Leflunomide and Hydroxychloroquine combination therapy
for primary Sjögren*s Syndrome

Primary Sjögren*s Syndrome (pSS) affects 0.5-1% of the general population 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. In a
recent phase 2a trial, patients with pSS were randomized to leflunomide
(LEF)/hydroxychloroquine (HCQ) treatment or placebo, daily for 24 weeks.
Twenty-one patients received LEF/HCQ therapy and eight received placebo.
Overall, LEF/HCQ appeared to be safe. From 0 to 24 weeks, ESSDAI score was on
average 4.35 points lower in the LEF/HCQ group compared to the placebo group
(p=0.0078). 11 of 21 LEF/HCQ-treated patients showed a clinical response.
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.

This study has been transitioned to CTIS with ID 2024-510904-36-00 check the CTIS register for the current data.

To 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) and to evaluate the capacity of molecular fingerprints in
prediction of therapy response.

Single-center, randomized, double-blind placebo controlled trial, followed by a
single arm cross-over open extension

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).

Patients will visit the outpatient clinic 14 times (including screening visit
and safety checks) in a period of 48 weeks. At baseline and with 8-week
intervals an extensive clinical assessment will be performed, evaluating
patient*s symptoms (ESSDAI and EULAR Sjögren's Syndrome Patient Reported Index
or ESSPRI), quality of life (Short Form (36) Health Survey or SF-36), EQ-5D
-5L, fatigue (Multidimensional Fatigue Inventory or MFI) and oral and ocular
dryness (Visual Analogue Scale-scores or VAS-scores). In addition, blood
samples will be drawn 9 times. As is common practice in all patients using LEF,
physical and laboratory examination will be performed every 2-4 weeks in the
first three months, and after that monthly (in total 11 times), in order to
preserve their safety. These safety checks (consisting of measurement of blood
pressure and laboratory parameters (liver function by ALAT, creatinine ratio,
hemoglobulin level, platelets and leucocytes) will be executed by a specialized
rheumatology nurse in the UMCU or by the general practitioner of the
participating patient. When performed by the general practitioner, the results
will be sent to the research team for interpretation.
Healthy controls will visit the outpatient clinic 7 times in a period of 48
weeks. During these visits gut and skin microbiome will be gathered and people
will be asked about nutrition (20-30 min. per visit).