Rituximab in ANCA-Associated Vasculitis: Fad or Fact?

A number of case reports and case series of patients with Wegener’s granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome have supported the use of rituximab (RTX) for the treatment of refractory ANCA-associated vasculitis (AAV). Whether B cell depletion with RTX could replace cyclophosphamide as a first-line therapy for patients with severe AAV remains to be proven. Two studies, recently published in the New England Journal of Medicine , have examined the efficacy of RTX in inducing remission in patients with severe AAV. Copyright © 2010 S. Karger AG, Basel Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises 3 heterogeneous syndromes: Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA) and the Churg-Strauss syndrome [1] . These 3 multisystem disorders are characterized by necrotizing small vessel vasculitis with a predilection for the kidneys, lungs and peripheral nervous system that share the occurrence of ANCA in most patients at the time of initial presentation [2–5] . Untreated, systemic AAV follows a progressive course with a fatal outcome due to vital organ failure. The combination of high-dose glucocorticosteroids (GCS) and cyPublished online: December 16, 2010 Fernando C. Fervenza, MD, PhD Division of Nephrology and Hypertension Mayo Clinic College of Medicine 200 First Street, SW, Rochester, MN 55901 (USA) Tel. +1 507 266 7083, Fax +1 507 266 7891, E-Mail fervenza.fernando @ mayo.edu © 2010 S. Karger AG, Basel 1660–2110/11/1182–0182$38.00/0 Accessible online at: www.karger.com/nec D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /1 /2 01 7 12 :2 5: 22 A M Rituximab in ANCA-Associated Vasculitis: Fad or Fact? Nephron Clin Pract 2011;118:c182–c188 c183 body directed against CD20+ B cells [17] . Treatment with 4 weekly doses of RTX at 375 mg/m 2 led to clinical remission 2 months after the start of therapy. This initial success prompted the use of the same RTX regimen in an additional 10 patients with PR3-ANCA-positive WG who were resistant or had contraindications to the use of CYC [18] . Clinical remission, commensurate with a significant decrease in ANCA levels, was induced in all patients, and all patients were able to discontinue GCS over the course of 5 months. Adverse effects were minimal and generally related to the first infusion. These encouraging results were confirmed by a subsequent prospective open-label pilot trial in 10 patients with active and refractory ANCA-positive WG or MPA treated with the same RTX dosing regimen and a strictly protocolized oral GCS tapering [19] . Again, remission was induced in all patients. Although 1 patient relapsed once peripheral blood B lymphocytes had recovered, when retreated with the same regimen he achieved complete remission. These results suggest that either B lymphocytes or short-lived plasma cells (or both) rather than long-lived plasma cells are the cellular source of ANCA [17–19] . In these studies, ANCA titers declined in all of the patients and became negative in most following RTX therapy. Long-lived plasma cells are not affected by anti-CD20 therapy. Consequently, as in other autoimmune diseases [20] , B lymphocytes and short-lived plasma cells (which are dependent on antigen-specific B lymphocyte progenitors) seem to be primarily responsible for autoantibody production. Furthermore, ANCA level increases coincided or followed B lymphocyte reconstitution [19] . These findings suggest that, like in rheumatoid arthritis [21, 22] , autoantibody production is dependent on B lymphocytes. This is in contrast to total immunoglobulin G and protective antibodies, which are produced by long-lived plasma cells and unaffected by RTX therapy [21] . However, it is possible that in different diseases, autoantibodies may be produced by different types of plasma cells, e.g. SLE, since treatment with RTX has no effect on anti-double-stranded DNA antibody levels in these patients [23] . Following our initial observations, a number of case reports and case series of patients with WG, MPA and Churg-Strauss syndrome have supported the use of RTX for the treatment of refractory AAV [24–33] , as well as for maintenance therapy in patients with AAV [34] . A number of subsequent reports, however, have cast doubt on the efficacy of RTX in refractory WG [35, 36] . Failure to therapy was attributed to patients having a granulomatous as opposed to a vasculitic form of the disease, implying that RTX is ineffective in patients in whom granulomatous manifestations predominated. In our experience, however, both vasculitic and granulomatous forms of AAV respond to RTX, indicating that factors other than differences in disease manifestations explain the observed discrepancy in outcome, e.g. differences in RTX dosing [18, 19] . Until recently, that was all the evidence supporting the use of B-cell target therapy in patients with severe AAV. Whether B cell depletion with RTX could replace CYC as a first-line therapy for patients with severe AAV remained to be proven. Two studies published in the New England Journal of Medicine examined the efficacy of RTX in inducing remission in patients with severe AAV [37, 38] . The cardinal differences between the studies are outlined in table 1 . In the first study, ‘Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis’ (RITUXVAS), Jones et al. [37] , randomized 44 patients with newly diagnosed AAV and renal involvement to receive standard GCS regimen plus either RTX (375 mg/m 2 i.v. weekly ! 4) with 2 intravenous CYC pulses given concomitantly with the 1st and 3rd RTX infusion (33 patients, the RTX group), or intravenous CYC for 3–6 months followed by azathioprine (11 patients, the control group) [37] . The rate of sustained remission [defined as BVAS (Birmingham Vasculitis Activity Score) of 0 for 6 6 months] at 12 months was similar in both treatment arms. GFR improved equally in both groups. Similarly, the percentage of severe adverse events, another of the primary endpoints of the study, was not different between the groups (RTX 42%; control 36%), and although 6 deaths occurred among patients treated with the combination of RTX and CYC, the percentage of deaths was the same in both treatment groups (18%). In the same issue of the journal, the results of a much larger study were also reported in ‘Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis’ (RAVE), a report on a multicenter randomized, doubleblind, double placebo-controlled trial conducted to evaluate the efficacy and safety of RTX for remission induction in severe AAV in comparison to CYC [38] . A total of 197 patients with severe WG or MPA (3: 1), all positive for PR3-ANCA or MPO-ANCA (2: 1), were randomized to receive treatment with RTX (375 mg/m 2 i.v. weekly ! 4) or CYC (2 mg/kg/d p.o.) in combination with GCS. Initial GCS treatment was the same in both groups (1–3 g i.v. methylprednisolone) and was followed by rigorously protocolized GCS tapering, aimed at complete discontinuation of GCS by month 5. Once remission was achieved, patients on CYC were switched to maintenance therapy with azathioprine, while patients on RTX were switched to placebo. Equally distributed among the groups were D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /1 /2 01 7 12 :2 5: 22 A M Fervenza Nephron Clin Pract 2011;118:c182–c188 c184 the disease severity, organ involvement, AAV type and ANCA type. The study also included an equal number of patients with newly diagnosed and relapsing disease. Sixty-three (64%) of the patients in the RTX arm versus 52 (53%) in the CYC arm achieved the primary endpoint of the study defined as disease remission with a BVAS/WG of 0 in the absence of GCS therapy at month 6, a result that met the criterion for noninferiority (p ! 0.001). There was no difference in treatment response within the subgroups of patients with major renal involvement (n = 99) or alveolar hemorrhage (n = 50). It should be noted that RITUXVAS used BVAS, whereas RAVE used BVAS/WG. BVAS scores are approximately twice the values of BVAS/WG [39] . A Table 1. Main characteristics of the trials