Predicting disease flare and treatment response in inflammatory bowel disease

预测炎症性肠病的疾病发作和治疗反应

• 批准号: MR/S034919/1
• 负责人: Charles Lees
• 金额: $ 155.59万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS034919%2F1
• 关键词: Predicting; disease; flare; treatment; response

BACKGROUND: Crohn's disease and ulcerative colitis are the common forms of inflammatory bowel disease (IBD) affecting up to 1 in 100 people in the Western world, with some of the highest prevalence rates in Scotland (>1.0%). Incidence rates are increasing sharply in the previously undeveloped world driven by a Western lifestyle. IBD typically manifests in adolescence / early adulthood with disturbed bowel function, a robust inflammatory response, systemic upset, psycho-social disturbance and substantial health-economic burden. Recent years have seen massive biotech / pharma investment in IBD with multiple different drug modalities now approved for use. However, remission rates are hitting a ceiling at 1 year of 30-40%, and no reliable biomarkers exist to aid with drug positioning. Management of IBD is further complicated by our inability to prognosticate on treatment response or disease progression.IBD develops in genetically susceptible individuals when there is a dysregulated mucosal immune response to a gut microbiota altered by Western diet and other environmental stimuli. A decade of gene discovery has yielded >250 susceptibility loci and multiple druggable targets. But it has not provided meaningful insights into disease phenotype or natural history. Having made substantial contributions to the UK and International IBD Genetics consortia, I have seen both the success of large sample sizes and the limitations of retrospective data capture in this highly complex and heterogenous disease. More recently, whilst working as a full-time NHS gastroenterologist, I have developed a programme of work to facilitate prospective biological and clinical data capture, both cost-effectively and at scale (recruiting 120-150 patients pcm). I now plan to expand this work to address a series of questions of fundamental importance to improving the outcomes of people with IBD.RESEARCH QUESTIONS:1. What aspects of disease phenotype, diet, lifestyle, genetics and the gut microbiota contribute to a) disease flare, b) disease progression & c) treatment response in IBD?2. How can we stratify patients based on disease biology and risk of progression?3. Based on this, how can we intervene to improve outcomes?4. Can we utilise disruptive digital healthcare technology to collect research data at scale, develop symptom and flare tracking devices for patientsRECENT WORK: I have established the PREdiCCt study (www.predicct.co.uk) which aims to establish the cause of disease flare in IBD. PREdiCCt is recruiting 3100 people with IBD (n=1041 on 03.10.18). Patients are recruited in clinical remission, with biomarker stratification (CRP & faecal calprotectin) and followed to disease flare. Baseline data is collected via 1. EMR extract; 2. Oshi patient app (PROs, lifestyle & environment); 3. 4-day weighed food diary; 4. stool collection on day 4; 5. a full blood panel; & 6. whole-genome (WGS) & metabolomic sequencing at Sanger Institute. The Oshi app (developed as the PREdiCCt data collection tool) then collects regular patient reported outcomes (q1m). PLANNED WORK: The PREdiCCt cohort will be consolidated and extended beyond 24 months and incorporate longitudinal sampling of dietary, lifestyle, psychological and inflammatory parameters with 3 monthly stool sampling for calprotectin and microbiome sequencing. It will be expanded to include additional patients from the UK; in N America users of the Oshi consumer App will be directly targeted for recruitment. This will significantly enhance the statistical power of the study and provide validation of innovative symptom tracking tools. The PREdiCCt-ACTIVE cohort will then be established by recruiting patients before they start a new treatment for their IBD, and followed to treatment response / non-response. A detailed molecular phenotyping experiment will be performed in a sub-group. In the process I will become a full-time academic gastroenterologist to lead this work and IBD in the UK.

背景技术背景：克罗恩病和溃疡性结肠炎是炎症性肠病（IBD）的常见形式，在西方世界影响高达1/100的人，其中苏格兰的患病率最高（>1.0%）。在西方生活方式的推动下，以前不发达的世界的发病率急剧上升。IBD通常在青春期/成年早期表现为肠功能紊乱、强烈的炎症反应、全身性不适、心理社会障碍和巨大的健康经济负担。近年来，生物技术/制药公司对IBD进行了大量投资，目前已批准使用多种不同的药物形式。然而，缓解率在1年达到30- 40%的上限，并且没有可靠的生物标志物来帮助药物定位。IBD的管理由于我们无法预测治疗反应或疾病进展而进一步复杂化。IBD在遗传易感个体中发展，当对西方饮食和其他环境刺激改变的肠道微生物群的粘膜免疫反应失调时。十年的基因发现已经产生了超过250个易感基因位点和多种药物靶点。但它并没有对疾病表型或自然史提供有意义的见解。在为英国和国际IBD遗传学联盟做出了重大贡献之后，我看到了大样本量的成功和这种高度复杂和异质性疾病的回顾性数据采集的局限性。最近，在担任全职NHS胃肠病学家的同时，我制定了一项工作计划，以促进前瞻性的生物和临床数据采集，既具有成本效益又具有规模（每厘米招募120-150名患者）。我现在计划扩展这项工作，以解决一系列对改善IBD患者预后具有根本重要性的问题。研究问题：1.疾病表型、饮食、生活方式、遗传学和肠道微生物群的哪些方面有助于a）疾病爆发，B）疾病进展和c）IBD的治疗反应？2.我们如何根据疾病生物学和进展风险对患者进行分层？3.在此基础上，我们如何进行干预以改善结果？4.我们能否利用颠覆性的数字医疗技术来大规模收集研究数据，为患者开发症状和爆发跟踪设备？最近的工作：我已经建立了PREdiCCt研究（www.predicct.co.uk），旨在确定IBD疾病爆发的原因。PREdiCCt正在招募3100名IBD患者（2018年10月3日，n=1041）。招募临床缓解的患者，进行生物标志物分层（CRP和粪便钙卫蛋白），并随访至疾病发作。通过1收集基线数据。EMR提取物; 2. Oshi患者应用程序（PRO，生活方式和环境）; 3. 4-日称重食物日记; 4.第4天收集粪便; 5.全套血液检查; 6.桑格研究所的全基因组（WGS）和代谢组学测序。Oshi应用程序（作为PREdiCCt数据收集工具开发）然后收集定期患者报告的结局（q1 m）。计划工作：PREdiCCt队列将合并并延长至24个月以上，并纳入饮食、生活方式、心理和炎症参数的纵向采样，以及3个月一次的粪便采样，用于钙卫蛋白和微生物组测序。它将扩大到包括来自英国的更多患者;在北美，Oshi消费者应用程序的用户将直接成为招募的目标。这将显著增强研究的统计能力，并为创新的症状跟踪工具提供验证。然后将通过在患者开始IBD新治疗前招募患者，并随访至治疗应答/无应答，建立PREdiCCt-ACTIVE队列。将在亚组中进行详细的分子表型实验。在这个过程中，我将成为一名全职学术胃肠病学家，领导这项工作和英国的IBD。

项目成果

COVID-19 vaccine-induced antibody and T-cell responses in immunosuppressed patients with inflammatory bowel disease after the third vaccine dose (VIP): a multicentre, prospective, case-control study.

• DOI: 10.1016/s2468-1253(22)00274-6
• 发表时间: 2022-11
• 期刊: LANCET GASTROENTEROLOGY & HEPATOLOGY
• 影响因子: 35.7
• 作者: Alexander, James L.;Liu, Zhigang;Sandoval, Diana Munoz;Reynolds, Catherine;Ibraheim, Hajir;Anandabaskaran, Sulak;Saifuddin, Aamir;Seoane, Rocio Castro;Anand, Nikhil;Nice, Rachel;Bewshea, Claire;D'Mello, Andrea;Constable, Laura;Jones, Gareth R.;Balarajah, Sharmili;Fiorentino, Francesca;Sebastian, Shaji;Irving, Peter M.;Hicks, Lucy C.;Williams, Horace R. T.;Kent, Alexandra J.;Linger, Rachel;Parkes, Miles;Kok, Klaartje;Patel, Kamal V.;Teare, Julian P.;Altmann, Daniel M.;Goodhand, James R.;Hart, Ailsa L.;Lees, Charlie W.;Boyton, Rosemary J.;Kennedy, Nicholas A.;Ahmad, Tariq;Powell, Nick
• 通讯作者: Powell, Nick

Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease: results from the IMmunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study.

• DOI: 10.1111/apt.17170
• 发表时间: 2022-10
• 期刊: ALIMENTARY PHARMACOLOGY & THERAPEUTICS
• 影响因子: 7.6
• 作者: Chanchlani, Neil;Lin, Simeng;Auth, Marcus K.;Lee, Chai Leng;Robbins, Helena;Looi, Shi;Murugesan, Senthil, V;Riley, Tom;Preston, Cathryn;Stephenson, Sophie;Cardozo, Wendy;Sonwalkar, Sunil A.;Allah-Ditta, Mohammed;Mansfield, Lynne;Durai, Dharmaraj;Baker, Mark;London, Ian;London, Emily;Gupta, Sanjay;Di Mambro, Alex;Murphy, Aisling;Gaynor, Edward;Jones, Kelsey D. J.;Claridge, Andrew;Sebastian, Shaji;Ramachandran, Sankaranarayanan;Selinger, Christian P.;Borg-Bartolo, Simon P.;Knight, Paul;Sprakes, Michael B.;Burton, Julie;Kane, Patricia;Lupton, Stephanie;Fletcher, Aimee;Gaya, Daniel R.;Colbert, Roghan;Seenan, John Paul;MacDonald, Jonathan;Lynch, Lucy;McLachlan, Iain;Shields, Stephanie;Hansen, Richard;Gervais, Lisa;Jere, Mwansa;Akhtar, Muhammad;Black, Karen;Henderson, Paul;Russell, Richard K.;Lees, Charlie W.;Derikx, Lauranne A. A. P.;Lockett, Melanie;Betteridge, Frederica;De Silva, Aminda;Hussenbux, Arif;Beckly, John;Bendall, Oliver;Hart, James W.;Thomas, Amanda;Hamilton, Ben;Gordon, Claire;Chee, Desmond;McDonald, Timothy J.;Nice, Rachel;Parkinson, Marian;Gardner-Thorpe, Helen;Butterworth, Jeff R.;Javed, Asima;Al-Shakhshir, Sarah;Yadagiri, Rekha;Maher, Sebrene;Pollok, Richard C. G.;Ng, Tze;Appiahene, Priscilla;Donovan, Fiona;Lok, James;Chandy, Rajiv;Jagdish, Reema;Baig, Daniyal;Mahmood, Zahid;Marsh, Liane;Moss, Allison;Abdulgader, Amin;Kitchin, Angus;Walker, Gareth J.;George, Becky;Lim, Yuen-Hui;Gulliver, James;Bloom, Stuart;Theaker, Holly;Carlson, Sean;Cummings, J. R. Fraser;Livingstone, Robert;Beale, Amanda;Carter, Josiah O.;Bell, Andrew;Coulter, Archibald;Snook, Jonathon;Stone, Helen;Kennedy, Nicholas A.;Goodhand, James R.;Ahmad, Tariq
• 通讯作者: Ahmad, Tariq

The Global Incidence of Peptic Ulcer Disease Is Decreasing Since the Turn of the 21st Century: A Study of the Organisation for Economic Co-Operation and Development (OECD)

• DOI: 10.14309/ajg.0000000000001843
• 发表时间: 2022-09-01
• 期刊: AMERICAN JOURNAL OF GASTROENTEROLOGY
• 影响因子: 9.8
• 作者: Azhari, Hassan;King, James A.;Kaplan, Gilaad G.
• 通讯作者: Kaplan, Gilaad G.

Adalimumab and Infliximab Impair SARS-CoV-2 Antibody Responses: Results from a Therapeutic Drug Monitoring Study in 11 422 Biologic-Treated Patients.

• DOI: 10.1093/ecco-jcc/jjab153
• 发表时间: 2022-03-14
• 期刊: Journal of Crohn's & colitis
• 作者: Chanchlani N;Lin S;Chee D;Hamilton B;Nice R;Arkir Z;Bewshea C;Cipriano B;Derikx LAAP;Dunlop A;Greathead L;Griffiths RL;Ibraheim H;Kelleher P;Kok KB;Lees CW;MacDonald J;Sebastian S;Smith PJ;McDonald TJ;Irving PM;Powell N;Kennedy NA;Goodhand JR;Ahmad T
• 通讯作者: Ahmad T

SARS-CoV-2 vaccination for patients with inflammatory bowel disease: a British Society of Gastroenterology Inflammatory Bowel Disease section and IBD Clinical Research Group position statement.

• DOI: 10.1016/s2468-1253(21)00024-8
• 发表时间: 2021-03
• 期刊: The lancet. Gastroenterology & hepatology
• 作者: Alexander JL;Moran GW;Gaya DR;Raine T;Hart A;Kennedy NA;Lindsay JO;MacDonald J;Segal JP;Sebastian S;Selinger CP;Parkes M;Smith PJ;Dhar A;Subramanian S;Arasaradnam R;Lamb CA;Ahmad T;Lees CW;Dobson L;Wakeman R;Iqbal TH;Arnott I;Powell N;Inflammatory Bowel Disease section of the British Society of Gastroenterology and the the Inflammatory Bowel Disease Clinical Research Group
• 通讯作者: Inflammatory Bowel Disease section of the British Society of Gastroenterology and the the Inflammatory Bowel Disease Clinical Research Group