Predictive Biomarkers of Methotrexate Treatment Response in Patients with Rheumatoid Arthritis: A Systematic Review.

Background

Methotrexate (MTX) is the most used anti-rheumatic drug for the treatment of early rheumatoid arthritis (ERA) patients, with an adequate response rate of only 30-40%. Thus, early detection of response failure is very crucial to prevent permanent disability.

Objectives

We aimed to provide an update on the current evidence of potential predictive biomarkers of MTX treatment response (MTX-TR) in patients with ERA. Materials and

Methods

PubMed/MEDLINE, Scopus, EBSCO, and Cochrane Library were searched for studies that investigated a multitude of predictive metabolites of MTX-TR in ERA patients during the 2000-2024 period. This study was registered in PROSPERO (ID: CRD42024547651).

Results

We determined that 31 out of 102 metabolites studied were the best predictive of MTX-TR in ERA, using clinical response (DAS28-ESR score). Our results on serum protein profiles revealed that higher pre-treatment levels of myeloid-related proteins, MTX-polyglutamates, choline, inosine, hypoxanthine, guanosine, nicotinamide, and diglyceride, and lower pre-treatment levels of N-methyl isoleucine, 2,3-dihydroxy butanoic acid, nor-nicotine, glucosylceramide, and itaconic acid, were associated with a good MTX-TR. However, lower baseline plasma itaconate and its derivatives and haptoglobin, but a higher baseline level of galactosylated glycans (FA2G) of IgG1, were associated with a good response to MTX. The results on immune cell biology indicated that higher pre-treatment of regulatory B cells, lower pre-treatment of Treg, and RDW were correlated with a good MTX-TR. The results on inflammatory biomarkers showed that a lower IL-1ra/IL1B ratio and IL-6 levels after MTX indicated a good response.

Conclusions

This study provides an update on the current evidence of the potential predictive metabolites for the best MTX-TR in ERA patients. We revealed that few biomarkers resulted in a remission state of patients with ERA. These biomarkers are promising but not yet ready for routine clinical use; they warrant validation in larger prospective trials. We recommend that, for the implementation of personalized medicine, these biomarkers should be the first-line biomarkers for use in routine clinical practice after validation.