Background Methotrexate (MTX) is an anchor drug widely used in rheumatoid arthritis (RA). Higher dosage of MTX leads to more favorable outcome and its dose-dependent toxicity, therefore has gained much more importance. MTX-induced liver injury is a representative of this type of toxicity and the histological features resemble those of non-alcoholic steatohepatitis (NASH)1. A folic acid supplement improves the tolerability of MTX, while the efficacy was decreased by increasing the total dose of a folic acid. Bezafibrate, a peroxisome proliferator-activated receptor (PPAR) pan-agonist, is a lipid-lowering drug and also ameliorates NASH2
Objectives We investigated the efficacy of bezafibrate on MTX-induced liver toxicity and the influence on RA disease activity.
Methods Eleven RA patients on MTX who developed acute liver toxicity were enrolled in the study. The baseline clinical details of these patients were scrutinized for details regarding the values of serum aspirate aminotransferase (AST), alanine aminotransferase (ALT) and weekly MTX dose, Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR). All patients were given 400 mg of bezafibrate within the first two months after the onset of liver injury and were observed for 6 months. DAS28-ESR was reevaluated at week 24. MTX dose adjustments were permitted if disease activity did not reach the optimal level or adverse events were observed. AST and ALT values and weekly MTX dose at week 24 for each patient were compared to those at enrollement. European League Against Rheumatism (EULAR) response at week 24 was calculated from the DAS28-ESR score.
Results At the time of inclusion, mean weekly MTX dose was 10.0 mg (range 6-16 mg). Mean AST and ALT values were 70.6 IU/L (normal 7-38 IU/L) and 85.6 IU/L (normal 4-36 IU/L), respectively and these values showed rapid improvement after starting bezafibrate. 72.7% of patients achieved normalization of these values at week 24 (Figure 1). Two out of eleven patients successfully increased weekly MTX dose and no patient needed to reduce the dose due to liver toxicity. DAS28-ESR based EULAR response at week 24 was good in one of these patients and moderate in two. DAS28-ESR deteriorated in two patients. Finally, there were no serious adverse events with regard to using bezafibrate.
Conclusions Taken together, although it is a small prospective study, bezafibrate ameliorates MTX-induced liver toxicity without exerting negative impact on disease activity.
Langman G, Hall PM, Todd G. Role of non-alcoholic steatohepatitis in methotorexate-induced liver injury. J Gastroenterol Hepatol 2001;16:1395-1401.
Tatsuya N, Yoichi I, Shigeru N, et al. Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARδ agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet. Eur. J. Pharmacol 2006;536:182-191.
Disclosure of Interest None Declared