Современные представления о патогенезе и принципах наружной терапии атопического дерматита у детей
https://doi.org/10.15690/vsp.v15i6.1655
Аннотация
статье анализируются современные данные о патогенезе атопического дерматита. Обсуждается роль нарушения структуры дермального барьера в развитии пищевой аллергии, приводятся результаты, подтверждающие теорию чрескожной сенсибилизации к аллергенам наряду с наследственными и экзогенными факторами. Современная локальная терапия атопического дерматита с использованием топических глюкокортикостероидов (тГКС), направленная на уменьшение выраженности симптомов заболевания, зачастую сопряжена с риском развития осложнений. Приводятся данные об эффективном использовании топических ингибиторов кальциневрина (тИК) в качестве средств, нивелирующих побочные эффекты тГКС. Продемонстрированы результаты возможного применения пимекролимуса в виде 1% крема с целью постепенной отмены тГКС при долгосрочном использовании. Представлены данные обзоров и метаанализов за последнее десятилетие, демонстрирующие, что не существует никаких доказательств того, что использование тИК связано с повышенным риском развития лимфомы. Авторами сделан вывод, что пимекролимус в виде 1% крема является оптимальным средством топической терапии у детей с легкой и среднетяжелой формой заболевания, а также препаратом для проактивной терапии атопического дерматита в течение длительного периода времени с целью предотвращения обострений.
Об авторах
Н. Н. Мурашкин
Научный центр здоровья детей
Первый Московский государственный медицинский университет им. И.М. Сеченова
Россия
Россия
доктор медицинских наук, заведующий отделением дерматологии НЦЗД, профессор кафедры педиатрии и детской ревматологии 1 МГМУ им. И.М. Сеченова Адрес: 119991, Москва, Ломоносовский пр-т, д. 2, стр. 1, тел.: +7 (499) 134-08-89
А. И. Материкин
Научный центр здоровья детей
Россия
Москва, Российская Федерация
Россия
Москва, Российская Федерация
Э. Т. Амбарчян
Научный центр здоровья детей
Россия
Москва, Российская Федерация
Россия
Москва, Российская Федерация
Р. В. Епишев
Научный центр здоровья детей
Россия
Москва, Российская Федерация
Россия
Москва, Российская Федерация
Список литературы
1. Bos JD, Kapsenberg ML, Smitt JH. Pathogenesis of atopic eczema. Lancet. 1994;343(8909):1338–1341. doi: 10.1016/s0140-6736(94)92473-2.
2. Leung DY, Bieber T. Atopic dermatitis. Lancet. 2003; 361(9352):151–160. doi: 10.1016/S0140-6736(03)12193-9.
3. Morar N, Willis-Owen SA, Moffatt MF, Cookson WO. The genetics of atopic dermatitis. J Allergy Clin Immunol. 2006;118(1):24–34. doi: 10.1016/j.jaci.2006.03.037.
4. Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016; 387(10023):1109–1122. doi: 10.1016/S0140-6736(15)00149-X.
5. Williams H, Flohr C. How epidemiology has challenged 3 prevailing concepts about atopic dermatitis. J Allergy Clin Immunol. 2006;118(1):209–213. doi: 10.1016/j.jaci.2006.04.043.
6. Elias PM, Steinhoff M. “Outside-to-inside” (and now back to “outside”) pathogenic mechanisms in atopic dermatitis. J Invest Dermatol. 2008;128(5):1067–1070. doi: 10.1038/jid.2008.88.
7. Apfelbacher CJ, Diepgen TL, Schmitt J. Determinants of eczema: population-based cross- sectional study in Germany. Allergy. 2011;66(2):206–213. doi: 10.1111/j.1398- 9995.2010.02464.x.
8. Thomsen SF, Ulrik CS, Kyvik KO, et al. Importance of genetic factors in the etiology of atopic dermatitis: a twin study. Allergy Asthma Proc. 2007;28(5):535–539. doi: 10.2500/aap2007.28.3041.
9. Ellinghaus D, Baurecht H, Esparza-Gordillo J, et al. High-density genotyping study identifies four new susceptibility loci for atopic dermatitis. Nat Genet. 2013;45(7):808–812. doi: 10.1038/ng.2642.
10. Esparza-Gordillo J, Weidinger S, Folster-Holst R, et al. A common variant on chromosome 11q13 is associated with atopic dermatitis. Nat Genet. 2009;41(5):596–601. doi: 10.1038/ng.347.
11. Paternoster L, Standl M, Chen CM, et al. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis. Nat Genet. 2012;44(2):187–192. doi: 10.1038/ng.1017.
12. Sun LD, Xiao FL, Li Y, et al. Genome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population. Nat Genet. 2011;43(7):690–694. doi: 10.1038/ng.851.
13. Hirota T, Takahashi A, Kubo M, et al. Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population. Nat Genet. 2012;44(11):1222–1226. doi: 10.1038/ng.2438.
14. Paternoster L, Standl M, Waage J, et al. Multi-ethnic genomewide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis. Nat Genet. 2015;47(12): 1449–1456. doi: 10.1038/ng.3424.
15. Flohr C, Mann J. New insights into the epidemiology of childhood atopic dermatitis. Allergy. 2014;69(1):3–16. doi: 10.1111/all.12270.
16. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med. 2011;365(14): 1315–1327. doi: 10.1056/NEJMra1011040.
17. Baurecht H, Irvine AD, Novak N, et al. Toward a major risk factor for atopic eczema: meta-analysis of filaggrin polymorphism data. J Allergy Clin Immunol. 2007;120(6):1406– 1412. doi: 10.1016/j.jaci.2007.08.067.
18. Nemoto-Hasebe I, Akiyama M, Nomura T, et al. Clinical severity correlates with impaired barrier in filaggrin-related eczema. J Invest Dermatol. 2009;129(3):682–689. doi: 10.1038/jid.2008.280.
19. Jarrett R, Salio M, Lloyd-Lavery A, et al. Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite-derived phospholipase. Sci Transl Med. 2016;8(325):325ra318. doi: 10.1126/scitranslmed.aad6833.
20. Samuelov L, Sprecher E. Peeling off the genetics of atopic dermatitis-like congenital disorders. J Allergy Clin Immunol. 2014; 134(4):808–815. doi: 10.1016/j.jaci.2014.07.061.
21. Kezic S, Novak N, Jakasa I, et al. Skin barrier in atopic dermatitis. Front Biosci (Landmark Ed). 2014;19:542–556. doi: 10.2741/4225.
22. Werfel T, Heratizadeh A, Niebuhr M, et al. Exacerbation of atopic dermatitis on grass pollen exposure in an environmental challenge chamber. J Allergy Clin Immunol. 2015;136(1):96–103.e9. doi: 10.1016/j.jaci.2015.04.015.
23. Suarez-Farinas M, Tintle SJ, Shemer A, et al. Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities. J Allergy Clin Immunol. 2011;127(4):954–964.e4. doi: 10.1016/j.jaci.2010.12.1124.
24. Islam SA, Luster AD. T cell homing to epithelial barriers in allergic disease. Nat Med. 2012;18(5):705–715. doi: 10.1038/nm.2760.
25. Imai Y, Yasuda K, Sakaguchi Y, et al. Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice. Proc Natl Acad Sci U S A. 2013; 110(34):13921–13926. doi: 10.1073/pnas.1307321110.
26. Salimi M, Barlow JL, Saunders SP, et al. A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. J Exp Med. 2013;210(13):2939–2950. doi: 10.1084/jem.20130351.
27. Flohr C, Yeo L. Atopic dermatitis and the hygiene hypothesis revisited. In: Shiohara T, editor. Pathogenesis and management of atopic dermatitis. Current Problems in Dermatology, Vol. 41. Basel: Karger Medical and Scientific Publishers; 2011. p. 1–34. doi: 10.1159/000323290.
28. Sulzberger MB, Witten VH. Allergic dermatoses due to drugs. Postgrad Med. 1952;11(6):549–557.
29. Sulzberger MB, Witten VH, Zimmerman EH. The effects of oral cortisone acetate on patch test reactions to eczematogenous contact allergens. Acta Derm Venereol Suppl (Stockh). 1952;32(29):343–352.
30. Akdis CA, Akdis M, Bieber T, et al. Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report. Allergy. 2006;61(8):969–987. doi: 10.1111/j.1398-9995.2006.01153.x.
31. Darsow U, Wollenberg A, Simon D, et al. ETFAD/EADV eczema task force 2009 position paper on diagnosis and treatment of atopic dermatitis. J Eur Acad Dermatol Venereol. 2010;24(3):317–328. doi: 10.1111/j.1468-3083.2009.03415.x.
32. Hoare C, Li Wan Po A, Williams H. Systematic review of treatments for atopic eczema. Health Technol Assess. 2000;4(37): 1–191. doi: 10.3310/hta4370.
33. Ring J, Alomar A, Bieber T, et al. Guidelines for treatment of atopic eczema (atopic dermatitis). Part I. J Eur Acad Dermatol Venereol. 2012;26(8):1045–1060. doi: 10.1111/j.1468-3083.2012.04635.x.
34. Ring J, Alomar A, Bieber T, et al. Guidelines for treatment of atopic eczema (atopic dermatitis). Part II. J Eur Acad Dermatol Venereol. 2012;26(9):1176–1193. doi: 10.1111/j.1468-3083.2012.04636.x.
35. Werfel T, Wittmann M. Regulatory role of T lymphocytes in atopic dermatitis. Chem Immunol Allergy. 2008;94:101–111. doi: 10.1159/000154935.
36. Werfel T, Erdmann S, Fuchs T, et al. Approach to suspected food allergy in atopic dermatitis. Guideline of the Task Force on Food Allergy of the German Society of Allergology and Clinical Immunology (DGAKI) and the Medical Association of German Allergologists (ADA) and the German Society of Pediatric Allergology (GPA). J Dtsch Dermatol Ges. 2009;7(3):265–271. doi: 10.1111/j.1610-0387.2008.06901.x.
37. Harvey PW, Healing G, Rees SJ, et al. Glucocorticosteroid interactions with natural toxins: a mini review. Nat Toxins. 1994; 2(6):341–346. doi: 10.1002/nt.2620020601.
38. Charman CR, Morris AD, Williams HC. Topical corticosteroid phobia in patients with atopic eczema. Br J Dermatol. 2000; 142(5):931–936. doi: 10.1046/j.1365-2133.2000.03473.x.
39. Haeck IM, Rouwen TJ, Timmer-de Mik L, et al. Topical corticosteroids in atopic dermatitis and the risk of glaucoma and cataracts. J Am Acad Dermatol. 2011;64(2):275–281. doi: 10.1016/j.jaad.2010.01.035.
40. Siegfried EC, Jaworski JC, Kaiser JD, Hebert AA. Systematic review of published trials: long-term safety of topical corticosteroids and topical calcineurin inhibitors in pediatric patients with atopic dermatitis. BMC Pediatr. 2016;16:75. doi: 10.1186/s12887-016-0607-9.
41. Wollenberg A, Bieber T. Topical immunomodulatory agents and their targets in inflammatory skin diseases. Transplant Proc. 2001; 33(3):2212–2216. doi: 10.1016/S0041- 1345(01)01944-3.
42. Reitamo S, Rissanen J, Remitz A, et al. Tacrolimus ointment does not affect collagen synthesis: results of a single-center randomized trial. J Invest Dermatol. 1998;111(3):396– 398. doi: 10.1046/j.1523-1747.1998.00323.x.
43. Meingassner JG, Grassberger M, Fahrngruber H, et al. A novel antiinflammatory drug, SDZ ASM 981, for the topical and oral treatment of skin diseases: in vivo pharmacology. Br J Dermatol. 1997;137(4): 568–576. doi: 10.1111/j.1365-2133.1997.tb03788.x.
44. Stuetz A, Grassberger M, Meingassner JG. Pimecrolimus (Elidel, SDZ ASM 981) — preclinical pharmacologic profile and skin selectivity. Semin Cutan Med Surg. 2001;20(4):233–241. doi: 10.1053/sder.2001.29066.
45. Siegfried E, Korman N, Molina C, et al. Safety and efficacy of early intervention with pimecrolimus cream 1% combined with corticosteroids for major flares in infants and children with atopic dermatitis. J Dermatolog Treat. 2006;17(3):143–150. doi: 10.1080/09546630600647297.
46. Sigurgeirsson B, Ho V, Ferrandiz C, et al. Effectiveness and safety of a prevention-of- flare-progression strategy with pimecrolimus cream 1% in the management of paediatric atopic dermatitis. J Eur Acad Dermatol Venereol. 2008;22(11):1290–1301. doi: 10.1111/j.1468-3083.2008.02785.x.
47. Wahn U, Bos JD, Goodfield M, et al. Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children. Pediatrics. 2002;110(1 Pt 1):e2. doi: 10.1542/peds.110.1.e2.
48. Chen SL, Yan J, Wang FS. Two topical calcineurin inhibitors for the treatment of atopic dermatitis in pediatric patients: a meta-analysis of randomized clinical trials. J Dermatolog Treat. 2010;21(3):144–156. doi: 10.3109/09546630903401470.
49. Zuberbier T, Brautigam M. Long-term management of facial atopic eczema with pimecrolimus cream 1% in paediatric patients with mild to moderate disease. J Eur Acad Dermatol Venereol. 2008;22(6):718–721. doi: 10.1111/j.1468-3083.2008.02586.x.
50. Werfel T. Topical use of pimecrolimus in atopic dermatitis: update on the safety and efficacy. J Dtsch Dermatol Ges. 2009;7(9): 739–742. doi: 10.1111/j.1610-0387.2009.07141.x.
51. Kapp A, Papp K, Bingham A, et al. Long-term management of atopic dermatitis in infants with topical pimecrolimus, a nonsteroid anti-inflammatory drug. J Allergy Clin Immunol. 2002;110(2): 277–284. doi: 10.1067/mai.2002.126500.
52. Zuberbier T, Heinzerling L, Bieber T, et al. Steroid-sparing effect of pimecrolimus cream 1% in children with severe atopic dermatitis. Dermatology. 2007;215(4):325–330. doi: 10.1159/000107627.
53. Tang TS, Bieber T, Williams HC. Are the concepts of induction of remission and treatment of subclinical in.ammation in atopic dermatitis clinically useful? J Allergy Clin Immunol. 2014;133(6): 1615–1625.e1. doi: 10.1016/j.jaci.2013.12.1079.
54. Hanifin J, Gupta AK, Rajagopalan R. Intermittent dosing of fluticasone propionate cream for reducing the risk of relapse in atopic dermatitis patients. Br J Dermatol. 2002;147(3):528–537. doi: 10.1046/j.1365-2133.2002.05006.x.
55. Peserico A, Stadtler G, Sebastian M, et al. Reduction of relapses of atopic dermatitis with methylprednisolone aceponate cream twice weekly in addition to maintenance treatment with emollient: a multicentre, randomized, double-blind, controlled study. Br J Dermatol. 2008;158(4):801–807. doi: 10.1111/j.1365-2133.2008.08436.x.
56. Paller AS, Eicheneld LF, Kirsner RS, et al. Three times weekly tacrolimus ointment reduces relapse in stabilized atopic dermatitis: a new paradigm for use. Pediatrics. 2008;122(6):e1210–1218. doi: 10.1542/peds.2008-1343.
57. Thaci D, Reitamo S, Gonzalez Ensenat MA, et al. Proactive disease management with 0.03% tacrolimus ointment for children with atopic dermatitis: results of a randomized, multicentre, comparative study. Br J Dermatol. 2008;159(6):1348–1356. doi: 10.1111/j.1365-2133.2008.08813.x.
58. Ruer-Mulard M, Aberer W, Gunstone A, et al. Twice-daily versus once-daily applications of pimecrolimus cream 1% for the prevention of disease relapse in pediatric patients with atopic dermatitis. Pediatr Dermatol. 2009;26(5):551–558. doi: 10.1111/j.1525- 1470.2009.00981.x.
59. Sigurgeirsson B, Boznanski A, Todd G, et al. Safety and efficacy of pimecrolimus in atopic dermatitis: a 5-year randomized trial. Pediatrics. 2015;135(4):597–606. doi: 10.1542/peds.2014-1990.
60. Ho VC, Gupta A, Kaufmann R, et al. Safety and efficacy of nonsteroid pimecrolimus cream 1% in the treatment of atopic dermatitis in infants. J Pediatr. 2003;142(2):155–162. doi: 10.1067/mpd.2003.65.
61. Kaufmann R, Folster-Holst R, Hoger P, et al. Onset of action of pimecrolimus cream 1% in the treatment of atopic eczema in infants. J Allergy Clin Immunol. 2004;114(5):1183– 1188. doi: 10.1016/j.jaci.2004.08.015.
62. Lubbe J, Friedlander SF, Cribier B, et al. Safety, efficacy, and dosage of 1% pimecrolimus cream for the treatment of atopic dermatitis in daily practice. Am J Clin Dermatol. 2006;7(2): 121–131. doi: 10.2165/00128071-200607020-00005.
63. Ring J, Abraham A, de Cuyper C, et al. Control of atopic eczema with pimecrolimus cream 1% under daily practice conditions: results of a >2000 patient study. J Eur Acad Dermatol Venereol. 2008;22(2):195–203. doi: 10.1111/j.1468-3083.2007.02368.x.
64. Papp KA, Werfel T, Folster-Holst R, et al. Long-term control of atopic dermatitis with pimecrolimus cream 1% in infants and young children: a two-year study. J Am Acad Dermatol. 2005;52: 240–246. doi: 10.1016/j.jaad.2004.09.016.
65. McKenna SP, Whalley D, de Prost Y, et al. Treatment of paediatric atopic dermatitis with pimecrolimus (Elidel, SDZ ASM 981): impact on quality of life and health-related quality of life. J Eur Acad Dermatol Venereol. 2006;20(3):248–254. doi: 10.1111/j.1468-3083.2006.01383.x.
66. Whalley D, Huels J, McKenna SP, Van Assche D. The benefit of pimecrolimus (Elidel, SDZ ASM 981) on parents’ quality of life in the treatment of pediatric atopic dermatitis. Pediatrics. 2002;110(6): 1133–1136. doi: 10.1542/peds.110.6.1133.
67. Staab D, Kaufmann R, Brautigam M, Wahn U. Treatment of infants with atopic eczema with pimecrolimus cream 1% improves parents’ quality of life: a multicenter, randomized trial. Pediatr Allergy Immunol. 2005; 16(6):527–533. doi: 10.1111/j.1399-3038.2005.00306.x.
68. Alomar A, Berth-Jones J, Bos JD, et al. The role of topical calcineurin inhibitors in atopic dermatitis. Br J Dermatol. 2004; 151 Suppl 70:3–27. doi: 10.1111/j.1365-2133.2004.06269.x..
69. Siegfried EC, Jaworski JC, Hebert AA. Topical calcineurin inhibitors and lymphoma risk: evidence update with implications for daily practice. Am J Clin Dermatol. 2013;14(3):163– 178. doi: 10.1007/s40257-013-0020-1.
70. Haapasaari KM, Risteli J, Karvonen J, Oikarinen A. Effect of hydrocortisone, methylprednisolone aceponate and momethasone furoate on collagen synthesis in human skin in vivo. Skin Pharmacol. 1997;10(5–6):261–264. doi: 10.1159/000211513.
71. Langley RG, Luger TA, Cork MJ, et al. An update on the safety and tolerability of pimecrolimus cream 1%: evidence from clinical trials and post-marketing surveillance. Dermatology. 2007;215 Suppl 1:27–44. doi: 10.1159/000102118.
72. Lebwohl M, Gower T. A safety assessment of topical calcineurin inhibitors in the treatment of atopic dermatitis. Med Gen Med. 2006;8(4):8.
73. Legendre L, Barnetche T, Mazereeuw-Hautier J, et al. Risk of lymphoma in patients with atopic dermatitis and the role of topical treatment: A systematic review and meta-analysis. J Am Acad Dermatol. 2015;72(6):992–1002. doi: 10.1016/j.jaad.2015.02.1116.
74. Tennis P, Gelfand JM, Rothman KJ. Evaluation of cancer risk related to atopic dermatitis and use of topical calcineurin inhibitors. Br J Dermatol. 2011;165(3):465–473. doi:10.1111/j.1365-2133.2011.10363.x.
75. Thaci D, Salgo R. The topical calcineurin inhibitor pimecrolimus in atopic dermatitis: a safety update. Acta Dermatovenerol Alp Pannonica Adriat. 2007;16(2):58, 60–62.
76. Thaci D, Salgo R. Malignancy concerns of topical calcineurin inhibitors for atopic dermatitis: facts and controversies. Clin Dermatol. 2010;28(1):52–56. doi:10.1016/j.clindermatol.2009.04.001.
77. Luger TA, et al. [Therapy of atopic eczema with calcineurin inhibitors. (In German).] J Dtsch Dermatol Ges. 2005;3(5):385–391.
78. Ring J, Barker J, Behrendt H, et al. Review of the potential photococarcinogenicity of topical calcineurin inhibitors: position statement of the European Dermatology Forum. J Eur Acad Dermatol Venereol. 2005 Nov;19(6):663–671. doi: 10.1111/j.1468- 3083.2005.01315.x.
79. Mandelin J, Remitz A, Virtanen H, Reitamo S. Recall antigen reactions in patients with atopic dermatitis treated with tacrolimus ointment for 1 year. J Allergy Clin Immunol. 2008;121(3):777–779. doi: 10.1016/j.jaci.2007.12.1179.
Рецензия
Для цитирования:
Мурашкин Н.Н., Материкин А.И., Амбарчян Э.Т., Епишев Р.В. Современные представления о патогенезе и принципах наружной терапии атопического дерматита у детей. Вопросы современной педиатрии. 2016;15(6):584-589. https://doi.org/10.15690/vsp.v15i6.1655
For citation:
Murashkin N.N., Materikin A.I., Ambarchyan E.T., Epishev R.V. Current Views on the Pathogenesis and Principles of External Treatment of Atopic Dermatitis in Children. Current Pediatrics. 2016;15(6):584-589. (In Russ.) https://doi.org/10.15690/vsp.v15i6.1655
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