Optimizing DMARD therapy for primary Sjogren's Syndrome - Leflunomide and Hydroxychloroquine combination therapy for patients with primary Sjogren's Syndrome

PSS affects ~1% of the general population, which makes it the second most
prevalent autoimmune rheumatic disorder after rheumatoid arthritis. Despite the
efforts to treat pSS successfully, advances in pSS treatment remain quite
disappointing, and no successful therapy is available. There is a large unmet
medical need to inhibit morbidity, including severe dryness and fatigue that
these patients experience, and to reduce the risk of extraglandular disease and
B cell malignancies. Also, guidelines to assess which patients should be
treated with immunosuppressive drugs are lacking. Currently, the implementation
of novel biologicals like rituximab is hampered by lack of sufficient clinical
efficacy and the high cost/effectiveness ratio. In addition, this latter drug
is not easy to administer and safety in pSS patients remains to be
demonstrated.
Based on the pivotal role of B cells, T cells and pDCs in pSS and the
complementary properties of Leflunomide (LEF) and Hydroxychloroquine (HCQ) to
target these, we thus aim to demonstrate that the combination of LEF and HCQ
leads to a more efficient inhibition of immune activation compared to these
single DMARDs culminating in a higher clinical efficacy in pSS.
The current clinical study exploits advances on a recently discovered
conceptual framework of pSS pathogenesis and implements the beneficial effects
of DMARD combination therapy seen in e.g. RA.

In a clinical trial it will be investigated to what extent combination therapy
with LEF and HCQ will 1) inhibit disease activity, in particular improvement of
ESSDAI and dryness and 2) inhibit activity of (autoreactive) B-cells, T-cells
and pDCs. In addition, we will study 3) early biomarkers and in vitro bioassays
to predict response to therapy

Double-blind placebo controlled trial

For 24 weeks, patients will orally receive 1 capsule with LEF (20 mg) and 2
with HCQ (200 mg), once per day as compared to three capsules with placebo .
For patients with a bodyweight <60 kg, HCQ doses will be reduced to 200 mg once
a day.

Patients participating in the study will be taking medication (3 capsules/day)
for 24 weeks. They will visit the outpatient clinic 12 times in a period of 24
weeks. During part of the visits an extensive clinical assessment is performed,
evaluating patient*s symptoms (ESSDAI and ESSPRI), quality of life (SF-36),
fatigue (MFI), oral and ocular dryness (VAS-scores). In addition, patients will
undergo biopsy of the parotid gland twice (before baseline and after 24 weeks
of treatment) and blood samples will be drawn four times. During the other
visits patients will undergo physical and laboratory examination in order to
preserve their safety. At baseline, a chest X-ray and assessment of
lungcapacity will be performed, these will be repeated only on indication. At
last, patient will undergo MRI of the salivary glands and 18F-FDG PET/CT scan
(head to hip) twice.