1. Eczema in children Hugo Van Bever Department of Pediatrics National University Singapore APAPARI Workshop, Hanoi, May 2008

2. Mechanisms of Eczema in Children 1. ALLERGY 2. SKIN BARRIER DYSFUNCTIONS ?

3. Kalliomaki M, Lancet. 2001; 357:1076 Incidence of eczema at 2 years in children given probiotics from birth 50% decrease… IgE-mediated reactions persist !

4. AD and BMT 1.Complete correction of the Wiskott-Aldrich syndrome by allergenic bone-marrow transplantation. Parkman et al. NEJM 1978, 298, 921. 2. Transfer of atopy following bone marrow transplantation. Bellou A, et al. Ann Allergy Asthma Immunol 1997, 78, 513.

5. Atopic dermatitis 1. SKIN DISORDER 2. ALLERGIC DISEASE 3. Combination ?

6. Eczema in Singapore Children Results of ISAAC Questionnaire Survey 1 year period prevalence of 20.8% from a questionnaire cum clinical examination survey in schoolchildren (Tay YK et al Br J Dermatol 2002) Wang XS et al. Arch Dis Child. 2004, Tan TN et al., Pediatr Allergy Immunol. 2005, Asian Pac J Allergy Immunol. 2006

7. The Asian Skin 1.Ethnic differences in the pattern of skin diseases seen in a dermatology department – atopic dermatitis is more common among Asian referrals in Leicestershire. Sladden et al. Clin Exp Dermatol 1991, 16, 348. 2.The effect of lifestyle on wheeze, atopy, and bronchial hyperreactivity in Asian and white children. Carey et al. Am J Respir Crit Care Med. 1996, 154, 537. 3.Atopic dermatitis in children in the United States, 1997 – 2004: visit trends, patient and provider characteristics, and prescribing patterns. Horii et al. Pediatrics 2007, 120, e527. AD in Asians… 1. more common 2. more severe (?)

8. Eczema SKIN BARRIER DYSFUNCTIONS

9. New perspectives on epidermal barrier dysfunction in atopic dermatitis: Gene–environment interactions. Michael J Cork et al. J Allergy Clin Immunol 2006, 118, 3 – 21. “… on the importance of epidermal barrier dysfunction in genetically predisposed individuals …”

10. Skin barrier dysfunction in AD 1. dry skin – increased transepidermal water loss 2. reduced content of ceramides 3. changes in stratum corneum pH level 4. overexpression of chymotryptic enzyme “ Stratum corneum chymotryptic enzyme (SCCE) “ 5. altered keratinocyte cytokine profile

11. 1. Chymotrypsin (SCCE) 2. Filaggrin Two (of the many) new players in eczema…

12. Filaggrin gene - FLG is located within “the epidermal differentiation complex (EDC) on chromosome 1q21. - Function: to aggregate keratin filaments  formation of stratum corneum  maintaining the barrier function of the skin. - Associated with ichtyosis, AD, and psoriasis

13. FLG polymorphisms  R501X  228del4 Complete loss of FLG expression ICHTHYOSIS VULGARIS (= FLG null alleles)

14. Phenotype (ECZEMA) Environment Genes DEVELOPMENT (EPIGENETICS) Dynamics of gene expression (methylation processes) Area of new research…

15. Impaired skin epidermal barrier allergen penetration  IgE ALLERGIC MARCH Eczema severity Asthma Rhinitis (different type of allergy?) = 2 nd event…

16. Extrinsic versus intrinsic eczema IgE Altered skin barrier EXT INT AD

17. AD:  2 features severe allergy severity of AD Skin barrier features allergy The environment

18. The rising prevalence of atopic eczema and environmental trauma to the skin. Cork et al. Dermat Pract 2002, 10, 22. UK data1960 - 19811995 - 2001 Personal use of soap -detergent 76 million £453 million £ Water for personal washing 11 L /day51 L/day Increased skin barrier dysfunctions

19. Pathogenesis of AD SKIN BARRIER DYSFUNC TIONS ALLERGY genes environment ECZEMA

20. HYPOTHETIC MODEL OF AD PHASE 1: Non-allergic inflammation - ichtyosis – pruritus - auto-immunity (?) PHASE 2: Allergic inflammation - food (  through urticaria) - inhalants PHASE 3: Infectious inflammation - Staph colonization - Viral colonization early infancy early childhood late childhood adulthood

21. HYPOTHETIC MODEL OF AD PHASE 1: Non-allergic inflammation - ichtyosis – pruritus - auto-immunity (?) PHASE 2: Allergic inflammation - food (  through urticaria) - inhalants PHASE 3: Infectious inflammation - Staph colonization - Viral colonization early infancy early childhood late childhood adulthood moisturizing allergen avoidance antiseptics > antibiotics