rspНаучно-практическая ревматологияRheumatology Science and Practice1995-44841995-4492IMA-PRESS, LLC10.14412/1995-4484-2018-35-40rsp-2688Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL RESEARCHПрименение канакинумаба при болезни Стилла взрослыхTherapy with canakinumab for adult-onset still's diseaseНасоновЕ. Л.NasonovE. L.

115522 Москва, Каширское шоссе, 34А;

кафедра ревматологии Института профессионального образования, 119991 Москва, ул. Трубецкая, 8, стр. 2

34A, Kashirskoe Shosse, Moscow 115522;

Department of Rheumatology, Institute of Professional Education, 8, Trubetskaya St., Build. 2, Moscow 119991

nasonov@irramn.ruФГБНУ «Научно-исследовательский институт ревматологии им. В.А. Насоновой» ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет)РоссияV.A. Nasonova Research Institute of Rheumatology; I.M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of RussiaRussian Federation201803042019560приложение 43540Copyright © Насонов Е.Л., 20192019Насонов Е.Л.Nasonov E.L.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://rsp.mediar-press.net/rsp/article/view/2688

Болезнь Стилла у детей (системный ювенильный идиопатический артрит – ЮИА) и у взрослых (болезнь Стилла взрослых – БСВ) рассматриваются как несемейные системные аутовоспалительные заболевания неизвестной этиологии, в основе которых лежат сходные иммунопатогенетические механизмы. В основе патогенеза БСВ лежат генетически-детерминированные нарушения механизмов врожденного иммунитета, а молекулярную основу иммунопатогенеза составляют NLRP3-инфламмасома-зависимые механизмы воспаления, характеризующиеся гиперпродукцией «провоспалительных» цитокинов – интерлейкина 1 (ИЛ1) и ИЛ18. Препаратами «первой линии» лечения БСВ являются нестероидные противовоспалительные препараты, глюкокортикоиды, метотрексат и другие базисные противовоспалительные препараты, а при их недостаточной эффективности – генно-инженерные биологические препараты. Представлен обзор данных литературы, касающийся применения моноклональных антител к ИЛ1β при БСВ, свидетельствующих о хороших перспективах применения канакинумаба при этом заболевании, не только при резистентности к стандартной терапии, но и в качестве терапии «первого ряда» в дебюте болезни.

Still's disease in children (systemic-onset juvenile idiopathic arthritis, SoJIA) and in adults (adult-onset Still's disease) are considered as non-familial systemic autoinflammatory diseases of unknown etiology driven by similar immunopathogenetic mechanisms. The adult-onset Still's disease pathogenesis is based on genetically determined innate immunity disturbances and molecular basis of immunopathogenesis consists of NLRP3 inflammasomedependent mechanisms of inflammation characterized by hyperproduction of proinflammatory cytokines interleukin (IL) 1 and IL18. Nonsteroidal anti-inflammatory drugs, glucocorticoids, methotrexate and other disease modifying drugs are considered as «first line» medications for the treatment of adult-onset Still's disease and if they fail biologicals are recommended. A review of the literature data concerning anti-IL1 monoclonal antibodies administration in adult-onset Still's disease is presented, indicating good prospects for the use of canakinumab not only in case of resistance to standard therapy, but also as a «first-line» therapy in the onset of the disease.

болезнь Стилла взрослыхинтерлейкин 1канакинумабadult-onset Still's diseaseinterleukin 1canakinumabReferencesStill GF. On a form of chronic joint disease in children. Med Chir Trans. 1897;80:47-60. doi: 10.1177/095952879708000106Still GF. On a form of chronic joint disease in children. Med Chir Trans. 1897;80:47-60. doi: 10.1177/095952879708000106Bywaters EG. Still's disease in the adult. Ann Rheum Dis. 1971;30:121-33. doi: 10.1136/ard.30.2.121Bywaters EG. Still's disease in the adult. Ann Rheum Dis. 1971;30:121-33. doi: 10.1136/ard.30.2.121McGonagle D, McDermott MF. A proposed classification of the immunological diseases. PLOS Med. 2006;3:e297. doi: 10.1371/journal.pmed.0030297McGonagle D, McDermott MF. A proposed classification of the immunological diseases. PLOS Med. 2006;3:e297. doi: 10.1371/journal.pmed.0030297Peckham D, Scambler T, Savic S, McDermott MF. The burgeoning field of innate immune-mediated disease and autoinflammation. J Pathol. 2017;241:123-39. doi: 10.1002/path.4812Peckham D, Scambler T, Savic S, McDermott MF. The burgeoning field of innate immune-mediated disease and autoinflammation. J Pathol. 2017;241:123-39. doi: 10.1002/path.4812Nirmala N, Brachat A, Feist E, et al. Gene-expression analysis of adult-onset Still's disease and systemic juvenile idiopathic arthritis is consistent with a continuum of a single disease entity. Pediatr Rheumatol Online J. 2015;13:50. doi: 10.1186/s12969-015-0047-3Nirmala N, Brachat A, Feist E, et al. Gene-expression analysis of adult-onset Still's disease and systemic juvenile idiopathic arthritis is consistent with a continuum of a single disease entity. Pediatr Rheumatol Online J. 2015;13:50. doi: 10.1186/s12969-015-0047-3Efthimiou P, Moorthy LN, Mavragani CP, et al. Adult Onset Still's Disease and Autoinflammation. Int J Inflam. 2012;2012:964751. doi: 10.1155/2012/9647Efthimiou P, Moorthy LN, Mavragani CP, et al. Adult Onset Still's Disease and Autoinflammation. Int J Inflam. 2012;2012:964751. doi: 10.1155/2012/9647Feist E, Mitrovic S, Fautrel B. Mechanisms, biomarkers and targets for adult-onset Still's disease. Nat Rev Rheumatol. 2018;14(10):603-18. doi: 10.1038/s41584-018-0081-xFeist E, Mitrovic S, Fautrel B. Mechanisms, biomarkers and targets for adult-onset Still's disease. Nat Rev Rheumatol. 2018;14(10):603-18. doi: 10.1038/s41584-018-0081-xFautrel B. Adult-onset Still disease. Best Pract Res Clin Rheumatol. 2008;22:773-92. doi: 10.1016/j.berh.2008.08.006Fautrel B. Adult-onset Still disease. Best Pract Res Clin Rheumatol. 2008;22:773-92. doi: 10.1016/j.berh.2008.08.006Муравьев ЮВ, Насонов ЕЛ. Болезнь Стилла, развившаяся у взрослых. Научно-практическая ревматология. 2011;49(2):58-65. doi: 10.14412/1995-4484-2011-604Murav'ev YuV, Nasonov EL. Adult-onset Still's disease. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2011;49(2):58-65 (In Russ.). doi: 10.14412/1995-4484-2011-604Gerfaud-Valentin M, Jamilloux Y, Iwaz J, Seve P. Adult-onset Still’s disease. Autoimmun Rev. 2014;13:708-22. doi: 10.1016/j.autrev.2014.01.058Gerfaud-Valentin M, Jamilloux Y, Iwaz J, Seve P. Adult-onset Still’s disease. Autoimmun Rev. 2014;13:708-22. doi: 10.1016/j.autrev.2014.01.058Giacomelli R, Ruscitti P, Shoenfeld Y. A comprehensive review on adult onset Still's disease. J Autoimmun. 2018 Sep;93:24-36. doi: 10.1016/j.jaut.2018.07.0Giacomelli R, Ruscitti P, Shoenfeld Y. A comprehensive review on adult onset Still's disease. J Autoimmun. 2018 Sep;93:24-36. doi: 10.1016/j.jaut.2018.07.0Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol. 1992;19:424-30.Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol. 1992;19:424-30.Fautrel B, Zing E, Golmard JL, et al. Proposal for a new set of classification criteria for adult-onset Still disease. Medicine. 2002;81:194-200. doi: 10.1097/00005792-200205000-00003Fautrel B, Zing E, Golmard JL, et al. Proposal for a new set of classification criteria for adult-onset Still disease. Medicine. 2002;81:194-200. doi: 10.1097/00005792-200205000-00003Lebrun D, Mestrallet S, Dehoux M, et al. Validation of the Fautrel classification criteria for adult-onset Still's disease. Semin Arthritis Rheum. 2018;47:578-85. doi: 10.1016/j.semarthrit.2017.07.005Lebrun D, Mestrallet S, Dehoux M, et al. Validation of the Fautrel classification criteria for adult-onset Still's disease. Semin Arthritis Rheum. 2018;47:578-85. doi: 10.1016/j.semarthrit.2017.07.005Mitrovic S, Fautrel B. New markers for adult-onset Still's disease. Joint Bone Spine. 2018;85:285-93. doi: 10.1016/j.jbspin.2017.05.011Mitrovic S, Fautrel B. New markers for adult-onset Still's disease. Joint Bone Spine. 2018;85:285-93. doi: 10.1016/j.jbspin.2017.05.011Mavragani CP, Spyridakis EG, Koutsilieris M. Adult-Onset Still's Disease: From Pathophysiology to Targeted Therapies. Int J Inflam. 2012;2012:879020. doi: 10.1155/2012/879020Mavragani CP, Spyridakis EG, Koutsilieris M. Adult-Onset Still's Disease: From Pathophysiology to Targeted Therapies. Int J Inflam. 2012;2012:879020. doi: 10.1155/2012/879020Maria AT, Le Quellec A, Jorgensen C, et al. Adult onset Still's disease (AOSD) in the era of biologic therapies: dichotomous view for cytokine and clinical expressions. Autoimmun Rev. 2014;13:1149-59. doi: 10.1016/j.autrev.2014.08.032Maria AT, Le Quellec A, Jorgensen C, et al. Adult onset Still's disease (AOSD) in the era of biologic therapies: dichotomous view for cytokine and clinical expressions. Autoimmun Rev. 2014;13:1149-59. doi: 10.1016/j.autrev.2014.08.032Govoni M, Bortoluzzi A, Rossi D, Modena V. How I treat patients with adult onset Still's disease in clinical practice. Autoimmun Rev. 2017 Oct;16(10):1016-23. doi: 10.1016/j.autrev.2017.07.017Govoni M, Bortoluzzi A, Rossi D, Modena V. How I treat patients with adult onset Still's disease in clinical practice. Autoimmun Rev. 2017 Oct;16(10):1016-23. doi: 10.1016/j.autrev.2017.07.017Mimura T, Kondo Y, Ohta A, et al. Evidence-based clinical practice guideline for adult Still's disease. Mod Rheumatol. 2018;28(5):736-57. doi: 10.1080/14397595.2018Mimura T, Kondo Y, Ohta A, et al. Evidence-based clinical practice guideline for adult Still's disease. Mod Rheumatol. 2018;28(5):736-57. doi: 10.1080/14397595.2018Ruscitti P, Giacomelli R. Pathogenesis of adult onset still's disease: current understanding and new insights. Expert Rev Clin Immunol. 2018;14(11):965-76. doi: 10.1080/1744666X.2018.15Ruscitti P, Giacomelli R. Pathogenesis of adult onset still's disease: current understanding and new insights. Expert Rev Clin Immunol. 2018;14(11):965-76. doi: 10.1080/1744666X.2018.15Girard C, Rech J, Brown M, et al. Elevated serum levels of free interleukin-18 in adult-onset Still's disease. Rheumatology (Oxford). 2016;55(12):2237-47. doi: 10.1093/rheumatology/kew300Girard C, Rech J, Brown M, et al. Elevated serum levels of free interleukin-18 in adult-onset Still's disease. Rheumatology (Oxford). 2016;55(12):2237-47. doi: 10.1093/rheumatology/kew300Inoue N, Shimizu M, Tsunoda S, et al. Cytokine profile in adultonset Still's disease: Comparison with systemic juvenile idiopathic arthritis. Clin Immunol. 2016;169:8-13. doi: 10.1016/j.clim.2016.05.010Inoue N, Shimizu M, Tsunoda S, et al. Cytokine profile in adultonset Still's disease: Comparison with systemic juvenile idiopathic arthritis. Clin Immunol. 2016;169:8-13. doi: 10.1016/j.clim.2016.05.010Ichida H, Kawaguchi Y, Sugiura T, et al. Clinical manifestations of Adult-onset Still's disease presenting with erosive arthritis: Association with low levels of ferritin and Interleukin-18. Arthritis Care Res (Hoboken). 2014;66(4):642-6. doi: 10.1002/acr.22194Ichida H, Kawaguchi Y, Sugiura T, et al. Clinical manifestations of Adult-onset Still's disease presenting with erosive arthritis: Association with low levels of ferritin and Interleukin-18. Arthritis Care Res (Hoboken). 2014;66(4):642-6. doi: 10.1002/acr.22194Zhou S, Qiao J, Bai J, et al. Biological therapy of traditional therapy-resistant adult-onset Still's disease: an evidence-based review. Ther Clin Risk Manag. 2018;14:167-71. doi: 10.2147/TCRM.S15Zhou S, Qiao J, Bai J, et al. Biological therapy of traditional therapy-resistant adult-onset Still's disease: an evidence-based review. Ther Clin Risk Manag. 2018;14:167-71. doi: 10.2147/TCRM.S15Ruscitti P, Ursini F, Cipriani P, et al. Biologic drugs in adult onset Still's disease: a systematic review and meta-analysis of observational studies. Expert Rev Clin Immunol. 2017;13(11):1089-97. doi: 10.1080/1744666X.2017.1375853Ruscitti P, Ursini F, Cipriani P, et al. Biologic drugs in adult onset Still's disease: a systematic review and meta-analysis of observational studies. Expert Rev Clin Immunol. 2017;13(11):1089-97. doi: 10.1080/1744666X.2017.1375853Gerfaud-Valentin M, Maucort-Boulch D, Hot A, et al. Adultonset Still disease: manifestations, treatments, outcome, and prognostic factors in 57 patients. Medicine. 2014;93:91-9. doi: 10.1097/MD.0000000000000021Gerfaud-Valentin M, Maucort-Boulch D, Hot A, et al. Adultonset Still disease: manifestations, treatments, outcome, and prognostic factors in 57 patients. Medicine. 2014;93:91-9. doi: 10.1097/MD.0000000000000021Vitale A, Insalaco A, Sfriso P, et al. A snapshot on the on-label and off-label use of the interleukin-1 inhibitors in Italy among rheumatologists and pediatric rheumatologists: a nationwide multi-center retrospective observational study. Front Pharmacol. 2016;7:380. doi: 10.3389/fphar.2016.00380Vitale A, Insalaco A, Sfriso P, et al. A snapshot on the on-label and off-label use of the interleukin-1 inhibitors in Italy among rheumatologists and pediatric rheumatologists: a nationwide multi-center retrospective observational study. Front Pharmacol. 2016;7:380. doi: 10.3389/fphar.2016.00380Cipriani P, Ruscitti P, Carubbi F, et al. Tocilizumab for the treatment of adult-onset Still's disease: results from a case series. Clin Rheumatol. 2014;33:49-55. doi: 10.1007/s10067-013-2381-5Cipriani P, Ruscitti P, Carubbi F, et al. Tocilizumab for the treatment of adult-onset Still's disease: results from a case series. Clin Rheumatol. 2014;33:49-55. doi: 10.1007/s10067-013-2381-5Ma Y, Wu M, Zhang X, et al. Efficacy and safety of tocilizumab with inhibition of interleukin-6 in adult-onset Still's disease: A meta-analysis. Mod Rheumatol. 2018;28(5):849-57. doi: 10.1080/14397595.2017.1416924Ma Y, Wu M, Zhang X, et al. Efficacy and safety of tocilizumab with inhibition of interleukin-6 in adult-onset Still's disease: A meta-analysis. Mod Rheumatol. 2018;28(5):849-57. doi: 10.1080/14397595.2017.1416924Kaneko Y, Kameda H, Ikeda K, et al. Tocilizumab in patients with adult-onset Still's disease refractory to glucocorticoid treatment: A randomised, double-blind, placebo-controlled phase III trial. Ann Rheum Dis. 2018 Oct 2. pii: annrheumdis-2018-213920. doi: 10.1136/annrheumdis-2018-213Kaneko Y, Kameda H, Ikeda K, et al. Tocilizumab in patients with adult-onset Still's disease refractory to glucocorticoid treatment: A randomised, double-blind, placebo-controlled phase III trial. Ann Rheum Dis. 2018 Oct 2. pii: annrheumdis-2018-213920. doi: 10.1136/annrheumdis-2018-213Pouchot J, Sampalis JS, Beaudet F, et al. Adult Still's disease: manifestations, disease course, and outcome in 62 patients. Medicine (Baltimore). 1991;70:118-36. doi: 10.1097/00005792-199103000-00004Pouchot J, Sampalis JS, Beaudet F, et al. Adult Still's disease: manifestations, disease course, and outcome in 62 patients. Medicine (Baltimore). 1991;70:118-36. doi: 10.1097/00005792-199103000-00004Ruscitti P, Cipriani P, Masedu F, et al. Adult onset Still's disease: evaluation of prognostic tools and validation of the systemic score, by analysis of 100 cases from three centers. BMC Med. 2016;14:194. doi: 10.1186/s12916-016-0738-8Ruscitti P, Cipriani P, Masedu F, et al. Adult onset Still's disease: evaluation of prognostic tools and validation of the systemic score, by analysis of 100 cases from three centers. BMC Med. 2016;14:194. doi: 10.1186/s12916-016-0738-8Ruperto N, Quartier P, Wulffraat N, et al. A phase II, multicenter, open-label study evaluating dosing and preliminary safety and efficacy of canakinumab in systemic juvenile idiopathic arthritis with active systemic features. Arthritis Rheum. 2012;64:557-67. doi: 10.1002/art.33342Ruperto N, Quartier P, Wulffraat N, et al. A phase II, multicenter, open-label study evaluating dosing and preliminary safety and efficacy of canakinumab in systemic juvenile idiopathic arthritis with active systemic features. Arthritis Rheum. 2012;64:557-67. doi: 10.1002/art.33342Ruperto N, Brunner HI, Quartier P, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367:2396-406. doi:10.1056/NEJMoa1205099Ruperto N, Brunner HI, Quartier P, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367:2396-406. doi:10.1056/NEJMoa1205099Ruperto N, Brunner HI, Quartier P, et al. Canakinumab in patients with systemic juvenile idiopathic arthritis and active systemic features: results from the 5-year long-term extension of the phase III pivotal trials. Ann Rheum Dis. 2018 Sep 29. pii: annrheumdis-2018- 213150. doi: 10.1136/annrheumdis-2018-213150Ruperto N, Brunner HI, Quartier P, et al. Canakinumab in patients with systemic juvenile idiopathic arthritis and active systemic features: results from the 5-year long-term extension of the phase III pivotal trials. Ann Rheum Dis. 2018 Sep 29. pii: annrheumdis-2018- 213150. doi: 10.1136/annrheumdis-2018-213150Brunner HI, Ruperto N, Quartier P, et al. Efficacy and Safety of Canakinumab in Children with Systemic Juvenile Idiopathic Arthritis: Results from the Phase 3 Extension Study [abstract]. Arthritis Rheum. 2015;67 Suppl 10:Abstract Number: 2422.Brunner HI, Ruperto N, Quartier P, et al. Efficacy and Safety of Canakinumab in Children with Systemic Juvenile Idiopathic Arthritis: Results from the Phase 3 Extension Study [abstract]. Arthritis Rheum. 2015;67 Suppl 10:Abstract Number: 2422.Grom AA, Ilowite NT, Pascual V, et al. Paediatric Rheumatology International Trials Organisation and the Pediatric Rheumatology Collaborative Study Group. Rate and Clinical Presentation of Macrophage Activation Syndrome in Patients With Systemic Juvenile Idiopathic Arthritis Treated With Canakinumab. Arthritis Rheum. 2016;68(1):218-28. doi: 10.1002/art.39407Grom AA, Ilowite NT, Pascual V, et al. Paediatric Rheumatology International Trials Organisation and the Pediatric Rheumatology Collaborative Study Group. Rate and Clinical Presentation of Macrophage Activation Syndrome in Patients With Systemic Juvenile Idiopathic Arthritis Treated With Canakinumab. Arthritis Rheum. 2016;68(1):218-28. doi: 10.1002/art.39407Brunner HI, Ruperto N, Quartier P, et al. Efficacy and Safety of Canakinumab in Patients with Systemic Juvenile Idiopathic Arthritis: Results from an Open-Label Long-Term Follow-up Study. Arthritis Rheum. 2016;68 Suppl 10. Number: 2374.Brunner HI, Ruperto N, Quartier P, et al. Efficacy and Safety of Canakinumab in Patients with Systemic Juvenile Idiopathic Arthritis: Results from an Open-Label Long-Term Follow-up Study. Arthritis Rheum. 2016;68 Suppl 10. Number: 2374.Brunner HI, Ruperto N, Quartier P, et al. Long-Term Efficacy and Safety of Canakinumab in Patients with Active Systemic Juvenile Idiopathic Arthritis (SJIA): Results from a PHASE III Extension Study. Arthritis Rheum. 2016;68 Suppl 10. Abstract Number: 3007.Brunner HI, Ruperto N, Quartier P, et al. Long-Term Efficacy and Safety of Canakinumab in Patients with Active Systemic Juvenile Idiopathic Arthritis (SJIA): Results from a PHASE III Extension Study. Arthritis Rheum. 2016;68 Suppl 10. Abstract Number: 3007.Ruperto N, Brunner HI, Quartier P, et al.Treating To Target with Canakinumab in Patients with Active Systemic Juvenile Idiopathic Arthritis: Results from The Long-Term Extension The Phase III Pivotal Trial. Ann Rheum Dis. 2016;75:401-2. doi: 10.1136/annrheumdis-2016-eular.2658Ruperto N, Brunner HI, Quartier P, et al.Treating To Target with Canakinumab in Patients with Active Systemic Juvenile Idiopathic Arthritis: Results from The Long-Term Extension The Phase III Pivotal Trial. Ann Rheum Dis. 2016;75:401-2. doi: 10.1136/annrheumdis-2016-eular.2658Ruperto N, Brunner HI, Quartier P, et al, on behalf of PRINTO/PRCSG. Long-Term Efficacy and Safety of Canakinumab in Patients with Systemic Juvenile Idiopathic Arthritis (SJIA): 5-Year Follow-up of An Open-Label Trial. Ann Rheum Dis. 2016;75:265-6. doi: 10.1136/annrheumdis-2016- eular.3835Ruperto N, Brunner HI, Quartier P, et al, on behalf of PRINTO/PRCSG. Long-Term Efficacy and Safety of Canakinumab in Patients with Systemic Juvenile Idiopathic Arthritis (SJIA): 5-Year Follow-up of An Open-Label Trial. Ann Rheum Dis. 2016;75:265-6. doi: 10.1136/annrheumdis-2016- eular.3835Horneff G, Peitz J, Kekow J, Foell D. Canakinumab for first line steroid-free treatment in a child with systemic-onset juvenile idiopathic arthritis. Scand J Rheumatol. 2017;46(6):500-1. doi: 10.1080/03009742.2017.1288827Horneff G, Peitz J, Kekow J, Foell D. Canakinumab for first line steroid-free treatment in a child with systemic-onset juvenile idiopathic arthritis. Scand J Rheumatol. 2017;46(6):500-1. doi: 10.1080/03009742.2017.1288827Orrock JE, Ilowite NT. Canakinumab for the treatment of active systemic juvenile idiopathic arthritis. Expert Rev Clin Pharmacol. 2016;9(8):1015-24. doi: 10.1080/17512433.2016.1204910Orrock JE, Ilowite NT. Canakinumab for the treatment of active systemic juvenile idiopathic arthritis. Expert Rev Clin Pharmacol. 2016;9(8):1015-24. doi: 10.1080/17512433.2016.1204910Sun H, Van LM, Floch D, et al. Pharmacokinetics and pharmacodynamics of canakinumab in patients with systemic juvenile idiopathic arthritis. J Clin Pharmacol. 2016;56:1516-27. doi: 10.1002/jcph.754Sun H, Van LM, Floch D, et al. Pharmacokinetics and pharmacodynamics of canakinumab in patients with systemic juvenile idiopathic arthritis. J Clin Pharmacol. 2016;56:1516-27. doi: 10.1002/jcph.754Kontzias A, Efthimiou P. The use of Canakinumab, a novel IL-1beta long-acting inhibitor, in refractory adult-onset Still's disease. Semin Arthritis Rheum. 2012;42:201-5. doi: 10.1016/j.semarthrit.2012.03.004Kontzias A, Efthimiou P. The use of Canakinumab, a novel IL-1beta long-acting inhibitor, in refractory adult-onset Still's disease. Semin Arthritis Rheum. 2012;42:201-5. doi: 10.1016/j.semarthrit.2012.03.004Banse C, Vittecoq O, Benhamou Y, et al. Reactive macrophage activation syndrome possibly triggered by canakinumab in a patient with adult-onset Still's disease. Joint Bone Spine. 2013;80:653-5. doi: 10.1016/j.jbspin.2013.04.011Banse C, Vittecoq O, Benhamou Y, et al. Reactive macrophage activation syndrome possibly triggered by canakinumab in a patient with adult-onset Still's disease. Joint Bone Spine. 2013;80:653-5. doi: 10.1016/j.jbspin.2013.04.011Eriksson P, Jacobs C, Soderkvist P. A patient with a phenotype of adult-onset Still disease, but a genotype typical of cryopyrin-associated periodic fever syndrome. J Rheumatol. 2013;40:1632-3. doi: 10.3899/jrheum.130325Eriksson P, Jacobs C, Soderkvist P. A patient with a phenotype of adult-onset Still disease, but a genotype typical of cryopyrin-associated periodic fever syndrome. J Rheumatol. 2013;40:1632-3. doi: 10.3899/jrheum.130325Barsotti S, Neri R, Iacopetti V, et al.. Successful treatment of refractory adult-onset Still disease with canakinumab: A case report. J Clin Rheumatol. 2014;20:121. doi: 10.1097/rhu.00000000000000Barsotti S, Neri R, Iacopetti V, et al.. Successful treatment of refractory adult-onset Still disease with canakinumab: A case report. J Clin Rheumatol. 2014;20:121. doi: 10.1097/rhu.00000000000000Lo Gullo A, Caruso A, Pipitone N, et al. Canakinumab in a case of adult onset Still's disease: efficacy only on systemic manifestations. Joint Bone Spine. 2014;81:376-7. doi: 10.1016/j.jbspin.2013.12.011Lo Gullo A, Caruso A, Pipitone N, et al. Canakinumab in a case of adult onset Still's disease: efficacy only on systemic manifestations. Joint Bone Spine. 2014;81:376-7. doi: 10.1016/j.jbspin.2013.12.011Rossi-Semerano L, Fautrel B, Wendling D, et al. Tolerance and efficacy of off-label anti-interleukin-1 treatments in France: A nationwide survey. Orphanet J Rare Dis. 2015;10:19.Rossi-Semerano L, Fautrel B, Wendling D, et al. Tolerance and efficacy of off-label anti-interleukin-1 treatments in France: A nationwide survey. Orphanet J Rare Dis. 2015;10:19.Colafrancesco S, Priori R, Valesini G, et al. Response to interleukin-1 inhibitors in 140 Italian patients with adult-onset Still's disease: A multicentre retrospective observational study. Front Pharmacol. 2017;8:369. doi: 10.3389/fphar.2017.00369Colafrancesco S, Priori R, Valesini G, et al. Response to interleukin-1 inhibitors in 140 Italian patients with adult-onset Still's disease: A multicentre retrospective observational study. Front Pharmacol. 2017;8:369. doi: 10.3389/fphar.2017.00369Feist E, Quartier P, Fautrel B, et al. Efficacy and safety of canakinumab in patients with Still's disease: exposure-response analysis of pooled systemic juvenile idiopathic arthritis data by age groups. Clin Exp Rheumatol. 2018;36:668-75.Feist E, Quartier P, Fautrel B, et al. Efficacy and safety of canakinumab in patients with Still's disease: exposure-response analysis of pooled systemic juvenile idiopathic arthritis data by age groups. Clin Exp Rheumatol. 2018;36:668-75.Feist E, Quartier P, Fautrel B, et al. Efficacy and safety of canakinumab in patients with Still's disease: a pooled analysis of sjia data by age groups. Ann Rheum Dis. 2018;76(Suppl 2):395-6. doi: 10.1136/annrheumdis-2017-eular.1979Feist E, Quartier P, Fautrel B, et al. Efficacy and safety of canakinumab in patients with Still's disease: a pooled analysis of sjia data by age groups. Ann Rheum Dis. 2018;76(Suppl 2):395-6. doi: 10.1136/annrheumdis-2017-eular.1979Sinha A, Patti R, Ambesh P, et al. Severe pulmonary hypertension due to adult-onset Still's disease. J Investig Med High Impact Case Rep. 2018;6:2324709618757260. doi: 10.1177/2324709618757260Sinha A, Patti R, Ambesh P, et al. Severe pulmonary hypertension due to adult-onset Still's disease. J Investig Med High Impact Case Rep. 2018;6:2324709618757260. doi: 10.1177/2324709618757260Ugurlu S, Guzelant G, Yurttas B, et al. Canakinumab treatment in adult-onset Still's disease: case series. Ann Rheum Dis. 2018;76(Suppl 2):514. doi: 10.1136/annrheumdis-2018-eular.7187Ugurlu S, Guzelant G, Yurttas B, et al. Canakinumab treatment in adult-onset Still's disease: case series. Ann Rheum Dis. 2018;76(Suppl 2):514. doi: 10.1136/annrheumdis-2018-eular.7187Athanassiou P, Basdragianni D, Tzanavari A, et al. Adult Still's disease: successful treatment with canakinumab. Osteoporos Int. 2014;25:S424.Athanassiou P, Basdragianni D, Tzanavari A, et al. Adult Still's disease: successful treatment with canakinumab. Osteoporos Int. 2014;25:S424.Galozzi P, Baggio C, Bindoli S, et al. Development and Role in Therapy of Canakinumab in Adult-Onset Still's Disease. Front Pharmacol. 2018 Sep 21;9:1074. doi: 10.3389/fphar.2018.01074Galozzi P, Baggio C, Bindoli S, et al. Development and Role in Therapy of Canakinumab in Adult-Onset Still's Disease. Front Pharmacol. 2018 Sep 21;9:1074. doi: 10.3389/fphar.2018.01074Junge G, Mason J, Feist E. Adult onset Still's disease-The evidence that anti-interleukin-1 treatment is effective and well-tolerated (a comprehensive literature review). Semin Arthritis Rheum. 2017;47(2):295-302. doi: 10.1016/j.semarthrit.2017.06.006Junge G, Mason J, Feist E. Adult onset Still's disease-The evidence that anti-interleukin-1 treatment is effective and well-tolerated (a comprehensive literature review). Semin Arthritis Rheum. 2017;47(2):295-302. doi: 10.1016/j.semarthrit.2017.06.006Brachat AH, Grom AA, Wulffraat N, et al. Pediatric Rheumatology International Trials Organization (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG). Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy. Arthritis Res Ther. 2017;19(1):13. doi: 10.1186/s13075-016-1212Brachat AH, Grom AA, Wulffraat N, et al. Pediatric Rheumatology International Trials Organization (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG). Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy. Arthritis Res Ther. 2017;19(1):13. doi: 10.1186/s13075-016-1212Colafrancesco S, Priori R, Valesini G, et al. Response to Interleukin-1 Inhibitors in 140 Italian Patients with Adult-Onset Still's Disease: A Multicentre Retrospective Observational Study. Front Pharmacol. 2017 Jun 13;8:369. doi: 10.3389/fphar.2017.00369Colafrancesco S, Priori R, Valesini G, et al. Response to Interleukin-1 Inhibitors in 140 Italian Patients with Adult-Onset Still's Disease: A Multicentre Retrospective Observational Study. Front Pharmacol. 2017 Jun 13;8:369. doi: 10.3389/fphar.2017.00369Hong D, Yang Z, Han S, et al. Interleukin 1 inhibition with anakinra in adult-onset Still disease: A meta-analysis of its efficacy and safety. Drug Des Devel Ther. 2014;8:2345-57. doi: 10.2147/DDDT.S73428Hong D, Yang Z, Han S, et al. Interleukin 1 inhibition with anakinra in adult-onset Still disease: A meta-analysis of its efficacy and safety. Drug Des Devel Ther. 2014;8:2345-57. doi: 10.2147/DDDT.S73428

The authors declare that there are no conflicts of interest present.