BACKGROUND: Crohn's disease (CD) is a disease with an impaired immune response characterized by chronic, relapsing-remitting, and progressive inflammation mainly affecting the gastrointestinal tract. Certolizumab pegol (CZP) is a biological agent that regulates the impaired immune response by controlling tumour necrosis factor-α (TNFα). However, the efficacy and safety of long-term administration of CZP for people with CD with inflammation under control are not well understood.
OBJECTIVES: To assess the efficacy and safety of CZP for maintenance of remission in people with CD.
SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, WHO ICTRP, and conference abstracts from inception to 23 March 2022. We contacted pharmaceutical companies involved with the production of CZP for further relevant information.
SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing CZP with placebo in adults with CD.
DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. The main outcomes were failure to maintain clinical remission at week 26, failure to maintain clinical response at week 26, and serious adverse events. We planned to perform meta-analyses including all available studies if similar enough for pooling to be appropriate and calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes and mean differences with 95% CIs for continuous outcomes. We analyzed the number needed to treat for an additional beneficial outcome (NNTB) and the number needed to treat for an additional harmful outcome (NNTH) to indicate the magnitude of treatment effects. The same two review authors independently evaluated the risk of bias by using the Cochrane RoB 2 tool and evaluated the certainty of evidence using the GRADE framework.
MAIN RESULTS: We identified one study meeting our prespecified eligibility criteria. The included study enrolled 428 adults with CD who responded to induction therapy with CZP 400 mg at weeks 0, 2, and 4. The study evaluated long-term efficacy and safety of CZP administered subcutaneously every four weeks compared with placebo. The proportion of participants who failed to maintain clinical remission at week 26 was 52.3% (113/216) in the CZP group compared to 71.7% (152/212) in the placebo group. Treatment of CZP probably results in a large reduction in failure to maintain clinical remission at week 26 (RR 0.73, 95% CI 0.63 to 0.85). The NNTB was 5 (95% CI 4 to 9). We judged this outcome at low risk of bias. Using the GRADE assessment, we judged the certainty of evidence as moderate due to the low number of events occurred. The proportion of participants who failed to maintain clinical response at week 26 was 37.5% (81/216) in the CZP group compared to 64.2% (136/212) in the placebo group. Treatment of CZP probably results in a large reduction in failure to maintain clinical response at week 26 (RR 0.58, 95% CI 0.48 to 0.71). The NNTB was 4 (95% CI 3 to 5). We judged this outcome at low risk of bias. Using the GRADE assessment, we judged the certainty of evidence as moderate due to the low number of events occurred. The proportion of participants who developed serious adverse events was 5.6% (12/216) in the CZP group compared to 6.6% (14/212) in the placebo group. Treatment of CZP may lead to no difference in serious adverse events compared to placebo when used as a remission maintenance treatment (RR 0.84, 95% CI 0.40 to 1.78). The NNTB was 95 (95% CI NNTH 19 to NNTB 25). We evaluated the risk of bias for this outcome as low. We evaluated the certainty of evidence as low due to the low number of events occurred and the CIs were not sufficiently narrow.
AUTHORS' CONCLUSIONS: CZP probably results in a large reduction in failure to maintain clinical remission and response at week 26 in people with CD. The evidence suggests that CZP may lead to no difference in serious adverse events compared to placebo when used as a remission maintenance treatment. However, the current studies are limited to 26 weeks of follow-up and only included adults. Therefore, these conclusions cannot be used to guide longer term treatment or for treatment in children at present.
ANTECEDENTES: Un tercio de los pacientes con enfermedad de Crohn (CD) o la colitis ulcerosa (CU) que reciben anti-TNF no responden al tratamiento, y una proporción experiencia de la pérdida correspondiente de respuesta o intolerancia.
OBJETIVO: Investigar la eficacia y seguridad de un segundo agente anti-TNF tras el fracaso primario / secundario o intolerancia a un primer fármaco.
MÉTODOS: Ninguno
Criterios de inclusión: los estudios que evalúan la eficacia de infliximab (IFX), adalimumab (ADA) y certolizumab pegol-(CZP) como el segundo anti-TNF en EC o CU.
Estrategia de búsqueda: Búsquedas bibliográficas (PubMed / Embase).
SÍNTESIS: porcentaje de respuesta / remisión; Se realizó el metanálisis mediante el método de la varianza inversa.
RESULTADOS: Se incluyeron 46 estudios (37 CD, 8 UC, 1 pouchitis). Los estudios constan de CD 32 de conmutación de IFX → ADA, 4 IFX → CZP y 1 ADA → IFX. En general, el segundo anti-TNF tras el fracaso de IFX en CD remisión inducida en el 43% y la respuesta en el 63% de los pacientes. La tasa de remisión fue mayor cuando el motivo para retirar el primero anti-TNF fue la intolerancia (61%) que después de secundaria (45%) o fallo primario (30%); las tasas de respuesta fueron, respectivamente, 72%, 62% y 53%. Todos los estudios de la UC cambiaron IFX → ADA, seis de ellos las tasas de remisión de informes que van desde 0% a 50%. Tasa de eventos adversos varió de 0% a 81% en CD, la mayoría de ellos leve (evento adverso grave 0-21%, tasa de interrupción <20%).
Conclusiones: La eficacia de un segundo anti-TNF en pacientes con EC depende en gran medida de la causa para la conmutación. La tasa de remisión es mayor cuando el motivo para retirar el primero anti-TNF es la intolerancia (61%), en comparación con secundaria (45%) o fallo primario (30%). Se necesitan más estudios de interruptor ADA → IFX para evaluar esta estrategia. PROSPERO-registro-número: CRD42014012943.
ANTECEDENTES: Los agentes biológicos se han usado ampliamente en el tratamiento de la enfermedad de Crohn (EC). Estos fármacos conllevan el riesgo de inmunosupresión excesiva, lo que indica posibles infecciones oportunistas, incluyendo infecciones virales oportunistas, pero no metanálisis se ha centrado siempre en este tema.
OBJETIVO: Evaluar si existe una asociación entre el tratamiento con agentes biológicos y el riesgo de infecciones virales oportunistas e infecciones graves en pacientes con EC.
MÉTODOS: Una búsqueda de bases de datos en línea se llevó a cabo y la selección de la literatura se llevó a cabo de acuerdo con los criterios de inclusión y exclusión de los títulos de lectura, resúmenes y textos completos. Se evaluó la heterogeneidad de estudio y el sesgo de publicación. Si se debe elegir un modelo de efectos fijos o un modelo de efectos aleatorios dependido en el resultado de la prueba de heterogeneidad.
RESULTADOS: Se observó una significación estadística en los eventos de infección viral oportunista entre el grupo de agentes biológicos y el grupo placebo. Sin embargo, nuestro análisis no observó diferencias estadísticamente significativas entre los dos grupos, cuando se llevaron a cabo análisis combinados para el herpes zoster y el herpes simplex por separado. Se observó una tendencia de riesgo en el grupo de agentes biológicos en el análisis para el herpes zoster. Más análisis destinados a las medidas de resultado e incluyendo la influenza y las infecciones graves se llevaron a cabo por separado, pero sin significación estadística se encuentran en ellos.
CONCLUSIÓN: El uso Agentes biológicos podría aumentar el riesgo de infecciones virales oportunistas en pacientes con EC, pero no el riesgo de herpes simplex y graves infecciones. Se necesitan más ensayos controlados aleatorios (ECA) para llegar a la conclusión de que podrían elevar el riesgo de herpes zoster.
Crohn's disease (CD) is a disease with an impaired immune response characterized by chronic, relapsing-remitting, and progressive inflammation mainly affecting the gastrointestinal tract. Certolizumab pegol (CZP) is a biological agent that regulates the impaired immune response by controlling tumour necrosis factor-α (TNFα). However, the efficacy and safety of long-term administration of CZP for people with CD with inflammation under control are not well understood.
OBJECTIVES:
To assess the efficacy and safety of CZP for maintenance of remission in people with CD.
SEARCH METHODS:
We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, WHO ICTRP, and conference abstracts from inception to 23 March 2022. We contacted pharmaceutical companies involved with the production of CZP for further relevant information.
SELECTION CRITERIA:
We included randomized controlled trials (RCTs) comparing CZP with placebo in adults with CD.
DATA COLLECTION AND ANALYSIS:
Two review authors independently selected studies and extracted data. The main outcomes were failure to maintain clinical remission at week 26, failure to maintain clinical response at week 26, and serious adverse events. We planned to perform meta-analyses including all available studies if similar enough for pooling to be appropriate and calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes and mean differences with 95% CIs for continuous outcomes. We analyzed the number needed to treat for an additional beneficial outcome (NNTB) and the number needed to treat for an additional harmful outcome (NNTH) to indicate the magnitude of treatment effects. The same two review authors independently evaluated the risk of bias by using the Cochrane RoB 2 tool and evaluated the certainty of evidence using the GRADE framework.
MAIN RESULTS:
We identified one study meeting our prespecified eligibility criteria. The included study enrolled 428 adults with CD who responded to induction therapy with CZP 400 mg at weeks 0, 2, and 4. The study evaluated long-term efficacy and safety of CZP administered subcutaneously every four weeks compared with placebo. The proportion of participants who failed to maintain clinical remission at week 26 was 52.3% (113/216) in the CZP group compared to 71.7% (152/212) in the placebo group. Treatment of CZP probably results in a large reduction in failure to maintain clinical remission at week 26 (RR 0.73, 95% CI 0.63 to 0.85). The NNTB was 5 (95% CI 4 to 9). We judged this outcome at low risk of bias. Using the GRADE assessment, we judged the certainty of evidence as moderate due to the low number of events occurred. The proportion of participants who failed to maintain clinical response at week 26 was 37.5% (81/216) in the CZP group compared to 64.2% (136/212) in the placebo group. Treatment of CZP probably results in a large reduction in failure to maintain clinical response at week 26 (RR 0.58, 95% CI 0.48 to 0.71). The NNTB was 4 (95% CI 3 to 5). We judged this outcome at low risk of bias. Using the GRADE assessment, we judged the certainty of evidence as moderate due to the low number of events occurred. The proportion of participants who developed serious adverse events was 5.6% (12/216) in the CZP group compared to 6.6% (14/212) in the placebo group. Treatment of CZP may lead to no difference in serious adverse events compared to placebo when used as a remission maintenance treatment (RR 0.84, 95% CI 0.40 to 1.78). The NNTB was 95 (95% CI NNTH 19 to NNTB 25). We evaluated the risk of bias for this outcome as low. We evaluated the certainty of evidence as low due to the low number of events occurred and the CIs were not sufficiently narrow.
AUTHORS' CONCLUSIONS:
CZP probably results in a large reduction in failure to maintain clinical remission and response at week 26 in people with CD. The evidence suggests that CZP may lead to no difference in serious adverse events compared to placebo when used as a remission maintenance treatment. However, the current studies are limited to 26 weeks of follow-up and only included adults. Therefore, these conclusions cannot be used to guide longer term treatment or for treatment in children at present.
