{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T11:35:30Z","timestamp":1789990530215,"version":"4.0.1"},"reference-count":28,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2010,2,26]],"date-time":"2010-02-26T00:00:00Z","timestamp":1267142400000},"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":[[2010,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Intracellular methotrexate (MTX) polyglutamates (MTXGlu) have been shown to be potentially useful biomarkers of clinical response in adult patients with rheumatoid arthritis. The present study was undertaken to measure intracellular MTXGlu concentrations in a cohort of patients with juvenile idiopathic arthritis (JIA) to determine the predictors of MTXGlu variability in these patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Blood samples were obtained from patients with JIA who were being treated with a stable dose of MTX for \u22653 months. Clinical data were collected by chart review. Concentrations of MTXGlu<jats:sub>1\u20137<\/jats:sub> in red blood cell lysates were quantitated using an innovative ion\u2010pairing chromatography procedure, with detection by mass spectrometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Patients with JIA from a single center (n = 99; mean \u00b1 SD age 117.8 \u00b1 56.5 months, 69 female) were included in the analysis. The mean \u00b1 SD dose of MTX was 0.51 \u00b1 0.25 mg\/kg per week, with a median treatment duration of 18 months (interquartile range 3\u2013156 months). MTX was administered subcutaneously in 66 patients (67%). Fifty\u2010six patients (57%) had active arthritis at the time of the clinic visit. Total intracellular MTXGlu (MTXGlu<jats:sub>TOT<\/jats:sub>) concentrations varied 40\u2010fold, with a mean \u00b1 SD total concentration of 85.8 \u00b1 48.4 nmoles\/liter. Concentrations of each MTXGlu subtype (MTXGlu<jats:sub>1\u20137<\/jats:sub>) were measured individually and as a percentage of MTXGlu<jats:sub>TOT<\/jats:sub> in each patient. MTXGlu<jats:sub>3<\/jats:sub> was the most prominent subtype identified, comprising 42% of MTXGlu<jats:sub>TOT<\/jats:sub>, and the interindividual variability in the concentration of MTXGlu<jats:sub>3<\/jats:sub> was the most highly correlated with that of MTXGlu<jats:sub>TOT<\/jats:sub> (r = 0.96). The route of MTX administration was significantly associated with MTXGlu<jats:sub>1\u20135<\/jats:sub> subtypes; higher concentrations of MTXGlu<jats:sub>1 + 2<\/jats:sub> were observed in patients receiving oral doses of MTX, whereas higher concentrations of MTXGlu<jats:sub>3\u20135<\/jats:sub> were observed in patients receiving subcutaneous doses of MTX (<jats:italic>P<\/jats:italic> &lt; 0.0001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In this cohort of patients with JIA, the MTXGlu<jats:sub>TOT<\/jats:sub> concentration varied 40\u2010fold. Individual MTXGlu metabolites (MTXGlu<jats:sub>1\u20137<\/jats:sub>), which have, until now, not been previously reported in patients with JIA, were detected. The route of MTX administration contributed to the variability in concentrations of MTXGlu<jats:sub>1\u20135<\/jats:sub>.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.27434","type":"journal-article","created":{"date-parts":[[2010,2,26]],"date-time":"2010-02-26T23:51:18Z","timestamp":1267228278000},"page":"1803-1812","source":"Crossref","is-referenced-by-count":59,"title":["Analysis of intracellular methotrexate polyglutamates in patients with juvenile idiopathic arthritis: Effect of route of administration on variability in intracellular methotrexate polyglutamate concentrations"],"prefix":"10.1002","volume":"62","author":[{"given":"Mara L.","family":"Becker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon","family":"van Haandel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Gaedigk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Lasky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Hoeltzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Stobaugh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Steven","family":"Leeder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2010,5,28]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.20288"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.20167"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200109)44:9<1984::AID-ART346>3.0.CO;2-B"},{"key":"e_1_2_7_5_2","first-page":"2501","article-title":"Guidelines for blood test monitoring of methotrexate toxicity in juvenile idiopathic arthritis","volume":"31","author":"Ortiz\u2010Alvarez O","year":"2004","journal-title":"J Rheumatol"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.090826"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780390214"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116884"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)39298-0"},{"key":"e_1_2_7_10_2","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0083-6729(03)01012-4","article-title":"Membrane transport of folates","volume":"66","author":"Matherly LH","year":"2004","journal-title":"Vitam Horm"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112088"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00257362"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M401725200"},{"key":"e_1_2_7_14_2","first-page":"844","article-title":"Lack of correlation between pharmacokinetics and efficacy of low dose methotrexate in patients with rheumatoid arthritis","volume":"22","author":"Lafforgue P","year":"1995","journal-title":"J Rheumatol"},{"key":"e_1_2_7_15_2","first-page":"1573","article-title":"Plasma levels after oral methotrexate in children with juvenile rheumatoid arthritis","volume":"20","author":"Ravelli A","year":"1993","journal-title":"J Rheumatol"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/anr.1780320604"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2004.033399"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.20460"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.1097\/00008571-200411000-00004"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.24034"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.24653"},{"key":"e_1_2_7_22_2","first-page":"390","article-title":"International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001","volume":"31","author":"Petty RE","year":"2004","journal-title":"J Rheumatol"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/rcm.2074"},{"key":"e_1_2_7_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/rcm.4300"},{"key":"e_1_2_7_25_2","doi-asserted-by":"publisher","DOI":"10.1373\/49.10.1632"},{"key":"e_1_2_7_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780400703"},{"key":"e_1_2_7_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.20167"},{"key":"e_1_2_7_28_2","first-page":"179","article-title":"The role of subcutaneous administration of methotrexate in children with juvenile idiopathic arthritis who have failed oral methotrexate","volume":"31","author":"Alsulfyani K","year":"2003","journal-title":"J Rheumatol"},{"key":"e_1_2_7_29_2","volume-title":"Applied pharmacokinetics: principles of therapeutic drug monitoring","author":"Everens WE","year":"1986"}],"container-title":["Arthritis &amp; Rheumatism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fart.27434","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.27434","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T13:43:17Z","timestamp":1698759797000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/art.27434"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,5,28]]},"references-count":28,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2010,6]]}},"alternative-id":["10.1002\/art.27434"],"URL":"https:\/\/doi.org\/10.1002\/art.27434","archive":["Portico"],"relation":{},"ISSN":["0004-3591","1529-0131"],"issn-type":[{"value":"0004-3591","type":"print"},{"value":"1529-0131","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,5,28]]}}}