Leflunomide is an immunomodulatory agent effective in the treatment of rheumatoid arthritis as shown in phase II and III clinical trials (1,2). In addition, it has been proved useful in the prevention of acute rejection in animal models of allotransplantation (3) and xenotransplantation (4). To our knowledge there is not published experience of leflunomide use in human transplantation.
A 55-year-old woman had been diagnosed with rheumatoid arthritis in 1991. During the following years, disease-modifying antirheumatic drugs, mainly methotrexate and sulfasalazine, and other drugs such as nonsteroidal anti-inflammatory ones and steroids were used to alleviate signs and symptoms. Since 1997, nephrotic syndrome and progressive renal failure due to amyloidosis were noted, and she began renal replacement therapy with peritoneal dialysis in September 1999. Despite antirheumatic treatments, she showed persistent inflammatory signs, multiple joint tenderness and swelling, and morning stiffness. Leflunomide 100 mg daily for 3 days and then 10 mg daily was prescribed, with important improvement in signs and symptoms. Two months later, a cadaveric renal transplantation was performed. Initial triple-drug therapy with tacrolimus (0.1 mg/kg b.i.d.), mycophenolate (500 mg b.i.d.), and steroids was used for immunosuppression. The graft did not function immediately. Leflunomide was withdrawn on the first day of transplantation due to the absence of clinical experience with this drug in human kidney transplantation. On the third posttransplantation day, 3 days after this withdrawal, severe polyarthritis emerged and leflunomide 10 mg daily was restarted. Inflammatory signs and symptoms improved again. Delayed graft function due to biopsy-confirmed acute tubular necrosis lasted 2 weeks and finally diuresis began, with decreasing serum creatinine level. Fourteen days after transplantation, she was receiving quadruple-drug therapy, and severe diarrhea led to mycophenolate reduction to 250 mg b.i.d. and finally to mycophenolate withdrawn. Four months after renal transplantation, rheumatoid arthritis is clinically inactive, her serum creatinine level is 0.9 mg/dl, and she is maintained on tacrolimus, leflunomide, and prednisone.
Our patient illustrates the use of leflunomide in combination with other more widely used immunosuppressants for the prevention of acute rejection after organ transplantation. Particularly, its use in combination with tacrolimus could be of special interest. In our patient, the combination with mycophenolate led to very severe diarrhea, impossible to control until mycophenolate withdrawal.
Julio Pascual
Javier Orte
Roberto Marc´en
Javier Burgos
Joaqu´in Ortu˜no
REFERENCES
1. Mladenovic V, Domljan Z, Rozman B, et al. Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis: results of a randomized, placebo-controlled, phase II study. Arthritis Rheum 1995; 38: 1595.
2. Smolen JS, Kalden JR, Scott DL, et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. Lancet 1999; 353: 259.
3. Rastellini C, Cicalese L, Leach R, et al. Prolonged survival of islet allografts following combined therapy with tacrolimus and leflunomide. Transplant Proc 1999; 31: 646.
4. Yin DP, Sankary HN, Shen J, et al. Efficacy of FK506, leflunomide, anti-CD4 and CTLA4Ig treatments in rat to mouse pancreas xenograft transplantation. Transplant Proc 2000; 32: 1003.
