14,640
Views
118
CrossRef citations to date
0
Altmetric
Special Review: IL-6 inhibitor

IL-6 inhibitor for the treatment of rheumatoid arthritis: A comprehensive review

ORCID Icon, ORCID Icon, &
Pages 258-267 | Received 12 Sep 2018, Accepted 31 Oct 2018, Published online: 03 Jan 2019

References

  • Kishimoto T. Interleukin-6: from basic science to medicine-40 years in immunology. Annu Rev Immunol. 2005;23:1–21.
  • Houssiau FA, Devogelaer JP, Van Damme J, de Deuxchaisnes CN, Van Snick J. Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum. 1988;31(6):784–8.
  • Ospelt C. Synovial fibroblasts in 2017. RMD Open. 2017;3(2):e000471.15
  • Okamoto H, Yamamura M, Morita Y, Harada S, Makino H, Ota Z. The synovial expression and serum levels of interleukin-6, interleukin-11, leukemia inhibitory factor, and oncostatin M in rheumatoid arthritis. Arthritis Rheum. 1997;40(6):1096–105.
  • MacNaul KL, Hutchinson NI, Parsons JN, Bayne EK, Tocci MJ. Analysis of IL-1 and TNF-alpha gene expression in human rheumatoid synoviocytes and normal monocytes by in situ hybridization. J Immunol. 1990;145:4154–66.
  • Schinnerling K, Aguillon JC, Catalan D, Soto L. The role of interleukin-6 signalling and its therapeutic blockage in skewing the T cell balance in rheumatoid arthritis. Clin Exp Immunol. 2017;189(1):12–20.
  • Hata H, Sakaguchi N, Yoshitomi H, Iwakura Y, Sekikawa K, Azuma Y, et al. Distinct contribution of IL-6, TNF-α, IL-1, and IL-10 to T cell? mediated spontaneous autoimmune arthritis in mice. J Clin Invest. 2004;114(4):582–8.
  • Sasai M, Saeki Y, Ohshima S, Nishioka K, Mima T, Tanaka T, et al. Delayed onset and reduced severity of collagen-induced arthritis in interleukin-6-deficient mice. Arthritis Rheum. 1999;42(8):1635–43.
  • Tada Y, Ho A, Koh DR, Mak TW. Collagen-induced arthritis in CD4- or CD8-deficient mice: CD8+ T cells play a role in initiation and regulate recovery phase of collagen-induced arthritis. J Immunol. 1996;156(11):4520–6.
  • Kagari T, Doi H, Shimozato T. The importance of IL-1 beta and TNF-alpha, and the noninvolvement of IL-6, in the development of monoclonal antibody-induced arthritis. J Immunol. 2002;169(3):1459–66.
  • Sato K, Tsuchiya M, Saldanha J, Koishihara Y, Ohsugi Y, Kishimoto T, Bendig MM. Reshaping a human antibody to inhibit the interleukin 6-dependent tumor cell growth. Cancer Res. 1993;53(4):851–6.
  • Ogata A, Hirano T, Hishitani Y, Tanaka T. Safety and efficacy of tocilizumab for the treatment of rheumatoid arthritis. Clin Med Insights Arthritis Musculoskelet Disord. 2012;5:27–42.
  • Ogata A, Morita T, Yoshida Y, Tanaka T. Subcutaneous formulation of tocilizumab for treatment of rheumatoid arthritis. Ther Deliv. 2015;6(3):283–95.
  • Turkstra E, Ng SK, Scuffham PA. A mixed treatment comparison of the short-term efficacy of biologic disease modifying anti-rheumatic drugs in established rheumatoid arthritis. Curr Med Res Opin. 2011;27(10):1885–97.
  • Jones G, Darian-Smith E, Kwok M, Winzenberg T. Effect of biologic therapy on radiological progression in rheumatoid arthritis: what does it add to methotrexate? Biologics 2012;6:155–61.
  • Koike T, Harigai M, Inokuma S, Ishiguro N, Ryu J, Takeuchi T. Effectiveness and safety of tocilizumab: postmarketing surveillance of 7901 patients with rheumatoid arthritis in Japan. J Rheumatol. 2014;4:15–23.
  • ohleder N, Aringer M, Boentert M. Role of interleukin-6 in stress, sleep, and fatigue. Ann N Y Acad Sci. 2012;1261:88–96.
  • Maes M, Scharpé S, Meltzer HY, Bosmans E, Suy E, Calabrese J, Cosyns P. Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic-pituitary-adrenal axis in severe depression. Psychiatry Res. 1993;49(1):11–27.
  • Fragiadaki K, Tektonidou MG, Konsta M, Chrousos GP, Sfikakis PP. Sleep disturbances and interleukin 6 receptor inhibition in rheumatoid arthritis. J Rheumatol. 2012;39(1):60–2.
  • Gossec L, Steinberg G, Rouanet S, Combe B. 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;33:664–70.
  • Townes SV, Furst DE, Thenkondar A. The impact of tocilizumab on physical function and quality of life in patients with rheumatoid arthritis: a systematic literature review and interpretation. Open Access Rheumatol. 2012;4:87–92.
  • Harrold LR, John A, Reed GW, Haselkorn T, Karki C, Li Y, et al. Impact of tocilizumab monotherapy on clinical and patient-reported quality-of-life outcomes in patients with rheumatoid arthritis. Rheumatol Ther. 2017;4(2):405–17.
  • Tanaka Y, Kameda H, Saito K, Kaneko Y, Tanaka E, Yasuda S, et al. IL-6 affect the Effect of subcutaneous tocilizumab treatment on work/housework status in biologic-naïve rheumatoid arthritis patients using inverse probability of treatment weighting: FIRST ACT-SC study. Arthritis Res Ther. 2018;20:151.
  • Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113(9):1271–6.
  • Nakazawa S, Tomosugi N, Kawabata H, Ishikawa T, Nishikawa T, Yoshizaki K. 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):3627–34.
  • Fève B, Bastard JP. The role of interleukins in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol. 2009;5(6):305–11.
  • Ogata A, Morishima A, Hirano T, Hishitani Y, Hagihara K, Shima Y, et al. Improvement of HbA1c during treatment with humanised anti-interleukin 6 receptor antibody, tocilizumab. Ann Rheum Dis. 2011;70(6):1164–5.
  • Hagihara K, Nishikawa T, Isobe T, Song J, Sugamata Y, Yoshizaki K. IL-6 plays a critical role in the synergistic induction of human serum amyloid A (SAA) gene when stimulated with proinflammatory cytokines as analyzed with an SAA isoform real-time quantitative RT-PCR assay system. Biochem Biophys Res Commun. 2004;314:363–9.
  • Yoshizaki K. Basic and Clinical Significance of Interleukin 6 (IL-6) AA Amyloidosis. Proceedings of the XIIIth International Symposium on Amyloidosis; 2012 May 6–10, Groningen, Netherlands. p. 394–7.
  • Nishida S, Hagihara K, Shima Y, Kawai M, Kuwahara Y, Arimitsu J, et al. Rapid improvement of AA amyloidosis with humanised anti-interleukin 6 receptor antibody treatment. Ann Rheum Dis. 2009;68(7):1235–6.
  • Nishimoto N, Terao K, Mima T, Nakahara H, Takagi N, Kakehi T. 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):3959–64.
  • Ogata A, Atsumi T, Fukuda T, Hirabayashi Y, Inaba M, Ishiguro NK, et al. Results of switching from intravenous to subcutaneous tocilizumab monotherapy in patients with rheumatoid arthritis: extension of the MUSASHI study. Arthritis Care Res (Hoboken). 2015;67(10):1354–62.
  • Saiki O, Uda H. Successful extension of tocilizumab infusion intervals from 4 weeks to 6 or 5 weeks in 90% of RA patients with good response to 4-week intervals. Clin Exp Rheumatol. 2017;35(4):666–70.
  • Ogata A, Amano K, Dobashi H, Inoo M, Ishii T, Kasama T, et al. Longterm safety and efficacy of subcutaneous tocilizumab monotherapy: results from the 2-year open-label extension of the MUSASHI study. J Rheumatol. 2015;42(5):799–809.
  • Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54:26–37.
  • Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 2004;363(9410):675–81.
  • Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ, 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.
  • Nishimoto N, Hashimoto J, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, 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):1162–7.
  • Nishimoto N, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Azuma J, 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;19:12–9.
  • Genovese MC, McKay JD, Nasonov EL, Mysler EF, da Silva NA, Alecock E, 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):2968–80.
  • Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, 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):1516–23.
  • Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, 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):987–97.
  • Kremer JM, Blanco R, Brzosko M, Burgos-Vargas R, Halland AM, Vernon E, 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):609–21.
  • Ogata A, Tanimura K, Sugimoto T, Inoue H, Urata Y, Matsubara 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):344–54.
  • Burmester GR, Rubbert-Roth A, Cantagrel A, Hall S, Leszczynski P, Feldman D, et al. Efficacy and safety of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional DMARDs in patients with RA at week 97 (SUMMACTA). Ann Rheum Dis. 2016;75(1):68–74.
  • Kivitz A, Olech E, Borofsky M, Zazueta BM, Navarro-Sarabia F, Radominski SC, et al. Subcutaneous tocilizumab versus placebo in combination with disease-modifying antirheumatic drugs in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2014;66(11):1653–61.
  • Ogata A, Tanaka Y, Ishii T, Kaneko M, Miwa H, Ohsawa S, et al. A randomized, double-blind, parallel-group, phase III study of shortening the dosing interval of subcutaneous tocilizumab monotherapy in patients with rheumatoid arthritis and an inadequate response to subcutaneous tocilizumab every other week: results of the 12-week double-blind period. Mod Rheumatol. 2018;28:76–84.
  • Dougados M, Kissel K, Sheeran T, Tak PP, Conaghan PG, Mola EM, 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.
  • Kaneko Y, Atsumi T, Tanaka Y, Inoo M, Kobayashi-Haraoka H, Amano K, et al. Comparison of adding tocilizumab to methotrexate with switching to tocilizumab in patients with rheumatoid arthritis with inadequate response to methotrexate: 52-week results from a prospective, randomised, controlled study (SURPRISE study). Ann Rheum Dis. 2016;75(11):1917–23.
  • Burmester GR, Rigby WF, van Vollenhoven RF, Kay J, Rubbert-Roth A, Kelman A, et al. Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial. Ann Rheum Dis. 2016;75(6):1081–91.
  • Bijlsma JWJ, Welsing PMJ, Woodworth TG, Middelink LM, Pethö-Schramm A, Bernasconi C, 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):343–55.
  • Gabay C, Emery P, van Vollenhoven R, Dikranian A, Alten R, Pavelka K, 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):1541–50.
  • Dougados M, Kissel K, Conaghan PG, Mola EM, Schett G, Gerli R, et al. Clinical, radiographic and immunogenic effects after 1 year of tocilizumab-based treatment strategies in rheumatoid arthritis: the ACT-RAY study. Ann Rheum Dis. 2014;73(5):803–9.
  • Smolen JS, Landewe R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76:960–77.
  • Burmester GR, Choy E, Kivitz A, Ogata A, Bao M, Nomura A, et al. Low immunogenicity of tocilizumab in patients with rheumatoid arthritis. Ann Rheum Dis. 2017;76(6):1078–85.
  • Leffers HC, Ostergaard M, Glintborg B, Krogh NS, Foged H, Tarp U, et al. Efficacy of abatacept and tocilizumab in patients with rheumatoid arthritis treated in clinical practice: results from the nationwide Danish DANBIO registry. Ann Rheum Dis. 2011;70(7):1216–22.
  • Hishitani Y, Ogata A, Shima Y, Hirano T, Ebina K, Kunugiza Y, et al. Retention of tocilizumab and anti-tumour necrosis factor drugs in the treatment of rheumatoid arthritis. Scand J Rheumatol. 2013;42(4):253–9.
  • Choy EH, Bernasconi C, Aassi M, Molina JF, Epis OM. Treatment of rheumatoid arthritis with anti-tumor necrosis factor or tocilizumab therapy as first biologic agent in a global comparative observational study. Arthritis Care Res (Hoboken). 2017;69(10):1484–94.
  • Nishimoto N, Amano K, Hirabayashi Y, Horiuchi T, Ishii T, Iwahashi M, et al. Drug free REmission/low disease activity after cessation of tocilizumab (Actemra) Monotherapy (DREAM) study. Mod Rheumatol. 2014;24(1):17–25.
  • Huizinga TW, Conaghan PG, Martin-Mola E, Schett G, Amital H, Xavier RM, et al. Clinical and radiographic outcomes at 2-years and the effect of tocilizumab discontinuation following sustained remission in the second and third year of the ACT-RAY study. Ann Rheum Dis. 2015;74(1):35–43.
  • Kaneko Y, Kato M, Tanaka Y, Inoo M, Kobayashi-Haraoka H, Amano K, et al. Tocilizumab discontinuation after attaining remission in patients with rheumatoid arthritis who were treated with tocilizumab alone or in combination with methotrexate: results from a prospective randomised controlled study (the second year of the SURPRISE study). Ann Rheum Dis. 2018;77(9):1268–75.
  • Nishimoto N, Amano K, Hirabayashi Y, Horiuchi T, Ishii T, Iwahashi M, et al. Retreatment efficacy and safety of tocilizumab in patients with rheumatoid arthritis in recurrence (RESTORE) study. Mod Rheumatol. 2014;24(1):26–32.
  • Fortunet C, Pers YM, Lambert J, Godfrin-Valnet M, Constant E, Devilliers H, et al. Tocilizumab induces corticosteroid sparing in rheumatoid arthritis patients in clinical practice. Rheumatology (Oxford). 2015;54(4):672–7.
  • Kremer JM, Rigby W, Singer NG, Birchwood C, Gill D, Reiss W, et al. Sustained response following discontinuation of methotrexate in patients with rheumatoid arthritis treated with subcutaneous tocilizumab: results from a randomized, controlled trial. Arthritis Rheumatol. 2018;70(8):1200.
  • Schiff MH, Kremer JM, Jahreis A, Vernon E, Isaacs JD, van Vollenhoven RF. Integrated safety in tocilizumab clinical trials. Arthritis Res Ther. 2011;13(5):R141.
  • Nishimoto N, Ito K, Takagi N. Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis: meta-analysis of six initial trials and five long-term extensions. Mod Rheumatol. 2010;20(3):222–32.
  • Mohan S, Michalska M, Yourish J, Pei J, Gale S, Birchwood C, et al. Long-term safety of tocilizumab from large clinical trial and postmarketing populations. Ann Rheum Dis. 2017;76 (suppl 2):95.
  • Bykerk VP, Ostör AJ, Alvaro-Gracia J, Pavelka K, Ivorra JA, Graninger W, 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):1950–4.
  • Kivitz A, Olech E, Borofsky MA, Zazueta B, Navarro-Sarabia F, Radominski SC, et al. Two-year efficacy and safety of subcutaneous tocilizumab in combination with disease-modifying antirheumatic drugs including escalation to weekly dosing in rheumatoid arthritis. J Rheumatol. 2018;45(4):456–64.
  • Choy E, Caporali R, Xavier R, Fautrel B, Sanmarti R, Bao M, et al. Subcutaneous tocilizumab in rheumatoid arthritis: findings from the common-framework phase 4 study programme TOZURA conducted in 22 countries. Rheumatology (Oxford). 2018;57(3):499–507.
  • Atsumi T, Fujio K, Yamaoka K, Tomobe M, Kuroyanagi K, Kameda H. Safety and effectiveness of subcutaneous tocilizumab in patients with rheumatoid arthritis in a real-world clinical setting. Mod Rheumatol. 2018;28(5):780–88.
  • Singh JA, Wells GA, Christensen R, Tanjong Ghogomu E, Maxwell L, Macdonald JK, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011;(2):CD008794.
  • Campbell L, Chen C, Bhagat SS, Parker RA, Östör AJ. Risk of adverse events including serious infections in rheumatoid arthritis patients treated with tocilizumab: a systematic literature review and meta-analysis of randomized controlled trials. Rheumatology (Oxford). 2011;50(3):552–62.
  • Sakai R, Cho SK, Nanki T, Watanabe K, Yamazaki H, Tanaka M, et al. Head-to-head comparison of the safety of tocilizumab and tumor necrosis factor inhibitors in rheumatoid arthritis patients (RA) in clinical practice: results from the registry of Japanese RA patients on biologics for long-term safety (REAL) registry. Arthritis Res Ther. 2015;17:74.
  • Fujiwara H, Nishimoto N, Hamano Y, Asanuma N, Miki S, Kasayama S, et al. Masked early symptoms of pneumonia in patients with rheumatoid arthritis during tocilizumab treatment: a report of two cases. Mod Rheumatol. 2009;19(1):64–8.
  • Atsumi T, Ando Y, Matsuda S, Tomizawa S, Tanaka R, Takagi N, et al. Prodromal signs and symptoms of serious infections with tocilizumab treatment for rheumatoid arthritis: text mining of the Japanese postmarketing adverse event-reporting database. Mod Rheumatol. 2018;28(3):435–43.
  • Kourbeti IS, Ziakas PD, Mylonakis E. Biologic therapies in rheumatoid arthritis and the risk of opportunistic infections: a meta-analysis. Clin Infect Dis. 2014;58(12):1649–57.
  • Rutherford AI, Patarata E, Subesinghe S, Hyrich KL, Galloway JB. Opportunistic infections in rheumatoid arthritis patients exposed to biologic therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Rheumatology (Oxford). 2018;57(6):997–1001.
  • Yun H, Xie F, Delzell E, Chen L, Levitan EB, Lewis JD, et al. Risks of herpes zoster in patients with rheumatoid arthritis according to biologic disease modifying therapy. Arthritis Care Res (Hoboken). 2015;67(5):731–6.
  • Sout A, Maneiro JR, Salgado E, Carmona L, Gomez-Reino JJ. Risk of tuberculosis in patients with chronic immune-mediated inflammatory diseases treated with biologics and tofacitinib a systematic review and meta-analysis of randomized controlled trials and long-term extension studies. Rheumatology 2014;53:1872–85.
  • Ogata A, Mori M, Hashimoto S, Yano Y, Fujikawa T, Kawai M, et al. Minimal influence of tocilizumab on IFN-gamma synthesis by tuberculosis antigens. Mod Rheumatol. 2010;20(2):130–3.
  • Mori S, Sugimoto M. Pneumocystis jirovecii infection: an emerging threat to patients with rheumatoid arthritis. Rheumatology (Oxford). 2012;51(12):2120–30.
  • Chen LF, Mo YQ, Jing J, Ma JD, Zheng DH, Dai L. Short-course tocilizumab increases risk of hepatitis B virus reactivation in patients with rheumatoid arthritis: a prospective clinical observation. Int J Rheum Dis. 2017;20(7):859–69.
  • Ahn SS, Jung SM, Song JJ, Park YB, Park JY, Lee SW. Safety of tocilizumab in rheumatoid arthritis patients with resolved hepatitis B virus infection: data from real-world experience. Yonsei Med J. 2018;59(3):452–6.
  • Moots RJ, Sebba A, Rigby W, Ostor A, Porter-Brown B, Donaldson F, 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;56:541–9.
  • Bernad A, Kopf M, Kulbacki R, Weich N, Koehler G, Gutierrez-Ramos JC. Interleukin-6 is required in vivo for the regulation of stem cells and committed progenitors of the hematopoietic system. Immunity. 1994;1(9):725–31.
  • Wright HL, Cross AL, Edwards SW, Moots RJ. Effects of IL-6 and IL-6 blockade on neutrophil function in vitro and in vivo. Rheumatology (Oxford). 2014;53(7):1321–31.
  • Suwa T, Hogg JC, English D, Van Eeden SF. Interleukin-6 induces demargination of intravascular neutrophils and shortens their transit in marrow. Am J Physiol Heart Circ Physiol. 2000;279(6):H2954–60.
  • Kaser A, Brandacher G, Steurer W, Kaser S, Offner FA, Zoller H, et al. Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis. Blood. 2001;98(9):2720–5.
  • Gainsford T, Nandurkar H, Metcalf D, Robb L, Begley CG, Alexander WS. The residual megakaryocyte and platelet production in c-mpl-deficient mice is not dependent on the actions of interleukin-6, interleukin-11, or leukemia inhibitory factor. Blood. 2000;95:528–34.
  • Kim SC, Solomon DH, Rogers JR, Gale S, Klearman M, Sarsour K, et al. Cardiovascular safety of tocilizumab versus tumor necrosis factor inhibitors in patients with rheumatoid arthritis: a multi-database cohort study. Arthritis Rheumatol. 2017;69:1154–64.
  • Xie F, Yun H, Levitan EB, Muntner P, Curtis JR. Tocilizumab and the risk for cardiovascular disease: a direct comparison among biologic disease-modifying antirheumatic drugs for rheumatoid arthritis patients. Arthritis Care Res (Hoboken). 2018 [Sep 3]. [Epub ahead of print]. doi: 10.1002/acr.23737
  • Ljung L, Rantapää-Dahlqvist S, Jacobsson LT, Askling J. Response to biological treatment and subsequent risk of coronary events in rheumatoid arthritis. Ann Rheum Dis. 2016;75(12):2087–94.
  • Choy E, Ganeshalingam K, Semb AG, Szekanecz Z, Nurmohamed M. Cardiovascular risk in rheumatoid arthritis: recent advances in the understanding of the pivotal role of inflammation, risk predictors and the impact of treatment. Rheumatology (Oxford). 2014;53(12):2143–54.
  • Hashizume M, Mihara M. TNF-α, IL-6 and serum from RA patients each atherogenic effects of TNF-α and IL-6 via up-regulation of scavenger receptors. Cytokine. 2012;58(3):424–30.
  • Schieffer B, Selle T, Hilfiker A, Hilfiker-Kleiner D, Grote K, Tietge UJ, et al. Impact of interleukin-6 on plaque development and morphology in experimental atherosclerosis. Circulation. 2004;110(22):3493–500.
  • Genovese MC, Kremer JM, van Vollenhoven RF, Alten R, Scali JJ, Kelman A, et al. Transaminase levels and hepatic events during tocilizumab treatment: pooled analysis of long-term clinical trial safety data in rheumatoid arthritis. Arthritis Rheumatol. 2017;69(9):1751–61.
  • Takeuchi T, Thorne C, Karpouzas G, Sheng S, Xu W, Rao R, F, et al. Sirukumab for rheumatoid arthritis: the phase III SIRROUND-D study. Ann Rheum Dis. 2017;76(12):2001–8.
  • Nishikawa T, Hagihara K, Serada S, Isobe T, Matsumura A, Song J, et al. Transcriptional complex formation of c-Fos, STAT3, and hepatocyte NF-1 alpha is essential for cytokine-driven C-reactive protein gene expression. J Immunol. 2008;180(5):3492–501.
  • Streetz KL, Luedde T, Manns MP, Trautwein C. Interleukin 6 and liver regeneration. Gut. 2000;47(2):309–12.
  • Xie F, Yun H, Bernatsky S, Curtis JR. Brief report: risk of gastrointestinal perforation among rheumatoid arthritis patients receiving tofacitinib, tocilizumab, or other biologic treatments. Arthritis Rheumatol. 2016;68(11):2612–7.
  • Strangfeld A, Richter A, Siegmund B, Herzer P, Rockwitz K, Demary W, 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):504–10.
  • Jin X, Zimmers TA, Zhang Z, Pierce RH, Koniaris LG. Interleukin-6 is an important in vivo inhibitor of intestinal epithelial cell death in mice. Gut. 2010;59(2):186–96.
  • Kuhn KA, Manieri NA, Liu TC, Stappenbeck TS. IL-6 stimulates intestinal epithelial proliferation and repair after injury. PLoS One. 2014;9(12):e114195.
  • Simon TA, Thompson A, Gandhi KK, Hochberg MC, Suissa S. Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis. Arthritis Res Ther. 2015;17:212.
  • Rubbert-Roth A, Sebba A, Brockwell L, Kelman A, Porter-Brown B, Pulley J, et al. Malignancy rates in patients with rheumatoid arthritis treated with tocilizumab. RMD Open. 2016;2(1):e000213.
  • Kim SC, Pawar A, Desai RJ, Gale S, Klearman M, Sarsour K, et al. No difference in the risk of malignancy in tocilizumab versus TNF inhibitor initiators in patients with rheumatoid arthritis: a multi-database cohort study. Ann Rheum Dis. 2018;77(2):50.
  • Chang Q, Daly L, Bromberg J. The IL-6 feed-forward loop: a driver of tumorigenesis. Semin Immunol. 2014;26(1):48–53.
  • Tsukamoto H, Fujieda K, Senju S, Ikeda T, Oshiumi H, Nishimura Y. Immune-suppressive effects of interleukin-6 on T-cell-mediated anti-tumor immunity. Cancer Sci. 2018;109(3):523–30.
  • Singh N, Hofmann TJ, Gershenson Z, Levine BL, Grupp SA, Teachey DT, et al. Monocyte lineage-derived IL-6 does not affect chimeric antigen receptor T-cell function. Cytotherapy. 2017;19(7):867–80.
  • Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016;127(26):3321–30.
  • Gallucci RM, Simeonova PP, Matheson JM, Kommineni C, Guriel JL, Sugawara T, et al. Impaired cutaneous wound healing in interleukin-6-deficient and immunosuppressed mice. FASEB J. 2000;14(15):2525–31.
  • Yoshizaki K, Nishimoto N, Matsumoto K, Tagoh H, Taga T, Deguchi Y, et al. Interleukin 6 and expression of its receptor on epidermal keratinocytes. Cytokine. 1990;2(5):381–7.
  • Goodman SM, Springer B, Guyatt G, Abdel MP, Dasa V, George M, et al. 2017 American College of Rheumatology/American Association of hip and knee surgeons guideline for the perioperative management of antirheumatic medication in patients with rheumatic diseases undergoing elective total hip or total knee arthroplasty. Arthritis Care Res (Hoboken). 2017;69(8):1111–24.
  • Hirao M, Hashimoto J, Tsuboi H, Nampei A, Nakahara H, Yoshio N, et al. Laboratory and febrile features after joint surgery in patients with rheumatoid arthritis treated with tocilizumab. Ann Rheum Dis. 2009;68(5):654–7.
  • Momohara S, Hashimoto J, Tsuboi H, Miyahara H, Nakagawa N, Kaneko A, et al. Analysis of perioperative clinical features and complications after orthopaedic surgery in rheumatoid arthritis patients treated with tocilizumab in a real-world setting: results from the multicentre TOcilizumab in Perioperative Period (TOPP) study. Mod Rheumatol. 2013;23(3):440–9.
  • 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.
  • Nakajima K, Watanabe O, Mochizuki M, Nakasone A, Ishizuka N, Murashima A. Pregnancy outcomes after exposure to tocilizumab: a retrospective analysis of 61 patients in Japan. Mod Rheumatol. 2016;26(5):667–71.
  • Kopf M, Baumann H, Freer G, Freudenberg M, Lamers M, Kishimoto T, et al. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature. 1994;368(6469):339–42.
  • Sakurai T, Takai R, Bürgin H, Ishihara K, Sakamoto Y, Amano J, et al. The effects of interleukin-6 signal blockade on fertility, embryo-fetal development, and immunization in vivo. Birth Defects Res B Dev Reprod Toxicol. 2012;95(4):304–17.
  • Prins JR, Gomez-Lopez N, Robertson SA. Interleukin-6 in pregnancy and gestational disorders. J Reprod Immunol. 2012;95(1–2):1–14.
  • June RR, Olsen NJ. Room for more IL-6 blockade? Sarilumab for the treatment of rheumatoid arthritis. Expert Opin Biol Ther. 2016;16(10):1303–9.
  • Raimondo MG, Biggioggero M, Crotti C, Becciolini A, Favalli EG. Profile of sarilumab and its potential in the treatment of rheumatoid arthritis. Drug Des Devel Ther. 2017;11:1593–603.
  • Fontes JA, Rose NR, Čiháková D. The varying faces of IL-6: from cardiac protection to cardiac failure. Cytokine. 2015;74(1):62–8.
  • McGinnis GR, Ballmann C, Peters B, Nanayakkara G, Roberts M, Amin R, et al. Interleukin-6 mediates exercise preconditioning against myocardial ischemia reperfusion injury. Am J Physiol Heart Circ Physiol. 2015;308(11):H1423–33.
  • Fahmi A, Smart N, Punn A, Jabr R, Marber M, Heads R. p42/p44-MAPK and PI3K are sufficient for IL-6 family cytokines/gp130 to signal to hypertrophy and survival in cardiomyocytes in the absence of JAK/STAT activation. Cell Signal. 2013;25(4):898–909.
  • McFarland-Mancini MM, Funk HM, Paluch AM, Zhou M, Giridhar PV, Mercer CA, et al. Differences in wound healing in mice with deficiency of IL-6 versus IL-6 receptor. J Immunol. 2010;184(12):7219–28.
  • Sommer J, Engelowski E, Baran P, Garbers C, Floss DM, Scheller J. Interleukin-6, but not the interleukin-6 receptor plays a role in recovery from dextran sodium sulfate-induced colitis. Int J Mol Med. 2014;34(3):651–60.
  • Chehboun S, Labrecque-Carbonneau J, Pasquin S, Meliani Y, Meddah B, Ferlin W, et al. Epstein-Barr virus-induced gene 3 (EBI3) can mediate IL-6 trans-signaling. J Biol Chem. 2017;292(16):6644–56.
  • Garbers C, Spudy B, Aparicio-Siegmund S, Waetzig GH, Sommer J, Hölscher C, et al. An interleukin-6 receptor-dependent molecular switch mediates signal transduction of the IL-27 cytokine subunit p28 (IL-30) via a gp130 protein receptor homodimer. J Biol Chem. 2013;288(6):4346–54.
  • Petes C, Mariani MK, Yang Y, Grandvaux N, Gee K. Interleukin (IL)-6 inhibits IL-27- and IL-30-Mediated inflammatory responses in human monocytes. Front Immunol. 2018;9:256.