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1.
BMC Dermatol ; 20(1): 6, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32867747

RESUMO

BACKGROUND: Specific species of ceramides (Cer), major constituents of lipids in the stratum corneum (SC), are decreased and are correlated with SC barrier and water-holding functions in the skin of patients with atopic dermatitis (AD) or psoriasis (Pso). However, possible correlations between Cer subclass ratios and skin properties in barrier-disrupted skin and in healthy skin remain unclear. The objective of this study was to identify a new marker to evaluate skin properties and epidermal differentiation in SC not only in barrier-disrupted skin but also in healthy skin. METHODS: The Cer subclass ratios in the SC of healthy control subjects and in patients with AD or Pso were evaluated. Correlations with candidate markers and facial skin features of healthy Japanese females (20-74 years old, n = 210) were investigated. Variations of markers during epidermal differentiation were studied in human epidermis and in cultured keratinocytes. RESULTS: The ratios of Cer [NP]/[NS], Cer [NH]/[NS], Cer [NP]/[AS], Cer [NH]/[NS], Cer [NDS]/[AS], Cer [AH]/[AS] and Cer [EOP]/[AS] showed significant differences between non-lesional skin of AD patients and normal skin of healthy control subjects, as well as Pso patients and their healthy control subjects. The Cer [NP]/[NS] ratio was correlated with SC functional parameters (transepidermal water loss and capacitance) and with skin appearance (texture, scaling and color) even in the cheek skin of healthy female subjects. The Cer [NP]/[NS] ratio in the SC was approximately 18-times higher than in living keratinocytes, and it increased as they differentiated. CONCLUSIONS: The Cer [NP]/[NS] ratio in the SC is a potential marker for skin properties and epidermal differentiation in barrier-disrupted skin as well as in healthy skin.


Assuntos
Ceramidas/análise , Dermatite Atópica/patologia , Epiderme/química , Psoríase/patologia , Adulto , Idoso , Biomarcadores/análise , Estudos de Casos e Controles , Diferenciação Celular , Células Cultivadas , Dermatite Atópica/diagnóstico , Epiderme/patologia , Feminino , Humanos , Queratinócitos/química , Queratinócitos/citologia , Lipídeos/análise , Pessoa de Meia-Idade , Psoríase/diagnóstico , Adulto Jovem
2.
Am J Hum Genet ; 107(3): 527-538, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32758447

RESUMO

Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E-08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E-09); this effect was stronger when including IL36RN mutations (1.48E-13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.


Assuntos
Inflamação/genética , Interleucinas/genética , Peroxidase/genética , Psoríase/genética , Dermatopatias/genética , Adulto , Animais , Citocinas/genética , Armadilhas Extracelulares/genética , Feminino , Humanos , Inflamação/patologia , Interleucina-1/genética , Interleucinas/metabolismo , Masculino , Camundongos , Mutação/genética , Neutrófilos/metabolismo , Psoríase/patologia , Doenças Raras/enzimologia , Doenças Raras/genética , Doenças Raras/patologia , Pele/enzimologia , Pele/patologia , Dermatopatias/patologia
3.
Am J Hum Genet ; 107(3): 539-543, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32758448

RESUMO

The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused our attention on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole-exome sequencing of 19 unrelated affected individuals, we identified a subject harboring a homozygous splice-site mutation (c.2031-2A>C) in MPO. This encodes myeloperoxidase, an essential component of neutrophil azurophil granules. MPO screening in conditions phenotypically related to GPP uncovered further disease alleles in one subject with acral pustular psoriasis (c.2031-2A>C;c.2031-2A>C) and in two individuals with acute generalized exanthematous pustulosis (c.1705C>T;c.2031-2A>C and c.1552_1565del;c.1552_1565del). A subsequent analysis of UK Biobank data demonstrated that the c.2031-2A>C and c.1705C>T (p.Arg569Trp) disease alleles were also associated with increased neutrophil abundance in the general population (p = 5.1 × 10-6 and p = 3.6 × 10-5, respectively). The same applied to three further deleterious variants that had been genotyped in the cohort, with two alleles (c.995C>T [p.Ala332Val] and c.752T>C [p.Met251Thr]) yielding p values < 10-10. Finally, treatment of healthy neutrophils with an MPO inhibitor (4-Aminobenzoic acid hydrazide) increased cell viability and delayed apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers. These findings identify MPO as a genetic determinant of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored.


Assuntos
Doenças Neurodegenerativas/genética , Peroxidase/genética , Psoríase/genética , Dermatopatias/genética , Ácido 4-Aminobenzoico/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular/efeitos dos fármacos , Feminino , Genótipo , Humanos , Mutação com Perda de Função/genética , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/patologia , Neutrófilos/efeitos dos fármacos , Peroxidase/antagonistas & inibidores , Fenótipo , Psoríase/tratamento farmacológico , Psoríase/patologia , Pele/efeitos dos fármacos , Pele/patologia , Dermatopatias/tratamento farmacológico , Dermatopatias/patologia
4.
PLoS One ; 15(7): e0235091, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32609733

RESUMO

Genital psoriasis affects 2-5% of psoriasis patients; generalised plaque or intertriginous psoriasis also affects the genital area in 29-40% of cases. Anogenital psoriasis has been associated with significant quality of life impairments, but little is known about specific patient needs/treatment goals. This study aimed to examine the overall and sex-related disease burden, patient needs and treatment benefits in patients with anogenital psoriasis, compared to patients with psoriasis not affecting the anal/genital areas. Within the cross-sectional nationwide survey, 2,009 participants were consecutively recruited in 157 randomly assigned German dermatology practices and clinics, according to the following inclusion criteria aged 18 years or over; diagnosis of psoriasis vulgaris; ability to answer the questionnaires; and written informed consent. Based on a high-resolution grid on the topical distribution of psoriasis, two groups were formed: anogenital psoriasis (n = 622) and comparison group (n = 1,303). Clinical severity was assessed by the Psoriasis Area and Severity Index (PASI). Patients completed the EuroQoL visual analogue scale (EQ VAS), the Dermatology Life Quality Index (DLQI), and the Patient Benefit Index (PBI). Patients with anogenital psoriasis had higher PASI (13.0±10.6 vs. 8.9±7.6, P < 0.001) and more DLQI impairments (8.9±6.9 vs. 7.0±6.2, P = 0.002) than controls. At the item-level, they also reported more sex-related DLQI impairments (DLQI-i9: 0.5±0.8 vs. 0.3±0.7, P < 0.001) and treatment needs (PBI-i17: 2.2±1.8 vs. 1.9±1.8, P = 0.001). A great percentage of missing/not-relevant responses was found for sex-related items (23.3-41.9%). These results suggest that the assessment of sex-related impairments and treatment needs should be prioritised in patients with anogenital psoriasis. Questionnaires may be used as a less uncomfortable way for patients to discuss their genital lesions and sexual function during healthcare visits. However, the great percentage of missing/not-relevant responses to sex-related items calls for in-depth assessments and effective patient-physician communication regarding these sensitive topics.


Assuntos
Assistência Centrada no Paciente , Psoríase/patologia , Adolescente , Adulto , Idoso , Canal Anal/patologia , Estudos Transversais , Feminino , Genitália/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Relações Médico-Paciente , Psoríase/epidemiologia , Qualidade de Vida , Índice de Gravidade de Doença , Fatores Sexuais , Adulto Jovem
5.
Proc Natl Acad Sci U S A ; 117(28): 16465-16474, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32601220

RESUMO

Under steady-state conditions, the immune system is poised to sense and respond to the microbiota. As such, immunity to the microbiota, including T cell responses, is expected to precede any inflammatory trigger. How this pool of preformed microbiota-specific T cells contributes to tissue pathologies remains unclear. Here, using an experimental model of psoriasis, we show that recall responses to commensal skin fungi can significantly aggravate tissue inflammation. Enhanced pathology caused by fungi preexposure depends on Th17 responses and neutrophil extracellular traps and recapitulates features of the transcriptional landscape of human lesional psoriatic skin. Together, our results propose that recall responses directed to skin fungi can directly promote skin inflammation and that exploration of tissue inflammation should be assessed in the context of recall responses to the microbiota.


Assuntos
Arthrodermataceae/fisiologia , Microbiota , Psoríase/imunologia , Pele/microbiologia , Animais , Arthrodermataceae/classificação , Arthrodermataceae/genética , Arthrodermataceae/isolamento & purificação , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/microbiologia , Feminino , Humanos , Imunidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Psoríase/microbiologia , Psoríase/patologia , Pele/imunologia , Pele/patologia , Simbiose , Células Th17/imunologia
6.
BMC Dermatol ; 20(1): 3, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32434510

RESUMO

BACKGROUND: Having psoriasis in hard-to-treat areas, i.e. the scalp, face, palms, soles, nails, and genitals, respectively, can impair patients' quality of life. We investigated the prevalence of hard-to-treat body locations of psoriasis, and described patients' clinical and demographic characteristics, and quality of life impacts in a population-based cohort. METHODS: We performed a cross-sectional study using a total of 4016 adults (≥18 years) with psoriasis from the Danish Skin Cohort. Groups were compared to patients without involvement of hard-to-treat areas. RESULTS: The most frequently affected hard-to-treat area was the scalp (43.0%), followed by the face (29.9%), nails (24.5%), soles (15.6%), genitals (14.1%), and palms (13.7%), respectively. Higher prevalence was generally seen with increasing psoriasis severity. Among all patients 64.8, 42.4, and 21.9% of patients had involvement of ≥1, ≥2, or ≥ 3 hard-to-treat areas. Those with involvement of certain hard-to-treat areas such as hands, feet, and genitals had clinically relevant DLQI impairments. Having involvement of one hard-to-treat area was significantly associated with other hard-to-treat areas affected even after adjusting for age, sex, and psoriasis severity. CONCLUSION: Psoriasis commonly affects hard-to-treat locations, even in patients with mild disease. For some of these areas, patient-reported disease burden, e.g. as measured by DLQI, is impaired.


Assuntos
Psoríase/epidemiologia , Adulto , Estudos Transversais , Dinamarca/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/patologia , Psoríase/terapia , Índice de Gravidade de Doença
7.
BMC Med Genet ; 21(1): 103, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398022

RESUMO

BACKGROUND: To date, the fundamental pathophysiology underlying the occurrence and progression of psoriasis are still unanswered questions. Genome-wide association surveys have revealed that TNFAIP3 and TNIP1 were key biomarkers for psoriasis. Here, we intended to conduct a survey on the association between TNFAIP3 and TNIP1 gene polymorphisms and psoriasis risk. METHODS: A comprehensive search of four online databases-China National Knowledge Infrastructure (CNKI), PubMed, Embase, and Cochrane Library was undertaken up to August 25, 2019. We chose allele genetic model to deal with the original data. Newcastle-Ottawa scale (NOS) was used to evaluate the risk bias of each study. The RevMan 5.3 software was used to calculate the combined odds ratio and 95% confidence interval. RESULTS: In total, we included 13 case-control studies consist of 13,908 psoriasis patients and 20,051 controls in this work. Our results demonstrated that rs610604 in TNFAIP3 polymorphism was significantly associated with psoriasis risk using random-effect model (G vs. T, OR = 1.19, 95% CI: 1.09-1.31, P = 0.0002), and a significant association between rs17728338 in TNIP1 polymorphism and psoriasis vulnerability using fixed-effect model (A vs. G, OR = 1.69, 95% CI:1.58-1.80, P < 0.00001). CONCLUSIONS: Our findings indicated that rs610604 in TNFAIP3 and rs17728338 in TNIP1 gene polymorphisms were associated with psoriasis susceptibility.


Assuntos
Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Psoríase/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , China/epidemiologia , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Psoríase/epidemiologia , Psoríase/patologia
8.
J Ayub Med Coll Abbottabad ; 32(1): 64-67, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468758

RESUMO

BACKGROUND: Patient suffering from psoriasis can be severely affected in their day to day activities and it may also result in reduced work efficiency and absenteeism from work leading to financial burden on the patient's family. This study was conducted using Dermatology Life Quality Index to assess the quality of life of a patient suffering from psoriasis being treated at a military hospital. METHODS: This cross-sectional study was conducted in the outpatient unit of Department of Dermatology, Combined Military Hospital Abbottabad from 1st October 2013 to 31stJune 2014. The demographic data and Dermatology Life Quality Index of patients of psoriasis were recorded using a standard questionnaire and their final score was calculated to assess the effect of disease on patient's life. Extent/ severity of disease were assessed according to the body surface area involved. The data was analysed using SPSS- 18. Mean and SD for numerical variables and frequencies and percentages for categorical were calculated. RESULTS: A total of 160 patients fulfilling the inclusion criteria were included in the study. Mean age of the patients was 40.48 years (±12.58 years) with minimum age of 18 years and maximum of 74 years. 118 patients were males were (73.8%) and 42 were females (26.2%). Twenty (12.5%) patients had no effect on their life by the disease while 5 (3.1%) had extremely large effect. Most patients, i.e., 68 (42.5%) had moderate effect on their lives. 69 patients had mild psoriasis as per body surface area involved, 70 had moderate disease and 21 had severe disease. CONCLUSIONS: Psoriasis affects quality of life of patients not only physically but also psychologically and financially even when patients are under treatment. Psychological aspects also need to be addressed while treating the physical morbidity.


Assuntos
Psoríase , Qualidade de Vida/psicologia , Adolescente , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/epidemiologia , Psoríase/patologia , Psoríase/fisiopatologia , Psoríase/psicologia , Índice de Gravidade de Doença , Estresse Psicológico , Inquéritos e Questionários , Adulto Jovem
9.
Am J Trop Med Hyg ; 103(1): 206-208, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32342842

RESUMO

Leprosy presents with erythematous or pigmented patches, plaques, and nodules with loss of sensation and nerve thickening. Psoriasis presents as sharply demarcated erythematous plaques with overlying silvery scales. The controversial relationship between both has existed since biblical times when psoriasis was considered to be a form of leprosy. Records of leprosy patients have depicted a rarity of the coexistence of psoriasis, leading to a hypothesis that both rarely develop in the same patient. We report a rare coexistence of both diseases.


Assuntos
Hanseníase Virchowiana/complicações , Psoríase/complicações , Humanos , Hanseníase Virchowiana/diagnóstico , Hanseníase Virchowiana/patologia , Masculino , Pessoa de Meia-Idade , Psoríase/diagnóstico , Psoríase/patologia , Pele/patologia
10.
Clin Sci (Lond) ; 134(7): 907-920, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32236445

RESUMO

BACKGROUND: Increased keratinocyte proliferation occurs in the skin of psoriatic patients and is supposed to play a role in the pathogenesis of this disorder. Compounds interfering with keratinocyte proliferation could be useful in the management of psoriatic patients. AIM: To investigate whether albendazole, an anti-helmintic drug that regulates epithelial cell function in various systems, inhibits keratinocyte proliferation in models of psoriasis. METHODS: Aldara-treated mice received daily topical application of albendazole. Keratinocyte proliferation and keratin (K) 6 and K16 expression were evaluated by immunohistochemistry and Western blotting and inflammatory cells/mediators were analysed by immunohistochemistry and real-time PCR. In human keratinocytes (HEKa and HaCaT) treated with albendazole, cell cycle and proliferation, keratins and cell cycle-associated factors were evaluated by flow cytometry, colorimetric assay and Western blotting respectively. RESULTS: Aldara-treated mice given albendazole exhibited reduced epidermal thickness, decreased number of proliferating keratinocytes and K6/K16 expression. Reduction of CD3- and Ly6G-positive cells in the skin of albendazole-treated mice associated with inhibition of IL-6, TNF-α, IL-1ß, IL-17A, IL-36, CCL17, CXCL1, CXCL2 and CXCL5 expression. Treatment of keratinocytes with albendazole reduced K6/K16 expression and reversibly inhibited cell growth by promoting accumulation of cells in S-phase. This phenomenon was accompanied by down-regulation of CDC25A, a phosphatase regulating progression of cell cycle through S-phase, and PKR-dependent hyper-phosphorylation of eIF2α, an inhibitor of CDC25 translation. In Aldara-treated mice, albendazole activated PKR, enhanced eIF2α phosphorylation and reduced CDC25A expression. CONCLUSIONS: Data show that albendazole inhibits keratinocyte proliferation and exerts therapeutic effect in a murine model of psoriasis.


Assuntos
Albendazol/farmacologia , Proliferação de Células/efeitos dos fármacos , Fármacos Dermatológicos/farmacologia , Queratinócitos/efeitos dos fármacos , Psoríase/tratamento farmacológico , Pele/efeitos dos fármacos , Animais , Linhagem Celular , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Fator de Iniciação 2 em Eucariotos/metabolismo , Humanos , Imiquimode , Mediadores da Inflamação/metabolismo , Queratinócitos/metabolismo , Queratinócitos/patologia , Queratinas/genética , Queratinas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fosforilação , Psoríase/induzido quimicamente , Psoríase/metabolismo , Psoríase/patologia , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Transdução de Sinais , Pele/metabolismo , Pele/patologia , Fosfatases cdc25/metabolismo , eIF-2 Quinase/metabolismo
11.
Artigo em Inglês | MEDLINE | ID: mdl-32267715

RESUMO

The skin is essential for terrestrial life. It is responsible for regulating water permeability and functions as a mechanical barrier that protects against environmental insults such as microbial infection, ultraviolet light, injury, and heat and cold, which could damage the cells of the body and compromise survival of the organism. This barrier is provided by the outer layer, the epidermis, which is composed predominantly of keratinocytes; keratinocytes undergo a program of differentiation to form the stratum corneum comprising the cornified squame "bricks" and lipid "mortar." Dysregulation of this differentiation program can result in skin diseases, including psoriasis and nonmelanoma skin cancers, among others. Accumulating evidence in the literature indicates that the water-, glycerol-, and hydrogen peroxide-transporting channel aquaporin-3 (AQP3) plays a key role in various processes involved in keratinocyte function, and abnormalities in this channel have been observed in several human skin diseases. Here, we discuss the data linking AQP3 to keratinocyte proliferation, migration, differentiation, and survival as well as its role in skin properties and functions like hydration, water retention, wound healing, and barrier repair. We also discuss the mechanisms regulating AQP3 levels, localization, and function and the anomalies in AQP3 that are associated with various skin diseases.


Assuntos
Aquaporina 3/metabolismo , Epiderme/metabolismo , Queratinócitos/metabolismo , Psoríase/metabolismo , Água/metabolismo , Animais , Diferenciação Celular , Movimento Celular , Proliferação de Células , Epiderme/patologia , Humanos , Queratinócitos/patologia , Estado de Hidratação do Organismo , Permeabilidade , Psoríase/patologia , Transdução de Sinais , Cicatrização
12.
J Dermatolog Treat ; 31(5): 470-475, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32202943

RESUMO

Background: Relative Psoriasis Area and Severity Index (PASI) improvement, also called 'PASI response', is recommended in major guidelines for assessment of treatment response in psoriasis patients. However, under certain circumstances it has some limitations, e.g. when baseline values are missing or during long-term treatment. Improvement of health-related quality of life (HrQoL) can be measured by the Dermatology Life Quality Index (DLQI).Objective: To evaluate the association of HrQoL and relative and absolute PASI outcomes during therapy.Material and methods: Data of plaque psoriasis patients of two clinical trials (CLEAR and SCULPTURE) were pooled. The rates of patients achieving DLQI 0/1 at week 16 were compared for different categories of absolute PASI and PASI response values. The correlation of DLQI and absolute or relative PASI goals was assessed over 52 weeks.Results: One thousand and fifty-four patients with available assessments of PASI and DLQI were included. 76% of the patients with an absolute PASI ≤ 2 (N = 548) and patients with a 90% improvement in PASI (N = 559) achieved DLQI 0/1 at week 16. Achievement of DLQI 0/1 was equally reflected by absolute PASI and PASI response.Conclusion: Absolute PASI appeared to be a feasible alternative to PASI response for determining treatment success, reflecting HrQoL improvements in an equal manner.


Assuntos
Psoríase/patologia , Qualidade de Vida , Adulto , Ensaios Clínicos como Assunto , Fármacos Dermatológicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Resultado do Tratamento
15.
Minerva Med ; 111(3): 254-265, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32166932

RESUMO

With the discovery of the IL-23 / Th17 axis, the treatment of psoriasis has entered a new era. The aim of this study was to explore the progress of biologics and janus kinases (JAK) inhibitors targeting IL-23/Th17 axis in the treatment of psoriasis. review of English-language article was performed. Search terms included IL-17, IL-23, biologics, monoclonal antibodies, neutralizing antibodies, JAK, inhibitors, Psoriasis Area Severity Index and psoriasis. Data were selected from two phase 2 clinical trials; and nine phase 3 randomized, double-blind clinical trials; and other clinical trials. This review analyzes skin lesion clearance and major adverse reactions of 9 mAbs including mirikizumab and bimekizumab. At the same time, the research progress and prospects of three non-IgG small molecule biologics are analyzed too. This paper also compares the efficacy and limitations of biologics targeting the IL-23/Th17 axis with non-biologics acting on the JAK-signal transducer and activator of transcription pathway. The IL-17A/F inhibitors and non-IgG small molecule biologics that are being studied will bring a revolutionary development to the treatment of psoriasis. Topical application of JAK inhibitors can not only achieve the purpose of treating psoriasis, but also reduce the amounts of systemic medication, and reduces side effects. Each drug has its own indication, and the effect of the drug can be better achieved by selecting the indication for the drug.


Assuntos
Produtos Biológicos/uso terapêutico , Interleucina-17/antagonistas & inibidores , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Psoríase/terapia , Anticorpos Monoclonais Humanizados , Anticorpos Neutralizantes/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Subunidade p19 da Interleucina-23/metabolismo , Psoríase/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Interleucina-17/antagonistas & inibidores , Índice de Gravidade de Doença , Células Th17/citologia , Células Th17/imunologia
16.
PLoS One ; 15(3): e0230585, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32191772

RESUMO

BACKGROUND: The aim of this study was to validate the English version of the Itch Cognition Questionnaire in a sample of patients with chronic itch due to psoriasis or atopic dermatitis. An English-language version of an instrument assessing itch-related cognitions is needed since cognitions can contribute to a worsening of itch, and chronic itch is prevalent in English-speaking counties and internationally. METHODS: The German Itch Cognitions Questionnaire was translated into English, and cognitive interviewing was conducted to finalize item wording. Internal and test-retest reliability, item discrimination, responsiveness to change, and construct, convergent, and discriminant validity were assessed in a national sample of 137 individuals with chronic itch due to atopic dermatitis or psoriasis recruited online. RESULTS: Internal reliability was high with Cronbach's alphas of 0.93 for the Catastrophizing subscale and 0.88-0.90 for Coping. The Pearson's correlation assessing 1-month test-retest reliability for the Catastrophizing subscale was r = 0.62 and for the Coping subscale was r = 0.61. The corrected item-total correlation revealed that items were relatively consistent with the scores for the subscales (with correlations ranging from 0.58 to 0.79), indicating very good item discrimination. Results of factor analysis, convergent and discriminant, and responsiveness to change analyses provided evidence for validity. CONCLUSIONS: This study showed good psychometric characteristics of the English version of the Itch Cognitions Questionnaire. We suggest that future studies investigate the use of the measure in clinical practice to assist with treatment planning and outcome assessment related to itch as well as address study limitations such as sampling and replication.


Assuntos
Cognição/fisiologia , Prurido/patologia , Psicometria/métodos , Adaptação Psicológica , Adolescente , Adulto , Catastrofização , Eczema/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/patologia , Qualidade de Vida , Índice de Gravidade de Doença , Inquéritos e Questionários , Tradução , Adulto Jovem
17.
J Dermatolog Treat ; 31(5): 460-469, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32045314

RESUMO

Introduction: The primary objective of the study was to evaluate the measurement properties of the patient-reported four-item Psoriasis Symptom Scale (PSS).Methods: Analysis of phase-III data on the efficacy of risankizumab to assess psychometric characteristics of the PSS in patients with moderate-to-severe psoriasis.Results: PSS items had a good range of symptom severity coverage. The PSS had good test-retest reliability (ICCs >0.90). Convergent and discriminant validity was indicated by moderate-to-strong correlations between the PSS and Dermatology Life Quality Index (DLQI), PSS pain item and EQ-5D pain/discomfort item at week 12 (0.63), and moderate negative correlation with EQ-Visual Analog Scale score at week 12 (-0.37). Known groups validity demonstrated as mean PSS total scores varied by Psoriasis Area and Severity Index (PASI) and Static Physician's Global Assessment (sPGA) defined groups (p < .0001). PSS total scores were responsive to changes in PASI score (p < .0001) and sPGA (p < .0001). PSS minimal, clinical, and meaningful change is estimated to be 1 to 2 points; a preliminary responder definition is a total change score of 3 to 4 points.Conclusions: The PSS is a short, valid unidimensional measure of psoriasis symptom severity, well suited for use in clinical trials.


Assuntos
Psoríase/patologia , Psicometria/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Fármacos Dermatológicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Prurido/etiologia , Psoríase/complicações , Psoríase/tratamento farmacológico , Qualidade de Vida , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Adulto Jovem
18.
EBioMedicine ; 52: 102645, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014819

RESUMO

BACKGROUND: TLRs are some of the actively pursued drug-targets in immune disorders. Owing to a recent surge in the cognizance of TLR structural biology and signalling pathways, numerous therapeutic modulators, ranging from low-molecular-weight organic compounds to polypeptides and nucleic acid agents have been developed. METHODS: A penetratin-conjugated small peptide (TIP3), derived from the core ß-sheet of TIRAP, was evaluated in vitro by monitoring the TLR-mediated cytokine induction and quantifying the protein expression using western blot. The therapeutic potential of TIP3 was further evaluated in TLR-dependent in vivo disease models. FINDINGS: TIP3 blocks the TLR4-mediated cytokine production through both the MyD88- and TRIF-dependent pathways. A similar inhibitory-effect was exhibited for TLR3 but not on other TLRs. A profound therapeutic effect was observed in vivo, where TIP3 successfully alleviated the inflammatory response in mice model of collagen-induced arthritis and ameliorated the disease symptoms in psoriasis and SLE models. INTERPRETATION: Our data suggest that TIP3 may be a potential lead candidate for the development of effective therapeutics against TLR-mediated autoimmune disorders. FUNDING: This work was supported by the National Research Foundation of Korea (NRF-2019M3A9A8065098, 2019M3D1A1078940 and 2019R1A6A1A11051471). The funders did not have any role in the design of the present study, data collection, data analysis, interpretation, or the writing of the manuscript.


Assuntos
Glicoproteínas de Membrana/química , Peptídeos/química , Peptídeos/farmacologia , Conformação Proteica em Folha beta , Receptores de Interleucina-1/química , Receptor 4 Toll-Like/química , Sequência de Aminoácidos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Autoimunidade , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Modelos Moleculares , Óxido Nítrico/metabolismo , Peptídeos/metabolismo , Psoríase/tratamento farmacológico , Psoríase/imunologia , Psoríase/metabolismo , Psoríase/patologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de Interleucina-1/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade , Receptor 4 Toll-Like/metabolismo , Receptores Toll-Like/metabolismo
19.
Sci Adv ; 6(2): eaax5849, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31934626

RESUMO

Psoriasis is a common chronic skin disorder characterized by keratinocyte hyperproliferation with altered differentiation accompanied by inflammation and increased angiogenesis. It remains unclear whether the first events that initiate psoriasis development occur in keratinocytes or inflammatory cells. Here, using different psoriasis mouse models, we showed that conditional deletion of Flt1 or Nrp1 in epidermal cells inhibited psoriasis mediated by Vegfa overexpression or c-Jun/JunB deletion. Administration of anti-Nrp1 antibody reverted the psoriasis phenotype. Using transcriptional and chromatin profiling of epidermal cells following Vegfa overexpression together with Flt1 or Nrp1 deletion, we identified the gene regulatory network regulated by Vegfa/Nrp1/Flt1 during psoriasis development and uncovered a key role of Fosl1 in regulating the chromatin remodeling mediated by Vegfa overexpression in keratinocytes. In conclusion, our study identifies an epidermal autonomous function of Vegfa/Nrp1/Flt1 that mediates psoriatic-like disease and demonstrates the clinical relevance of blocking Vegfa/Nrp1/Flt1 axis in psoriasis.


Assuntos
Células Epidérmicas/metabolismo , Neuropilina-1/metabolismo , Psoríase/metabolismo , Psoríase/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Anticorpos Bloqueadores/farmacologia , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Células Epidérmicas/efeitos dos fármacos , Células Epidérmicas/patologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Camundongos Knockout , Fenótipo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Psoríase/genética , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Transcrição Genética/efeitos dos fármacos
20.
Biomolecules ; 10(2)2020 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-31991752

RESUMO

(1) Background: Withania somnifera Dunal (Ashwagandha) is a widely used medicinal herb in traditional medicinal systems with extensive research on various plant parts. Surprisingly, seeds of W. somnifera have never been investigated for their therapeutic potential. (2) Methods: W. somnifera seeds were extracted for fatty acids (WSSO) using super critical fluid extraction, and was analyzed by gas chromatography. Its therapeutic potential in psoriasis-like skin etiologies was investigated using a 12-O tetradecanoyl phorbol 13-acetate (TPA)-induced psoriatic mouse model. Psoriatic inflammation along with psoriatic lesions and histopathological scores were recorded. WSSO was also tested on murine macrophage (RAW264.7), human epidermoid (A431), and monocytic (THP-1) cells, stimulated with TPA or lipo poly-saccharide (LPS) to induce pro-inflammatory cytokine (IL-6 and TNF-α) release. NFκB promoter activity was also measured by luciferase reporter assay. (3) Results: Topical application of WSSO with concurrent oral doses significantly reduced inflammation-induced edema, and repaired psoriatic lesions and associated histopathological scores. Inhibition of pro-inflammatory cytokines release was observed in WSSO-treated A431 and THP-1 cells, along with reduced NFκB expression. WSSO also inhibited reactive nitrogen species (RNS) in LPS-stimulated RAW264.7 cells. (4) Conclusion: Here we show that the fatty acids from W. somnifera seeds have strong anti-inflammatory properties, along with remarkable therapeutic potential on psoriasis-like skin etiologies.


Assuntos
Inflamação/tratamento farmacológico , Interleucina-6/genética , Psoríase/tratamento farmacológico , Fator de Necrose Tumoral alfa/genética , Withania/química , Animais , Modelos Animais de Doenças , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/patologia , Camundongos , Psoríase/induzido quimicamente , Psoríase/genética , Psoríase/patologia , Células RAW 264.7 , Sementes/química , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/patologia , Acetato de Tetradecanoilforbol/toxicidade
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