Treatment with rituximab in patients with mixed cryoglobulinemia syndrome: Results of multicenter cohort study and review of the literature
ABSTRACT 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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ABSTRACT: Cryoglobulinemic vasculitis (CV) involving small- and medium-sized vessels is very frequently associated with hepatitis C virus and may be responsible for multiple organ involvement and skin ulcers (SU). Skin ulcers are often non-healing cutaneous lesions, possibly complicated by local infection and gangrene; they may severely affect the patients׳ quality of life and the overall prognosis. Therefore, the treatment of cryoglobulinemic SU is particularly challenging in the clinical practice. The present work evaluated the prevalence and correlations of cryoglobulinemic SU with other clinico-epidemiological features of CV; moreover, our long-term experience with the management strategies of these cutaneous lesions was compared with the world literature on this topic. The study included 126 CV patients (24 male and 102 female, aged 69 ± 11.2 SD years, disease duration 7 ± 6.9 SD years), followed at our Rheumatology Unit during the past decade. All patients were carefully evaluated regarding the entire cryoglobulinemic syndrome with particular concern for clinical characteristics and treatment of SU. Among 126 CV patients, 36 individuals (29%) experienced at least one episode of SU, more commonly localized at the lower limbs. Patients with complicating SU showed significantly higher percentage of purpuric manifestations (p < 0.01) and liver (p < 0.001), peripheral nerve (p < 0.02), and/or thyroid involvement (p = 0.019). Therapeutic approach to SU included both systemic (immunosuppressors, corticosteroids, and/or plasma exchange) and local treatments. Local treatments consisted of sharp or surgical debridement as well as interactive dressing according to the condition of wound bed, perilesional skin, and the possible presence of infection, detected in 29 of 36 (81%) individuals in our Rheumatology unit. All patients underwent analgesic treatment for SU-related background pain as well as procedural pain, which was critical for an effective local SU management. The large majority of patients with SU healed at a variable time interval according to the severity of the single lesion; only five patients with very severe, non-healing SU needed amputation. The updated review of the literature revealed the presence of SU in around a quarter of CV patients. Among systemic treatments, the anti-CD20 monoclonal antibody rituximab represents one of the most effective and frequently employed therapies; however, the available data focusing on local therapeutic approach are generally limited to anecdotal observations. Overall, the treatment of cryoglobulinemic SU should be tailored to the single patient׳s conditions using combined systemic and local treatments; lesional sharp debridement and interactive dressing as well as procedural pain management were decisive, particularly for more severe, non-healing cutaneous lesions. Copyright © 2014 Elsevier Inc. All rights reserved.Seminars in Arthritis and Rheumatism 10/2014; 44(5). DOI:10.1016/j.semarthrit.2014.10.004 · 3.63 Impact Factor
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ABSTRACT: HCV chronic infection is characterized by possible development of both hepatic and extrahepatic manifestations. The infection by this both hepatotropic and lymphotropic virus is responsible for polyoligoclonal B-lymphocyte expansion, leading to several immune-mediated disorders. Mixed cryoglobulinemia syndrome that in some cases may evolve to frank B-cell non-Hodgkin's lymphoma is the prototype of HCV-driven autoimmune and lymphoproliferative disorders. The HCV oncogenic potential has been suggested by several clinicoepidemiological and laboratory studies; it includes hepatocellular carcinoma, B-cell non-Hodgkin's lymphoma and papillary thyroid cancer. The definition HCV syndrome refers to the complex of HCV-driven diseases; these latter are characterized by heterogeneous geographical distribution, suggesting a role of other important genetic and/or environmental cofactors. The natural history of HCV syndrome is the result of a multifactorial and multistep pathogenetic process, which may evolve from mild manifestations to systemic autoimmune disorders, and less frequently to malignant neoplasias. The present updated review analyzes the clinical and pathogenetic aspects of the main HCV-associated diseases.Expert Review of Clinical Immunology 01/2015; 11(1):15-31. DOI:10.1586/1744666X.2015.997214 · 3.34 Impact Factor
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ABSTRACT: Rituximab is approved for the treatment of granulomatosis with polyangiitis and microscopic polyangiitis. Our objective was to review published clinical evidence on the efficacy of rituximab in the treatment of eosinophilic granulomatosis and polyangiitis (EGPA). We describe a case of refractory EGPA with severe vasculitic neuropathy, which responded impressively to B-cell-depleting therapy. A systematic search of the English literature was also performed to capture all available clinical evidence on the use of rituximab in EGPA. We identified a total of 73 EGPA patients who have been treated with rituximab, all data coming from case series or isolated case reports. The majority of patients (85.1%) were treated for refractory or relapsing disease; a mean (SD) of 2.1 (0.9) different immunosuppressive agents were used prior to rituximab administration. Efficacy of RTX therapy was significant in the majority of cases and in a wide variety of disease manifestations; however, a lack of standardized assessment of disease activity before and after treatment was observed in many reports. Overall, 54.0% of patients were treated with a single cycle of rituximab and only 10.8% experienced relapses of the disease. Few significant side effects were observed during a highly variable period of follow-up (3 months to 5 years), mainly severe infections and allergic reactions. RTX seems to be effective in cases of severe EGPA refractory to standard of care immunosuppressive treatment, although support comes from case reports and non-controlled studies. Copyright © 2015 Elsevier Inc. All rights reserved.Seminars in arthritis and rheumatism 03/2015; DOI:10.1016/j.semarthrit.2015.03.004 · 3.63 Impact Factor