CJASN ePress. Published on June 26, 2014 as doi: 10.2215/CJN.00100114 Article

Long-Term Follow-Up of Cyclophosphamide Compared with for Initial Maintenance Therapy in ANCA-Associated Vasculitis

| Michael Walsh,* Mikkel Faurschou,† Annelies Berden,‡ Oliver Flossmann,§ Ingeborg Bajema,‡ Peter Hoglund, Rona Smith,¶ Wladimir Szpirt,** Kerstin Westman,†† Charles D. Pusey,‡‡ and David R.W. Jayne,¶ for the European Vasculitis Study Group *Departments of Medicine and Clinical Abstract Epidemiology and Background and objectives Treatment with azathioprine within 3 months of remission induction with Biostatistics, Population cyclophosphamide is a common treatment strategy for patients with ANCA-associated vasculitis. This study Health Research Institute, comprised patients undergoing long-term follow-up who were randomly allocated to azathioprine after 3–6 McMaster University and months or after 12 months of cyclophosphamide treatment. Population Health Research Institute, Hamilton, Ontario, Design, setting, participants, & measurements Patients from 39 European centers between 1995 and 1997 with a Canada; †Departments of new diagnosis of ANCA-associated vasculitis that involved the kidneys or another vital organ were eligible. At Infectious Diseases and the time of diagnosis, participants were randomly allocated to convert to azathioprine after 3–6months(the Rheumatology and **Nephrology, azathioprine group) or after 12 months of cyclophosphamide (the cyclophosphamide group). Patients who did Copenhagen University not achieve a remission within 6 months were excluded. This study assessed relapses, ESRD, and death during Hospital, Rigshospitalet, long-term follow-up. Copenhagen, Denmark; ‡Department of Results Patients were allocated to the azathioprine group (n=71) and the cyclophosphamide group (n=73). Of Pathology, Leiden University Medical these patients, 63 (43.8%) developed a relapse, 35 (24.3%) developed a renal relapse, 13 (9.0%) developed ESRD, Center, Leiden, The and 21 (14.6%) died. Although there were worse outcomes in the azathioprine group, none were statistically Netherlands; §Renal significant. The subdistribution hazard ratio [sHR] for relapse was 1.63 (95% confidence interval [95% CI], 0.99 to Unit, Royal Berkshire 2.71), the composite of relapse or death hazard ratio [HR] was 1.59 (95% CI, 1.00 to 2.54), the ESRD sHR was 1.71 Hospital, Reading, United Kingdom; | (95% CI, 0.56 to 5.19), and the death HR was 0.75 (95% CI, 0.32 to 1.79). Competence Centre for Clinical Research, Conclusions It remains uncertain whether converting to azathioprine after 3–6 months of induction cyclophos- University Hospital Lund, ¶ phamide therapy is as effective as converting after 12 months. Outcomes are still poor for this group of patients Lund, Sweden; Renal and further research is required to determine the optimal timing of maintenance therapy. Unit, Addenbrooke’s Hospital, Cambridge, Clin J Am Soc Nephrol 9: ccc–ccc, 2014. doi: 10.2215/CJN.00100114 United Kingdom; ††Department of Nephrology and Transplantation, Skane Introduction (CYCAZAREM) trial tested the effect of replacing daily University Hospital, ’ Malmo¨,Sweden;and Granulomatosis with polyangiitis (Wegener s) and oral cyclophosphamide with azathioprine after induc- ‡‡ microscopic polyangiitis (MPA) are commonly asso- Department of tion of remission rather than after 1 year of treatment in Medicine, Imperial ciated with ANCA and are collectively referred to as patients with generalized AAV and a serum creat- College London, ANCA-associated vasculitis (AAV). Initial immuno- inine#5.6 mg/dl at presentation (7). At the time the Hammersmith Hospital, suppressive therapy with cyclophosphamide and glu- trial closed (18 months after treatment started), 21 pa- London, United cocorticoids is the standard of care for patients with tients had a relapse of AAV with almost equal numbers Kingdom generalized disease (1,2). Although cyclophospha- observed between groups. Similarly, almost equal Correspondence: mide is effective at inducing remission of the disease, numbers experienced severe or life-threatening adverse Dr. Michael Walsh, relapses are common irrespective of treatment. Fur- events. Because no significant differences were ob- Department of thermore, cyclophosphamide is associated with in- served between treatment groups, the trial concluded Clinical Epidemiology creasing toxicity as cumulative doses rise. The risks that cyclophosphamide can be withdrawn after induc- and Biostatistics, of infections in the short term and malignancy in the tion of remission and a minimum of 3 months of cyclo- Population Health – Research Institute, longer term are of particular concern (3 6). phosphamide therapy is given. McMaster University, Several strategies to reduce exposure to cyclophos- Whether the reduction in cyclophosphamide expo- 1200 Main Street W, phamide and mitigate its toxic effects while retaining sure in the first year of treatment affects the long-term Hamilton, ON L8N disease control have been tested in randomized con- course of AAV is uncertain. Recent experiences reduc- 4A6, Canada. Email: – lastwalsh1975@ trolled trials (7 11). The Cyclophosphamide versus ing cyclophosphamide exposure by use of pulses rather gmail.com Azathioprine for Early Remission Phase of Vasculitis than daily dosing resulted in an increased risk for www.cjasn.org Vol 9 September, 2014 Copyright © 2014 by the American Society of Nephrology 1 2 Clinical Journal of the American Society of Nephrology

relapse, and replacing cyclophosphamide with Study Outcomes also suggested a higher risk and greater need for later The primary outcome was first relapse. Relapse was (12,13). Similarly, introduction of aza- defined as new or worsened disease activity that occurred thioprine as early replacement for cyclophosphamide was after an initial remission and required a change in therapy. associated with more relapses over 5 years in a retrospective Efficacy was further compared by assessing the outcomes cohort study (14). Given the uncertainty of the long-term of the composite of relapse and all-cause mortality, the consequences of early substitution of azathioprine for cyclo- incidence rate of relapses, renal relapse (i.e., relapse that phosphamide in generalized AAV, we conducted extended included a renal manifestation), and medication exposure follow-up of patients enrolled in the CYCAZREM trial. after the end of the trial. Safety was assessed by comparing the outcomes of all-cause mortality, ESRD (i.e., need for permanent dialysis or renal transplantation), and fre- Materials and Methods quency of malignancies. Design The CYCAZAREM trial was conducted in accordance Statistical Analyses with the Declaration of Helsinki and the protocol is pre- All patients who entered remission between 3 and 6 viously described and available online (www.vasculitis. months after trial registration were included in all analyses. fl org) (7). Brie y, CYCAZAREM was an open-label, two- Descriptive data are presented as the median (25th to 75th parallel-group randomized controlled trial that recruited percentile) for continuous variables and as the frequency from 39 centers in 11 European countries between 1995 (percentage) for categorical data. and 1997. Patients were centrally allocated to one of two The outcomes were assessed using time-to-event analy- treatment groups by the method of minimization. ses. The effect of treatment assignment on the primary outcome (relapse) was estimated using competing risk Patients regression methods which jointly model the subdistribu- Eligible patients had granulomatosis with polyangiitis, tions of the primary and competing event (15). The sub- MPA, or the renal limited form of MPA with renal in- distribution hazard ratio (sHR) was calculated for the time volvement and/or threatened loss of other vital organ to first relapse for patients in the azathioprine group com- function. Patients had either a positive ANCA test by pared with those in the cyclophosphamide group while fl fi immuno uorescence or ELISA or vasculitis con rmed by a considering the competing risk of death. The competing biopsy. Patients with severe renal involvement with a risk paradigm was used because death may informatively . serum creatinine level of 5.6 mg/dl or that required di- censor patients (e.g., if one of the treatments increased the alysis were excluded. Registered patients that met the el- risk of early death, such as by infections, and thereby re- fi igibility criteria and achieved disease remission, de ned as moved patients from the risk set for relapse). Similarly, we theabsenceofdiseaseactivitydocumentedwithaBir- used competing risk models to assess renal relapses using mingham vasculitis activity score of zero, between 3 and both death and ESRD as competing risks and for the out- 6 months went on to receive randomized treatment. come of ESRD using death as a competing risk. We as- sessed all-cause mortality using a Cox proportional Treatment hazard model because there is no competing risk, and All patients received the same remission-induction ther- we calculated the hazard ratio (HR). We calculated the apy composed of daily oral cyclophosphamide 2 mg/kg incidence rate ratio (IRR) for all relapses over the entire per day (reduced by 25 mg per day for age.60 years) and a follow-up period. tapering course of daily oral prednisolone (initially at 1 The frequency of patients with at least one malignancy was mg/kg per day) until remission. Those in remission be- compared using Fisher’s exact test. Medication exposure was tween 3 and 6 months after trial registration were ran- assessed by comparing the frequency of any use of predni- domly assigned to either stop cyclophosphamide and sone, cyclophosphamide, and other immunosuppressants commence 2 mg/kg azathioprine immediately (azathio- during each predefined time period after the end of the orig- prine group) or continue cyclophosphamide treatment un- inal trial (i.e., 18–24, 25–36, 37–48, and 49–60 months of follow- til 12 months (cyclophosphamide group). All patients up). Treatment groups were compared independently for received 1.5 mg/kg azathioprine daily between months each time period using Fisher’s exact test. 12 and 18. After 18 months, patients were treated accord- Estimates of the effect of allocation to the azathioprine ing to local standards of care both in terms of maintenance group, their 95% confidence intervals (95% CIs), and treatment and for the treatment of relapses. associated P values were calculated for each outcome. A The use of prophylaxis against Pneumocystis jiroveci,gas- two-tailed P value ,0.05 was considered significant for all tritis, fungal infection, and fractures was determined by analyses with no adjustments made for multiple compar- local standards of practice. isons. Subgroup analyses were performed to determine whether treatment effects were different for patients Data Collection who were positive for an anti-proteinase 3 (PR3) Within-trial data were collected prospectively between compared with patients who were negative for an anti- 1995 and 1999 when the trial closed. Investigators com- PR3 antibody. Sensitivity analyses were performed by pleted standardized data abstraction forms between 2005 adjusting for anti-PR3 antibody status and for serum cre- and 2008 to assess long-term outcomes. Data from the last atinine, important risk factors for relapse. All analyses in-trial follow-up were used when patients were lost to were performed with Stata 11 MP software (College Sta- long-term follow-up. tion, TX). Clin J Am Soc Nephrol 9: ccc–ccc, September, 2014 Early Azathioprine in Vasculitis, Walsh et al. 3

Results observed between groups with regard to the proportion of Figure 1 summarizes the flow of patients. Of the 158 pa- patients receiving cyclophosphamide, corticosteroids, and/or tients registered, 144 (93%) were randomized to either the aza- other immunosuppressants during months 19–60 (Table 2). thioprine group (71 allocated to azathioprine after 3–6months Subgroup analysis of patients who were positive for anti- of cyclophosphamide) or the cyclophosphamide group (73 al- PR3 antibody compared with those who were negative for located to azathioprine after 12 months of cyclophosphamide). anti-PR3 antibody did not reveal a significant difference Of these patients, 125 (87%) completed long-term follow-up between the azathioprine and cyclophosphamide groups (63 of 71 [89%] in the azathioprine group and 62 of 73 [85%] in (interaction P=0.71). Of patients who were positive for anti- the cyclophosphamide group). All analyses included all 144 PR3 antibody, 27 (61%) in the azathioprine group and 19 patients. These 144 patients contributed a total of 1016 patient- (41%) in the cyclophosphamide group had at least one re- years of follow-up with a median follow-up time of 8.5 years. lapse (sHR, 1.66; 95% CI, 0.93 to 2.98). Of patients who were Patient characteristics are summarized in Table 1. negative for anti-PR3 antibody, 10 (37%) in the azathioprine group and seven (26%) in the cyclophosphamide group had Efficacy Outcomes at least one relapse (sHR, 1.57; 95% CI, 0.59 to 4.18). In the Sixty-three patients experiencedarelapse:37(52%)inthe sensitivity analysis adjusted for serum creatinine and pro- azathioprine group and 26 (36%) in the cyclophosphamide teinase 3 status, the sHR for the azathioprine group was not group (sHR, 1.63; 95% CI, 0.99 to 2.71; P=0.06) (Figure 2). The substantially changed (sHR, 1.56; 95% CI, 0.93 to 2.63). composite outcome of relapse and death was also more com- mon in the azathioprine group (HR, 1.59; 95% CI, 1.00 to 2.54; Safety Outcomes P=0.05). The incidence of relapse was not significantly higher The groups did not differ significantly with respect to in the azathioprine group (IRR, 1.25; 95% CI, 0.86 to 1.82; any of the safety outcomes. Death occurred in nine patients P=0.22). Of first relapses, 19 (27%) were renal in the azathio- (13%) in the azathioprine group and 12 patients (16%) in prine group compared with 16 (22%) in the cyclophospha- the cyclophosphamide group (HR, 0.75; 95% CI, 0.32 to mide group (sHR, 1.25; 95% CI, 0.65 to 2.43; P=0.50). ESRD 1.79; P=0.52). The distribution of causes of death did not occurred in eight patients (11%) in the azathioprine group and differ significantly between groups (Table 3). Malignancies five patients (7%) in the cyclophosphamide group (sHR, 1.71; occurred in six patients (8%) in the azathioprine group and 95% CI, 0.56 to 5.19; P=0.35). No significant differences were 11 patients (15%) in the cyclophosphamide group (P=0.30).

Figure 1. | Patient flow. AZA, azathioprine group; CYC, cyclophosphamide group. 4 Clinical Journal of the American Society of Nephrology

Table 1. Patient characteristics

Characteristic AZA (n=71) CYC (n=73) All

Age (yr) 56 (47–66) 57 (45–67) 57 (47–67) Women 41 (58) 35 (48) 76 (53) GPA 46 (65) 46 (63) 92 (64) Anti-PR3+ 44 (62) 46 (63) 90 (63) Creatinine (mg/dl) 1.6 (0.93–2.41) 2.35 (1.21–3.51) 1.79 (1.09–2.99) Birmingham vasculitis activity score 17.5 (7.5–24) 16 (10–24) 17 (10–24)

Data are presented as the median (interquartile range; 25th to 75th percentile) or n (%). GPA, granulomatosis with polyangiitis/We- gener’s; anti-PR3+, anti-proteinase 3 antibody or positive for cytoplasmic ANCA if an ELISA was not performed; AZA, azathioprine group; CYC, cyclophosphamide group.

Figure 2. | Cumulative incidence of relapse of ANCA-associated vasculitis by allocated maintenance treatment group. Cumulative incidence is adjusted for the competing risk of death. AZA, azathioprine group; CYC, cyclophosphamide group.

Discussion follow-up studies based on randomized trials assessing We assessed the long-term outcomes of patients with strategies to reduce cyclophosphamide exposure in AAV generalized AAV that started maintenance therapy with demonstrated a higher relapse risk in the treatment groups azathioprine immediately after remission induction or after with limited or no cyclophosphamide exposure (12,13). 12 months of cyclophosphamide therapy. Earlier initiation of Furthermore, the relative increase in relapse risk observed azathioprine did not result in a statistically significant loss of after cyclophosphamide -sparing therapy in these studies efficacy although relapses were numerically more frequent was comparable with the increase in relapse risk observed and immunosuppressive drugs and glucocorticoids were in the azathioprine group in our study (12,13). The consis- used more frequently. Although there is no clear disadvan- tency of these findings suggests that low cumulative cy- tage associated with early initiation of azathioprine, further clophosphamide exposure during the initial 6–12 months research is required to determine whether this treatment of treatment may increase longer-term relapse risk despite regimen increases the long-term risk of relapse. the lack of statistical significance in individual trials. Cyclophosphamide-related side effects such as infec- If higher initial exposure to cyclophosphamide reduces tions, hemorrhagic cystitis, infertility, and malignancy the risk of relapse in the long-term, the choice of induction raised serious concerns over its safety and prompted regimen may be tailored to patients’ risk of relapse and several trials exploring treatment regimens to limit expo- risk of cyclophosphamide-related comorbidity. For exam- sure in AAV. However, cyclophosphamide is recognized as ple, patients with a high risk of a relapse and a low risk of one of the factors that transformed outcomes for patients cyclophosphamide-induced complications may rationally with AAV, and reducing its use could inadvertently opt for longer durations of cyclophosphamide therapy. In the worsen disease activity–related outcomes. Two long-term past, the need for further cyclophosphamide exposure as a Clin J Am Soc Nephrol 9: ccc–ccc, September, 2014 Early Azathioprine in Vasculitis, Walsh et al. 5

Table 2. Therapy beyond the 18-month trial period for patients in the CYCAZAREM trial

Cyclophosphamide Other Immunosuppressantsa Prednisolone Time after Randomization (mo) CYC AZA P Value CYC AZA P Value CYC AZA P Value

19–24 9 (17) 6 (11) 0.58 37 (68) 36 (69) .0.99 47 (81) 46 (82) 0.99 25–36 4 (8) 6 (12) 0.74 28 (56) 30 (64) 0.53 35 (65) 40 (77) 0.20 37–48 2 (4) 4 (8) 0.68 23 (47) 28 (59) 0.23 28 (53) 31 (61) 0.43 49–60 1 (2) 4 (8) 0.36 20 (43) 27 (60) 0.14 21 (42) 28 (56) 0.23

Data are presented as n (%). During all time intervals, patients with missing data were excluded from analysis. P values were obtained by Fisher’s exact test. CYCAZAREM, Cyclophosphamide versus Azathioprine for Early Remission Phase of Vasculitis. aAzathioprine, methotrexate, , gusperimus, dapsone, infliximab, and/or mycophenolate mofetil.

the risk of disease relapse. Thus, we are unable to exclude Table 3. Contributing causes of death the possibility that a clinically important increase in the Cause of CYC AZA P long-term risk of relapse with early conversion to azathio- Death (n=12) (n=9) Valuea prine exists. Furthermore, there was a modest difference in the serum creatinine concentrations at the time of random- Active 0 1 0.49 ization. However, adjustment for potential confounders vasculitis such as creatinine did not materially alter the results. We Infection 4 8 0.24 also lack information to determine the severity of the re- Malignancy 3 3 0.99 Cardiovascular 6 1 0.11 lapses that occurred after the 18-month trial period. A Unknown 4 2 0.68 qualitative difference in the severity of relapses could make the observed difference in the frequency of relapses more Patients can have more than one contributing cause of death. or less clinically relevant. Data on cumulative drug doses – CYC, cyclophosphamide group; AZA, azathioprine group. during months 19 60 were not collected, and a more de- aP value from Fisher’s exact test. tailed comparison of drug exposures in the two treatment groups was not possible. Further follow-up and epidemi- ologic data, as well as data from other ongoing trials, will help further clarify the potential risks and benefits of early result of major relapses of AAV, and therefore higher life- conversion to azathioprine and the risks of increased cy- time cumulative doses, was part of the motivation for ini- clophosphamide exposure (e.g.,malignancy). tial cyclophosphamide-sparing regimens. However, in the era Uncertainty remains regarding whether initiating azathi- of increasing choices of induction agents (e.g., ) for oprine 3–6 months after induction of remission with cyclo- major relapses, this may be less of a concern for the treat- phosphamide is less effective for the prevention of relapses ment of newly diagnosed disease. Furthermore, if higher than initiating azathioprine after 12 months of cyclophos- initial exposure to cyclophosphamide results in fewer re- phamide treatment. There may be a trade-off between the lapses, the lifetime exposure to cyclophosphamide may ac- higher risk of relapse and the risk of other adverse outcomes tually be reduced in selected patients. that are likely associated with higher cyclophosphamide ex- In our long-term follow-up study, almost one half of all posure. Further study is required to determine whether patients experienced a relapse and more than one half some patients should have the initiation of azathioprine ther- continued to receive immunosuppressive drugs up to 5 years apy delayed after achieving a clinical remission. after diagnosis. Furthermore, 21% of patients developed ESRD or died. These findings highlight that although outcomes have Acknowledgments improved for patients with AAV, a need for more effective and This trial was supported by grants from the European League safer treatment remains, which is a message that has not against Rheumatism, the European Union European Commu- changed substantially in 20 years (15). Future clinical trials will nity Systemic Vasculitis Trial project (BMH1-CT93-1078 and need to evaluate longer-term outcomes. CIDP-CT94-0307), and the European Union Associated Vasculitis Our study has several notable strengths. It builds on one European Randomized Trial project (BMH4-CT97-2328 and IC20- of the few randomized controlled trials to assess early con- CT97-0019). M.W. is supported by a Kidney Research Scientist version from cyclophosphamide to azathioprine, a practice Core Education National Training New Investigator Award from that has been widely adopted (1,2,16). Patient follow-up the Canadian Institutes of Health Research, Kidney Foundation of was largely complete and the consistency of results within Canada, and Canadian Society of Nephrology. C.D.P. is supported and between trials strengthens the findings. Finally, our by the National Institute for Health Research Biomedical Research findings were consistent between subgroups and in sensi- Centre. D.R.W.J. is supported by the Cambridge Biomedical Re- tivity analyses, which suggests they are robust. search Centre. Our results must also be considered in the context of their M.W. and M.F. had full access to all of the data in the study and limitations. The trial, although large for a rare disease, was take responsibility for the integrity of the data and the accuracy of the not adequately powered to detect moderate differences in data analysis. 6 Clinical Journal of the American Society of Nephrology

The CYCAZAREM investigators are: Belgium: Erasmus Hospital, contribution of adverse events and active vasculitis. Ann Rheum Brussels—D. Abramowicz, M. Wissing; Universitaire Ziekenhuis, Dis 69: 1036–1043, 2010 6. Heijl C, Harper L, Flossmann O, Stu¨cker I, Scott DG, Watts RA, Leuven—D. Blockmans; Edith Cavell Medical Institute, Brussels— Hoglund P, Westman K, Mahr A; European Vasculitis Study — ¨ P. Madhoun; AZ VUB, Brussels J. Sennesael; IMC de Tournai, Group (EUVAS): Incidence of malignancy in patients treated for Tournai—J. Stolear. Czech Republic: Charles University Hospital, antineutrophil cytoplasm antibody-associated vasculitis: Follow- Prague—V. Tesar, V. Chabova, I. Rychlik. Denmark: Rigshospitalet, up data from European Vasculitis Study Group clinical trials. Ann Copenhagen—N. Rasmussen. Finland: University of Helsinki, Rheum Dis 70: 1415–1421, 2011 — — 7. Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Helsinki A. Ekstrand, C. Grönhagen Riska. France: Hôpital Dadoniene´ J, Ekstrand A, Gaskin G, Gregorini G, de Groot K, Necker, Paris—P. Lesavre; Centre Hospitalier, Valenciennes—P. Gross W, Hagen EC, Mirapeix E, Pettersson E, Siegert C, Sinico A, Vanhille. Ireland: St. James Hospital, Dublin—C. Feighery. Ger- Tesar V,Westman K, Pusey C; European Vasculitis Study Group: A many: The Medical School, Hannover—K. de Groot; Heidelberg randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med University Hospital, Heidelberg—K. Andrassy, O. Hergesell; 349: 36–44, 2003 — Klinikum Mannheim, Mannheim F. van der Woude, R. Nowack; 8. De Groot K, Rasmussen N, Bacon PA, Tervaert JW, Feighery C, Rheumaklinik, Bad Bramstedt—W. Gross, W. Schmitt; Heinrich Gregorini G, Gross WL, Luqmani R, Jayne DR: Randomized trial Heine Universität, Düsseldorf—M. Schneider, C. Specker; Klinikum of cyclophosphamide versus methotrexate for induction of re- Nürnberg, Nürnberg—H. Rupprecht, P. Weber, S. Weidner. Italy: mission in early systemic antineutrophil cytoplasmic antibody- — associated vasculitis. Arthritis Rheum 52: 2461–2469, 2005 Spedali Civili, Brescia G. Gregorini; Ospedale San Carlo Borromeo, 9. de Groot K, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, Milan—A. Sinico. Lithuania: University fo Vilnius, Vilnius—J. Gross WL, Luqmani R, Pusey CD, Rasmussen N, Sinico RA, Tesar Dadonieme. The Netherlands: University Hospital, Groningen—C. V, Vanhille P, Westman K, Savage CO; EUVAS (European Vas- Kallenberg, C. Stegeman; Eemland Hospital, Amersfoort—C. Hagen, culitis Study Group): Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody- E. van Gurp; Leiden University Medical Center, Leiden—C. Siegert, associated vasculitis: A randomized trial. Ann Intern Med 150: — C. Verburgh; University of Maastricht, Maastricht J.W. Cohen 670–680, 2009 Tervaert. Spain: Hospital Clinic I Provincal, Barcelona—E. Mirapeix; 10. Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh Hospital Germans Trias i Pujol, Badalona—A. Serra; Hospital Doc- CA, Savage CO, Segelmark M, Tesar V, van Paassen P, Walsh D, tor Josep Trueta, Girona—M. Valles; Hospital Princeps d’Espana,~ Walsh M, Westman K, Jayne DR; European Vasculitis Study — — Group: Rituximab versus cyclophosphamide in ANCA-associated Llobregat R. Poveda; Fundació Puigvert, Barcelona J. Ballarin. renal vasculitis. N Engl J Med 363: 211–220, 2010 Sweden: Huddinge University Hospital, Huddinge—E. Pettersson, 11. Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, A. Bruchfeld; Danderyds Sjukhus, Danderyds—G. Germanis; Uni- Kallenberg CG, St Clair EW, Turkiewicz A, Tchao NK, Webber L, versity Hospital of Lund, Lund—D. Selga; Karolinska Sjukhuset, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza Stockholm—Z. Heigl, I. Lundberg, E. Svenungssen. United King- FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, — dom: Imperial College, London G. Gaskin; Southmead Hospital, Stegeman C, Ytterberg SR, Specks U, Group R-IR; RAVE-ITN Bristol—P. Mathieson; Ipswich Hospital, Ipswich—R. Watts; Research Group: Rituximab versus cyclophosphamide for Leicester General Hospital, Leicester—J. Feehally; Royal Free Hos- ANCA-associated vasculitis. N Engl J Med 363: 221–232, 2010 pital, London—A. Burns; Western General Hospital, Edinburgh—R. 12. Faurschou M, Westman K, Rasmussen N, de Groot K, Flossmann — O, Ho¨glund P, Jayne DR; European Vasculitis Study Group: Brief Luqmani; Queen Elizabeth II Hospital, Birmingham P. Bacon, D. report: Long-term outcome of a randomized clinical trial Adu, C. Savage. comparing methotrexate to cyclophosphamide for remission induction in early systemic antineutrophil cytoplasmic antibody- Disclosures associated vasculitis. Arthritis Rheum 64: 3472–3477, 2012 None. 13. Harper L, Morgan MD, Walsh M, Hoglund P, Westman K, Flossmann O, Tesar V, Vanhille P, de Groot K, Luqmani R, Flores- Suarez LF, Watts R, Pusey C, Bruchfeld A, Rasmussen N, References Blockmans D, Savage CO, Jayne D; EUVAS investigators: Pulse 1. Lapraik C, Watts R, Bacon P, Carruthers D, Chakravarty K, D’Cruz D, versus daily oral cyclophosphamide for induction of remission in Guillevin L, Harper L, Jayne D, Luqmani R, Mooney J, Scott D; BSR ANCA-associated vasculitis: Long-term follow-up. Ann Rheum and BHPR Standards, Guidelines and Audit Working Group: BSR and Dis 71: 955–960, 2012 BHPR guidelines for the management of adults with ANCA associ- 14. Sanders JS, Slot MC, Stegeman CA: Maintenance therapy for ated vasculitis. Rheumatology (Oxford) 46: 1615–1616, 2007 vasculitis associated with antineutrophil cytoplasmic autoanti- 2. Mukhtyar C, Guillevin L, Cid MC, Dasgupta B, de Groot K, Gross bodies. N Engl J Med 349: 2072–2073, author reply 2072–2073, W, Hauser T, Hellmich B, Jayne D, Kallenberg CG, Merkel PA, 2003 Raspe H, Salvarani C, Scott DG, Stegeman C, Watts R, Westman 15. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, K, Witter J, Yazici H, Luqmani R; European Vasculitis Study Travis WD, Rottem M, Fauci AS: Wegener granulomatosis: An Group: EULAR recommendations for the management of primary analysis of 158 patients. Ann Intern Med 116: 488–498, 1992 small and medium vessel vasculitis. Ann Rheum Dis 68: 310– 16. Menahem S, Hiremagalur B, Mudge D, Toussaint N, Walters G; 317, 2009 Caring for Australians with Renal Impairment (CARI): The CARI 3. Talar-Williams C, Hijazi YM, Walther MM, Linehan WM, guidelines. Induction and maintenance therapy in ANCA- Hallahan CW, Lubensky I, Kerr GS, Hoffman GS, Fauci AS, associated systemic vasculitis. Nephrology (Carlton) 13[Suppl 2]: Sneller MC: Cyclophosphamide-induced cystitis and bladder S24–S36, 2008 cancer in patients with Wegener granulomatosis. Ann Intern Med 17. Fine JP: Regression modeling of competing crude failure proba- 124: 477–484, 1996 bilities. Biostatistics 2: 85–97, 2001 4. Westman KW, Bygren PG, Olsson H, Ranstam J, Wieslander J: Received: Accepted: Relapse rate, renal survival, and cancer morbidity in patients with January 22, 2014 April 28, 2014 Wegener’s granulomatosis or microscopic polyangiitis with renal involvement. J Am Soc Nephrol 9: 842–852, 1998 M.W. and M.F. contributed equally to this work. 5. Little MA, Nightingale P, Verburgh CA, Hauser T, De Groot K, Savage C, Jayne D, Harper L; European Vasculitis Study (EUVAS) Published online ahead of print. Publication date available at www. Group: Early mortality in systemic vasculitis: Relative cjasn.org.