TY - JOUR
T1 - A meta-analysis of methotrexate polyglutamates in relation to efficacy and toxicity of methotrexate in inflammatory arthritis, colitis and dermatitis
AU - van de Meeberg, Maartje M.
AU - Hebing, Renske C. F.
AU - Nurmohamed, Michael T.
AU - Fidder, Herma H.
AU - Heymans, Martijn W.
AU - Bouma, Gerd
AU - de Bruin-Weller, Marjolein S.
AU - Tekstra, Janneke
AU - van den Bemt, Bart
AU - de Jonge, Robert
AU - Bulatović Ćalasan, Maja
N1 - Funding Information: We thank authors for sending us the requested data. We thank Prof. Dr Ir. R. de Vet (E&B Xpert, Department Epidemiology & Biostatistics, Amsterdam UMC, The Netherlands) for her help with the methodology. Publisher Copyright: © 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
KW - immune-mediated inflammatory diseases
KW - methotrexate
KW - pharmacodynamics
KW - therapeutic drug monitoring
UR - http://www.scopus.com/inward/record.url?scp=85142266824&partnerID=8YFLogxK
U2 - https://doi.org/10.1111/bcp.15579
DO - https://doi.org/10.1111/bcp.15579
M3 - Review article
C2 - 36326810
SN - 0306-5251
VL - 89
SP - 61
EP - 79
JO - British journal of clinical pharmacology
JF - British journal of clinical pharmacology
IS - 1
ER -