What snewin atopicdermatitis. Dagmar Simon Universitätsklinik für Dermatologie, Inselspital, Universitätsspital Bern

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1 What snewin atopicdermatitis Dagmar Simon Universitätsklinik für Dermatologie, Inselspital, Universitätsspital Bern

2 Impairedskinbarrierand Th2 inflammation Environment CD4, CD8 IL-4 IL-5 IL-13 IFN-γ DC IgE B cells IgE Mast cells Eosinophils Epidermal barrier Skin inflammation

3 Impaired skin barrier: Filaggrin Loss-of-function mutations (R5 10X; 2282del4) associated with AD Filaggringene expression is modulated by AD inflammation (IL-4, IL-13, IL-25) Increased risk for development of sensitization allergens (cat, food (peanut), association AD and asthma) haptens(nickel) Palmer CNA et al; NatGenet 2006; 38: MorarN et al; J InvestDermatol 2007;127: Rogers AJ et al; JACI 2007;120: Howell MD et al. J Allergy Clin Immunol 2007;120: Novak N, Simon D; Allergy 2011.

4 Impaired skin barrier: Protease inhibitors Normal skin AD Protease inhibitors Protease inhibitors Proteases Proteases Polymorphisms with mis-sense function of SPINK5 gene coding serine protease inhibitor LEKTI associated with AD Cork M et al., J Invest Dermatol 2009;129:

5 Impaired skin barrier: Antimicrobial peptides β-defensins(hbd-1-4), cathelicidin(ll-37) 2 functions: AMPs permeabilize membrane of microbes, cell lysis Modulate immune function: recruit T cells, DC, monocytes, neutrophils induce cytokine and chemokine production by keratinocytes HBD-2, HBD-3, LL-37 are reduced in AD skin Th2 cytokines inhibit the expression of HBD-2, HBD-3 and LL-37 by keratinocytes Low expression of LL-37 predisposes for HSV (Eczema herpeticum) Howell MD et al; Clin Immunol 2006;121: Howell MD et al; J Invest Dermatol 2005;125: Menzies BE, Kenoyer A. Infect Immun 2005;73:

6 Restoringtheskinbarrier Emollients, ointments Enriched with moisturizers, lipids, ceramides Wetwraps Protease inhibitors: first clinical trials disappointing Vitamin D3 binds to vit.d responsive element on cathelicidin promotor production of cathelicidin 14 AE vs. placebo; cholecalciferol 4000IU/d, 21days Increase of cathelicidinexpression in AE skin Calcineurin inhibitors In vitro, pimecrolimusenhances production of cathelicidin, HBD2, HBD3 by keratinocytes Fölster-Holst R et al. Allergy 2010;65: Hata TR et al.; J Allergy Clin Immunol 2008;122: Büchau AS et al.; J Invest Dermatol 2008;128:

7 Exogenousfactors Environment Bacteria: Staphylococcus aureus Soap and detergents Exogenous proteases Corticosteroids

8 Staphylococcus aureus Colonization in 90% of skin lesions, also on non-lesional skin as risk factor for infection toxins with superantigenicproperties, activation and proliferation of T cells Produce lipoteichoicacid, stimulate epidermal cytokine gene expression Specific IgEto St. aureus mast cell degranulation, pruritus AD patients as potential reservoir of MRSA Bogunewicz M, Leung DM. J Allergy Clin Immunol 2010,125:4-13.

9 Soap and detergents Irritants, disturb acid ph(acidic mantle) Increase TEWL Emulsify skin surface lipids Further increaseof surfaceph in AD Activationof proteases followed by increased desquamation

10 House dustmites Exogenous proteases cleave adhesion proteins cause inflammation independent of IgE activate PAR2 on keratinocytes Altered expression of the protease inhibitor cystatin A, no inhibition of exogenous proteases Breakdown of barrier paves way to IgE sensitization

11 Corticosteroids The potential harm of CS TCS treated skin is thinner than untreated skin Increase TEWL Decrease amount of intercellular lipid lamellae Reduced number of membrane-coated granules in Stratum granulosum Induce expression of proteases (KKL7) CS damage skin barrier proinflammatory cytokines inflammation is suppressed by CS rebound after stopping CS

12 Avoidance of triggers Staph.aureus Antimicrobial intervention: disinfectants, bleach baths, silver, silk Cave: topical antibiotics vaccinations Syndets, oil bath HDM Reduce exposure, specific immunotherapy in allergic patients CS Short term therapy

13 Specificimmunotherapy HDM astriggerforae SIT (sc): 81 AE patientswithsensitizationtohdm 20, or SQ-U, weekly, 1 year Decrease of SCORAD, dose-dependent Use of topical corticosteroids reduced SLIT: SCORAD decreased>30% in 59% of patients Werfel T et al.; Allergy 2006;61: CadarioG et al.; CurrMed Res Opin2007; 23:

14 Inflammation: Th2 and beyond Skin inflammation DC IgE CD4, CD8 IL-4 IL-5 IL-13 IFN-γ Eosinophils B cells IgE Mast cells

15 AD inflammation MainlyT cells, bear skin homing factor (CLA) Expression of IL-4, IL-5, IL-13 in acute lesions Increased expression of FcεRI on epidermal DC Elevated IgE, sensitization to environmental allergens Severe AD and allergies/asthma associated with bacterial (St.aureus) and viral (eczema herpeticum) infections Sensitization through the skin

16 Proactive therapy non-lesional ADskin is inflamed to reduce AD exacerbations Fluticasone2x per week reduced risk to develop flare-ups (cream: 5.8; ointment 1.9) Tacrolimusointment 2x per week over 12 months reduced number of exacerbations (0.1 in adults, 0.03 in children) Berth-Jones J et al. Brit Med J 2003;326: Wollenberg A et al.; Allergy 2008;63: Thaci D et al.; Br J Dermatol 2008;159:

17 T reg and Th17cells T reg Numbers increased in AD, but Lose immunosuppressive activity after stimulation with St.aureus toxin (SEB) Th17 In acute lesions IL-17 secretion is enhanced upon SEB stimulation IL-17-induced AMP production is abolished by IL- 4, IL-13 Epicutaneoussensitization local and systemic Th17 response influx in airways: asthma

18 New cytokines IL-9 Th2 cytokine Enhances inflammation, infiltration of eosinophilsand mast cells, subepithelial fibrosis IL-21 Inflammation and scratching increase IL-21 expression in AD skin activation and migration of DC to lymph nodes sensitization to environmental allergens IL-22 downregulatesgenes coding proteins of epidermal differentiation complex barrier dysfunction remodelling

19 AD and itch IL-31 Cytokine produced by T cells, enhanced production upon SEB stimulation enhanced in AD skin Activates IL-31 receptor on primary sensory neurons in dorsal root ganglia H4 receptor Stimulation of H4 on T cells results in IL-31 release DC stimulated via H4, produce pro-inflammatory cytokines

20 New therapeutic approaches Epithelium Filaggrin Anti-IL-17 Blocking IL-21/IL-21R Specific Immunotherapy Th17 IL-17 Th22 IL-22 Th9 IL-21 IL-9 DC T reg IL-10 T cells IL-25 IL-5 TNF-α Th2 IL-13 B cells IgE Histamine IL-31 Neurons Eosinophils Mast cells Anti-IL-22 Anti-IL-9 Anti-CD20 Anti-IgE Blocking H4 receptor Blocking IL-31/IL-31R Makrophages Fibroblasts Simon D, Novak N. Allergy 2011

21 BiologicsforAD Alefacept: LFA-3/IgGfusion protein, inhibition of APC-T cell costimulation, apoptosis of T cells, effective in 2 pilot studies Rituximab: anti-cd20 Ab, depletion of B cells, no decrease of IgE, effective in pilot study Mepolizumab: anti-il-5 Ab, depletes eosinophils, slight effect Omalizumab: anti-ige Ab, controversial reports Simon et al.; J Allergy Clin Immunol 2008:122: Simon et al.; J Allergy Clin Immunol 2008;121: Oldhoff JM et al. Allergy 2005;60: , 2006;54: Belloni B et al.; J Allergy Clin Immunol 2007;120: Sheinkopf LE et al.; Allergy Asthma Proc 2008;29: Heil et al.; JDDG 2010;8:990-8.

22 Alitretinoin 9-cis retinoicacid, agonistof RAR and RXR 6 patientswithad treatedforchronichand eczema Improvement of palmar and extrapalmar lesions (>50% decreaseof SCORAD, mtlss, PGA after 12 weeks) Well tolerated, nodrynessof skin Grahovac M et al.; Br J Dermatol 2010;162:217.

23 AD and EoE AD frequently associated with allergic rhinitis and bronchial asthma eosinophilic esophagitis(eoe) EoE: symptoms: abdominal pain, heartburn, vomiting, dysphagia, food impaction, failure to thrive Prevalence: 23-55/ inhabitants IgE sensitization in >80% of EoE patients Associated allergies Children: egg, milk, wheat, soy, peanut Adults: pollen, pollen associated food allergens

24 Subgroups of AD Baseline therapy & anti-inflammatory therapy A + Skin barrier Skin barrier impairment impairment Bacterial/ Bacterial/ viral infections viral infections Allergic Allergic sensitizations sensitizations IgE IgE IgE-mediated IgE-mediated autoreactivity autoreactivity B cells Pruritus T cell B cells subtypes Pruritus T cell subtypes Patient selection FLG genotyping/ Raman spectroscopy TLR genotyping, history for EH, bacterial infections clinically relevant sensitisations Elevated serum IgE, concomitant asthma Autoantibodies (immunoblot), Patch testing, Proliferation assays Severe AD Anti-IL-9; IL-17 or IL-22 blocking antibodies ALL - Protection - Compensation of filaggrin deficit Restoration of AMPs Specific Immunotherapy Anti-IgE antibody Immuno suppressive therapy Anti-CD20 antibody Anti-IL-9; IL-17 or IL-22 blocking antibodies Blocking IL31/IL-31R, H4R antagonists Individualized therapy Simon D, Novak N. Allergy2011