Rituximab in ANCA-associated vasculitis: a revolution?

On 19 April 2011, the US Food and Drug Administration (FDA) approved rituximab in combination with glucocorticosteroids for the treatment of two forms of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV): granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis. Rituximab is the first FDA approved drug for ANCA-associated vasculitis. It is to be expected that also the European Medicines Agency (EMEA) will approve rituximab in the next coming years. Patients and doctors applaud for the approval of this drug: there is hope that rituximab will replace in the future the current standard therapy with cyclophosphamide. Rituximab is a generic monoclonal anti-CD20 antibody that selectively depletes B lymphocytes but no plasma cells. It is licensed for B-cell lymphoma and rheumatoid arthritis. Since the discovery of ANCA in granulomatosis with polyangiitis (Wegener’s), microscopic polyangiitis and the Churg–Strauss Syndrome intensive studies have been performed to demonstrate the pathogenesis of ANCA in small vessel vasculitis [1]. Initially, most studies were performed on myeloperoxidase (MPO)–ANCA in rats demonstrating that MPO–ANCA alone is sufficient to cause disease [2–4]. In crucial experiments performed in MPO knockout mice that were immunized with mouse MPO, it was demonstrated that the transfer of MPO– ANCA could induce a mild form of vasculitis [5]. Additionally, Huugen et al. [6] demonstrated that a full-blown form of vasculitis developed when MPO–ANCA was transferred in combination with LPS. For the other form of ANCA that is specific for small vessel vasculitis, i.e. proteinase 3 (PR3)-ANCA, it has been much more difficult than for MPO–ANCA to demonstrate pathogenicity in animal models. Only in 2010, Primo et al. [7] demonstrated the transfer of splenocytes from PR3-immunized non-obese diabetic (NOD) mice into immunodeficient NOD miceinduced glomerulonephritis. More recently, Little et al. [8] reported during the 15th International Vasculitis and ANCA Workshop in Chapel Hill, USA, that mice with a humanized immune system could develop severe pulmonary and renal vasculitis after infusion of human PR3ANCA in combination with LPS. So, although ANCA is sufficient to cause disease in animal models, it is clear that additional environmental factors may amplify the disease phenotype. Important environmental factors are silica and infections [9, 10]. Especially in PR3-ANCA-associated vasculitis, it has been hypothesized that Staphylococcus aureus plays a pivotal role [11]. Not only the antibody plays a pivotal role in disease pathogenesis but also the antigen is crucial. Recently, the group of Ron Falk demonstrated that epigenetic control of the antigen is disturbed in patients with AAV [12]. Since AAV is induced by ANCA, the rationale for rituximab to deplete CD201 precursors of ANCA-secreting plasma cells was logic. B cells, however, are not only precursors of plasma cells: they have also other pathophysiological roles in AAV. Importantly, it has been demonstrated that activated B cells closely correlate with the disease activity [13]. Furthermore, autoantigen-specific B cells are present at sites of inflammation where tertiary lymphoid-like organs are formed [14]. B cells may produce pro-inflammatory cytokines and may present antigens to T cells. Importantly, it was recently demonstrated that rituximab also induces changes in T-cell populations, e.g., T helper 17 cells, that are relevant for AAV pathogenesis [15, 16]. These possibilities provided the basis for the hypothesis that rituximab therapy may be effective in AAV. Cyclophosphamide has been used since the 1960s to treat AAV and this alkylating agent has been considered the best drug for this severe disease. Currently, the standard therapy consists in cyclophosphamide intake, either orally or intravenously, for 3–6 months and then subsequently maintenance therapy with azathioprine. Furthermore, there is evidence that plasma exchange is beneficial in severe cases of vasculitis and possibly also in moderate severe cases. Despite this current therapy, the outcome of AAV is poor. Mortality is still 15–25% after 2 years and at least 20% of survivors of ANCA-associated renal vasculitis develop end-stage renal disease. Survivors have markedly increased rates of cardiovascular disease and have an increased rate of developing malignancies. Furthermore, AAV is a relapsing disease in which patients with PR3-ANCA experience 0.20 relapses per patient per year. Although relapse rates in MPO–ANCA are substantially