{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T09:49:58Z","timestamp":1770284998907,"version":"3.49.0"},"reference-count":32,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2013,10,28]],"date-time":"2013-10-28T00:00:00Z","timestamp":1382918400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2013,11]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To investigate whether baseline concentrations of one\u2010carbon metabolism biomarkers are associated with treatment nonresponse and adverse events in rheumatoid arthritis (RA) patients receiving methotrexate (MTX).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A prospective derivation cohort (n = 285) and validation cohort (n = 102) of RA patients receiving MTX were studied. Concentrations of plasma homocysteine, serum vitamin B<jats:sub>12<\/jats:sub>, serum folate, erythrocyte vitamin B<jats:sub>6<\/jats:sub>, and erythrocyte folate were determined at baseline and after 3 months of treatment. Nonresponse after 3 months was assessed using the Disease Activity Score in 28 joints (DAS28) and the European League Against Rheumatism (EULAR) response criteria. Adverse events at 3 months were assessed using biochemical parameters and health status questionnaires. Analyses were corrected for baseline DAS28, age, sex, MTX dose, comedications, and presence of the methylenetetrahydrofolate reductase 677TT genotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the derivation cohort, the mean DAS28 scores at baseline and 3 months were 4.94 and 3.12, respectively, and 78% of patients experienced adverse events. This was similar between the 2 cohorts, despite a lower MTX dose in the validation cohort. Patients with lower levels of erythrocyte folate at baseline had a higher DAS28 at 3 months in both the derivation cohort (\u03b2 = \u22120.15, <jats:italic>P<\/jats:italic> = 0.037) and the validation cohort (\u03b2 = \u22120.20, <jats:italic>P<\/jats:italic> = 0.048). In line with these results, lower baseline erythrocyte folate levels were linearly associated with a 3\u2010month DAS28 of &gt;3.2 in both cohorts (derivation cohort, <jats:italic>P<\/jats:italic> = 0.049; validation cohort, <jats:italic>P<\/jats:italic> = 0.021) and with nonresponse according to the EULAR criteria (derivation cohort, <jats:italic>P<\/jats:italic> = 0.066; validation cohort, <jats:italic>P<\/jats:italic> = 0.027). None of the other biomarkers (levels at baseline or changes over 3 months) were associated with the DAS28 or treatment nonresponse. Baseline levels of the biomarkers and changes in levels after 3 months were not associated with incidence of adverse events.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>A low baseline concentration of erythrocyte folate is associated with high disease activity and nonresponse at 3 months after the start of MTX treatment and could be used in prediction models for MTX outcome. None of the investigated one\u2010carbon metabolism biomarkers were associated with incidence of adverse events at 3 months.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.38113","type":"journal-article","created":{"date-parts":[[2013,10,28]],"date-time":"2013-10-28T15:25:54Z","timestamp":1382973954000},"page":"2803-2813","source":"Crossref","is-referenced-by-count":36,"title":["Association of Low Baseline Levels of Erythrocyte Folate With Treatment Nonresponse at Three Months in Rheumatoid Arthritis Patients Receiving Methotrexate"],"prefix":"10.1002","volume":"65","author":[{"given":"M. C. F. J.","family":"de Rotte","sequence":"first","affiliation":[{"name":"Erasmus University Medical Center Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P. H. P.","family":"de Jong","sequence":"additional","affiliation":[{"name":"Erasmus University Medical Center Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. M. F.","family":"Pluijm","sequence":"additional","affiliation":[{"name":"Erasmus University Medical Center Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Bulatovi\u0107 \u0106alasan","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht and Wilhelmina Children's Hospital Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P. J.","family":"Barendregt","sequence":"additional","affiliation":[{"name":"Maasstad Hospital Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D.","family":"van Zeben","sequence":"additional","affiliation":[{"name":"Sint Franciscus Gasthuis Hospital Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P. A.","family":"van der Lubbe","sequence":"additional","affiliation":[{"name":"Vlietland Hospital Schiedam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P. B.","family":"de Sonnaville","sequence":"additional","affiliation":[{"name":"Admiraal de Ruyter Hospital Goes The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.","family":"Lindemans","sequence":"additional","affiliation":[{"name":"Erasmus University Medical Center Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. M. W.","family":"Hazes","sequence":"additional","affiliation":[{"name":"Erasmus University Medical Center Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R.","family":"de Jonge","sequence":"additional","affiliation":[{"name":"Erasmus University Medical Center Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,10,28]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.2217\/pgs.11.86"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2009.123919"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kep392"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.22640"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2011-200942"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.20188"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2010.5"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2004.033399"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27201"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2474-10-71"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27584"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1515\/CCLM.2006.178"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2012.07.007"},{"key":"e_1_2_7_15_1","first-page":"391","article-title":"Stability of red blood cell folate in whole blood and haemolysate","volume":"56","author":"Zemlin AE","year":"2010","journal-title":"Clin Lab"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780380107"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780390105"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.080576"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2011-201162"},{"key":"e_1_2_7_20_1","article-title":"Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis","author":"Ortiz Z","year":"2000","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.21295"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00216-012-6581-7"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.24653"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.111593"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/41.6.658"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.58.2.79"},{"key":"e_1_2_7_27_1","first-page":"441","article-title":"Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease prevention","volume":"25","author":"Morgan SL","year":"1998","journal-title":"J Rheumatol"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1991.180"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.3945\/jn.111.153056"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0007114511000407"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.093690"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e3283500202"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780330102"}],"container-title":["Arthritis &amp; Rheumatism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fart.38113","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.38113","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,30]],"date-time":"2023-10-30T06:08:57Z","timestamp":1698646137000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/art.38113"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,10,28]]},"references-count":32,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2013,11]]}},"alternative-id":["10.1002\/art.38113"],"URL":"https:\/\/doi.org\/10.1002\/art.38113","archive":["Portico"],"relation":{},"ISSN":["0004-3591","1529-0131"],"issn-type":[{"value":"0004-3591","type":"print"},{"value":"1529-0131","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,10,28]]}}}