Support for further study of leflunomide–hydroxychloroquine for primary Sjögren’s syndrome
medwireNews: Findings from RepurpSS-I, a small phase 2a trial, suggest that leflunomide–hydroxychloroquine combination therapy has a favorable safety profile and gives rise to a clinical response in patients with primary Sjögren’s syndrome.
This trial was designed on the basis of preclinical evidence suggesting “a complementary and additive immune-inhibitory effect of leflunomide and hydroxychloroquine,” along with “the acceptable safety profiles of the two drugs and their previous approval for use in multiple rheumatic musculoskeletal diseases,” explain Joel van Roon (University Medical Center Utrecht, the Netherlands) and colleagues.
The RepurpSS-I investigators report in The Lancet Rheumatology that average EULAR Sjögren’s syndrome disease activity index (ESSDAI) scores improved from 10.40 points at baseline to 6.60 points at week 24 among the 21 patients who were randomly assigned to receive leflunomide 20 mg/day together with hydroxychloroquine 200 mg once or twice daily based on bodyweight.
On the other hand, average ESSDAI scores worsened from 9.10 to 10.40 points for the seven patients given placebo, giving a significant mean between-group difference of 4.35 points after adjustment for baseline values.
All participants had moderate-to-active disease (ESSDAI score ≥5 points) and a lymphocytic focus score of 1 or higher in labial salivary gland biopsy specimens; all but one were women, and the average age was 54.7 and 53.5 years in the leflunomide–hydroxychloroquine and placebo arms, respectively.
van Roon and team note that the combination treatment was also associated with a reduction in EULAR Sjögren’s syndrome patient reported index scores, as well as better social function and mental health on the Short Form-36 questionnaire and “an unprecedented improvement in saliva output.”
They say that participants treated with the combination experienced a reduction in B-cell hyperactivity from baseline to week 24, with the reduction in mean serum immunoglobulin greater than that reported in previous studies of either agent alone. However, they caution that “no conclusions can be drawn with respect to additive clinical effects of the combination,” because leflunomide and hydroxychloroquine monotherapies were not tested in the RepurpSS-I trial as they “did not reach clinical endpoints in previous studies.”
The researchers report that the leflunomide–hydroxychloroquine combination was well tolerated, with no unexpected adverse events related to treatment. The most frequently reported adverse event in the active treatment arm was gastrointestinal discomfort (52 vs 25% in the placebo arm), followed by diarrhea (38 vs 0%) and weight loss of more than 2 kg (14 vs 0%).
“Larger follow-up trials of leflunomide–hydroxychloroquine combination therapy are needed to verify the promising results of this study,” conclude van Roon and colleagues.
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