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Factors associated with toxicity, final dose, and efficacy of methotrexate in patients with rheumatoid arthritis

M Hoekstra¹, A E van Ede², C J Haagsma¹, M A F J van de Laar¹, T W J Huizinga³, M W M Kruijsen¹, R F J M Laan²

¹ Department of Rheumatology, Medisch Spectrum Twente, Enschede, The Netherlands
² Department of Rheumatology, University Medical Centre Nijmegen, The Netherlands
³ Department of Rheumatology, Leiden University Medical Centre, The Netherlands

Correspondence to:
Correspondence to:
Dr M Hoekstra, Department of Rheumatology, Medisch Spectrum Twente, Enschede, Postbus 50000, 7500 KA Enschede, The Netherlands;
mhoekstra{at}introweb.nl

Objective: To study factors associated with toxicity, final dose, and efficacy of methotrexate (MTX) in patients with rheumatoid arthritis (RA).

Methods: Data were used from a randomised clinical 48 week trial on 411 patients with RA all treated with MTX, comparing folates and placebo. Logistic regression was used to study the relation between baseline variables and various dependent factors, including hepatotoxicity (alanine aminotransferase 3xupper limit of normal), MTX withdrawal, final MTX dose 15 mg/week, and MTX efficacy.

Results: Addition of folates to MTX treatment was strongly related to the lack of hepatotoxicity. Next to this, high body mass index was related to the occurrence of hepatotoxicity. Prior gastrointestinal (GI) events and younger age were related to the adverse event, diarrhoea. Hepatotoxicity and GI adverse events were the main reason for MTX withdrawal, which in turn was associated with the absence of folate supplementation, body mass index, prior GI events, and female sex. Renal function (creatinine clearance 50 ml/min) was not associated with toxicity. Reaching a final dose of MTX of 15 mg/week was related to folate supplementation and the absence of prior GI events. Efficacy of MTX treatment was associated with low disease activity at baseline, male sex, use of non-steroidal anti-inflammatory drugs (NSAIDs), and lower creatinine clearance.

Conclusions: MTX toxicity, final dose, and efficacy are influenced by folate supplementation. Baseline characteristics predicting the outcome of MTX treatment are mainly prior GI events, body mass index, sex, use of NSAIDs, and creatinine clearance.

Keywords: methotrexate; toxicity; efficacy; rheumatoid arthritis

Abbreviations: BMI, body mass index; DAS, disease activity score; DMARD, disease modifying antirheumatic drug; GI, gastrointestinal; MTX, methotrexate; RA, rheumatoid arthritis; RCT, randomised controlled trial

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