References

medsovet

Медицинский Совет

Meditsinskiy sovet = Medical Council

2079-701X2658-5790

REMEDIUM GROUP Ltd.

10.21518/2079-701X-2020-17-57-64

medsovet-5877

Research Article

Актуальная проблема

Actual problem

Т2-ассоциированные заболевания: в фокусе коморбидный пациент

T2-associated diseases: focus on the comorbid patient

https://orcid.org/0000-0002-1166-9717

Kузубовa

Н. А.

Kuzubova

N. A.

Кузубова Наталия Анатольевна, доктор медицинских наук, заместитель директора по научной работе Научно-исследовательского института пульмонологии

197022, Санкт-Петербург, ул. Льва Толстого, д. 6/8

Natalia A. Kuzubova, Dr. of Sci. (Med.), Deputy Director of Research Institute of Pulmonology

6–8, Lev Tolstoy St., St Petersburg, 197022

kuzubova@mail.ru

https://orcid.org/0000-0003-4678-3904

Tитовa

О. Н.

Titova

O. N.

Титова Ольга Николаевна, доктор медицинских наук, профессор, директор Научно-исследовательского института пульмонологии

197022, Санкт-Петербург, ул. Льва Толстого, д. 6/8

Olga N. Titova, Dr. of Sci. (Med.), Professor, Director of Research Institute of Pulmonology

6–8, Lev Tolstoy St., St Petersburg, 197022

Первый Санкт-Петербургский государственный медицинский университет им. академика И.П. ПавловаРоссияPavlov First Saint Petersburg State Medical UniversityRussian Federation

2020

21112020

0175764

2020

Kузубовa Н.А., Tитовa О.Н.

Kuzubova N.A., Titova O.N.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.med-sovet.pro/jour/article/view/5877

Т2-ассоциированные заболевания представляют собой группу гетерогенных иммуноопосредованных заболеваний, таких как бронхиальная астма (БА), хронический полипозный риносинусит (ХПРС), атопический дерматит (АтД), объединенных общими патогенетическими механизмами, в основе которых лежит иммунный ответ 2-го типа (Т2-воспаление). Интерлейкины 4 и 13 (ИЛ-4, ИЛ-13) играют ключевую роль в Т2-воспалении, активируя множественные медиаторы и типы клеток, участвуя в дифференцировке Т-лимфоцитов и переключении В-лимфоцитов на продукцию специфического иммуноглобулина E (IgE), способствуют миграции эозинофилов в ткани и ремоделированию дыхательных путей (ДП). Выбор оптимальной таргетной терапии исходя из патогенеза Т2-ассоциированных заболеваний и наличия коморбидных заболеваний является стратегически важной задачей с учетом требований персонифицированной медицины. В статье обсуждается современная терминология Т2-воспаления, ключевые цитокины, вовлеченные в патогенез атопических заболеваний, биомаркеры Т2-воспаления как критерии доказательства Т2-воспаления, место анти-ИЛ-4-/ИЛ-13- таргетной биологической терапии в международных руководствах по терапии тяжелой БА (Глобальной инициативы по БА GINA 2020 и рекомендаций Европейской академии аллергии и клинической иммунологии EAACI 2020), влияние препарата дупилумаб на такие клинически значимые исходы, как снижение частоты тяжелых обострений и улучшение функции легких, снижение потребности в пероральных глюкокортикостероидах (ГКС) у пациентов с БА, доказательная база препарата дупилумаб у пациентов с ХПРС и АтД, а также дальнейшие перспективные научные направления для применения анти-ИЛ-4-/ИЛ-13-таргетной терапии.

T2-associated diseases are a group of heterogeneous immune-mediated diseases such as bronchial asthma (BA), chronic rhinosinusitis with nasal polyps (CRSwNP), atopic dermatitis (AD), based common pathogenetic mechanisms with the type 2 immune response (T2 inflammation). Interleukins 4 and 13 (IL-4, IL-13) play a key role in T2 inflammation, activating multiple mediators and types of cell, participating in the differentiation of T-lymphocytes and switching B-lymphocytes to the production of specific immunoglobulin E (IgE), promote migration eosinophils in tissue and airway remodeling. Taking into account pathogenesis of the T2-related diseases and presence of comorbid diseases is a strategically important goal for the optimal targeted therapy. The article discusses the contemporary terminology of T2 inflammation, key cytokines involved in the pathogenesis of atopic diseases, biomarkers of T2 inflammation as criteria for proving T2 inflammation, the place of anti-IL-4/IL-13 targeted biological therapy in international Guidelines for the treatment of severe BA GINA 2020 and EACCI 2020 recommendations, the effect of dupilumab on such clinically significant outcomes as a decrease in the frequency of severe exacerbations and an improvement in lung function, a decrease in the need for oral glucocorticosteroids (GCS) in patients with BA, the evidence base for dupilumab in patients with CRSwNP and AD, as well as further promising research directions for use antiIL-4/IL-13 targeted therapy.

Т2-ассоциированные заболеванияТ2-воспалениеинтерлейкины 4 и 13биологическая терапиядупилумаб

T2-associated diseasesT2-inflammationinterleukins 4 and 13biological therapydupilumab

References1

Croisant S. Epidemiology of asthma: prevalence and burden of disease. Adv Exp Med Biol. 2014;795:17–29. doi: 10.1007/978-1-4614-8603-9_2.

Ledford D.K., Lockey R.F. Asthma and comorbidities. Curr Opin Allergy Clin Immunol. 2013;13(1)78–86. doi: 10.1097/ACI.0b013e32835c16b6.

Brunner P.M., Silverberg J.I., Guttman-Yassky E., Paller A.S., Kabashima K., Amagai M. et al. Increasing comorbidities suggest that atopic dermatitis is a systemic disorder. J Invest Dermatol. 2017;137(1):18–25. doi: 10.1016/j.jid.2016.08.022.

Zheng T., Yu J., Oh M.H., Zhu Z. The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma. Allergy Asthma Immunol Res. 2011;3(2):67–73. doi: 10.4168/aair.2011.3.2.67.

Gandhi N.A., Bennett B.L., Graham N.M., Pirozzi G., Stahl N., Yancopoulos G.D. Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov. 2016;15(1):35–50. doi: 10.1038/nrd4624.

Muraro A., Lemanske R.F. Jr., Hellings P.W., Akdis C.A., Bieber T., Casale T.B. et al. Precision medicine in patients with allergic diseases: Airway diseases and atopic dermatitis-PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2016;137(5):1347–1358. doi: 10.1016/j.jaci.2016.03.010.

Wenzel S.E. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18(5):716–725. doi: 10.1038/nm.2678.

Braido F., Tiotiu A., Kowal K., Mihaicuta S., Novakova P., Oguzulgen I.K. Phenotypes/endotypes-driven treatment in asthma. Curr Opin Allergy Clin Immunol. 2018;18(3):184–189. doi: 10.1097/ACI.0000000000000440.

Gandhi N.A., Pirozzi G., Graham N.M.H. Commonality of the IL-4/IL-13 pathway in atopic diseases. Expert Rev Clin Immunol. 2017;13(5):425–437. doi: 10.1080/1744666X.2017.1298443.

Buzney C.D., Gottlieb A.B., Rosmarin D. Asthma and Atopic Dermatitis: A Review of Targeted Inhibition of Interleukin-4 and Interleukin-13 As Therapy for Atopic Disease. J Drugs Dermatol. 2016;15(2):165–171. Available at: https://pubmed.ncbi.nlm.nih.gov/26885783.

Matsunaga K., Katoh N., Fujieda S., Izuhara K., Oishi K. Dupilumab: Basic aspects and applications to allergic diseases. Allergol Int. 2020;69(2):187– 196. doi: 10.1016/j.alit.2020.01.002.

Barnes P.J. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol. 2008;8(3):183–192. doi: 10.1038/nri2254.

Holgate S.T. Pathogenesis of asthma. Clin Exp Allergy. 2008;38(6):872–897. doi: 10.1111/j.1365-2222.2008.02971.x.

Schleimer R.P., Berdnikovs S. Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases. J Allergy Clin Immunol. 2017;139(6):1752–1761. doi: 10.1016/j.jaci.2017.04.010.

Allen J.E., Sutherland T.E. Host protective roles of type 2 immunity: parasite killing and tissue repair, flip sides of the same coin. Semin Immunol. 2014;26(4):329–340. doi: 10.1016/j.smim.2014.06.003.

Gallo R.L., Nizet V. Innate barriers against infection and associated disorders. Drug Discov Today Dis Mech. 2008;5(5):145–152. doi: 10.1016/j.ddmec.2008.04.009.

Abbas A.K., Lichtman A.H., Pillai S. Cellular and Molecular Immunology. 9th еd. Elsevier; 2018. 608 р. Available at: https://www.elsevier.com/books/cellular-and-molecular-immunology/abbas/978-0-323-47978-3.

Kato A. Immunopathology of chronic rhinosinusitis. Allergol Int. 2015;64(2):121–130. doi: 10.1016/j.alit.2014.12.006.

Ramanathan M. Jr., Lee W.K., Spannhake E.W., Lane A.P. Th2 cytokines associated with chronic rhinosinusitis with polyps down-regulate the antimicrobial immune function of human sinonasal epithelial cells. Am J Rhinol. 2008;22(2):115–121. doi: 10.2500/ajr.2008.22.3136.

Wise S.K., Laury A.M., Katz E.H., Den Beste K.A., Parkos C.A., Nusrat A. Interleukin-4 and interleukin-13 compromise the sinonasal epithelial barrier and perturb intercellular junction protein expression. Int Forum Allergy Rhinol. 2014;4(5):361–370. doi: 10.1002/alr.21298.

Schleimer R.P. Immunopathogenesis of Chronic Rhinosinusitis and Nasal Polyposis. Annu Rev Pathol. 2017;12:331–357. doi: 10.1146/annurevpathol-052016-100401.

Fahy J.V. Type 2 inflammation in asthma – present in most, absent in many. Nat Rev Immunol. 2015;15(1):57–65. doi: 10.1038/nri3786.

Corren J. Role of interleukin-13 in asthma. Curr Allergy Asthma Rep. 2013;13(5):415–420. doi: 10.1007/s11882-013-0373-9.

Firszt R., Francisco D., Church T.D., Thomas J.M., Ingram J.L., Kraft M. Interleukin-13 induces collagen type-1 expression through matrix metalloproteinase-2 and transforming growth factor-β1 in airway fibroblasts in asthma. Eur Respir J. 2014;43(2):464–473. doi: 10.1183/09031936.00068712.

Fehrenbach H., Wagner C., Wegmann M. Airway remodeling in asthma: what really matters. Cell Tissue Res. 2017;367(3):551–569. doi: 10.1007/s00441-016-2566-8.

Agache I., Akdis C., Akdis M., Canonica G.W., Casale T., Chivato T. et al. EAACI Biologicals Guidelines-Recommendations for severe asthma. Allergy. 2020 Jun 2. doi: 10.1111/all.14425.

Seys S.F., Scheers H., Van den Brande P., Marijsse G., Dilissen E., Van Den Bergh A. et al. Cluster analysis of sputum cytokine-high profiles reveals diversity in T(h)2-high asthma patients. Respir Res. 2017;18(1):39. doi: 10.1186/s12931-017-0524-y.

Woodruff P.G., Modrek B., Choy D.F., Jia G., Abbas A.R., Ellwanger A. et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009;180(8):796. Am J Respir Crit Care Med. 2009;180(5):388–395. doi: 10.1164/rccm.200903-0392OC.

Peters M.C., Mekonnen Z.K., Yuan S., Bhakta N.R., Woodruff P.G., Fahy J.V. Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma. J Allergy Clin Immunol. 2014;133(2):388–394. doi: 10.1016/j.jaci.2013.07.036.

Robinson D., Humbert M., Buhl R., Cruz A.A., Inoue H., Korom S. et al. Revisiting Type 2-high and Type 2-low airway inflammation in asthma: current knowledge and therapeutic implications. Clin Exp Allergy. 2017;47(2):161–175. doi: 10.1111/cea.12880.

McGregor M.C., Krings J.G., Nair P., Castro M. Role of Biologics in Asthma. Am J Respir Crit Care Med. 2019;199(4):433–445. doi: 10.1164/rccm.201810-1944CI.

Fajt M.L., Wenzel S.E. Development of New Therapies for Severe Asthma. Allergy Asthma Immunol Res. 2017;9(1):3–14. doi: 10.4168/aair.2017.9.1.3.

Small P., Keith P.K., Kim H. Allergic rhinitis. Allergy Asthma Clin Immunol. 2018;14(S2):51. doi: 10.1186/s13223-018-0280-7.

Giavina-Bianchi P., Aun M.V., Takejima P., Kalil J., Agondi R.C. United airway disease: current perspectives. J Asthma Allergy. 2016;9:93–100. doi: 10.2147/JAA.S81541.

Samitas K., Carter A., Kariyawasam H.H., Xanthou G. Upper and lower airway remodelling mechanisms in asthma, allergic rhinitis and chronic rhinosinusitis: The one airway concept revisited. Allergy. 2018;73(5):993–1002. doi: 10.1111/all.13373.

Eifan A.O., Durham S.R. Pathogenesis of rhinitis. Clin Exp Allergy. 2016;46(9):1139–1151. doi: 10.1111/cea.12780.

Stevens W.W., Peters A.T., Tan B.K., Klingler A.I., Poposki J.A., Hulse K.E., Grammer L.C. et al. Associations Between Inflammatory Endotypes and Clinical Presentations in Chronic Rhinosinusitis. J Allergy Clin Immunol Pract. 2019;7(8):2812–2820.e3. doi: 10.1016/j.jaip.2019.05.009.

Ненашева Н.М., Курбачева О.М., Авдеев С.Н., Федосенко С.В., Емельянов А.В., Белевский А.С. и др. Практические рекомендации по выбору иммунобиологического препарата для лечения тяжелой бронхиальной астмы Т2-эндотипа. Пульмонология. 2020;30(2):227–244. doi: 10.18093/0869-0189-2020-30-2-227-244.

Nenasheva N.M., Kurbacheva O.M., Avdeev S.N., Fedosenko S.V., Emelyanov A.V., Belevskiy A.S. et al. Practical recommendations for choosing an immunobiological preparation for the treatment of severe bronchial asthma of T2-endotype. Рulmonologiya = Russian Pulmonology. 2020;30(2):227–244. (In Russ.) doi: 10.18093/0869-0189-2020-30-2-227-244.

Bice J.B., Leechawengwongs E., Montanaro A. Biologic targeted therapy in allergic asthma. Ann Allergy Asthma Immunol. 2014;112(2):108–115. doi: 10.1016/j.anai.2013.12.013.

Castro M., Corren J., Pavord I.D., Maspero J., Wenzel S., Rabe K.F. et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378(26):2486–2496.

Israel E., Reddel H.K. Severe and Difficult-to-Treat Asthma in Adults. N Engl J Med. 2017;377(10):965–976. doi: 10.1056/NEJMra1608969.

Rabe K.F., Nair P., Brusselle G., Maspero J.F., Castro M., Sher L. et al. Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med. 2018;378(26):2475–2485. doi: 10.1056/NEJMoa1804093.

Shinkai A., Yoshisue H., Koike M., Shoji E., Nakagawa S., Saito A. et al. A novel human CC chemokine, eotaxin-3, which is expressed in IL-4- stimulated vascular endothelial cells, exhibits potent activity toward eosinophils. J Immunol. 1999;163(3):1602–1610. Available at: https://pubmed.ncbi.nlm.nih.gov/10415065.

Yoshifuku K., Matsune S., Ohori J., Sagara Y., Fukuiwa T., Kurono Y. IL-4 and TNF-alpha increased the secretion of eotaxin from cultured fibroblasts of nasal polyps with eosinophil infiltration. Rhinology. 2007;45(3):235–241. Available at: https://pubmed.ncbi.nlm.nih.gov/17956026.

Bachert C., Han J.K., Desrosiers M., Hellings P.W., Amin N., Lee S.E. et al. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials. Lancet. 2019;394(10209):1638–1650. doi: 10.1016/S0140-6736(19)31881-1.

Fokkens W.J., Lund V.J., Hopkins C., Hellings P.W., Kern R., Reitsma S. et al. European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Rhinology. 2020;58(S29):1–464. doi: 10.4193/Rhin20.600.

Gooderham M.J., Hong H.C., Eshtiaghi P., Papp K.A. Dupilumab: A review of its use in the treatment of atopic dermatitis. J Am Acad Dermatol. 2018;78(3S1):28–36. doi: 10.1016/j.jaad.2017.12.022.

Beck L.A., Thaçi D., Deleuran M., Blauvelt A., Bissonnette R., de BruinWeller M. et al. Dupilumab Provides Favorable Safety and Sustained Efficacy for up to 3 Years in an Open-Label Study of Adults with Moderate-to-Severe Atopic Dermatitis. Am J Clin Dermatol. 2020;21(4):567– 577. doi: 10.1007/s40257-020-00527-x.

The authors declare that there are no conflicts of interest present.