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Immune deviation in atopic eczema is crucial

Immune deviation in atopic eczema is crucial. Johannes Ring, Kilian Eyerich, Stephan Weidinger, Ulf Darsow Klinik und Poliklinik für Dermatologie und Allergologie am Biederstein Technische Universität München, Munich, Bavaria, Germany GA2LEN Center of Excellence EU frame program

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Immune deviation in atopic eczema is crucial

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  1. Immune deviation in atopic eczema is crucial Johannes Ring, Kilian Eyerich, Stephan Weidinger, Ulf Darsow Klinik und Poliklinik für Dermatologie und Allergologie am Biederstein Technische Universität München, Munich, Bavaria, Germany GA2LEN Center of Excellence EU frame program Christine Kühne Center for Allergy Research and Education (CK-CARE) XXII World Allergy Congress (WAC) 4-8 december 2011, Cancun Mexico

  2. Suetonius, Vita Caesarum „catarrhus und Brustenge zur Zeit der Frühlingswinde....juckende Hautstellen, mit einem Instrument gekratzt...“ Enkel Claudius: Rhinonkonjunktivitis, Urgroßneffe Britannicus: Pferdeallergie (Ring, Hautarzt 1981)

  3. Imperator Octavian (Augustus) Aetius from Amida: „ekzema“ (ek zeo= aufkochen, 600 AD) Mercuriali: „Lactumen“ (like burnt mild in a pot) (1571) Willan: „Eczema“ (1808) Brocq, Jacquet: „Neurodermite“ (1892) Besnier: „Prurigo diathésique“ (1901) Coca, Cooke: „Atopy“ (1923) Wise, Sulzberger: „Atopic dermatitis/atopic eczema“ (1933) Schnyder, Borelli: „Neurodermitis constitutionalis sive atopica“ (1968) Atopic eczema/dermatitis syndrome AEDS (EAACI 2001) Eczema (WAO nomenclature 2004) Atopic Eczema: History

  4. “Atopy”=Familial tendency to develop certain diseases (asthma, rhinoconjunctivitis, atopic eczema) based on hypersensitivity of skin and mucous membranes against environmental substances together with increased IgE production and/or altered non-specific reactivity Ring J, Handbook of Atopic Eczema 1991

  5. WAO Task Force on Allergy Nomenclature: “Atopy” := Familial tendency to produce IgE immune response to low doses of allergensand to develop typical symptoms such asasthma, rhinoconjunctivitis or eczema (Johansson et al JACI 2004)

  6. 17.2% of childhood population in U.S. 15.6% prevalence in European children 24% prevalence in 56 year old Japanese children 6 –19 % in preschool children in Germany Atopic eczema: Prevalence Laughter et al. JAAD 2000;43:649 Schultz Larsen F, et al. JAAD 1996;34:760 Sugiura H, et al. Acta Derm Venereol 1998;78:293 Ring et al, Weißbuch Allergie in Deutschland 2004

  7. Hypothetical concepts to explain increase in prevalence of atopic diseases • Increased awareness and improved diagnostics • Psycho-social influences (acceleration of life) • Allergen exposure • Decreased stimulation of the immune system (“jungle” or “hygiene” hypothesis) • Underlying disease • Medication (eg antacids) • Environmental pollution (tobacco smoke, traffic exhaust) • Climate change

  8. The Farmhouse Story • Protective effect for respiratory atopy, hay fever, asthma and IgE-sensitization (Gassner, 1981, Braun-Fahrländer 1999, Riedler 2000, Ernst 2000, Downs 2001) • No protection for atopic eczema after birth (Braun-Fahrländer 1999, Riedler 2000, Kilpelainen 2000, von Ehrenstein 2000, Schäfer et al 2001, Ring et al 2006) • Protective influence, when mother was working in the stable during pregnancy (Roduit et al, 2011) Hygiene hypothesis does not work for atopic eczema, only for respiratory atopy!

  9. ETS: Atopic Eczema and Association to Urinary Cotinine/Creatinine Ratio MIRIAM – Study Augsburg 1996/1998 %Prevalence Atopic Eczema OR (95%CI) 6 8 Association to CCR per 100 ng/mg 6-8 years old children N=451 6 N=1132 4 N=673 4 2 2 1 0 Parents without Atopy Parents with Atopy total 0 Parents without Atopy Parents with Atopy total 6 yrs old children 6-8 years old children Krämer et al, Br J Dermatol (Dec) 2003

  10. Traffic exposure and Allergy: Own Studies MIRIAM Augsburg 1996 WIKA Study NRW 1991-1997 40 Sensibilisierung (RAST) gegen Pollen (Birke, Gras, Beifuß) Symptome einer allergischen Rhinitis 30 20 Traffic exposure study Düsseldorf 1996 Pollen- Sensibilisierung %-Anteil Mädchen mit 10 339 433 341 0 <4000 Kfz >4000 Kfz >10000 Kfz Verkehrsstärke

  11. Determinantsof Allergic Inflammation Genetic susceptibility adjuvant causative Adjuvant Factors: DEP, VOC, Ozone, ETS Allergen- exposure Lack of Protective Factors Allergic Sensitisation infection vaccination nutrition Hyperreactivity Airway / Skin Air Pollution Irritant Gases, ETSExercise Infection Allergic Diseases Behrendt, 2000

  12. Pathogenesis of atopic eczema Genetic background Environment Disturbed skin barrier Physical factors: Heat, sweating Psychosomatic influence Allergens/ Haptens, Irritants Immune deviation Microorganisms (Malassezia furfur, Staph. aureus) Disturbed barrier, elevated TEWL, Xerotis cutis Itch /scratch, hyperreactive Immune system Superinfection (Impetigo, Eczema herp.)

  13. Atopic eczema: diagnostic criteria • 1980 (Hanifin and Rajka): diagnostic criteria based on „major“ and „minor“ clinical features • 1994 (Williams et al): UK working party‘s diagnostic criteria • 1982 (Ring) quoted in „Allergy in practice“, Springer, Berlin 2005 • Diagnosis of atopic eczema • (4 out of 6 positive, Ring 1982) • Typical morphology (IE, L, P) and age – dependent localization • Early onset and chronic/relapsing course • Pruritus • Stigmata • Personal and/or family history of atopy • IgE-Sensitization (SPT or RAST)

  14. Atopic eczema Food allergy Asthma Rhinitis Atopic eczema is typically the first manifestation of atopy Incidence 0 5 10 15 Age (Years) IgE levels in blood Atopic eczema is (in most cases) the first manifestation of the atopic disposition

  15. Atopic eczema: Etiopathophysiology Genetic background Dry skin / defective barrier Microbial colonization Autonomic nervous system dysregulation Psychosomatic interaction Inflammation: Non-immune (irritant) Allergic DTH (Th1) Allergic atopic (Th2, IgE) Autoimmune (IgE against epidermal proteins)

  16. Allergens S.aureus HDM P P P P P P P P LC Th1 Th2 IL-13 IL-4 B Effects of epidermal barrier disturbance

  17. Asthma Atopic Eczema Rhinitis IgE Atopic Diseases and IgE Sensitization

  18. Increased serum total IgE Specific IgE-Antibodies against common environmental allergens Often positive Prick-Test-Reactions Tendency to microbial colonisation and infection Increased number and activation of eosinophile leukocytes in blood and tissue Decreased cellular (Th1) immunity („minimal cutaneous immunodeficiency“) Altered prevalence rates of contact allergies (allergen-specific?) Atopic Eczema: Immunological findings

  19. Individuals with a Th2 phenotype disease (such as atopic eczema or allergic asthma) are relatively protected against development of Th1 phenotype disease (such as diabetes mellitus, rheumatoid arthritis or psoriasis) Th1/Th2-Hypothesis

  20. CRH, GHRH TRH, LHRH Hypothalamus Pituitary FSH LH ACTH GH PRL TSH endorphins Adrenals Gonads corticol epinephine oestradiol testosterone Central and peripheral lymphoid organs and tissues Kuper CF et al, 2002 Psychoneuroimmunology Neuroendocrine System – Immune System Interactions

  21. Mechanisms of disturbed skin barrier function Abnormal lipid patterns (eg ceramides) Abnormal lipid synthesis and metabolism (eg sphingomyelinase, glucocerebrosidase) Increased protease activity (eg SCCE) Serin protease inhibitor defect (eg LEKTI 1) Structural mutations (eg filaggrin, hornerin?)

  22. Allergen uptake: Summary Epithelial alteration Transcytosis (Processing) Paracellular transit: Enhanced uptake Transcellular transport

  23. Atopy patch test (APT) Epicutaneous patch test with allergens known to elicit IgE-mediated reactions, for the provocation of eczematous skin lesions due to these allergensRing J et al. JACI 1989; 82: 195 House dust mite patch tests in atopic eczemaMitchell E et al. Lancet 1982; 1: 127-130 Aim: evaluation of the clinical relevance of (multiple) IgE-mediated sensitizations in patients with AE Controlled model for inflammation in AE

  24. Patients in remission phase Lyophilized aeroallergens (house dust mite, cat dander, grass and birch pollen) Allergen doses: 5.000-7.000 PNU/g or 200 IR/g Vehicle: petrolatum, Large Finn Chambers Application for 48 h on clinically uninvolved, not pretreated back skin (no tape stripping) Evaluation after 48 and 72 h (ETFAD key*), Exclusion of questionable reactions Atopy Patch Test (APT): method(European Task Force Atopic Dermatitis ETFAD) * Darsow, Ring. Clin Exp Dermatol 2000; 25: 544-551 / Allergo J 2001; 10: 201-209

  25. Atopie-Patch-Test: 48 h Control Grass pollen D. pter. Control Cat Allergen 200 IR/g in Vaselin

  26. APT in Europe

  27. Test Sensitivity Specificity SPT sIgE APTSPT sIgEAPT D. pter. 68%* 72%*45%50%* 53%*64% Cat dander 79%* 80%*14%71%* 69%*91% Grass pollen 80%* 84%* 28%*54%* 53%*91%* Birch pollen 69%* 73%* 15%57%* 52%*83% Referring to predictive history of eczema exacerbations in pollen season, or in direct contact with allergen, n = 314 * Agreement with history (2-sided Pr > |Z| < 0.01) Diagnostic methods for relevance of aeroallergen sensitization

  28. 0.3 0.2 0.2 150 0.1 0.1 extent of atopic eczema Number of grass pollen 100 mean deviations from individual means 0.0 0.0 -0.1 -0.1 50 Itch / -0.2 -0.2 0 -0.3 -0.3 May Jun Jul Aug 1999 1999 1999 1999

  29. Initiation Th 2 Chronification Th 1 Perpetuation Autoimmune Life of „atopic“ skin lesions

  30. Hom s 1 Hom s 2 Hom s 3 Hom s 4 Homologues SART-1 (Esophageal Ca. Ag) -NAC(nascent peptide associated complex) Bcl 7 b Calcium binding protein IgE-reactive Autoallergens in Human Epidermis

  31. Treatment of disturbed skin barrier Emollients, barrier – repairing agents Antiinflammatory treatment (topical) Corticosteroids Calcineurin inhibitors Antimicrobial treatment Phototherapy UVA-1 UVB PUVA Systemic Immunosuppressives Antihistamines Educational Programs Evidence-Based Treatment of Atopic Eczema Darsow et al JEADV 2009

  32. Guidelines for diagnosis and treatment of atopic eczema: EADV Eczema Task Force Darsow U et al. JEADV 2010; 24: 317-328

  33. Diagnosis Disease Elicitors/trigger factors (=allergy diagnosis) Severity Treatment Avoidance strategies Basic skin care (Emollients, oilbaths) Antipruriginous (wet wraps, antihistamines) Antiinflammatory (steroids, UV, topical immunomodulators) Antimicrobial (colourings, antiseptics, antibiotics) Psychosomatic counselling Atopic Eczema: Management

  34. Atopic eczema: Avoidance strategies Irritants (e.g. clothing) Aeroallergens (e.g. encasings) Food allergens, pseudoallergens (e.g. diet) Microbial antigens (superantigens) Climate therapy (high altitude, sea-level) Psychosomatic counselling

  35. Davos, Progress in Allergy, Dermatology and Immunology Congress 8 – 10 September 2012

  36. Acute antiinflammatory treatment Special treament of chronic lesions Identification of individual provocation factors (Allergy Diagnostics) and specific avoidance recommendations Atopic eczema management:3 Step Schedule

  37. Topical glucocorticosteroids in atopic eczema Hydrocortisone Fluocortinbutyl ester 17-Hydroxycortisone butyrate Prednicarbate Methylprednisolone aceponate Momethasone furoate In infected skin: combined with antiseptics or antibiotics

  38. Systemic Azathioprine Mycophenolate Mofetil Interferon Biologics (anti-IgE, anti-IL 5) Cyclosporin A Sirolimus Topical Calcineurin Inhibitors Tacrolimus Pimecrolimus Immunosuppressives / Immunomodulators

  39. Structure of eczema school • Six weekly meetings of 2 h each (eg Wednesday 19.00 – 21.00) • Group size maximum of 6 parents/children/adolescents • Interdisciplinary team consisting of Dermatologist / Pediatrician, Psychologist, Nurse, Nutrition expert

  40. Contents of Training Program "medical"clinical picture, etiology, pathophysiologyskin care/treatment: emollients, non-steroidal ointments, antibiotics, steroids, complications complementary therapiesprovocation factors and avoidance "psychosocial" self-perception, itching-scratching behaviour improvement of self-efficacy, adequate coping stress reduction, relaxation techniques social competence training "nutrition" adaequate nutrition in children diagnostic and therapeutic diets

  41. Block 130 h: Medizin, Psychologie, Pädagogik, Ernährung Block 210 h: Teilnahme an einer Schulung, eine Sitzung mit Supervision www.disa.de (allinfo, AG- Neurodermitis) "train the trainer"

  42. Concept of eczema school Active Coping Improved QoL Better skin condition Knowledge Behaviour Perception

  43. Interdisciplinary Teamwork TOPICAL AND SYSTEMIC TREATMENT IDENTIFICATION OF PROVO- CATION FACTORS Practical management dietician NUTRITION dermatologistpediatrician HABIT REVERSAL TECHNIQUES SELF- MANAGEMENT RELAXATION TECHNIQUES qualified nurse psychologist/ psycho-therapeutic medicine

  44. A = Avoidance strategies B = Basic antiinflammatory treatment C = Care (skin, airways) D = Direct symptom relief E = Empowerment of patient (Educational programs eg „Eczema school“) The A B C of patient management in allergy(Ring 2006)

  45. Talk more about desired effects than about side-effects Give hope Illustrate your message with real experience – even if only anecdotal Motivate patient to take own responsibility („you will be your own skin doctor“) Turn off the clock! Trust yourself and your suggestive power!

  46. Heidrun Behrendt Carsten Schmidt-Weber U. Darsow K. Brockow K. Eyerich J. Gutermuth M. Mempel M. Ollert F. Pfab C. Schnopp C. Traidl-Hoffmann S. Weidinger Thanks to

  47. 7th Georg Rajka International Symposium on Atopic Dermatitis, Moshi, Tansania 15 – 18 January 2012

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