{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T06:08:58Z","timestamp":1793686138438,"version":"4.5.1"},"reference-count":56,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Therapeutic Advances in Musculoskeletal"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Methotrexate (MTX) is the first-line treatment for rheumatoid arthritis (RA), and folic acid is routinely co-prescribed to prevent folate deficiency. However, no consensus exists regarding the optimal dose and frequency of folic acid supplementation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives:<\/jats:title>\n                    <jats:p>This study aimed to compare the incidence of major adverse cardiovascular events (MACE) in RA patients receiving high versus low doses of folic acid alongside MTX.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design:<\/jats:title>\n                    <jats:p>A population-based retrospective cohort study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>RA patients using MTX without baseline MACE were recruited retrospectively from a citywide database in Hong Kong between 2006 and 2015 and followed until 2018. The primary outcome was the first occurrence of MACE. Cox regression analyses with time-varying covariates were used to assess the association between folic acid dosage and incident MACE, adjusting for demographics, traditional cardiovascular risk factors, markers of inflammation and anti-rheumatic drug use.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>A total of 8405 RA patients on MTX were identified. Of these, 6854 (78.5%) were female and the mean age was 56.0\u2009\u00b1\u200913.5\u2009years. Among the cohort, 2967 patients (35.3%) received \u2a7e5\u2009mg of folic acid daily, while 5438 (64.7%) received 0\u2013&lt;5\u2009mg. After a median follow-up of 9\u2009years (interquartile range: 5\u2009years), 504 patients (6.0%) developed MACE. Multivariable analyses showed that the use of folic acid \u2a7e5\u2009mg daily was associated with a significantly higher risk of MACE (adjusted hazard ratios were 1.34 (95% confidence interval (CI) 1.09\u20131.64) in the erythrocyte sedimentation rate model and 1.39 (95% CI 1.14\u20131.71) in the C-reactive protein model) compared to lower doses. The association remained significant after inverse probability treatment weighting and machine-learning gradient boosted regression modelling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>High-dose folic acid supplementation may be associated with an increased risk of MACE in RA patients taking MTX.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/1759720x261423837","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T00:35:05Z","timestamp":1772152505000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":3,"title":["High-dose folic acid supplement is associated with increased cardiovascular risk in rheumatoid arthritis patients on methotrexate"],"prefix":"10.1177","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5665-1609","authenticated-orcid":false,"given":"Huan","family":"Meng","sequence":"first","affiliation":[{"name":"Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7113-9390","authenticated-orcid":false,"given":"Ho","family":"So","sequence":"additional","affiliation":[{"name":"Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianfeng","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingzhao","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven H.","family":"Lam","sequence":"additional","affiliation":[{"name":"Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong"},{"name":"Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University, and Liverpool Heart and Chest Hospital, Liverpool, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Kwok","sequence":"additional","affiliation":[{"name":"Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6410-8852","authenticated-orcid":false,"given":"Lai-Shan","family":"Tam","sequence":"additional","affiliation":[{"name":"Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, 999077, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2022-223356"},{"issue":"12","key":"e_1_3_4_3_2","first-page":"2374","article-title":"Folate, homocysteine, and cobalamin status in patients with rheumatoid arthritis treated with methotrexate, and the effect of low dose folic acid supplement","volume":"31","author":"Hornung N","year":"2004","unstructured":"Hornung N, Ellingsen T, Stengaard-Pedersen K, et al. Folate, homocysteine, and cobalamin status in patients with rheumatoid arthritis treated with methotrexate, and the effect of low dose folic acid supplement. 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