GOALS AND BACKGROUND: Ustekinumab (UST) is a monoclonal antibody inhibitor of IL-12/IL-23 approved for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). We conducted a meta-analysis to compare rates of adverse events (AEs) in randomized controlled trials (RCTs) of UST for all indications.
STUDY: A systematic search was performed of MEDLINE, Embase, and PubMed databases through November 2019. Study inclusion included RCTs comparing UST to placebo or other biologics in patients aged 18 years or older with a diagnosis of an autoimmune condition.
RESULTS: Thirty RCTs with 16,068 patients were included in our analysis. Nine thousand six hundred and twenty-six subjects were included in the UST vs placebo analysis. There was no significant difference in serious or mild/moderate AEs between UST and placebo with an OR of 0.83 (95% CI 0.66, 1.05) and 1.08 (95% CI 0.99, 1.18), respectively, over a median follow-up time of 16 weeks. In a sub-analysis of CD and UC trials, no difference in serious or mild/moderate AEs in UST versus placebo was seen.
CONCLUSIONS: UST was not associated with an increase in short-term risk of AEs.
BACKGROUND & AIMS: There is debate over whether patients with inflammatory bowel diseases (IBD) treated with biologics that are not tumor necrosis factor antagonists (such as vedolizumab or ustekinumab) should receive concomitant treatment with immunomodulators. We conducted a meta-analysis to compare the efficacy and safety of concomitant immunomodulator therapy vs vedolizumab or ustekinumab monotherapy.
METHODS: In a systematic search of publications, through July 31, 2019, we identified 33 studies (6 randomized controlled trials and 27 cohort studies) of patients with IBD treated with vedolizumab or ustekinumab. The primary outcome was clinical benefit, including clinical remission, clinical response, or physician global assessment in patients who did vs did not receive combination therapy with an immunomodulator. Secondary outcomes were endoscopic improvement and safety. We performed random-effects meta-analysis and estimated odds ratio (OR) and 95% CIs.
RESULTS: Overall, combination therapy was not associated with better clinical outcomes in patients receiving vedolizumab (16 studies: OR, 0.84; 95% CI, 0.68-1.05; I2=13.9%; Q test P=.17) or ustekinumab (15 studies: OR, 1.1; 95% CI, 0.87-1.38; I2=11%; Q test P=.28). Results were consistent in subgroup analyses, with no difference in clinical remission or response in induction vs maintenance studies or in patients with Crohn's disease vs ulcerative colitis in studies of vedolizumab. Combination therapy was not associated with better endoscopic outcomes in patients receiving vedolizumab (3 studies: OR, 1.13; 95% CI, 0.48-2.68; I2=0; Q test P=.96) or ustekinumab (2 studies: OR, 0.58; 95% CI, 0.21-1.16; I2=47%; Q test P=.17). Combination therapy was not associated with an increase in adverse events during vedolizumab therapy (4 studies: OR, 1.17; 95% CI, 0.75-1.84; I2=0; Q test P=.110).
CONCLUSIONS: In a meta-analysis of data from studies of patients with IBD, we found that combining vedolizumab or ustekinumab with an immunomodulator is no more effective than monotherapy in induction or maintenance of remission.
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 and Aim. Crohn's disease (CD) is a chronic inflammatory condition of the gastrointestinal tract with the potential to progress to a severe debilitating state. Treatment with biological agents is highly efficient, improving both short-term outcomes and long-term prognosis. Nonetheless, up to 60% of patients receiving biological therapy will exhibit nonresponse at some point. The optimal management of such patients is not clearly defined. Besides traditional anti-TNF agents (infliximab, adalimumab, and certolizumab), alternative biological therapies (natalizumab, vedolizumab, and ustekinumab) are currently available for the treatment of CD. Our aim was to analyze all available evidence regarding efficacy of a second biological in "biological-treatment-experienced" patients. Methods. A systematic review of the literature was conducted using specific criteria for selecting relevant randomized clinical trials evaluating response to administration of secondary biological therapy in "anti-TNF-experienced" CD patients. Data from these studies was used to perform (a) traditional meta-analysis to ascertain the effect of secondary treatment versus placebo and (b) network meta-analysis to compare indirectly the efficacy of available biological agents. Results. Out of initially 977 studies, only eight were included for analysis, providing a total of 1281 treated and 733 placebo-receiving CD patients. Treatment with a second biological was found to be superior to placebo for both induction of remission (OR 2.2, 95% CI 1.7 to 3) and response (OR 1.9, 95% CI 1.5 to 2.5), with global rates of 24% and 42%, respectively (placebo rate: 11% and 27%, p<0.0001 for both). Indirect comparisons performed with network meta-analysis suggest no specific agent is clearly superior to others, with relatively better results observed for adalimumab in inducing disease remission. Conclusion. In anti-TNF-experienced CD patients, secondary biological administration may be efficient, while no specific agent seems to outperform the others. Further research is needed to identify optimal management strategies for this challenging subset of patients.
BACKGROUND AND AIMS: We sought to analyze whether response to second-line biologic varies depending on reason for discontinuation of primary anti-TNF agent (primary non-response [PNR], secondary loss of response [LOR] after initial response, or intolerance), through a systematic review and meta-analysis.
METHODS: Through a systematic search through May 31, 2017, we identified 8 randomized controlled trials (RCTs) of biologics in patients with IBD with prior exposure to anti-TNF agents, that stratified response to second-line therapy by reason for discontinuing primary anti-TNF therapy (PNR vs. LOR vs. intolerance). We estimated relative risk (RR) [and 95% confidence interval (CI)] of achieving clinical remission in patients with PNR as compared to patients with LOR, and intolerance, through random effects meta-analysis.
RESULTS: As compared to patients who discontinued prior anti-TNF due to intolerance, patients with prior PNR were 24% less likely to achieve remission with second-line biologics (RR,0.76 [0.61-0.96]). As compared to patients who discontinued prior anti-TNF due to LOR, patients with prior PNR were 27% less likely to achieve remission with induction therapy with second-line biologics (RR,0.73 [0.56-0.97]), particularly to ustekinumab (RR,0.64 [0.52-0.80]). There was no difference in response to vedolizumab in patients with prior PNR or LOR to anti-TNF agents (RR,1.16 [0.85-1.58]).
CONCLUSION: Patients with PNR to anti-TNF agents are less likely to respond to second-line non-TNF biologics, as compared to patients who discontinued therapy due to secondary LOR or intolerance. This may be attributed to underlying pharmacokinetics and pharmacodynamics of anti-TNF agents in patients with PNR.
AIM: An indirect comparison of ustekinumab versus vedolizumab in patients with active moderate-to-severe Crohn's disease who were nonresponsive or intolerant to previous TNF-antagonist therapy.
METHODS: A systematic review was performed in Medline via PubMed, Embase, Cochrane Library, until 30 April 2017. Inclusion criteria were: randomized controlled trials, patients treated for Crohn's disease, ustekinumab or vedolizumab therapy. Included trials were critically appraised and afterward indirect comparison by Bucher was conducted; the manuscript was prepared in accordance to the PRISMA requirements.
RESULTS: Five randomized controlled trials were included and assessed for homogeneity; they occurred eligible for indirect comparison referring to induction or maintenance phase of TNF-antagonist failure population treatment; no statistically significant differences in clinical response (relative benefit [RB]: 1.14; 95% CI: 0.65-1.99; p = 0.64) as well as in clinical remission (RB: 1.16; 95% CI: 0.54-2.48; p = 0.71) in induction phase of therapy were revealed; no significant disparity was presented in a maintenance phase in clinical remission (RB: 0.72; 95% CI: 0.30-1.68; p = 0.44). No significant differences were also revealed in primary and secondary nonresponders subpopulations in clinical response. Indirect comparison of the safety profile presented no statistically significant difference between the biologics (relative risk [RR]: 0.93; 95% CI: 0.81-1.08; p = 0.35).
CONCLUSION: No significant differences between vedolizumab and ustekinumab in clinical response and clinical remission for induction and remission in maintenance phase of TNF refractory patients therapy were revealed. In addition, no significant disparities in the risk of adverse events suggest a similar safety profile.
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.
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.
Antecedentes: Ustekinumab (CNTO 1275) y briakinumab (ABT-874) son anticuerpos monoclonales que se dirigen a la subunidad p40 estándar de las citocinas interleucina-12 e interleuquina-23 (IL-12 / 23p40), implicadas en la patogénesis de la enfermedad de Crohn . Los objetivos de esta revisión fueron evaluar la eficacia y seguridad de los anticuerpos anti-IL-12 / 23p40 para la inducción de la remisión en la enfermedad de Crohn. Métodos de búsqueda: Se realizaron búsquedas en las siguientes bases de datos desde el inicio hasta el 12 de septiembre de 2016: PubMed, MEDLINE, EMBASE y la Biblioteca Cochrane (CENTRAL). Se buscaron referencias y resúmenes de conferencias para identificar estudios adicionales. Se incluyeron ensayos controlados aleatorios (ECA) en los que se compararon anticuerpos monoclonales contra IL-12 / 23p40 con placebo u otro comparador activo en pacientes con enfermedad de Crohn activa. Recopilación y análisis de datos: Dos autores seleccionaron independientemente los estudios para su inclusión y extrajeron los datos. La calidad metodológica se evaluó mediante la herramienta Cochrane de riesgo de sesgo. El resultado primario fue la incapacidad para inducir la remisión clínica, definida como un índice de actividad de la enfermedad de Crohn (CDAI) <150 puntos. Los resultados secundarios incluyeron fracaso para inducir mejoría clínica, eventos adversos, eventos adversos graves y retiros debido a eventos adversos. La mejoría clínica se definió como una disminución de> 70 o> 100 puntos en el CDAI desde la línea de base. Se calculó la razón de riesgo (RR) y los intervalos de confianza del 95% (IC del 95%) para cada resultado. Los datos se analizaron en base a la intención de tratar. La calidad general de la evidencia que apoya los resultados se evaluó utilizando los criterios GRADE. Seis ECA (n = 2324 pacientes) cumplieron con los criterios de inclusión. Se asignó un bajo riesgo de sesgo a todos los estudios. Los dos ensayos de briakinumab no se agruparon debido a las diferencias en las dosis y los puntos de tiempo para el análisis. En ambos estudios no hubo diferencias estadísticamente significativas en las tasas de remisión. Un estudio (n = 79) comparó dosis de 1 mg / kg y 3 mg / kg con placebo. En el grupo de briakinumab, el 70% (44/63) de los pacientes no entraron en la remisión clínica a las 6 ó 9 semanas, en comparación con el 81% (13/16) de los pacientes con placebo (RR 0,86; IC del 95%: 0,65 a 1,14). El análisis de subgrupos no reveló diferencias significativas por dosis. El otro estudio de briakinumab (n = 230) comparó dosis intravenosas de 200 mg, 400 mg y 700 mg con placebo. El ochenta y cuatro por ciento (154/184) de los pacientes con briakinumab no entraron en la remisión clínica a las seis semanas en comparación con el 91% (42/46) de los pacientes con placebo (RR 0,92, IC del 95%: 0,83 a 1,03). El análisis de subgrupos no reveló diferencias significativas por dosis. Los análisis de GRADE de los estudios de briakinumab evaluaron la calidad general de la evidencia de la remisión clínica de resultado como baja. Basándose en los resultados de estos dos estudios, los fabricantes de briakinumab pararon la producción de este medicamento. Los estudios con ustekinumab se agruparon a pesar de las diferencias en las dosis intravenosas (es decir, 1 mg / kg, 3 mg / kg, 4,5 mg / kg y 6 mg / kg), sin embargo, el grupo de dosis subcutánea no se incluyó en el análisis, Subcutáneo era equivalente a la dosificación intravenosa. Hubo una diferencia estadísticamente significativa en las tasas de remisión. En la semana seis, el 84% (764/914) de los pacientes tratados con ustekinumab no entraron en la remisión, comparado con el 90% (367/406) de los pacientes tratados con placebo (RR 0,92, IC del 95%: 0,88 a 0,96; El análisis de subgrupos mostró una diferencia estadísticamente significativa para el grupo de dosis de 6,0 mg / kg (evidencia de calidad moderada). Hubo diferencias estadísticamente significativas en la mejoría clínica entre el ustekinumab y los pacientes tratados con placebo. En el grupo ustekinumab, el 55% (502/914) de los pacientes no mejoraron clínicamente (es decir, 70 puntos de disminución de la puntuación CDAI), en comparación con el 71% (287/406) de los pacientes tratados con placebo (RR 0,78; IC del 95%: 0,71 a 0,85; 3 estudios). El análisis de subgrupos reveló diferencias significativas en comparación con el placebo para los subgrupos de dosis de 1 mg / kg, 4,5 mg / kg y 6 mg / kg. De forma similar, para una disminución de 100 puntos en CDAI, el 64% (588/914) de los pacientes en el grupo ustekinumab no mejoraron clínicamente en comparación con el 78% (318/406) de los pacientes placebo (RR 0,82; IC del 95%: 0,77 a 0,88; 3 estudios, evidencia de alta calidad). El análisis de subgrupos mostró una diferencia significativa en comparación con el placebo para los grupos de dosis de 4,5 mg / kg y 6,0 mg / kg (evidencia de alta calidad). No hubo diferencias estadísticamente significativas en la incidencia de eventos adversos, eventos adversos graves o retirada debido a eventos adversos. 62% (407/637) de los pacientes tratados con placebo (RR 0,97; IC del 95%: 0,90 a 1,04; 4 estudios; evidencia de alta calidad) . El cinco por ciento (75/1386) de los pacientes tratados con ustekinumab presentaron un efecto adverso grave en comparación con el 6% (41/637) de los pacientes tratados con placebo (RR 0,83, IC del 95%: 0,58 a 1,20, 4 estudios y pruebas de calidad moderada). Los eventos adversos más comunes en los pacientes con briakinumab fueron reacciones en el sitio de inyección e infecciones. Las infecciones fueron el evento adverso más frecuente en pacientes con ustekinumab. El empeoramiento de la enfermedad de Crohn y las infecciones graves fueron los eventos adversos graves más comunes. Conclusiones de los autores: La evidencia de alta calidad sugiere que el ustekinumab es eficaz para la inducción de la remisión clínica y la mejora clínica en pacientes con enfermedad de Crohn moderada a grave. Evidencia de moderada a alta calidad sugiere que la dosis óptima de ustekinumab es de 6 mg / kg. Briakinumab y ustekinumab parecen ser seguros. Evidencia de calidad moderada sugiere que no hay un mayor riesgo de eventos adversos graves. Se necesitan estudios futuros para determinar la eficacia a largo plazo y la seguridad de ustekinumab en pacientes con enfermedad de Crohn moderada a grave.
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.
Ustekinumab (UST) is a monoclonal antibody inhibitor of IL-12/IL-23 approved for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). We conducted a meta-analysis to compare rates of adverse events (AEs) in randomized controlled trials (RCTs) of UST for all indications.
STUDY:
A systematic search was performed of MEDLINE, Embase, and PubMed databases through November 2019. Study inclusion included RCTs comparing UST to placebo or other biologics in patients aged 18 years or older with a diagnosis of an autoimmune condition.
RESULTS:
Thirty RCTs with 16,068 patients were included in our analysis. Nine thousand six hundred and twenty-six subjects were included in the UST vs placebo analysis. There was no significant difference in serious or mild/moderate AEs between UST and placebo with an OR of 0.83 (95% CI 0.66, 1.05) and 1.08 (95% CI 0.99, 1.18), respectively, over a median follow-up time of 16 weeks. In a sub-analysis of CD and UC trials, no difference in serious or mild/moderate AEs in UST versus placebo was seen.
CONCLUSIONS:
UST was not associated with an increase in short-term risk of AEs.
