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Therapeutic Implications of a Barrier-Based Pathogenesis of Atopic Dermatitis

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Abstract

Excessive Th2 cell signaling and IgE production play key roles in the pathogenesis of atopic dermatitis (AD). Yet, recent information suggests that the inflammation in AD instead is initiated by inherited insults to the barrier, including a strong association between mutations in FILAGGRIN and SPINK5 in Netherton syndrome, the latter of which provides an important clue that AD is provoked by excess serine protease activity. But acquired stressors to the barrier may also be required to initiate inflammation in AD, and in addition, microbial colonization by Staphylococcus aureus both amplifies inflammation, but also further stresses the barrier in AD. Therapeutic implications of these insights are as follows: While current therapy has been largely directed toward ameliorating Th2-mediated inflammation and/or pruritus, these therapies are fraught with short-term and potential long-term risks. In contrast, “barrier repair” therapy, with a ceramide-dominant triple-lipid mixture of stratum corneum lipids, is more logical, of proven efficacy, and it provides a far-improved safety profile.

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Notes

  1. Reductions in inflammation alone can, however, reduce TEWL due to the “vicious cycle” that is operative in AD (Elias et al. [70]).

  2. Data on file with Promius Pharma, Bridgewater, NJ, USA.

Abbreviations

AD:

Atopic dermatitis

AMP:

Antimicrobial peptides

Cer:

Ceramides

FLG:

Filaggrin

FFA:

Free fatty acids

hBD:

Human β-defensins

hCAP:

Human cathelicidin

IV:

Ichthyosis vulgaris

LB:

Lamellar bodies

LEKTI:

Lymphoepithelial Kazal-type inhibitor

NS:

Netherton syndrome

PAR2:

Plasminogen activator type 2 receptor

SP:

Serine protease

SC:

Stratum corneum

t-UCA:

Trans-urocanic acid

References

  1. Sugarman JL, Fluhr JW, Fowler AJ et al (2003) The objective severity assessment of atopic dermatitis score: an objective measure using permeability barrier function and stratum corneum hydration with computer-assisted estimates for extent of disease. Arch Dermatol 139:1417–1422

    Article  PubMed  Google Scholar 

  2. Seidenari S, Giusti G (1995) Objective assessment of the skin of children affected by atopic dermatitis: a study of pH, capacitance and TEWL in eczematous and clinically uninvolved skin. Acta Derm Venereol 75:429–433

    PubMed  CAS  Google Scholar 

  3. Proksch E, Folster-Holst R, Jensen JM (2006) Skin barrier function, epidermal proliferation and differentiation in eczema. J Dermatol Sci 43:159–169

    Article  PubMed  CAS  Google Scholar 

  4. Chamlin SL, Kao J, Frieden IJ et al (2002) Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: changes in barrier function provide a sensitive indicator of disease activity. J Am Acad Dermatol 47:198–208

    Article  PubMed  Google Scholar 

  5. Baker BS (2006) The role of microorganisms in atopic dermatitis. Clin Exp Immunol 144:1–9

    Article  PubMed  CAS  Google Scholar 

  6. Elias PM, Wood LC, Feingold KR (1999) Epidermal pathogenesis of inflammatory dermatoses. Am J Contact Dermat 10:119–126

    Article  PubMed  CAS  Google Scholar 

  7. Elias PM, Feingold KR (2001) Does the tail wag the dog? Role of the barrier in the pathogenesis of inflammatory dermatoses and therapeutic implications. Arch Dermatol 137:1079–1081

    PubMed  CAS  Google Scholar 

  8. Taieb A (1999) Hypothesis: from epidermal barrier dysfunction to atopic disorders. Contact Dermat 41:177–180

    Article  CAS  Google Scholar 

  9. Grimalt R, Mengeaud V, Cambazard F (2007) The steroid-sparing effect of an emollient therapy in infants with atopic dermatitis: a randomized controlled study. Dermatology 214:61–67

    Article  PubMed  CAS  Google Scholar 

  10. Elias PM (2005) Stratum corneum defensive functions: an integrated view. J Invest Dermatol 125:183–200

    PubMed  CAS  Google Scholar 

  11. Elias PM (2007) The skin barrier as an innate immune element. Sem Immunopath 29:3–14

    Article  Google Scholar 

  12. Denda M, Nakatani M, Ikeyama K, Tsutsumi M, Denda S (2007) Epidermal keratinocytes as the forefront of the sensory system. Exp Dermatol 16:157–161

    Article  PubMed  CAS  Google Scholar 

  13. Caubet C, Jonca N, Brattsand M et al (2004) Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7. J Invest Dermatol 122:1235–1244

    Article  PubMed  CAS  Google Scholar 

  14. Brattsand M, Stefansson K, Lundh C, Haasum Y, Egelrud T (2005) A proteolytic cascade of kallikreins in the stratum corneum. J Invest Dermatol 124:198–203

    Article  PubMed  CAS  Google Scholar 

  15. Braff MH, Di Nardo A, Gallo RL (2005) Keratinocytes store the antimicrobial peptide cathelicidin in lamellar bodies. J Invest Dermatol 124:394–400

    Article  PubMed  CAS  Google Scholar 

  16. Oren A, Ganz T, Liu L, Meerloo T (2003) In human epidermis, beta-defensin 2 is packaged in lamellar bodies. Exp Mol Pathol 74:180–182

    Article  PubMed  CAS  Google Scholar 

  17. Fallon PG, Sasaki T, Sandilands A et al (2009) A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nat Genet 41:602–608

    Article  PubMed  CAS  Google Scholar 

  18. Scharschmidt TC, Man MQ, Hatano Y et al (2009) Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens. J Allergy Clin Immunol 124:496–506, 506.e1–6

    Article  PubMed  CAS  Google Scholar 

  19. Schmuth M, Crumrine D, Presland RB et al (2005) Basis for the epidermal functional abnormalities in granular layer-absent (AGL) vs. -present (PGL) ichthyosis vulgaris. J Invest Dermatol 124:A72

    Google Scholar 

  20. Ohman H, Vahlquist A (1994) In vivo studies concerning a pH gradient in human stratum corneum and upper epidermis. Acta Derm Venereol 74:375–379

    PubMed  CAS  Google Scholar 

  21. Hachem JP, Man MQ, Crumrine D et al (2005) Sustained serine proteases activity by prolonged increase in pH leads to degradation of lipid processing enzymes and profound alterations of barrier function and stratum corneum integrity. J Invest Dermatol 125:510–520

    Article  PubMed  CAS  Google Scholar 

  22. Demerjian M, Hachem JP, Tschachler E et al (2008) Acute modulations in permeability barrier function regulate epidermal cornification: role of caspase-14 and the protease-activated receptor type 2. Am J Pathol 172:86–97

    Article  PubMed  CAS  Google Scholar 

  23. Briot A, Deraison C, Lacroix M et al (2009) Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J Exp Med 206:1135–1147

    Article  PubMed  CAS  Google Scholar 

  24. Irvine AD, McLean WH (2006) Breaking the (un)sound barrier: filaggrin is a major gene for atopic dermatitis. J Invest Dermatol 126:1200–1202

    Article  PubMed  CAS  Google Scholar 

  25. Hudson TJ (2006) Skin barrier function and allergic risk. Nat Genet 38:399–400

    Article  PubMed  CAS  Google Scholar 

  26. Fleckman P, Brumbaugh S (2002) Absence of the granular layer and keratohyalin define a morphologically distinct subset of individuals with ichthyosis vulgaris. Exp Dermatol 11:327–336

    Article  PubMed  Google Scholar 

  27. Howell MD, Kim BE, Gao P et al (2007) Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 120:150–155

    Article  PubMed  CAS  Google Scholar 

  28. Bieber T (2008) Atopic dermatitis. N Engl J Med 358:1483–1494

    Article  PubMed  CAS  Google Scholar 

  29. O'Regan GM, Sandilands A, McLean WH, Irvine AD (2008) Filaggrin in atopic dermatitis. J Allergy Clin Immunol 122:689–693

    Article  PubMed  CAS  Google Scholar 

  30. Sandilands A, Smith FJ, Irvine AD, McLean WH (2007) Filaggrin’s fuller figure: a glimpse into the genetic architecture of atopic dermatitis. J Invest Dermatol 127:1282–1284

    Article  PubMed  CAS  Google Scholar 

  31. Lynley AM, Dale BA (1983) The characterization of human epidermal filaggrin. A histidine-rich, keratin filament-aggregating protein. Biochim Biophys Acta 744:28–35

    Article  PubMed  CAS  Google Scholar 

  32. Harding CR, Scott IR (1983) Histidine-rich proteins (filaggrins): structural and functional heterogeneity during epidermal differentiation. J Mol Biol 170:651–673

    Article  PubMed  CAS  Google Scholar 

  33. Fleckman P, Dale BA, Holbrook KA (1985) Profilaggrin, a high-molecular-weight precursor of filaggrin in human epidermis and cultured keratinocytes. J Invest Dermatol 85:507–512

    Article  PubMed  CAS  Google Scholar 

  34. Takahashi M, Tezuka T, Katunuma N (1996) Filaggrin linker segment peptide and cystatin alpha are parts of a complex of the cornified envelope of epidermis. Arch Biochem Biophys 329:123–126

    Article  PubMed  CAS  Google Scholar 

  35. Steinert PM, Marekov LN (1995) The proteins elafin, filaggrin, keratin intermediate filaments, loricrin, and small proline-rich proteins 1 and 2 are isodipeptide cross-linked components of the human epidermal cornified cell envelope. J Biol Chem 270:17702–17711

    Article  PubMed  CAS  Google Scholar 

  36. Scott IR, Harding CR, Barrett JG (1982) Histidine-rich protein of the keratohyalin granules. Source of the free amino acids, urocanic acid and pyrrolidone carboxylic acid in the stratum corneum. Biochim Biophys Acta 719:110–117

    PubMed  CAS  Google Scholar 

  37. Rawlings AV, Scott IR, Harding CR, Bowser PA (1994) Stratum corneum moisturization at the molecular level. J Invest Dermatol 103:731–741

    Article  PubMed  CAS  Google Scholar 

  38. Scott IR, Harding CR (1986) Filaggrin breakdown to water binding compounds during development of the rat stratum corneum is controlled by the water activity of the environment. Dev Biol 115:84–92

    Article  PubMed  CAS  Google Scholar 

  39. Abe T, Ohkido M, Yamamoto K (1978) Studies on skin surface barrier functions:—skin surface lipids and transepidermal water loss in atopic skin during childhood. J Dermatol 5:223–229

    PubMed  CAS  Google Scholar 

  40. Werner Y, Lindberg M (1985) Transepidermal water loss in dry and clinically normal skin in patients with atopic dermatitis. Acta Derm Venereol 65:102–105

    PubMed  CAS  Google Scholar 

  41. Fartasch M, Diepgen TL (1992) The barrier function in atopic dry skin. Disturbance of membrane-coating granule exocytosis and formation of epidermal lipids? Acta Derm Venereol Suppl (Stockh) 176:26–31

    CAS  Google Scholar 

  42. Hubiche T, Ged C, Benard A et al (2007) Analysis of SPINK 5, KLK 7 and FLG genotypes in a French atopic dermatitis cohort. Acta Derm Venereol 87:499–505

    Article  PubMed  CAS  Google Scholar 

  43. Elias P, Williams M, Crumrine D, Schmuth M (2010) Disorders of cornification (the ichthyoses): key clinical features, biochemical genetics, cellular pathogenesis, and diagnostic ultrastructure. In: Current problems in dermatology. Karger, Basel, p 110

  44. Scharschmidt T, Hatano Y, Man M et al (2008) Mice with deficiency in epidermal filaggrin display heightened susceptibility to hapten-induced atopic dermatitis. J Instr Dev 128:S92

    Google Scholar 

  45. Krien P, Kermici M (2000) Evidence for the existence of a self-regulated enzymatic process within human stratum corneum—an unexpected role for urocanic acid. J Invest Dermatol 115:414–420

    Article  PubMed  CAS  Google Scholar 

  46. Sprecher E, Chavanas S, DiGiovanna JJ et al (2001) The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis. J Invest Dermatol 117:179–187

    Article  PubMed  CAS  Google Scholar 

  47. Nylander-Lundqvist E, Back O, Egelrud T (1996) IL-1 beta activation in human epidermis. J Immunol 157:1699–1704

    PubMed  CAS  Google Scholar 

  48. Elias PM (1996) Stratum corneum architecture, metabolic activity and interactivity with subjacent cell layers. Exp Dermatol 5:191–201

    Article  PubMed  CAS  Google Scholar 

  49. Roelandt T, Thys B, Heughebaert C et al (2009) LEKTI-1 in sickness and in health. Int J Cosmet Sci 31:247–254

    Article  PubMed  CAS  Google Scholar 

  50. Walley AJ, Chavanas S, Moffatt MF et al (2001) Gene polymorphism in Netherton and common atopic disease. Nat Genet 29:175–178

    Article  PubMed  CAS  Google Scholar 

  51. Vasilopoulos Y, Cork MJ, Murphy R et al (2004) Genetic association between an AACC insertion in the 3′UTR of the stratum corneum chymotryptic enzyme gene and atopic dermatitis. J Invest Dermatol 123:62–66

    Article  PubMed  CAS  Google Scholar 

  52. Weidinger S, Baurecht H, Wagenpfeil S et al (2008) Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk. J Allergy Clin Immunol 122(560–8):e4

    PubMed  Google Scholar 

  53. Hachem JP, Crumrine D, Fluhr J et al (2003) pH directly regulates epidermal permeability barrier homeostasis, and stratum corneum integrity/cohesion. J Invest Dermatol 121:345–353

    Article  PubMed  CAS  Google Scholar 

  54. Di Nardo A, Wertz P, Giannetti A, Seidenari S (1998) Ceramide and cholesterol composition of the skin of patients with atopic dermatitis. Acta Derm Venereol 78:27–30

    Article  PubMed  Google Scholar 

  55. Imokawa G, Abe A, Jin K et al (1991) Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin? J Invest Dermatol 96:523–526

    Article  PubMed  CAS  Google Scholar 

  56. Hachem JP, Wagberg F, Schmuth M et al (2006) Serine protease activity and residual LEKTI expression determine phenotype in Netherton syndrome. J Invest Dermatol 126:1609–1621

    Article  PubMed  CAS  Google Scholar 

  57. Hachem JP, Houben E, Crumrine D et al (2006) Serine protease signaling of epidermal permeability barrier homeostasis. J Invest Dermatol 126:2074–2086

    Article  PubMed  CAS  Google Scholar 

  58. Man MQ, Barish GD, Schmuth M et al (2008) Deficiency of PPARbeta/delta in the epidermis results in defective cutaneous permeability barrier homeostasis and increased inflammation. J Invest Dermatol 128:370–377

    Article  PubMed  CAS  Google Scholar 

  59. Sator PG, Schmidt JB, Honigsmann H (2003) Comparison of epidermal hydration and skin surface lipids in healthy individuals and in patients with atopic dermatitis. J Am Acad Dermatol 48:352–358

    Article  PubMed  Google Scholar 

  60. Schlievert PM, Case LC, Strandberg KL, Abrams BB, Leung DY (2008) Superantigen profile of Staphylococcus aureus isolates from patients with steroid-resistant atopic dermatitis. Clin Infect Dis 46:1562–1567

    Article  PubMed  Google Scholar 

  61. Lomholt H, Andersen KE, Kilian M (2005) Staphylococcus aureus clonal dynamics and virulence factors in children with atopic dermatitis. J Invest Dermatol 125:977–982

    Article  PubMed  CAS  Google Scholar 

  62. Wehner J, Neuber K (2001) Staphylococcus aureus enterotoxins induce histamine and leukotriene release in patients with atopic eczema. Br J Dermatol 145:302–305

    Article  PubMed  CAS  Google Scholar 

  63. Leung DY, Harbeck R, Bina P et al (1993) Presence of IgE antibodies to staphylococcal exotoxins on the skin of patients with atopic dermatitis. Evidence for a new group of allergens. J Clin Invest 92:1374–1380

    Article  PubMed  CAS  Google Scholar 

  64. Sonkoly E, Muller A, Lauerma AI et al (2006) IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol 117:411–417

    Article  PubMed  CAS  Google Scholar 

  65. Aberg KM, Man MQ, Gallo RL et al (2008) Co-regulation and interdependence of the mammalian epidermal permeability and antimicrobial barriers. J Invest Dermatol 128:917–925

    Article  PubMed  CAS  Google Scholar 

  66. Ong PY, Ohtake T, Brandt C et al (2002) Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 347:1151–1160

    Article  PubMed  CAS  Google Scholar 

  67. Miller SJ, Aly R, Shinefeld HR, Elias PM (1988) In vitro and in vivo antistaphylococcal activity of human stratum corneum lipids. Arch Dermatol 124:209–215

    Article  PubMed  CAS  Google Scholar 

  68. Bibel DJ, Aly R, Shinefield HR (1992) Antimicrobial activity of sphingosines. J Invest Dermatol 98:269–273

    Article  PubMed  CAS  Google Scholar 

  69. Nomura I, Goleva E, Howell MD et al (2003) Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J Immunol 171:3262–3269

    PubMed  CAS  Google Scholar 

  70. Elias PM, Hatano Y, Williams ML (2008) Basis for the barrier abnormality in atopic dermatitis: outside–inside–outside pathogenic mechanisms. J Allergy Clin Immunol 121:1337–1343

    Article  PubMed  CAS  Google Scholar 

  71. Elias PM, Steinhoff M (2008) “Outside-to-inside” (and now back to “outside”) pathogenic mechanisms in atopic dermatitis. J Invest Dermatol 128:1067–1070

    Article  PubMed  CAS  Google Scholar 

  72. Cork MJ, Danby SG, Vasilopoulos Y et al (2009) Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol 129:1892–1908

    Article  PubMed  CAS  Google Scholar 

  73. Cork MJ, Robinson DA, Vasilopoulos Y et al (2006) New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene–environment interactions. J Allergy Clin Immunol 118:3–21, quiz 22–3

    Article  PubMed  CAS  Google Scholar 

  74. Garg A, Chren MM, Sands LP et al (2001) Psychological stress perturbs epidermal permeability barrier homeostasis: implications for the pathogenesis of stress-associated skin disorders. Arch Dermatol 137:53–59

    PubMed  CAS  Google Scholar 

  75. Choi EH, Man MQ, Xu P et al (2007) Stratum corneum acidification is impaired in moderately aged human and murine skin. J Invest Dermatol 127:2847–2856

    Article  PubMed  CAS  Google Scholar 

  76. Choi EH, Demerjian M, Crumrine D et al (2006) Glucocorticoid blockade reverses psychological stress-induced abnormalities in epidermal structure and function. Am J Physiol Regul Integr Comp Physiol 291:R1657–R1662

    Article  PubMed  CAS  Google Scholar 

  77. Bisgaard H, Simpson A, Palmer CN et al (2008) Gene–environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure. PLoS Med 5:e131

    Article  PubMed  CAS  Google Scholar 

  78. Jeong SK, Kim HJ, Youm JK et al (2008) Mite and cockroach allergens activate protease-activated receptor 2 and delay epidermal permeability barrier recovery. J Invest Dermatol 128:1930–1939

    Article  PubMed  CAS  Google Scholar 

  79. Novak N, Baurecht H, Schafer T et al (2008) Loss-of-function mutations in the filaggrin gene and allergic contact sensitization to nickel. J Invest Dermatol 128:1430–1435

    Article  PubMed  CAS  Google Scholar 

  80. Kurahashi R, Hatano Y, Katagiri K (2008) IL-4 suppresses the recovery of cutaneous permeability barrier functions in vivo. J Invest Dermatol 128:1329–1331

    Article  PubMed  CAS  Google Scholar 

  81. Hatano Y, Terashi H, Arakawa S, Katagiri K (2005) Interleukin-4 suppresses the enhancement of ceramide synthesis and cutaneous permeability barrier functions induced by tumor necrosis factor-alpha and interferon-gamma in human epidermis. J Invest Dermatol 124:786–792

    Article  PubMed  CAS  Google Scholar 

  82. Altrichter S, Kriehuber E, Moser J et al (2008) Serum IgE autoantibodies target keratinocytes in patients with atopic dermatitis. J Invest Dermatol 128:2232–2239

    Article  PubMed  CAS  Google Scholar 

  83. Temeck J (2005) Protopic and Elidel presentation for FDA regulatory briefing on January 14, 2005

  84. Stern RS (2006) Topical calcineurin inhibitors labeling: putting the “box” in perspective. Arch Dermatol 142:1233–1235

    Article  PubMed  Google Scholar 

  85. Fleischer AB Jr (2006) Black box warning for topical calcineurin inhibitors and the death of common sense. Dermatol Online J 12:2

    PubMed  Google Scholar 

  86. Arellano FM, Wentworth CE, Arana A, Fernandez C, Paul CF (2007) Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis. J Invest Dermatol 127:808–816

    Article  PubMed  CAS  Google Scholar 

  87. Kameda G, Kramm C, Stege H et al (2003) Unexpected high serum levels of tacrolimus after a single topical application in an infant. J Pediatr 143:280

    PubMed  Google Scholar 

  88. Allen A, Siegfried E, Silverman R et al (2001) Significant absorption of topical tacrolimus in 3 patients with Netherton syndrome. Arch Dermatol 137:747–750

    PubMed  CAS  Google Scholar 

  89. Moskowitz DG, Fowler AJ, Heyman MB et al (2004) Pathophysiologic basis for growth failure in children with ichthyosis: an evaluation of cutaneous ultrastructure, epidermal permeability barrier function, and energy expenditure. J Pediatr 145:82–92

    Article  PubMed  CAS  Google Scholar 

  90. Paller AS, Eichenfield LF, Kirsner RS et al (2008) Three times weekly tacrolimus ointment reduces relapse in stabilized atopic dermatitis: a new paradigm for use. Pediatrics 122:e1210–e1218

    Article  PubMed  Google Scholar 

  91. Wahn U, Bos JD, Goodfield M et al (2002) Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children. Pediatrics 110:e2

    Article  PubMed  Google Scholar 

  92. Ehrchen J, Sunderkotter C, Luger T, Steinhoff M (2008) Calcineurin inhibitors for the treatment of atopic dermatitis. Expert Opin Pharmacother 9:3009–3023

    Article  PubMed  CAS  Google Scholar 

  93. Jain AB, Yee LD, Nalesnik MA et al (1998) Comparative incidence of de novo nonlymphoid malignancies after liver transplantation under tacrolimus using surveillance epidemiologic end result data. Transplantation 66:1193–1200

    Article  PubMed  CAS  Google Scholar 

  94. Hickey JR, Robson A, Barker JN, Smith CH (2005) Does topical tacrolimus induce lentigines in children with atopic dermatitis? A report of three cases. Br J Dermatol 152:152–154

    Article  PubMed  CAS  Google Scholar 

  95. Cook BA, Warshaw EM (2009) Role of topical calcineurin inhibitors in the treatment of seborrheic dermatitis: a review of pathophysiology, safety, and efficacy. Am J Clin Dermatol 10:103–118

    Article  PubMed  Google Scholar 

  96. Luger T, Paul C (2007) Potential new indications of topical calcineurin inhibitors. Dermatology 215(Suppl 1):45–54

    Article  PubMed  CAS  Google Scholar 

  97. Schachner LA, Lamerson C, Sheehan MP et al (2005) Tacrolimus ointment 0.03% is safe and effective for the treatment of mild to moderate atopic dermatitis in pediatric patients: results from a randomized, double-blind, vehicle-controlled study. Pediatrics 116:e334–e342

    Article  PubMed  Google Scholar 

  98. Paller A, Eichenfield LF, Leung DY, Stewart D, Appell M (2001) A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol 44:S47–S57

    PubMed  CAS  Google Scholar 

  99. Kim M, Jung M, Hong SP et al (2009) Topical calcineurin inhibitors compromise stratum corneum integrity, epidermal permeability and antimicrobial barrier function. Exp Dermatol 19:501–510

    Article  PubMed  CAS  Google Scholar 

  100. Rodriguez-Martin M, Hupe M, Man M, Naya J, Elias P (2009) Topical imiquimod and calcipotriol stimulate antimicrobial peptide expression in mouse epidermis. J Invest Dermatol 129:S72

    Google Scholar 

  101. Goksugur N, Ozbostanci B, Goksugur SB (2007) Molluscum contagiosum infection associated with pimecrolimus use in pityriasis alba. Pediatr Dermatol 24:E63–E65

    Article  PubMed  Google Scholar 

  102. Papp KA, Werfel T, Folster-Holst R et al (2005) Long-term control of atopic dermatitis with pimecrolimus cream 1% in infants and young children: a two-year study. J Am Acad Dermatol 52:240–246

    Article  PubMed  Google Scholar 

  103. Segura S, Romero D, Carrera C, Iranzo P, Estrach T (2005) Eczema herpeticum during treatment of atopic dermatitis with 1% pimecrolimus cream. Acta Derm Venereol 85:524–525

    PubMed  Google Scholar 

  104. Berger TG, Duvic M, Van Voorhees AS, VanBeek MJ, Frieden IJ (2006) The use of topical calcineurin inhibitors in dermatology: safety concerns. Report of the American Academy of Dermatology Association Task Force. J Am Acad Dermatol 54:818–823

    Article  PubMed  Google Scholar 

  105. Langley RG, Luger TA, Cork MJ, Schneider D, Paul C (2007) An update on the safety and tolerability of pimecrolimus cream 1%: evidence from clinical trials to post-marketing surveillance. Dermatology 215(Suppl 1):27–44

    Article  PubMed  CAS  Google Scholar 

  106. Kao JS, Fluhr JW, Man MQ et al (2003) Short-term glucocorticoid treatment compromises both permeability barrier homeostasis and stratum corneum integrity: inhibition of epidermal lipid synthesis accounts for functional abnormalities. J Invest Dermatol 120:456–464

    Article  PubMed  CAS  Google Scholar 

  107. Elias PM (2008) Barrier-repair therapy for atopic dermatitis: corrective lipid biochemical therapy. Exp Rev Dermatol 3:441–452

    Article  CAS  Google Scholar 

  108. Ong PY (2009) Emerging drugs for atopic dermatitis. Expert Opin Emerg Drugs 14:165–179

    Article  PubMed  CAS  Google Scholar 

  109. Voegeli R, Rawlings AV, Breternitz M et al (2009) Increased stratum corneum serine protease activity in acute eczematous atopic skin. Br J Dermatol 161:70–77

    Article  PubMed  CAS  Google Scholar 

  110. Elias PM, Schmuth M (2009) Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Opin Allergy Clin Immunol 9:437–446

    Article  PubMed  CAS  Google Scholar 

  111. Cork MJ, Britton J, Butler L et al (2003) 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. Br J Dermatol 149:582–589

    Article  PubMed  CAS  Google Scholar 

  112. Elias PM (2006) Epilogue: fixing the barrier—theory and rational deployment. In: Elias PM, Feingold KR (eds) Skin barrier. Taylor & Francis, New York, pp 591–600

    Google Scholar 

  113. Sugarman J, Parish L (2009) Efficacy of a lipid-based, barrier repair formulation in moderate-to-severe pediatric atopic dermatitis. J Drugs Dermatol 8:1106–1111

    PubMed  Google Scholar 

  114. Simpson E, Berry T, Tofte S, Hanifin JM, Eichenfield L (2008) EpiCeram for the treatment of mild-to-moderate atopic dermatitis—a pilot study. IID 2008 Kyoto, Japan

  115. Hatano Y, Man MQ, Uchida Y et al (2010) Murine atopic dermatitis responds to peroxisome proliferator-activated receptors alpha and beta/delta (but not gamma) and liver X receptor activators. J Allergy Clin Immunol 125(160–9):e1–e5

    PubMed  Google Scholar 

  116. Hatano Y, Man MQ, Uchida Y et al (2009) Maintenance of an acidic stratum corneum prevents emergence of murine atopic dermatitis. J Invest Dermatol 129:1824–1835

    Article  PubMed  CAS  Google Scholar 

  117. Galli SJ, Tsai M, Piliponsky AM (2008) The development of allergic inflammation. Nature 454:445–454

    Article  PubMed  CAS  Google Scholar 

  118. De Benedetto A, Qualia CM, Baroody FM, Beck LA (2008) Filaggrin expression in oral, nasal, and esophageal mucosa. J Invest Dermatol 128:1594–1597

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by NIH grants R01-AR019098 and R01-AI059311, DOD grant W81XWH-05-2-0094, and the Medical Research Service, Department of Veterans Affairs. Dr. Matthias Schmuth, Chairman, Department of Dermatology, Innsbruck Medical University, Innsbruck, Austria provided multiple insights that substantially improved the content of this manuscript.

Conflict of Interest Statement

Dr. Elias is a co-inventor of the optimal ratio, triple-lipid therapy for atopic dermatitis. He also is a consultant for Promius Pharma, LLC and Pediapharm, Inc., which market EpiCeram® in the USA and Canada, respectively.

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Authors and Affiliations

  1. Dermatology Service (190), Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA, 94121, USA

    Peter M. Elias & Joan S. Wakefield

  2. Department of Dermatology, University of California, San Francisco, CA, USA

    Peter M. Elias & Joan S. Wakefield

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  1. Peter M. Elias
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  2. Joan S. Wakefield
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Correspondence to Peter M. Elias.

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Elias, P.M., Wakefield, J.S. Therapeutic Implications of a Barrier-Based Pathogenesis of Atopic Dermatitis. Clinic Rev Allerg Immunol 41, 282–295 (2011). https://doi.org/10.1007/s12016-010-8231-1

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  • DOI: https://doi.org/10.1007/s12016-010-8231-1

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