title: Topical Mineralocorticoid Receptor Blockade Limits Glucocorticoid-Induced Epidermal Atrophy in Human Skin.
abstract: A major deleterious side effect of glucocorticoids is skin atrophy. Glucocorticoids activate the glucocorticoid and the mineralocorticoid (MR) receptor, both present in the epidermis. We hypothesized that glucocorticoid-induced epidermal atrophy may be related to inappropriate occupancy of MR by glucocorticoids. We evaluated whether epidermal atrophy induced by the topical glucocorticoid clobetasol could be limited by coadministration of MR antagonist. In cultured human skin explants, the epidermal atrophy induced by clobetasol was significantly limited by MR antagonism (canrenoate and eplerenone). Blockade of the epithelial sodium channel ENaC by phenamil was also efficient, identifying a role of MR-ENaC cascade in keratinocytes, acting through restoration of clobetasol-induced impairment of keratinocyte proliferation. In the SPIREPI randomized double-blind controlled trial, gels containing clobetasol, the MR antagonist spironolactone, both agents, or placebo were applied on four zones of the forearms of 23 healthy volunteers for 28 days. Primary outcome was histological thickness of the epidermis with clobetasol alone or clobetasol+spironolactone. Spironolactone alone did not affect the epidermal thickness but coapplication of clobetasol and spironolactone significantly limited clobetasol-induced atrophy and was well tolerated. Altogether, these findings identify MR as a factor regulating epidermal homeostasis and suggest that topical MR blockade could limit glucocorticoid-induced epidermal atrophy.
authors: Assistance Publique Hopitaux de Paris (APHP), Hôpital Bichat Claude Bernard, Département de Dermatologie, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France. Electronic address: eve.maubec@inserm.fr.
authors: Eve
authors: E
authors: Maubec
authors: Université Paris Diderot, Sorbonne Paris Cité, Paris, France; UMR 1137, INSERM, IAME, Paris, France; APHP, Hôpital Bichat Claude Bernard, Département de Biostatistiques, Paris, France.
authors: Cédric
authors: C
authors: Laouénan
authors: APHP, Hôpital Bichat Claude Bernard, Département d'Anatomopathologie, Paris, France.
authors: Lydia
authors: L
authors: Deschamps
authors: UMR 938, INSERM, Centre de Recherches St Antoine, Paris, France; Université Pierre et Marie Curie, Paris, France.
authors: Van Tuan
authors: VT
authors: Nguyen
authors: Assistance Publique Hopitaux de Paris (APHP), Hôpital Bichat Claude Bernard, Département de Dermatologie, Paris, France.
authors: Isabelle
authors: I
authors: Scheer-Senyarich
authors: APHP, Hôpital Bichat Claude Bernard, Département de Radiologie, Paris, France.
authors: Anne-Catherine
authors: AC
authors: Wackenheim-Jacobs
authors: Assistance Publique Hopitaux de Paris (APHP), Hôpital Bichat Claude Bernard, Département de Dermatologie, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors: Maud
authors: M
authors: Steff
authors: Université Pierre et Marie Curie, Paris, France; UMR 1138, INSERM, Centre de Recherche des Cordeliers, Paris, France.
authors: Stéphanie
authors: S
authors: Duhamel
authors: Université Paris Diderot, Sorbonne Paris Cité, Paris, France; UMR 1137, INSERM, IAME, Paris, France; APHP, Hôpital Bichat Claude Bernard, Centre d'Investigation Clinique 007, Paris, France.
authors: Sarah
authors: S
authors: Tubiana
authors: Assistance Publique Hopitaux de Paris (APHP), Hôpital Bichat Claude Bernard, Département de Dermatologie, Paris, France.
authors: Nesrine
authors: N
authors: Brahimi
authors: APHP, Hôpital Necker-Enfants Malades, Département d'Anatomie et Cytologie Pathologiques, Paris, France.
authors: Stéphanie
authors: S
authors: Leclerc-Mercier
authors: Assistance Publique Hopitaux de Paris (APHP), Hôpital Bichat Claude Bernard, Département de Dermatologie, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors: Béatrice
authors: B
authors: Crickx
authors: Université Pierre et Marie Curie, Paris, France; UMR 1138, INSERM, Centre de Recherche des Cordeliers, Paris, France.
authors: Claudine
authors: C
authors: Perret
authors: Hôpital Cochin Tarnier, Département de Dermatologie, Paris, France; Université Paris Descartes, Paris, France.
authors: Selim
authors: S
authors: Aractingi
authors: Université Paris Diderot, Sorbonne Paris Cité, Paris, France; UMR 1138, INSERM, Centre de Recherche des Cordeliers, Paris, France; APHP, Hôpital Bichat Claude Bernard, Département de Physiologie, Paris, France.
authors: Brigitte
authors: B
authors: Escoubet
authors: Université Paris Diderot, Sorbonne Paris Cité, Paris, France; UMR 1137, INSERM, IAME, Paris, France; APHP, Hôpital Bichat Claude Bernard, Centre d'Investigation Clinique 007, Paris, France.
authors: Xavier
authors: X
authors: Duval
authors: APHP, Hôpital Bichat Claude Bernard, Département de Pharmacie, Paris, France; Université Paris Descartes, Chimie ParisTech, Paris, France; UMR 8151, CNRS, Paris, France; UMR 1022, INSERM, Paris, France.
authors: Philippe
authors: P
authors: Arnaud
authors: Université Pierre et Marie Curie, Paris, France; UMR 1138, INSERM, Centre de Recherche des Cordeliers, Paris, France.
authors: Frederic
authors: F
authors: Jaisser
authors: Université Paris Diderot, Sorbonne Paris Cité, Paris, France; UMR 1137, INSERM, IAME, Paris, France; APHP, Hôpital Bichat Claude Bernard, Département de Biostatistiques, Paris, France.
authors: France
authors: F
authors: Mentré
authors: Université Pierre et Marie Curie, Paris, France; UMR 1138, INSERM, Centre de Recherche des Cordeliers, Paris, France.
authors: Nicolette
authors: N
authors: Farman
mesh_terms: D000287:Administration, Topical; D000328:Adult; D001284:Atrophy / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D001707:Biopsy, Needle; D002990:Clobetasol / Q000008:administration & dosage*; D046169:Dermoscopy / Q000379:methods; D004311:Double-Blind Method; D004817:Epidermis / Q000187:drug effects / Q000473:pathology*; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects*; D064368:Healthy Volunteers; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage*; D018161:Receptors, Mineralocorticoid / Q000187:drug effects*; D012016:Reference Values; D018570:Risk Assessment; D013148:Spironolactone / Q000008:administration & dosage*; D018709:Statistics, Nonparametric; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D005938:Glucocorticoids; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D002990:Clobetasol