Topical calcineurin inhibitors compromise stratum corneum integrity, epidermal permeability and antimicrobial barrier function

Kim, Minjeong; Jung, Minyoung; Hong, Soon-Tae; Jeon, Hyerin; Kim, Min Jung; Cho, Mee Yon; Lee, Seung Hun; Man, Mao‐Qiang; Elias, Peter M.; Choi, Eung Ho

doi:10.1111/j.1600-0625.2009.00941.x

Cited by 55 publications

(43 citation statements)

References 51 publications

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“…Previous studies have shown that histamine stimulates melanocyte proliferation and melanogenesis in vitro [24,25,26,27,28,29,30,31,32]. We now show here that topical histamine consistently induces repigmentation in stable, nonsegmental vitiligo in humans, in parallel with increased melanin indices in histamine-treated normal mouse skin.…”

Section: Discussionsupporting

confidence: 55%

“…In part due to uncertainty about its etiology, optimal treatments are not yet available, although many approaches, including laser, high-potency topical steroids, topical immunomodulators, herbal medicines, as well as melanocyte/epidermal transplantation have yielded mixed results [13,14,15,16,17,18,19,20]. Notably, the efficacy of most of these regimens is not only moderate, but also costly [21,22], and can provoke substantial side effects such as skin infections [23,24,25,26], skin atrophy, and/or disturbed epidermal permeability barrier homeostasis [27,28], which is already compromised in vitiligo [29]. …”

Section: Introductionmentioning

confidence: 99%

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Topical Histamine Stimulates Repigmentation of Nonsegmental Vitiligo by a Receptor-Dependent Mechanism

Li¹,

Xu²,

Lin

et al. 2017

Skin Pharmacol Physiol

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Background: Though vitiligo is a common depigmentary disorder, it still represents a substantial therapeutic challenge. Therapeutic options are limited in part due to its uncertain etiology. Objective: Because recent studies suggest that histamine stimulates melanogenesis in vitro, we determined here whether topical histamine stimulates repigmentation in patients with stable, nonsegmental vitiligo. Methods: A total of 23 otherwise normal volunteers with vitiligo, including 14 males and 9 females aged 6-59 years (mean age 29.2 ± 2.8), were enrolled in this study. 1% histamine in distilled water was applied to the lesions twice daily for 5 weeks, while comparable lesions, treated with distilled water alone, served as the controls. The melanin index was measured on the uninvolved and lesional skin sites before and after 5 weeks of treatments using the melanin/erythema probe connected to a Courage-Khazaka MPA5 (Cologne, Germany). Changes in epidermal permeability barrier were also assessed at the same time point. To determine whether histamine-induced repigmentation is receptor-dependent, both ears of C57BL/6J mice were treated topically with 5% cimetidine, a histamine type 2 receptor (H2r) antagonist, twice daily for 10 days. One hour after each cimetidine application, the right ear was treated topically with 10% histamine, while vehicle alone was applied to the left ear. Changes in melanin index were measured 24 h after the last application of histamine and vehicle as described in the human study. Results: In patients with vitiligo treated with vehicle alone for 5 weeks, the melanin index remained unchanged, while topical histamine treatment increased the melanin index by 38% (p < 0.001 vs. both vehicle and pretreatment), which was paralleled by a >60% reduction in lesion surface area. Moreover, topical histamine accelerated permeability barrier recovery. No adverse events were observed following histamine applications. In mice, topical histamine significantly increased the melanin index, while topical co-applications of the H2r antagonist (cimetidine) prevented the expected histamine-induced increase in melanin index. Conclusions: These studies indicate that topical histamine or an H2r agonist could be useful for treating nonsegmental vitiligo, but further clinical studies in large populations will be required to validate the efficacy and safety of this approach.

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Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Topical Histamine Stimulates Repigmentation of Nonsegmental Vitiligo by a Receptor-Dependent Mechanism

Li¹,

Xu²,

Lin

et al. 2017

Skin Pharmacol Physiol

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“…Reductions in inflammation alone can, however, reduce TEWL due to the 'vicious cycle' that is operative in AD. As noted above, recent studies have shown that topical immunomodulators compromise barrier function in normal skin 83 , as do topical glucocorticoids 76,84 . Thus, as AD improves, continued topical applications of steroids and immunosuppressants (IS) likely begin to compromise barrier function.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Therapeutic Implications of a Barrier-based Pathogenesis of Atopic Dermatitis

Elias

2010

Ann Dermatol

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In this review, I first provide relevant background information about normal epidermal barrier structure and function. I then update recent information about how inherited defects in either filaggrin and/or in the serine protease inhibitor, lymphoepithelial Kazal-type inhibitor 1, converge to stimulate the development of atopic dermatitis (AD). Next I explain the multiple mechanisms whereby a primary barrier abnormality in AD can lead to inflammation. Furthermore, I explore how certain acquired stressors, such as a reduced external humidity, high pH soaps/surfactants, psychological stress, as well as secondary Staphylococcus aureus infections initiate or further aggravate AD. Finally, and most importantly, I compare various therapeutic paradigms for AD, highlighting the risks and benefits of glucocorticoids and immunomodulators vs. corrective, lipid replacement therapy. (Ann Dermatol 22(3) 245∼254, 2010)

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“…In contrast to topical steroids, pimecrolimus and tacrolimus do not induce skin atrophy, and thus calcineurin inhibitors are suitable for longterm maintenance therapy even on the head, neck and intertriginous areas [96][97][98]. Topical calcineurin inhibitors influence the epidermal barrier function in several ways, and a beneficial effect is observed by improving SC hydration and reducing TEWL [100,103].…”

Section: Topical Calcineurin Inhibitorsmentioning

confidence: 99%

“…The calcineurin inhibitor-induced impairment of the permeability and antimicrobial barrier could be prevented by emollient treatment [103].…”

Section: Topical Calcineurin Inhibitorsmentioning

confidence: 99%

Pharmacological Targeting of the Epidermal Barrier

Kemény¹,

Nagy²,

Csoma³

et al. 2016

CPD

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The most important function of the skin is to form a barrier between the body and the external environment. The epidermal barrier prevents transepidermal water loss from the skin, but also serves as a barrier to the entry of harmful environmental allergic, toxic or infectious substances. Inherited defects in the genes encoding the components of the epidermal barrier result in the development of rare genetic disorders, whereas polymorphisms in these genes together with environmental factors cause frequent inflammatory skin diseases, such as atopic dermatitis. In this review, components of the skin-barrier function will be reviewed with special emphasis on how the altered epidermal barrier might be repaired. The different strategies to increase the transdermal penetration of drugs is also discussed.3

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Topical calcineurin inhibitors compromise stratum corneum integrity, epidermal permeability and antimicrobial barrier function

Cited by 55 publications

References 51 publications

Topical Histamine Stimulates Repigmentation of Nonsegmental Vitiligo by a Receptor-Dependent Mechanism

Topical Histamine Stimulates Repigmentation of Nonsegmental Vitiligo by a Receptor-Dependent Mechanism

Therapeutic Implications of a Barrier-based Pathogenesis of Atopic Dermatitis

Pharmacological Targeting of the Epidermal Barrier

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