Current status and prospects of IL-6–targeting therapy

References

• Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol. 1996;14(1):397–440.
   Google Scholar
• Hirano T, Yasukawa K, Harada H, et al. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature. 1986 Nov 6-12;324(6092):73–76.
   Google Scholar
• Kishimoto T. Interleukin-6: from basic science to medicine–40 years in immunology. Annu Rev Immunol. 2005;23(1):1–21.
   Google Scholar
• Suematsu S, Matsuda T, Aozasa K, et al. IgG1 plasmacytosis in interleukin 6 transgenic mice. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7547–7551.
   Google Scholar
• Kopf M, Baumann H, Freer G, et al. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature. 1994 Mar 24;368(6469):339–342.
   Google Scholar
• Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015 May;16(5):448–457.
   Google Scholar
• Narazaki M, Kishimoto T. The two-faced cytokine IL-6 in host defense and diseases. Int J Mol Sci. 2018 Nov 9;19(11):3528.
   Google Scholar
• Kang S, Tanaka T, Narazaki M, et al. Targeting interleukin-6 signaling in clinic. Immunity. 2019 Apr 16;50(4):1007–1023.
   Google Scholar
• Kishimoto T. IL-6: from arthritis to CAR-T-cell therapy and COVID-19. Int Immunol. 2021 Sep 25;33(10):515–519.
   Google Scholar
• Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014 Sep 4;6(10):a016295.
   Google Scholar
• Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004 Jul;4(7):499–511.
   Google Scholar
• Zimmermann M, Aguilera FB, Castellucci M, et al. Chromatin remodelling and autocrine TNFalpha are required for optimal interleukin-6 expression in activated human neutrophils. Nat Commun. 2015 Jan 23;6(1):6061.
   Google Scholar
• Garbers C, Heink S, Korn T, et al. Interleukin-6: designing specific therapeutics for a complex cytokine. Nat Rev Drug Discov. 2018 Jun;17(6):395–412.
   Google Scholar
• Ogura H, Murakami M, Okuyama Y, et al. Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction. Immunity. 2008 Oct 17;29(4):628–636.
   Google Scholar
• Ma J, Zhang FL, Zhou G, et al. Different characteristics of hepcidin expression in IL-6+/+ and IL-6-/- neurons and astrocytes treated with lipopolysaccharides. Neurochem Res. 2018 Aug;43(8):1624–1630.
   Google Scholar
• Zhang F, Wei K, Slowikowski K, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol. 2019 Jul;20(7):928–942.
   Google Scholar
• Yoshizaki K, Matsuda T, Nishimoto N, et al. Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman’s disease. Blood. 1989 Sep;74(4):1360–1367.
   Google Scholar
• Emilie D, Liozon E, Crevon MC, et al. Production of interleukin 6 by granulomas of giant cell arteritis. Hum Immunol. 1994 Jan;39(1):17–24.
   Google Scholar
• Feist E, Mitrovic S, Fautrel B. Mechanisms, biomarkers and targets for adult-onset Still’s disease. Nat Rev Rheumatol. 2018 Oct;14(10):603–618.
   Google Scholar
• Liu Y, Xia C, Chen J, et al. Elevated circulating pro-inflammatory low-density granulocytes in adult-onset Still’s disease. Rheumatology (Oxford). 2021 Jan 5;60(1):297–303.
   Google Scholar
• Fujihara K, Bennett JL, de Seze J, et al. Interleukin-6 in neuromyelitis optica spectrum disorder pathophysiology. Neurol Neuroimmunol Neuroinflamm. 2020 Sep 3;7(5):e841.
   Google Scholar
• Kong BS, Kim Y, Kim GY, et al. Increased frequency of IL-6-producing non-classical monocytes in neuromyelitis optica spectrum disorder. J Neuroinflammation. 2017 Sep 25;14(1):191.
   Google Scholar
• Sachdeva M, Duchateau P, Depil S, et al. Granulocyte-macrophage colony-stimulating factor inactivation in CAR T-cells prevents monocyte-dependent release of key cytokine release syndrome mediators. J Biol Chem. 2019 Apr 5;294(14):5430–5437.
   Google Scholar
• Zhou Y, Fu B, Zheng X, et al. Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients. Natl Sci Rev. 2020 Jun;7(6):998–1002.
   Google Scholar
• Kang S, Tanaka T, Inoue H, et al. IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome. Proc Natl Acad Sci U S A. 2020 Sep 8;117(36):22351–22356.
   Google Scholar
• 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 May 1;14(9):1942–1951.
   Google Scholar
• 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 Nov 15;89(22):10998–11001.
   Google Scholar
• Murakami M, Kamimura D, Hirano T. Pleiotropy and specificity: insights from the interleukin 6 family of cytokines. Immunity. 2019 Apr 16;50(4):812–831.
   Google Scholar
• Nanki T, Onoue I, Nagasaka K, et al. Suppression of elevations in serum C reactive protein levels by anti-IL-6 autoantibodies in two patients with severe bacterial infections. Ann Rheum Dis. 2013 Jun;72(6):1100–1102.
   Google Scholar
• Rose-John S. IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci. 2012;8(9):1237–1247.
   Google Scholar
• Heink S, Yogev N, Garbers C, et al. Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells. Nat Immunol. 2017 Jan;18(1):74–85.
   Google Scholar
• 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 Aug 15;82(4):1120–1126.
   Google Scholar
• Muller-Newen G, Kuster A, Hemmann U, et al. Soluble IL-6 receptor potentiates the antagonistic activity of soluble gp130 on IL-6 responses. J Immunol. 1998 Dec 1;161(11):6347–6355.
   Google Scholar
• Yamasaki K, Taga T, Hirata Y, et al. Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. Science. 1988 Aug 12;241(4867):825–828.
   Google Scholar
• Hirata Y, Taga T, Hibi M, et al. Characterization of IL-6 receptor expression by monoclonal and polyclonal antibodies. J Immunol. 1989 Nov 1;143(9):2900–2906.
   Google Scholar
• Sato K, Tsuchiya M, Saldanha J, et al. Reshaping a human antibody to inhibit the interleukin 6-dependent tumor cell growth. Cancer Res. 1993 Feb 15;53(4):851–856.
   Google Scholar
• Klein B, Wijdenes J, Zhang XG, et al. Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia. Blood. 1991 Sep 1;78(5):1198–1204.
   Google Scholar
• Yoshizaki K, Nishimoto N, Mihara M, et al. Therapy of rheumatoid arthritis by blocking IL-6 signal transduction with a humanized anti-IL-6 receptor antibody. Springer Semin Immunopathol. 1998;20(1–2):247–259.
   Google Scholar
• Nishimoto N, Kanakura Y, Aozasa K, et al. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood. 2005 Oct 15;106(8):2627–2632.
   Google Scholar
• Narazaki M, Tanaka T, Kishimoto T. The role and therapeutic targeting of IL-6 in rheumatoid arthritis. Expert Rev Clin Immunol. 2017 Jun;13(6):535–551.
   Google Scholar
• Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis. 2010 Jun;69(6):964–975.
   Google Scholar
• 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 May 4;381(9877):1541–1550.
   Google Scholar
• Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014 Mar;73(3):492–509.
   Google Scholar
• Nishimoto N, Yoshizaki K, Maeda K, et al. Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin 6 receptor antibody MRA in rheumatoid arthritis. Phase I/II clinical study. J Rheumatol. 2003 Jul;30(7):1426–1435.
   Google Scholar
• Frey N, Grange S, Woodworth T. Population pharmacokinetic analysis of tocilizumab in patients with rheumatoid arthritis. J Clin Pharmacol. 2010 Jul;50(7):754–766.
   Google Scholar
• 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 Nov 15;112(10):3959–3964.
   Google Scholar
• 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 Jun;67(6):1424–1437.
   Google Scholar
• 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. 2017 May;76(5):840–847.
   Google Scholar
• Rose-John S. The soluble interleukin 6 receptor: advanced therapeutic options in inflammation. Clin Pharmacol Ther. 2017 Oct;102(4):591–598.
   Google Scholar
• Miao S, Fan L, Zhao L, et al. Physicochemical and biological characterization of the proposed biosimilar tocilizumab. Biomed Res Int. 2017;2017:4926168.
   Google Scholar
• Zhang H, Wang H, Wei H, et al. A phase I clinical study comparing the tolerance, immunogenicity, and pharmacokinetics of proposed biosimilar BAT1806 and reference tocilizumab in healthy Chinese men. Front Pharmacol. 2020;11:609522.
   Google Scholar
• Zhang H, Li X, Liu J, et al. A randomized phase-I pharmacokinetic trial comparing the potential biosimilar tocilizumab (QX003S) with the reference product (Actemra((R))) in Chinese healthy subjects. Ann Med. 2021 Dec;53(1):375–383.
   Google Scholar
• Schwabe C, Illes A, Ullmann M, et al. Pharmacokinetics and pharmacodynamics of a proposed tocilizumab biosimilar MSB11456 versus both the US-licensed and EU-approved products: a randomized, double-blind trial. Expert Rev Clin Immunol. 2022 Mar 31;18(5):533–543.
   Google Scholar
• 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 Aug;15(9):966–974.
   Google Scholar
• Kretsos K, Golor G, Jullion A, et al. Safety and pharmacokinetics of olokizumab, an anti-IL-6 monoclonal antibody, administered to healthy male volunteers: a randomized phase I study. Clin Pharmacol Drug Dev. 2014 Sep;3(5):388–395.
   Google Scholar
• Nasonov E, Fatenejad S, Feist E, et al. Olokizumab, a monoclonal antibody against interleukin 6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by methotrexate: efficacy and safety results of a randomised controlled phase III study. Ann Rheum Dis. 2021 Aug 3;81(4):469–479.
   Google Scholar
• Aletaha D, Bingham CO 3rd, Tanaka Y, et al. Efficacy and safety of sirukumab in patients with active rheumatoid arthritis refractory to anti-TNF therapy (SIRROUND-T): a randomised, double-blind, placebo-controlled, parallel-group, multinational, phase 3 study. Lancet. 2017 Mar 25;389(10075):1206–1217.
   Google Scholar
• Takeuchi T, Thorne C, Karpouzas G, et al. Sirukumab for rheumatoid arthritis: the phase III SIRROUND-D study. Ann Rheum Dis. 2017 Dec;76(12):2001–2008.
   Google Scholar
• Avci AB, Feist E, Burmester GR. Targeting IL-6 or IL-6 receptor in rheumatoid arthritis: what’s the difference? BioDrugs. 2018 Dec;32(6):531–546.
   Google Scholar
• Kaur S, Bansal Y, Kumar R, et al. A panoramic review of IL-6: structure, pathophysiological roles and inhibitors. Bioorg Med Chem. 2020 Mar 1;28(5):115327.
   Google Scholar
• Russell B, Moss C, George G, et al. Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence. Ecancermedicalscience. 2020;14:1022.
   Google Scholar
• 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 Jun;50(6):1761–1769.
   Google Scholar
• Hiroshima R, Kawakami K, Iwamoto T, et al. Analysis of C-reactive protein levels and febrile tendency after joint surgery in rheumatoid arthritis patients treated with a perioperative 4-week interruption of tocilizumab. Mod Rheumatol. 2011 Feb;21(1):109–111.
   Google Scholar
• Suwa T, Hogg JC, English D, et al. Interleukin-6 induces demargination of intravascular neutrophils and shortens their transit in marrow. Am J Physiol Heart Circ Physiol. 2000 Dec;279(6):H2954–60.
   Google Scholar
• Moots RJ, Sebba A, Rigby W, et al. Effect of tocilizumab on neutrophils in adult patients with rheumatoid arthritis: pooled analysis of data from phase 3 and 4 clinical trials. Rheumatology (Oxford). 2017 Apr 1;56(4):541–549.
   Google Scholar
• 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 May;113(9):1271–1276.
   Google Scholar
• Song SN, Iwahashi M, Tomosugi N, et al. Comparative evaluation of the effects of treatment with tocilizumab and TNF-alpha inhibitors on serum hepcidin, anemia response and disease activity in rheumatoid arthritis patients. Arthritis Res Ther. 2013 Oct 2;15(5):R141.
   Google Scholar
• Gossec L, Steinberg G, Rouanet S, et al. Fatigue in rheumatoid arthritis: quantitative findings on the efficacy of tocilizumab and on factors associated with fatigue. The French multicentre prospective PEPS study. Clin Exp Rheumatol. 2015 Sep-Oct;33(5):664–670.
   Google Scholar
• Kaser A, Brandacher G, Steurer W, et al. Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis. Blood. 2001 Nov 1;98(9):2720–2725.
   Google Scholar
• 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 Nov;47(11):1635–1640.
   Google Scholar
• 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 Nov;54(11):3551–3563.
   Google Scholar
• Finzel S, Kraus S, Figueiredo CP, et al. Comparison of the effects of tocilizumab monotherapy and Adalimumab in combination with methotrexate on bone erosion repair in rheumatoid arthritis. Ann Rheum Dis. 2019 Sep;78(9):1186–1191.
   Google Scholar
• Ducreux J, Durez P, Galant C, et al. Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15–23.
   Google Scholar
• Humby F, Durez P, Buch MH, et al. Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial. Lancet. 2021 Jan 23;397(10271):305–317.
   Google Scholar
• Chatzidionysiou K, Circiumaru A, Rethi B, et al. Tocilizumab decreases T cells but not macrophages in the synovium of patients with rheumatoid arthritis while it increases the levels of serum interleukin-6 and RANKL. RMD Open. 2021 Jun;7(2):e001662.
   Google Scholar
• 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 May;66(5):1185–1194.
   Google Scholar
• Schraml BU, Hildner K, Ise W, et al. The AP-1 transcription factor Batf controls T(H)17 differentiation. Nature. 2009 Jul 16;460(7253):405–409.
   Google Scholar
• 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 Jun 4;110(23):9409–9414.
   Google Scholar
• Samson M, Audia S, Janikashvili N, et al. Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis. Arthritis Rheum. 2012 Aug;64(8):2499–2503.
   Google Scholar
• Pesce B, Soto L, Sabugo F, et al. Effect of interleukin-6 receptor blockade on the balance between regulatory T cells and T helper type 17 cells in rheumatoid arthritis patients. Clin Exp Immunol. 2013 Mar;171(3):237–242.
   Google Scholar
• 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 Jan 21;17(1):10.
   Google Scholar
• Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 2010 Jul;40(7):1830–1835.
   Google Scholar
• Nakamura S, Suzuki K, Iijima H, et al. Identification of baseline gene expression signatures predicting therapeutic responses to three biologic agents in rheumatoid arthritis: a retrospective observational study. Arthritis Res Ther. 2016 Jul 19;18(1):159.
   Google Scholar
• 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 May;63(5):1255–1264.
   Google Scholar
• Tasaki S, Suzuki K, Kassai Y, et al. Multi-omics monitoring of drug response in rheumatoid arthritis in pursuit of molecular remission. Nat Commun. 2018 Jul 16;9(1):2755.
   Google Scholar
• Nakajima T, Watanabe R, Hashimoto M, et al. Neutrophil count reduction 1 month after initiating tocilizumab can predict clinical remission within 1 year in rheumatoid arthritis patients. Rheumatol Int. 2021 Jul 9. DOI:10.1007/s00296-021-04944-x.
   Google Scholar
• Nishimoto N, Amano K, Hirabayashi Y, et al. Drug free REmission/low disease activity after cessation of tocilizumab (Actemra) Monotherapy (DREAM) study. Mod Rheumatol. 2014 Jan;24(1):17–25.
   Google Scholar
• Spencer S, Kostel Bal S, Egner W, et al. Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses. J Exp Med. 2019 Sep 2;216(9):1986–1998.
   Google Scholar
• Koike T, Harigai M, Inokuma S, et al. Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients. Ann Rheum Dis. 2011 Dec;70(12):2148–2151.
   Google Scholar
• Navarini AA, French LE, Hofbauer GF. Interrupting IL-6-receptor signaling improves atopic dermatitis but associates with bacterial superinfection. J Allergy Clin Immunol. 2011 Nov;128(5):1128–1130.
   Google Scholar
• Massolino RI, Hissaria P, Lee A, et al. Tocilizumab-induced drug reaction with eosinophilia and systemic symptoms (DRESS) in a patient with rheumatoid arthritis. Rheumatol Adv Pract. 2018;2(2):rky029.
   Google Scholar
• Bloomfield M, Parackova Z, Cabelova T, et al. Anti-IL6 autoantibodies in an infant with CRP-less septic shock. Front Immunol. 2019;10:2629.
   Google Scholar
• Morel J, Constantin A, Baron G, et al. Risk factors of serious infections in patients with rheumatoid arthritis treated with tocilizumab in the French registry REGATE. Rheumatology (Oxford). 2017 Oct 1;56(10):1746–1754.
   Google Scholar
• 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 Apr;54(4):601–608.
   Google Scholar
• Yokota S, Imagawa T, Mori M, 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 Mar 22;371(9617):998–1006.
   Google Scholar
• Miyamae T, Yokoya S, Yamanaka H, et al. Effect of tocilizumab on growth impairment in systemic juvenile idiopathic arthritis with long-term corticosteroid therapy. Mod Rheumatol. 2014 Jul;24(4):567–571.
   Google Scholar
• De Benedetti F, Brunner H, Ruperto N, et al. Catch-up growth during tocilizumab therapy for systemic juvenile idiopathic arthritis: results from a phase III trial. Arthritis Rheumatol. 2015 Mar;67(3):840–848.
   Google Scholar
• Stone JH, Tuckwell K, Dimonaco S, et al. Trial of tocilizumab in giant-cell arteritis. N Engl J Med. 2017 Jul 27;377(4):317–328.
   Google Scholar
• Nakaoka Y, Isobe M, Takei S, et al. Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis: results from a randomised, double-blind, placebo-controlled, phase 3 trial in Japan (the TAKT study). Ann Rheum Dis. 2018 Mar;77(3):348–354.
   Google Scholar
• Mekinian A, Resche-Rigon M, Comarmond C, et al. Efficacy of tocilizumab in Takayasu arteritis: multicenter retrospective study of 46 patients. J Autoimmun. 2018 Jul;91:55–60.
   Google Scholar
• Ma 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 Sep;28(5):849–857.
   Google Scholar
• Kaneko 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 Dec;77(12):1720–1729.
   Google Scholar
• Tanaka T, Narazaki M, Kishimoto T. Immunotherapeutic implications of IL-6 blockade for cytokine storm. Immunotherapy. 2016 Jul;8(8):959–970.
   Google Scholar
• 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 Feb;45(2):e124–e131.
   Google Scholar
• Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054–1062.
   Google Scholar
• Mazzoni A, Salvati L, Maggi L, et al. Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent. J Clin Invest. 2020 Sep 1;130(9):4694–4703.
   Google Scholar
• Labo N, Ohnuki H, Tosato G. Vasculopathy and coagulopathy associated with SARS-CoV-2 infection. Cells. 2020 Jun 30;9(7):1583.
   Google Scholar
• Kenny G, Mallon PWG. Tocilizumab for the treatment of non-critical COVID-19 pneumonia: an overview of the rationale and clinical evidence to date. Expert Rev Clin Pharmacol. 2021 Oct;14(10):1279–1287.
   Google Scholar
• Aziz M, Haghbin H, Abu Sitta E, et al. Efficacy of tocilizumab in COVID-19: a systematic review and meta-analysis. J Med Virol. 2021 Mar;93(3):1620–1630.
   Google Scholar
• Hariyanto TI, Hardyson W, Kurniawan A. Efficacy and safety of tocilizumab for coronavirus disease 2019 (Covid-19) patients: a systematic review and meta-analysis. Drug Res (Stuttg). 2021 May;71(5):265–274.
   Google Scholar
• Patel S, Saxena B, Mehta P. Recent updates in the clinical trials of therapeutic monoclonal antibodies targeting cytokine storm for the management of COVID-19. Heliyon. 2021 Feb;7(2):e06158.
   Google Scholar
• Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015 Jul 14;85(2):177–189.
   Google Scholar
• 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 Mar 1;108(9):3701–3706.
   Google Scholar
• Xie Q, Zheng T, Sun M, et al. A meta-analysis to determine the efficacy and safety of tocilizumab in neuromyelitis optica spectrum disorders. Mult Scler Relat Disord. 2020 Oct;45:102421.
   Google Scholar
• 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 Nov;28(11):1203–1207.
   Google Scholar
• Yamamura T, Kleiter I, Fujihara K, et al. Trial of satralizumab in neuromyelitis optica spectrum disorder. N Engl J Med. 2019 Nov 28;381(22):2114–2124.
   Google Scholar
• Bahn RS. Graves’ ophthalmopathy. N Engl J Med. 2010 Feb 25;362(8):726–738.
   Google Scholar
• Khong JJ, McNab AA, Ebeling PR, et al. Pathogenesis of thyroid eye disease: review and update on molecular mechanisms. Br J Ophthalmol. 2016 Jan;100(1):142–150.
   Google Scholar
• Perez-Moreiras JV, Gomez-Reino JJ, Maneiro JR, et al. Efficacy of tocilizumab in patients with moderate-to-severe corticosteroid-resistant graves orbitopathy: a randomized clinical trial. Am J Ophthalmol. 2018 Nov;195:181–190.
   Google Scholar
• Bartalena L, Kahaly GJ, Baldeschi L, et al. The 2021 European group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy. Eur J Endocrinol. 2021 Aug 27;185(4):G43–G67.
   Google Scholar
• Dalmau J, Lancaster E, Martinez-Hernandez E, et al. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011 Jan;10(1):63–74.
   Google Scholar
• Lee WJ, Lee ST, Moon J, et al. Tocilizumab in autoimmune encephalitis refractory to rituximab: an institutional Cohort study. Neurotherapeutics. 2016 Oct;13(4):824–832.
   Google Scholar
• Nosadini M, Thomas T, and Eyre M, et al. International consensus recommendations for the treatment of pediatric NMDAR antibody encephalitis. Neurol Neuroimmunol Neuroinflamm. 2021 Jul;8(5). DOI:10.1212/NXI.0000000000001052.
   Google Scholar
• Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis. 2007 Jul;66(7):940–944.
   Google Scholar
• Gao X, Jia G, Guttman A, et al. Osteopontin links myeloid activation and disease progression in systemic sclerosis. ell Rep Med. 2020 Nov 17;1(8):100140.
   Google Scholar
• 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 Jun 25;387(10038):2630–2640.
   Google Scholar
• Khanna D, Lin CJF, Furst DE, et al. Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2020 Oct;8(10):963–974.
   Google Scholar
• Avina-Zubieta JA, Thomas J, Sadatsafavi M, et al. Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis. 2012 Sep;71(9):1524–1529.
   Google Scholar
• Peters MJ, Symmons DP, McCarey D, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis. 2010 Feb;69(2):325–331.
   Google Scholar
• Pierini FS, Botta E, Soriano ER, et al. Effect of tocilizumab on LDL and HDL characteristics in patients with rheumatoid arthritis. An Observational Study. Rheumatol Ther. 2021 Jun; 8(2):803–815
   Google Scholar
• Greco D, Gualtierotti R, Agosti P, et al. Anti-atherogenic modification of serum lipoprotein function in patients with rheumatoid arthritis after tocilizumab treatment, a pilot study. J Clin Med. 2020 Jul 8;9(7):2157.
   Google Scholar
• Singh S, Fumery M, Singh AG, et al. Comparative risk of cardiovascular events with biologic and synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a systematic review and meta-analysis. Arthritis Care Res (Hoboken). 2020 Apr;72(4):561–576.
   Google Scholar
• Zamani P, Schwartz GG, Olsson AG, et al. Inflammatory biomarkers, death, and recurrent nonfatal coronary events after an acute coronary syndrome in the MIRACL study. J Am Heart Assoc. 2013 Jan 28;2(1):e003103.
   Google Scholar
• Kleveland O, Kunszt G, Bratlie M, et al. Effect of a single dose of the interleukin-6 receptor antagonist tocilizumab on inflammation and troponin T release in patients with non-ST-elevation myocardial infarction: a double-blind, randomized, placebo-controlled phase 2 trial. Eur Heart J. 2016 Aug 7;37(30):2406–2413.
   Google Scholar
• Carroll MB, Haller C, Smith C. Short-term application of tocilizumab during myocardial infarction (STAT-MI). Rheumatol Int. 2018 Jan;38(1):59–66.
   Google Scholar
• Meyer MAS, Wiberg S, Grand J, et al. Treatment effects of interleukin-6 receptor antibodies for modulating the systemic inflammatory response after out-of-hospital cardiac arrest (The IMICA Trial): a double-blinded, placebo-controlled, single-center, randomized, clinical trial. Circulation. 2021 May 11;143(19):1841–1851.
   Google Scholar
• Bonelli M, Radner H, Kerschbaumer A, et al. Tocilizumab in patients with new onset polymyalgia rheumatica (PMR-SPARE): a phase 2/3 randomised controlled trial. Ann Rheum Dis. 2022 Feb 24;81(6):838–844.
   Google Scholar
• Chandran S, Leung J, Hu C, et al. Interleukin-6 blockade with tocilizumab increases Tregs and reduces T effector cytokines in renal graft inflammation: a randomized controlled trial. Am J Transplant. 2021 Jul;21(7):2543–2554.
   Google Scholar
• Marrie RA, Hitchon CA, Walld R, et al. Increased burden of psychiatric disorders in rheumatoid arthritis. Arthritis Care Res (Hoboken). 2018 Jul;70(7):970–978.
   Google Scholar
• Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010 Mar 1;67(5):446–457.
   Google Scholar
• Tiosano S, Yavne Y, Watad A, et al. The impact of tocilizumab on anxiety and depression in patients with rheumatoid arthritis. Eur J Clin Invest. 2020 Sep;50(9):e13268.
   Google Scholar
• Sun Y, Wang D, Salvadore G, et al. The effects of interleukin-6 neutralizing antibodies on symptoms of depressed mood and anhedonia in patients with rheumatoid arthritis and multicentric Castleman’s disease. Brain Behav Immun. 2017 Nov;66:156–164.
   Google Scholar
• Okuda Y, Ohnishi M, Matoba K, et al. Comparison of the clinical utility of tocilizumab and anti-TNF therapy in AA amyloidosis complicating rheumatic diseases. Mod Rheumatol. 2014 Jan;24(1):137–143.
   Google Scholar
• Akiyama M, Kaneko Y, Takeuchi T. Effectiveness of tocilizumab in Behcet’s disease: a systematic literature review. Semin Arthritis Rheum. 2020 Aug;50(4):797–804.
   Google Scholar
• Kirino Y, Takase-Minegishi K, Tsuchida N, et al. Tocilizumab in VEXAS relapsing polychondritis: a single-center pilot study in Japan. Ann Rheum Dis. 2021 Nov;80(11):1501–1502.
   Google Scholar
• Stroud CR, Hegde A, Cherry C, et al. Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade. J Oncol Pharm Pract. 2019 Apr;25(3):551–557.
   Google Scholar
• Jin L, Sun Z, Liu H, et al. Inflammatory monocytes promote pre-engraftment syndrome and tocilizumab can therapeutically limit pathology in patients. Nat Commun. 2021 Jul 6;12(1):4137.
   Google Scholar
• Elsbernd PM, Hoffman WR, Carter JL, et al. Interleukin-6 inhibition with tocilizumab for relapsing MOG-IgG associated disorder (MOGAD): a case-series and review. Mult Scler Relat Disord. 2021 Feb;48:102696.
   Google Scholar
• Sieper J, Porter-Brown B, Thompson L, et al. Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann Rheum Dis. 2014 Jan;73(1):95–100.
   Google Scholar
• Sieper J, Braun J, Kay J, 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 Jun;74(6):1051–1057.
   Google Scholar
• Mease PJ, Gottlieb AB, Berman A, et al. The efficacy and safety of clazakizumab, an anti-interleukin-6 monoclonal antibody, in a phase IIb study of adults with active psoriatic arthritis. Arthritis Rheumatol. 2016 Sep;68(9):2163–2173.
   Google Scholar
• Kennedy GA, Tey SK, Buizen L, et al. A phase 3 double-blind study of the addition of tocilizumab vs placebo to cyclosporin/methotrexate GVHD prophylaxis. Blood. 2021 Apr 8;137(14):1970–1979.
   Google Scholar
• Rutherford AI, Subesinghe S, Hyrich KL, et al. Serious infection across biologic-treated patients with rheumatoid arthritis: results from the British society for rheumatology biologics register for rheumatoid arthritis. Ann Rheum Dis. 2018 Jun;77(6):905–910.
   Google Scholar
• Yun H, Xie F, Delzell E, et al. Comparative risk of hospitalized infection associated with biologic agents in rheumatoid arthritis patients enrolled in medicare. Arthritis Rheumatol. 2016 Jan;68(1):56–66.
   Google Scholar
• 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 Feb 3;15(2):103–113.
   Google Scholar
• Taniguchi K, Wu LW, Grivennikov SI, et al. A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature. 2015 Mar 5;519(7541):57–62.
   Google Scholar
• 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 Mar;76(3):504–510.
   Google Scholar
• Weber-Schoendorfer C, Schaefer C. Pregnancy outcome after tocilizumab therapy in early pregnancy-a case series from the German embryotox pharmacovigilance center. Reprod Toxicol. 2016 Apr;60:29–32.
   Google Scholar
• Nakajima K, Watanabe O, Mochizuki M, et al. Pregnancy outcomes after exposure to tocilizumab: a retrospective analysis of 61 patients in Japan. Mod Rheumatol. 2016 Sep;26(5):667–671.
   Google Scholar
• Hoeltzenbein M, Beck E, Rajwanshi R, 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 Oct;46(2):238–245.
   Google Scholar
• Saito J, Yakuwa N, Kaneko K, et al. Tocilizumab during pregnancy and lactation: drug levels in maternal serum, cord blood, breast milk and infant serum. Rheumatology (Oxford). 2019 Aug 1;58(8):1505–1507.
   Google Scholar
• Saito J, Yakuwa N, Takai C, et al. Tocilizumab concentrations in maternal serum and breast milk during breastfeeding and a safety assessment in infants: a case study. Rheumatology (Oxford). 2018 Aug 1;57(8):1499–1501.
   Google Scholar
• De Benedetti F, Brunner HI, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012 Dec 20;367(25):2385–2395.
   Google Scholar
• Russo RA, Katsicas MM. Patients with very early-onset systemic juvenile idiopathic arthritis exhibit more inflammatory features and a worse outcome. J Rheumatol. 2013 Mar;40(3):329–334.
   Google Scholar
• Mallalieu NL, Wimalasundera S, Hsu JC, et al. Intravenous dosing of tocilizumab in patients younger than two years of age with systemic juvenile idiopathic arthritis: results from an open-label phase 1 clinical trial. Pediatr Rheumatol Online J. 2019 Aug 22;17(1):57.
   Google Scholar
• Kaneshiro S, Ebina K, Hirao M, et al. The efficacy and safety of additional administration of tacrolimus in patients with rheumatoid arthritis who showed an inadequate response to tocilizumab. Mod Rheumatol. 2017 Jan;27(1):42–49.
   Google Scholar
• Lerner A, Neidhofer S, Reuter S, et al. MMP3 is a reliable marker for disease activity, radiological monitoring, disease outcome predictability, and therapeutic response in rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2018 Aug;32(4):550–562.
   Google Scholar
• Ghang B, Kwon O, Hong S, et al. Neutrophil-to-lymphocyte ratio is a reliable marker of treatment response in rheumatoid arthritis patients during tocilizumab therapy. Mod Rheumatol. 2017 May;27(3):405–410.
   Google Scholar
• Naka T, Fujimoto M. LRG is a novel inflammatory marker clinically useful for the evaluation of disease activity in rheumatoid arthritis and inflammatory bowel disease. Immunol Med. 2018 Jun;41(2):62–67.
   Google Scholar
• Shimabukuro-Vornhagen A, Godel P, Subklewe M, et al. Cytokine release syndrome. J Immunother Cancer. 2018 Jun 15;6(1):56.
   Google Scholar
• Illei GG, Shirota Y, Yarboro CH, et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum. 2010 Feb;62(2):542–552.
   Google Scholar
• 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 Mar;63(3):609–621.
   Google Scholar
• 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 Sep;66(9):1162–1167.
   Google Scholar
• Bijlsma JWJ, Welsing PMJ, 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 Jul 23;388(10042):343–355.
   Google Scholar
• Yamaguchi N, Ohshima S, Umeshita-Sasai M, et al. Synergistic effect on the attenuation of collagen induced arthritis in tumor necrosis factor receptor I (TNFRI) and interleukin 6 double knockout mice. J Rheumatol. 2003 Jan;30(1):22–27.
   Google Scholar