{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T17:57:37Z","timestamp":1793901457871,"version":"4.8.0"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,1,5]],"date-time":"2024-01-05T00:00:00Z","timestamp":1704412800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,1,5]],"date-time":"2024-01-05T00:00:00Z","timestamp":1704412800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82070027"],"award-info":[{"award-number":["82070027"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pediatr Rheumatol"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Mevalonate kinase deficiency (MKD) and TNF receptor-associated periodic syndrome (TRAPS) are categorized as systemic autoinflammatory diseases (SAIDs), which are rare diseases characterized by early onset, severe conditions, and challenging diagnosis and treatment. Although different SAIDs have varying standard treatments, some SAIDs are poorly controlled after routine treatment, seriously affecting the growth and development of children and their quality of life. This study aims to provide more treatment strategies for SAIDs.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Case presentation<\/jats:title>\n                <jats:p>We present two Chinese patients with MKD and TRAPS who were resistant to TNF- (tumor necrosis factor-) \u03b1 blockade. After using etanercept, baricitinib, and glucocorticoid, patients with MKD and TRAPS still had periodic fever and rash. Due to the unavailability of IL-1 antagonists in the Chinese Mainland, we started administering intravenous tocilizumab (TCZ) at a dosage of 240\u00a0mg every three weeks. They had not experienced fever or rash after receiving one or two doses of TCZ. Before treatment with TCZ in the MKD patient, white blood cell (WBC) count, and TNF-\u03b1 level were normal, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) increased significantly, and IL-6 increased slightly. After treatment with TCZ, ESR and CRP levels returned to normal; however, IL-6 increased occasionally. In the TRAPS patient, ESR, CRP, WBC, IL-6, and TNF-\u03b1 levels were increased significantly. After TCZ treatment, ESR, CRP, WBC, IL-6, and TNF-\u03b1 levels returned to normal. The two patients were treated with TCZ for more than six months and achieved clinical and serological remission. Furthermore, they had no adverse reactions after injection of TCZ.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>In the absence of IL-1 antagonists in mainland China, tocilizumab emerges as an alternative drug in SAIDs that are resistant to TNF-\u03b1 blockade.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12969-023-00952-2","type":"journal-article","created":{"date-parts":[[2024,1,5]],"date-time":"2024-01-05T12:02:35Z","timestamp":1704456155000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Tocilizumab for treating mevalonate kinase deficiency and TNF receptor-associated periodic syndrome: a case series and literature review"],"prefix":"10.1186","volume":"22","author":[{"given":"Yandie","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4930-9493","authenticated-orcid":false,"given":"Meiping","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,5]]},"reference":[{"issue":"1","key":"952_CR1","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.iac.2018.08.004","volume":"39","author":"L Broderick","year":"2019","unstructured":"Broderick L. Hereditary Autoinflammatory disorders: Recognition and Treatment. Immunol Allergy Clin North Am. 2019;39(1):13\u201329.","journal-title":"Immunol Allergy Clin North Am"},{"issue":"1","key":"952_CR2","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/S0092-8674(00)80721-7","volume":"97","author":"MF McDermott","year":"1999","unstructured":"McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, et al. Germline mutations in the extracellular domains of the 55\u00a0kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 1999;97(1):133\u201344.","journal-title":"Cell"},{"key":"952_CR3","doi-asserted-by":"crossref","unstructured":"Moghaddas F. Monogenic autoinflammatory disorders: beyond the periodic fever. Intern Med J 2019.","DOI":"10.1111\/imj.14414"},{"issue":"8","key":"952_CR4","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1038\/ni.3487","volume":"17","author":"MK Akula","year":"2016","unstructured":"Akula MK, Shi M, Jiang Z, Foster CE, Miao D, Li AS, et al. Control of the innate immune response by the mevalonate pathway. Nat Immunol. 2016;17(8):922\u20139.","journal-title":"Nat Immunol"},{"issue":"4","key":"952_CR5","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1038\/sj.ejhg.5200614","volume":"9","author":"L Cuisset","year":"2001","unstructured":"Cuisset L, Drenth JP, Simon A, Vincent MF, van der Velde VS, van der Meer JW, et al. Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome. Eur J Hum Genet. 2001;9(4):260\u20136.","journal-title":"Eur J Hum Genet"},{"key":"952_CR6","doi-asserted-by":"crossref","unstructured":"van der Hilst JCH, Bodar EJ, Barron KS, Frenkel J, Drenth JPH, van der Meer JWM et al. Long-Term Follow-Up, Clinical Features, and Quality of Life in a Series of 103 Patients With Hyperimmunoglobulinemia D Syndrome. Medicine.2008;87(6):301\u2013\u200910.","DOI":"10.1097\/MD.0b013e318190cfb7"},{"key":"952_CR7","first-page":"3514645","volume":"2018","author":"NK Rafiq","year":"2018","unstructured":"Rafiq NK, Lachmann H, Joensen F, Herlin T, Brogan PA. Tocilizumab for the Treatment of Mevalonate Kinase Deficiency. Case Rep Pediatr. 2018;2018:3514645.","journal-title":"Case Rep Pediatr"},{"key":"952_CR8","doi-asserted-by":"crossref","unstructured":"Musters A, Tak PP, Baeten DL, Tas SW. Anti-interleukin 6 receptor therapy for hyper-IgD syndrome. BMJ Case Rep.2015;2015.","DOI":"10.1136\/bcr-2015-210513"},{"issue":"2","key":"952_CR9","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1097\/01.RHU.0000442576.41537.de","volume":"20","author":"HM Shendi","year":"2014","unstructured":"Shendi HM, Devlin LA, Edgar JD. Interleukin 6 blockade for hyperimmunoglobulin D and periodic fever syndrome. J Clin Rheumatol. 2014;20(2):103\u20135.","journal-title":"J Clin Rheumatol"},{"issue":"2","key":"952_CR10","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1093\/rheumatology\/keu341","volume":"54","author":"M Stoffels","year":"2015","unstructured":"Stoffels M, Jongekrijg J, Remijn T, Kok N, van der Meer JW, Simon A. TLR2\/TLR4-dependent exaggerated cytokine production in hyperimmunoglobulinaemia D and periodic fever syndrome. Rheumatology (Oxford). 2015;54(2):363\u20138.","journal-title":"Rheumatology (Oxford)"},{"issue":"6 Suppl 94","key":"952_CR11","first-page":"46","volume":"33","author":"T Lane","year":"2015","unstructured":"Lane T, Gillmore JD, Wechalekar AD, Hawkins PN, Lachmann HJ. Therapeutic blockade of interleukin-6 by tocilizumab in the management of AA amyloidosis and chronic inflammatory disorders: a case series and review of the literature. Clin Exp Rheumatol. 2015;33(6 Suppl 94):46\u201353.","journal-title":"Clin Exp Rheumatol"},{"issue":"6","key":"952_CR12","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.1016\/j.semarthrit.2020.03.005","volume":"50","author":"F Rodrigues","year":"2020","unstructured":"Rodrigues F, Philit J, Giurgea I, Anglicheau D, Roux J, Hoyeau N, et al. AA amyloidosis revealing mevalonate kinase deficiency: a report of 20 cases including two new French cases and a comprehensive review of literature. Semin Arthritis Rheum. 2020;50(6):1370\u20133.","journal-title":"Semin Arthritis Rheum"},{"issue":"4","key":"952_CR13","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1002\/art.37827","volume":"65","author":"T Lane","year":"2013","unstructured":"Lane T, Loeffler JM, Rowczenio DM, Gilbertson JA, Bybee A, Russell TL, et al. AA amyloidosis complicating the hereditary periodic fever syndromes. Arthritis Rheum. 2013;65(4):1116\u201321.","journal-title":"Arthritis Rheum"},{"issue":"11","key":"952_CR14","doi-asserted-by":"publisher","first-page":"2795","DOI":"10.1002\/art.39763","volume":"68","author":"NM ter Haar","year":"2016","unstructured":"ter Haar NM, Jeyaratnam J, Lachmann HJ, Simon A, Brogan PA, Doglio M, et al. The phenotype and genotype of mevalonate kinase Deficiency: a series of 114 cases from the Eurofever Registry. Arthritis & Rheumatology. 2016;68(11):2795\u2013805.","journal-title":"Arthritis & Rheumatology"},{"issue":"3","key":"952_CR15","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1084\/jem.20102049","volume":"208","author":"AC Bulua","year":"2011","unstructured":"Bulua AC, Simon A, Maddipati R, Pelletier M, Park H, Kim KY, et al. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med. 2011;208(3):519\u201333.","journal-title":"J Exp Med"},{"issue":"12","key":"952_CR16","doi-asserted-by":"publisher","first-page":"2160","DOI":"10.1136\/annrheumdis-2013-204184","volume":"73","author":"HJ Lachmann","year":"2014","unstructured":"Lachmann HJ, Papa R, Gerhold K, Obici L, Touitou I, Cantarini L, et al. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever\/EUROTRAPS international registry. Ann Rheum Dis. 2014;73(12):2160\u20137.","journal-title":"Ann Rheum Dis"},{"issue":"3","key":"952_CR17","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1080\/1744666X.2019.1571410","volume":"15","author":"J Sanchez-Manubens","year":"2019","unstructured":"Sanchez-Manubens J, Iglesias E, Anton J. Canakinumab for the treatment of hyperimmunoglobulin D syndrome. Expert Rev Clin Immunol. 2019;15(3):215\u201320.","journal-title":"Expert Rev Clin Immunol"},{"key":"952_CR18","doi-asserted-by":"crossref","unstructured":"Bettiol A, Lopalco G, Emmi G, Cantarini L, Urban ML, Vitale A et al. Unveiling the efficacy, Safety, and Tolerability of Anti-interleukin-1 Treatment in Monogenic and Multifactorial Autoinflammatory diseases. Int J Mol Sci2019;20(8).","DOI":"10.3390\/ijms20081898"},{"issue":"3 Suppl 77","key":"952_CR19","first-page":"99","volume":"31","author":"G Horneff","year":"2013","unstructured":"Horneff G, Rhouma A, Weber C, Lohse P. Macrophage activation syndrome as the initial manifestation of tumour necrosis factor receptor 1-associated periodic syndrome (TRAPS). Clin Exp Rheumatol. 2013;31(3 Suppl 77):99\u2013102.","journal-title":"Clin Exp Rheumatol"},{"key":"952_CR20","doi-asserted-by":"crossref","unstructured":"Nishimoto N, Kishimoto T. Humanized antihuman IL-6 receptor antibody, tocilizumab. Handb Exp Pharmacol.2008(181):151\u201360.","DOI":"10.1007\/978-3-540-73259-4_7"},{"issue":"4","key":"952_CR21","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1080\/25785826.2018.1524105","volume":"41","author":"T Koga","year":"2018","unstructured":"Koga T, Kawakami A. Diagnosis and treatment of autoinflammatory diseases in adults: a clinical approach from rheumatologists. Immunol Med. 2018;41(4):177\u201380.","journal-title":"Immunol Med"},{"issue":"2","key":"952_CR22","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1586\/ecp.13.1","volume":"6","author":"X Zhang","year":"2013","unstructured":"Zhang X, Morcos PN, Saito T, Terao K. Clinical pharmacology of tocilizumab for the treatment of systemic juvenile idiopathic arthritis. Expert Rev Clin Pharmacol. 2013;6(2):123\u201337.","journal-title":"Expert Rev Clin Pharmacol"},{"issue":"4","key":"952_CR23","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1002\/art.30215","volume":"63","author":"PM Vaitla","year":"2011","unstructured":"Vaitla PM, Radford PM, Tighe PJ, Powell RJ, McDermott EM, Todd I, et al. Role of interleukin-6 in a patient with tumor necrosis factor receptor-associated periodic syndrome: assessment of outcomes following treatment with the anti-interleukin-6 receptor monoclonal antibody tocilizumab. Arthritis Rheum. 2011;63(4):1151\u20135.","journal-title":"Arthritis Rheum"},{"issue":"1","key":"952_CR24","doi-asserted-by":"publisher","first-page":"35","DOI":"10.5152\/eurjrheumatol.2014.14053","volume":"2","author":"N Akasbi","year":"2015","unstructured":"Akasbi N, Soyfoo MS. Successful treatment of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) with tocilizumab: a case report. Eur J Rheumatol. 2015;2(1):35\u20136.","journal-title":"Eur J Rheumatol"},{"issue":"16","key":"952_CR25","doi-asserted-by":"publisher","first-page":"2069","DOI":"10.2169\/internalmedicine.54.3371","volume":"54","author":"T Hosoya","year":"2015","unstructured":"Hosoya T, Mizoguchi F, Hasegawa H, Miura K, Koike R, Kubota T, et al. A case presenting with the clinical characteristics of Tumor Necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) without TNFRSF1A mutations successfully treated with Tocilizumab. Intern Med. 2015;54(16):2069\u201372.","journal-title":"Intern Med"},{"issue":"11","key":"952_CR26","doi-asserted-by":"publisher","first-page":"1943","DOI":"10.1007\/s00296-015-3305-2","volume":"35","author":"F La Torre","year":"2015","unstructured":"La Torre F, Muratore M, Vitale A, Moramarco F, Quarta L, Cantarini L. Canakinumab efficacy and long-term tocilizumab administration in tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Rheumatol Int. 2015;35(11):1943\u20137.","journal-title":"Rheumatol Int"},{"issue":"12","key":"952_CR27","doi-asserted-by":"publisher","first-page":"3586","DOI":"10.1182\/blood.V85.12.3586.bloodjournal85123586","volume":"85","author":"JP Drenth","year":"1995","unstructured":"Drenth JP, van Deuren M, van der Ven-Jongekrijg J, Schalkwijk CG, van der Meer JW. Cytokine activation during attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Blood. 1995;85(12):3586\u201393.","journal-title":"Blood"},{"issue":"2","key":"952_CR28","doi-asserted-by":"publisher","first-page":"e1227","DOI":"10.1136\/rmdopen-2020-001227","volume":"6","author":"JB Kuemmerle-Deschner","year":"2020","unstructured":"Kuemmerle-Deschner JB, Gautam R, George AT, Raza S, Lomax KG, Hur P. Systematic literature review of efficacy\/effectiveness and safety of current therapies for the treatment of cryopyrin-associated periodic syndrome, hyperimmunoglobulin D syndrome and tumour necrosis factor receptor-associated periodic syndrome. RMD Open. 2020;6(2):e1227.","journal-title":"RMD Open"},{"issue":"7","key":"952_CR29","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1136\/annrheumdis-2021-221801","volume":"81","author":"M Romano","year":"2022","unstructured":"Romano M, Arici ZS, Piskin D, Alehashemi S, Aletaha D, Barron KS, et al. The 2021 EULAR\/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist. Ann Rheum Dis. 2022;81(7):907\u201321.","journal-title":"Ann Rheum Dis"},{"issue":"21","key":"952_CR30","doi-asserted-by":"publisher","first-page":"9801","DOI":"10.1073\/pnas.0914118107","volume":"107","author":"A Simon","year":"2010","unstructured":"Simon A, Park H, Maddipati R, Lobito AA, Bulua AC, Jackson AJ, et al. Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome. Proc Natl Acad Sci U S A. 2010;107(21):9801\u20136.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"12","key":"952_CR31","doi-asserted-by":"publisher","first-page":"2035","DOI":"10.1136\/annrheumdis-2011-201197","volume":"71","author":"LJ Dickie","year":"2012","unstructured":"Dickie LJ, Aziz AM, Savic S, Lucherini OM, Cantarini L, Geiler J, et al. Involvement of X-box binding protein 1 and reactive oxygen species pathways in the pathogenesis of tumour necrosis factor receptor-associated periodic syndrome. Ann Rheum Dis. 2012;71(12):2035\u201343.","journal-title":"Ann Rheum Dis"},{"issue":"8","key":"952_CR32","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1038\/ni.1748","volume":"10","author":"K Chen","year":"2009","unstructured":"Chen K, Xu W, Wilson M, He B, Miller NW, Bengten E, et al. Immunoglobulin D enhances immune surveillance by activating antimicrobial, proinflammatory and b cell-stimulating programs in basophils. Nat Immunol. 2009;10(8):889\u201398.","journal-title":"Nat Immunol"},{"key":"952_CR33","doi-asserted-by":"publisher","first-page":"152089","DOI":"10.1016\/j.semarthrit.2022.152089","volume":"57","author":"J Sota","year":"2022","unstructured":"Sota J, Vitale A, Lopalco G, Pereira R, Giordano HF, Antonelli I, et al. Efficacy and safety of tocilizumab in adult-onset still\u2019s disease: real-life experience from the international AIDA registry. Semin Arthritis Rheum. 2022;57:152089.","journal-title":"Semin Arthritis Rheum"},{"issue":"3","key":"952_CR34","doi-asserted-by":"publisher","first-page":"e13936","DOI":"10.1111\/ijcp.13936","volume":"75","author":"S Kir","year":"2021","unstructured":"Kir S, Ozgen M, Zontul S. Adult-onset still\u2019s disease and treatment results with tocilizumab. Int J Clin Pract. 2021;75(3):e13936.","journal-title":"Int J Clin Pract"},{"issue":"5","key":"952_CR35","doi-asserted-by":"publisher","first-page":"R141","DOI":"10.1186\/ar3455","volume":"13","author":"MH Schiff","year":"2011","unstructured":"Schiff MH, Kremer JM, Jahreis A, Vernon E, Isaacs JD, van Vollenhoven RF. Integrated safety in tocilizumab clinical trials. Arthritis Res Ther. 2011;13(5):R141.","journal-title":"Arthritis Res Ther"}],"container-title":["Pediatric Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12969-023-00952-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12969-023-00952-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12969-023-00952-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,5]],"date-time":"2024-01-05T12:04:45Z","timestamp":1704456285000},"score":1,"resource":{"primary":{"URL":"https:\/\/ped-rheum.biomedcentral.com\/articles\/10.1186\/s12969-023-00952-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,5]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["952"],"URL":"https:\/\/doi.org\/10.1186\/s12969-023-00952-2","relation":{},"ISSN":["1546-0096"],"issn-type":[{"value":"1546-0096","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,5]]},"assertion":[{"value":"19 December 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 December 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 January 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":"This study was approved by the Ethical Committee, Children\u2019s Hospital, Zhejiang University School of Medicine (2020-IRB-028). Written consent was obtained from the parents of patients for participating their children in this report of the patients.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written consent was obtained from the parents of patients for publishing this report.","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":"11"}}