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Special Review: IL-6 inhibitor

Interleukin-6 in juvenile idiopathic arthritis

Pages 275-286 | Received 12 Nov 2018, Accepted 24 Jan 2019, Published online: 08 Mar 2019

References

  • Petty RE, Laxer RM, Wedderburn LR. Juvenile Idiopathic Arthritis. Textb Pediatr Rheumatol. 7th ed. Philadelphia, PA: Elsevier; 2016. p. 188–204.
  • Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16(5):448–57.
  • Rose-John S, Scheller J, Elson G, Jones SA. Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol. 2006;80(2):227–36.
  • Chalaris A, Rabe B, Paliga K, Lange H, Laskay T, Fielding CA. Apoptosis is a natural stimulus of IL6R shedding and contributes to the proinflammatory trans-signaling function of neutrophils. Blood. 2007;110(6):1748–55.
  • Schumacher N, Meyer D, Mauermann A, von der Heyde J, Wolf J, Schwarz J, et al. Shedding of endogenous interleukin-6 Receptor (IL-6R) is governed by a disintegrin and metalloproteinase (ADAM) proteases while a full-length IL-6R isoform localizes to circulating microvesicles. J Biol Chem. 2015;290(43):26059–71.
  • Yan I, Schwarz J, Lücke K, Schumacher N, Schumacher V, Schmidt S, et al. ADAM17 controls IL-6 signaling by cleavage of the murine IL-6Rα from the cell surface of leukocytes during inflammatory responses. J Leukoc Biol. 2016;99(5):749–60.
  • Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31:390–2.
  • Hinks A, Marion MC, Cobb J, Comeau ME, Sudman M, Ainsworth HC, et al. Brief report: the genetic profile of rheumatoid factor-positive polyarticular juvenile idiopathic arthritis resembles that of adult rheumatoid arthritis . Arthritis Rheumatol. 2018;70(6):957–62.
  • Mangge H, Kenzian H, Gallistl S, Neuwirth G, Liebmann P, Kaulfersch W, et al. Serum cytokines in juvenile rheumatoid arthritis. Correlation with conventional inflammation parameters and clinical subtypes. Arthritis Rheum. 1995;38(2):211–20.
  • Saxena N, Aggarwal A, Misra R. Elevated concentrations of monocyte derived cytokines in synovial fluid of children with enthesitis related arthritis and polyarticular types of juvenile idiopathic arthritis. J Rheumatol. 2005;32:1349–53.
  • Altobelli E, Angeletti PM, Piccolo D, De Angelis R. Synovial fluid and serum concentrations of inflammatory markers in rheumatoid arthritis, psoriatic arthritis and osteoarthitis: a systematic review. Curr Rheumatol Rev. 2017;13:170–9.
  • Eberhard BA, Laxer RM, Andersson U, Silverman ED. Local synthesis of both macrophage and T cell cytokines by synovial fluid cells from children with juvenile rheumatoid arthritis. Clin Exp Immunol. 2008;96(2):260–6.
  • De Benedetti F, Massa M, Pignatti P, Albani S, Novick D, Martini A. Serum soluble interleukin 6 (IL-6) receptor and IL-6/soluble IL-6 receptor complex in systemic juvenile rheumatoid arthritis. J Clin Invest. 1994;93(5):2114–9.
  • Szymańska-kłauza J, Cebula-Obrzut B, Smolewski P, Stanczyk J, Smolewska E. Imbalance of Th17 and T-regulatory cells in peripheral blood and synovial fluid in treatment naïve children with juvenile idiopathic arthritis. Cejoi. 2014;39:71–6.
  • De Benedetti F, Massa M, Robbioni P, Ravelli A, Burgio GR, Martini A. Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis. Arthritis Rheum. 1991;34(9):1158–63.
  • De Benedetti F, Robbioni P, Massa M, Viola S, Albani S, Martini A. Serum interleukin-6 levels and joint involvement in polyarticular and pauciarticular juvenile chronic arthritis. Clin Exp Rheumatol. 1992;10(5):493–8.
  • Murakami M, Harada M, Kamimura D, Ogura H, Okuyama Y, Kumai N, et al. Disease-association analysis of an inflammation-related feedback loop. Cell Rep. 2013;3(3):946–59.
  • Harada M, Kamimura D, Arima Y, Kohsaka H, Nakatsuji Y, Nishida M, et al. Temporal expression of growth factors triggered by epiregulin regulates inflammation development. J Immunol. 2015;194(3):1039–46.
  • Tu Z, Xue H, Chen W, Cao L, Zhang W. Identification of potential peripheral blood diagnostic biomarkers for patients with juvenile idiopathic arthritis by bioinformatics analysis. Rheumatol Int. 2017;37(3):423–34.
  • Caiello I, Minnone G, Holzinger D, Vogl T, Prencipe G, Manzo A, et al. IL-6 amplifies TLR mediated cytokine and chemokine production: implications for the pathogenesis of rheumatic inflammatory diseases. PLoS One. 2014;9:4–13.
  • Bleil J, Maier R, Syrbe U, Sieper J, Appel H. In situ analysis of interleukin-6 expression at different sites of zygapophyseal joints from patients with ankylosing spondylitis in comparison to controls. Scand J Rheumatol. 2015;44(4):296–301.
  • François RJ, Neure L, Sieper J, Braun J. Immunohistological examination of open sacroiliac biopsies of patients with ankylosing spondylitis: detection of tumour necrosis factor α in two patients with early disease and transforming growth factor β in three more advanced cases. Ann Rheum Dis. 2006;65:713–20.
  • Šahmatova L, Sügis E, Šunina M, Hermann H, Prans E, Pihlap M, et al. Signs of innate immune activation and premature immunosenescence in psoriasis patients. Sci Rep. 2017;7:1–13.
  • Li DH, He CR, Liu FP, Li J, Gao JW, Li Y, et al. Annexin A2, up-regulated by IL-6, promotes the ossification of ligament fibroblasts from ankylosing spondylitis patients. Biomed Pharmacother. 2016;84:674–9.
  • Pesenacker AM, Bending D, Ursu S, Wu Q, Nistala K, Wedderburn LR, et al. CD161 defines the subset of FoxP3 + T cells capable of producing proinflammatory cytokines. Blood. 2013;121(14):2647–58.
  • Wehrens EJ, Vastert SJ, Mijnheer G, Meerding J, Klein M, Wulffraat NM, et al. Anti-tumor necrosis factor α targets protein kinase B/c-akt-induced resistance of effector cells to suppression in juvenile idiopathic arthritis. Arthritis Rheum. 2013;65(12):3279–84.
  • de Jager W, Vastert SJ, Beekman JM, Wulffraat NM, Kuis W, Coffer PJ, et al. Defective phosphorylation of interleukin-18 receptor beta causes impaired natural killer cell function in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2009;60(9):2782–93.
  • Cifaldi L, Prencipe G, Caiello I, Bracaglia C, Locatelli F, De Benedetti F, et al. Inhibition of natural killer cell cytotoxicity by interleukin-6: implications for the pathogenesis of macrophage activation syndrome. Arthritis Rheumatol. 2015;67(11):3037–46.
  • Put K, Vandenhaute J, Avau A, van Nieuwenhuijze A, Brisse E, Dierckx T, et al. Inflammatory gene expression profile and defective interferon-γ and granzyme K in natural killer cells from systemic juvenile idiopathic arthritis patients. Arthritis Rheumatol. 2017;69(1):213–24.
  • Honke N, Ohl K, Wiener A, Bierwagen J, Peitz J, Di Fiore S, et al. The p38-mediated rapid down-regulation of cell surface gp130 expression impairs interleukin-6 signaling in the synovial fluid of juvenile idiopathic arthritis patients. Arthritis Rheumatol. 2014;66(2):470–8.
  • De Jager W, Hoppenreijs EPAH, Wulffraat NM, Wedderburn LR, Kuis W, Prakken BJ. Blood and synovial fluid cytokine signatures in patients with juvenile idiopathic arthritis: a cross-sectional study. Ann Rheum Dis. 2007;66(5):589–98.
  • Barnes MG, Grom AA, Thompson SD, Griffin TA, Pavlidis P, Itert L, et al. Subtype-specific peripheral blood gene expression profiles in recent-onset juvenile idiopathic arthritis. Arthritis Rheum. 2009;60(7):2102–12.
  • Ombrello MJ, Arthur VL, Remmers EF, Hinks A, Tachmazidou I, Grom AA, et al. Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications. Ann Rheum Dis. 2017;76(5):906–13.
  • Hinks A, Cobb J, Marion MC, Prahalad S, Sudman M, Bowes J, et al. Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nat Genet. 2013;45(6):664–9.
  • Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1998;102(7):1369–76.
  • Ziaee V, Maddah M, Moradinejad M-H, Rezaei A, Zoghi S, Sadr M, et al. Association of interleukin-6 single nucleotide polymorphisms with juvenile idiopathic arthritis. Clin Rheumatol. 2017;36(1):77–81.
  • Ravelli A, Consolaro A, Horneff G, Laxer RM, Lovell DJ, Wulffraat NM, et al. Treating juvenile idiopathic arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2018;77(6):819–28.
  • Hu Z, Jiang K, Frank MB, Chen Y, Jarvis JN. Modeling transcriptional rewiring in neutrophils through the course of treated juvenile idiopathic arthritis. Sci Rep. 2018;8:1–10.
  • Woo P, Humphries SE. IL-6 polymorphisms: a useful genetic tool for inflammation research? J Clin Invest. 2013;123(4):1413–4.
  • Giancane G, Alongi A, Ravelli A. Update on the pathogenesis and treatment of juvenile idiopathic arthritis. Curr Opin Rheumatol. 2017;29(5):523–9.
  • Merashli M, Marco GD, Podgorski M, McGonagle D, Marzo-Ortega H. Evidence of response to IL-6 inhibition in some cases of refractory spondyloarthritis associated peripheral synovitis. Ann Rheum Dis. 2016;75(7):1418–20.
  • Lekpa FK, Poulain C, Wendling D, Soubrier M, De Bandt M, Berthelot JM, et al. Is IL-6 an appropriate target to treat spondyloarthritis patients refractory to anti-TNF therapy? A multicentre retrospective observational study. Arthritis Res Ther. 2012;14(2):R53.
  • Ogata A, Kumanogoh A, Tanaka T. Pathological role of interleukin-6 in psoriatic arthritis. Arthritis. 2012;2012:1–6.
  • Sieper J, Porter-Brown B, Thompson L, Harari O, Dougados M. Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann Rheum Dis. 2014;73(1):95–100.
  • Sieper J, Braun J, Kay J, Badalamenti S, Radin AR, Jiao L, et al. Sarilumab for the treatment of ankylosing spondylitis: results of a phase II, randomised, double-blind, placebo-controlled study (ALIGN). Ann Rheum Dis. 2015;74(6):1051–57.
  • Mease PJ, Gottlieb AB, Berman A, Drescher E, Xing J, Wong R, et al. The efficacy and safety of Clazakizumab, an anti–interleukin-6 monoclonal antibody, in a phase IIb study of adults with active psoriatic athritis. Arthritis Rheumatol. 2016;68(9):2163–73.
  • FitzGerald O. Spondyloarthropathies: IL-6 blockade in psoriatic arthritis - a new therapeutic option?. Nat Rev Rheumatol. 2016;12(6):318–19.
  • Scott LJ. Sarilumab: first global approval. Drugs. 2017;77(6):705–12.
  • Beukelman T, Patkar NM, Saag KG, Tolleson-Rinehart S, Cron RQ, DeWitt EM, et al. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res. 2011;63(4):465–82.
  • Ringold S, Weiss PF, Beukelman T, DeWitt EM, Ilowite NT, Kimura Y, et al. 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Rheum. 2013;65:2499–512.
  • Yokota S, Miyamae T, Imagawa T, Iwata N, Katakura S, Mori M, et al. Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2005;52(3):818–25.
  • Woo P, Wilkinson N, Prieur A-M, Southwood T, Leone V, Livermore 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 cli. Arthritis Res Ther. 2005;7(6):R1281.
  • Yokota S, Imagawa T, Mori M, Miyamae T, Aihara Y, Takei 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. 2008;371(9617):998–1006.
  • De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Wright S, Calvo I, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367(25):2385–95.
  • Imagawa T, Yokota S, Mori M, Miyamae T, Takei S, Imanaka H, et al. Safety and efficacy of tocilizumab, an anti-IL-6-receptor monoclonal antibody, in patients with polyarticular-course juvenile idiopathic arthritis. Mod Rheumatol. 2012;22(1):109–15.
  • Brunner HI, Ruperto N, Zuber Z, Keane C, Harari O, Kenwright A, et al. Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial. Ann Rheum Dis. 2015;74(6):1110–17.
  • Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum. 1997;40(7):1202–09.
  • Yokota S, Imagawa T, Mori M, Miyamae T, Takei S, Iwata N, et al. Longterm safety and effectiveness of the anti-interleukin 6 receptor monoclonal antibody tocilizumab in patients with systemic juvenile idiopathic arthritis in Japan. J Rheumatol. 2014;41(4):759–67.
  • Opoka-Winiarska V, Żuber Z, Alexeeva E, Chasnyk V, Nikishina I, Dębowska G, et al. Long-term, interventional, open-label extension study evaluating the safety of tocilizumab treatment in patients with polyarticular-course juvenile idiopathic arthritis from Poland and Russia who completed the global, international CHERISH trial. Clin Rheumatol. 2018;37(7):1807–16.
  • Yokota S, Itoh Y, Morio T, Origasa H, Sumitomo N, Tomobe M, 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. 2016;75(9):1654–60.
  • Bielak M, Husmann E, Weyandt N, Haas JP, Hügle B, Horneff G, et al. IL-6 blockade in systemic juvenile idiopathic arthritis - achievement of inactive disease and remission. Pediatr Rheumatol. 2018;16:1–8.
  • Pacharapakornpong T, Vallibhakara SAO, Lerkvaleekul B, Vilaiyuk S. Comparisons of the outcomes between early and late tocilizumab treatment in systemic juvenile idiopathic arthritis. Rheumatol Int. 2017;37(2):251–55.
  • 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):123–37.
  • Inaba Y, Ozawa R, Imagawa T, Mori M, Hara Y, Miyamae T, et al. Radiographic improvement of damaged large joints in children with systemic juvenile idiopathic arthritis following tocilizumab treatment. Ann Rheum Dis. 2011;70(9):1693–95.
  • Inaba Y, Ozawa R, Aoki C, Imagawa T, Mori M, Hara R, et al. Radiologic analysis of the effect of tocilizumab on hands and large joints in children with systemic juvenile idiopathic arthritis. Mod Rheumatol. 2013;23(4):667–73.
  • Aoki C, Inaba Y, Choe H, Kaneko U, Hara R, Miyamae T, et al. Discrepancy between clinical and radiological responses to tocilizumab treatment in patients with systemic-onset juvenile idiopathic arthritis. J Rheumatol. 2014;41(6):1171–77.
  • Tozawa Y, Fujita S, Abe S, Kitamura K, Kobayashi I. Radiological improvement by tocilizumab in polyarticular juvenile idiopathic arthritis. Pediatr Int. 2015;57(2):307–10.
  • Kostik MM, Dubko MF, Masalova VV, Snegireva LS, Kornishina TL, Chikova IA, et al. Successful treatment with tocilizumab every 4 weeks of a low disease activity group who achieve a drug-free remission in patients with systemic-onset juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2015;13:4.
  • Kostik MM, Isupova EA, Chikova IA, Dubko MF, Masalova VV, Snegireva LS, et al. Reasons for inactive disease and flare in systemic onset juvenile idiopathic arthritis patients during tocilizumab treatment. Clin Exp Rheumatol. 2018;36(2):335–41.
  • Beukelman T, Xie F, Chen L, Baddley JW, Delzell E, Grijalva CG, et al. Rates of hospitalized bacterial infection associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum. 2012;64(8):2773–80.
  • Salonen PH, Saila H, Salonen JH, Linna M, Helminen M, Kauppi MJ. Pneumonia in children with juvenile idiopathic arthritis in Finland 1999-2014: a nationwide retrospective register linkage study. Clin Exp Rheumatol. 2018;36:502–7.
  • Machado SH, Xavier RM. Safety of tocilizumab in the treatment of juvenile idiopathic arthritis. Expert Opin Drug Saf. 2017;16(4):493–500.
  • Horneff G. Biologic-associated infections in pediatric rheumatology. Curr Rheumatol Rep. 2015;17:66.
  • Tarp S, Amarilyo G, Foeldvari I, Christensen R, Woo JMP, Cohen N, et al. Efficacy and safety of biological agents for systemic juvenile idiopathic arthritis: a systematic review and meta-analysis of randomized trials. Rheumatology. 2016;55(4):669–79.
  • Beukelman T, Xie F, Baddley JW, Chen L, Delzell E, Grijalva CG, et al. Incidence of selected opportunistic infections among children with juvenile idiopathic arthritis. Arthritis Rheum. 2013;65(5):1384–89.
  • Nimmrich S, Horneff G. Incidence of herpes zoster infections in juvenile idiopathic arthritis patients. Rheumatol Int. 2015;35(3):465–70.
  • Kawada JI, Iwata N, Kitagawa Y, Kimura H, Ito Y. Prospective monitoring of Epstein-Barr virus and other herpesviruses in patients with juvenile idiopathic arthritis treated with methotrexate and tocilizumab. Mod Rheumatol. 2012;22(4):565–70.
  • Kawada J-I, Kitagawa Y, Iwata N, Ito Y. Clinical characteristics of influenza virus infection in juvenile idiopathic arthritis patients treated with tocilizumab. Mod Rheumatol. 2013;23(5):972–6.
  • Pfeil J, Grulich-Henn J, Wenning D, Breil T, Günther P, Lutz T. Multiple upper gastrointestinal perforations in a 15-year-old patient treated with tocilizumab. Rheumatology. 2014;53(9):1713–14.
  • Kessler EA, Vora SS, Verbsky JW. Risk of significant cytopenias after treatment with tocilizumab in systemic juvenile arthritis patients with a history of macrophage activation syndrome. Pediatr Rheumatol. 2012;10:8–11.
  • Yasuoka R, Iwata N, Abe N, Kohagura T, Nakaseko H, Shimizu M, et al. Risk factors for hypersensitivity reactions to tocilizumab introduction in systemic juvenile idiopathic arthritis. Mod Rheumatol. 2018;1–4.
  • Ye W, Fifield MC, Mayhew A, Nasser S, Östör AJK. Successful tocilizumab desensitization in an adult with juvenile idiopathic arthritis. Scand J Rheumatol. 2016;45(1):75–76.
  • Yokota S, Imagawa T, Mori M, Miyamae T, Takei S, Iwata N, et al. Long-term treatment of systemic juvenile idiopathic arthritis with tocilizumab: results of an open-label extension study in Japan. Ann Rheum Dis. 2013;72(4):627–28.
  • Jeyaratnam J, ter Haar NM, Lachmann HJ, Kasapcopur O, Ombrello AK, Rigante D, et al. The safety of live-attenuated vaccines in patients using IL-1 or IL-6 blockade: an international survey. Pediatr Rheumatol 2018;16:4–9.
  • Shinoki T, Hara R, Kaneko U, Miyamae T, Imagawa T, Mori M, et al. Safety and response to influenza vaccine in patients with systemic-onset juvenile idiopathic arthritis receiving tocilizumab. Mod Rheumatol. 2012;22(6):871–76.
  • Hoeltzenbein M, Beck E, Rajwanshi R, Gøtestam Skorpen C, Berber E, Schaefer C, et al. Tocilizumab use in pregnancy: analysis of a global safety database including data from clinical trials and post-marketing data. Semin Arthritis Rheum. 2016;46(2):238–45.
  • Kearsley-Fleet L, Beresford MW, Davies R, De Cock D, Baildam E, Foster HE, et al. Short-term outcomes in patients with systemic juvenile idiopathic arthritis treated with either tocilizumab or anakinra. Rheumatology. 2019;58(1):94–102.
  • Horneff G, Schulz AC, Klotsche J, Hospach A, Minden K, Foeldvari I, et al. Experience with etanercept, tocilizumab and interleukin-1 inhibitors in systemic onset juvenile idiopathic arthritis patients from the BIKER registry. Arthritis Res Ther. 2017;19:1–13.
  • Amarilyo G, Tarp S, Foeldvari I, Cohen N, Pope TD, Woo JMP, et al. Biological agents in polyarticular juvenile idiopathic arthritis: a meta-analysis of randomized withdrawal trials. Semin Arthritis Rheum. 2016;46(3):312–18.
  • Horneff G, Klein A, Klotsche J, Minden K, Huppertz HI, Weller-Heinemann F, et al. Comparison of treatment response, remission rate and drug adherence in polyarticular juvenile idiopathic arthritis patients treated with etanercept, adalimumab or tocilizumab. Arthritis Res Ther. 2016;18(1):272.
  • Kearsley-Fleet L, Davies R, Baildam E, Beresford MW, Foster HE, Southwood TR, et al. Factors associated with choice of biologic among children with Juvenile Idiopathic Arthritis: results from two UK paediatric biologic registers. Rheumatology. 2016;55(9):1556–65.
  • Woerner A, Uettwiller F, Melki I, Mouy R, Wouters C, Bader-Meunier B, et al. Biological treatment in systemic juvenile idiopathic arthritis: achievement of inactive disease or clinical remission on a first, second or third biological agent. RMD Open. 2015;1:1–9.
  • Brachat AH, Grom AA, Wulffraat N, Brunner HI, Quartier P, Brik R, et al. Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy. Arthritis Res Ther. 2017;19:1–10.
  • Hügle B, Schippers A, Fischer N, Ohl K, Denecke B, Ticconi F, et al. Transcription factor motif enrichment in whole transcriptome analysis identifies STAT4 and BCL6 as the most prominent binding motif in systemic juvenile idiopathic arthritis. Arthritis Res Ther. 2018;20:1–11.
  • Lerkvaleekul B, Vilaiyuk S. Early reduction of serum interleukin-6 levels as a predictor of clinical remission in systemic juvenile idiopathic arthritis. Asian Pacific J Allergy Immunol. 2018.
  • Kaminiarczyk-Pyzalka D, Adamczak K, Mikos H, Klimecka I, Moczko J, Niedziela M. Proinflammatory cytokines in monitoring the course of disease and effectiveness of treatment with etanercept (ETN) of children with oligo- and polyarticular juvenile idiopathic arthritis (JIA). Clin Lab. 2014;60(9):1481–90.
  • Muramatsu S, Kubo R, Nishida E, Morita A. Serum interleukin-6 levels in response to biologic treatment in patients with psoriasis. Mod Rheumatol. 2017;27(1):137–41.
  • Wang XB, Ellis JJ, Pennisi DJ, Song X, Batra J, Hollis K, et al. Transcriptome analysis of ankylosing spondylitis patients before and after TNF-α inhibitor therapy reveals the pathways affected. Genes Immun. 2017;18(3):184–90.
  • Bracaglia C, de Graaf K, Pires Marafon D, Guilhot F, Ferlin W, Prencipe G, et al. Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Ann Rheum Dis. 2017;76(1):166–72.
  • Strippoli R, Carvello F, Scianaro R, De Pasquale L, Vivarelli M, Petrini S, et al. Amplification of the response to toll-like receptor ligands by prolonged exposure to interleukin-6 in mice: implication for the pathogenesis of macrophage activation syndrome. Arthritis Rheum. 2012;64(5):1680–88.
  • Gorelik M, Fall N, Altaye M, Barnes MG, Thompson SD, Grom AA, et al. Follistatin-like protein 1 and the ferritin/erythrocyte sedimentation rate ratio are potential biomarkers for dysregulated gene expression and macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol. 2013;40(7):1191–9.
  • Grom AA, Horne A, De Benedetti F. Macrophage activation syndrome in the era of biologic therapy. Nat Rev Rheumatol. 2016;12(5):259–68.
  • Yokota S, Itoh Y, Morio T, Sumitomo N, Daimaru K, Minota S. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis under treatment with tocilizumab. J Rheumatol. 2015;42(4):712–22.
  • Shimizu M, Nakagishi Y, Kasai K, Yamasaki Y, Miyoshi M, Takei S, 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. 2012;58(2):287–94.
  • Schulert GS, Minoia F, Bohnsack J, Cron RQ, Hashad S, KonÉ-Paut I, et al. Effect of biologic therapy on clinical and laboratory features of macrophage activation syndrome associated with systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2018;70(3):409–19.
  • Yoshimura T, Sonoda KH, Ohguro N, Ohsugi Y, Ishibashi T, Cua DJ, et al. Involvement of Th17 cells and the effect of anti-IL-6 therapy in autoimmune uveitis. Rheumatology (Oxford). 2009;48(4):347–54.
  • Lin P. Targeting interleukin-6 for noninfectious uveitis. Clin Ophthalmol. 2015;9:1697–702.
  • Adán A, Mesquida M, Llorenç V, Espinosa G, Molins B, Hernández MV, et al. Tocilizumab treatment for refractory uveitis-related cystoid macular edema. Graefes Arch Clin Exp Ophthalmol. 2013;251(11):2627–32.
  • Tappeiner C, Mesquida M, Adán A, Anton J, Ramanan AV, Carreno E, et al. Evidence for tocilizumab as a treatment option in refractory uveitis associated with juvenile idiopathic arthritis. J Rheumatol. 2016;43(12):2183–8.
  • Tsang AC, Roth J, Gottlieb C. Tocilizumab for severe chronic anterior uveitis associated with juvenile idiopathic arthritis in a pediatric patient. Ocul Immunol Inflamm. 2014;22(2):155–7.
  • Calvo-Río V, Santos-Gómez M, Calvo I, González-Fernández MI, López-Montesinos B, Mesquida M, et al. Anti–interleukin-6 receptor tocilizumab for severe juvenile idiopathic arthritis–associated uveitis refractory to anti–tumor necrosis factor therapy: a multicenter study of twenty-five patients. Arthritis Rheumatol. 2017;69(3):668–75.
  • Simon D, Lucidarme N, Prieur A-M, Ruiz J-C, Czernichow P. Treatment of growth failure in juvenile chronic arthritis. Horm Res. 2002;58(Suppl 1):28–32.
  • Bechtold S, Simon D. Growth abnormalities in children and adolescents with juvenile idiopathic arthritis. Rheumatol Int. 2014;34(11):1483–8.
  • De Benedetti F, Alonzi T, Moretta A, Lazzaro D, Costa P, Poli V, et al. Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I. A model for stunted growth in children with chronic inflammation. J Clin Invest. 1997;99(4):643–50.
  • De Benedetti F, Rucci N, Del Fattore A, Peruzzi B, Paro R, Longo M, et al. Impaired skeletal development in interleukin-6-transgenic mice: a model for the impact of chronic inflammation on the growing skeletal system. Arthritis Rheum. 2006;54(11):3551–63.
  • Bharucha KN, Brunner HI, Calvo Penadés I, Nikishina I, Rubio-Pérez N, Oliveira S, et al. Growth during tocilizumab therapy for polyarticular-course juvenile idiopathic arthritis: 2-year data from a phase III clinical trial. J Rheumatol. 2018;45(8):1173–79.
  • De Benedetti F, Brunner H, Ruperto N, Schneider R, Xavier R, Allen R, et al. Catch-up growth during tocilizumab therapy for systemic juvenile idiopathic arthritis: results from a phase III trial. Arthritis Rheumatol. 2015;67(3):840–48.
  • Nakajima S, Naruto T, Miyamae T, Imagawa T, Mori M, Nishimaki S, et al. Improvement of reduced serum cartilage oligomeric matrix protein levels in systemic juvenile idiopathic arthritis patients treated with the anti-interleukin-6 receptor monoclonal antibody tocilizumab. Mod Rheumatol. 2009;19(1):42–6.