ARTHRITIS & RHEUMATISM Vol. 62, No. 3, March 2010, pp 908–910 © 2010, American College of Rheumatology LETTERS DOI 10.1002/art.27310 Rituximab monotherapy, rather than rituximab plus antiviral drugs, for initial treatment of severe hepatitis C virus–associated mixed cryoglobulinemia syndrome: comment on the article by Terrier et al To the Editor: We read with interest the recent article by Terrier et al (1) in which the authors report on the long-term followup of patients with severe hepatitis C virus–associated mixed cryo- globulinemia (HCV-MC) syndrome who were treated with rituximab, with or without concomitant antiviral therapy. In our opinion, the relevance of the 2 key points of the article should be better dissected. While the reported followup data may offer support for the efficacy and safety of long-term rituximab therapy, any preferential use of the combination regimen in HCV-related vasculitis, as proposed by Terrier et al, is probably premature at this time. A combination regimen may attack the chronic infectious and autoimmune disorder with synergistic effects and surely deserves investigation (1,2), but adequate studies are still needed. Since the same group has previously excluded rituximab monotherapy in therapeutic flow-charts for MC (3), we will focus on this issue. The study by Terrier and colleagues was a retrospec- tive nonrandomized study comparing rituximab monotherapy with combination therapy (1). The patients in the 2 groups were quite heterogeneous with regard to both previous history and clinical involvement, and in the study, skin and articular manifestations were a criterion for response to treatment but not a criterion for study inclusion. Furthermore, the authors state that one-half of the patients treated with rituximab alone were unresponsive to previous antiviral therapies, while also stating that rituximab alone was used for patients for whom antiviral therapy was contraindicated or in whom tolerance to antiviral therapy was poor. It is conceivable that patients never treated before with antiviral therapy may better respond to rituximab plus antiviral therapy than to rituximab alone in larger studies. However, this raises the main question (2) of whether it is better to start directly with combination therapy or with monotherapy (presumably, rituximab) in severe HCV-MC (more data are needed for “HCV-related vasculitis,” with 3 patients in the study by Terrier et al lacking cryoglobulins [1]). The combination regimen, even as employed by Terrier and colleagues (i.e., with antiviral therapy started 1 month after rituximab), does not sufficiently distinguish between the effi- cacy and safety of the antiviral therapy versus the B cell depletive treatment. Response to and side effects of either therapy may occur later and should be differentiated as early as possible, while also considering subsequent, very long-term treatment decisions. Whether the benefits of combination therapy outweigh the problems with differential identification of responses/side effects in severe cases deserves further investigation. Rituximab monotherapy alone may be similarly effective but more convenient as initial therapy, and antiviral therapy may be introduced later, once the efficacy and safety of rituximab have been better evaluated. This usually takes at least 4–6 months. (We are using antiviral therapy, in such a sequential schedule, 6 months after rituximab.) Combination therapy from the beginning might indeed be more convenient in subsets of MC, but such subsets have to be defined. Second, a small number of cases of HCV-MC that arise are resistant to effective antiviral therapy, which can lead to HCV RNA negativization (4), supporting the concept that autoimmune-related events are not driven by chronic infection in some patients (2) (Figure 1). Even in a phase of the disease that is dependent on both the infectious trigger and down- stream B cell hyperactivation, however, a monotherapy di- rected at only 1 of the 2 pathogenetic components may be sufficient and safer (2) (Figure 1). Randomized trials and laboratory research are needed to better clarify these issues. A multicenter, randomized, long-term controlled trial comparing rituximab monotherapy versus conventional treatment in patients with MC that is either unresponsive to or with contraindications to antiviral therapy has been recently concluded (De Vita S: personal communication). Better recommendations for rituximab monotherapy in MC are awaited. Dr. De Vita has received consulting fees, speaking fess, and/or honoraria from Roche (less than $10,000). Salvatore De Vita, MD Luca Quartuccio, MD University of Udine Udine, Italy 1. Terrier B, Saadoun D, Sene D, Sellam J, Perard L, Coppere B, et al. Efficacy and tolerability of rituximab with or without PEGylated interferon alfa-2b plus ribavirin in severe hepatitis C virus–related Figure 1. Targeting hepatitis C virus (HCV), autoimmunity, or both in mixed cryoglobulinemia syndrome. Infection and autoreactivity may play one role in sustaining B cell autoimmunity or autoimmune disease and a different role in B cell expansion. There may be a strong rationale for using monotherapy against HCV or against downstream biologic events, or for using a combination therapy, and they all may be useful in a single case at different stages of disease. 908