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Review

Subcutaneous tocilizumab: recent advances for the treatment of rheumatoid arthritis

ORCID Icon, ORCID Icon, &
Pages 639-648 | Received 23 Feb 2019, Accepted 10 May 2019, Published online: 05 Jun 2019

References

  • Mclnnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365:2205–2219.
  • Kishimoto T. Interleukin-6: from basic science to medicine – 40 years in immunology. Annu Rev Immunol. 2005;23:1–21.
  • Ogata A, Tanaka T. Tocilizumab for the treatment of rheumatoid arthritis and other systemic autoimmune diseases: current perspectives and future directions. Int J Rheumatol. 2012;2012:946048.
  • Sato K, Tsuchiya M, Saldanha J, et al. Reshaping a human antibody to inhibit the interleukin-6 dependent tumor cell growth. Cancer Res. 1993;53:851–856.
  • Ogata A, Hirano T, Hishitani Y, et al. Safety and efficacy of tocilizumab for the treatment of rheumatoid arthritis. Clin Med Insights Arthritis Musculoskelet Disord. 2012;5:27–42.
  • Ogata A, Kato Y, Higa S, et al. IL-6 inhibitor for the treatment of rheumatoid arthritis: acomprehensive review. Mod Rheumatol. 2019;29(2):258–267.
  • Ogata A, Morita T, Yoshida Y, et al. Subcutaneous formulation of tocilizumab for treatment of rheumatoid arthritis. Ther Deliv. 2015;6:283–295.
  • Houssiau FA, Devogelaer JP, Van Damme J, et al. Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum. 1988;31:784–788.
  • Ospelt C. Synovial fibroblasts in 2017. RMD Open. 2017 15;3:e000471.
  • Okamoto H, Yamamura M, Morita Y, et al. The synovial expression and serum levels of interleukin-6, interleukin-11, leukemia inhibitory factor, and oncostatin M in rheumatoid arthritis. Arthritis Rheum. 1997;40:1096–1105.
  • MacNaul KL, Hutchinson NI, Parsons JN, et al. Analysis of IL-1 and TNF-alpha gene expression in human rheumatoid synoviocytes and normal monocytes by in situ hybridization. J Immunol. 1990;145:4154–4166.
  • Schinnerling K, Aguillon JC, Catalan D, et al. The role of interleukin-6 signalling and its therapeutic blockage in skewing the T cell balance in rheumatoid arthritis. Clin Exp Immunol. 2017;189:12–20.
  • Hata H, Sakaguchi N, Yoshitomi H, 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;114:582–588.
  • 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;42:1635–1643.
  • Tada Y, Ho A, Koh DR, et al. 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;156:4520–4526.
  • 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;169:1459–1466.
  • 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;27:1885–1897.
  • Jones G, Darian-Smith E, Kwok M, et al. Effect of biologic therapy on radiological progression in rheumatoid arthritis: what does it add to methotrexate? Biologics. 2012;6:155–161.
  • Rohleder 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, et al. Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic-pituitary-adrenal axis in severe depression. Psychiatry Res. 1993;49:11–27.
  • Fragiadaki K, Tektonidou MG, Konsta M, et al. Sleep disturbances and interleukin 6 receptor inhibition in rheumatoid arthritis. J Rheumatol. 2012;39:60–62.
  • 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;33:664–670.
  • 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, et al. Impact of tocilizumab monotherapy on clinical and patient-reported quality-of-life outcomes in patients with rheumatoid arthritis. Rheumatol Ther. 2017;4:405–417.
  • Tanaka Y, Kameda H, Saito K, 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, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271–1276.
  • 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;116:3627–3634.
  • Fève B, Bastard JP. The role of interleukins in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol. 2009;5:305–311.
  • 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;70:1164–1165.
  • Yoshizaki K Basic and clinical significance of interleukin 6 (IL-6) in AA amyloidosis. Proceedings of the XIIIth International Symposium on Amyloidosis, 2102 May 6-10, 2012, Groningen, Netherlands; p 394–397.
  • Nishida S, Hagihara K, Shima Y, et al. Rapid improvement of AA amyloidosis with humanised anti-interleukin 6 receptor antibody treatment. Ann Rheum Dis. 2008;68:1235–1236.
  • Dinoia L, Lopalco G, Cantarini L, et al. Long-term tocilizumab efficacy in a patient with psoriatic arthritis and AA amyloidosis. Clin Exp Rheumatol. 2017;35:170–171.
  • Hagihara K, Nishikawa T, Isobe T, et al. 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. Bbrc. 2004;314:363–369.
  • 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;112:3959–3964.
  • Kawashiri SY, Kawakami A, Iwamoto N, et al. Disease activity score 28 may overestimate the remission induction of rheumatoid arthritis patients treated with tocilizumab: comparison with the remission by the clinical disease activity index. Mod Rheumatol. 2011;21(4):365–369.
  • 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;35:666–670.
  • Gardette A, Ottaviani S, Sellam J, et al. Body mass index and response to tocilizumab in rheumatoid arthritis: a real life study. Clin Rheumatol. 2016;35:857–861.
  • Breedveld FC, Weisman MH, Kavanaugh AF, 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, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomized controlled trial. Lancet. 2004;363:675–681.
  • 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;69:88–96.
  • 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;66:1162–1167.
  • 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;19:12–19.
  • 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;72:43–50.
  • Kaneko Y, Atsumi T, Tanaka Y, 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;75:1917–1923.
  • Burmester GR, Rigby WF, van Vollenhoven RF, et al. Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial. Ann Rheum Dis. 2016;75:1081–1091.
  • 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;388:343–355.
  • 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;381:1541–1550.
  • Dougados M, Kissel K, Conaghan PG, 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;73:803–809.
  • Huizinga TW, Conaghan PG, Martin-Mola E, 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;74:35–43.
  • Kaneko Y, Kato M, Tanaka Y. 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;77:1268–1275.
  • Mueller RB, Graninger W, Sidiropoulos P, et al. Median time to low disease activity is shorter in tocilizumab combination therapy with csDMARDs as compared to tocilizumab monotherapy in patients with active rheumatoid arthritis and inadequate responses to csDMARDs and/or TNF inhibitors: sub-analysis of the swiss and Austrian patients from the ACT-SURE study. Clin Rheumatol. 2017;36:2187–2192.
  • Smolen JS, Landewe R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76:960–977.
  • Burmester GR, Choy E, Kivitz A, et al. Low immunogenicity of tocilizumab in patients with rheumatoid arthritis. Ann Rheum Dis. 2017;76:1078–1085.
  • Strand V, Balsa A, Al-Saleh J, et al. Immunogenicity of biologics in chronic inflammatory diseases: a systematic review. BioDrugs. 2017;31:299–316.
  • Leffers HC, Ostergaard M, Glintborg B, 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;70:1216–1222.
  • Hishitani Y, Ogata A, Shima Y, et al. Retention of tocilizumab and anti-tumour necrosis factor drugs in the treatment of rheumatoid arthritis. Scand J Rheumatol. 2013;42:253–259.
  • Choy EH, Bernasconi C, Aassi M, et al. 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;69:1484–1494.
  • 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;24:17–25.
  • Nishimoto N, Amano K, Hirabayashi Y, et al. Retreatment efficacy and safety of tocilizumab in patients with rheumatoid arthritis in recurrence (RESTORE) study. Mod Rheumatol. 2014;24:26–32.
  • Fortunet C, Pers YM, Lambert J, et al. Tocilizumab induces corticosteroid sparing in rheumatoid arthritis patients in clinical practice. Rheumatology (Oxford). 2015;54:672–677.
  • Kremer JM, Rigby W, Singer NG, 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;70:1200–1208.
  • Singh JA, Wells GA, Christensen R, 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, et al. 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;50:552–562.
  • Fujiwara H, Nishimoto N, Hamano Y, et al. Masked early symptoms of pneumonia in patients with rheumatoid arthritis during tocilizumab treatment: a report of two cases. Mod Rheumatol. 2009;19:64–68.
  • 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;56:541–549.
  • Wright HL, Cross AL, Edwards SW, et al. Effects of IL-6 and IL-6 blockade on neutrophil function in vitro and in vivo. Rheumatology (Oxford). 2014;53:1321–1331.
  • 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;279:H2954–60.
  • Crowson CS, Liao KP, Davis JM 3rd, et al. Rheumatoid arthritis and cardiovascular disease. Am Heart J. 2013;166:622–628.e1.
  • Ljung L, Rantapää-Dahlqvist S, Jacobsson LT, et al. Response to biological treatment and subsequent risk of coronary events in rheumatoid arthritis. Ann Rheum Dis. 2016;75:2087–2094.
  • Kim SC, Solomon DH, Rogers JR, et al. Cardiovascular safety of tocilizumab versus tumor necrosis factor inhibitors in patients with rheumatoid Arthritis: a multi-database cohort study. Arthritis Rheumatol. 2017;69:1154–1164.
  • 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;58:424–430.
  • Schieffer B, Selle T, Hilfiker A, et al. Impact of interleukin-6 on plaque development and morphology in experimental atherosclerosis. Circulation. 2004;110:3493–3500.
  • Genovese MC, Kremer JM, van Vollenhoven RF, 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;69:1751–1761.
  • Strangfeld A, Richter ASiegmund 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;76:504–510.
  • Ohta S, Tsuru T, Terao K, et al. Mechanism-based approach using a biomarker response to evaluate tocilizumab subcutaneous injection in patients with rheumatoid arthritis with an inadequate response to synthetic DMARDs (MATSURI study). J Clin Pharmacol. 2014;54:109–119.
  • Zhang X, Chen YC, Fettner S, et al. Pharmacokinetics and pharmacodynamics of tocilizumab after subcutaneous administration in patients with rheumatoid arthritis. Int J Clin Pharmacol Ther. 2013;51:620–630.
  • 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;66:344–354.
  • Ogata A, Amano K, Dobashi H, 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;42:799–809.
  • Ogata A, Atsumi T, Fukuda T, et al. Sustainable efficacy of switching from intravenous to subcutaneous tocilizumab monotherapy in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2015;67:1354–1362.
  • Burmester GR, Rubbert-Roth A, Ag C, 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;73:69–74.
  • Burmester GR, Rubbert-Roth A, Cantagrel A, 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;75:68–74.
  • Kivitz A, Wallace T, Olech E, et al. Long-term wafety and efficacy of subcutaneously administered tocilizumab for adult rheumatoid arthritis: amulticenter phase 3b long-term extension study. Rheumatol Ther. 2016;3:291–304.
  • Kivitz A, Olech E, Borofsky MA, et al. Subcutaneous tocilizumab vs placebo in combination with disease modifying antirheumatic drugs in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2014;66:1653–1661.
  • Abdallah H, Hsu JC, Lu P, et al. Pharmacokinetic and pharmacodynamic analysis of subcutaneous tocilizumab in patients with rheumatoid arthritis from 2 randomized, controlled trials: SUMMACTA and BREVACTA. J Clin Pharmacol. 2017;57:459–468.
  • Choy E, Caporali R, Xavier R, et al. Subcutaneous tocilizumab in rheumatoid arthritis: findings from the common-framework phase 4 study programme TOZURA conducted in 22 countries. Rheumatology (Oxford). 2018;57:499–507.
  • Choy E, Caporali R, Xavier R, et al. Effects of concomitant glucocorticoids in TOZURA, a common-framework study programme of subcutaneous tocilizumab in rheumatoid arthritis. Rheumatology (Oxford). 2019 Jan 10. Epub ahead of print.
  • Atsumi T, Fujio K, Yamaoka K, et al. Safety and effectiveness of subcutaneous tocilizumab in patients with rheumatoid arthritis in a real-world clinical setting. Mod Rheumatol. 2018;28:780–788.
  • Lauper K, Mongin D, Iannone F, et al. Comparative effectiveness of subcutaneous tocilizumab versus intravenous tocilizumab in a pan-European collaboration of registries. RMD Open. 2018;4:e000809.
  • Pomponio G, Tontini C, Angeletti A, et al. Efficacy and safety of intravenous and subcutaneous tocilizumab in a cohort of patients affected by rheumatoid arthritis in real-life. Ann Rheum Dis. 2017;76(suppl2):1189.
  • Joffres L, Ricard E, Pereira Gillion C, et al. Stable efficacy and safety after switching from tocilizumab intravenous to subcutaneous in rheumatoid arthritis: result of a cohort of 200 patients. Ann Rheum Dis. 2017;76(suppl2):1191.
  • Iwamoto N, Fukui S, Umeda M, et al. Evaluation of switching from intravenous to subcutaneous formulation of tocilizumab in patients with rheumatoid arthritis. Mod Rheumatol. 2016;26:662–666.
  • Darloy J, Segaud N, Salmon JH, et al. Tocilizumab effectiveness after switching from intravenous to subcutaneous route in patients with rheumatoid arthritis: the RoSwitch study. Rheumatol Ther. 2019;6:61–75.
  • Mena-Vázquez N, Manrique-Arija S, Rojas-Giménez M, et al. Analysis of effectiveness, safety and optimization of tocilizumab in a cohort of patients with rheumatoid arthritis in clinical practice. Reumatol Clin. 2019;15:21–26.
  • Bird P, Peterfy C, Countryman P, et al. AC-CUTE: an open-label study to evaluate progression of structural joint damage and inflammation in subjects with moderate to severe rheumatoid arthritis. Int J Rheumatol. 2018;2018:8721753.
  • Okano T, Inui K, Yamada Y, et al. The comparison of the ultrasonographic synovial findings between intravenous administration and subcutaneous injection of tocilizumab. Ann Rheum Dis. 2018;77(suppl):A615.
  • Behrens F, Englbrecht M, Biewer WA, et al. Tocilizumab S.C. improvement of the depressiveness, fatigue and pain in RA therapy. Ann Rheum Dis. 2018;77(suppl):A952.
  • Strand V, Michalska M, Birchwood C, et al. Impact of tocilizumab administered intravenously or subcutaneously on patient-reported quality-of life outcomes in patients with rheumatoid arthritis. RMD Open. 2018;4:e000602.
  • Ogata A, Tanaka Y, Ishii T, 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.
  • Ogata A, Tanaka Y, Ishii T, et al. Long-term safety and efficacy of weekly subcutaneous tocilizumab monotherapy in patients with rheumatoid arthritis who had an inadequate response to subcutaneous tocilizumab every other week: results from the open-label extension of the SHINOBI study. Mod Rheumatol. 2018 Oct 9;1–22. Epub ahead of print.
  • Kivitz A, Olech E, Borofsky MA, 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;45:456–464.
  • Sanmarti R, Veale DJ, Martin-Mola E, et al. Reducing or maintaining the dose of subcutaneous tocilizumab in patients with rheumatoid arthritis in clinical remission: a randomized, open‐label trial. Arthritis Rheumatol. 2019 April 4; in press. DOI:10.1002/art.40905.
  • June RR, Olsen NJ. Room for more IL-6 blockade? Sarilumab for the treatment of rheumatoid arthritis. Expert Opin Biol Ther. 2016;16:1303–1309.
  • Raimondo MG, Biggioggero M, Crotti C, et al. Profile of sarilumab and its potential in the treatment of rheumatoid arthritis. Drug Des Devel Ther. 2017;11:1593–1603.
  • Fontes JA, Rose NR, Čiháková D. The varying faces of IL-6: from cardiac protection to cardiac failure. Cytokine. 2015;74:62–68.
  • McGinnis GR, Ballmann C, Peters B, et al. Interleukin-6 mediates exercise preconditioning against myocardial ischemia reperfusion injury. Am J Physiol Heart Circ Physiol. 2015;308:H1423–33.
  • Fahmi A, Smart N, Punn A, et al. 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;25:898–909.
  • McFarland-Mancini MM, Funk HM, Paluch AM, et al. Differences in wound healing in mice with deficiency of IL-6 versus IL-6 receptor. J Immunol. 2010;184:7219–7228.
  • Sommer J, Engelowski E, Baran P, et al. Interleukin-6, but not the interleukin-6 receptor plays a role in recovery from dextran sodium sulfate-induced colitis. Int J Mol Med. 2014;34:651–660.
  • Chehboun S, Labrecque-Carbonneau J, Pasquin S, et al. Epstein-barr virus-induced gene 3 (EBI3) can mediate IL-6 trans-signaling. J Biol Chem. 2017;292:6644–6656.
  • Garbers C, Spudy B, Aparicio-Siegmund S, 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;288:4346–4354.
  • Petes C, Mariani MK, Yang Y, et al. Interleukin (IL)-6 inhibits IL-27- and IL-30-mediated inflammatory responses in human monocytes. Front Immunol. 2018;9:256.

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