We evaluated the safety and efficacy of leflunomide in patients with lupus nephritis in a prospective open label study. Nineteen consecutive patients who fulfilled the revised American College of Rheumatology criteria for systemic lupus erythematosus (SLE)¹ and with proteinuria ⩾2 g/day were invited to participate. The patients were chosen because of previous treatment related toxicities (six patients with severe sepsis) or a contraindication to the use of cyclophosphamide (one patient newly diagnosed with lupus nephritis and cryptococcal meningitis) or lack of response to immunosuppressive treatments including cyclophosphamide (mean (SD) cumulative dose 9 (6) g), azathioprine or ciclosporin for at least 6 months with persistent proteinuria ⩾2 g/day for at least 3 months (12 patients). Two patients were excluded because of increased liver enzymes (one patient) and refusal to give consent (one patient). The study protocol was approved by the local ethics committee and consent forms were signed by all 17 subjects.

Previous immunosuppressive drugs were discontinued for 4 weeks before entering the study. All patients were given an initial loading dose of leflunomide 100 mg daily for 3 days, followed by 20 mg daily for the remainder of the study (52 weeks). Prednisolone dosage was tapered from an initial dose of 0.5 mg/kg/day (up to 30 mg daily) according to a standard protocol. Fourteen patients receiving angiotensin converting enzyme inhibitors at baseline were allowed to continue at the same dose. Clinical and laboratory evaluations were assessed monthly for 6 months, then every 2 months up to 12 months. The primary end point was the number of patients achieving complete or partial response of nephritis (see table 1 for the definition of response). The secondary end points included changes in proteinuria, SLE Disease Activity Index (SLEDAI),² C3, C4, and anti-dsDNA levels (measured by enzyme linked immunosorbent assay (ELISA), Diastat; Axis-Shield Diagnostics, Dundee, UK), and prednisolone dosage after treatment.

At entry, the median (interquartile range (IQR)) duration between the last biopsy and starting leflunomide was 16 (11–44) months. Eleven (65%) of 17 patients had nephrotic syndrome and 8/17 (47%) patients had active sediments. Median (IQR) activity index and chronicity index were 3 (1–4) and 1 (0–2), respectively.

At the final visit, 13/17 (76%) patients had achieved a response (table 1). Complete response was seen in 5/17 (29%), partial response in 8/17 (47%), and treatment failure in 4/17 (24%). Figure 1 summarises the changes in proteinuria, creatinine clearance, and SLEDAI of all the 12 patients who completed the trial. Mean (SD) serum albumin increased significantly from 30.5 (5.8) g/l to 35.6 (8.6) g/l (p = 0.012). Serum complement 3 (C3) level increased from 0.59 (0.24) g/l to 0.78 (0.29) g/l (p = 0.046), serum C4 level increased from 0.11 (0.07) g/l to 0.17 (0.08) g/l (p = 0.016), and anti-dsDNA decreased from 350 (314) IU/ml to 84 (113) IU/ml (p = 0.008). Microscopic haematuria resolved in 6/7 patients. Steroid dosages were reduced in 9/12 (75%) patients, with a significant reduction from a mean (SD) of 20.2 (9.4) mg/day to 11.6 (5.5) mg/day (p = 0.03).

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Figure 1

 Changes in SLEDAI, proteinuria, and creatinine clearance after leflunomide treatment. Data are expressed as mean (SD). (A) The mean SLEDAI declined from 11.9 (4.8) to 5.4 (4.5) (p = 0.002). (B) Proteinuria reduced significantly from 3.5 (1.3) g/day to 1.7 (1.5) g/day (p = 0.002) for the whole group. A comparison of patients with proliferative and patients with membranous nephritis showed that proteinuria decreased significantly only in patients with membranous nephritis (proliferative nephritis: 3.3 (1.4) g/day to 1.9 (1.1) g/day; membranous nephritis: 3.7 (1.1) g/day to 1.3 (0.9) g/day, p = 0.000). (C) The creatinine clearance rate remained stable and within the normal range (96 (37) ml/min at baseline v 96 (40) ml/min at the end of the study).

The obvious weakness in this study includes the relatively small numbers of patients who completed the trial, and the follow up was too short to examine the efficacy of leflunomide for long term renal preservation. In addition, our patients were a heterogeneous group with different renal histological classes who had been treated previously with multiple immunosuppressive agents for variable lengths of time. For these reasons, the possibility that the observed improvement, was due in part to corticosteroid or other immunosuppressant drugs given previously cannot be excluded in the absence of a control group. Another limitation includes the correlation of the clinical response with renal histological features that were obtained at a mean of 16 months before leflunomide treatment. Furthermore, repeat renal histology was not available after treatment. In conclusion, leflunomide is a safe and probably efficacious treatment in patients with lupus nephritis who do not respond or cannot tolerate conventional treatments.