Combination Leflunomide-Hydroxychloroquine Promising for Sjogren's Syndrome

By Marilynn Larkin

April 07, 2020

NEW YORK (Reuters Health) - A combination of two approved drugs, leflunomide and hydroxychloroquine, was safe and elicited a clinical response in a phase-2a trial for Sjogren's syndrome.

For the 24-week trial, Dr. Joel Adrianus Gijsbert van Roon of University Medical Center Utrecht and colleagues randomized 20 women and one man to 20 mg leflunomide and 400 mg hydroxychloroquine daily, and eight women to placebo. One patient in the placebo group required high-dose prednisone to treat polymyalgia rheumatica at week 13 and was excluded from the primary analysis.

Patients had a European League Against Rheumatism Sjogren's syndrome disease activity index (ESSDAI) score of 5 or higher, and a lymphocytic focus score of 1 or higher in labial salivary gland biopsy specimens. Mean disease duration was about eight years.

The primary endpoint was the between-group difference in change in ESSDAI scores from 0 to 24 weeks, adjusted for baseline ESSDAI score

As reported in The Lancet Rheumatology, the mean difference in the adjusted ESSDAI score was -4.35 in the leflunomide-hydroxychloroquine group compared with placebo.

No serious adverse events occurred in the intervention group, whereas two occurred in the placebo group (hospital admission for pancreatitis and hospital admission for nephrolithiasis).

The most common adverse events in the intervention group were gastrointestinal discomfort (52% vs. 25% for placebo); modest transient increases in alanine aminotransferase (48% vs.13%); and short episodes of general malaise and shivering (43% vs. 13%).

Dr. Astrid Rasmussen of Oklahoma Medical Research Foundation in Oklahoma City, author of a related editorial, told Reuters Health by email that the trial "addresses the unmet need (for) treatment...that goes beyond amelioration of local dryness."

"The most interesting part of the proposal is that, besides attaining clinically relevant improvement in disease activity and measures of well-being, it does so by repurposing old drugs," she noted. "Both hydroxychloroquine and leflunomide have been used in the treatment of rheumatological diseases for many years, and their safety profile has been well tested."

"Now, this group of investigators are translating the observed synergy of the two drugs in vitro into potential new therapeutic strategies for Sjogren's syndrome," she said. "While this generates enthusiasm, it is still too early to know if the results derived from a small, proof-of-concept trial will be replicated in larger, multicenter, randomized controlled trials. Until that time, it is premature to apply this in clinical practice."

Sjogren's syndrome expert Dr. Andres Pinto, chair and professor in the Department of Oral and Maxillofacial Medicine and Diagnostic Sciences at Case Western Reserve University in Cleveland, Ohio, commented by email, "This study uses two medications that independently have some usefulness in primary Sjogren's. The strength of the study, in my view, is the measurement of clinical, biological, histologic and proteomic markers. There is still more research required to assess longer term efficacy and safety."

"I liked the efforts to discern an inflammatory endotype - that is, a group of biomarkers - that potentially could predict response to therapy," he told Reuters Health.

That said, he added, "I would like to see a phase 3 study to confirm these preliminary findings. This study is based on less than 30 patients."

Dr. van Roon did not respond to requests for a comment.

SOURCE: and The Lancet Rheumatology, online March 26, 2020.