Background/Purpose: Methotrexate (MTX) is the most commonly prescribed disease modifying anti-rheumatic drugs (DMARDs) for the treatment of RA due to its high efficacy and favorable safety profile. However, a higher incidence of MTX toxicity at dose >7.5mg/week has been reported in East Asia, especially in Japan, possibly due to a different genetic background in regard to MTX metabolism. Therefore, it is common to start MTX in a lower dose and to titrate it up slowly to target of 15-20 mg/ week. This approach can be associated with a significant delay in reaching a “therapeutic MTX dose” in RA patients. The aim of this study is to investigate as to whether a certain starting dose of MTX is associated with an increased MTX-toxicity in Korean patients with RA.

Methods: In this retrospective cohort study 2361 MTX-naïve RA patients, in whom MTX was initiated between 2009 and 2018, were included. Patients were divided into a low (≤7.5mg/week), moderate (10-12.5 mg/week) and high (≥15 mg/week) dosing groups. A MTX toxicity is defined as an increase of post-MTX AST or ALT >80 mg/dL. Groups were compared using chi-square and one-way analysis of variance. Factors associated with toxicity on liver were examined using logistic regression analyses. All analyses were performed by using SPSS (IBM SPSS statistics version 25).

Results: The mean age was 54.1 +/- 13.9 year. Women were dominant (79.6%). 31 (1.3%) and 5 (0.2%) patients had hepatitis B and C virus infection, respectively. There was no significant difference in age, sex, underlying liver disease between the three dosing groups. 1756 (74.4%) patients were taking glucocorticoids (prednisolone equivalent 7.7 +/- 4.8 mg/day) and 321 (13.6%) patients were taking leflunomide or sulfasalazine. The mean starting MTX dose was 11.1 +/- 3.0 mg/week. 522 (22.1%) patients, 1162 (49.2%) and 677 (28. 7%) patients started MTX ≤7.5mg/ week, 10-12.5 mg/week and ≥15 mg/week, respectively. All patients received folate supplementation. Liver toxicity was observed in 30 (1.3 %) patients. The rate of liver toxicity did not differ among the groups (1.5% in the low vs. 0.9% in the moderate vs. 1.6% in the high dosing group, P = 0.38). In logistic regression analyses, clinical parameters including age, sex, body mass index and initial MTX dose were not associated with an increased risk of a hepatotoxicity either.

Conclusion: This study demonstrated clearly that the initial MTX dose up to 15 mg /week was not associated with an increased toxicity on liver in Korean patients with RA. Therefore, MTX can be started at 15 mg/week in Korean patients with RA without a safety concern on liver toxicity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/high-initial-methotrexate-dose-is-not-associated-with-an-increased-risk-of-liver-toxicity-in-korean-patients-with-rheumatoid-arthritis/