In Reply to ‘Rituximab and B-Cell Return in ANCA-Associated Vasculitis’

Abstract

We appreciate the constructive comments of Wilde et al1Wilde B. Witzke O. Cohen Tervaert J.W. Rituximab and B-cell return in ANCA-associated vasculitis.Am J Kidney Dis. 2014; 63 (1066)Google Scholar on our review.2Kallenberg C.G. Stegeman C.A. Abdulahad W.H. Heeringa P. Pathogenesis of ANCA-associated vasculitis: new possibilities for intervention.Am J Kidney Dis. 2013; 62: 1176-1187Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar In their letter, the authors propose that analyzing the cytokine profile of regulatory (IL-10+) and effector (IL-6+/TNF-α+) B cells that return after rituximab treatment is a useful method to predict disease relapse. Although we support this type of analysis in general, we also acknowledge that this approach has certain limitations. As is well known, the cytokine profile of B cells is identified indirectly following ex vivo exposure to oligonucleotides containing the immunostimulatory CpG motif for 66 hours, with restimulation by phorbol 12-myristate 13-acetate/ionomycin for another 4 hours. Wilde et al3Wilde B. Thewissen M. Damoiseaux J. et al.Regulatory B cells in ANCA-associated vasculitis.Ann Rheum Dis. 2013; 72: 1416-1419Crossref PubMed Scopus (94) Google Scholar analyzed regulatory B cells in ANCA-associated vasculitis (AAV) in this way. However, this type of analysis requires a large amount of B cells, which is not available in most cases following B-cell depletion caused by rituximab. In addition, ex vivo stimulation may change the normal distribution of B-cell subsets, which may lead to a flawed conclusion. In this regard, Bunch et al4Bunch D.O. McGregor J.G. Khandoobhai N.B. et al.Decreased CD5+ B cells in active ANCA vasculitis and relapse after rituximab.Clin J Am Soc Nephrol. 2013; 8: 382-391Crossref PubMed Scopus (73) Google Scholar recently have noted that declining percentages of CD5+ B cells after rituximab treatment were associated with a shorter time to disease relapse in patients with AAV. These CD5+ B cells were noted to be IL-10–producing regulatory cells.5Gary-Gouy H. Harriague J. Bismuth G. et al.Human CD5 promotes B-cell survival through stimulation of autocrine IL-10 production.Blood. 2002; 100: 4537-4543Crossref PubMed Scopus (164) Google Scholar, 6Blair P.A. Noreña L.Y. Flores-Borja F. et al.CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients.Immunity. 2010; 32: 129-140Abstract Full Text Full Text PDF PubMed Scopus (1191) Google Scholar The practical approach of determining CD5+ B cells following rituximab treatment seems to be more efficient than ex vivo culturing of B cells followed by intracellular cytokine detection because CD5 is a surface marker and no stimulation is required for quantifying these B-cell subsets. Therefore, determination of the percentage of CD5+ B cells following rituximab treatment might be a more practical indicator of disease activity, remission, and future relapse in AAV. Financial Disclosure: The authors declare that they have no relevant financial interests. Rituximab and B-Cell Return in ANCA-Associated VasculitisAmerican Journal of Kidney DiseasesVol. 63Issue 6PreviewNew insights into the pathogenesis of autoimmune diseases have implications for therapy.1 One such new therapeutic approach is the use of B-cell–depleting therapy, as discussed by Kallenberg et al.1 In ANCA-associated vasculitis (AAV), rituximab has been found to be beneficial.2 However, in the RAVE (Rituximab in ANCA-Associated Vasculitis) trial, one-third of the patients (n=24) treated with rituximab experienced a relapse within the first 18 months of remission.2 The relapse was preceded by B-cell return in 21 of 24 patients. Full-Text PDF