Filaggrin and Atopic Dermatitis: Clinical and Pathogenetic Parallels and Therapeutic Possibilities

Atopic dermatitis (AtD) is multifactorial inflammatory skin disease, one of the aspects of its pathogenesis is epidermal barrier dysfunction. Early development of AtD is associated with filaggrin dysfunction. Filaggrin is a protein involved in aggregation of keratin filaments in the upper layers of epidermis and the retention of lipids and proteins between corneocytes. Frequently, filaggrin dysfunction can be accompanied with secondary infection and high risk of other allergic diseases development. This can happen due to disturbance in terminal differentiation of epidermal cells and, as consequence, malfunction of epidermal barrier. Thus, the long regular use of emollients is the basis of AtD therapy. New class of emollients (“emollents plus”) allowed us to achieve more significant treatment results in patients with AtD. These emollients reduce inflammatory process activity in the skin by replacing structural components of abnormal epidermal barrier.

1. Maliyar K, Sibbald C, Pope E, et al. Diagnosis and Management of Atopic Dermatitis. Adv Skin Wound Care. 2018;31(12):538-550. doi: 10.1097/01.asw.0000547414.38888.8d

2. Drucker AM, Wang AR, Li WQ, et al. The Burden of Atopic Dermatitis: Summary of a Report for the National Eczema Association. J Investig Dermatol. 2017;137(1):26-30. doi: 10.1016/j.jid.2016.07.012

3. Xu X, van Galen LS, Koh MJ., et al. Factors influencing quality of life in children with atopic dermatitis and their caregivers: A crosssectional study. Sci Rep. 2019;9(1):15990. doi: 10.1038/s41598-019-51129-5

4. Mallol J, Crane J, von Mutius E, et al. The International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three: A global synthesis. Allergol Immunopathol. 2013;41(2):73-85. doi: 10.1016/j.aller.2012.03.001

5. Asher MI, Montefort S, Bjorksten B, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 2006;368(9537):733-743. doi: 10.1016/s0140-6736(06)69283-0

6. Larsen FS, Hanifin JM. Epidemiology of atopic dermatitis. Immunol Allergy Clin North Am. 2002;22(1):1-24. doi: 10.1016/s0889-8561(03)00066-3

7. National Center for Health Statistics. National Health and Nutrition Examination Survey (NHANES) body composition procedures manual. Centers for Disease Control and Prevention. Hyattsville, MD; 2006.

8. Deckers I.A., McLean S., Linssen S., et al. Investigating international time trends in the incidence and prevalence of atopic eczema 1990-2010: A systematic review of epidemiologic studies. PLoS One. 2012;7(7):e39803. doi: 10.1371/journal.pone.0039803

9. Kowalska-Olędzka E, Czarnecka M, Baran A. Epidemiology of atopic dermatitis in Europe. J Drug Assess. 2019;8(1):126-128. doi: 10.1080/21556660.2019.1619570

10. Shaw TE, Currie GP, Koudelka CW, Simpson EL. Eczema prevalence in the United States: data from the 2003 National Survey of Children's Health. J Invest Dermatol. 2011;131(1):67-73. doi: 10.1038/jid.2010.251

11. Yang G, Seok JK, Kang HC, et al. Skin Barrier Abnormalities and Immune Dysfunction in Atopic Dermatitis. Int J Mol Sci. 2020;21(8):2867. doi: 10.3390/ijms21082867

12. Kubo A, Nagao K, Amagai M. Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases. J Clin Invest. 2012;122(2):440-447. doi: 10.1172/JCI57416

13. Michael JC, Simon GD, Yiannis V, et al. Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol. 2009;129(8):1892-1908. doi: 10.1038/jid.2009.133

14. Bosko CA. Skin Barrier Insights: From Bricks and Mortar to Molecules and Microbes. J Drugs Dermatol. 2019;18(1s):s63-s67.

15. Wickett RR, Visscher MO. Structure and function of the epidermal barrier. Am J Infect Control. 2006;34(10):S98-S110. doi: 10.1016/j.ajic.2006.05.295

16. Matsui T, Amagai M. Dissecting the formation, structure and barrier function of the stratum corneum. Int Immunol. 2015;27(6):269-280. doi: 10.1093/intimm/dxv013

17. Segre JA. Epidermal barrier formation and recovery in skin disorders. J Clin Invest. 2006;116(5):1150-1158. doi: 10.1172/JCI28521

18. Natsuga K. Epidermal barriers. Cold Spring Harb Perspect Med. 2014;4(4):a018218. doi: 10.1101/cshperspect.a018218

19. Munoz-Garcia A, Thomas CP Keeney DS, et al. The importance of the lipoxygenase-hepoxilin pathway in the mammalian epidermal barrier. Biochim Biophys Acta. 2014;1841(3):401-408. doi: 10.1016/j.bbalip.2013.08.020

20. Nakagawa N, Sakai S, Matsumoto M, et al. Relationship between NMF (lactate and potassium) content and the physical properties of the stratum corneum in healthy subjects. J Invest Dermatol. 2004;122(3):755-763. doi: 10.1111/j.0022-202X.2004.22317.x

21. Sroka-Tomaszewska J, Trzeciak M. Molecular Mechanisms of Atopic Dermatitis Pathogenesis. Int J Mol Sci. 2021;22(8):4130. doi: 10.3390/ijms22084130

22. Presland RB, Haydock PV, Fleckman P, et al. Characterization of the human epidermal profilaggrin gene. Genomic organization and identification of an S-100-like calcium binding domain at the amino terminus. J Biol Chem. 1992;267:23772-23781.

23. Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006;38(4):441-446. doi: 10.1038/ng1767

24. Brown SJ, Irvine AD. Atopic eczema and the filaggrin story. Semin Cutan Med Surg. 2008;27(2):128-137. doi: 10.1016/j.sder.2008.04.001

25. Izadi N, Luu M, Ong PY, Tam JS. The Role of Skin Barrier in the Pathogenesis of Food Allergy. Children (Basel). 2015;2(3):382-402. doi: 10.3390/children2030382

26. Osawa R, Akiyama M, Shimizu H. Filaggrin gene defects and the risk of developing allergic disorders. Allergol Int. 2011;60(1):1-9. doi: 10.2332/allergolint.10-RAI-0270

27. Brown SJ, McLean WH. Eczema genetics: current state of knowledge and future goals. J Invest Dermatol. 2009;129(3):543-552. doi: 10.1038/jid.2008.413

28. O'Regan GM, Sandilands A, McLean WHI, Irvine AD. Filaggrin in atopic dermatitis. J Allergy Clin Immunol. 2008;122(4):689-693. doi: 10.1016/j.jaci.2008.08.002

29. 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

30. McPherson T. Current Understanding in Pathogenesis of Atopic Dermatitis. Indian J Dermatol. 2016;61(6):649-655. doi: 10.4103/0019-5154.193674

31. McAleer MA, Irvine AD. The multifunctional role of filaggrin in allergic skin disease. J Allergy Clin Immunol. 2013;131(2):280-291. doi: 10.1016/j.jaci.2012.12.668

32. Zheng T, Yu J, Oh MH, Zhu Z. The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma. Allergy Asthma Immunol Res. 2011;3(2):6773. doi: 10.4168/aair.2011.3.2.67

33. Belgrave DC, Granell R, Simpson A, et al. Developmental profiles of eczema, wheeze, and rhinitis: two population-based birth cohort studies. PLoS Med. 2014;11(10):e1001748. doi: 10.1371/journal.pmed.1001748

34. Irvine A.D., Mina-Osorio P. Disease trajectories in childhood atopic dermatitis: an update and practitioner's guide. Br J Dermatol. 2019;181(5):895-906. doi: 10.1111/bjd.17766

35. Chan A, Terry W, Zhang H, et al. Filaggrin mutations increase allergic airway disease in childhood and adolescence through interactions with eczema and aeroallergen sensitization. Clin Exp Allergy. 2018;48(2):147-155. doi: 10.1111/cea.13077

36. Venkataraman D, Soto-Ramfrez N, Kurukulaaratchy RJ, et al. Filaggrin loss-of-function mutations are associated with food allergy in childhood and adolescence. J Allergy Clin Immunol. 2014;134(4):876-882.e4. doi: 10.1016/j.jaci.2014.07.033

37. Rodnguez E, Baurecht H, Herberich E, et al. Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease. J Allergy Clin Immunol. 2009;123(6):1361-1370. e7. doi: 10.1016/j.jaci.2009.03.036

38. Miajlovic H, Fallon PG, Irvine AD, Foster TJ. Effect of filaggrin breakdown products on growth of and protein expression by Staphylococcus aureus. J Allergy Clin Immunol. 2010;126(6):1184-1190. doi: 10.1016/j.jaci.2010.09.015

39. Rabinowitz LG, Esterly NB. Atopic dermatitis and ichthyosis vulgaris. Pediatr Rev. 1994;15(6):220-226; quiz 226. doi: 10.1542/pir.15-6-220

40. Sehgal VN, Khurana A, Mendiratta V, et al. Atopic dermatitis: Clinical connotations, especially a focus on concomitant atopic undertones in immunocompromised/susceptible genetic and metabolic disorders. Indian J Dermatol. 2016;(61):241-250. doi: 10.4103/0019-5154.182433

41. Howell MD, Kim BE, Gao P, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2007;120(1):150-155. doi: 10.1016/j.jaci.2007.04.031

42. Arakawa H, Shimojo N, Katoh N, et al. Consensus statements on pediatric atopic dermatitis from dermatology and pediatrics practitioners in Japan: Goals of treatment and topical therapy. Allergol Int. 2020;69(1):84-90. doi: 10.1016/j.alit.2019.08.006

43. Wollenberg A, Barbarot S, Bieber T, et al. Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part I. J Eur Acad Dermatol Venereol. 2018;32(5):657-682.

44. Reda AM, Ayman E, Ebraheem AI, et al. A practical algorithm for topical treatment of atopic dermatitis in the Middle East empha-sizing the importance of sensitive skin areas. J Dermatolog Treat. 2019;30(4):366-373. doi: 10.1080/09546634.2018.1524823

45. Catherine M., Nebus J. Management of patients with atopic dermatitis: the role of emollient therapy. Dermatol Res Pract. 2012;2012:836931. doi: 10.1155/2012/836931

46. Eichenfield LF, Tom WL, Berger TG, 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(1):116-132. doi: 10.1016/j.jaad.2014.03.023

47. Hebert AA, Rippke, F, Weber TM, et al. Efficacy of Nonprescription Moisturizers for Atopic Dermatitis: An Updated Review of Clinical Evidence. Am J Clin Dermatol. 2020;21(5):641-655. doi: 10.1007/s40257-020-00529-9

48. Simpson EL, Berry TM, Brown PA, Hanifin JM. A pilot study of emollient therapy for the primary prevention of atopic dermatitis. J Am Acad Dermatol. 2010;63(4):587-593. doi: 10.1016/j.jaad.2009.11.011

49. Simpson EL, Chalmers JR, Hanifin JM, et al. Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. J Allergy Clin Immunol. 2014;134(4):818-823. doi: 10.1016/j.jaci.2014.08.005

50. Lowe A, Su J, Tang M, et al. PEBBLES study protocol: a randomised controlled trial to prevent atopic dermatitis, food allergy and sensitisation in infants with a family history of allergic disease using a skin barrier improvement strategy. BMJ Open. 2019;9(3):e024594. doi: 10.1136/bmjopen-2018-024594

51. L0drup Carlsen KC, Rehbinder EM, Skjerven HO, et al. Preventing atopic dermatitis and ALLergies in children — the PreventADALL study. Allergy. 2018; 73(10):2063-2070. doi: 10.1111/all.13468

52. Purnamawati S, Indrastuti N, Danarti R, Saefudin T. The Role of Moisturizers in Addressing Various Kinds of Dermatitis: A Review. Clin Med Res. 2017;15(3-4):75-87. doi: 10.3121/cmr.2017.1363

53. Grimalt R, Mengeaud V, Cambazard F. The steroid-sparing effect of an emollient therapy in infants with atopic dermatitis: a randomized controlled study. Dermatology. 2007;214(1):61-67. doi: 10.1159/000096915

54. Hon KL, Pong NH, Wang SS, et al. Acceptability and efficacy of an emollient containing ceramide-precursor lipids and moisturizing factors for atopic dermatitis in pediatric patients. Drugs R D. 2013;13(1):37-42. doi: 10.1007/s40268-013-0004-x

55. Wollenberg A, Folster-Holst R, Saint Aroman M, et al. Effects of a protein-free oat plantlet extract on microinflammation and skin barrier function in atopic dermatitis patients. J Eur Acad Dermatol Venereol. 2018;32 (Suppl 1):1-15. doi: 10.1111/jdv.14846

56. Topical skin care compositions. Patent. Publication Number: WO 2018/198039 A1. Publication Date: 01.11.2018. International Application No: PCT/IB2018/052866. International Filing Date: 25.04.2018. Applicant: DR. REDDY'S LABORATORIES LIMITED.

57. Mohammed D, Crowther JM, Matts PJ, et al. Influence of niacinamide containing formulations on the molecular and biophysical properties of the stratum corneum. Int J Pharm. 2013;441(1-2):192-201. doi: 10.1016/j.ijpharm.2012.11.043

58. Coderch L, Lopez O, de la Maza A, Parra JL. Ceramides and skin function. Am J Clin Dermatol. 2003;4(2):107-129. doi: 10.2165/00128071-200304020-00004

59. Kim ME, Kim HK, Kim DH, et al. Glycyrrhetinic acid from licorice root impairs dendritic cells maturation and Th1 immune responses. Immunopharmacol Immunotoxicol. 2013;35(3):329-335. doi: 10.3109/08923973.2013.768636

60. Akihisa T, Kojima N, Kikuchi T, et al. Anti-inflammatory and chemopreventive effects of triterpene cinnamates and acetates from shea fat. J Oleo Sci. 2010;59(6):273-280. doi: 10.5650/jos.59.273

61. Scapagnini G, Davinelli S, Di Renzo L, et al. Cocoa bioactive compounds: significance and potential for the maintenance of skin health. Nutrients. 2014;6(8):3202-3213. doi: 10.3390/nu6083202

62. Abril-Gil M, Massot-Cladera M, Perez-Cano FJ, et al. A diet enriched with cocoa prevents IgE synthesis in a rat allergy model. Pharmacol Res. 2012;65(6):603-608. doi: 10.1016/j.phrs.2012.02.001

63. Mandawgade SD, Patravale VB. Formulation and evaluation of exotic fat based cosmeceuticals for skin repair. Indian J Pharm Sci. 2008;70(4):539-542. doi: 10.4103/0250-474X.44615