Anti-CD20 monoclonal antibody therapy for type II mixed cryoglobulinemia syndrome

INTERVENTION: NON‐Rituximab (RTX) GROUP (conventional treatment, i.e., as chosen by the expert clinician in that individual patient among the following): 1. Glucocorticoids (maximal initial dose of 1 mg/kg/day of prednisone equivalents) with or without preceding 6‐methylprednisolone pulses (500 to 1000 mg/day for 3 consecutive days), with subsequent reduction of the glucocorticoid dosage in the following months. 2. Azathioprine or cyclophosphamide, orally at 1‐2 mg/kg/day, with or without glucocorticoids (as in point 1); if response was observed, azathioprine or cyclophosphamide might be suspended after the end of month +6 after randomization, and then reintroduced if clinical relapse occurred (as it occurs in the current clinical practice). 3. Plasmapheresis, with or without glucocorticoids (as in point 1); if response was observed, plasmapheresis could be suspended after the end of month +6 after randomization, and then reintroduced if clinical relapse occurred (current clinical practice). At least two plasmapheretic procedures per week were required in the first month after randomization, with subsequent reductions according to the response observed and to local protocols. Rituximab (RTX) GROUP: RTX 1 g intravenously on days 0 and 14, with premedication with 100 mg of methylprednisolone intravenously, paracetamol 1000 mg orally, and clorpheniramine maleate 10 mg intravenously, before each infusion. Only glucocorticoids were allowed as concomitant treatment, at the same dose given before randomization if already administered, or lower; if introduced with RTX, only low doses (= 0.1 mg/kg/day of prednisone equivalents) were allowed. In case of clinical disease relapse in this Group, retreatment with RTX, at the same schedule, was permitted in case of previous response to RTX. Patients failing treatment in non‐RTX Group could be switched to RTX in an open‐label extension manner (RTX‐switch Group). Patients were randomized to treatment stratified for the following three disease CONDITION: Mixed cryoglobulinemia HCV‐ related or unrelated ; Haematological Disorders ; Cryoglobulinaemia PRIMARY OUTCOME: The proportion of patients surviving on treatment at the end and 12 months after randomization, i.e., after a follow‐up considered sufficient to assess both the efficacy and safety of treatment. ; Efficacy and safety issues were in fact considered equally relevant in the long term, and a single end point integrating both of them was then chosen. Survival of treatment was statistically higher in RTX Group in comparison to non‐RTX Group (conventional treatment). INCLUSION CRITERIA: 1. Patients with CV with type II cryoglobulins 2. HCV? related or unrelated, classified according to published criteria 3. With positive serum cryoglobulins 4. Suffered from severe active CV manifestations, i.e., skin ulcers, active glomerulonephritis, or worsening or refractory peripheral neuropathy 5. In patients with HCV‐related CV, study inclusion implied that antiviral therapy with interferon plus ribavirin had failed, had been poorly tolerated, or was considered contraindicated 6. Patients aged 18‐80 years 7. Negative for antibodies against the human immunodeficiency virus (HIV), hepatitis B virus core antigen, and for hepatitis B virus surface antigen SECONDARY OUTCOME: 1. The proportion of patients surviving on treatment at the end month +24, i.e., to evaluate the long‐term efficacy and safety of treatment; 2. The proportion of patients surviving on treatment at the end month +6, i.e., to evaluate the short‐term efficacy and safety of treatment; 3. The proportion of patients surviving on treatment at the end month +3, i.e., to evaluate the very early efficacy and safety of treatment; 4. Superiority of RTX to decrease the global disease activity, as defined by the Birmingham Vasculitis Activity Score (BVAS); 5. Superiority of RTX for response in the single CV manifestations considered in the randomization scheme.; 6. Efficacy of RTX in patients where conventional treatment had failed; 7. Duration of response to RTX and efficacy of retreatment; 8. Assessment of the profile of side effects of RTX, both in the short and the long term