BACKGROUND: Starting biologic treatment early in the course of inflammatory bowel disease (IBD) may associate with higher efficacy, especially in Crohn's disease (CD).
METHODS: A systematic review and individual-patient-data meta-analysis of all placebo-controlled trials of biologics approved for IBD at study inception (Oct 2015), using Vivli data-sharing platform. The primary outcome was the proportional biologic/placebo treatment effect on induction-of-remission in patients with short-duration (≤18months) versus long-duration disease (>18months) analyzed separately for CD and ulcerative colitis (UC). We used meta-regression to examine the impact of patients' characteristics on the primary outcome. Study PROSPERO registration: CRD42018041961.
RESULTS: We included 25 trials, testing infliximab, adalimumab, certolizumab, golimumab, natalizumab or vedolizumab (6,168 CD, 3,227 UC patients). In CD, induction-of-remission rates were higher in pooled placebo and active arms' patients with short-disease duration≤18 months (41.4%, 244/589) compared with disease-duration>18months (29.8%, 852/2857, meta-analytically estimated OR=1.33, 95%CI:1.09-1.64). The primary outcome, proportional biologic/placebo treatment effect on induction-of-remission, was not different in short-duration disease ≤18 months (n= 589, OR 1.47, 95%CI:1.01-2.15) compared with longer disease-duration (n=2857, OR 1.43, 95%CI:1.19-1.72). In UC trials, both the proportional biologic/placebo remission-induction effect and the pooled biologic-placebo effect were stable regardless of disease duration. Primary outcome results remained unchanged when tested using alternative temporal cut-offs and when modelled for individual-patients' co-variates, including prior anti-TNFs exposure.
CONCLUSION: There are higher rates of induction-of-remission with biologics and with placebo in early CD, resulting in a treatment-to-placebo effect ratio which is similar across disease durations. No such relationships between disease-duration and outcomes is found in UC.
BACKGROUND & AIMS: It is not clear whether concomitant therapy with corticosteroids and anti-tumor necrosis factor (TNF) agents is more effective at inducing remission in patients with Crohn's disease (CD) than anti-TNF monotherapy. We aimed to determine whether patients with active CD receiving corticosteroids during induction therapy with anti-TNF agents had higher rates of clinical improvement than patients not receiving corticosteroids during induction therapy.
METHODS: We systematically searched the MEDLINE, Embase, and CENTRAL databases, through January 20, 2016, for randomized trials of anti-TNF agents approved for treatment of CD and identified 14 trials (5 of adalimumab, 5 of certolizumab, and 4 of infliximab). We conducted a pooled meta-analysis of individual patient and aggregated data from these trials. We compared data from participants who continued oral corticosteroids during induction with anti-TNF therapy to those treated with anti-TNF agents alone. The endpoints were clinical remission (CD activity index [CDAI] scores <150) and clinical response (a decrease in CDAI of 100 points) at the end of induction (weeks 4-14 of treatment).
RESULTS: We included 4354 patients who received induction therapy with anti-TNF agents, including 1653 [38.0%] who were receiving corticosteroids. The combination of corticosteroids and an anti-TNF agent induced clinical remission in 32.0% of patients, whereas anti-TNF monotherapy induced clinical remission in 35.5% of patients (odds ratio [OR], 0.93; 95% CI, 0.74-1.17). The combination of corticosteroids and an anti-TNF agent induced a clinical response in 42.7% of patients, whereas anti-TNF monotherapy induced a clinical response in 46.8% (OR 0.84; 95% CI, 0.73-0.96). These findings did not change with adjustment for baseline CDAI scores and concurrent use of immunomodulators.
CONCLUSIONS: Based on a meta-analysis of data from randomized trials of anti-TNF therapies in patients with active CD, patients receiving corticosteroids during induction therapy with anti-TNF agents did not have higher rates of clinical improvement compared with patients not receiving corticosteroids during induction therapy. Given these findings and the risks of corticosteroid use, clinicians should consider early weaning of corticosteroids during induction therapy with anti-TNF agents for patients with corticosteroid-refractory CD.
Background: Crohn disease (CD) is a chronic inflammatory disease that affects quality of life. There are several drugs available for the treatment of CD, but their relative efficacy is unknown due to a lack of high-quality head-to-head randomized controlled trials. Aim: To perform a mixed comparison of the efficacy and safety of biosimilars, biologics and JAK1 inhibitors for CD. Methods: We searched PubMed, Web of Science, embase and the Cochrane Library for randomized controlled trials (RCTs) up to Dec. 28, 2020. Only RCTs that compared the efficacy or safety of biosimilars, biologics and JAK1 inhibitors with placebo or another active agent for CD were included in the comparative analysis. Efficacy outcomes were the induction of remission, maintenance of remission and steroid-free remission, and safety outcomes were serious adverse events (AEs) and infections. The Bayesian method was utilized to compare the treatments. The registration number is CRD42020187807. Results: Twenty-eight studies and 29 RCTs were identified in our systematic review. The network meta-analysis demonstrated that infliximab and adalimumab were superior to certolizumab pegol (OR 2.44, 95% CI 1.35–4.97; OR 2.96, 95% CI 1.57–5.40, respectively) and tofacitinib (OR 2.55, 95% CI 1.27–5.97; OR 3.10, 95% CI 1.47–6.52, respectively) and revealed the superiority of CT-P13 compared with placebo (OR 2.90, 95% CI 1.31–7.59) for the induction of remission. Infliximab (OR 7.49, 95% CI 1.85–34.77), adalimumab (OR 10.76, 95% CI 2.61–52.35), certolizumab pegol (OR 4.41, 95% CI 1.10–21.08), vedolizumab (OR 4.99, 95% CI 1.19–25.54) and CT-P13 (OR 10.93, 95% CI 2.10–64.37) were superior to filgotinib for the maintenance of remission. Moreover, infliximab (OR 3.80, 95% CI 1.49–10.23), adalimumab (OR 4.86, 95% CI 1.43–16.95), vedolizumab (OR 2.48, 95% CI 1.21–6.52) and CT-P13 (OR 5.15, 95% CI 1.05–27.58) were superior to placebo for steroid-free remission. Among all treatments, adalimumab ranked highest for the induction of remission, and CT-P13 ranked highest for the maintenance of remission and steroid-free remission. Conclusion: CT-P13 was more efficacious than numerous biological agents and JAK1 inhibitors and should be recommended for the treatment of CD. Further head-to-head RCTs are warranted to compare these drugs.
Background: Fatigue is a common and burdensome symptom experienced by individuals with inflammatory bowel disease (IBD). The subjective, complex nature of fatigue can often hamper its’ management, and the effectiveness of treatments for fatigue in IBD remains unknown. The aim of this Cochrane review was to assess the efficacy and safety of pharmacological and non-pharmacological interventions for managing fatigue in IBD. Methods: A systematic search was conducted up to July 2018, and the search was rerun in October 2019. All randomised controlled trials (RCTs) of pharmacological and non-pharmacological interventions in children or adults with IBD, where fatigue was assessed as a primary or secondary outcome were included. Data were extracted and study quality was independently assessed by two authors. Standard Cochrane methodological procedures were used. Results: Fourteen RCTs were included (3741 participants; all adults; 6 in Crohn’s disease (CD); 2 in ulcerative colitis (UC); 6 in both CD and UC), with five potentially relevant studies identified from the updated search (to be assessed for inclusion at the next update). The interventions varied widely and included nine pharmacological trials, four non-pharmacological trials, and one multimodular trial. Only four trials were designed specifically as interventions for managing fatigue and one meta-analysis was possible, due to the diversity and limited number of studies for each intervention. We found that adalimumab 40mg administered every other week (only for those known to respond to adalimumab induction therapy), self-directed stress management and physical activity advice may reduce fatigue but the evidence is very uncertain. The evidence suggest ferric maltol results in a slight increase in fatigue and electroacupuncture may result in a large reduction in fatigue and increase in quality of life. There is no evidence of effect for adalimumab maintenance therapy, adalimumab administered 40mg weekly, agaricus blazei murill-based mushroom extract, omega 3, guided stress management or cognitive behavioural therapy that is likely to have a clinically meaningful improvement on fatigue. Reporting in some of the trials was insufficient to assess the efficacy and safety of some therapies, including vitamin D3 supplementation, ferumoxytol, vedolizumab, tight control customised management and solution focused therapy. Conclusions: The effects of pharmacological and non-pharmacological interventions on fatigue in individuals with IBD are uncertain. It is difficult to draw firm conclusions regarding the efficacy and safety of interventions, as there is insufficient quantity and quality of evidence available. Further RCTs with larger number of participants are required to assess the potential benefits and harms of therapies, particularly interventions specifically designed for fatigue management.
BACKGROUND: There are limited data to inform positioning of agents for treating moderate-severe Crohn's disease (CD).
AIM: We assessed comparative efficacy and safety of first-line (biologic-naïve) and second-line (prior exposure to anti-tumour necrosis factor [TNF]-α) agents) biologic therapy for moderate-severe CD, through a systematic review and network meta-analysis, and appraised quality of evidence (QoE) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
METHODS: We identified randomised controlled trials (RCTs) in adults with moderate-severe CD treated with approved anti-TNF agents, anti-integrin agents and anti-IL12/23 agents, first-line or second-line, and compared with placebo or another active agent. Efficacy outcomes were induction and maintenance of clinical remission; safety outcomes were serious adverse events and infections. Network meta-analyses were performed, and ranking was assessed using surface under the cumulative ranking (SUCRA) probabilities.
RESULTS: No head-to-head trials were identified. In biologic-naïve patients, infliximab (SUCRA,0.93) and adalimumab (SUCRA,0.75) were ranked highest for induction of clinical remission (moderate QoE). In patients with prior anti-TNF exposure, adalimumab (SUCRA, 0.91; low QoE, in patients with prior response or intolerance to anti-TNF agents) and ustekinumab (SUCRA, 0.71) were ranked highest for induction of clinical remission. In patients with response to induction therapy, adalimumab (SUCRA, 0.97) and infliximab (SUCRA, 0.68) were ranked highest for maintenance of remission. Ustekinumab had lowest risk of serious adverse events (SUCRA, 0.72) and infection (SUCRA, 0.71; along with infliximab, SUCRA, 0.83) in maintenance trials.
CONCLUSION: Indirect comparisons suggest that infliximab or adalimumab may be preferred first-line agents, and ustekinumab a preferred second-line agent, for induction of remission in patients with moderate-severe CD. Head-to-head trials are warranted.
No se ha evaluado sistemáticamente el riesgo global de infección con agentes biológicos contemporáneos en el tratamiento de la enfermedad de Crohn (CD) y la colitis ulcerosa (UC). Métodos: Se realizó PubMed y Cochrane base de datos de la literatura de búsqueda para evaluar aleatorizado, placebo-control de ensayos de biológicos en el tratamiento de UC y CD. El metanálisis se realizó utilizando un modelo de efectos aleatorios DerSimonian y Laird. Se determinó el riesgo relativo (RR) de daño contra placebo; El número necesario para dañar (NNH) fue reportado cuando fue apropiado. Se evaluó la heterogeneidad y el sesgo de publicación. RESULTADOS: Se incluyeron 14 ensayos (6 UC y 8 CD) evaluando 5107 pacientes. Para los agentes antitumorales de factor de necrosis utilizados en el tratamiento de la UC, el golimumab {NNH de 9,3, RR = 1,4 (intervalo de confianza del 95% [IC], 1,04-1,8)} y estudios combinados de infliximab y adalimumab (NNH = 17,2, RR = 1,2 [IC del 95%, 1,0 - 1,3]) tuvieron un riesgo estadísticamente significativo mayor para cualquier infección versus placebo. El riesgo no aumentó significativamente en los ensayos de factor de necrosis antitumoral en CD (RR = 1,1 [IC del 95%, 0,8 - 1,5]). Por el contrario, los agentes anti-integrina en la UC (RR = 1,0 [IC del 95%, 0,9-1,2]) o CD (RR = 1,1 [IC del 95%, 0,97-1,3]) no confirió un riesgo excesivo de infección estadísticamente significativo placebo. CONCLUSIONES: La terapia con factor de necrosis antitumoral, pero no con terapia antiintelina, se asocia con un mayor riesgo de infección que el placebo en el tratamiento de la UC. Ninguna de las clases de terapia se asocia con mayor riesgo de infección que el placebo en el tratamiento del CD. Nuestros hallazgos pueden ayudar a orientar las discusiones centradas en el paciente con respecto al riesgo de infección con agentes biológicos.
Medical treatment for fistulizing Crohn's disease (FCD) is changing rapidly over the time by the introduction of novel therapeutic medicines, while no global consensus is available. This study aims to accomplish a systematic review and meta-analysis on the efficacy of tumor necrosis factor-alpha antibodies (anti-TNF-α antibodies) versus placebo in FCD. A systematic review of published literature was carried out till December 2016, and a meta-analysis of identified studies was done. Data have been explored from PubMed, Scopus, Cochrane Library Database, and Web of Science. Predefined exclusion criteria for included studies in meta-analysis are based on search methodology and are as follows: Randomized clinical trial about Crohn's disease (CD) patients without fistula, pediatrics CD, randomized clinical trials about pregnant women with FCD, nonhuman studies, randomized clinical trials with surgical therapies interventions, conference abstracts, case reports, and language other than English studies. All randomized placebo-controlled trials were included. To assess risk of bias, Jadad score was applied to evaluate trials' methodological quality. Relative risk (RR) and 95% confidence intervals were computed using Mantel-Haenszel and/or Rothman-Boice (for fixed effects) or Der Simonian-Laird (for random effects) techniques. Nine studies attained defined inclusion criteria. The meta-analysis results showed that anti-TNF-α antibodies are remarkably more effective in comparison to placebo for fistula closure maintenance (RR = 2.36; 95% confidence interval: 1.58-3.55; P < 0.0001) in patients with FCD, whereas anti-TNF-α antibodies were not superior to placebo neither in fistula improvement nor in fistula closure. We concluded that adalimumab and certolizumab pegol are both effective in fistula closure maintenance in adult patients with FCD.
BACKGROUND: Crohn disease (CD) is an inflammatory bowel disease which occurs especially in developed countries of Western Europe and North America. The aim of the study was to compare the safety profile of biologic drugs in patients with CD.
METHODOLOGY: A systematic literature search was performed using PubMed, Embase, and CENTRAL databases, until April 27, 2016. We included randomized controlled trials (RCTs) that compared the safety of biologic drugs (infliximab, adalimumab, vedolizumab, certolizumab pegol, and ustekinumab) with one another or with placebo in patients with CD. The network meta-analysis (NMA) was conducted for an induction phase (6-10 weeks) and maintenance phase (52-56 weeks) with a Bayesian hierarchical random effects model in the ADDIS(®) software. The PROSPERO registration number was CRD42016032606.
RESULTS: Ten RCTs were included in the systematic review with NMA. In the case of the induction phase, the NMA could be conducted for the assessment of the relative safety profile of adalimumab, vedolizumab, certolizumab pegol, and ustekinumab, and in the case of the maintenance phase-of infliximab, adalimumab, and vedolizumab. There were no significant differences in the rate of adverse events in patients treated with biologics. Statistical analysis revealed that vedolizumab had the greatest probability of being the safest treatment in most endpoints in the induction phase and adalimumab-in the maintenance phase.
CONCLUSIONS: No significant differences between the biologics in the relative safety profile analysis were observed. Further studies are needed to confirm our findings, including head-to-head comparisons between the analyzed biologics.
INTRODUCCIÓN Y OBJETIVOS: Existe un debate sobre si los pacientes con enfermedad de Crohn que inician la terapia del factor de necrosis anti-tumoral (TNF) después de la terapia inmunomoduladora no deben continuar recibiendo inmunomoduladores concomitantes. Hemos llevado a cabo un meta-análisis de subgrupos de los ensayos controlados aleatorios (ECA) de los agentes anti-TNF para comparar la eficacia y seguridad de la terapia inmunomoduladora concomitante frente a la monoterapia con anti-TNF.
MÉTODOS: Se realizó una revisión sistemática de la literatura publicada desde 1980 hasta 2008 y se identificaron 11 ECA de agentes anti-TNF en pacientes con luminal o enfermedad de Crohn fistulizante. Se excluyeron los ECA de pacientes que eran ingenuos a los anti-TNF y la terapia inmunomoduladora. Los criterios de valoración primarios fueron la respuesta clínica en las semanas 4-14 y 24-30 y la remisión en las semanas 24-30. Los objetivos secundarios fueron lugar de la perfusión o reacciones en el lugar de la inyección y los eventos adversos seleccionados. Un subgrupo priori se realizaron análisis para evaluar cierre de la fístula y la eficacia y seguridad de la terapia de combinación con diversos agentes anti-TNF.
RESULTADOS: En general, la terapia de combinación no fue más efectiva que la monoterapia en la inducción de la remisión de 6 meses (odds ratio [OR] = 1,02; intervalo de confianza del 95% [IC]: 0,80 a 1,31), lo que induce una respuesta (OR, 1,08; 95% CI, 0,79 a 1,48), el mantenimiento de una respuesta (OR, 1,53; IC del 95%, 0,67-3,49), o inducir parcial (OR, 1,25; IC del 95%, 0,84-1,88) o cierre de la fístula completa (OR, 1,10; 95 % CI, 0,68 a 1,78). En los análisis de subgrupos de los agentes anti-TNF individuales, la terapia de combinación no fue más eficaz que la monoterapia en la inducción de la remisión de 6 meses en los pacientes tratados con infliximab (OR, 1,73; IC del 95%, 0,97-3,07), adalimumab (OR, 0,88; 95 % CI, 0,58 a 1,35), o pegol (OR, 0,93; IC 95%, 0,65-1,34). , La terapia de combinación en general no se asoció con un aumento de los eventos adversos, pero la inclusión de infliximab se asoció con menos reacciones en el lugar de inyección (OR, 0,46;.; IC del 95%, 0,26-0,79)
Conclusiones Sobre la base de un meta-análisis, el uso continuado de la terapia inmunomoduladora después de comenzar la terapia anti-TNF no es más eficaz que la monoterapia con anti-TNF en la inducción o el mantenimiento de respuesta o remisión. Se necesitan ECAs para evaluar adecuadamente la eficacia de la terapia continuada inmunomodulador después de que se inició la terapia anti-TNF.
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.
Starting biologic treatment early in the course of inflammatory bowel disease (IBD) may associate with higher efficacy, especially in Crohn's disease (CD).
METHODS:
A systematic review and individual-patient-data meta-analysis of all placebo-controlled trials of biologics approved for IBD at study inception (Oct 2015), using Vivli data-sharing platform. The primary outcome was the proportional biologic/placebo treatment effect on induction-of-remission in patients with short-duration (≤18months) versus long-duration disease (>18months) analyzed separately for CD and ulcerative colitis (UC). We used meta-regression to examine the impact of patients' characteristics on the primary outcome. Study PROSPERO registration: CRD42018041961.
RESULTS:
We included 25 trials, testing infliximab, adalimumab, certolizumab, golimumab, natalizumab or vedolizumab (6,168 CD, 3,227 UC patients). In CD, induction-of-remission rates were higher in pooled placebo and active arms' patients with short-disease duration≤18 months (41.4%, 244/589) compared with disease-duration>18months (29.8%, 852/2857, meta-analytically estimated OR=1.33, 95%CI:1.09-1.64). The primary outcome, proportional biologic/placebo treatment effect on induction-of-remission, was not different in short-duration disease ≤18 months (n= 589, OR 1.47, 95%CI:1.01-2.15) compared with longer disease-duration (n=2857, OR 1.43, 95%CI:1.19-1.72). In UC trials, both the proportional biologic/placebo remission-induction effect and the pooled biologic-placebo effect were stable regardless of disease duration. Primary outcome results remained unchanged when tested using alternative temporal cut-offs and when modelled for individual-patients' co-variates, including prior anti-TNFs exposure.
CONCLUSION:
There are higher rates of induction-of-remission with biologics and with placebo in early CD, resulting in a treatment-to-placebo effect ratio which is similar across disease durations. No such relationships between disease-duration and outcomes is found in UC.
