To determine the predictors of elevated transaminases in an incident user cohort of older adult patients with rheumatic diseases receiving methotrexate (MTX) using elements derived from an electronic health record.


Using a national, administrative database of patients seen through the Veterans Health Administration that included pharmacy and laboratory data, we performed an observational cohort study of veterans ages ≥65 years who were new users of MTX to identify risk factors for elevated transaminases.


We studied 659 incident users of MTX. We found a 6% incidence of moderate (≥1.5 × the upper limit of normal) elevations in aspartate aminotransferase or alanine aminotransferase over a mean followup period of 7 months. We identified predictors of moderate transaminase elevations to include obesity (per body mass index ≥30 kg/m2), total cholesterol >240 mg/dl, pre-MTX liver function test (LFT) elevations, use of biologic agents, and lack of folic acid supplementation. A patient with these characteristics and >3 comorbid conditions would be predicted to have a 90% chance of developing a moderate transaminase elevation in the 7 months after starting MTX.


Moderate LFT abnormalities were uncommon in the first 7 months of MTX use, but were more likely to occur in patients with obesity, untreated high cholesterol, pre-MTX LFT elevations, biologic agent use, and lack of folic acid supplementation. Future work should aim to develop a robust, automated prediction rule for identifying patients at high risk for MTX-related liver toxicity.