BACKGROUND: This systematic review update summarizes the current evidence on the use of natalizumab for induction of remission in Crohn's disease (CD).
OBJECTIVES: To determine the efficacy and safety of natalizumab for induction of remission in CD.
SEARCH METHODS: We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD Group Specialized Trials Register, and clinicaltrials.gov from inception to 10 May 2018.
SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing natalizumab to a placebo or control therapy for induction of remission in CD.
DATA COLLECTION AND ANALYSIS: Two authors independently screened studies, extracted data and assessed methodological quality using the Cochrane risk of bias tool. The primary outcome was failure to enter clinical remission. Secondary outcomes included clinical response, mean change in Crohn's Disease Activity Index (CDAI), adverse events (AEs), withdrawal due to AEs and serious AEs. For dichotomous outcomes, we calculated the risk ratio (RR) and 95% confidence interval (95% CI). For continuous outcomes we calculated the mean difference (MD) and 95% CI. Data were pooled for meta-analysis when the interventions, patient groups and outcomes were sufficiently similar (determined by consensus). We used GRADE to assess the overall quality of the evidence.
MAIN RESULTS: A total of five RCTs (1771 participants) were included. Four studies (1692 participants) compared one, two or three infusions of natalizumab (300 mg or 3 mg/kg or 6mg/kg) to placebo. One study (79 participants) compared three infusions of natalizumab (300 mg) and infliximab (5 mg/kg) to infliximab and placebo. Four studies were rated as low risk of bias. One study was rated as unclear risk of bias for selective reporting.One, two and three infusions of natalizumab were superior to placebo for induction of remission and clinical response. Infusions were administered at weeks zero, four and eight. After one infusion, 76% (849/1117) of natalizumab participants failed to enter remission at 4 weeks compared to 83% (411/494) of placebo participants (RR 0.91, 95% CI 0.86 to 0.96, 3 studies, GRADE high quality). At 4 weeks, the RR for clinical response was 0.78 (95% CI 0.66 to 0.92, 3 studies, 1611 participants, GRADE moderate quality). After two infusions, after 8 weeks, 66% (693/1049) of natalizumab participants failed to enter remission compared to 77% (382/494) of placebo participants (RR 0.85, 95% CI 0.76 to 0.95; 3 studies, GRADE moderate quality). At 8 weeks, the RR for clinical response was 0.73 (95% CI 0.58 to 0.91, 3 studies, 1543 participants, GRADE low quality). After three infusions, at 12 weeks, 61% (596/983) of natalizumab participants failed to enter remission compared to 73% (313/431) of placebo participants (RR 0.85, 95% CI 0.78 to 0.92, 2 studies, GRADE high quality). At 12 weeks, the RR for clinical response was 0.76 (95% CI 0.67 to 0.86, 2 studies, 1414 participants, GRADE high quality). One study (507 participants) reported on change in CADI from baseline. Natalizumab participants had a larger drop in mean CDAI scores than placebo participants at 4, 8 and 12 weeks.The rates of AEs, withdrawals due to AEs and serious AEs were similar across groups at 4, 8 and 12 weeks. After one infusion, 74% (50/68) of natalizumab participants experienced an AE compared to 81% (51/63) of placebo participants (RR 0.91, 95% CI 0.75 to 1.09, GRADE moderate quality). Withdrawal due to an AE occurred in 1% (1/68) of natalizumab participants and 3% of placebo participants (RR 0.46, 95% CI 0.04 to 4.98, GRADE low quality). SAEs occurred in 10% (7/68) of natalizumab participants compared to 11% (7/63) of placebo participants (RR 0.93, 95% CI 0.34 to 2.49, GRADE low quality). After two infusions, 86% (57/66) of natalizumab participants experienced an AE compared to 81% (51/63) of placebo participants (RR 1.07, 95% CI 0.92 to 1.24, GRADE moderate quality). Withdrawal due to an AE occurred in 3% (2/66) natalizumab participants compared to 3% (2/63) placebo participants (RR 0.95, 95% CI 0.14 to 6.57, GRADE low quality). SAEs occurred in 9% (6/66) of natalizumab participants and 11% (7/63) of placebo participants (RR 0.82, 95% CI 0.29 to 2.30, GRADE low quality). After three infusions, 86% (848/984) of natalizumab participants experienced an AE compared to 83% (359/431) placebo participants (RR 1.03, 95% CI 0.98 to 1.08, GRADE high quality). Withdrawals due to AEs occurred in 8% (82/984) of natalizumab participants compared to 10% (45/431) of placebo participants (RR 0.86, 95% CI 0.59 to 1.26, GRADE moderate quality). SAEs occurred in 7% (65/983) of natalizumab participants and 8% (36/431) of placebo participants (RR 0.76. 95% CI 0.37 to 1.56, GRADE low quality). Adverse events included headache, nausea, nasopharyngitis, abdominal pain, fatigue, vomiting, and exacerbation of CD.The study comparing combination therapy with natalizumab and infliximab to infliximab and placebo demonstrated similar remission rates at 10 weeks. Sixty-four per cent (33/52) of participants assigned to natalizumab and infliximab failed to achieve remission compared to 70% (19/27) assigned to placebo and infliximab (RR 0.90, 95% CI 0.65 to 1.24, GRADE moderate quality). The rates of AEs (moderate quality evidence), withdrawals due to AEs (low quality evidence) and serious AEs (low quality evidence) were similar across groups at 10 weeks. Adverse events included headache, exacerbation of CD, nausea, and nasopharyngitis.Natalizumab is associated with the development of progressive multifocal leukoencephalopathy (PML) resulting in some patient deaths. There are currently no tests which can reliably predict those at risk of developing PML.
AUTHORS' CONCLUSIONS: High quality data suggest that natalizumab is effective for induction of clinical remission and response in some patients with moderately to severely active CD. However, none of the included studies had the power to detect rare but serious adverse events such as PML. Due to the association with PML, and the availability of alternative agents that are not associated with PML, natalizumab is not likely to be used in patients who fail currently available medical therapy. The use of natalizumab in select patients (e.g. patients allergic to different biologics) needs to be carefully considered against the potential risk of developing PML. Futher studies of natalizumab are not likely to be done.
BACKGROUND & AIMS: Endpoints in randomized controlled trials (RCTs) of Crohn's disease (CD) are evolving. We performed a systematic review of efficacy and safety outcomes reported in placebo-controlled RCTs of patients with CD.
METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched to March 1, 2017 for placebo-controlled RCTs of adult patients with CD treated with aminosalicylates, immunomodulators, corticosteroids, biologics, and oral small molecules. Efficacy and safety outcomes, definitions, and measurement tools were collected and stratified by decade of publication.
RESULTS: 116 RCTs (81 induction, 44 maintenance, 7 postoperative prevention trials, enrolling 27,263 patients) were included. Clinical efficacy endpoints were reported in all trials, most commonly measured using the Crohn's Disease Activity Index. Thirty-eight unique definitions of clinical response or remission and 32 definitions of loss of response were identified. Definitions of endoscopic response, remission, and endoscopic healing were also heterogeneous, evaluated using the Crohn's Disease Endoscopic Index of Severity, Simple Endoscopic Score for Crohn's Disease, ulcer resolution, and Rutgeerts' Score for post-operative endoscopic appearance. Histologic outcomes were reported in 11.1%, 2.3%, and 14.3% of induction, maintenance, and postoperative prevention trials, respectively. Biomarker outcomes were reported in 81.5%, 68.2%, and 42.9% of induction, maintenance, and postoperative prevention trials, respectively. Safety outcomes were reported in 93.8%, 97.7%, and 85.7% of induction, maintenance, and postoperative prevention trials, respectively.
CONCLUSIONS: In this systematic review, we highlight the heterogeneity in definitions of response and remission and the evolution of outcomes reported in placebo-controlled CD RCTs. Establishing a core outcome set to standardize efficacy and safety endpoint definitions is a research priority in this field.
Background: Over the last decade, biologics have gained an important place for the treatment of moderate to severe inflammatory bowel disease (IBD), and many randomized control trials have evaluated their efficacy. Aim: The goal of this review is to analyze the results of these trials and to highlight the evidence and indications emerging from these studies for their implementation in the management of IBD patients. Methods: A PubMed search was realized to screen high-quality clinical trials studying biologic agents currently available in clinics for the treatment of IBD. Words used were: “infliximab,” “adalimumab,” “certolizumab,” “golimumab,” “natalizumab,” “vedolizumab,” “ustekinumab,” “azathioprine,” “methotrexate,” “Crohn's disease,” and “ulcerative colitis.” Results: In Crohn's disease, studies supporting induction and maintenance therapies were documented for infliximab, adalimumab, certolizumab, natalizumab, vedolizumab, and ustekinumab. Infliximab, adalimumab, and certolizumab have evidences for fistulizing Crohn's disease and only infliximab and adalimumab have evidences for mucosal healing. In ulcerative colitis, studies supporting induction, maintenance, and mucosal healing were found with infliximab, adalimumab, golimumab, and vedolizumab. Only infliximab was associated with evidences for combination therapy with thiopurine and acute severe colitis in ulcerative colitis. Conclusion: Management with biologics in IBD patients is well validated by high-quality clinical trials.
OBJETIVO: Evaluar la eficacia y seguridad de la integrina antagonistas, incluyendo natalizumab y Vedolizumab, en la enfermedad de Crohn (EC).
MÉTODOS: Se realizó una búsqueda bibliográfica en PubMed, MEDLINE, EMBASE y la Cochrane Library para detectar citas de enero 1990-agosto 2014. Se realizó el análisis de datos utilizando Review Manager versión 5.2.
RESULTADOS: Un total de 1.340 pacientes de cinco estudios estuvieron involucrados en este meta-análisis. Durante 6-12 semanas de tratamiento, los antagonistas de la integrina aumentaron la tasa de respuesta clínica y remisión con CI OR = 1,69, 95%: 1,37 a 2,09 y 1,84 IC del 95%: 1,44 a 2,34, respectivamente. No se encontraron diferencias significativas entre los antagonistas de la integrina y tratamientos placebo en cuanto a sus efectos adversos (OR = 1,07, IC del 95%: 0,83 a 1,38) y reacciones adversas graves (OR = 0,81, IC 95%: 0,57 a 1,15).
Conclusión: Los resultados demuestran la eficacia y seguridad de antagonistas de la integrina para el tratamiento de CD, aunque las estrategias de tratamiento variaron.
La enfermedad inflamatoria intestinal, incluyendo sus 2 entidades colitis ulcerosa y enfermedad de Crohn, es una condición médica crónica que se caracteriza por la inflamación destructiva del tracto intestinal. Biológicos representan una clase de agentes terapéuticos con potencial intervención inmune. Estos agentes bloquean la cascada proinflamatoria que desencadena la activación y proliferación de los linfocitos T a nivel del intestino, por lo tanto, restablecer el equilibrio entre la pro- y anti-inflamatorias mensajes. Los 7 biológicos que muestran beneficios clínicos en la enfermedad inflamatoria intestinal son anticuerpos monoclonales. La siguiente revisión sistemática analiza la farmacocinética y la eficacia del infliximab bloqueadores del factor de necrosis tumoral, adalimumab, certolizumab pegol, y golimumab. Además, se describe la α4 inhibidores de la integrina natalizumab y Vedolizumab, que están dirigidos contra moléculas de adhesión celular, así como el bloqueador de ustekinumab interleuquina 12/23.
OBJETIVO: Estudiar la eficacia comparativa de la terapia biológica en el tratamiento de los pacientes-biológicos naïve con enfermedad de Crohn (CD).
Pacientes y métodos: Se realizó una revisión sistemática de ensayos controlados aleatorios publicados entre el 1 de enero de 1985 al 30 de septiembre de 2013, la comparación de los agentes biológicos (infliximab [IFX], adalimumab [ADA], certolizumab pegol, natalizumab, Vedolizumab y ustekinumab) entre sí o con placebo para inducir y mantener la remisión clínica en adultos con moderada a severa CD. Para aumentar la comparabilidad entre los ensayos, nos centramos en un subgrupo de pacientes-biológicos naïve para el punto final de la inducción y de respuesta al tratamiento de inducción para el punto final de mantenimiento. Seguimos un enfoque meta-análisis de la red bayesiana.
RESULTADOS: Se identificaron 17 ensayos controlados aleatorios de buena calidad metodológica comparar 6 agentes biológicos con placebo, con una comparación directa de agentes biológicos. En la red meta-análisis, se observó que IFX (riesgo relativo [RR], 6,11; 95% intervalo de credibilidad [CRI], 2,49-18,29) y ADA (RR, 2,98; 95% CRI, 1.12 a 8.18), pero no pegol certolizumab (RR, 1,48; 95% CrI, 0,76-2,93), el natalizumab (RR, 1,36; 95% CrI, 0,69-2,86), Vedolizumab (RR, 1,40; 95% CrI, 0,63-3,28), y ustekinumab (RR, 0,61; 95% CRI, 0,15 a 2,49), tenían más probabilidades de inducir la remisión que el placebo. Se observaron resultados similares para el mantenimiento de la remisión. Infliximab tenía la más alta probabilidad de ser clasificado como el agente más eficaz para la inducción (86%) y ADA para el mantenimiento de la remisión (48%).
CONCLUSIÓN: Sobre la base de la red de meta-análisis, IFX puede ser el agente más eficaz para la inducción de remisión en la EC en pacientes biológicos naïve. En ausencia de tratamiento de comparación cabeza a cabeza, la confianza en estas estimaciones es bajo. Se requieren estudios de eficacia comparativos futuros.
OBJETIVOS: La enfermedad (CD) y la colitis ulcerosa de Crohn (CU) son enfermedades inflamatorias del tracto gastrointestinal de etiología desconocida. La evidencia para el tratamiento de la enfermedad con terapias biológicas existe, pero no hay revisión sistemática y meta-análisis ha examinado esta cuestión en su totalidad.
MÉTODOS: MEDLINE, EMBASE y el Registro Cochrane Central de Ensayos Controlados Se realizaron búsquedas (hasta diciembre de 2010). Ensayos que reclutaron adultos con EC activa o latente o de la UC y comparar las terapias biológicas (anti-factor de necrosis tumoral α-(TNF) o anticuerpos natalizumab) con placebo fueron elegibles. Los datos dicotómicos síntomas se agruparon para obtener el riesgo relativo (RR) de la imposibilidad de lograr la remisión de la enfermedad activa y RR de recaída de la actividad en la enfermedad de reposo una vez que la remisión se había producido, con un intervalo de confianza del 95% (IC).
RESULTADOS: La estrategia de búsqueda identificó 3.061 citas, de las cuales 27 eran elegibles. Anticuerpos anti-TNF y natalizumab fueron superiores al placebo en la inducción de la remisión de la EC luminal (RR = 0,87 no se hace remisión, IC 95% 0.80-0.94 y RR = 0,88, IC 95% 0.83-0.94, respectivamente). Anticuerpos anti-TNF también fueron superiores al placebo en la prevención de la recaída de la EC luminal (RR de recaída = 0,71, IC 95% 0,65-0,76). Infliximab fue superior al placebo en la inducción de la remisión de moderada a severamente activa la Universidad de California (RR = 0,72, IC 95% 0.57-0.91).
CONCLUSIONES: Las terapias biológicas fueron superiores al placebo en la inducción de la remisión de la EC y la CU activa, y en la prevención de la recaída de la EC en reposo.
This systematic review update summarizes the current evidence on the use of natalizumab for induction of remission in Crohn's disease (CD).
OBJECTIVES:
To determine the efficacy and safety of natalizumab for induction of remission in CD.
SEARCH METHODS:
We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD Group Specialized Trials Register, and clinicaltrials.gov from inception to 10 May 2018.
SELECTION CRITERIA:
We included randomized controlled trials (RCTs) comparing natalizumab to a placebo or control therapy for induction of remission in CD.
DATA COLLECTION AND ANALYSIS:
Two authors independently screened studies, extracted data and assessed methodological quality using the Cochrane risk of bias tool. The primary outcome was failure to enter clinical remission. Secondary outcomes included clinical response, mean change in Crohn's Disease Activity Index (CDAI), adverse events (AEs), withdrawal due to AEs and serious AEs. For dichotomous outcomes, we calculated the risk ratio (RR) and 95% confidence interval (95% CI). For continuous outcomes we calculated the mean difference (MD) and 95% CI. Data were pooled for meta-analysis when the interventions, patient groups and outcomes were sufficiently similar (determined by consensus). We used GRADE to assess the overall quality of the evidence.
MAIN RESULTS:
A total of five RCTs (1771 participants) were included. Four studies (1692 participants) compared one, two or three infusions of natalizumab (300 mg or 3 mg/kg or 6mg/kg) to placebo. One study (79 participants) compared three infusions of natalizumab (300 mg) and infliximab (5 mg/kg) to infliximab and placebo. Four studies were rated as low risk of bias. One study was rated as unclear risk of bias for selective reporting.One, two and three infusions of natalizumab were superior to placebo for induction of remission and clinical response. Infusions were administered at weeks zero, four and eight. After one infusion, 76% (849/1117) of natalizumab participants failed to enter remission at 4 weeks compared to 83% (411/494) of placebo participants (RR 0.91, 95% CI 0.86 to 0.96, 3 studies, GRADE high quality). At 4 weeks, the RR for clinical response was 0.78 (95% CI 0.66 to 0.92, 3 studies, 1611 participants, GRADE moderate quality). After two infusions, after 8 weeks, 66% (693/1049) of natalizumab participants failed to enter remission compared to 77% (382/494) of placebo participants (RR 0.85, 95% CI 0.76 to 0.95; 3 studies, GRADE moderate quality). At 8 weeks, the RR for clinical response was 0.73 (95% CI 0.58 to 0.91, 3 studies, 1543 participants, GRADE low quality). After three infusions, at 12 weeks, 61% (596/983) of natalizumab participants failed to enter remission compared to 73% (313/431) of placebo participants (RR 0.85, 95% CI 0.78 to 0.92, 2 studies, GRADE high quality). At 12 weeks, the RR for clinical response was 0.76 (95% CI 0.67 to 0.86, 2 studies, 1414 participants, GRADE high quality). One study (507 participants) reported on change in CADI from baseline. Natalizumab participants had a larger drop in mean CDAI scores than placebo participants at 4, 8 and 12 weeks.The rates of AEs, withdrawals due to AEs and serious AEs were similar across groups at 4, 8 and 12 weeks. After one infusion, 74% (50/68) of natalizumab participants experienced an AE compared to 81% (51/63) of placebo participants (RR 0.91, 95% CI 0.75 to 1.09, GRADE moderate quality). Withdrawal due to an AE occurred in 1% (1/68) of natalizumab participants and 3% of placebo participants (RR 0.46, 95% CI 0.04 to 4.98, GRADE low quality). SAEs occurred in 10% (7/68) of natalizumab participants compared to 11% (7/63) of placebo participants (RR 0.93, 95% CI 0.34 to 2.49, GRADE low quality). After two infusions, 86% (57/66) of natalizumab participants experienced an AE compared to 81% (51/63) of placebo participants (RR 1.07, 95% CI 0.92 to 1.24, GRADE moderate quality). Withdrawal due to an AE occurred in 3% (2/66) natalizumab participants compared to 3% (2/63) placebo participants (RR 0.95, 95% CI 0.14 to 6.57, GRADE low quality). SAEs occurred in 9% (6/66) of natalizumab participants and 11% (7/63) of placebo participants (RR 0.82, 95% CI 0.29 to 2.30, GRADE low quality). After three infusions, 86% (848/984) of natalizumab participants experienced an AE compared to 83% (359/431) placebo participants (RR 1.03, 95% CI 0.98 to 1.08, GRADE high quality). Withdrawals due to AEs occurred in 8% (82/984) of natalizumab participants compared to 10% (45/431) of placebo participants (RR 0.86, 95% CI 0.59 to 1.26, GRADE moderate quality). SAEs occurred in 7% (65/983) of natalizumab participants and 8% (36/431) of placebo participants (RR 0.76. 95% CI 0.37 to 1.56, GRADE low quality). Adverse events included headache, nausea, nasopharyngitis, abdominal pain, fatigue, vomiting, and exacerbation of CD.The study comparing combination therapy with natalizumab and infliximab to infliximab and placebo demonstrated similar remission rates at 10 weeks. Sixty-four per cent (33/52) of participants assigned to natalizumab and infliximab failed to achieve remission compared to 70% (19/27) assigned to placebo and infliximab (RR 0.90, 95% CI 0.65 to 1.24, GRADE moderate quality). The rates of AEs (moderate quality evidence), withdrawals due to AEs (low quality evidence) and serious AEs (low quality evidence) were similar across groups at 10 weeks. Adverse events included headache, exacerbation of CD, nausea, and nasopharyngitis.Natalizumab is associated with the development of progressive multifocal leukoencephalopathy (PML) resulting in some patient deaths. There are currently no tests which can reliably predict those at risk of developing PML.
AUTHORS' CONCLUSIONS:
High quality data suggest that natalizumab is effective for induction of clinical remission and response in some patients with moderately to severely active CD. However, none of the included studies had the power to detect rare but serious adverse events such as PML. Due to the association with PML, and the availability of alternative agents that are not associated with PML, natalizumab is not likely to be used in patients who fail currently available medical therapy. The use of natalizumab in select patients (e.g. patients allergic to different biologics) needs to be carefully considered against the potential risk of developing PML. Futher studies of natalizumab are not likely to be done.
