a randomized, controlled trial - loyola medicine...design: randomized, controlled trial with at leas...

Methylprednisolone and Cyclophosphamide, Alone or in Combination, in Patients with Lupus Nephritis A Randomized, Controlled Trial

Mark F. Gourley, MD; Howard A. Austin III, MD; Dorothy Scott, MD; Cheryl H. Yarboro, RN; Ellen M. Vaughan, RN; Joanne Muir, RN; Dimitrios T. Boumpas, MD; John H. Klippel, MD; James E. Balow, MD; and Alfred D. Steinberg, MD

Background: Uncertainty exists about the efficacy and toxicity of bolus therapy with methylprednisolone or of the combination of methylprednisolone and cyclophosphamide in the treatment of lupus nephritis.

Objective: To determine 1) whether intensive bolus therapy with methylprednisolone is an adequate substitute for bolus therapy with cyclophosphamide and 2) whether the combination of methylprednisolone and cyclophosphamide is superior to bolus therapy with methylprednisolone or cyclophosphamide alone.

Design: Randomized, controlled trial with at least 5 years of follow-up.

Setting: Government referral-based research hospital.

Patients: 82 patients with lupus nephritis who had 10 or more erythrocytes per high-power field, cellular casts, proteinuria (>1 g of protein per day), and a renal biopsy specimen that showed proliferative nephritis.

Interventions: Bolus therapy with methylprednisolone (1 g/m2 body surface area), given monthly for at least 1 year; bolus therapy with cyclophosphamide (0.5 to 1.0 g/m2 body surface area), given monthly for 6 months and then quarterly; or bolus therapy with both methylprednisolone and cyclophosphamide.

Measurements: 1) Renal remission (defined as <10 dysmorphic erythrocytes per high-power field, the absence of cellular casts, and excretion of <1 g of protein per day without doubling of the serum creatinine level), 2) prevention of doubling of the serum creatinine level, and 3) prevention of renal failure requiring dialysis.

Results: Renal remission occurred in 17 of 20 patients in the combination therapy group (85%), 13 of 21 patients in the cyclophosphamide group (62%), and 7 of 24 patients in the methylprednisolone group (29%) (P < 0.001). Twenty-eight patients (43%) did not achieve renal remission. By life-table analysis, the likelihood of remission during the study period was greater in the combination therapy group than in the methylprednisolone group (P = 0.028). Combination therapy and cyclophosphamide therapy were not statistically different. Adverse events were amenorrhea (seen in 41 % of the cyclophosphamide group, 43% ofthe combination therapy group, and 7.4% of the methylprednisolone group), cervical dysplasia (seen in 11 % of the cyclophosphamide group, 7.1% of the combination therapy group, and 0% of the methylprednisolone group), avascular necrosis (seen in 11% of the cyclophosphamide group, 18% of the combination therapy group, and 22% of the methylprednisolone group), herpes zoster (seen in

15% of the cyclophosphamide group, 21% of the combination therapy group, and 3.7% of the methylprednisolone group) and at least one infection (seen in 26% of the cyclophosphamide group, 32% of the combination therapy group, and 7.4% of the methylprednisolone group).

Conclusions: Monthly bolus therapy with methylprednisolone was less effective than monthly bolus therapy with cyclophosphamide. A trend toward greater efficacy with combination therapy was seen.

Ann Intern Med. 1996;125:549-557.

From the National Institutes of Health, Bethesda, Maryland. For current author addresses, see end of text.

Therapy for patients with life-threatening systemic lupus erythematosus has included high

doses of corticosteroids and cytotoxic or cytostatic drugs (1-20). Cyclophosphamide, given in intermittent intravenous boluses, has been widely used to treat renal (1-6, 8, 15, 21) and central nervous system disease (2, 3, 6, 7, 19-21), but this therapy is sometimes withheld in the hope that disease might be controlled with corticosteroids or other immunosuppressive drugs. Moreover, some patients do not respond adequately to therapy with intermittent boluses of cyclophosphamide, and these patients might benefit from more intensive therapy.

In a previous study (3), monthly administration of methylprednisolone (1.0 g/m2 body surface area) was less effective than bolus therapy with cyclophosphamide. However, the limited duration of the methylprednisolone regimen (6 months) might have been insufficient to treat lupus nephritis. To address this concern, we evaluated patients receiving methylprednisolone once a month for 1 year; additional boluses were given as needed to control disease. We compared these patients with patients receiving our standard therapy: intermittent boluses of cyclophosphamide. A group of patients randomly assigned to receive both cyclophosphamide and methylprednisolone was also included for three major reasons: 1) some patients with lupus nephritis respond inadequately to boluses of cyclophosphamide, 2) anecdotal experience had suggested that cyclophosphamide therapy might be more effective for all

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patients when given with substantial doses of corticosteroids, and 3) animal studies had shown the advantage of combined chemotherapy for lupus nephritis (22, 23). Our study design was modified from previous designs so that therapy could be intensified for patients with refractory or relapsing disease.

Methods

Patient Selection

We enrolled 82 patients with lupus nephritis into this randomized, parallel study at the Clinical Center of the National Institutes of Health (Bethesda, Maryland) between 1986 and 1990. To enter the study, patients had to have both glomerulonephritis and a diagnosis of systemic lupus erythematosus (24). Glomerulonephritis was defined as a sediment on two or more urinalyses that showed either 10 or more erythrocytes per high-power field or erythrocyte or leukocyte casts (without evidence of infection) or both, plus histologic evidence of active proliferative lupus glomerulonephritis on a renal biopsy specimen obtained within 3 months of study entry (provided that a biopsy could be done safely). Scores for renal histologic activity and chronicity were assessed as reported elsewhere (25).

All eligible patients were invited to participate. Exclusion criteria were 1) receipt of cytotoxic drug treatment for more than 2 weeks during the 6 weeks before study entry or receipt of cyclophosphamide

Figure 1. Treatment regimens and decision pathways used in this clinical trial for lupus nephritis.

therapy for more than 10 weeks at any time; 2) receipt of pulse therapy with corticosteroids during the 6 weeks before study entry; 3) need (at the time of study entry) for oral corticosteroids in dosages greater than 0.5 mg of a prednisone equivalent per kilogram of body weight per day to control extrarenal disease; 4) active or chronic infection; 5) pregnancy; 6) the presence of only one kidney; 7) insulin-dependent diabetes mellitus; and 8) allergy to methylprednisolone or cyclophosphamide.

Study Design

The protocol that we used was approved by the NIDDK/NIAMS (National Institute of Diabetes and Digestive and Kidney Diseases/National Institute of Arthritis and Musculoskeletal and Skin Diseases) Institutional Review Board (86-AR-0189). After giving signed, written informed consent, patients were randomly assigned to one of three treatment groups by drawing from a masked card sequence arranged from a table of random numbers. Each group received one of the following regimens: 1) intravenous methylprednisolone (1 g/m2 body surface area), given as boluses over 60 minutes on 3 consecutive days followed by at least 12 consecutive monthly single infusions; 2) intravenous cyclophosphamide, given as boluses once a month for 6 consecutive months and then once every 3 months for at least 2 more years; and 3) the combination of these two regimens.

After a patient completed 1 year of study, a decision about whether therapy would be modified was made on the basis of the patient's renal status at that time (Figure 1). In patients receiving methylprednisolone, therapy was discontinued if urine studies showed that renal remission had occurred. Renal remission was defined as the presence of fewer than 10 dysmorphic erythrocytes per high-power field, the absence of cellular casts, and excretion of less than 1 g of protein per day. If a renal remission was not evident, the patient continued to receive methylprednisolone every month for 6 more months. After the additional 6 months, if renal remission was still not evident, the patient received treatment for another 6 months. Therapy with methylprednisolone was limited to a maximum of 36 monthly boluses.

At 1 year, patients who had been receiving cyclophosphamide alone or in combination with methylprednisolone continued to receive or began to receive cyclophosphamide alone, once every 3 months, if the results of urine studies were substantially improved. Substantial improvement was defined as a reduction of at least 50% in 1) the number of dysmorphic erythrocytes seen in urine samples, 2) the number of cellular casts, and 3) proteinuria, without a doubling of the serum creatinine level.

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Quarterly administration of cyclophosphamide was continued for 2 years after renal remission occurred, after which time therapy was stopped.

After the first year of the study, patients in any treatment group who were no longer receiving monthly therapy but who had evidence of the reactivation of glomerular disease had their originally assigned regimens reinstituted as if they were beginning therapy from enrollment. Reactivation of glomerular disease was defined as new active nephritis with an increase of at least 50% (relative to the lowest reproducible values obtained during the study) in at least two of the following: number of dysmorphic erythrocytes (>10 per high-power field), number of cellular casts, proteinuria (>1 g of protein per day), or serum creatinine level. One year after the reinstitution of therapy, patients were again evaluated for evidence of active glomerulonephritis (as described above). As before, patients could be withdrawn from therapy, could restart treatment, or could continue to receive cyclophosphamide every 3 months. Patients could restart therapy no more than twice; if therapy failed more than three times, patients were declared to be nonresponders.

Treatment and Follow-up

Cyclophosphamide was infused for 60 minutes at an initial dose of 0.75 g/m2 body surface area. If the leukocyte nadir was greater than 3000 cells/mm3, the cyclophosphamide dose was increased by 25%, to a maximum of 1 g/m2 body surface area. The dose was reduced by 25% for leukocyte counts less than 1500 cells/mm3. Patients with a creatinine clearance of less than 30 mL/min received an initial dose of 0.5 g/m2 body surface area, and subsequent doses were adjusted on the basis of the lowest leukocyte count. Patients treated with cyclophosphamide were hydrated, and diuretics were used to maintain neutral fluid balance. Thiethylperazine, 10 mg, with 25 mg of diphenhydramine or 0.25 mg of lorazepam, was administered orally or intravenously every 6 hours for nausea.

After the middle of 1990, patients were treated in a day hospital setting, where they received intravenous saline, 200 mL per hour for 10 hours. Mesna (2-mercaptoethanesulfonate), at 20% of the cyclophosphamide dose, was infused intravenously for 10 minutes before cyclophosphamide was administered and every 3 hours thereafter, for a total of four doses. Ondansetron, 8 mg, was given every 4 hours beginning 4 hours after infusion of cyclophosphamide, for a total of three doses. Dexamethasone, 10 mg, was given 4 hours after administration of cyclophosphamide (26). Patients were instructed to continue oral hydration after discharge from the day hospital to maintain a dilute and frequent diuresis for at least 24 hours after infusion of cyclophosphamide.

All patients were initially given oral prednisone, 0.5 mg/kg per day 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 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 per day for 2 weeks. Blood pressure was closely monitored and was maintained within 110 to 130/70 to 85 mm Hg with antihypertensive therapy.

The intervals at which patients were followed were dictated by the activity of lupus and nephritis. In general, all patients were seen monthly during the first year of the study and every 3 months thereafter. At each study visit, patients were questioned about and examined for adverse events.

Outcome Measures The primary study outcome was the response to

the study drugs as defined by 1) the percentage of patients who achieved renal remission, 2) the number of nonresponders (nonresponse was defined as >10 erythrocytes per high-power field, cellular casts, proteinuria [>1 g of protein per day], and doubling of the serum creatinine level), and 3) the percentage of adverse events. The outcome data, with the exception of data on adverse events, were collected in a blinded manner on 1 May 1995, 5 years after the last patient was enrolled in the study.

Secondary outcome measures were renal failure that required dialysis (end-stage renal disease), stable doubling of the serum creatinine level, and number of renal relapses (renal relapse was defined as a reactivation of renal disease after 6 or more months of remission).

Approximately one fifth of the patients (17 of 82) were censored during the study period. Three patients in the methylprednisolone group were censored because of pregnancy (1 patient), failure to return for follow-up (1 patient), and a protocol violation (1 patient did not receive additional methylprednisolone per the protocol). Six patients in the cyclophosphamide group were censored because of pregnancy (2 patients), failure to return for follow-up (2 patients), and death (2 patients). Eight patients in the combination therapy group were censored because of pregnancy (1 patient), allergy to methylprednisolone (2 patients), failure to return for follow-up (2 patients), a protocol violation (1 patient did not receive additional methylprednisolone because of avascular necrosis), excessive nausea and vomiting (1 patient), and death (1 patient).

A total of 4656 patient-months of follow-up were accumulated (1374 patient-months in the methylprednisolone group, 1613 patient-months in the cyclophosphamide group, and 1669 patient-months in the combination therapy group). Mean patient-months



Table 1 . Patient Characteristics at Study Entry

Characteristic Methylprednisolone Cyclophosphamide Combination Therapy Group (n = 27) Group (n = 27) Group (n = 28)

Age, n <19 years 4 6 3 20-29 years 12 8 10 30-39 years 7 5 10 40-49 years 2 7 4 >50 years 2 1 1

Mean age, y 30 30 31 Sex, n

Female 22 21 25 Male 5 6 3

Race or ethnicity, n White 22 17 18 Black 4 7 7 Asian 0 1 1 Hispanic 1 2 2

Duration of nephritis, mo* 31 ± 8.6 24 ± 6.9 39 ± 13.6 Highest dose of prednisone, mg*i 56 ± 3.6 51. ±3.3 42 ± 7.1 Serum creatinine level, ixmoilL* 100 ± 12.1 106 ±9.6 100 ±8.1 Hematocrit* 0.34 ± 0.12 0.33 ±0.10 0.30 ± 0.08 C3 level, g/L* 0.69 ± 0.04 0.69 ± 0.04 0.67 ± 0.04 Protein level in urine, g/d* 4.5 ± 0.9 3.7 ± 0.6 3.7 ± 0.5 Erythrocytes per high-power field, n* 19 ± 3.6 25 ± 4.4 26 ± 3.8 Renal activity index score* 8.3 ± 0.8 9.8 ± 0.6 8.2 ± 0.7 Chronicity index score* 2.7 ± 0.5 3.2 ± 0.2 2.8 ± 0.4

* Values are expressed as the mean ± SE. t The highest dose of prednisone that a patient received for a minimum of 1 month at any time before study entry. * The groups appear to be clinically equivalent, but the hematocrit of the combination therapy group is statistically significantly lower than that of the other groups.

of follow-up (censored patients were followed until the time of censorship, and noncensored patients were followed for the entire study period) were 59.7 in the methylprednisolone group, 59.6 in the cyclophosphamide group, and 50.9 in the combination therapy group (P > 0.2). Follow-up for the patients who were not censored (patients who achieved remission or were nonresponders) ranged from 5 years to 8.5 years; follow-up for censored patients ranged from 2 months to 5 years.

Statistical Analysis

Multiple groups were compared by using analyses of variance and by comparing group means and medians by either the two-tailed Mest or the Wil-coxon signed-rank test, as appropriate. All contingency tables were tested using the chi-square test or the Fisher exact test. Cumulative survival analysis was used in evaluating the time to doubling of the serum creatinine level and the time to remission. Survival curves were derived using the Kaplan-Meier method (27) and were statistically tested with the Gehan (28) or Mantel-Haenszel tests (29, 30).

Results

Overall Measures

Randomization produced three treatment groups that were similar in age, sex, race, duration of renal involvement, maximum dose of prednisone, serum creatinine level, C3 level, degree of proteinuria, de

gree of hematuria, and renal activity and chronicity indices (Table 1) and in World Health Organization classification (Table 2). The combination therapy group tended to have a longer duration of nephritis, less exposure to prednisone, a lower hematocrit, and a greater degree of hematuria. Renal biopsies were done for 79 of the 82 patients (Table 2). Biopsies were not done for the other 3 patients because of anticoagulation therapy, thrombocytopenia, or uncontrolled hypertension. Twenty-seven patients were randomly assigned to receive methylprednisolone, 27 were randomly assigned to receive cyclophosphamide, and 28 were randomly assigned to receive combination therapy.

The methylprednisolone group had the most persons whose serum creatinine levels doubled (serum creatinine levels doubled in 4 patients in the methylprednisolone group, 1 patient in the cyclophospha-

Table 2 . Renal Histologic Features at Study Entry by Light and Electron Microscopy

Treatment Group Patients Patients Who Had Biopsy*

World Health Organization Classification

III IV

Methylprednisolone Cyclophosphamide Combination therapy

27 27 28

27 26 26

6 21 6 20 5 21

* Three patients did not have biopsy because of thrombocytopenia, anticoagulation therapy, or poorly controlled hypertension.



Table 3. Patients Who Achieved Remission or Were Nonresponders

Outcome Methylprednisolone Group (n = 27)

Cyclophosphamide Group (n = 27)

Combination Therapy Group (n = 28)

Achieved remission* Declared a nonresponder* Censoredt Serum creatinine level doubled Developed end-stage renal disease

7 17 3 4 3

13 8 6 1 1

17 3 8 0 0

* Comparison of number of remissions with number of nonresponders in the uncensored group differ according to treatment group (P = 0.0008) t All censored patients coded as nonresponders (P = 0.032).

mide group, and no patients in the combination therapy group). Four patients (3 in the methylprednisolone group and 1 in the cyclophosphamide group) developed end-stage renal disease. Thirty-seven of 65 noncensored patients (57%) who entered the study had remission; 28 of the 65 (43%) did not. Most remissions occurred in the groups that received cyclophosphamide (17 patients in the combination therapy group, 13 patients in the cyclophosphamide group, and 7 patients in the methylprednisolone group had remissions). The number of nonresponders was highest in the methylprednisolone group (n = 17); the cyclophosphamide group had 8 nonresponders, and the combination therapy group had 3 nonresponders. Analysis of the entire cohort (patients who had renal remission, nonresponders, and censored patients) done using the complete contingency (Table 3) showed significant differences among the study groups (P > 0.001). Seven of 27 patients in the methylprednisolone group (26%) had renal remission compared with 13 of 27 patients in the cyclophosphamide group (48%; P = 0.038) and 17 of 28 patients receiving combination therapy (61%; P < 0.001). Remission rates in the cyclophosphamide and combination therapy groups were not statistically significantly different (P = 0.16). According to a conservative estimate in which all censored patients who were coded as nonresponders, the comparison of remission in the combination therapy group with remission in the methylprednisolone group still achieved statistical significance (P = 0.02). Other group comparisons done using this worst-case scenario did not reach statistical significance (P > 0.2)

The proportion of persons who had relapse after achieving remission and maintaining it for 1 year was greater in the methylprednisolone group (4 of 11 [36%]) than in the cyclophosphamide group (1 of 14 [7%]) and the combination therapy group (0 of 17 [0%]). More patients in the methylprednisolone group than in the combination therapy group had relapse (P = 0.016), but none of the differences in the other two-way comparisons between groups was statistically significant.

Life-Table Analyses

The effect of therapy on renal function was evaluated by life-table analyses (Figure 2). When serum creatinine levels doubled, they did so relatively early in the study. The cumulative probability of a doubling of the serum creatinine level at 5 years was approximately 25% in the methylprednisolone group and 0% in the combination therapy group (P = 0.055). Comparison of this end point in the cyclophosphamide group with that in the groups receiving methylprednisolone showed no difference (P = 0.16V

Figure 2. Probability that the serum creatinine level would not double during the study period by treatment group. Kaplan-Meier survival analyses are shown. The number of patients at risk in each group is shown above the survival curve for each year of the study. The probability that the serum creatinine level would not double during the study did not differ in the combination therapy group (MP + CY) and the cyclophosphamide group (CY) (P > 0.2). The probability that the serum creatinine level would not double tended to be greater for the methylprednisolone group (MP) than for the combination therapy group (P = 0.057). The symbols represent either an event or the censorship of an individual patient.



Figure 3. Probability of remission during the study period by treatment group. The number of patients at risk in each group is shown above the survival curve for each year of the study. The combination therapy group (MP + CY) differs from the methylprednisolone group (MP) (P = 0.028); the cyclophosphamide group (CY) did not differ from the combination therapy group (P> 0.2) or the methylprednisolone group (P = 0.16).

The probabilities of achieving remission during the study while receiving the assigned study treatment are shown in Figure 3. Patients were included in this analysis from study entry until they were censored or until remission was recorded. The greatest probability of responding to therapy was seen in the groups that received cyclophosphamide. The probability of having remission was decreased in the methylprednisolone group compared with the combination therapy group (P = 0.028) but was not significantly decreased in the methylprednisolone group compared with the cyclophosphamide group. Figure 3 suggests that receiving methylprednisolone for more than 2 years does not increase the likelihood of renal remission beyond that seen at 2 years. Moreover, the survival curves show that the combination therapy group had remission more often

and more rapidly than did the methylprednisolone group.

Laboratory Values and Renal Outcome

Changes in the laboratory values used to compare patients who achieved remission with nonre-sponders are shown in Table 4. This table shows the values of the two groups at study entry and at 1 year. The groups were not statistically significantly different at study entry. At 1 year, all values tended to have improved in each group; the most marked improvement was seen in the values of patients who responded to therapy during the study period. The patients who ultimately had remission had significantly lower DNA antibody titers; lower erythrocyte sedimentation rates; lower degrees of proteinuria; lower serum creatinine levels; lower degrees of hematuria; greater C3, C4, and CH50 levels; and greater hematocrits at 1 year than at baseline. Furthermore, the group that had renal remission had significantly greater C3, C4, and CH50 levels; lower DNA antibody titers; and a lesser degree of proteinuria than did nonresponders after 1 year of therapy.

Adverse Events We recorded adverse events throughout the study

(Table 5). Dysplasia of the cervix was seen in five patients (three in the cyclophosphamide group and two in the combination therapy group), and vaginal adenosis was diagnosed in one patient in the cyclophosphamide group. Major infections (pneumonia caused by Legionella and herpes zoster) were seen in two patients in the methylprednisolone group. In the cyclophosphamide group, pneumonia (caused by Mycoplasma pneumoniae in two of three patients), Campylobacter jejuni enteritis, herpes zoster, and neutropenic fever (in one patient) were seen. The most frequent complication in the combination therapy group was herpes zoster (six cases were seen).

Table 4. Laboratory Values of Nonresponders and Patients Achieving Remission at Study Entry and at 1 Year*

Laboratory Value Nonresponders (n = = 28)t Patients Achieving Remission (n = 37)

At Study At 1 P Value At Study AM P Value Entry* Year Entry* Year

Median DNA antibody titer, U 320 160 >0.2 160 10§ 0.0071 C3 level, g/L 0.67 0.82 0.0302 0.72 0.99§ >0.001 C4 level, g/L 0.11 0.15 >0.2 0.15 0.25§ 0.0278 CH50 level, kU/L 36.5 53.5 0.0584 46.7 76.5§ <0.001 Serum creatinine level, nmol/L 120.0 100.6 >0.2 105.1 102.0 >0.2 Erythrocyte sedimentation rate, mm/h 64 51 0.1985 72 36 <0.001 Hematocrit 0.33 0.35 >0.2 0.33 0.36 0.0021 Protein in urine, g/d 3.57 1.17 <0.001 3.51 0.47§ <0.001 Erythrocytes in urine per high-power field, n 19 6 0.0051 25 6 <0.001

* Values are means unless otherwise noted. t A response could occur at any time after 1 year of study therapy. * No statistically significant differences were found between the groups at study entry. § Statistically significantly different (P < 0.05) after 1 year of therapy for nonresponders compared with patients achieving remission.



Table 5. Occurrence of Adverse Events during the Study Period*

Adverse Event Methylprednisolone Group Cyclophosphamide Combination Therapy Group Group

n (OL\ n (/o)

Newly diagnosed avascular necrosis 6(22) 3(11) 5(18) Amenorrhea 2(10) 11 (52) 12(57) One or more infectionst 2 (7.4) 7(26) 9(32) Pulmonary infection 1 (3.7) 3(11) 2(7.1) Gastrointestinal infection 0(0) 1 (3.7) 1 (3.6) Cardiovascular infection 0(0) 0(0) 1 (3.6) Neutropenic fever 0(0) 1 (3.7) 1 (3.6) Herpes zoster infection 1 (3.7) 4(15) 6(21) Cervical dysplasia 0(0) 3(11) 2(7.1) Death 0(0) 2 (7.4) 1 (3.6)

* The percentage of patients having adverse events is similar among the study groups for all events except amenorrhea, the incidence of which was increased in patients treated with cyclophosphamide (P < 0.001).

t Some patients had infections at more than one location.

Clostridium difficile enteritis, neutropenic fever, bacterial endocarditis on prosthetic heart valves, and two cases of pneumonia were also seen in the combination therapy group. No cases of hemorrhagic cystitis due to cyclophosphamide occurred.

Acute bronchospasm was seen in three patients while they were receiving methylprednisolone alone or in combination with cyclophosphamide. Laryngeal edema occurred in some patients, all of whom recovered from these episodes. Therapy with methylprednisolone was subsequently successfully continued after pretreatment with diphenhydramine in two patients; this therapy was withdrawn in another patient. Both bronchospasm and anaphylaxis have previously been reported in patients receiving intravenous corticosteroid therapy (31).

Three deaths occurred during the study period. Two patients in the cyclophosphamide group died. The first, a 49-year-old man with a long history of smoking and a positive result on an antiphospho-lipid serologic test, died of myocardial infarction. The second, an 18-year-old woman, died of disseminated intravascular coagulopathy. One patient in the combination therapy group died: a 29-year-old woman who had a severe reactivation of both renal and extrarenal lupus while she was receiving quarterly therapy with cyclophosphamide. She developed profound thrombocytopenia and died of infectious complications.

Avascular necrosis, a common event in persons treated with steroids, was seen in all three treatment groups and was most prevalent in the groups that received methylprednisolone. The most common site of avascular necrosis was the hip (11 patients). Sustained amenorrhea was common in patients who received cyclophosphamide. Eleven patients in the cyclophosphamide group, 12 patients in the combination therapy group, and 2 patients in the methylprednisolone group developed amenor

rhea; all were women younger than 40 years of age (P < 0.01).

Discussion

Patients with lupus nephritis were randomly assigned to receive one of three bolus therapy regimens: methylprednisolone, cyclophosphamide, or both methylprednisolone and cyclophosphamide. Only 45% of patients had complete renal remission (defined as normal sediment and excretion of < 1.0 g of protein per day). In most patients, however, renal function was preserved; only five developed renal failure that required dialysis (this failure was reversible in one patient in the methylprednisolone group), and all failures occurred during the first year of therapy. Overall, more treatment failures (defined as proteinuria or the presence of nephritic sediment or a doubling of serum creatinine level, or both, at the end of treatment) were seen in the methylprednisolone group than in the other two groups. The combination therapy group had the fewest nonresponders and the fewest relapses. Patients receiving combination therapy appeared to be more responsive than the patients receiving cyclophosphamide alone; the latter patients were more responsive than the patients receiving methylprednisolone alone.

In this study, we used monthly bolus therapy with methylprednisolone for as long as 3 years (a maximum of 36 monthly pulses at 1 g/m2 body surface area). Nevertheless, the number of patients who achieved remission was lowest in the methylprednisolone group. The number of patients whose serum creatinine levels doubled or who progressed to end-stage renal disease was greatest in the methylprednisolone group; this group also had the most relapses. Thus, bolus therapy with methylpred-



nisolone does not appear to be an adequate substitute for therapy with cyclophosphamide, even when methylprednisolone is given monthly for as long as 3 years.

Although we do not consider bolus therapy with methylprednisolone to be qualitatively equivalent to daily oral corticosteroid therapy, differences between oral steroid and cyclophosphamide regimens did not become obvious in previous studies of lupus nephritis until after 6 years of follow-up (2). Therefore, we may have seen greater separation between the methylprednisolone group and the cyclophosphamide group if follow-up had been longer.

Combination therapy tended to lead to fewer pulses of cyclophosphamide and methylprednisolone, quicker time to renal response, and the highest proportion of patients achieving a remission. In most cases, combination therapy comprised monthly prednisolone therapy for 1 year plus monthly cyclophosphamide therapy for 6 months, followed by cyclophosphamide treatment every 3 months. This regimen may be advantageous for patients with relatively aggressive lupus nephritis. However, patients receiving combination therapy are subject to the side effects caused by both cyclophosphamide and prednisolone, and it might be prudent to reserve such therapy for patients with the most aggressive cases of lupus nephritis.

Evaluating outcome measures in patients with lupus nephritis is difficult. Until about 25 years ago, the outcome of interest was death as a result of renal failure. Subsequently, with advances in the treatment of lupus nephritis, the widespread availability of chronic renal dialysis, and the technology of renal transplantation, outcome measures have evolved. Because end-stage renal disease appears to occur less rapidly with early aggressive intervention, including the careful control of blood pressure, we have used 1) stable doubling of the serum creatinine level and 2) renal remission (stable clearing of sediment and proteinuria without a doubling of the serum creatinine level) as surrogate renal outcome measures.

Approximately 20% of patients were censored during this 5-year study; this percentage was consistent with our a priori expectations and previous experience (3). We saw no evidence that the data were skewed by censorship. Moreover, doing a conservative data analysis that included censored patients as nonresponders did not change the differences between groups. Additional prednisone for extrarenal disease activity was given to only two patients. One of these patients was in the methylprednisolone group, the other was in the cyclophosphamide group, and both were nonresponders. Our data do not suggest that an additional 2 weeks of

prednisone for extrarenal disease had a confounding effect on a favorable renal outcome.

Although the number of patients who received methylprednisolone pulses was small, we are concerned about the relatively frequent occurrence of such steroid-induced adverse events as avascular necrosis, infections, and acute bronchospasm in these patients. The use of boluses of methylprednisolone has previously been associated with adverse events (31-33). Although our study did not include a group that received oral prednisone only, the group in our study that received intravenous boluses of methylprednisolone had far fewer infectious complications than did patients who received oral prednisone in previous studies (2, 6). The incidence of sustained amenorrhea and infections are of particular concern in patients treated with cyclophosphamide. Three patients who were receiving cyclophosphamide died (one patient in the combination therapy group and two patients in the cyclophosphamide group); it is unclear whether these deaths were related to the study drugs. Hemorrhagic cystitis has not occurred thus far. We have not found an increased number of hematologic malignant conditions in patients receiving cyclophosphamide pulses, who have now been followed for many years (2).

We recognize that therapy with the drugs used in this study is a stop-gap approach to lupus, and we await newer, less toxic, and more specific intervention strategies. Moreover, our study represents only a small incremental advance in our knowledge. However, for patients with lupus nephritis, such increments are crucial. Our randomized trial, with 5 years of follow-up, provides data that can serve as a more solid basis for therapeutic choices that will maintain renal function with the most effective and least toxic regimens available and with an appreciation of the adverse events that can accompany those choices.

Acknowledgments: The authors thank the members of Arthritis and Rheumatism Branch senior staff, medical staff fellows, clinical associates, Clinical Center nursing staff, and the referring physicians, without whose assistance this study would not have been possible.

Grant Support: In part by a fellowship from the Arthritis Foundation (Dr. Gourley).

Requests for Reprints: Mark Gourley, MD, Section of Rheumatology, Washington Hospital Center, 110 Irving Street NW, Washington, DC 20010-2975.

Current Author Addresses: Dr. Gourley: Section of Rheumatology, Washington Hospital Center, 110 Irving Street NW, Washington, DC 20010-2975. Dr. Austin: National Institutes of Health, Building 10, Room 3N112, Bethesda, MD 20892. Dr. Scott: Food and Drug Administration, Center for Biologies Evaluation and Research, Building 29, Room 232, Bethesda, MD 20892.



Ms. Yarboro: National Institutes of Health, Building 10, Room 9S210, Bethesda, MD 20892-1828. Ms. Vaughan: National Institutes of Health, Building 10, Room 9S228, Bethesda, MD 20892-1828. Ms. Muir: National Institutes of Health, Executive Plaza North, Room 718, Bethesda, MD 20892. Dr. Boumpas: National Institutes of Health, Building 10, Room 9S209, Bethesda, MD 200892-1828. Dr. Klippel: National Institutes of Health, Building 10, Room 9S205, Bethesda, MD 20892-1828. Dr. Balow: National Institutes of Health, Building 10, Room 9N222, Bethesda, MD 20892. Dr. Steinberg: Mitretek Systems, 7525 Colshire Drive, McLean, VA 22102.

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