Combination Therapy with Pulse Cyclophosphamide plus Pulse Methylprednisolone Improves Long-Term Renal Outcome without Adding Toxicity in Patients with Lupus Nephritis

Proliferative lupus nephritis is characteristically a protracted disease with a waxing and waning course (1, 2). Open-label and controlled clinical trials have shown that cyclophosphamide is superior to corticosteroids in preserving renal function; only a minority of patients treated with cyclophosphamide reach end-stage renal disease (314). Some retrospective analyses, however, have reported a less favorable effect of pulse cyclophosphamide therapy (1517). Lupus nephritis can reactivate after an initial response, and the cumulative renal damage may cause subsequent decline in renal function (1820). Moreover, immunosuppressive therapy can be associated with adverse effects that are not evident during short-term clinical trials (21). Such complications must be weighed against morbidity from uncontrolled disease and the need for extended therapy. Long-term follow-up is therefore essential to assess the riskbenefit ratio of various immunosuppressive therapies. Because immunosuppressive treatment regimens have dramatically reduced the frequency of end-stage renal disease, alternative outcomes to end-stage renal disease are needed as practical end points in clinical studies. In the analysis of a previous randomized, controlled trial (3), we used the composite outcome of renal response as the primary outcome. In that analysis, treatment with pulse cyclophosphamide, alone or in combination with pulse methylprednisolone, was superior to pulse methylprednisolone alone in inducing renal responses. In the same trial, combination therapy resulted in a higher rate of renal responses and fewer relapses compared with cyclophosphamide alone; however, these differences were not statistically significant after a median follow-up of 5 years (3). We report the results of extended follow-up and long-term effectiveness of these treatment regimens, as well as morbidity and mortality, in patients participating in this trial. Methods Patients Treatment during Protocol Details of the treatment protocol have been published elsewhere (3). In brief, 82 patients with proliferative lupus nephritis were enrolled in a randomized, controlled study at the Clinical Center of the National Institutes of Health, Bethesda, Maryland, between 1986 and 1990. Initial analysis was based on data collected through 1 May 1995 [3]. Patients were randomly assigned to receive one of three regimens: 1) intravenous methylprednisolone, 1 g/m2 of body surface area, administered as a monthly bolus for at least 12 months and up to 36 months; 2) intravenous cyclophosphamide, targeting 1 g/m2 of body surface area, as a monthly bolus for 6 consecutive months and then once every 3 months for at least 24 additional months; or 3) the combination of these two regimens. After the first year of the study, patients in any treatment group who were no longer receiving monthly therapy but had evidence of active glomerular disease were recycled to their originally assigned regimens. Recycling could not take place more than twice; if therapy failed three times, patients were considered nonresponders. All patients initially received oral prednisone, 0.5 mg/kg of body weight daily, for 4 weeks. The prednisone dose was then tapered by 5 mg every other day each week to the minimal dose required to control extrarenal disease or to 0.25 mg/kg every other day, whichever was greater. For severe extrarenal flares of lupus, patients were permitted to receive prednisone, 1.0 mg/kg, daily for 2 weeks. Post-Protocol Treatment After completion of protocol treatment, therapy was dictated by clinical need and was determined by the patients' primary rheumatologist or nephrologist after consultation with the investigators at the National Institutes of Health. Follow-up We conducted a systematic follow-up of all patients through August 1999. The study was done under a protocol examining the natural history of systemic lupus erythematosus that was approved by the institutional review board of National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. All surviving patients were contacted and asked to return for evaluation. Patients who were unable or unwilling to return were asked to complete a standardized questionnaire about their renal status, current therapy, immunosuppressive therapy since the end of the protocol, and comorbid conditions. A copy of their medical records was also obtained with their permission. Family and physicians of deceased patients were contacted to collect data on the cause of death. Patients evaluated at the National Institutes of Health underwent a detailed history and physical examination; laboratory studies; cardiac work-up (electrocardiography and echocardiography); bone densitometry (if not performed within 1 year of the follow-up visit) and magnetic resonance imaging of both hips unless they had a history of hip replacement or previous magnetic resonance imaging showing avascular necrosis. Data collection focused on determining renal outcomes (defined as persistent increase in serum creatinine concentration by at least 50%, persistent doubling of serum creatinine concentration, or end-stage renal disease) and illnesses associated with lupus nephritis or its treatment. Definitions Patients Patients who completed the protocol (protocol completers) were classified as responders or nonresponders on the basis of prespecified criteria. Protocol noncompleters were patients who underwent randomization but whose response to therapy could not be evaluated because they died before reaching an end point, did not return for follow-up, or were excluded because of protocol violation. Renal Outcomes Renal response was defined as an erythrocyte count less than 10 cells per high-power field in a centrifuged 50-mL urine sample, absence of cellular casts, and proteinuria less than 1 g/d. Response criteria were applied to protocol completers at the 5-year study visit. Patients were classified as nonresponders if they did not fulfill the above criteria for response at their 5-year visit or had received additional immunosuppressive therapy for worsening lupus nephritis beyond that allowed in the protocol before the end of 5-year follow-up. Renal insufficiency was analyzed according to two grades of decreased renal function: increase in serum creatinine concentration to 50% or more or 100% or more (doubling) above the lowest concentration observed for at least 1 month during the protocol. End-stage renal disease was defined as receipt of renal replacement therapy (dialysis or kidney transplantation). Treatment failure was defined as the composite of any of the following events: need for immunosuppressive therapy not dictated by the protocol, doubling of serum creatinine concentration (compared with the lowest concentration during protocol treatment), or death. Nonrenal Outcomes Avascular necrosis of the bone was ascertained by performing screening magnetic resonance imaging of the hips. Ovarian failure was defined as sustained amenorrhea occurring before 45 years of age. Osteoporosis was defined according to the guidelines of the American College of Rheumatology (22). Ischemic heart disease was defined as history of myocardial infarction or coronary revascularization procedure or typical angina with a positive result on a stress test or ischemic changes on electrocardiography. Valvular heart disease was defined as a significant valvular abnormality on echocardiography, such as valvular thickening associated with vegetation, regurgitation, or stenosis. Hypertension was defined as sustained systolic blood pressure of 140 mm Hg or greater, sustained diastolic blood pressure of 90 mm Hg or greater, or receipt of antihypertensive medications. Hyperlipidemia was defined as a low-density lipoprotein cholesterol level greater than 3.36 mmol/L (130 mg/dL) or receipt of a cholesterol-lowering agent. Serious infection was any infection requiring intravenous antibiotics or hospitalization. Statistical Analysis For categorical outcome measures, we calculated the relative risk and 95% CIs. Survival data were plotted by using the KaplanMeier method, and the significance of differences between groups was tested by using the BreslowGehanWilcoxon test. We used an intention-to-treat approach to compare the effectiveness of the three treatments. For this analysis, we included all 82 enrolled patients and analyzed them as being in the treatment group to which they were assigned, regardless of the actual duration of treatment. A composite outcome was used to assess treatment failure, in which therapy was considered to have failed at the earliest time at which patients required additional immunosuppressive therapy, had a doubled serum creatinine concentration, or died. Additional immunosuppressive therapy was defined as any immunosuppressive therapy not specified in the protocol, given for any reason and at any time after enrollment in the study. For example, if someone assigned to the methylprednisolone group was classified as a nonresponder after 3 years of therapy and was treated with cyclophosphamide, he or she would be classified as having had an event in the intention-to-treat survival analysis. Similarly, if a patient assigned to the cyclophosphamide group was still an active participant at the end of the protocol and continued to receive cyclophosphamide, he or she would be considered as someone who received additional immunosuppressive therapy and thus reached the composite end point (had an event). If a patient finished the protocol period as a responder but had a flare requiring immunosuppressive therapy after the protocol, he or she would be considered as someone with an event at that point. Protocol noncompleters were treated in the same manner. If a patient was withdrawn from the protocolfor example, because of pregnancyand required immunosuppressive therapy after her pregnancy, she would