RESUMO
Methotrexate (MTX) has been used in the treatment of psoriasis and other dermatological diseases for more than 50 years. However, there is limited evidence regarding its effect, dose and monitoring, and a lack of consensus regarding how the drug should be used in daily practice. Although the use of MTX is governed by guidelines, such as the European S3-Guidelines and the National Institute for Health and Care Excellence (NICE) guideline, it is important to discuss and adjust these guidelines to national standards. An expert meeting was held in Denmark at the end of 2014, in order to reach consensus regarding the use of MTX in dermatological practice in Denmark. Participants included dermatologists, hepatologists, paediatricians, clinical biochemists and a rheumatologist. Topics discussed were: liver disease monitoring, teratogenic effects of MTX, risk of cancer, and use of MTX in children. We report here the conclusions of this expert meeting regarding use of MTX in dermatological practice.
Assuntos
Dermatologia/normas , Imunossupressores/administração & dosagem , Metotrexato/administração & dosagem , Psoríase/tratamento farmacológico , Adulto , Fatores Etários , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Criança , Consenso , Dinamarca , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Imunossupressores/efeitos adversos , Testes de Função Hepática , Masculino , Metotrexato/efeitos adversos , Neoplasias/induzido quimicamente , Neoplasias/diagnóstico , Segurança do Paciente , Gravidez , Complicações na Gravidez/induzido quimicamente , Complicações na Gravidez/diagnóstico , Psoríase/diagnóstico , Psoríase/imunologia , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Occupational contact dermatitis among hairdressers is frequent, owing to daily exposure to irritants and allergens. OBJECTIVES: To identify sensitization to the most common allergens associated with the occupation of hairdressing. METHODS: Patch test results of 399 hairdressers and 1995 matched controls with contact dermatitis, registered by the Danish Contact Dermatitis Group between January 2002 and December 2011, were analysed. All patients were patch tested with the European baseline series, and hairdressers were additionally tested with the hairdressing series. RESULTS: Occupational contact dermatitis (p < 0.001) and hand eczema (p < 0.001) were observed significantly more often among hairdressers than among controls. Atopic dermatitis was less commonly observed among hairdressers (21.3%) than among controls (29.4%) (p < 0.01). Allergens from the European baseline series with a statistically significant association with the occupation of hairdressing were p-phenylenediamine, thiuram mix, and benzocaine. Frequent sensitizers from the hairdressing series were ammonium persulfate, toluene-2,5-diamine, 3-aminophenol, and 4-aminophenol. Cysteamine hydrochloride and chloroacetamide emerged as new sensitizers. CONCLUSIONS: These results indicate a healthy worker effect among hairdressers diagnosed with eczema. Ammonium persulfate and p-phenylenediamine remain frequent sensitizers in hairdressers with contact dermatitis. Cysteamine hydrochloride and chloroacetamide should be included in future surveillance studies.
Assuntos
Alérgenos/efeitos adversos , Barbearia , Corantes/efeitos adversos , Dermatite Alérgica de Contato/etiologia , Dermatite Ocupacional/etiologia , Tinturas para Cabelo/efeitos adversos , Acetamidas/efeitos adversos , Adolescente , Adulto , Idoso , Aminofenóis/efeitos adversos , Sulfato de Amônio/efeitos adversos , Benzocaína/efeitos adversos , Cisteamina/efeitos adversos , Dinamarca/epidemiologia , Dermatite Alérgica de Contato/epidemiologia , Dermatite Ocupacional/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes do Emplastro , Fenilenodiaminas/efeitos adversos , Tiram/efeitos adversos , Adulto JovemRESUMO
Mitogen-activated protein kinase (MAPK) AP kinase 2 (MK2) is a serine/threonine kinase that is phosphorylated and activated by p38 MAPK. MK2 regulates the expression of various proinflammatory cytokines including TNF-alpha, IL-1beta, IL-6, and IL-8. Recently, MK2 was demonstrated to be activated in lesional psoriatic epidermis. This study investigates for the first time the role of MK2 in skin inflammation using the model of oxazolone-induced acute allergic contact dermatitis in mice. We show that oxazolone treatment leads to increased expression and sustained activation of both p38 MAPK and MK2. The inflammatory response was determined by ear thickness, myeloperoxidase activity, and histology after oxazolone challenge. Pretreatment with the p38 MAPK inhibitor SB202190 and genetic ablation of MK2 inhibit this inflammatory response. In particular, IL-1beta and, to a smaller but significant extent, also TNF-alpha and IFN-gamma expression were decreased in MK2 knockout mice compared with wild-type mice. These results indicate that MK2 is a potential target for the treatment of inflammatory skin diseases.
Assuntos
Dermatite Alérgica de Contato/etiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Oxazolona/toxicidade , Proteínas Serina-Treonina Quinases/fisiologia , Animais , Imidazóis/farmacologia , Interferon gama/genética , Interleucina-1beta/genética , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/farmacologia , RNA Mensageiro/análise , Fator de Necrose Tumoral alfa/genética , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologiaRESUMO
The activity of the p38 mitogen-activated protein kinases (MAPKs) is increased in lesional psoriatic skin, supporting a possible role of these kinases in the pathogenesis of psoriasis. Recently, increased focal activation of the downstream target mitogen- and stress-activated protein kinase 1 (MSK1) was demonstrated in psoriatic epidermis. The purpose of this study is to investigate MSK2 and the transcription factor cyclic adenosine monophosphate response element-binding protein (CREB) in psoriatic skin and in cultured normal human keratinocytes. In lesional psoriatic skin, significantly increased MSK2 (Ser196) and CREB (Ser133) activation was demonstrated by phospho blotting. Immunofluorescence staining of phosphorylated MSK2 (Ser196) revealed colocalization with phosphorylated MSK1 (Thr 581) in the epidermis. Keratinocyte cultures stimulated with anisomycin and IL-1beta showed increased MSK2 (Ser196) and CREB (Ser133) phosphorylation. Such activation was abolished during preincubation with a p38 inhibitor. Keratinocytes transfected with small interfering RNA showed a stronger decrease in CREB phosphorylation in MSK1/2 double-transfected cells than in MSK1 and MSK2 single-transfected cells. This study demonstrate for the first time the expression of MSK2 in keratinocytes and increased MSK2 and CREB activation in lesional psoriatic skin. Our results indicate that the p38-MAPK/MSK1/MSK2 and CREB signalling pathway may play a role in the pathogenesis of psoriasis.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Epiderme/metabolismo , Psoríase/etiologia , Proteínas Quinases S6 Ribossômicas 90-kDa/fisiologia , Adulto , Células Cultivadas , Reações Cruzadas , Imunofluorescência , Humanos , Fosforilação , Psoríase/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/análise , Proteínas Quinases S6 Ribossômicas 90-kDa/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologiaRESUMO
IL-20 is a novel member of the IL-10 cytokine family with pleiotropic effects. Current knowledge of what triggers and regulates IL-20 gene expression is sparse. The aim of this study was to investigate the regulation of IL-20 expression in cultured normal human keratinocytes. The expression of IL-20 was rapidly induced by proinflammatory stimuli, in particular IL-1beta, IL-6, and UVB irradiation. Using kinase inhibitors and small-interfering RNA, we discovered that the p38 mitogen-activated protein kinase (MAPK) as well as inhibitory kappaB kinase-NF-kappaB signaling pathways are crucial for IL-20 expression. By electrophoretic mobility shift assay two kappaB-binding sites were identified upstream from the start codon in the IL-20 gene. Supershift analysis revealed binding of the p50/p65 heterodimer. Furthermore, the p38 MAPK was shown to exert its effects on IL-20 expression through activation of the downstream kinase mitogen- and stress-activated kinase 1 (MSK1), indicating transactivation of NF-kappaB driven IL-20 messenger RNA transcription as an important mechanism of action. IL-20 is assumed to be a key cytokine in the pathogenesis of psoriasis and possibly cancer, and therefore the p38 MAPK, MSK1, and NF-kappaB may be important new molecular targets for the modulation of IL-20 expression in these diseases.
Assuntos
Interleucina-1beta/farmacologia , Interleucinas/genética , Queratinócitos/fisiologia , Sistema de Sinalização das MAP Quinases/imunologia , Subunidade p50 de NF-kappa B/metabolismo , Fator de Transcrição RelA/metabolismo , Adulto , Células Cultivadas , Dimerização , Células Epidérmicas , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Humanos , Interleucina-1alfa/farmacologia , Interleucina-6/farmacologia , Interleucinas/metabolismo , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , MAP Quinase Quinase Quinase 3/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Subunidade p50 de NF-kappa B/química , Regiões Promotoras Genéticas/fisiologia , RNA Mensageiro/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Fator de Transcrição RelA/química , Raios Ultravioleta , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Mitogen- and stress-activated protein kinase 1 (MSK1) is a downstream target of both the p38 and extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinases (MAPKs). MSK1 stimulates transcription of different pro-inflammatory genes through activation of transcription factors. The purpose of this study was to investigate the expression and activation of MSK1 in lesional psoriatic skin and its role in cytokine production in cultured normal human keratinocytes. Western blotting revealed a consistent and significant increase in phosphorylated (activated) MSK1(Ser376) in lesional psoriatic skin. Immunofluorescence staining revealed the phosphorylated MSK1(Thr581) to be localized in the basal layers of the epidermis in lesional psoriatic skin. No staining was found in non-lesional psoriatic skin. Cultured human keratinocytes incubated with anisomycin or IL-1beta resulted in the phosphorylation of the p38 MAPK and MSK1(Ser376). MSK1(Ser376) phosphorylation was inhibited by pre-incubation with the p38 inhibitor SB 202190. Transfection of the keratinocytes with specific MSK1 small interfering RNA resulted in 80% reduction of MSK1 expression and 51, 40, and 31% decrease in IL-6, IL-8, and tumor necrosis factor-alpha protein production, respectively. This study demonstrates for the first time the expression of MSK1 in epidermal keratinocytes and increased activation focally in psoriatic epidermis. As MSK1 regulates the production of pro-inflammatory cytokines, it may play a role in the pathogenesis of psoriasis.