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Archives of Dermatological Research Mar 2023Treatment of congenital ichthyoses primarily focuses on reversing skin scaling and is not pathogenesis based. Recent studies showed Th17 immune skewing, as in psoriasis,... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Treatment of congenital ichthyoses primarily focuses on reversing skin scaling and is not pathogenesis based. Recent studies showed Th17 immune skewing, as in psoriasis, across the spectrum of ichthyosis, suggesting that targeting this pathway might broadly reduce disease severity.
OBJECTIVE
To determine whether secukinumab, an IL-17A inhibitor, can improve ichthyosis across several congenital ichthyosis subtypes.
DESIGN
Exploratory 16-week double-blind, randomized, placebo-controlled trial comparing secukinumab 300 mg every 4wks to placebo (1:1 randomization) in adults with the four major congenital ichthyosis subtypes (NCT03041038), followed by a 16-week open-label phase to evaluate response of the placebo-first group and a 20-week extension for safety. Significant differences in secukinumab- vs. placebo-treated subjects at Wk16 in the Ichthyosis Area Severity Index (IASI) score and lack of increased mucocutaneous bacterial and/or fungal infections were the co-primary efficacy and safety endpoints, respectively.
SETTING
Two tertiary referral centers: Northwestern University Feinberg School of Medicine, Chicago, and Mount Sinai Icahn School of Medicine, New York.
PARTICIPANTS
Twenty subjects ≥ 18 yo with genotype-confirmed epidermolytic ichthyosis, Netherton syndrome, lamellar ichthyosis, or congenital ichthyosiform erythroderma with at least moderate erythroderma.
RESULTS
IL-17A inhibition did not significantly reduce severity or increase mucocutaneous infections among the 18 who completed the 16-week double-blind phase. Five patients with 29-50% clinical improvement at Wk32 requested drug continuation. Th17-related biomarkers were not significantly reduced vs. baseline or placebo-treated levels.
LIMITATIONS
Small sample size; heterogeneous ichthyosis subsets.
CONCLUSION
IL-17 inhibition with secukinumab is safe, but not efficacious across the spectrum of adult ichthyoses.
GOV REGISTRATION NUMBER
NCT03041038; first posted on 02/02/2017.
Topics: Adult; Humans; Ichthyosis, Lamellar; Antibodies, Monoclonal; Interleukin-17; Ichthyosis; Psoriasis; Ichthyosiform Erythroderma, Congenital; Severity of Illness Index; Double-Blind Method; Treatment Outcome
PubMed: 35218370
DOI: 10.1007/s00403-022-02325-3 -
Pediatric Dermatology 2024Ichthyoses are a heterogeneous group of skin disorders characterized by scaling and erythema. Recognizing the variability of scale and erythema by region and ichthyosis...
BACKGROUND
Ichthyoses are a heterogeneous group of skin disorders characterized by scaling and erythema. Recognizing the variability of scale and erythema by region and ichthyosis subtype, we developed the Ichthyosis Scoring System (ISS) to quantify severity. We previously found ISS to have high inter- and intrarater reliability in evaluating photographic images. To confirm ISS clinical utility, we examined its performance at the 2022 Foundation for Ichthyosis and Related Skin Types conference.
METHODS
Sixty-five participants were evaluated by 3 of 9 medical professionals trained to score ichthyosis scale and erythema using ISS. Intrarater and interrater intraclass correlation coefficients (ICC) were analyzed using one-way and two-way random effects models, respectively.
RESULTS
Intrarater reliability was excellent (ICC = 0.931, 95% CI, 0.921-0.940) for scale and good (ICC = 0.876, 95% CI, 0.853-0.899) for erythema scoring. Compared to photo validation with excellent intrarater reliability ratings for both scale (ICC = 0.956, 95% CI, 0.925-0.974) and erythema (ICC = 0.913, 95% CI, 0.855-0.949), ISS demonstrated equivalent reliability for live use. Overall interrater reliability for 10 body sites showed excellent (ICC >0.9) and good (ICC >0.75) agreement and consistency for both scale and erythema. Palms were an exception, demonstrating moderate (ICC >0.5) interrater agreement and consistency for erythema evaluation.
CONCLUSIONS
ISS is a reliable measure of global and regional ichthyosis severity during in-person evaluations. Ease-of-use, accessibility, and content validity in both live and photographic evaluation endorse ISS as a standard for ichthyosis severity analysis.
Topics: Humans; Reproducibility of Results; Severity of Illness Index; Observer Variation; Ichthyosis; Ichthyosis, Lamellar; Erythema
PubMed: 38234066
DOI: 10.1111/pde.15508 -
Journal of Preventive Medicine and... Sep 2020Ichthyoses include a heterogeneous group of skin diseases often characterized by persistent scaling and hyperkeratosis with variable erythema, pruritus, and sweating... (Review)
Review
INTRODUCTION
Ichthyoses include a heterogeneous group of skin diseases often characterized by persistent scaling and hyperkeratosis with variable erythema, pruritus, and sweating impairment. The aim of our review was to assess the quality of life in patients with ichthyosis.
METHODS
In July 2018 we performed a systematic search in the electronic database PubMed (MEDLINE). The MESH term "quality of life" was combined, through the Boolean operator AND with the key word "ichthyosis". We considered eligible for the systematic review studies written in English.
RESULTS
The literature search yielded 63 publications, but 7 studies were included in the review. Studies were published in 2003-2014 and involved a minimum of 10 and a maximum of 235 patients. Authors used 5 types of tools: Dermatology Life Quality Index (DLQI), Dermatitis Family Impact Questionnaire (DFI), Nottingham Health Profile (NHP) questionnaire, Short Form Questionnaire 36 and 12 (SF-36, SF-12). Many patients reported worse scores than general population. Patients referred physical problems related to pain (which negatively influenced the mobility).
CONCLUSIONS
Ichthyosis considerably impaired the QoL, especially for paediatric patients. Further studies and efforts should be done to manage and treat the pain.
Topics: Humans; Ichthyosis; Quality of Life; Surveys and Questionnaires
PubMed: 33150225
DOI: 10.15167/2421-4248/jpmh2020.61.3.1450 -
JCI Insight Feb 2024Atopic dermatitis (AD) is a persistent skin disease typified by symptoms of dry skin and recurrent eczema. Patients with AD are at heightened risk for Staphylococcus...
Atopic dermatitis (AD) is a persistent skin disease typified by symptoms of dry skin and recurrent eczema. Patients with AD are at heightened risk for Staphylococcus aureus infection. Group 2 innate lymphoid cells (ILC2s) are mainly activated by epithelial cell-derived cytokines IL-33 and involved in the pathogenesis of AD. However, little is known about the effect of skin delipidization on the epithelial cell-derived cytokines and dermal ILC2s in AD. In our study, we investigated the mechanism by which S. aureus infection modulates and exacerbates the pathogenesis of dry skin, leading to type 2 inflammation in the context of innate immunity. In vivo, we found that S. aureus infection aggravated delipidization-induced dermal IL-33 release and dermal ILC2 accumulation, which exacerbated skin inflammation. We also noticed that Il33fl/fl K14cre mice and Tlr2-/- mice exhibited attenuated skin inflammation. In vitro, treatment with necroptosis inhibitors reduced IL-33 release from S. aureus-infected keratinocytes. Mechanistically, we observed an increase in the necroptosis-associated kinases, MLKL and RIPK3, in S. aureus-infected mice, indicating that IL-33 release was associated with necroptotic cell death responses. Our results reveal that S. aureus infection-elicited keratinocyte necroptosis contributes to IL-33-mediated type 2 inflammation, which exacerbates the pathogenesis of dry skin.
Topics: Humans; Mice; Animals; Immunity, Innate; Staphylococcus aureus; Interleukin-33; Necroptosis; Lymphocytes; Dermatitis, Atopic; Inflammation; Cytokines; Staphylococcal Infections; Ichthyosis; Receptor-Interacting Protein Serine-Threonine Kinases; Protein Kinases
PubMed: 38319737
DOI: 10.1172/jci.insight.166821 -
Clinical and Experimental Dermatology Dec 2022For disorders of keratinization, topical treatment alone may be ineffective, and systemic retinoid therapy may be indicated. Treatment with systemic retinoids...
For disorders of keratinization, topical treatment alone may be ineffective, and systemic retinoid therapy may be indicated. Treatment with systemic retinoids (acitretin, isotretinoin and alitretinoin) has been shown to be effective in reducing disease severity; however, potentially rare adverse effects (AEs) may occur, including hyperostotic skeletal changes. The true prevalence of this AE in adult patients administered life-long therapy is unknown. We identified 3 of 127 (2.4%) patients (with ichthyosis or Darier disease) who had been prescribed isotretinoin with or without acitretin, and who developed radiological signs and clinical symptoms of hyperostosis and ligamentous ossification. This clinical review highlights the significance of retinoid-induced skeletal hyperostosis in patients prescribed long-term, high-dose retinoid therapy for disorders of keratinization. Patients commencing systemic retinoid therapy, particularly women of childbearing age, should be counselled about this important and potentially serious AE, especially if long-term treatment is indicated.
Topics: Adult; Humans; Female; Acitretin; Isotretinoin; Alitretinoin; Hyperostosis; Ichthyosis
PubMed: 35988035
DOI: 10.1111/ced.15382 -
JAMA Dermatology Apr 2022A comprehensive, user-friendly system to assess global ichthyosis disease burden is imperative to improving the care of patients with ichthyosis, identifying appropriate...
IMPORTANCE
A comprehensive, user-friendly system to assess global ichthyosis disease burden is imperative to improving the care of patients with ichthyosis, identifying appropriate participants for clinical trials, and quantifying treatment outcomes. To our knowledge, there is currently no validated scale to objectively and systematically measure ichthyosis severity across the entire body.
OBJECTIVE
To create and evaluate a comprehensive and user-friendly instrument to measure total body ichthyosis severity in adults and children.
DESIGN, SETTING, PARTICIPANTS
In this qualitative study, ichthyosis experts participated in the content development of the Ichthyosis Scoring System (ISS). The body was divided into 10 regions, and Likert scales (0-4) were created to quantify scale and erythema, with extensive descriptors and photographic standards. An 83-image teaching set was created from photographs of participants with ichthyosis. Two cohorts of dermatologists (11 total) independently scored all test photographs twice to evaluate interrater and intrarater reliabilities. Participants were enrolled worldwide from referral centers and patient advocacy groups. Participants of all ages, races, and ethnicities were included in the creation of ISS, and dermatologists with varying experience and areas of expertise participated as raters to evaluate the ISS. The study was conducted from 2019 to 2021, and the data were analyzed in 2021.
MAIN OUTCOMES AND MEASURES
Intraclass correlation coefficients determined overall reliabilities.
RESULTS
Across both cohorts of 11 dermatologists in total, the intraclass correlation coefficients for total, scale and erythema scores were greater than 0.90 (95% CI, 0.77-0.97), greater than 0.91 (95% CI, 0.79-0.98), and greater than 0.88 (95% CI, 0.72-0.97), respectively. Most body sites exhibited moderate to good interrater reliabilities for scale and erythema. Intrarater reliabilities were good to excellent.
CONCLUSIONS AND RELEVANCE
The results of this qualitative study demonstrate reproducibility and suggest that the ISS is a reliable system to measure global ichthyosis severity in adults and children.
Topics: Adult; Child; Erythema; Humans; Ichthyosis; Ichthyosis, Lamellar; Observer Variation; Photography; Reproducibility of Results; Severity of Illness Index
PubMed: 35171201
DOI: 10.1001/jamadermatol.2021.5917 -
The Journal of Clinical Investigation Sep 2020The biology of harlequin ichthyosis (HI), a devastating skin disorder caused by loss-of-function mutations in the gene ABCA12, is poorly understood, and to date, no...
The biology of harlequin ichthyosis (HI), a devastating skin disorder caused by loss-of-function mutations in the gene ABCA12, is poorly understood, and to date, no satisfactory treatment has been developed. We sought to investigate pathomechanisms of HI that could lead to the identification of new treatments for improving patients' quality of life. In this study, RNA-Seq and functional assays were performed to define the effects of loss of ABCA12 using HI patient skin samples and an engineered CRISPR/Cas9 ABCA12 KO cell line. The HI living skin equivalent (3D model) recapitulated the HI skin phenotype. The cytokines IL-36α and IL-36γ were upregulated in HI skin, whereas the innate immune inhibitor IL-37 was strongly downregulated. We also identified STAT1 and its downstream target inducible nitric oxide synthase (NOS2) as being upregulated in the in vitro HI 3D model and HI patient skin samples. Inhibition of NOS2 using the inhibitor 1400W or the JAK inhibitor tofacitinib dramatically improved the in vitro HI phenotype by restoring the lipid barrier in the HI 3D model. Our study has identified dysregulated pathways in HI skin that are feasible therapeutic targets.
Topics: ATP-Binding Cassette Transporters; Amidines; Benzylamines; Cell Culture Techniques; Cells, Cultured; Drug Delivery Systems; Gene Knockdown Techniques; Humans; Ichthyosis, Lamellar; Inflammation; Interleukin-1; Loss of Function Mutation; Models, Biological; Nitric Oxide Synthase Type II; Piperidines; Pyrimidines; STAT1 Transcription Factor
PubMed: 32544098
DOI: 10.1172/JCI132987 -
The Journal of Dermatology Mar 2022This is the English version of guidelines for the management of asteatosis 2021 in Japan. Asteatosis is a synonym of xerosis found in a wide range of diseases that...
This is the English version of guidelines for the management of asteatosis 2021 in Japan. Asteatosis is a synonym of xerosis found in a wide range of diseases that induce dry skin through impaired functions of either water retention of the stratum corneum or skin covering with acid mantle. Patients with asteatosis may be accompanied by pruritus. Moisturizers are the first-line treatment for asteatosis and their adequate use must be recommended. The main purpose of the present guidelines is to define skin symptoms requiring treatment with moisturizers for medical use in patients with asteatosis. If the deterioration of marked scaling or scratch marks is predicted, therapeutic intervention with moisturizers for medical use should be considered even in the absence of pruritus. Regarding six important points requiring decision-making in clinical practice (clinical questions), we evaluated the balance between the benefits and harm of medical interventions in reference to previous reports of clinical research, and presented the recommendation grades and evidence levels to optimize the patient outcome by medical interventions.
Topics: Emollients; Humans; Ichthyosis; Japan; Pruritus; Skin
PubMed: 34970776
DOI: 10.1111/1346-8138.16293 -
JAMA Dermatology Jul 2023
Topics: Humans; Netherton Syndrome; Pyrimidines; Sulfonamides
PubMed: 37163259
DOI: 10.1001/jamadermatol.2023.0561 -
Journal of Dermatological Science Sep 2022Sjögren-Larsson syndrome (SLS) is a neurocutaneous disorder whose causative gene is the fatty aldehyde dehydrogenase ALDH3A2 and of which ichthyosis is the major skin...
BACKGROUND
Sjögren-Larsson syndrome (SLS) is a neurocutaneous disorder whose causative gene is the fatty aldehyde dehydrogenase ALDH3A2 and of which ichthyosis is the major skin symptom. The stratum corneum contains a variety of ceramides, among which ω-O-acylceramides (acylceramides) and protein-bound ceramides are essential for skin permeability barrier formation.
OBJECTIVES
To determine the ceramide classes/species responsible for SLS pathogenesis and the enzymes that are impaired in SLS.
METHODS
Genomic DNA was collected from peripheral blood samples from an SLS patient and her parents, and whole-genome sequencing and Sanger sequencing were performed. Lipids were extracted from stratum corneum samples from the SLS patient and healthy volunteers and subjected to ceramide profiling via liquid chromatography coupled with tandem mass spectrometry.
RESULTS
A duplication (c.55_130dup) and a missense mutation (p.Lys447Glu) were found in the patient's ALDH3A2 gene. The patient had reduced levels of all acylceramide classes, with total acylceramide levels at 25 % of healthy controls. Reductions were also observed for several nonacylated ceramides: ceramides with phytosphingosine or 6-hydroxysphingosine in the long-chain base moiety were reduced to 24 % and 41 % of control levels, respectively, and ceramides with an α-hydroxy fatty acid as the fatty acid moiety were reduced to 29 %. The fatty acid moiety was shortened in many nonacylated ceramide classes.
CONCLUSION
These results suggest that reduced acylceramide levels are a primary cause of the ichthyosis symptoms of SLS, but reductions in other ceramide classes may also be involved.
Topics: Ceramides; Epidermis; Fatty Acids; Female; Humans; Ichthyosis; Ichthyosis, Lamellar; Sjogren-Larsson Syndrome
PubMed: 35973883
DOI: 10.1016/j.jdermsci.2022.08.003