Mycophenolate mofetil versus tacrolimus for active lupus nephritis: an extended observation of a randomized controlled trial.

OBJECTIVES: To report data on extended follow-up of a randomized controlled trial comparing the efficacy of mycophenolate mofetil (MMF) and tacrolimus (Tac) in the treatment of active lupus nephritis. METHODS: SLE patients with biopsy confirmed active nephritis (ISN/RPS class III, IV or V) were randomized to receive prednisolone (0.6mg/kg/day for 6 weeks and tapered) with either (1) Tacrolimus (0.06-0.1mg/kg/day); or (2) MMF (2-3gm/day) for 6 months. At the end of the induction phase, patients who achieved complete clinical response or very good partial response were shifted to azathioprine (2mg/kg/day) for maintenance. Re-induction with oral cyclophosphamide (CYC; 2mg/kg/day) was given to poor responders unless they could not tolerate. The primary outcome was the changes in proteinuria and clearance clearance (CrCl) at the end of the induction phase whereas the secondary outcomes were the occurrence of renal flares and decline of CrCl by ≥30% on follow-up of the participants. The cumulative incidence of the outcomes of interest was evaluated by Kaplan Meier's analysis. RESULTS: 109 patients (90% women; age 35.9±13 years) were recruited and randomized (56 MMF, 53 Tac) – 76(70%) had creatinine clearance (CrCl) ≤90ml/min, 43(39%) had nephrotic range of proteinuria (≥3.5g/day) and 46(42%) were hypertensive at entry. The distribution of histological classes was: IVG/IVS(44%), V or V+IV/III(39%) and III(17%). The histologic activity and chronicity scores were 8.0±3.5 and 2.7±1.6, respectively. At the time of analysis, 90 patients (46 MMF, 44 Tac) had completed ≥6 months' follow-up. Significant improvement in C3,C4, anti-dsDNA levels, serum albumin and proteinuria were observed in both groups at 6 months (p<0.01 in all). MMF-treated patients had overall significant improvement in CrCl (76.0±27 at baseline to 88.4±32 ml/min at 6m; p=0.03) but patients treated with Tac did not have significant change in CrCl (79.2±32 to 80.0±31 ml/min; p=0.85). 38(83%) patients in the MMF group and 38(86%) patients in the Tac group achieved complete or partial response. Re-induction therapies were given to 8(17%) MMF-treated and 6(14%) Tac-treated patients. After a median follow-up of 30 months since study entry, 10(22%) patients in the MMF group experienced renal flares (6 proteinuric and 4 nephritic), whereas in the Tac group, renal flares occurred in 14(32%) patients (12 proteinuric and 2 nephritic). The cumulative risks of renal flares at 36 months were 31% and 36% in the MMF and Tac groups, respectively (p=0.68). Loss of CrCl by ≥30% compared to baseline occurred in 5 (11%) and 12 (27%) patients, respectively, in the MMF and Tac treatment groups (p=0.06). In the MMF arm, 3 patients died and 2 developed end stage renal disease (ESRD), whereas in the Tac arm, 1 patient died and 2 developed ESRD. 26 episodes of infective complications were reported in the MMF group but only 9 episodes were reported in the Tac group of patients (p<0.01). CONCLUSION: Both MMF and Tac, in combination with prednisolone, are effective induction regimens for active lupus nephritis. After shifting to azathioprine for maintenance, numerically more patients in the Tac group had renal flares and deterioration of renal function. Infective complications were less common in Tac-treated patients.