{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T17:38:57Z","timestamp":1779903537452,"version":"3.53.1"},"reference-count":21,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T00:00:00Z","timestamp":1715040000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T00:00:00Z","timestamp":1715040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pediatr Rheumatol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Low-dose weekly methotrexate (MTX) is the mainstay of treatment in juvenile idiopathic arthritis. Unfortunately, a substantial part of patients has insufficient efficacy of MTX. A potential cause of this inadequate response is suboptimal drug adherence. The aim of this study was to assess MTX adherence in juvenile idiopathic arthritis patients by quantification of MTX concentrations in plasma. Secondly, the association between MTX concentrations and either self-reported adherence issues, or concomitant use of biologics was examined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This was a retrospective, observational study using plasma samples from juvenile idiopathic arthritis patients. An ultrasensitive liquid chromatography-tandem mass spectrometry method was developed for quantification of MTX and its metabolite 7-hydroxy-MTX in plasma. The determined MTX plasma concentrations in juvenile idiopathic arthritis patients were compared with corresponding adherence limits, categorising them as either adherent or possibly non-adherent to MTX therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Plasma samples of 43 patients with juvenile idiopathic arthritis were analysed. Adherence to MTX in this population was 88% shortly after initiation of MTX therapy and decreased to 77% after one year of treatment. Teenagers were more at risk for non-adherence (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.002). We could not find an association between MTX adherence with either self-reported adherence issues, nor with the use of concomitant biological treatment (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20091.00 and\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.27, respectively; Fisher\u2019s Exact).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Quantification of MTX in plasma is a feasible and objective method to assess adherence in patients using low-dose weekly MTX. In clinical practice, the use of this method could be a helpful tool for physicians to refute or support suspicion of non-adherence to MTX therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12969-024-00988-y","type":"journal-article","created":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T03:01:47Z","timestamp":1715050907000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Adherence to low-dose methotrexate in children with juvenile idiopathic arthritis using a sensitive methotrexate assay"],"prefix":"10.1186","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6496-937X","authenticated-orcid":false,"given":"Julia E.","family":"M\u00f6hlmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sytze","family":"de Roock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelies C.","family":"Egas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelien ter","family":"Weijden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martijn J. H.","family":"Doeleman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alwin D. R.","family":"Huitema","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthijs","family":"van Luin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost F.","family":"Swart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,7]]},"reference":[{"key":"988_CR1","doi-asserted-by":"crossref","unstructured":"Ferrara G, Mastrangelo G, Barone P, La Torre F, Martino S, Pappagallo G, et al. Methotrexate in juvenile idiopathic arthritis: advice and recommendations from the MARAJIA expert consensus meeting. Pediatric Rheumatology. BioMed Central Ltd. 16, 2018.","DOI":"10.1186\/s12969-018-0255-8"},{"issue":"9","key":"988_CR2","doi-asserted-by":"publisher","first-page":"1484","DOI":"10.1136\/annrheumdis-2011-200942","volume":"71","author":"M Bulatovi\u0107","year":"2012","unstructured":"Bulatovi\u0107 M, Heijstek MW, Van Dijkhuizen EHP, Wulffraat NM, Pluijm SMF, De Jonge R. Prediction of clinical non-response to methotrexate treatment in juvenile idiopathic arthritis. Ann Rheum Dis. 2012;71(9):1484\u20139.","journal-title":"Ann Rheum Dis"},{"issue":"1","key":"988_CR3","doi-asserted-by":"publisher","first-page":"e000171","DOI":"10.1136\/rmdopen-2015-000171","volume":"2","author":"HF Hope","year":"2016","unstructured":"Hope HF, Bluett J, Barton A, Hyrich KL, Cordingley L, Verstappen SMM. Psychological factors predict adherence to methotrexate in rheumatoid arthritis; findings from a systematic review of rates, predictors and associations with patient-reported and clinical outcomes. RMD Open. 2016;2(1):e000171.","journal-title":"RMD Open"},{"issue":"1","key":"988_CR4","doi-asserted-by":"publisher","first-page":"15","DOI":"10.11648\/j.ajcem.20170501.14","volume":"5","author":"M Humayun Kabir","year":"2017","unstructured":"Humayun Kabir M. Drug compliance in children with juvenile idiopathic arthritis and reasons for poor compliance. Am J Clin Experimental Med. 2017;5(1):15.","journal-title":"Am J Clin Experimental Med"},{"issue":"2","key":"988_CR5","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1007\/s00296-010-1774-x","volume":"32","author":"CF Pelajo","year":"2012","unstructured":"Pelajo CF, Sgarlat CM, Lopez-Benitez JM, Oliveira SKF, Rodrigues MCF, Sztajnbok FR, et al. Adherence to methotrexate in juvenile idiopathic arthritis. Rheumatol Int. 2012;32(2):497\u2013500.","journal-title":"Rheumatol Int"},{"key":"988_CR6","doi-asserted-by":"crossref","unstructured":"Filocamo G, Consolaro A, Schiappapietra B, Dalpr\u00e0 S, Lattanzi B, Magni-Manzoni S et al. A new approach to clinical care of juvenile idiopathic arthritis: the juvenile arthritis multidimensional assessment report. J Rheumatol. 2011.","DOI":"10.3899\/jrheum.100930"},{"issue":"5","key":"988_CR7","doi-asserted-by":"publisher","first-page":"690","DOI":"10.3899\/jrheum.171087","volume":"45","author":"LA Favier","year":"2018","unstructured":"Favier LA, Taylor J, Rich KL, Jones KB, Vora SS, Harris JG, et al. Barriers to adherence in juvenile idiopathic arthritis: a multicenter collaborative experience and preliminary results. J Rheumatol. 2018;45(5):690\u20136.","journal-title":"J Rheumatol"},{"key":"988_CR8","doi-asserted-by":"crossref","unstructured":"Bulatovi\u0107 M, Heijstek MW, Verkaaik M, Van Dijkhuizen EHP, Armbrust W, Hoppenreijs EPA et al. High prevalence of methotrexate intolerance in juvenile idiopathic arthritis: development and validation of a methotrexate intolerance severity score. Arthritis Rheum. 2011.","DOI":"10.1002\/art.30367"},{"issue":"6","key":"988_CR9","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1136\/ard.2006.067835","volume":"66","author":"N Costedoat-Chalumeau","year":"2007","unstructured":"Costedoat-Chalumeau N, Amoura Z, Hulot JS, Aymard G, Leroux G, Marra D, et al. Very low blood hydroxychloroquine concentration as an objective marker of poor adherence to treatment of systemic lupus erythematosus. Ann Rheum Dis. 2007;66(6):821\u20134.","journal-title":"Ann Rheum Dis"},{"issue":"5","key":"988_CR10","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1161\/HYPERTENSIONAHA.117.09631","volume":"70","author":"P Gupta","year":"2017","unstructured":"Gupta P, Patel P, \u0160trauch B, Lai FY, Akbarov A, Gulsin GS, et al. Biochemical screening for nonadherence is Associated with blood pressure reduction and improvement in adherence. Hypertension. 2017;70(5):1042\u20138.","journal-title":"Hypertension"},{"issue":"9","key":"988_CR11","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1136\/annrheumdis-2019-215446","volume":"78","author":"J Bluett","year":"2019","unstructured":"Bluett J, Riba-Garcia I, Verstappen SMM, Wendling T, Ogungbenro K, Unwin RD, et al. Development and validation of a methotrexate adherence assay. Ann Rheum Dis. 2019;78(9):1192\u20137.","journal-title":"Ann Rheum Dis"},{"issue":"3","key":"988_CR12","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1002\/mpo.2950220307","volume":"22","author":"KA Skoglund","year":"1994","unstructured":"Skoglund KA, S\u00f6derh\u00e4ll S, Beck O, Peterson C, Wennberg M, Hayder S, et al. Plasma and urine levels of methotrexate and 7-hydroxymethotrexate in children with all during maintenance therapy with weekly oral methotrexate. Med Pediatr Oncol. 1994;22(3):187\u201393.","journal-title":"Med Pediatr Oncol"},{"issue":"4","key":"988_CR13","doi-asserted-by":"publisher","first-page":"197","DOI":"10.5152\/eurjrheum.2022.21090","volume":"9","author":"R Bakry","year":"2022","unstructured":"Bakry R, Klein MA, Horneff G. Oral or parenteral methotrexate for the treatment of Polyarticular Juvenile Idiopathic Arthritis. Eur J Rheumatol. 2022;9(4):197\u2013205.","journal-title":"Eur J Rheumatol"},{"key":"988_CR14","doi-asserted-by":"crossref","unstructured":"Hawwa AF, AlBawab AQ, Rooney M, Wedderburn LR, Beresford MW, McElnay JC. Methotrexate polyglutamates as a potential marker of adherence to long-term therapy in children with juvenile idiopathic arthritis and juvenile dermatomyositis: an observational, cross-sectional study. Arthritis Res Ther. 2015;17(1).","DOI":"10.1186\/s13075-015-0814-z"},{"issue":"11","key":"988_CR15","doi-asserted-by":"publisher","first-page":"1843","DOI":"10.3109\/10428190903216812","volume":"50","author":"J Carlos Jaime-P\u00e9rez","year":"2009","unstructured":"Carlos Jaime-P\u00e9rez J, G\u00f3mez-Almaguer D, Sandoval-Gonz\u00e1lez A, Chapa-Rodr\u00edguez A, Gon\u00e1zlez-Llano O. Random serum methotrexate determinations for assessing compliance with maintenance therapy for childhood acute lymphoblastic leukemia. Leuk Lymphoma. 2009;50(11):1843\u20137.","journal-title":"Leuk Lymphoma"},{"issue":"10","key":"988_CR16","doi-asserted-by":"publisher","first-page":"3569","DOI":"10.1182\/blood.V92.10.3569","volume":"92","author":"FM Balis","year":"1998","unstructured":"Balis FM, Holcenberg JS, Poplack DG, Ge J, Sather HN, Murphy RF, et al. 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Arthritis Rheum. 1992;35(7):761\u20134.","journal-title":"Arthritis Rheum"},{"issue":"6","key":"988_CR19","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1002\/art.1780350603","volume":"35","author":"D Oguey","year":"1992","unstructured":"Oguey D, K\u00f6lliker F, Gerber NJ, Reichen J. Effect of food on the bioavailability of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 1992;35(6):611\u20134.","journal-title":"Arthritis Rheum"},{"issue":"4","key":"988_CR20","first-page":"630","volume":"22","author":"RA Hamilton","year":"1995","unstructured":"Hamilton RA, Kremer JM. The effects of food on methotrexate absorption. J Rheumatol. 1995;22(4):630\u20132.","journal-title":"J Rheumatol"},{"issue":"8201","key":"988_CR21","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1016\/S0140-6736(80)92105-4","volume":"2","author":"CR Pinkerton","year":"1980","unstructured":"Pinkerton CR, Welshman SG, Glasgow JF, Bridges JM. Can food influence the absorption of methotrexate in children with acute lymphoblastic leukaemia? Lancet. 1980;2(8201):944\u20136.","journal-title":"Lancet"}],"container-title":["Pediatric Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12969-024-00988-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12969-024-00988-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12969-024-00988-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T03:04:10Z","timestamp":1715051050000},"score":1,"resource":{"primary":{"URL":"https:\/\/ped-rheum.biomedcentral.com\/articles\/10.1186\/s12969-024-00988-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,7]]},"references-count":21,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["988"],"URL":"https:\/\/doi.org\/10.1186\/s12969-024-00988-y","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-4001976\/v1","asserted-by":"object"}]},"ISSN":["1546-0096"],"issn-type":[{"value":"1546-0096","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,7]]},"assertion":[{"value":"23 February 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 April 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 May 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"In compliance with ethical standards, patient materials were stored after written informed consent was acquired. Ethical approvals by the institutional Medical Ethics Committee of Utrecht were obtained under protocol numbers 11-499c and 14\u2013684.","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":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"52"}}