Terapevticheskii arkhivTerapevticheskii arkhivТерапевтический архив0040-36602309-5342LLC Obyedinennaya Redaktsiya30619Editorial articleПередовая статьяNew approaches to pharmacotherapy for rheumatoid arthritis: perspective for use of tocilizumab (monoclonal antibodies to interleukin-6 receptor)Новые подходы к фармакотерапии ревматоидного артрита: перспективы применения тоцилизумаба (моноклональные антитела к рецептору интерлейкина-6)NasonovEvgeniy L'vovichНасоновЕвгений Львович

акад. РАМН, дир. НИИ ревматологии РАМН, тел.: 8-499-614-44-90; Научно-исследовательский институт ревматологии РАМН

sokrat@irramn.ruNasonovE L

Institute of Rheumatology, Russian Academy of Medical Sciences

Научно-исследовательский институт ревматологии РАМНInstitute of Rheumatology, Russian Academy of Medical Sciences15052010825NO5 (2010)ТОМ 82, №5 (2010)647109042020Copyright ©; 2010, Consilium MedicumCopyright ©; 2010, ООО "Консилиум Медикум"2010Consilium MedicumООО "Консилиум Медикум"https://creativecommons.org/licenses/by-nc-sa/4.0https://ter-arkhiv.ru/0040-3660/article/view/30619

The author considers a role of interleukin-6 (IL-6) as a cytokine, elevated concentrations of which in serum and synovial fluid correlate with the activity of articular inflammation and the development of systemic manifestations in rheumatoid arthritis (RA). There is strong evidence suggesting that effective treatment with gene-engineering biologicals causes a reduction in IL-6 concentrations. Detailed information is given on the novel drug tocilizumab that is humanized monoclonal antibodies (IgG1) and the first and only agent that is able to suppress IL-6-dependent inflammatory reactions and is permitted for use in RA.

Рассмотрена роль интерлейкина-6 (ИЛ-6) как цитокина, увеличение концентрации которого в сыворотке и синовиальной жидкости коррелирует с активностью суставного воспаления и развитием системных проявлений при ревматоидном артрите (РА). Представлены убедительные данные, свидетельствующие, что эффективное лечение с применением генно-инженерных биологических препаратов сопровождается снижением концентрации ИЛ-6. Приведена подробная информация о новом препарате тоцилизумаб, который представляет собой гуманизированные моноклональные антитела (IgG1) и является первым и единственным препаратом, способным подавлять зависимые от ИЛ-6 воспалительные реакции, разрешенным к применению при РА.

rheumatoid arthritisinterleukin-6tocilizumabревматоидный артритинтерлейкин-6тоцилизумабGabriel S. The epidemiology of rheumatoid arthritis. Rheum. Dis. Clin. N. Am. 2001; 27: 269-281.Насонов Е. Л., Каратеев Д. Е., Балабанова Р. М. Ревматоидный артрит. В кн.: Насонов Е. Л., Насонова В. А. (ред.). Ревматология: Нац. руководство. М.: Изд. группа "ГЭОТАР-Медиа"; 2008. 290-331.Фоломеева О. М., Галушко Е. А., Эрдес Ш. Ф. Распространенность ревматических заболеваний в популяции населения России и США. Науч.-практ. ревматол. 2008; 4: 4- 14.Pincus T., Callahan L. What is the natural history of rheumatoid arthritis. Rheum. Dis. Clin. N. Am. 1993; 4: 123.Насонов Е. Л. Фармакотерапия ревматоидного артрита - взгляд в 21 век. Клин. мед. 2005; 6: 8-12.Smolen J. S., Aletaha D., Koeller M. et al. New therapies for treatment of rheumatoid arthritis. Lancet 2007; 370: 1861- 1871.van Vollenhoven R. F. Treatment of rheumatoid arthritis: state of the art 2009. Nat. Rev. Rheumatol. 2009; 5: 531-541.Furst D. E., Keystone E. C., Kirkham B. et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2008. Ann. Rheum. Dis. 2008; 67: iii2-iii25.9. Du Pan S. M., Dehler S., Ciurea A. et al. Comparison of drug retention rates and causes of drug discontinuation between anti-tumor necrosis factor agents in rheumatoid arthritis. Arthr. Care Res. 2009; 61: 560-568.Brennan F., McInnes I. B. Evidence that cytokines play a role in rheumatoid arthritis. J. Clin. Invest. 2008; 118: 3537-3545.Nishimoto N., Kishimoto T. Interleukin 6, from bench to bedside. Nat. Clin. Prac. Rheumatol. 2006; 11: 619-626.Насонов Е. Л. Новые возможности фармакотерапии ревматических болезней - ингибирование интерлейкина-6. Клин. фармакол. и тер. 2008; 1: 60-67.Dayer J.-M., Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology 2009; 1-9, October 2003, on line.Rose-John S., Scheller J., Elson G. et al. Interleukin-6 is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J. Leukocyte Biol. 2006; 80: 227-237.Foseca J. E., Santos M. J., Canhao H., Choy E. Interleukin-6 as a key player in systemic inflammation and joint destruction. Autoimmune Rev. 2009. doi:10.1016/j.autrev.2009.012Miossec P., Korn T., Kuchroo V. K. Interleukin-17 and type 17 helper cells. N. Engl. J. Med/ 2009; 361: 888.Sato K., Tsuchiya M., Saldanha J. et al. Reshaping a human antibody to inhibit the iterleukin-6-dependent tumor cell growth. Cancer Res. 1993; 53: 851-856.Nishimoto N., Yoshizaki K., Maeda K. et al. Toxicity, pharmacokinetics, and dose finding study of repetitive treatment with humanized anti-interleukin-6 receptor antibody, MRA, in rheumatoid arthritis. Phase I/II clinical study. J. Rheumatol. 2003; 30: 1426-1435.Aletaha D., Landewee R., Karonitsch T. et al. Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EUEAR/ACR collaborative recommendations. Arthr. Care Res. 2008; 59: 1371-1377.Guidance for industry. Clinical development programs for drugs, devices, and biological products for the treatment of rheumatoid arthritis. (RA). WY: UA. Food and "Drug administration. Center for drug evaluation and research; 1999.Mima T., Nishimoto N. Clinical value of blocking IL-6 receptor. Curr. Opin. Rheumatol. 2009; 21: 224-230.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: 88-86.Maini R., Taylor P., Szechinski J. et al. Double-blind randomized controlled clinical trial of the interleukin 6 receptor antagonist, tocilizumab in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthr. and Rheum. 2006; 54: 2817-2129.Nishimoto N., Hashimoto J., Miasaka 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. Am. Rheum. Dis. 2007; 66: 1162-1167Kremer J., Fleischmann R., Brzezicki J. et al. Tocilizumab inhibits structural joint damage, improved physical function, and increase DAS28 remission rates in RA patients who respond inadequately to methotrexate: the LITHE study. Am. Rheum. Dis. 2009; 68 (suppl. 3): 122, abstr. OP-0157.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, placebo-controlled, randomized trial. Lancet 2008; 371: 987-997.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 biologies: results from a 24-week multicenter randomized placebo-controlled trial. Ann. Rheum. Dis. 2008; 67: 1516-1523.Nishimoto N. et al. Efficacy and safety of tocilizumab in monotherapy, an anti-IL-6-receptor monoclonal antibody, in patients with active rheumatoid arthritis: results from a 24 week double-blind phase III study. Ann. Rheum. Dis. 2006; 65: 59.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. and Rheum. 2008; 58: 2968-2980.Choy E., Isenberg D. A., Garrood T. et al. Therapeutic benefit after blocking interleukin-6 activity in rheumatoid arthritis with an anti-interleukin 6 receptor monoclonal antibody. Arthr. and Rheum. 2002; 46: 3143-3150.Nishimoto N., Yoshizaka K., Miaysaka N. et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter. double-blind, placebo-controlled trial. Arthr. and Rheum. 2004; 50: 1761-1769.Smolen J., Martin-Mola E., Rubbert-Roth A. et al. Efficacy and safety of tocilizumab In rheumatoid arthritis in patients above and below 65 years of age with inadequate response to DMARDs. In: Annual European congress of rheumatology, 11-14 June 2008. Paris; 2008. Abstr. FRI0164.Genovese M. et al. Efficacy of tocilizumab in combination with DMARDS is superior to DMARDS alone in moderate-to-severe rheumatoid arthritis based on ACR criteria: a pooled analysis of clinical trial data from OPTION and TOWARD. In: Annual European congress of rheumatology, 11-14 June 2008. Paris; 2008. Abstr. THU0185.Beaulieu A. et al. Treatment with the humanized anti-interleukin-6 receptor antibody tocilizumab results in rapid improvements in the signs and symptoms of rheumatoid arthritis: Results from a pooled analysis of clinical trial data from OPTION and TOWARD. In: Annual European congress of rheumatology, 11-14 June 2008. Paris; 2008. Abstr. THU0184.Rubbert-Roth A., Finch A. Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review. Arthr. Res. Ther. 2009; 11 (suppl. 1): S1, on line.van Vollenhoven R. F. Switching between anti-tumor necrosis factors: trying to get a handle on a complex issue. Ann. Rheum. Dis. 2007; 66: 849-851.Emery P., Keystone E., Tony H. P. et al. Patients achieve significant improvement in rheumatoid arthritis (RA) outcome with tocilizumab (TCZ) regardless of prior inadequate response (IR) to TNF antagonist. Arthr. and Rheum. 2008; 58 (suppl.): S533, abstr. 990.Насонов Е. Л. Метотрексат. Перспективы применения в медицине. М.: Изд-во "Филоматис"; 2005.Breedveld F. C., Weisman M. H., Kavanaugh A. F. et al. The PREMIER Study. A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthr. and Rheum. 2006; 54: 26-37.Heiberg M. S., Rodevand E., Mikkelsen C. et al. Adalimumab plus methotrexate are more effective than adalimumab alone in patients with established rheumatoid arthritis: results from a 6-month longitudinal, observational, multicenter study. Ann. Rheum. Dis. 2006; 65: 1379-1383.Bathon J. M., Martin R. W., Fleischmann R. M. et al. Comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N. Engl. J. Med. 2000; 343: 1586-1593.Genovese M. C., Bathon J. M., Martin R. W. et al. Etanercept versus mjethotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcome. Arthr. and Rheum 2002; 46; 1443-0450.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.Genovese M., Siri D., Tomsic M. et al. Tocilizumab (TCZ) monotherapy improves rheumatoid arthritis (RA) outcome regardless of disease duration. Arthr. and Rheum.2008; 58 (suppl.): S532, abstr. 988.Jones G., Gomez-Reino J. J., Lowenstein M. B. et al. Efficacy of tocilizumab (TCZ) vs methotrexate (MIX) monotherapy in patients with rheumatoid arthritis (RA) with no prior MIX or DMARD exposure. Ann. Rheum. Dis. 2009; 68 (suppl. 3): 440, abstr. FRI0252.Smolen J. et al. Tocilizumab rapidly and significantly reduces DAS28 in patients with rheumatoid arthritis inadequately responding to DMARDs: Pooled analysis. In: Annual European congress of rheumatology, 11-14 June 2008. Paris; 2008. Abstr. FRI0172.Smolen J. S., Churchill M., Rizzo W. et al. Tocilizumab treatment results in rapid improvements in the signs and symptoms to moderate-to-severe rheumatoid arthritis in four patients populations with different prior therapy exposure. Arthr. and Rheum. 2008; 58 (suppl.): S532, abstr. 989.Nishimoto N., Miyasaka N., Yamamoto K. et al. Long-term safety and efficacy of tocilizumab an antiinterleukin-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study); evidence of safety and efficacy in a 5-year extension study. Ann. Rheum. Dis. 2009; 68: 1580-1584.Smolen J. S., Alten R. H. E., Gomez-Reino J. et al. Efficacy of tocilizumab (TCZ) in rheumatoid arthritis (RA): interim analysis of long-term extension trials of up to 2.5 years. Ann. Rheum. Dis. 2009; 68 (suppl. 3): 401, abstr. FRI0133.Hirabayashi Y., Ishii T., Hangae H. Clinical efficacy of tocilizumab in patients with active rheumatoid arthritis in real clinical practice. Rheumatol. Int. 2009; 22 August, on line.van Vollenhoven R., Rubbert-Roth A., Cantagrel A. et al. Long-term safety and tolerability of tocilizumab in patients with a mean treatment duration of 1,5 years. Ann. Rheum. Dis. 2009; 68 (suppl. 3): 8, abstr. SAT0111.van Vollenhoven R. F., Nishimoto N., Yamanaka H. et al. Experience with mycobactenum tuberculosis infection reported in the tocilizumab worldwide RA safety database. Ann. Rheum. Dis. 2009; 68 (suppl. 3): 567, abstr. SAT0081.Koike R., Harigai M., Atsumi T. et al. Japan College of Rheumatology 2009 guidelines for the use of tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, in rheumatoid arthritis. Mod. Rheumatol. 2009, on line.