{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T15:39:33Z","timestamp":1784302773735,"version":"3.55.0"},"reference-count":85,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>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\u201340%. 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\u20132024 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\u2013polyglutamates, 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.<\/jats:p>","DOI":"10.3390\/metabo15110715","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T18:21:46Z","timestamp":1762194106000},"page":"715","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Predictive Biomarkers of Methotrexate Treatment Response in Patients with Rheumatoid Arthritis: A Systematic Review"],"prefix":"10.3390","volume":"15","author":[{"given":"Adla B.","family":"Hassan","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, College of Medicine and Health Sciences, Arabian Gulf University, Manama 26671, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0976-6892","authenticated-orcid":false,"given":"Rowida M.","family":"Hamid","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy, National University, Khartoum, Sudan"},{"name":"College of Medicine and Health Sciences, Arabian Gulf University, Manama 26671, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saja H.","family":"Alamien","sequence":"additional","affiliation":[{"name":"College of Medicine and Health Sciences, Arabian Gulf University, Manama 26671, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Namaa A.","family":"Khalil","sequence":"additional","affiliation":[{"name":"Medical Skills and Simulation Center (MSSC), College of Medicine and Health Sciences, Arabian Gulf University, Manama 26671, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5872-0901","authenticated-orcid":false,"given":"Duaij Salman","family":"Saif","sequence":"additional","affiliation":[{"name":"College of Medicine and Health Sciences, Arabian Gulf University, Manama 26671, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7773-2039","authenticated-orcid":false,"given":"Mohammed","family":"Elfaki","sequence":"additional","affiliation":[{"name":"Medical Skills and Simulation Center (MSSC), College of Medicine and Health Sciences, Arabian Gulf University, Manama 26671, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8990-1320","authenticated-orcid":false,"given":"Haitham","family":"Jahrami","sequence":"additional","affiliation":[{"name":"College of Medicine and Health Sciences, Arabian Gulf University, Manama 26671, Bahrain"},{"name":"Government Hospitals, Manama 329, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/S0889-857X(21)00458-0","article-title":"Epidemiology of rheumatoid arthritis","volume":"21","author":"Alarcon","year":"1995","journal-title":"Rheum. 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