Induction treatment of proliferative lupus nephritis with leflunomide combined with prednisone: a prospective multi-centre observational study

Abstract

To evaluate the efficacy and safety of leflunomide in the treatment of proliferative lupus nephritis, a prospective multi-centre observational study was conducted. Patients with biopsy proven proliferative lupus nephritis were assigned to receive either leflunomide or cyclophosphamide with concomitant prednisone. Leflunomide was given orally with a loading dose of 1 mg/kg/day for 3 days followed by 30 mg/day. Intravenous cyclophosphamide was administered monthly at a dose of 0.5 g/m² of body-surface area. A total of 110 patients were enrolled, 70 in the leflunomide group and 40 in the cyclophosphamide group. The complete remission rate in the leflunomide group was 21% and partial remission rate 52%, as compared with 18% and 55%, respectively, in the cyclophosphamide group. Renal parameters and systemic lupus erythematosus disease activity index improved significantly and similarly in both groups. Serum creatinine decreased or stabilized in both treatment groups. No significant difference was noted with respect to clinical outcome between groups. Repeat biopsy also showed a significant reduction of active lesions in kidney pathology after 6 months of leflunomide treatment. Major adverse events, similar in both treatment groups, included infection, alopecia and hypertension. Leflunomide, compared with cyclophosphamide, in combination with prednisone was effective in the induction therapy of proliferative lupus nephritis and was generally well-tolerated.

Keywords

leflunomide lupus nephritis multi-centre observational study

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References

1 Cameron JS . Lupus nephritis. J Am Soc Nephrol 1999; 10: 413 – 424 .

2 Ward MM Pyun E Studenski S . Mortality risks associated with specific clinical manifestations of systemic lupus erythematosus. Arch Intern Med 1996; 156: 1337 – 1344 .

3 Flanc RS Roberts MA Strippoli GFM Chadban SJ Kerr PG Atkins RC . Treatment of diffuse proliferative lupus nephritis: a meta-analysis of randomized controlled trials. Am J Kidney Dis 2004; 43: 197 – 208 .

4 Houssiau FA . Cyclophosphamide in lupus nephritis. Lupus 2005; 14: 53 – 58 .

5 Kalden JR Schattenkircheer M Sörensen H . The efficacy and safety of leflunomide in patients with active rheumatoid arthritis: a five-year follow-up study. Arthritis Rheum 2003; 48: 1513 – 1520 .

6 Strand V Cohen S Schiff M . Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Arch Intern Med 1999; 159: 2542 – 2550 .

7 Smolen JS Kalden JR Scott DL . ; and the European Leflunomide Study Group.

Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blinded, randomized, multicentre trial.

Lancet 1999; 353: 259 – 266 .

8 Remer CF Weisman MH Wallace DJ . Benefits of leflunomide in systemic lupus erythematosus: a pilot observational study. Lupus 2001; 10: 480 – 483 .

9 Tam LS Li EK Wong CK Lam CWK Szeto CC . Double-blind, randomized, placebo-controlled pilot study of leflunomide in systemic lupus erythematosus. Lupus 2004; 13: 601 – 604 .

10.

10 Hochberg MC for the Diagnostic and Therapeutic Criteria Committee of the American College of Rheumatology.

Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus.

Arthritis Rheum 1997; 40: 1725 [letter].

11.

11 Hahan BH . Pathogenesis of systemic lupus erythematosus. In: S Ruddy ED Harris CB Sledge , (eds), Kelley’s textbook of Rheumatology. Philadelphia : WB, Saunders ; 2001. p. 1089–1090.

12.

12 Rückermann K Fairbanks LD Carrey LA . Leflunomide inhibits pyrimidine de novo synthesis in mitogen-stimulated T lymphocytes from healthy humans. J Biol Chem 1998; 273: 21682 – 21691 .

13.

13 Breedveld FC Dayer JM . Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis 2000; 59: 841 – 849 .

14.

14 Xu X Williams JW Bremer EG Finnegan A Chong ASF . Inhibition of protein tyrosine phosphorylation in T cells by a novel immunosuppressive agent, leflunomide. J Biol Chem 1995; 272: 12398 – 12403 .

15.

15 Siemasko KF Chong A Williams JW Bremer EG Finnegan A . Regulation of B cell function by the immunosuppressive agent leflunomide. Transplantation 1996; 61: 635 – 642 .

16.

16 Pinschewer DD Ochsenbein AF Fehr T Zinkernagel RM . Leflunomide-mediated suppression of antiviral antibody and T cell responses: differential restoration by uridine. Transplantation 2001; 72: 712 – 719 .

17.

17 Cao WW Kao PN Aoki Y Xu JC Shorthouse RA Morris RE . A novel mechanism of action of the immunomodulatory drug, leflunomide: augmentation of the immunosuppressive cytokine, TGF-beta 1, and suppression of the immunostimulatory cytokine IL-2. Transplant Proc 1996; 28: 3079 – 3080 .

18.

18 Manna SK Aggarwal BB . Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-κB activation and gene expression. J Immunol 1999; 162: 2095 – 2102 .

19.

19 Bartlett RR Popovic S Raiss RX . Development of autoimmunity in MRL/lpr mice and the effects of drugs on this murine disease. Scand J Rheumatol 1988; 75(Suppl): 290 – 299 .

20.

20 Xu X Blinder L Shen J . In vivo mechanism by which leflunomide controls lymphoproliferative and autoimmune disease in MRL/MpJ-lpr/lpr Mice. J Immunol 1997; 159: 167 – 174 .

21.

21 Ding L Zhao MH Zou WZ Liu YC Wang HY . Mycophenolate mofetil combined with prednisone for diffuse proliferative lupus nephritis: a histopathological study Lupus 2004; 13: 113 – 118 .

22.

22 Van Riel . PLCM, Smolen, JS, Emery, P, et al. Leflunomide: a manageable safety profile J Rheumatol 2004; 71(Suppl): 21 – 24 .

23.

23 Waldman JS Knight DA Blinder L . Inhibition of cytomegalovirus in vitro and in vivo by the experimental immunosuppessive agent leflunomide. Intervirology 1999; 42: 412 – 418 .

24.

24 Knight DA Hejmanowski AQ Dierksheide JE . Inhibition of herpes simplex type 1 by the experimental immunosuppressive agent leflunomide. Transplantation 2001; 73: 358 – 399 .