Myelosuppressive and hepatotoxic potential of leflunomide and methotrexate combination in a rat model of rheumatoid arthritis

Background: Safety of the combination of leflunomide and methotrexate was examined in several studies with inconclusive results. The present study was designed to compare the efficacy and safety of the combination of leflunomide and methotrexate in adjuvant-induced arthritis (AIA) in rats focusing on immunosuppressive and hepatotoxic effects. Methods: Eighty four rats were divided into seven groups. Group 1: Sham control, group 2: the vehicle control, group 3: methotrexate group, group 4-5: leflunomide (5 and 10 mg/kg/day) groups, group 6-7: combination 1 and 2 [methotrexate + leflunomide (5 and 10 mg/kg/day)] groups, respectively. Results: The current results indicated that combination therapies improved the ankle circumference and clinical scores compared to monotherapies: histopathological examination confirmed these findings. The myelosuppressive effect of leflunomide (10 mg/kg/day) was comparable to that produced by methotrexate as indicated by the complete blood count and bone marrow cellularity; however their combination resulted in greater toxicity. Furthermore, methotrexate greatly affected the splenic histopathology compared to leflunomide and the combination therapy produced a greater effect compared to leflunomide not methotrexate. Differently, assessment of the hepatotoxic potential of the two drugs highlighted that leflunomide induced a dose-dependent increase in the fibrosis score which was higher in their magnitude than that induced by methotrexate. Leflunomide (10 mg/kg/day) and combination 2 groups showed the greatest degree of liver fibrosis. Conclusions: In rats with AIA, current drug combinations provided higher therapeutic benefit compared to monotherapies, however, greater toxicities were observed. Therefore, continuous monitoring of hematologic parameters and liver function will be recommended in clinical settings. (C) 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.