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  • 1. Blackwell Science, LtdOxford, UKNEPNephrology1320-53582005 Asian Pacific Society of Nephrology105504510Original Article MMF in proliferative lupus nephritisLM Ong et al. NEPHROLOGY 2005; 10, 504–510 doi:10.1111/j.1440-1797.2005.00444.x Original Article Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis LOKE MENG ONG,1 LAI SEONG HOOI,2 TECK ONN LIM,3 BAK LEONG GOH,4 GHAZALI AHMAD,4 ROZINA GHAZALLI,1 SUE MEI TEO,5 HIN SENG WONG,6 SI YEN TAN,7 WAN SHAARIAH,8 CHWEE CHOON TAN9 and ZAKI MORAD6 1 Department of Medicine, Penang Hospital, 2Hemodialysis Unit Sultanah Aminah Hospital, Johor Bahru, 3Clinical Research Centre, Kuala Lumpur Hospital, 4Department of Nephrology, Selayang Hospital, 5Hemodialysis Unit, Ipoh Hospital, 6Department of Nephrology, Kuala Lumpur Hospital, 7Department of Renal Medicine, University of Malaya Medical Centre, 8Hemodialysis Unit, Seremban Hospital and 9Hemodialysis Unit, Tengku Ampuan Rahimah Hospital, Malaysia SUMMARY: Background: The aim of the present study was to evaluate the efficacy of mycophenolate mofetil in the induc- tion therapy of proliferative lupus nephritis. Methods: Forty-four patients from eight centres with newly diagnosed lupus nephritis World Health Organiza- tion class III or IV were randomly assigned to either mycophenolate mofetil (MMF) 2 g/day for 6 months or intravenous cyclophosphamide (IVC) 0.75–1 g/m2 monthly for 6 months in addition to corticosteroids. Results: Remission occurred in 13 out of 25 patients (52%) in the IVC group and 11 out of 19 patients (58%) in the MMF group (P = 0.70). There were 12% in the IVC group and 26% in the MMF group that achieved com- plete remission (P = 0.22). Improvements in haemoglobin, the erythrocyte sedimentation rate, serum albumin, serum complement, proteinuria, urinary activity, renal function and the Systemic Lupus Erythematosus Disease Activity Index score were similar in both groups. Twenty-four follow-up renal biopsies at the end of therapy showed a significant reduction in the activity score in both groups. The chronicity index increased in both groups but was only significant in the IVC group. Adverse events were similar. Major infections occurred in three patients in each group. There was no difference in gastrointestinal side-effects. Conclusions: MMF in combination with corticosteroids is an effective induction therapy for moderately severe proliferative lupus nephritis. KEY WORDS: intravenous cyclophosphamide, mycophenolate mofetil, proliferative lupus nephritis, randomized controlled trial. Systemic lupus erythematosus (SLE) is a multisystem disease to improve renal survival compared with steroids alone.2–4 characterized by abnormalities of T and B cells and produc- Cyclophosphamide is associated with amenorrhea and tion of autoantibodies. Renal involvement occurs in sterility, increased risk of infections such as herpes zoster, approximately 40–75% of patients and is associated with haemorrhagic cystitis, bladder cancers, leukaemias and increased morbidity and mortality.1 Severe proliferative other malignancies. As SLE is predominantly a disease of lupus nephritis is associated with a poor renal prognosis and women of child-bearing age, the possibility of irreversible requires aggressive therapy. Addition of cytotoxic agents to infertility is a major concern. A safer yet effective alterna- corticosteroids has been shown to improve the outcome of tive therapy is needed. severe lupus nephritis in randomized controlled studies and Mycophenolic acid (MPA) is a relatively specific inhib- meta-analyses.2–4 In the National Institute of Health studies, itor of lymphocyte proliferation. It inhibits inosine mono- intravenous pulse cyclophosphamide (IVC) has been shown phosphate dehydrogenase, the rate-limiting enzyme in the de novo synthesis of purine. Lymphocytes are critically Correspondence: Dr Lai Seong Hooi, Haemodialysis Unit, Sultanah dependent on this pathway while other cells are able to use Aminah Hospital, 80100, Johor Bahru, Malaysia. Email: alternative salvage pathways. Mycophenolate mofetil laihooi@pd.jaring.my (MMF), the ester of MPA, has been more effective in reduc- Accepted for publication 7 June 2005. ing the acute rejection rate in renal transplantation com- © 2005 Asian Pacific Society of Nephrology.
  • 2. MMF in proliferative lupus nephritis 505 pared with azathioprine.5 In murine models of lupus rate, urinalysis, 24 h urine protein, renal profile, liver function test, nephritis, MMF attenuates the severity of renal disease and fasting lipids, fasting glucose, antidouble stranded DNA antibody, com- significantly prolongs survival.6–8 MMF has also been used in plement C3 and C4 concentration and the Systemic Lupus Erythema- tosus Disease Activity Index (SLEDAI) score.15 the treatment of human glomerulonephritis, lupus nephritis and other autoimmune diseases.9–12 The success of these Renal biopsy was classified by the WHO classification by a single reports prompted this investigator-initiated study to evalu- histopathologist blinded to the treatment assignment. Staining of ate the efficacy of MMF in the treatment of proliferative slides included haematoxylin and eosin, periodic acid–Schiff and sil- lupus nephritis in Malaysia. ver stains, and immunoflourescence for IgG, IgA, IgM and C3. A sec- ond renal biopsy was required at 6 months if the patient had active urinary sediments (presence of cellular casts or at least five red blood SUBJECTS AND METHODS cells (RBC) per high-power field (HPF) of centrifuged urine), pro- teinuria of at least 1 g per day or a rise in serum creatinine of more We conducted a prospective, randomized, open-labelled clinical trial at eight centres in Malaysia. The study was conducted in accordance with than 50% compared with the baseline. Activity and chronicity index the Declaration of Helsinki and Good Clinical Practice guidelines. scores were determined by the same histopathologist.14 The activity Ethics committee approval was obtained and all patients gave written score was the sum of the scores (on a scale of 1–3) of endocapillary informed consent. An independent clinical research organization proliferation, karyorrhexis and fibrinoid necrosis (with the score mul- (CRO) managed and monitored the trial. The CRO undertook data tiplied by 2), cellular crescents (with the score multiplied by 2), hya- management including data quality assurance. Data on efficacy and line deposits, leucocyte exudation and interstitial inflammation. The safety were verified against the source document. maximum score is 24. The chronicity score was the sum of the scores (on a scale of 1–3) for glomerular sclerosis, fibrous crescents, tubular Study patients and randomization atrophy and interstitial fibrosis. The maximum score is 12. The primary outcome was remission of nephritis (combined par- Between January 2001 and December 2002 patients who had SLE tial and complete remission) at 6 months defined as stabilization or fulfilling American Rheumatism Association criteria with newly improvement in renal function, urinary RBC of less than 10 per HPF diagnosed World Health Organization (WHO) class III or IV lupus and reduction of proteinuria to less than 3 g/day if baseline pro- nephritis and aged 16 years or older were enrolled into the study.13,14 teinuria was more than 3 g/day and at least a 50% reduction in pro- Exclusion criteria were serum creatinine more than 200 mmol/L, white teinuria or to less than 1 g/day if the baseline proteinuria was in the blood cell (WBC) count of less than 3.5 ¥ 109/L, evidence of major subnephrotic range. Stabilization of renal function was defined as a infection, history of cancer, alcohol or substance abuse, active peptic change in serum creatinine concentration of less than 20% com- ulcer disease, pregnant or lactating women, known allergy to MMF pared with the baseline concentration and improvement in renal or cyclophosphamide and the use of study drugs in the preceding function was defined as a reduction in serum creatinine of at least 6 months. 20% compared with the baseline. Complete remission (CR) was Eligible patients were randomized centrally in a one-to-one ratio to similarly defined except for reduction of proteinuria to less than receive MMF or IVC. This was done within 1 month of the renal 0.3 g/day. biopsy. The randomization code was generated separately for each par- Secondary end-points were improvement in the SLEDAI score, ticipating centre by using the random permuted block method with complement concentration, death and commencement of permanent randomly varying block size. dialysis or renal transplantation. At the end of the 6 month study, all patients were traced for patient and kidney survival. This was reported as of 31 December 2004. Immunosuppressive protocol Statistical methods Patients were given either MMF (CellCept) 1.0 g orally twice daily for 6 months plus corticosteroids or intravenous cyclophosphamide (IVC) Simon’s optimal two-stage design was used for the trial.16 In the first 0.75–1 g/m2 monthly for 6 months plus corticosteroids. Dosage adjust- stage, nine patients were randomly selected for treatment with MMF. If ments for MMF were required if the WBC count was less than one or more patients responded to treatment, the trial could proceed to 3.5 ¥ 109/L and for dose dependent side-effects (e.g. gastrointestinal a second stage where 17 patients would be treated. A parallel group of toxicity). The dose was halved or stopped and reviewed within 2 weeks. randomly selected patients of equal number to the MMF arm would be The dosage of IVC was adjusted to keep the WBC nadir between 3.5 treated with IVC. and 4.0 ¥ 109/L at 10–14 days after administration. IVC was withheld if The sample size estimate was based on the assumption that had the the WBC count was less than 3.5 ¥ 109/L and reviewed within 2 weeks. remission rate in the MMF arm been 5% at 6 months we would regard The starting dose of prednisolone was 60 mg/day for 4–6 weeks, then this as an ‘uninteresting’ response rate. The target response rate was 40 mg/day for 2 weeks. The dose was reduced by 5 mg/day every 25%. For alpha risk = 0.05 and beta risk = 0.2 (80% power), the 2 weeks until 20 mg/day, then 2.5 mg/day every 2 weeks until 12.5 mg/ required sample size was nine patients for the first stage and 17 patients day followed by 2.5 mg/day reduction every 4 weeks until a mainte- for the second stage. nance dose of between 5–10 mg/day was achieved. Neither patients nor Results of the efficacy analysis were reported as the proportion of the clinical team were blinded to treatment allocation. They could subjects (with 95% confidence intervals (CI)) with remission. All end- request that the patient drop out of the trial at any time in case of point analyses were performed on an intention-to-treat basis, with ran- adverse events or non-response. domized patients who had received at least a dose of study treatment included in the analyses. Repeated measure ANOVA was used to analyse Study assessments and endpoints all serial measurements. The study visit was the repeated measure factor while the between group factor was the study treatment group. The Patients were reviewed fortnightly for 6 months. Evaluation included Cockcroft and Gault formula was used to compute the creatinine physical examination, full blood count, the erythrocyte sedimentation clearance.17
  • 3. 506 LM Ong et al. RESULTS agents. Six patients (23.1%) in the IVC group and eight patients (32%) in the MMF group had received either Of the 54 subjects screened and randomized, two patients angiotensin-converting enzyme inhibitors or angiotensin assigned to the IVC group defaulted before receiving the receptor blockers during the trial. drug and one was withdrawn because of the exclusion cri- teria; seven patients in the MMF arm were withdrawn because of the exclusion criteria. The main reason for with- Primary outcome drawal was reclassification of the renal biopsies by the trial histopathologist into a different WHO grade of lupus Remission occurred in 13 patients (52%, 95% CI 32%, nephritis. Forty-one of the 44 patients who received the 72%) in the IVC group and 11 (58%, 95% CI 36%, 80%) in study drugs completed therapy (Fig. 1). One patient in the MMF group (P = 0.70). Complete remission was the IVC group withdrew from the study prematurely at achieved in three patients (12%, 95% CI 0%, 25%) in the 3 months because of persistent leucopenia. Two patients in IVC group and five patients (26%, 95% CI 7%, 46%) in the the MMF arm did not complete the trial; one withdrew MMF group (P = 0.22). The mean time to remission was voluntarily after 3 months and another patient developed 11.7 ± 7.3 weeks and 12.4 ± 5.0 weeks (P = 0.80) for the end-stage renal failure (ESRF) at 5 months. IVC and MMF groups, respectively. The mean time to com- Baseline characteristics of the patients were similar plete remission was 11.4 ± 9.4 weeks for the IVC group and except for significantly higher proteinuria in the IVC group 13.0 ± 5.7 weeks for the MMF group (P = 0.77). compared with the MMF group (Table 1). Five patients in Proteinuria decreased in both arms (Fig. 2). Although the MMF group and 12 patients in the IVC group had neph- the IVC group had a higher baseline proteinuria, the reduc- rotic syndrome at presentation. There was also imbalance in tion in proteinuria over time was parallel to the MMF group. the ethnic distribution but this was not statistically signifi- Proteinuria decreased from 3.0 ± 1.8 g at baseline to cant (P = 0.41). Renal impairment (creatinine clearance 1.9 ± 1.5 g at 6 months in the IVC arm and from 1.8 ± 1.2 g less than 60 mL/min) was present at baseline in eight to 1.1 ± 0.6 g at baseline and at 6 months, respectively, in patients (32%) in the IVC group and seven patients the MMF group. The improvement in proteinuria was (36.8%) in the MMF group. reflected by an upward trend in serum albumin in both The mean ± standard deviation (SD) cumulative dose of groups. The mean serum albumin increased from a baseline steroids was 96.6 ± 42.5 mg/kg for the IVC group and of 28 ± 6 g/L to 34.5 ± 6.3 g/L at 6 months in the IVC group 87.2 ± 42.8 mg/kg for the MMF group (P = 0.47). Twenty and from 30.3 ± 7.9 g/L to 36.7 ± 4.3 g/L in the MMF group. patients (80%) received at least six doses of IVC while five Serum creatinine remained stable in both groups. At the patients received between three to five pulses. The mean end of 6 months there was no significant difference in the monthly dose of IVC was 713.5 ± 11.9 mg/m2 and the mean serum creatinine between groups (mean serum creatinine cumulative dose was 121.6 ± 26 mg/kg. The mean daily dose was 94.4 ± 61.5 mmol/L and 109.5 ± 168.4 mmol/L in the of MMF given was 1.6 ± 0.1 g and the mean cumulative IVC and MMF groups, respectively. Creatinine clearance dose was 5.5 ± 1.7 g/kg. One patient was converted from at 6 months was better in the MMF group (mean MMF to IVC at 5 months due to lack of efficacy. 95.0 ± 36.3 mL/min) compared with the IVC group Blood pressure (BP) control was similar. The systolic and (81.5 ± 30.4 mL/min) but this was not statistically signifi- diastolic BP decreased over time in both groups. Twenty- cant (Fig. 3). nine patients (65.9%) were treated with antihypertensive There was improvement in other indices of SLE and lupus nephritis activity. These included the SLEDAI score, serum C3 and C4 concentration, erythrocyte sedimentation rate (ESR), urinary RBC and urinary casts (Table 2). There Subjects screened were no significant differences in these parameters between and randomized groups. (n = 54) One patient in the MMF group developed ESRF. The patient had been dialysis-dependent 2 months before IVC MMF recruitment. At randomization the patient had not been on (n = 28) (n = 26) dialysis for 1 month and had a serum creatinine of 160 mmol, and was therefore eligible. There were, however, severe chronic changes on the renal biopsy (chronicity Excluded from trial Received treatment as randomized Received treatment as randomized Excluded from trial index score 11/12). She was withdrawn after receiving MMF (n = 3) (n = 25) (n = 19) (n = 7) for 5 months. Early Number completed Number completed Early Histopathology termination trial trial termination (n = 1) (n = 24) (n = 17) (n = 2) Twenty (10 in the IVC group and 10 in the MMF group) of the 34 patients with indications for repeat renal biopsy Fig. 1 Trial profile. IVC, intravenous cyclophosphamide; underwent the procedure. Three patients had early termi- MMF, mycophenolate mofetil. nation while consent was not obtained from 11 patients.
  • 4. MMF in proliferative lupus nephritis 507 Table 1 Baseline characteristics of trial patients by treatment group Characteristic IVC (n = 25) MMF (n = 19) Mean age (SD) (years) 30.5 (8.7) 31.3 (9.9) Body mass index, mean (SD) (kg/m2) 21.2 (3.8) 21.8 (3.2) Ethic group, n (%) Malay 14 (56) 8 (42.1) Chinese 10 (40) 10 (52.6) Indian 0 (0) 1 (5.3) Siamese 1 (4) 0 (0) No. females (%) 22 (88) 15 (79) Duration of SLE, mean (SD) (months) 32 (33.6) 48.7 (72.7) Duration of lupus nephritis, mean (SD) (months) 7.2 (9.8) 5.9 (7) Total SLEDAI score, mean (SD) 14.8 (6.3) 15.8 (7.7) Systolic blood pressure, mean (SD) (mmHg) 130.2 (20.2) 127.9 (19.2) Diastolic blood pressure, mean (SD) (mmHg) 83.9 (11.9) 85.4 (11) Hemoglobin, mean (SD) (g/dL) 10.7 (1.8) 11 (1.5) White blood cell count, mean (SD) (¥109/L) 8.6 (3.5) 8.1 (4) Platelet count, mean (SD) (¥109/L) 265.2 (73.7) 255.8 (74.8) ESR, mean (SD) (mm) 57 (36.4) 56.2 (41) Creatinine, mean (SD) (mmol/L)† 94.0 (40.2) 96.5 (37.3) Creatinine clearance, mean (SD) (mL/min) 77.2 (28.9) 76.8 (32.5) Albumin, mean (SD) (g/L) 28.0 (6.0) 30.3 (7.9) Anti-dsDNA antibody raised, n (%) 16 (64) 12 (63.2) C3, mean (SD) (mg/dL)‡ 54.2 (14.4) 63.7 (26.8) C4, mean (SD) (mg/dL)§ 14.0 (5.7) 16.9 (14.3) Proteinuria, mean (SD) (g/day)* 3.0 (1.8) 1.8 (1.2) Red blood cells per HPF, mean (SD) 13.7 (17.2) 14.2 (17.8) Renal histology Class III, n (%) 2 (8) 1 (5.3) Class III with membranous change, n (%) 0 (0) 1 (5.3) Class IV, n (%) 17 (68) 10 (52.6) Class IV with membranous change, n (%) 6 (24) 7 (36.8) Activity index score, mean (SD) 9.0 (4.1) 8.6 (2.9) Chronicity index score, mean (SD) 2.8 (1.7) 3.2 (2.6) †Normal range for serum creatinine is 50–120 mmol/L. ‡Normal range for C3 is 88–200 mg/dL. §Normal range for C4 is 16–47 mg/dL. *P = 0.02 for comparison between groups. ESR, erythrocyte sedimentation rate; HPF, high-power field; IVC, intravenous cyclophosphamide; MMF, mycophe- nolate mofetil; SLE, systemic lupus erythematosus; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index. +SD /IVC IVC +SD /IVC IVC 5 -SD /MMF MMF -SD /MMF MMF 120 4 100 Mean ± SD 3 Mean ± SD 80 2 1 60 0 0 1 2 3 4 5 6 40 Month 0 1 2 3 4 5 6 Month Fig. 2 Mean 24 h urine protein (g/L). P = 0.042 for compari- son between groups. P < 0.0001 for change over time. IVC, Fig. 3 Mean creatinine clearance (mL/min). P-value not sig- intravenous cyclophosphamide; MMF, mycophenolate mofetil. nificant for comparison between groups (P = 0.37). P = 0.0031 for change over time.
  • 5. 508 LM Ong et al. There were no significant differences in proteinuria, urinary Adverse events red cells or serum creatinine at baseline or at 6 months between the 20 patients who underwent biopsy and those There was no difference (P = 0.18) in the rate of adverse who did not (14 patients). events at 6 months between groups (0.48 and 0.60 episodes Among 24 patients who had a second renal biopsy (the per patient-month for the IVC and MMF groups, respec- 20 above and four others that were not indicated per pro- tively). There was one patient with oligomenorrhoea in the tocol), the baseline activity and chronicity index scores IVC group and none in the MMF group. were similar between groups (Table 3). There was a signifi- Leucopenia (defined as WBC count of less than cant improvement in the activity score on the follow-up 3.5 ¥ 109/L) occurred more frequently in patients on IVC biopsy. The chronicity index increased over the 6 months. (52% of patients) compared with MMF (36.8% of patients), This was significant in the IVC group but not in the MMF but this did not reach statistical significance (P = 0.32). The group. Mean activity and chronicity index scores on the WBC count showed a saw-tooth pattern with IVC as it follow-up biopsy were not significantly different between reached a nadir approximately 2 weeks following adminis- groups. tration. There was no statistical difference in the mean Three patients (27.3%) in the IVC group had downgrad- WBC between groups (P = 0.78). ing in the WHO classification from IV at baseline to III There was no difference in the incidence of infections (two patients) and V (one patient) on the follow-up biopsy. between groups. Pneumonia or septicaemia occurred in In the MMF group, six patients (46.2%) downgraded from three patients in each group. Herpes zoster occurred in six class IV to I (one patient), II (two patients) and V (three patients (three patients on IVC and three patients on patients). One patient in the MMF group upgraded from MMF). Gastrointestinal disturbances were similar in both class III to IV. The difference was not statistically significant groups. The incidence of gastrointestinal adverse events was between groups. 0.07 episodes per patient-month in the IVC group and 0.08 episodes per patient-month in the MMF group (P = 0.68). On 31 December 2004, all 44 patients were reassessed for kidney and patient survival on an intention-to-treat basis. Table 2 Secondary end-points There was one death in each group. One had gone into ESRF 5 months into the trial (on MMF), started on contin- Parameter IVC MMF uous ambulatory peritoneal dialysis (CAPD) and died Mean change in SLEDAI -6.8 (6.6) -7.2 (7.7) 21 months later of cardiomyopathy. The other (from the score (SD)†* IVC group) went into ESRF 6 months after the end of the Mean change in C3, mg/dL 29.9 (28.8) 16.1 (34.2) trial and died 27 months after that of septicaemia while on (SD)†* CAPD. Another patient on IVC went into ESRF Mean change in C4, mg/dL 6.1 (8.0) 2.5 (21.2) 15 months after the trial ended and is alive on CAPD after (SD)†* 18 months. No. deaths (%) 0 (0) 0 (0) The mean follow up for the whole group was Permanent dialysis, no. (%)* 0 (0) 1 (4) 37.8 ± 7 months, range 24.2–47.7 months. Patient survival was 94% at 36 months for both groups (log rank P = 0.88). †Change at 6 months from baseline value. *P-value not significant Kidney survival was 92% for the IVC group and 94% for the for comparison between groups. (P-values: Systemic Lupus Erythema- MMF group at 36 months (log rank P = 0.75). All patients tosus Disease Activity Index (SLEDAI), 0.86; C3, 0.1714; C4, 0.4531; permanent dialysis, 0.38.) P < 0.0001 for change in SLEDAI over time. were on various doses of oral prednisolone. The main cyto- P < 0.0001 for change in C3 over time. P = 0.12 for change in C4 over toxic agents the patients were prescribed after the 6 months time. IVC, intravenous cyclophosphamide; MMF, mycophenolate trial was at the discretion of the attending nephrologists mofetil. (Table 4). No one on MMF induction remained on MMF. Table 3 Activity and chronicity index of renal biopsies at baseline and at 6 months among the 24 patients with follow-up biopsies Activity index, mean (95% CI) Chronicity index, mean (95% CI) IVC (n = 11) MMF (n = 13) IVC (n = 11) MMF (n = 13) Baseline 9.4 9.7 2.4 2.9 (6.2, 12.5) (8.0, 11.4) (1.6, 3.2) (1.7, 4.1) Follow-up 4.6 3.7 4.4 3.6 (2.5, 6.8) (2.5, 4.9) (3.2, 5.5) (2.9, 4.3) Change from baseline -4.7* -6.3** 2.0*** 1.0**** (-8.7, -0.7) (-8.2, -4.5) (0.9, 3.1) (-0.1, 2.1) P-value not significant for comparison of activity index and chronicity index between groups at baseline and on the follow-up biopsy. *P = 0.03 for comparison of baseline and follow-up activity index for the intravenous cyclophosphamide (IVC) group. **P < 0.0001 for comparison of baseline and follow-up activity index for the mycophenolate mofetil (MMF) group. ***P = 0.003 for comparison of baseline and follow-up chronicity index for the IVC group. ****P = 0.08 for comparison of baseline and follow-up chronicity index for the MMF group.
  • 6. MMF in proliferative lupus nephritis 509 Table 4 Main cytotoxic drugs used postinduction (all were on teinuria was more marked in the IVC arm at commence- prednisolone) ment, 3.0 ± 1.8 g compared with the MMF group MMF group IVC group 1.8 ± 1.2 g/day (P = 0.02), which may have favoured a better outcome for the MMF arm. (n = 19) (n = 25) There is a suggestion that severe lupus nephritis behaves n % n % differently in various ethnic groups and results might not be generalized across borders.20 Our results are comparable to Azathioprine 7 37 11 44 those of Appel.19 In another study from the US with mixed Cyclosporine 1 5 0 0 ethnic groups, remission with IVC induction was achieved IVC 5 26 6 24 IVC then azathioprine 1 5 4 16 in 83% of patients.21 Excellent results were reported in IVC then cyclosporine 1 5 0 0 Chinese patients in the trial by Chan.12 Our cohort of None 4 21 4 16 patients was heterogenous and half were non-Chinese. MMF was efficacious with respect to other secondary IVC, intravenous cyclophosphamide; MMF, mycophenolate mofetil. end-points including activity of urinary sediment, renal function, haematological parameters and the SLEDAI index score. This index has been shown to be responsive to The most common cytotoxics used after 6 months of induc- changes in disease activity.22,23 In the study by Gladman, the tion therapy were azathioprine (n = 18) or IVC (n = 17). SLEDAI was more sensitive than the Systemic Lupus Activ- Eight patients were on prednisolone alone and one was on ity Measure (SLAM) or British Isles Lupus Activity Group cyclosporine. (BILAG) systems in detecting changes in severity of SLE over time.22 In most trials on the treatment of lupus nephri- DISCUSSION tis, the outcome was focused on renal end-points. In the present study, we used the SLEDAI index to evaluate the The aim of the present study was to demonstrate the efficacy overall effect of the study drugs on SLE activity. of MMF as an induction therapy for proliferative lupus Our data suggests that a significant proportion of nephritis. Mycophenolate mofetil was an attractive agent patients with lupus nephritis did respond clinically and his- due to its specific inhibition of lymphocyte activation and tologically to MMF at 6 months. The histology results had been shown to be effective in preventing acute rejec- should be interpreted with caution as biopsies were not per- tion in renal transplant recipients.5 Its efficacy in lupus formed routinely at the end of the treatment period and nephritis was not established at the time of the study’s only 60% of patients with indications for repeat biopsy had design. If the target response rate was changed to a higher one done. percentage than 25% a smaller sample size would have been The short-term adverse event profile of MMF and IVC needed. We took a more cautious approach with a phase II were similar. Most events were mild and only two patients trial design and excluded patients with severe renal impair- dropped out due to adverse events. The incidence of gas- ment. The results may not be applicable to patients with the trointestinal disturbance was not increased with MMF. We most severe forms of lupus nephritis. did not observe a leucocyte-sparing effect with MMF, The dose of IVC was the standard one applied at the although the incidence of leucopenia was more common in time and the mean monthly dose was slightly lower than the the IVC group. This was expected with intermittent boluses target of 0.75 g/m2. Subsequent to the trial the efficacy of of IVC and showed that adequate dose of the drug was deliv- lower dose IVC was reported.18 In the present study we ered. The incidence of amenorrhea has been shown to be achieved a total remission rate of 54.5% (52% with IVC and lower with MMF compared with IVC.19,21 The trial of 58% with MMF) and a complete remission rate of 18.2% 6 months was not designed to study this and a longer follow (12% with IVC and 26% with MMF) over 6 months. There up would be needed. has been no uniformly accepted definition of remission. In MMF provides an addition to our therapeutic armamen- most studies, remission is a composite of improvement in tarium in treating moderately severe proliferative lupus proteinuria, urinary sediments and renal function. The lit- nephritis. The cost of MMF would limit its long-term use in erature differs widely in defining proteinuria. Using 50% developing countries. As yet, no study has been done on the reduction in proteinuria for partial remission (PR) and pro- cost effectiveness of MMF in the treatment of lupus nephri- teinuria of less than 500 mg/day for CR, Appel achieved a tis compared with other cytotoxic agents. A possible strat- PR rate of 20.3% with IVC and 29.6% with MMF and a CR egy is to use MMF for induction and other agents during the rate of 5.8% and 19.7%, respectively, over 24 weeks.19 An maintenance phase. earlier randomized controlled study by Chan reported a The medium-term follow-up data (up to 48 months) is 1 year complete remission rate of 81% and 76% with MMF reassuring as patient and kidney survival is more than 90%, and oral cyclophosphamide for 6 months, respectively, fol- which is in keeping with recent reports.18,21 The protocol lowed by azathioprine in both groups and a PR rate of 14% was not designed to document relapse rates and adverse in each group.12 Patients with proteinuria of less than 0.3 g events beyond 6 months. The first 6 months of treatment per day were considered to have CR while patients with PR did not have any effect on the 3–4 year outcome of kidney had a urinary protein excretion of 0.3–3 g per day. The and patient survival. Beyond 6 months, it was unfortunate 6 month results were not reported. In the present study, pro- that many patients on both arms received IVC as this was
  • 7. 510 LM Ong et al. the preference of the local investigators. Continuation of 7. Van Bruggen MC, Walgreen B, Rijke TP, Berden JH. Attenuation long-term MMF therapy was prevented by the high cost of of murine lupus nephritis by mycophenolate mofetil. J. Am. Soc. the drug. Nephrol. 1998; 9: 1407–15. 8. Jonsson CA, Svensson L, Carlsten H. Beneficial effect of the In conclusion, we have provided additional evidence inosine monophosphate dehydrogenase inhibitor mycophenolate that MMF 2 g/day in conjunction with corticosteroids is an mofetil on survival and severity of glomerulonephritis in systemic effective induction therapy for patients with moderately lupus erythematosus (SLE)-prone MRLlpr/lpr mice. Clin. Exp. severe proliferative lupus nephritis. A larger trial would be Immunol. 1999; 116: 534–41. required to confirm the therapeutic equivalence of MMF to 9. Dooley MA, Cosio FG, Nachman PH et al. Mycophenolate IVC. mofetil therapy in lupus nephritis: Clinical observations. J. Am. Soc. Nephrol. 1999; 10: 833–9. 10. Glicklich D, Acharya A. Mycophenolate mofetil therapy for lupus ACKNOWLEDGEMENTS nephritis refractory to intravenous cyclophosphamide. Am. J. Kid- ney Dis. 1998; 32: 318–22. We would like to thank the Director General of Health, 11. Briggs WA, Choi MJ, Scheel PJ Jr. Successful mycophenolate Ministry of Health Malaysia for permission to publish this mofetil treatment of glomerular disease. Am. J. Kidney Dis. 1998; paper. We thank Professor Phaik-Leng Cheah, histopathol- 31: 213–17. ogist, University Malaya Medical Centre for interpreting 12. Chan TM, Li FK, Tang C et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. N. Engl. J. the renal biopsies. We thank Roche Malaysia for supplying Med. 2000; 343: 1156–62. mycophenolate mofetil for the study. We are indebted to the 13. Tan EM, Cohen AS, Fries J. The 1982 revised criteria for the clas- staff of the Clinical Research Centre, Kuala Lumpur sification of systemic lupus erythematosus. Arthritis Rheum. 1982; Hospital who managed the trial and provided the study 25: 1271–7. monitoring, randomization, data management, safety sur- 14. Churg J, Bernstein J, Glassock RJ. Lupus nephritis. In: Churg J, veillance and biostatistics services. Bernstein J, Glassock RJ, eds. Renal Diseases. Classification and Atlas of Glomerular Diseases. New York: Igaku-Shoin, 1995; 151–6. 15. Bombardier C, Gladman DD, Urowitz MB et al. Derivation of the REFERENCES SLEDAI. A disease activity index for lupus patients. The Com- mittee on Prognosis Studies in SLE. Arthritis Rheum. 1992; 35: 1. Golbus J, McCune WJ. Lupus nephritis. Classification, prognosis, 630–40. immunopathogenesis, and treatment. Rheum. Dis. Clin. North 16. Simon R. Optimal two-stage designs for phase II clinical trials. Am. 1994; 20: 213–42. Control. Clin. Trials. 1989; 10: 1–10. 2. 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