RESUMO
Many patients with psoriasis fail to respond to biologic drugs either initially or lose response over time, the latter having predominantly been linked to low circulating drug levels. We examined how serum drug levels varied over three treatment cycles of stable maintenance therapy with either adalimumab or infliximab among a total of 28 patients with psoriasis (22 men, mean age 48.6 years, mean treatment time 6.2 years) and whether there was an association with various patient-specific factors. The range for all concentrations was 1.1 to 24.3 µg/mL for adalimumab and 0.0 to 180.6 µg/mL for infliximab. There was a consistent inverse association between body mass index (BMI) and trough and maximum serum concentrations of adalimumab (P < .05 for all comparisons) and a positive, less consistent, association between age and maximum serum concentration of infliximab (P < .05 for both comparisons). Patient-specific factors, such as BMI and age, can help predict fluctuations in serum concentrations of biologics used for psoriasis.
Assuntos
Produtos Biológicos , Psoríase , Adalimumab , Fatores Biológicos , Produtos Biológicos/efeitos adversos , Etanercepte , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade , Psoríase/diagnóstico , Psoríase/tratamento farmacológicoRESUMO
Hidradenitis suppurativa (HS), a relatively common and chronic inflammatory skin disorder. HS can have debilitating consequences if not diagnosed and treated appropriately. Clinically defined by recurrent, inflamed nodules in intertriginous regions (i.e., axillary, inguinal, and perianal areas), HS can cause intense pain and, in severe disease stages, lead to the formation of fistulas, sinus tracts, and extensive scarring. Postpubertal onset and female preponderance further characterize HS. Numerous pathogenic mechanisms have been proposed in HS, including immune dysregulation, genetics, smoking, and obesity; however, the exact etiology remains to be elucidated. The association of HS with inflammatory bowel disease, cardiovascular disease risk factors, and psychiatric disorders suggests HS is a systemic disease. HS significantly impairs quality of life in patients in excess versus other skin diseases. Unfortunately, experiences indicate long diagnostic delays, which in many cases might be due to disease unawareness among physicians. Increased knowledge of HS is therefore important in order to optimize disease management and ultimately improve the quality of life of patients.
RESUMO
The chronic skin inflammation psoriasis is crucially dependent on the IL-23/IL-17 cytokine axis. Although IL-23 is expressed by psoriatic keratinocytes and immune cells, only the immune cell-derived IL-23 is believed to be disease relevant. Here we use a genetic mouse model to show that keratinocyte-produced IL-23 is sufficient to cause a chronic skin inflammation with an IL-17 profile. Furthermore, we reveal a cell-autonomous nuclear function for the actin polymerizing molecule N-WASP, which controls IL-23 expression in keratinocytes by regulating the degradation of the histone methyltransferases G9a and GLP, and H3K9 dimethylation of the IL-23 promoter. This mechanism mediates the induction of IL-23 by TNF, a known inducer of IL-23 in psoriasis. Finally, in keratinocytes of psoriatic lesions a decrease in H3K9 dimethylation correlates with increased IL-23 expression, suggesting relevance for disease. Taken together, our data describe a molecular pathway where epigenetic regulation of keratinocytes can contribute to chronic skin inflammation.
Assuntos
Epigênese Genética , Histona-Lisina N-Metiltransferase/genética , Subunidade p19 da Interleucina-23/genética , Psoríase/genética , Pele/metabolismo , Proteína Neuronal da Síndrome de Wiskott-Aldrich/genética , Adulto , Animais , Modelos Animais de Doenças , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Histona-Lisina N-Metiltransferase/deficiência , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Inflamação , Interleucina-17/genética , Interleucina-17/metabolismo , Subunidade p19 da Interleucina-23/deficiência , Queratinócitos/metabolismo , Queratinócitos/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Cultura Primária de Células , Regiões Promotoras Genéticas , Psoríase/metabolismo , Psoríase/patologia , Transdução de Sinais , Pele/patologia , Proteína Neuronal da Síndrome de Wiskott-Aldrich/deficiênciaRESUMO
Autoinflammatory syndromes associated with hidradenitis suppurativa (HS) and/or acne are rare but potentially debilitating disorders if not diagnosed and treated correctly. They share a common pathogenesis involving a dysregulated innate immune system with abnormal interleukin (IL)-1 signaling leading to sterile neutrophilic inflammation. The clinical features are recurrent episodes of fever, painful arthritis, and skin lesions consistent with HS, acne, and pyoderma gangrenosum (PG) accompanied by elevated systemic inflammatory markers in blood. So far, several clinically different syndromes have been reported in the literature including pyoderma gangrenosum, acne, and pyogenic arthritis (PAPA), pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH), pyoderma gangrenosum, acne, and spondyloarthritis (PASS), pyoderma gangrenosum, acne, pyogenic arthritis, and hidradenitis suppurativa (PAPASH), psoriatic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PsAPASH), and pyoderma gangrenosum, acne, and ulcerative colitis (PAC). The rarity of the syndromes complicates the establishment of evidence-based treatment guidelines. Furthermore, treatment can be challenging due to lack of response to standard treatment modalities. Therefore, it is important to increase the awareness about these diseases in order to optimize disease management and ultimately improve the quality of life of patients.
