New Clinical End-points in Patients With Primary Sjögren's Syndrome

Inclusion Criteria: * Cohort 1 * Having given written informed consent prior to undertaking any study-related procedures. * Patients with pSS according to ACR/EULAR 2016 criteria or AECG 2002 criteria * With a high level of symptoms (ESSPRI ≥ 5) and low systemic disease activity (ESSDAI \< 5). * Negative pregnancy test (serum at screening) * Use highly reliable contraception during research treatment from the screening and for two years after stopping treatment. * Cohort 2 * Having given written informed consent prior to undertaking any study-related procedures. * Patients with pSS according to ACR/EULAR 2016 criteria or AECG 2002 criteria * With moderate/high systemic disease activity, as defined by ESSDAI ≥ 5. * Negative pregnancy test (serum at screening) * Use highly reliable contraception during research treatment from the screening and for two years after stopping treatment Exclusion Criteria: * For both cohorts: * Age \< 18 years * Pregnant or breastfeeding women or women wanted to conceive either during or within two years after the end of the treatment period * Women of childbearing potential not using highly effective methods of contraception (as defined in section 6.3) * Participation in another interventional trial * Contra-indication to HCQ: pre-existing retinopathy, hypersensitivity to HCQ or to any of the excipients of the specialty used * Contra-indication to MMF: hypersensitivity to mycophenolate mofetil, acid mycophenolic, mycophenolate sodium or to any of the excipients of the specialty used * Contra-indication tor LEF: hypersensitivity to the active substance, the main active metabolite teriflunomide or to any excipients of the specialty used. * Concomitant treatment with corticosteroids more than 10 mg/day of prednisone equivalent at screening or inclusion (randomisation) * Concomitant treatment with other immunomodulators including methotrexate, azathioprine, cyclophosphamide, cyclosporine and tacrolimus * Previous treatment with HCQ, LEF, MMF in the last 3 months * Previous treatment with rituximab, other B-cell targeted biologic therapy or cyclophosphamide in the last 6 months * Previous treatment with anti-TNF, abatacept, tocilizumab or belimumab or any other biologic in the setting of a past clinical trial in the last 3 months * Severe life-threatening systemic involvement requiring cyclophosphamide or high dose corticosteroids, or any drug considered as an exclusion criteria * Impairment of other severe immunodeficiency states * Patients with active malignancy or history of malignancy within the last 5 years except non-melanoma skin cancer * Patients with history of gastrointestinal tract ulceration, hemorrhage and perforation * Patients with history of cardiomyopathy * Patients with known hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome * Serious infection in the past month * Evidence of active tuberculosis infection * Active HCV (positive PCR) * Active HBV infection (positivity for HBS antigen, or positivity for anti-HBC antibody without any HBS antigen) * HIV infection (positive serology) * Positive SARS-Cov2 PCR (if vaccinated for COVID-19, no PCR is required; if history of COVID-19 infection, positive serology is sufficient) * Cytopenia defined as neutrophils \< 1.0 G/L, lymphocytes \< 0.5 G/L, Hb \< 10 g/dl or platelets \< 100 G/L * Moderate to severe renal insufficiency (GFR \< 30 ml/min) * Severe hypogammaglobulinemia defined as gamma globulins or IgG \< 5 g/l Reduced hepatic function: AST or ALT \> 2x ULN (re-testing is allowed, see section 5.10) * Prolonged ECG's corrected QT interval (\>500 ms) * Known history of maculopathy * Patients will be informed of the risk of alcohol consumption and will be recommended to avoid alcohol during the entire study * Not affiliated to a social security regime (specific for France)