Maintenance Immunosuppression in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Abstract

Commentary on Hiemstra TF, Walsh M, Mahr A, et al; for the European Vasculitis Study Group (EUVAS). Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial. JAMA. 2010;304(21):2381-2388. Commentary on Hiemstra TF, Walsh M, Mahr A, et al; for the European Vasculitis Study Group (EUVAS). Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial. JAMA. 2010;304(21):2381-2388. Although antineutrophil cytoplasmic antibody–associated vasculitis (AAV), typified by Wegener granulomatosis and microscopic polyangiitis, is relatively uncommon, it has devastating consequences if untreated. Additionally, the propensity of AAV to occur in the more vulnerable older age group and progress rapidly makes it imperative to reach a correct diagnosis and implement effective treatment.1Booth A.D. Pusey C.D. Jayne D.R. Renal vasculitis—an update in 2004.Nephrol Dial Transplant. 2004; 19: 1964-1968Crossref PubMed Scopus (30) Google Scholar, 2Exley A.R. Bacon P.A. Luqmani R.A. Kitas G.D. Carruthers D.M. Moots R. Examination of disease severity in systemic vasculitis from the novel perspective of damage using the vasculitis damage index (VDI).Br J Rheumatol. 1998; 37: 57-63Crossref PubMed Scopus (100) Google Scholar Even with prompt diagnosis, treatment is difficult and may be complicated by relapsing disease. Accordingly, Hiemstra et al, writing on behalf of the European Vasculitis Study Group (EUVAS),3Hiemstra T.F. Walsh M. Mahr A. et al.European Vasculitis Study Group (EUVAS)Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial.JAMA. 2010; 304: 2381-2388Crossref PubMed Scopus (446) Google Scholar recently reported a study published in 2010 by the Journal of the American Medical Association of maintenance immunosuppression after induction of remission in patients with AAV. Although early studies showed that treatment with corticosteroid monotherapy modified the outcome of AAV, mortality remained close to 50%. Only after cyclophosphamide therapy was introduced in the 1980s did 1-year patient survival become >80%.4Nachman 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 After these advances in the initial phase of AAV therapy, both the long-term implications related to its significant relapse rate and the serious effects of prolonged exposure to cyclophosphamide were recognized. The need to lower cyclophosphamide exposure and change to medications with a safer adverse-effect profile seemed evident not only to enhance patient and kidney survival, but also to optimize quality of life. This led to the concept of induction followed by maintenance therapy, raising the question of what is the ideal maintenance therapy.2Exley A.R. Bacon P.A. Luqmani R.A. Kitas G.D. Carruthers D.M. Moots R. Examination of disease severity in systemic vasculitis from the novel perspective of damage using the vasculitis damage index (VDI).Br J Rheumatol. 1998; 37: 57-63Crossref PubMed Scopus (100) Google Scholar, 4Nachman 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, 5Jayne D. Rasmussen N. Andrassy K. et al.European Vasculitis Study GroupA randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies.N Engl J Med. 2003; 349: 36-44Crossref PubMed Scopus (1176) Google Scholar, 6Hogan S.L. Falk R.J. Chin H. et al.Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis.Ann Intern Med. 2005; 143: 621-631Crossref PubMed Scopus (369) Google Scholar, 7Abdou N.I. Kullman G.J. Hoffman G.S. et al.Wegener's granulomatosis: survey of 701 patients in North America Changes in outcome in the 1990s.J Rheumatol. 2002; 29: 309-316PubMed Google Scholar, 8Srouji I.A. Andrews P. Edwards C. Lund V.J. Patterns of presentation and diagnosis of patients with Wegener's granulomatosis: ENT aspects.J Laryngol Otol. 2007; 121: 653-658Crossref PubMed Scopus (59) Google Scholar Several additional advances have changed the face of AAV management, including the finding of a specific and sensitive antibody that tracks the disease, and perhaps more importantly, the formation of collaborative groups to study these rare diseases. EUVAS, one of these collaborative networks, is dedicated to advancing this field from uncontrolled, retrospective, single-center treatment studies to the more informative, but difficult and expensive, randomized controlled trials (RCTs). These collaborative efforts have been critical in generating knowledge to improve the outcomes of patients affected by this rare, albeit lethal, disease.9Jayne D.R. Rasmussen N. Treatment of antineutrophil cytoplasm autoantibody-associated systemic vasculitis: initiatives of the European Community Systemic Vasculitis Clinical Trials Study Group.Mayo Clin Proc. 1997; 72: 737-747Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar The IMPROVE (International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides) trial3Hiemstra T.F. Walsh M. Mahr A. et al.European Vasculitis Study Group (EUVAS)Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial.JAMA. 2010; 304: 2381-2388Crossref PubMed Scopus (446) Google Scholar was an open-label multicenter RCT to assess whether mycophenolate mofetil (MMF) reduces the risk of relapse compared with azathioprine in patients with AAV in remission. Proper assessment of maintenance therapy requires that successful induction has been achieved. Managing the impact of uncontrolled disease necessitates the exclusion of resistant patients, as well as appropriately timed conversion from induction to maintenance therapy. Accordingly, IMPROVE assessed 175 patients with AAV receiving glucocorticoids and cyclophosphamide for eligibility and randomly assigned 156 of these patients deemed to be in remission within 6 months of induction therapy. In this study, 6 patients were appropriately excluded during induction because of progression of disease or failure to respond to treatment. This design choice had important implications; specifically, not restricting induction to either a fixed time or a specific treatment regimen provided 2 important options that maximized the likelihood of successful induction therapy before randomization to maintenance therapy. This is particularly relevant in AAV trials given that there currently is no specific immunologic measure that confirms activity versus quiescence. Imbalance in disease activity at entry to a study could lead to an error in inference of the benefits or harms of treatment during the maintenance phase. In this study, the equality of the groups at randomization is indicated by the similarity in time to remission (97 vs 102 days), similarity in demographic and laboratory characteristics, and very similar cumulative exposure to cyclophosphamide, prednisolone, and plasma exchange. The primary outcome variable was relapse-free survival, defined as time from remission to the first relapse, with secondary end points including the Vasculitis Damage Index, estimated glomerular filtration rate, and proteinuria. Relapse was defined as recurrence of symptoms attributable to active vasculitis and major relapses were defined as the new appearance of major organ involvement. The duration of the observation period also is an important quality indicator of the trial given that the primary end point was time-dependent relapse-free survival. The mean observation period was 39 (range, 0.66-53.6) months. This follow-up compares very favorably with other maintenance studies of AAV and encompasses the time frame in which most relapses occur.4Nachman 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, 5Jayne D. Rasmussen N. Andrassy K. et al.European Vasculitis Study GroupA randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies.N Engl J Med. 2003; 349: 36-44Crossref PubMed Scopus (1176) Google Scholar, 10Pagnoux C. Mahr A. Hamidou M.A. et al.French Vasculitis Study GroupAzathioprine or methotrexate maintenance for ANCA-associated vasculitis.N Engl J Med. 2008; 359: 2790-2803Crossref PubMed Scopus (519) Google Scholar, 11Iatrou C. Zerbala S. Revela I. et al.Mycophenolate mofetil as maintenance therapy in patients with vasculitis and renal involvement.Clin Nephrol. 2009; 72: 31-37Crossref PubMed Google Scholar, 12Rhee E.P. Laliberte K.A. Niles J.L. Rituximab as maintenance therapy for anti-neutrophil cytoplasmic antibody-associated vasculitis.Clin J Am Soc Nephrol. 2010; 5: 1394-1400Crossref PubMed Scopus (102) Google Scholar, 13Szpirt W.M. Heaf J.G. Petersen J. Plasma exchange for induction and cyclosporine A for maintenance of remission in Wegener's granulomatosis—a clinical randomized controlled trial.Nephrol Dial Transplant. 2011; 26: 206-213Crossref PubMed Scopus (94) Google Scholar The effect of treatment on outcomes was assessed using Cox proportional hazards models with the allocated treatment as the predictor variable. There were more relapses in the MMF group (42 of 76 patients) compared with the azathioprine group (30 of 80 patients), resulting in an unadjusted hazard ratio (HR) of 1.69 (95% confidence interval [CI], 1.06-2.70; P = 0.03) and more major relapses (18 vs 10) in the MMF group. Even after adjusting for important prespecified factors, including age, sex, diagnostic subtype, route of cyclophosphamide administration, and baseline creatinine level, the HR for relapse remained significantly greater in the MMF group at 1.80 (95% CI, 1.10-2.93; P = 0.02). Crossover numbers are important in an intention-to-treat analysis because they have the potential to obfuscate the trial interpretation, but the small percentage that crossed over (5%; n = 8) makes this an unlikely factor to have influenced the primary findings. Tolerance to treatment medication also is an important component of any study, as well as to the clinical relevance of the findings. Determining tolerance requires repeated assessment during the study time frame of the prescribed versus used amount of drug. Although this is not a required component of an intention-to-treat analysis, it was determined in this study and found to be similar in both groups. More granularity to this assessment can be made by looking at adverse events. There were 22 severe adverse events in 13 patients in the azathioprine group and 8 patients in the MMF group (HR, 0.53; 95% CI, 0.23-1.18; P = 0.12). In addition to finding no differences in the frequency of serious adverse events, the investigators found no differences in any of the adverse-event categories, including infectious, hematologic, cardiovascular, or malignancy domains. At its most extreme, intolerance leads to drug withdrawal. This occurred in 6 patients in the azathioprine group and 2 patients in the MMF group, a difference that was neither statistically significant nor clinically meaningful. As in every trial, there are limitations. The MMF dosage chosen may have been insufficient for patients with AAV. In earlier studies, up to 3 g/d of MMF was used as maintenance therapy in both lupus nephritis and kidney transplant trials.14Contreras G. Pardo V. Leclercq B. et al.Sequential therapies for proliferative lupus nephritis.N Engl J Med. 2004; 350: 971-980Crossref PubMed Scopus (707) Google Scholar, 15Halloran P. Mathew T. Tomlanovich S. Groth C. Hooftman L. Barker C. Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection The International Mycophenolate Mofetil Renal Transplant Study Groups.Transplantation. 1997; 63: 39-47Crossref PubMed Scopus (536) Google Scholar However, adverse events generally increased with the higher dosage with little added benefit in terms of efficacy. Today, 2 g/d of MMF is the standard dosage used in the field of solid-organ transplantation, although admittedly not usually as monotherapy. Additional support for using the 2-g/d dosage of MMF comes from pharmacokinetic studies that have shown adequate trough levels and areas under the curve with this dosage.16Zahr N. Arnaud L. Marquet P. et al.Mycophenolic acid area under the curve correlates with disease activity in lupus patients treated with mycophenolate mofetil.Arthritis Rheum. 2010; 62: 2047-2054PubMed Google Scholar, 17Gourishankar S. Houde I. Keown P.A. et al.The CLEAR Study: a 5-day, 3-g loading dose of mycophenolate mofetil versus standard 2-g dosing in renal transplantation.Clin J Am Soc Nephrol. 2010; 5: 1282-1289Crossref PubMed Scopus (48) Google Scholar Also, although 156 patients is a significant sample size in comparison to other trials in glomerulonephritis, the overall numbers are small and the study was completed in a European population dominated by whites, raising uncertainty about the study's generalizability. Specific genetic factors related to ancestry could influence both the severity of disease and pharmacokinetics of the therapy. Whether new insights into this disease and its treatments will emerge from better understanding of the pharmacogenetic variations known to alter the pharmacokinetics and/or pharmacodynamics of immunosuppressive agents remains to be determined.18Rovin B.H. McKinley A.M. Birmingham D.J. Can we personalize treatment for kidney diseases?.Clin J Am Soc Nephrol. 2009; 4: 1670-1676Crossref PubMed Scopus (22) Google Scholar Last, even this RCT is not statistically powered with a long enough follow-up to examine less common adverse effects of therapy, such as late-onset malignancy. Earlier studies have addressed other options in maintenance therapy in patients with AAV, including continuing low-dose cyclophosphamide therapy, switching to methotrexate or azathioprine therapy, or the introduction of newer therapies, such as MMF, calcineurin inhibitors (cyclosporine), and even rituximab.5Jayne D. Rasmussen N. Andrassy K. et al.European Vasculitis Study GroupA randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies.N Engl J Med. 2003; 349: 36-44Crossref PubMed Scopus (1176) Google Scholar, 10Pagnoux C. Mahr A. Hamidou M.A. et al.French Vasculitis Study GroupAzathioprine or methotrexate maintenance for ANCA-associated vasculitis.N Engl J Med. 2008; 359: 2790-2803Crossref PubMed Scopus (519) Google Scholar, 11Iatrou C. Zerbala S. Revela I. et al.Mycophenolate mofetil as maintenance therapy in patients with vasculitis and renal involvement.Clin Nephrol. 2009; 72: 31-37Crossref PubMed Google Scholar, 12Rhee E.P. Laliberte K.A. Niles J.L. Rituximab as maintenance therapy for anti-neutrophil cytoplasmic antibody-associated vasculitis.Clin J Am Soc Nephrol. 2010; 5: 1394-1400Crossref PubMed Scopus (102) Google Scholar, 13Szpirt W.M. Heaf J.G. Petersen J. Plasma exchange for induction and cyclosporine A for maintenance of remission in Wegener's granulomatosis—a clinical randomized controlled trial.Nephrol Dial Transplant. 2011; 26: 206-213Crossref PubMed Scopus (94) Google Scholar However, most were single-center or nonrandomized studies in which the possibility of bias, small sample size, and inadequate observation time limited study quality and broad clinical applicability. These limitations are particularly important in AAV maintenance studies, in which there is a need to assess both the risk of relapse with withdrawal versus the risk of ongoing immunosuppression. Without sufficient study numbers and a complete spectrum of patients at risk, assessment of maintenance immunosuppression versus the consequences of a severe relapse is difficult to determine. All these agents showed promise, but larger multicenter randomized trials need to be conducted to properly assess their efficacy. Another agent previously tested as maintenance therapy in AAV was the soluble fusion protein etanercept, designed to inhibit tumor necrosis factor. One study tested whether adding this agent versus placebo to a regimen of either daily oral cyclophosphamide or methotrexate (both with corticosteroids) was more effective in maintaining remission.19Wegener's Granulomatosis Etanercept Trial (WGET) Research GroupEtanercept plus standard therapy for Wegener's granulomatosis.N Engl J Med. 2005; 352: 351-361Crossref PubMed Scopus (793) Google Scholar No benefit in the rate or severity of relapse was observed, but a significantly higher rate of solid tumor formation was noted in those receiving etanercept; therefore, this therapy is no longer recommended for the treatment of AAV.20Stone J.H. Holbrook J.T. Marriott M.A. et al.Wegener's Granulomatosis Etanercept Trial Research GroupSolid malignancies among patients in the Wegener's Granulomatosis Etanercept Trial.Arthritis Rheum. 2006; 54: 1608-1618Crossref PubMed Scopus (177) Google Scholar Even before IMPROVE, the best available evidence in the literature supported the use of azathioprine, 1-2 mg/kg/d, for 6-18 months postinduction. This recommendation was based on an RCT by the same EUVAS group.5Jayne D. Rasmussen N. Andrassy K. et al.European Vasculitis Study GroupA randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies.N Engl J Med. 2003; 349: 36-44Crossref PubMed Scopus (1176) Google Scholar They found azathioprine to be as effective as cyclophosphamide in preventing relapses, but associated with less toxicity. In another maintenance RCT, azathioprine was compared with methotrexate.10Pagnoux C. Mahr A. Hamidou M.A. et al.French Vasculitis Study GroupAzathioprine or methotrexate maintenance for ANCA-associated vasculitis.N Engl J Med. 2008; 359: 2790-2803Crossref PubMed Scopus (519) Google Scholar In this study, neither the relapse rate (36% vs 33%, respectively; P = 0.7) nor time to relapse was different. Although the absolute number of side effects was similar, the severity of adverse events in the methotrexate treatment group was significantly greater. The IMPROVE study3Hiemstra T.F. Walsh M. Mahr A. et al.European Vasculitis Study Group (EUVAS)Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial.JAMA. 2010; 304: 2381-2388Crossref PubMed Scopus (446) Google Scholar provides strong evidence that azathioprine is superior to MMF as maintenance therapy in patients with AAV and should be considered the first line of treatment. Azathioprine already has been shown in an RCT to be equally efficacious as low-dose cyclophosphamide, but with significantly less toxicity.5Jayne D. Rasmussen N. Andrassy K. et al.European Vasculitis Study GroupA randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies.N Engl J Med. 2003; 349: 36-44Crossref PubMed Scopus (1176) Google Scholar However, the question addressed in the IMPROVE study was still relevant given the significant amount of data that until recently has suggested that MMF is superior to azathioprine as maintenance therapy in other conditions, including lupus nephritis and solid-organ transplant.14Contreras G. Pardo V. Leclercq B. et al.Sequential therapies for proliferative lupus nephritis.N Engl J Med. 2004; 350: 971-980Crossref PubMed Scopus (707) Google Scholar, 15Halloran P. Mathew T. Tomlanovich S. Groth C. Hooftman L. Barker C. Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection The International Mycophenolate Mofetil Renal Transplant Study Groups.Transplantation. 1997; 63: 39-47Crossref PubMed Scopus (536) Google Scholar, 21Houssiau F.A. D'Cruz D. Sangle S. et al.MAINTAIN Nephritis Trial GroupAzathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial.Ann Rheum Dis. 2010; 69: 2083-2089Crossref PubMed Scopus (366) Google Scholar However, this trial showed a significantly higher relapse rate in the MMF group compared with azathioprine, particularly in the major relapse category. In addition, there were no significant differences in adverse effects between the 2 agents. Although it was not mentioned in the article, azathioprine also is significantly less expensive than MMF, an important consideration, particularly in developing countries where financial constraints often limit access to more expensive medications. Certainly this is not the end of the story. The significant relapse and adverse-event rates observed with either agent in this trial indicate suboptimal therapy, and more effective methods for assessing patient response, allowing early adjustment of either the dose or type of medication, remain elusive. Our present approach, which lumps microscopic polyangiitis and Wegener granulomatosis with antineutrophil cytoplasmic antibody–positive and –negative patients, indicates an additional significant gap in our knowledge. Thus, organizations such as EUVAS need to be supported to answer these questions and should be expanded to include other rare kidney diseases. Regardless of the limitations, important conclusions can be drawn from this well-designed and executed RCT in AAV. Azathioprine, one of the oldest and best known of the immunosuppressive drugs, was found, in this study, to be a more effective agent than MMF in preventing relapse in these diseases with no difference in toxicity. This trial should cement azathioprine as first-line maintenance therapy in AAV. Financial Disclosure: The authors declare that they have no relevant financial interests.