Personalized methotrexate treatment in immune-mediated inflammatory diseases: a narrative review

Abstract

Background and Objective: Low-dose methotrexate (MTX) is a key drug in the treatment of immune-mediated inflammatory diseases (IMIDs). Although treatment is effective and safe, 30–40% of patients discontinue due to either adverse events (AEs) or inefficacy (non-response). Effective treatment early in the disease course is key for control and to prevent irreversible damage. Personalizing treatment of MTX would (I) select the right drug for the right patient in order to achieve fast disease control and prevent adverse events, and (II) apply therapeutic drug monitoring (TDM) to optimize drug dosing. The aim of this narrative review is to present a comprehensive update on the options available to personalize MTX treatment for IMID patients. Methods: To this end, a PubMed literature search from 1980 to 2025 was performed. Key Content and Findings: Thus far, erythrocytes are commonly used as a matrix for TDM of low-dose MTX due to their abundance and ease of access. But extended studies are needed to investigate the effects of MTX on the immune effector cells (various immune cell types) or target tissues (mucosa, synovium, skin). The role of gut microbiota is an emerging field of research with respect to MTX response. Response prediction and TDM of MTX have been largely investigated in rheumatoid arthritis (RA) compared to other IMIDs. Therapeutic cut-off windows have been determined in RA for response and for hepatotoxicity. Before considering switching the type of medication in cases of non-response and toxicity, alternate dosing schemes of MTX may be considered. Conclusions: Studies investigating the extrapolation of observations from RA into other IMIDs are needed. Lastly, combining prediction models and TDM may guide personalized treatments of MTX. Clinical implementation studies are necessary to demonstrate their value.