Cyclophosphamide for severe lupus nephritis: Where are we now?

Abstract

Renal disease is a major complication of systemic lupus erythematosus. If not managed appropriately, the condition can culminate in renal failure and even death. Despite the use of cyclophosphamide (CYC) in the treatment of severe lupus glomerulonephritis for more than 3 decades, the optimal route of administration, dosage, and duration of therapy remain undefined. This situation is partly related to the lack of well-designed prospective studies comparing different CYC-containing regimens. The paucity of such data also reflects the technical difficulties in organizing clinical trials in lupus nephritis. First, a sizable sample is needed to reveal a small difference between treatment regimens. This is difficult to achieve in areas where lupus nephritis is not very prevalent. Second, in multicenter or multinational trials, it may be difficult to ensure that a treatment/ monitoring protocol is strictly and uniformly followed. Third, because a very long period of observation may be necessary to reveal a difference between treatment arms, investigators often have to invest a considerable amount of time, effort, and perseverance into their studies. A common pitfall of existing treatment trials in lupus nephritis is the protocol design. Because of the difficulty in patient recruitment, only 2–3 treatment regimens are usually tested in a study. Investigators often compare regimens that are frequently prescribed by physicians in their localities. Although conclusions generated from such studies are likely valid, the lack of data regarding the treatment efficacy of a wellestablished protocol in the same group of patients makes it unsound to claim that a certain treatment regimen is “an alternative” to one reported in a different study. An example of the lack of perfection in study design is the pilot randomized trial comparing continuous daily oral CYC with mycophenolate mofetil (MMF) as initial therapy for severe lupus nephritis, conducted by Chan et al (1) in Chinese patients. Although MMF was safe and as effective as oral CYC in this study, it is difficult to convince physicians who have been prescribing the intravenous pulse CYC regimen that MMF is as good as their “routine.” While one may compare the efficacy of treatment regimens by examining data obtained in different studies, interpretation can be confounded by discrepancies in the ethnic composition of the cohorts and the severity of renal disease at study entry. The lack of simultaneously obtained data regarding the treatment efficacy of a widely used protocol in the same study can lead to the impression that a therapeutic regimen, though effective in certain patients, may not necessarily be equally effective in patients of another ethnic group or in a different locality. In choosing a treatment regimen for severe lupus nephritis, the risk-to-benefit ratio has to be considered. There is evidence that a longer course of pulse CYC and the oral route of CYC administration, which often results in a higher cumulative dose, albeit more effective in the intermediate-term, are associated with an increase in frequency of adverse events such as menstrual disturbances, herpes zoster, and cervical carcinoma in-situ (2,3). A major concern regarding the use of CYC in young patients is gonadal toxicity. From the experience of investigators at the National Institutes of Health (NIH) (4) and a previous study at this institution (5), the risk of infertility in women is related to the cumulative dose of CYC. Thus, there is a trend to use regimens that are less toxic. Examples are a shortened course of oral CYC (6–8) or intravenous pulse CYC (9) compared with the NIH protocols (10), as well as use of newer immunosuppressive agents such as MMF for the initial treatment of lupus nephritis (1). However, the lack of long-term data is the major deterrent to the use of these newer regimens in high-risk patients. A recent trend in the management of lupus nephritis is the division of the treatment schedule into an Chi Chiu Mok, MD, FRCP: Tuen Mun Hospital, Hong Kong, China. Address correspondence and reprint requests to Chi Chiu Mok, MD, FRCP, Department of Medicine, Tuen Mun Hospital, Tsing Chung Koon Road, New Territories, Hong Kong, China. E-mail: ccmok2005@yahoo.com. Submitted for publication July 5, 2004; accepted in revised form August 23, 2004.