A meta-analysis of methotrexate polyglutamates in relation to efficacy and toxicity of methotrexate in inflammatory arthritis, colitis and dermatitis

Maartje M. van de Meeberg, Renske C. F. Hebing, Michael T. Nurmohamed, Herma H. Fidder, Martijn W. Heymans, Gerd Bouma, Marjolein S. de Bruin-Weller, Janneke Tekstra, Bart van den Bemt, Robert de Jonge, Maja Bulatović Ćalasan

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10 Citations (Scopus)


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-PG total; 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.

Original languageEnglish
Pages (from-to)61-79
Number of pages19
JournalBritish journal of clinical pharmacology
Issue number1
Early online date2022
Publication statusPublished - Jan 2023


  • immune-mediated inflammatory diseases
  • methotrexate
  • pharmacodynamics
  • therapeutic drug monitoring

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