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1.
N Engl J Med ; 389(17): 1579-1589, 2023 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-37888917

RESUMO

BACKGROUND: Prurigo nodularis is a chronic, debilitating, and severely pruritic neuroimmunologic skin disease. Nemolizumab, an interleukin-31 receptor alpha antagonist, down-regulates key pathways in the pathogenesis of prurigo nodularis. METHODS: In this phase 3, double-blind, multicenter, randomized trial, we assigned adults with moderate-to-severe prurigo nodularis to receive an initial 60-mg dose of nemolizumab followed by subcutaneous injections of 30 mg or 60 mg (depending on baseline weight) every 4 weeks for 16 weeks or matching placebo. The primary end points were an itch response (a reduction of ≥4 points on the Peak Pruritus Numerical Rating Scale [PP-NRS; scores range from 0 to 10, with higher scores indicating more severe itch]) and an Investigator's Global Assessment (IGA) response (a score of 0 [clear] or 1 [almost clear] on the IGA [scores range from 0 to 4] and a reduction from baseline to week 16 of ≥2 points). There were five key secondary end points. RESULTS: A total of 274 patients underwent randomization; 183 were assigned to the nemolizumab group, and 91 to the placebo group. Treatment efficacy was shown with respect to both primary end points at week 16; a greater percentage of patients in the nemolizumab group than in the placebo group had an itch response (56.3% vs. 20.9%; strata-adjusted difference, 37.4 percentage points; 95% confidence interval [CI], 26.3 to 48.5), and a greater percentage in the nemolizumab group had an IGA response (37.7% vs. 11.0%; strata-adjusted difference, 28.5 percentage points; 95% CI, 18.8 to 38.2) (P<0.001 for both comparisons). Benefits were observed for the five key secondary end points: itch response at week 4 (41.0% vs. 7.7%), PP-NRS score of less than 2 at week 4 (19.7% vs. 2.2%) and week 16 (35.0% vs. 7.7%), and an improvement of 4 or more points on the sleep disturbance numerical rating scale (range, 0 [no sleep loss] to 10 [unable to sleep at all]) at week 4 (37.2% vs. 9.9%) and week 16 (51.9% vs. 20.9%) (P<0.001 for all comparisons). The most common individual adverse events were headache (6.6% vs. 4.4%) and atopic dermatitis (5.5% vs. 0%). CONCLUSIONS: Nemolizumab monotherapy significantly reduced the signs and symptoms of prurigo nodularis. (Funded by Galderma; ClinicalTrials.gov number, NCT04501679; EudraCT number, 2019-004789-17.).


Assuntos
Anticorpos Monoclonais Humanizados , Prurigo , Receptores de Interleucina , Adulto , Humanos , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/etiologia , Método Duplo-Cego , Prurigo/tratamento farmacológico , Prurigo/complicações , Prurido/tratamento farmacológico , Prurido/etiologia , Índice de Gravidade de Doença , Resultado do Tratamento , Receptores de Interleucina/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico
2.
J Immunotoxicol ; 13(5): 738-44, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27258892

RESUMO

Irritant contact dermatitis is the most common work-related skin disease, especially affecting workers in "wet-work" occupations. This study was conducted to investigate the association between single nucleotide polymorphisms (SNPs) within the major histocompatibility complex (MHC) and skin irritant response in a group of healthcare workers. 585 volunteer healthcare workers were genotyped for MHC SNPs and patch tested with three different irritants: sodium lauryl sulfate (SLS), sodium hydroxide (NaOH) and benzalkonium chloride (BKC). Genotyping was performed using Illumina Goldengate MHC panels. A number of SNPs within the MHC Class I (OR2B3, TRIM31, TRIM10, TRIM40 and IER3), Class II (HLA-DPA1, HLA-DPB1) and Class III (C2) genes were associated (p < 0.001) with skin response to tested irritants in different genetic models. Linkage disequilibrium patterns and functional annotations identified two SNPs in the TRIM40 (rs1573298) and HLA-DPB1 (rs9277554) genes, with a potential impact on gene regulation. In addition, SNPs in PSMB9 (rs10046277 and ITPR3 (rs499384) were associated with hand dermatitis. The results are of interest as they demonstrate that genetic variations in inflammation-related genes within the MHC can influence chemical-induced skin irritation and may explain the connection between inflamed skin and propensity to subsequent allergic contact sensitization.


Assuntos
Cisteína Endopeptidases/genética , Dermatite Irritante/genética , Antígenos HLA/genética , Pessoal de Saúde , Receptores de Inositol 1,4,5-Trifosfato/genética , Polimorfismo de Nucleotídeo Único , Pele/imunologia , Adolescente , Adulto , Idoso , Compostos de Benzalcônio , Dermatite Irritante/imunologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Cadeias beta de HLA-DP/genética , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Testes Cutâneos , Dodecilsulfato de Sódio , Hidróxido de Sódio , Ubiquitina-Proteína Ligases/genética , Adulto Jovem
3.
J Occup Environ Med ; 58(8): 753-9, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27206134

RESUMO

OBJECTIVE: The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) within genes involved in inflammation, skin barrier integrity, signaling/pattern recognition, and antioxidant defense with irritant susceptibility in a group of health care workers. METHODS: The 536 volunteer subjects were genotyped for selected SNPs and patch tested with three model irritants: sodium lauryl sulfate (SLS), sodium hydroxide (NaOH), and benzalkonium chloride (BKC). Genotyping was performed on genomic DNA using Illumina Goldengate custom panels. RESULTS: The ACACB (rs2268387, rs16934132, rs2284685), NTRK2 (rs10868231), NTRK3 (rs1347424), IL22 (rs1179251), PLAU (rs2227564), EGFR (rs6593202), and FGF2 (rs308439) SNPs showed an association with skin response to tested irritants in different genetic models (all at P < 0.001). Functional annotations identified two SNPs in PLAU (rs2227564) and ACACB (rs2284685) genes with a potential impact on gene regulation. In addition, EGF (rs10029654), EGFR (rs12718939), CXCL12 (rs197452), and VCAM1 (rs3917018) genes showed an association with hand dermatitis (P < 0.005). CONCLUSIONS: The results demonstrate that genetic variations in genes related to inflammation and skin homeostasis can influence responses to irritants and may explain inter-individual variation in the development of subsequent contact dermatitis.


Assuntos
Dermatite de Contato/genética , Pessoal de Saúde , Irritantes/efeitos adversos , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Compostos de Benzalcônio/efeitos adversos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Testes do Emplastro , Dodecilsulfato de Sódio/efeitos adversos , Hidróxido de Sódio/efeitos adversos , Adulto Jovem
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