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• W2079295501 abstract "Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small-vessel vasculitis that primarily comprises 2 clinical syndromes: granulomatosis with polyangiitis and microscopic polyangiitis. Cyclophosphamide and glucocorticoids have traditionally been used for induction of remission. However, more recent studies have shown that rituximab is as effective as cyclophosphamide for induction therapy in patients with newly diagnosed severe AAV and superior for patients with relapsing AAV. There is also accumulating evidence indicating a potential role of rituximab for maintenance therapy in AAV. In this article, we will review the evidence supporting the various treatment choices for patients with AAV. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small-vessel vasculitis that primarily comprises 2 clinical syndromes: granulomatosis with polyangiitis and microscopic polyangiitis. Cyclophosphamide and glucocorticoids have traditionally been used for induction of remission. However, more recent studies have shown that rituximab is as effective as cyclophosphamide for induction therapy in patients with newly diagnosed severe AAV and superior for patients with relapsing AAV. There is also accumulating evidence indicating a potential role of rituximab for maintenance therapy in AAV. In this article, we will review the evidence supporting the various treatment choices for patients with AAV. Clinical Summary•Rituximab is as effective as Cyclophosphamide in inducing remission in severe AAV.•Rituximab is the preferred agent when treating patients with relapsing AAV and in patients where fertility is a concern.•Rituximab monotherapy is effective as maintenance therapy in AAV.•MMF and high-dose corticosteroids may be a treatment option for patients who are MPO-ANCA positive and have mild renal impairment. •Rituximab is as effective as Cyclophosphamide in inducing remission in severe AAV.•Rituximab is the preferred agent when treating patients with relapsing AAV and in patients where fertility is a concern.•Rituximab monotherapy is effective as maintenance therapy in AAV.•MMF and high-dose corticosteroids may be a treatment option for patients who are MPO-ANCA positive and have mild renal impairment. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) refers to a multisystem small-vessel vasculitis that is composed of 3 heterogenous clinical syndromes including microscopic polyangiitis (MPA), granulomatosis polyangiitis (GPA, formerly Wegener's granulomatosis), and eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome).1Jennette J.C. Falk R.J. Andrassy K. et al.Nomenclature of systemic vasculitides. Proposal of an international consensus conference.Arthritis Rheum. 1994; 37: 187-192Crossref PubMed Scopus (3735) Google Scholar AAV primarily affects the kidneys, lungs, and peripheral nervous system and is characterized by the presence of necrotizing lesions in small vessels. In most patients ANCA is present in the serum at the time of initial diagnosis.2Guillevin L. Durand-Gasselin B. Cevallos R. et al.Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients.Arthritis Rheum. 1999; 42: 421-430Crossref PubMed Scopus (731) Google Scholar, 3Finkielman J.D. Lee A.S. Hummel A.M. et al.ANCA are detectable in nearly all patients with active severe Wegener's granulomatosis.Am J Med. 2007; 120: 643.e9-643.e14Abstract Full Text Full Text PDF Scopus (215) Google Scholar, 4Keogh K.A. Specks U. Churg-Strauss syndrome: clinical presentation, antineutrophil cytoplasmic antibodies, and leukotriene receptor antagonists.Am J Med. 2003; 115: 284-290Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar The 2 major patterns seen by indirect immunofluorescence when sera of patients containing ANCA are incubated with ethanol-fixed neutrophils include cytoplasmic ANCA (C-ANCA) and perinuclear ANCA (P-ANCA) patterns.5Niles J.L. Pan G.L. Collins A.B. et al.Antigen-specific radioimmunoassays for anti-neutrophil cytoplasmic antibodies in the diagnosis of rapidly progressive glomerulonephritis.J Am Soc Nephrol. 1991; 2: 27-36PubMed Google Scholar The C-ANCA pattern represents diffuse granular staining in the cytoplasm that is seen mostly in patients with GPA and is caused by antibodies against proteinase-3 (PR3).6Hagen E.C. Daha M.R. Hermans J. et al.Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR Project for ANCA Assay Standardization.Kidney Int. 1998; 53: 743-753Crossref PubMed Scopus (678) Google Scholar On the other hand, the P-ANCA pattern is most commonly seen in patients with MPA and represents perinuclear staining. In contrast to the C-ANCA pattern, the P-ANCA pattern can be caused by various different antibodies targeting cationic granule constituents that rearrange around the negatively charged nucleus under ethanol fixation conditions. Because only antibodies against myeloperoxidase (MPO) causing a P-ANCA pattern are of interest in the context of AAV, confirmation of MPO specificity by enzyme-linked immunoabsorbent assay is mandatory in the diagnostic evaluation of patients suspected of having AAV.6Hagen E.C. Daha M.R. Hermans J. et al.Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR Project for ANCA Assay Standardization.Kidney Int. 1998; 53: 743-753Crossref PubMed Scopus (678) Google Scholar Immunosuppressive therapy is indicated in all patients with active AAV. Without therapy, the disease follows a progressive course and results in vital organ failure with fatal outcomes once there is evidence of kidney involvement.7Walton E.W. Giant-cell granuloma of the respiratory tract (Wegener's granulomatosis).Br Med J. 1958; 2: 265-270Crossref PubMed Scopus (655) Google Scholar The choice of therapy may depend on disease activity, but treatment typically consists of 2 phases: (1) a remission induction phase, with the goal of therapy being the interruption of active inflammation to prevent tissue damage and allow recovery; and (2) a remission maintenance phase, in which therapy aims to prevent relapses, ideally without the use of glucocorticoids. In this article, we will review standard induction therapy as well as new therapeutic approaches with the use of rituximab. We will also review the role of rituximab for maintenance therapy. Before the introduction of high-dose glucocorticoids in combination with cyclophosphamide (CYC), AAV was considered to be fatal once there was evidence of kidney involvement.7Walton E.W. Giant-cell granuloma of the respiratory tract (Wegener's granulomatosis).Br Med J. 1958; 2: 265-270Crossref PubMed Scopus (655) Google Scholar In 1973, the first series of 15 patients who were treated with CYC (2 mg/kg per day) in combination with prednisone was published.8Fauci A.S. Wolff S.M. Wegener's granulomatosis: studies in eighteen patients and a review of the literature. 1973.Medicine (Baltimore). 1994; 73: 315-324PubMed Google Scholar In this study, 13 of the 15 patients achieved remission. Follow-up studies of larger cohorts observed for longer periods of time provided similar data with a 75% rate of complete remission and 80% rate of survival.9Fauci A.S. Haynes B.F. Katz P. Wolff S.M. Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years.Ann Intern Med. 1983; 98: 76-85Crossref PubMed Scopus (1696) Google Scholar, 10Hoffman G.S. Kerr G.S. Leavitt R.Y. et al.Wegener granulomatosis: an analysis of 158 patients.Ann Intern Med. 1992; 116: 488-498Crossref PubMed Scopus (2597) Google Scholar The continued use of corticosteroids plus CYC changed AAV from a uniformly fatal disease to a chronic and relapsing condition. However, CYC-based therapy is associated with significant short- and long-term toxicities including bone marrow suppression (2%); infection (46%); malignancies, particularly bladder cancer (2.8%); and infertility (57%).10Hoffman G.S. Kerr G.S. Leavitt R.Y. et al.Wegener granulomatosis: an analysis of 158 patients.Ann Intern Med. 1992; 116: 488-498Crossref PubMed Scopus (2597) Google Scholar In an attempt to lower the exposure to the cumulative dose of CYC, intravenous (IV) CYC pulse therapy was suggested. The European Vasculitis Study Group (EUVAS) conducted a randomized controlled trial (CYCLOPS Trial—Randomized Trial of Daily Oral vs Pulse Cyclophosphamide as Therapy for AAV) to evaluate the efficacy of IV CYC given as 3 IV pulses of CYC, 15 mg/kg, given 2 weeks apart, followed by pulses at 3-week intervals (15 mg/kg IV or 5 mg/kg orally on 3 consecutive days, at the physician's discretion) until remission, and then for another 3 months vs oral CYC given at a dose of 2 mg/kg per day, until remission, followed by 1.5 mg/kg per day for another 3 months.11de Groot K. Harper L. Jayne D.R. et al.Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial.Ann Intern Med. 2009; 150: 670-680Crossref PubMed Scopus (708) Google Scholar There were no differences in the rate or time to remission between the 2 treatment arms (88.1% in the IV group vs 87.7% in the oral group). There was a higher reported rate of leukopenia in the oral CYC arm compared with the IV CYC arm. However, there was no difference in the rate of serious infections or any other adverse events between the 2 arms.11de Groot K. Harper L. Jayne D.R. et al.Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial.Ann Intern Med. 2009; 150: 670-680Crossref PubMed Scopus (708) Google Scholar The relapse rate was numerically higher in the IV CYC group (19%) compared with the oral CYC group (9%). This difference did not reach statistical significance, and the study was not powered to evaluate the effect of the intervention on relapse. However, the long-term follow-up of the CYCLOPS trial did show a significantly higher rate of relapse in the IV arm (39.5%) compared with the oral arm (20.8%) (P = .029).12Harper L. Morgan M.D. Walsh M. et al.Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up.Ann Rheum Dis. 2012; 71: 955-960Crossref PubMed Scopus (296) Google Scholar There were no differences in kidney function, survival, or adverse events between the 2 treatment arms.12Harper L. Morgan M.D. Walsh M. et al.Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up.Ann Rheum Dis. 2012; 71: 955-960Crossref PubMed Scopus (296) Google Scholar CYCLOPS showed that oral and IV CYC are possible options for induction therapy. However, providers should be aware that IV CYC is not superior to the oral formulation, and, when used for the same duration of therapy, it may be associated with a higher rate of relapse. In our practice, we prefer the oral formulation because necessary dose adjustments can be implemented promptly in the event of leukopenia or severe infection. In comparison, the bone marrow effects of IV CYC pulses are longer lasting, and, once administered, their effect cannot be easily reversed. However, we do consider IV CYC in patients in whom fertility is a concern, in those who may have issues with compliance, or in those who experience severe nausea with the use of oral CYC. Although treatment with CYC induced remission in most patients, the optimal duration of therapy was unclear. In an open-label trial by Langford and colleagues, in which patients were switched to methotrexate therapy after induction was achieved by CYC, the median duration to remission was 3 months,13Langford C.A. Talar-Williams C. Barron K.S. Sneller M.C. A staged approach to the treatment of Wegener's granulomatosis: induction of remission with glucocorticoids and daily cyclophosphamide switching to methotrexate for remission maintenance.Arthritis Rheum. 1999; 42: 2666-2673Crossref PubMed Scopus (207) Google Scholar indicating that duration of therapy with CYC could be shortened. Similar results were obtained from the trial by EUVAS in which patients were treated with 3 months of CYC (2 mg/kg per day) and prednisolone, and then, once remission was achieved, they were randomized to either azathioprine (2 mg/kg per day) or continuation of CYC at a lower dose of CYC (1.5 mg/kg per day) for a total of 12 months. The relapse rate was no different between the azathioprine and the CYC arm (15.7% vs 13.7%).14Jayne D. Rasmussen N. Andrassy K. et al.A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies.N Engl J Med. 2003; 349: 36-44Crossref PubMed Scopus (1187) Google Scholar This confirmed that CYC use could be limited to the duration required to induce remission, which is typically 3 to 6 months and does not need to be extended beyond 6 months. Consequently, after remission has been achieved, CYC should be discontinued and replaced with a less toxic alternative such as azathioprine. CYC is associated with significant short- and long-term side effects, and strategies to lower the associated morbidity and mortality should be implemented. One of the most common side effects of CYC is bone marrow suppression, leukopenia, and subsequently an increased risk of infection.14Jayne D. Rasmussen N. Andrassy K. et al.A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies.N Engl J Med. 2003; 349: 36-44Crossref PubMed Scopus (1187) Google Scholar Therefore, it is recommended that all patients on daily oral CYC therapy have a complete blood count (CBC) performed at least every 2 weeks (ideally weekly) while on CYC. Dose adjustments should be made to maintain a total white blood cell count above 3500/mm3 and an absolute neutrophil count above 1500/mm3. If patient is receiving IV CYC, then CBC should be performed before each dose (on average once every 2 weeks). In addition, to prevent infection with Pneumocystis jiroveci, all patients should receive prophylaxis with either sulfamethoxazole/trimethoprim or an alternative agent.15Ognibene F.P. Shelhamer J.H. Hoffman G.S. et al.Pneumocystis carinii pneumonia: a major complication of immunosuppressive therapy in patients with Wegener's granulomatosis.Am J Respir Crit Care Med. 1995; 151: 795-799PubMed Google Scholar We recommend that the oral dose of CYC be reduced by 25% in patients over the age of 60 years or creatinine more than 2.5 mg/dL to 1.5 mg/kg per day for induction therapy. For example, a 62-year-old male patient with a serum creatinine of 3 mg/dL who weighs 80 kg should receive no more than 125 mg of oral CYC per day (1.5 mg/kg per day). The risk of malignancy with CYC is substantial with the hazard of neoplasia roughly correlated to the cumulative dose and duration of cytotoxic therapy.16Baltus J.A. Boersma J.W. Hartman A.P. Vandenbroucke J.P. The occurrence of malignancies in patients with rheumatoid arthritis treated with cyclophosphamide: a controlled retrospective follow-up.Ann Rheum Dis. 1983; 42: 368-373Crossref PubMed Scopus (117) Google Scholar, 17Grunwald H.W. Rosner F. Acute leukemia and immunosupressive drug use: a review of patients undergoing immunosuppressive therapy for non-neoplastic diseases.Arch Intern Med. 1979; 139: 461-466Crossref PubMed Scopus (128) Google Scholar, 18Smith A.G. Prentice A.G. Lucie N.P. Browning J.D. Dagg J.H. Rowan R.M. Acute myelogenous leukaemia following cytotoxic therapy: five cases and a review.Q J Med. 1982; 51: 227-240PubMed Google Scholar Faurschou and colleagues have investigated the incidence of malignancies associated with CYC exposure in a cohort of 293 patients with GPA.19Faurschou M. Sorensen I.J. Mellemkjaer L. et al.Malignancies in Wegener's granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients.J Rheumatol. 2008; 35: 100-105PubMed Google Scholar The risk of malignancy was not increased for patients who never received CYC or for patients treated with cumulative CYC doses of 36 g or less.19Faurschou M. Sorensen I.J. Mellemkjaer L. et al.Malignancies in Wegener's granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients.J Rheumatol. 2008; 35: 100-105PubMed Google Scholar In contrast, high risks of leukemia (standardized incidence ratio 59.0, 95% confidence interval 12-172) and bladder cancer (standardized incidence ratio 9.5, 95% confidence interval 2.6-24) were observed for patients treated with cumulative CYC doses more than 36 g. These data would suggest that a patient who weighs 80 kg and is treated with CYC at a dose of 2.5 mg/kg per day for 6 months would exceed this threshold. Because AAV is a remitting and relapsing disease with the potential for significant cumulative CYC dosing, there is a substantial risk of late-occurring malignancies. The increased risk of transitional urothelial carcinoma and bladder cancer is related to the effect of acrolein (metabolite of CYC) on the urothelium.20Talar-Williams C. Hijazi Y.M. Walther M.M. et al.Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis.Ann Intern Med. 1996; 124: 477-484Crossref PubMed Scopus (503) Google Scholar Patients who receive oral CYC should be advised to take the dose all at once in the morning and to have adequate fluid intake throughout the day to keep the urine dilute and to minimize the contact time between acrolein and the urothelium. Patients can also be treated with 2-mercaptoethanesulphonate, which binds to acrolein and can lower the exposure. 2-Mercaptoethanesulphonate is easier to use in patients receiving IV CYC because it can be dosed on the day the patient receives IV CYC. All patients should have a biannual evaluation with urinalysis for detection of hematuria in addition to urine cytology. Should there be evidence of hematuria or abnormal urine cytology, this should be further pursued with cystoscopy. The other major concern limiting CYC utility is related to its gonadal toxicity. Data indicate that ovarian failure is seen in female patients of any age receiving a cumulative dose of as little as 28 g of CYC.21Mok C.C. Ying K.Y. Ng W.L. et al.Long-term outcome of diffuse proliferative lupus glomerulonephritis treated with cyclophosphamide.Am J Med. 2006; 119: 355.e25-355.e33Abstract Full Text Full Text PDF Scopus (135) Google Scholar, 22Pendse S. Ginsburg E. Singh A.K. Strategies for preservation of ovarian and testicular function after immunosuppression.Am J Kidney Dis. 2004; 43: 772-781Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar In addition, these authors found that the age at the onset of therapy was an additional independent factor associated with sterility.21Mok C.C. Ying K.Y. Ng W.L. et al.Long-term outcome of diffuse proliferative lupus glomerulonephritis treated with cyclophosphamide.Am J Med. 2006; 119: 355.e25-355.e33Abstract Full Text Full Text PDF Scopus (135) Google Scholar, 22Pendse S. Ginsburg E. Singh A.K. Strategies for preservation of ovarian and testicular function after immunosuppression.Am J Kidney Dis. 2004; 43: 772-781Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Although male infertility is harder to assess, studies have demonstrated that doses above 7.5 g/m2 of CYC can result in permanent oligospermia.23Meistrich M.L. Wilson G. Brown B.W. da Cunha M.F. Lipshultz L.I. Impact of cyclophosphamide on long-term reduction in sperm count in men treated with combination chemotherapy for Ewing and soft tissue sarcomas.Cancer. 1992; 70: 2703-2712Crossref PubMed Scopus (202) Google Scholar Therefore, all patients of child-bearing age should be advised on the potential side effect of infertility, and other therapies for induction therapy should be considered. Therapy with testosterone in males and gonadotrophin-releasing hormone such as leuprolide in females may be of some benefit.24Masala A. Faedda R. Alagna S. et al.Use of testosterone to prevent cyclophosphamide-induced azoospermia.Ann Intern Med. 1997; 126: 292-295Crossref PubMed Scopus (141) Google Scholar, 25Somers E.C. Marder W. Christman G.M. Ognenovski V. McCune W.J. Use of a gonadotropin-releasing hormone analog for protection against premature ovarian failure during cyclophosphamide therapy in women with severe lupus.Arthritis Rheum. 2005; 52: 2761-2767Crossref PubMed Scopus (233) Google Scholar Female and male patients should be offered cryopreservation of ova and sperms before treatment with CYC. As noted previously, introduction of CYC significantly improved the outcome of patients with AAV. However, despite the high rate of initial remission, follow-up studies with extended timelines revealed that close to half of the patients who responded to the initial therapy relapsed in the first 3 to 5 years, and treatment was associated with significant morbidity in up to 42% of patients, offsetting the benefits achieved from treatment with CYC.26Nachman P.H. Hogan S.L. Jennette J.C. Falk R.J. Treatment response and relapse in antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis.J Am Soc Nephrol. 1996; 7: 33-39PubMed Google Scholar In addition, approximately 10% of patients do not respond satisfactorily to standard treatment. These observations indicated the need for a more effective and less toxic alternative. Emerging evidence suggested a critical role for B lymphocytes in the pathogenesis of autoimmune diseases, including AAV.27Dorner T. Jacobi A.M. Lipsky P.E. B cells in autoimmunity.Arthritis Res Ther. 2009; 11: 247Crossref PubMed Scopus (113) Google Scholar First, B lymphocytes are the precursors for short-lived plasma cells, which are thought to be source of ANCAs that have been implicated in the pathogenesis of AAV.28Huugen D. Tervaert J.W. Heeringa P. Antineutrophil cytoplasmic autoantibodies and pathophysiology: new insights from animal models.Curr Opin Rheumatol. 2004; 16: 4-8Crossref PubMed Scopus (28) Google Scholar, 29Jennette J.C. Xiao H. Falk R.J. Pathogenesis of vascular inflammation by anti-neutrophil cytoplasmic antibodies.J Am Soc Nephrol. 2006; 17: 1235-1242Crossref PubMed Scopus (170) Google Scholar, 30Huang H. Benoist C. Mathis D. Rituximab specifically depletes short-lived autoreactive plasma cells in a mouse model of inflammatory arthritis.Proc Natl Acad Sci U S A. 2010; 107: 4658-4663Crossref PubMed Scopus (122) Google Scholar Second, the number of activated B lymphocytes seems to correlate with disease severity and activity.31Popa E.R. Stegeman C.A. Bos N.A. Kallenberg C.G. Tervaert J.W. Differential B- and T-cell activation in Wegener's granulomatosis.J Allergy Clin Immunol. 1999; 103: 885-894Abstract Full Text Full Text PDF PubMed Google Scholar Third, B lymphocytes have been identified in the granulomatous lesions of patients affected with GPA close to plasma cells and PR3-positive cells where selection and affinity maturation of autoreactive B lymphocytes may occur.32Voswinkel J. Mueller A. Kraemer J.A. et al.B lymphocyte maturation in Wegener's granulomatosis: a comparative analysis of VH genes from endonasal lesions.Ann Rheum Dis. 2006; 65: 859-864Crossref PubMed Scopus (135) Google Scholar In fact, the beneficial effect of CYC has been attributed to its effect on B lymphocytes.33Cupps T.R. Edgar L.C. Fauci A.S. Suppression of human B lymphocyte function by cyclophosphamide.J Immunol. 1982; 128: 2453-2457PubMed Google Scholar On the basis of this evidence, rituximab, a chimeric monoclonal antibody against CD20+ B cells, was initially used in treating a patient with AAV who was failing therapy with CYC and prednisone.34Specks U. Fervenza F.C. McDonald T.J. Hogan M.C. Response of Wegener's granulomatosis to anti-CD20 chimeric monoclonal antibody therapy.Arthritis Rheum. 2001; 44: 2836-2840Crossref PubMed Scopus (332) Google Scholar Several small prospective studies produced further evidence of its efficacy.35Keogh K.A. Ytterberg S.R. Fervenza F.C. Carlson K.A. Schroeder D.R. Specks U. Rituximab for refractory Wegener's granulomatosis: report of a prospective, open-label pilot trial.Am J Respir Crit Care Med. 2006; 173: 180-187Crossref PubMed Scopus (377) Google Scholar, 36Stasi R. Stipa E. Del Poeta G. Amadori S. Newland A.C. Provan D. Long-term observation of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with rituximab.Rheumatology (Oxford). 2006; 45: 1432-1436Crossref PubMed Scopus (199) Google Scholar, 37Mansfield N. Hamour S. Habib A.M. et al.Prolonged disease-free remission following rituximab and low-dose cyclophosphamide therapy for renal ANCA-associated vasculitis.Nephrol Dial Transplant. 2011; 26: 3280-3286Crossref PubMed Scopus (55) Google Scholar, 38Eriksson P. Nine patients with anti-neutrophil cytoplasmic antibody-positive vasculitis successfully treated with rituximab.J Intern Med. 2005; 257: 540-548Crossref PubMed Scopus (215) Google Scholar, 39Smith K.G. Jones R.B. Burns S.M. Jayne D.R. Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: remission, relapse, and re-treatment.Arthritis Rheum. 2006; 54: 2970-2982Crossref PubMed Scopus (345) Google Scholar These studies were followed by 2 major randomized controlled trials in 2010 and examined the efficacy of rituximab compared with CYC for remission induction in patients with severe AAV.40Stone J.H. Mferkel P.A. Spiera R. et al.Rituximab versus cyclophosphamide for ANCA-associated vasculitis.N Engl J Med. 2010; 363: 221-232Crossref PubMed Scopus (1926) Google Scholar, 41Jones R.B. Tervaert J.W. Hauser T. et al.Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis.N Engl J Med. 2010; 363: 211-220Crossref PubMed Scopus (1223) Google Scholar The first was the Rituximab in ANCA-Associated Vasculitis (RAVE) trial, a randomized, double-blind, double placebo-controlled, noninferiority trial that evaluated the efficacy of rituximab to CYC in inducing complete remission by 6 months in patients with severe AAV.40Stone J.H. Mferkel P.A. Spiera R. et al.Rituximab versus cyclophosphamide for ANCA-associated vasculitis.N Engl J Med. 2010; 363: 221-232Crossref PubMed Scopus (1926) Google Scholar Patients with newly diagnosed or relapsing disease and positive PR3- or MPO-ANCA and severe disease were eligible for the study. Severe disease was defined as vital organ involvement by AAV that posed an immediate threat to the function of that organ or the patient's life.42Etanercept plus standard therapy for Wegener's granulomatosis.N Engl J Med. 2005; 352: 351-361Crossref PubMed Scopus (800) Google Scholar A total of 197 patients with severe AAV (GPA to MPA ratio of 3:1) were enrolled in the study and were randomized 1:1 to receive either rituximab at a dose of 375 mg/m2 once weekly for 4 weeks or daily CYC at a dose of 2 mg/kg. All patients also received methylprednisolone (MTP) at a dose of 1 to 3 g IV followed by a protocolized tapering regimen of oral prednisone aimed at complete discontinuation of corticosteroids by 5 months. After achieving remission at months 3 to 6, patients in the CYC arm were switched to azathioprine at a dose of 2 mg/kg per day whereas those in the rituximab arm were switched to placebo. Sixty-four percent of patients in the rituximab vs 53% in the CYC arm achieved the primary endpoint of complete remission defined as a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) of 0 and complete discontinuation of corticosteroids by month 6, which met the noninferiority criterion (P < .001) and almost reached superiority (P = .09). Among patients with relapsing disease, rituximab was more effective compared with CYC, with 67% reaching the primary endpoint compared with 42% in the CYC arm (P = .01). The superiority persisted after adjusting for ANCA type and clinical site (P = .03). There was no difference in the rate of adverse events between the 2 arms. It is important to note that some of the long-term adverse events associated with CYC, which are primarily dependent on the cumulative dose of CYC (eg, malignancy or infertility), may not occur until after the trial period.43Fervenza F.C. Rituximab in ANCA-associated vasculitis: fad or fact?.Nephron Clin Pract. 2011; 118 (discussion c188): c182-c188Crossref PubMed Scopus (10) Google Scholar Results from another randomized controlled trial, the Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis trial, were reported in the same issue of the New England Journal of Medicine.41Jones R.B. Tervaert J.W. Hauser T. et al.Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis.N Engl J Med. 2010; 363: 211-220Crossref PubMed Scopus (1223) Google Scholar In this trial, 44 patients were randomly assigned in a 3:1 ratio to receive either rituximab at a dose of 375 mg/m2 weekly for 4 weeks plus 2 IV CYC pulses given with the first and third dose of rituximab or 3 to 6 months of IV pulse CYC followed by azathioprine. Both groups received standardized glucocorticoid doses. The primary endpoint results, which included the rate of sustained remission (absence of disease activity [BVAS of 0] for at least 6 months) (76% in rituximab vs 82% in CYC) and severe adverse events (42% in rituximab vs 36% in CYC), were similar between the 2 groups. On the basis of the RAVE trial results, the U.S. Food and Drug Administration (FDA) approved the use of rituximab for induction therapy in the treatment of severe GPA or MPA in April 2011, and many regulatory agencies across the globe subsequently followed suit. Although there was no difference in the rate of remission in patients with newly diagnosed AAV, rituximab proved to be super" @default.
• W2079295501 created "2016-06-24" @default.
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• W2079295501 date "2014-03-01" @default.
• W2079295501 modified "2023-09-27" @default.
• W2079295501 title "Treatment of ANCA-Associated Vasculitis: New Therapies and a Look at Old Entities" @default.
• W2079295501 cites W1530168030 @default.
• W2079295501 cites W1914343637 @default.
• W2079295501 cites W1964913193 @default.
• W2079295501 cites W1966546028 @default.
• W2079295501 cites W1969171525 @default.
• W2079295501 cites W1972895671 @default.
• W2079295501 cites W1979398789 @default.
• W2079295501 cites W1980974790 @default.
• W2079295501 cites W1981088341 @default.
• W2079295501 cites W1981535363 @default.
• W2079295501 cites W1981683920 @default.
• W2079295501 cites W1982851583 @default.
• W2079295501 cites W1982860902 @default.
• W2079295501 cites W1984702041 @default.
• W2079295501 cites W1988376766 @default.
• W2079295501 cites W1990393482 @default.
• W2079295501 cites W1997620292 @default.
• W2079295501 cites W1997786943 @default.
• W2079295501 cites W2001052817 @default.
• W2079295501 cites W2004194066 @default.
• W2079295501 cites W2005449894 @default.
• W2079295501 cites W2006128121 @default.
• W2079295501 cites W2007778318 @default.
• W2079295501 cites W2008688804 @default.
• W2079295501 cites W2011309580 @default.
• W2079295501 cites W2011557149 @default.
• W2079295501 cites W2011779958 @default.
• W2079295501 cites W2014430306 @default.
• W2079295501 cites W2016609532 @default.
• W2079295501 cites W2017094546 @default.
• W2079295501 cites W2019229100 @default.
• W2079295501 cites W2022071767 @default.
• W2079295501 cites W2022495067 @default.
• W2079295501 cites W2023473273 @default.
• W2079295501 cites W2026990270 @default.
• W2079295501 cites W2035000560 @default.
• W2079295501 cites W2036292718 @default.
• W2079295501 cites W2038766585 @default.
• W2079295501 cites W2042927558 @default.
• W2079295501 cites W2043793244 @default.
• W2079295501 cites W2045762096 @default.
• W2079295501 cites W2046059252 @default.
• W2079295501 cites W2053136851 @default.
• W2079295501 cites W2053683902 @default.
• W2079295501 cites W2054445837 @default.
• W2079295501 cites W2054663993 @default.
• W2079295501 cites W2056074194 @default.
• W2079295501 cites W2056134409 @default.
• W2079295501 cites W2058416888 @default.
• W2079295501 cites W2058445558 @default.
• W2079295501 cites W2059227619 @default.
• W2079295501 cites W2059903231 @default.
• W2079295501 cites W2062059206 @default.
• W2079295501 cites W2062964048 @default.
• W2079295501 cites W2063340779 @default.
• W2079295501 cites W2065132929 @default.
• W2079295501 cites W2071782320 @default.
• W2079295501 cites W2077515951 @default.
• W2079295501 cites W2079079419 @default.
• W2079295501 cites W2080567030 @default.
• W2079295501 cites W2080663859 @default.
• W2079295501 cites W2081738712 @default.
• W2079295501 cites W2084056567 @default.
• W2079295501 cites W2086422365 @default.
• W2079295501 cites W2093336544 @default.
• W2079295501 cites W2094092745 @default.
• W2079295501 cites W2097453206 @default.
• W2079295501 cites W2100809783 @default.
• W2079295501 cites W2101840353 @default.
• W2079295501 cites W2102133319 @default.
• W2079295501 cites W2102286533 @default.
• W2079295501 cites W2102454572 @default.
• W2079295501 cites W2102737116 @default.
• W2079295501 cites W2104587334 @default.
• W2079295501 cites W2108974311 @default.
• W2079295501 cites W2109207289 @default.
• W2079295501 cites W2123444939 @default.
• W2079295501 cites W2124208349 @default.
• W2079295501 cites W2124670599 @default.
• W2079295501 cites W2126169144 @default.
• W2079295501 cites W2126583107 @default.
• W2079295501 cites W2126694261 @default.
• W2079295501 cites W2127740453 @default.
• W2079295501 cites W2131457901 @default.
• W2079295501 cites W2132376753 @default.
• W2079295501 cites W2136149088 @default.
• W2079295501 cites W2139747034 @default.
• W2079295501 cites W2141186997 @default.
• W2079295501 cites W2141356919 @default.

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