Background: In a prospective, single-center open study, we evaluated the very long-term effects of rituximab (RTX) administered to patients with severe mixed cryoglobulinemia (MC). Methods: RTX was administered to 31 patients with MC (type II in 29 cases and type III in 2) with diffuse membranoproliferative glomerulonephritis (16 cases), peripheral neuropathy (26) and large skin ulcers (7). All but 4 patients had serum anti-hepatitis C virus antibodies. RTX was administered at a dose of 375 mg/m2, according to a ‘4 + 2' protocol (days 1, 8, 15 and 22 plus 1 dose 1 and 2 months later). No other immunosuppressive drugs were added. Response was evaluated over a very long-term follow-up (mean 72.47 months, range 30-148). Results: Complete remission of pretreatment active manifestations was observed in all cases of purpuric lesions and non-healing vasculitic ulcers, and in 80% of the peripheral neuropathies. Cryoglobulinemic nephropathy significantly improved during follow-up, starting from the 2nd month after RTX (serum creatinine from 2.1 ± 1.7 to 1.5 ± 1.6 mg/dl, p ≤ 0.05; 24-hour proteinuria from 2.3 ± 2.1 to 0.9 ± 1.9 g/24 h, p ≤ 0.05). Improvement of cryoglobulinemic serological hallmarks, such as cryocrit and low complement C4, were observed. No clinically relevant side effects were recorded. Re-induction with RTX was carried out in 9 relapsed patients after a mean of 31.1 months (12-54), again with beneficial effects. The survival rate was 75% at 6 years and the probability of remaining symptom-free for 10 years without any therapy was of about 60% after a single ‘4 + 2' infusion cycle, while the probability of living symptom-free 5 years after relapsing was 80% if given the same treatment. Conclusion: In this open, prospective study, RTX appeared to be very effective and safe in the treatment of the most severe cases of MC.

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