Adalimumab para inducir la remisión de la enfermedad de Crohn
Resumen
Antecedentes
El adalimumab es un anticuerpo monoclonal IgG1 que ataca y bloquea el factor de necrosis tumoral alfa, una citoquina proinflamatoria implicada en la patogénesis de la enfermedad de Crohn (EC). En una proporción significativa de pacientes con EC el tratamiento convencional o el tratamiento con productos biológicos fracasa o causa eventos adversos significativos. El adalimumab puede ser una alternativa efectiva para estos pacientes.
Objetivos
Los objetivos de esta revisión fueron evaluar la eficacia y la seguridad del adalimumab para la inducción de la remisión en la EC.
Métodos de búsqueda
Se hicieron búsquedas en MEDLINE, Embase, CENTRAL, el Registro Especializado de Ensayos Controlados del Grupo Cochrane IBD, ClinicalTrials.Gov y en el registro de ensayos de la Organización Mundial de la Salud (ICTRP) desde su inicio hasta el 16 de abril 2019. Se hicieron búsquedas en las referencias y resúmenes de congresos para identificar estudios adicionales.
Criterios de selección
Se incluyeron ensayos controlados aleatorizados (ECA) que compararon cualquier dosis de adalimumab con placebo o un comparador activo en pacientes con EC activa.
Obtención y análisis de los datos
Dos autores de la revisión, de forma independiente, cribaron estudios, extrajeron los datos y evaluaron el sesgo con la herramienta Cochrane de «Riesgo de sesgo». El resultado primario fue el fracaso para lograr la remisión clínica, según que definieron los estudios originales. La remisión clínica se definió como una puntuación del Crohn’s Disease Activity Index (CDAI) de menos de 150 puntos. Los resultados secundarios incluyeron: el fracaso para lograr la respuesta clínica (definida como una disminución del CDAI de > 100 puntos o > 70 puntos del valor inicial), el fracaso para lograr la remisión y la respuesta endoscópica, el fracaso para lograr la remisión y la respuesta histológica, el fracaso para lograr la abstinencia de corticosteroides, los eventos adversos (EA) y los eventos adversos graves (EAG), la abstinencia del estudio debido a los EA y la calidad de vida medida por un instrumento validado. Para los resultados dicotómicos, se calculó el riesgo relativo (RR) y los intervalos de confianza del 95% (IC del 95%). Los datos se agruparon para el análisis si los participantes, las intervenciones, los resultados y el marco temporal eran similares. Los datos se analizaron por intención de tratar (intention‐to‐treat analysis). La certeza de la evidencia general se evaluó con los criterios GRADE.
Resultados principales
Se incluyeron tres ECA con placebo (714 participantes adultos). Los participantes tuvieron EC de moderada a severamente activa (CDAI 220 a 450). Dos estudios se calificaron como de riesgo de sesgo bajo y un estudio se calificó como de riesgo de sesgo poco claro. El 76% (342/451) de los pacientes tratados con adalimumab no lograron la remisión clínica a las cuatro semanas en comparación con el 91% (240/263) de los pacientes tratados con placebo (RR 0,85; IC del 95%: 0,79 a 0,90; evidencia de certeza alta). El 44% (197/451) de los participantes con adalimumab en comparación con el 66% (173/263) de los participantes con placebo no lograron una respuesta clínica de 70 puntos a las cuatro semanas (RR 0,68; IC del 95%: 0,59 a 0,79; evidencia de certeza alta). A las cuatro semanas, el 57% (257/451) de los participantes con adalimumab no lograron una respuesta clínica de 100 puntos en comparación con el 76% (199/263) de los participantes con placebo (RR 0,77; IC del 95%: 0,69 a 0,86; evidencia de certeza alta). El 62% (165/268) de los participantes con adalimumab presentaron un EA en comparación con el 72% (188/263) de los participantes del grupo placebo (RR 0,90; IC del 95%: 0,74 a 1,09; evidencia de certeza moderada). El 2% (6/268) de los participantes con adalimumab presentaron un EAG en comparación con el 5% (13/263) de los participantes del grupo placebo (RR 0,44; IC del 95%: 0,17 a 1,15; evidencia de certeza baja). Por último, el 1% (3/268) de los participantes con adalimumab se retiraron debido a los EA en comparación con el 3% (8/268) de los participantes en el grupo placebo (RR 0,38; IC del 95%: 0,11 a 1,30; evidencia de certeza baja). Los eventos adversos informados con frecuencia incluyeron reacciones en el sitio de la inyección, dolor abdominal, fatiga, empeoramiento de la EC y náuseas. Los datos de calidad de vida no permitieron realizar el metanálisis. Tres estudios informaron de una mejor calidad de vida a las cuatro semanas con adalimumab (medido con el Inflammatory Bowel Disease Questionnaire o el Short‐Form 36; evidencia de certeza moderada). La remisión y la respuesta endoscópica, la remisión y la respuesta histológica y el retiro de corticosteroides no se informaron en los estudios incluidos.
Conclusiones de los autores
La evidencia de certeza alta indica que el adalimumab es superior al placebo para la inducción de la remisión clínica y la respuesta clínica en pacientes con EC de moderada a gravemente activa. Aunque las tasas de EA, EAG y retiros debidos a EA fueron inferiores en los participantes con adalimumab en comparación con el grupo placebo, no se conoce con certeza el efecto del adalimumab sobre los EA debido al bajo número de eventos. Por lo tanto, no se pueden establecer conclusiones firmes con respecto a la seguridad del adalimumab en la EC. Se requieren estudios adicionales para analizar la efectividad y seguridad a largo plazo del uso de adalimumab en pacientes con EC.
PICO
Resumen en términos sencillos
Adalimumab para el tratamiento de la enfermedad de Crohn activa
¿Qué es la enfermedad de Crohn?
La enfermedad de Crohn es una enfermedad intestinal en la cual se inflaman las paredes del tracto gastrointestinal. Puede verse afectada cualquier parte del tracto gastrointestinal, desde la boca hasta el ano. Los síntomas incluyen dolor abdominal, diarrea sanguinolenta y pérdida de peso. Cuando los pacientes con enfermedad de Crohn presentan síntomas se considera que la enfermedad está «activa». Se considera que la enfermedad está en «remisión» cuando cesan los síntomas.
¿Qué es el adalimumab?
El adalimumab es un fármaco biológico que ayuda a reducir la inflamación y aliviar el dolor en pacientes con afecciones inflamatorias como la enfermedad de Crohn. El adalimumab funciona al unirse al factor de necrosis tumoral alfa y bloquear el efecto inflamatorio, lo que resulta en la reducción del dolor por inflamación en pacientes con enfermedad de Crohn. Para la enfermedad de Crohn activa, por lo general se inyecta el adalimumab debajo de la piel en una dosis inicial de 160 mg, seguida de una dosis de 80 mg dos semanas después.
¿Qué examinaron los investigadores?
Los investigadores examinaron si el adalimumab podría llevar a la remisión a los pacientes con enfermedad de Crohn de moderada a severamente activa. También analizaron si el adalimumab podría ayudar con los síntomas de la enfermedad de Crohn y si estaba asociado con algún daño (es decir, efectos secundarios). Se revisó la literatura médica hasta el 16 de abril 2019.
¿Qué encontraron los investigadores?
Los investigadores encontraron tres estudios con un total de 714 pacientes adultos (> 18 años). Todos estos pacientes tenían enfermedad de Crohn de moderada a severamente activa. Un total de 451 participantes fueron tratados con adalimumab y 268 con placebo (un medicamento falso). Fueron más los pacientes que lograron remisión o mejoría de sus síntomas en el grupo de tratamiento con adalimumab que los que fueron tratados con placebo. Las tasas de efectos secundarios (adalimumab: 62%, placebo: 72%), efectos secundarios graves (adalimumab: 2%, placebo: 5%) y retiro del estudio debido a efectos secundarios (adalimumab: 1%, placebo: 3%) fueron inferiores en los participantes con adalimumab que en los participantes con placebo. Los efectos secundarios que se informaron con frecuencia incluyeron reacciones en el sitio de la inyección, dolor abdominal, fatiga, empeoramiento de la enfermedad de Crohn y náuseas.
Conclusiones
La evidencia de certeza alta indica que el tratamiento con adalimumab es mejor que el placebo para inducir la remisión y mejorar los síntomas en pacientes con enfermedad de Crohn de moderada a gravemente activa. Los efectos secundarios fueron menores en los pacientes tratados con adalimumab en comparación con los del grupo placebo. Sin embargo, no se conoce con certeza el efecto del adalimumab sobre los efectos secundarios debido al bajo número de eventos, por lo tanto, no se pueden establecer conclusiones firmes con respecto a los daños (efectos secundarios) del adalimumab en el tratamiento de la enfermedad de Crohn. Se requieren estudios adicionales para analizar los efectos beneficiosos y perjudiciales a largo plazo del uso de adalimumab en pacientes con enfermedad de Crohn.
Authors' conclusions
Summary of findings
| Adalimumab compared with placebo for induction of remission in Crohn's disease | ||||||
| Patient or population: Patients with active Crohn's disease Settings: Outpatient Intervention: Adalimumab Comparison: Placebo | ||||||
| OutcomesAnalysis 1.4 | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Risk with placebo | Risk with Adalimumab | |||||
| Failure to achieve clinical remission Follow‐up: 4 weeks | 913 per 1000 | 776 per 1000 | RR 0.85 (0.79 to 0.90) | 714 participants | ⊕⊕⊕⊕ High | Clinical remission was defined as CDAI < 150. |
| Failure to achieve clinical response (70‐point response) Follow‐up: 4 weeks | 658 per 1000 | 447 per 1000 | RR 0.68 (0.59 to 0.79) | 714 participants | ⊕⊕⊕⊕ High | Clinical response was defined as a reduction of at least 70 points in the CDAI score from baseline. |
| Failure to achieve clinical response (100‐point response) Follow‐up: 4 weeks | 757 per 1000 | 583 per 1000 | RR 0.77 (0.69 to 0.86) | 714 participants | ⊕⊕⊕⊕ High | Clinical response was defined as a reduction of at least 100 points in the CDAI score from baseline. |
| Endoscopic response | Not reported | This outcome was not reported. | ||||
| Quality of life (QoL) Inflammatory Bowel Disease Questionnaire (IBDQ) (scale: 32 to 224; higher score = better QoL) Follow‐up: 4 weeks Short‐Form 36 health survey (SF‐36) (scale: 0 to 100; higher score = better QoL) Follow‐up: 4 weeks | One study reported significantly higher IBDQ scores at week 4 in the adalimumab 160 mg/80 mg and 80 mg/40 mg dose groups compared to placebo. One study reported a mean IBDQ score at 4 weeks of 150 in the adalimumab group compared to 139 in the placebo group (P < 0.001). One study reported significantly higher SF‐36 scores in adalimumab 160 mg/80 mg and 80 mg/40 mg dose groups at four weeks compared to placebo. IBDQ scores were higher at 4 weeks in the adalimumab 160 mg/80 mg group compared to placebo (P > 0.05). | 714 participants | ⊕⊕⊕⊝1 Moderate | Data did not allow for meta‐analysis (means and/or standard deviations not reported). An increase in the IBDQ score of 16 to 32 points from baseline constitutes the lower and upper bounds of clinically meaningful improvement in QoL. | ||
| Adverse events Follow‐up: 4 weeks | 715 per 1000 | 643 per 1000 | RR 0.90 (0.74 to 1.09) | 531 participants | ⊕⊕⊕⊝2 Moderate | The most commonly reported adverse events included injection site reactions, abdominal pain, fatigue, worsening Crohn's disease and nausea. |
| Serious adverse events Follow‐up: 4 weeks | 49 per 1000 | 22 per 1000 | RR 0.44 (0.17 to 1.15) | 531 participants | ⊕⊕⊝⊝3 | The most commonly reported serious adverse events included infections, worsening Crohn's disease, abscesses and dehydration. |
| Withdrawals due to adverse events Follow‐up: 4 weeks | 30 per 1000 | 12 per 1000 | RR 0.38 ( 0.11 to 1.30) | 531 participants | ⊕⊕⊝⊝4 | Adverse events that led to study withdrawal included worsening Crohn's disease, abdominal abscess and liver abscess. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to serious imprecision (narrative synthesis was conducted, estimates were not precise). 2 Downgraded one level due to serious inconsistency (I² = 53%). 3 Downgraded two levels due to very serious imprecision (19 events). 4 Downgraded two levels due to very serious imprecision (11 events). | ||||||
Background
Description of the condition
Crohn’s disease (CD) is a chronic remitting and relapsing inflammatory disease potentially affecting any region of the gastrointestinal tract (GI) in a transmural pattern (Baumgart 2012). A heterogeneous disease, CD is most commonly diagnosed through colonoscopy, computerized tomography scan or magnetic resonance imaging. Typical symptoms include abdominal pain, diarrhea, rectal bleeding, and weight loss. Potential complications of CD include intestinal obstruction and perforation of the small intestine or colon, abscesses, fistula, and intestinal bleeding. In addition, 6 to 40% of patients experience extraintestinal symptoms including spondyloarthritis, cutaneous manifestations, ocular inflammation, sclerosing cholangitis and hypercoagulability (Lichtenstein 2009).
The incidence of inflammatory bowel disease (IBD) has steadily increased in Western nations in the twentieth and twenty‐first centuries. The prevalence of IBD in Western countries is approximately 0.5% of the general population and thus, IBD is now considered a global disease (Kaplan 2015). In North America, the lowest estimate of the incidence rate for CD is estimated at 6.30 per 100,000 person‐years and the highest estimate of the incidence rate is estimated at 23.82 per 100,000 person‐years (Ng 2017). CD is known to have a bimodal (i.e. two modes) age distribution at diagnosis. There are increased diagnoses of CD in the second and third decade of life, followed by a smaller peak of diagnosis in the sixth or seventh decade (Loftus 2002).
The pathophysiology of CD remains to be fully elucidated, however an interaction between environmental and genetic factors is likely involved. The genes associated with CD play a role in innate immunity, epithelial barrier homeostasis and integrity, lymphocyte (i.e. a type of white blood cell that is part of the immune defence) differentiation and autophagy, which is the body's way of cleaning out damaged cells (Tsianos 2012). CD is likely an exaggerated immune response from an antigen presentation, with an increased response of Th1 cells and cytokines (i.e. cells secreted by the immune system) such as IL‐12 and tumor necrosis factor‐alpha (TNF‐α) (Thoreson 2007).
There are currently multiple medications that can be used for the treatment of CD. Medical therapies for CD include corticosteroids such as prednisone which help reduce inflammation. Immunosupressants including azathioprine, cyclosporine, 6‐mercaptopurine and methotrexate are also used for the treatment of CD. These drugs suppress the functioning of the immune system. If patients do not respond to these standard treatments or, if they lose response, biologics are then prescribed. Some common biologics include infliximab, certolizumab pegol and adalimumab.
Description of the intervention
Adalimumab is an IgG1 monoclonal antibody that targets TNF‐α (Cassinotti 2008). Adalimumab was first approved by the US Food and Drug Administration in 2002 for the treatment of rheumatoid arthritis. Since then, it has been approved for the treatment of many conditions including juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, iritis, plaque psoriasis, CD and ulcerative colitis (FDA 2011). Adalimumab is used in moderate to severe cases of CD for symptom control and inducing and maintaining clinical remission (Cassinotti 2008).
How the intervention might work
TNF‐α is a pro‐inflammatory cytokine that is part of the acute phase response (Thomson 2012). TNF‐α is important in the cascade of cytokines that lead to neutrophil (i.e. a type of white blood cell that fights infection) migration, T‐cell proliferation, macrophage activation, and immune cell survival (Tracey 2008). Patients with CD have higher concentrations of TNF‐α in their intestinal mucosa, along with decreased apoptosis (i.e. normal death of cells) in inflamed tissue. TNF‐α blockers such as adalimumab have been demonstrated to increase intestinal T‐cell and monocyte (i.e. a type of white blood cell that fights bacteria, viruses and fungi) apoptosis in patients with CD (Asgharpour 2013; Sabatino 2004).
Why it is important to do this review
CD can be debilitating to a person's quality of life during an exacerbation, and the first goal of treatment during this period is to induce a treatment response. CD is conventionally treated with systematic or local corticosteroids and immunosuppressives (Hovde 2012). However, a significant proportion of patients fail therapy or fail to enter remission with these medications. In addition, more than 50% of patients treated acutely with corticosteroids will either become resistant or steroid‐dependent (Lichtenstein 2009). These medications are also associated with significant adverse effects. Adalimumab has been used as a treatment for moderate to severe CD and the CLASSIC I trial suggests that adalimumab may be more effective than placebo at inducing remission in these patients (Hanauer 2006). The introduction of novel biologic agents has changed the landscape of the management of CD, offering effective and rapid clinical response with minimal adverse effects. A Cochrane review will synthesize the available evidence on the efficacy and safety of adalimumab for induction of remission in CD and will allow for an assessment of the overall quality of the evidence supporting its use.
Objectives
The primary objectives of this review were to assess the efficacy and safety of adalimumab for induction of remission in participants with active moderate to severe CD.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials (RCTs) that assessed efficacy and safety of adalimumab for induction of remission in CD were considered for inclusion. Studies published as abstracts were only included if the authors could be reached for further information regarding efficacy and safety outcomes.
Types of participants
Participants of any age diagnosed with CD, as defined by conventional clinical, radiological, endoscopic or histological criteria were considered for inclusion. Participants must have had active CD at study entry to be included.
Types of interventions
Studies comparing adalimumab to placebo or an active comparator were considered for inclusion.
Types of outcome measures
Primary outcomes
The primary outcome was the proportion of participants who failed to achieve clinical remission, as defined by the original studies.
Secondary outcomes
Secondary outcome measures included the proportion of CD participants:
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Who failed to achieve clinical response;
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Who failed to achieve endoscopic remission;
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Who failed to achieve endoscopic response;
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Who failed to achieve histologic remission;
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Who failed to achieve histologic response;
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Who failed to achieve steroid withdrawal;
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With adverse events (AEs);
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With serious adverse events (SAEs);
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Who withdrew from the study due to AEs; and
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Quality of life measured by a validated instrument such as the Inflammatory Bowel Disease Questionnaire (IBDQ) or the Short Form‐36 (SF‐36) survey.
Search methods for identification of studies
Electronic searches
We searched the following databases from inception to 16 April 2019 to identify applicable studies:
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MEDLINE;
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Embase;
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CENTRAL (Cochrane Library);
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The Cochrane IBD Group Specialized Register;
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Clinicaltrials.gov; and
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WHO trials registry (ICTRP)
The search strategies are listed in Appendix 1.
Searching other resources
Additional studies were identified by manually searching the reference lists of relevant papers. In addition, conference proceedings from Digestive Disease Week, United European Gastroenterology Week and the European Crohn's and Colitis Organisation Congress for the last five years were handsearched to find studies only reported in abstract form. We also contacted leaders in the field and the manufacturers of adalimumab to identify any unpublished studies.
Data collection and analysis
Selection of studies
We reviewed the studies and abstracts that were identified by the literature search. Two authors (MA and JC) independently screened the titles and abstracts from the search results based on the prespecified inclusion criteria. Any disagreements were resolved by discussion and consensus or by consulting with a third author (TN).
Data extraction and management
Data were independently extracted by two authors (MA and JC) using a standardized extraction form. Any disagreements were first discussed and then brought to a third author (TN) for resolution, as required. If data were not available, the study authors were contacted for additional information.
The following information was extracted:
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General information (type of publication, title, journal, year);
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Study design features (method of randomization, concealment of allocation and blinding, power calculation, a priori and posthoc analyses, dates of enrolment and follow‐up, study duration, number of centers and location, and study withdrawals);
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Intervention (dose and type of medication, and whether adalimumab was compared to placebo or active comparator);
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Eligibility (number of participants screened and randomized);
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Participant characteristics (age, sex, disease severity, current and prior medications);
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Follow‐up (dates of follow‐up along with withdrawals and number of participants lost to follow‐up); and
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Primary and secondary outcomes.
Assessment of risk of bias in included studies
The Cochrane 'Risk of bias' tool was used by two authors (MA and JC) to independently assess the methodological quality of the included studies. Any disagreements regarding the risk of bias were first discussed and then brought to a third author (TN) for resolution, as required (Higgins 2011a).
The following characteristics pertaining to methodological quality were used in this assessment:
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Random sequence generation;
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Allocation concealment;
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Blinding of participants, investigators and outcome assessors;
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Incomplete outcome data;
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Selective outcome reporting; and
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Other potential sources of bias.
Based on these criteria, studies were judged to have a low, high or unclear risk of bias for each category.
The overall certainty of the evidence supporting the primary and secondary outcomes was assessed using the GRADE approach (Schünemann 2011). For the 'Summary of findings' table, we included the following outcomes: failure to achieve clinical remission (at study end point), failure to achieve clinical response, endoscopic response, quality of life, adverse events, serious adverse events and study withdrawal due to adverse events. Evidence from RCTs started as high quality, and was downgraded based on the following:
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Risk of bias;
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Indirect evidence;
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Inconsistency (unexplained heterogeneity);
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Imprecision (sparse data); and
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Reporting bias (publication bias).
After considering each of these factors, the overall quality of evidence for each outcome was judged to be high quality (further research is very unlikely to change our confidence in the estimate of effect); moderate quality (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate); low quality (further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate); or very low quality (we are very uncertain about the estimate) (Guyatt 2008).
Measures of treatment effect
Review Manager 5 (RevMan5) was used to analyze the data on an intention‐to‐treat (ITT) basis. For relevant outcomes in the identified studies reported in a dichotomous manner, we calculated the risk ratio (RR) and corresponding 95% confidence interval (CI). For continuous outcomes, we calculated the mean difference (MD) with 95% CI.
Unit of analysis issues
For trials with multiple arms (e.g. different dose groups), we divided the placebo group across treatment groups so that independent comparisons could be performed between each treatment group and the split placebo group (Higgins 2011b). For trials with an odd number of participants, groups were divided in a way so that the placebo group for the lower dose arm had the larger number of participants. This helps avoid overestimating the effects of the higher dose arm. Any cross‐over studies had only the first part included in order to avoid potential carry‐over effects. We determined the appropriate fixed intervals for follow‐up for outcomes that are measured at different time points (Higgins 2011b). Lastly, for recurring events (i.e. AEs), the primary endpoint defined by the study was used.
Dealing with missing data
We contacted study authors for missing data. Given our ITT analysis, missing data for dichotomous outcomes were assumed to be treatment failures. We conducted a sensitivity analysis to determine the impact on results from the assumption of treatment failure for missing dichotomous data. For missing continuous outcomes, we conducted an available case analysis.
Assessment of heterogeneity
Heterogeneity was assessed using the I² statistic and the Chi² test (Higgins 2003). We considered an I² value of less than 25% to indicate low heterogeneity, a value of greater than 50% to indicate moderate heterogeneity and a value greater than 75% to indicate high heterogeneity. For the Chi² test, a P value of 0.10 was considered statistically significant. We investigated potential explanations for heterogeneity by visually inspecting the forest plot. We performed a sensitivity analysis excluding any outlier studies to see if this helped to explain the heterogeneity.
Assessment of reporting biases
Reporting bias was assessed by comparing outcomes listed in protocols to those reported in the published manuscripts. If we did not have access to the study protocols, we used the outcomes listed in the methods section of the published manuscript to compare the reported outcomes. If a sufficient number of studies were included (> 10) in a pooled analysis, a funnel plot was used to assess for potential publication bias (Egger 1997).
Data synthesis
Data from individual trials were combined for meta‐analysis when interventions, participant groups and outcomes were sufficiently similar (determined by consensus). For dichotomous outcomes, we calculated the pooled RR with corresponding 95% CI. For continuous outcomes measured with the same scale, we calculated the pooled MD with 95% CI. When different scales were used to measure the same underlying construct (e.g. quality of life), we calculated the standardized mean difference (SMD) with 95% CI. If no heterogeneity was present, a fixed‐effect model was used to pool data. However, if there was heterogeneity (I² ranging from 50 to 75%) a random‐effects model was used. We did not pool data for meta‐analysis if there was a high degree of heterogeneity (I² > 75%).
Subgroup analysis and investigation of heterogeneity
Planned subgroup analysis included:
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Participant characteristics (e.g. disease duration, disease severity, disease extent, concomitant medication, and previous exposure to anti‐TNF‐α therapy); and
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Drug doses and routes of administration.
Sensitivity analysis
Sensitivity analysis was used to examine the following variables on the pooled effect:
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Random‐effects versus fixed‐effects modelling;
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Low risk of bias versus unclear or high risk of bias;
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Relevant loss to follow‐up (> 10%): best‐case versus worst‐case scenario; and
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Full‐text manuscripts versus abstract or unpublished studies.
Results
Description of studies
Results of the search
A literature search was conducted on 16 April 2019 and identified 1492 records. No additional studies were identified through searching of conference abstracts and grey literature. After the duplicates were removed, a total of 1082 records remained for review of titles and abstracts. Two authors (MA and JC) independently reviewed the titles and abstracts and 41 studies were then selected for full‐text review. Twenty‐seven reports of three studies were then excluded with reasons, leaving 14 reports of three studies (714 participants) that met the predefined inclusion criteria (Hanauer 2006; Sandborn 2007; Watanabe 2012, see Figure 1).
Study flow diagram.
Included studies
All of the included studies were double‐blind, randomized, placebo‐controlled trials assessing participants with moderate to severely active CD based on a Crohn's Disease Activity Index (CDAI) score ranging from 220 to 450. See Characteristics of included studies for additional details for each study.
Hanauer 2006 (CLASSIC‐1) was a multicenter, randomized, double‐blind, placebo‐controlled trial. Participants were TNF‐α naive. The participants were randomized to receive subcutaneous injections at weeks 0 and 2 with adalimumab 40 mg/20 mg (n = 74) , 80 mg/40 mg (n = 75) , 160 mg/80 mg (n = 76) or placebo (n = 74). The primary outcome was clinical remission (CDAI < 150 points) at four weeks and the secondary outcomes included clinical response (70‐point or 100‐point response) at four weeks.
Sandborn 2007 was a multicenter, randomized, double‐blind, placebo‐controlled trial. Participants were previously treated with infliximab and had either lost response or had become intolerant to the drug. The participants were randomly assigned to receive either subcutaneous injections of adalimumab (n = 159), 160 mg at week 0 and 80 mg at week two, or placebo (n = 166) at weeks zero and two and followed through week four. The primary outcome was induction of remission (CDAI < 150 points) at week four. Secondary outcomes included the proportion of participants achieving clinical response (70‐point and 100‐point), changes from baseline in the CDAI total score, IBDQ total score, C‐reactive protein concentration, and improvement in the number of draining fistulas and fistula remission at week four.
Watanabe 2012 was a randomized, double‐blind clinical trial with an induction and maintenance phase. For the purposes of this review, only the induction phase of the study was assessed. Participants were previously treated with infliximab or were TNF‐α naive. The participants were randomized to receive adalimumab 160 mg/ 80mg (n = 33), adalimumab 80 mg/ 40 mg (n = 34) or placebo (n = 23) at weeks zero and two. The primary outcome was the proportion of participants in clinical remission (CDAI < 150) at week four. The secondary outcomes included the proportion of participants in clinical remission at week two and with clinical response (70‐point and 100‐point) at week two and four. Additional secondary outcomes included changes from baseline in CDAI and International Organization of Inflammatory Bowel Disease scores at week two and changes from baseline in SF‐36 Mental Component Summary scores and SF‐36 Physical Component Summary scores, and IBDQ scores in each treatment group at week four.
Excluded studies
Three studies were excluded because the studies were not RCTs (Bossa 2012; Hyams 2012; Wu 2016).
Risk of bias in included studies
The risk of bias analysis is summarized in Figure 2.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
All of the studies described using randomization procedures, however only Hanauer 2006 and Sandborn 2007 described their methods for randomization. Hanauer 2006 allocated participants using a telephone‐based interactive response system and was rated at low risk of bias for allocation concealment. Sandborn 2007 used a computer‐generated randomization scheme and was rated as at low risk of bias for allocation concealment. Watanabe 2012 did not describe the randomization method and was therefore rated as at unclear risk of bias for allocation concealment.
Blinding
Hanauer 2006 utilized an identically appearing placebo and was rated at low risk of bias. Sandborn 2007 and Watanabe 2012 studies did not describe their methods of blinding and were therefore rated as having unclear risk of bias for blinding. Outcome assessors were blinded in the Hanauer 2006 and Sandborn 2007 studies and these studies were rated as having low risk of bias for outcome assessment. Watanabe 2012 did not describe outcome assessment and was rated as being unclear for this item.
Incomplete outcome data
All the studies were rated as having low risk of bias for incomplete outcome data (Hanauer 2006; Sandborn 2007; Watanabe 2012). Dropouts between treatment and control groups had similar reasons for withdrawal.
Selective reporting
All studies reported on their prespecified primary and secondary outcomes and were rated as having low risk of bias for selective reporting (Hanauer 2006; Sandborn 2007; Watanabe 2012).
Other potential sources of bias
All of the studies appeared to be free from other sources of bias and were rated as having low risk of bias (Hanauer 2006; Sandborn 2007; Watanabe 2012).
Effects of interventions
See: Summary of findings for the main comparison
Failure to achieve clinical remission at four weeks
All of the included studies (714 participants) reported on clinical remission (CDAI < 150) at four weeks (Hanauer 2006; Sandborn 2007; Watanabe 2012). The results showed that the adalimumab group had a higher clinical remission rate compared to placebo. Seventy‐six percent (342/451) of adalimumab participants failed to achieve clinical remission at four weeks compared to 91% (240/263) of placebo participants (RR 0.85, 95% CI 0.79 to 0.90, I² = 12%, GRADE high‐certainty evidence; See Analysis 1.1). A sensitivity analysis based on a random‐effects model produced similar results (RR 0.85, 95% CI 0.78 to 0.91). Similarly, a sensitivity analysis excluding the study assessed to be at unclear risk of bias produced similar results (RR 0.84, 95% CI 0.79 to 0.91).
In the 160 mg/80 mg dose group, 73% (196/268) of participants in the adalimumab group failed to achieve clinical remission compared to 93% (187/202) of placebo participants (RR 0.82, 95% CI 0.75 to 0.88, I² = 0%; See Analysis 1.1). In the 80 mg/40 mg dose group, 78% (85/109) of participants in the adalimumab group failed to achieve clinical remission compared to 89% (32/36) of placebo participants (RR 0.88, 95% CI 0.75 to 1.02, I² = 2%; See Analysis 1.1). Lastly, in the 40 mg/20 mg dose group, 82% (61/74) of participants in the adalimumab group failed to achieve clinical remission compared to 84% (21/25) of placebo participants (RR 0.98, 95% CI 0.80 to 1.20; See Analysis 1.1). Overall, the 160 mg/80mg dose group appeared to be the most effective for inducing clinical remission at four weeks. However, the test for subgroup differences by dose showed no difference between the dose subgroups (test for subgroup differences Chi² = 3.10, df = 2, P = 0.21, I² = 35.5%; See Analysis 1.1).
Hanauer 2006 enrolled participants who were TNF‐α naive and Sandborn 2007 enrolled participants who had previously been treated with infliximab which allowed for a subgroup analysis by previous exposure to TNF‐α. Among TNF‐α naive participants, 74% (167/225) of the adalimumab group failed to achieve clinical remission at four weeks compared to 88% (65/74) of the placebo group (RR 0.84, 95% CI 0.75 to 0.95; See Analysis 1.2). Among TNF‐α exposed participants, 79% (125/159) of the adalimumab group failed to achieve clinical remission at four weeks compared to 93% (155/166) of the placebo group (RR 0.84, 95% CI 0.77 to 0.92; See Analysis 1.2). The test for subgroup differences showed no difference between the TNF‐α exposure subgroups (test for subgroup differences Chi² = 0.00, df = 1, P = 0.96, I² = 0%; See Analysis 1.2).
Failure to achieve clinical response at four weeks
70‐point clinical response
All of the included studies (714 participants) reported on clinical response defined as a 70‐point reduction in the CDAI score (Hanauer 2006; Sandborn 2007; Watanabe 2012). Forty‐four percent (197/451) of adalimumab participants failed to achieve a 70‐point clinical response at four weeks compared to 66% (173/263) of placebo participants (RR 0.68, 95% CI 0.59 to 0.79, I² = 0%, GRADE high‐certainty evidence; See Analysis 1.3).
The results showed that the 160 mg/80 mg and 80 mg/40 mg dose groups had a higher 70‐point clinical response rate compared to the placebo group. In the 160 mg/80 mg dose group, 44% (118/268) in the adalimumab group failed to achieve a 70‐point clinical response compared to 66% (134/203) of the placebo group (RR 0.69, 95% CI 0.59 to 0.82, I² = 3%; See Analysis 1.3). In the 80 mg/40 mg dose group 41% (45/109) in the adalimumab group failed to achieve a 70‐point clinical response compared to 67% (24/36) of the placebo group (RR 0.62, 95% CI 0.45 to 0.85, I² = 0%; See Analysis 1.3). Lastly, in the 40 mg/20 mg dose group, 46% (34/74) of adalimumab participants failed to achieve a 70‐point clinical response compared to 63% (15/24) of the placebo group (RR 0.74, 95% CI 0.49 to 1.09; See Analysis 1.3). Overall, the 160 mg/80mg dose group appeared to be the most effective for the induction of a 70‐point clinical response at four weeks. However, the test for subgroup differences by dose showed no difference between the dose subgroups (test for subgroup differences Chi² = 0.52, df = 2, P = 0.77, I² = 0%; See Analysis 1.3).
Among TNF‐α naive participants, 43% (96/225) of the adalimumab group failed to achieve a 70‐point clinical response at four weeks compared to 64% (47/74) of the placebo group (RR 0.67, 95% CI 0.53 to 0.85; See Analysis 1.4). Among TNF‐α exposed participants, 48% (77/159) of the adalimumab group failed to achieve a 70‐point clinical response at four weeks compared to 66% (110/166) of the placebo group (RR 0.73, 95% CI 0.60 to 0.89; See Analysis 1.4). The test for subgroup differences showed no difference between the TNF‐α exposure subgroups (test for subgroup differences Chi² = 0.30, df = 1, P = 0.58, I² = 0%; See Analysis 1.4).
100‐point clinical response
All of the included studies (714 participants) assessed clinical response defined as a reduction of 100 points in the CDAI score (Hanauer 2006; Sandborn 2007; Watanabe 2012). The results showed that the adalimumab group had a higher 100‐point clinical response rate compared to the placebo group. Fifty‐seven percent (257/451) of adalimumab participants failed to achieve a 100‐point clinical response at four weeks compared to 76% (199/263) of participants in the placebo group (RR 0.77, 95% CI 0.69 to 0.86, I² = 0%, GRADE high‐certainty evidence; See Analysis 1.5).
The rates of 100‐point clinical response were different across the three dose groups. In the 160 mg/80 mg dose group, 54% (146/268) of the adalimumab group failed to achieve a 100‐point clinical response compared to 76% (153/202) of the placebo group (RR 0.76, 95% CI 0.66 to 0.86, I² = 0%; See Analysis 1.5). In the 80 mg/40 mg dose group, 57% (62/109) of the adalimumab group failed to achieve a 100‐point clinical response compared to 75% (27/36) of the placebo group (RR 0.76, 95% CI 0.59 to 0.98, I² = 23%; See Analysis 1.5). Lastly, in the 40 mg/20 mg dose group, 66% (49/74) of the adalimumab group failed to achieve a 100‐point clinical response compared to 76% (19/25) of the placebo group (RR 0.87, 95% CI 0.66 to 1.15; See Analysis 1.5). Overall, the 160 mg/80 mg dose group appeared to be the most effective for inducing a 100‐point clinical response at four weeks. However, the test for subgroup differences by dose showed no difference between the dose subgroups (test for subgroup differences Chi² = 0.87, df = 2, P = 0.65, I² = 0%; See Analysis 1.5).
Among TNF‐α naive participants, 55% (124/225) of the adalimumab group failed to achieve a 100‐point clinical response at four weeks compared to 74% (55/74) of the placebo group (RR 0.74, 95% CI 0.62 to 0.89; See Analysis 1.6). Among TNF‐α exposed participants, 62% (98/159) of the adalimumab group failed to achieve a 100‐point clinical response at 4 weeks compared to 75% (125/166) of the placebo group (RR 0.82, 95% CI 0.70 to 0.88; See Analysis 1.6). The test for subgroup differences showed no difference between the TNF‐α exposure subgroups (test for subgroup differences Chi² = 0.69, df = 1, P = 0.41, I² = 0%; See Analysis 1.6).
Quality of life
All of the included studies (714 participants) reported on quality of life as an outcome (Hanauer 2006; Sandborn 2007; Watanabe 2012). Hanauer 2006 reported significantly higher IBDQ scores at week four in the adalimumab 160 mg/80 mg and 80 mg/40 mg dose groups compared to placebo. Sandborn 2007 reported a mean IBDQ score at four weeks of 150 in the adalimumab group compared to 139 in the placebo group (P < 0.001). Watanabe 2012 reported significantly higher SF‐36 scores in adalimumab 160 mg/80 mg and 80 mg/40 mg dose groups at four weeks compared to placebo. Watanabe 2012 also reported that IBDQ scores were higher at four weeks in the adalimumab 160 mg/80 mg group compared to placebo, although the difference was not statistically significant. We conducted a narrative synthesis for this outcome and the estimates were not precise. Thus, we downgraded one level to moderate‐certainty evidence due to serious imprecision.
Adverse events
All of the included studies (714 participants) reported on the proportion of participants that developed an AE (Hanauer 2006; Sandborn 2007; Watanabe 2012). Sixty‐two per cent (165/268) of participants in the adalimumab group experienced an AE compared to 71% (188/263) of participants in the placebo group (RR 0.90, 95% CI 0.74 to 1.09, I² = 53 %, GRADE moderate‐certainty evidence; See Analysis 1.7). We downgraded one level to moderate‐certainty evidence due to serious inconsistency (I² = 53%). The most commonly reported AEs included injection site reactions, abdominal pain, fatigue, worsening CD and nausea.
Serious adverse events
All of the included studies (714 participants) reported on the proportion of participants that developed an SAE (Hanauer 2006; Sandborn 2007; Watanabe 2012). Two per cent (6/268) of adalimumab participants experienced a SAE compared to 5% (13/263) participants in the placebo group (RR 0.44, 95% CI 0.17 to 1.15, I² = 0%, GRADE low‐certainty evidence; See Analysis 1.8). We downgraded two levels to low‐certainty evidence due to very serious imprecision (19 events). The most commonly reported SAEs were related to the underlying CD including infections, CD flares, abscesses and dehydration.
Withdrawals due to adverse events
All of the included studies (714 participants) reported on withdrawals due to AEs (Hanauer 2006; Sandborn 2007; Watanabe 2012). One per cent (3/268) of adalimumab participants withdrew due to an AE compared to 3% (8/268) of participants in the placebo group (RR 0.38, 95% CI 0.11 to 1.30; I² = 0%, GRADE low‐certainty evidence; See Analysis 1.9). We downgraded two levels to low‐certainty evidence due to very serious imprecision (11 events). Adverse events that led to study withdrawal included worsening CD, abdominal abscesses and liver abscesses.
Other outcomes and analyses
Endoscopic remission, endoscopic response, histologic remission, histologic response and steroid withdrawal were not reported in the included studies. The data did not allow for planned subgroup analyses by disease duration, disease severity, disease extent, concomitant medication, and route of administration. None of the included studies had loss to follow‐up rates greater than 10%, thus a prespecified sensitivity analysis based on best‐case versus worst‐case scenarios was not undertaken. None of the included studies was published as an abstract only, thus a prespecified sensitivity analysis based on full‐text manuscripts versus abstracts or unpublished studies was not undertaken.
Discussion
Summary of main results
This systematic review included three studies (714 adult participants) evaluating the safety and efficacy of adalimumab in moderate to severely active CD. The Hanauer 2006 (CLASSIC‐1) study was a multicenter, randomized, double‐blind, placebo‐controlled trial. The participants were randomized to receive subcutaneous injections at weeks 0 and two with adalimumab 40 mg/20 mg (n = 74) , 80 mg/40 mg (n = 75) , 160 mg/80 mg (n = 76) or placebo (n = 74). The primary outcome was clinical remission (CDAI < 150 points) at four weeks and the secondary outcomes included clinical response (70‐point or 100‐point response) at four weeks. The Sandborn 2007 study randomly assigned participants to receive subcutaneous injections of adalimumab at 160 mg at week 0, 80 mg at week two or placebo at 0 and two weeks. The primary outcome was clinical remission at week four (CDAI < 150) and the secondary outcomes were a decrease from baseline of CDAI of 70 points or more (70‐point response) or of 100 points or more (100‐point response) at four weeks. The last included study was the Watanabe 2012 study which included 90 participants who were randomly assigned to receive adalimumab 160 mg/80 mg (n = 33), adalimumab 80 mg/40 mg (n = 34), or placebo (n = 23) at baseline and week two. The primary outcome was clinical remission (CDAI < 150) at four weeks. The secondary outcomes included the proportion of participants in clinical remission at week two and clinical response CR‐100 or clinical response CR‐70 (CDAI decrease of ≥ 100 or ≥ 70 from baseline) at week two and four.
The three included studies all assessed clinical remission (CDAI < 150 points) at four weeks as an outcome (Hanauer 2006; Sandborn 2007; Watanabe 2012). High‐certainty evidence suggested that adalimumab was superior to placebo for induction of clinical remission at four weeks. High‐certainty evidence also suggested that adalimumab was more effective than placebo for inducing 70‐point and 100‐point clinical response at four weeks. Subgroup analysis suggested that the 160 mg/80 mg dose group may be the most effective for inducing clinical remission and clinical response. However, the test for subgroup differences by dose showed no difference between the dose subgroups. Further research is needed to determine the optimal dose of adalimumab. Subgroup analysis suggested that previous exposure to TNF‐α may have no impact upon the efficacy of adalimumab, as efficacy rates were similar in the TNF‐α naive and TNF‐α exposed subgroups.
All three studies also assessed AEs, SAEs and withdrawal due to AEs (Hanauer 2006; Sandborn 2007; Watanabe 2012). Although the rates of AEs, SAEs and withdrawals due to AEs were lower in adalimumab participants compared to placebo, we are uncertain about the effect of adalimumab on AEs due to the low number of events. Therefore, no firm conclusions can be drawn regarding the safety of adalimumab in CD. Commonly reported AEs included injection site reactions, abdominal pain, fatigue, CD aggravation and nausea. Commonly reported SAEs included infections, CD flares, abscesses and dehydration.
Overall completeness and applicability of evidence
The results of this Cochrane review are applicable for people with moderate to severe CD (CDAI 220 to 450). Study participants included people who were TNF‐α naive and those who had previous treatment with infliximab and had lost response or had become intolerant to the drug. However, the overall evidence cannot be considered complete. The three included studies (714 participants) assessed the treatment of CD with adalimumab and reported data on clinical remission, clinical response, quality of life, AEs, SAEs and withdrawals due to AEs. Some of the prespecified secondary outcomes, including endoscopic remission, endoscopic response, histologic remission, histologic response and steroid withdrawal, were not reported in the included studies. Additionally, other outcomes such as AEs, SAEs, and withdrawals due to AEs only included a small number of reported events.
Quality of the evidence
Two of the included studies were judged to be at low risk of bias (Hanauer 2006; Sandborn 2007). Watanabe 2012 was judged to be at unclear risk of bias for random sequence generation, allocation concealment and blinding. The GRADE analysis indicated that the overall certainty of the evidence supporting the primary outcome clinical remission at four weeks was high. The GRADE analyses also indicated the overall certainty of the evidence supporting the secondary outcomes 70‐point and 100‐point clinical response was high. The overall certainty of evidence for AEs was rated as moderate due to high heterogeneity (I² = 53%) and the overall certainty of evidence for SAEs and withdrawal due to AEs was low due to very serious imprecision.
Potential biases in the review process
A comprehensive literature search was performed to reduce the potential for bias in study selection. In addition, two authors independently screened, extracted data and assessed study quality in an effort to minimize bias. The limitations of this review include the small number of included RCTs and sparse data. The short follow‐up time is also a limitation because the included reviews only assessed outcomes at four weeks, which may not have been enough time to capture AEs related to the drug. Lastly, despite the rising use of endoscopic outcomes in CD studies, none of the included studies used endoscopic remission or response as an outcome. Further research is necessary to assess the impact of adalimumab on these outcomes.
Agreements and disagreements with other studies or reviews
We identified two other systematic reviews that assessed the efficacy and safety of adalimumab therapy in CD patients (Huang 2011; Song 2014). Huang 2011 was a meta‐analysis that assessed the efficacy and safety of adalimumab for inducing and maintaining remission in participants with moderate to severe CD. The meta‐analysis included four RCTs (Colombel 2007; Hanauer 2006; Sandborn 2007; Sandborn 2009), and the results concluded that adalimumab was effective and significantly improved the quality of life of participants with CD (Colombel 2007; Hanauer 2006; Sandborn 2007; Sandborn 2009). Song 2014 was also a meta‐analysis that assessed the efficacy and safety of adalimumab in patients with moderate to severe CD. This systematic review included six RCTs that met the inclusion criteria (Colombel 2007; Dewint 2014; Hanauer 2006; Rutgeerts 2012; Sandborn 2007; Watanabe 2012). The results showed that adalimumab was effective for achieving short‐term clinical response or remission, long‐term remission and complete fistula healing in CD participants. Both of these reviews reached the same conclusion as ours, however, they included maintenance trials in addition to induction trials.
Study flow diagram.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 Adalimumab versus placebo, Outcome 1 Failure to achieve clinical remission at 4 weeks: subgroup by dose.
Comparison 1 Adalimumab versus placebo, Outcome 2 Failure to achieve clinical remission at 4 weeks: subgroup by previous TNF‐α exposure).
Comparison 1 Adalimumab versus placebo, Outcome 3 Failure to achieve clinical response at 4 weeks (70‐point response): subgroup by dose.
Comparison 1 Adalimumab versus placebo, Outcome 4 Failure to achieve clinical response (70‐point response) at 4 weeks: subgroup by previous TNF‐α exposure).
Comparison 1 Adalimumab versus placebo, Outcome 5 Failure to achieve clinical response at 4 weeks (100‐point response): subgroup by dose.
Comparison 1 Adalimumab versus placebo, Outcome 6 Failure to achieve clinical response (100‐point response) at 4 weeks: subgroup by previous TNF‐α exposure).
Comparison 1 Adalimumab versus placebo, Outcome 7 Adverse events.
Comparison 1 Adalimumab versus placebo, Outcome 8 Serious adverse events.
Comparison 1 Adalimumab versus placebo, Outcome 9 Withdrawals due to adverse events.
| Adalimumab compared with placebo for induction of remission in Crohn's disease | ||||||
| Patient or population: Patients with active Crohn's disease Settings: Outpatient Intervention: Adalimumab Comparison: Placebo | ||||||
| OutcomesAnalysis 1.4 | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Risk with placebo | Risk with Adalimumab | |||||
| Failure to achieve clinical remission Follow‐up: 4 weeks | 913 per 1000 | 776 per 1000 | RR 0.85 (0.79 to 0.90) | 714 participants | ⊕⊕⊕⊕ High | Clinical remission was defined as CDAI < 150. |
| Failure to achieve clinical response (70‐point response) Follow‐up: 4 weeks | 658 per 1000 | 447 per 1000 | RR 0.68 (0.59 to 0.79) | 714 participants | ⊕⊕⊕⊕ High | Clinical response was defined as a reduction of at least 70 points in the CDAI score from baseline. |
| Failure to achieve clinical response (100‐point response) Follow‐up: 4 weeks | 757 per 1000 | 583 per 1000 | RR 0.77 (0.69 to 0.86) | 714 participants | ⊕⊕⊕⊕ High | Clinical response was defined as a reduction of at least 100 points in the CDAI score from baseline. |
| Endoscopic response | Not reported | This outcome was not reported. | ||||
| Quality of life (QoL) Inflammatory Bowel Disease Questionnaire (IBDQ) (scale: 32 to 224; higher score = better QoL) Follow‐up: 4 weeks Short‐Form 36 health survey (SF‐36) (scale: 0 to 100; higher score = better QoL) Follow‐up: 4 weeks | One study reported significantly higher IBDQ scores at week 4 in the adalimumab 160 mg/80 mg and 80 mg/40 mg dose groups compared to placebo. One study reported a mean IBDQ score at 4 weeks of 150 in the adalimumab group compared to 139 in the placebo group (P < 0.001). One study reported significantly higher SF‐36 scores in adalimumab 160 mg/80 mg and 80 mg/40 mg dose groups at four weeks compared to placebo. IBDQ scores were higher at 4 weeks in the adalimumab 160 mg/80 mg group compared to placebo (P > 0.05). | 714 participants | ⊕⊕⊕⊝1 Moderate | Data did not allow for meta‐analysis (means and/or standard deviations not reported). An increase in the IBDQ score of 16 to 32 points from baseline constitutes the lower and upper bounds of clinically meaningful improvement in QoL. | ||
| Adverse events Follow‐up: 4 weeks | 715 per 1000 | 643 per 1000 | RR 0.90 (0.74 to 1.09) | 531 participants | ⊕⊕⊕⊝2 Moderate | The most commonly reported adverse events included injection site reactions, abdominal pain, fatigue, worsening Crohn's disease and nausea. |
| Serious adverse events Follow‐up: 4 weeks | 49 per 1000 | 22 per 1000 | RR 0.44 (0.17 to 1.15) | 531 participants | ⊕⊕⊝⊝3 | The most commonly reported serious adverse events included infections, worsening Crohn's disease, abscesses and dehydration. |
| Withdrawals due to adverse events Follow‐up: 4 weeks | 30 per 1000 | 12 per 1000 | RR 0.38 ( 0.11 to 1.30) | 531 participants | ⊕⊕⊝⊝4 | Adverse events that led to study withdrawal included worsening Crohn's disease, abdominal abscess and liver abscess. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to serious imprecision (narrative synthesis was conducted, estimates were not precise). 2 Downgraded one level due to serious inconsistency (I² = 53%). 3 Downgraded two levels due to very serious imprecision (19 events). 4 Downgraded two levels due to very serious imprecision (11 events). | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Failure to achieve clinical remission at 4 weeks: subgroup by dose Show forest plot | 3 | 714 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.79, 0.90] |
| 1.1 160mg/80mg | 3 | 470 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.75, 0.88] |
| 1.2 80mg/40mg | 2 | 145 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.75, 1.02] |
| 1.3 40mg/20mg | 1 | 99 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.80, 1.20] |
| 2 Failure to achieve clinical remission at 4 weeks: subgroup by previous TNF‐α exposure) Show forest plot | 2 | 624 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.79, 0.91] |
| 2.1 TNF‐α naive | 1 | 299 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.75, 0.95] |
| 2.2 TNF‐α exposed | 1 | 325 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.77, 0.92] |
| 3 Failure to achieve clinical response at 4 weeks (70‐point response): subgroup by dose Show forest plot | 3 | 714 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.59, 0.79] |
| 3.1 160mg/80mg | 3 | 471 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.69 [0.59, 0.82] |
| 3.2 80mg/40mg | 2 | 145 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.45, 0.85] |
| 3.3 40mg/20mg | 1 | 98 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.49, 1.09] |
| 4 Failure to achieve clinical response (70‐point response) at 4 weeks: subgroup by previous TNF‐α exposure) Show forest plot | 2 | 624 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.61, 0.82] |
| 4.1 TNF‐α naive | 1 | 299 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.67 [0.53, 0.85] |
| 4.2 TNF‐α exposed | 1 | 325 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.73 [0.60, 0.89] |
| 5 Failure to achieve clinical response at 4 weeks (100‐point response): subgroup by dose Show forest plot | 3 | 714 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.69, 0.86] |
| 5.1 160mg/80mg | 3 | 470 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.76 [0.66, 0.86] |
| 5.2 80mg/40mg | 2 | 145 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.76 [0.59, 0.98] |
| 5.3 40mg/20mg | 1 | 99 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.66, 1.15] |
| 6 Failure to achieve clinical response (100‐point response) at 4 weeks: subgroup by previous TNF‐α exposure) Show forest plot | 2 | 624 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.70, 0.88] |
| 6.1 TNF‐α naive | 1 | 299 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.62, 0.89] |
| 6.2 TNF‐α exposed | 1 | 325 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.70, 0.95] |
| 7 Adverse events Show forest plot | 3 | 531 | Risk Ratio (M‐H, Random, 95% CI) | 0.90 [0.74, 1.09] |
| 8 Serious adverse events Show forest plot | 3 | 531 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.44 [0.17, 1.15] |
| 9 Withdrawals due to adverse events Show forest plot | 3 | 531 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.38 [0.11, 1.30] |
