Rituximab in refractory antineutrophil cytoplasmic antibody-associated vasculitis: what is the current evidence?

Antineutrophil cytoplasmic antibody (ANCA)associated vasculitis (AAV) is recognized as a chronic, relapsing and potentially fatal disease. Cyclophosphamide and steroids remain the mainstay of treatment of AAV [1]. Unfortunately, in up to 10% of patients, disease remains refractory despite conventional therapy [1]. In addition, conventional therapy has some serious side effects and hence limits its long-term use. For these refractory patients and those intolerant of conventional therapy, there are limited therapeutic options. B-lymphocytes have been implicated in the pathogenesis of AAV, by being the precursors of plasma cells (PCs), which produce ANCA [2] and in the formation of granuloma in Wegener’s granulomatosis (WG) [3]. Apart from the important role in antibody production, B-cells can also affect other aspects of the immune regulation such as immune response regulation, antigen presentation and cytokine production. This has been recognized in autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus, where the disease process is B-cell dependent and antibody independent [4,5]. Rituximab (RIT) is a chimeric monoclonal anti-CD20 antibody, which depletes B-lymphocytes, and has been proposed as salvage therapy for refractory disease. RIT consists of human constant regions linked to murine variable domains [6]. The murine Fab domain of RIT binds the CD20 antigen, which is a transmembrane protein located on the surface of mature B-cells. The CD20 antigen is involved in regulation of the transmembrane calcium conductance and cell-cycle progression during human B-cell activation [7]. B-cell activation may differentiate into either shortlived (in the absence of T-cell help) or long-lived PCs that are regulated by ligation of CD40 provided by helper T-cells [8] (Figure 1). RIT acts through antibody-mediated apoptosis, antibody-dependent cellularcytotoxicity and complement-mediated toxicity [9]. RIT induces 98% depletion of peripheral blood B-cells, but only 40–70% of lymph node B-cells are depleted [2]. Long-lived PCs do not express CD20 and this may explain why RIT-induced depletion of CD20þ B-cells in some cases does not decrease either total serum IgG levels or ANCA levels [2,10]. The rationale behind the use of RIT in AAV is based on the following three assumptions.