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Revisión sistemática

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Ustekinumab Does Not Increase Risk of Adverse Events: A Meta-Analysis of Randomized Controlled Trials.

Revista Digestive diseases and sciences
Año 2021
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Este artículo incluye 25 Estudios primarios 31 Estudios primarios (25 referencias)

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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.

Revisión sistemática

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Systematic Review and Network Meta-Analysis: Comparative Efficacy and Safety of Biosimilars, Biologics and JAK1 Inhibitors for Active Crohn Disease

Autores Wu G , Yang Y , Liu M , Wang Y , Guo Q
Revista Frontiers in pharmacology
Año 2021
Enlaces Pubmed DOI PubMed Central

Este artículo incluye 28 Estudios primarios 31 Estudios primarios (28 referencias)

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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.

Revisión sistemática

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No Benefit of Concomitant Immunomodulator Therapy on Efficacy of Biologics That are Not Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Diseases: a Meta-Analysis.

Revista Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
Año 2021
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Este artículo incluye 33 Estudios primarios 35 Estudios primarios (33 referencias)

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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.

Revisión sistemática

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Heterogeneity in Definitions of Efficacy and Safety Endpoints for Clinical Trials of Crohn's Disease: A Systematic Review for Development of a Core Outcome Set.

Revista Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
Año 2018
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Este artículo incluye 67 Estudios primarios 68 Estudios primarios (67 referencias)

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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.

Revisión sistemática

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Systematic review with network meta-analysis: Efficacy of induction therapy with a second biological agent in anti-TNF-experienced Crohn's disease patients

Revista Gastroenterology research and practice
Año 2018
Enlaces Pubmed DOI PubMed Central

Este artículo incluye 8 Estudios primarios 8 Estudios primarios (8 referencias)

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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.

Revisión sistemática

No clasificado

Primary Non-Response to Tumor Necrosis Factor Antagonists is Associated with Inferior Response to Second-line Biologics in Patients with Inflammatory Bowel Diseases: A Systematic Review and Meta-analysis.

Revista Journal of Crohn's & colitis
Año 2018
Enlaces Pubmed DOI PubMed Central

Este artículo incluye 9 Estudios primarios 9 Estudios primarios (9 referencias)

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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.

Revisión sistemática

No clasificado

An indirect comparison of ustekinumab and vedolizumab in the therapy of TNF-failure Crohn's disease patients.

Autores Kawalec P , Moćko P
Revista Journal of comparative effectiveness research
Año 2018
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Este artículo incluye 5 Estudios primarios 6 Estudios primarios (5 referencias)

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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.

Revisión sistemática

No clasificado

Systematic review and network meta-analysis: first- and second-line biologic therapies for moderate-severe Crohn's disease.

Revista Alimentary pharmacology & therapeutics
Año 2018
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Este artículo incluye 15 Estudios primarios 18 Estudios primarios (15 referencias)

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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.

Revisión sistemática

No clasificado

Home Idiomas Ingresar a Epistemonikos Búsqueda avanzada Eficacia y seguridad de ustekinumab en la terapia de inducción de pacientes con enfermedad de Crohn refractaria a TNF-α: una revisión sistemática y meta-análisis.

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Revista Journal of comparative effectiveness research
Año 2017
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Este artículo incluye 2 Estudios primarios 4 Estudios primarios (2 referencias)

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El objetivo de la revisión sistemática y del meta-análisis fue evaluar la eficacia y seguridad de ustekinumab en la terapia de inducción de pacientes con insuficiencia de TNF-α con enfermedad de Crohn. Se incluyeron ensayos controlados aleatorios que compararon la eficacia (respuesta clínica y remisión) y el perfil de seguridad del ustekinumab en el fracaso del TNF-α. Los pacientes con enfermedad de Crohn ; Se analizaron también los no respondedores primarios y secundarios de TNF-α o los pacientes intolerantes. Los estudios incluidos fueron evaluados críticamente según el protocolo de la declaración PRISMA; Se realizó la agregación de datos con un software RevMan (®). Resultados: Tres ensayos controlados aleatorios se revelaron en la revisión sistemática, pero sólo dos de ellos (CERTIFI y UNITI-1) fueron homogéneos para ser incluidos en el metanálisis; La agregación de datos sólo para la fase de inducción de la terapia fue posible. La respuesta clínica fue significativamente mayor en los pacientes que recibieron ustekinumab en comparación con los pacientes con placebo en un grupo de pacientes con fracaso antagonista de TNF-α (beneficio relativo [RB] = 1,62; IC del 95%: 1,28-2,04) y en los siguientes subgrupos: secundarios no respondedores RB = 1,98; IC del 95%: 1,49-2,63), pacientes intolerantes (RB = 1,47; IC del 95%: 1,01-2,13) ​​y pacientes que fallaron al menos dos antagonistas del TNF-α (RB = 2,19; IC del 95%: 1,53- 3.14), pero en el caso de los no respondedores primarios, se presentó insignificante (RB = 1,22; IC del 95%: 0,76-1,98). La remisión clínica en la población con fracaso del antagonista del TNF-α fue significativamente mayor en los pacientes que recibieron ustekinumab en comparación con placebo (RB = 1,72; IC del 95%: 1,17-2,53). El análisis combinado reveló que el riesgo de eventos adversos en la fase de inducción del tratamiento no fue significativamente diferente (relación de riesgo = 0,96; IC del 95%: 0,86-1,06) entre los grupos ustekinumab y placebo. CONCLUSIÓN: La respuesta clínica fue significativamente mayor para los pacientes con fracaso antagonista de TNF-α que recibieron ustekinumab, así como en subgrupos de pacientes no respondedores secundarios o intolerantes, pero no en el caso de los no respondedores primarios. Ustekinumab ocurrido tan seguro como placebo en la inducción, así como en una fase de mantenimiento de la terapia.

Revisión sistemática

No clasificado

Ustekinumab (Stelara)

Autores [No se listan los autores]
Libro CADTH Common Drug Reviews
Año 2017
Enlaces Pubmed

Este artículo incluye 1 Estudio primario 1 Estudios primarios (1 referencia)

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Crohn’s disease is a chronic form of inflammatory bowel disease that can affect any part of the gastrointestinal tract but most commonly affects the ileum, colon, and rectum. Common gastrointestinal symptoms experienced by patients with Crohn’s disease include abdominal pain, rectal bleeding, fatigue, vomiting, diarrhea, perianal disease, weight loss, and bloating.1–3 According to Crohn’s and Colitis Canada, there are approximately 129,000 Canadians living with Crohn’s disease (one in 150 people), and it is estimated that 5,700 new cases of Crohn’s disease are diagnosed each year.1 Ustekinumab (Stelara) is a fully human immunoglobulin G1 kappa monoclonal antibody that binds to the shared p40 subunit of interleukin (IL)-12 and IL-23.4 Ustekinumab is already approved by Health Canada for the treatment of adults with chronic moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy, and for the treatment of adult patients with active psoriatic arthritis, alone or in combination with methotrexate.4 The current indication under review is for the treatment of adult patients with moderately to severely active Crohn’s disease, who have had an inadequate response with, loss of response to, or intolerance to either immunomodulators or one or more tumour necrosis factor (TNF) alpha antagonists, or have had an inadequate response with, intolerance to, or demonstrated dependence on corticosteroids. The recommended dosage for ustekinumab in the treatment of Crohn’s disease is an initial single intravenous (IV) induction dose based on body weight (approximating 6 mg/kg), followed by a 90 mg subcutaneous (SC) maintenance dose eight weeks later, then one dose every eight weeks thereafter as maintenance treatment. For some patients (e.g., “those with low inflammatory burden,” per the product monograph), an alternative maintenance regimen of ustekinumab 90 mg SC every 12 weeks may be administered at the discretion of the treating physician. Patients who inadequately respond to the 90 mg SC every 12 weeks regimen may be switched to the every eight weeks regimen. Immunomodulators and/or corticosteroids may be continued during treatment with ustekinumab. The product monograph recommends that, in patients who have responded to treatment with ustekinumab, corticosteroids may be reduced or discontinued in accordance with standard of care.4 The objective of this report is to perform a systematic review of the beneficial and harmful effects of ustekinumab in accordance with the Health Canada–approved indication for the treatment of Crohn’s disease. Only Health Canada–approved dosage regimens for ustekinumab for Crohn’s disease were included in this review. Ustekinumab has been previously reviewed through the CADTH Common Drug Review (CDR) for the treatment of plaque psoriasis and psoriatic arthritis.5,6