hydroxychloroquine (HCQ) in combination was associated with a greater reduction in disease activity than placebo, according to new trial results reported at the European Alliance of Associations for Rheumatology (EULAR) 2025 Annual Meeting.
In the randomized controlled RepurpSS-II trial, the LEF-HCQ combination produced a mean decrease in EULAR Sjögren syndrome disease activity index (ESSDAI) score of 4.13 points ( P = .001) relative to placebo after 24 weeks of treatment.
There were also greater reductions in serum immunoglobulin G, rheumatoid factor, and complement component 4 with the combination than with placebo.
However, there were no differences between the groups in terms of patients' symptoms as measured by the EULAR Sjögren syndrome patient reported index (ESSPRI) or its separate components.
There were also no differences between the groups in improving dryness as measured using the Schirmer and unstimulated saliva tests.
Confirmatory Trial
Wing-Yi Wong, MD
'The major challenge in this disease is the lack of standard treatments, despite the need,' said Wing-Yi Wong, MD, a PhD student at University Medical Center Utrecht, Utrecht, the Netherlands, who presented the findings as a late-breaking abstract.
'Many trials in the past 40 years have failed to show clinical efficacy,' Wong added. One of the few trials that had proven promising previously, however, was the RepurpSS-I trial, which had tested a combination of LEF at a dose of 20 mg/d and HCQ at a dose of 400 mg/d given for 24 weeks vs placebo.
RepurpSS-II was set up to confirm the findings of RepurpSS-I. Published in The Lancet Rheumatology in 2020, RepurpSS-I had shown that LEF-HCQ reduced ESSDAI a mean of 4.29 points more than that with placebo.
Trial Designs and RepurpSS-II Population
RepurpSS-I was a phase 2a trial, and RepurpSS-II was a phase b2 trial. Entry criteria were similar for both trials: Primary Sjögren disease diagnosis, an ESSDAI ≥ 5, and no significant comorbidities. Women of a child-bearing age also had to be taking reliable contraception.
Both RepurpSS trials included 24-week double-blind treatment phases, with RepurpSS-II adding a single-arm crossover extension for a further 24 weeks.
A total of 37 people with primary Sjögren disease had been screened for inclusion in RepurpSS-I, 29 were included, 21 of whom were treated with the LEF-HCQ combination and eight with placebo.
For RepurpSS-II, 85 of 233 people who were considered for inclusion were screened, and 46 were included in the trial. Of these, 21 were treated with LEF-HCQ and 25 with placebo.
Among the reasons for not screening or including more people in RepurpSS-II were comorbidities; current or recent treatment with LEF, HCQ, or other disease-modifying antirheumatic drugs; and not meeting other entry criteria.
Participants in the LEF-HCQ and placebo groups of RepurpSS-II were demographically similar: The mean age was 55 years; 90.5% and 96.0%, respectively, were women; and the mean disease durations were 6.5 years and 10.0 years, respectively.
Mean ESSDAI scores at baseline were 9.52 in the LEF-HCQ group and 9.88 in the placebo group, and mean ESSPRI scores were 7.00 and 6.83, respectively.
Other Findings
Exploratory analyses using the Sjögren's Tool for Assessing Response (STAR) and the Composite of Relevant Endpoints for Sjögren Syndrome (CRESS) also favored LEF-HCQ.
'STAR and CRESS scores are two novel composite endpoints that includes patient-reported outcomes together with objective measures of dryness alongside the clinical ESSDAI,' Wong said.
She reported that there was a 'significantly higher percentage of responders' in the LEF-HCQ group using both measures vs placebo.
Adverse event rates were similar between groups: A total of 58 events occurred in the LEF-HCQ group and 57 in the placebo group. Most of these events were considered as mild (77.6% for LEF-HCQ and 66.7% for placebo), with gastrointestinal discomfort and respiratory infections among the most commonly reported.
Two severe adverse events occurred, one in each group, and were deemed unrelated to the study treatment. The one in the LEF-HCQ group was a non-ST elevation myocardial infarction, and the one in the placebo group was an allergic reaction to antibiotic treatment.
A total of 14 patients in the LEF-HCQ group completed the double-blind phase, and nine chose to enter the 24-week, open-label extension. Although completed, results of this phase are pending.
'Overall, the combination treatment was well tolerated, and leflunomide-hydroxychloroquine is realistic treatment option, which is affordable, accessible, and widely available,' Wong concluded.
This study was funded by the Dutch independent government body ZonMw . Wong and fellow investigators for the RepurpSS-II study had no relevant conflicts of interest.
