{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T01:32:39Z","timestamp":1791423159806,"version":"4.3.3"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2020,3,17]],"date-time":"2020-03-17T00:00:00Z","timestamp":1584403200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2020,3,17]],"date-time":"2020-03-17T00:00:00Z","timestamp":1584403200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pediatr Res"],"published-print":{"date-parts":[[2020,12]]},"DOI":"10.1038\/s41390-020-0843-4","type":"journal-article","created":{"date-parts":[[2020,3,17]],"date-time":"2020-03-17T09:03:45Z","timestamp":1584435825000},"page":"934-939","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Comparison of serum biomarkers for the diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis during tocilizumab therapy"],"prefix":"10.1038","volume":"88","author":[{"given":"Hitoshi","family":"Irabu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Shimizu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuya","family":"Kaneko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natsumi","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mao","family":"Mizuta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuo","family":"Nakagishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Yachie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,3,17]]},"reference":[{"key":"843_CR1","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1038\/nrrheum.2011.68","volume":"7","author":"ED Mellins","year":"2011","unstructured":"Mellins, E. D., Macaubas, C. & Grom, A. A. Pathogenesis of systemic juvenile idiopathic arthritis: some answers, more questions. Nat. Rev. Rheumatol. 7, 416\u2013426 (2011).","journal-title":"Nat. Rev. Rheumatol."},{"key":"843_CR2","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/gene.2012.3","volume":"13","author":"A Ravelli","year":"2012","unstructured":"Ravelli, A., Grom, A. A., Behrens, E. M. & Cron, R. Q. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun. 13, 289\u2013298 (2012).","journal-title":"Genes Immun."},{"key":"843_CR3","first-page":"1133","volume":"34","author":"EM Behrens","year":"2007","unstructured":"Behrens, E. M. et al. Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis. J. Rheumatol. 34, 1133\u20131138 (2007).","journal-title":"J. Rheumatol."},{"key":"843_CR4","doi-asserted-by":"publisher","first-page":"R1281","DOI":"10.1186\/ar1826","volume":"7","author":"P Woo","year":"2005","unstructured":"Woo, P. et al. Open label phase II trial of single, ascending doses of MRA in Caucasian children with severe systemic juvenile idiopathic arthritis: proof of principle of the efficacy of IL-6 receptor blockade in this type of arthritis and demonstration of prolonged clinical improvement. Arthritis Res. Ther. 7, R1281\u2013R1288 (2005).","journal-title":"Arthritis Res. Ther."},{"key":"843_CR5","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1002\/art.20944","volume":"52","author":"S Yokota","year":"2005","unstructured":"Yokota, S. et al. Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 52, 818\u2013825 (2005).","journal-title":"Arthritis Rheum."},{"key":"843_CR6","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1016\/S0140-6736(08)60454-7","volume":"371","author":"S Yokota","year":"2008","unstructured":"Yokota, S. et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 371, 998\u20131006 (2008).","journal-title":"Lancet"},{"key":"843_CR7","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.cyto.2012.02.006","volume":"58","author":"M Shimizu","year":"2012","unstructured":"Shimizu, M. et al. Tocilizumab masks the clinical symptoms of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome: the diagnostic significance of interleukin-18 and interleukin-6. Cytokine 58, 287\u2013294 (2012).","journal-title":"Cytokine"},{"key":"843_CR8","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1002\/acr.23277","volume":"70","author":"GS Schulert","year":"2018","unstructured":"Schulert, G. S. et al. Effect of biologic therapy on clinical and laboratory features of macrophage activation syndrome associated with systemic juvenile idiopathic arthritis. Arthritis Care Res. 70, 409\u2013419 (2018).","journal-title":"Arthritis Care Res."},{"key":"843_CR9","first-page":"390","volume":"31","author":"RE Petty","year":"2001","unstructured":"Petty, R. E. et al. International league of associations for rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton. J. Rheumatol. 31, 390\u2013392 (2001).","journal-title":"J. Rheumatol."},{"key":"843_CR10","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1002\/art.39332","volume":"2016","author":"A Ravelli","year":"2016","unstructured":"Ravelli, A. et al. classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European League Against Rheumatism\/American College of Rheumatology\/Paediatric Rheumatology International Trials Organisation collaborative initiative. Arthritis Rheumatol. 2016, 566\u2013576 (2016).","journal-title":"Arthritis Rheumatol."},{"key":"843_CR11","doi-asserted-by":"publisher","first-page":"2396","DOI":"10.1056\/NEJMoa1205099","volume":"367","author":"N Ruperto","year":"2012","unstructured":"Ruperto, N. et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N. Engl. J. Med. 367, 2396\u20132406 (2012).","journal-title":"N. Engl. J. Med."},{"key":"843_CR12","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.1002\/art.1780340912","volume":"34","author":"F de Benedetti","year":"1991","unstructured":"de Benedetti, F. et al. Correlation of interleukin-6 levels with joint involvement and thrombocytosis in patients with systemic juvenile rheumatoid arthritis. Arthritis Rheum. 34, 1158\u20131163 (1991).","journal-title":"Arthritis Rheum."},{"key":"843_CR13","doi-asserted-by":"publisher","first-page":"2385","DOI":"10.1056\/NEJMoa1112802","volume":"367","author":"F De Benedetti","year":"2012","unstructured":"De Benedetti, F. et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N. Engl. J. Med. 367, 2385\u20132395 (2012).","journal-title":"N. Engl. J. Med."},{"key":"843_CR14","doi-asserted-by":"publisher","first-page":"712","DOI":"10.3899\/jrheum.140288","volume":"42","author":"S Yokota","year":"2015","unstructured":"Yokota, S. et al. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis under treatment with tocilizumab. J. Rheumatol. 42, 712\u2013722 (2015).","journal-title":"J. Rheumatol."},{"key":"843_CR15","doi-asserted-by":"publisher","first-page":"1654","DOI":"10.1136\/annrheumdis-2015-207818","volume":"75","author":"S Yokota","year":"2016","unstructured":"Yokota, S. et al. Tocilizumab in systemic juvenile idiopathic arthritis in a real-world clinical setting: results from 1 year of postmarketing surveillance follow-up of 417 patients in Japan. Ann. Rheum. Dis. 75, 1654\u20131660 (2016).","journal-title":"Ann. Rheum. Dis."},{"key":"843_CR16","doi-asserted-by":"publisher","first-page":"2918","DOI":"10.1182\/blood.V78.11.2918.2918","volume":"78","author":"JI Henter","year":"1991","unstructured":"Henter, J. I. et al. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood 78, 2918\u20132922 (1991).","journal-title":"Blood"},{"key":"843_CR17","doi-asserted-by":"publisher","first-page":"4100","DOI":"10.1182\/blood.V89.11.4100","volume":"89","author":"Y Osugi","year":"1997","unstructured":"Osugi, Y. et al. Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis. Blood 89, 4100\u20134103 (1997).","journal-title":"Blood"},{"key":"843_CR18","doi-asserted-by":"publisher","first-page":"984","DOI":"10.1016\/j.jpeds.2011.11.046","volume":"160","author":"XJ Xu","year":"2012","unstructured":"Xu, X. J. et al. Diagnostic accuracy of a specific cytokine pattern in hemophagocytic lymphohistiocytosis in children. J. Pediatr. 160, 984\u2013990 (2012).","journal-title":"J. Pediatr."},{"key":"843_CR19","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1136\/annrheumdis-2015-209020","volume":"76","author":"C Bracaglia","year":"2017","unstructured":"Bracaglia, C. et al. Elevated circulating levels of interferon-\u03b3 and interferon-\u03b3-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Ann. Rheum. Dis. 76, 166\u2013172 (2017).","journal-title":"Ann. Rheum. Dis."},{"key":"843_CR20","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1093\/rheumatology\/keu524","volume":"54","author":"K Put","year":"2015","unstructured":"Put, K. et al. Inflammatory gene expression profile and defective interferon-\u03b3 and granzyme K in natural killer cells from systemic juvenile idiopathic arthritis patients. Rheumatology 54, 1507\u20131517 (2015).","journal-title":"Rheumatology"},{"key":"843_CR21","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.cyto.2019.03.018","volume":"119","author":"M Mizuta","year":"2019","unstructured":"Mizuta, M. et al. Clinical significance of serum CXCL9 levels as a biomarker for systemic juvenile idiopathic arthritis associated macrophage activation syndrome. Cytokine 119, 182\u2013187 (2019).","journal-title":"Cytokine"},{"key":"843_CR22","doi-asserted-by":"publisher","first-page":"108252","DOI":"10.1016\/j.clim.2019.108252","volume":"208","author":"M Takakura","year":"2019","unstructured":"Takakura, M. et al. Comparison of serum biomarkers for the diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Clin. Immunol. 208, 108252 (2019).","journal-title":"Clin. Immunol."},{"key":"843_CR23","first-page":"69","volume":"10","author":"I Engelberts","year":"1991","unstructured":"Engelberts, I. et al. Evaluation of measurement of human TNF in plasma by ELISA. Lymphokine Cytokine Res. 10, 69\u201376 (1991).","journal-title":"Lymphokine Cytokine Res."},{"key":"843_CR24","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1093\/infdis\/169.2.420","volume":"169","author":"P Aukrust","year":"1994","unstructured":"Aukrust, P. et al. Serum levels of tumor necrosis factor-a (TNF-a) and soluble TNF receptors in human immunodeficiency virus type I infection. Correlations to clinical immunologic, and virologic parameters. J. Infect. Dis. 169, 420\u2013424 (1994).","journal-title":"J. Infect. Dis."},{"key":"843_CR25","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/0165-2478(94)90138-4","volume":"41","author":"R Zangerle","year":"1994","unstructured":"Zangerle, R. et al. Tumor necrosis factor alpha and soluble tumor necrosis factor receptors in individuals with human immunodeficiency virus infection. Immunol. Lett. 41, 229\u2013234 (1994).","journal-title":"Immunol. Lett."},{"key":"843_CR26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1600-0609.1995.tb01618.x","volume":"54","author":"A Diez-Ruiz","year":"1995","unstructured":"Diez-Ruiz, A. et al. Soluble receptors for tumour necrosis factor in clinical laboratory diagnosis. Eur. J. Haematol. 54, 1\u20138 (1995).","journal-title":"Eur. J. Haematol."},{"key":"843_CR27","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1111\/cei.13026","volume":"191","author":"M Shimizu","year":"2018","unstructured":"Shimizu, M., Inoue, N., Mizuta, M., Nakagishi, Y. & Yachie, A. Characteristic elevation of soluble TNF receptor II: I ratio in macrophage activation syndrome with systemic juvenile idiopathic arthritis. Clin. Exp. Immunol. 191, 349\u2013355 (2018).","journal-title":"Clin. Exp. Immunol."},{"key":"843_CR28","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/j.clim.2015.06.005","volume":"160","author":"M Shimizu","year":"2015","unstructured":"Shimizu, M. et al. Interleukin-18 for predicting the development of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Clin. Immunol. 160, 277\u2013281 (2015).","journal-title":"Clin. Immunol."}],"container-title":["Pediatric Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/s41390-020-0843-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41390-020-0843-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41390-020-0843-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,20]],"date-time":"2023-05-20T21:30:34Z","timestamp":1684618234000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41390-020-0843-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,17]]},"references-count":28,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["843"],"URL":"https:\/\/doi.org\/10.1038\/s41390-020-0843-4","relation":{},"ISSN":["0031-3998","1530-0447"],"issn-type":[{"value":"0031-3998","type":"print"},{"value":"1530-0447","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,17]]},"assertion":[{"value":"8 November 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 January 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 February 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 March 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Informed consent was obtained from all participants.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Patient consent"}}]}}