Search

Summary: Background: Therapeutic drug monitoring (TDM) has the potential to improve efficacy and diminish side effects. Measuring methotrexate‐polyglutamate (MTX‐PG) in erythrocytes might enable TDM for methotrexate in patients with Crohn's disease (CD). Aim: To investigate the relationship between MTX‐PGs and methotrexate drug survival, efficacy and toxicity Methods: In a multicentre prospective cohort study, patients with CD starting subcutaneous methotrexate without biologics were included and followed for 12 months. Primary outcome was subcutaneous methotrexate discontinuation or requirement for step‐up therapy. Secondary outcomes included faecal calprotectin (FCP), Harvey Bradshaw Index (HBI), hepatotoxicity and gastrointestinal intolerance. Erythrocyte MTX‐PGs were analysed at weeks 8, 12, 24 and 52 or upon treatment discontinuation. Results: We included 80 patients with CD (mean age 55 ± 13y, 35% male) with a median FCP of 268 μg/g (IQR 73–480). After the 12‐month visit, 21 patients (26%) were still on subcutaneous methotrexate monotherapy. Twenty‐one patients stopped because of disease activity, 29 because of toxicity, and four for both reasons. Five patients ended study participation or stopped methotrexate for another reason. A higher MTX‐PG3 concentration was associated with a higher rate of methotrexate drug survival (HR 0.86, 95% CI 0.75–0.99), lower FCP (β −3.7, SE 1.3, p < 0.01) and with biochemical response (FCP ≤250 if baseline >250 μg/g; OR 1.1, 95% CI 1.0–1.3). Higher MTX‐PGs were associated with less gastrointestinal intolerance. There was no robust association between MTX‐PGs and HBI or hepatotoxicity. Conclusions: Higher MTX‐PG3 concentrations are related to better methotrexate drug survival and decreased FCP levels. Therefore, MTX‐PG3 could be used for TDM if a target concentration can be established. [ABSTRACT FROM AUTHOR]

Aims: In immune‐mediated inflammatory diseases (IMIDs), early symptom control is a key therapeutic goal. Methotrexate (MTX) is the first‐line treatment across IMIDs. However, MTX is underutilized and suboptimally dosed, partly due to the inability of making individualized treatment decisions through therapeutic drug monitoring (TDM). To implement TDM in clinical practice, establishing a relationship between drug concentration and disease activity is paramount. In this meta‐analysis, we investigated the relationship between concentrations of MTX polyglutamates (MTX‐PG) in erythrocytes and efficacy as well as toxicity across IMIDs. Methods: Studies analysing MTX‐PG in relation to disease activity and/or toxicity were included for inflammatory arthritis (rheumatoid [RA] and juvenile idiopathic arthritis [JIA]), inflammatory bowel disease (Crohn's and ulcerative colitis) and dermatitis (psoriasis and atopic dermatitis). Meta‐analyses were performed resulting in several summary effect measures: regression coefficient (β), correlation coefficient and mean difference (of MTX‐PG in responders vs. nonresponders) for IMIDs separately and collectively. Results: Twenty‐five studies were included. In RA and JIA, higher MTX‐PG was significantly associated with lower disease activity at 3 months (β: −0.002; 95% confidence interval [CI]: −0.004 to −0.001) and after 4 months of MTX use (β: −0.003; 95% CI: −0.005 to −0.002). Similarly, higher MTX‐PG correlated with lower disease activity in psoriasis (R: −0.82; 95% CI: −0.976 to −0.102). Higher MTX‐PG was observed in RA, JIA and psoriasis responders (mean difference: 5.2 nmol/L MTX‐PGtotal; P <.01). Conclusion: We showed that higher concentrations of erythrocyte MTX‐PG were associated with lower disease activity in RA, JIA and psoriasis. These findings are an important step towards implementation of TDM for MTX treatment across IMIDs. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to van de Meeberg et al papers. To view these articles, visit https://doi.org/10.1111/apt.17719 and https://doi.org/10.1111/apt.17743 [ABSTRACT FROM AUTHOR]