Atopic dermatitis •strongly pruritic chronic or chronically relapsing non-infectious dermatitis with variable morphology and clinical course, usually starting during early childhood • •often associated with positive personal or family history of allergic rhinitis, conjunctivitis and bronchial asthma. •genetic predisposition •In about 80% associated with IgE levels • • Atopic dermatitis -epidemiology •Incidence in population: 0,5 - 5% •(higher incidence – scandinavian countries) • • infants 20% • children under 2 y 15% • children under 14 y 12% • adults 2-5% • Atopic dermatitis • two forms, same clinical picture • • extrinsic 80% elevated IgE • sensitization to airborne • and/or food allergens (sIgE) • - association with allergic • rhinoconjunctivitis and/or • allergic asthma • • • intrinsic 20% normal levels of IgE skin barrier disturbace Etiopathogenesis of AD: unknown genetic predisposition 1) skin barrier disturbance 2) hyperreactivity of the skin environmental triggers: 1) irritant substances, allergens 2) stress 3) many others …. I. skin barrier disturbance •Genetically conditioned: •Filaggrin: null mutation of FLG R501X and 2282del4 alleles lead to increased permeability of skin barrier and they are • associated with AD (in about 50% cases), as well as with ichtyosis vulgaris •Claudin- 1, corneodesmosin •Increased activity of serin proteases Genes involved in AD geny AE skin barrier disturbance •Defective synthesis of ceramides • (takes place in lamellar bodies in granular layer of epidermis) • ß • decreased ability to bind water in the skin • skin barrier disturbance AD and skin barrier •Defective structure and function of skin • barrier • Þ insufficient hydration (TEWL ) • ß • dryness - xerosis • ß • increased irritability of the skin • possibility of contact sensitization II: Immunological abnormalities in AD biphasic model of AD (Th2 à Th1 shift) •Ag IL-2 , IFNg • IgE Th1h1 48 h • IL-12 • FeεRI IL-12 • • LB • • TCR • MHCII IL-4, IL-13 • Ag • Th2 B-ly IgE • • • • • IL-5 MBP 24 h • • Eo ECP • EDN III. Staphyloccus aureus and AD •colonization of AD lesions in 74 - 96% atopic patients, 30 - 56% even on „healthy“ skin • •Mechanisms: •Defective skin barrier with „naked“ laminin and fibronectin • enables SA binding the skin • •Decreased defensive mechanisms:Ldefective signallization via • TLR 2 • ¯b2 defensine a kathelicidine • ¯ production of IFN g • •1) Toxic effect: staphylococcal exfoliatine a •2) Stimulation of sIgE production (sIgE à stimulation of basophils à histamine) •3) superantigens: SEA- SEE a TSST-1 • • • • - without previous processing by LC • - able to bridge V b chain of TC Receptor, • - not necessary exact conformity of all 5 • subunits of the receptor • 1000x stimulation • - non-specific but huge stimulation of Tly • (1 SA even 20% of circulating lymph.) • • Grafika2 Staphyloccus aureus and AD Triggering and mainaining factors of AD •Allergy ( house dust mites, pollen, pets, • molds, foods – milk, eggs, wheat, soya, nutts, fish) •Microbes – Staphylococcus aureus •Irritant substances (water,detergents etc.) •- climatic (temperature, wind, low humidity ..) •Psychological stress • Clinical picture of AD •AD in infants • •Exudative form – acute eczema •(oozing, crusting) • • ¨ location - periorally • - periorbitally • • ¨ possibility of spreading - erythroderma • • Atopic dermatitis – Infant AD Obrázek1a Infant AD Obrázek6 Obrázek5 Clinical picture of AD •AD in children and adolescents • •Decrease of exudation - lichenification • • ¨ most often – flexural eczema • - facial eczema • ¨ less often - erythroderma • Atopic dermatitis – flexural eczema Obrázek1b Obrázek1c Atopic dermatitis – erytrodermic form Obrázek Obrázek9 Obrázek10 Obrázek11 Clinical picture of AD •AD in adults •(about 15% of cases appear after puberty) • •head& neck •flexural •prurigininous •neurodermitic •erythrodermic • chronic course acute flares possible ~AUT0011 Adult AD – pruriginous form Obrázek12 Obrázek13 Obrázek14 Obrázek15 Adult AD – neurodermitic form Obrázek16 Obrázek17 Obrázek18 Adult AD – erythrodermic form Obrázek20 foto 70 008 AD in adults •¨ atypical forms - nummular, dyshidrotic, • hyperkeratotic forms • •¨ minimal forms - cheilitis sicca, stomatitis • angularis, pulpitis sicca, • intertrigo retroauricularis, aj. • Adult AD - dyshidrotic form Obrázek21 AD eyelid dermatitis, lip dermatitis Obrázek24 Obrázek25 Obrázek26 AD retroauricular dermatitis Obrázek27 Obrázek28 Complications of AD •¨ bacterial - impetiginization (St. aureus) •¨ viral – herpetication-HSV, warts, mollusca •¨ fungal (Tr. rubrum, Pityrosporum ovale) •¨ contact sensitization (nickel, fragrances, KS…) • • • • •¨ association: • alopecia areata • ichtyosis vulgaris • vitiligo 1-895a I~000023 Eczema atopicum herpeticatum Obrázek29 Obrázek30 Obrázek31 Obrázek32 Eczema atopicum – verrucae vulgares – warts Obrázek33 Obrázek34 Treatment of AD • mild form of AD (30-40% of patients): • education of pacient ( or parents) • identification of triggering factor • and their elimination • emmolients and baths • topical corticosteroids • pimecrolimus • antihistamines during flares Treatment of AD • mid-severe form of AD (40-50% of patients): • treatment similar as in mild form • + tacrolimus • or • hospitalization – lab. and clinical tests (triggers) • traditional topical treatment /tar/ • or • phototherapy (UVB 311nm, UVA-1) • • Tacrolimus (PROTOPIC oinment) Protopic 001 • Topical Immunomodulator • Blocks calcineurin • antiinflammatory • antipruritic • Long - term treatment • No skin atrophy Treatment of AD • severe form of AD (5-10% patients): • phototherapy (PUVA, UVA-1) • systemic corticosteroids (short courses) • imunosupressives: cyclosporine A, MMF, AZT,MTX • new therapies: i.v. Ig • JAK, PDE ihibitors • biologicals (dupilumab....) New treatments of AD Reference u autora Dupilumab - mechanism of action 39 human IgG4 class monoclonal antibody that specifically binds to the α subunit of the IL-4 and 13 receptors, thereby blocking the activation of protein kinases JAK 1 or 3 or TYK2 Dupilumab je lidská monoklonální protilátka třidy IgG4, která se specificky váže na podjednotku receptoru IL-4Ra a přerušuje signalizační kaskádu zprostředkovanou cytokiny IL-4 a IL-13. Vazba cytokinů IL-4 a IL-13 na jejich příslušné receptorové komplexy vede k aktivaci protein kináz JAK1 nebo JAK3 nebo Tyk2 a následně k fosforylaci transkripčního faktoru STAT6. Přípravek ovlivňuje úsek imunitní odpovědi proti parazitárním infekcím(helmintozý). Effect of dupilumab treatment •