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Maintenance Therapy for Lupus Nephritis — Something Old, Something New
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     From a historical perspective, there are few diseases for which the cause, natural history, and response to treatment have been as complex or difficult to define as those of systemic lupus erythematosus (SLE). In large part, this is because SLE represents a clinical syndrome rather than a unique disease entity. The apparent diversity of pathogenic mechanisms operating in individual patients, which parallels the diversity observed in various animal models of SLE, underscores the fact that the disease phenotype arises from a variable mixture of environmental factors, the hormonal milieu, genes that contribute to an autoimmune diathesis, and other causes of immunoregulatory imbalance. Thus, given the remarkable heterogeneity of factors that may converge to cause this syndrome, it would be astonishing if particular treatments were to have consistent effects on the natural history of disease in all subgroups of patients with SLE and lupus nephritis.

    What are the bases for the current best practices in the treatment of lupus nephritis? On the model of precedents in oncology, it is conventional to divide the treatment of chronic autoimmune diseases, such as SLE and lupus nephritis, into induction and maintenance phases. Controversy abounds over the recommendations for both induction and maintenance treatment of lupus nephritis. Early controlled trials of induction therapies for lupus nephritis conducted by both the National Institutes of Health (NIH) and the Mayo Clinic indicated (on the basis of improvements in or stability of renal function, degree of proteinuria, and nephritic urinary sediment) that cytotoxic drugs had an advantage over corticosteroids alone. In the Mayo Clinic study,1 the early advantages of cyclophosphamide as induction therapy dissipated over time when corticosteroids alone were used as maintenance therapy. In the early NIH studies,2 all regimens of corticosteroids, cyclophosphamide, and azathioprine used for both induction and extended maintenance were associated with similar, low risks of renal failure throughout the first five years of treatment. Detection of a significant reduction in the risk of renal failure with cytotoxic-drug treatment required longer observation; this effect would have been missed if the treatment and follow-up had been truncated — a frequent weakness of contemporary studies of lupus nephritis. A second study from the NIH3 subsequently showed that quarterly intravenous pulses of cyclophosphamide for maintenance therapy conferred a significant advantage over a short course of induction therapy alone for patients with severe lupus nephritis.

    Because of concern about the long-term risk posed by extended courses of cyclophosphamide, some clinicians prefer to substitute azathioprine for maintenance therapy after induction with cyclophosphamide. Studies are in progress in Europe to define further the role of azathioprine maintenance therapy in lupus nephritis. During the past decade, there have been reports of the use of mycophenolate mofetil or sequential mycophenolate mofetil and azathioprine for induction and maintenance treatment of lupus nephritis. Although the initial report suggested that cyclophosphamide and mycophenolate mofetil were equivalent for induction,4 extended follow-up showed that, during maintenance therapy with azathioprine, relapse was more frequent among patients who had received induction therapy with mycophenolate mofetil than among those who had received cyclophosphamide.5

    Even though intravenous pulse cyclophosphamide is widely (but not universally) accepted as the standard of induction therapy for proliferative lupus nephritis, there is intense interest in defining the maintenance regimen with the highest therapeutic index (that is, the most favorable ratio of benefits to risks). In this issue of the Journal, Contreras and colleagues report the results of a prospective controlled trial comparing three maintenance regimens: quarterly intravenous injections of cyclophosphamide (pulse cyclophosphamide), oral mycophenolate mofetil, and oral azathioprine.6 Randomization took place after patients had received four to six monthly intravenous doses of cyclophosphamide given as induction therapy. Of the 59 patients with proliferative or mixed membranous and proliferative lupus nephritis who were enrolled in the study, 46 percent were black, 49 percent were Hispanic, and 5 percent were white.

    On the basis of improvements in renal function, degree of proteinuria, serum albumin levels, and lupus antibodies and complement values, cyclophosphamide induction therapy led to substantial improvements in all groups between study entry and random assignment to the various maintenance therapies. Remission of nephritis occurred in 83 percent of patients during the pulse-cyclophosphamide induction phase, and the proportions of patients who met the criteria for remission (some degree of reduction in proteinuria and stable or improved serum creatinine levels) were evenly distributed among the three maintenance-therapy groups. During the maintenance phase, the doses of cyclophosphamide (mean, slightly more than 500 mg per square meter of body-surface area) were lower than the doses recommended on the basis of the NIH studies.7

    Overall survival among patients was significantly higher with azathioprine than with cyclophosphamide as maintenance therapy. There were no significant differences in actuarial renal survival, but event-free survival (based on a composite end point of death and renal failure) was significantly better in both the azathioprine and the mycophenolate mofetil groups than in the cyclophosphamide group. Relapse-free survival was significantly better with mycophenolate mofetil than with cyclophosphamide. Finally, the rate of unscheduled hospital admissions, total hospital days, and the number of infectious episodes were significantly higher in the cyclophosphamide group than in either the azathioprine or the mycophenolate mofetil group. The authors conclude that after induction therapy with cyclophosphamide, both azathioprine and mycophenolate mofetil offer better benefit–risk profiles for maintenance therapy than does cyclophosphamide.

    Although it was not stated as an initial hypothesis, it seems likely that the present study was conceived as a test of whether azathioprine and mycophenolate mofetil might be equivalent to cyclophosphamide in terms of efficacy in the maintenance treatment of proliferative lupus nephritis. The authors conclude that both agents actually surpass cyclophosphamide from the perspectives of both efficacy and safety. In our opinion, it is important to recognize that the argument for the superior efficacy of azathioprine and mycophenolate mofetil for lupus nephritis emerged only when the authors combined the outcomes of patient survival and renal survival. Moreover, there were no significant differences among the treatment groups in renal survival — a fact that modulates to some degree the authors' claim that azathioprine and mycophenolate mofetil are superior to cyclophosphamide.

    There are other reasons to challenge the strength of the authors' interpretation and the universal applicability of the study results. The risks of death, renal failure, and relapse of nephritis were higher than expected during maintenance therapy with cyclophosphamide. Furthermore, the racial and ethnic distribution of subjects participating in the study by Contreras et al. was not representative of the general population of patients with SLE in the United States. Indeed, some studies have shown that cyclophosphamide has a particularly abysmal record in preventing renal failure among black patients with severe lupus nephritis.8 The extraordinarily high rate of infections in the cyclophosphamide group may have been misattributed to that drug. The dose of cyclophosphamide was less than that conventionally used, and the infectious diathesis may have been due to the higher dose of adjunctive corticosteroids used in this group. In this regard, other recent studies have shown by multivariate analysis that the dosage of corticosteroids is the overriding independent determinant of the risk of infection among patients with SLE.9 Finally, the rates of relapse during maintenance therapy with azathioprine and mycophenolate mofetil seem to be lower than would normally be expected.5

    None of these potential caveats are meant to undermine the value of this controlled trial examining the risks and benefits of widely used maintenance therapies for proliferative lupus nephritis. In our opinion, the most reliable take-home message of the study by Contreras et al. is that azathioprine and mycophenolate mofetil are good options for maintenance therapy in patients with proliferative lupus nephritis. Nonetheless, there is clearly a need for further studies, with longer follow-up, conducted in a more broadly representative population of patients with SLE.

    Source Information

    From the Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md.

    References

    Donadio JV Jr, Holley KE, Ferguson RH, Ilstrup DM. Treatment of diffuse proliferative lupus nephritis with prednisone and combined prednisone and cyclophosphamide. N Engl J Med 1978;299:1151-1155.

    Austin HA III, Klippel JH, Balow JE, et al. Therapy of lupus nephritis: controlled trial of prednisone and cytotoxic drugs. N Engl J Med 1986;314:614-619.

    Boumpas DT, Austin HA III, Vaughan EM, et al. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 1992;340:741-745.

    Chan TM, Li FK, Tang CSO, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. N Engl J Med 2000;343:1156-1162.

    Chan T-M, Wong W-S, Lau C-S, et al. Prolonged follow-up of patients with diffuse proliferative lupus nephritis (DPLN) treated with prednisolone and mycophenolate mofetil (MMF). J Am Soc Nephrol 2001;12:195A-195A. abstract.

    Contreras G, Pardo V, Leclercq B, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004;350:971-980.

    Balow JE, Boumpas DT, Austin HA III. Lupus nephritis. In: Brady HR, Wilcox CS, eds. Therapy in nephrology and hypertension. 2nd ed. London: W.B. Saunders, 2003:153-64.

    Dooley MA, Hogan S, Jennette JC, Falk R. Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Kidney Int 1997;51:1188-1195.

    Gladman DD, Hussain F, Ibanez D, Urowitz MB. The nature and outcome of infection in systemic lupus erythematosus. Lupus 2002;11:234-239.

    Related Letters:

    Sequential Therapies for Proliferative Lupus Nephritis

    Yee C.-S., Gordon C., Gelber A. C., Christopher-Stine L., Fine D. M., Farhey Y., Hess E., Contreras G., Lenz O., Roth D.(James E. Balow, M.D., and)