In the Literature

Maintenance Immunosuppression in Antineutrophil CytoplasmicAntibody–Associated Vasculitis

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 We-

gener granulomatosis and microscopic polyangiitis, isrelatively uncommon, it has devastating consequencesif untreated. Additionally, the propensity of AAV tooccur in the more vulnerable older age group andprogress rapidly makes it imperative to reach a correctdiagnosis and implement effective treatment.1,2 Evenwith prompt diagnosis, treatment is difficult and maybe complicated by relapsing disease. Accordingly,Hiemstra et al, writing on behalf of the EuropeanVasculitis Study Group (EUVAS),3 recently reporteda study published in 2010 by the Journal of theAmerican Medical Association of maintenance immu-nosuppression after induction of remission in patientswith AAV.

Although early studies showed that treatment withcorticosteroid monotherapy modified the outcome ofAAV, mortality remained close to 50%. Only aftercyclophosphamide therapy was introduced in the 1980sdid 1-year patient survival become �80%.4 Afterthese advances in the initial phase of AAV therapy,both the long-term implications related to its signifi-cant relapse rate and the serious effects of prolongedexposure to cyclophosphamide were recognized. Theneed to lower cyclophosphamide exposure and changeto medications with a safer adverse-effect profileseemed evident not only to enhance patient and kid-ney survival, but also to optimize quality of life. Thisled to the concept of induction followed by mainte-nance therapy, raising the question of what is the idealmaintenance therapy.2,4-8

Several additional advances have changed the faceof AAV management, including the finding of a spe-cific and sensitive antibody that tracks the disease,and perhaps more importantly, the formation of collab-orative groups to study these rare diseases. EUVAS,one of these collaborative networks, is dedicated to

Originally published online April 20, 2011.Address correspondence to Daniel Cattran, MD, 585 University

Ave, NCSB Space 11C-1256, Toronto, ON M5G 2N2, Canada.E-mail: daniel.cattran@uhn.on.ca

© 2011 by the National Kidney Foundation, Inc.0272-6386/$36.00

doi:10.1053/j.ajkd.2011.03.006

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advancing this field from uncontrolled, retrospective,single-center treatment studies to the more informa-tive, but difficult and expensive, randomized con-trolled trials (RCTs). These collaborative efforts havebeen critical in generating knowledge to improve theoutcomes of patients affected by this rare, albeitlethal, disease.9

WHAT DOES THIS IMPORTANT STUDY SHOW?

The IMPROVE (International MycophenolateMofetil Protocol to Reduce Outbreaks of Vasculiti-des) trial3 was an open-label multicenter RCT toassess whether mycophenolate mofetil (MMF) re-duces the risk of relapse compared with azathioprinein patients with AAV in remission. Proper assessmentof maintenance therapy requires that successful induc-tion has been achieved. Managing the impact ofuncontrolled disease necessitates the exclusion ofresistant patients, as well as appropriately timed con-version from induction to maintenance therapy. Ac-cordingly, IMPROVE assessed 175 patients with AAVreceiving glucocorticoids and cyclophosphamide foreligibility and randomly assigned 156 of these pa-tients deemed to be in remission within 6 months ofinduction therapy. In this study, 6 patients were appro-priately excluded during induction because of progres-sion of disease or failure to respond to treatment. Thisdesign choice had important implications; specifi-cally, not restricting induction to either a fixed time ora specific treatment regimen provided 2 importantoptions that maximized the likelihood of successfulinduction therapy before randomization to mainte-nance therapy. This is particularly relevant in AAVtrials given that there currently is no specific immuno-logic measure that confirms activity versus quies-cence. Imbalance in disease activity at entry to a studycould lead to an error in inference of the benefits orharms of treatment during the maintenance phase. Inthis study, the equality of the groups at randomizationis indicated by the similarity in time to remission (97vs 102 days), similarity in demographic and labora-tory characteristics, and very similar cumulative expo-sure to cyclophosphamide, prednisolone, and plasmaexchange.

The primary outcome variable was relapse-free

survival, defined as time from remission to the first

Am J Kidney Dis. 2011;57(6):818-821

In the Literature

relapse, with secondary end points including the Vas-culitis Damage Index, estimated glomerular filtrationrate, and proteinuria. Relapse was defined as recur-rence of symptoms attributable to active vasculitisand major relapses were defined as the new appear-ance of major organ involvement. The duration of theobservation period also is an important quality indica-tor of the trial given that the primary end point wastime-dependent relapse-free survival. The mean obser-vation period was 39 (range, 0.66-53.6) months. Thisfollow-up compares very favorably with other mainte-nance studies of AAV and encompasses the timeframe in which most relapses occur.4,5,10-13 The effectof treatment on outcomes was assessed using Coxproportional hazards models with the allocated treat-ment as the predictor variable. There were morerelapses in the MMF group (42 of 76 patients) com-pared 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 MMFgroup. Even after adjusting for important prespecifiedfactors, including age, sex, diagnostic subtype, routeof cyclophosphamide administration, and baseline cre-atinine level, the HR for relapse remained signifi-cantly greater in the MMF group at 1.80 (95% CI,1.10-2.93; P � 0.02). Crossover numbers are impor-tant in an intention-to-treat analysis because they havethe potential to obfuscate the trial interpretation, butthe small percentage that crossed over (5%; n � 8)makes this an unlikely factor to have influenced theprimary findings.

Tolerance to treatment medication also is an impor-tant component of any study, as well as to the clinicalrelevance of the findings. Determining tolerance re-quires repeated assessment during the study timeframe of the prescribed versus used amount of drug.Although this is not a required component of anintention-to-treat analysis, it was determined in thisstudy and found to be similar in both groups. Moregranularity to this assessment can be made by lookingat adverse events. There were 22 severe adverseevents in 13 patients in the azathioprine group and 8patients in the MMF group (HR, 0.53; 95% CI,0.23-1.18; P � 0.12). In addition to finding no differ-ences in the frequency of serious adverse events, theinvestigators found no differences in any of the ad-verse-event categories, including infectious, hemato-logic, cardiovascular, or malignancy domains. At itsmost extreme, intolerance leads to drug withdrawal.This occurred in 6 patients in the azathioprine groupand 2 patients in the MMF group, a difference thatwas neither statistically significant nor clinically mean-

ingful.

Am J Kidney Dis. 2011;57(6):818-821

As in every trial, there are limitations. The MMFdosage chosen may have been insufficient for patientswith AAV. In earlier studies, up to 3 g/d of MMF wasused as maintenance therapy in both lupus nephritisand kidney transplant trials.14,15 However, adverseevents generally increased with the higher dosagewith little added benefit in terms of efficacy. Today, 2g/d of MMF is the standard dosage used in the field ofsolid-organ transplantation, although admittedly notusually as monotherapy. Additional support for usingthe 2-g/d dosage of MMF comes from pharmacoki-netic studies that have shown adequate trough levelsand areas under the curve with this dosage.16,17

Also, although 156 patients is a significant samplesize in comparison to other trials in glomerulonephri-tis, the overall numbers are small and the study wascompleted in a European population dominated bywhites, raising uncertainty about the study’s general-izability. Specific genetic factors related to ancestrycould influence both the severity of disease and phar-macokinetics of the therapy. Whether new insightsinto this disease and its treatments will emerge frombetter understanding of the pharmacogenetic varia-tions known to alter the pharmacokinetics and/orpharmacodynamics of immunosuppressive agents re-mains to be determined.18 Last, even this RCT is notstatistically powered with a long enough follow-up toexamine less common adverse effects of therapy, suchas late-onset malignancy.

HOW DOES THIS STUDY COMPARE WITHPRIOR STUDIES?

Earlier studies have addressed other options inmaintenance therapy in patients with AAV, includingcontinuing low-dose cyclophosphamide therapy,switching to methotrexate or azathioprine therapy, orthe introduction of newer therapies, such as MMF,calcineurin inhibitors (cyclosporine), and even ritux-imab.5,10-13 However, most were single-center or non-randomized studies in which the possibility of bias,small sample size, and inadequate observation timelimited study quality and broad clinical applicability.These limitations are particularly important in AAVmaintenance studies, in which there is a need to assessboth the risk of relapse with withdrawal versus therisk of ongoing immunosuppression. Without suffi-cient study numbers and a complete spectrum ofpatients at risk, assessment of maintenance immuno-suppression versus the consequences of a severe re-lapse is difficult to determine. All these agents showedpromise, but larger multicenter randomized trials needto be conducted to properly assess their efficacy.

Another agent previously tested as maintenancetherapy in AAV was the soluble fusion protein etaner-

cept, designed to inhibit tumor necrosis factor. One

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Cattran and Hladunewich

study tested whether adding this agent versus placeboto a regimen of either daily oral cyclophosphamide ormethotrexate (both with corticosteroids) was moreeffective in maintaining remission.19 No benefit in therate or severity of relapse was observed, but a signifi-cantly higher rate of solid tumor formation was notedin those receiving etanercept; therefore, this therapy isno longer recommended for the treatment of AAV.20

Even before IMPROVE, the best available evidencein the literature supported the use of azathioprine, 1-2mg/kg/d, for 6-18 months postinduction. This recommen-dation was based on an RCT by the same EUVASgroup.5 They found azathioprine to be as effective ascyclophosphamide in preventing relapses, but associatedwith less toxicity. In another maintenance RCT, azathio-prine was compared with methotrexate.10 In this study,neither the relapse rate (36% vs 33%, respectively; P �0.7) nor time to relapse was different. Although theabsolute number of side effects was similar, the severityof adverse events in the methotrexate treatment groupwas significantly greater.

WHAT SHOULD CLINICIANS ANDRESEARCHERS DO?

The IMPROVE study3 provides strong evidencethat azathioprine is superior to MMF as maintenancetherapy in patients with AAV and should be consid-ered the first line of treatment. Azathioprine alreadyhas been shown in an RCT to be equally efficacious aslow-dose cyclophosphamide, but with significantlyless toxicity.5 However, the question addressed in theIMPROVE study was still relevant given the signifi-cant amount of data that until recently has suggestedthat MMF is superior to azathioprine as maintenancetherapy in other conditions, including lupus nephritisand solid-organ transplant.14,15,21 However, this trialshowed a significantly higher relapse rate in the MMFgroup compared with azathioprine, particularly in themajor relapse category. In addition, there were nosignificant differences in adverse effects between the2 agents. Although it was not mentioned in the article,azathioprine also is significantly less expensive thanMMF, an important consideration, particularly in de-veloping countries where financial constraints oftenlimit access to more expensive medications.

Certainly this is not the end of the story. Thesignificant relapse and adverse-event rates observedwith either agent in this trial indicate suboptimaltherapy, and more effective methods for assessingpatient response, allowing early adjustment of eitherthe dose or type of medication, remain elusive. Ourpresent approach, which lumps microscopic polyangi-itis and Wegener granulomatosis with antineutrophilcytoplasmic antibody–positive and –negative pa-

tients, indicates an additional significant gap in our

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knowledge. Thus, organizations such as EUVAS needto be supported to answer these questions and shouldbe expanded to include other rare kidney diseases.

Regardless of the limitations, important conclu-sions can be drawn from this well-designed and ex-ecuted RCT in AAV. Azathioprine, one of the oldestand best known of the immunosuppressive drugs, wasfound, in this study, to be a more effective agent thanMMF in preventing relapse in these diseases with nodifference in toxicity. This trial should cement azathio-prine as first-line maintenance therapy in AAV.

Daniel C. Cattran, MDMichelle A. Hladunewich, MD

Toronto Glomerulonephritis RegistryUniversity Health Network

Toronto, Canada

ACKNOWLEDGEMENTSFinancial Disclosure: The authors declare that they have no

relevant financial interests.

REFERENCES1. Booth AD, Pusey CD, Jayne DR. Renal vasculitis—an up-

date in 2004. Nephrol Dial Transplant. 2004;19(8):1964-1968.2. Exley AR, Bacon PA, Luqmani RA, Kitas GD, Carruthers

DM, Moots R. Examination of disease severity in systemic vascu-litis from the novel perspective of damage using the vasculitisdamage index (VDI). Br J Rheumatol. 1998;37(1):57-63.

3. Hiemstra TF, Walsh M, Mahr A, et al; for the EuropeanVasculitis Study Group (EUVAS). Mycophenolate mofetil vs aza-thioprine for remission maintenance in antineutrophil cytoplasmicantibody-associated vasculitis: a randomized controlled trial. JAMA.2010;304(21):2381-2388.

4. Nachman PH, Hogan SL, Jennette JC, Falk RJ. Treatmentresponse and relapse in antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J AmSoc Nephrol. 1996;7(1):33-39.

5. Jayne D, Rasmussen N, Andrassy K, et al; for the EuropeanVasculitis Study Group. A randomized trial of maintenance therapyfor vasculitis associated with antineutrophil cytoplasmic autoanti-bodies. N Engl J Med. 2003;349(1):36-44.

6. Hogan SL, Falk RJ, Chin H, et al. Predictors of relapse andtreatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Ann Intern Med. 2005;143(9):621-631.

7. Abdou NI, Kullman GJ, Hoffman GS, et al. Wegener’sgranulomatosis: survey of 701 patients in North America. Changesin outcome in the 1990s. J Rheumatol. 2002;29(2):309-316.

8. Srouji IA, Andrews P, Edwards C, Lund VJ. Patterns ofpresentation and diagnosis of patients with Wegener’s granuloma-tosis: ENT aspects. J Laryngol Otol. 2007;121(7):653-658.

9. Jayne DR, Rasmussen N. Treatment of antineutrophil cyto-plasm autoantibody-associated systemic vasculitis: initiatives ofthe European Community Systemic Vasculitis Clinical Trials StudyGroup. Mayo Clin Proc. 1997;72(8):737-747.

10. Pagnoux C, Mahr A, Hamidou MA, et al; French VasculitisStudy Group. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med. 2008;359(26):2790-2803.

11. Iatrou C, Zerbala S, Revela I, et al. Mycophenolate mofetilas maintenance therapy in patients with vasculitis and renal involve-

ment. Clin Nephrol. 2009;72(1):31-37.

Am J Kidney Dis. 2011;57(6):818-821

In the Literature

12. Rhee EP, Laliberte KA, Niles JL. Rituximab as mainte-nance therapy for anti-neutrophil cytoplasmic antibody-associatedvasculitis. Clin J Am Soc Nephrol. 2010;5(8):1394-1400.

13. Szpirt WM, Heaf JG, Petersen J. Plasma exchange forinduction and cyclosporine A for maintenance of remission inWegener’s granulomatosis—a clinical randomized controlled trial.Nephrol Dial Transplant. 2011;26(1):206-213.

14. Contreras G, Pardo V, Leclercq B, et al. Sequential therapies forproliferative lupus nephritis. N Engl J Med. 2004;350(10):971-980.

15. Halloran P, Mathew T, Tomlanovich S, Groth C, HooftmanL, Barker C. Mycophenolate mofetil in renal allograft recipients: apooled efficacy analysis of three randomized, double-blind, clini-cal studies in prevention of rejection. The International Mycophe-nolate Mofetil Renal Transplant Study Groups. Transplantation.1997;63(1):39-47.

16. Zahr N, Arnaud L, Marquet P, et al. Mycophenolic acid areaunder the curve correlates with disease activity in lupus patientstreated with mycophenolate mofetil. Arthritis Rheum. 2010;62(7):

2047-2054.

Am J Kidney Dis. 2011;57(6):818-821

17. Gourishankar S, Houde I, Keown PA, et al. The CLEARStudy: a 5-day, 3-g loading dose of mycophenolate mofetil versusstandard 2-g dosing in renal transplantation. Clin J Am SocNephrol. 2010;5(7):1282-1289.

18. Rovin BH, McKinley AM, Birmingham DJ. Can we person-alize treatment for kidney diseases? Clin J Am Soc Nephrol.2009;4(10):1670-1676.

19. Wegener’s Granulomatosis Etanercept Trial (WGET) Re-search Group. Etanercept plus standard therapy for Wegener’s granu-lomatosis. N Engl J Med. 2005;352(4):351-361.

20. Stone JH, Holbrook JT, Marriott MA, et al; Wegener’s Granu-lomatosis Etanercept Trial Research Group. Solid malignancies amongpatients in the Wegener’s Granulomatosis Etanercept Trial. ArthritisRheum. 2006;54(5):1608-1618.

21. Houssiau FA, D’Cruz D, Sangle S, et al; MAINTAINNephritis Trial Group. Azathioprine versus mycophenolate mofetilfor long-term immunosuppression in lupus nephritis: results fromthe MAINTAIN Nephritis Trial. Ann Rheum Dis. 2010;69(12):2083-

2089.

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