Asunto(s)
Enfermedades Autoinmunes , Enfermedades Cutáneas Vesiculoampollosas , Humanos , Enfermedades Autoinmunes/tratamiento farmacológico , Inmunoglobulinas Intravenosas/uso terapéutico , Estudios Retrospectivos , Enfermedades Cutáneas Vesiculoampollosas/tratamiento farmacológico , Tiempo de Tratamiento , Resultado del TratamientoRESUMEN
BACKGROUND: Neutrophil (polymorphonuclear) granulocytes (PMN) have been shown to contribute to the pathogenesis of psoriasis by releasing interleukin-17 and LL37-DNA complexes via neutrophil extracellular traps (NETs), webs of chromatin strands decorated with antimicrobial peptides, in psoriatic skin. Fumaderm® , a fumaric acid ester (FAE) formulation consisting of different FAE salts, has been successfully used to treat psoriasis for decades. Most recently, FAE treatment was reported to inhibit NET formation in murine epidermolysis bullosa acquisita. OBJECTIVES: To elucidate the effect of FAE treatment on human psoriasis and healthy donor NET formation. RESULTS: Among the compounds present in the FAE formulation, dimethyl fumarate (DMF) pretreatment of human psoriasis and healthy donor PMN resulted in a consistent inhibitory effect on NET formation in response to phorbol 12-myristate 13-acetate but not to platelet activating factor and ionomycin. This effect was l-glutathione (GSH) dependent and involved a decrease in reactive oxygen species (ROS) production, a key event in NET formation. In contrast, G-protein-coupled signalling and protein synthesis were not involved. Monomethyl fumarate (MMF) was found to slightly reduce ROS production without affecting NET formation. CONCLUSIONS: We report DMF as a potent, stimulus-specific, GSH- and ROS-dependent modulator of NET formation. Our results support the notion that modulation of NET formation contributes to the beneficial effects of FAEs in a variety of inflammatory conditions.
Asunto(s)
Fármacos Dermatológicos/farmacología , Dimetilfumarato/farmacología , Trampas Extracelulares/efectos de los fármacos , Psoriasis/tratamiento farmacológico , Análisis de Varianza , Antioxidantes/farmacología , Caspasas/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Fumaratos/farmacología , Proteínas de Unión al GTP/metabolismo , Glutatión/metabolismo , Humanos , Ionomicina/farmacología , Factor de Activación Plaquetaria/farmacología , Especies Reactivas de Oxígeno/metabolismo , Superóxidos/metabolismo , Acetato de Tetradecanoilforbol/farmacologíaAsunto(s)
Adalimumab/uso terapéutico , Antiinflamatorios/uso terapéutico , Anticuerpos Antinucleares/sangre , Psoriasis/tratamiento farmacológico , Adulto , Quimioterapia Combinada , Femenino , Humanos , Inmunosupresores/uso terapéutico , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Psoriasis/sangre , Estudios Retrospectivos , Índice de Severidad de la EnfermedadAsunto(s)
Anticuerpos Antinucleares/metabolismo , Fármacos Dermatológicos/uso terapéutico , Psoriasis/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/inmunología , Ustekinumab/uso terapéutico , Anticuerpos Antinucleares/efectos de los fármacos , Productos Biológicos/inmunología , Productos Biológicos/uso terapéutico , Fármacos Dermatológicos/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Psoriasis/inmunología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Ustekinumab/inmunologíaRESUMEN
BACKGROUND: Infliximab is successfully used to treat psoriasis and psoriatic arthritis. However, some patients lose therapeutic response after several cycles. Antibodies to infliximab (infliximab-Abs) are induced during treatment in a subgroup of patients and are thought to be associated with loss of response (LOR). Routine screening for infliximab-Abs is expensive and not regularly performed. A reliable and affordable method for identifying patients who are at risk for LOR to infliximab is desirable. OBJECTIVES: To analyse the development of antinuclear antibodies (ANA)/antidouble-stranded DNA antibodies (anti-dsDNA) over time in patients with psoriasis receiving infliximab. To analyse if there is an association between ANA titres/anti-dsDNA concentrations, infliximab-Ab status and LOR. METHODS: A retrospective data analysis of 29 patients with psoriasis receiving infliximab was carried out. ANA titres and anti-dsDNA concentrations were regularly monitored in these patients and sera were tested for infliximab-Abs by enzyme-linked immunosorbent assay. RESULTS: Median ANA titres increased from 1 : 80 [interquartile range (IQR) 0 to 1 : 320, n = 29] pretreatment, to 1 : 1280 (IQR 1 : 640 to 1 : 1920, n = 15) after infusion 10, and 1 : 1920 (IQR 1 : 1280 to 1 : 2560, n = 10) after infusion 20. Infliximab-Abs were found in 21% of patients. Infliximab-Ab-positive patients and patients with LOR had significantly higher pretreatment anti-dsDNA concentrations and higher pretreatment ANA titres than infliximab-Ab-negative and responsive patients, respectively. CONCLUSIONS: The results of this study suggest a role for autoantibodies in the identification of patients with psoriasis at higher risk of developing infliximab-Abs and of LOR under treatment with infliximab.