Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: A long‐term follow‐up of predictors, surveillance, and outcome in clinical practice

Abstract

Aim To assess predictors of alanine aminotransferase (ALT) elevation in methotrexate (MTX) treated rheumatoid arthritis (RA) patients, and to describe the monitoring of liver enzymes, including handling and outcome of elevated ALT. Methods All RA patients starting MTX in January, 2005 to April, 2013 at a rheumatology clinic, (Uppsala University Hospital, Sweden) were identified from electronic medical records. Clinical and laboratory data were obtained from medical records, supplemented by telephone interviews. Predictors for ALT >1.5× over the upper limit of normal (ULN) were identified by multiple regression analysis. Results The study comprised 213 RA patients starting MTX. During a mean follow‐up of 4.3 years, 6288 ALT tests were performed; 7% of tests with ALT were >ULN. ALT >1.5× ULN was observed in 44 (21%) patients and the strongest predictor was a pre‐treatment elevation of ALT (adjusted odds ratio = 6.8, 95% CI 2.2‐20.5). Recurrent elevations occurred in 70% of patients who continued treatment, and the proportion was similar in those with and without interventions, for example MTX dose reduction (67% vs 73%, P = 0.43). Seven patients (3%) permanently stopped MTX due to ALT elevation, and two were eventually diagnosed with non‐alcoholic fatty liver disease. No patient developed hepatic failure. Conclusion Only a small number of ALT tests performed during MTX therapy in RA capture an elevation. A pre‐treatment elevation of ALT was the strongest predictor for early and recurrent ALT elevations during therapy. This study supports a more individualized approach to monitoring and handling of ALT elevations during MTX therapy in RA than recommended in current guidelines.

Genetic Polymorphisms of GGH and ABCC2 Are Associated with Methotrexate Intolerance in Patients with Rheumatoid Arthritis

“…MTX represents the first-line treatment for patients with RA, either in monotherapy or in combination with other drugs [ 14 ]. MTX is efficacious against both inflammatory symptoms and radiographic destruction [ 15 ]; however, intolerance and adverse effects are common and may lead to MTX discontinuation [ 16 ]. Therefore, reliable biomarkers to predict MTX intolerance or toxicity in patients with RA should be identified.…”

“…Our results showed a high prevalence (47%) of intolerant patients compared with values reported in the literature, which may be explained by the use of different definitions of “intolerance”. We considered “intolerant” as a patient who suffered from any type of side effect, while previous studies were focused on a specific type of intolerance or adverse event [ 11 , 16 ].…”

“…According to several studies, the MTHFR variants A1298C and C677T are two of the most important polymorphisms associated with MTX toxicity [ 16 , 19 , 20 , 21 ]. The MTHFR A1298C polymorphism has been reported to lead to a 60% reduction in enzymatic activity in patients homozygous for 1298C, causing MTX intolerance [ 22 ].…”

Machine learning-based prediction of relapse in rheumatoid arthritis patients using data on ultrasound examination and blood test

“…In the remaining seven features, ALT and height were significantly lower in patients with relapse. ALT is not well-characterized as a prognostic factor, but the elevation is a marker of liver toxicity in RA treatment 25 . There is a possibility that patients with lower ALT may receive lower-intensity therapies, contributing to higher relapse risk.…”

Patients With IBD Receiving Methotrexate Are at Higher Risk of Liver Injury Compared With Patients With Non-IBD Diseases: A Meta-Analysis and Systematic Review

“…Recently, Gelfand et al conducted a population-based study, which included 28,030, 5,687, and 6,520 patients with RA, Ps, and PsA, respectively, and reported the incidence rates of liver disease outcomes not exceeding 10 incidence rates per 1,000 person-years ( 13 ). Karlsson Sundbaum et al performed 6,288 alanine aminotransferase (ALT) tests during a long-term follow-up of 213 RA patients receiving MTX and found only 7% of ALT tests were over the upper limit of normal (ULN) ( 14 ).…”