Treatment with rituximab in patients with mixed cryoglobulinemia syndrome: Results of multicenter cohort study and review of the literature

ObjectiveMixed cryoglobulinemia syndrome (MCs) is a systemic vasculitis characterized by multiple organ involvement due to the vascular deposition of immune-complexes, mainly the cryoglobulins. B-lymphocyte expansion represents the underlying pathological alteration frequently triggered by hepatitis C virus (HCV) infection. The treatment of MCs syndrome is generally based on antiviral drugs and/or immunosuppressors, among which rituximab, an anti-CD20 monoclonal antibody, has been usefully employed for both cutaneous and visceral MCs organ involvement. This multicenter study retrospectively evaluated the effects of rituximab in a large series of patients with active MCs. The observed results were compared to those emerging from the updated review of the literature on this topic.MethodsThe study included 87 patients (male/female 19/68, mean age 62.3 ± 11.4SD years, mean disease duration 9 ± 6.2SD years, HCV infection in 92% of cases) with active cryoglobulinemic vasculitis evaluated before rituximab monotherapy and after 6-month follow-up by means of main clinico-serological parameters. A PubMed search up to May 31, 2011, was done to find published clinical studies, including case reports of MCs treated with rituximab.ResultsA significant clinical improvement was observed in a relevant percentage of cases, regardless the presence/absence of associated HCV infection; namely, complete/partial remission of pre-treatment active manifestations was observed in 74% of skin purpuric lesions, up to 87% of non-healing vasculitic leg ulcers, and 44% of the peripheral neuropathy, mainly paresthesias (patient's visual analogical scale from 62 ± 25 to 37 ± 27; p ≤ .0001). Moreover, cryoglobulinemic nephropathy, observed in 38 patients, significantly improved in 95% of cases (serum creatinine from 1.8 ± 1.1SD to 1.4 ± 0.8SD mg/dl, p ≤ .0001; 24-hour proteinuria from 2.2 ± 2.1SD to 0.9 ± 1.7SD g/24 h, p ≤ .0001), with complete remission in the 50%. Among 6 patients with complicating non-Hodgkin's B-cell lymphoma a complete or partial remission was observed in 5/6. A complete remission of abdominal vasculitis was also observed in one patient. These beneficial effects were mirrored by the improvement of cryoglobulinemic serological hallmarks, namely cryocrit and low complement C4, in half cases.The safety of rituximab was confirmed by the small number of side effects recorded during the 6-month follow-up.On the whole, the results of the present study are in keeping with those reported in 39 papers present in world literature, including a total of 279 MCs patients.ConclusionsRituximab may be regarded as useful and safe pathogenetic treatment of cryoglobulinemic vasculitis. The actual role of this drug should be definitely confirmed by randomized controlled trials, as well as its position in the therapeutical strategy, mainly with respect to antiviral treatment in HCV-associated MCs.

► The treatment of MCs is based on etiological, pathogenetic, and/or symptomatic therapies.
► Among pathogenetic treatments, rituximab is increasingly used during the last decade.
► Our study shows the efficacy and safety of rituximab in a series 87 MCs patients.
► Skin lesions, neuropathy, and nephropathy were particularly responsive to rituximab.
► An updated review of published reports on this topic is done.