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

Rheumatology Unit, Department of Internal Medicine, University of Modena e Reggio Emilia, Medical School, Via del Pozzo 71, Modena, Italy.
Autoimmunity reviews (Impact Factor: 7.93). 07/2011; 11(1):48-55. DOI: 10.1016/j.autrev.2011.07.005
Source: PubMed


Mixed 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.
The 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.
A 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/24h, 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.
Rituximab 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.

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    • "In particular, the EUSTAR multicentre study analyzed the efficacy and safety of RTX in a relatively large series of patients, showing that the drug was able to significantly improve the extent of skin sclerosis in patients with diffuse SSc subset; moreover, in individuals with interstitial lung disease RTX was able to prevent a further decline of FVC compared to controls [31]. The clinical usefulness was associated with elevated patients' compliance and safety of RTX treatment as previously observed in other autoimmune rheumatic disorders [7] [8] [9] [10] [11] [12] [13] [17] [18] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32]. "
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    Autoimmunity reviews 07/2015; 14(11). DOI:10.1016/j.autrev.2015.07.008 · 7.93 Impact Factor
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    • "Furthermore, concerning the potential risk of RTX treatment of patients with chronic viral infection, this study may confirm the safety of RTX in HCV patients with chronic liver disease. In fact, clinical/biohumoral parameters, including platelets, and albumine, in addition to liver stiffness, generally improved during therapy, thus confirming previous data [13,15,42]. "
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    ABSTRACT: Mixed cryoglobulinemia (MC) is a HCV-related lymphoproliferative disorder generally associated with advanced liver disease. Liver stiffness has been significantly correlated with histopathological stage of fibrosis. Moreover, it was influenced by necroinflammatory activity. Rituximab (RTX) is a chimeric anti-CD20 monoclonal antibody inducing transient B lymphocytes depletion that was shown to be useful and safe in the majority of HCV MC patients, leading also to improvement of cirrhotic syndrome. Aim of this study was to evaluate the modifications of liver stiffness following RTX treatment in HCV-related MC patients.Materials and methods: Fourteen consecutive patients (10 F, 4 M; mean age 60.43 +/- 43) with HCV-related chronic hepatitis (n = 10) or cirrhosis (n = 4) and MC, eligible for RTX treatment, were prospectively enrolled. Intravenous injection of 1 g of RTX was performed at day 0 and at day 15. Assessment of stiffness was carried out by Fibroscan(R) (Echosens, Paris-France) at baseline, 15 days after the first infusion, and at month 1, 3 and 6 after therapy. MC symptoms significantly improved during the study, especially during the first 3 months. Liver stiffness observed 3 months after treatment was significantly reduced when compared with pre-treatment values (p = 0.01). This difference disappeared after 6 months of follow-up. Cytofluorimetric analysis showed a decrease of CD19+ peripheral blood cells, with the nadir at month 3 after therapy and B cell compartment reconstitution after 6 months. This study, for the first time showed that RTX-treatment in HCV-related MC induces a reduction of liver stiffness that is strictly associated with the B-cell depletion.
    Journal of Translational Medicine 01/2014; 12(1):21. DOI:10.1186/1479-5876-12-21 · 3.93 Impact Factor
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    • "The safety of RTX was confirmed by the small number of side effects recorded during the 6-month follow-up. According to these results, RTX may be regarded as a useful and safe pathogenetic treatment of cryoglobulinemic vasculitis.59,60 From analysis of these and other published studies, RTX appears a very powerful tool for the treatment of small-vessel vasculitides. "
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    ABSTRACT: Vasculitis syndromes are relative rare conditions but can cause significant mortality and morbidity if not treated adequately. Recent advances in immunosuppressant therapy have radically changed the course of these diseases. However, the standard therapy is not always well tolerated by patients, and some cases are refractory to treatment. New therapeutic possibilities have emerged with the use of so-called "biologics," a new class of genetically engineered drugs used for inflammatory rheumatic diseases, including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. In the present review, summarized are the most recent data on the efficacy and safety of biologics in the treatment of vasculitis syndromes that cannot be treated with standard therapy.
    Biologics: Targets & Therapy 10/2012; 6:371-8. DOI:10.2147/BTT.S37537
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