Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC5310.15690/vramn.v70i2.1310PROCEEDINGS of the GENERAL MEETING of the Department of Medical Sciences, RASМАТЕРИАЛЫ ОБЩЕГО СОБРАНИЯ ОТДЕЛЕНИЯ МЕДИЦИНСКИХ НАУК РАНAUTOIMMUNE RHEUMATIC DISEASES — PROBLEMS OF IMMUNOPATHOLOGY AND PERSONALIZED TREATMENTАУТОИММУННЫЕ РЕВМАТИЧЕСКИЕ ЗАБОЛЕВАНИЯ — ПРОБЛЕМЫ ИММУНОПАТОЛОГИИ И ПЕРСОНИФИЦИРОВАННОЙ ТЕРАПИИNasonovE. L.НасоновЕ. Л.
Russian Federation

академик РАН, доктор медицинских наук, профессор, директор НИИ ревматологии им. В.А. НасоновойАдрес: 115522, Москва, Каширское шоссе, д. 34 А, тел: +7 (499) 614-44-90

sokrat@irramn.ruAleksandrovaE. N.АлександроваЕ. Н.
Russian Federation

доктор медицинских наук, заведующая лабораторией иммунологии и молекулярной биологии ревматических заболеваний НИИ ревматологии им. В.А. НасоновойАдрес: 115522, Москва, Каширское шоссе, д. 34 А, тел: +7 (499) 614-09-33

irramnlab@rambler.ruNovikovA. A.НовиковА. А.
Russian Federation

кандидат биологических наук, ведущий научный сотрудник лаборатории иммуно-логии и молекулярной биологии ревматических заболеваний НИИ ревматологии им. В.А. НасоновойАдрес: 115522, Москва, Каширское шоссе, д. 34 А, тел: +7 (499)-614-09-33

irramnlab@rambler.ruV.A. Nasonova Research Institute for Rheumatology, Moscow, Russian FederationНИИР им. В.А. Насоновой, Москва, Российская Федерация08042015702Vestnik Rossiiskoi akademii medetsinskikh nauk / Annals of the Russian academy of medical sciencesВестник Российской академии медицинских наук16918207082015Copyright ©; 2015, "Paediatrician" Publishers LLCCopyright ©; 2015, Издательство "Педиатръ"2015"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/article/view/53

By current standards autoimmunity is a complex pathological process based on a violation of tolerance and, consequently, the pathological immune response against its own tissues components (autoantigens) leading to the development of a wide range of autoimmune diseases in humans. In recent years, multiple immune disorders both acquired and / or congenital (associated with polymorphisms of genes that regulate immune response) have been transcribed. These disorders occur at the cellular and humoral levels: thymus, intestines, peripheral blood immune cells, including T and B lymphocytes, macrophages, dendritic cells, Treg-cells (Treg), components of complement system, cytokines and others. The interaction between the development of autoimmune rheumatic (ARD) and autoinflammatory diseases and syndromes is detected; a classification of immune-inflammatory diseases is designed. The article describes the results of our studies on the treatment of ARD using innovative genetically engineered biological agents and on the research of pathogenetic mechanisms and diagnostics of ARD based on immunological and molecular biological diagnostic techniques of a wide range of molecular and cellular biomarkers (autoantibodies, inflammatory acute phase proteins, cytokines, chemokines, markers of activation of the vascular endothelium, the components of the complement system, lymphocyte subpopulations, products of metabolism of bone and cartilage tissue, genetic, epigenetic, transcriptomic markers). The approaches to personalized treatment of ARD are presented.

По современным представлениям аутоиммунитет — это комплексный патологический процесс, в основе которого лежит нарушение толерантности и, как следствие, патологический иммунный ответ в отношении компонентов собственных тканей (аутоантигенов), приводящий к развитию широкого спектра аутоиммунных заболеваний человека. В последние годы были расшифрованы многообразные нарушения иммунитета, приобретенные и/или врожденные (связаны с полиморфизмом генов, регулирующих иммунный ответ), которые реализуются на клеточном и гуморальном уровне: тимус, кишечник, иммунные клетки периферической крови, включая Т и В лимфоциты, макрофаги, дендритные клетки, регуляторные Т клетки (Трег), компоненты системы комплемента, цитокины и другие. Установлена связь между развитием аутоиммунных ревматических (АРЗ) и аутовоспалительных заболеваний и синдромов, разработана классификация иммуновоспалительных заболеваний человека. В статье рассмотрены результаты собственных исследований, касающихся лечения АРЗ с использованием инновационных генно-инженерных биологических препаратов, изучения патогенетических механизмов и диагностики АРЗ на основе иммунологических и молекулярно-биологических методов исследования широкого спектра молекулярных и клеточных биомаркеров (аутоантитела, острофазовые белки воспаления, цитокины, хемокины, маркеры активации сосудистого эндотелия, компоненты системы комплемента, субпопуляции лимфоцитов, продукты метаболизма костной и хрящевой ткани, генетические, эпигенетические, транскриптомные маркеры). Также освещены подходы к персонифицированной терапии АРЗ.

autoimmune rheumatic diseasesbiomarkersautoantibodiescytokinesgenetically engineered biological agentsаутоиммунные ревматические болезнибиомаркерыаутоантителацитокиныгенно-инженерные биологические препараты1.Cho J.H., Gregersen P.K. Genomics and the multifactorial nature of human autoimmune disease. New Engl. J. Med. 2011; 365: 1612–1623.2.Wahren-Herlenius M., Dorner T. Immunopathogenetic mechanisms of systemic autoimmune diseases. Lancet. 2013; 382: 819–831.3.McInnes I.B., Schett G. The pathogenesis of rheumatoid arthritis. New Engl. J. Med. 2011; 365: 2205–2219.4.Lopalco G., Cantini L., Vatale A., Iannone F., Anelli M.G., Andreozzi L., Lapadula G., Galeazzi M., Rigante D. Interleukin-1 as a common denomination from autoinflammatory to autoimmune disorders: premises, perils, and perspectives. Mediators Inflam. 2015; ID 194864.5.McGonagle D., McDermott M.F. A proposed classification of the immunological diseases. PLoS Med. 2006; 3: 1242–1248.6.Nasonov E.L., Nasonova V.A. Revmatologiya. Natsional'noe rukovodstvo [Rheumatology. National Guidelines]. Moscow, GEOTAR-Media, 2008. P. 290–331.7.Goldblatt F., O`Neill S.G. Clinical aspects of autoimmune rheumatic diseases. Lancet. 2013; 382: 797–808.8.Nasonov E.L., Aleksandrova E.N., Avdeeva A.S., Rubtsov Yu.P. T-regulatory cells in rheumatic diseases. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2014; 52: 430–437.9.Anti-V-kletochnaya terapiya v revmatologii: fokus na rituksimab. Pod red. E.L. Nasonova [Anti-B-cell Therapy in Rheumatology: a Focus on Rituximab. Edited by E.L. Nasonov]. Moscow, IMA-PRESS, 2012. 344 p.10.Genno-inzhenernye biologicheskie preparaty v lechenii revmatoidnogo artrita. Pod red. E.L. Nasonova [Genetically Engineered Biological Agents in the Treatment of Rheumatoid Arthritis. Edited by E.L. Nasonov]. Moscow, IMA-PRESS, 2013. 549 p.11.Murphy G., Lisnevskaia L., Isenberg D. Systemic lupus erythematosus and other autoimmune rheumatic diseases: challenges to treatment. Lancet. 2013; 382: 809–818.12.Chatzidionysiou K., Lie E., Nasonov E., Lukina G., Hetland M.L., Tarp U., Ancuta I., Pavelka K., Nordström D.C., Gabay C., Can-hão H., Tomsic M., van Riel P.L., Gomez–Reino J., Kvien T.K., van Vollenhoven R.F. Highest clinical effectiveness of Rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries. Ann. Rheum. Dis. 2011; 70: 1575–1580.13.Chatzidionysiou K., Lie E., Nasonov E., Lukina G., Hetland M.L., Tarp U., van Riel P.L., Nordström D.C., Gomez-Reino J., Pavelka K., Tomsic M., Kvien T.K., van Vollenhoven R.F., Gabay C. Effectiveness of disease-modifying antirheumatic drug co therapy with methotrexate and leflunomide in Rituximab treated rheumatoid arthritis patients: results of a 1 year follow-up study from the CERERRA collaboration. Ann. Rheum. Dis. 2012; 71: 374–377.14.Panasyuk E.Yu., Amirdzhanova V.N., Avdeeva A.S., Luchikhina E.L., Aleksandrova E.N., Novikov A.A., Nasonov E.L. Experience in the application of tocilizumab in rheumatoid arthritis patients (according to a multicenter study LORNET). Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2013; 21 (5): 104–110.15.Pchelintseva A.O., Panasyuk E.Yu., Ryabitseva O.F., Mazurov V.I., Salikhov Shch.G., Sizikov A.E., Ivanova O.N., Sorotskaya V.N., Semagina O.V., Vinogradova I.B., Kulikov A.I., Denisov L.N., Nasonov E.L. Application of etanercept in patients with rheumatoid arthritis (the results of a multicenter study of the Russian standard). Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2013; 51: 639–645.16.Pavelka K., Szekanecz Z., Damjanov N., Majdan M., Nasonov E., Mazurov V., Fabo T., Bananis E., Jones H., Szumski A., Koenig A.S., Tang B., Kotak S., Vasilescu R. Induction of response with etanercept methotrexate therapy in patients with moderate actiove rheumatoid arthritis in Central and Eastern Europe in the preserve study. Clinical Rheumatology. 2013; 32: 1275–1281.17.Smolen J.S., Nash P., Durez P., Hall S., Ilivanova E. Maintenance, reduction or withdrawal of Etanercept: a randomized controlled trial in moderate rheumatoid arthritis patients achieving low disease activity with etanercept methotrexate therapy. Lancet. 2013; 381 (91): 918–929.18.Karateev D.E., Nasonov E.L., Denisov L.N., Mazurov V.I., Arutyunov G.P., Zhugrova E.S., Ilivanova E.P., Zhilyaev E.V., Lytkina K.A., Korshunov N.I., Stanislav M.L., Uspenskii Yu.P., Andrianova I.A., Belousova L.N., Matsievskaya G.K., Saikovskii R.S., Ardashev V.N. New possibilities of therapy of rheumatoid arthritis: the Russian experience of certolizumab pegol. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2011; 2: 104–110.19.Karateev D.E., Nasonov E.L., Luchikhina E.L., Mazurov V.I., Salikhov I.G., Shmidt E.I., Shostak N.A. The efficacy and safety of treatment with adalimumab patients with active rheumatoid arthritis resistant to standard therapy: results of a national study of Russian. Terapevticheskii arkhiv = Therapeutic archive. 2012; 8: 22–28.20.Nasonov E.L., Karateev D.E., Lukina G.V. Pharmacotherapy of rheumatoid arthritis in the early 21st century: Russian and international experience. Terapevticheskii arkhiv = Therapeutic archive. 2013; 8: 20–28.21.Anan'eva L.P., Solov'ev S.K., Beketova T.V., Vasil'ev V.I., Antelava O.A., Aleksandrova E.N., Koneva O.A., Tsanyan M.E., Desinova O.B., Logvinenko O.A., Volkov A.V., Khelkovskaya-Sergeeva A.N., Novikov A.A., Aleksankin A.A., Nasonov E.L. Anti-B-cell therapy for immuno rheumatic diseases: efficacy and tolerability in 229 patients. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2014; 52: 495–507.22.Genovese M.C., McKay J.G., Nasonov E.L., Mysler E.F., da Silva N.A., Alecock E., Woodworth T., Gomez-Reino J.J. 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: 2968–2980.23.Genovese M.C., Covarrubias A., Leon G., Mysler E., Keiserman M., Valente R., Nash P., Simon-Campos J.A., Porawska W., Box J., Legerton C., Nasonov E., Durez P., Aranda R., Pappu R., Delaet I., Teng J., Alten R. Sudcutaneous abatacept versus intravenous abatacept. A phase IIIb non inferiority study in patients with inadequate response to methotrexate. Arthritis Rheum. 2011; 63: 2854–2864.24.Genovese M.C., Pachero Tena C., Covarrubias A., Leon G., Mys-ler E., Keiserman M., Valente R., Nash P., Simon-Campos J.A., Box J., Legerton C.W., Nasonov E., Durez P., Aranda R., Pappu R., Delaet I., Teng J., Alten R. Subcutaneous abatacept for the treatment of rheumatoid arthritis: longterm Data from the ACQUIRE trial. J. Rheumatol. 2014; 41: 629–639.25.Navarra S.V., Guzman R.M., Gallacher A.E., Hall S., Levy R.A., Jimenez R.E., Li K.M., Thomas M., Kim H.O., Lron M.G., Tanasescu C., Nasonov E.L., Lan J.L., Pineda L., Zhong Z.J., Freimuth W., Petri M.A. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomized, placebo controlled, phase 3 trial. Lancet. 2011; 377: 721–731.26.Smolen J.S., Aletaha D., Bijsma J.W.J., Breedveld F.C., Boum- pas D., Burmester G., Combe B., Cutolo M., de Wit M., Douga-dos M., Emery P, Gibofsky A., Gomez-Reino J.J., Heijde D. For the T2T Expert Committee. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann. Rheum. Dis. 2010; 69: 631–637.27.Smolen J.S., Landewe R., Breedveld F.C., Buch M., Burmester G., Dougados M., Emery P., Gaujoux-Viala C., Gossec L., Nam J., Ramiro S., Winthrop K., de Wit M., Aletaha D., Betteridge N., Bijlsma J.W., Boers M., Buttgereit F., Combe B., Cutolo M., Damjanov N., Hazes J.M., Kouloumas M., Kvien T.K., Mariette X., Pavelka K., van Riel P.L., Rubbert-Roth A., Scholte-Voshaar M.,Scott D.L., Sokka-Isler T., Wong J.B., van der Heijde D. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease modifying antirheumatic drugs: 2013 update. Ann. Rheum. Dis. 2014; 73: 492–509.28.Nasonov E.L., Karateev D.E. Does Russia need a treat-to-target initiative? Adopting a global strategy to improve outcome locally. Rheumatology (Oxford). 2015; 54: 381–382.29.Nasonov E.L., Karateev D.E., Chichasova N.V. EULAR recommendations for the treatment of rheumatoid arthritis - 2013: a general overview and discussion of the problem. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2013; 51: 609–622.30.Nasonov E.L., Karateev D.E., Chichasova N.V. EULAR recommendations for the treatment of rheumatoid arthritis - 2013: the place of methotrexate. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2014; 52 (1): 8–26.31.Karateev D.E., Luchikhina E.L., Murav'ev Yu.V., Nasonov E.L., Smirnov A.V., Luchikhina E.L., Aleksandrova E.N., Lukina G.V., Volkov A.V., Novikov A.A., Novikova D.S., Avdeeva A.S., Demidova N.V., Popkova T.V., Olyunin Yu.A., Grineva G.I., Lopareva E.V. First Russian strategic research pharmacotherapy of rheumatoid arthritis (REMARKA). Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2013; 21; 51: 117–125.32.Karateev D.E., Luchikhina E.L., Demidova N.V., Murav'ev Yu.V., Nasonov E.L., Kanonirova M.A., Kasumova K.A., Smirnov A.V., Luchikhina E.L., Aleksandrova E.N., Lukina G.V., Volkov A.V., Novikov A.A., Novikova D.S., Avdeeva A.S., Demidova N.V., Popkova T.V., Olyunin Yu.A., Grineva G.I. First Russian strategic study of pharmacotherapy of rheumatoid arthritis (remark): Results of treatment of 130 patients for 12 months. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2014; 52: 607–614.33.Nasonov E.L., Mazurov V.I., Karateev D.E., Lukina G.V., Zhilyaev E.V., Amirdzhanova V.N., Murav'ev Yu.V., Chichasova N.V. Draft recommendations for the treatment of rheumatoid arthritis, the Russian public organization "Association of Rheumatologists of Russia in 2014 (Part 1)". Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2014; 52: 477–494.34.Nasonov E.L., Aleksandrova E.N. Modern technologies and prospects of laboratory diagnosis of rheumatic diseases. Terapevticheskii arkhiv = Therapeutic archive. 2010; 5: 5–9.35.Aleksandrova E.N., Novikov A.A., Nasonov E.L. Modern standards of laboratory diagnosis of rheumatic diseases and their use in clinical practice. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2013; 51: 368–376.36.Tozzoli R., Bonaguri C., Melegari A., Antico A., Bassetti D., Bizzaro N. Current state of diagnostic technologies in the autoimmunology laboratory. Clin. Chem. Lab. Med. 2013; 51: 129–138.37.Novikov A.A., Aleksandrova E.N., Nasonov E.L. Proteomic research in rheumatology. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2012; 50: 19–24.38.Novikov A.A., Aleksandrova E.N., Nasonov E.L. Development and application of diagnostic index based on multivariable analysis of biomarkers to determine the activity of rheumatoid arthritis. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2014; 52 (1): 72–78.39.Satoh M., Tanaka S., Chan E.K.L. The uses and misuses of multiplex autoantibody assays in systemic autoimmune rheumatic diseases. Frontiers Immunol. 2015; 6: 1–4. Doi:10.3389/ fimmu.2015.00181.40.Meroni P.L., Biggioggero M., Pierangeli S.S., Sheldon J., Zegers I., Borghi M.O. Standardization of autoantibody testing: a paradigm for serology in rheumatic diseases. Nat. Rev. Rheumatol. 2014; 10: 35–42.41.Bizzaro N., Tozzoli R., Shoenfeld Y. Are we at a stage to predict autoimmune rheumatic diseases? Arthritis Rheum. 2007; 56: 1736– 1744.42.Agmon-Levin N., Damoiseaux J., Kallenberg C., Sack U., Witte T., Herold M., Bossuyt X., Musset L., Cervera R., Plaza-Lopez A., Dias C., Sousa M.J., Radice A., Eriksson C., Hultgren O., Viander M., Khamashta M., Regenass S., Andrade L.E., Wiik A., Tincani A., Rönnelid J., Bloch D.B., Fritzler M.J., Chan E.K., Garcia-De La Torre I., Konstantinov K.N., Lahita R., Wilson M., Vainio O., Fabien N., Sinico R.A., Meroni P., Shoenfeld Y. International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies. Ann. Rheum. Dis. 2014; 73: 17–23.43.Meroni P.L., Schur P.H. ANA screening: an old test with new recommendations. Ann. Rheum. Dis. 2010; 69: 1420–1422.44.Willitzki A., Hiemann R., Peters V., Guttek K., Goihl A., Hartig R., Conrad K., Bogdanos D.P., Reinhold D., Roggenbuck D. New platform technology for comprehensive serological diagnostics of autoimmune diseases. Clin. Dev. Immunol. 2012; 2012: 284740. Doi: 10.1155/2012/284740.45.Avdeeva A.S., Aleksandrova E.N., Novikov A.A., Smirnov A.V., Cherkasova M.V., Nasonov E.L. The relationship of antibodies to modified citrullinated vimentiv and markers of bone and cartilage destruction in rheumatoid arthritis. Int. J. Rheumatol. 2014; ID464585.46.Shi J., van Veelen P.A., Machler M., Janssen G.M., Drijfhout J.W., Huizinga T.W., Toes R.E., Trouw L.A. Carbamylation and antibodies against carbamylated proteins in autoimmunity and other pathologies. Autoimmune Rev. 2014; 13: 225–230.47.Maksymowych W.P., van der Heijde D., Allaart C.F. 14–3–3η is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage. Arthritis Res. & Ther. 2014; 16: 99.48.Centola M., Cavet G., Shen Y., Ramanujan S., Knowlton N., Swan K.A., Turner M., Sutton C., Smith D.R., Haney D.J., Chernoff D., Hesterberg L.K., Carulli J.P., Taylor P.C., Shadick N.A., Weinblatt M.E., Curtis J.R. Development of a multi biomarker disease activity test for rheumatoid arthritis. PLoS One. 2013; 8: 60635.49.Novikov A.A., Aleksandrova E.N., Gerasimov A.N, Cherkasova M.V., Karateev DE, Luchikhina E.L., Nasonov E.L. Multivariable analysis of biomarkers in the laboratory diagnosis of early rheumatoid arthritis. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2013;51:111–116.50.Nasonov E.L. Rheumatoid arthritis: the problem and the importance of personalized medicine. Terapevticheskii arkhiv = Therapeutic archive. 2012;5:5–9.51.Robinson W.H., Lindstrom T.M., Cheung R.K., Sokolove J. Mechanistic biomarkers for clinical decision making in rheumatic diseases. Nat. Rev. Rheumatol. 2013; 9: 267–276.52.Avdeeva A.S., Aleksandrova E.N., Nasonov E.L. Clinical significance of matrix metalloproteinases in rheumatoid arthritis. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2014; 52: 79–84.53.Avdeeva A.S., Novikov A.A., Aleksandrova E.N., Karateev D.E., Luchikhina E.L., Nasonov E.L. Dynamics of cytokine levels during therapy with methotrexate and adalimumab in patients with early rheumatoid arthritis. (Research REMARKA). Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2014; 52: 254–262.54.Van Schouwenburg R.A., Rispens T., Wolbink G.J. Immunogenicity of anti-TNF biologics therapy for rheumatoid arthritis. Nat. Rev. Rheumatol. 2013; 9: 164–172.55.Suponitskaya E.V., Aleksandrova E.N., Aleksankin A.P., Nasonov E.L. Effect of treatment of genetically engineered biologicals on a subpopulation of B lymphocytes. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2015; 53: 78–83.56.Suponitskaya E.V., Aleksandrova E.N., Nasonov E.L. Clinical significance of BAFF / BLyS and APRIL in systemic lupus erythematosus. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2014; 52: 545–5523.