The combination’s statistically significant effect on the European League Against Rheumatism (EULAR) Sjögren’s syndrome disease activity index (ESSDAI) score at 24 weeks, the primary endpoint of the small, double-blind, placebo-controlled trial, suggests that the combination should be studied further in larger trials, according to first author Eefje Hanna Martine van der Heijden, MD, a rheumatologist at University Medical Center Utrecht (the Netherlands), and colleagues.
The investigators decided to study leflunomide and hydroxychloroquine, which target overlapping and distinct immunopathologic pathways, because data support the safety of each drug individually, and a previous in vitro study by the authors indicated that they have complementary effects when administered together.
“To our knowledge, this is the first randomized, placebo-controlled clinical trial in patients with primary Sjögren’s syndrome that shows significant clinical efficacy, as measured by ESSDAI, and is associated with significant improvements in other clinical parameters, including dryness and fatigue,” the investigators wrote.
Dr. van der Heijden and colleagues screened 37 patients from the outpatient clinic of their medical center and enrolled 29 (28 women) who met American-European Consensus Criteria into their study. They had moderate to active disease, defined as an ESSDAI score of 5 or higher, and a lymphocytic focus score of 1 or higher in labial salivary gland biopsy specimens that were obtained before inclusion. The population’s average age was approximately 54 years. They had an average disease duration of about 8 years, a mean ESSDAI score of about 9, and mean EULAR Sjögren’s syndrome patient reported index (ESSPRI) score of 6.7. A total of 21 patients were randomized to leflunomide 20 mg and hydroxychloroquine 400 mg daily, and 8 patients were randomized to placebos. Baseline characteristics were similar between groups, but mean serum IgG level was 19.4 g/L in the treatment group and 13.8 g/L in the placebo group. One patient in the placebo group developed polymyalgia rheumatica and required high-dose prednisone treatment. The investigators excluded this patient from the primary analysis.
At 24 weeks, the mean difference in ESSDAI score in the leflunomide-hydroxychloroquine group, compared with the placebo group, was –4.35 points after adjustment for baseline values. This difference was statistically significant.
Secondary endpoints in the study showed inconsistent statistically significant differences between the treatment groups at 8, 16, and 24 weeks. The total ESSPRI score at 16 weeks was 1.66 points lower in the treatment group than in the placebo group. Stimulated whole saliva production was increased in the leflunomide-hydroxychloroquine group at 16 weeks, compared with the placebo group. Unstimulated whole saliva production at 24 weeks was higher in the leflunomide-hydroxychloroquine group than in controls. The investigators found no differences between groups in visual analog scores for ocular or oral dryness.
No patient in the leflunomide-hydroxychloroquine group had a serious adverse event. Two serious adverse events (hospital admission for pancreatitis and hospital admission for nephrolithiasis) occurred in the placebo group. The most common adverse events in the leflunomide-hydroxychloroquine group were GI discomfort (52% vs. 25% in the placebo group), modest transient increases in ALT (48% vs. 13%), and short episodes of general malaise and shivering (43% vs. 13%).
In an accompanying Astrid Rasmussen, MD, PhD, of the Oklahoma Sjögren’s Syndrome Center of Research Translation at the Oklahoma Medical Research Foundation in Oklahoma City, wrote that the trial by Dr. van der Heijden and colleagues was limited by a small sample size and short duration. In addition, some of the findings were unexplained, such as modest changes in secondary endpoints and a concomitant decrease in ESSDAI scores at 8 weeks for both study groups.,
Nevertheless, the study provides reason to think in new ways about old drugs, wrote Dr. Rasmussen. “Combination or sequential use of existing agents that target different aspects of immune dysregulation, while having acceptable safety profiles and cost-benefit ratios, should represent an avenue of further exploration. Just as importantly, subphenotyping patients on the basis of their underlying pathogenic processes and identifying sensitive outcome measures could transform the current enthusiasm for identifying effective treatments for Sjögren’s syndrome into a reality for the patients that need them the most.”
The study was funded by ZonMw. The authors of the study reported no conflicts of interest. Dr. Rasmussen reported having no conflicts of interest.
SOURCE: van der Heijden EHM et al. Lancet Rheumatol. 2020 Mar 26. .