Cryoglobulinemia vasculitis (CV) is a systemic immune-mediated small vessel vasculitis. Rituximab proved effective on main vasculitis signs, with a complete clinical response of 65%. However, CV relapse is noted in up to 40% of patients. Following rituximab, serum Blys concentration significantly increased and may favor relapses. Tribeca is a multicentre randomized controled study comparing safety and efficacy of belimumab to placebo in non infectious cryoglobulinemia vasculitis.
Age > 18 years
Written inform consent
Active mixed cryoglobulinemia vasculitis, at initiation of rituximab, define by a. a clinically active vasculitis with skin, joint, renal, peripheral nerve, central neurological, digestive, pulmonary and/or cardiac involvement , b. history of positive cryoglobulinemia and/or positive Rheumatoid factor associated with low C4 complement level , and/or a monoclonal component (IgM Kappa) and/or a histologal proof of vasculitis in the affected organs
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Patient with a vasculitis unrelated to cryoglobulinemia
Patient with non active cryoglobulinemia vasculitis, at initiation of rituximab. Patients with mixed inactive vasculitis following rituximab administration may be included.
365 days Prior to Investigational Medicinal Product (Belimumab or placebo):: Any biologic investigational agent (e.g., abetimus sodium, anti CD40L antibody, BG9588/ IDEC 131) Investigational agent applies to any drug not approved for sale in the country in which it is being used
180 Days Prior to Investigational Medicinal Product (Belimumab or placebo):: Intravenous cyclophosphamide
Parallel
Belimumab
DrugBelimumab administered subcutaneously 200mg weekly from week 1 to week 24. Both arms will have the same corticosteroid tapering scheme, with an initial dose of 30 mg/day. The following schedule of reduction of prednisone will apply to both groups as long as the disease is inactive: * 30 mg/day week (W)0-W2, * 20 mg/day W2-W4 * 15 mg/day W4-W6, * 10 mg/day W6-W8, * 5 mg/day W8-W10 Between W10-W12 the strategy for stopping glucocorticoids is left to the investigator's discretion. Stopping glucocorticoid therapy at W12. At each step, the prednisone dose will be reduced only in the absence of signs of vasculitis activity.
Placebo
DrugBoth arms will have the same corticosteroid tapering scheme, with an initial dose of 30 mg/day. The following schedule of reduction of prednisone will apply to both groups as long as the disease is inactive: * 30 mg/day week (W)0-W2, * 20 mg/day W2-W4 * 15 mg/day W4-W6, * 10 mg/day W6-W8, * 5 mg/day W8-W10 Between W10-W12 the strategy for stopping glucocorticoids is left to the investigator's discretion. Stopping glucocorticoid therapy at W12. At each step, the prednisone dose will be reduced only in the absence of signs of vasculitis activity.
Complete clinical response rate at week 25 with corticosteroid withdrawal at week 12
Complete clinical response is defined by remission of all affected organs involved at baseline and the absence of clinical relapse. * Skin and articular remissions * Renal remission * Neurological remission * Digestive remission * Cardiac remission * Central nervous system remission * Pulmonary remission
Safety W25
Frequency and severity of adverse clinical events
Safety W48
Frequency and severity of adverse clinical events
Response W13
The complete clinical response is defined by the remission of all affected organs involved at baseline and the absence of clinical relapse. Partial clinical response The partial clinical response is defined by the improvement and / or remission of more than half of the organ involvement present at baseline and the absence of clinical relapse. No clinical response Patients with no clinical response at W4 will be defined by worsening of ulcers or cutaneous necrosis, worsening peripheral neurological involvement or by persistence of active renal involvement defined by persistence of proteinuria\> 1.5 g / 24h or proteinuria/creatinuria \<150 mg/mmol).
Response W25
The complete clinical response is defined by the remission of all affected organs involved at baseline and the absence of clinical relapse. Partial clinical response The partial clinical response is defined by the improvement and / or remission of more than half of the organ involvement present at baseline and the absence of clinical relapse. No clinical response Patients with no clinical response at W4 will be defined by worsening of ulcers or cutaneous necrosis, worsening peripheral neurological involvement or by persistence of active renal involvement defined by persistence of proteinuria\> 1.5 g / 24h or proteinuria/creatinuria \<150 mg/mmol).
Immunomonitoring W13
deep immunophenotyping, cytokines production, clonal IgM memoryCD21-/low cells) description
Immunomonitoring W25
deep immunophenotyping, cytokines production, clonal IgM memoryCD21-/low cells) description
Immunomonitoring W48
deep immunophenotyping, cytokines production, clonal IgM memoryCD21-/low cells) description
renal response W13
Renal remission is evaluated biologically (proteinuria \<0.5g/24h or proteinuria/creatinuria \<50 mg/mmol).
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