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 20-30% • children under 2 y 15-20% • children under 14 y 15% • adults 2-10% • Atopic dermatitis usually starts early in life Onset usually between 3 and 6 months, 60% in the first year of life Early onset form Infancy1 85% of childhood onset occurs before 5 years of age 70% of childhood AD does not persist by 8 years of age Childhood2,3 Risk factors for persistence: later onset, gender (female), severity, atopic comorbidities, family history of atopy Sometimes AD occurs in adulthood Late onset form Adolescence3-5 Baby Crawling AD=atopic dermatitis 1. Eichenfeld LF, et al. J Am Acad Dermatol 2014;70(2):338-51; 2. Silverberg NB, Durán-McKinster C. Dermatol Clin 2017;35:351-63; 3. Kim JP, et al. J Am Acad Derm 2016;75:681-87 e11; 4. Wen HJ, et al. Br J Dermatol 2009;161(5):1166-72; 5. Mortz CG, et al. Allergy 2015;70(7):836-45 DS External Use Abbreviations AD=atopic dermatitis References 1.Eichenfeld LF, Tom WL, Chamlin SL, et al. Guidelines of care for the management of atopic dermatitis: Part 1: Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol 2014;70(2):338-51 (Page 4). 2.Silverberg NB, Durán-McKinster C. Special considerations for therapy of pediatric atopic dermatitis. Dermatol Clin 2017;35:351-63 (Page 1). 3.Kim JP, Chao LX, Simpson EL, et al. Persistence of atopic dermatitis (AD): A systematic review and meta-analysis. J Am Acad Dermatol 2016;75:681-87.e11 (Pages 1,4, and 5). 4.Wen HJ, Chen PC, Chiang TL, et al. Predicting risk for early infantile atopic dermatitis by hereditary and environmental factors. Br J Dermatol 2009;161(5):1166-72 (Page 1). 5.Mortz CG, Andersen KE, Dellgren C, et al. Atopic dermatitis from adolescence to adulthood in the TOACS cohort: prevalence, persistence and comorbidities. Allergy 2015;70(7):836-45 (Pages 1 and 8). 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: genetic predisposition 1) skin barrier dysfunction 2) abnormal immune activation environmental triggers: 1) irritant substances, allergens 2) stress 3) many others …. I. skin barrier dysfunction •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, loricrin, involucrin •Increased activity of serin proteases Mutation of key genes for structural epidermal proteins FLG OVOL1 SPINK5 ACTL9 COL29A1 LAMA3 CLDN1 Stratum corneum Stratum granulosum Stratum spinosum Stratum basale Adapted from © CFCF / https://commons.wikimedia.org/wiki/File:502_Layers_of_epidermis.jpg / CC BY 3.0 1. Hoffjan S & Stemmler S. Arch Dermatol Res 2015;307(8):659-70; 2. Esaki H et al. J Allergy Clin Immunol 2015;135(1):153-63; 3. Stemmler S et al. BMC Dermatol 2014;14:17; 4. Söderhäll C et al. PLoS Biol 2007;5(9):e242; 5. Yang T et al. Genes Dev 2004;18(19):2354-8; Lee B et al. Dev Cell 2014;29(1):47-58 DS External Use Key Points: •Many polymorphisms in both the innate and adaptive immune system. •Maternal genotype influences are independent of the child’s genotype. References: 1.Hoffjan S, Stemmler S. Unravelling the complex genetic background of atopic dermatitis: from genetic association results towards novel therapeutic strategies. Arch Dermatol Res 2015;307(8):659-70 2.Esaki H Ewald DA, Ungar B et al. Identification of novel immune and barrier genes in atopic dermatitis by means of laser capture microdissection. J Allergy Clin Immunol 2015;135(1):153-63 3.Stemmler S, Parwez Q, Petrasch-Parwez E et al. Association of variation in the LAMA3 gene, encoding the alpha-chain of laminin 5, with atopic dermatitis in a German case–control cohort. BMC Dermatol 2014;14:17 4.Söderhäll C, Marenholz I, Kerscher T et al. Variants in a Novel Epidermal Collagen Gene (COL29A1) Are Associated with Atopic Dermatitis. PLoS Biol 2007;5(9):e242 5.Yang T, Liang D, Koch PJ et al. Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5−/− mice. Genes Dev 2004;18(19):2354-8 6.Lee B, Villarreal-Ponce A, Fallahi M et al. Transcriptional mechanisms link epithelial plasticity to adhesion and differentiation of epidermal progenitor cells. Dev Cell 2014;29(1):47-58 Image Permission: Image redrawn – adapted from https://commons.wikimedia.org/wiki/File:502_Layers_of_epidermis.jpg This file is licensed under the Creative Commons Attribution 3.0 Unported license.You are free: to share – to copy, distribute and transmit the work to remix – to adapt the work Under the following conditions: attribution – You must attribute the work in the manner specified by the author or licensor (but not in any way that suggests that they endorse you or your use of the work). QC complete December 20, 2019. skin barrier disturbance •defective synthesis of ceramides • (in lamellar bodies in granular layer of epidermis) • ß • decreased ability to bind water in the skin • 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. Immune dysregulation •Ag IL-2 , IFNg • IgE Th1 chronic • IL-12 • FeεRI IL-12 Th17 • • LB • Th22 • kerat. TCR • MHCII IL-4, IL-13 • Ag • Th2 B-ly IgE • • • • • ILC2 IL-5 • IL-13 Eo MBP acute • • ECP • EDN Phenotypes of AD according to the activiation of Th cell populations 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 • Atopic march 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 Diagnosis according to Hanifin and Rajka (1980) Requires the presence of at least 3 basic features: ♦ •Pruritus •Typical morphology and distribution •Flexural lichenification or linearity in adults •Facial and extensor involvement in children •Chronic or chronically relapsing course •Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis) • Requires the presence of at least 3 minor features: •Keratoconus •Anterior subcapsular cataracts •Orbital darkening •Facial pallor/erythema •Pityriasis alba •Anterior neck folds •Itch when sweating •Intolerance to wool and lipid solvents •Perifollicular accentuation •Food intolerance •Course from environmental/emotional factors •White dermographism/delayed blanching • •Xerosis •Ichthyosis/palmar hyperlinearity/ keratosis pilaris •Immediate (type 1) skin test reactivity •Elevated serum IgE •Early age of onset •Tendency towards cutaneous infections (especially Staphylococcus aureus or herpes simplex) •Nonspecific hand or foot dermatitis •Nipple eczema •Cheilitis •Recurrent conjunctivitis •Dennie–Morgan infraorbital fold Atopic dermatitis diagnosis = ≥3 basic features + ≥3 minor features IgE=immunoglobulin E Hanifin JM, Rajka G. Acta Derm Venereol 1980;92 Suppl:44-7 DS Internal Use Abbreviations IgE=immunoglobulin E Reference Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh) 1980;92 Suppl:44-7 (Table II) Differential diagnoses to consider in adult patients with suspected severe AD AD=atopic dermatitis Simpson EL et al. J Am Acad Dermatol 2017;77(4):623-33 Condition Clinical features Contact dermatitis Atypical or localized distribution Severe, suberythrodermic psoriasis Less pruritus and lack of eczematous change such as oozing/crusting Severe seborrheic dermatitis Lack of pruritus with greasy scale in scalp Scabies infestation Inguinal, axillary, and genital papules Widespread tinea corporis Annular papulosquamous lesions without eczematous change Cutaneous T-cell lymphoma Lack of classic eczematous skin changes such as oozing and crusting DS External Use Reference: Simpson EL, Bruin-Weller M, Flohr C et al. When does atopic dermatitis warrant systemic therapy? Recommendations from an expert panel of the International Eczema Council. J Am Acad Dermatol 2017;77:623-33 (Table I). QC complete December 20, 2019. 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 Benefits vs. risks of topical corticosteroids in atopic dermatitis BENEFIT Large body of evidence on efficacy1: •Decreases acute and chronic signs of AD •Decrease in pruritus ♦ RISK Adverse events: •Skin atrophy •Telangiectasias (spider veins) •Ecchymosis (bruising) •Stretch marks •Hypertrichosis (excessive hair growth) •Rosacea-like dermatitis •Systemic effects (adrenal suppression) AD=atopic dermatitis 1. Eichenfield LF, et al. J Am Acad Dermatol 2014;71(1):116-32; 2. Wollenberg A, et al. J Eur Acad Dermatol Venereol 2018;32:657-82 DS External Use Lilly Disclaimer (Legal requirement): info on other treatments is for answering participant questions only Abbreviations AD=atopic dermatitis References 1.Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: Part 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol 2014;71(1):116-32 (pages 7 and 8). 2.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):657-82 (pages 670 and 671). 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 BENEFIT Demonstrated efficacy in short-term trials and up to 12 months: •Decreases in physician’s global evaluation scores •Decrease in percentage BSA involved •Decrease in patient-reported signs and symptoms of AD •No risk of skin atrophy ♦ RISK Adverse events: •Transient burning sensation at site of application •Their onset of action is slower than in TCS •Generalized cases of viral infections (eczema herpeticum and molluscatum) •Black box warning of rare case of malignancy (skin cancer and lymphoma – not proven later) • AD=atopic dermatitis; BSA=body surface area 1. Eichenfield LF, et al. J Am Acad Dermatol 2014;71(1):116-32; 2. Wollenberg A, et al. J Eur Acad Dermatol Venereol 2018;32:657-82 Benefits vs. risks of topical calcineurin inhibitors in atopic dermatitis DS External Use Lilly Disclaimer (Legal requirement): info on other treatments is for answering participant questions only Abbreviations AD=atopic dermatitis; BSA=body surface area References 1.Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: Part 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol 2014;71(1):116-32 (pages 7 and 8) 2.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):657-82 (pages 670 and 671) 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....) European treatment recommendations for adults with atopic dermatitis Severe SCORAD >50 or persistent AD Hospitalization, PUVA,a systemic immunosuppression: cyclosporine A,b short course of oral corticosteroids,b dupilumab,a,b MTX,c AZA,c MMFc; alitretinoina,c Baseline Basic therapy Education, emollients, bath oils, avoidance of clinically relevant allergens (encasings, if diagnosed by allergy tests) Mild SCORAD <25 or transient AD Reactive therapy with TCS (class IIb) or TCI,b,e antiseptics including silverb,e and silver-coated textilesa,e Moderate SCORAD 25–50 or recurrent AD Proactive therapy with topical tacrolimusb or TCS (class II or class IIIc), wet wrap therapy, UV therapy (UVB 311 nm,d medium-dose UVA1), psychosomatic counselling, climate therapy aLicensed indication; bOff-label use; cNarrow-band UVB; dTreatments with particular restrictions on use AD=atopic dermatitis; AZA=azathioprine; MMF=mycophenolate mofetil; MTX=methotrexate; PUVA=psoralen and ultraviolet A; SCORAD=SCORing Atopic Dermatits; TCI=topical calcineurin inhibitor; TCS=topical corticosteroids; UV=ultraviolet Wollenberg A, et al. J Eur Acad Dermatol Venereol 2018;32:657-82. DS External Use Baricitinib: An evolution in the treatment of atopic dermatitis. SlideSource, 28.10.2020 Abbreviations AD=atopic dermatitis; AZA=azathioprine; MMF=mycophenolate mofetil; MTX=methotrexate; PUVA=psoralen and ultraviolet A; SCORAD=SCORing Atopic Dermatits; TCI=topical calcineurin inhibitor; TCS=topical corticosteroids; UV=ultraviolet Key Points •Treatment recommendations were based on consensus achieved among the nominated members of the European interdisciplinary expert group •The recommendations include the following stipulations: •For every phase, additional therapeutic options should be considered •Add antiseptics/antibiotics in cases of superinfection •Consider compliance and diagnosis, if therapy has been insufficiently effective •Separate treatment recommendations were compiled for children with AD •Identifying individual trigger factors is crucial in the management of AD, and their avoidance allows longer phases of remission or total clearance of symptoms •It is important to differentiate between the genetic predisposition towards hypersensitive, dry skin with barrier dysfunction – largely corresponding to ichthyosis vulgaris – which cannot be ‘cured’, and the inflammatory skin lesions that can be treated and can disappear Reference 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;32:657-82 (Figure 1) New treatments of AD Reference u autora Dupilumab - mechanism of action 46 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 • JAK pathway in AD