(3): 283 Annals of the Rheumatic Diseases Author Keyword(s) Vol Page Published Online First: 20 July 2007.2006.Of the Rheumatic Diseases_ 2008;67:283-287 Copyright 2008 BMJ Publishing Group Ltd AP-HP, Hpital Piti-Salptrire, Service de Mdecine Interne, Paris, France Correspondence to: Professor P Cacoub, AP-HP, Hpital Piti-Salptrire, Service de Mdecine Interne, Paris, F-75013 France; patrice.Accepted 28 June 2007 ABSTRACT Mixed cryoglobulinemia (MC) vasculitis represents aplication of the B cell response to a variety of chronic inflammatory diseases.Reports describe the use of monoclonal antibodies directed to CD20 antigen (rituximab), a transmembrane protein expressed on pre-B lymphocytes and mature lymphocytes.Goal of this article is therefore to review published data in order to better analyse the efficacy and tolerance of rituximab treatment in patients with MC vasculitis.Systematic review of the literature and exclusion of review papers, 13 manuscripts were identified that reported on a total number of 57 cases of MC secondary to hepatitis C virus (HCV) infection (75.Mixed cryoglobulinemia (24.Previous treatments failed to control the main signs of vasculitis; these were either HCV (n = 37) or immunomodulating treatments.Patients (48 out of 57) received four weekly consecutive intravenous infusions of 375 mg/m2 of rituximab.Duration of follow-up after rituximab therapy was 9.Rituximab infusions had great efficacy on the main vasculitis signs, with a clinical response in 80-93% patients.Relapse of MC was noted in 14 out of 36 (39%) patients.Relatively small number of side effects were reported.Conclude that rituximab therapy for patients with mixed cryoglobulinemia vasculitis, HCV-induced or essential, shows great efficacy on the main vasculitis signs in the majority of reported patients.Relapse of cryoglobulinemia vasculitis was frequently noted.Controlled trials with long-term study are needed to form definitive conclusions on the benefit/risk ratio of rituximab therapy in such patients.Mixed cryoglobulinemia (MC) is a systemic vasculitis characterised by the proliferation of B-cell clones producing pathogenic IgM with rheumatoid factor activity.To clinical manifestations ranging from MC syndrome (purpura, arthralgia, asthenia) to more serious lesions with neurological and renal involvement.Since 1990, it has been established that hepatitis C virus (HCV) infection is associated with most cases of MC.The one hand, 60-90% of patients with MC are HCV-infected.The other, 36-55% of HCV-infected patients have a positive mixed cryoglobulin.To 15-20% of HCV-MC patients will present a MC-associated systemic vasculitis that may be severe enough to cause death.Limited data are available regarding the treatment of patients with MC systemic vasculitis.Patients with HCV infection, interferon (IFN)- monotherapy is associated with a relatively poor response and a high relapse rate, especially in severe cases.Thebination of pegylated IFN (peg-IFN ) with ribavirin, which is the current standard for the treatment of patients with chronic HCV infection, has shown better efficacy, with up to 77% of patients showingplete remission.Poor tolerability (in many cases) of conventional anti-HCV therapy, including flu-like symptoms, lends further importance to the development of additional therapeutic approaches.Of corticosteroids, cyclophosphamide, and plasmapheresis, both in HCV-MC patients with no response or intolerance to HCV treatment and in patients with non-HCV MC, may lead to life-threatening RESULTS Overall, 13 manuscripts reported on a total number of 57 cases that were analysed in detail for the present study.Were two large uncontrolled series of 20 and 15 patients, and two smaller series of 6 and 5 patients.Other publications reported either single or two case reports.The baseline characteristics of patients with cryoglobulinemia vasculitis who received anti-CD20 antibody (rituximab) treatment are summarised in .Total of 57 patients, mainly of female gender (79%) with a mean age of 59 years, had cryoglobulinemia vasculitis secondary to chronic active HCV infection (75.Essential mixed cryoglobulinemia (24.Previous treatments failed to control the main signs of vasculitis; these were either HCV treatment (n = 37) or immunomodulating treatments (corticosteroids, immunosuppressive drugs, plasma exchanges).Main clinical manifestations of cryoglobulinemia vasculitis were skin involvement (84.(61.Neuropathy (54.Glomerulonephritis (31.VIEW THIS TABLE: TABLE 1 Main baseline characteristics of patients with cryoglobulinemia vasculitis who received anti-CD20 antibody (rituximab) treatment The main indication for rituximab therapy was non-responsiveness to other previous treatments (n = 50), intolerance to previous treatments (n = 3), associated lymphoma (n = 2), or first-line therapy for cryoglobulinemia vasculitis (n = 2).Patients (48 out of 57) received four weekly consecutive intravenous infusions of 375 mg/m2 of rituximab.Other cases (9 out of 57), however, the rituximab treatment protocol was different.The Rocatello _et al_ series, five out of six patients received four weekly consecutive intravenous infusions of 375 mg/m2 of rituximab followed by two more infusions at months 1 and 2.The patient reported by Ghobrial _et al_, who also had Waldenstrm disease, eight weekly consecutive intravenous infusions of 375 mg/m2 of rituximab were given.The case reported by Koukoulaki _et al_, the patient received four weekly consecutive intravenous infusions of 375 mg/m2 of rituximab, followed by two 1 g infusions at months 4 and 4.In the case reported by Lamprecht _et al_, 500 mg of rituximab was given every 3 weeks for a total of six infusions.Patient of Ghijsels _et al_ received four weekly consecutive intravenous infusions of 375 mg/m2 of rituximab, followed by a second series of four courses of rituximab at the same dosage 2 months later.The mean duration of follow-up after rituximab therapy was 9.To 24).Evolution of the cryoglobulinemia vasculitis features after rituximab infusions are given in .Infusions had great efficacy on the main vasculitis signs, with a clinical response (partial +plete/total) in 32 out of 40 (80%) patients for skin involvement, 27 out of 34 (79.27 out of 29 (93.Neuropathy, and 15 out of 18 (83.However, a relapse of cryoglobulinemia vasculitis was noted in 14 out of 36 (39%) patients (13 HCV-infected, 1 HCV negative) within a few days to 19 months (mean 6.After the last rituximab infusion.Of the 14 relapse patients hadplete remission after a second course of rituximab.Plus follow up HCV viral load was available in only five reported patients, whereas in the large study of Sansonno the mean HCV viral load increased at month 6 and month 12.Was no significant difference in the efficacy of rituximab therapy when patients presented with HCV-induced or essential cryoglobulinemia vasculitis ().VIEW THIS TABLE: TABLE 2 Main course of cryoglobulinemia vasculitis features after anti-CD20 antibody (rituximab) infusion VIEW THIS TABLE: TABLE 3 Main course of cryoglobulinemia vasculitis features after anti-CD20 antibody (rituximab) infusion in patients with or without HCV infection A relatively small number of side effects were reported.The short term follow-up they included: bradycardia (3), hypotension (2), infection (in three renal transplant patients), mild alanine aminotransferase (ALT) elevation (3), retinal arterial thrombosis (1), panniculitis of elbows and knees (1), and serum sickness (1).Were reported; one occurred 12 months after rituximab infusion in an HCV-infected patient with renal insufficiency, and the second occurred 2 months after rituximab infusion in an HCV-negative renal transplant patient due to Cryptococcus neoformans meningoencephalitis.Long-term follow-up (>12 months), there were two cases of lymphoma and one of breast cancer.DISCUSSION Although this literature review does not allow a definite conclusion to be drawn regarding the role of rituximab in the therapeutic options of patients presenting with cryoglobulinemia vasculitis, it gives important information concerning its efficacy and short-term tolerance.We analysed the efficacy, aplete response was reported in one-third to two-thirds of patients, depending on the main targeted organ (skin, nerve, kidney, joint).Partial responses were noted in 80-93% of reported patients.Results are encouraging considering that most patients presented with a very severe form of systemic cryoglobulinemia vasculitis that was resistant or intolerant to other previous treatments.A disease remains life threatening, with a mortality rate ranging from 15-20% in HCV-MC patients and up to 50% in non-HCV-MC patients.Main predictors of poor oue are older age and renal insufficiency (present in one-third of the cases treated with rituximab).Most reported cases (75%) were secondary to HCV infection.Has been some debate about the best therapeutic management of HCV MC patients (ie, anti-HCV, immunomodulating drugs or both).Is noteworthy that in one of the two large open studies using rituximab, HCV MC patients were described as "non-responders or intolerant to interferon monotherapy".Treatment, however, is known to have a poor response on the main symptoms of cryoglobulinemia vasculitis (ie, less than 10% except for purpuric skin lesions).This poor efficacy is related to the low percentage (less than 15%) of long term sustained viral clearance.Recent data with the best available HCV treatment (peg-IFN plus ribavirin), which results in a sustained viral clearance in up to 55% of patients, showed much better responses, with aplete clinical response of cryoglobulinemia vasculitis in up to 77% of patients.The poor tolerability of HCV therapy often leads to decrease the doses or duration of treatment with lower clinical and virological responses.Rituximab, a clinical response was noted in two-thirds of patients, but 39% of them developed a relapse after a mean delay of 6.In this setting, rituximab cannot be seen as a curative treatment as long as the viral antigenic trigger of the vasculitis remains.Sequential treatment strategy may therefore give better results.Would begin with rituximab to block the B-cell activation and the TH1 cytokine-chemokine cascade involved in the inflammatory part of vasculitis, and be followed by anti-HCV treatment with peg-IFN plus ribavirin to clear the antigenic trigger and block the causative agent.A strategy may also allow major side effects due to conventional treatments such as corticosteroids, immunosuppressive drugs and plasma exchanges to be obviated.Due to the very small number of patients with non-HCV systemic cryoglobulinemia vasculitis, it is difficult toe to a clear conclusion in this setting, although rituximab therapy seems to have similar efficacy on the main involved organs ().Form of the disease is close to non-Hodgkins lymphoma and may also be sensitive to CD20 blockade.Limitations due to HCV disease (viremia) will be absent, suggesting that autoimmune-disease-associated MC would be the perfect situation to use rituximab.The safety of rituximab monotherapy has been well established in patients with non-Hodgkins lymphoma, with the main adverse events being mild to moderate infusion-related reactions occurring after the first infusion.Database of patients having received rituximab in clinical trials and/or clinical practice now includes almost 750 000 patients, making rituximab the only antibody in this setting to have such an extensive safety analysis.Therefore, we were not surprised at the small number of side effects reported in patients with cryoglobulinemia vasculitis.Caution is still warranted in this latter indication for the following reasons: no control trial was available, all data came from only small series or case reports, most cases reported on short-term follow-up, and in a large number of cases there was insufficient data to analyse, particularly regarding the course of HCV viral load and liver enzymes.Assessment of the long-term effects of prolonged B-cell depletion is still required.We acknowledge some limitations to our analysis.There is a potential role that negative publication bias may play in the currently favourable view of rituximab therapy for MC in the literature.Studies employing rituximab do not indicate what types of glucocorticoid regimens were used coitantly with the rituximab.Gives the potentially misleading impression that rituximab alone might have been responsible for the beneficial effects reported.Of the two series, the remaining reports are small, and different with regards to patient population, rituximab regimen, oue definitions, and use of concurrent therapies.Published cases reported on short or mid term follow up, and we need to know on the long-term effects of prolonged B-cell depletion.CONCLUSION Rituximab therapy for patients with mixed cryoglobulinemia vasculitis, HCV-induced or essential, shows a great efficacy on the main vasculitis signs in the majority of reported patients.Relapse of cryoglobulinemia vasculitis was frequently noted.Controlled trials with long-term study are necessary to conclude definitively on the benefit/risk ratio of rituximab therapy in such patients.FOOTNOTES PETING INTERESTS: None declared.ONLINE FIRST 20 JULY 2007 REFERENCES Gorevic PD, Kassab HJ, Levo Y, Kohn R, Meltzer M, Prose P, _et al_.Clinical aspects and long-term follow-up of 40 patients.J Med_ 1980; 69: 287-308.JC, Clauvel JP, Danon F, Klein M, Seligmann M.Clinical significance of cryoglobulins.Report of 86 cases.J Med_ 1974; 57: 775-88.P, Poynard T, Ghillani P, Charlotte F, Olivi M, Piette JC, _et al_.Manifestations of chronic hepatitis C.Group.Virus C.Rheum_ 1999; 42: 2204-12.D, Limal N, Cacoub P.C virus-associated extrahepatic manifestations: a review.Brain Dis_ 2004; 19: 357-81.R, Bellavita P, Fenili D, Vicari O, Marchesi D, Sironi PL, _et al_.Alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus.Engl J Med_ 1994; 330: 751-6.P, Saadoun D, Sene D, Limal N, Piette JC.Of hepatitis C virus-related systemic vasculitis.2005; 32: 2078-82.P, Saadoun D, Limal N, Sene D, Lidove O, Piette JC.Alpha-2b and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis.2005; 52: 911-5.F, Russo D, Fuga G, Patriarca F, Ermacora A, Baccarani M.The treatment of type II mixed cryoglobulinemia.84: 1157-8.F, De Vita S, Russo D, Michelutti A, Fanin R, Ferraccioli G, _et al_.For the treatment of type II mixed cryoglobulinemia.Rheum_ 2002; 46: 2252-4.K, Sadeghi S, Liebman HA.Of refractory antibody mediated autoimmune disorders with an anti-CD20 monoclonal antibody (rituximab).Rheum Dis_ 2002; 61: 922-4.F, De Vita S, Mazzaro C, Sacco S, Damiani D, De Marchi G, _et al_.And safety of rituximab in type II mixed cryoglobulinemia.2003; 101: 3827-34.D, De Re V, Lauletta G, Tucci FA, Boiocchi M, Dammacco F.Treatment of mixed cryoglobulinemia resistant to interferon alpha with an anti-CD20.2003; 101: 3818-26.D, Baldovino S, Rossi D, Mansouri M, Naretto C, Gennaro M, _et al_.Effects of anti-CD20 monoclonal antibody treatment of cryoglobulinaemic glomerulonephritis.Dial Transplant_ 2004; 19: 3054-61.P, Lerin-Lozano C, Merz H, Dennin RH, Gause A, Voswinkel J, _et al_.Induces remission in refractory HCV associated cryoglobulinaemic vasculitis.Rheum Dis_ 2003; 62: 1230-3.IM, Uslan DZ, Call TG, Witzig TE, Gertz MA.Increase in the cryoglobulin level after rituximab therapy for type II cryoglobulinemia secondary to Waldenstrom macroglobulinemia does not indicate failure of response.J Hematol_ 2004; 77: 329-30.E, Lerut E, Vanrenterghem Y, Kuypers D.Monoclonal antibody (rituximab) treatment for hepatitis C-negative therapy-resistant essential mixed cryoglobulinemia with renal and cardiac failure.J Kidney Dis_ 2004; 43: e34-8.Rezai S, Priori R, Magrini L, Valesini G.Sickness associated with rituximab in a patient with hepatitis C virus-related mixed cryoglobulinaemia.(Oxford)_ 2005; 44: 406.G, Ribes D, Kamar N, Mehrenberger M, Esposito L, Guitard J, _et al_.For de novo mixed cryoglobulinemia in renal transplant patients.2005; 80: 1560-4.M, Abeygunasekara SC, Smith KG, Jayne DR.Of refractory hepatitis C-negative cryoglobulinaemic vasculitis after rituximab and infliximab.Dial Transplant_ 2005; 20: 213-6.H, Korganow AS, Pasquali JL, Martin T.Inefficiency during type I cryoglobulinaemia.(Oxford)_ 2005; 44: 410-1.Soardo G, Romano G, Zaja F, Scott CA, De Marchi G, _et al_.Treatment for glomerulonephritis in HCV-associated mixed cryoglobulinaemia: efficacy and safety in the absence of steroids.(Oxford)_ 2006; 45: 842-6.FZ, Ahern M, Smith M.Of cryoglobulinemia associated peripheral neuropathy with rituximab.Rheumatol_ 2006; 33: 1197-8.D, Bieche I, Maisonobe T, Asselah T, Laurendeau I, Piette JC, _et al_.Chemokines and type 1 cytokines in the pathogenesis of hepatitis C virus-associated mixed cryoglobulinemia vasculitis neuropathy.Rheum_ 2005; 52: 2917-25.M, Rufibach K, Salles G, Leoncini-Franscini L, Leger-Falandry C, Cogliatti S, _et al_.Agent rituximab in patients with follicular or mantle cell lymphoma: clinical and biological factors that are predictive of response and event-free survival as well as the effect of rituximab on the immune system: a study of the Swiss Group for Clinical Cancer Research (SAKK).Oncol_ 2005; 16: 1675-82.P.Intensive insulin therapy protects kidneys in critically ill patients
Rifampicin induces mdr1 expression in candida albicans
