{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T19:52:43Z","timestamp":1761162763542,"version":"build-2065373602"},"reference-count":48,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2017,6,22]],"date-time":"2017-06-22T00:00:00Z","timestamp":1498089600000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100006260","name":"Rheumatology Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006260","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010400","name":"Children's Mercy Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010400","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["T32\u2010HD069038"],"award-info":[{"award-number":["T32\u2010HD069038"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accpjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacotherapy"],"published-print":{"date-parts":[[2017,6]]},"abstract":"\n Study Objective<\/jats:title>\n \n To evaluate the relationship between plasma cytokine levels with disease activity and therapeutic response in patients with juvenile idiopathic arthritis (JIA) after initiating methotrexate (\n MTX<\/jats:styled-content>\n ) therapy.\n <\/jats:p>\n <\/jats:sec>\n \n Design<\/jats:title>\n Single\u2010center observational prospective cohort study.<\/jats:p>\n <\/jats:sec>\n \n Setting<\/jats:title>\n Outpatient pediatric rheumatology clinic at a tertiary care academic pediatric hospital.<\/jats:p>\n <\/jats:sec>\n \n Patients<\/jats:title>\n \n The study included 61 patients diagnosed with JIA who started therapy with standard\u2010dose\n MTX<\/jats:styled-content>\n 15\u00a0mg\/m\n 2<\/jats:sup>\n \/week. At 3\u00a0months, treating physicians were given the option of maintaining the\n MTX<\/jats:styled-content>\n dose, increasing the\n MTX<\/jats:styled-content>\n dose, or adding etanercept (ETN), based on their clinical judgment.\n <\/jats:p>\n <\/jats:sec>\n \n Measurements and Main Results<\/jats:title>\n \n Patients were evaluated at baseline, 3\u00a0months (51 patients), and 6\u00a0months (35 patients). Plasma samples from each visit were analyzed for interleukin (\n IL<\/jats:styled-content>\n )\u20101\u03b1,\n IL<\/jats:styled-content>\n \u20101\u03b2,\n IL<\/jats:styled-content>\n \u20101Ra,\n IL<\/jats:styled-content>\n \u20106, and tumor necrosis factor\u2010\u03b1 (\n TNF<\/jats:styled-content>\n \u2010\u03b1). Cytokine concentrations were evaluated for relationships with disease activity using the 71\u2010joint count Juvenile Arthritis Disease Activity Score (\n JADAS<\/jats:styled-content>\n ). Therapeutic response was assessed by changes in\n JADAS<\/jats:styled-content>\n . Failure to respond to standard\u2010dose\n MTX<\/jats:styled-content>\n was defined as the need for the addition of ETN or a\n MTX<\/jats:styled-content>\n dose increase at or before the 3\u2010month visit. Increased disease severity at baseline was associated with increased\n IL<\/jats:styled-content>\n \u20106 (p=0.01) and\n TNF<\/jats:styled-content>\n \u2010\u03b1 (p=0.008) levels. Initiation of\n MTX<\/jats:styled-content>\n was associated with reductions in\n IL<\/jats:styled-content>\n \u20101\u03b1 (p=0.009),\n IL<\/jats:styled-content>\n \u20101\u03b2 (p=0.01),\n IL<\/jats:styled-content>\n \u20101Ra (p=0.007), and\n IL<\/jats:styled-content>\n \u20106 (p=0.03) levels; however, reductions in\n JADAS<\/jats:styled-content>\n were only associated with reductions in\n IL<\/jats:styled-content>\n \u20106 (p=0.009) and\n TNF<\/jats:styled-content>\n \u2010\u03b1 levels (p=0.02). Compared with responders, patients failing to respond to standard\u2010dose\n MTX<\/jats:styled-content>\n had increased\n TNF<\/jats:styled-content>\n \u2010\u03b1 levels at baseline (p=0.02) and at 3\u00a0months (p=0.005). Reductions in\n JADAS<\/jats:styled-content>\n by 6\u00a0months were observed following either the addition of ETN (p=0.009) or an increase in\n MTX<\/jats:styled-content>\n dose (p=0.007), but the addition of ETN was associated with a median 7\u2010fold increase in\n TNF<\/jats:styled-content>\n \u2010\u03b1 levels (p=0.003) that corresponded with clinical response.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Plasma cytokine levels were responsive to\n MTX<\/jats:styled-content>\n therapy in patients with JIA, but only\n TNF<\/jats:styled-content>\n \u2010\u03b1 and\n IL<\/jats:styled-content>\n \u20106 levels were consistently associated with disease activity and therapeutic response. Increased\n TNF<\/jats:styled-content>\n \u2010\u03b1 levels at baseline were associated with failure to respond to standard\u2010dose\n MTX<\/jats:styled-content>\n and the need for more aggressive drug therapy. Initiation of ETN resulted in increased\n TNF<\/jats:styled-content>\n \u2010\u03b1 levels that corresponded with therapeutic response, suggesting a potential clinical benefit of monitoring\n TNF<\/jats:styled-content>\n \u2010\u03b1 levels as a pharmacodynamic marker of etanercept activity.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/phar.1938","type":"journal-article","created":{"date-parts":[[2017,5,5]],"date-time":"2017-05-05T09:26:44Z","timestamp":1493976404000},"page":"700-711","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Cytokine Biomarkers of Disease Activity and Therapeutic Response after Initiating Methotrexate Therapy in Patients with Juvenile Idiopathic Arthritis"],"prefix":"10.1002","volume":"37","author":[{"given":"Ryan S.","family":"Funk","sequence":"first","affiliation":[{"name":"Department of Pharmacy Practice University of Kansas Medical Center Kansas City Kansas"},{"name":"Division of Clinical Pharmacology and Therapeutic Innovation Children's Mercy Kansas City Kansas City Missouri"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcia A.","family":"Chan","sequence":"additional","affiliation":[{"name":"Division of Allergy, Asthma and Immunology Children's Mercy Kansas City Kansas City Missouri"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mara L.","family":"Becker","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology and Therapeutic Innovation Children's Mercy Kansas City Kansas City Missouri"},{"name":"Division of Rheumatology Children's Mercy Kansas City Kansas City Missouri"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,6,22]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.23177"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.20460"},{"key":"e_1_2_7_4_1","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1002\/art.24087","article-title":"Time to treatment as an important factor for the response to methotrexate in juvenile idiopathic arthritis","volume":"1","author":"Albers HM","year":"2009","journal-title":"Arthritis Rheum"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.131503"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/ket490"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2011.293"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199204163261602"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.22087"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.20288"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/23808993.2016.1133234"},{"key":"e_1_2_7_12_1","article-title":"Treatment of juvenile idiopathic arthritis: a revolution in care","volume":"13","author":"Stoll ML","year":"2014","journal-title":"Pediatr Rheumatol Online J"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780391013"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01451007"},{"key":"e_1_2_7_15_1","first-page":"1481","article-title":"Proinflammatory cytokines in monitoring the course of disease and effectiveness of treatment with etanercept (ETN) of children with oligo\u2010 and polyarticular juvenile idiopathic arthritis (JIA)","volume":"9","author":"Kaminiarczyk\u2010Pyzalka D","year":"2014","journal-title":"Clin Lab"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.55.4.243"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780340912"},{"key":"e_1_2_7_18_1","first-page":"493","article-title":"Serum interleukin\u20106 levels and joint involvement in polyarticular and pauciarticular juvenile chronic arthritis","volume":"5","author":"Benedetti F","year":"1992","journal-title":"Clin Exp Rheumatol"},{"key":"e_1_2_7_19_1","first-page":"561","article-title":"Study of IL\u20102, IL\u20106, TNF alpha, IFN gamma and beta in the serum and synovial fluid of patients with juvenile chronic arthritis","volume":"5","author":"Lepore L","year":"1994","journal-title":"Clin Exp Rheumatol"},{"key":"e_1_2_7_20_1","first-page":"2359","article-title":"Cytokine levels in serum and synovial fluid of patients with juvenile rheumatoid arthritis","volume":"12","author":"Madson KL","year":"1994","journal-title":"J Rheumatol"},{"key":"e_1_2_7_21_1","first-page":"779","article-title":"Circulating levels of interleukin 1 beta and of interleukin 1 receptor antagonist in systemic juvenile chronic arthritis","volume":"6","author":"Benedetti F","year":"1995","journal-title":"Clin Exp Rheumatol"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/34.5.454"},{"key":"e_1_2_7_23_1","first-page":"1403","article-title":"Differences in synovial fluid cytokine levels between juvenile and adult rheumatoid arthritis","volume":"7","author":"Benedetti F","year":"1997","journal-title":"J Rheumatol"},{"key":"e_1_2_7_24_1","first-page":"1349","article-title":"Elevated concentrations of monocyte derived cytokines in synovial fluid of children with enthesitis related arthritis and polyarticular types of juvenile idiopathic arthritis","volume":"7","author":"Saxena N","year":"2005","journal-title":"J Rheumatol"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s100670200012"},{"key":"e_1_2_7_26_1","first-page":"30","article-title":"Cytokine levels in serum of patients with juvenile rheumatoid arthritis","volume":"1","author":"Yilmaz M","year":"2001","journal-title":"Clin Rheumatol"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2006.061853"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2014.224"},{"key":"e_1_2_7_29_1","first-page":"390","article-title":"International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001","volume":"2","author":"Petty RE","year":"2004","journal-title":"J Rheumatol"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.24516"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/ket470"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12969-016-0085-5"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/cei.12782"},{"key":"e_1_2_7_34_1","first-page":"253","article-title":"Relation of interleukin\u20106, TNF\u2010alpha and interleukin\u20101alpha with disease activity and severity in juvenile idiopathic arthritis patients","volume":"3","author":"Spirchez M","year":"2012","journal-title":"Clin Lab"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.34659"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1080\/03009740601089234"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pedneo.2015.09.010"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2014-000036"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38296"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/pr.2013.187"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.20944"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20050473"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2014-205351"},{"key":"e_1_2_7_44_1","first-page":"14","article-title":"Etanercept increases tumor necrosis factor\u2010alpha level but not sFas level in patients with rheumatoid arthritis","volume":"1","author":"Kotyla P","year":"2015","journal-title":"Isr Med Assoc J"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2008.07.002"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar3140"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/apa.13319"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/ket152"},{"key":"e_1_2_7_49_1","article-title":"MRP8\/14 serum levels as a predictor of response to starting and stopping anti\u2010TNF treatment in juvenile idiopathic arthritis","volume":"200","author":"Anink J","year":"2015","journal-title":"Arthritis Res Ther"}],"container-title":["Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fphar.1938","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accpjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/phar.1938","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T17:06:24Z","timestamp":1761066384000},"score":1,"resource":{"primary":{"URL":"https:\/\/accpjournals.onlinelibrary.wiley.com\/doi\/10.1002\/phar.1938"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6]]},"references-count":48,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2017,6]]}},"alternative-id":["10.1002\/phar.1938"],"URL":"https:\/\/doi.org\/10.1002\/phar.1938","archive":["Portico"],"relation":{},"ISSN":["0277-0008","1875-9114"],"issn-type":[{"type":"print","value":"0277-0008"},{"type":"electronic","value":"1875-9114"}],"subject":[],"published":{"date-parts":[[2017,6]]},"assertion":[{"value":"2017-06-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}