PERSISTENT SUBCLINICAL INFLAMMATION IN THE SKIN AS A RISK FACTOR FOR RELAPSE IN ATOPIC DERMATITIS: FROM PATHOPHYSIOLOGY TO TREATMENT

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract


Lowgrade cutaneous inflammation, which persists after induction of remission of atopic dermatitis (AD), determines the risk of repeated relapses and progression of the disease. It has been well established that subclinical inflammation in the skin of atopic patients may be inhibited by topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI), and proactive courses of these drugs prolong remission of the disease. In terms of prolonged application, TCI have some advantages over TCS in the context of safety. However, the routine use of TCI in AD is constrained by many practitioners who do not accept the concept of subclinical chronic inflammation and the strategy of maintenance antiinflammatory therapy on areas prone to repeated relapses, as well as obsolete myths about the association of TCI application with increased risk of cutaneous lymphoma. The review presents modem data on the pathophysiology of AD with a focus on subclinical skin inflammation, which persists after regression of acute manifestations of the disease, and the possibilities of suppressing this inflammation with TCI. Data on the safety of TCI for longterm use and the absence of prooncogenic potential are given. In addition, the relevance and expediency of pimecrolimus use in children under 2 years of age are emphasized.

Restricted Access

O V Kalyuzhin

I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation

Email: kalyuzhin@list.ru
8 - 2, Trubetskaya str., Moscow, 119991, Russia

  1. Deckers IAG, McLean S, Linssen S, Mommers M, van Schayck CP, Sheikh A. Investigating International Time Trends in the Incidence and Prevalence of Atopic Eczema 1990-2010: A Systematic Review of Epidemiological Studies. Kirk M, ed. PLoS ONE. 2012;7:e39803. doi: 10.1371/journal. pone.0039803.
  2. Andersen YMF, Egeberg A, Skov L, Thyssen JP Comorbidities of Atopic Dermatitis: Beyond Rhinitis and Asthma. Curr Dermatol Rep. 2017;6:35-41. doi: 10.1007/s13671-017-0168-7.
  3. Bin L, Leung DYM. Genetic and epigenetic studies of atopic dermatitis. Allergy Asthma Clin Immunol. 2016;12:52. doi: 10.1186/s13223-016-0158-5.
  4. Kim JE, Kim JS, Cho DH, Park HJ. Molecular Mechanisms of Cutaneous Inflammatory Disorder: Atopic Dermatitis. Jackson C, ed. Int J Mol Cell Med. 2016;17:1234. DOI: 10.3390/ ijms17081234.
  5. Van den Oord RAHM, Sheikh A. Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis. The BMJ. 2009;339:b2433. doi: 10.1136/bmj.b2433.
  6. Tang TS, Bieber T Williams HC. Are the concepts of induction of remission and treatment of subclinical inflammation in atopic dermatitis clinically useful? J Allergy Clin Immunol. 2014;133:1615-1625.e1. doi: 10.1016/j.jaci.2013.12.1079.
  7. Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016;387:1109-1122. doi: 10.1016/S0140-6736(15)00149-X.
  8. Agrawal R, Woodfolk JA. Skin Barrier Defects in Atopic Dermatitis. Curr Allergy Asthma Rep. 2014;14:433. DOI: 10.1007/ s11882-014-0433-9.
  9. Janssens M, van Smeden J, Gooris GS. Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients. J Lipid Res. 2012;53:2755-2766. doi: 10.1194/jlr.P030338.
  10. Van Smeden J, Janssens M, Kaye EC, Caspers PJ, Lavrijsen AP, Vreeken RJ et al. The importance of free fatty acid chain length for the skin barrier function in atopic eczema patients. Exp Dermatol. 2014;23:45-52. doi: 10.1111/exd.12293.
  11. Brown SJ, McLean WHI. One remarkable molecule: Filaggrin. J Investig Dermatol. 2012;132(3 Pt 2):751-762. DOI: 10.1038/ jid.2011.393.
  12. Cabanillas B, Novak N. Atopic dermatitis and filaggrin. Curr Opin Immunol. 2016;42:1-8. doi: 10.1016/j.coi.2016.05.002.
  13. Harding CR, Aho S, Bosko CA. Filaggrin - revisited. Int J Cosmet Sci. 2013;35:412-423. doi: 10.1111/ics.12049.
  14. Dennin M, Lio PA. Filaggrin and childhood eczema. Arch Dis Child. Published Online First. 2017 Jul 22. pii: archdischild-2017-313010. doi: 10.1136/archdischild-2017-313010.
  15. Thyssen JP, Kezic S. Causes of epidermal filaggrin reduction and their role in the pathogenesis of atopic dermatitis. J Allergy Clin Immunol. 2014;134:792-799. DOI: 10.1016/j. jaci.2014.06.014.
  16. Scharschmidt TC, Man MQ, Hatano Y, Crumrine D, Gunathilake R, Sundberg JP et al. Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens. J Allergy Clin Immunol. 2009;124:496-506.e6. doi: 10.1016/j.jaci.2009.06.046.
  17. Kawasaki H, Nagao K, Kubo A, Hata T, Shimizu A, Mizuno H et al. Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice. J Allergy Clin Immunol. 2012;129:1538-1546. DOI: 10.1016/j. jaci.2012.01.068.
  18. Kezic S, O’Regan GM, Lutter R, Jakasa I, Koster ES, Saunders S et al. Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency. J Allergy Clin Immunol. 2012;129:1031-1039.e1. doi: 10.1016/j.jaci.2011.12.989.
  19. Zaniboni MC, Samorano LP, Orfali RL, Aoki V. Skin barrier in atopic dermatitis: beyond filaggrin. Anais Brasileiros de Dermatologia. 2016;91:472-478. doi: 10.1590/abd1806-4841.20164412.
  20. Kirschner N, Rosenthal R, Furuse M, Moll I, Fromm M, Brandner JM. Contribution of tight junction proteins to ion, macromolecule, and water barrier in keratinocytes. J Invest Dermatol. 2013;133:1161-1169. doi: 10.1038/jid.2012.507.
  21. Yokouchi M, Kubo A, Kawasaki H, Yoshida K, Ishii K, Furuse M et al. Epidermal tight junction barrier function is altered by skin inflammation, but not by filaggrin-deficient stratum corneum. J Dermatol Sci. 2015;77:28-36. DOI: 10.1016/j. jdermsci.2014.11.007.
  22. Moy AP, Murali M, Kroshinsky D, Duncan LM, Nazarian RM. Immunologic overlap of helper T-cell subtypes 17 and 22 in erythrodermic psoriasis and atopic dermatitis. JAMA Dermatol. 2015;151:753-760. doi: 10.1001/jamaderma-tol.2015.2.
  23. Kim BS. Innate Lymphoid Cells in the Skin. J Investig Dermatol. 2015;135:673-678. doi: 10.1038/jid.2014.401.
  24. Howell MD, Fairchild HR, Kim BE, Bin L, Boguniewicz M, Redzic JS et al. Th2 cytokines act on S100/A11 to down-regulate keratinocyte differentiation. J Investig Dermatol. 2008;128:2248-2258. doi: 10.1038/jid.2008.74.
  25. Noda S, Krueger JG, Guttman-Yassky E. The translational revolution and use of biologics in patients with inflammatory skin diseases. J Allergy Clin Immunol. 2015;135:324-336. doi: 10.1016/j.jaci.2014.11.015.
  26. Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, Debenedetto A et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2007;120:150-155. doi: 10.1016/j.jaci.2007.04.031.
  27. Kim BE, Leung DY, Boguniewicz M, Howell MD. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin Immunol. 2008;126:332-337. doi: 10.1016/j.clim.2007.11.006.
  28. McAleer MA, Irvine AD. The multifunctional role of filaggrin in allergic skin disease. J Allergy Clin Immunol. 2013;131:280-291. doi: 10.1016/j.jaci.2012.12.668.
  29. Ziegler SF. Thymic stromal lymphopoietin (TSLP) and allergic disease. J Allergy Clin Immunol. 2012;130:845-852. doi: 10.1016/j.jaci.2012.07.010.
  30. Cornelissen C, Marquardt Y, Czaja K, Wenzel J, Frank J, Luscher-Firzlaff J et al. IL-31 regulates differentiation and filaggrin expression in human organotypic skin models. J Allergy Clin Immunol. 2012;129:426-433. DOI: 10.1016/j. jaci.2011.10.042.
  31. Ezzat MH, Hasan ZE, Shaheen KY Serum measurement of interleukin-31 (IL-31) in paediatric atopic dermatitis: Elevated levels correlate with severity scoring. J Eur Acad Dermatol Venereol. 2011;25:334-339. doi: 10.1111/j.1468-3083.2010.03794.x.
  32. Yamanaka K, Mizutani H. The role of cytokines/chemokines in the pathogenesis of atopic dermatitis. Curr Probl Dermatol. 2011;41:80-92. doi: 10.1159/000323299.
  33. Fedenko ES, Elisyutina OG, Filimonova TM, Boldyreva MN, Burmenskaya OV, Rebrova OY et al. Cytokine gene expression in the skin and peripheral blood of atopic dermatitis patients and healthy individuals. Self Nonself. 2011;2:120-124. doi: 10.4161/self.2.2.16939.
  34. Gittler JK, Shemer A, Suarez-Farinas M, Fuentes-Duculan J, Gulewicz KJ, Wang CQ et al. Progressive activation of Th2/ Th22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol. 2012;130:1344-1354. doi: 10.1016/j.jaci.2012.07.012.
  35. Toda M, Leung DY, Molet S, Boguniewicz M, Taha R, Christodoulopoulos P et al. Polarized in vivo expression of IL-11 and IL-17 between acute and chronic skin lesions. J Allergy Clin Immunol. 2003;111:875-881.
  36. Van Drongelen V, Haisma EM, Out-Luiting JJ, Nibbering PH, El Ghalbzouri A. Reduced filaggrin expression is accompanied by increased Staphylococcus aureus colonization of epidermal skin models. Clin Exp Allergy. 2014;44:1515-1524. doi: 10.1111/cea.12443.
  37. Ganem MB, De Marzi MC, Fernandez-Lynch MJ, Jancic C, Vermeulen M, Geffner J et al. Uptake and intracellular trafficking of superantigens in dendritic cells. PLoS One. 2013;8:e66244. doi: 10.1371/journal.pone.0066244.
  38. Nakamura Y, Oscherwitz J, Cease KB, Chan SM, Munoz-Planillo R, Hasegawa M et al. Staphylococcus 6-toxin promotes mouse allergic skin disease by inducing mast cell degranulation. Nature. 2013;503:397-401. DOI: 10.1038/ nature12655.
  39. Javad G, Taheri Sarvtin M, Hedayati MT, Hajheydari Z, Yazdani J, Shokohi T. Evaluation of Candida Colonization and Specific Humoral Responses against Candida albicans in Patients with Atopic Dermatitis. Biomed Res Int. 2015;2015:849206. doi: 10.1155/2015/849206.
  40. Альбанова ВИ. Малассезии: недооцененный обитатель кожи. Иммунопатология, аллергология, инфектология. 2017;(2):24-31. doi: 10.14427/jipai.2017.2.24
  41. Oh MH, OH SY, Lu J, Lou H, Myers AC, Zhu Z et al. TRPA1-Dependent Pruritus in IL-13-Induced Chronic Atopic Dermatitis. J Immunol (Baltimore, Md : 1950). 2013;191:5371-5382. doi: 10.4049/jimmunol.1300300.
  42. Cevikbas F, Wang X, Akiyama T, Kempkes C, Savinko T, Antal A et al. Sensory Neuron-expressed Interleukin-31 Receptor Mediates T-helper Cell-dependent Itch: Involvement of TRPV1 and TRPA1. J Allergy Clin Immunol. 2014;133:448-460.e7. doi: 10.1016/j.jaci.2013.10.048.
  43. Czarnowicki T, Krueger JG, Guttman-Yassky E. Skin barrier and immune dysregulation in atopic dermatitis: An evolving story with important clinical implications. J Aller gy Clin Immunol Pract. 2014;2:371-379. DOI: 10.1016/j. jaip.2014.03.006.
  44. Jensen JM, Pfeiffer S, Witt M, Brautigam M, Neumann C, Weichenthal M et al. Different effects of pimecrolimus and betamethasone on the skin barrier in patients with atopic dermatitis. J Allergy Clin Immunol. 2009;123:1124-1133. doi: 10.1016/j.jaci.2009.03.032.
  45. Tang TS, Bieber T, Williams HC. Are the concepts of induction of remission and treatment of subclinical inflammation in atopic dermatitis clinically useful? J Allergy Clin Immunol. 2014;133:1615-1625.e1. doi: 10.1016/j.jaci.2013.12.1079.
  46. Simon D, Vassina E, Yousefi S, Kozlowski E, Braathen LR, Simon HU. Reduced dermal infiltration of cytokine-expressing inflammatory cells in atopic dermatitis after short-term topical tacrolimus treatment. J Allergy Clin Immunol. 2004;114:887-895. doi: 10.1016/j.jaci.2004.05.066.
  47. Suarez-Farinas M, Tintle SJ, Shemer A, Chiricozzi A, Nograles K, Cardinale I et al. Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities. J Allergy Clin Immunol. 2011;127:954-64.e1-4. doi: 10.1016/j.jaci.2010.12.1124.
  48. Islam SA, Luster AD. T-cell homing to epithelial barriers in allergic disease. Nature medicine. 2012;18:10.1038/nm.2760. doi: 10.1038/nm.2760.
  49. Прошутинская ДВ, Чикин ВВ, Знаменская ЛФ, Монахов КН, Заславский ДВ, Минеева АА. Федеральные клинические рекомендации по ведению больных атопическим дерматитом. М.: Российское общество дерматовенерологов и косметологов; 2015. Доступно по http://www. ismos.ru/guidelines/doc/atopicheskij_dermatit.pdf. Ссылка активна на 14.10.2017
  50. Атопический дерматит у детей. Клинические рекомендации. Минздрав России; 2014. Доступно по http://www. pediatr-russia.ru/sites/default/files/file/kr_ad.pdf. Ссылка активна на 14.10.2017.
  51. 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 Pediatrics. 2016;16:75. doi: 10.1186/s12887-016-0607-9.
  52. Legendre L, Barnetche T, Mazereeuw-Hautier J, Meyer N, Murrell D, Paul C. 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;72:992-1002. doi: 10.1016/j.jaad.2015.02.1116.
  53. Siegfried EC, Jaworski JC, Hebert AA. Topical Calcineurin Inhibitors and Lymphoma Risk: Evidence Update with Implications for Daily Practice. J Am Acad Dermatol. 2013;14:163-178. doi: 10.1007/s40257-013-0020-1.
  54. Carr WW Topical Calcineurin Inhibitors for Atopic Dermatitis: Review and Treatment Recommendations. Paediatric Drugs. 2013;15:303-310. doi: 10.1007/s40272-013-0013-9.
  55. Huang X, Xu B. Efficacy and Safety of Tacrolimus versus Pimecrolimus for the Treatment of Atopic Dermatitis in Children: A Network Meta-Analysis. Dermatology. 2015;231:41-49. doi: 10.1159/000381948.
  56. Luger T, Boguniewicz M, Carr W, Cork M, Deleuran M, Eichenfield L et al. Pimecrolimus in atopic dermatitis: Consensus on safety and the need to allow use in infants. Pediatr Allergy Immunol. 2015;26:306-315. doi: 10.1111/pai.12331.
  57. Wong ITY, Tsuyuki RT, Cresswell-Melville A, Doiron P, Drucker AM. Guidelines for the management of atopic dermatitis (eczema) for pharmacists. Canadian Pharmacists Journal: CPJ. 2017;150:285-297. doi: 10.1177/1715163517710958.
  58. Eichenfield LF, Tom WL, Berger TG, Krol A, Paller AS, Schwarzenberger K et al. Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014;71:116-132. doi: 10.1016/j.jaad.2014.03.023.
  59. Papp KA, Werfel T, Fölster-Holst R, Ortonne JP, Potter PC, de Prost Y 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.
  60. Paul C, Cork M, Rossi AB, Papp KA, Barbier N, de Prost Y. Safety and tolerability of 1% pimecrolimus cream among infants: experience with 1133 patients treated for up to 2 years. Pediatrics. 2006;117:e118-128. doi: 10.1542/peds.2005-1188.

Views

Abstract - 4

PDF (Russian) - 0

Refbacks

  • There are currently no refbacks.

Copyright (c) 2017 Russian Allergological Journal

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies