{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T05:16:30Z","timestamp":1783401390721,"version":"3.54.6"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T00:00:00Z","timestamp":1780704000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T00:00:00Z","timestamp":1780704000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"JSPS KAKENHI","award":["24K18642"],"award-info":[{"award-number":["24K18642"]}]},{"name":"TSUCHIYA MEMORIAL MEDICAL FOUNDATION"},{"DOI":"10.13039\/501100003790","name":"Hiroshima University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003790","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Rheumatol"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Folic acid is routinely co-administered with methotrexate (MTX) to reduce toxicity; however, the optimal dose remains unclear. This study investigated whether increasing the weekly folic acid dose from 5 to 10\u00a0mg reduces MTX-related toxicity in patients receiving stable-dose MTX therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this single-center, open-label, randomized controlled trial, 44 patients with rheumatic diseases on stable-dose MTX either received 10\u00a0mg (ARM-1) or 5\u00a0mg (ARM-2) of folic acid per week for 12\u00a0weeks. Liver damage, other MTX-related toxicities, and erythrocyte MTX-polyglutamate (MTX-PG) concentrations were compared between groups using logistic regression analysis or analysis of covariance. Japan Registry of Clinical Trials (number: jRCT1061230085).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Forty-two patients completed the study. The presence of liver damage at Day 84 did not differ significantly between the two groups (OR 0.41, 95% CI, 0.01\u20135.75,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.506). Adjusted mean differences in aspartate transaminase and alanine transaminase at Day 84 between the groups were\u2009\u2212\u20090.33 U\/L (95% CI,\u2009\u2212\u20092.68 to 2.02;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.779) and\u2009\u2212\u20090.44 U\/L (95% CI,\u2009\u2212\u20095.39 to 4.51;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.859). Comparison of outcomes between groups at Day 84 showed no significant differences in any outcomes, except for fatigue severity (adjusted mean difference,\u2009\u2212\u20090.87; 95% CI,\u2009\u2212\u20091.71 to\u2009\u2212\u20090.04;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.041). Baseline fatigue was associated with baseline MTX-PG2 or MTX-PG1-2 concentrations (OR, 1.06;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.049 or OR, 1.03;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.040, respectively).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Increasing folic acid dose to 10\u00a0mg\/week showed little effect on reducing MTX-related toxicity, although it may improve fatigue in selected patients.<\/jats:p>\n                    <jats:p>\n                      <jats:table-wrap>\n                        <jats:table>\n                          <jats:tbody>\n                            <jats:tr>\n                              <jats:td align=\"left\" colspan=\"2\">\n                                <jats:bold>Key Points<\/jats:bold>\n                                \u2022\u00a0\n                                <jats:italic>Increasing the weekly folic acid dose from 5 mg to 10 mg showed no additional benefit in reducing methotrexate-related toxicity in patients on stable-dose MTX.<\/jats:italic>\n                                \u2022\u00a0\n                                <jats:italic>Higher-dose folic acid was associated with improved fatigue severity, indicating a potential therapeutic option for patients who develop fatigue.<\/jats:italic>\n                              <\/jats:td>\n                            <\/jats:tr>\n                          <\/jats:tbody>\n                        <\/jats:table>\n                      <\/jats:table-wrap>\n                    <\/jats:p>\n                  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This study was registered with the Japan Registry of Clinical Trials (reference number: jRCT1061230085).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Y. Yoshida received honoraria for the speakers bureau from Eisai, Asahi Kasei, Daiichi-Sankyo, AstraZeneca, Boehringer Ingelheim, AbbVie, Astellas, and Taisho Pharmaceutical Co. Ltd.\u00a0S. Hirata received speaker fees, consultancy fees, research grants, and honoraria from AbbVie, Asahi-Kasei Pharma, Astellas, AstraZeneca, Ayumi, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead Sciences, Glaxo SmithKline, Janssen, Nihon-Kayaku, Novartis, Otsuka Pharmaceutical, Pfizer, Sandoz, Taisho, Tanabe Pharma, and UCB.\u00a0The authors declare no conflicts of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}