外用皮質類固醇常見的副作用有皮膚萎縮及微細血管擴張。皮膚經長時間使用外用皮質類固醇，在停止使用後，有時會造成皮膚炎的反彈現象--出現發紅、脫皮、及皮膚乾燥。臨床上這種在停用外用皮質類固醇後出現皮膚炎的惡化現象，稱為「戒斷性皮膚炎」。 戒斷性皮膚炎其機轉仍未被研究透徹。有的假說認為是不平衡的一氧化氮造成血管的代償性擴張，或是滲透性和抗菌性皮膚屏障功能不佳所致。雖然外用皮質類固醇可以改善發炎，但同時也造成皮膚屏障功能的破壞，此時脆弱的皮膚容易導致炎症的發生。外用皮質類固醇的使用時，無論是短期使用或長期使用，都會對形成屏障功能的過程出現明顯的干擾：例如影響去氧核醣核酸的形成、細胞分裂速率、脂質形成、角質細胞分化、膜狀體形成，進而導致滲透性皮膚屏障功能的缺失及角質層含水量的減少，此現象尤其在使用中效及強效的外用皮質類固醇時更常發生。本論文我們研究：不論原先皮膚疾病為何，皮膚經長期使用外用皮質類固醇後，停用所引起的戒斷性皮膚炎。我們認為屏障修復治療可以預防經長期外用皮質類固醇的皮膚在停用後，其戒斷性皮膚炎的發生。此屏障修復治療的原理不單只是保濕作用，而是皮膚角質層同時也提供其他包括抗菌在內的防護能力。此研究我們同時探討外用抗組織胺可以有效改善皮膚炎，其不僅促進表皮的分化及增生，也有利於角質層細胞間脂質膜狀層的形成。由此外用抗組織胺可作為長期外用皮質類固醇停用後，所引起的戒斷性皮膚炎的屏障修復治療的良好選項。在本論文中以小鼠實驗模式，我們證實了(1)皮膚經過長時間外用皮質類固醇，停用後所產生的皮膚屏障功能異常及角質細胞衍生的細胞因子聯續反應；(2)抗組織胺拮抗劑具有抗炎效用及促進表皮屏障功能；(3) cimetidine(抗組織胺第二型受體拮抗劑)透過影響皮膚屏障功能的不同層面(機械屏障、滲透屏障、抗菌屏障)，可以避免皮質類固醇所引起的戒斷性皮膚炎。我的研究結果提供了未來在臨床治療及預防皮質類固醇所引起的戒斷性皮膚炎的嶄新的治療面向。

Skin atrophy and telangiectasia are common side effects of topical corticosteroid (TCS). Rebound flare of dermatitis or hypersensitive skin often occurs after the cessation of TCS of long term use, resulting in a rapidly evolving complex with intense redness, scaling, and dryness of skin. Withdrawal dermatitis (WD) clinically appears sometimes as the dermatitis which flares after discontinuation of TCS. The mechanism of this specific WD remains not yet fully investigated. Some hypotheses include compensatory vessel dilation induced by unbalanced nitric oxide or negative effects on the skin barrier including permeability and antimicrobial functions. Although TCS can improve the inflammation, but it has been shown that TCS also impairs skin barrier function and could affect the evolution of these dermatoses, making skin more vulnerable to a new inflammatory flare. TCS use, both short-term and long-term, profoundly interferes with barrier maturation processes (for examples, DNA synthesis, mitotic rate, lipid synthesis, keratinocyte differentiation, and lamellar body formation), thereby resulting in permeability barrier disruption and decreases in water content of the stratum corneum (SC), especially with mid- or high-strength TCSs. Here we investigated the WD resulted from cessation of long term application of TCS, regardless of the original dermatoses. We proposed that barrier repair therapy might prevent the WD resulting from cessation of long-term application of TCSs. The rationale for barrier repair therapy goes beyond trapping moisture and preventing dry skin because of the numerous protective functions of SC, including its antimicrobial function. Here we revealed that topical antihistamines can improve contact dermatitis effectively; not only topical antihistamines can enhance epidermal differentiation and proliferation, but also it can facilitate the formation of intercellular lipid bilayers in the SC. Therefore, topical antihistamines can be one of the good candidate of barrier therapies for WD induced by TCSs. In my thesis, we demonstrated that (1) the barrier abnormalities and keratinocyte-derived cytokine cascade develop after discontinuation of TCS in long-term treatments in skin, using murine models; (2) topical application of antihistamine receptor antagonist possesses anti-inflammatory effects as well as enhances epidermal barrier functions in murine models; (3) cimetidine can prevent WD of TCSs from several different aspects of skin barrier (mechanical barrier, permeability barrier, antimicrobial barrier) in murine models. My results provide an evident basis for topical cimetidine as the new aspect of therapies for WD of TCSs in human which can be further studied in the future.

Aberg KM, Radek KA, Choi EH, Kim DK, Demerjian M, Hupe M, Kerbleski J, Gallo RL, Ganz T, Mauro T, Feingold KR, Elias PM. 2007. Psychological stress downregulates epidermal antimicrobial peptide expression and increases severity of cutaneous infections in mice. J Clin Invest 117(11):3339–3349.
Ahn SK, Bak HN, Park BD, Kim YH, Youm JK, Choi EH, Hong SP, Lee SH. Effects of a multilamellar emulsion on glucocorticoid-induced epidermal atrophy and barrier impairment. J Dermatol 33(2):80-90.
Ashida Y, Denda M, Hirao T. 2001. Histamine H1 and H2 receptor antagonists accelerate skin barrier repair and prevent epidermal hyperplasia induced by barrier disruption in a dry environment. J Invest Dermatol 116(2):261–5.
Bäumer W, Stahl J, Sander K, Petersen LJ, Paps J, Stark H, Kietzmann M, Olivry T. 2011. Lack of preventing effect of systemically and topically administered histamine H(1) or H(4) receptor antagonists in a dog model of acute atopic dermatitis. Exp Dermatol 20(7):577–81.
Belsito DV, Kerdel FA, Potozkin J, Soter NA. 1990. Cimetidine-induced augmentation of allergic contact hypersensitivity reactions in mice. J Invest Dermatol 94(4):441–5.
Björnberg A. 1982. Erythema craquelé provoked by corticosteroids on normal skin. Acta Derm Venereol 62(2):147-51.
Brattsand M, Stefansson K, Lundh C, Haasum Y, Egelrud T. 2005. A proteolytic cascade of kallikreins in the stratum corneum. J Invest Dermatol 124(1):198–203.
Braff MH, Hawkins MA, Di Nardo A, Lopez-Garcia B, Howell MD, Wong C, Lin K, Streib JE, Dorschner R, Leung DY, Gallo RL. 2005. Structure-function relationships among human cathelicidin peptides: dissociation of antimicrobial properties from host immunostimulatory activities. J Immunol 174(7):4271–4278.
Brenner M, Hearing VJ. 2008. The protective role of melanin against UV damage in human skin. Photochem Photobiol 84(3):539–49.
Buddenkotte J, Maurer M, Steinhoff M. 2010. Histamine and antihistamines in atopic dermatitis. Adv Exp Med Biol 709:73–80.
Caubet C, Jonca N, Brattsand M, Guerrin M, Bernard D, Schmidt R, Egelrud T, Simon M, Serre G. 2004. Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7. J. Invest Dermatol 122(5):1235-1244.
Chapman SJ, Walsh A. 1990. Desmosomes, corneosomes and desquamation. An ultrastructural study of adult pig epidermis. Arch Dermatol Res 282(5):304–10.
Chapman KE, Coutinho AE, Zhang Z, Kipari T, Savill JS, Seckl JR. 2013. Changing glucocorticoid action: 11b-hydroxysteroid dehydrogenase type 1 in acute and chronic inflammation. J Steroid Biochem Mol Biol 137:82-92.
Chen H, Toh TK, Szeverenyi I, Ong RT, Theng CT, McLean WH, Seielstad M, Lane EB. 2009. Association of skin barrier genes within the PSORS4 locus is enriched in Singaporean Chinese with early-onset psoriasis. J Invest Dermatol 129(3):606–14.
Chen W, Liao CY, Hung CL, Lin TK, Sheu HM, Zouboulis CC. 2006. Potent corticosteroids inhibit lipogenesis in sebaceous glands. Dermatology 213(3):264-5.
Chu CY. 2005. The use of 1% pimecrolimus cream for the treatment of steroid induced rosacea. Br J Dermatol 152(2):396-9.
Cork MJ, Britton J, Butler L, Young S, Murphy R, Keohane SG. 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(3):582–589.
Cork MJ, Danby SG, Vasilopoulos Y, Hadgraft J, Lane ME, Moustafa M, Guy RH, Macgowan AL, Tazi-Ahnini R, Ward SJ. 2009. Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol 129(8):1892-908.
Cork MJ, Robinson DA, Vasilopoulos Y, Ferguson A, Moustafa M, MacGowan A, Duff GW, Ward SJ, Tazi-Ahnini R. 2006. New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions. J Allergy Clin Immunol 118(1):3-22.
Darmstadt GL, Badrawi N, Law PA, Ahmed S, Bashir M, Iskander I, Al Said D, El Kholy A, Husein MH, Alam A, Winch PJ, Gipson R, Santosham M. 2004. Topically applied sunflower seed oil prevents invasive bacterial infections in preterm infants in Egypt: a randomized, controlled clinical trial. Pediatr Infect Dis J 23(8):719-25.
Darmstadt GL, Saha SK, Ahmed AS, Chowdhury MA, Law PA, Ahmed S, Alam MA, Black RE, Santosham M. 2005. Effect of topical treatment with skin barrier-enhancing emollients on nosocomial infections in preterm infants in Bangladesh: a randomised controlled trial. Lancet 365(9464):1039-45.
Darmstadt GL, Saha SK, Ahmed AS, Choi Y, Chowdhury MA, Islam M, Law PA, Ahmed S. 2007. Effect of topical emollient treatment of preterm neonates in Bangladesh on invasion of pathogens into the bloodstream. Pediatr Res 61(5 Pt 1):588-93.
Denda M. 2000. New strategies to improve skin barrier homeostasis. Adv Drug Deliv Rev 54:S123–30.
Denda M, Fuziwara S, Inoue K. 2004. Association of cyclic adenosine monophosphate with permeability barrier homeostasis of murine skin. J Invest Dermatol 122(1):140-6.
Denda M, Nakatani M, Ikeyama K, Tsutsumi M, Denda S. 2007. Epidermal keratinocytes as the forefront of the sensory system. Exp Dermatol 16(3):157-61.
Denda M, Sato J, Masuda Y, Tsuchiya T, Koyama J, Kuramoto M, Elias PM, Feingold KR. 1998b. Exposure to a dry environment enhances epidermal permeability barrier function. J Invest Dermatol 111(5):858-63.
Denda M, Tsuchiya T, Hosoi J, Koyama J. 1998a. Immobilization-induced and crowded environment-induced stress delay barrier recovery in murine skin. Br J Dermatol 138(5):780-5.
Denda M, Tsuchiya T, Elias PM, Feingold KR. 2000. Stress alters cutaneous permeability barrier homeostasis. Am J Physiol Regul Integr Comp Physiol 278(2):R367-72.
Diepgen TL. 2002. Long-term treatment with cetirizine of infants with atopic dermatitis: a multi-country, double-blind, randomized, placebo-controlled trial (the ETAC trial) over 18 months. Pediatr Allergy Immunol 13(4):278–86.
Demerjian M, Choi EH, Man MQ, Chang S, Elias PM, Feingold KR. 2009. Activators of PPARs and LXR Decrease the Adverse Effects of Exogenous Glucocorticoids on the Epidermis. Exp Dermatol 18(7):643–649.
Egelrud T. Desquamation in the stratum corneum. Acta Derm Venereol Suppl (Stockh) 2000; 208:44–5.
Elias PM. 2006. “Epilogue: fixing the barrier—theory and rational deployment,” in Skin Barrier, P. M. Elias and K. R. Feingold, Eds., pp. 591–600, Taylor & Francis, New York, NY, USA
Elias PM. 2007. The skin barrier as an innate immune element. Sem Immunopath. 29(1):3–14.
Elias PM. 2010. Therapeutic implications of a barrier-based pathogenesis of atopic dermatitis. Ann Dermatol 22(3):245–54.
Elias PM, Bonar L, Grayson S, Baden HP. 1983. X-ray diffraction analysis of stratum corneum membrane couplets. J Invest Dermatol 80(3):213–4.
Elias PM, Choi EH. 2005. Interactions among stratum corneum defensive functions. Exp Dermatol 14(10):719–26.
Elias PM, Crumrine D, Rassner U, Hachem JP, Menon GK, Man W, Choy MH, Leypoldt L, Feingold KR, Williams ML. 2004. Basis for abnormal desquamation and permeability barrier dysfunction in RXLI. J Invest Dermatol 122(2):314–9.
Elias PM, Feingold KR. 2001. Role of the barrier in the pathogenesis of inflammatory dermatoses and therapeutic implications. Arch Dermatol 137:1079–81.
Elias PM, Hatano Y, Williams ML. 2008a. Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms. J Allergy Clin Immunol 121(6):1337–43.
Elias PM, Menon GK. 1991. Structural and lipid biochemical correlates of the epidermal permeability barrier. Adv Lipid Res 24:1–26.
Elias PM, Schmuth M. 2009. Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Opin Allergy Clin Immunol 9(5):437–46.
Elias PM, Steinhoff M. 2008. Outside-to-inside (and now back to outside) pathogenic mechanisms in atopic dermatitis. J Invest Dermatol 128(5):1067–70.
Elias PM, Wakefield JS. 2011. Therapeutic implications of a barrier-based pathogenesis of atopic dermatitis. Clin Rev Allergy Immunol 41(3):282–95.
Elias PM, Wakefield JS. 2014. Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis. J Allergy Clin Immunol 134(4):781-91.
Elias PM, Williams ML. Encyclopedia of Human Biology. Elsevier; 2014. Evolution: Skin Color. In Press
Elias PM, Williams ML, Crumrine D, Schmuth M. 2010. Ichthyoses - clinical, biochemical, pathogenic, and diagnostic assessment, 39. S. Kargar AG: Basel, 144p
Elias PM, Williams ML, Holleran WM, Jiang YJ, Schmuth M. 2008b. Pathogenesis of permeability barrier abnormalities in the ichthyoses: inherited disorders of lipid metabolism. J Lipid Res 49(4):697–714.
Elias PM, Wood LC, Feingold KR. 1997. Relationship of the epidermal permeability barrier to irritant contact dermatitis. Immunol Allergy Clin North America 17(3):417–430.
Elias PM, Wood LC, Feingold KR. 1999. Epidermal pathogenesis of inflammatory dermatoses. Am J Contact Dermat 10(3):119–26.
Endo Y, Kikuchi T, Takeda Y, Nitta Y, Rikiishi H, Kumagai K. 1992. GM-CSF and G-CSF stimulate the synthesis of histamine and putrescine in the hematopoietic organs in vivo. Immunol Lett 33(1):9–13.
Endo Y, Nakamura M, Nitta Y, Kumagai K. 1995. Effects of macrophage depletion on the induction of histidine decarboxylase by lipopolysaccharide, interleukin 1 and tumour necrosis factor. Br J Pharmacol 114(1):187–93.
Eschler DC, Klein PA. 2010. An evidence-based review of the efficacy of topical antihistamines in the relief of pruritus. J Drugs Dermatol 9(8):992–7.
Fartasch M. 1997. Epidermal barrier in disorders of the skin. Microsc Res Tech 38(4):361-72.
Feingold KR. 2007. Thematic review series: skin lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis. J Lipid Res 48(12):2531–46.
Feingold KR. 2009. The outer frontier: the importance of lipid metabolism in the skin. J Lipid Res 50:S417–22.
Feingold KR, Man MQ, Menon GK, Cho SS, Brown BE, Elias PM. 1990. Cholesterol synthesis is required for cutaneous barrier function in mice. J Clin Invest 86(5):1738–1745.
Fowler AJ, Sheu MY, Schmuth M, Kao J, Fluhr JW, Rhein L, Collins JL, Willson TM, Mangelsdorf DJ, Elias PM, Feingold KR. 2003. Liver X receptor activators display anti-inflammatory activity in irritant and allergic contact dermatitis models: liver-X-receptor-specific inhibition of inflammation and primary cytokine production. J Invest Dermatol 120(2):246–55.
Fujiwara S, Okubo Y, Irisawa R, Tsuboi R. 2010. Rosaceiform dermatitis associated with topical tacrolimus treatment. J Am Acad Dermatol 62(6):1050-2.
Ghadially R, Halkier-Sorensen L, Elias PM. 1992. Effects of petrolatum on stratum corneum structure and function. J Am Acad Dermatol 26(3 Pt 2):387-96.
Ghadially R, Reed JT, Elias PM. 1996. Stratum corneum structure and function correlates with phenotype in psoriasis. J Invest Dermatol 107(4):558-64.
Goding CR. 2007. Melanocytes: the new Black. Int J Biochem Cell Biol 39(2):275–9.
Goldman D. 2001. Tacrolimus ointment for the treatment of steroid-induced rosacea: a preliminary report. J Am Acad Dermatol 44(6):995-8.
Greaves MW. 2005. Antihistamines in dermatology. Skin Pharmacol Physiol 18:220–9.
Grether-Beck S, Felsner I, Brenden H, Kohne Z, Majora M, Marini A, Jaenicke T, Rodriguez-Martin M, Trullas C, Hupe M, Elias PM, Krutmann J. 2012. Urea uptake enhances barrier function and antimicrobial defense in humans by regulating epidermal gene expression. J Invest Dermatol 132(6):1561-72.
Gruber R, Elias PM, Crumrine D, Lin TK, Brandner JM, Hachem JP, Presland RB, Fleckman P, Janecke AR, Sandilands A, McLean WH, Fritsch PO, Mildner M, Tschachler E, Schmuth M. 2011. Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function. Am J Pathol. 178(5): 2252-63.
Gschwandtner M, Mommert S, Köther B, Werfel T, Gutzmer R. 2011. The histamine H4 receptor is highly expressed on plasmacytoid dendritic cells in psoriasis and histamine regulates their cytokine production and migration. J Invest Dermatol 131(8):1668–76.
Gunathilake R, Schmuth M, Scharschmidt TC, Gruber R, Grabher D, Leslie KS, Maurer TA, Mauro TM, Elias PM. 2010. Epidermal barrier dysfunction in non-atopic HIV: evidence for an “inside-to-outside” pathogenesis. J Invest Dermatol 130(4):1185–8.
Gunathilake R, Schurer NY, Shoo BA, Celli A, Hachem JP, Crumrine D, Sirimanna G, Feingold KR, Mauro TM, Elias PM. 2009. pH-regulated mechanisms account for pigment-type differences in epidermal barrier function. J Invest Dermatol 129(7):1719–29.
Hachem JP, Behne M, Aronchik I, Demerjian M, Feingold KR, Elias PM, Mauro TM. 2005a. Extracellular pH controls NHE1 expression in epidermis and keratinocytes: implications for barrier repair. J Invest Dermatol 125(4):790–7.
Hachem JP, Crumrine D, Fluhr J, Brown BE, Feingold KR, Elias PM. 2003. pH directly regulates epidermal permeability barrier homeostasis, and stratum corneum integrity/cohesion. J Invest Dermatol 121(2):345–53.
Hachem JP, Houben E, Crumrine D, Man MQ, Schurer N, Roelandt T, Choi EH, Uchida Y, Brown BE, Feingold KR, Elias PM. 2006a. Serine protease signaling of epidermal permeability barrier homeostasis. J Invest Dermatol 126(9):2074–86.
Hachem JP, Man MQ, Crumrine D, Uchida Y, Brown BE, Rogiers V, Roseeuw D, Feingold KR, Elias PM. 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(3):510–20.
Haftek M, Simon M, Serre G. Corneodesmosomes: Pivotal Actors in the Stratum Corneum Cohesion and Desquamation. In: Elias PM, Feingold KR, eds. Skin Barrier. New York: Taylor & Francis, 2006:171-190.
Haratake A, Uchida Y, Schmuth M, Tanno O, Yasuda R, Epstein JH, Elias PM, Holleran WM. 1997. UVB-induced alterations in permeability barrier function: roles for epidermal hyperproliferation and thymocyte-mediated response. J Invest Dermatol 108(5):769–75.
Hatano Y, Elias PM, Crumrine D, Feingold KR, Katagiri K, Fujiwara S. 2011. Efficacy of combined peroxisome proliferator-activated receptor-alpha ligand and glucocorticoid therapy in a murine model of atopic dermatitis. J Invest Dermatol 131(9):1845–1852.
Hatano Y, Man MQ, Uchida Y, Crumrine D, Mauro TM, Feingold KR, Elias PM, Holleran WM. 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(1):160–9.
Hatano Y, Man MQ, Uchida Y, Crumrine D, Scharschmidt TC, Kim EG, Mauro TM, Feingold KR, Elias PM, Holleran WM. 2009. Maintenance of an acidic stratum corneum prevents emergence of murine atopic dermatitis. J Invest Dermatol 129(7):1824–35.
Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM, Schunack W, Levi R, Haas HL. 1997. International Union of Pharmacology. XIII. Classification of histamine receptors. Pharmacol Rev 49(3):253–78.
Holleran WM, Uchida Y, Halkier-Sorensen L, Haratake A, Hara M, Epstein JH, Elias PM. 1997. Structural and biochemical basis for the UVB-induced alterations in epidermal barrier function. Photodermatol Photoimmunol Photomed 13(4):117–28.
Hong SP, Kim MJ, Jung MY, Jeon H, Goo J, Ahn SK, Lee SH, Elias PM, Choi EH. 2008. Biopositive effects of low-dose UVB on epidermis: coordinate upregulation of antimicrobial peptides and permeability barrier reinforcement. J Invest Dermatol 128(12):2880–7.
Hou M, Man M, Man W, Zhu W, Hupe M, Park K, Crumrine D, Elias PM, Man MQ. 2012. Topical hesperidin improves epidermal permeability barrier function and epidermal differentiation in normal murine skin. Exp Dermatol 21(5):337-40.
Hou M. Sun R, Hupe M, Kim PL, Park K, Crumrine D, Lin TK, Santiago JL, Mauro TM, Elias PM, Man MQ. 2013. Topical apigenin improves epidermal permeability barrier homeostasis in normal murine skin by divergent mechanisms. Exp Dermatol 22(3):210–215.
Hou SY, Mitra AK, White SH, Menon GK, Ghadially R, Elias PM. 1991. Membrane structures in normal and essential fatty acid-deficient stratum corneum: characterization by ruthenium tetroxide staining and x-ray diffraction. J Invest Dermatol 96(2):215-23.
Irvine AD, McLean WH, Leung DY. 2011. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med 365(14):1315–27.
Ishida-Yamamoto A, Igawa S, Kishibe M. 2011. Order and disorder in corneocyte adhesion. J Dermatol 38:645–54.
Itoi S, Terao M, Murota H, Katayama I. 2013. 11b-Hydroxysteroid dehydrogenase 1 contributes to the pro-inflammatory response of keratinocytes. Biochem Biophys Res Commun 440(2):265-70.
Jablonski NG. 1999. A possible link between neural tube defects and ultraviolet light exposure. Med Hypotheses 52(6):581–2.
Joseph MH, Kennett GA. 1983. Corticosteroid response to stress depends upon increased tryptophan availability. Psychopharmacology (Berl) 79(1):79-81.
Janssens AS, Heide R, den Hollander JC, Mulder PG, Tank B, Oranje AP. 2005. Mast cell distribution in normal adult skin. J Clin Pathol 58(3):285–9.
Kao JS, Fluhr JW, Man MQ, Fowler AJ, Hachem JP, Crumrine D, Ahn SK, Brown BE, Elias PM, Feingold KR. 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(3):456-64.
Kawashima M, Tango T, Noguchi T, Inagi M, Nakagawa H, Harada S. 2003. Addition of fexofenadine to a topical corticosteroid reduces the pruritus associated with atopic dermatitis in a 1-week randomized, multicentre, double-blind, placebo-controlled, parallel-group study. Br J Dermatol 148(6):1212–21.
Kim M, Jung M, Hong SP, Jeon H, Kim MJ, Cho MY, Lee SH, Man MQ, Elias PM, Choi EH. 2010. Topical calcineurin inhibitors compromise stratum corneum integrity, epidermal permeability and antimicrobial barrier function. Exp Dermatol. 19(6):501-10.
Kim HJ, Park HJ, Yun JN, Jeong SK, Ahn SK, Lee SH. 2011. Pseudoceramide-containing physiological lipid mixture reduces adverse effects of topical steroids. Allergy Asthma Immunol Res 3(2):96-102.
Kim SY, Bae CD. 1998. Calpain inhibitors reduce the cornified cell envelope formation by inhibiting proteolytic processing of transglutaminase 1. Exp Mol Med 30(4):257–62.
King CS, Barton SP, Nicholls S, Marks R. The change in properties of the stratum corneum as a function of depth. Br J Dermatol. 1979; 100(2):165–72.
Kircik LH, Del Rosso JQ. 2011. Nonsteroidal treatment of atopic dermatitis in pediatric patients with a ceramide-dominant topical emulsion formulated with an optimized ratio of physiological lipids. J Clin Aesthet Dermatol 4(1):25-31.
Klein PA, Clark RA. 1999. An evidence-based review of the efficacy of antihistamines in relieving pruritus in atopic dermatitis. Arch Dermatol 135(12):1522–5.
Kligman A.M. 1976. Letter: Topical steroid addicts. JAMA 235(15):1550.
Kligman AM, Frosch PJ. 1979. Steroid addiction. Int J Dermatol 18(1):23-31.
Kobayashi M, Kabashima K, Nakamura M, Tokura Y. 2009. Downmodulatory effects of the antihistaminic drug bepotastine on cytokine/chemokine production and CD54 expression in human keratinocytes. Skin Pharmacol Physiol 22(1):45–8.
Koizumi H, Ohkawara A. 1999. H2 histamine receptor-mediated increase in intracellular Ca2+ in cultured human keratinocytes. J Dermatol Sci 21(2):127–32.
Kömüves LG, Hanley K, Lefebvre AM, Man MQ, Ng DC, Bikle DD, Williams ML, Elias PM, Auwerx J, Feingold KR. 2000. Stimulation of PPARalpha promotes epidermal keratinocyte differentiation in vivo. J Invest Dermatol 115(3):353-60.
Kömüves LG, Hanley K, Man MQ, Elias PM, Williams ML, Feingold KR. 2000. Keratinocyte differentiation in hyperproliferative epidermis: topical application of PPARalpha activators restores tissue homeostasis. J Invest Dermatol 115(3):361–7.
Kömüves LG, Schmuth M, Fowler AJ, Elias PM, Hanley K, Man MQ, Moser AH, Lobaccaro JM, Williams ML, Mangelsdorf DJ, Feingold KR. 2002. Oxysterol stimulation of epidermal differentiation is mediated by liver X receptor-beta in murine epidermis. J Invest Dermatol 118(1):25-34.
Lee DH, Li K, Suh DH. 2008. Pimecrolimus 1% cream for the treatment of steroid induced rosacea: an 8-week split-face clinical trial. Br J Dermatol 158(5):1069-76.
Levi-Schaffer F, Eliashar R. 2009. Mast cell stabilizing properties of antihistamines. J Invest Dermatol 129(11):2549–51.
Lin JY, Fisher DE. 2007. Melanocyte biology and skin pigmentation. Nature 445(7130):843–50.
Liu ZH, Du XH. 2008. Quality of life in patients with facial steroid dermatitis before and after treatment. J Eur Acad Dermatol Venereol 22(6):663-669.
Ljubojeviae S, Basta-Juzbasiae A, Lipozenèiae J. 2002. Steroid dermatitis resembling rosacea: aetiopathogenesis and treatment. J Eur Acad Dermatol Venereol 16(2):121-6.
Lin TK, Crumrine D, Ackerman LD, Santiago JL, Roelandt T, Uchida Y, Hupe M, Fabriàs G, Abad JL, Rice RH, Elias PM. 2012. Cellular changes that accompany shedding human corneocytes. J Invest Dermatol 132(10):2430–2439.
Lin TK, Man MQ, Santiago JL, Scharschmidt TC, Hupe M, Martin-Ezquerra G, Youm JK, Zhai Y, Trullas C, Feingold KR, Elias PM. 2014. Paradoxical benefits of psychological stress in inflammatory dermatoses models are glucocorticoid mediated. J Invest Dermatol 134(12):2890-7.
Lin TK, Santiago JL. 2013. Corticosteroids, psychological stress, and dermatitis. The Journal of Skin Barrier Research 15(2): 42-8.
Liu J, Man WY, Lv CZ, Song SP, Shi YJ, Elias PM, Man MQ. 2010. Epidermal permeability barrier recovery is delayed in vitiligo-involved sites. Skin Pharmacol Physiol 23(4):193–200.
Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA. 2004. New insights into atopic dermatitis. J Clin Invest 113(5):651-7.
Lubach D, Kietzmann M. 1988. Investigation of the skin thinning effect of prednicarbate and other corticoids in mouse skin. Skin Pharmacol 1(3):200-6.
Macharia WM, Anabwani GM, Owili DM. 1991. Effects of skin contactants on evolution of atopic dermatitis in children: A case control study. Trop Doct 21(3): 104-106.
Man M, Hupe M, Mackenzie D, Kim H, Oda Y, Crumrine D, Lee SH, Martin-Ezquerra G, Trullas C, Mauro TM, Feingold KR, Elias PM, Man MQ. 2011. A topical Chinese herbal mixture improves epidermal permeability barrier function in normal murine skin. Exp Dermatol 20(3):285–288.
Man MQ, Choi EH, Schmuth M, Crumrine D, Uchida Y, Elias PM, Holleran WM, Feingold KR. 2006. Basis for improved permeability barrier homeostasis induced by PPAR and LXR activators: liposensors stimulate lipid synthesis, lamellar body secretion, and post-secretory lipid processing. J Clin Invest 126(2):386-92.
Man MQ, Feingold KR, Elias PM. 1993. Exogenous lipids influence permeability barrier recovery in acetone-treated murine skin. Arch Dermatol 129(6):728–38.
Man MQ M, Feingold KR, Thornfeldt CR, Elias PM. 1996. Optimization of physiological lipid mixtures for barrier repair. J Invest Dermatol 106(5):1096–1101.
Man MQ, Hatano Y, Lee SH, Man M, Chang S, Feingold KR, Leung DY, Holleran W, Uchida Y, Elias PM. 2008. Characterization of a hapten-induced, murine model with multiple features of atopic dermatitis: structural, immunologic, and biochemical changes following single versus multiple oxazolone challenges. J Invest Dermatol 128(1):79–86.
Man MQ, Lin TK, Santiago JL, Celli A, Zhong L, Huang ZM, Roelandt T, Hupe M, Sundberg JP, Silva KA, Crumrine D, Martin-Ezquerra G, Trullas C, Sun R, Wakefield JS, Wei ML, Feingold KR, Mauro TM, Elias PM. 2014. Basis for enhanced barrier function of pigmented skin. J Invest Dermatol 134(9):2399-407.
Menon GK, Elias PM. 1997. Morphologic basis for a pore-pathway in mammalian stratum corneum. Skin Pharmacol 10(5-6):235–46.
Marshall RC, Burrows M, Brookes LG, du Vivier A. 1981. The effects of topical and systemic glucocorticosteroids on DNA synthesis in different tissues of the hairless mouse. Br J Dermatol 105(5):517-20.
Matsubara M, Tamura T, Ohmori K, Hasegawa K. 2005. Histamine H1 receptor antagonist blocks histamine-induced proinflammatory cytokine production through inhibition of Ca2+-dependent protein kinase C, Raf/MEK/ERK and IKK/I kappa B/NF-kappa B signal cascades. Biochem Pharmacol 69(3):433–49.
Miyamura Y, Coelho SG, Wolber R, Miller SA, Wakamatsu K, Zmudzka BZ, Ito S, Smuda C, Passeron T, Choi W, Batzer J, Yamaguchi Y, Beer JZ, Hearing VJ. 2007. Regulation of human skin pigmentation and responses to ultraviolet radiation. Pigment Cell Res 20(1):2–13.
Mueller KP, Neuhauss SC. 2014. Sunscreen for fish: co-option of UV light protection for camouflage. PLoS ONE 9(1):e87372.
Naoe Y, Hata T, Tanigawa K, Kimura H, Masunaga T. 2010. Bidimensional analysis of desmoglein 1 distribution on the outermost corneocytes provides the structural and functional information of the stratum corneum. J Dermatol Sci 57(3):192–8.
Nemes Z, Steinert PM. 1999. Bricks and mortar of the epidermal barrier. Exp Mol Med 31(1):5–19.
Nickoloff BJ, Naidu Y. 1994. Perturbation of epidermal barrier function correlates with initiation of cytokine cascade in human skin. J Am Acad Dermatol 30(4):535–46.
Nopper AJ, Horii KA, Sookdeo-Drost S, Wang TH, Mancini AJ, Lane AT. 1996. Topical ointment therapy benefits premature infants. J Pediatr 128(5 Pt 1):660-9.
Oda T, Morikawa N, Saito Y, Masuho Y, Matsumoto S. 2000. Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes. J Biol Chem 275(47):36781–6.
Oren A, Ganz T, Liu L, Meerloo T. 2003. In human epidermis, beta-defensin 2 is packaged in lamellar bodies. Exp Mol Pathol 74(2):180–2.
Ovaere P, Lippens S, Vandenabeele P, Declercq W. 2009. The emerging roles of serine protease cascades in the epidermis. Trends Biochem Sci 34(9):453–463.
Ohman H, Vahlquist A. 1998. The pH gradient over the stratum corneum differs in X-linked recessive and autosomal dominant ichthyosis: a clue to the molecular origin of the “acid skin mantle”? J Invest Dermatol 111(4):674–7.
Pavlinkova G, Yanagawa Y, Kikuchi K, Iwabuchi K, Onoé K. 2003. Effects of histamine on functional maturation of dendritic cells. Immunobiology 207(5):315–25.
Pérez P. 2011. Glucocorticoid receptors, epidermal homeostasis and hair follicle differentiation. Dermatoendocrinol 3(3):166-74.
Rapaport MJ, Rapaport V. 1999. Eyelid dermatitis to red face syndrome to cure: clinical experience in 100 cases. J Am Acad Dermatol 41(3 Pt 1):435-42.
Rapaport MJ, Lebwohl M. 2003. Corticosteroid addiction and withdrawal in theatopic: the red burning skin syndrome. Clin Dermatol 21(3):201-14.
Rapaport MJ, Rapaport VH. 2004. Serum nitric oxide levels in “red” patients: separating corticosteroid-addicted patients from those with chronic eczema. Arch Dermatol 140(8):1013-4.
Rathi SK, Kumrah L. 2011. Topical corticosteroid-induced rosacea-like dermatitis: a clinical study of 110 cases. Indian J Dermatol Venereol Leprol 77(1):42-6.
Rawlings AV. 2010. Recent advances in skin ‘barrier’ research. J Pharm Pharmacol 62(6):671–7.
Rawlings AV, Scott IR, Harding CR, Bowser PA. 1994. Stratum corneum moisturization at the molecular level. J Invest Dermatol 103(5):731–41.
Reed JT, Ghadially R, Elias PM. 1995. Skin type, but neither race nor gender, influence epidermal permeability barrier function. Arch Dermatol 131(10):1134–8.
Roelandt T, Heughebaert C, Bredif S, Giddelo C, Baudouin C, Msika P, Roseeuw D, Uchida Y, Elias PM, Hachem JP. 2012. Cannabinoid receptors 1 and 2 oppositely regulate epidermal permeability barrier status and differentiation. Experimental Dermatology 21(9):688–693.
Ramos-e-Silva M, Jacques Cd. 2012. Epidermal barrier function and systemic diseases. Clin Dermatol 30(3):277-9.
Sandilands A, Sutherland C, Irvine AD, McLean WH. 2009. Filaggrin in the frontline: role in skin barrier function and disease. J Cell Sci 122(Pt 9):1285–94.
Schallreuter KU, Kothari S, Chavan B, Spencer JD. 2008. Regulation of melanogenesis--controversies and new concepts. Exp Dermatol 17(5):395–404.
Schmuth M, Gruber R, Elias PM, Williams ML. 2007. Ichthyosis update: towards a function-driven model of pathogenesis of the disorders of cornification and the role of corneocyte proteins in these disorders. Adv Dermatol 23:231–256.
Schmuth M, Jiang YJ, Dubrac S, Elias PM, Feingold KR. 2008. Thematic Review Series: Skin Lipids. Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology. J Lipid Res 49(3):499–509.
Sevilla LM, Latorre V, Sanchis A, Pérez P. 2013. Epidermal inactivation of the glucocorticoid receptor triggers skin barrier defects and cutaneous inflammation. J Invest Dermatol 133(2):361-70.
Sheu HM, Lee JY, Chai CY, Kuo KW. 1997. Depletion of stratum corneum intercellular lipid lamellae and barrier function abnormalities after long-term topical corticosteroids. Br J Dermatol 136(6):884-90.
Sheu HM, Lee JY, Kuo KW, Tsai JC. 1998. Permeability barrier abnormality of hairless mouse epidermis after topical corticosteroid: characterization of stratum corneum lipids by ruthenium tetroxide staining and high-performance thin-layer chromatography. J Dermatol 25(5):281-9.
Sheu HM, Tai CL, Kuo KW, Yu HS, Chai CY. 1991. Modulation of epidermal terminal differentiation in patients after long-term topical corticosteroids. J Dermatol 18(8):454-64.
Sheu HM, Tsai JC, Lin TK, Wong TW, Lee JY. 2003. Modified Nile red staining method for improved visualization of neutral lipid depositions in stratum corneum. J Formos Med Assoc 102(9):656-60.
Sheu MY, Fowler AJ, Kao J, Schmuth M, Schoonjans K, Auwerx J, Fluhr JW, Man MQ, Elias PM, Feingold KR. 2002. Topical peroxisome proliferator activated receptor-alpha activators reduce inflammation in irritant and allergic contact dermatitis models. J Invest Dermatol 118(1):94–101.
Shimizu T, Nishihira J, Watanabe H, Abe R, Ishibashi T, Shimizu H. 2004. Cetirizine, an H1-receptor antagonist, suppresses the expression of macrophage migration inhibitory factor: its potential anti-inflammatory action. Clin Exp Allergy 34(1):103–9.
Slominski A, Wortsman J, Tuckey RC, Paus R. 2007. Differential expression of HPA axis homolog in the skin. Mol Cell Endocrinol 265–266:143–149.
Slominski A, Zbytek B, Nikolakis G, Manna PR, Skobowiat C, Zmijewski M, Li W, Janjetovic Z, Postlethwaite A, Zouboulis CC, Tuckey RC. 2013. Steroidogenesis in the skin: Implications for local immune functions. J Steroid Biochem Mol Biol 137:107–123.
Slominski AT, Zmijewski MA, Skobowiat C, Zbytek B, Slominski RM, Steketee JD. 2012. Sensing the environment: regulation of local and global homeostasis by the skin's neuroendocrine system. Adv Anat Embryol Cell Biol 212:v, vii, 1-115.
Sneddon IB. 1976. The treatment of steroid-induced rosacea and perioral dermatitis. Dermatologica 152 Suppl 1:231-7.
Stamatas GN, de Sterke J, Hauser M, von Stetten O, van der Pol A. 2008. Lipid uptake and skin occlusion following topical application of oils on adult and infant skin. J Dermatol Sci 50(2):135-42.
Staumont-Sallé D, Abboud G, Brénuchon C, Kanda A, Roumier T, Lavogiez C, Fleury S, Rémy P, Papin JP, Bertrand-Michel J, Tercé F, Staels B, Delaporte E, Capron M, Dombrowicz D. 2008. Peroxisome proliferator-activated receptor alpha regulates skin inflammation and humoral response in atopic dermatitis. J Allergy Clin Immunol 121(4):962-8.
Strange A, Capon F, Spencer CC. 2010. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet 42(11):985–90.
Sugarman JL. 2008. The epidermal barrier in atopic dermatitis, Seminars in Cutaneous Medicine and Surgery 27(2):108–114.
Sugarman JL, Parish LC. 2009. Efficacy of a lipid-based barrier repair formulation in moderate-to-severe pediatric atopic dermatitis. J Drugs Dermatol 8(12):1106-11.
Sul GD, Park HJ, Bae JH, Hong KD, Park BD, Chun J, Jeong SK, Lee SH, Ahn SK, Kim HJ. 2013. Preventive effects of multi-lamellar emulsion on low potency topical steroid induced local adverse effect. Ann Dermatol 25(1):5-11.
Sun C, Mathur P, Dupuis J, Tizard R, Ticho B, Crowell T, Gardner H, Bowcock AM, Carulli J. 2006. Peptidoglycan recognition proteins Pglyrp3 and Pglyrp4 are encoded from the epidermal differentiation complex and are candidate genes for the Psors4 locus on chromosome 1q21. Hum Genet 119(1-2):113–25.
Szczepanowska J, Reich A, Szepietowski JC. 2008. Emollients improve treatment results with topical corticosteroids in childhood atopic dermatitis: a randomized comparative study. Pediatr Allergy Immunol 19(7):614-8.
Tadicherla S, Ross K, Shenefelt PD, Fenske NA. 2009. Topical corticosteroids in dermatology. J Drugs Dermatol 8(12):1093-105.
Takei K, Denda S, Kumamoto J, Denda M. 2013. Low environmental humidity induces synthesis and release of cortisol in an epidermal organotypic culture system. Exp Dermatol 22(10):662-4.
Travis ER, Wang YM, Michael DJ, Caron MG, Wightman RM. 2000. Differential quantal release of histamine and 5-hydroxytryptamine from mast cells of vesicular monoamine transporter 2 knockout mice. Proc Natl Acad Sci USA 97(1):162–7.
Tschachler E. 2007. Psoriasis: the epidermal component. Clin Dermatol 25(6):589–95.
Voegeli R, Rawlings AV, Breternitz M, Doppler S, Schreier T, Fluhr JW. 2009. Increased stratum corneum serine protease activity in acute eczematous atopic skin. Br J Dermatol 161:70–7.
Wang KY, Tanimoto A, Yamada S, Guo X, Ding Y, Watanabe T, Watanabe T, Kohno K, Hirano K, Tsukada H, Sasaguri Y. 2010. Histamine regulation in glucose and lipid metabolism via histamine receptors: model for nonalcoholic steatohepatitis in mice. Am J Pathol 177(2):713–23
Wood LC, Elias PM, Calhoun C, Tsai JC, Grunfeld C, Feingold KR. 1996. Barrier disruption stimulates interleukin-1 alpha expression and release from a preformed pool in murine epidermis. J Invest Dermatol 106:397-403.
Wood LC, Jackson SM, Elias PM, Grunfeld C, Feingold KR. 1992. Cutaneous barrier perturbation stimulates cytokine production in the epidermis of mice. J Clin Invest 90(2):482–7.
Yamaguchi K, Motegi K, Kurimoto M, Endo Y. 2000. Induction of the activity of the histamine-forming enzyme, histidine decarboxylase, in mice by IL-18 and by IL-18 plus IL-12. Inflamm Res 49(10):513–9.
Young A, Sheehan J. UV-induced pigmentation in human skin. In Giacomoni P, ed. Sun Protection in Man. New-York: Elsevier Science, 2001:357-375.
Zheng PS, Lavker RM, Lehmann P, Kligman AM. 1984. Morphologic investigations on the rebound phenomenon after corticosteroid-induced atrophy in human skin. J Invest Dermatol 82(4):345-52.
Zeeuwen PL, Cheng T, Schalkwijk J. 2009. The biology of cystatin M/E and its cognate target proteases. J Invest Dermatol 129(6):1327–38.