BACKGROUND: Psoriasis is a chronic inflammatory disease that predominantly affects the skin. Adalimumab (HUMIRA(®), AbbVie, Maidenhead, UK), etanercept (Enbrel(®), Pfizer, New York, NY, USA) and ustekinumab (STELARA(®), Janssen Biotech, Inc., Titusville, NJ, USA) are the three biological treatments currently licensed for psoriasis in children.
OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and ustekinumab within their respective licensed indications for the treatment of plaque psoriasis in children and young people.
DATA SOURCES: Searches of the literature and regulatory sources, contact with European psoriasis registries, company submissions and clinical study reports from manufacturers, and previous National Institute for Health and Care Excellence (NICE) technology appraisal documentation.
REVIEW METHODS: Included studies were summarised and subjected to detailed critical appraisal. A network meta-analysis incorporating adult data was developed to connect the effectiveness data in children and young people and populate a de novo decision-analytic model. The model estimated the cost-effectiveness of adalimumab, etanercept and ustekinumab compared with each other and with either methotrexate or best supportive care (BSC), depending on the position of the intervention in the management pathway.
RESULTS: Of the 2386 non-duplicate records identified, nine studies (one randomised controlled trial for each drug plus six observational studies) were included in the review of clinical effectiveness and safety. Etanercept and ustekinumab resulted in significantly greater improvements in psoriasis symptoms than placebo at 12 weeks' follow-up. The magnitude and persistence of the effects beyond 12 weeks is less certain. Adalimumab resulted in significantly greater improvements in psoriasis symptoms than methotrexate for some but not all measures at 16 weeks. Quality-of-life benefits were inconsistent across different measures. There was limited evidence of excess short-term adverse events; however, the possibility of rare events cannot be excluded. The majority of the incremental cost-effectiveness ratios for the use of biologics in children and young people exceeded NICE's usual threshold for cost-effectiveness and were reduced significantly only when combined assumptions that align with those made in the management of psoriasis in adults were adopted.
LIMITATIONS: The clinical evidence base for short- and long-term outcomes was limited in terms of total participant numbers, length of follow-up and the absence of young children.
CONCLUSIONS: The paucity of clinical and economic evidence to inform the cost-effectiveness of biological treatments in children and young people imposed a number of strong assumptions and uncertainties. Health-related quality-of-life (HRQoL) gains associated with treatment and the number of hospitalisations in children and young people are areas of considerable uncertainty. The findings suggest that biological treatments may not be cost-effective for the management of psoriasis in children and young people at a willingness-to-pay threshold of £30,000 per quality-adjusted life-year, unless a number of strong assumptions about HRQoL and the costs of BSC are combined. Registry data on biological treatments would help determine safety, patterns of treatment switching, impact on comorbidities and long-term withdrawal rates. Further research is also needed into the resource use and costs associated with BSC. Adequately powered randomised controlled trials (including comparisons against placebo) could substantially reduce the uncertainty surrounding the effectiveness of biological treatments in biologic-experienced populations of children and young people, particularly in younger children. Such trials should establish the impact of biological therapies on HRQoL in this population, ideally by collecting direct estimates of EuroQol-5 Dimensions for Youth (EQ-5D-Y) utilities.
STUDY REGISTRATION: This study is registered as PROSPERO CRD42016039494.
FUNDING: The National Institute for Health Research Health Technology Assessment programme.
ANTECEDENTES: La psoriasis es una enfermedad crónica de la piel que puede desarrollarse a cualquier edad. Las estimaciones para los Estados Unidos y Europa sugieren que la psoriasis representa el 4% de las enfermedades de la piel en los niños. En la mayoría de los casos, la afección es leve y puede ser tratada con cremas. Sin embargo, un pequeño porcentaje de los niños tienen la enfermedad moderada a grave que requiere medicamentos, tales como la ciclosporina o metotrexato, y algunos requerirá inyecciones con agentes biológicos más nuevos, como los fármacos anti-TNF (factor de necrosis tumoral). Los medicamentos anti-TNF (entre ellos etanercept, infliximab y adalimumab) están diseñados para reducir la inflamación en el cuerpo causado por el factor de necrosis tumoral. La evidencia de la seguridad y la eficacia de estos agentes biológicos en la psoriasis pediátrica es deficiente.
Evaluar la eficacia y seguridad de los agentes anti-TNF para el tratamiento de la psoriasis pediátrica.
Métodos de búsqueda: Se realizaron búsquedas en las siguientes bases de datos hasta julio de 2015: el Grupo Cochrane de Piel Registro Especializado, el Registro Cochrane Central de Ensayos Controlados (CENTRAL, 2015, No. 6), MEDLINE (desde 1946), EMBASE (desde 1974), y LILACS (desde 1982). También se realizaron búsquedas en 13 registros de ensayos y se verificaron las listas de referencias de los estudios incluidos y los artículos de revisión importantes para futuras referencias de ensayos controlados aleatorios (ECA) relevantes. Se realizaron búsquedas manuales y resúmenes de congresos intentó establecer contacto con los autores del ensayo y las compañías farmacéuticas relevantes. Se realizaron búsquedas en las bases de datos de efectos adversos de la Agencia de Medicamentos y Alimentos de los Estados Unidos y Europea de Medicamentos.
Se incluyeron todos los ECA pertinentes que evaluaron la eficacia y seguridad de los agentes anti-TNF para el tratamiento de la psoriasis en placas crónica en individuos menores de 18 años de edad.
Recopilación y análisis de datos: Dos revisores verificaron de forma independiente los títulos y resúmenes y realizaron la extracción de datos y la evaluación de "Riesgo de sesgo" de los estudios incluidos. Un revisor introdujo los datos en Review Manager (RevMan), y un segundo revisor verificó los datos. También se intentó obtener datos poco claros de los autores del ensayo cuando sea posible.Los resultados primarios fueron el número evaluada por el investigador de participantes que lograron una mejora del 75% en el Área de Psoriasis y el Índice de Gravedad-75 (PASI 75) en comparación con el valor basal, la mejora en la calidad de vida utilizando un instrumento como el Índice de Calidad de Vida en Dermatología Infantil (ICVID), y efectos adversos. Nuestros resultados secundarios incluyeron la proporción de participantes que alcanzaron un PASI 50 y Evaluación Global del Médico (PGA).
Resultados principales: Se incluyó un estudio con 211 participantes (edad media 13 años), en el que el etanercept (dosis varió de 0,8 a 50 mg por kilogramo de peso corporal) se comparó con el placebo. El seguimiento fue durante un periodo de 48 semanas.En la semana 12, el 57% frente al 11% que recibieron etanercept o placebo, respectivamente, consiguieron un PASI 75 (cociente de riesgos 4,95, 95% intervalo de confianza (IC) 2,83 a 8,65; evidencia de alta calidad). reducción absoluta del riesgo y el número necesario a tratar para obtener un beneficio con etanercept fue de 45% (IC del 95%: 33.95 a 56.40) y 2 (95% IC 1,77 a 2,95), respectivamente.El porcentaje de mejora de la línea de base de las puntuaciones ICVID en la semana 12 fue mejor en el grupo de etanercept que el grupo de placebo (52,3% frente a 17,5%, respectivamente (P = 0,0001)). Análisis entre los grupos mostró un tamaño del efecto que era clínicamente importante (diferencia media 2,30, IC del 95%: 0,85 a 3.75; evidencia de alta calidad). Sin embargo, medias, medianas y resultados mínima diferencia importante y los resultados de la calidad de vida pediátrica, Stein Impacto en la escala de la familia, y Harter de autopercepción perfil para las puntuaciones de los niños deben ser interpretados con cautela, ya que no eran resultados predefinidos.se reportaron tres eventos adversos graves, pero se resolvieron sin secuelas. Muertes u otros eventos tales como tumores malignos, infecciones oportunistas, tuberculosis o desmielinización no se informaron en el estudio incluido.Además, el 13% de los participantes en el grupo de placebo y el 53% en el grupo de etanercept tuvieron un PGA de desaparición total o parcial (cociente de riesgos 3,96; IC del 95% 2.36 a la 6,66; evidencia de alta calidad) en la semana 12.
Conclusiones de los revisores: Esta revisión encontró sólo un ECA evaluar el uso de este tipo de terapia biológica. Aunque el riesgo de sesgo de publicación fue alta, ya que sólo se incluyó un ECA patrocinadas por la industria, el riesgo de la asignación, la selección, rendimiento, desgaste, y los sesgos de notificación selectivos para todos los resultados (a excepción de ICVID) fue baja y no a corto plazo No se encontraron efectos adversos graves.Podemos concluir, en base a este único estudio incluido, que etanercept parece ser eficaz y seguro (al menos en el corto plazo) para el tratamiento de la psoriasis pediátrica. Sin embargo, como el sistema GRADE no se refiere a los estudios individuales, sino a un conjunto de pruebas, vamos a esperar los resultados de los estudios en curso en una futura actualización de esta revisión. Además, los estudios futuros deben evaluar criterios de valoración de la calidad de vida establecieron a priori y estandarizar las medidas de resultado primarias tales como el PASI 75, y deben incluir el PGA como un criterio de valoración secundario. Además, recopilar y reportar eventos adversos de manera uniforme se requieren para evaluar mejor la seguridad.
Psoriasis is a chronic inflammatory disease that predominantly affects the skin. Adalimumab (HUMIRA(®), AbbVie, Maidenhead, UK), etanercept (Enbrel(®), Pfizer, New York, NY, USA) and ustekinumab (STELARA(®), Janssen Biotech, Inc., Titusville, NJ, USA) are the three biological treatments currently licensed for psoriasis in children.
OBJECTIVE:
To determine the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and ustekinumab within their respective licensed indications for the treatment of plaque psoriasis in children and young people.
DATA SOURCES:
Searches of the literature and regulatory sources, contact with European psoriasis registries, company submissions and clinical study reports from manufacturers, and previous National Institute for Health and Care Excellence (NICE) technology appraisal documentation.
REVIEW METHODS:
Included studies were summarised and subjected to detailed critical appraisal. A network meta-analysis incorporating adult data was developed to connect the effectiveness data in children and young people and populate a de novo decision-analytic model. The model estimated the cost-effectiveness of adalimumab, etanercept and ustekinumab compared with each other and with either methotrexate or best supportive care (BSC), depending on the position of the intervention in the management pathway.
RESULTS:
Of the 2386 non-duplicate records identified, nine studies (one randomised controlled trial for each drug plus six observational studies) were included in the review of clinical effectiveness and safety. Etanercept and ustekinumab resulted in significantly greater improvements in psoriasis symptoms than placebo at 12 weeks' follow-up. The magnitude and persistence of the effects beyond 12 weeks is less certain. Adalimumab resulted in significantly greater improvements in psoriasis symptoms than methotrexate for some but not all measures at 16 weeks. Quality-of-life benefits were inconsistent across different measures. There was limited evidence of excess short-term adverse events; however, the possibility of rare events cannot be excluded. The majority of the incremental cost-effectiveness ratios for the use of biologics in children and young people exceeded NICE's usual threshold for cost-effectiveness and were reduced significantly only when combined assumptions that align with those made in the management of psoriasis in adults were adopted.
LIMITATIONS:
The clinical evidence base for short- and long-term outcomes was limited in terms of total participant numbers, length of follow-up and the absence of young children.
CONCLUSIONS:
The paucity of clinical and economic evidence to inform the cost-effectiveness of biological treatments in children and young people imposed a number of strong assumptions and uncertainties. Health-related quality-of-life (HRQoL) gains associated with treatment and the number of hospitalisations in children and young people are areas of considerable uncertainty. The findings suggest that biological treatments may not be cost-effective for the management of psoriasis in children and young people at a willingness-to-pay threshold of £30,000 per quality-adjusted life-year, unless a number of strong assumptions about HRQoL and the costs of BSC are combined. Registry data on biological treatments would help determine safety, patterns of treatment switching, impact on comorbidities and long-term withdrawal rates. Further research is also needed into the resource use and costs associated with BSC. Adequately powered randomised controlled trials (including comparisons against placebo) could substantially reduce the uncertainty surrounding the effectiveness of biological treatments in biologic-experienced populations of children and young people, particularly in younger children. Such trials should establish the impact of biological therapies on HRQoL in this population, ideally by collecting direct estimates of EuroQol-5 Dimensions for Youth (EQ-5D-Y) utilities.
STUDY REGISTRATION:
This study is registered as PROSPERO CRD42016039494.
FUNDING:
The National Institute for Health Research Health Technology Assessment programme.
