背景：皮質類固醇外用劑(Topical corticosteroids: TCS)是目前在皮膚發炎性疾病最有效之治療劑，然而TCS在抗發炎的同時，不可避免的，會引起角質層結構異常，最終導致表皮的障壁功能異常。而且，長期使用TCS，於突然停藥後，常會出現令人困擾且難以治療的戒斷皮膚炎(withdrawal dermatitis: WD)，其機轉並不清楚。最近的研究，證實在單純表皮障壁破壞的情形下，會導致一連串由表皮細胞啟動的細胞激素反應(包含:TNF-α, IL-1α, IL-1β)，最終可能導致皮膚炎。
我們推測:因皮質類固醇外用劑(TCS)使用所導致的表皮障壁破壞，最後將可能誘發戒斷皮膚炎的產生,由於TCS 的強力抗發炎效果，前述皮膚炎反應在TCS使用期間被暫時抑制，然而一旦停用TCS後，戒斷皮膚炎就會表現出來。

研究目的：闡明外用皮質類固醇停用後，引發戒斷皮膚炎的可能機轉。

實驗方法：我們以無毛鼠為實驗對象,連續塗抹0.064% betamethasone dipropionate ointment六週，於擦藥期間及停藥後兩週內，測定皮膚障壁功能的改變(經皮水分喪失(TEWL)、角質層脂肪)，以及與障壁功能缺損相關的細胞激素 (TNF-α、IL1-α、 IL1-β、IKK1、 IKK2及NF-kB) 表現的變化。
結果：於外用皮質類固醇停用後3 天，表皮角質層功能之指標TEWL， 呈現有意義之上升，同時以mRNA in hybridization、免疫組織化學染色及西方墨點法檢測，顯示表皮內之TNF-α、IL1-α、 IL1-β、IKK1、 IKK2及NF-kB均有顯著增加。於停止TCS後一週，伴隨著表皮角質層功能恢復正常，表皮內發炎細胞激素消失。於塗藥及停藥期間，上述幾種發炎激素在真皮內都沒有表現上升。在塗抹TCS的同時，給予Petrolatum或0.1% tacrolimus，可以減少障壁功能的缺損與細胞激素的產生。

結論：我們的研究提供了表皮障壁破壞與戒斷皮膚炎兩者間之重要關係。皮質類固醇所導致的障壁破壞，會啟動由表皮層產生的一系列細胞激素反應；上述的反應，和用膠布撕離角質層或丙酮處理導致單純障壁功能缺損所引起的反應類似。我們建議，使用外用皮質類固醇藥劑時，需要同時給予保濕劑的補充(例如:Petrolatum或乳液)，以改善皮膚障壁功能，或是在適當的時候併用其他非類固醇抗發炎藥劑，來減少及預防戒斷皮膚炎的產生。

Background: Topical corticosteroids (TCS) are one of the most efficient therapeutic modalities for inflammatory cutaneous disorders. However, TCS induce structural abnormalities of stratum corneum, resulting in permeability barrier disruption. Furthermore, withdrawal dermatitis (WD) following discontinuation of long-term TCS therapy is one of the most troublesome adverse events in clinical practice. The mechanism of WD is still not well understood. Recent studies demonstrated that epidermal barrier perturbation induces a cytokine cascade, including IL1-α, IL1-β and TNF-α, leading to cutaneous inflammation. In light of aforementioned reasons, we hypothesize that barrier disruption caused by long-term TCS therapy may trigger a cutaneous cytokine cascade, which would play an important role in the WD following discontinuation of TCS.

Objectives: The aim of this study was to elucidate the possible mechanism of the WD following discontinuation of TCS.

Methods: Hairless mice were treated once daily with 0.064% betamethasone dipropionate ointment for six-week. After discontinuation of TCS, We examined the skin barrier function changes (transepidermal water loss, stratum corneum lipids) and expression of cytokines (IL1-α, IL1-β, TNF-α) and their downstream pathway signaling (IKK-1, IKK2, NF-kB) in HRS hairless mice by Western blot, in situ hybridization and immunohistochemical analysis during the following 2 weeks.

Results: We observed an obvious up-regulation of epidermal IL1-α, IL1-β, TNF-α, IKK1 and IKK2 protein and mRNA at 3 days after stopping TCS accompanied by a significant higher TEWL. The disappearance of these cytokines in the epidermis is accompanied by the normalization of TEWL one week after stopping TCS. Only negligible amounts of aforementioned cytokines were observed in the dermis. Furthermore, concurrent application of petrolatum or 0.1% tacrolimus(Protopic@) ointment during TCS treatment may minimize the barrier impairment and decrease the production of cytokines.

Conclusions: In light of these observations, the TCS-induced barrier disruption results in a epidermal-derived cytokine cascade similar to those of permeability barrier insults by acetone or tape stripping. We suggest that concurrent application of skin care products to improve the barrier homeostasis during TCS treatment should become a standard part of the TCS management.

Ahn, S. K., H. N. Bak, et al. (2006). "Effects of a multilamellar emulsion on glucocorticoid-induced epidermal atrophy and barrier impairment." J Dermatol 33(2): 80-90.
Barker, J. N., R. S. Mitra, et al. (1991). "Keratinocytes as initiators of inflammation." Lancet 337(8735): 211-214.
Bjornberg, A. (1982). "Erythema craquele provoked by corticosteroids on normal skin." Acta Derm Venereol 62(2): 147-151.
Chu, C. Y. (2005). "The use of 1% pimecrolimus cream for the treatment of steroid-induced rosacea." Br J Dermatol 152(2): 396-399.
Demerjian, M., E. H. Choi, et al. (2009). "Activators of PPARs and LXR decrease the adverse effects of exogenous glucocorticoids on the epidermis." Exp Dermatol 18(7): 643-649.
Elias, P. M., L. C. Wood, et al. (1999). "Epidermal pathogenesis of inflammatory dermatoses." Am J Contact Dermat 10(3): 119-126.
Fartasch, M. (1997). "Epidermal barrier in disorders of the skin." Microsc Res Tech 38(4): 361-372.
Fisher, L. B. and H. I. Maibach (1971). "The effect of corticosteroids on human epidermal mitotic activity." Arch Dermatol 103(1): 39-44.
Fujiwara, S., Y. Okubo, et al. (2010). "Rosaceiform dermatitis associated with topical tacrolimus treatment." J Am Acad Dermatol 62(6): 1050-1052.
Ghadially, R., L. Halkier-Sorensen, et al. (1992). "Effects of petrolatum on stratum corneum structure and function." J Am Acad Dermatol 26(3 Pt 2): 387-396.
Ghadially, R., J. T. Reed, et al. (1996). "Stratum corneum structure and function correlates with phenotype in psoriasis." J Invest Dermatol 107(4): 558-564.
Goldman, D. (2001). "Tacrolimus ointment for the treatment of steroid-induced rosacea: a preliminary report." J Am Acad Dermatol 44(6): 995-998.
Harding, C. R. (2004). "The stratum corneum: structure and function in health and disease." Dermatol Ther 17 Suppl 1: 6-15.
Held, E., H. Lund, et al. (2001). "Effect of different moisturizers on SLS-irritated human skin." Contact Dermatitis 44(4): 229-234.
Horiuchi, Y., S. J. Bae, et al. (2005). "FK506 (tacrolimus) inhibition of intracellular production and enhancement of interleukin 1alpha through glucocorticoid application to chemically treated human keratinocytes." Skin Pharmacol Physiol 18(5): 241-246.
Jensen, J. M., S. Pfeiffer, et al. (2009). "Different effects of pimecrolimus and betamethasone on the skin barrier in patients with atopic dermatitis." J Allergy Clin Immunol 123(5): 1124-1133.
Kao, J. S., J. W. Fluhr, 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(3): 456-464.
Kim, M., M. Jung, et al. (2009). "Topical calcineurin inhibitors compromise stratum corneum integrity, epidermal permeability and antimicrobial barrier function." Exp Dermatol.
Kligman, A. M. (1976). "Letter: Topical steroid addicts." JAMA 235(15): 1550.
Kligman, A. M. and P. J. Frosch (1979). "Steroid addiction." Int J Dermatol 18(1): 23-31.
Lan, C. C., H. S. Yu, et al. (2005). "FK506 inhibits tumour necrosis factor-alpha secretion in human keratinocytes via regulation of nuclear factor-kappaB." Br J Dermatol 153(4): 725-732.
Lange, K., A. Gysler, et al. (1997). "Prednicarbate versus conventional topical glucocorticoids: pharmacodynamic characterization in vitro." Pharm Res 14(12): 1744-1749.
Lee, D. H., K. Li, et al. (2008). "Pimecrolimus 1% cream for the treatment of steroid-induced rosacea: an 8-week split-face clinical trial." Br J Dermatol 158(5): 1069-1076.
Liu, Z. H. and X. H. Du (2008). "Quality of life in patients with facial steroid dermatitis before and after treatment." J Eur Acad Dermatol Venereol 22(6): 663-669.
Loden, M. and E. Barany (2000). "Skin-identical lipids versus petrolatum in the treatment of tape-stripped and detergent-perturbed human skin." Acta Derm Venereol 80(6): 412-415.
Lubach, D. and M. Kietzmann (1988). "Investigation of the skin thinning effect of prednicarbate and other corticoids in mouse skin." Skin Pharmacol 1(3): 200-206.
Man, M. M., K. R. Feingold, et al. (1996). "Optimization of physiological lipid mixtures for barrier repair." J Invest Dermatol 106(5): 1096-1101.
Marshall, R. C., M. Burrows, et al. (1981). "The effects of topical and systemic glucocorticosteroids on DNA synthesis in different tissues of the hairless mouse." Br J Dermatol 105(5): 517-520.
Nickoloff, B. J. and Y. Naidu (1994). "Perturbation of epidermal barrier function correlates with initiation of cytokine cascade in human skin." J Am Acad Dermatol 30(4): 535-546.
Rapaport, M. J. and M. Lebwohl (2003). "Corticosteroid addiction and withdrawal in the atopic: the red burning skin syndrome." Clin Dermatol 21(3): 201-214.
Rapaport, M. J. and V. Rapaport (1999). "Eyelid dermatitis to red face syndrome to cure: clinical experience in 100 cases." J Am Acad Dermatol 41(3 Pt 1): 435-442.
Rapaport, M. J. and V. H. Rapaport (2004). "Serum nitric oxide levels in "red" patients: separating corticosteroid-addicted patients from those with chronic eczema." Arch Dermatol 140(8): 1013-1014.
Rolfe, K. J., J. C. Crow, et al. (2002). "The effect of topical corticosteroids on Ki67 and p53 expression in vulval lichen sclerosus." Br J Dermatol 147(3): 503-508.
Sheu, H. M. and C. H. Chang (1991). "Alterations in water content of the stratum corneum following long-term topical corticosteroids." J Formos Med Assoc 90(7): 664-669.
Sheu, H. M., J. Y. Lee, et al. (1997). "Depletion of stratum corneum intercellular lipid lamellae and barrier function abnormalities after long-term topical corticosteroids." Br J Dermatol 136(6): 884-890.
Sheu, H. M., J. Y. Lee, et al. (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): 281-289.
Sheu HM, L. J., Tsai JC (1999). "Side effects of topical corticosteroids - II. Withdrawal dermatitis and its management." Dermatol Sinica 17: 300-315.
Sheu, H. M., C. L. Tai, et al. (1991). "Modulation of epidermal terminal differentiation in patients after long-term topical corticosteroids." J Dermatol 18(8): 454-464.
Simon, G. A. and H. I. Maibach (1998). "Relevance of hairless mouse as an experimental model of percutaneous penetration in man." Skin Pharmacol Appl Skin Physiol 11(2): 80-86.
Sneddon, I. B. (1976). "The treatment of steroid-induced rosacea and perioral dermatitis." Dermatologica 152 Suppl 1: 231-237.
Tomita, Y. and H. Tagami (1989). "Steroid-withdrawal rosacea-like dermatitis." J Dermatol 16(4): 335-337.
Tsai, J. C., K. R. Feingold, et al. (1994). "Permeability barrier disruption alters the localization and expression of TNF alpha/protein in the epidermis." Arch Dermatol Res 286(5): 242-248.
Wood, L. C., P. M. Elias, et al. (1996). "Barrier disruption stimulates interleukin-1 alpha expression and release from a pre-formed pool in murine epidermis." J Invest Dermatol 106(3): 397-403.
Wood, L. C., S. M. Jackson, et al. (1992). "Cutaneous barrier perturbation stimulates cytokine production in the epidermis of mice." J Clin Invest 90(2): 482-487.
Yang, L., M. Mao-Qiang, et al. (1995). "Topical stratum corneum lipids accelerate barrier repair after tape stripping, solvent treatment and some but not all types of detergent treatment." Br J Dermatol 133(5): 679-685.
Zheng, P. S., R. M. Lavker, et al. (1984). "Morphologic investigations on the rebound phenomenon after corticosteroid-induced atrophy in human skin." J Invest Dermatol 82(4): 345-352.