ARTHRITIS & RHEUMATISM Vol. 46, No. 8, August 2002, pp 2029–2033 DOI 10.1002/art.10467 © 2002, American College of Rheumatology Efficacy of Selective B Cell Blockade in the Treatment of Rheumatoid Arthritis Evidence for a Pathogenetic Role of B Cells Salvatore De Vita, Francesco Zaja, Stefania Sacco, Alessandro De Candia, Renato Fanin, and Gianfranco Ferraccioli Objective. The pathogenetic role of B cells in rheumatoid arthritis (RA) is under debate, but it is currently believed to be marginal. The availability of selective anti–B cell treatment provides a unique oppor- tunity to clarify this issue. This study was undertaken to investigate the effects of B cell blockade in the treatment of refractory RA, and to evaluate the implications with regard to the role of B cells in the disease. Methods. Five female patients with active, evolv- ing erosive RA were treated with rituximab, an anti- CD20 chimeric monoclonal antibody. All 5 patients had been nonresponders to combination therapy with meth- otrexate plus cyclosporin A. Two of the 5 had also failed to respond to anti–tumor necrosis factor  therapy. All of these treatments were discontinued 1 month before institution of anti-CD20 therapy. Results. Marked clinical improvement was ob- served in 2 patients (American College of Rheumatology 70% response [ACR70] and ACR50, respectively), start- ing at the end of the second month after institution of anti-CD20 therapy (month 2) and lasting until month 10 in 1 patient (articular relapse) and month 12 in the other (last followup). ACR20 response was observed in 2 additional patients, lasting until month 5 and month 7, respectively (articular relapse in both). Decrease or normalization of serum C-reactive protein and rheuma- toid factor levels were observed in these patients. In contrast, patient 3 had no response to the treatment. RA synovitis and evolving erosive damage were decreased in patients exhibiting a major response, as demonstrated by imaging studies. Conclusion. Our finding of the clinical efficacy of selective B cell blockade indicates that B cells play a critical role in rheumatoid synovitis, at least in a subset of patients. Qualitative or quantitative differences in B cell commitment in RA pathobiology might have a function in the different responses observed. The key biologic targets of the currently recom- mended treatments for rheumatoid arthritis (RA), in- cluding aggressive combination therapy and tumor ne- crosis factor  (TNF) blockade, are represented by T cells, monocytes, macrophages, and synovial fibroblasts (1). A fraction of RA patients remain nonresponders to such treatments, however, due to still-undefined mech- anisms of resistance. Because of the high prevalence of RA, the clinical impact of this subgroup is important. B cells have been shown to participate in chronic rheumatoid synovitis. They undergo antigen-dependent clonal expansion, affinity maturation, and differentia- tion into plasma cells, and produce rheumatoid factor (RF), a well-recognized prognostic factor for aggressive RA (2,3). Although B cells are believed to have a pathogenetic role in rheumatoid synovitis, including immune complex–mediated inflammation and antigen presentation, this is currently believed to be marginal with respect to T cell and synoviocyte dysregulation. This has led to the belief that treatments directed at B cells alone, if they exist, are unlikely to be effective as monotherapy in RA (2). However, results of very recent studies with human RA synovium–SCID mouse chime- Salvatore De Vita, MD, Francesco Zaja, MD, Stefania Sacco, MD, Alessandro De Candia, MD, Renato Fanin, MD, Gianfranco Ferraccioli, MD: University of Udine, Udine, Italy. Address correspondence and reprint requests to Gianfranco Ferraccioli, MD, Department of Rheumatology, DPMSC, University of Udine, P.zza S. Maria della Misericordia 1, 33100 Udine, Italy. E-mail: gf.ferraccioli@med.uniud.it. Submitted for publication August 13, 2001; accepted in revised form May 3, 2002. 2029