{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:52:26Z","timestamp":1788871946526,"version":"build-2803163510"},"reference-count":50,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2014,11,25]],"date-time":"2014-11-25T00:00:00Z","timestamp":1416873600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["T32-HD069038"],"award-info":[{"award-number":["T32-HD069038"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000960","name":"American College of Rheumatology Research and Education Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000960","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001797","name":"Pharmaceutical Research and Manufacturers of America Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001797","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010400","name":"Children's Mercy Kansas City","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100010400","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Kansas City Area Life Sciences Institute"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2014,12]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Folates exist as a fluctuating pool of polyglutamated metabolites that may serve as a clinical marker of methotrexate (MTX) activity. This study was undertaken to evaluate circulating folate content and folate polyglutamate distribution in juvenile idiopathic arthritis (JIA) patients and in a cell culture model based on MTX exposure and folate supply.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Blood, plasma, and red blood cell (RBC) measurements of MTX and folates were obtained from previously published data sets and an additional analysis of JIA patients receiving MTX (n = 98) and those not receiving MTX (n = 78). Erythroblastoid cells maintained in culture were exposed to MTX and grown under varying levels of folic acid supplementation. Samples were analyzed for cellular folate and MTX content.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Circulating folate levels were lower in JIA patients receiving MTX, with reduced levels of blood, plasma, and RBC 5\u2010methyl\u2010tetrahydrofolate (5mTHF) (\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.0001). Average polyglutamate chain length (Glu\n                      <jats:sub>avg<\/jats:sub>\n                      ) of RBC 5mTHF was elevated in JIA patients receiving MTX (median \u00b1 interquartile range 5.63 \u00b1 0.15 versus 5.54 \u00b1 0.11 in those not receiving MTX;\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.001) and correlated with both RBC MTX accumulation (\n                      <jats:italic>P<\/jats:italic>\n                      = 0.02) and reduced plasma 5mTHF levels (\n                      <jats:italic>P<\/jats:italic>\n                      = 0.008). MTX exposure and folate deprivation in erythroblastoid cells resulted in a depletion of bioactive folate species that was associated with a shift to higher Glu\n                      <jats:sub>avg<\/jats:sub>\n                      values for several species, most notably tetrahydrofolate (THF) and 5,10\u2010methylene\u2010tetrahydrofolate (CH\n                      <jats:sub>2<\/jats:sub>\n                      THF). Increased Glu\n                      <jats:sub>avg<\/jats:sub>\n                      resulted from the depletion of short\u2010chain and the accumulation of long\u2010chain glutamate species.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings indicate that folate content and polyglutamate distribution are responsive markers of MTX activity and folate supply in vivo and in vitro, and may provide novel clinical markers of pharmacologic activity of MTX.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.38865","type":"journal-article","created":{"date-parts":[[2014,9,3]],"date-time":"2014-09-03T14:53:09Z","timestamp":1409755989000},"page":"3476-3485","source":"Crossref","is-referenced-by-count":15,"title":["Folate Depletion and Increased Glutamation in Juvenile Idiopathic Arthritis Patients Treated With Methotrexate"],"prefix":"10.1002","volume":"66","author":[{"given":"Ryan S.","family":"Funk","sequence":"first","affiliation":[{"name":"Children's Mercy Kansas City, Kansas City, Missouri and the University of Kansas Medical Center Kansas City Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon","family":"van Haandel","sequence":"additional","affiliation":[{"name":"Children's Mercy Kansas City Kansas City Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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