Improved (4 Plus 2) Rituximab Protocol for Severe Cases of Mixed Cryoglobulinemia: A 6-Year Observational Study

Abstract

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.

The challenge of treating hepatitis C virus-associated cryoglobulinemic vasculitis in the era of anti-CD20 monoclonal antibodies and direct antiviral agents

“…Our group also showed that mixed peripheral neuropathy improved within 5 months after administering Rituximab [32]. Moreover, Rituximab treatment has been found to deplete bone marrow B-cell clonal expansion resulting in a decrease of serum cryoglobulins and rheumatoid factor, and in a normalisation of C4 levels [41–45]. …”

“…Our recently published study, which represents the largest single-center cohort of patients with MC and renal involvement prospectively treated with Rituximab [41], showed a greater than 90% rate of any response (CR+PR) at the end of follow-up.…”

Hepatitis C virus infection and chronic kidney disease: Time for reappraisal

“…The cumulative probability of survival in patients with CryoVas MPGN was less than 60% at 5 years and most deaths in the pre-rituximab era were due to liver failure and infections [83,84]. A recently reported cohort of patients treated with an intensive ''4 plus 2 rituximab infusion protocol" showed a 75% survival rate at 6 years, with a 60% probability of remaining symptomfree for 10 years without any therapy [85].…”

“…It should be combined with immunosuppression not only to avoid postapheresis rebound of cryoglobulinemia but also because of the added effects of the anti-B lymphocyte activity of the standard immunosuppressive drugs (cyclophosphamide, and, more recently, mycophenolate mofetil). However, rituximab alone or in combination with methylprednisolone pulses has proved to be safer and comparably effective in open studies [85]. In such cases, an unsolved issue is the time when to start DAAs, i.e., during or after the critical phase.…”

High-Dose Rituximab Ineffective for Focal Segmental Glomerulosclerosis: A Long-Term Observation Study

“…Moreover, RTX is a valuable option in the treatment of several connective tissue diseases [11,12,13] and immune-meditated glomerular diseases such as idiopathic membranous nephropathy [14,15] and Henoch-Schonlein purpura nephritis [16]. RTX has emerged as an alternative treatment of frequently relapsing, steroid-dependent or steroid-resistant nephrotic syndrome in children [17,18,19,20].…”