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1.
Exp Dermatol ; 33(3): e15040, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38429888

RESUMO

The effect of persistent skin inflammation on extracutaneous organs and blood is not well studied. Patients with recessive dystrophic epidermolysis bullosa (RDEB), a severe form of the inherited blistering skin disorder, have widespread and persistent skin ulcers, and they develop various complications including anaemia, hyperglobulinaemia, hypoalbuminaemia and secondary amyloidosis. These complications are associated with the bioactivities of IL-6, and the development of secondary amyloidosis requires the persistent elevation of serum amyloid A (SAA) level. We found that patients with RDEB had significantly higher serum levels of IL-6 and SAA compared to healthy volunteers and patients with psoriasis or atopic dermatitis. Both IL-6 and SAA were highly expressed in epidermal keratinocytes and dermal fibroblasts of the skin ulcer lesions. Keratinocytes and fibroblasts surrounding the ulcer lesions are continuously exposed to Toll-like receptor (TLR) ligands, pathogen-associated and damage-associated molecular pattern molecules. In vitro, TLR ligands induced IL-6 expression via NF-κB in normal human epidermal keratinocytes (NHEKs) and dermal fibroblasts (NHDFs). SAA further induced the expression of IL-6 via TLR1/2 and NF-κB in NHEKs and NHDFs. The limitation of this study is that NHEKs and NHDFs were not derived from RDEB patients. These observations suggest that TLR-mediated persistent skin inflammation might increase the risk of IL-6-related systemic complications, including RDEB.


Assuntos
Amiloidose , Epidermólise Bolhosa Distrófica , Interleucina-6 , Humanos , Amiloidose/metabolismo , Amiloidose/patologia , Colágeno Tipo VII/metabolismo , Epidermólise Bolhosa Distrófica/metabolismo , Epidermólise Bolhosa Distrófica/patologia , Fibroblastos/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Queratinócitos/metabolismo , NF-kappa B/metabolismo , Proteína Amiloide A Sérica/metabolismo , Receptores Toll-Like/metabolismo
2.
N Engl J Med ; 390(6): 530-535, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38324486

RESUMO

Dystrophic epidermolysis bullosa is a rare genetic disease caused by damaging variants in COL7A1, which encodes type VII collagen. Blistering and scarring of the ocular surface develop, potentially leading to blindness. Beremagene geperpavec (B-VEC) is a replication-deficient herpes simplex virus type 1-based gene therapy engineered to deliver functional human type VII collagen. Here, we report the case of a patient with cicatrizing conjunctivitis in both eyes caused by dystrophic epidermolysis bullosa who received ophthalmic administration of B-VEC, which was associated with improved visual acuity after surgery.


Assuntos
Colágeno Tipo VII , Epidermólise Bolhosa Distrófica , Terapia Genética , Humanos , Vesícula/etiologia , Cicatriz/etiologia , Colágeno Tipo VII/genética , Epidermólise Bolhosa Distrófica/complicações , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/terapia , Conjuntivite/etiologia
3.
Exp Dermatol ; 33(2): e15035, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38389191

RESUMO

Epidermolysis bullosa (EB) is a heritable skin blistering disease caused by variants in genes coding for proteins that secure cell-cell adhesion and attachment of the epidermis to the dermis. Interestingly, several proteins involved in inherited EB are also associated with autoimmune blistering diseases (AIBD). In this study, we present a long-term follow-up of 15 patients suffering from recessive dystrophic or junctional EB. From these patients, 62 sera were analysed for the presence of autoantibodies associated with AIBD. We show that patients suffering from recessive dystrophic EB (RDEB) are more susceptible to developing autoantibodies against skin proteins than patients suffering from junctional EB (70% vs. 20%, respectively). Interestingly, no correlation with age was observed. Most patients showed reactivity to Type XVII collagen/linear IgA bullous dermatosis autoantigen (n = 5; 33%), followed by BP230 (n = 4; 27%), Type VII collagen (n = 4; 27%) and laminin-332 (n = 1; 7%). The pathogenicity of these autoantibodies remains a subject for future experiments.


Assuntos
Doenças Autoimunes , Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa Juncional , Epidermólise Bolhosa , Humanos , Epidermólise Bolhosa Distrófica/genética , Autoanticorpos , Pele/metabolismo , Epidermólise Bolhosa/metabolismo , Epidermólise Bolhosa Juncional/genética
4.
Stem Cell Res ; 75: 103306, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38271763

RESUMO

We have generated MLi005-A, a new induced pluripotent stem cell (iPSC) line derived from skin fibroblasts of a male patient with dominant dystrophic epidermolysis bullosa (DDEB). This iPSC line may be used as a model system for studies on skin integrity, the extracellular matrix and skin barrier function. The characterization of the MLi005-A cell line consisted of molecular karyotyping, next-generation sequencing of the COL7A1 alleles, pluripotency and differentiation potentials testing by immunofluorescence of associated markers in vitro. The MLi-005A line has been also tested for ability to differentiate into fibroblasts and keratinocytes and markers associated with these cell types.


Assuntos
Epidermólise Bolhosa Distrófica , Células-Tronco Pluripotentes Induzidas , Humanos , Masculino , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Colágeno Tipo VII/genética , Colágeno Tipo VII/metabolismo , Pele/metabolismo , Queratinócitos/metabolismo
5.
JAMA Dermatol ; 160(3): 297-302, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38294784

RESUMO

Importance: New gene therapies can offer substantial benefits to patients, particularly those with rare diseases who have few therapeutic options. In May 2023, the US Food and Drug Administration (FDA) approved the first topical gene therapy, beremagene geperpavec (B-VEC), for treating both autosomal recessive and autosomal dominant dystrophic epidermolysis bullosa (DEB). However, FDA approval was based on limited data in patients with autosomal dominant disease, even though they comprise approximately 50% of all DEB cases. Objective: To estimate projected spending in the US on B-VEC therapy for treating autosomal recessive and autosomal dominant DEB. Design, Setting, and Participants: This economic evaluation used data from the National Epidermolysis Bullosa Registry to estimate the current population of US patients with autosomal dominant and autosomal recessive DEB, with the aim of estimating US spending on B-VEC therapy from an all-payers perspective during 1- and 3-year periods after FDA approval. A base-case cost of $300 000 per patient per year was assumed based on a report from the manufacturer (Krystal Biotech). Exposure: Treatment with B-VEC. Main Outcomes and Measures: Estimated overall spending on B-VEC in the first year and over a 3-year period after FDA approval. Several prespecified sensitivity analyses with different assumptions about the eligible patient population and the cost of therapy were performed, and lifetime total costs of treatment per patient were estimated. Results: The estimated number of US patients with DEB who were eligible for treatment with B-VEC in the first year after FDA approval was 894. The estimated total expenditure for B-VEC therapy was $268 million (range, $179 million-$357 million). Over a 3-year period, estimated spending was $805 million (range, $537 million-$1.1 billion). Estimated lifetime total costs per patient were $15 million (range, $10 million-$20 million) per patient with autosomal recessive DEB and $17 million (range, $11 million-$22 million) for patients with autosomal dominant DEB. Conclusions and Relevance: Results of this economic evaluation suggest that the FDA's broad indication for the use of B-VEC in treating both autosomal recessive and autosomal dominant DEB will have significant implications for payers.


Assuntos
Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa , Humanos , Epidermólise Bolhosa Distrófica/tratamento farmacológico , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa/genética , Análise Custo-Benefício
6.
Adv Skin Wound Care ; 37(2): 1-4, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38241457

RESUMO

ABSTRACT: Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr) is a rare subtype of dystrophic epidermolysis bullosa, and traditional treatments have limited efficacy. Dupilumab has demonstrated remarkable efficacy in relieving pruritus. In this case study, after traditional treatment failed, providers recommended the patient begin dupilumab to treat his pruritus. The patient was administrated a loading dose of 600 mg of dupilumab and a dose of 300 mg every 2 weeks. The Dermatology Life Quality Index and Pruritic Numeric Rating Scale were used to assess the patient's situation. After several months, the patient's DEB-Pr was considered in remission. Dupilumab may be a better choice than immunosuppressants for the treatment of pruritus in patients with DEB-Pr.


Assuntos
Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa , Humanos , Epidermólise Bolhosa Distrófica/complicações , Epidermólise Bolhosa Distrófica/tratamento farmacológico , Prurido/tratamento farmacológico , Prurido/etiologia , Anticorpos Monoclonais Humanizados/uso terapêutico
7.
Int J Mol Sci ; 25(2)2024 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-38255836

RESUMO

Antisense oligonucleotides (ASOs) represent an emerging therapeutic platform for targeting genetic diseases by influencing various aspects of (pre-)mRNA biology, such as splicing, stability, and translation. In this study, we investigated the potential of modulating the splicing pattern in recessive dystrophic epidermolysis bullosa (RDEB) patient cells carrying a frequent genomic variant (c.425A > G) that disrupts splicing in the COL7A1 gene by using short 2'-O-(2-Methoxyethyl) oligoribo-nucleotides (2'-MOE ASOs). COL7A1-encoded type VII collagen (C7) forms the anchoring fibrils within the skin that are essential for the attachment of the epidermis to the underlying dermis. As such, gene variants of COL7A1 leading to functionally impaired or absent C7 manifest in the form of extensive blistering and wounding. The severity of the disease pattern warrants the development of novel therapies for patients. The c.425A > G variant at the COL7A1 exon 3/intron 3 junction lowers the efficiency of splicing at this junction, resulting in non-functional C7 transcripts. However, we found that correct splicing still occurs, albeit at a very low level, highlighting an opportunity for intervention by modulating the splicing reaction. We therefore screened 2'-MOE ASOs that bind along the COL7A1 target region ranging from exon 3 to the intron 3/exon 4 junction for their ability to modulate splicing. We identified ASOs capable of increasing the relative levels of correctly spliced COL7A1 transcripts by RT-PCR, sqRT-PCR, and ddPCR. Furthermore, RDEB-derived skin equivalents treated with one of the most promising ASOs exhibited an increase in full-length C7 expression and its accurate deposition along the basement membrane zone (BMZ).


Assuntos
Epidermólise Bolhosa Distrófica , Humanos , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/terapia , Splicing de RNA , Pele , Íntrons , Precursores de RNA , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/uso terapêutico , Colágeno Tipo VII/genética
8.
Adv Ther ; 41(2): 867-877, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38170434

RESUMO

Epidermolysis bullosa (EB) is a group of rare, difficult-to-treat, inherited multisystem diseases affecting epithelial integrity. Impaired wound healing is central and can lead to serious clinical complications, deformities, and symptoms with a devastating impact on quality of life (QoL). Dressing changes and wound care are central to the management of EB. Recently Oleogel-S10 (also known as birch bark extract or birch triterpenes) was approved in Europe and the UK for treating EB wounds. This approval was based on data from the EASE phase 3 study, which demonstrated Oleogel-S10 accelerated wound healing, reduced total wound burden, and decreased the frequency of dressing changes in patients with EB. A retrospective analysis of medical records was conducted for up to 24 months in 13 patients with EB treated with Oleogel-S10 through an early access programme in Colombia. Effectiveness was assessed by measuring body surface area percentage (BSAP) and total body wound burden (EBDASI). Tolerability and safety were monitored throughout. This is the first report to evaluate the effectiveness of Oleogel-S10 in clinical practice. The results showed a reduction in percentage of BSA affected, from a mean of 27.3% at baseline to 10.4% at 24-month follow-up, despite treatment interruptions. A reduction in EBDASI skin activity score of - 16.2 (24 months) together with a reduced skin damage index score of - 15.4 (18 months) was also observed. Physicians, patients, and caregivers perceived faster wound closure. Adherence with therapy by patients was good, and patients expressed satisfaction with treatment and reported improvements in self-esteem, productivity, and social interaction. Oleogel-S10 was well tolerated; however, two patients reported worsening wounds related to gauze adherence. Two deaths during treatment interruption were reported and was not considered related to Oleogel-S10. This study supports the effectiveness of Oleogel-S10 in a real-world scenario in a country with scarce resources for the treatment of EB.


Assuntos
Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa , Humanos , Epidermólise Bolhosa Distrófica/complicações , Epidermólise Bolhosa Distrófica/tratamento farmacológico , Qualidade de Vida , Estudos Retrospectivos , Cicatrização , Epidermólise Bolhosa/complicações , Epidermólise Bolhosa/tratamento farmacológico , Compostos Orgânicos
10.
J Eur Acad Dermatol Venereol ; 38(1): 112-123, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37669776

RESUMO

BACKGROUND: While most cutaneous squamous cell carcinomas (cSCCs) are treatable, certain high-risk cSCCs, such as those in recessive dystrophic epidermolysis bullosa (RDEB) patients, are particularly aggressive. Owing to repeated wounding, inflammation and unproductive healing, RDEB patients have a 68% cumulative risk of developing life-threatening cSCCs by the age of 35, and a 70% risk of death by the age of 45. Despite aggressive treatment, cSCC represents the leading cause of premature mortality in these patients, highlighting an unmet clinical need. Increasing evidence points to a role of altered metabolism in the initiation and maintenance of cSCC, making metabolism a potential therapeutic target. OBJECTIVES: We sought to determine the feasibility of targeting tumour cell energetics as a strategy to selectively hinder the growth advantage of aggressive cSCC. METHODS: We evaluated the cell energetics profiles of RDEB-SCC cells by analysing available gene expression data against multiple gene signatures and single-gene targets linked to metabolic reprogramming. Additionally, we employed real-time metabolic profiling to measure glycolysis and respiration in these cells. Furthermore, we investigated the anti-neoplastic properties of the metformin against human and murine high-risk cSCCs in vitro and in vivo. RESULTS: Gene expression analyses highlighted a divergence in cell energetics profiles between RDEB-SCC and non-malignant RDEB keratinocytes, with tumour cells demonstrating enhanced respiration and glycolysis scores. Real-time metabolic profiling supported these data and additionally highlighted a metabolic plasticity of RDEB-SCC cells. Against this background, metformin exerted an anti-neoplastic potential by hampering both respiration and glycolysis, and by inhibiting proliferation in vitro. Metformin treatment in an analogous model of fast-growing murine cSCC resulted in delayed tumour onset and slower tumour growth, translating to a 29% increase in median overall survival. CONCLUSIONS: Our data indicate that metformin exerts anti-neoplastic properties in aggressive cSCCs that exhibit high-risk features by interfering with respiration and glycolytic processes.


Assuntos
Carcinoma de Células Escamosas , Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa , Neoplasias Cutâneas , Humanos , Animais , Camundongos , Carcinoma de Células Escamosas/metabolismo , Neoplasias Cutâneas/genética , Fosforilação Oxidativa , Epidermólise Bolhosa/complicações , Epidermólise Bolhosa Distrófica/tratamento farmacológico , Epidermólise Bolhosa Distrófica/genética
15.
J Dermatol ; 51(3): 441-447, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38115742

RESUMO

Refractory pruritus is the most distressing, disease-related symptom in patients with dystrophic epidermolysis bullosa (DEB), inducing an itch-scratch-blister cycle. Chronic inflammation is a hallmark of DEB, thus upregulation of inflammatory cytokines and Janus kinase (JAK) signaling may play a role in DEB-related pruritus. We retrospectively reviewed the medical records of DEB patients with refractory pruritus who were treated with either baricitinib, a JAK1/2 inhibitor, or upadacitinib, a selective JAK1 inhibitor. Patients received baricitinib (4 mg) or upadacitinib (15 mg) once a day for 2-32 weeks. A total of 12 DEB patients (six recessive DEB and six dominant DEB) were included in this study. The mean±SD baseline pruritus visual analog scale (VAS) score was 7.5 ± 1.7. Upadacitinib or baricitinib treatment resulted in a rapid and sustained decrease in itch. Four out of 12 patients (33.3%) and seven out of 10 patients (70%) showed a decrease of at least 3 points in the pruritus VAS score from baseline at weeks 2 and 4, respectively. The mean percentage changes from baseline in pruritus VAS scores at weeks 2 and 4 were -42.9% and -52.7%, respectively. Subgroup analysis showed greater reductions in the pruritus VAS score in the baricitinib group (n = 5) compared to the upadacitinib group (n = 7), and in patients with epidermolysis bullosa pruriginosa (n = 3) compared to other subtypes of DEB (n = 9); however, these differences did not reach statistical significance. Three out of 10 (33.3%) patients showed at least a 2-point reduction in pain intensity from baseline at week 4. Eight out of 12 patients (66.7%) also showed a reduction in the number of new blisters, which correlated with a reduction in the pruritus score. No patient discontinued treatment because of serious adverse events. Our results suggest that JAK1 or JAK1/2 inhibitors could be a promising treatment option for DEB-related pruritus. Long-term safety should be assessed in future studies.


Assuntos
Azetidinas , Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa , Inibidores de Janus Quinases , Purinas , Pirazóis , Sulfonamidas , Humanos , Epidermólise Bolhosa Distrófica/complicações , Epidermólise Bolhosa Distrófica/tratamento farmacológico , Estudos Retrospectivos , Prurido/tratamento farmacológico , Prurido/etiologia , Vesícula , Inibidores de Janus Quinases/uso terapêutico , Janus Quinase 1
16.
Child Care Health Dev ; 50(1): e13194, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38108617

RESUMO

BACKGROUND: Epidermolysis bullosa (EB) is a group of rare, congenital skin disorders, characterized by skin fragility and formation of blisters. The gross motor outcomes of children with EB are not known. OBJECTIVES: The primary objective of the study was to measure the proportion of gross motor delay in children with EB. The secondary objectives were to measure the difference in gross motor outcomes between EB sub-types and change in gross motor outcomes over time. METHODS: Children with EB, aged between one month and five and a half years of age, attending the Sydney Children's Hospital, Epidermolysis Bullosa Clinic, were eligible. Carers completed Ages and Stages Questionnaires, Third Edition, on behalf of their children. Questionnaires were scored, and outcomes were compared to age-expected norms. RESULTS: There were 24 participants to complete a questionnaire. Eleven participants completed additional questionnaires over the 24 month study duration. The proportion of children with EB with gross motor delay was greater than age-expected norms (29.17% vs. 2.5%). The delay occurred in children with recessive dystrophic (80%) and epidermolysis bullosa simplex (33.33%) sub-types, but not dominant dystrophic (0%). No children with Junctional EB or Kindler EB joined this study. CONCLUSIONS: This study demonstrates a difference in gross motor outcomes in children with EB. Children with recessive dystrophic and epidermolysis bullosa simplex should be prioritized for monitoring of, and intervention for, gross motor outcomes through multidisciplinary care. Further research investigating long-term outcomes for children with EB and the effectiveness of interventions would be beneficial.


Assuntos
Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa Simples , Epidermólise Bolhosa Juncional , Epidermólise Bolhosa , Criança , Humanos , Lactente , Epidermólise Bolhosa Simples/complicações , Epidermólise Bolhosa Distrófica/complicações , Epidermólise Bolhosa/complicações , Epidermólise Bolhosa Juncional/complicações
18.
J Dermatolog Treat ; 34(1): 2253943, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37968922

RESUMO

Inherited epidermolysis bullosa is a heterogeneous group of hereditary skin diseases characterized by skin (mucosa) fragility, which leads to blistering. Junctional epidermolysis bullosa is associated with mutations in genes expressing proteins of the dermo-epidermal junction. Dupilumab, an antibody that directly targets interleukin (IL)-4 receptor alpha, may be an effective treatment for dystrophic epidermolysis bullosa. We describe a case of junctional epidermolysis bullosa that improved with dupilumab.


Assuntos
Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa Juncional , Epidermólise Bolhosa , Humanos , Epidermólise Bolhosa Juncional/tratamento farmacológico , Epidermólise Bolhosa Juncional/genética , Pele/metabolismo , Colágenos não Fibrilares , Epidermólise Bolhosa Distrófica/tratamento farmacológico , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa/genética
19.
Soins ; 68(880): 36-38, 2023 Nov.
Artigo em Francês | MEDLINE | ID: mdl-37931996

RESUMO

Despite an increase in life expectancy and quality of life for patients suffering from severe forms of hereditary epidermolysis bullosa, the occurrence of one or more cutaneous squamous cell carcinomas remains a sometimes serious complication, sometimes life-threatening as early as adolescence. These carcinomas occur preferably on chronic wounds or dystrophic scars in areas not exposed to the sun, and are generally multifocal and recurrent. Their clinical and histological diagnosis is difficult. Regular medical and paramedical monitoring of the skin during dressing repairs enables early detection and rapid, curative surgical management. The pathophysiology of these cutaneous carcinomas is the subject of research aimed at proposing non-surgical alternatives to the patients concerned.


Assuntos
Carcinoma de Células Escamosas , Epidermólise Bolhosa Distrófica , Neoplasias Cutâneas , Adolescente , Humanos , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Epidermólise Bolhosa Distrófica/complicações , Epidermólise Bolhosa Distrófica/patologia , Qualidade de Vida , Pele/patologia
20.
Soins ; 68(880): 33-35, 2023 Nov.
Artigo em Francês | MEDLINE | ID: mdl-37931995

RESUMO

The occurrence of cutaneous squamous cell carcinoma is a frequent and potentially serious complication in people with recessive dystrophic epidermolysis bullosa and junctional epidermolysis bullosa with chronic leg sores. Early diagnosis of early-stage carcinomas enables limited surgical excision and rapid healing without sequelae. Screening during skin care of patients at risk is therefore of major interest, and any atypical lesion should be shown to a doctor specializing in the disease and biopsied at the slightest doubt, preferably in an expert center for the disease.


Assuntos
Carcinoma de Células Escamosas , Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa Juncional , Neoplasias Cutâneas , Humanos , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Epidermólise Bolhosa Distrófica/complicações , Epidermólise Bolhosa Distrófica/patologia , Epidermólise Bolhosa Juncional/complicações , Epidermólise Bolhosa Juncional/patologia
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