Оптимизация подходов к ведению взрослых пациентов с тяжелым атопическим дерматитом: анализ результатов реальной клинической практики

Фомина Д.С., Сердотецкова С.А., Чернов А.А., Лебедкина М.С., Нуртазина А.Ю., Гаджиева М.К., Мухина О.А., Бобрикова Е.Н. Оптимизация подходов к ведению взрослых пациентов с тяжелым атопическим дерматитом: анализ результатов реальной клинической практики. Consilium Medicum. 2021; 23 (8): 654–661. DOI: 10.26442/20751753.2021.8.201115

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Fomina DS, Serdotetskova SA, Chernov AA, Lebedkina MS, Nurtazina AIu, Gadzhieva MK, Mukhina OA, Bobrikova EN. Optimization of approaches to the management of adult patients with severe atopic dermatitis: analysis of real clinical practice outcomes. Consilium Medicum. 2021; 23 (8): 654–661. DOI: 10.26442/20751753.2021.8.201115

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Аннотация

Атопический дерматит (АтД) – мультифакторное генетически детерминированное иммуноопосредованное заболевание кожи. Оно трудно поддается лечению и существенно влияет на качество жизни. Разработка комплексного подхода к лечению пациентов с учетом сопутствующих атопических заболеваний, внедрение валидизированных инструментов контроля и выделение клинических характеристик, определяющих отдельные фенотипы тяжелых форм заболевания, особенно актуальны для пациентов с резистентностью к стандартным методам терапии. Для лечения резистентной группы пациентов с АтД среднетяжелой и тяжелой степенями тяжести в Российской Федерации разрешен к применению таргетный биологический препарат дупилумаб, подавляющий функции двух ключевых цитокинов Т2-воспаления – интерлейкина-4 и 13. В статье представлен личный опыт авторов индивидуального подхода к выбору терапии при ведении данной когорты пациентов в рутинной клинической практике. Определены отягощающие критерии, которые служат основанием при формировании индивидуального портрета пациента для применения биологической терапии (дупилумаб) при тяжелом АтД.

Ключевые слова: атопический дерматит, таргетная биологическая терапия, дупилумаб, мультиморбидность, бронхиальная астма, фенотипы

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Atopic dermatitis (AD) is a multifactorial genetically determined immune-mediated skin disease. It is difficult to treat and significantly affects patients’ quality of life. The development of an integrated approach focusing on atopic multimorbidity, implementation of validated control tools and distinction of clinical parameters specific for different phenotypes of severe forms of disease is especially relevant to patients resistant to standard therapy techniques. Dupilumab, a biologic, is approved for the treatment of the resistant group of patients with moderate to severe AD in the Russian Federation. Dupilumab inhibits the functions of two key cytokines of T2-mediated inflammation – IL-4 and IL-13. The article presents personal experience of the authors concerning individual approach to the choice of therapy for the management of this cohort of patients in routine clinical practice. The disease aggravating criteria were determined, which are fundamental for the formation of individual patient portrait for the biologic (dupilumab) treatment for severe AD.

Keywords: atopic dermatitis, targeted biologic therapy, dupilumab, multimorbidity, bronchial asthma, phenotypes.

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Список литературы

1. Атопический дерматит. Проект клинических рекомендаций. 2020 г. РААКИ. Режим доступа: https://raaci.ru/dat/pdf/KR/atopic_dermatitis_2020.pdf. Ссылка активна на 26.08.2021 [Atopicheskii dermatit. Proekt klinicheskikh rekomendatsii. 2020 g. RAAKI. Available at: https://raaci.ru/dat/pdf/KR/atopic_dermatitis_2020.pdf. Accessed: 26.08.2021 (in Russian)].
2. Silverberg JI. Public Health Burden and Epidemiology of Atopic Dermatitis. Dermatol Clin. 2017;35(3):283-9. DOI:10.1016/j.det.2017.02.002
3. Esnault S, Benbernou N, Lavaud F, et al. Differential spontaneous expression of mRNA for IL-4, IL-10, IL-13, IL-2 and interferongamma (IFN-gamma) in peripheral blood mononuclear cells (PBMC) fr om atopic patients. Clin Exp Immunol. 1996;103(1):111-8.
4. Werner Y, Lindberg M. Transepidermal water loss in dry and clinically normal skin in patients with atopic dermatitis. Acta Derm Venereol. 1985;65(2):102-5.
5. Jujo K, Renz H, Abe J, et al. Decreased interferon gamma and increased interleukin-4 production in atopic dermatitis promotes IgE synthesis. J Allergy Clin Immunol. 1992;90(3 Pt. 1):323-31.
6. Kaminishi K, Soma Y, Kawa Y, et al. Flow cytometric analysis of IL-4, IL-13 and IFN-gamma expression in peripheral blood mononuclear cells and detection of circulating IL-13 in patients with atopic dermatitis provide evidence for the involvement of type 2 cytokines in the disease. J Dermatol Sci. 2002;29(1):19-25.
7. Howell MD, Kim BE, Gao P, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2009;124(3 Suppl. 2):R7-12.
8. Wollenberg A, Wagner M, Gunther S, et al. Plasmacytoid dendritic cells: a new cutaneous dendritic cell subset with distinct role in inflammatory skin diseases. J Invest Dermatol. 2002;119(5):1096-102.
9. Howell MD, Wollenberg A, Gallo RL, et al. Cathelicidin deficiencypredisposes to eczema herpeticum. J Allergy Clin Immunol. 2006;117(4):836-41.
10. Kerschenlohr K, Decard S, Przybilla B, et al. Atopy patch test reactions show a rapid influx of inflammatory dendritic epidermal cells (IDEC) in extrinsic and intrinsic atopic dermatitis patients. J Allergy Clin Immunol. 2003;111:869-74.
11. Wollenberg A, Kraft S, Hanau D, et al. Immunomorphological and ultrastructural characterization of Langerhans cells and a novel, inflammatory dendritic epidermal cell (IDEC) population in lesional skin of atopic eczema. J Invest Dermatol. 1996;106(3):446-53.
12. Danso MO, Van Drongelen V, Mulder A, et al. TNF-alpha and Th2 cytokines induce atopic dermatitis-like features on epidermal differentiation proteins and stratum corneum lipids in human skin equivalents. J Invest Dermatol. 2014;134(7):1941-50.
13. Van den Oord RA, Sheikh A. Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis. BMJ. 2009;339:b2433 DOI:10.1136/bmj.b2433
14. Paller AS, Spergel JM, Mina-Osorio P, Irvine AD. The atopic march and atopic multimorbidity: Many trajectories, many pathways. J Allergy Clin Immunol. 2019;143(1):46-55. DOI:10.1016/j.jaci.2018.11.006
15. Breiteneder H, Peng YQ, Agache I. Biomarkers for diagnosis and prediction of therapy responses in allergic diseases and asthma. Allergy. 2020;75(12):3039-68. DOI:10.1111/all.14582
16. Belgrave DCM, Simpson A, Buchan IE, Custovic A. Atopic dermatitis and respiratory allergy: what is the link. Curr Dermatol Rep. 2015;4:221e227.
17. Simpson EL. Comorbidity in atopic dermatitis. Curr Dermatol Rep. 2012;1:29-38.
18. Brunner PM, Silverberg JI, Guttman-Yassky E, et al. Increasing comorbidities suggest that atopic dermatitis is a systemic disorder. J Invest Dermatol. 2017;137:18-25.
19. Yaghmaie P, Koudelka CW, Simpson EL. Mental health comorbidity in patients with atopic dermatitis. J Allergy Clin Immunol. 2013;131:428-33.
20. Czarnowicki T, He H, Krueger JG, Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics. J Allergy Clin Immunol. 2019;143(1):1-11. DOI:10.1016/j.jaci.2018.10.032
21. Mulick AR, Allen V, Williams HC, et al. Classifying atopic dermatitis: protocol for a systematic review of subtypes (phenotypes) and associated characteristics. BMJ Open. 2018;8(9):e023097. DOI:10.1136/bmjopen-2018-023097
22. Bieber T, D'Erme AM, Akdis CA, et al. Clinical phenotypes and endophenotypes of atopic dermatitis: Where are we, and wh ere should we go? J Allergy Clin Immunol. 2017;139(4S):S58-64. DOI:10.1016/j.jaci.2017.01.008
23. Salvador JF. Atopic Dermatitis in Adults: A Diagnostic Challenge. J Investig Allergol Clin Immunol. 2017;27(2):78-88. DOI:10.18176/jiaci.013
24. Seegräber M, Srour J, Walter A, et al. Dupilumab for treatment of atopic dermatitis. Expert Rev Clin Pharmacol. 2018;11(5):467-74. DOI:10.1080/17512433.2018.1449642
25. Tavecchio S, Angileri L, Pozzo GF, et al. Efficacy of Dupilumab on Different Phenotypes of Atopic Dermatitis: One-Year Experience of 221 Patients. J Clin Med. 2020;9(9):2684. DOI:10.3390/jcm9092684
26. Simpson EL, Bieber T, Guttman-Yassky E, et al.Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med. 2016;375(24):2335-48. DOI:10.1056/NEJMoa1610020
27. Silverberg JI, Yosipovitch G, Simpson EL. Dupilumab treatment results in early and sustained improvements in itch in adolescents and adults with moderate to severe atopic dermatitis: Analysis of the randomized phase 3 studies SOLO 1 and SOLO 2, AD ADOL, and CHRONOS. J Am Acad Dermatol. 2020;82(6):1328-36. DOI:10.1016/j.jaad.2020.02.060
28. Deleuran M, Thaçi D, Beck LA. Dupilumab shows long-term safety and efficacy in patients with moderate to severe atopic dermatitis enrolled in a phase 3 open-label extension study. J Am Acad Dermatol. 2020;82(2):377-88. DOI:10.1016/j.jaad.2019.07.074
29. Cork MJ, Thaçi D, Eichenfield LF. Dupilumab in adolescents with uncontrolled moderate-to-severe atopic dermatitis: results from a phase IIa open-label trial and subsequent phase III open-label extension. Br J Dermatol. 2020;182(1):85-96. DOI:10.1111/bjd.18476
30. Ariëns LFM, Bakker DS, van der Schaft J, et al. Dupilumab in atopic dermatitis: rationale, latest evidence and place in therapy. Ther Adv Chronic Dis. 2018;9(9):159-70. DOI:10.1177/2040622318773686
31. Mortz CG, Andersen KE, Dellgren C, et al. Atopic dermatitis from adolescence to adulthood in the TOACS cohort: prevalence, persistence and comorbidities. Allergy. 2015;70(7):836-45. DOI:10.1111/all.12619
32. Arima K, Gupta S, Gadkari A, et al. Burden of atopic dermatitis in Japanese adults: Analysis of data from the 2013 National Health and Wellness Survey. J Dermatol. 2018;45(4):390-6. DOI:10.1111/1346-8138.14218
33. Wan J, Mitra N, Hoffstad OJ, et al. Margolis Longitudinal atopic dermatitis control and persistence vary with timing of disease onset in children: A cohort study. J Am Acad Dermatol. 2019;81(6):1292-9. DOI:10.1016/j.jaad.2019.05.016
34. Baum S, Porat S, Lyakhovitsky A, et al. Adult Atopic Dermatitis in Hospitalized Patients: Comparison between Those with Childhood-Onset and Late-Onset Disease. Dermatology. 2019;235(5):365-71. DOI:10.1159/000499708
35. Jo CE, Georgakopoulos JR, Ladda M, et al. Evaluation of long-term efficacy, safety, and reasons for discontinuation of dupilumab for moderate to severe atopic dermatitis in clinical practice: A retrospective cohort study. J Am Acad Dermatol. 2020;82(6):1530-2. DOI:10.1016/j.jaad.2020.02.029
36. Armario-Hita JC, Pereyra-Rodriguez J, Silvestre JF, et al. Treatment of moderate-to-severe atopic dermatitis with dupilumab in real clinical practice: a multicentre, retrospective case series. Br J Dermatol. 2019;181(5):1072-74. DOI:10.1111/bjd.18041
37. Cabanillas B, BrehlerA-C, Novak N. Atopic dermatitis phenotypes and the need for personalized medicine. Curr Opin Allergy Clin Immunol. 2017;17(4):309-15. DOI:10.1097/ACI.0000000000000376
38. Fernández-Soto R, Navarrete-Rodríguez EM, Del-Rio-Navarro BE, et al. Allergy: Pattern of sensitization over the past 11 years. Allergol Immunopathol (Madr). 2018;46(6):557-64. DOI:10.1016/j.aller.2018.01.005
39. Crameri R, Weichel M, Flückiger S, et al. Fungal allergies: A yet unsolved problem. Chem Immunol Allergy. 2006;91:121-33.
40. Hamilos DL. Chronic rhinosinusitis: Epidemiology and medical management. J Allergy Clin Immunol. 2011;128:693-707.

________________________________________________

1. Atopicheskii dermatit. Proekt klinicheskikh rekomendatsii. 2020 g. RAAKI. Available at: https://raaci.ru/dat/pdf/KR/atopic_dermatitis_2020.pdf. Accessed: 26.08.2021 (in Russian).
2. Silverberg JI. Public Health Burden and Epidemiology of Atopic Dermatitis. Dermatol Clin. 2017;35(3):283-9. DOI:10.1016/j.det.2017.02.002
3. Esnault S, Benbernou N, Lavaud F, et al. Differential spontaneous expression of mRNA for IL-4, IL-10, IL-13, IL-2 and interferongamma (IFN-gamma) in peripheral blood mononuclear cells (PBMC) fr om atopic patients. Clin Exp Immunol. 1996;103(1):111-8.
4. Werner Y, Lindberg M. Transepidermal water loss in dry and clinically normal skin in patients with atopic dermatitis. Acta Derm Venereol. 1985;65(2):102-5.
5. Jujo K, Renz H, Abe J, et al. Decreased interferon gamma and increased interleukin-4 production in atopic dermatitis promotes IgE synthesis. J Allergy Clin Immunol. 1992;90(3 Pt. 1):323-31.
6. Kaminishi K, Soma Y, Kawa Y, et al. Flow cytometric analysis of IL-4, IL-13 and IFN-gamma expression in peripheral blood mononuclear cells and detection of circulating IL-13 in patients with atopic dermatitis provide evidence for the involvement of type 2 cytokines in the disease. J Dermatol Sci. 2002;29(1):19-25.
7. Howell MD, Kim BE, Gao P, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2009;124(3 Suppl. 2):R7-12.
8. Wollenberg A, Wagner M, Gunther S, et al. Plasmacytoid dendritic cells: a new cutaneous dendritic cell subset with distinct role in inflammatory skin diseases. J Invest Dermatol. 2002;119(5):1096-102.
9. Howell MD, Wollenberg A, Gallo RL, et al. Cathelicidin deficiencypredisposes to eczema herpeticum. J Allergy Clin Immunol. 2006;117(4):836-41.
10. Kerschenlohr K, Decard S, Przybilla B, et al. Atopy patch test reactions show a rapid influx of inflammatory dendritic epidermal cells (IDEC) in extrinsic and intrinsic atopic dermatitis patients. J Allergy Clin Immunol. 2003;111:869-74.
11. Wollenberg A, Kraft S, Hanau D, et al. Immunomorphological and ultrastructural characterization of Langerhans cells and a novel, inflammatory dendritic epidermal cell (IDEC) population in lesional skin of atopic eczema. J Invest Dermatol. 1996;106(3):446-53.
12. Danso MO, Van Drongelen V, Mulder A, et al. TNF-alpha and Th2 cytokines induce atopic dermatitis-like features on epidermal differentiation proteins and stratum corneum lipids in human skin equivalents. J Invest Dermatol. 2014;134(7):1941-50.
13. Van den Oord RA, Sheikh A. Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis. BMJ. 2009;339:b2433 DOI:10.1136/bmj.b2433
14. Paller AS, Spergel JM, Mina-Osorio P, Irvine AD. The atopic march and atopic multimorbidity: Many trajectories, many pathways. J Allergy Clin Immunol. 2019;143(1):46-55. DOI:10.1016/j.jaci.2018.11.006
15. Breiteneder H, Peng YQ, Agache I. Biomarkers for diagnosis and prediction of therapy responses in allergic diseases and asthma. Allergy. 2020;75(12):3039-68. DOI:10.1111/all.14582
16. Belgrave DCM, Simpson A, Buchan IE, Custovic A. Atopic dermatitis and respiratory allergy: what is the link. Curr Dermatol Rep. 2015;4:221e227.
17. Simpson EL. Comorbidity in atopic dermatitis. Curr Dermatol Rep. 2012;1:29-38.
18. Brunner PM, Silverberg JI, Guttman-Yassky E, et al. Increasing comorbidities suggest that atopic dermatitis is a systemic disorder. J Invest Dermatol. 2017;137:18-25.
19. Yaghmaie P, Koudelka CW, Simpson EL. Mental health comorbidity in patients with atopic dermatitis. J Allergy Clin Immunol. 2013;131:428-33.
20. Czarnowicki T, He H, Krueger JG, Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics. J Allergy Clin Immunol. 2019;143(1):1-11. DOI:10.1016/j.jaci.2018.10.032
21. Mulick AR, Allen V, Williams HC, et al. Classifying atopic dermatitis: protocol for a systematic review of subtypes (phenotypes) and associated characteristics. BMJ Open. 2018;8(9):e023097. DOI:10.1136/bmjopen-2018-023097
22. Bieber T, D'Erme AM, Akdis CA, et al. Clinical phenotypes and endophenotypes of atopic dermatitis: Where are we, and wh ere should we go? J Allergy Clin Immunol. 2017;139(4S):S58-64. DOI:10.1016/j.jaci.2017.01.008
23. Salvador JF. Atopic Dermatitis in Adults: A Diagnostic Challenge. J Investig Allergol Clin Immunol. 2017;27(2):78-88. DOI:10.18176/jiaci.013
24. Seegräber M, Srour J, Walter A, et al. Dupilumab for treatment of atopic dermatitis. Expert Rev Clin Pharmacol. 2018;11(5):467-74. DOI:10.1080/17512433.2018.1449642
25. Tavecchio S, Angileri L, Pozzo GF, et al. Efficacy of Dupilumab on Different Phenotypes of Atopic Dermatitis: One-Year Experience of 221 Patients. J Clin Med. 2020;9(9):2684. DOI:10.3390/jcm9092684
26. Simpson EL, Bieber T, Guttman-Yassky E, et al.Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med. 2016;375(24):2335-48. DOI:10.1056/NEJMoa1610020
27. Silverberg JI, Yosipovitch G, Simpson EL. Dupilumab treatment results in early and sustained improvements in itch in adolescents and adults with moderate to severe atopic dermatitis: Analysis of the randomized phase 3 studies SOLO 1 and SOLO 2, AD ADOL, and CHRONOS. J Am Acad Dermatol. 2020;82(6):1328-36. DOI:10.1016/j.jaad.2020.02.060
28. Deleuran M, Thaçi D, Beck LA. Dupilumab shows long-term safety and efficacy in patients with moderate to severe atopic dermatitis enrolled in a phase 3 open-label extension study. J Am Acad Dermatol. 2020;82(2):377-88. DOI:10.1016/j.jaad.2019.07.074
29. Cork MJ, Thaçi D, Eichenfield LF. Dupilumab in adolescents with uncontrolled moderate-to-severe atopic dermatitis: results from a phase IIa open-label trial and subsequent phase III open-label extension. Br J Dermatol. 2020;182(1):85-96. DOI:10.1111/bjd.18476
30. Ariëns LFM, Bakker DS, van der Schaft J, et al. Dupilumab in atopic dermatitis: rationale, latest evidence and place in therapy. Ther Adv Chronic Dis. 2018;9(9):159-70. DOI:10.1177/2040622318773686
31. Mortz CG, Andersen KE, Dellgren C, et al. Atopic dermatitis from adolescence to adulthood in the TOACS cohort: prevalence, persistence and comorbidities. Allergy. 2015;70(7):836-45. DOI:10.1111/all.12619
32. Arima K, Gupta S, Gadkari A, et al. Burden of atopic dermatitis in Japanese adults: Analysis of data from the 2013 National Health and Wellness Survey. J Dermatol. 2018;45(4):390-6. DOI:10.1111/1346-8138.14218
33. Wan J, Mitra N, Hoffstad OJ, et al. Margolis Longitudinal atopic dermatitis control and persistence vary with timing of disease onset in children: A cohort study. J Am Acad Dermatol. 2019;81(6):1292-9. DOI:10.1016/j.jaad.2019.05.016
34. Baum S, Porat S, Lyakhovitsky A, et al. Adult Atopic Dermatitis in Hospitalized Patients: Comparison between Those with Childhood-Onset and Late-Onset Disease. Dermatology. 2019;235(5):365-71. DOI:10.1159/000499708
35. Jo CE, Georgakopoulos JR, Ladda M, et al. Evaluation of long-term efficacy, safety, and reasons for discontinuation of dupilumab for moderate to severe atopic dermatitis in clinical practice: A retrospective cohort study. J Am Acad Dermatol. 2020;82(6):1530-2. DOI:10.1016/j.jaad.2020.02.029
36. Armario-Hita JC, Pereyra-Rodriguez J, Silvestre JF, et al. Treatment of moderate-to-severe atopic dermatitis with dupilumab in real clinical practice: a multicentre, retrospective case series. Br J Dermatol. 2019;181(5):1072-74. DOI:10.1111/bjd.18041
37. Cabanillas B, BrehlerA-C, Novak N. Atopic dermatitis phenotypes and the need for personalized medicine. Curr Opin Allergy Clin Immunol. 2017;17(4):309-15. DOI:10.1097/ACI.0000000000000376
38. Fernández-Soto R, Navarrete-Rodríguez EM, Del-Rio-Navarro BE, et al. Allergy: Pattern of sensitization over the past 11 years. Allergol Immunopathol (Madr). 2018;46(6):557-64. DOI:10.1016/j.aller.2018.01.005
39. Crameri R, Weichel M, Flückiger S, et al. Fungal allergies: A yet unsolved problem. Chem Immunol Allergy. 2006;91:121-33.
40. Hamilos DL. Chronic rhinosinusitis: Epidemiology and medical management. J Allergy Clin Immunol. 2011;128:693-707.

Авторы

Д.С. Фомина*1,2, С.А. Сердотецкова1, А.А. Чернов1,3, М.С. Лебедкина2, А.Ю. Нуртазина1,2, М.К. Гаджиева1, О.А. Мухина1, Е.Н. Бобрикова1

1 ГБУЗ «Городская клиническая больница №52» Департамента здравоохранения г. Москвы, Москва, Россия;
2 ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия;
3 ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России, Москва, Россия
*daria_fomina@mail.ru

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Daria S. Fomina*1,2, Sofya A. Serdotetskova1, Anton A. Chernov1,3, Marina S. Lebedkina2, Asel Iu. Nurtazina1,2, Mirada K. Gadzhieva1, Olga A. Mukhina1, Elena N. Bobrikova1

1 City Clinical Hospital №52, Moscow, Russia;
2 Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia;
3 Russian Medical Academy of Continuous Professional Education, Moscow, Russia
*daria_fomina@mail.ru

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