T. Huynh

An IL-17–dominant immune profile is shared across the major orphan forms of ichthyosis

Background: The ichthyoses are rare genetic disorders associated with generalized scaling, erythema, and epidermal barrier impairment. Pathogenesis‐based therapy is largely lacking because the underlying molecular basis is poorly understood. Objective: We sought to characterize molecularly cutaneous inflammation and its correlation with clinical and barrier characteristics. Methods: We analyzed biopsy specimens from 21 genotyped patients with ichthyosis (congenital ichthyosiform erythroderma, n = 6; lamellar ichthyosis, n = 7; epidermolytic ichthyosis, n = 5; and Netherton syndrome, n = 3) using immunohistochemistry and RT‐PCR and compared them with specimens from healthy control subjects, patients with atopic dermatitis (AD), and patients with psoriasis. Clinical measures included the Ichthyosis Area Severity Index (IASI), which integrates erythema (IASI‐E) and scaling (IASI‐S); transepidermal water loss; and pruritus. Results: Ichthyosis samples showed increased epidermal hyperplasia (increased thickness and keratin 16 expression) and T‐cell and dendritic cell infiltrates. Increases of general inflammatory (IL‐2), innate (IL‐1&bgr;), and some TH1/interferon (IFN‐&ggr;) markers in patients with ichthyosis were comparable with those in patients with psoriasis or AD. TNF‐&agr; levels in patients with ichthyosis were increased only in those with Netherton syndrome but were much lower than in patients with psoriasis and those with AD. Expression of TH2 cytokines (IL‐13 and IL‐31) was similar to that seen in control subjects. The striking induction of IL‐17–related genes or markers synergistically induced by IL‐17 and TNF‐&agr; (IL‐17A/C, IL‐19, CXCL1, PI3, CCL20, and IL36G; P < .05) in patients with ichthyosis was similar to that seen in patients with psoriasis. IASI and IASI‐E scores strongly correlated with IL‐17A (r = 0.74, P < .001) and IL‐17/TNF–synergistic/additive gene expression. These markers also significantly correlated with transepidermal water loss, suggesting a link between the barrier defect and inflammation in patients with ichthyosis. Conclusion: Our data associate a shared TH17/IL‐23 immune fingerprint with the major orphan forms of ichthyosis and raise the possibility of IL‐17–targeting strategies.

Alterations in B-cell subsets in pediatric patients with early atopic dermatitis

Background B cells undergo maturation and class‐switching in response to antigen exposure and T‐cell help. Early B‐cell differentiation has not been defined in patients with early‐onset atopic dermatitis (AD). Objective We sought to define the frequency of B‐cell subsets associated with progressive B‐cell maturation and IgE class‐switching. Methods We studied 27 children and 34 adults with moderate‐to‐severe AD (mean SCORAD score, 55 and 65, respectively) and age‐matched control subjects (15 children and 27 adults). IgD/CD27 and CD24/CD38 core gating systems and an 11‐color flow cytometric panel were used to determine the frequencies of circulating B‐cell subsets. Serum total and allergen‐specific IgE (sIgE) levels were measured by using ImmunoCAP. Results Compared with adults, children showed T‐cell predominance in the skin. Circulating CD19+CD20+ B‐cell counts were lower in patients with pediatric AD than in control subjects (24% vs 33%, P = .04), whereas CD3+ T‐cell counts were higher (62% vs 52%, P = .05). A decreased B‐cell/T‐cell lymphocyte ratio with age was observed only in pediatric control subjects (r = −0.48, P = .07). In pediatric patients with AD, a positive correlation was observed between B‐cell/T‐cell ratio and nonswitched memory B‐cell counts (r = 0.42, P = .03). Higher frequencies of positive sIgE levels were seen in pediatric patients with AD (P < .0001). Diverse sIgE levels correlated with SCORAD scores and age of pediatric patients with AD (P < .01). Positive correlations were observed between activated B‐cell and memory T‐cell counts (P < .02). In patients with AD, IgE sensitization to most allergens clustered with age, TH1, TH2, total IgE levels, and B‐cell memory subsets. Conclusions Peripheral B and T cells are altered in pediatric patients with early AD, but T cells predominate in skin lesions.

Early-onset pediatric atopic dermatitis is characterized by T H 2/T H 17/T H 22-centered inflammation and lipid alterations

Background: Although atopic dermatitis (AD) often starts in early childhood, detailed tissue profiling of early‐onset AD in children is lacking, hindering therapeutic development for this patient population with a particularly high unmet need for better treatments. Objective: We sought to globally profile the skin of infants with AD compared with that of adults with AD and healthy control subjects. Methods: We performed microarray, RT‐PCR, and fluorescence microscopy studies in infants and young children (<5 years old) with early‐onset AD (<6 months disease duration) compared with age‐matched control subjects and adults with longstanding AD. Results: Transcriptomic analyses revealed profound differences between pediatric patients with early‐onset versus adult patients with longstanding AD in not only lesional but also nonlesional tissues. Although both patient populations harbored TH2‐centered inflammation, pediatric AD also showed significant TH17/TH22 skewing but lacked the TH1 upregulation that characterizes adult AD. Pediatric AD exhibited relatively normal expression of epidermal differentiation and cornification products, which is downregulated in adults with AD. Defects in the lipid barrier (eg, ELOVL fatty acid elongase 3 [ELOVL3] and diacylglycerol o‐acyltransferase 2 [DGAT2]) and tight junction regulation (eg, claudins 8 and 23) were evident in both groups. However, some lipid‐associated mediators (eg, fatty acyl‐CoA reductase 2 and fatty acid 2‐hydroxylase) showed preferential downregulation in pediatric AD, and lipid barrier genes (FA2H and DGAT2) showed inverse correlations with transepidermal water loss, a functional measure of the epidermal barrier. Conclusions: Skin samples from children and adult patients with AD share lipid metabolism and tight junction alterations, but epidermal differentiation complex defects are only present in adult AD, potentially resulting from chronic immune aberration that is not yet present in early‐onset disease.

Multiple sclerosis association with psoriasis: a large U.S. population, single centre, retrospective cross-sectional study

cutaneous vasculitis and arthritis. Possible immune complex syndrome. Mayo Clin Proc 1973; 48: 340–348. 5 Messiaen T, Van Damme B, Kuypers D, Maes B, Vanrenterghem Y. Crescentic glomerulonephritis complicating the course of a hypocomplementemic urticarial vasculitis. Clin Nephrol 2000; 54: 409–412. 6 Grotz W, Baba H, Becker J et al. Hypocomplementemic urticarial vasculitis syndrome. An interdisciplinary challenge. Dtsch Arztebl Int 2009; 106: 756–763. 7 Mehregan D, Hall M, Gibson L. Urticarial vasculitis? A histopathological and clinical review of 72 cases. J Am Acad Dermatol 1992; 26: 441–448. 8 Aydogan K, Karadogan S, Adim S et al. Hypocomplementemic urticarial vasculitis: a rare presentation of systemic lupus erythematosus. Int J Dermatol 2006; 45: 1057–1061. 9 Ghazanfar MN, Thomsen SF. Omalizumab for urticarial vasculitis: case report and review of the literature. Case Rep Dermatol Med 2015; 2015: 576893. 10 Diez LS, Tamayo LM, Cardona R. Omalizumab: therapeutic option in chronic spontaneous urticaria difficult to control with associated vasculitis, report of three cases. Biomedica 2013; 33: 503–512. 11 Kaplan AP, Gim enez-Arnau AM, Saini SS. Mechanisms of action that contribute to efficacy of omalizumab in chronic spontaneous urticaria. Allergy 2017; 72: 519–533.

The spectrum of manifestations in desmoplakin gene (DSP) spectrin repeat 6 domain mutations: Immunophenotyping and response to ustekinumab

Background The immune abnormalities underlying the ichthyoses are poorly understood. Objective To determine the immunophenotype of an ichthyosis resulting from mutations in the spectrin repeat 6 (SR6) domain of desmoplakin gene (DSP) and target therapy on the basis of molecular pathogenesis. Methods Immunophenotyping was performed by using the blood and skin of a girl with SR6 region DSP mutations causing erythroderma/ichthyosis and cardiomyopathy. Results On the basis of the discovery of T helper 1 and T helper 17/interleukin 23 skewing in the skin and T helper 17/interleukin 22 skewing in blood, ustekinumab therapy was initiated. Ustekinumab was also administered to a boy with an SR6 region DSP mutation and ichthyosis without cardiomyopathy. Both children responded despite previous poor responses to immunosuppressants and retinoids. Limitations Small number of patients and immunophenotyping in only 1 patient. Conclusion An understanding of the molecular basis of inflammation in rare cutaneous disorders can lead to targeted therapy, which promises to be more beneficial than broad immunosuppressants.

Langerhans cell histiocytosis: A neoplastic disorder driven by Ras-ERK pathway mutations

&NA; Langerhans cell histiocytosis (LCH) is a disorder of myeloid neoplasia of dendritic cells that affects 1 in 200,000 children <15 years of age and even fewer adults. LCH presents with a spectrum of clinical manifestations. High‐risk stratification is reserved for infiltration of blood, spleen, liver, and lungs. After decades of debate on the disease pathogenesis, a neoplastic mechanism is now favored on the basis of LCH cell clonality, rare cases of familial clustering, and recent evidence of mutations involving the Ras/Raf/MEK (mitogen‐activated protein kinase kinase)/ERK (extracellular signal‐regulated kinase) pathway in lesional biopsy specimens. Somatic mutations are most often found in BRAF (BRAFV600E in 47.1% of reported patients) and MAP2K1 (21.7%) and uncommonly found in MAP3K1 or ARAF. Increased levels of phospho‐ERK in lesional tissue, activation of Ras/Raf/MEK/ERK signaling with these mutations in vitro, and the mutual exclusivity of these mutations in a given patient suggest a central role for activation of the Ras/Raf/MEK/ERK oncogenic pathway in LCH. Immunohistochemical assessment of lesional tissue using the VE1 BRAFV600E mutation–specific antibody can serve as a screening tool for BRAFV600E‐positive LCH. Case reports suggest that BRAFV600E‐positive LCH unresponsive to standard therapy might respond to B‐Raf‐MEK pathway inhibition, but rigorous randomized clinical trials have yet to be performed.

Ichthyosis molecular fingerprinting shows profound TH17 skewing and a unique barrier genomic signature

Background: Ichthyoses are a group of rare skin disorders lacking effective treatments. Although genetic mutations are progressively delineated, comprehensive molecular phenotyping of ichthyotic skin could suggest much‐needed pathogenesis‐based therapy. Objective: We sought to profile the molecular fingerprint of the most common orphan ichthyoses. Methods: Gene, protein, and serum studies were performed on skin and blood samples from 29 patients (congenital ichthyosiform erythroderma, n = 9; lamellar ichthyosis, n = 8; epidermolytic ichthyosis, n = 8; and Netherton syndrome, n = 4), as well as age‐matched healthy control subjects (n = 14), patients with psoriasis (n = 30), and patients with atopic dermatitis (AD; n = 16). Results: Using criteria of a fold change of greater than 2 and a false discovery rate of less than 0.05, 132 differentially expressed genes were shared commonly among all ichthyoses, including many IL‐17 and TNF‐&agr;–coregulated genes, which are considered hallmarks of psoriasis (defensin beta 4A, kynureninase, and vanin 3). Although striking upregulation of TH17 pathway genes (IL17F and IL36B/G) resembling that seen in patients with psoriasis was common to all patients with ichthyoses in a severity‐related manner, patients with Netherton syndrome showed the greatest T‐cell activation (inducible costimulator [ICOS]) and a broader immune phenotype with TH1/IFN‐&ggr;, OASL, and TH2/IL‐4 receptor/IL‐5 skewing, although less than seen in patients with AD (all P < .05). Ichthyoses lacked the epidermal differentiation and tight junction alterations of patients with AD (loricrin, filaggrin, and claudin 1) but showed characteristic alterations in lipid metabolism genes (ELOVL fatty acid elongase 3 and galanin), with parallel reductions in extracellular lipids and corneocyte compaction in all ichthyoses except epidermolytic ichthyosis, suggesting phenotypic variations. Transepidermal water loss, a functional barrier measure, significantly correlated with IL‐17–regulated gene expression (IL17F and IL36A/IL36B/IL36G). Conclusion: Similar to patients with AD and psoriasis, in whom cytokine dysregulation and barrier impairment orchestrate disease phenotypes, psoriasis‐like immune dysregulation and lipid alterations characterize the ichthyoses. These data support the testing of IL‐17/IL‐36–targeted therapeutics for patients with ichthyosis similar to those used in patients with psoriasis.

Malignant melanoma associated with chronic once daily aspirin exposure in males: a large, single-center, urban, U.S. patient population cohort study from the Research on Adverse Drug events And Reports (RADAR) project

To the Editor: Conflicting evidence exists for the risk of malignant melanoma (MM) subsequent to chronic aspirin exposure. Although a study in the Journal of the American Academy of Dermatology demonstrated that chronic aspirin exposure before and after MM diagnosis in a large midwestern US population was associated with overall prolonged survival, the risk of MM subsequent to chronic aspirin exposure remains uncertain. The aim of this study, which was also conducted within a large midwestern US patient population, was to determine whether there was a detectable risk for MM after 1 year or more of chronic aspirin exposure. Using the methodology of the ‘‘Research on Adverse Drug events And Report’’, the Northwestern Medicine Enterprise Data Warehouse,

Hidradenitis suppurativa association at the time of, or subsequent to, diagnosis of inflammatory bowel disease in a large U.S. patient population

associated with milder skin symptoms. We report the case of a woman affected by atopic dermatitis and asthma in childhood who developed at the age of 63 years conjunctivitis associated with blepharitis without causative contact allergen identification at skin testing. She received multiple topical and systemic treatments including cyclosporine 2 mg/kg/ day stopped after 4 days because of digestive adverse effects. She was examined at the age of 72 years for severe ulcerated keratoconjunctivitis complicated of corneal ulcers with reduced visual acuity, justifying the introduction of azathioprine (AZ) 100 mg/ day. Ulceration and keratitis improved, but one year later, a papulopustular eruption on the face led to the clinical and pathological diagnosis of rosacea (Fig. 1). Under doxycycline 200 mg/day, lesions disappeared in 4 weeks and doxycycline was tapered to 50 mg/day in the following 3 months. Although not described as rosacea trigger, AZ was strongly suspected, and AZ dosing was progressively decreased over 3 months. At 25 mg AZ/day, keratoconjunctivitis relapsed requiring to increase AZ doses. Milder rosacea relapses were observed when AZ was increased to 50 mg/day. After a year under careful ophthalmological and dermatological monitoring, a maintenance dose of 50 mg alternating with 25 mg/day AZ was found able to control keratoconjunctivitis and blepharitis, without recurring signs of rosacea. Overall, AZ was helpful to control severe atopic keratoconjunctivitis, but triggered rosacea with a dose–response effect. This observation highlights that skin symptoms in a person under AZ for atopic keratoconjunctivitis can be caused by other disorders than AD, such as rosacea, and that AZ-induced rosacea, although possibly rare or underreported, exists. A statement of all funding sources that supported the work: 1. V edie A-L, Ezzedine K, Amazan E, Boralevi F, Milpied B, Ta€ıeb A, et al. Long-Term Use of Systemic Treatments for Moderate-to-Severe Atopic Dermatitis in Adults: A Monocentric Retrospective Study. Acta Derm Venereol. 2016 Mar 1.