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Review

The role and therapeutic targeting of IL-6 in rheumatoid arthritis

, &
Pages 535-551 | Received 24 Oct 2016, Accepted 13 Feb 2017, Published online: 03 Mar 2017

References

  • McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205–2219.
  • Hirano T, Matsuda T, Turner M, et al. Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol. 1988;18(11):1797–1801.
  • Frisell T, Saevarsdottir S, Askling J. Family history of rheumatoid arthritis: an old concept with new developments. Nat Rev Rheumatol. 2016;12(6):335–343.
  • Linn-Rasker SP, van der Helm-van Mil AH, van Gaalen FA, et al. Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles. Ann Rheum Dis. 2006;65(3):366–371.
  • Hendler A, Mulli TK, Hughes FJ, et al. Involvement of autoimmunity in the pathogenesis of aggressive periodontitis. J Dent Res. 2010;89(12):1389–1394.
  • Klareskog L, Stolt P, Lundberg K, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006;54(1):38–46.
  • Wegner N, Wait R, Sroka A, et al. Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and alpha-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum. 2010;62(9):2662–2672.
  • Kimura A, Naka T, Nohara K, et al. Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells. Proc Natl Acad Sci U S A. 2008;105(28):9721–9726.
  • Kishimoto T. Interleukin-6: from basic science to medicine–40 years in immunology. Annu Rev Immunol. 2005;23:1–21.
  • Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014;6(10):a016295.
  • Tanaka T, Narazaki M, Kishimoto T. Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol. 2012;52:199–219.
  • Chihara N, Aranami T, Sato W, et al. Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica. Proc Natl Acad Sci U S A. 2011;108(9):3701–3706.
  • Kerkman PF, Rombouts Y, van der Voort EI, et al. Circulating plasmablasts/plasmacells as a source of anticitrullinated protein antibodies in patients with rheumatoid arthritis. Ann Rheum Dis. 2013;72(7):1259–1263.
  • Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235–238.
  • Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 2010;40(7):1830–1835.
  • Ma CS, Deenick EK, Batten M, et al. The origins, function, and regulation of T follicular helper cells. J Exp Med. 2012;209(7):1241–1253.
  • Jones GW, Jones SA. Ectopic lymphoid follicles: inducible centres for generating antigen-specific immune responses within tissues. Immunology. 2016;147(2):141–151.
  • Humby F, Bombardieri M, Manzo A, et al. Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium. Plos Med. 2009;6(1):e1.
  • Marin V, Montero-Julian FA, Gres S, et al. The IL-6-soluble IL-6Ralpha autocrine loop of endothelial activation as an intermediate between acute and chronic inflammation: an experimental model involving thrombin. J Immunol. 2001;167(6):3435–3442.
  • Hurst SM, Wilkinson TS, McLoughlin RM, et al. Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation. Immunity. 2001;14(6):705–714.
  • Xing Z, Gauldie J, Cox G, et al. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest. 1998;101(2):311–320.
  • Kaplanski G, Marin V, Montero-Julian F, et al. IL-6: a regulator of the transition from neutrophil to monocyte recruitment during inflammation. Trends Immunol. 2003;24(1):25–29.
  • Hashizume M, Hayakawa N, Suzuki M, et al. IL-6/sIL-6R trans-signalling, but not TNF-alpha induced angiogenesis in a HUVEC and synovial cell co-culture system. Rheumatol Int. 2009;29(12):1449–1454.
  • Fava RA, Olsen NJ, Spencer-Green G, et al. Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J Exp Med. 1994;180(1):341–346.
  • Esser S, Lampugnani MG, Corada M, et al. Vascular endothelial growth factor induces VE-cadherin tyrosine phosphorylation in endothelial cells. J Cell Sci. 1998;111(Pt 13):1853–1865.
  • Lo CW, Chen MW, Hsiao M, et al. IL-6 trans-signaling in formation and progression of malignant ascites in ovarian cancer. Cancer Res. 2011;71(2):424–434.
  • Romano M, Sironi M, Toniatti C, et al. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity. 1997;6(3):315–325.
  • Hashizume M, Hayakawa N, Mihara M. IL-6 trans-signalling directly induces RANKL on fibroblast-like synovial cells and is involved in RANKL induction by TNF-alpha and IL-17. Rheumatology (Oxford). 2008;47(11):1635–1640.
  • Guerne PA, Desgeorges A, Jaspar JM, et al. Effects of IL-6 and its soluble receptor on proteoglycan synthesis and NO release by human articular chondrocytes: comparison with IL-1. Modulation by dexamethasone. Matrix Biol. 1999;18(3):253–260.
  • Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J. 1990;265(3):621–636.
  • Hashizume M, Higuchi Y, Uchiyama Y, et al. IL-6 plays an essential role in neutrophilia under inflammation. Cytokine. 2011;54(1):92–99.
  • Kaser A, Brandacher G, Steurer W, et al. Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis. Blood. 2001;98(9):2720–2725.
  • Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113(9):1271–1276.
  • Neumann FJ, Ott I, Marx N, et al. Effect of human recombinant interleukin-6 and interleukin-8 on monocyte procoagulant activity. Arterioscler Thromb Vasc Biol. 1997;17(12):3399–3405.
  • Ridker PM, Rifai N, Stampfer MJ, et al. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000;101(15):1767–1772.
  • Solomon DH, Goodson NJ, Katz JN, et al. Patterns of cardiovascular risk in rheumatoid arthritis. Ann Rheum Dis. 2006;65(12):1608–1612.
  • Gough AK, Lilley J, Eyre S, et al. Generalised bone loss in patients with early rheumatoid arthritis. Lancet. 1994;344(8914):23–27.
  • De Benedetti F, Rucci N, Del Fattore A, 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):3551–3563.
  • Haddad F, Zaldivar F, Cooper DM, et al. IL-6-induced skeletal muscle atrophy. J Appl Physiol (1985). 2005;98(3):911–917.
  • Schaap LA, Pluijm SM, Deeg DJ, et al. Inflammatory markers and loss of muscle mass (sarcopenia) and strength. Am J Med. 2006;119(6):526.e9–526.e17.
  • Dann SM, Spehlmann ME, Hammond DC, et al. IL-6-dependent mucosal protection prevents establishment of a microbial niche for attaching/effacing lesion-forming enteric bacterial pathogens. J Immunol. 2008;180(10):6816–6826.
  • Grivennikov S, Karin E, Terzic J, et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009;15(2):103–113.
  • Scheller J, Chalaris A, Schmidt-Arras D, et al. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813(5):878–888.
  • Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11(5):373–384.
  • Scher JU, Sczesnak A, Longman RS, et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife. 2013;2:e01202.
  • Maeda Y, Kurakawa T, Umemoto E, et al. Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine. Arthritis Rheumatol. 2016;68(11):2646–2661.
  • Ohzato H, Yoshizaki K, Nishimoto N, et al. Interleukin-6 as a new indicator of inflammatory status: detection of serum levels of interleukin-6 and C-reactive protein after surgery. Surgery. 1992;111(2):201–209.
  • Huang QQ, Pope RM. The role of toll-like receptors in rheumatoid arthritis. Curr Rheumatol Rep. 2009;11(5):357–364.
  • Huang QQ, Sobkoviak R, Jockheck-Clark AR, et al. Heat shock protein 96 is elevated in rheumatoid arthritis and activates macrophages primarily via TLR2 signaling. J Immunol. 2009;182(8):4965–4973.
  • Ospelt C, Brentano F, Rengel Y, et al. Overexpression of toll-like receptors 3 and 4 in synovial tissue from patients with early rheumatoid arthritis: toll-like receptor expression in early and longstanding arthritis. Arthritis Rheum. 2008;58(12):3684–3692.
  • De Jonge E, Friederich PW, Vlasuk GP, et al. Activation of coagulation by administration of recombinant factor VIIa elicits interleukin 6 (IL-6) and IL-8 release in healthy human subjects. Clin Diagn Lab Immunol. 2003;10(3):495–497.
  • Sanchez-Pernaute O, Filkova M, Gabucio A, et al. Citrullination enhances the pro-inflammatory response to fibrin in rheumatoid arthritis synovial fibroblasts. Ann Rheum Dis. 2013;72(8):1400–1406.
  • Fishman D, Faulds G, Jeffery R, 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):1369–1376.
  • Hou H, Wang C, Sun F, et al. Association of interleukin-6 gene polymorphism with coronary artery disease: an updated systematic review and cumulative meta-analysis. Inflamm Res. 2015;64(9):707–720.
  • Akira S, Kishimoto T. IL-6 and NF-IL6 in acute-phase response and viral infection. Immunol Rev. 1992;127:25–50.
  • Vanden Berghe W, De Bosscher K, Boone E, et al. The nuclear factor-kappaB engages CBP/p300 and histone acetyltransferase activity for transcriptional activation of the interleukin-6 gene promoter. J Biol Chem. 1999;274(45):32091–32098.
  • Yamamoto M, Yamazaki S, Uematsu S, et al. Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IkappaBzeta. Nature. 2004;430(6996):218–222.
  • Zhang Q, Zhao K, Shen Q, et al. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature. 2015;525(7569):389–393.
  • Ito K, Lim S, Caramori G, et al. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. Faseb J. 2001;15(6):1110–1112.
  • Carpio LR, Bradley EW, McGee-Lawrence ME, et al. Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling. Sci Signal. 2016;9(440):ra79.
  • Stein B, Yang MX. Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa B and C/EBP beta. Mol Cell Biol. 1995;15(9):4971–4979.
  • Taganov KD, Boldin MP, Chang KJ, et al. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A. 2006;103(33):12481–12486.
  • Matsushita K, Takeuchi O, Standley DM, et al. Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature. 2009;458(7242):1185–1190.
  • Mino T, Murakawa Y, Fukao A, et al. Regnase-1 and roquin regulate a common element in inflammatory mRNAs by spatiotemporally distinct mechanisms. Cell. 2015;161(5):1058–1073.
  • Masuda K, Ripley B, Nishimura R, et al. Arid5a controls IL-6 mRNA stability, which contributes to elevation of IL-6 level in vivo. Proc Natl Acad Sci U S A. 2013;110(23):9409–9414.
  • Zaman MM, Masuda K, Nyati KK, et al. Arid5a exacerbates IFN-gamma-mediated septic shock by stabilizing T-bet mRNA. Proc Natl Acad Sci U S A. 2016;113(41):11543–11548.
  • Saito Y, Kagami S, Sanayama Y, et al. AT-rich-interactive domain-containing protein 5A functions as a negative regulator of retinoic acid receptor-related orphan nuclear receptor gammat-induced Th17 cell differentiation. Arthritis Rheumatol. 2014;66(5):1185–1194.
  • Paonessa G, Graziani R, de Serio A, et al. Two distinct and independent sites on IL-6 trigger gp 130 dimer formation and signalling. Embo J. 1995;14(9):1942–1951.
  • Boulanger MJ, Chow DC, Brevnova EE, et al. Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex. Science. 2003;300(5628):2101–2104.
  • Grotzinger J, Kernebeck T, Kallen KJ, et al. IL-6 type cytokine receptor complexes: hexamer, tetramer or both? Biol Chem. 1999;380(7–8):803–813.
  • Skiniotis G, Boulanger MJ, Garcia KC, et al. Signaling conformations of the tall cytokine receptor gp130 when in complex with IL-6 and IL-6 receptor. Nat Struct Mol Biol. 2005;12(6):545–551.
  • Oberg HH, Wesch D, Grussel S, et al. Differential expression of CD126 and CD130 mediates different STAT-3 phosphorylation in CD4+CD25- and CD25high regulatory T cells. Int Immunol. 2006;18(4):555–563.
  • Garbers C, Monhasery N, Aparicio-Siegmund S, et al. The interleukin-6 receptor Asp358Ala single nucleotide polymorphism rs2228145 confers increased proteolytic conversion rates by ADAM proteases. Biochim Biophys Acta. 2014;1842(9):1485–1494.
  • Narazaki M, Yasukawa K, Saito T, et al. Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130. Blood. 1993;82(4):1120–1126.
  • Schaper F, Rose-John S. Interleukin-6: biology, signaling and strategies of blockade. Cytokine Growth Factor Rev. 2015;26(5):475–487.
  • Hibi M, Murakami M, Saito M, et al. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell. 1990;63(6):1149–1157.
  • Murakami M, Narazaki M, Hibi M, et al. Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family. Proc Natl Acad Sci U S A. 1991;88(24):11349–11353.
  • Narazaki M, Witthuhn BA, Yoshida K, et al. Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130. Proc Natl Acad Sci U S A. 1994;91(6):2285–2289.
  • Kishimoto T, Akira S, Narazaki M, et al. Interleukin-6 family of cytokines and gp130. Blood. 1995;86(4):1243–1254.
  • Naka T, Narazaki M, Hirata M, et al. Structure and function of a new STAT-induced STAT inhibitor. Nature. 1997;387(6636):924–929.
  • Minamoto S, Ikegame K, Ueno K, et al. Cloning and functional analysis of new members of STAT induced STAT inhibitor (SSI) family: SSI-2 and SSI-3. Biochem Biophys Res Commun. 1997;237(1):79–83.
  • Narazaki M, Fujimoto M, Matsumoto T, et al. Three distinct domains of SSI-1/SOCS-1/JAB protein are required for its suppression of interleukin 6 signaling. Proc Natl Acad Sci U S A. 1998;95(22):13130–13134.
  • Nicholson SE, de Souza D, Fabri LJ, et al. Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130. Proc Natl Acad Sci U S A. 2000;97(12):6493–6498.
  • Masuda K, Ripley B, Nyati KK, et al. Arid5a regulates naive CD4+ T cell fate through selective stabilization of Stat3 mRNA. J Exp Med. 2016;213(4):605–619.
  • Taga T, Narazaki M, Yasukawa K, et al. Functional inhibition of hematopoietic and neurotrophic cytokines by blocking the interleukin 6 signal transducer gp130. Proc Natl Acad Sci U S A. 1992;89(22):10998–11001.
  • Nishimoto N, Yoshizaki K, Miyasaka N, et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 2004;50(6):1761–1769.
  • Takagi N, Mihara M, Moriya Y, et al. Blockage of interleukin-6 receptor ameliorates joint disease in murine collagen-induced arthritis. Arthritis Rheum. 1998;41(12):2117–2121.
  • Sasai M, Saeki Y, Ohshima S, et al. Delayed onset and reduced severity of collagen-induced arthritis in interleukin-6-deficient mice. Arthritis Rheum. 1999;42(8):1635–1643.
  • Ohshima S, Saeki Y, Mima T, et al. Interleukin 6 plays a key role in the development of antigen-induced arthritis. Proc Natl Acad Sci U S A. 1998;95(14):8222–8226.
  • Tanaka T, Narazaki M, Ogata A, et al. A new era for the treatment of inflammatory autoimmune diseases by interleukin-6 blockade strategy. Semin Immunol. 2014;26(1):88–96.
  • Nishimoto N, Miyasaka N, Yamamoto K, et al. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod Rheumatol. 2009;19(1):12–19.
  • Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008;371(9617):987–997.
  • Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008;58(10):2968–2980.
  • Weinblatt ME, Kremer J, Cush J, et al. Tocilizumab as monotherapy or in combination with nonbiologic disease-modifying antirheumatic drugs: twenty-four-week results of an open-label, clinical practice study. Arthritis Care Res (Hoboken). 2013;65(3):362–371.
  • Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008;67(11):1516–1523.
  • Nishimoto N, Hashimoto J, Miyasaka N, et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis. 2007;66(9):1162–1167.
  • Kremer JM, Blanco R, Brzosko M, et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum. 2011;63(3):609–621.
  • Dougados M, Kissel K, Sheeran T, et al. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis. 2013;72(1):43–50.
  • Yazici Y, Curtis JR, Ince A, et al. Early effects of tocilizumab in the treatment of moderate to severe active rheumatoid arthritis: a one-week sub-study of a randomised controlled trial (Rapid Onset and Systemic Efficacy [ROSE] study). Clin Exp Rheumatol. 2013;31(3):358–364.
  • Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010;69(1):88–96.
  • Gabay C, Emery P, Van Vollenhoven R, et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet. 2013;381(9877):1541–1550.
  • Ogata A, Tanimura K, Sugimoto T, et al. Phase III study of the efficacy and safety of subcutaneous versus intravenous tocilizumab monotherapy in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2014;66(3):344–354.
  • Burmester GR, Rubbert-Roth A, Cantagrel A, et al. A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study). Ann Rheum Dis. 2014;73(1):69–74.
  • Hirabayashi Y, Munakata Y, Miyata M, et al. Clinical and structural remission rates increased annually and radiographic progression was continuously inhibited during a 3-year administration of tocilizumab in patients with rheumatoid arthritis: A multi-center, prospective cohort study by the Michinoku Tocilizumab Study Group. Mod Rheumatol. 2016. doi:10.3109/14397595.2016.1160991. [Epub ahead of print]
  • Bijlsma JW, Welsing PM, Woodworth TG, et al. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet. 2016;388(10042):343–355.
  • Bykerk VP, Ostor AJ, Alvaro-Gracia J, et al. Tocilizumab in patients with active rheumatoid arthritis and inadequate responses to DMARDs and/or TNF inhibitors: a large, open-label study close to clinical practice. Ann Rheum Dis. 2012;71(12):1950–1954.
  • Koike T, Harigai M, Inokuma S, et al. Effectiveness and safety of tocilizumab: postmarketing surveillance of 7901 patients with rheumatoid arthritis in Japan. J Rheumatol. 2014;41(1):15–23.
  • Yamamoto K, Goto H, Hirao K, et al. Longterm Safety of Tocilizumab: results from 3 Years of Followup Postmarketing Surveillance of 5573 Patients with Rheumatoid Arthritis in Japan. J Rheumatol. 2015;42(8):1368–1375.
  • Strangfeld A, Richter A, Siegmund B, et al. Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs. Ann Rheum Dis. 2017;76(3):504–510.
  • Gabay C, McInnes IB, Kavanaugh A, et al. Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis. Ann Rheum Dis. 2015;75(10):1806–1812.
  • Singh JA, Saag KG, Bridges SL Jr., et al. 2015 American college of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):1–26.
  • Thiolat A, Semerano L, Pers YM, et al. Interleukin-6 receptor blockade enhances CD39+ regulatory T cell development in rheumatoid arthritis and in experimental arthritis. Arthritis Rheumatol. 2014;66(2):273–283.
  • Kikuchi J, Hashizume M, Kaneko Y, et al. Peripheral blood CD4(+)CD25(+)CD127(low) regulatory T cells are significantly increased by tocilizumab treatment in patients with rheumatoid arthritis: increase in regulatory T cells correlates with clinical response. Arthritis Res Ther. 2015;17:10.
  • Roll P, Muhammad K, Schumann M, et al. In vivo effects of the anti-interleukin-6 receptor inhibitor tocilizumab on the B cell compartment. Arthritis Rheum. 2011;63(5):1255–1264.
  • Muhammad K, Roll P, Seibold T, et al. Impact of IL-6 receptor inhibition on human memory B cells in vivo: impaired somatic hypermutation in preswitch memory B cells and modulation of mutational targeting in memory B cells. Ann Rheum Dis. 2011;70(8):1507–1510.
  • Daien CI, Gailhac S, Audo R, et al. High levels of natural killer cells are associated with response to tocilizumab in patients with severe rheumatoid arthritis. Rheumatology (Oxford). 2015;54(4):601–608.
  • Nakahara H, Song J, Sugimoto M, et al. Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis. Arthritis Rheum. 2003;48(6):1521–1529.
  • Nishida S, Hagihara K, Shima Y, et al. Rapid improvement of AA amyloidosis with humanised anti-interleukin 6 receptor antibody treatment. Ann Rheum Dis. 2009;68(7):1235–1236.
  • Song SN, Tomosugi N, Kawabata H, et al. Down-regulation of hepcidin resulting from long-term treatment with an anti-IL-6 receptor antibody (tocilizumab) improves anemia of inflammation in multicentric Castleman disease. Blood. 2010;116(18):3627–3634.
  • Gualtierotti R, Ingegnoli F, Griffini S, et al. Prothrombotic biomarkers in patients with rheumatoid arthritis: the beneficial effect of IL-6 receptor blockade. Clin Exp Rheumatol. 2016;34(3):451–458.
  • Ogata A, Morishima A, Hirano T, et al. Improvement of HbA1c during treatment with humanised anti-interleukin 6 receptor antibody, tocilizumab. Ann Rheum Dis. 2011;70(6):1164–1165.
  • Rao VU, Pavlov A, Klearman M, et al. An evaluation of risk factors for major adverse cardiovascular events during tocilizumab therapy. Arthritis Rheumatol. 2015;67(2):372–380.
  • Lally L, Forbess L, Hatzis C, et al. A prospective open label phase IIa trial of tocilizumab in the treatment of polymyalgia rheumatica. Arthritis Rheumatol. 2016;68(10):2550–2554.
  • Villiger PM, Adler S, Kuchen S, et al. Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2016;387(10031):1921–1927.
  • Phase III GiACTA study shows Roche’s Actemra/RoActemra is superior to steroids alone in maintaining steroid-free remission for people with giant cell arteritis. Roche Media release. [cited 2016 Nov 12]. Available from: http://www.roche.com/media/store/releases.htm
  • Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016;387(10038):2630–2640.
  • Araki M, Matsuoka T, Miyamoto K, et al. Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study. Neurology. 2014;82(15):1302–1306.
  • Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–1518.
  • Teachey DT, Rheingold SR, Maude SL, et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood. 2013;121(26):5154–5157.
  • Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–1517.
  • Fitzgerald JC, Weiss SL, Maude SL, et al. Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Crit Care Med. 2017;45(2):e124–131.
  • Tanaka T, Narazaki M, Kishimoto T. Immunotherapeutic implications of IL-6 blockade for cytokine storm. Immunotherapy. 2016;8(8):959–970.
  • van Rhee F, Wong RS, Munshi N, et al. Siltuximab for multicentric Castleman’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2014;15(9):966–974.
  • Kim GW, Lee NR, Pi RH, et al. IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future. Arch Pharm Res. 2015;38(5):575–584.
  • Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16(5):448–457.
  • Smolen JS, Weinblatt ME, Sheng S, et al. a human anti-interleukin-6 monoclonal antibody: a randomised, 2-part (proof-of-concept and dose-finding), phase II study in patients with active rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis. 2014;73(9):1616–1625.
  • Takeuchi T, Thorne C, Karpouzas G, et al. Results of a phase 3, randomized, double-blind, placebo-controlled study of the efficacy and safety of sirukumab, an anti-il-6 cytokine monoclonal antibody, in patients with active rheumatoid arthritis despite disease-modifying anti-rheumatic drug treatment (Sirround-D). Value Health. 2016;19(7):A531.
  • Chaudhari K, Rizvi S, Syed BA. Rheumatoid arthritis: current and future trends. Nat Rev Drug Discov. 2016;15(5):305–306.
  • Weinblatt ME, Mease P, Mysler E, et al. The efficacy and safety of subcutaneous clazakizumab in patients with moderate-to-severe rheumatoid arthritis and an inadequate response to methotrexate: results from a multinational, phase IIb, randomized, double-blind, placebo/active-controlled, dose-ranging study. Arthritis Rheumatol. 2015;67(10):2591–2600.
  • Genovese MC, Fleischmann R, Furst D, et al. Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study. Ann Rheum Dis. 2014;73(9):1607–1615.
  • Takeuchi T, Tanaka Y, Yamanaka H, et al. Efficacy and safety of olokizumab in Asian patients with moderate-to-severe rheumatoid arthritis, previously exposed to anti-TNF therapy: results from a randomized phase II trial. Mod Rheumatol. 2016;26(1):15–23.
  • Genovese MC, Fleischmann R, Kivitz AJ, et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a phase III study. Arthritis Rheumatol. 2015;67(6):1424–1437.
  • Burmester GR, Lin Y, Patel R, et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis. 2016. doi:10.1136/annrheumdis-2016-210310. [Epub ahead of print]
  • Fleischmann R, van Adelsberg J, Lin Y, et al. Sarilumab and non-biologic disease-modifying antirheumatic drugs in patients with active RA and inadequate response or intolerance to TNF inhibitors. Arthritis Rheumatol. 2017;69(2):277–290.
  • Boyapati A, Msihid J, Fiore S, et al. Sarilumab plus methotrexate suppresses circulating biomarkers of bone resorption and synovial damage in patients with rheumatoid arthritis and inadequate response to methotrexate: a biomarker study of MOBILITY. Arthritis Res Ther. 2016;18(1):225.
  • Igawa T, Ishii S, Tachibana T, et al. Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. Nat Biotechnol. 2010;28(11):1203–1207.
  • Hong SS, Choi JH, Lee SY, et al. A novel small-molecule inhibitor targeting the IL-6 receptor beta subunit, Glycoprotein 130. J Immunol. 2015;195(1):237–245.
  • Jones SA, Scheller J, Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest. 2011;121(9):3375–3383.
  • Nowell MA, Richards PJ, Horiuchi S, et al. Soluble IL-6 receptor governs IL-6 activity in experimental arthritis: blockade of arthritis severity by soluble glycoprotein 130. J Immunol. 2003;171(6):3202–3209.
  • Nowell MA, Williams AS, Carty SA, et al. Therapeutic targeting of IL-6 trans signaling counteracts STAT3 control of experimental inflammatory arthritis. J Immunol. 2009;182(1):613–622.
  • Barkhausen T, Tschernig T, Rosenstiel P, et al. Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model. Crit Care Med. 2011;39(6):1407–1413.
  • van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367(6):508–519.
  • Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet. 2013;381(9865):451–460.
  • Kubo S, Nakayamada S, Tanaka Y. Baricitinib for the treatment of rheumatoid arthritis. Expert Rev Clin Immunol. 2016;12(9):911–919.
  • Takeuchi T, Tanaka Y, Iwasaki M, et al. Efficacy and safety of the oral Janus kinase inhibitor peficitinib (ASP015K) monotherapy in patients with moderate to severe rheumatoid arthritis in Japan: a 12-week, randomised, double-blind, placebo-controlled phase IIb study. Ann Rheum Dis. 2016;75(6):1057–1064.
  • Nishimoto N, Terao K, Mima T, et al. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008;112(10):3959–3964.
  • Fujimoto M, Serada S, Suzuki K, et al. Leucine-rich alpha2 -glycoprotein as a potential biomarker for joint inflammation during anti-interleukin-6 biologic therapy in rheumatoid arthritis. Arthritis Rheumatol. 2015;67(8):2056–2060.

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