Rapid improvement of prurigo nodularis with cyclosporine treatment

Wiznia, Lauren E.; Callahan, Shields; Cohen, David E.; Orlow, Seth J.

doi:10.1016/j.jaad.2018.02.024

Cited by 28 publications

(17 citation statements)

References 5 publications

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“…The 4 weeks treatment with aprepitant led to significant reduction of itch intensity. This is in line with other therapies, like cyclosporine treatment, were intensity reduction can be achieved within 2–4 weeks But, as expected, complete healing of PN lesions was not achieved. This would necessitate long‐term treatment of several months …”

Section: Discussionsupporting

confidence: 89%

Neurokinin 1 receptor antagonists exhibit peripheral effects in prurigo nodularis including reduced ERK1/2 activation

Agelopoulos

Rülander

Dangelmaier

et al. 2019

Acad Dermatol Venereol

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Background Aprepitant is a neurokinin 1 receptor (NK1R) antagonist used for its antipruritic properties in dermatoses and systemic diseases. The mode of action is still unclear. A peripheral effect is assumed as aprepitant shows efficacy in inflammatory skin diseases including prurigo nodularis (PN). Objectives To investigate the peripheral effects of NK1R antagonism in PN and cell culture models. Methods Subjects with PN received an aprepitant treatment. Clinical, morphological and immunohistochemical changes were investigated in skin biopsies before and after treatment. Expression of NK1R was analysed by immunohistochemistry and for downstream pathways ((p)ERK1/2) by Western blotting in PN patients and matched healthy volunteers. Effects of NK1R blocking were analysed in cell cultures of primary keratinocytes by Western blotting for (p)ERK1/2 and by qPCR for NK1R, interleukin (IL)‐1beta, IL‐6, IL‐8 and TNFalpha. Results Aprepitant treatment showed significant reduction in pruritus intensity (P < 0.05) in PN and relevant immunohistochemical changes (down: CD5, CD25, up: CD79a, IL4). NK1R expression was higher in keratinocytes of PN patients compared to healthy controls. After treatment, epidermal NK1R expression increased while expression and activation of ERK1/2 decreased. In vitro, receptor up‐regulation and reduced expression and activation of ERK1/2 were confirmed and reduced IL‐expression shown when blocking NK1R. Conclusion Our data confirm that NK1R antagonists such as aprepitant exhibit effects in the skin. Epidermal receptor expression, epidermal inflammatory ILs, ERK1/2 MAPK signalling and cutaneous inflammatory infiltrate were targets of NK1R antagonism. This may explain partly the antipruritic effect of NK1R antagonists next to its role in the central nervous system.

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Section: Discussionsupporting

confidence: 89%

Neurokinin 1 receptor antagonists exhibit peripheral effects in prurigo nodularis including reduced ERK1/2 activation

Agelopoulos

Rülander

Dangelmaier

et al. 2019

Acad Dermatol Venereol

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“…The 4 weeks treatment with aprepitant led to significant reduction of itch intensity. This is in line with other therapies, like cyclosporine treatment, were intensity reduction can be achieved within 2-4 weeks 33 But, as expected, complete healing of PN lesions was not achieved. This would necessitate long-term treatment of several months.…”

Section: Discussionsupporting

confidence: 89%

264 Neurokinin 1 receptor antagonists exhibit peripheral effects in prurigo nodularis including reduced ERK1/2 activation

Agelopoulos

Rülander

Dangelmaier

et al. 2019

Journal of Investigative Dermatology

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Background Aprepitant is a neurokinin 1 receptor (NK1R) antagonist used for its antipruritic properties in dermatoses and systemic diseases. The mode of action is still unclear. A peripheral effect is assumed as aprepitant shows efficacy in inflammatory skin diseases including prurigo nodularis (PN).Objectives To investigate the peripheral effects of NK1R antagonism in PN and cell culture models.Methods Subjects with PN received an aprepitant treatment. Clinical, morphological and immunohistochemical changes were investigated in skin biopsies before and after treatment. Expression of NK1R was analysed by immunohistochemistry and for downstream pathways ((p)ERK1/2) by Western blotting in PN patients and matched healthy volunteers. Effects of NK1R blocking were analysed in cell cultures of primary keratinocytes by Western blotting for (p)ERK1/2 and by qPCR for NK1R, interleukin (IL)-1beta, IL-6, IL-8 and TNFalpha.Results Aprepitant treatment showed significant reduction in pruritus intensity (P < 0.05) in PN and relevant immunohistochemical changes (down: CD5, CD25, up: CD79a, IL4). NK1R expression was higher in keratinocytes of PN patients compared to healthy controls. After treatment, epidermal NK1R expression increased while expression and activation of ERK1/2 decreased. In vitro, receptor up-regulation and reduced expression and activation of ERK1/2 were confirmed and reduced IL-expression shown when blocking NK1R.Conclusion Our data confirm that NK1R antagonists such as aprepitant exhibit effects in the skin. Epidermal receptor expression, epidermal inflammatory ILs, ERK1/2 MAPK signalling and cutaneous inflammatory infiltrate were targets of NK1R antagonism. This may explain partly the antipruritic effect of NK1R antagonists next to its role in the central nervous system. Rolf Dierichs foundation, DFG -Deutsche Forschungsgemeinschaft; grant numbers: STA1159/4-1; AG271/1-1. expressed in various cell types in the skin including keratinocytes, mast cells and fibroblasts. 7 Sensory neurons release SP directly into peripheral tissues, 8,9 where it has an efferent roleThe paper presents partial results of the doctor thesis of FR and JD. JEADV Results Effects of blocking of NK1R in vivoPruritus intensity and scratch symptoms Prurigo nodularis lesions improved slightly after aprepitant treatment (Fig. 1).

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“…Methotrexate, a potent anti‐inflammatory drug, used successfully in chronic prurigo, inhibits production of IL‐4, IL‐13, IFNγ, and TNFα induced by T‐cell activation . Ciclosporine, which decreases T‐lymphocyte production of several proinflammatory cytokines , improves prurigo nodularis within approximately 3 weeks …”

mentioning

confidence: 99%

“…9,10 Ciclosporine, which decreases T-lymphocyte production of several proinflammatory cytokines, improves prurigo nodularis within approximately 3 weeks. 11 Secukinumab, a monoclonal anti-IL-17A antibody, licensed for plaque psoriasis and psoriasis arthritis, has been shown to effectively reduce itch in psoriasis patients. 12 It would be therefore tempting to study IL-17 inhibitors on patients with chronic prurigo.…”

mentioning

confidence: 99%