Ингибиция интерлейкина 6 — новые возможности фармакотерапии иммуновоспалительных ревматических заболеваний

1. <div><p>Choy E.H., Panayi G.S. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001;344:907-16.</p><p>McInnes I.B., Shett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011;365:2205-19.</p><p>Новиков А.А., Александрова Е.Н., Диатроптова М.А., Насонов Е.Л. Роль цитокинов в патогенезе ревматоидного артрита. Науч-практич ревматол 2010;2:71-82.</p><p>Генно-инженерные биологические препараты в лечении ревматоидного артрита. Под ред. Е.Л. Насонова. М.: ИМА-ПРЕСС, 2013;549 с.</p><p>Heinrich P.C., Behrmann I., Haan S. et al. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 2003;374(Pt 1):1-20.</p><p>Jones S.A., Richards PJ., Scheller J., Rose-John S. IL-6 transsignaling: the in vivo consequences. J Interferon Cytokine Res 2005;25:241-53.</p><p>Mihara M., Hashizume M., Yoshida H. et al. IL6/IL-6 receptor system and its role in physiological and pathological conditions. Clin Sci 2012;122;143—59.</p><p>Gabay C., Kushner I. Acute-phase proteins and other systemic responses to inflammation. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999;340:448-54.</p><p>Andrews N.C. Anemia of inflammation: the cytokine-hepcidin link. J Clin Invest 2004;113:1251-3.</p><p>Chrousos G.P. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med 1995;332:1351-62.</p><p>Dayer J.M., Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology (Oxford) 2010;49:15-24.</p><p>Hashizume M., Mihara M. The roles of interleukin-6 in the pathogenesis of rheumatoid arthritis. Arthritis 2011;2011:765624. doi:10.1155/2011/765624.</p><p>Edwards C.J., Williams E. The role of interleukin 6 in rheumatoid arthritis. Osteoporosis Int 2010;13 Mаr [Epub ahead of print].</p><p>Kimursa A., Kishimoto T. IL6: regulator of T reg/Th17 balance. Eur J Immunol 2010;40:1830-5.</p><p>Sato K., Tsuchiya M., Saldanha J. et al. Reshaping a human antibody to inhibit the interleukin-6-dependent tumor cell growth. Cancer Res 1993;53:851-6.</p><p>Smolen J., Beaulieu A., Ruddert-Roth A. et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebocontrolled, randomized trial. Lancet 2008;371:987-97.</p><p>Genovese M.C., McKay J.D., Nasonov E.L. 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. Arthr Rheum 2008;58:2968-80.</p><p>Nishimoto N., Hashimoto J., Miaysaka 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 randomized controlled trial of tocilizumab. Ann Rheum Dis 2007;66:1162-7.</p><p>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;19:12-9.</p><p>Kremer J.L., Blanco R., Brzosko M. et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate at 1 year; the Lithe study. Arthr Rheum 2011;63:609-21.</p><p>Emery P., Keystone E., Tony H.-P. et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-TNF biologics: results from a 24-week multicenter randomized placebo-controlled trial. Ann Rheum Dis 2008;67:1516-23.</p><p>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.</p><p>Yazici Y., Curtis J.R., Ince A. et al. Efficacy of tocilizumab in patients with moderate to severe rheumatoid arthritis and previously inadequate response to disease-modifying antirheumatic drugs: the ROSE study. Ann Rheum Dis 2011 [Epub ahead of print].</p><p>Dougados M., Kissel K., Sheeran T. et al. Adding tocilizumab or switching to tociluzumab monotherapy in methotrexate inadequate responders: 24-week symtomatic and structural results od a 2-year randomized controlled strategy trial in rheumatoid arthritis (ACT-RAY) Ann Rheum Dis 2012 [Epub ahead of print].</p><p>Bykerk V., Ostor A., Alvaro-Gracia J. et al. Tocilizumab in patients with active rheumatoid arthritis and an inadequate response to DMARDs and/or the TNF inhibitor therapy: a large open-label study close to clinical precice Ann Rheum Dis 2012 [Epub ahead of print].</p><p>Bykerk V., Ostor A., Ivora J.A.R. et al. Comparison of tocilizum-ab as monotherapy or with add-on disease-modifying antirheumatic drugs in patients with rheumatoid arthritis and an inadequate response to previous treatments. Arthr Rheum 2011;63(Suppl):S866.</p><p>Weinblatt E., Kremer J.M., Cush J.J. et al. Tocilizumab monotherapy and tocilizumab plus disease-modifying antirheumatic drugs in a US Rheumatoid Arthritis population with inadequate response to amti-tumor necrosis factor agents. Arthr Rheum 2011;63(Suppl):S162.</p><p>Burmester G.R., Feist E., Kellner H. et al. Effectiveness and safety of the interleukin 6-receptor antagonist tocilizumab after 4 and 24 weeks in patients with avtive rheumatoid arthritis: the first phase IIIb real-life study (TAMARA). Ann Rheum Dis 2011;70:755-9.</p><p>Панасюк Е.Ю., Амирджанова В.Н., Авдеева А.С., Лучихина Е.Л., Александрова Е.Н., Новиков А.А., Насонов Е.Л. и представители исследовательских центров. Опыт применения тоцилизумаба у больных ревматоидным артритом (по данным многоцентрового исследования ЛОРНЕТ). Науч-практич ревматол 2013;51:104-10.</p><p>Smolen J., Martinez-Avila J., Aletaha D. Tocilizumab inhibits progression of joint damage in rheumatoid arthritis irrespective of its anti-inflammatory effects: dissociation of the linl between inflammation and destruction. Ann Rheum Dis 2011 [Epub ahead of print].</p><p>Nishimto 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 [Epub ahead of print].</p><p>Mao Mao An, Zui Zou, Hei Shen et al. The addition of tocilizumab to DMARD therapy for rheumatoid arthritis: a meta-analysis of randomized controlled trials. Eur J Clin Pharmacol 2010 [Epub ahead of print].</p><p>Singh J.A., Beg S., Lopez-Olivo M.A. Tocilizumab for rheumatoid arthritis: a Cochrane systemic review. J Rheumatol 2010 [Epub ahead of print].</p><p>Schoels M., van der Heijde D., Breedveld F. et al. Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systemic literature review and metaanalysis informing a consensus statement. Ann Rheum Dis 2012; Nov 12 [Epub ahead of print].</p><p>Smolen J.S., Schoels M.M., Nishimoto N. et al. Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions. Ann Rheum Dis 2012 [Epub ahead of print].</p><p>Shakib J., Sepehr F., Smith B. Safety, pharmacokinetics and pharmacodynamics of ALD518 (BMS-945429), a high-affinity monoclonal antibody directed against interleukin-6 (IL-6) administered by subcutaneous injection: a phase I trial. Arthr Rheum 2010;62(Suppl 10):1124.</p><p>Mease P., Strand V., Shalamberidze L. et al. A phase II, doubleblind, randomized, placebо-controlled study of BMS945429 (ADL518) in patients with rheumatoid arthritis with an inadequate respose to methotrexate. Ann Rheum Dis 2012;Feb [Epub ahead of print].</p><p>Strand V., Shalamberidze L., Dimic A. et al. BMS-945429 (ALD518), a high-affinity anti-interleukin-6 monoclonal antibody, is associated with improvements in health-related quality of life in patients with rheumatoid arthritis and inadequate response to methotrexate. Ann Rheum Dis 2011;70(Suppl 3):621.</p><p>Taub R. Hepatoprotection via the IL-6/Stat3 pathway. J Clin Invest 2003;112:978-80.</p><p>ClinicalTrials.gov. Phase IIB rheumatoid arthritis dose ranging study for BMS-945429 in subjects who are not responding to methotrexate. 2011. Accessed 10/21/11 at: http://clinicaltrials.gov/ct2/show/NCT01373151</p><p>Sanofi and Regeneron report positive phase 2b trial results with sarilumab in rheumatoid arthritis [press release]. Paris, France and Tarrytown, NY: PR Newswire; July 12, 2011. Accessed 10/21/11 at: http://www.reuters.com/article/2011/07/12/idUS215877+12 Jul-2011+PRN20110712</p><p>Radin A.R., Mellis S.J., Jasson M. et al. REGN88/SAR153191, a fully-human interleukin-6 receptor monoclonal antibody, reduced acute phase reactants in patients with rheumatoid arthritis: preliminary observations from phase 1 studies. Arthr Rheum 2010; S1121</p><p>ClinicalTrials.gov. Evaluation of SAR153191 (REGN88) on top of methotrexate in rheumatoid arthritis patients (MOBILITY). 2011. Accessed 10/21/11 at: http://clinicaltrials.gov/ct2/show/NCT01061736</p><p>ClinicalTrials.gov. Effect of SAR153191 (REGN88) with methotrexate in patients with active rheumatoid arthritis who failed TNF-а blockers. 2011. Accessed 10/21/11 at: http://clinicaltrials.gov/ct2/show/NCT01217814</p><p>ClinicalTrials.gov. Long term evaluation of SAR153191 (REGN88) on top of disease modifying anti-rheumatic drugs in rheumatoid arthritis patients (ABILITY). 2011. Accessed 10/21/11 at: http://clinicaltrials.gov/ct2/show/NCT01146652</p><p>Xu Z., Bouman-Thio E., Comisar C. et al. Pharmacokinetics, pharmacodynamics and safety of a human anti-IL-6 monoclonal antibody (sirukumab) in healthy subjects in a first-in-human study. Br J Clin Pharmacol 2011;72:270-81.</p><p>Hsu B., Zhou B., Smolen J.S., Weinblatt M.E. Proof-of-concept for CNTO 136, a human anti-interleukin-6 monoclonal antibody, in a multicenter, randomized, double-blind, placebo-controlled, phase 2 study in patients with active rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis 2011;70(Suppl 3):459.</p><p>ClinicalTrials.gov. A study of the effectiveness and safety of CNTO 136 in patients with active rheumatoid arthritis despite methotrexate therapy. 2011. Accessed 10/21/11 at: http://clinicaltrials. gov/ct2/show/NCT00718718</p><p>Hickling M., Golor G., Jullion A. et al. Safety and pharmacokinetics of CDP6038, an anti-IL-6 monoclonal antibody, administered by subcutaneous injection and intravenous infusion to healthy male volunteers: a phase 1 study. Ann Rheum Dis 2011;70(Suppl 3):471.</p><p>ClinicalTrials.gov. To evaluate the blood levels and safety of IV and subcutaneous CDP6038 in subjects with rheumatoid arthritis using methotrexate. 2010. Accessed 10/21/11 at: http://clinical-trials.gov/ct2/show/NCT01009242</p><p>ClinicalTrials.gov. Open-label study to assess the safety and efficacy of CDP6038 in patients who completed RA0056. 2011. Accessed 10/21/11 at: http://clinicaltrials.gov/ct2/show/NCT01296711</p><p>ClinicalTrials.gov. Efficacy and safety of CDP6038 in patients with rheumatoid arthritis with an unsuccessful response to antitumor necrosis factor (anti-TNF) therapy. 2011. Accessed 10/21/11 at: http://clinicaltrials.gov/ct2/show/NCT01242488</p><p>Mihara M., Takagi N., Takeda Y. et al. IL-6 receptor blockage inhibits the onset of autoimmune kidney disease in NZB/W F1 mice. Clin Exp Immunol 1998;112:397-402.</p><p>Liang B., Gardner D.B., Griswold D.E. et al. Anti-interleukin-6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus. Immunology 2006;119:296-305.</p><p>Pflegerl P., Vesely P., Hantusch B. et al. Epidermal loss of JunB leads to a SLE phenotype due to hyper IL-6 signaling. Proc Natl Acad Sci USA 2009;106:20423-8.</p><p>Kitaba S., Murota H., Terao M. et al. Blockade of interleukin-6 receptor alleviates disease in mouse model of scleroderma. Am J Pathol 2012;80:165-76.</p><p>Yoshizaki A., Yanaba K., Ogawa A. et al. Immunization with DNA topoisomerase I and Freund’s complete adjuvant induces skin and lung fibrosis and autoimmunity via interleukin-6 signaling. Arthr Rheum 2011;63:3575-85.</p><p>Okiyama N., Sugihara T., Iwakura Y. et al. Therapeutic effects of interleukin-6 blockade in a murine model of polymyositis that does not require interleukin-17A. Arthr Rheum 2009;60:2505-12.</p><p>Woo P., Wilkinson N., Prieur A.M. et al. Open label phase II trial of single, ascending doses of MRA in Caucasian children with severe systemic juvenile idiopathic arthritis: proof of principle of the efficacy of IL-6 receptor blockade in this type of arthritis and demonstration of prolonged clinical improvement. Arthr Res Ther 2005;7:R1281-R1288.</p><p>Yokota S., Miyamae T., Imagawa T. et al. Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Arthr Rheum 2005;52:818-25.</p><p>Yokota S., Imagawa T., Mori M. et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomized, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 2008;371:998-1006.</p><p>De Benedetti F., Brunner H., Ruperto N. et al. Tocilizumab in patients with systemic juvenile idiopathic arthritis: efficacy data from the placebo-controlled 12-week part of the phase 3 TENDER trial. Arthr Rheum 2010;62(Suppl 10):1434.</p><p>De Benedetti F., Brunner H., Ruperto N. et al. Efficacy and safety of tocilizumab (TCZ) in patients with systemic juvenile idiopathic arthritis (SJIA): tender 52-week data. Pediat Rheumatol 2011;9(Suppl 1):164.</p><p>Illei G.G., Shirota Y., Yarboro C.H. 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. Arthr Rheum 2010;62:542-52.</p><p>Maeshima K., Ishii K., Torigoe M. et al. Successful tocilizumab and tacrolimus treatment in a patient with rheumatoid arthritis complicated by systemic lupus erythematosus. Lupus 2012 [Epub ahead of print].</p><p>Makol A., Gibson L.E., Michet C.J. Successful use of interleukin 6 antagonist tocilizumab in a patient with refractory cutaneous lupus and urticarial vasculitis. J Clin Rheumatol 2012;18:92-5.</p><p>Shima Y., Kuwahara Y., Murota H. et al. The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab. Rheumatology (Oxford) 2010;49:2408-12.</p><p>Elhai M., Meunier M., Matucci-Cerinic M. et al. Outcome of patients with systemic sclerosic-associqted polyarthritis and myopathy treated with tocilizumab or abatacept; a EUSTAR observational study. Ann Rheum Dis 2012, Dec 19[Epub ahead of print].</p><p>Narazaki M., Hagihara K., Shima Y. et al. Therapeutic effect of tocilizumab on two patients with polymyositis. Rheumatology (Oxford) 2011;50:1344-6.</p><p>Seitz M., Reichenbach S., Bonel H.M. et al. Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series. Swiss Med Wkly 2011;141:w13156.</p><p>Beyer C., Axmann R., Sahinbegovic E. et al. Anti-interleukin 6 receptor therapy as rescue treatment for giant cell arteritis. Ann Rheum Dis 2011;70:1874-5.</p><p>Sciascia S., Rossi D., Roccatello D. Interleukin 6 blockade as steroid-sparing treatment for 2 patients with giant cell arteritis. J Rheumatol 2011;38:2080-1.</p><p>Salvarani C., Magnani L., Catanoso M. et al. Tocilizumab: a novel therapy for patients with large-vessel vasculitis. Rheumatology (Oxford) 2012;51:151-6.</p><p>Vinit J., Bielefeld P., Muller G. et al. Efficacy of tocilizumab in refractory giant cell arteritis. Joint Bone Spine 2012;79:317-8.</p><p>Christidis D., Jain S., Das Gupta B. Successful use of tocilizumab in polymyalgic onset biopsy positive GCA with large vessel involvement. BMJ Case Reports 2011 [Epub ahead of print].</p><p>Nishimoto N., Nakahara H., Yoshio-Hoshino N. et al. Successful treatment of a patient with Takayasu arteritis using a humanized anti-interleukin-6 receptor antibody. Arthr Rheum 2008;58:1197-200.</p><p>Salvarani C., Magnani L., Catanoso M.G. et al. Rescue treatment with tocilizumab for Takayasu arteritis resistant to TNF-а blockers. Clin Exp Rheumatol 2012 [Epub ahead of print].</p><p>Bredemeier M., Rocha C.M., Barbosa M.V. et al. One-year clinical and radiological evolution of a patient with refractory Takayasu’s arteritis under treatment with tocilizumab. Clin Exp Rheumatol 2012 [Epub ahead of print].</p><p>Cohen C., Mekinian A., Saidenberg-Kermanach N. et al. Efficacy of tocilizumab in rituximab-refractory cryoglobulinemia vasculitis. Ann Rheum Dis 2012;71:628-9.</p><p>Sumida K., Ubara Y., Suwabe T. et al. Complete remission of myeloperoxidase-antineutrophil cytoplasmic antibody-associated crescentic glomerulonephritis complicated with rheumatoid arthritis using a humanized anti-interleukin 6 receptor antibody. Rheumatology (Oxford) 2011;50:1928-30.</p><p>Sumida K., Ubara Y., Takemoto F. et al. Successful treatment with humanized anti-interleukin 6 receptor antibody for multidrug-refractory and anti-tumour necrosis factor-resistant systemic rheumatoid vasculitis. Clin Exp Rheumatol 2011;29 (1 Suppl 64):S133.</p><p>Hagihara K., Kawase I., Tanaka T. et al. Tocilizumab ameliorates clinical symptoms in polymyalgia rheumatica. J Rheumatol 2010;37:1075-6.</p><p>Kawai M., Hagihara K., Hirano T. et al. Sustained response to tocilizumab, anti-interleukin-6 receptor antibody, in two patients with refractory relapsing polychondritis. Rheumatology (Oxford) 2009;48:318-9.</p><p>Narshi C.B., Allard S.A. Sustained response to tocilizumab, anti-IL-6 antibody, following anti-TNF-? failure in a patient with relapsing polychondritis complicated by aortitis. Rheumatology (Oxford) 2012;51:952-3.</p><p>Iwamoto M., Nara H., Hirata D. et al. Humanized monoclonal anti-interleukin-6 receptor antibody for treatment of intractable adult-onset Still’s disease. Arthr Rheum 2002;46:3388-9.</p><p>Nakahara H., Mima T., Yoshino-Hoshino N. et al. A case report of a patient with refractory adult-onset Still’s disease who was successfully treated with tocilizumab over 6 years. Mod Rheumatol 2009;19:69-72.</p><p>De Bandt M., Saint-Marcoux B. Tocilizumab for multirefractory adult-onset Still's disease. Ann Rheum Dis 2009;68:153-4.</p><p>Matsumoto K., Nagashima T., Takatori S. et al. Glucocorticoid and cyclosporine refractory adult onset Still's disease successfully treated with tocilizumab. Clin Rheumatol 2009;28:485-7.</p><p>Cunha M.L., Wagner J., Osawa A. et al. The effect of tocilizum-ab on the uptake of 18FDG-PET imaging in patients with adult-onset Still’s disease. Rheumatology (Oxford) 2010;49:1014-6.</p><p>Sumida K., Ubara Y., Hoshino J. et al. Etanercept-refractory adult-onset Still’s disease with thrombotic thrombocytopenic purpura successfully treated with tocilizumab. Clin Rheumatol 2010;29:1191-4.</p><p>Yoshimura M., Makiyama J., Koga T. et al. Successful treatment with tocilizumab in a patient with refractory adult-onset Still's disease (AOSD) Clin Exp Rheumatol 2010;28:141-2.</p><p>Perdan-Pirkmajer K., Praprotnik S., Tomsic M. A case of refractory adult-onset Still’s disease successfully controlled with tocilizumab and a review of the literature. Clin Rheumatol 2010;29:1465-7.</p><p>Naniwa T., Ito R., Watanabe M. et al. Case report: successful use of short-term add-on tocilizumab for multirefractory systemic flare of adult-onset Still’s disease. Clin Rheumatol 2010 [Epub ahead of print].</p><p>Kishida D., Okuda Y., Ohnishi M. et al. Successful tocilizumab treatment in a patient with adult-onset Still’s disease complicated by chronic active hepatitis B and amyloid A amyloidosis. Mod Rheumatol 2011;21:215-8.</p><p>Thonhofer R., Hiller M., Just H. et al. Treatment of refractory adult-onset Still’s disease with tocilizumab: report of two cases and review of the literature. Rheumatol Int 2011;31:1653-6.</p><p>Sabnis G.R., Gokhale Y.A., Kulkarni U.P. Tocilizumab in refractory adult-onset Still’s disease with aseptic meningitis-efficacy of interleukin-6 blockade and review of the literature. Semin Arthr Rheum 2011;40:365-8.</p><p>Rech J., Ronneberger M., Englbrecht M. et al. Successful treatment of adult-onset Still’s disease refractory to TNF and IL-1 blockade by IL-6 blockade. Ann Rheum Dis 2011;70:390-2.</p><p>Kobayashi M., Takahashi Y., Yamashita H. et al. Benefit and a possible risk of tocilizumab therapy for adult-onset Still's disease accompanied by macrophage-activation syndrome. Mod Rheumatol 2011;21:92-6.</p><p>Puechal X., DeBandt M., Berthelot J.M. et al. Tocilizumab in refractory adult Still’s disease. Arthr Care Res 2011;63:155-9.</p><p>Sekkach Y., Elqatni M., Khattabi A.E. et al. Antagonists of interleukin-6 (tocilizumab), in adult refractory still disease. Presse Med 2011;40:e333—7.</p><p>Suematsu R., Ohta A., Matsuura E. et al. Therapeutic response of patients with adult Still’s disease to biologic agents: multicenter results in Japan. Mod Rheumatol 2011 [Epub ahead of print].</p><p>Okuda Y., Takasugi K. Successful use of a humanized anti-interleukin-6 receptor antibody, tocilizumab, to treat amyloid A amyloidosis complicating juvenile idiopathic arthritis. Arthr Rheum 2006;54:2997-3000.</p><p>Nishida S., Hagihara K., Shima Y. et al. Rapid improvement of AA amyloidosis with humanised anti-interleukin 6 receptor antibody treatment. Ann Rheum Dis 2009;68:1235-6.</p><p>Sato H., Sakai T., Sugaya T. et al. Tocilizumab dramatically ameliorated life-threatening diarrhea due to secondary amyloidosis associated with rheumatoid arthritis. Clin Rheumatol 2009;28:1113-6.</p><p>Inoue D., Arima H., Kawanami C. et al. Excellent therapeutic effect of tocilizumab on intestinal amyloid a deposition secondary to active rheumatoid arthritis. Clin Rheumatol 2010;29:1195-7.</p><p>De la Torre M., Arboleya L., Pozo S. et al. Rapid and sustained response to tocilizumab, anti-interleukin-6 receptor antibody, in a patient with nephritic syndrome secondary to systemic juvenile idiopathic arthritis-related amyloidosis. NDT Plus 2011;4:178-80.</p><p>Magro-Checa C., Navas-Parejo Casado A., Borrego-Garcia E. et al. Successful use of tocilizumab in a patient with nephritic syndrome due to a rapidly progressing AA amyloidosis to latent tuberculosis. Amyloid 2011;18:235-9.</p><p>Hattori Y., Ubara Y., Sumida K. et al. Tocilizumab improves cardiac disease in a hemodialysis patient with AA amyloidosis secondary to rheumatoid arthritis. Amyloid 2012;19:37-40.</p><p>Ogata A., Umegaki N., Katayama I. et al. Psoriatic arthritis in two patients with an inadequate response to treatment with tocilizumab. Joint Bone Spine 2012;79:85-7.</p><p>Hughes M., Chinoy H. Succesful use of tocilizumab in a patients with psoriatic arthritis. Rheumatology (Oxford) 2013; Feb 18 [Epub ahead of print].</p><p>Tanaka T., Kuwahara Y., Shima Y. et al. Successful treatment of reactive arthritis with a humanized anti-interleukin-6 receptor antibody, tocilizumab. Arthr Rheum 2009;61:1762-4.</p><p>Henes J.C., Horger M., Guenaydin I. et al. Mixed response to tocilizumab for ankylosing spondylitis. Ann Rheum Dis 2010;69:2217-8.</p><p>Wendling D., Bossert M., Prati C. Short-term effect of IL-6 inhibition in spondylarthritis. Joint Bone Spine 2010;77:624-5.</p><p>Brulhart L., Nissen M.J., Chevallier P. et al. Tocilizumab in a patient with ankylosing spondylitis and Crohn's disease refractory to TNF antagonists. Joint Bone Spine 2010;77:625-6.</p><p>Shima Y., Tomita T., Ishii T. et al. Tocilizumab, a humanized anti-interleukin-6 receptor antibody, ameliorated clinical symptoms and MRI findings of a patient with ankylosing spondylitis. Mod Rheumatol 2011;21:436-9.</p><p>Cohen J.D., Ferreira R., Jorgensen C. Ankylosing spondylitis refractory to tumor necrosis factor blockade responds to tocilizumab. J Rheumatol 2011;38:1527.</p><p>Koumakis E., Feydy A., Kahan A. et al. Interleukin 6 blockade in spondyloarthritis. J Rheumatol 2012;39:1097-8.</p><p>Sieper J., Porter-Brown B., Thompson L. et al. Assesment of short-term symptomatic efficacy of tocilizumab in ankylosing spondilitis: results of randomised, placebo-controlled trials. Ann Reum Dis 2013; June 13 [Epub ahead of print].</p><p>Lekpa F.K., Poulain C., Wendling D. et al. Is IL-6 an appropriate target to treatment spondyloarthritis patients refractory to anti-TNF therapy? A multicentre retrospective observational study. Arthr Res Ther 2012;14:R53.</p><p>Hirano T., Ohguro N., Hohki S. et al. A case of Behcet’s disease treated with a humanized anti-interleukin-6 receptor antibody, tocilizumab. Mod Rheumatol 2012;22:298-302.</p><p>Shapiro L.S., Farrell J., Haghighi A.B. Tocilizumab treatment for neuro-Behcet’s disease, the first report. Clin Neurol Neurosurg 2011;114:297-8.</p><p>Diamantopoulos A.P., Hatemi G. Lack of efficacy of tocilizumab in mucocutaneous Behcet’s syndrome: report of two cases. Rheumatology (Oxford) 2013;Apr 4 [Epub ahead of print].</p><p>Pinto J.L., Mora G.E. Fernandez-Avila D.G. et al. Tocilizumab in a patients with tophaceous gout resistant to treatment. Rheumatol Clin 2013;9:178-80.</p><p>Tsokos G.C. Systemic lupus erythematosus. New Engl J Med 2011;365:2110-21.</p><p>Shin M.S., Lee N., Kang I. Effector T-cell subsets in systemic lupus erythematosus: update focusing on Th17 cells. Curr Opin in Rheumatol 2011;5:444-8.</p><p>Obermoser G., Pascual V. The interferon-а signature of systemic lupus erythematosus. Lupus 2010;19;1012—9.</p><p>Rhodes B., Furnrohr B.G., Vyse T.J. C-reactive protein in rheumatology: biology and genetics. Nat Revi Rheumatol 2011;7:282-9.</p><p>Tackey E., Lipsky P.E., Illei GG. Rationale for interleukin-6 blockade in systemic lupus erythematosus. Lupus 2004;13:339-43.</p><p>Linker-Israeli M., Deans R.J., Wallace D.J. et al. Elevated levels of endogenous IL-6 in systemic lupus erythematosus: a putative role in pathogenesis. J Immunol 1991;147:117-23.</p><p>Peterson E., Robertson A.D., Emlen W. Serum and urinary interleukin-6 in systemic lupus erythematosus. Lupus 1996;5:571-5.</p><p>Grondal G., Gunnarsson I., Ronnelid J. et al. Cytokine production, serum levels and disease activity in systemic lupus erythematosus. Clin Exp Rheumatol 2000;18;565—70.</p><p>Iwano M., Dohi K., Hirata E. et al. Urinary levels of IL-6 in patients with active lupus nephritis. Clin Nephrol 1993;40:16-21.</p><p>Malide D., Russo P., Bendayan M. Presence of tumor necrosis factor alpha and interleukin-6 in renal mesangial cells of lupus nephritis patients. Human Pathol 1995;26:558-64.</p><p>Herrera-Esparza R., Barbosa-Cisneros O.V., Illalobos-Hurtado R., Avalos-Diaz E. Renal expression of IL-6 and TNFα genes in lupus nephritis. Lupus 1998;7:154-8.</p><p>Tsai G.Y., Wu T.H., Yu C.L. et al. Increased excretions of β2-microglobulin, IL-6, and IL-8 and decreased excretion of Tamm-Horsfall glycoprotein in urine of patients with active lupus nephritis. Nephron 2000;85:207-14.</p><p>Hirohata S., Miyamoto T. Elevated levels of interleukin-6 in cerebrospinal fluid from patients with systemic lupus erythematosus and central nervous system involvement. Arthr Rheum 1990;33:644-9.</p><p>Hagiwara E., Gourley M.F., Lee S., Klinman D.M. Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of interleukin-10: interferon-γ-secreting cells in the peripheral blood. Arthr Rheum 1996;39:379-85.</p><p>Swaak G., van den Brink H.G., Aarden L.A. Cytokine production (IL-6 and TNFα) in whole blood cell cultures of patients with systemic lupus erythematosus. Scand J Rheumatol 1996;25:233-8.</p><p>Klashman D.J., Martin R.A., Martinez-Maza O., Stevens R.H. In vitro regulation of B cell differentiation by interleukin-6 and soluble CD23 in systemic lupus erythematosus B cell subpopulations and antigen-induced normal B cells. Arthr Rheum 1991;34:276-86.</p><p>Kitani A., Hara M., Hirose T. et al. Autostimulatory effects of IL-6 on excessive B cell differentiation in patients with systemic lupus erythematosus: analysis of IL-6 production and IL-6R expression. Clin Exp Immun 1992;88:75-83.</p><p>Suzuki H., Yasukawa K., Saito T. et al. Serum soluble interleukin-6 receptor in MRL/lpr mice is elevated with age and mediates the interleukin-6 signal. Eur J Immunol 1993;23:1078-82.</p><p>Tang B., Matsuda T., Akira S. et al. Age-associated increase in interleukin 6 in MRL/lpr mice. Int Immunol 1991;3:273-8.</p><p>Alarcon-Riquelme M.E., Moller G., Fernandez C. Age-dependent responsiveness to interleukin-6 in B lymphocytes from a systemic lupus erythematosus-prone (NZB x NZW)F1 hybrid. Clin Immunol Immunopath 1992;62:264-9.</p><p>Mihara M., Fukui H., Koishihara Y. et al. Immunologic abnormality in NZB/W F1 mice. Thymus-independent expansion of B cells responding to interleukin-6. Clin Exp Immunol 1990;82:533-7.</p><p>Mihara M., Ohsug Y. Possible role of IL-6 in pathogenesis of immune complex-mediated glomerulonephritis in NZB/W F1 mice: induction of IgG class anti-DNA autoantibody production. Intern Arch Allergy Appl Immunol 1990;93:89-92.</p><p>Ryffel B., Car B.D., Gunn H. et al. Interleukin-6 exacerbates glomerulonephritis in (NZBxNZW)F1 mice. Amer J Pathol 1994;144:927-37.</p><p>Finck B.K., Chan B., Wofsy D. Interleukin 6 promotes murine lupus in NZB/NZW F1 mice. J Clin Inves 1994;94:585-91.</p><p>Mihara M., Takagi N., Takeda Y., Ohsugi Y. IL-6 receptor blockage inhibits the onset of autoimmune kidney disease in NZB/WF1 mice. Clin Exp Immunol 1998;112:397-402.</p><p>Liang B., Gardner D.B., Griswold D.E. et al. Anti-interleukin-6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus. Immunology 2006;119:296-305.</p><p>Pflegerl P., Vesely P., Hantusch B. et al. Epidermal loss of JunB leads to a SLE phenotype due to hyper IL-6 signaling. Proc Natl Acad Sci USA 2009;106:20423-8.</p><p>Gabrielli A., Avvedimento E.V., Krieg T. Mechanisms of disease: Scleroderma. New Engl J Med 2009;360:1989-2003.</p><p>Barnes T.C., Anderson M.E., Moots R.J. The many faces of interleukin-6 (IL-6): the role of IL-6 in inflammation, vasculopathy and fibrosis in systemic sclerosis. Int J Rheumatol 2011;2011:Article ID 721608.</p><p>Muangchan C., Pope J.E. Interleukin 6 in systemic sclerosis and potential implications for targeted therapy. J Rheumatol 2012;39:1120-4.</p><p>Needleman B.W., Wigley F.M., Stair R.W. Interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor alpha, and interferon-gamma levels in sera from patients with scleroderma. Arthr Rheum 1992;35:67-72.</p><p>Koch A.E., Kronfeld-Harrington L.B., Szekanecz Z. et al. In situ expression of cytokines and cellular adhesion molecules in the skin of patients with systemic sclerosis. Their role in early and late disease. Pathobiology 1993;61:239-46.</p><p>Stuart R.A., Littlewood A.J., Maddison PJ., Hall N.D. Elevated serum interleukin-6 levels associated with active disease in systemic connective tissue disorders. Clin Exp Rheumatol 1995;13:17-22.</p><p>Hasegawa M., Sato S., Fujimoto M. et al. Serum levels of interleukin 6 (IL-6), oncostatin M, soluble IL-6 receptor, and soluble gp130 in patients with systemic sclerosis. J Rheumatol 1998;25:308-13.</p><p>Sato S., Hasegawa M., Takehara K. Serum levels of interleukin-6 and interleukin-10 correlate with total skin thickness score in patients with systemic sclerosis. J Dermatol Sci 2001;27:140-6.</p><p>Scala E., Pallotta S., Frezzolini A. et al. Cytokine and chemokine levels in systemic sclerosis: relationship with cutaneous and internal organ involvement. Clin Exp Immunol 2004;138:540-6.</p><p>Matsushita T., Hasegawa M., Hamaguchi Y. et al. Longitudinal analysis of serum cytokine concentrations in systemic sclerosis: association of interleukin 12 elevation with spontaneous regression of skin sclerosis. J Rheumatol 2006;33:275-84.</p><p>Nihtyanova S., Black C.M., Denton C.P. A clinically defined subset of dcSSc is associated with elevated serum IL-6 level [abstract]. Arthr Rheum 2009;60(Suppl):440.</p><p>Gourh P., Arnett F.C., Assassi S. et al. Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations. Arthr Res Ther 2009;11:R147.</p><p>Pope J., Harding S., Khimdas S. et al. C-reactive protein is associated with high disease activity in SSc. Results from the Canadian Scleroderma Research Group (CSRG) [abstract]. Arthr Rheum 2009;60(Suppl):471.</p><p>Аігуєгпіпі S., De Santis M., Tolusso B. et al. Skin ulcers in systemic sclerosis: Determinants of presence and predictive factors of healing. J Am Acad Dermatol 2009;60:426-35.</p><p>Feghali C.A., Bost K.L., Boulware D.W., Levy L.S. Mechanisms of pathogenesis in scleroderma. I. Overproduction of interleukin 6 by fibroblasts cultured from affected skin sites of patients with scleroderma. J Rheumatol 1992;19:1207-11.</p><p>Feghali C.A., Bost K.L., Boulware D.W., Levy L.S. Control of IL-6 expression and response in fibroblasts from patients with systemic sclerosis. Autoimmunity 1994;17:309-18.</p><p>Zurita-Salinas C., Richaud-Patin Y., Krötzsch-Gömez E. et al. Spontaneous cytokine gene expression by cultured skin fibroblasts of systemic sclerosis. Correlation with collagen synthesis. Rev Invest Clin 1998;50:97-104.</p><p>Yamamoto T., Katayama I., Nishioka K. Fibroblast proliferation by bleomycin stimulated peripheral blood mononuclear cell factors. J Rheumatol 1999;26:609-15.</p><p>Kawaguchi Y., Harigai M., Suzuki K. et al. Interleukin 1 receptor on fibroblasts from systemic sclerosis patients induces excessive functional responses to interleukin 1 beta. Biochem Biophys Res Commun 1993;190:154-61.</p><p>Takemura H., Suzuki H., Fujisawa H. et al. Enhanced interleukin 6 production by cultured fibroblasts from patients with systemic sclerosis in response to platelet derived growth factor. J Rheumatol 1998;25:1534-9.</p><p>Kadono T., Kikuchi K., Ihn H. et al. Increased production of interleukin 6 and interleukin 8 in scleroderma fibroblasts. J Rheumatol 1998;25:296-301.</p><p>Kawaguchi Y., Hara M., Wright T.M. Endogenous IL-1-alpha from systemic sclerosis fibroblasts induces IL-6 and PDGF-A. J Clin Invest 1999;103:1253-60.</p><p>Kawaguchi Y., McCarthy S.A., Watkins C., Wright T.M. Autocrine activation by interleukin 1-alpha induces the fibrogenic phenotype of systemic sclerosis fibroblasts. J Rheumatol 2004;31:1946-54.</p><p>Fukasawa C., Kawaguchi Y., Harigai M. et al. Increased CD40 expression in skin fibroblasts from patients with systemic sclerosis (SSc): Role of CD40-CD154 in the phenotype of SSc fibroblasts. Eur J Immunol 2003;33:2792-800.</p><p>Kawai M., Masuda A., Kuwana M. A CD40-CD154 interaction in tissue fibrosis. Arthr Rheum 2008;58:3562-73.</p><p>Aqache I., Radoi M., Duca L. Platelet activation in patients with systemic scleroderma-pattern and significance. Rom J Intern Med 2007;45:183-91.</p><p>Kondo K., Okada T., Matsui T. et al. Establishment and characterization of a human B cell line from the lung tissue of a patient with scleroderma; extraordinary high level of IL-6 secretion by stimulated fibroblasts. Cytokine 2001;13:220-6.</p><p>Crestani B., Seta N., De Bandt M. et al. Interleukin 6 secretion by monocytes and alveolar macrophages in systemic sclerosis with lung involvement. Am J Respir Crit Care Med 1994;149:1260-5.</p><p>Giacomelli R., Cipriani P., Danese C. et al. Peripheral blood mononuclear cells of patients with systemic sclerosis produce increased amounts of interleukin 6, but not transforming growth factor beta 1. J Rheumatol 1996;23:291-6.</p><p>Gurram M., Pahwa S., Frieri M. Augmented interleukin-6 secretion in collagen-stimulated peripheral blood mononuclear cells from patients with systemic sclerosis. Ann Allergy 1994;73:493-6.</p><p>Hasegawa M., Sato S., Ihn H., Takehara K. Enhanced production of interleukin-6 (IL-6), oncostatin M and soluble IL-6 receptor by cultured peripheral blood mononuclear cells from patients with systemic sclerosis. Rheumatology 1999;38:612-7.</p><p>Barnes T.C., Spiller D.G., Anderson M.E. et al. Endothelial activation and apoptosis mediated by neutrophil-dependent interleukin 6 trans-signaling: A novel target for systemic sclerosis? Ann Rheum Dis 2011;70:366-72.</p><p>Dalakas M.C. Inflammatory muscle diseases: a critical review on pathogenesis and therapies. Curr Opin Pharmacol 2010;10:346-52.</p><p>Pedersen B.K., Febbraio M.A. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev 2008;88:1379-1406.</p><p>Carson J.A., Baltgalvis K.A. Interleukin 6 as a key regulator of muscle mass during cachexia. Exercise Sport Sci Rev 2010;38:168-76.</p><p>Gabay С., Gay-Croisier F., Roux-Lombard P. et al. Elevated serum levels of interleukin-1 receptor antagonist in polymyositis/dermatomyositis: a biologic marker of disease activity with a possible role in the lack of acute-phase protein response. Arthr Rheum 1994;37:1744-51.</p><p>Lundberg I., Ulfgren A.K., Nyberg P. Cytokine production in muscle tissue of patients with idiopathic inflammatory myopathies. Arthr Rheum 1997;40:865-74.</p><p>Lepidi H., Frances V., Figarella-Branger D. et al. Local expression of cytokines in idiopathic inflammatory myopathies. Neur Appl Neurobiol 1998;24:73-9.</p><p>Okada M., Kitahara M., Kishimoto S. et al. IL-6/BSF-2 functions as a killer helper factor in the in vitro induction of cytotoxic T cells. J Immunol 1988;141:1543-9.</p><p>Bilgic H., Ytterberg S.R., Amin S. Interleukin-6 and type I interferon-regulated genes and chemokines Mark disease activity in dermatomyositis. Arthr Rheum 2009;60:3436-46.</p><p>Scuderi F., Mannella F., Marino M. et al. IL-6-deficient mice show impaired inflammatory response in a model of myosin-induced experimental myositis. J Neuroimmun 2006;176:9-15.</p><p>Okiyama N., Sugihara T., Iwakura Y. et al. Therapeutic effects of interleukin-6 blockade in a murine model of polymyositis that does not require interleukin-17A. Arthr Rheum 2009;60:2505-12.</p><p>Noris M., Daina E., Gamba S. et al. Interleukin-6 and RANTES in Takayasu arteritis a guide for therapeutic decisions? Circulation 1999;100:55-60.</p><p>Park M.C., Lee S.W., Park Y.B., Lee S.K. Serum cytokine profiles and their correlations with disease activity in Takayasu’s arteritis. Rheumatology (Oxford) 2006;45:545-8.</p><p>Garcia-Martinеz A., Hernandez-Rodrigues J., Espigol-Frigole G. et al. Clinical relevance of persistently elevated circulating cytokines (tumor necrosis factor а and interleukin-6) in the long-term followup of patients with giant cell arteriitis. Arthr Care Res (Hoboken) 2010;62:835-41.</p><p>Martinez-Taboada V.M., Alvarez L., Ruiz Soto M. et al. Giant cell arteriitis and polymyalgia rheumatica: role of cytokines in the pathogenesis and implications for treatment. Cytokine 2008;44:207-20.</p><p>Deng J., Younge B.R., Olshen R.A. et al. Th17 and Th1 T cell responses in giant cell arteriitis. Circulation 2010;121:906-15.</p><p>Espigol-Frigole G., Corbera-Bellalta M., Planas-Rigol E. et al. Incresed IL-17 expression in temporal artery lesions is a predictor of sustained response to glucocorticoid treatment in patients with giant-cell arteritis. Ann Rheum Dis 2012;Sep 19 [Epub ahead of print].</p><p>Hernandez-Rodriquez J., Segarra M., Vilardell C. et al. Elevated production of interleukin-6 is associated with a lower incidence of disease-related ischemic events in patients with giant-cell arteritis: angiogenic activity of interleukin-6 as a potential protective mechanism. Circulation 2003;107:2428-34.</p><p>Nakahama H., Okada M., Miyazaki M. et al. Distinct responses of interleukin-6 and other laboratory parameters to treatment in a patient with polyarteritis nodosa: a case report. Angiology 1992;43:512-6.</p><p>Muller Kobold A.C., van Wijk R.T., Franssen C.F.M. et al. In vitro up-regulation of E-selectin and induction of interleukin-6 in endothelial cells by autoantibodies in Wegener’s granulomatosis and microscopic polyangiitis. Clin Exp Rheumatol 1999;17:433-40</p><p>Popa E.R., Franssen C.F.M., Limburg P.C. et al. In vitro cytokine production and proliferation of T cells from patients with anti-proteinase 3- and antimyeloperoxidase-associated vasculitis, in response to proteinase 3 and myeloperoxidase. Arthr Rheum 2002;46:1894-904</p></div><br />