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.

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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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    ABSTRACT: . The treatment of systemic sclerosis (SSc) represents a great clinical challenge because of the complex disease pathogenesis including vascular, fibrotic, and immune T- and B-lymphocyte-mediated alterations. Therefore, SSc should be treated by combined or sequential therapies according to prevalent clinico-pathogenetic phenotypes. Some preliminary data suggest that rituximab (RTX) may downregulate the B-cell over expression and correlated immunological abnormalities. . Here, we describe a series of 10 SSc patients (4 M and 6 F, mean age 46±13.5SD years, mean disease duration 6.3±2.7SD years; 5 pts had limited and 5 diffuse SSc cutaneous subset) treated with one or more cycles of RTX (4 weekly infusions of 375 mg/m2). The main indications to RTX were interstitial lung fibrosis, cutaneous, and/or articular manifestations unresponsive to previous therapies; ongoing treatments remained unchanged in all cases. The effects of RTX were evaluated after 6 months of the first cycle and at the end of long-term follow-up period (37±21SD months, range 18-72 months). An updated review of the world literature was also done. . RTX significantly improved the extent of skin sclerosis in patients cwith diffuse SSc at 6 months evaluation (modified Rodnan skin score from 25±4.3 to 17.2±4.6; p =.022). A clinical improvement of other cutaneous manifestations, namely hypermelanosis (7/7), pruritus (6/8), and calcinosis (3/6) was observed. Moreover, arthritis revealed particularly responsive to RTX showing a clear-cut reduction of swollen and tender joints in 7/8 patients; while lung fibrosis detected in 8/10 remained stable in 6/8 and worsened in 2/8 at the end of follow-up. Pro-inflammatory cytokines, namely IL6, IL15, IL17, and IL23, evaluated in 3 patients with diffuse cutaneous SSc, showed a more or less pronounced reduction after the first RTX cycle. These observations are in keeping with the majority of previous studies including 6 single case reports and 10 SSc series (from 5 to 43 pts), which frequently reported the beneficial effects of RTX on some SSc manifestations, particularly cutaneous sclerosis, along with the improvement/stabilization of lung fibrosis. Possible discrepancies among different clinical studies can be related to the etiopathogenetic complexity of SSc and not secondarily to the patients' selection and disease duration at the time of the study. . The present study and previous clinical trials suggest a possible therapeutical role of RTX in SSc, along with its good safety profile. The specific activity of RTX on B-cell-driven autoimmunity might explain its beneficial effects on some particular SSc clinical symptoms, namely the improvement of skin and articular involvement, and possibly the attenuation of lung fibrosis. Copyright © 2015. Published by Elsevier B.V.
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    • "Given the intricate link between mixed cryoglobulinemia and aberrant B lymphocyte antibody production, proliferation, and elimination, the anti-CD20 monoclonal antibody, Rituximab, has been frequently used to control disease. A variety of small reports have demonstrated clinical efficacy in the setting of moderate disease and have highlighted that relapses recur in the setting of B lymphocyte recovery[13,21,47,48]. The patient presented in this report received successful Rituximab therapy that led to a complete elimination of peripheral CD20+ B lymphocytes, as verified by flow cytometry. "

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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.
    Full-text · Article · Jan 2014 · Journal of Translational Medicine
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