CHICAGO – Combination therapy with leflunomide and hydroxychloroquine met all goals for efficacy, safety, and tolerability among patients with primary Sjögren’s syndrome in a randomized, placebo-controlled pilot study, lending support to evidence suggesting the two drugs have additive benefits.
Sharon Worcester/MDedge News
Dr. Joel A.G. van Roon
The combined treatment was associated with a statistically significant decrease in the EULAR Sjögren’s syndrome disease activity index (ESSDAI) over 24 weeks – the primary endpoint of the study – in 21 patients in the treatment group. The ESSDAI score on combination treatment dropped from about 10 at baseline to about 6 at 24 weeks, compared with no change from a baseline of about 10 in eight patients in the placebo group. An ESSDAI decrease of 3 or more points occurred in 11 patients in the combination therapy group, compared with none in the placebo group, Joel A.G. van Roon, PhD, a researcher in the Laboratory of Translational Immunology at the University Medical Center Utrecht, the Netherlands, reported in a late-breaking poster at the annual meeting of the American College of Rheumatology.
Both leflunomide and hydroxychloroquine have been shown to inhibit B-cell hyperactivity, but the clinical benefits have been modest and not statistically significant. Since the two agents have complementary inhibitory properties on different immune cells – including B and T cells and plasmacytoid dendritic cells, and based on in vitro findings of additive benefits with respect to inhibition of T- and B-cell activation and CXCL13 production, Dr. van Roon and his colleagues conducted this double-blind, single-center, proof-of-concept pilot study (REPURpSS-1) to assess the efficacy, safety, and tolerability of combined treatment in primary Sjögren’s syndrome.
In all, 29 patients with clinically active disease, defined by ESSDAI of 5 or greater, were randomized 2:1 to receive either 20 mg of leflunomide daily plus 400 mg of hydroxychloroquine daily or placebo/placebo for 24 weeks.
Secondary endpoints such as oral dryness also improved significantly in the treatment group versus the placebo group. Stimulated whole saliva flow increased from about 800 mcL/5 min to about 1,400 mcL/5 min and decreased from about 1,250 to about 1,000 mcL/5 min in the groups, respectively. Median EULAR Sjögren’s syndrome patient reported index (ESSPRI), ESSPRI pain, and ESSPRI fatigue scores, as well as Physician’s and Patient’s Global Assessment scores each improved significantly in the treatment group (at least P less than .05 in all cases) but not in the placebo groups, said Dr. van Roon.
Additionally, serum IgG, IgM rheumatoid factor, and chemokine CXCL13 – a marker for lymphoid neogenesis – decreased significantly, and complement components 3 and 4 (C3 and C4) increased significantly by 24 weeks in the treatment group, but not in the placebo group. B-cell hyperactivity as measured by serum IgG decreased from about 20 g/L to about 14 g/L versus no change from about 15 g/L at baseline in the placebo group, he noted.
“Overall, combination leflunomide and hydroxychloroquine was safe and well tolerated, but larger randomized, controlled trials are needed to confirm the observed effects and to identify potential biomarkers for response,” he concluded.
This study was supported by ZonMw (the Netherlands Organization for Health Research and Development). Dr. van Roon reported having no relevant disclosures.
SOURCE: van Roon JAG et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L10.