Mycophenolate Mofetil or Intravenous Cyclophosphamide for Lupus Nephritis
Ellen M. Ginzler, M.D., M.P.H., Mary Anne Dooley, M.D., M.P.H., Cynthia Aranow, M.D., Mimi Y. Kim, Sc.D., Jill Buyon, M.D., Joan T. Merrill, M.D., Michelle Petri, M.D., M.P.H., Gary S. Gilkeson, M.D., Daniel J. Wallace, M.D., Michael H. Weisman, M.D., and Gerald B. Appel, M.D.
Background Since anecdotal series and small, prospective, controlledtrials suggest that mycophenolate mofetil may be effective fortreating lupus nephritis, larger trials are desirable.
Methods We conducted a 24-week randomized, open-label, noninferioritytrial comparing oral mycophenolate mofetil (initial dose, 1000mg per day, increased to 3000 mg per day) with monthly intravenouscyclophosphamide (0.5 g per square meter of body-surface area,increased to 1.0 g per square meter) as induction therapy foractive lupus nephritis. A change to the alternative regimenwas allowed at 12 weeks in patients who did not have an earlyresponse. The study protocol specified adjunctive care and theuse and tapering of corticosteroids. The primary end point wascomplete remission at 24 weeks (normalization of abnormal renalmeasurements and maintenance of baseline normal measurements).A secondary end point was partial remission at 24 weeks.
Results Of 140 patients recruited, 71 were randomly assignedto receive mycophenolate mofetil and 69 were randomly assignedto receive cyclophosphamide. At 12 weeks, 56 patients receivingmycophenolate mofetil and 42 receiving cyclophosphamide hadsatisfactory early responses. In the intention-to-treat analysis,16 of the 71 patients (22.5 percent) receiving mycophenolatemofetil and 4 of the 69 patients receiving cyclophosphamide(5.8 percent) had complete remission, for an absolute differenceof 16.7 percentage points (95 percent confidence interval, 5.6to 27.9 percentage points; P=0.005), meeting the prespecifiedcriteria for noninferiority and demonstrating the superiorityof mycophenolate mofetil to cyclophosphamide. Partial remissionoccurred in 21 of the 71 patients (29.6 percent) and 17 of the69 patients (24.6 percent), respectively (P=0.51). Three patientsassigned to cyclophosphamide died, two during protocol therapy.Fewer severe infections and hospitalizations but more diarrheaoccurred among those receiving mycophenolate.
Conclusions In this 24-week trial, mycophenolate mofetil wasmore effective than intravenous cyclophosphamide in inducingremission of lupus nephritis and had a more favorable safetyprofile.
Source Information
From the Division of Rheumatology, State University of New York Downstate Medical Center, Brooklyn (E.M.G., C.A.); the Department of Medicine, University of North Carolina, Chapel Hill (M.A.D.); the Division of Biostatistics, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, N.Y. (M.Y.K.); Hospital for Joint Diseases of New York University School of Medicine, New York (J.B.); the Department of Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City (J.T.M.); the Department of Medicine, Johns Hopkins School of Medicine, Baltimore (M.P.); the Medical University of South Carolina, Charleston (G.S.G.); Cedars–Sinai Medical Center, Los Angeles (D.J.W., M.H.W.); and the Division of Nephrology, Columbia University Medical Center, New York (G.B.A.).
Address reprint requests to Dr. Ginzler at the Division of Rheumatology, SUNY Downstate Medical Center, 450 Clarkson Ave., Box 42, Brooklyn, NY 11203, or at ellen.ginzler{at}downstate.edu.
Lv, J., Zhang, H., Cui, Z., Su, T., Zhang, Y., Wang, H.
(2008). Delayed severe pneumonia in mycophenolate mofetil-treated patients with IgA nephropathy. Nephrol Dial Transplant
23: 2868-2872
[Abstract][Full Text]
Singh, A. K., Kelley, K., Agarwal, R.
(2008). Interpreting Results of Clinical Trials: A Conceptual Framework. CJASN
3: 1246-1252
[Full Text]
Traitanon, O, Avihingsanon, Y, Kittikovit, V, Townamchai, N, Kanjanabuch, T, Praditpornsilpa, K, Wongchinasri, J, Tungsanga, K, Eiam-Ong, S
(2008). Efficacy of enteric-coated mycophenolate sodium in patients with resistant-type lupus nephritis: a prospective study. Lupus
17: 744-751
[Abstract]
Chan, T.
(2008). Mycophenolate mofetil in the treatment of lupus nephritis - 7 years on. Lupus
17: 617-621
F, L., Y, T., X, P., L, W., H, W., Z, S., H, Z., Z, H.
(2008). A prospective multicentre study of mycophenolate mofetil combined with prednisolone as induction therapy in 213 patients with active lupus nephritis. Lupus
17: 622-629
[Abstract]
Vento, M., Perez Aytes, A., Ledo, A., Boso, V., Carey, J. C.
(2008). Mycophenolate Mofetil During Pregnancy: Some Words of Caution. Pediatrics
122: 184-185
[Full Text]
Neumann, I., Fuhrmann, H., Fang, I-F., Jaeger, A., Bayer, P., Kovarik, J.
(2008). Association between mycophenolic acid 12-h trough levels and clinical endpoints in patients with autoimmune disease on mycophenolate mofetil. Nephrol Dial Transplant
0: gfn360v1-gfn360
[Abstract][Full Text]
Joy, M. S., La, M., Bo Xiao,
(2008). Individualizing Therapy in Patients With Chronic Kidney Disease. Journal of Pharmacy Practice
21: 225-236
[Abstract]
Houssiau, F., Ginzler, E.
(2008). Current treatment of lupus nephritis. Lupus
17: 426-430
[Abstract]
Clark, W. F., Sontrop, J. M.
(2008). What Have We Learned about Optimal Induction Therapy for Lupus Nephritis (III through V) from Randomized, Controlled Trials?. CJASN
3: 895-898
[Full Text]
Hu, W., Liu, C., Xie, H., Chen, H., Liu, Z., Li, L.
(2008). Mycophenolate mofetil versus cyclophosphamide for inducing remission of ANCA vasculitis with moderate renal involvement. Nephrol Dial Transplant
23: 1307-1312
[Abstract][Full Text]
Kim, Y. G., Kim, H. W., Cho, Y. M., Oh, J. S., Nah, S.-S., Lee, C.-K., Yoo, B.
(2008). The difference between lupus nephritis class IV-G and IV-S in Koreans: focus on the response to cyclophosphamide induction treatment. Rheumatology (Oxford)
47: 311-314
[Abstract][Full Text]
Bertsias, G, Ioannidis, J P A, Boletis, J, Bombardieri, S, Cervera, R, Dostal, C, Font, J, Gilboe, I M, Houssiau, F, Huizinga, T, Isenberg, D, Kallenberg, C G M, Khamashta, M, Piette, J C, Schneider, M, Smolen, J, Sturfelt, G, Tincani, A, van Vollenhoven, R, Gordon, C, Boumpas, D T
(2008). EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics. Ann Rheum Dis
67: 195-205
[Abstract][Full Text]
Kasitanon, N., Petri, M., Haas, M., Magder, L.S., Fine, D.M.
(2008). Mycophenolate mofetil as the primary treatment of membranous lupus nephritis with and without concurrent proliferative disease: a retrospective study of 29 cases. Lupus
17: 40-45
[Abstract]
Garg, A. X., Greene, T., Levin, N. W.
(2008). A well-conducted randomized trial that establishes no benefit of therapy is an important medical advance. Nephrol Dial Transplant
23: 52-55
[Full Text]
Chen, Y. E., Korbet, S. M., Katz, R. S., Schwartz, M. M., Lewis, E. J., for the Collaborative Study Group,
(2008). Value of a Complete or Partial Remission in Severe Lupus Nephritis. CJASN
3: 46-53
[Abstract][Full Text]
Sinclair, A., Appel, G., Dooley, M.A., Ginzler, E., Isenberg, D., Jayne, D., Wofsy, D., Solomons, N.
(2007). Mycophenolate mofetil as induction and maintenance therapy for lupus nephritis: rationale and protocol for the randomized, controlled Aspreva Lupus Management Study (ALMS). Lupus
16: 972-980
[Abstract]
Petri, M.
(2007). Disease activity assessment in SLE: do we have the right instruments?. Ann Rheum Dis
66: iii61-iii64
[Abstract][Full Text]
de Castro, W.P., Morales, J.V., Wagner, M.B., Graudenz, M., Edelweiss, M.I., Goncalves, L.F.
(2007). Hypertension and Afro-descendant ethnicity: a bad interaction for lupus nephritis treated with cyclophosphamide?. Lupus
16: 724-730
[Abstract]
El Sebaaly, Z., Charpentier, B., Snanoudj, R.
(2007). Fetal malformations associated with mycophenolate mofetil for lupus nephritis. Nephrol Dial Transplant
22: 2722-2722
[Full Text]
Walsh, M., James, M., Jayne, D., Tonelli, M., Manns, B. J., Hemmelgarn, B. R.
(2007). Mycophenolate Mofetil for Induction Therapy of Lupus Nephritis: A Systematic Review and Meta-Analysis. CJASN
2: 968-975
[Abstract][Full Text]
Contreras, G., Sosnov, J.
(2007). Role of Mycophenolate Mofetil in the Treatment of Lupus Nephritis. CJASN
2: 879-882
[Full Text]
Kone-Paut, I., Piram, M., Guillaume, S., Tran, T.A.
(2007). Review: Lupus in adolescence. Lupus
16: 606-612
[Abstract]
Ranchin, B., Fargue, S.
(2007). Review: New treatment strategies for proliferative lupus nephritis: keep children in mind!. Lupus
16: 684-691
[Abstract]
Zhu, B., Chen, N., Lin, Y., Ren, H., Zhang, W., Wang, W., Pan, X., Yu, H.
(2007). Mycophenolate mofetil in induction and maintenance therapy of severe lupus nephritis: a meta-analysis of randomized controlled trials. Nephrol Dial Transplant
22: 1933-1942
[Abstract][Full Text]
Czock, D., Rasche, F. M., Carius, A., Glander, P., Budde, K., Bauer, S., Keller, F., von Muller, L.
(2007). Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid After Enteric-Coated Mycophenolate Versus Mycophenolate Mofetil in Patients With Progressive IgA Nephritis. J Clin Pharmacol
47: 850-859
[Abstract][Full Text]
Wilson, E. C. F., Jayne, D. R. W., Dellow, E., Fordham, R. J.
(2007). The cost-effectiveness of mycophenolate mofetil as firstline therapy in active lupus nephritis. Rheumatology (Oxford)
46: 1096-1101
[Abstract][Full Text]
Parker, B., Bruce, I.
(2007). High dose methylprednisolone therapy for the treatment of severe systemic lupus erythematosus. Lupus
16: 387-393
[Abstract]
Stassen, P. M, Cohen Tervaert, J. W., Stegeman, C. A
(2007). Induction of remission in active anti-neutrophil cytoplasmic antibody-associated vasculitis with mycophenolate mofetil in patients who cannot be treated with cyclophosphamide. Ann Rheum Dis
66: 798-802
[Abstract][Full Text]
Zandi, M. S, Coles, A. J
(2007). Notes on the kidney and its diseases for the neurologist. J. Neurol. Neurosurg. Psychiatry
78: 444-449
[Abstract][Full Text]
Stassen, P. M., Kallenberg, C. G. M., Stegeman, C. A.
(2007). Use of mycophenolic acid in non-transplant renal diseases. Nephrol Dial Transplant
22: 1013-1019
[Full Text]
Bastian, H. M., Alarcon, G. S., Roseman, J. M., McGwin, G. Jr, Vila, L. M., Fessler, B. J., Reveille, J. D., for the LUMINA study group,
(2007). Systemic lupus erythematosus in a multiethnic US cohort (LUMINA) XL II: factors predictive of new or worsening proteinuria. Rheumatology (Oxford)
46: 683-689
[Abstract][Full Text]
Houssiau, F
(2007). Thirty years of cyclophosphamide: assessing the evidence. Lupus
16: 212-216
[Abstract]
Jayne, D
(2007). Current management of lupus nephritis: popular misconceptions. Lupus
16: 217-220
[Abstract]
Haubitz, M
(2007). Exploring new territory: the move towards individualised treatment. Lupus
16: 227-231
[Abstract]
Nihtyanova, S. I., Brough, G. M., Black, C. M., Denton, C. P.
(2007). Mycophenolate mofetil in diffuse cutaneous systemic sclerosis--a retrospective analysis. Rheumatology (Oxford)
46: 442-445
[Abstract][Full Text]
Pisoni, C. N., Cuadrado, M. J., Khamashta, M. A., Hughes, G. R. V., D'Cruz, D. P.
(2007). Mycophenolate mofetil treatment in resistant myositis. Rheumatology (Oxford)
46: 516-518
[Abstract][Full Text]
Alperovich, G, Rama, I, Lloberas, N, Franquesa, M, Poveda, R, Goma, M, Herrero-Fresneda, I, Cruzado, J M, Bolanos, N, Carrera, M, Grinyo, J M, Torras, J
(2007). New immunosuppresor strategies in the treatment of murine lupus nephritis. Lupus
16: 18-24
[Abstract]
Micheloud, D, Nuno, L, Rodriguez-Mahou, M, Sanchez-Ramon, S, Ortega, M C, Aguaron, A, Junco, E, Carbone, J, Fernandez-Cruz, E, Carreno, L, Lopez-Longo, F J
(2006). Efficacy and safety of Etanercept, high-dose intravenous gammaglobulin and plasmapheresis combined therapy for lupus diffuse proliferative nephritis complicating pregnancy. Lupus
15: 881-885
[Abstract]
Doria, A, Iaccarino, L, Arienti, S, Rampudda, M E, Canova, M G, Rondinone, R, Todesco, S
(2006). Mycophenolate mofetil and systemic lupus erythematosus. Lupus
15: 44-54
[Abstract]
Sinclair, A, Baildon, R
(2006). Mycophenolate mofetil: an overview. Lupus
15: 70-77
Adler, M., Chambers, S., Edwards, C., Neild, G., Isenberg, D.
(2006). An assessment of renal failure in an SLE cohort with special reference to ethnicity, over a 25-year period. Rheumatology (Oxford)
45: 1144-1147
[Abstract][Full Text]
Preddie, D. C., Markowitz, G. S., Radhakrishnan, J., Nickolas, T. L., D'Agati, V. D., Schwimmer, J. A., Gardenswartz, M., Rosen, R., Appel, G. B.
(2006). Mycophenolate Mofetil for the Treatment of Interstitial Nephritis. CJASN
1: 718-722
[Abstract][Full Text]
Ponticelli, C.
(2006). New Therapies for Lupus Nephritis. CJASN
1: 863-868
[Full Text]
(2006). Additional articles abstracted in ACP Journal Club. Evid. Based Med.
11: 94-94
[Full Text]
Tse, K C, Tang, C S., Lio, W I, Lam, M F, Chan, T M
(2006). Quality of life comparison between corticosteroidand-mycofenolate mofetil and corticosteroidand-oral cyclophosphamide in the treatment of severe lupus nephritis. Lupus
15: 371-379
[Abstract]
D'Cruz, D. P
(2006). Systemic lupus erythematosus.. BMJ
332: 890-894
[Full Text]
Dooley, M A
(2006). Mycophenylate mofetil: what role in the treatment of lupus?. Lupus
15: 179-182
[Abstract]
Karassa, F. B., Killen, J. P., Ginzler, E. M., Dooley, M. A., Kim, M. Y.
(2006). Mycophenolate mofetil or intravenous cyclophosphamide in lupus nephritis.. NEJM
354: 764-765
[Full Text]
Petri, M., Brodsky, R.
(2006). High-Dose Cyclophosphamide and Stem Cell Transplantation for Refractory Systemic Lupus Erythematosus. JAMA
295: 559-560
[Full Text]
McCune, W. J.
(2005). Mycophenolate Mofetil for Lupus Nephritis.. NEJM
353: 2282-2284
[Full Text]
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