Leflunomide and Hydroxychloroquine combination therapy
for primary Sjögren’s Syndrome

Primary Sjögren’s Syndrome (pSS) affects 0.5-1% of the general population (female to male ration 9:1) which makes it the second most prevalent autoimmune rheumatic disorder after rheumatoid arthritis (RA). There is still a large unmet medical need to inhibit morbidity, including severe dryness and invalidating fatigue, and to reduce the risk development of extraglandular manifestations and B cell malignancies (34). Currently, no therapeutic option is available for this debilitating disease.
Recently, we conducted a randomized, double-blind, placebo-controlled, monocenter, phase 2a trial in patients with pSS. Clinically active (European Sjogren syndrome disease-activity index/ESSDAI≥5) patients were randomized to receive leflunomide (LEF) 20mg and hydroxychloroquine (HCQ) 400mg daily or placebo/placebo (2:1) for 24 weeks. Twenty-one patients received LEF/HCQ therapy and eight received placebo. Overall, LEF/HCQ appeared to be safe and showed a meaningful clinical improvement. From 0 to 24 weeks, ESSDAI scores, the primary clinical endpoint, were on average 4.35 points (95% CI -7.44707 to -1.25178, p=0.0078) lower in the LEF/HCQ group compared to the placebo group (47).
Hence, repurposing LEF and HCQ using combination-therapy for the treatment of pSS holds great therapeutic potential. However, the small sample size warrants replication in larger RCTs before its implementation in daily clinical practice. We hypothesize that the combination of LEF/HCQ significantly and safely inhibits activity of primary Sjögren’s syndrome and molecular fingerprints will allow prediction of therapy response as well as identification of pathways that confer lack of response.

Objectives:
1) Assess clinical efficacy and safety of Leflunomide/Hydroxychloroquine in pSS patients in a phase IIb placebo-controlled randomized clinical trial at 24 weeks, followed by a single-arm crossover and an open extension (total duration of 48 weeks)
2) Identify predictive clinical or molecular measures for response to therapy.
3) Pinpoint underlying molecular pathways associated with lack of clinical response.
Study design: Single-center, randomized, double-blind placebo controlled trial, followed by a single arm cross-over open extension
Study population: In total 52 patients with primary Sjögren’s syndrome, 18-75 years, will be treated with either verum (n=26) or placebo (n=26).

Intervention: For 24 weeks, patients will receive 1 capsule with LEF (20 mg) and 2 capsules with HCQ (2x 200 mg) orally once per day as compared to 1 capsule with LEF-placebo and 2 capsules with HCQ-placebo once per day. For patients with a bodyweight <60 kg the HCQ dosage will be reduced to 200 mg a day. After 24 weeks all patients remain blinded and placebo-patients will receive LEF and HCQ (open label extension).

Main study parameters/endpoints: Primary endpoint is change in ESSDAI scores from baseline to endpoint at 24 weeks. The secondary endpoint includes changes in unstimulated/stimulated whole saliva output, ESSPRI (European SS patient reported index), ocular dryness and serological and blood inflammatory features at 24 weeks interval. Exploratory endpoints include: ESSDAI and UWS at 48 weeks and other clinical measures at 48 weeks (ESSPRI, etc.) and the validation of possible biomarkers to predict response to therapy.

We hypothesize that the combination of LEF/HCQ significantly and safely inhibits activity of primary Sjögren’s syndrome and molecular fingerprints will allow prediction of therapy response as well as identification of pathways that confer lack of response.

Baseline, week 8, week 16, week 24, week 32, week 40, week 48.

Intervention: For 24 weeks, patients will receive 1 capsule with LEF (20 mg) and 2 capsules with HCQ (2x 200 mg) orally once per day as compared to 1 capsule with LEF-placebo and 2 capsules with HCQ-placebo once per day. . For patients with a bodyweight <60 kg the HCQ dosage will be reduced to 200 mg a day. After 24 weeks all patients remain blinded and placebo-patients will receive LEF and HCQ (open label extension).