RESUMEN
BACKGROUND: IL-22 is potentially a pathogenic cytokine in patients with atopic dermatitis (AD), but the molecular effects of IL-22 antagonism have not been defined in human subjects. OBJECTIVE: We sought to evaluate the cellular and molecular effects of IL-22 blockade in tissues from patients with moderate-to-severe AD. METHODS: We assessed lesional and nonlesional skin from 59 patients with moderate-to-severe AD treated with anti-IL-22 (fezakinumab) versus placebo (2:1) using transcriptomic and immunohistochemistry analyses. RESULTS: Greater reversal of the AD genomic profile was seen with fezakinumab versus placebo, namely 25.3% versus 10.5% at 4 weeks (P = 1.7 × 10-5) and 65.5% versus 13.9% at 12 weeks (P = 9.5 × 10-19), respectively. Because IL-22 blockade showed clinical efficacy only in patients with severe AD, we used baseline median IL-22 mRNA expression to stratify for high (n = 30) and low (n = 29) IL-22 expression groups. Much stronger mean transcriptomic improvements were seen with fezakinumab in the IL-22-high drug-treated group (82.8% and 139.4% at 4 and 12 weeks, respectively) than in the respective IL-22-high placebo-treated group (39.6% and 56.3% at 4 and 12 weeks) or the IL-22-low groups. Significant downregulations of multiple immune pathways, including TH1/CXCL9, TH2/CCL18/CCL22, TH17/CCL20/DEFB4A, and TH22/IL22/S100A's, were restricted to the IL-22-high drug group (P < .05). Consistently, tissue predictors of clinical response were mostly genes involved in T-cell and dendritic cell activation and differentiation. CONCLUSIONS: This is the first report showing a profound effect of IL-22 blockade on multiple inflammatory pathways in AD. These data, supported by robust effects in patients with high IL-22 baseline expression, suggest a central role for IL-22 in AD, indicating the need for a precision medicine approach for improving therapeutic outcomes in patients with AD.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Dermatitis Atópica/tratamiento farmacológico , Regulación de la Expresión Génica/efectos de los fármacos , Interleucinas/biosíntesis , Piel/metabolismo , Adulto , Anticuerpos Monoclonales Humanizados , Dermatitis Atópica/inmunología , Dermatitis Atópica/metabolismo , Dermatitis Atópica/patología , Femenino , Regulación de la Expresión Génica/inmunología , Humanos , Interleucinas/inmunología , Masculino , Persona de Mediana Edad , Piel/inmunología , Piel/patología , Células TH1/inmunología , Células TH1/metabolismo , Células TH1/patología , Células Th17/inmunología , Células Th17/metabolismo , Células Th17/patología , Células Th2/inmunología , Células Th2/metabolismo , Células Th2/patología , Interleucina-22RESUMEN
BACKGROUND: Interleukin 22 promotes epidermal hyperplasia and inhibits skin barrier function. OBJECTIVE: Evaluate interleukin 22 blockade in adults with moderate-to-severe atopic dermatitis (AD). METHODS: We performed a randomized, double-blind, placebo-controlled trial with intravenous fezakinumab monotherapy every 2 weeks for 10 weeks, with follow-up assessments until 20 weeks. The change in SCOring AD (SCORAD) score from baseline at 12 weeks served as the primary end point. RESULTS: At 12 weeks, the mean declines in SCORAD for the entire study population were 13.8 ± 2.7 in the fezakinumab arm and 8.0 ± 3.1 in the placebo arm (P = .134). In the severe AD patient subset (with a baseline SCORAD of ≥50), SCORAD decline was significantly stronger in the drug-treated patients than placebo-treated patients at 12 weeks (21.6 ± 3.8 vs 9.6 ± 4.2, P = .029) and 20 weeks (27.4 ± 3.9 vs 11.5 ± 5.1, P = .010). At 12 weeks, improvements in body surface area involvement in the entire population were significantly stronger in the drug-treated than placebo-treated patients (12.4% ± 2.4 vs 6.2% ± 2.7; P = .009), and in the severe AD subset, the decline in Investigator Global Assessment was significantly higher in the drug-treated than placebo-treated patients (0.7 ± 0.2 vs 0.3 ± 0.1; P = .034). All scores showed progressive improvements after last dosing (10 weeks) until end of study (20 weeks). Common adverse events were upper respiratory tract infections. LIMITATIONS: The limited sample size and lack of assessment with Eczema Area and Severity Index and a pruritus numerical rating scale were limiting factors. Significance was primarily obtained in severe AD. CONCLUSION: Fezakinumab was well-tolerated, with sustained clinical improvements after last drug dosing.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales Humanizados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Infusiones Intravenosas , Interleucinas/inmunología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Interleucina-22RESUMEN
Ingenol mebutate gel, a topical field treatment for actinic keratosis (AK), elicits inflammatory application-site reactions in most patients. This analysis explored the relationship between the intensity of local skin reactions (LSRs) and AK clearance, measured by the reduction in AK count from baseline in 218 patients who were treated for AK on the face in the pivotal Phase 3 studies. The analysis modeled the AK count at week 8, adjusted for baseline count, with the composite LSR score at 1 day after the last treatment application for each patient as a predictor to estimate the mean and 90% prediction interval for the percent reduction in AK count. The predicted mean percent reduction in AK count was higher in patients with higher composite LSR scores. Lower composite scores demonstrated a variable, less predictive percentage reduction in efficacy. Therefore, a large inflammatory reaction from ingenol mebutate gives a more reliable prognosis for improved AK clearance.
J Drugs Dermatol. 2017;16(2):112-114.
.Asunto(s)
Diterpenos/uso terapéutico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Dermatosis Facial/tratamiento farmacológico , Queratosis Actínica/tratamiento farmacológico , Administración Cutánea , Ensayos Clínicos Fase III como Asunto , Diterpenos/administración & dosificación , Diterpenos/efectos adversos , Método Doble Ciego , Dermatosis Facial/patología , Geles , Humanos , Queratosis Actínica/patología , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de RegresiónRESUMEN
Background: Ingenol mebutate gel 0.015% provides high clearance rates for actinic keratosis (AK) on the face and scalp but causes transient local skin responses (LSRs).
Objective: This study sought to determine whether the application of 1% dimethicone would decrease ingenol mebutate-associated LSRs and/or affect efficacy during the treatment of multiple AKs on the face.
Methods: Ingenol mebutate gel 0.015% was applied for 3 days to two 25 cm2 areas, each containing 3 to 8 AKs on the face of each subject, followed by application of 1% dimethicone lotion in an investigator-blinded manner to one randomly selected AK-containing area until LSRs were no longer present.
Results: In total, 20 subjects were enrolled and completed the study. Topical 1% dimethicone lotion applied during and after treatment of facial AK with ingenol mebutate gel 0.015% reduced mean total LSR scores at days 8 and 15 compared with ingenol mebutate gel only, although the difference was not statistically significant. Efficacy was equivalent between the two treatment arms.
Limitations: The study evaluated a relatively small number of subjects, all of whom were white.
Conclusions: The application of 1% dimethicone following ingenol mebutate gel 0.015% produced a trend toward lower severity of some LSRs, with no difference in efficacy.
J Drugs Dermatol. 2017;16(5):432-436.
.Asunto(s)
Dimetilpolisiloxanos/administración & dosificación , Diterpenos/administración & dosificación , Queratosis Actínica/diagnóstico , Queratosis Actínica/tratamiento farmacológico , Crema para la Piel/administración & dosificación , Administración Cutánea , Anciano , Anciano de 80 o más Años , Fármacos Dermatológicos/administración & dosificación , Fármacos Dermatológicos/efectos adversos , Dimetilpolisiloxanos/efectos adversos , Diterpenos/efectos adversos , Composición de Medicamentos , Quimioterapia Combinada , Cara/patología , Femenino , Geles , Humanos , Masculino , Persona de Mediana Edad , Crema para la Piel/efectos adversos , Resultado del TratamientoRESUMEN
Ingenol mebutate gel is a topical field treatment of actinic keratosis (AK). One of several proposed mechanisms of action for ingenol mebutate is induction of cell death in proliferating keratinocytes, suggesting a preferential action on AKs rather than healthy skin. Local skin reactions (LSRs) during 2 sequential 4-week cycles of AK treatment with ingenol mebutate gel 0.015% on the face or scalp were evaluated to test the hypothesis that reapplication of the study product would produce lower LSR scores than during the first treatment cycle. In this unblinded study, 20 participants with AKs on the face or scalp were treated with ingenol mebutate gel 0.015% once daily for 3 days in 2 sequential 4-week cycles. Composite LSR scores were evaluated during both cycles. The composite LSR score during the second cycle was found to be significantly lower than the first cycle (P=.0002). The proportion of participants who experienced LSRs in the second treatment cycle was less than the first cycle. Ingenol mebutate gel 0.015% may cumulatively reduce the burden of sun-damaged skin over 2 treatment cycles by targeting and removing transformed keratinocytes.
Asunto(s)
Diterpenos/uso terapéutico , Queratosis Actínica/tratamiento farmacológico , Administración Tópica , Anciano , Anciano de 80 o más Años , Diterpenos/administración & dosificación , Femenino , Geles , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND: Little is known about postoperative preferences regarding dermatologic surgery. OBJECTIVE: To determine patient preferences for postoperative follow-up after dermatologic surgery, desired follow-up interval, reasons for desired follow-up or lack thereof, and factors that may be associated with these preferences. MATERIALS AND METHODS: Patients who underwent Mohs micrographic surgery or excision within 24 months of Mohs micrographic surgery or excision were retrospectively surveyed regarding their postoperative follow-up preferences. Procedure, tumor attributes, complications, and medications were recorded. RESULTS: Eighty-nine percent of patients considered postoperative follow-up important, with 55% opting for follow-up within 4 weeks and an additional 29.1% within 2 to 3 months. After multivariate analyses, there were no significantly associated covariates of interest regarding preference for follow-up. Reasons for desiring follow-up included to ensure the wound healed well (50%), to ensure the cancer had not returned (27.9%), and to examine the rest of the skin (18.6%). CONCLUSION: A majority of patients desired postoperative follow-up visits for a variety of reasons. Anticipation of postoperative concerns should be included in dermatologic surgery planning.
Asunto(s)
Actitud , Continuidad de la Atención al Paciente , Cirugía de Mohs , Cuidados Posoperatorios/psicología , Anciano , Femenino , Encuestas de Atención de la Salud , Hospitales Universitarios , Humanos , Masculino , Persona de Mediana Edad , Cirugía de Mohs/psicología , Análisis Multivariante , Servicio Ambulatorio en Hospital , Satisfacción del Paciente , Neoplasias Cutáneas/cirugíaRESUMEN
BACKGROUND: Little is known about patient preferences for preoperative consultation in dermatologic surgery. OBJECTIVE: To determine patient preferences for separate- versus same-day preoperative consultation and factors that may be associated with these preferences. METHODS AND MATERIALS: Patients who underwent Mohs micrographic surgery (MMS) or excision at our institution within 24 months were retrospectively surveyed regarding their preferences for a separate- or same-day preoperative consultation. Procedure, tumor attributes, complications, and medications were recorded. RESULTS: Sixty-seven percent of patients preferred same-day preoperative consultation and surgery. Patients preferring same-day surgery were more likely to have a larger preoperative tumor size, whereas those preferring separate-day surgery were more likely to have had a history of complications. LIMITATIONS: This was a retrospective study performed at a single academic center. CONCLUSION: A majority of patients preferred same-day preoperative consultation and surgery. Tumor size and prior complications should be considered in preoperative planning for dermatologic surgery.
Asunto(s)
Procedimientos Quirúrgicos Dermatologicos , Prioridad del Paciente , Derivación y Consulta , Anciano , Procedimientos Quirúrgicos Ambulatorios , Toma de Decisiones , Demografía , Femenino , Humanos , Masculino , Complicaciones Posoperatorias , Estudios Retrospectivos , Encuestas y CuestionariosAsunto(s)
Anestesia/métodos , Terapia Electroconvulsiva/métodos , Adolescente , Adulto , Anestésicos Intravenosos , Catatonia/psicología , Catatonia/terapia , Femenino , Humanos , Masculino , Metohexital , Comodidad del Paciente , Propofol , Trastornos Psicóticos/psicología , Trastornos Psicóticos/terapiaRESUMEN
Disseminated superficial actinic porokeratosis (DSAP) is a chronic condition characterized by numerous atrophic papules and patches with a distinctive peripheral keratotic ridge, typically found on sun-exposed areas. Treatment of DSAP is warranted not only for cosmetic and symptomatic benefits but also to prevent malignant transformation. Successful treatment of DSAP often is difficult and frequently requires the use of multiple modalities. Ingenol mebutate gel 0.05% is a topical medication primarily used for the treatment of actinic keratosis (AK) by inducing cell death. We report a case of DSAP treated effectively with ingenol mebutate gel 0.05%.
Asunto(s)
Fármacos Dermatológicos/uso terapéutico , Diterpenos/uso terapéutico , Poroqueratosis/tratamiento farmacológico , Administración Cutánea , Adulto , Fármacos Dermatológicos/administración & dosificación , Diterpenos/administración & dosificación , Femenino , Geles , Humanos , Poroqueratosis/patología , Resultado del TratamientoAsunto(s)
Aminoquinolinas/administración & dosificación , Antineoplásicos/administración & dosificación , Neoplasias de los Genitales Masculinos/tratamiento farmacológico , Enfermedad de Paget Extramamaria/tratamiento farmacológico , Escroto , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Humanos , Imiquimod , Masculino , Insuficiencia del TratamientoRESUMEN
BACKGROUND: Ingenol mebutate gel is a topical field treatment for actinic keratosis (AK). The treatment elicits application-site reactions in most patients. This analysis evaluated the relationship between the severity of reactions and the speed of their resolution. METHODS: Patients in Phase III studies were treated for AKs on the face (n=218), scalp (n=56), and trunk and extremities (n=209). All of the patients were treated with either ingenol mebutate gel 0.015% once daily for three consecutive days (face/scalp) or ingenol mebutate gel 0.05% once daily for two consecutive days (trunk/extremities). Local skin reactions (LSRs) were assessed on a 5-point scale from 0 to 4 in six categories, yielding composite scores in the range of 0 to 24. RESULTS: The composite LSR score on the day after the last application of ingenol mebutate gel was an important predictor of the speed of resolution of LSRs. The rate of resolution was greatest for AKs treated on the face, followed by the scalp, and then the trunk and extremities. All patients were expected to have minimal LSR scores for the face and scalp at 2 weeks, and for the trunk and extremities at 4 weeks. CONCLUSION: The absolute reduction in LSR scores was proportional to the composite LSR score on the day after the last application of ingenol mebutate gel treatment. The rate of resolution for LSRs was dependent on the anatomic site treated as well as the day 4 composite score.
RESUMEN
Acne scarring is a consequence of abnormal resolution of wound healing after damage that occurs in the sebaceous follicle during acne inflammation. No trial to date has evaluated the efficacy of the combination of microdermabrasion and photodynamic therapy for acne scarring. This single-center, double-blinded pilot study enrolled subjects with moderate-to-severe acne scarring who were randomly assigned in a blinded fashion to use aminolevulinic acid and vehicle in a split-face fashion after full-face treatment with microdermabrasion. On average, 80 percent of the patients displayed more improvement in scarring on the aminolevulinic acid split face versus the vehicle split face after five treatments. Using two different noninvasive mechanisms of targeting acne scarring provided for a safe treatment regimen characterized by more efficacious results with respect to higher rates of scarring improvement.