6. The brick wall analogy of the stratum corneum of the epidermal barrier

7. New perspectives on epidermal barrier dysfunction in atopic dermatitis: Gene–environment interactions. Cork MJ JACI 2006; 118:3 . Serin leukoprotease inhibitor - (MastCell Chymase) “ mattone” “ mattone” malta

8. Corneodesmosomes are not only broken down by endogenous proteases . Once a flare of AD has been triggered, cells within the inflammatory infiltrate produce secondary proteases , which can also break down the skin barrier. The stratum corneum is also exposed to many exogenous proteases from the environment, such as Staphylococcus aureus and house dust mites. New perspectives on epidermal barrier dysfunction in atopic dermatitis: Gene–environment interactions. Cork MJ JACI 2006; 118:3 . Serin leukoprotease inhibitor - (MastCell Chymase)

9. New insights into the mechanism and management of allergic diseases: atopic dermatitis Novak Allergy 2009;64:265 The first level of the barrier is the mechanical skin barrier represented by the stratum corneum and the upper part of the skin. The second level of the skin barrier is represented by structures of the innate immune system such as pattern recognition receptors expressed by skin cells or antimicrobial peptides. The third level of the skin barrier is represented by the cellular defense of components of the adaptive immune system.

10. FLG EXPRESSION AND PUTATIVE FUNCTIONS IN THE SKIN BARRIER. O’Regan JACI 2008;122:689

11. Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/ American Academy of Allergy, Asthma and Immunology/ PRACTALL Consensus Report JACI 2006;118:152 Relative significance of exacerbating factors in patients with AD from infancy to adulthood. 2°y sIgE

13. TRIGGER FACTORS DRY SKIN IRRITANTS EMOTIONAL STRES ALLERGENS HEAT AND SWEATING INFECTIONS

15. Further Exploring the Brain–Skin Connection: Stress Worsens Dermatitis via Substance P-dependent Neurogenic Inflammation in Mice S Pavlovic J Invest Dermatol 2008;128:434

16. Further Exploring the Brain–Skin Connection: Stress Worsens Dermatitis via Substance P-dependent Neurogenic Inflammation in Mice S Pavlovic J Invest Dermatol 2008;128:434

17. Further Exploring the Brain–Skin Connection: Stress Worsens Dermatitis via Substance P-dependent Neurogenic Inflammation in Mice S Pavlovic J Invest Dermatol 2008;128:434

18. Further Exploring the Brain–Skin Connection: Stress Worsens Dermatitis via Substance P-dependent Neurogenic Inflammation in Mice S Pavlovic J Invest Dermatol 2008;128:434

21. RECOGNITION OF PATHOGENICALLY RELEVANT HOUSE DUST MITE HYPERSENSITIVITY IN ADULTS WITH ATOPIC DERMATITIS: A NEW APPROACH? Shah JACI 2002; 109: 1012 A ) Increased dermatitis after 4-days application of Dp solution to the left cubital fossa B ) no immediate response after the first application of control solution C ) Immediate contact urticaria after the first application of Dp allergen solution Type IV Type I A B C

22. Mite serine protease activates protease-activated receptor-2 and induces cytokine release in human keratinocytes Kato Allergy 2009;64:1366 Release of interleukin (IL)-8 ( A ) and granulocytemacrophage colony-stimulating factor (GM-CSF) ( B ) from primary human keratinocytes stimulated with whole mite culture (WCE) and rDer f

23. Mite serine protease activates protease-activated receptor-2 and induces cytokine release in human keratinocytes Kato Allergy 2009;64:1366 Release of interleukin (IL)-8 (A) and granulocytemacrophage colony-stimulating factor (GM-CSF) (B) from primary human keratinocytes stimulated with whole mite culture (WCE) and rDer f Protease activating receptor peptides

31. Superantigens are molecules which short-circuit the immune system , resulting in massive activation of T-cells rather than the usual, carefully controlled response to foreign antigens. It is believed that they do this by binding to both the variable region of the beta-chain of the T-cell receptor (V-beta) and to MHC II molecules, cross-linking them in a non-specific way. This results in polyclonal T-cell activation rather than the usual situation where only the few clones of T-cells responsive to a particular antigen presented by the MHC II molecule are activated. Schlievert JACI 2010;125:39

32. Model for the activation of CD41 T cells and macrophages by the superantigen (SAg) SEB compared with antigenic peptide activation of the same cells. Schlievert JACI 2010;125:39 Superantigens stimulate T-cell proliferation by forming a cross-bridge between certain variable parts of the b-chains of T-cell receptors (Vb-TCRs) and invariant regions on either or both of the a and b–chains of MHC II molecules on antigen-presenting cells

34. Skin from SEB patch test site showing positive staining of stratum corneum (open arrow) and deeper epidermis (solid arrow) , endothelium (small arrowhead), and perivascular areas (large arrowhead), with mAb to SEB. Control skin AD + SEB Application of Staphylococcal enterotoxin B (SEB) on normal and atopic skin induces up-regulation of T cells by a superantigen-mediated mechanism. Skov L, J Allergy Clin Immunol 2000;105:820-6.

35. SEB applied to healthy and atopic skin leads to clinical reactions and increased skinfold thickness SLS: Sodium lauryl sulfate SEB: Staphylococcal enterotoxin B Application of Staphylococcal enterotoxin B (SEB) on normal and atopic skin induces up-regulation of T cells by a superantigen-mediated mechanism. Skov L, J Allergy Clin Immunol 2000;105:820-6.

39. Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/ American Academy of Allergy, Asthma and Immunology/ PRACTALL Consensus Report JACI 2006;118:152 prevention

40. Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/ American Academy of Allergy, Asthma and Immunology/ PRACTALL Consensus Report JACI 2006;118:152 prevention ?

41. Differential In Situ Cytokine Gene Expression in Acute versus Chronic Atopic Dermatitis Hamid Q, J Clin Invest 1994;94:870-6. P<0.01 normal-appearing skin in patients with AD is not immunologically normal. IL-4 mRNA

47. Written action plans: Potential for improving outcomes in children with atopic dermatitis. Chisolm SS. J Am Acad Dermatol 2008;59:677 Envisoap Envioil Envicer3 Enviplus Idrocristalli Envicon pH=5.5

48. Written action plans: Potential for improving outcomes in children with atopic dermatitis. Chisolm SS. J Am Acad Dermatol 2008;59:677

49. WRITTEN ACTION PLANS: what is it? Bhogal S, Cochrane Database Syst Rev 2006;3:CD005306. ‘‘ . . .[a] written set of instructions given to patients/parents that: 1. was intended to stay in their hands until the next visit (thus excluding pharmacy prescriptions); 2. provided instructions for daily treatment ; 3. provided instructions for initiation/step-up treatment in the event of deterioration ; and 4. provided information regarding when to seek urgent medical consultation .’’

51. Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/ American Academy of Allergy, Asthma and Immunology/ PRACTALL Consensus Report JACI 2006;118:152 Basic treatment Basic therapy ofAD should comprise optimal skin care, addressing the skin barrier defect with regular use of emollients and skin hydration , along with identification and avoidance of specific and nonspecific trigger factors . Mild syndets with an adjusted pH value (acidified to pH 5.5-6.0 in order to protect the acid mantle of the skin) should be used for cleansing. Regular medical supervision , together with education of the patient or care providers and appropriate psychosocial support , is needed.

54. Dosage: fingertip unit

55. Comparison of parent knowledge, therapy utilization and severity of atopic eczema before and after explanation and demonstration of topical therapies by a specialist dermatology nurse M.J.CORK, Br J Dermatol 2003; 149: 582 The mean quantity (g) of emollient cream ⁄ ointment being used per week reported at each clinic visit plotted against the mean investigator’s assessment of severity of the eczema using the six area, six sign atopic dermatitis severity score (SASSAD) at each visit. 54 g weekly 426 g weekly * * * * * * * * * *

56. Comparison of parent knowledge, therapy utilization and severity of atopic eczema before and after explanation and demonstration of topical therapies by a specialist dermatology nurse M.J.CORK, Br J Dermatol 2003; 149: 582 % children whose eczema was controlled (six area, six sign atopic dermatitis severity score, SASSAD <5) with emollients alone at each clinic visit. SASSAD at each clinic visit, for every patient entered into the study plotted against the amount of emollient cream ⁄ ointment (g) being used per week .

63. Dermal Hyaluronan Is Rapidly Reduced by Topical Treatment with Glucocorticoids C Gebhardt J Invest Dermatol 2009;129:1892 Dexamethasone reduces the dermal HA content in vivo. Immunohistochemical staining of Hyaluronan (HA) in human skin treated with 0.1% dexamethasone ointment three times daily (b) or left untreated (a) from the same individual and from a similar location. untreated 0.1% dexamethasone

64. Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/ American Academy of Allergy, Asthma and Immunology/ PRACTALL Consensus Report JACI 2006;118:152 Topical treatment: Topical glucocorticosteroids. To avoid steroid overuse and steroid-related side effects “… during acute flares, steroids should be used in combination with baseline emollient skin care…” ( ‘‘Water-in-oil’’ )

67. Classes of Topical Corticosteroids Class 1: Superpotent Corticosteroids: These are used in chronic inflammation of the skin where the skin is thickened ( lichenified ), pigmented and/or thick scaled. A few examples of superpotent steroids are clobetasole propionate and halobetasole propionate. Indications of superpotent steroids include neurodermatitis, thick scaled psoriasis etc. Class 2: Potent Corticosteroids: These are used in chronic inflammation where the thickness, pigmentation or scales are less than the above lesions. Examples of potent steroids are betamethasone dipropionate , halcinonide , fluocinonide . Indications of potent steroids are: lichen planus, neurodermatitis, moderately severe psoriasis vulgaris, chronic eczema etc.

68. Classes of Topical Corticosteroids Class 3: Upper Mid-Strength Corticosteroids: These are used in sub acute inflammation of the skin. Examples of upper mid-strength steroids are betamethasone valerate and fluticasone propionate . Uses in sub acute dermatitis, infective eczema, psoriasis, severe seborrheic dermatitis etc. Class 4: Mid-Strength Corticosteroids: These are used in sub acute and acute inflammation of the skin. Examples of mid-strength steroids are mometasone furoate , fluocinolone acetonide 0.025% , and triamcinolone acetonide . Uses in sub acute dermatitis, infective eczema, moderately severe seborrheic dermatitis, psoriasis, atopic dermatitis, alopecia areata etc.

69. Classes of Topical Corticosteroids Class 5: Lower Mid-Strength Corticosteroids: These are used in sub acute and acute inflammation of the skin. Examples of lower mid-strength corticosteroids are hydrocortisone butyrate , fluticasone propionate . Uses in infective eczema, seborrheic dermatitis, mild psoriasis etc. Class 6: Mild Corticosteroids: These are used in acute and sub acute inflammation of the skin. Examples of mild corticosteroids are desonide , fluocinolone 0.01%, clobetasone. Uses in sub acute and acute dermatitis, mild seborrheic dermatitis etc. Class 7: Least Potent Corticosteroids: These are used in mild acute and sub acute inflammation of the skin. Steroid responsive skin diseases of the face, flexures, and napkin area have to be treated with this class of topical steroids to avoid damage to the skin. Example of least potent steroids is hydrocortisone 1%.

70. Potenza degli steroidi topici Abbreviazioni: c:crema, p=pomata, u=unguento, lp= lipocrema, l= lozione, e= emulsione, s=soluzione, sch= schiuma, g= gel STEROIDI TOPICI MOLTO POTENTI (GRADO II) Alcinonide 0,1% c. Halciderm Amcinonide 0,1% p. Amcinil Betametasone dipropionato 0,05% u c Diprosone; Betamesol; Betametasone dipropionato Diflucortolone valerato 0,3% c. p. u. Nerisona forte, Temetex forte, Cortical, Dervin Fluocinonide 0,05% p. g. l. Flu 21, Topsyn STEROIDI TOPICI SUPERPOTENTI (GRADO I) Clobetasolo propionato 0,05% p. u. s. sch. Clobesol; Olux sch

71. STEROIDI TOPICI POTENTI B (GRADO IV) Alclometasone dipropionato 0,1% c. u. l. Legederm Beclometasone dipropionato 0,025% c. Menaderm simplex; Beclometasone Doc Betametasone benzoato o,1% c. l. g. Beben Budesonide 0,025 c. u. Bidien; Preferid STEROIDI TOPICI POTENTI A (GRADO III) Betametasone dipropionato 0,05% c. u. s. Diprosone, Betamesol, Betanesone dipropionato Sandoz Betametasone valerato 0,1% c. u. e. s. Ecoval 70, Bettamousse, Betesil cerotti Desossimetasone 0,025% e. Flubason Diflucortolone valerato 0,1% c. u. s. Nerisona, Temetex, Dermaval, Cortical 0,2, Flu-cortanest Fluticasone propionato 0,05% c.; 0,005% u. Flixoderm crema e unguento Metilprednisolone aceponato 0,1% c. u .s. Advantan, Avancort Mometasone furoato 0,1% c. u .s. Altosone, Elocon

72. STEROIDI TOPICI DI POTENZA MINIMA A (GRADO VI) Clobetasone butirrato 0,05% c. Eumovate Fluocinolone acetonide 0,01% glicole Localyn glicole Fluocortin butilestere 0,02% c. p. Vaspit STEROIDI TOPICI DI POTENZA MINIMA B (GRADO VII) Idrocortisone da 0,05 a 1% c. p. Lenirit; Dermocortal; Cortidro; Dermadex c Fluocinolone acetonide 0,01% glicole Localyn glicole Fluocortin butilestere 0,02% c. p. Vaspit Desametasone 0,2% c. u. Dermadex; Soldesam Flumetasone Solo in associazione Metiprednisolone Solo in associazione STEROIDI TOPICI DI MEDIA POTENZA (GRADO V) Betametasone benzoato 0,025% c. Beben crema dermica Betametasone valeroacetato 0,05% p. u. l. Beta 21 Desonide 0,05% c. e. l. Sterades; Reticus Idrocortisone butirrato 0,1% c. p. l. e. Locoidon Fluocinolone acetonide 0,025% p.l. c. Localyn; Fluocit; Fluovitef; Omniderm; Sterolone; Ultraderm; Boniderma; Dermolin; Fluvean Triamcitolone Acetonide 0,1% c Ledercort A10

75. Randomised controlled trial of short bursts of a potent topical corticosteroid versus prolonged use of a mild preparation for children with mild or moderate atopic eczema Thomas K S BMJ 2002;324:1–7 Outcome measures of children with mild to moderate atopic eczema treated with short bursts of a potent topical corticosteroid (potent arm) or continuous use of a mild preparation (mild arm).

78. Twice weekly fluticasone propionate added to emollient maintenance treatment to reduce risk of relapse in atopic dermatitis: randomised, double blind, parallel group study. Berth-Jones J, BMJ 2003;326:1367. Kaplan-Meier plot showing the probability of remaining free from relapse during the 16 week maintenance phase.

80. Reduction of relapses of atopic dermatitis with methylprednisolone aceponate cream twice weekly in addition to maintenance treatment with emollient: a multicentre, randomized, double-blind, controlled study. Peserico A, Br J Dermatol 2008;158:801-7.

81. Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment. Wollenberg Allergy2008;63:742.

82. Intermittent therapy for flare prevention and long-term disease control instabilized atopic dermatitis: a randomized comparison of 3-times-weekly applications of tacrolimus ointment versus vehicle. Breneman D, J Am Acad Dermatol 2008;58:990-9.

84. Three times weekly tacrolimus ointment reduces relapse in stabilized atopic dermatitis: a new paradigm for use. Paller AS, Pediatrics 2008;122:e1210-8.

85. Three times weekly tacrolimus ointment reduces relapse in stabilized atopic dermatitis: a new paradigm for use. Paller AS, Pediatrics 2008;122:e1210-8. % patients who achieved clear or almost clear status (Phase I).

86. Three times weekly tacrolimus ointment reduces relapse in stabilized atopic dermatitis: a new paradigm for use. Paller AS, Pediatrics 2008;122:e1210-8. Kaplan-Meier plot of the probability of remaining free from relapse. The median time to first relapse was 116 days for tacrolimus versus 31 days for vehicle ( P=0.04 ).

90. Different effects of pimecrolimus and betamethasone on the skin barrier in patients with atopic dermatitis Jensen JACI 2009;123: 1124 Proliferation rate and epidermal thickness.

103. Treatment of patients with atopic dermatitis using wet-wrap dressings with diluted steroids and/or emollients. An expert panel’s opinion and review of the literature Oranje AP, JEADV 2006,20:1277 Wet-wrap treatment in children with atopic dermatitis Oranje and coworkers (unpublished data) observed an initial impressive improvement after 3 to 7 days, but after 4 weeks worsening and stabilizing of AD to mild to moderate severity was observed. We call this the ‘broken stick effect’

124. MgCl salt Skin barrier Skin hydration Inflammation Allantoin Hydration Skin barrier Repair Urea A Skin hydration NaCl salt urea’s effects Loden,ActaDermVen.2002;82:45 Thornfeldt,DermSurg.2005;31:873 Proksch,IntJDerm.2005;44:151 Hagstromer,SkinPhaApSkinPhy.2001;14:27 Bathing in a complementary salt solution S.aureus attachment Akiyama J Dermat Sci 1998;16:216

130. Antibiotics for the allergist La Shell Ann Allergy Asthma Immunol 2009;102:1 Silver also has antimicrobial properties, and the use of silver-coated textiles has been associated with reduced S aureus colonization and AD severity as well. Gauger A, J Eur Acad Dermatol Venereol. 2006;20:534 –541.

147. The case for steroid–antibiotic combinations. Leyden JJ, Br J Dermatol. 1977;96:179 –187.

158. A child with AD superinfected with toxin-secreting Staphylococcus aureus. Colonization by toxin-secreting S aureus can induce secretion of IL-31 and exacerbate pruritus and inflammation .

159. Nearly all patients with AD may be colonized with S aureus . This is likely the result of a combination of host factors including skin barrier dysfunction as well as impaired host immune responses in AD.