Systemic Diseases

Abstract

Mixed cryoglobulinemia (MC) is a systemic vasculitis that affects small- and medium-sized vessels. Renal involvement is considered a major cause of morbidity and mortality (1). Hepatitis C virus (HCV) infection is detected in more than 90% of patients with MC. The treatment therefore has two targets: to induce a sustained virologic response (SVR) and to control the downstream B cell clonal expansion producing a pathogenic IgM with rheumatoid factor activity. Targeting only one of these goals leads to short-lived or incomplete responses. Thus, Saadoun et al. have designed a prospective cohort study to compare the effects of antiviral therapy alone (control group) with those of antiviral combined with rituximab (RTX), a chimeric anti-CD20 monoclonal antibody (called subsequently RTX group). The therapeutic schedule was four weekly intravenous infusions of RTX during the first month, each at 375 mg/m2 in most patients, followed in month 2 by antiviral combination with Peg-IFN-α/ribavirin for 48 weeks, whatever the HCV genotype. The mode of distribution between both groups is not clearly indicated by the authors. Inclusion criteria were chronic active HCV infection, signs of MC vasculitis, and a minimum of 6 months of follow-up after discontinuing any treatment. Patients with hepatitis B surface antigen or anti-HIV antibodies were excluded. Ninety-three HCV-MC patients with a median age of 60 years were included. Main clinical features of MC included polyneuropathy (72%), purpura (66.6%), and kidney involvement (33.3%). Thirteen patients had B cell non-Hodgkin lymphoma. Forty-two patients were naïve to antiviral therapy, whereas the remaining 51 were resistant to a previous antiviral treatment. Characteristics of the patients were rather similar in both groups; the most striking difference was the presence of kidney involvement: 18.2% in the control group and 55% in the RTX group. The virologic response did not differ between the two groups: SVR was achieved in approximately 60% of the patients. Severe liver fibrosis was independently associated with viral persistence. Petrarca et al. have reported safety and efficacy of RTX in 19 patients with HCV-MC and severe liver disease (15 had liver cirrhosis, with ascitic decompensation in 6 patients) (2). A clinical response was obtained in approximately 73% of patients in both groups. However, the time to clinical remission was shorter in the RTX group: 5.4 months versus 8.4 months (P < 0.004). Unsurprisingly the immunologic response rate was higher in the RTX group. B cell depletion in the peripheral blood was achieved in all patients except one in the RTX group. Seventeen patients (18%) experienced a clinical relapse, equally distributed in the two groups and associated with immunologic and virologic relapses. After retreatment, most patients in both groups developed complete clinical responses. The overall median follow-up was 48 months. Five patients died (5.4%). No difference in survival was noted between the two groups. Treatment interruptions occurred in 11% of patients and were equally distributed between the two groups. Serum sickness was the most common benign adverse effect in the RTX group. However, Sene et al. have reported a severe flare-up of MC and serum sickness-like syndrome under RTX, especially in patients with high levels of serum cryoglobulin (3). The most striking difference between both therapeutic groups deals with the renal response. The rate of complete remission was much higher in the RTX group: 81% versus 40%. In the 21 patients with renal disease in the RTX group, proteinuria decreased from 3.5 to 0.35 g/d, and serum creatinine diminished from 217.5 to 137 μmol/L (whereas it increased from 150 to 169 μmol/L in the other group). No renal histopathological data are available. The combination of RTX and Peg-INF-α/ribavirin may be the first choice treatment of HCV-MC patients with kidney involvement (i.e., membranoproliferative GN). The value of RTX in HCV-MC patients is confirmed by the prospective randomized study of Dammacco et al. published in the same issue of Blood (4). It included only 22 patients. The therapeutic protocol was slightly different: four intravenous RTX infusions were performed initially, concomitantly with initiation of Peg-INF-α/ribavirin, and two additional RTX infusions were added on months 6 and 11. In the control group, only antiviral treatment was prescribed. The percentage of patients with kidney involvement was lower (22.7%) than in the study by Saadoun et al. Thus, only five and four patients had renal disease in the two groups, respectively. The renal response was similar, but no conclusion can be drawn from such a small sample of patients. Complete response of HCV-MC was achieved in 54.5% of patients in the RTX group versus 33.3% in the other. The beneficial effect of therapy may last for more than 3 years (4).