RESUMEN
BACKGROUND: Real-world evidence describing the benefits of recommended therapies and their impact on the quality of life (QoL) of chronic urticaria (CU) patients is limited. OBJECTIVE: To investigate disease burden, current treatment schedule, and the use of clinical resources by patients with H1 -antihistamine-refractory CU in Europe. METHODS: AWARE (A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation) is a global, prospective, non-interventional study in the real-world setting, sponsored by the manufacturer of omalizumab. Disease characteristics, pharmacological treatments, and health-related QoL of patients (N = 2727) ≥18 years of age diagnosed with H1 -antihistamine-refractory chronic spontaneous urticaria (without inducible urticaria) for >2 months are reported here. RESULTS: Of the 2727 patients included, 1232 (45.2%) and 1278 (46.9%) were successfully followed up for any assessment and for the key outcome, the urticaria control test (UCT) score, respectively, and patients with complete remission (14.1%) were excluded from analyses.The proportion of patients with uncontrolled CSU (UCT score <12) dropped from 78% (n/N = 1641/2104) at baseline to 28.7% (n/N = 269/936) after two years of participation in the AWARE study. In addition, the proportion of patients with no impact of CSU on their QoL (assessed by the Dermatological Life Quality Index) increased to 57% (n/N = 664/1164) from 18.7% (n/N = 491/2621) at baseline. Emergency room visits (2.4% [n/N = 7/296] vs 33.5% [n/N = 779/2322]) and hospital stays (1.7% [n/N = 5/296] vs 24.2% [n/N = 561/2322]) reduced at Month 24 vs baseline. Overall, 23.2% (n/N = 26/112) patients on non-sedating H1 -antihistamines (nsAH) and 41.9% (n/N = 44/105) patients on up-dosed nsAH had uncontrolled CSU (UCT <12) at Month 24. In omalizumab-treated patients, 27.1% (n/N = 78/288) had uncontrolled CSU at Month 24. CONCLUSION: These data confirm improvements for most patients with CSU over a 2-year follow-up period. Further studies are needed to understand the differences between guideline recommendations and reported management.
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Urticaria Crónica/tratamiento farmacológico , Resistencia a Medicamentos , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Pautas de la Práctica en Medicina/tendencias , Adulto , Antialérgicos/uso terapéutico , Urticaria Crónica/diagnóstico , Urticaria Crónica/inmunología , Costo de Enfermedad , Europa (Continente) , Femenino , Adhesión a Directriz/tendencias , Antagonistas de los Receptores Histamínicos H1/efectos adversos , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Omalizumab/uso terapéutico , Medición de Resultados Informados por el Paciente , Guías de Práctica Clínica como Asunto , Estudios Prospectivos , Calidad de Vida , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Indolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality of life. Masitinib inhibits KIT and LYN kinases that are involved in indolent systemic mastocytosis pathogenesis. We aimed to assess safety and efficacy of masitinib versus placebo in severely symptomatic patients who were unresponsive to optimal symptomatic treatments. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 study, we enrolled adults (aged 18-75 years) with indolent or smouldering systemic mastocytosis, according to WHO classification or documented mastocytosis based on histological criteria, at 50 centres in 15 countries. We excluded patients with cutaneous or non-severe systemic mastocytosis after a protocol amendment. Patients were centrally randomised (1:1) to receive either oral masitinib (6 mg/kg per day over 24 weeks with possible extension) or matched placebo with minimisation according to severe symptoms. The primary endpoint was cumulative response (≥75% improvement from baseline within weeks 8-24) in at least one severe baseline symptom from the following: pruritus score of 9 or more, eight or more flushes per week, Hamilton Rating Scale for Depression of 19 or more, or Fatigue Impact Scale of 75 or more. We assessed treatment effect using repeated measures methodology for rare diseases via the generalised estimating equation model in a modified intention-to-treat population, including all participants assigned to treatment minus those who withdrew due to a non-treatment-related cause. We assessed safety in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00814073. FINDINGS: Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n=71) or placebo (n=64). By 24 weeks, masitinib was associated with a cumulative response of 18·7% in the primary endpoint (122·6 responses of 656·5 possible responses [weighted generalised estimating equation]) compared with 7·4% for placebo (48·9 of 656·5; difference 11·3%; odds ratio 3·6; 95% CI 1·2-10·8; p=0·0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight [11%] of 70 in the masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment). INTERPRETATION: These study findings indicate that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis. FUNDING: AB Science (Paris, France).
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Mastocitosis Sistémica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Tiazoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Astenia/inducido químicamente , Benzamidas , Diarrea/inducido químicamente , Método Doble Ciego , Exantema/inducido químicamente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piperidinas , Piridinas , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Urticaria/inducido químicamente , Adulto JovenRESUMEN
BACKGROUND: Previous clinical trials have not evaluated improvement in nail psoriasis as a primary end point. OBJECTIVE: This phase 3 trial evaluated the safety and efficacy of adalimumab in patients with moderate-to-severe fingernail psoriasis and moderate-to-severe plaque psoriasis. METHODS: Patients were randomized 1:1 to 40 mg adalimumab every other week or placebo. The primary efficacy end point was at least 75% improvement in total-fingernail modified Nail Psoriasis Severity Index (NAPSI75) response rate at week 26. Ranked secondary end point scores evaluated at week 26 were total-fingernail NAPSI and modified NAPSI, nail pain, Nail Psoriasis Physical Functioning Severity, Brigham Scalp Nail Inverse Palmo-Plantar Psoriasis Index, and Physician's Global Assessment (fingernail psoriasis). RESULTS: Of the 217 randomized patients (108 received placebo and 109 received adalimumab), 188 (86.6%) completed 26 weeks of treatment (period A) or escaped early to the open-label period. The study met the primary end point (response rate of 3.4% with placebo vs 46.6% with adalimumab [P < .001]) and all ranked secondary end points. The serious adverse event rates (placebo vs adalimumab) in period A were 4.6% versus 7.3%; the serious infections rates were 1.9% versus 3.7%. LIMITATIONS: Patients with less than 5% BSA involvement were not eligible for enrollment. CONCLUSIONS: After 26 weeks of adalimumab treatment, significant improvements were seen in the primary and all ranked secondary end points and in signs and symptoms of moderate-to-severe nail psoriasis versus with placebo and no new safety risks were identified.
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Adalimumab/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedades de la Uña/tratamiento farmacológico , Psoriasis/tratamiento farmacológico , Adalimumab/efectos adversos , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Inyecciones Subcutáneas , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Enfermedades de la Uña/etiología , Enfermedades de la Uña/fisiopatología , Seguridad del Paciente , Psoriasis/complicaciones , Psoriasis/diagnóstico , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Mastocytosis (M) is a clonal myeloid-disabling disorder for which no curative therapy is currently available. Cladribine (2-chlorodeoxyadenosine [2-CdA]) is a synthetic purine analog cytoreductive treatment, for which efficacy is mostly reported in advanced M. Here we report, with a long-term follow-up period (>10 years) efficacy and safety in 68 adult patients with M (36 [53%] had indolent M and 32 [47%] had advanced M) treated by 2-CdA (0.14 mg/kg in infusion or subcutaneously, days 1-5; repeated at 4-12 weeks until 1 to 9 courses). Median 2-CdA courses number was 3.7 (1-9). The overall response rate was 72% (complete remission [R]/major/partial R: 0%/47%/25%) and according to indolent/advanced M was 92% (major/partial R: 56%/36%) and 50% (major/partial R: 37.5%/12.5%), respectively. Clinical improvement was observed for 10 of 11 mediator release and 6 of 7 mast cell infiltration-related symptoms including urticaria pigmentosa and organomegaly (P < .02). Serum tryptase levels decreased (P = .01). Median durations of response were 3.71 (0.1-8) and 2.47 (0.5-8.6) years for indolent and aggressive M, respectively. The most frequent grade 3/4 toxicities were lymphopenia (82%), neutropenia (47%), and opportunistic infections (13%). 2-CdA appears to provide a significant efficacy with some toxicity in various M subtypes, mostly in indolent M, refractory to multiple symptomatic therapies.
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Antineoplásicos/uso terapéutico , Cladribina/uso terapéutico , Mastocitosis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Hypertensive leg ulcer (HLU) is an inflammatory disease characterized by intense pain, alteration of vascularization, and skin necrosis. The optimal treatment relies on surgical removal of necrotic tissues covered by a split-skin graft. We studied the histomorphology of the lesions and investigated the involvement of inflammatory cells and cytokines to further define the physiopathology of HLU. We report epidermis acanthosis and a preferential occlusion of the precapillary arterioles with infiltration of neutrophils, macrophages, and T lymphocytes in the dermis. OSM, IL-1ß, and IL-6 were overexpressed in the ulcer, whereas the Th17-derived cytokines were not. In vitro, the addition of IL-1ß and OSM promoted acanthosis and destructuring of reconstructed epidermis. Exogenous IL-1ß and OSM synergistically induced epidermal acanthosis in mice. These data show that OSM and IL-1ß are not only a biological characteristic signature of HLU, but these cytokines reflect a specific inflammatory state, directly involved in the pathogenesis. We suggest that anti-cytokine biotherapies could be an alternative strategy to surgery to treat HLU.
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Hipertensión/complicaciones , Interleucina-1beta/metabolismo , Úlcera de la Pierna/complicaciones , Úlcera de la Pierna/patología , Melanosis/complicaciones , Melanosis/patología , Oncostatina M/metabolismo , Adulto , Anciano , Animales , Diferenciación Celular , Proliferación Celular , Constricción Patológica/complicaciones , Constricción Patológica/patología , Epidermis/patología , Femenino , Humanos , Hipertensión/metabolismo , Hipertensión/patología , Interleucina-6/metabolismo , Queratina-10/metabolismo , Queratinocitos/metabolismo , Queratinocitos/patología , Antígeno Ki-67/metabolismo , Úlcera de la Pierna/metabolismo , Leucocitos/patología , Masculino , Melanosis/metabolismo , Ratones , Ratones Endogámicos C57BL , Microvasos/patología , Modelos Biológicos , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patologíaRESUMEN
BACKGROUND: Patients with burning mouth syndrome (BMS) are frequently treated with antidepressants. Selective serotonin reuptake inhibitors (SSRIs) are increasingly used. Nonetheless, few studies have examined the effects of SSRIs in BMS. OBJECTIVE: We performed a retrospective study to confirm the need for a prospective study on this topic in the future. PATIENTS AND METHODS: 51 patients suffering from primary BMS were included in this study. RESULTS: The frequency of side effects due to SSRIs was low, with mainly digestive side effects. Treatment with SSRIs was more efficient in patients reporting a psychogenic origin for their symptoms. Antidepressants were more frequently stopped when patients did not declare such an origin. CONCLUSIONS: SSRIs appear to be effective and well tolerated. Declaring a psychogenic component may be considered as a potentiating or predictive factor for the efficacy of treatment with SSRIs. These results should be confirmed by a prospective randomised study.
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Antidepresivos Tricíclicos/uso terapéutico , Síndrome de Boca Ardiente/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Anciano , Síndrome de Boca Ardiente/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Keratinocytes play a crucial role in the regulation of skin inflammation, responding to environmental and immune cells stimuli. They produce soluble factors that can act in an autocrine or paracrine manner on immune cells or directly on aggressors. A screening of the activities of 36 cytokines on keratinocyte gene expression identified IL-17A, IL-22, oncostatin M, TNF-alpha, and IL-1alpha as potent cytokines in inducing cutaneous inflammation. These five proinflammatory cytokines synergistically increased production of CXCL8 and beta-defensin 2 (BD2). In addition, ex vivo studies on human skin explants demonstrated upregulation of BD2, S100A7, and CXCL8 expression in response to the same combination of cytokines. In vivo intradermal injection of these five cytokines in mouse increased CXCL1, CXCL2, CXCL3, S100A9, and BD3 expression, associated with neutrophil infiltration. We confirmed and extended this synergistic effect using quantitative real-time PCR analysis and observed increased expression of nine chemokines and 12 antimicrobial peptides. Production of CXCL, CXCL5, and CXCL8 by keratinocytes stimulated in the presence of this cytokine combination was associated with increased neutrophil chemotactic activity. Similarly, high production of BD2, BD3, and S100A7 was associated with an increased antimicrobial activity. Finally, the transcriptional profile observed in this in vitro model of inflammatory keratinocytes correlated with the one of lesional psoriatic skin. Our results demonstrate the important potentiating activities of IL-17A, IL-22, oncostatin M, TNF-alpha, and IL-1alpha on keratinocytes. This is particularly interesting in the context of psoriasis where these cytokines are overexpressed and could synergize to play an important role in upregulation of chemokines and antimicrobial peptides production.
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Dolor Crónico/epidemiología , Neuralgia/epidemiología , Enfermedades de la Piel/epidemiología , Actividades Cotidianas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Dolor Crónico/diagnóstico , Dolor Crónico/terapia , Costo de Enfermedad , Femenino , Francia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Neuralgia/diagnóstico , Neuralgia/terapia , Manejo del Dolor , Dimensión del Dolor , Factores de Riesgo , Índice de Severidad de la Enfermedad , Enfermedades de la Piel/diagnóstico , Enfermedades de la Piel/terapia , Adulto JovenRESUMEN
BACKGROUND: It is important to assess the burden of chronic urticaria (CU) with real-life studies. The AWARE study was performed in 36 countries over two years in CU patients resistant to H1-antihistamines. OBJECTIVES: To correlate patient-reported outcomes and available therapeutic options in CU patients. MATERIALS & METHODS: The AWARE study was a prospective, non-interventional, international study that included adult patients who have had H1-antihistamine-resistant CU for at least two months. The primary endpoints were the evolution of disease activity (UAS7), urticaria control (UCT), dermatological quality of life (DLQI) and treatment satisfaction (visual analogic scale) during a two-year follow-up. The data from French centres are reported. RESULTS: Ninety-two patients were included (mean age: 47.8 years; women: 70.7%; mean disease duration: 6.5 years; angioedema: 34.1%). The percentage of patients with CU treatment increased from 56.5% at inclusion to 86.0% after two years (for patients with non-sedative H1-antihistamines from 52.2% to 74.4%, and omalizumab from 2.2% to 25.6%). During the follow-up, the percentage of patients with UAS7 score <6 increased from 12.5% to 60.9%, and patients with well-controlled CU (UCT score >12) increased from 11.1% to 62.2%. The negative impact on quality of life (DLQI >10) decreased from 34.1% to 10.5%. The mean score of patient satisfaction for treatment increased from 4.6 to 7.6. CONCLUSION: The management of CU patients resistant to H1-antihistamines was not optimal at inclusion with uncontrolled disease, impaired quality of life and insufficient treatment. After a two-year follow-up, disease symptoms and quality of life improved, but the therapeutic management could be further optimized.
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Antialérgicos/uso terapéutico , Urticaria Crónica/tratamiento farmacológico , Recursos en Salud/estadística & datos numéricos , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Omalizumab/uso terapéutico , Adulto , Costo de Enfermedad , Resistencia a Medicamentos , Quimioterapia/normas , Eficiencia , Femenino , Estudios de Seguimiento , Francia , Humanos , Masculino , Persona de Mediana Edad , Medición de Resultados Informados por el Paciente , Satisfacción del Paciente , Estudios Prospectivos , Calidad de Vida , Índice de Severidad de la Enfermedad , Ausencia por Enfermedad/estadística & datos numéricosRESUMEN
DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome is a severe adverse drug reaction with significant mortality, characterized by erythroderma, fever, lymphadenopathy, and visceral involvement. We report a case of multivisceral DRESS syndrome with posterior multifocal placoid pigment epitheliopathy and acute tubulointerstitial nephritis responsible for dialysis-dependent acute kidney failure in the context of reactivation of Epstein-Barr virus infection. Because of resistance of the skin and kidney manifestations to prolonged corticosteroid therapy, a 6-month course of oral cyclophosphamide resulted in complete recovery of all symptoms. To our knowledge, this is the first case showing the efficacy of cyclophosphamide in severe DRESS syndrome.
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Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Ciclofosfamida/uso terapéutico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/tratamiento farmacológico , Eosinofilia/tratamiento farmacológico , Infecciones por Virus de Epstein-Barr/inducido químicamente , Oftalmopatías/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Corticoesteroides/uso terapéutico , Resistencia a Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Eosinofilia/inducido químicamente , Oftalmopatías/inducido químicamente , Femenino , Humanos , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: The AWARE study is an ongoing international study of patients with chronic urticaria refractory to H1-antihistamines. The aim of this study is to evaluate the burden of disease and the use of healthcare resources in real-life conditions. OBJECTIVES: To analyse the baseline data of French patients included in the AWARE study. MATERIALS & METHODS: AWARE is a prospective, non-interventional, international study that includes adult patients who have had chronic urticaria, refractory to at least one H1-antihistamine, for at least two months. RESULTS: Ninety-four patients (mean age: 47.9 years; 71.3% women) with chronic urticaria (50.0% spontaneous only, 9.6% inducible only, and 40.4% both) were included in French centres. The median duration from diagnosis was three years and angioedema was present in 31.5% of patients for the past six months. In 63.8% of cases, the patients received at least one treatment for urticaria (H1-antihistamine for 66.0%). Chronic urticaria was poorly controlled (UCT score <12) in 88.9% of patients and quality of life was severely impaired (mean DLQI score: 8.6). The use of healthcare resources was significant with frequent visits to general practitioners (80.8% of patients; mean: 8.1 visits). However, more than half of patients had not previously consulted a dermatologist. CONCLUSION: These baseline data of French patients in the AWARE study show that patients suffering from chronic urticaria, refractory to H1-antihistamines for a median of three years, are insufficiently treated and that their quality of life is impaired. Despite the significant use of healthcare resources, access to specialised consultations remains insufficient.
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Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Urticaria/tratamiento farmacológico , Adulto , Enfermedad Crónica , Europa (Continente) , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Medición de Resultados Informados por el Paciente , Satisfacción del Paciente , Estudios Prospectivos , Calidad de Vida , Estudios Retrospectivos , Encuestas y CuestionariosRESUMEN
BACKGROUND: Methotrexate is currently used to treat atopic dermatitis but has never been assessed versus cyclosporine in adults. OBJECTIVE: This study evaluated the efficacy and safety of methotrexate versus cyclosporine in patients with moderate-to-severe atopic dermatitis. METHODS: Patients were randomized to receive either oral methotrexate (15 mg/wk) or cyclosporine (2.5 mg/kg/d) for 8 weeks. The primary end point was a patient achieving 50% improvement in the SCORing Atopic Dermatitis index (SCORAD 50) at week 8. When the primary end point was not achieved, methotrexate was increased to 25 mg and cyclosporine to 5 mg during the next 16 weeks. The secondary end points were a patient achieving a 50% reduction in the Eczema Area Severity Intensity index (EASI 50) and SCORAD 50 at each visit (ClinicalTrials.gov no. NCT00809172). RESULTS: A total of 97 patients received methotrexate 15 mg (n = 50) or cyclosporine 2.5 mg (n = 47). Regarding the primary end point at week 8, methotrexate was inferior to cyclosporine because the proportion of patients with SCORAD 50 was 8% (4 of 50) in the methotrexate arm versus 42% (18 of 43) in the cyclosporine arm. The difference in percentages for the 2 treatment groups (2-sided 90% CI) was -34% (-48% to -20%). At week 8, methotrexate and cyclosporine dosages were increased in 56% and 49% of the patients, respectively. Regarding EASI 50, the noninferiority end point was reached at week 20 in 92% (22 of 24) of patients in the methotrexate arm and 87% (26 of 30) of patients in the cyclosporine arm. The treatment-related adverse events were more frequent with cyclosporine (P < .0001). CONCLUSIONS: Methotrexate 15 mg/wk was inferior to cyclosporine 2.5 mg/kg/d at week 8. Increasing the doses of methotrexate to 25 mg/wk induced a significant improvement versus cyclosporine at week 20.
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Ciclosporina/uso terapéutico , Dermatitis Atópica/tratamiento farmacológico , Fármacos Dermatológicos/uso terapéutico , Metotrexato/uso terapéutico , Adulto , Femenino , Humanos , Masculino , Índice de Severidad de la Enfermedad , Método Simple Ciego , Resultado del Tratamiento , Adulto JovenRESUMEN
In psoriasis, a specific cytokine network has been described to play a central role in the pathophysiology of the disease. Anti-cytokine therapeutic approaches have been largely developed and TNFα constitutes the main target. Adalimumab is a human anti-TNFα monoclonal antibody that has been reported to demonstrate clinical efficacy and safety, resulting in reversal of epidermal hyperplasia and cutaneous inflammation. We aimed to analyse changes in the skin inflammatory transcriptomic profile in psoriatic patients during adalimumab therapy. In addition, the circulating cytokine profile was analysed to define systemic inflammation. Eighteen patients with chronic plaque psoriasis were treated with adalimumab. After four and 16 weeks, clinical efficacy was assessed using PASI and DLQI, and skin mRNA profiles were determined and circulating cytokines quantified. We identified a rapid effect of adalimumab therapy on a large array of Th17 cytokines of the skin, which may account for the modification of keratinocyte expression profile and clinical response. In contrast, analysis of serum cytokine concentrations was uninformative, confirming the need for characterization of local cytokines in skin lesions. Finally, in non-responders, local cytokine expression was shown to be unchanged. We show that TNFα inhibition in psoriasis patients treated with adalimumab has a broad effect on the expression profile of cytokines and keratinocyte markers of skin inflammation, which may account for its clinical efficacy.
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Adalimumab/uso terapéutico , Antiinflamatorios/uso terapéutico , Citocinas/metabolismo , Psoriasis/tratamiento farmacológico , Psoriasis/inmunología , Piel/inmunología , Anticuerpos Monoclonales , Terapia Biológica , Perfilación de la Expresión Génica , Humanos , Glicoproteínas de Membrana/metabolismo , Psoriasis/metabolismo , ARN Largo no Codificante , ARN Mensajero/metabolismo , Índice de Severidad de la Enfermedad , Piel/metabolismo , Estadísticas no Paramétricas , Células Th17 , Resultado del TratamientoRESUMEN
BACKGROUND: Environmental factors play a major role on atopic dermatitis (AD) which shows a constant rise in prevalence in western countries over the last decades. The Hygiene Hypothesis suggesting an inverse relationship between incidence of infections and the increase in atopic diseases in these countries, is one of the working hypothesis proposed to explain this trend. OBJECTIVE: This study tested the efficacy and safety of oral administration of the bacterial lysate OM-85 (Broncho-Vaxom®, Broncho-Munal®, Ommunal®, Paxoral®, Vaxoral®), in the treatment of established AD in children. METHODS: Children aged 6 months to 7 years, with confirmed AD diagnosis, were randomized in a double-blind, placebo-controlled trial to receive, in addition to conventional treatment with emollients and topical corticosteroids, 3.5mg of the bacterial extract OM-85 or placebo daily for 9 months. The primary end-point was the difference between groups in the occurrence of new flares (NF) during the study period, evaluated by Hazard Ratio (HR) derived from conditional Cox proportional hazard regression models accounting for repeated events. RESULTS: Among the 179 randomized children, 170 were analysed, 88 in the OM-85 and 82 in the placebo group. As expected most children in both treatment groups experienced at least 1 NF during the study period (75 (85%) patients in the OM-85 group and 72 (88%) in the placebo group). Patients treated with OM-85 as adjuvant therapy had significantly fewer and delayed NFs (HR of repeated flares = 0.80; 95% confidence interval (CI): 0.67-0.96), also when potential confounding factors, as family history of atopy and corticosteroids use, were taken into account (HR = 0.82; 95% CI: 0.69-0.98). No major side effect was reported, with comparable and good tolerability for OM-85 and placebo. CONCLUSIONS: Results show an adjuvant therapeutic effect of a well standardized bacterial lysate OM-85 on established AD.
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Adyuvantes Farmacéuticos/uso terapéutico , Extractos Celulares/uso terapéutico , Dermatitis Atópica/tratamiento farmacológico , Administración Oral , Corticoesteroides , Extractos Celulares/efectos adversos , Niño , Preescolar , Dermatitis Atópica/epidemiología , Fármacos Dermatológicos/uso terapéutico , Método Doble Ciego , Femenino , Humanos , Lactante , Masculino , Prevalencia , Resultado del TratamientoRESUMEN
BACKGROUND: Acute-serum Amyloid A (A-SAA), one of the major acute-phase proteins, is mainly produced in the liver but extra-hepatic synthesis involving the skin has been reported. Its expression is regulated by the transcription factors NF-κB, C/EBPß, STAT3 activated by proinflammatory cytokines. OBJECTIVES: We investigated A-SAA synthesis by resting and cytokine-activated Normal Human Epidermal Keratinocytes (NHEK), and their inflammatory response to A-SAA stimulation. A-SAA expression was also studied in mouse skin and liver in a model mimicking psoriasis and in the skin and sera of psoriatic and atopic dermatitis (AD) patients. METHODS: NHEK were stimulated by A-SAA or the cytokines IL-1α, IL-17A, IL-22, OSM, TNF-α alone or in combination, previously reported to reproduce features of psoriasis. Murine skins were treated by imiquimod cream. Human skins and sera were obtained from patients with psoriasis and AD. A-SAA mRNA was quantified by RT qPCR. A-SAA proteins were dosed by ELISA or immunonephelemetry assay. RESULTS: IL-1α, TNF-α and mainly IL-17A induced A-SAA expression by NHEK. A-SAA induced its own production and the synthesis of hBD2 and CCL20, both ligands for CCR6, a chemokine receptor involved in the trafficking of Th17 lymphocytes. A-SAA expression was increased in skins and livers from imiquimod-treated mice and in patient skins with psoriasis, but not significantly in those with AD. Correlations between A-SAA and psoriasis severity and duration were observed. CONCLUSION: Keratinocytes could contribute to psoriasis pathogenesis via A-SAA production, maintaining a cutaneous inflammatory environment, activating innate immunity and Th17 lymphocyte recruitment.
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Dermatitis Atópica/patología , Interleucina-17/farmacología , Psoriasis/patología , Proteína Amiloide A Sérica/metabolismo , Piel/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Adulto , Anciano , Aminoquinolinas/farmacología , Animales , Células Cultivadas , Quimiocina CCL20/metabolismo , Quimiocina CCL20/farmacología , Citocinas/genética , Citocinas/metabolismo , Dermatitis Atópica/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Imiquimod , Interleucina-17/genética , Interleucina-17/metabolismo , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Psoriasis/metabolismo , Receptores CCR6/metabolismo , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/farmacología , Proteína Amiloide A Sérica/análisis , Proteína Amiloide A Sérica/genética , Piel/metabolismo , Células Th17/citología , Células Th17/metabolismoRESUMEN
BACKGROUND: Although the benefits of emollient therapy are widely accepted in atopic dermatitis, there is a relative lack of clinical evidence supporting their efficacy in these conditions. The aim of this study was to evaluate the efficacy, the tolerance and the effects on children's quality of life of a new moisturizer milk (Exomega milk) in childhood atopic dermatitis. METHODS: This controlled, randomized, multi-centric study had two parallel groups, involving children aged 6 months to 12 years, with mild and moderate atopic dermatitis (Scorad<35). The treated group applied the moisturizer milk twice a day for 2 months, in association with a cleansing bar. The non-treated group had only the cleansing bar. The use of strong and moderate topical corticoids was allowed and quantified. The following parameters were evaluated: Scorad, tolerance and the children's quality of life index. RESULTS: A total of 76 children (mean age 4 years) were included: 37 in the treated group, 39 in the non-treated group. After 2 months, the decrease of the Scorad index in the treated group was not statistically significant (p = 0.051) but detailed evaluation showed a significant improvement of xerosis (p = 0.01) and pruritus (p = 0.01) in the treated group compared with the non-treated group. Clinical improvement in the treated group after 2 months of treatment was correlated to a significant improvement of the children's quality of life index (p = 0.0011). Tolerance was good to excellent in 97% of cases. CONCLUSION: The milk emollient studied was found to provide an interesting auxiliary treatment in childhood atopic dermatitis since it gave positive results, in particular on xerosis and pruritus, as well as an improvement of the quality of life of the children.
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Dermatitis Atópica/tratamiento farmacológico , Fármacos Dermatológicos/uso terapéutico , Administración Cutánea , Niño , Preescolar , Dermatitis Atópica/patología , Dermatitis Atópica/psicología , Fármacos Dermatológicos/administración & dosificación , Femenino , Francia , Humanos , Lactante , Masculino , Calidad de Vida , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Resultado del TratamientoAsunto(s)
Alérgenos/efectos adversos , Curare/efectos adversos , Dermatitis Alérgica por Contacto/diagnóstico , Metenamina/análogos & derivados , Conservadores Farmacéuticos/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Alérgenos/administración & dosificación , Dermatitis Alérgica por Contacto/etiología , Femenino , Humanos , Masculino , Metenamina/administración & dosificación , Persona de Mediana Edad , Bloqueantes Neuromusculares/efectos adversos , Pruebas del Parche/métodos , Conservadores Farmacéuticos/administración & dosificación , Medición de RiesgoRESUMEN
Primary erythermalgia is a rare disorder characterized by recurrent attacks of red, warm and painful hands, and/or feet. We previously localized the gene for primary erythermalgia to a 7.94 cM region on chromosome 2q. Recently, Yang et al identified two missense mutations of the sodium channel alpha subunit SCN9A in patients with erythermalgia. The presence of voltage-gated sodium channels in sensory neurons is thought to play a crucial role in several chronic painful neuropathies. We examined four different families and two sporadic cases and detected missense sequence variants in SCN9A to be present in primary erythermalgia patients. A total of five of six mutations were located in highly conserved regions. One family with autosomal dominantly inherited erythermalgia was double heterozygous for two separate SCN9A mutations. These data establish primary erythermalgia as a neuropathic disorder and offers hope for treatment of this incapacitating painful disorder.
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Eritromelalgia/genética , Mutación , Enfermedades del Sistema Nervioso/genética , Canales de Sodio/genética , Adulto , Alanina , Secuencia Conservada , Cisteína , Eritromelalgia/patología , Femenino , Genes Dominantes , Heterocigoto , Humanos , Masculino , Mutación Missense , Canal de Sodio Activado por Voltaje NAV1.7 , Linaje , Polimorfismo Genético , TreoninaRESUMEN
Cytokines are key factors in the cross talk between the immune system and other systems including hepatic, nervous, cardiac and cutaneous systems, leading to an adaptive and integrated response of the organism to stress. They are also involved in the regulation of many processes, including hematopoiesis, the immune response and inflammation. IL-10 is one of the most important anti-inflammatory cytokines. Five cytokines structurally related to IL-10 have been described and presently form this family of cytokines: IL-19, IL-20, IL-22, IL-24 and IL-26. In contrast to IL-10, these cytokines display pro-inflammatory activities in different tissues, including skin. Indeed, some of them induce an inflammatory keratinocyte gene expression profile and an epidermis histology resembling psoriatic lesions. In this review, we discuss recent knowledge about the effects of cytokines of the IL-10 family on keratinocytes and their potential role in psoriasis, a cutaneous inflammatory disease.