Kirsten de Groot, MD; Lorraine Harper, MD, PhD; David R.W. Jayne, MD, PhD; Luis Felipe Flores Suarez, MD, PhD; Gina Gregorini, MD; Wolfgang L. Gross, MD; Rashid Luqmani, MD; Charles D. Pusey, MD, PhD; Niels Rasmussen, MD; Renato A. Sinico, MD; Vladimir Tesar, MD, PhD; Philippe Vanhille, MD; Kerstin Westman, MD, PhD; Caroline O.S. Savage, MD, PhD; EUVAS (European Vasculitis Study Group)
Note: Drs. de Groot and Harper contributed equally to the manuscript.
Acknowledgment: The authors thank the trial administrator, Lucy Jayne, Cambridge, United Kingdom, and Peter Nightingale, Wellcome Trust Clinical Research Facility, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom.
Grant Support: By the European Union (European Community Systemic Vasculitis Trial project, contract nos. BMH1-CT93-1078 and CIPD-CT94-0307, and Associated Vasculitis European Randomised Trial project, contract nos. BMH4-CT97-2328 and IC20-CT97-0019).
Potential Financial Conflicts of Interest: None disclosed.
Reproducible Research Statement:Study protocol: Available at http://www.vasculitis.org/protocols/CYCLOPS.pdf. Statistical code: Available from Dr. Harper (e-mail, L.firstname.lastname@example.org). Data set: Available to approved individuals through written agreements with the steering committee of the EUVAS network (contact Dr. Harper; e-mail, L.email@example.com).
Requests for Single Reprints: Lorraine Harper, MD, PhD, School of Immunity and Infection, College of Medical and Dental Sciences, Birmingham University, Birmingham B15 2TT, United Kingdom; e-mail, L.firstname.lastname@example.org.
Current Author Addresses: Dr. de Groot: Department of Nephrology and Rheumatology, Klinikum Offenbach GmbH, Starkenburgring 66, 63069 Offenbach/Main, Germany.
Drs. Harper and Savage: Division of Immunity and Infection, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
Dr. Jayne: Renal Unit, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, United Kingdom.
Dr. Flores Suarez: Instituto National de Ciencias Medicas y Nutrition, Salvador Zubiran Vasco de Quiroga 15, Colonia Seccion XVI, Tlalpan C.P. 14000, Mexico D.F., Mexico.
Dr. Gregorini: Department of Nephrology, Spedali Civili di Brescia, Piazza le Spedali Civili, 1, 25123 Brescia, Italy.
Dr. Gross: Department of Rheumatology, University of Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Dr. Luqmani: Nuffield Orthopaedic Centre, Windmill Road, Headington, Oxford OX3 7LD, United Kingdom.
Dr. Pusey: Renal Section, Division of Medicine, Imperial College London, Hammersmith Hospital, Ducane Road, London W12 0HS, United Kingdom.
Dr. Rasmussen: Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
Dr. Sinico: Renal and Clinical Immunology Unit, Ospedale San Carlo Borromeo, Via Pio II, 3 - 20153 Milan, Italy.
Dr. Tesar: Department of Nephrology, Charles University, Celetná 13, 116 36, Praha 1, Prague, Czech Republic.
Dr. Vanhille: Centre Hospitalier De Valenciennes, Avenue Désandrouin, 59300 Valenciennes, France.
Dr. Westman: Department of Nephrology and Transplantation, Malmö University Hospital, 205 02 Malmö, Sweden.
Author Contributions: Conception and design: K. de Groot, D.R.W. Jayne, R. Luqmani, C.D. Pusey, N. Rasmussen, R.A. Sinico, C.O.S. Savage.
Analysis and interpretation of the data: K. de Groot, L. Harper, D.R.W. Jayne, W.L. Gross, C.D. Pusey, N. Rasmussen, V. Tesar, K. Westman, C.O.S. Savage.
Drafting of the article: K. de Groot, L. Harper, D.R.W. Jayne, R. Luqmani, C.O.S. Savage.
Critical revision of the article for important intellectual content: K. de Groot, L. Harper, D.R.W. Jayne, L.F. Flores Suarez, W.L. Gross, R. Luqmani, C.D. Pusey, N. Rasmussen, R.A. Sinico, K. Westman, C.O.S. Savage.
Final approval of the article: K. de Groot, L. Harper, D.R.W. Jayne, L.F. Flores Suarez, G. Gregorini, W.L. Gross, R. Luqmani, C.D. Pusey, N. Rasmussen, R.A. Sinico, C.O.S. Savage.
Provision of study materials or patients: D.R.W. Jayne, L.F. Flores Suarez, G. Gregorini, W.L. Gross, R. Luqmani, V. Tesar, P. Vanhille, K. Westman, C.O.S. Savage.
Statistical expertise: D.R.W. Jayne.
Obtaining of funding: K. de Groot, D.R.W. Jayne, C.D. Pusey, N. Rasmussen.
Administrative, technical, or logistic support: K. de Groot, D.R.W. Jayne, N. Rasmussen.
Collection and assembly of data: K. de Groot, L. Harper, D.R.W. Jayne, L.F. Flores Suarez, R.A. Sinico.
ClinicalTrials.gov registration number: NCT00430105.
de Groot K., Harper L., Jayne D., Flores Suarez L., Gregorini G., Gross W., Luqmani R., Pusey C., Rasmussen N., Sinico R., Tesar V., Vanhille P., Westman K., Savage C., ; Pulse Versus Daily Oral Cyclophosphamide for Induction of Remission in Antineutrophil Cytoplasmic Antibody—Associated Vasculitis: A Randomized Trial. Ann Intern Med. 2009;150:670-680. doi: 10.7326/0003-4819-150-10-200905190-00004
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Published: Ann Intern Med. 2009;150(10):670-680.
Current therapies for antineutrophil cytoplasmic antibody (ANCA)â€“associated vasculitis are limited by toxicity.
To compare pulse cyclophosphamide with daily oral cyclophosphamide for induction of remission.
Randomized, controlled trial. Random assignments were computer-generated; allocation was concealed by faxing centralized treatment assignment to providers at the time of enrollment. Patients, investigators, and assessors of outcomes were not blinded to assignment.
42 centers in 12 European countries.
149 patients who had newly diagnosed generalized ANCA-associated vasculitis with renal involvement but not immediately life-threatening disease.
Pulse cyclophosphamide, 15 mg/kg every 2 to 3 weeks (76 patients), or daily oral cyclophosphamide, 2 mg/kg per day (73 patients), plus prednisolone.
Time to remission (primary outcome); change in renal function, adverse events, and cumulative dose of cyclophosphamide (secondary outcomes).
Groups did not differ in time to remission (hazard ratio, 1.098 [95% CI, 0.78 to 1.55]; PÂ = 0.59) or proportion of patients who achieved remission at 9 months (88.1% vs. 87.7%). Thirteen patients in the pulse group and 6 in the daily oral group achieved remission by 9 months and subsequently had relapse. Absolute cumulative cyclophosphamide dose in the daily oral group was greater than that in the pulse group (15.9 g [interquartile range, 11 to 22.5 g] vs. 8.2 g [interquartile range, 5.95 to 10.55 g]; PÂ < 0.001). The pulse group had a lower rate of leukopenia (hazard ratio, 0.41 [CI, 0.23 to 0.71]).
The study was not powered to detect a difference in relapse rates between the 2 groups. Duration of follow-up was limited.
The pulse cyclophosphamide regimen induced remission of ANCA-associated vasculitis as well as the daily oral regimen at a reduced cumulative cyclophosphamide dose and caused fewer cases of leukopenia.
The European Union.
May 25, 2009
Daily oral cyclophosphamide in ANCA associated vasculitis
Dear Editor, Groot et al reemphasize the advantages of pulse cyclophosphamide over daily oral cyclophosphamide in AAV(anca associated vasculitides) which is the mainstay of therapy for induction of remission(1).However in developing countries like India,tuberculosis is quite common,if fact it is sometime difficult to differentiate between active tuberculosis Vs AAV(mainly Wegener's granulomatosis) either clinically or by histopathology.In many cases latent tuberculosis may coexist.Oral daily cyclophosphamide is easier to withdraw in case of doubt of tuberculosis. Giving pulse cyclophosphamide may aggravate underlying tuberculosis which may be fatal, hence we recommend that in developing counties the treatment should be individualized.Where tuberculosis is adequately ruled out obviously pulse cyclophosphamide remains the first choice.
1.de Groot 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: 670-680
Stuart M. Levine
Johns Hopkins University
May 26, 2009
Re: Daily oral cyclophosphamide in ANCA associated vasculitis
To the editors: The study by de Groot and colleagues demonstrates that the higher cumulative dosing of traditional (2mg/kg) daily oral cyclophosphamide regimens offers no advantage over lower dose regimens delivered by intravenous pulse for the induction of remission in patients with ANCA-associated vasculitis. However, whether lower dose daily oral (ie. 1-1.25mg/kg)regimens with their lower risks of bone marrow and bladder toxicities, would be similarly efficacious in achieving remission was not evaluated. Prior to broadly recommending the use of intravenous pulse cyclophosphamide for the induction of remission in this patient population, such comparison studies with less toxic oral regimens would need to be performed.
ANAV Dept of Health. L'Hospitalet de l'Infant 43890, Spain
May 28, 2009
Approaches on ANCA-Associated Vasculitis Therapy
Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides are treated with a combination of high-dose corticosteroids and cyclophosphamide (CP) therapy to induce remission. Maintenance treatment is followed with less-toxic immunosuppressant as methotrexate or azathioprine (1). Theses immunosupressive regiments improve significantly survival, but are not exempt of secondary effects as toxicity and infections. Relapses rates and long term complications of the inflammatory process should also be considered.
Recent studies have proposed that intravenous pulses administration of cyclophosphamide reduced drug exposure and are likely to increase the safety of treatment as compared to daily oral CP (2). The paper by de Groot and colleagues (3) shows that CP pulses actually reduced cumulative dose of CP and leukopenia events, but remissions and relapsing rates were similar to those of the daily CP group, as were doses of corticosteroids.
Vasculitis as other immune diseases accelerates atherosclerosis. Despite that corticosteroids are thought to contribute to cardiovascular complications, inflammation represents itself a link between vasculitis and atherosclerosis. In patients with ANCA-associated vasculitis, cardiovascular diseases are a major cause of mortality. In patients with Wegener granulomatosis, increased number of both early and late cardiovascular events due to ischemic heart disease has been described (4). During active disease, the inflammatory process accelerates atherosclerotic process. This suggests that studies on prevention of cardiovascular risk factors and control of disease activity are needed, and also a deeper knowledge of factors, drivers of the vasculitic process and initiators of endothelial cell activation.
The increasingly understanding of the pathogenesis of these syndromes and the development of new therapies in autoimmune diseases has developed new studies on ANCA-associated vasculitis treatment. Drugs as mycophenolate mofetil, leflunomide and deoxyspergualin have been evaluated (2). In the last years, the advent of biological therapies in autoimmune disorders represents exciting new options. Blockage of CD-20 cells with Rituximab rise thrilling perspectives on this field (5). Currents studies on blocking signaling pathways are currently running.
1. Natchman PH. Vasculitis syndromes: which maintenance therapy for ANCA vasculitis? Nat Rev Nephrol. 2009; 5: 254-6 [PMID: 19384325]
2. Jayne D. Review article: Progress of treatment in ANCA-associated vasculitis. Nephrology (Carlton). 2009;14:42-8 [PMID: 19335843]
3. De Groot K, Harper L, Jayne DRW, Flores Suarez LF, Gregorini G, 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: 670-680. [PMID: 19451574]
4. Faurschou M, Mellemkjaer L, Sorensen IJ, Svalgaard Thomsen B, Dreyer L, Baslund B. Increased morbidity from ischemic heart disease in patients with Wegener's granulomatosis. Arthritis Rheum. 2009; 60(4):1187-92. [PMID: 19333952]
5. Pallan L, Savage CO, Harper L. ANCA-associated vasculitis: from bench research to novel treatments. Nat Rev Nephrol. 2009; 5: 278-86 [PMID: 19384329]
Lee A Hebert
The Ohio State University Medical Center
June 12, 2009
Dr. de Groot and her colleagues provide a balanced discussion of the strengths and weaknesses of their randomized trial (1). Unfortunately, that balance was lost in the abstract's Conclusions, which taken verbatim, clearly favors pulse (IV) cyclophosphamide over daily oral cyclophosphamide. The "back story", however, is far more complex and provides substantial support for the daily oral regimen, for example:
1) Recovery of kidney function may have been better with daily oral therapy. Note that the graph showing trends in eGFR censored the eGFR values after onset of ESRD. This inflated the eGFR in the pulse group because it had 5 ESRD events versus only 1 ESRD event in the daily oral group. We suggest the eGFR analysis be repeated after assigning an eGFR of 5 to each ESRD patient (2).
2) By 6 months into the study there were 4 ESRD cases in the pulse group and none in the daily oral group. This is consistent with the notion that administering cyclophosphamide "up front", when likely it is most needed, is better achieved with the daily oral regimen than the pulse regimen.
3) Measures of quantitative proteinuria are not provided. This is a key concern because proteinuria magnitude is the strongest single predictor of GFR decline (3), and it is likely that proteinuria during follow-up was higher in the pulse group because it had more frequent flares. If proteinuria data are provided, they should be presented as the protein/creatinine ratio of the intended 24-hr urine collections rather than the face value of the protein content of the intended 24-hr collections because the P/C ratio is a more reliable measure of proteinuria magnitude (4).
4) de Groot describes pulse cyclophosphamide as "simpler". However, in the U.S., pulse cyclophosphamide requires a visit to an infusion center at a cost in excess of $1,000/visit, along with loss of a day of work and other inconveniences. The pulse regimen is ideal for noncompliant patients, however, to subject every patient to IV cyclophosphamide when only a few will benefit does not seem justified.
In summary, de Groot's work is very important, however, it does not show that the pulse regimen is better than the daily oral regimen. Indeed, if the data on proteinuria and true eGFR trends are made available, the conclusion may be that the daily oral regimen was superior to the pulse regimen.
1. de Groot K, Harper L, Jayne DRW, Suarez LFF, Gregorini G, Gross WL, et al: Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis. Ann Int Med 2009;150:670-680.
2. McKinley A, Park E, Spetie D, Hackshaw K, Hebert LA, Rovin BH: Oral cyclophosphamide in the management of severe lupus glomerulonephritis: An under-utilized therapeutic option. Clin J Am Soc Nephrol (in revision).
3. Agarwal A, Haddad N, Hebert LA: Progression of kidney disease: diagnosis and management. Chap 30 in Evidence-based Nephrology, Molony D, Craig J (Eds), John Wiley & Sons, Hoboken, NJ, Dec 2008, pp 311-322.
4. Birmingham DJ, Rovin BH, Shidham G, Nagaraja HN, Zou X, Bissell M et al. Spot urine protein/creatinine ratios are unreliable estimates of 24 -h proteinuria in most systemic lupus erythematosus nephritis flares. Kidney Int 2007;72:865-870, 2007.
R. Brooks Robey
VA Medical Center & Dartmouth Medical School
June 23, 2009
CYCLOPS: Worth the wait?
Preliminary results from the European Vasculitis Study Group's CYCLOPS (Cyclophosphamide Daily Oral versus Pulsed) trial (1) have been cited since 2005 as a basis for abandoning routine daily oral cyclophosphamide therapy for ANCA-associated vasculitis in favor of intravenous pulse regimens (2, 3). As such, full publication of these results (4) has been eagerly anticipated. Upon review of these data, however, it is evident that this study fails to yield unambiguous new guidance regarding proper cyclophosphamide dosing schedule selection. The fundamental limitations are briefly addressed below.
Remission rates based on the aggregate Birmingham Vasculitis Activity Score (BVAS) (5) did not differ between treatment groups, but increased progression to end-stage renal disease (ESRD) was evident at all time points in patients receiving pulse therapy, despite slightly higher initial estimated glomerular filtration rates (4). If ESRD patients censored due to therapeutic unresponsiveness are included, the affected subgroup may comprise 10% of all pulse regimen recipients. This trend, which approached statistical significance, is troubling and suggests that lower cumulative doses or more infrequent cytotoxic therapy administration may be less efficacious in attenuating ANCA-associated renal vasculitis in a subset of high risk patients. Although a largely subjective and generic index of disease activity, the BVAS incorporates some objective markers of active renal vasculitis (e.g. increasing serum creatinine levels and active urinary sediment) (5) that, coupled with renal histopathologic examination, might be useful in identifying this high risk subgroup for individualized intensification of induction therapy.
More than twice as many relapses were observed in the pulse group than the daily oral group (4). Although this difference failed to achieve statistical significance, it is also not suggestive of equivalent therapeutic efficacy. Moreover, this study was neither designed nor powered to compare such differences (4). A planned long-term follow-up study of this patient cohort may yield more useful results, but it is clear that future studies should be specifically powered and designed to address such limitations.
Pulse therapy is a promising approach to minimizing cyclophosphamide toxicity, but examinations of associated therapeutic efficacy have been largely inconclusive due to small sample sizes. CYCLOPS exhibits similar limitations. The data suggest that pulse therapy may be equally efficacious for many, if not most, patients. Nonetheless, apparent heterogeneity in therapeutic responsiveness also suggests either a need for additional titration of pulse dosing to better balance competing considerations of efficacy and toxicity or for individualized intensification of induction therapy in identifiable high risk subgroups. The ineffective 3-month consolidation phase suggests an obvious target for reducing cumulative cyclophosphamide doses to accommodate changes in the induction phase.
In summary, the experimental design of CYCLOPS was shaped by practical considerations (4) that have ultimately undermined its ability to provide unambiguous guidance for pulse cyclophosphamide use in ANCA- associated vasculitides. Future efforts and available resources would seem best directed to a larger trial with more objective and immediate measures of disease activity and specific provisions to identify and address patient heterogeneity.
1. de Groot K, Jayne DRW, Tesar V, Savage COS. European, Multicenter Randomised Controlled Trial of Daily Oral Versus Pulse Cyclophosphamide for Induction of Remission in ANCA-Associated Systemic Vasculitis. J Am Soc Nephrol. 2005;16:7A (Abstract).
2. Falk RJ, Glassock RJ. Glomerular, Vasular, and Tubulointerstitial Diseases. Nephrol Self Assess Program. 2006;5(6):339-404.
3. Falk RJ, Hoffman GS. Controversies in small vessel vasculitis-- comparing the rheumatology and nephrology views. Curr Opin Rheumatol. 2007;19(1):1-9.
4. de Groot K, Harper L, Jayne DR, 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(10):670-80.
5. Luqmani RA, Bacon PA, Moots RJ, et al. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM. 1994;87(11):671-8.
University of Birmingham
July 6, 2009
We appreciate our colleagues' comments and are heartened to see that our analysis has stimulated further thought among clinicians. We agree with Dr Padhan that there may at times be difficulties in differentiating WegenerÃƒÂ¢Ã¢Â‚Â¬Ã¢Â„Â¢s granulomatosis from TB infection. However, studies suggest that the identification of combined cANCA by immunofluorescence and PR3 ELISA positivity has a low prevalence in TB(1). Even in those rare patients where there is diagnostic doubt but the balance of evidence favours ANCA- associated vasculitis, we believe that patients should be treated with pulse cyclophosphamide rather than daily oral cyclophosphamide. The cumulative dose when administered in a pulse dose is half that of the oral regime. For example, a 70kg person receives 1g pulse cyclophosphamide over 2 weeks compared with 2g with the oral regimen. In cases of suspected latent tuberculosis or a previous history of tuberculosis, cyclophosphamide should be administered together with isoniazide prophylaxis, irrespective of the cyclophosphamide regimen.
Drs Herbert et al suggest that there may be evidence to support use of the daily oral regime. End-stage renal failure (ESRF) occurred in 5 patients in the pulse limb compared with 1 in the oral group; this was not statistically significant. We performed the analysis comparing change in eGFR imputing eGFR for those patients who developed ESRF as requested at 5ml/min and there remained no difference in recovery of renal function between each limb (p=0.283). We disagree with the assertion that more ESRF in the pulse limb correlates with less rapid improvement in inflammation. There was no difference in rate of normalisation of CRP levels or BVAS, suggesting that there is no difference between the two regimens in achieving disease control. We agree that understanding the effects of treatment on proteinuria would be useful; unfortunately this data was not collected, as higher degrees of proteinuria (>1 g/g creatinine) is generally a rare condition in ANCA associated glomerulonephritis. The protocol used in the study gave the first 3 pulses intravenously; further pulses could be administered orally at the investigators discretion, which is a cost effective measure and is indeed our routine practice in our centres. As suggested this regimen is likely to improve compliance. In addition the regimen was associated with less leukopenia which in the longer term is likely to translate to better patient safety and less use of G-CSF. We believe that the data from our study supports the use of the pulsed regimen. Of course, differences in long-term disease control, toxicity and treatment-related damage might only be visible after a longer follow-up, these data have been collected and are currently being analysed.
As Dr Levine rightly comments there have been no trials of lower dose cyclophosphamide given in a daily manner compared to either a pulse or the historical standard dose of 2mg/kg cyclophosphamide per day. There would of course be differences in the kinetics between administering intravenous cyclophosphamide as a total dose at day 1 and a slower accumulation over 14 days of an equivalent total dose given as 1mg/kg/day that might have implications for response to treatment and rate of disease control. This trial supports the use of a lower cumulative dose cyclophosphamide administered in a pulsed manner and should now form the standard for future clinical trials testing different experimental regimens.
1. Teixeira L, Mahr A, Jaureguy F, Noel LH, Nunes H, Lefort A, et al. Low seroprevalence and poor specificity of antineutrophil cytoplasmic antibodies in tuberculosis. Rheumatology (Oxford) 2005;44(2):247-50.
VA Medcial Center and Dartmouth Medical School
Re: In response
In their response, Dr. Harper and colleagues note that five patients developed end-stage renal disease (ESRD) during pulse cyclophosphamide therapy versus a single individual receiving daily oral therapy, a difference that the authors assert "was not statistically significant". Although technically correct, it bears noting that this difference approached statistical significance (p = 0.105) despite the fact that at least three other patients developing ESRD in the pulse limb were censored from analysis and the study was probably not powered to definitively address such differences. As such, the authors' assertion is potentially misleading. We were disappointed that the authors neglected to respond to this and other concerns raised in our letter.
Department of Clinical Immunology and Rheumatology
August 26, 2009
Is pulse cyclophosphamide superior to a daily regimen for induction of remission in ANCA vasculitis
1. Pulse Versus Daily Oral Cyclophosphamide for Induction of Remission in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis A Randomized Trial; Kirsten de Groot, Lorraine Harper, David R.W. Jayne, et al; Ann Intern Med. 2009;150:670-680.
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