Эффективность и безопасность иммунобиологической терапии атопического дерматита у детей

В обзоре показано, что атопический дерматит (АтД) является хроническим воспалительным заболеванием кожи, возникающим в раннем возрасте у детей с наследственной предрасположенностью. В основе патогенеза АтД у большинства пациентов лежит воспалительная реакция 2-го типа, заключающаяся в сложном взаимодействии Т-хелперов 2-го типа (Th2), врождённых лимфоидных клеток, гранулоцитов (включая эозинофилы, тучные клетки и базофилы), цитокинов (интерлейкина (ИЛ)-4, -5, -13 и др.) и иммуноглобулина E. ИЛ-4 и ИЛ-13 заслуживают особого внимания, поскольку влияют сразу на несколько звеньев патогенеза АтД. Оба цитокина взаимодействуют с α-цепью рецептора ИЛ-4. Именно данная молекула является мишенью для дупилумаба - первого генно-инженерного биологически активного препарата, показавшего высокую эффективность в лечении АтД у детей 6-18 лет. Имеющиеся данные свидетельствуют о наличии у препарата как неспецифических (болезненность в месте инъекции, аллергическая реакция), так и специфических (конъюнктивиты, вторичные герпетические инфекции, эозинофилия) побочных реакций, что следует учитывать при назначении иммунобиологической терапии АтД. Заключение. Иммунобиологическая терапия препаратом дупилумаб детей разного возраста со среднетяжёлым и тяжёлым течением АтД обеспечивает высокую клиническую эффективность и хорошую безопасность.

Rasheed Z., Zedan K., Saif G.B., Salama R.H., Salem T., Ahmed A.A., et al. Markers of atopic dermatitis, allergic rhinitis and bronchial asthma in pediatric patients: correlation with filaggrin, eosinophil major basic protein and immunoglobulin E. Clin. Mol. Allergy. 2018; 16: 23. https://doi.org/10.1186/s12948-018-0102-y

Кубанов А.А., Богданова Е.В. Организация и результаты оказания медицинской помощи по профилю дерматовенерология в Российской Федерации. Итоги 2018 года. Вестник дерматологии и венерологии. 2019; 95(4): 8-23. https://doi.org/10.25208/0042-4609-2019-95-4-8-23

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. https://doi.org/10.1038/nrd4624

Смирнова Г.И. Атопический дерматит у детей: достижения и перспективы. Российский педиатрический журнал. 2017; 20(2): 99-107. https://doi.org/10.18821/1560-9561-2017-20-2-99-107

Leung D.Y., Guttman-Yassky E. Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches. J. Allergy. Clin. Immunol. 2014; 134(4): 769-79. https://doi.org/10.1016/j.jaci.2014.08.008

Tameez Ud. Din. A., Malik I., Arshad D., Tameez Ud. Din. A. Dupilumab for atopic dermatitis: the silver bullet we have been searching for? Cureus. 2020; 12(4): e7565. https://doi.org/10.7759/cureus.7565

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): 1347-58. https://doi.org/10.1016/j.jaci.2016.03.010

Meng Y., Wang C., Zhang L. Recent developments and highlights in allergic rhinitis. Allergy. 2019; 74(12): 2320-8. https://doi.org/10.1111/all.14067

Akdis M., Aab A., Altunbulakli C., Azkur K., Costa R.A., Crameri R., et al.Interleukins (from IL-1 to IL-38), interferons, transforming growth factor beta, and TNF-alpha: receptors, functions, and roles in diseases. J. Allergy Clin. Immunol. 2016; 138(4): 984-1010. https://doi.org/10.1016/j.jaci.2016.06.033

Xiong Y., Cui X., Li W., Lv J., Du L., Mi W., et al. BLT1 signaling in epithelial cells mediates allergic sensitization via promotion of IL-33 production. Allergy. 2019; 74(3): 495-506. https://doi.org/10.1111/all.13656

Boonpiyathad T., Sozener Z.C., Satitsuksanoa P., Akdis C.A. Immunologic mechanisms in asthma. Semin. Immunol. 2019; 46: 1013-33. https://doi.org/10.1016/j.smim.2019.101333

Sugita K., Steer C.A., Martinez-Gonzalez I., Altunbulakli C., Morita H., Castro-Giner F., et al. Type 2 innate lymphoid cells disrupt bronchial epithelial barrier integrity by targeting tight junctions through IL-13 in asthmatic patients. J. Allergy. Clin. Immunol. 2018; 141(1): 300-10. https://doi.org/10.1016/j.jaci.2017.02.038

Sugita K., Altunbulakli C., Morita H., Sugita A., Kubo T., Kimura R., et al. Human type 2 innate lymphoid cells disrupt skin keratinocyte tight junction barrier by IL-13. Allergy. 2019; 74(12): 2534-7. https://doi.org/10.1111/all.13935

Morrison B.E., Marcondes M.C., Nomura D.K., Sanchez-Alavez M., Sanchez-Gonzalez A., Saar I., et al. Cutting edge: IL-13Rα1 expression in dopaminergic neurons contributes to their oxidative stress-mediated loss following chronic peripheral treatment with lipopolysaccharide. J. Immunol. 2012; 189(12): 5498-502. https://doi.org/10.4049/jimmunol.1102150

Lowenthal J.W., Castle B.E., Christiansen J., Schreurs J., Rennick D., Arai N., et al. Expression of high affinity receptors for murine interleukin 4 (BSF-1) on hemopoietic and nonhemopoietic cells. J. Immunol. 1988; 140(2): 456-64.

Ma B., Wu Y., Chen B., Yao Y., Wang Y., Bai H., et al. Cyanidin-3-O-β-glucoside attenuates allergic airway inflammation by modulating the IL-4Rα-STAT6 signaling pathway in a murine asthma model.Int. Immunopharmacol. 2019; 69: 1-10. https://doi.org/10.1016/j.intimp.2019.01.008

Roy B., Bhattacharjee A., Xu B., Ford D., Maizel A.L., Cathcart M.K. IL-13 signal transduction in human monocytes: phosphorylation of receptor components, association with Jaks, and phosphorylation/activation of Stats. J. Leukoc. Biol. 2002; 72(3): 580-9.

Wollenberg A., Beck L.A., Blauvelt A., Simpson E.L., Chen Z., Chen Q., et al. Laboratory safety of dupilumab in moderate-to-severe atopic dermatitis: results from three phase III trials (Liberty ad solo 1, liberty ad solo 2, liberty ad chronos). Br. J. Dermatol. 2020; 182(5): 1120-35. https://doi.org/10.1111/bjd.18434

Simpson E.L., Paller A.S., Siegfried E.C., Boguniewicz M., Sher L., Gooderham M.J., et al. Efficacy and safety of dupilumab in adolescents with uncontrolled moderate to severe atopic dermatitis: a phase 3 randomized clinical trial. JAMA Dermatol. 2020; 156: 44-56. https://doi.org/10.1001/jamadermatol.2019.3336

Paller A.S., Siegfried E.C., Thaçi D., Wollenberg A., Cork M.J., Arkwright P.D., et al. Efficacy and safety of dupilumab with concomitant topical corticosteroids in children 6 to 11 years old with severe atopic dermatitis: A randomized, double-blinded, placebo-controlled phase 3 trial. J. Am. Acad. Dermatol. 2020; 83(5): 1282-93. https://doi.org/10.1016/j.jaad.2020.06.054

Ревякина В.А., Ларькова И.А., Кувшинова Е.Д., Мухортых В.А., Мельникова К.С. Клинический случай применения препарата Дупилумаб у ребёнка с атопическим дерматитом. Российский аллергологический журнал. 2021; 18(2): 115-22. https://doi.org/10.36691/RJA1424

Thibodeaux Q., Smith M.P., Ly K., Beck K., Liao W., Bhutani T. A review of dupilumab in the treatment of atopic diseases. Hum. Vaccin. Immunother. 2019; 15(9): 2129-39. https://doi.org/10.1080/21645515.2019.1582403

Bakker D.S., Ariens L.F.M., van Luijk C., van der Schaft J., Thijs J.L., Schuttelaar M.L.A., et al. Goblet cell scarcity and conjunctival inflammation during treatment with dupilumab in patients with atopic dermatitis. Br. J. Dermatol. 2019; 180(5): 1248-9. https://doi.org/10.1111/bjd.17538

Thyssen J.P. Could conjunctivitis in patients with atopic dermatitis treated with dupilumab be caused by colonization with Demodex and increased interleukin-17 levels? Br. J. Dermatol. 2018; 178(5): 1220. https://doi.org/10.1111/bjd.16330

Akinlade B., Guttman-Yassky E., de Bruin-Weller M., Simpson E.L., Blauvelt A., Cork M.J., et al. Conjunctivitis in dupilumab clinical trials. Br. J. Dermatol. 2019; 181(3): 459-73. https://doi.org/10.1111/bjd.17869

Bansal A., Simpson E.L., Paller A.S., Siegfried E.C., Blauvelt A., de Bruin-Weller M., et al. Conjunctivitis in dupilumab clinical trials for adolescents with atopic dermatitis or asthma. Am. J. Clin. Dermatol. 2021; 22(1): 101-15. https://doi.org/10.1007/s40257-020-00577-1

Halling A.S., Loft N., Silverberg J.I., Guttman-Yassky E., Thyssen J.P. Real-world evidence of dupilumab efficacy and risk of adverse events: A systematic review and meta-analysis. J. Am. Acad. Dermatol. 2021; 84(1): 139-47. https://doi.org/10.1016/j.jaad.2020.08.051

Blauvelt A., de Bruin-Weller M., Gooderham M., Cather J.C., Weisman J., Pariser D., et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet. 2017; 389(10086): 2287-303. https://doi.org/10.1016/S0140-6736(17)31191-1

Simpson E.L., Bieber T., Guttman-Yassky E., Beck L.A., Blauvelt A., Cork M.J., et al. SOLO 1 and SOLO 2 Investigators. Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N. Engl. J. Med. 2016; 375(24): 2335-48. https://doi.org/10.1056/NEJMoa1610020

Wang Y., Jorizzo J.L. Retrospective analysis of adverse events with dupilumab reported to the United States Food and Drug Administration. J. Am. Acad. Dermatol. 2021; 84(4): 1010-4. https://doi.org/10.1016/j.jaad.2020.11.042

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): 2486-96. https://doi.org/10.1056/NEJMoa1804092

Uchida H., Kamata M., Mizukawa I., Watanabe A., Agematsu A., Nagata M., et al. Real-world effectiveness and safety of dupilumab for the treatment of atopic dermatitis in Japanese patients: a single-centre retrospective study. Br. J. Dermatol. 2019; 181(5): 1083-5. https://doi.org/10.1111/bjd.18163

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): 2475-85. https://doi.org/10.1056/NEJMoa1804093

Yamauchi T., Sasaki S., Lee E.S., Tamura T., Seki M., Miwa T., et al. Dupilumab treatment ameliorates clinical and hematological symptoms, including blood eosinophilia, in patients with atopic dermatitis.Int. J. Dermatol. 2021; 60(2): 190-5. https://doi.org/10.1111/ijd.15183

Eger K., Pet L., Weersink E.J.M., Bel E.H.Complications of switching from anti-IL-5 or anti-IL-5R to dupilumab in corticosteroid-dependent severe asthma. J. Allergy. Clin. Immunol. Pract. 2021; 9(7): 2913-5. https://doi.org/10.1016/j.jaip.2021.02.042

Waldman R.A., DeWane M.E., Sloan B., Grant-Kels J.M. Characterizing dupilumab facial redness: A multi-institution retrospective medical record review. J. Am. Acad. Dermatol. 2020; 82(1): 230-2. https://doi.org/10.1016/j.jaad.2019.06.026

Egeberg A., Thyssen J.P. Factors associated with patient-reported importance of skin clearance among adults with psoriasis and atopic dermatitis. J. Am. Acad. Dermatol. 2019; 81(4): 943-9. https://doi.org/10.1016/j.jaad.2019.06.018

Fowler E., Silverberg J.I., Fox J.D., Yosipovitch G. Psoriasiform dermatitis after initiation of treatment with dupilumab for atopic dermatitis. Dermatitis. 2019; 30(3): 234-6. https://doi.org/10.1097/DER.0000000000000481

Varma A., Levitt J. Dupilumab-induced phenotype switching from atopic dermatitis to psoriasis. JAAD Case Rep. 2020; 6(3): 217-8. https://doi.org/10.1016/j.jdcr.2020.01.012

Safa G., Paumier V. Psoriasis induced by dupilumab therapy. Clin. Exp. Dermatol. 2019; 44(3): 49-50. https://doi.org/10.1111/ced.13901

Stout M., Guitart J., Tan T., Silverberg J.I. Psoriasis-like Dermatitis Developing in a patient with atopic dermatitis treated with Dupilumab. Dermatitis. 2019; 30(6): 376-8. https://doi.org/10.1097/DER.0000000000000509

Buhl T., Sulk M., Nowak P., Buddenkotte J., McDonald I., Aubert J., et al. Molecular and morphological characterization of inflammatory infiltrate in rosacea reveals activation of th1/th17 pathways. J. Invest. Dermatol. 2015; 135(9): 2198-208. https://doi.org/10.1038/jid.2015.141

de Beer F.S.A., Bakker D.S., Haeck I., Ariens L., van der Schaft J., et al. Dupilumab facial redness: Positive effect of itraconazole. JAAD Case Rep. 2019; 5(10): 888-91. https://doi.org/10.1016/j.jdcr.2019.07.020

Sparber F., De Gregorio C., Steckholzer S., Ferreira F.M., Dolowschiak T., Ruchti F., et al. The Skin Commensal Yeast Malassezia Triggers a Type 17 Response that Coordinates Anti-fungal Immunity and Exacerbates Skin Inflammation. Cell. Host. Microbe. 2019; 25(3): 389-403.e6. https://doi.org/10.1016/j.chom.2019.02.002

Смирнова Г.И. Атопический дерматит и инфекции кожи у детей. Российский педиатрический журнал. 2014; 2: 49-56.

Смирнова Г.И., Корсунский А.А. Нарушения микробиоты кожи и формирование атопического дерматита у детей. Российский педиатрический журнал. 2019; 22(4): 243-50. https://doi.org/10.18810/1560-9561-2019-22-4-243-250