Leflunomide versus azathioprine for maintenance therapy of lupus nephritis: a prospective, multicentre, randomised trial and long-term follow-up

Qiong Fu, Chunmei Wu, Min Dai, Suli Wang, Jianhua Xu, Lie Dai, Zhijun Li, Lan He, Xiaochun Zhu, Lingyun Sun, Liangjing Lu, Chunde Bao, Qiong Fu, Chunmei Wu, Min Dai, Suli Wang, Jianhua Xu, Lie Dai, Zhijun Li, Lan He, Xiaochun Zhu, Lingyun Sun, Liangjing Lu, Chunde Bao

Abstract

Objectives: Previous studies have compared mycophenolate mofetil and azathioprine as maintenance therapy for lupus nephritis (LN). Leflunomide is an immunosuppressant widely used in the treatment of rheumatoid arthritis. The aim of this investigator-initiated study was to compare the efficacy and safety of leflunomide versus azathioprine as maintenance therapy for LN.

Methods: 270 adult patients with biopsy-confirmed active LN from 7 Chinese Rheumatology Centres were enrolled. All patients received induction therapy with 6-9 months of intravenous cyclophosphamide plus glucocorticoids. Patients who achieved complete response (CR) or partial response (PR) were randomised to receive prednisone in combination with leflunomide or azathioprine as maintenance therapy for 36 months. The primary efficacy endpoint was the time to kidney flare. Secondary outcomes included clinical parameters, extrarenal flare and adverse effects.

Results: A total of 215 patients were randomly allocated to the leflunomide group (n=108) and azathioprine group (n=107). Kidney flares were observed in 17 (15.7%) leflunomide-treated patients and 19 (17.8%) azathioprine-treated patients. Time to kidney flare did not statistically differ (leflunomide: 16 months vs azathioprine: 14 months, p=0.676). 24-hour proteinuria, serum creatinine, serum albumin, serum C3 and serum C4 improved similarly. Extrarenal flare occurred in two patients from the azathioprine group and one patient from the leflunomide group. The incidence of adverse events was similar in the 2 groups: leflunomide 56.5% and azathioprine 58.9%.

Conclusions: The efficacy and safety profile of leflunomide are non-inferior to azathioprine for maintenance therapy of LN. Leflunomide may provide a new candidate for maintenance therapy in patients with LN.

Trial registration number: NCT01172002.

Keywords: Antirheumatic Agents; Lupus Erythematosus, Systemic; Lupus Nephritis.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Enrolment and randomisation. AZA, azathioprine; CR, complete response; CYC, cyclophosphamid; NR, no response; PR, partial response.
Figure 2
Figure 2
Time to kidney flare between LEF group and AZA group. The primary end point of the study was compared by using Kaplan-Meier survival curves. AZA, azathioprine; LEF, leflunomide.
Figure 3
Figure 3
Change from baseline in laboratory parameters. The differences in 24-hour proteinuria (A), serum albumin (B), SCr (C), eGFR (D), serum C3 (E) and SLEDAI (F) over a 3-year period between LEF and AZA groups were analysed. AZA, azathioprine; eGFR, estimated glomerular filtration rate; LEF, leflunomide; SCr, serum creatinine; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index.

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