Systemic sclerosis (SSc) is a severe autoimmune disease associating dysimmunity, vasculopathy and fibrosis. No curative treatment is available. Pre-clinical abnormalities can be found such as specific autoantibodies. The association of Raynaud phenomenon and SSc-specific anti-nuclear antibodies is the hallmark of pre-scleroderma subjects, among who around 47% declare a complete disease after five years. The aim of this study is to assess in this particular population the preventive effect of an anti-platelet treatment.

In this study, platelet activation is targeted as it could play a key role in the pathogenesis of SSc. It has been shown in several publications that platelets are activated in SSc with a correlation between the level of activation and disease activity. Secondary to this activation, soluble and membrane effectors were increased, and induced vascular damages and fibrosis. The results obtained in the laboratory (CNRS UMR-5164) directly involved platelets in this mechanism by inducing the thymic stromal lymphopoietin (TSLP) production by endothelial cells and by showing the pro-fibrotic effect of TSLP. In vivo data in SSc murine model recently obtained, confirmed the preventive role on fibrosis of clopidogrel. The early control of this platelet activation could prevent the course of events leading to SSc.

The therapeutic strategy assessed in this study will be the oral administration of clopidogrel (75 mg per day) during two years to subjects presenting an association of specific dysimmunity and Raynaud phenomenon (RP). The administration of clopidogrel will be double-blinded versus placebo.

Subjects will be included and treated during a 2-year period and will be followed for a period of 36 months after treatment, i.e. a total of 60 months. The follow-up will be every six months mainly comprising clinical examination, patient reported outcomes and blood sampling.

Inclusion Criteria:

• Patient over 18 years old, and less than 85 years old.
• Patient with positive AAN (AAN ≥ 1/160) with the following specificity: anti-Scl70 or anti-centromere or anti-RNApolIII, or any other auto-antibodies related to systemic sclerosis
• Patient with RP reported by the subject and confirmed by the physician.
• Patient affiliated to a health insurance system.
• Patient who accepts to participate to the study and signs an inform consent form.

Exclusion Criteria:

• Patient with an SSc diagnosis according to ACR/EULAR 2013 criteria.
• Patient with skin fibrosis at screening.
• Patient with antiplatelet treatment at screening.
• Patient with contraindications to clopidogrel.
• Patient treated by immunosuppressive agent at screening.
• Patient treated by anticoagulants at screening
• Pregnant or breastfeeding women.
• Women of childbearing age refusing effective contraception method during the study treatment (24 months).
• Incompetent adults (i.e. Individuals under the protection of a conservator)