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Defining Magnetic Resonance Imaging Treatment Response and Remission in Crohn's Disease: A Systematic Review. 界定克罗恩病的磁共振成像治疗反应和缓解:系统回顾
IF 8 2区 医学 Q1 Medicine Pub Date : 2024-01-27 DOI: 10.1093/ecco-jcc/jjad125
Bénédicte Caron, Vipul Jairath, Valérie Laurent, Jaap Stoker, Andrea Laghi, Geert R D'Haens, Silvio Danese, Laurent Peyrin-Biroulet

Background: Magnetic resonance imaging is increasingly used to assess treatment response in Crohn's disease clinical trials. We aimed to describe the definition of MRI response and remission as assessed by magnetic resonance enterography [MRE] to evaluate treatment efficacy in these patients.

Methods: Electronic databases were searched up to May 1, 2023. All published studies enrolling patients with inflammatory bowel disease and assessment of treatment efficacy with MRE were eligible for inclusion.

Results: Eighteen studies were included. All studies were performed in patients with Crohn's disease. The study period ranged from 2008 to 2023. The majority of studies used endoscopy as the reference standard [61.1%]. MRE response was defined in 11 studies [61.1%]. Five scores and nine different definitions were proposed for MRE response. MRE remission was defined in 12 studies [66.7%]. Three scores and nine different definitions for MRE remission were described. The MaRIA score was the most frequent index used to evaluate MRE response [63.6%] and remission [41.7%]. MRE response was defined as MaRIA score <11 in 63.6% of studies using this index. In 60% of studies using the MaRIA score, MRE remission was defined as MaRIA score <7. In addition, 11 different time points of assessment were reported, ranging from 6 weeks to years.

Conclusion: In this systematic review, significant heterogeneity in the definition of MRE response and remission evaluated in patients with Crohn's disease was observed. Harmonization of eligibility and outcome criteria for MRE in Crohn's Disease clinical trials is needed.

背景:在克罗恩病临床试验中,磁共振成像越来越多地用于评估治疗反应。我们旨在描述磁共振肠造影[MRE]评估的磁共振成像反应和缓解的定义,以评估这些患者的治疗效果:方法:检索了截至 2023 年 5 月 1 日的电子数据库。结果:共纳入 18 项研究:结果:共纳入 18 项研究。所有研究均针对克罗恩病患者。研究时间跨度为 2008 年至 2023 年。大多数研究将内镜检查作为参考标准[61.1%]。11项研究对MRE反应进行了定义[61.1%]。对 MRE 反应提出了五种评分和九种不同的定义。12 项研究对 MRE 缓解进行了定义[66.7%]。有三项评分和九种不同的 MRE 缓解定义。MaRIA评分是用于评估MRE反应[63.6%]和缓解[41.7%]的最常用指标。MRE反应被定义为MaRIA评分 结论:MRE反应和缓解之间存在显著的异质性:在本系统综述中,对克罗恩病患者进行的 MRE 反应和缓解评估的定义存在明显的异质性。需要统一克罗恩病临床试验中 MRE 的资格和结果标准。
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引用次数: 0
Durability of the First Biologic in Patients with Crohn's Disease: A Nationwide Study from the epi-IIRN. 克罗恩病患者首次使用生物制剂的持久性:epi-IIRN 全国性研究。
IF 8 2区 医学 Q1 Medicine Pub Date : 2024-01-27 DOI: 10.1093/ecco-jcc/jjad121
Ohad Atia, Chagit Friss, Gili Focht, Ramit Magen Rimon, Natan Ledderman, Shira Greenfeld, Amir Ben-Tov, Yiska Loewenberg Weisband, Eran Matz, Yuri Gorelik, Yehuda Chowers, Iris Dotan, Dan Turner

Background: In this nationwide study we aimed to compare the durability of the first initiated biologic in Crohn's disease [CD], stratified by monotherapy and combotherapy.

Methods: We used data from the epi-IIRN cohort, which includes 98% of the Israeli inflammatory bowel disease population [2005-2020]. Durability was defined as consistent treatment without surgery or added medications [except for combination therapy with thiopurines or methotrexate]. All comparisons were based on stringent propensity-score matching and paired time-to-event analyses.

Results: A total of 19 264 patients with CD were included, of whom 7452 [39%] received biologics with a median follow-up of 6.8 years (interquartile range [IQR] 3.6-10.7). Time to biologics decreased gradually from 6.7 years [IQR 2.7-10.4] in 2005 to 0.2 years [0.07-0.23] in 2020. The durability of the first biologic after 1 and 3 years was higher with adalimumab monotherapy [88%/61%] than vedolizumab monotherapy [81%/59%; n = 394 matched patients, p = 0.04] and similar between infliximab monotherapy and vedolizumab monotherapy [65%/43%; n = 182 matched patients, p = 0.1]. Durability was higher in adalimumab monotherapy vs infliximab monotherapy [83%/62% vs 71%/48% at 1/3 years; p <0.001] and it was similar in adalimumab monotherapy vs infliximab combotherapy [87%/63% vs 80%/58%, respectively; p = 0.1]. Durability was higher in combotherapy compared with monotherapy for both infliximab [85%/64% vs 67%/43%, respectively; n = 496 matched pairs, p <0.001], and adalimumab [93%/76% vs 82%/62%, respectively; n = 540 matched pairs, p <0.001].

Conclusion: Durability of the first biologic in CD was highest for adalimumab monotherapy. Combotherapy further increased the durability of adalimumab and infliximab. Unless otherwise indicated, our data may support using anti-tumour necrosis factors [TNFs] as first-line biologics in CD, particularly adalimumab if monotherapy is advised.

背景在这项全国性研究中,我们旨在比较克罗恩病[CD]首次使用生物制剂的耐久性,并按单一疗法和联合疗法进行分层:我们使用了 epi-IIRN 队列的数据,其中包括 98% 的以色列炎症性肠病患者(2005-2020 年)。耐久性的定义是在不进行手术或添加药物的情况下持续治疗[硫嘌呤或甲氨蝶呤联合疗法除外]。所有比较均基于严格的倾向分数匹配和配对时间-事件分析:共纳入19 264名CD患者,其中7 452人[39%]接受了生物制剂治疗,中位随访时间为6.8年(四分位数间距[IQR] 3.6-10.7)。使用生物制剂的时间从2005年的6.7年[IQR 2.7-10.4]逐渐降至2020年的0.2年[0.07-0.23]。阿达木单抗单药治疗[88%/61%]在1年和3年后首次使用生物制剂的耐久性高于维多珠单抗单药治疗[81%/59%;n = 394名匹配患者,p = 0.04],英夫利西单药治疗与维多珠单抗单药治疗的耐久性相似[65%/43%;n = 182名匹配患者,p = 0.1]。阿达木单抗单药治疗的耐久性高于英夫利西单药治疗[1/3年时,阿达木单抗单药治疗的耐久性为83%/62%,英夫利西单药治疗的耐久性为71%/48%;P阿达木单抗单药治疗CD的耐久性最高。联合疗法进一步提高了阿达木单抗和英夫利西单抗的耐久性。除非另有说明,我们的数据可能支持将抗肿瘤坏死因子[TNFs]作为CD的一线生物制剂,尤其是阿达木单抗(如果建议单药治疗)。
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引用次数: 0
Faecal Bacteriome and Metabolome Profiles Associated with Decreased Mucosal Inflammatory Activity Upon Anti-TNF Therapy in Paediatric Crohn's Disease. 儿科克罗恩病患者接受抗肿瘤坏死因子治疗后,粪便细菌组和代谢组图谱与黏膜炎症活动减少有关。
IF 8.3 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-01-27 DOI: 10.1093/ecco-jcc/jjad126
Jakub Hurych, Anna Mascellani Bergo, Tereza Lerchova, Lucie Hlinakova, Michal Kubat, Hana Malcova, Dita Cebecauerova, Jan Schwarz, Eva Karaskova, Tomas Hecht, Radim Vyhnanek, Lenka Toukalkova, Vojtech Dotlacil, Katerina Greinerova, Anabela Cizkova, Rudolf Horvath, Jiri Bronsky, Jaroslav Havlik, Ondrej Hradsky, Ondrej Cinek

Background and aims: Treatment with anti-tumour necrosis factor α antibodies [anti-TNF] changes the dysbiotic faecal bacteriome in Crohn's disease [CD]. However, it is not known whether these changes are due to decreasing mucosal inflammatory activity or whether similar bacteriome reactions might be observed in gut-healthy subjects. Therefore, we explored changes in the faecal bacteriome and metabolome upon anti-TNF administration [and therapeutic response] in children with CD and contrasted those to anti-TNF-treated children with juvenile idiopathic arthritis [JIA].

Methods: Faecal samples collected longitudinally before and during anti-TNF therapy were analysed with regard to the bacteriome by massively parallel sequencing of the 16S rDNA [V4 region] and the faecal metabolome by 1H nuclear magnetic resonance imaging. The response to treatment by mucosal healing was assessed by the MINI index at 3 months after the treatment started. We also tested several representative gut bacterial strains for in vitro growth inhibition by infliximab.

Results: We analysed 530 stool samples from 121 children [CD 54, JIA 18, healthy 49]. Bacterial community composition changed on anti-TNF in CD: three members of the class Clostridia increased on anti-TNF, whereas the class Bacteroidia decreased. Among faecal metabolites, glucose and glycerol increased, whereas isoleucine and uracil decreased. Some of these changes differed by treatment response [mucosal healing] after anti-TNF. No significant changes in the bacteriome or metabolome were noted upon anti-TNF in JIA. Bacterial growth was not affected by infliximab in a disc diffusion test.

Conclusions: Our findings suggest that gut mucosal healing is responsible for the bacteriome and metabolome changes observed in CD, rather than any general effect of anti-TNF.

背景和目的:使用抗肿瘤坏死因子α抗体[anti-TNF]治疗可改变克罗恩病[CD]患者粪便菌群失调的情况。然而,这些变化是否是由于粘膜炎症活动减少所致,或者在肠道健康的受试者中是否也可能观察到类似的细菌群反应,目前尚不清楚。因此,我们探讨了 CD 儿童服用抗肿瘤坏死因子后粪便细菌组和代谢组的变化[及治疗反应],并将其与服用抗肿瘤坏死因子的幼年特发性关节炎[JIA]儿童进行对比:方法:通过16S rDNA[V4区]大规模平行测序分析细菌组,通过1H核磁共振成像分析粪便代谢组。治疗开始 3 个月后,通过 MINI 指数评估了粘膜愈合对治疗的反应。我们还测试了英夫利昔单抗对几种代表性肠道细菌菌株体外生长的抑制作用:我们分析了 121 名儿童(CD 54 名,JIA 18 名,健康 49 名)的 530 份粪便样本。抗肿瘤坏死因子会改变 CD 患者的细菌群落组成:抗肿瘤坏死因子会增加梭状芽孢杆菌中的三个成员,而类杆菌则会减少。在粪便代谢物中,葡萄糖和甘油增加,而异亮氨酸和尿嘧啶减少。其中一些变化因抗 TNF 后的治疗反应[粘膜愈合]而不同。在 JIA 抗肿瘤坏死因子治疗后,细菌组或代谢组没有发生明显变化。在盘扩散试验中,英夫利西单抗对细菌生长没有影响:我们的研究结果表明,在 CD 中观察到的细菌组和代谢组变化是肠道粘膜愈合造成的,而不是抗肿瘤坏死因子的普遍影响。
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引用次数: 0
Alternative Endoscopy Reading Paradigms Determine Score Reliability and Effect Size in Ulcerative Colitis. 替代内镜阅读范式决定溃疡性结肠炎的评分可靠性和效应大小。
IF 8.3 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-01-27 DOI: 10.1093/ecco-jcc/jjad134
Walter Reinisch, Vivek Pradhan, Saira Ahmad, Zhen Zhang, Jeremy D Gale

Objective: Central reading of endoscopy is advocated by regulatory agencies for clinical trials in ulcerative colitis [UC]. It is uncertain whether the local/site reader should be included in the reading paradigm. We explore whether using locally- and centrally-determined endoscopic Mayo subscores [eMS] provide a reliable final assessment and whether the paradigm used has an impact on effect size.

Methods: eMS data from the TURANDOT [NCT01620255] study were used to retrospectively examine seven different reading paradigms (using the scores of local readers [LR], first central readers [CR1], second central readers [CR2], and various consensus reads [ConCR]) by assessing inter-rater reliabilities and their impact on the key study endpoint, endoscopic improvement.

Results: More than 40% of eMS scores between two trained central readers were discordant. Central readers had wide variability in scorings at baseline (intraclass correlation coefficient [ICC] of 0.475 [0.339, 0.610] for CR1 vs CR2). Centrally-read scores had variable concordance with LR (LR vs CR1 ICC 0.682 [0.575, 0.788], and LR vs CR2 ICC 0.526 [0.399, 0.653]). Reading paradigms with LR and CR which included a consensus, enhanced ICC estimates to >0.8. At Week 12, without the consensus reads, the CR1 vs CR2 ICC estimates were 0.775 [0.710, 0.841], and with consensus reads the ICC estimates were >0.9. Consensus-based approaches were most favourable to detect a treatment difference.

Conclusion: The ICC between the eMS of two trained and experienced central readers is unexpectedly low, which reinforces that currently used central reading processes are still associated with several weaknesses.

目的:监管机构主张在溃疡性结肠炎(UC)的临床试验中采用中央阅片。目前还不确定是否应将本地/现场阅片员纳入阅片范例。我们探讨了使用当地和中央确定的内镜梅奥评分[eMS]是否能提供可靠的最终评估,以及使用的范式是否会对效应大小产生影响。方法:使用TURANDOT [NCT01620255]研究的eMS数据回顾性地检查了七种不同的阅读范式(使用当地阅读者[LR]、第一中心阅读者[CR1]、第二中心阅读者[CR2]和各种共识阅读者[ConCR]的评分),评估了评分者间的可靠性及其对关键研究终点--内镜改善的影响:结果:超过 40% 的 eMS 评分在两名训练有素的中心阅读者之间不一致。中心阅读者的基线评分差异很大(CR1 与 CR2 的类内相关系数 [ICC] 为 0.475 [0.339, 0.610])。中心阅读得分与 LR 的一致性不一(LR vs CR1 ICC 0.682 [0.575, 0.788],LR vs CR2 ICC 0.526 [0.399, 0.653])。包含共识的 LR 和 CR 阅读范式可将 ICC 估计值提高到大于 0.8。第 12 周时,在没有共识读数的情况下,CR1 与 CR2 的 ICC 估计值为 0.775 [0.710, 0.841],而在有共识读数的情况下,ICC 估计值大于 0.9。基于共识的方法最有利于检测治疗差异:结论:两名训练有素、经验丰富的中心读片员的电子管理系统之间的 ICC 值出乎意料地低,这说明目前使用的中心读片流程仍存在一些缺陷。
{"title":"Alternative Endoscopy Reading Paradigms Determine Score Reliability and Effect Size in Ulcerative Colitis.","authors":"Walter Reinisch, Vivek Pradhan, Saira Ahmad, Zhen Zhang, Jeremy D Gale","doi":"10.1093/ecco-jcc/jjad134","DOIUrl":"10.1093/ecco-jcc/jjad134","url":null,"abstract":"<p><strong>Objective: </strong>Central reading of endoscopy is advocated by regulatory agencies for clinical trials in ulcerative colitis [UC]. It is uncertain whether the local/site reader should be included in the reading paradigm. We explore whether using locally- and centrally-determined endoscopic Mayo subscores [eMS] provide a reliable final assessment and whether the paradigm used has an impact on effect size.</p><p><strong>Methods: </strong>eMS data from the TURANDOT [NCT01620255] study were used to retrospectively examine seven different reading paradigms (using the scores of local readers [LR], first central readers [CR1], second central readers [CR2], and various consensus reads [ConCR]) by assessing inter-rater reliabilities and their impact on the key study endpoint, endoscopic improvement.</p><p><strong>Results: </strong>More than 40% of eMS scores between two trained central readers were discordant. Central readers had wide variability in scorings at baseline (intraclass correlation coefficient [ICC] of 0.475 [0.339, 0.610] for CR1 vs CR2). Centrally-read scores had variable concordance with LR (LR vs CR1 ICC 0.682 [0.575, 0.788], and LR vs CR2 ICC 0.526 [0.399, 0.653]). Reading paradigms with LR and CR which included a consensus, enhanced ICC estimates to >0.8. At Week 12, without the consensus reads, the CR1 vs CR2 ICC estimates were 0.775 [0.710, 0.841], and with consensus reads the ICC estimates were >0.9. Consensus-based approaches were most favourable to detect a treatment difference.</p><p><strong>Conclusion: </strong>The ICC between the eMS of two trained and experienced central readers is unexpectedly low, which reinforces that currently used central reading processes are still associated with several weaknesses.</p>","PeriodicalId":15547,"journal":{"name":"Journal of Crohns & Colitis","volume":null,"pages":null},"PeriodicalIF":8.3,"publicationDate":"2024-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10821708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10061509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Defining Comprehensive Disease Control for Use as a Treatment Target for Ulcerative Colitis in Clinical Practice: International Delphi Consensus Recommendations. 在临床实践中定义作为溃疡性结肠炎治疗目标的综合疾病控制:国际德尔菲共识建议》。
IF 8.3 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-01-27 DOI: 10.1093/ecco-jcc/jjad130
Stefan Schreiber, Silvio Danese, Axel Dignass, Eugeni Domènech, Massimo C Fantini, Marc Ferrante, Jonas Halfvarson, Ailsa Hart, Fernando Magro, Charlie W Lees, Salvo Leone, Marieke J Pierik, Michele Peters, Polly Field, Helen Fishpool, Laurent Peyrin-Biroulet

Background and aims: Treatment of ulcerative colitis [UC] requires a patient-centric definition of comprehensive disease control that considers improvements in aspects not typically captured by classical landmark trial endpoints. In an international initiative, we reviewed aspects of UC that affect patients and/or indicate mucosal inflammation, to achieve consensus on which aspects to combine in a definition of comprehensive disease control, using a modified Delphi process.

Methods: The Delphi panel comprised 12 gastroenterologists and one patient advocate. Two gastroenterologists were elected as chairs and did not vote. To inform statements, we asked 18 patients and the panel members about their experiences of remission and reviewed published literature. Panel members voted on statements anonymously in three rounds, with a live discussion before Round 3. Consensus was met if ≥67% of the panel agreed. Statements without consensus in Rounds 1 and 2 were revised or discarded after Round 3.

Results: The panel agreed to measure individual patient benefit using a definition of comprehensive disease control that combines aspects currently measured in trials [rectal bleeding, stool frequency, disease-related quality of life, endoscopy, histological inflammatory activity, inflammatory biomarkers, and corticosteroid use] with additional patient-reported symptoms [bowel urgency, abdominal pain, extraintestinal manifestations, fatigue, and sleep disturbance]. The panel agreed on scoring systems and thresholds for many aspects.

Conclusions: Using a robust methodology, we defined comprehensive disease control in UC. Next, we will combine the measurement and scoring of these aspects into a multicomponent tool and will adopt comprehensive disease control as a treatment target in clinical practice and trials.

背景和目的:溃疡性结肠炎(UC)的治疗需要一个以患者为中心的全面疾病控制定义,该定义应考虑到经典标志性试验终点通常无法捕捉到的方面的改善。在一项国际倡议中,我们回顾了溃疡性结肠炎对患者的影响和/或表明粘膜炎症的各个方面,以便通过改良的德尔菲过程就将哪些方面纳入全面疾病控制的定义达成共识:德尔菲小组由 12 位胃肠病学专家和一位患者权益倡导者组成。两名肠胃病学专家被选为主席,但不参与投票。为了给声明提供信息,我们向 18 名患者和小组成员询问了他们在缓解方面的经验,并查阅了已发表的文献。专家组成员分三轮对声明进行匿名投票,并在第三轮前进行现场讨论。如果≥67%的小组成员同意,则达成共识。第一轮和第二轮未达成共识的声明将在第三轮后进行修改或放弃:专家组同意使用全面疾病控制的定义来衡量患者的个体获益,该定义结合了目前在试验中衡量的方面[直肠出血、大便次数、疾病相关生活质量、内窥镜检查、组织学炎症活动、炎症生物标志物和皮质类固醇的使用]以及患者报告的其他症状[肠紧迫感、腹痛、肠道外表现、疲劳和睡眠障碍]。专家组就许多方面的评分系统和阈值达成了一致意见:结论:我们采用可靠的方法对 UC 疾病控制进行了全面定义。下一步,我们将把这些方面的测量和评分结合到一个多成分工具中,并在临床实践和试验中将全面疾病控制作为治疗目标。
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引用次数: 0
Regulatory Variants on the Leukocyte Immunoglobulin-Like Receptor Gene Cluster are Associated with Crohn's Disease and Interact with Regulatory Variants for TAP2. 白细胞免疫球蛋白样受体基因簇上的调节变异与克罗恩病有关,并与 TAP2 的调节变异相互作用。
IF 8 2区 医学 Q1 Medicine Pub Date : 2024-01-27 DOI: 10.1093/ecco-jcc/jjad127
Kwangwoo Kim, Shin Ju Oh, Junho Lee, Ayeong Kwon, Chae-Yeon Yu, Sangsoo Kim, Chang Hwan Choi, Sang-Bum Kang, Tae Oh Kim, Dong Il Park, Chang Kyun Lee

Background and aims: Crohn's disease [CD] has a complex polygenic aetiology with high heritability. There is ongoing effort to identify novel variants associated with susceptibility to CD through a genome-wide association study [GWAS] in large Korean populations.

Methods: Genome-wide variant data from 902 Korean patients with CD and 72 179 controls were used to assess the genetic associations in a meta-analysis with previous Korean GWAS results from 1621 patients with CD and 4419 controls. Epistatic interactions between CD-risk variants of interest were tested using a multivariate logistic regression model with an interaction term.

Results: We identified two novel genetic associations with the risk of CD near ZBTB38 and within the leukocyte immunoglobulin-like receptor [LILR] gene cluster [p < 5 × 10-8], with highly consistent effect sizes between the two independent Korean cohorts. CD-risk variants in the LILR locus are known quantitative trait loci [QTL] for multiple LILR genes, of which LILRB2 directly interacts with various ligands including MHC class I molecules. The LILR lead variant exhibited a significant epistatic interaction with CD-associated regulatory variants for TAP2 involved in the antigen presentation of MHC class I molecules [p = 4.11 × 10-4], showing higher CD-risk effects of the TAP2 variant in individuals carrying more risk alleles of the LILR lead variant (odds ratio [OR] = 0.941, p = 0.686 in non-carriers; OR = 1.45, p = 2.51 × 10-4 in single-copy carriers; OR = 2.38, p = 2.76 × 10-6 in two-copy carriers).

Conclusions: This study demonstrated that genetic variants at two novel susceptibility loci and the epistatic interaction between variants in LILR and TAP2 loci confer a risk of CD.

背景和目的:克罗恩病[CD]具有复杂的多基因遗传学,遗传率很高。目前,人们正努力通过在大量韩国人群中开展全基因组关联研究(GWAS)来确定与克罗恩病易感性相关的新型变异:方法:在一项荟萃分析中,利用来自 902 名韩国 CD 患者和 72 179 名对照者的全基因组变异数据,评估了与之前来自 1621 名 CD 患者和 4419 名对照者的韩国 GWAS 结果之间的遗传关联。使用带有交互作用项的多变量逻辑回归模型检验了感兴趣的 CD 风险变异之间的外显交互作用:结果:我们在ZBTB38附近和白细胞免疫球蛋白样受体[LILR]基因簇内发现了两个与CD风险相关的新遗传变异[p 结论:该研究证明了两个与CD风险相关的遗传变异:这项研究表明,两个新的易感基因位点上的遗传变异以及 LILR 和 TAP2 位点上的变异之间的表观相互作用会带来 CD 风险。
{"title":"Regulatory Variants on the Leukocyte Immunoglobulin-Like Receptor Gene Cluster are Associated with Crohn's Disease and Interact with Regulatory Variants for TAP2.","authors":"Kwangwoo Kim, Shin Ju Oh, Junho Lee, Ayeong Kwon, Chae-Yeon Yu, Sangsoo Kim, Chang Hwan Choi, Sang-Bum Kang, Tae Oh Kim, Dong Il Park, Chang Kyun Lee","doi":"10.1093/ecco-jcc/jjad127","DOIUrl":"10.1093/ecco-jcc/jjad127","url":null,"abstract":"<p><strong>Background and aims: </strong>Crohn's disease [CD] has a complex polygenic aetiology with high heritability. There is ongoing effort to identify novel variants associated with susceptibility to CD through a genome-wide association study [GWAS] in large Korean populations.</p><p><strong>Methods: </strong>Genome-wide variant data from 902 Korean patients with CD and 72 179 controls were used to assess the genetic associations in a meta-analysis with previous Korean GWAS results from 1621 patients with CD and 4419 controls. Epistatic interactions between CD-risk variants of interest were tested using a multivariate logistic regression model with an interaction term.</p><p><strong>Results: </strong>We identified two novel genetic associations with the risk of CD near ZBTB38 and within the leukocyte immunoglobulin-like receptor [LILR] gene cluster [p < 5 × 10-8], with highly consistent effect sizes between the two independent Korean cohorts. CD-risk variants in the LILR locus are known quantitative trait loci [QTL] for multiple LILR genes, of which LILRB2 directly interacts with various ligands including MHC class I molecules. The LILR lead variant exhibited a significant epistatic interaction with CD-associated regulatory variants for TAP2 involved in the antigen presentation of MHC class I molecules [p = 4.11 × 10-4], showing higher CD-risk effects of the TAP2 variant in individuals carrying more risk alleles of the LILR lead variant (odds ratio [OR] = 0.941, p = 0.686 in non-carriers; OR = 1.45, p = 2.51 × 10-4 in single-copy carriers; OR = 2.38, p = 2.76 × 10-6 in two-copy carriers).</p><p><strong>Conclusions: </strong>This study demonstrated that genetic variants at two novel susceptibility loci and the epistatic interaction between variants in LILR and TAP2 loci confer a risk of CD.</p>","PeriodicalId":15547,"journal":{"name":"Journal of Crohns & Colitis","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10256155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
ECCO Guidelines on Extraintestinal Manifestations in Inflammatory Bowel Disease. ECCO 炎症性肠病肠外表现指南。
IF 8 2区 医学 Q1 Medicine Pub Date : 2024-01-27 DOI: 10.1093/ecco-jcc/jjad108
Hannah Gordon, Johan Burisch, Pierre Ellul, Konstantinos Karmiris, Konstantinos Katsanos, Mariangela Allocca, Giorgos Bamias, Manuel Barreiro-de Acosta, Tasanee Braithwaite, Thomas Greuter, Catherine Harwood, Pascal Juillerat, Triana Lobaton, Ulf Müller-Ladner, Nurulamin Noor, Gianluca Pellino, Edoardo Savarino, Christoph Schramm, Alessandra Soriano, Jürgen Michael Stein, Mathieu Uzzan, Patrick F van Rheenen, Stephan R Vavricka, Maurizio Vecchi, Stephane Zuily, Torsten Kucharzik
{"title":"ECCO Guidelines on Extraintestinal Manifestations in Inflammatory Bowel Disease.","authors":"Hannah Gordon, Johan Burisch, Pierre Ellul, Konstantinos Karmiris, Konstantinos Katsanos, Mariangela Allocca, Giorgos Bamias, Manuel Barreiro-de Acosta, Tasanee Braithwaite, Thomas Greuter, Catherine Harwood, Pascal Juillerat, Triana Lobaton, Ulf Müller-Ladner, Nurulamin Noor, Gianluca Pellino, Edoardo Savarino, Christoph Schramm, Alessandra Soriano, Jürgen Michael Stein, Mathieu Uzzan, Patrick F van Rheenen, Stephan R Vavricka, Maurizio Vecchi, Stephane Zuily, Torsten Kucharzik","doi":"10.1093/ecco-jcc/jjad108","DOIUrl":"10.1093/ecco-jcc/jjad108","url":null,"abstract":"","PeriodicalId":15547,"journal":{"name":"Journal of Crohns & Colitis","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9668754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Discontinuation of Anti-Tumour Necrosis Factor Therapy in Patients with Perianal Fistulizing Crohn's Disease: Individual Participant Data Meta-Analysis of 309 Patients from 12 Studies. 肛周瘘性克罗恩病患者停用抗肿瘤坏死因子疗法:对 12 项研究中 309 名患者的个人参与者数据进行 Meta 分析。
IF 8.3 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-01-27 DOI: 10.1093/ecco-jcc/jjad118
Sebastiaan Ten Bokkel Huinink, Doranne Thomassen, Ewout W Steyerberg, Renske W M Pauwels, Maria J Casanova, Guillaume Bouguen, Joyce W Y Mak, Tamas Molnár, Alan J Lobo, Jacob B Seidelin, Aurelien Amiot, Geert D'Haens, Pauline Rivière, Luisa Guidi, Renata Bor, Wei-Chen Lin, Laurent Peyrin-Biroulet, Javier P Gisbert, C Janneke van der Woude, Annemarie C de Vries

Background: The risk of relapse after anti-tumour necrosis factor [TNF] therapy discontinuation in Crohn's disease patients with perianal fistulas [pCD] is unclear. We aimed to assess this risk.

Methods: A systematic literature search was conducted to identify cohort studies on the incidence of relapse following anti-TNF discontinuation in pCD patients. Individual participant data were requested from the original study cohorts. Inclusion criteria were age ≥16 years, pCD as a (co)indication for start of anti-TNF therapy, more than three doses, and remission of luminal and pCD at anti-TNF discontinuation. The primary outcome was the cumulative incidence of CD relapse using Kaplan-Meier estimates. Secondary outcomes included response to re-treatment and risk factors associated with relapse as assessed by Cox regression analysis.

Results: In total, 309 patients from 12 studies in ten countries were included. The median duration of anti-TNF treatment was 14 months [interquartile range 5.8-32.5]. Most patients were treated for pCD without active luminal disease [89%], received first-line anti-TNF therapy [87%], and continued immunomodulatory therapy following anti-TNF discontinuation [78%]. The overall cumulative incidence of relapse was 36% (95% confidence interval [CI] 25-48%) and 42% [95% CI 32-53%] at 1 and 2 years after anti-TNF discontinuation, respectively. Risk factors for relapse included smoking (hazard ratio [HR] 1.5 [1.0, 2.1]) and history of proctitis (HR 1.7 [1.1, 2.5]). The overall re-treatment response rate was 82%.

Conclusions: This individual participant data meta-analysis, on predominantly patients with pCD without active luminal disease and first-line anti-TNF therapy, shows that over half of patients remain in remission 2 years after anti-TNF discontinuation. Therefore, anti-TNF discontinuation may be considered in this subgroup.

背景:有肛周瘘管[pCD]的克罗恩病患者停止抗肿瘤坏死因子[TNF]治疗后的复发风险尚不明确。我们旨在评估这一风险:我们进行了系统性文献检索,以确定有关 pCD 患者停用抗 TNF 后复发率的队列研究。我们要求原始队列研究提供参与者的个人数据。纳入标准为年龄≥16岁、pCD为开始抗TNF治疗的(共同)指征、服用3次以上剂量、停用抗TNF时管腔和pCD缓解。主要结果是采用卡普兰-梅耶估计法计算的CD复发累积发生率。次要结果包括对再治疗的反应以及通过 Cox 回归分析评估的与复发相关的风险因素:共纳入了来自10个国家12项研究的309名患者。抗肿瘤坏死因子治疗的中位持续时间为14个月[四分位数间距为5.8-32.5]。大多数患者接受的是无活动性管腔疾病的pCD治疗[89%],接受的是一线抗TNF治疗[87%],并在停用抗TNF后继续接受免疫调节治疗[78%]。在停用抗-TNF 1 年和 2 年后,总的累积复发率分别为 36%(95% 置信区间 [CI] 25-48%)和 42% [95% CI 32-53%]。复发的风险因素包括吸烟(危险比 [HR] 1.5 [1.0, 2.1])和直肠炎病史(HR 1.7 [1.1, 2.5])。总体再治疗反应率为82%:这项个体参与者数据荟萃分析主要针对无活动性管腔疾病的 pCD 患者和一线抗肿瘤坏死因子治疗,结果表明,超过一半的患者在停用抗肿瘤坏死因子 2 年后病情仍在缓解。因此,该亚组患者可考虑停用抗肿瘤坏死因子治疗。
{"title":"Discontinuation of Anti-Tumour Necrosis Factor Therapy in Patients with Perianal Fistulizing Crohn's Disease: Individual Participant Data Meta-Analysis of 309 Patients from 12 Studies.","authors":"Sebastiaan Ten Bokkel Huinink, Doranne Thomassen, Ewout W Steyerberg, Renske W M Pauwels, Maria J Casanova, Guillaume Bouguen, Joyce W Y Mak, Tamas Molnár, Alan J Lobo, Jacob B Seidelin, Aurelien Amiot, Geert D'Haens, Pauline Rivière, Luisa Guidi, Renata Bor, Wei-Chen Lin, Laurent Peyrin-Biroulet, Javier P Gisbert, C Janneke van der Woude, Annemarie C de Vries","doi":"10.1093/ecco-jcc/jjad118","DOIUrl":"10.1093/ecco-jcc/jjad118","url":null,"abstract":"<p><strong>Background: </strong>The risk of relapse after anti-tumour necrosis factor [TNF] therapy discontinuation in Crohn's disease patients with perianal fistulas [pCD] is unclear. We aimed to assess this risk.</p><p><strong>Methods: </strong>A systematic literature search was conducted to identify cohort studies on the incidence of relapse following anti-TNF discontinuation in pCD patients. Individual participant data were requested from the original study cohorts. Inclusion criteria were age ≥16 years, pCD as a (co)indication for start of anti-TNF therapy, more than three doses, and remission of luminal and pCD at anti-TNF discontinuation. The primary outcome was the cumulative incidence of CD relapse using Kaplan-Meier estimates. Secondary outcomes included response to re-treatment and risk factors associated with relapse as assessed by Cox regression analysis.</p><p><strong>Results: </strong>In total, 309 patients from 12 studies in ten countries were included. The median duration of anti-TNF treatment was 14 months [interquartile range 5.8-32.5]. Most patients were treated for pCD without active luminal disease [89%], received first-line anti-TNF therapy [87%], and continued immunomodulatory therapy following anti-TNF discontinuation [78%]. The overall cumulative incidence of relapse was 36% (95% confidence interval [CI] 25-48%) and 42% [95% CI 32-53%] at 1 and 2 years after anti-TNF discontinuation, respectively. Risk factors for relapse included smoking (hazard ratio [HR] 1.5 [1.0, 2.1]) and history of proctitis (HR 1.7 [1.1, 2.5]). The overall re-treatment response rate was 82%.</p><p><strong>Conclusions: </strong>This individual participant data meta-analysis, on predominantly patients with pCD without active luminal disease and first-line anti-TNF therapy, shows that over half of patients remain in remission 2 years after anti-TNF discontinuation. Therefore, anti-TNF discontinuation may be considered in this subgroup.</p>","PeriodicalId":15547,"journal":{"name":"Journal of Crohns & Colitis","volume":null,"pages":null},"PeriodicalIF":8.3,"publicationDate":"2024-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10821706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9774570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Impact of Concomitant 5-Aminosalicylic Acid Therapy on Vedolizumab Efficacy and Safety in Inflammatory Bowel Disease: Post Hoc Analyses of Clinical Trial Data. 炎症性肠病患者同时接受 5-氨基水杨酸治疗对维多珠单抗疗效和安全性的影响:临床试验数据的事后分析。
IF 8 2区 医学 Q1 Medicine Pub Date : 2023-12-30 DOI: 10.1093/ecco-jcc/jjad113
Ryan C Ungaro, Harisha Kadali, Wenwen Zhang, Shashi Adsul, Walter Reinisch

Background and aims: The benefit of continuing 5-aminosalicylic acid [5-ASA] treatment when escalating to advanced therapies in patients with inflammatory bowel disease [IBD] is unclear. Vedolizumab is a gut-selective monoclonal anti-α4β7-integrin antibody used to treat moderate to severe IBD. Clinical trial data were analysed post hoc to assess the impact of 5-ASA co-treatment on vedolizumab efficacy and safety in patients with IBD.

Methods: Data were analysed from patients aged 18-80 years with moderate to severe ulcerative colitis [UC]/Crohn's disease [CD] receiving intravenous [IV]/subcutaneous [SC] vedolizumab. Efficacy data were from four studies [GEMINI 1 and 2 and VISIBLE 1 and 2]; safety data were from seven studies [GEMINI 1‒3 and long-term, VISIBLE 1, 2, and open-label extension]. The impact of 5-ASA co-treatment on clinical and endoscopic outcomes at Weeks 6 and 52 was assessed using multivariate analysis (adjusted odds ratios [aORs] with 95% confidence intervals [CIs]).

Results: There were no significant differences in UC clinical remission [Mayo score ≤2, no subscore >1] rates with vs without 5-ASA at Week 6 [20.7% vs 20.4%, respectively; aOR 0.77, 95% CI 0.43-1.38] or at Week 52 [45.1% vs 40.6%; aOR 1.14, 0.70-1.86], and in CD clinical remission [CD activity index score ≤150] rates at Week 6 [41.4% vs 35.1%; 1.26, 0.86-1.85] or at Week 52 [49.6% vs 37.8%; 1.35, 0.91-1.99]. The incidence of enteric and all infections in vedolizumab IV/SC-treated patients was low with and without 5-ASA.

Conclusion: Continuation of concomitant oral 5-ASA after starting vedolizumab had no significant impact on clinical and endoscopic outcomes.

Clinical trial identifiers: GEMINI 1: NCT00783718, EudraCT 2008-002782-32; GEMINI 2: NCT00783692, EudraCT 2008-00278-33; GEMINI 3: NCT01224171, EudraCT 2009-016488-12; GEMINI long-term safety study: NCT00790933, EudraCT 2008-002784-14; VISIBLE 1: NCT02611830, EudraCT 2015-000480-14; VISIBLE 2: NCT02611817, EudraCT 2015-000481-58; VISIBLE open-label extension: NCT02620046, EudraCT 2015-000482-31.

背景和目的:炎症性肠病[IBD]患者在升级到晚期疗法时继续接受5-氨基水杨酸[5-ASA]治疗的益处尚不明确。维多珠单抗是一种肠道选择性单克隆抗α4β7整合素抗体,用于治疗中度至重度IBD。我们对临床试验数据进行了事后分析,以评估5-ASA联合治疗对维多珠单抗在IBD患者中疗效和安全性的影响:分析了18-80岁中重度溃疡性结肠炎[UC]/克罗恩病[CD]患者接受静脉注射[IV]/皮下注射[SC]维多珠单抗治疗的数据。疗效数据来自四项研究[GEMINI 1和2以及VISIBLE 1和2];安全性数据来自七项研究[GEMINI 1-3和长期研究、VISIBLE 1、2以及开放标签扩展研究]。采用多变量分析(调整后的几率比[aORs],95%置信区间[CIs])评估了5-ASA联合治疗对第6周和第52周的临床和内镜结果的影响:第 6 周时,使用 5-ASA 与不使用 5-ASA 的 UC 临床缓解率[梅奥评分≤2,无子项评分>1]无明显差异[分别为 20.7% vs 20.4%;aOR 0.77,95% CI 0.43-1.38],第 52 周时也无明显差异[45.1% vs 40.6%;aOR 0.77,95% CI 0.43-1.38]。1%对40.6%;aOR 1.14,0.70-1.86],以及第6周[41.4%对35.1%;1.26,0.86-1.85]或第52周[49.6%对37.8%;1.35,0.91-1.99]的CD临床缓解率[CD活动指数评分≤150]。在使用和不使用5-ASA的情况下,维多珠单抗IV/SC治疗患者的肠道感染和所有感染的发生率都很低:结论:开始使用维多珠单抗后继续同时口服5-ASA对临床和内镜结果没有显著影响:GEMINI 1:NCT00783718,EudraCT 2008-002782-32;GEMINI 2:NCT00783692,EudraCT 2008-00278-33;GEMINI 3:NCT01224171,EudraCT 2009-016488-12;GEMINI长期安全性研究:NCT00790933,EudraCT 2008-002784-14;VISIBLE 1:NCT02611830, EudraCT 2015-000480-14;VISIBLE 2:NCT02611817, EudraCT 2015-000481-58;VISIBLE 开放标签扩展:NCT02620046,EudraCT 2015-000482-31。
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引用次数: 0
Declining Trends of Reoperations and Disease Behaviour Progression in Crohn's Disease over Different Therapeutic Eras-A Prospective, Population-Based Study from Western Hungary between 1977-2020, Data from the Veszprem Cohort. 不同治疗时期克罗恩病再手术和疾病行为进展的下降趋势--1977-2020 年匈牙利西部的前瞻性人群研究,来自 Veszprem 队列的数据。
IF 8 2区 医学 Q1 Medicine Pub Date : 2023-12-30 DOI: 10.1093/ecco-jcc/jjad117
Lorant Gonczi, Laszlo Lakatos, Petra A Golovics, Akos Ilias, Tunde Pandur, Gyula David, Zsuzsanna Erdelyi, Istvan Szita, Alex Al Khoury, Peter L Lakatos

Background and aims: Few population-based studies have investigated long-term surgery rates for Crohn's disease [CD]. Our aim was to analyse disease progression and surgery rates in a population-based cohort over different therapeutic eras, based on the time of diagnosis: cohort-A [1977-1995], cohort-B [1996-2008], and cohort-C [2009-2018].

Methods: A total of 946 incident CD patients were analysed (male/female: 496/450; median age at diagnosis: 28 years [y]; interquartile range [IQR]: 22-40]). Patient inclusion lasted between 1977 and 2018. Immunomodulators have become widespread in Hungary since the mid-1990s and biologic therapies since 2008. Patients were followed prospectively, with both in-hospital and outpatient records reviewed regularly.

Results: The probability of disease behaviour progression from inflammatory [B1] to stenosing or penetrating phenotype [B2/B3] significantly decreased (27.1 ± 5.3%/21.5 ± 2.5%/11.3 ± 2.2% in cohorts A/B/C, respectively, after 5 years; 44.3 ± 5.9%/30.6 ± 2.8%/16.1 ± 2.9% after 10 years, respectively; [pLogRank <0.001]). The probability of first resective surgery between cohorts A/B/C were 33.3 ± 3.8%/26.5 ± 2.1%/28.1 ± 2.4%, respectively, after 5 years; 46.1 ± 4.1%/32.6 ± 2.2%/33.0 ± 2.7% after 10 years, respectively; and 59.1 ± 4.0%/41.4 ± 2.6% [cohorts A/B] after 20 years. There was a significant decrease in first resective surgery risk between cohorts A and B [plog rank = 0.002]; however, no further decrease between cohorts B and C [plog rank = 0.665]. The cumulative probability of re-resection in cohorts A/B/C was decreasing over time (17.3 ± 4.1%/12.6 ± 2.6%/4.7 ± 2.0%, respectively, after 5 years [plog rank = 0.001]).

Conclusion: We report a continuous decline in reoperation rates and disease behaviour progression in CD over time, with the lowest values in the biologic era. In contrast, there was no further decrease in the probability of first major resective surgery after the immunosuppressive era.

背景和目的:很少有基于人群的研究调查了克罗恩病 [CD] 的长期手术率。我们的目的是根据诊断时间分析不同治疗时期人群队列中的疾病进展和手术率:队列-A [1977-1995年]、队列-B [1996-2008年]和队列-C [2009-2018年]:方法:共分析了 946 例 CD 患者(男性/女性:496/450;诊断时的中位年龄:28 岁;四分位数间距 [IQR]:22-40])。患者纳入时间为 1977 年至 2018 年。自 20 世纪 90 年代中期以来,免疫调节剂在匈牙利开始广泛使用,而生物疗法则自 2008 年开始使用。对患者进行了前瞻性随访,并定期审查院内和门诊记录:结果:从炎性表型[B1]发展为狭窄或穿透性表型[B2/B3]的概率显著下降(5年后,A/B/C组分别为27.1±5.3%/21.5±2.5%/11.3±2.2%;10年后分别为44.3±5.9%/30.6±2.8%/16.1±2.9%;[pLogRank 结论:我们的报告显示,随着时间的推移,CD 的再手术率和疾病行为进展持续下降,生物制剂时代的数值最低。相比之下,进入免疫抑制时代后,首次大面积切除手术的概率没有进一步下降。
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引用次数: 0
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Journal of Crohns & Colitis
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