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Background: Atopic dermatitis (AD) is a common chronic eczematous skin disease with severe pruritus. Several new therapeutic agents for AD such as dupilumab, an anti-IL-4Rα antibody, have been developed in recent years. We need to predict which agent is the best choice for each patient, but this remains difficult. Objective: Our aim was to examine clinical background factors and baseline biomarkers that could predict the achievement of improved clinical outcomes in patients with AD treated with dupilumab. Methods: A multicenter, prospective observational study was conducted on 110 patients with AD. The Eczema Area and Severity Index was used as an objective assessment, and the Patient-Oriented Eczema Measure and Numerical Rating Scale for Pruritus were used as patient-reported outcomes. In addition, some clinical background factors were evaluated. Results: The achievement of an absolute Eczema Area and Severity Index of 7 or less was negatively associated with current comorbidity of food allergy and baseline serum lactate dehydrogenase (LDH) levels. There were negative associations between achievement of a Patient-Oriented Eczema Measure score of 7 or less and duration of severe AD and between achievement of an itching Numerical Rating Scale for Pruritus score of 1 or less and current comorbidity of allergic conjunctivitis or baseline serum periostin level. Furthermore, signal detection analysis showed that a baseline serum LDH level less than 328 U/L could potentially be used as a cutoff value for predicting the efficacy of dupilumab. Conclusion: Baseline biomarkers such as LDH and periostin and clinical background factors such as current comorbidity of food allergy and a long period of severe disease may be useful indicators when choosing dupilumab for systemic treatment for AD, as they can predict the efficacy of dupilumab.
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BACKGROUND: No efficient treatment has yet been established for epidermolytic ichthyosis (EI), which is caused by pathogenic variants of KRT1 or KRT10. Patients with ichthyosis with confetti (IWC) have multiple normal-appearing spots, caused by the revertant somatic recombination of pathogenic variants that occurs at each spot independently. Additionally, some patients with EI have large areas of normal skin due to revertant postzygotic mosaicism. OBJECTIVES: To assess the feasibility of transplanting cultured epidermal autografts (CEAs) produced from revertant epidermal keratinocytes in patients with EI and IWC. METHODS: We performed a clinical trial of treatment with CEAs produced from each patient's own revertant epidermal keratinocytes as a proof-of-concept study. This was a single-arm, open, unmasked, uncontrolled, single-assignment, treatment-purpose study. The primary outcome was the percentage area that lacked recurrence of ichthyosis lesions 4 weeks after the final transplant. The secondary outcome was the percentage area lacking recurrence of ichthyosis lesions 24 weeks after the initial transplantation. The trial was registered with the Japan Registry of Clinical Trials (jRCTb041190097). RESULTS: We successfully produced CEAs from genetically confirmed revertant skin from two patients with mosaic EI and from one patient with IWC and confirmed by amplicon sequencing and droplet digital polymerase chain reaction analysis that the CEAs mainly consisted of revertant wild-type cells. Single-cell RNA sequencing analysis confirmed the normal proliferation and safety profiling of CEAs. CEAs were transplanted onto desquamated lesional sites in the patients. Four weeks post-transplantation, the percentage area lacking recurrence of ichthyosis lesions in the three patients was 40%, 100% and 100% respectively, although recurrence of ichthyosis lesions was seen at the site of CEA transplantation in all three patients at 24 weeks post-transplantation. CONCLUSIONS: CEAs from normal skin have the potential to be a safe and local treatment option for EI and IWC.
Epidermolytic ichthyosis is a rare skin condition that causes redness, blistering and thickening of the skin. There is currently no effective treatment for the disease, which is caused by mutations in the genes KRT1 or KRT10. People with a type of the disease called 'ichthyosis with confetti' have many normal-appearing spots that are caused by the natural repair of the gene mutations. Some people with epidermolytic ichthyosis have large areas of healthy skin as a result of genetic mutations having been corrected. In this study, we successfully produced skin grafts from the healthy skin of two patients with epidermolytic ichthyosis and one with 'ichthyosis with confetti'. We confirmed that the skin grafts mainly consisted of repaired skin cells. A technique called 'single-cell RNA sequencing' confirmed the skin cells in the skin grafts behaved like healthy skin cells and that the grafts were safe. Overall, our study findings suggest that skin grafts taken from skin consisting of genetically normal keratinocytes that have undergone self-repair have potential to be a safe treatment option for patients with severe epidermolytic ichthyosis and 'ichthyosis with confetti'.
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Hiperqueratosis Epidermolítica , Queratinocitos , Humanos , Hiperqueratosis Epidermolítica/genética , Hiperqueratosis Epidermolítica/patología , Masculino , Femenino , Queratinocitos/trasplante , Niño , Adulto , Trasplante de Piel/métodos , Autoinjertos , Epidermis/trasplante , Epidermis/patología , Queratina-10/genética , Adolescente , Estudios de Factibilidad , Queratina-1/genética , Adulto Joven , Prueba de Estudio Conceptual , Trasplante Autólogo , Resultado del Tratamiento , Preescolar , Mosaicismo , Ictiosis/genética , Ictiosis/cirugía , Ictiosis/patologíaRESUMEN
Autosomal recessive congenital ichthyoses (ARCI) is a genetically heterogeneous condition that can be caused by pathogenic variants in at least 12 genes, including ABCA12. ARCI mainly consists of congenital ichthyosiform erythroderma (CIE), lamellar ichthyosis (LI) and harlequin ichthyosis (HI). The objective was to determine previously unreported pathogenic variants in ABCA12 and to update genotype-phenotype correlations for patients with pathogenic ABCA12 variants. Pathogenic variants in ABCA12 were detected using Sanger sequencing or a combination of Sanger sequencing and whole-exome sequencing. To verify the pathogenicity of a previously unreported large deletion and intron variant, cDNA analysis was performed using total RNA extracted from hair roots. Genetic analyses were performed on the patients with CIE, LI, HI and non-congenital ichthyosis with unusual phenotypes (NIUP), and 11 previously unreported ABCA12 variants were identified. Sequencing of cDNA confirmed the aberrant splicing of the variant ABCA12 in the patients with the previously unreported large deletion and intron variant. Our findings expand the phenotype spectrum of ichthyosis patients with ABCA12 pathogenic variants. The present missense variants in ABCA12 are considered to be heterogenous in pathogenicity, and they lead to varying disease severities in patients with ARCI and non-congenital ichthyosis with unusual phenotypes (NIUP).
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Eritrodermia Ictiosiforme Congénita , Ictiosis Lamelar , Ictiosis , Humanos , Ictiosis Lamelar/genética , Ictiosis Lamelar/patología , ADN Complementario , Genes Recesivos , Mutación , Ictiosis/genética , Eritrodermia Ictiosiforme Congénita/genética , Estudios de Asociación Genética , Transportadoras de Casetes de Unión a ATP/genéticaAsunto(s)
Enzima Desubiquitinante CYLD , Neoplasias Cutáneas , Humanos , Enzima Desubiquitinante CYLD/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/diagnóstico , Femenino , Masculino , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/patología , Índice de Severidad de la Enfermedad , LinajeAsunto(s)
Autoanticuerpos , Dermatomiositis , Paniculitis , Humanos , Dermatomiositis/inmunología , Dermatomiositis/tratamiento farmacológico , Dermatomiositis/complicaciones , Dermatomiositis/patología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Paniculitis/patología , Paniculitis/diagnóstico , Paniculitis/inmunología , Paniculitis/tratamiento farmacológico , Enzimas Activadoras de Ubiquitina/inmunología , Enzimas Activadoras de Ubiquitina/antagonistas & inhibidores , Femenino , Piel/patología , Piel/inmunología , Resistencia a Medicamentos , Masculino , Torso , Persona de Mediana EdadAsunto(s)
Epidermólisis Ampollosa Simple , Queratina-14 , Humanos , Epidermólisis Ampollosa Simple/genética , Epidermólisis Ampollosa Simple/patología , Epidermólisis Ampollosa Simple/diagnóstico , Queratina-14/genética , Masculino , Piel/patología , Femenino , Dominios Proteicos , Análisis Mutacional de ADN , Mutación MissenseRESUMEN
Pathogenic variants in ABCA12 are important causative genetic defects for autosomal recessive congenital ichthyoses (ARCI), which include congenital ichthyosiform erythroderma (CIE), harlequin ichthyosis, and lamellar ichthyosis. In addition, pathogenic variants in ABCA12 are known to cause a localized nevoid form of CIE due to recessive mosaicism. We previously reported siblings who carried an ABCA12 variant but did not show a "congenital" phenotype. They were considered to have pityriasis rubra pilaris (PRP). Here, we present a further patient with ABCA12 variants whose phenotype was not congenital ichthyosis, in an independent family. Notably, these three patients had geographic unaffected areas. Such areas are not usually found in patients with ARCI who have ABCA12 variants, suggesting mild phenotypes for these patients. Interestingly, the histological features of the ichthyotic lesions in these patients resembled those of PRP. All three patients had homozygous pathogenic missense variants in ABCA12. Our findings expand the phenotypic spectrum of patients with ABCA12 variants.
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Eritrodermia Ictiosiforme Congénita , Ictiosis Lamelar , Ictiosis , Pitiriasis Rubra Pilaris , Humanos , Pitiriasis Rubra Pilaris/genética , Ictiosis Lamelar/genética , Eritrodermia Ictiosiforme Congénita/genética , Eritrodermia Ictiosiforme Congénita/patología , Fenotipo , Mutación , Transportadoras de Casetes de Unión a ATP/genéticaAsunto(s)
Dermatitis Atópica , Ictiosis Vulgar , Ictiosis Ligada al Cromosoma X , Ictiosis , Humanos , Dermatitis Atópica/complicaciones , Dermatitis Atópica/diagnóstico , Ictiosis Vulgar/complicaciones , Ictiosis Vulgar/diagnóstico , Ictiosis Vulgar/genética , Ictiosis Ligada al Cromosoma X/complicaciones , Ictiosis Ligada al Cromosoma X/diagnóstico , Ictiosis Ligada al Cromosoma X/genética , Ictiosis/diagnóstico , Ictiosis/genéticaAsunto(s)
Productos Biológicos , Exantema , Neumonía por Pneumocystis , Psoriasis , Humanos , Productos Biológicos/efectos adversos , Neumonía por Pneumocystis/diagnóstico , Neumonía por Pneumocystis/tratamiento farmacológico , Psoriasis/complicaciones , Psoriasis/diagnóstico , Psoriasis/tratamiento farmacológico , Enfermedad Aguda , Enfermedad CrónicaRESUMEN
BACKGROUND: Congenital ichthyoses sometimes present with severe skin symptoms that significantly affect the patient's quality of life (QOL). Symptomatic treatments are the mainstay therapies, and their efficacy is limited and inadequate. OBJECTIVE: To assess the disease severity and QOL in patients with congenital ichthyoses, and to investigate the effectiveness of current treatments. METHODS: We conducted a questionnaire-based Japan-wide epidemiological survey of patients with congenital ichthyosis who received medical care from 1 January 2016-31 December 2020. Effectiveness of past and current treatments was assessed. The outcomes were the physician's assessment, disease severity assessed using the clinical ichthyosis score (CIS), and the disease burden estimated using the Dermatology Life Quality Index (DLQI), the Children's Dermatology Life Quality Index (CDLQI), and the Infants' Dermatitis Quality of Life Index. RESULTS: One hundred patients with 14 ichthyosis subtypes from 47 institutes were included in the final analysis. The CDLQI score showed a positive correlation with CIS (rs = 0.59, p = 0.004), while the DLQI score showed no significant correlation (rs = 0.13, p = 0.33). All existing medications were effective for many patients. Etretinate improved QOL and reduced CIS, but side effects including bone growth retardation were reported. Decreased treatment willingness was observed in patients with very low and very high CIS. CONCLUSION: QOL scores were found to correlate with CIS in children, but not in adults. Considering the adverse events, it is speculated that etretinate is not indicated for children with mild cases. Petrolatum was the most commonly used medication, even in patients who were reluctant to receive treatment.