Background/Purpose: Previous studies have compared mycophenolate mofetil (MMF) and azathioprine (AZA) as maintenance therapy of lupus nephritis(LN). Leflunomide(LEF) is an immunosuppressive agent widely used in the treatment of rheumatoid arthritis. In 2009, China Food and Drug Administration approved leflunomide for the treatment of LN. However, a randomized controlled trial of LEF for the maintenance treatment in patients with LN has not been reported.The aim of the investigator-initiated study was to compare the efficacy and safety of LEF versus AZA as maintenance therapy for LN.

Methods:

270 adult patients with biopsy-confirmed active LN (class III/IV/Ⅴ) were enrolled in 7 Chinese rheumatology centers from 2010 to 2015. All patients received induction therapy with six monthly intravenous cyclophosphamide (0.5 g per square meter of body-surface area) plus steroids (starting from 1mg/kg/d and tapering according to protocol). The patients who achieved remission (complete or partial remission ,CR or PR) were randomized to receive prednisone (10mg/d) in combination with either oral LEF (20mg/d) or oral AZA (initial dose 50mg/d, and after one month increased to 100mg/d) as maintenance therapy for 24 months.

The primary efficacy end point was the rate of renal flare in 24 months. Secondary outcomes included clinical parameters, extrarenal flare and adverse effects. The clinical and laboratory parameters were compared during follow-up by using nonparametric statistical tests. Time to event analysis was performed by the Kaplan-Meier method. This study has been registered on ClinicalTrials.gov (NCT 01172002).

Results:

A total of 215 patients who had achieved CR or PR were randomly allocated to LEF group (n=108) and AZA group (n=107). The baseline clinical, biological and pathological characteristics of patients in two groups did not differ. Renal flares were observed in 12 (11.1%) LEF-treated and 15 (14.0%) AZA-treated patients (p=0.520). Time to renal flare did not statistically differ (LEF 9.83 months vs. AZA 10.93 months, p=0.241). For LN patients who achieved CR in induction phase, lower risk of renal flare was observed in LEF group than in AZA group (6.7% vs. 14.3 %, p=0.116). The CR rate in both groups continued to increase with time（LEF: from 60.2% to 87.7% after 24 months, and AZA: 71.9% to 88.7%). Over a 2-year period, 24h proteinuria, serum creatinine, serum albumin, serum C3 and serum C4 improved similarly in both groups. Sustained doubling of serum creatinine or end-stage renal failure was not observed in both groups. Extrarenal flare occurred in 2 patients from AZA group and 1 patient from LEF group.

The incidence of adverse events during the 2-year treatment was similar in the two groups: LEF (43.5%, 47/108) and AZA (42.1%, 45/107), respectively. There was no significant difference in the incidence of leukopenia (28.7% and 28.97%), abnormal elevation of liver enzyme (21.3% and 20.56%), and anaemia (12.0% and 12.2%) between groups.

Conclusion:

LEF is non-inferior to AZA for maintenance therapy of LN in terms of efficacy and safety profile. With maintenance therapy for 2 years, a trend of lower rate of relapse and higher CR rate was observed in the LEF group. LEF may become a new candidate medicine for maintenance therapy of LN.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/leflunomide-versus-azathioprine-for-maintenance-therapy-of-lupus-nephritis-a-prospective-multicenter-randomized-open-label-clinical-trial/