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-relatedprocedures.

• 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 andfor two years after stopping treatment.

• Cohort 2

• Having given written informed consent prior to undertaking any study-relatedprocedures.

• 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 andfor 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 withintwo 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 toany of the excipients of the specialty used

• Contra-indication to MMF: hypersensitivity to mycophenolate mofetil, acidmycophenolic, mycophenolate sodium or to any of the excipients of the specialty used

• Contra-indication tor LEF: hypersensitivity to the active substance, the main activemetabolite teriflunomide or to any excipients of the specialty used.

• Concomitant treatment with corticosteroids more than 10 mg/day of prednisoneequivalent 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 orcyclophosphamide in the last 6 months

• Previous treatment with anti-TNF, abatacept, tocilizumab or belimumab or any otherbiologic in the setting of a past clinical trial in the last 3 months

• Severe life-threatening systemic involvement requiring cyclophosphamide or high dosecorticosteroids, 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 yearsexcept non-melanoma skin cancer

• Patients with history of gastrointestinal tract ulceration, hemorrhage andperforation

• Patients with history of cardiomyopathy

• Patients with known hereditary deficiency of hypoxanthine-guaninephosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmillersyndrome

• 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-HBCantibody without any HBS antigen)

• HIV infection (positive serology)

• Positive SARS-Cov2 PCR (if vaccinated for COVID-19, no PCR is required; if historyof COVID-19 infection, positive serology is sufficient)

• Cytopenia defined as neutrophils < 1.0 G/L, lymphocytes < 0.5 G/L, Hb < 10 g/dl orplatelets < 100 G/L

• Moderate to severe renal insufficiency (GFR < 30 ml/min)

• Severe hypogammaglobulinemia defined as gamma globulins or IgG < 5 g/l Reducedhepatic 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 recommendedto avoid alcohol during the entire study

• Not affiliated to a social security regime (specific for France)