Efficacy and Safety of Elective Switching from Intravenous to Subcutaneous Infliximab [CT-P13]: A Multicentre Cohort Study.

BACKGROUND: Intravenous [IV] infliximab is a well-established therapy for inflammatory bowel diseases [IBD] patients. A subcutaneous [SC] formulation of infliximab [CT-P13] has recently been shown to be as effective as IV infliximab after two doses of IV induction in a randomised trial, but there are no data to support elective switching of patients on maintenance IV infliximab therapy. We aimed to assess the effectiveness of an elective switching programme to SC CT-P13 in patients treated with IV infliximab. METHODS: Patients on established maintenance IV infliximab, who switched to SC CT-P13, were included in this retrospective multicentre cohort study. Disease activity was monitored serially with the Harvey-Bradshaw Index [HBI] for Crohn's disease [CD] and the Simple Clinical Colitis Activity Index [SCCAI] for ulcerative colitis (UC) for up to 12 months at months 3, 6, and 12. Faecal calprotectin [FC] and C-reactive protein [CRP] were recorded at baseline and follow-up, if available. Infliximab trough levels were measured prior to switch and at months 3, 6, and 12 following switch. The primary outcome measure was treatment persistence at latest follow-up. Secondary outcome measures included infliximab pharmacokinetics [PK], safety, need for corticosteroid rescue therapy, and need for surgery. RESULTS: We included 181 patients, of whom 115 [63.5%] had CD. The majority [72.4%] were on 8-weekly dosing of intravenous infliximab prior to switching, and more than half [59.1%] were on concomitant immunomodulatory therapy. The majority of patients (CD: 106, 92.2%; UC: 46, 76.7%; and IBD unclassified [IBD-U]: 5, 83.3%) were in clinical remission. Treatment persistence rate was high [n = 167, 92.3%] and only 14 patients [7.7%] stopped treatment during the follow-up period. There was no significant difference between baseline and repeat measurements at 3, 6, or 12 months for HBI, SCCAI, CRP, or FC. Of the total cohort, 25 patients (13.8%) had perianal CD. Of these, only two patients [8%] had worsening of perianal CD and required antibiotic therapy and further examination under anaesthesia [EUA]. Both these patients also switched back to intravenous infliximab. Median infliximab level increased from a baseline of 8.9 µg/dl [range 0.4-16] to 16.0 µg/dl [range 2.3-16, p <0.001] at 3 months. Serum levels stayed stable at 6 months [median 16 µg/dl, range 0.3-17.2] and 12 months [median 16 µg/dl, range 0.3-19.1, both p <0.001 compared with baseline]. Among the variables examined, only antibodies to infliximab [ATI] was associated with infliximab levels (odds ratio [OR] -13.369, 95% CI -15.405, -11.333, p <0.001]. A total of 14 patients [7.7%] developed ATI; of these, nine [64.3%] were on concomitant immunomodulatory therapy. Immunomodulatory therapy was not significantly associated with development of ATI [p = 0.15]. In a subset of patients receiving escalated IV infliximab dosing frequency prior to switching, no difference in treatment persistence was observed in patients receiving weekly versus alternate weekly SC CT-P13. Patient acceptance and satisfaction rates with SC CT-P13 were very high. CONCLUSIONS: Among patients on IV infliximab maintenance therapy switched to SC CT-P13, we observed high treatment persistence rates and low rates of immunogenicity, with no change in clinical disease activity indices or biomarkers. Infliximab levels increased after switch to SC CT-P13, and only ATI was associated with serum infliximab levels. Patient acceptance and satisfaction rates were high with SC CT-P13.

Impact of COVID-19 on Endoscopy Training: Perspectives from a Global Survey of Program Directors and Endoscopy Trainers.

BACKGROUND/AIMS: The coronavirus disease of 2019 (COVID-19) pandemic has impacted the training of medical trainees internationally. The aim of this study was to assess the global impact of COVID-19 on endoscopy training from the perspective of endoscopy trainers and to identify strategies implemented to mitigate the impact on trainee education. METHODS: Teaching faculty of gastroenterology (GI) training programs globally were invited to complete a 36-question web-based survey to report the characteristics of their training programs and the impact of COVID-19 on various aspects of endoscopy training, including what factors decisions were based on. RESULTS: The survey response rate was 52.6% (305 out of 580 individuals); 92.8% reported a negative impact on endoscopy training, with suspension of elective procedures (77.1%) being the most detrimental factor. Geographic variations were noted, with European programs reporting the lowest percentage of trainee participation in procedures. A higher proportion of trainees in the Americas were allowed to continue performing procedures, and trainers from the Americas reported receiving the greatest support for endoscopy teaching. CONCLUSION: This study demonstrated that the COVID-19 pandemic has had a significant negative impact on GI endoscopy training internationally, as reported by endoscopy trainers. Focus-optimizing endoscopy training and assessment of competencies are necessary to ensure adequate endoscopy training.

British Society of Gastroenterology guidelines for the management of iron deficiency anaemia in adults.

Iron deficiency anaemia (IDA) is a major cause of morbidity and burden of disease worldwide. It can generally be diagnosed by blood testing and remedied by iron replacement therapy (IRT) using the oral or intravenous route. The many causes of iron deficiency include poor dietary intake and malabsorption of dietary iron, as well as a number of significant gastrointestinal (GI) pathologies. Because blood is iron-rich it can result from chronic blood loss, and this is a common mechanism underlying the development of IDA-for example, as a consequence of menstrual or GI blood loss.Approximately a third of men and postmenopausal women presenting with IDA have an underlying pathological abnormality, most commonly in the GI tract. Therefore optimal management of IDA requires IRT in combination with appropriate investigation to establish the underlying cause. Unexplained IDA in all at-risk individuals is an accepted indication for fast-track secondary care referral in the UK because GI malignancies can present in this way, often in the absence of specific symptoms. Bidirectional GI endoscopy is the standard diagnostic approach to examination of the upper and lower GI tract, though radiological scanning is an alternative in some situations for assessing the large bowel. In recurrent or refractory IDA, wireless capsule endoscopy plays an important role in assessment of the small bowel.IDA may present in primary care or across a range of specialties in secondary care, and because of this and the insidious nature of the condition it has not always been optimally managed despite the considerable burden of disease- with investigation sometimes being inappropriate, incorrectly timed or incomplete, and the role of IRT for symptom relief neglected. It is therefore important that contemporary guidelines for the management of IDA are available to all clinicians. This document is a revision of previous British Society of Gastroenterology guidelines, updated in the light of subsequent evidence and developments.

The UK physician workforce: one-third at increased risk of death from COVID-19.

INTRODUCTION: 21% of NHS staff are from Black, Asian and minority ethnic (BAME) backgrounds yet account for a disproportionately high number of medical-staff deaths from COVID-19. Using data from the published OpenSAFELY Collaborative, we analysed consultant physicians to determine those at increased risk of COVID-19 related death. METHODS: Data from 13,500 consultant physicians collected by the Royal College of Physicians were analysed to determine those at an increased risk of death from COVID-19, assuming no comorbidities. RESULTS: The data reveal a picture in which a third of consultant physicians have a hazard ratio (HR) >1 for dying from COVID-19; one in five have HR >2; one in 11, HR >3; and one in 40, HR >4. Of concern are the risks to male physicians aged ≥60 with HR >3.8. Sub-specialties including cardiology, endocrine and diabetes, gastroenterology, haematology, neurology and rheumatology have a greater risk profile due to high proportion of men, physicians of older age, and proportion of BAME individuals. CONCLUSION: A third of consultant physicians have an increased risk of a COVID-19-related death, and one in five have a higher relative risk (HR >2). The risk is mainly driven by age, gender, and ethnicity, the risk is highest in male consultant physicians over 60, especially from BAME backgrounds.

Rostering in a pandemic: Sustainability is key.

In preparation for the peak of the first wave of COVID-19, many healthcare organisations implemented emergency rotas to ensure they were adequately staffed. These rotas - while addressing the acute issues - are in many cases not sustainable. As we move past the peak and services start resuming, many organisations need to reassess their rotas. There are considerable wellbeing benefits to optimal rostering. In this article we discuss how best to achieve this and suggest a number of key principles, including the following: involvement of staff affected by the rota; taking into account individual circumstances; building in flexibility and adequate time for rest; and designing rotas for different grades of staff together to create stable teams.

National survey of UK endoscopists showing variation in diathermy practice for colonic polypectomy.

INTRODUCTION: Diathermy practice in colonic polypectomy has a poor evidence base. We surveyed endoscopists across the UK to gain an insight in current diathermy practice. METHODS: An eight-question survey was designed to be compact, easy to complete, while still capturing the relevant data. This national survey was circulated by the endoscopy committees of the British Society of Gastroenterology and Association of Coloproctology of Great Britain and Ireland. RESULTS: The survey was open between February and October 2016. Analysis showed: (1) 250/348 (71.8%) completed the full survey, 159 gastroenterologists (63.6%), 36 surgeons (14.4%), 34 gastroenterology trainees (13.6%), 21 others (8.4%); (2) predominant use of coagulation current for small pedunculated polypectomy, high rates of cold snare polypectomy for small sessile polyps (right 43.2% > left 34.4%); (3) a combination of coagulation and cutting current, or Endo Cut, was most popular for larger polypectomy; (4) low use of Endo Cut mode irrespective of size/location of polyp (17.2%-32.0%); (5) 204/250 (81.6%) used reduced current settings for right colon polypectomy; and (6) 208/250 (83.2%) were confident on knowledge and use of diathermy. CONCLUSION: This national survey exposes a wide variation in practice suggesting that colonoscopists employ diathermy modalities that they are comfortable with. As many complications are as direct result of thermal injury and polypectomy is the most frequent therapeutic intervention, appropriate training and formal guidance is lacking.

Circulating tumor DNA in patients with colorectal adenomas: assessment of detectability and genetic heterogeneity.

Improving early detection of colorectal cancer (CRC) is a key public health priority as adenomas and stage I cancer can be treated with minimally invasive procedures. Population screening strategies based on detection of occult blood in the feces have contributed to enhance detection rates of localized disease, but new approaches based on genetic analyses able to increase specificity and sensitivity could provide additional advantages compared to current screening methodologies. Recently, circulating cell-free DNA (cfDNA) has received much attention as a cancer biomarker for its ability to monitor the progression of advanced disease, predict tumor recurrence and reflect the complex genetic heterogeneity of cancers. Here, we tested whether analysis of cfDNA is a viable tool to enhance detection of colon adenomas. To address this, we assessed a cohort of patients with adenomas and healthy controls using droplet digital PCR (ddPCR) and mutation-specific assays targeted to trunk mutations. Additionally, we performed multiregional, targeted next-generation sequencing (NGS) of adenomas and unmasked extensive heterogeneity, affecting known drivers such as APC, KRAS and mismatch repair (MMR) genes. However, tumor-related mutations were undetectable in patients' plasma. Finally, we employed a preclinical mouse model of Apc-driven intestinal adenomas and confirmed the inability to identify tumor-related alterations via cfDNA, despite the enhanced disease burden displayed by this experimental cancer model. Therefore, we conclude that benign colon lesions display extensive genetic heterogeneity, that they are not prone to release DNA into the circulation and are unlikely to be reliably detected with liquid biopsies, at least with the current technologies.

Circulating plasma microRNAs as a screening method for detection of colorectal adenomas.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules. Reduced or increased levels of specific miRNAs are observed in colon and other cancers, supporting their role in carcinogenesis. Detection of colorectal polyps is the cornerstone of the Bowel Cancer Screening Programme in the UK. However, uptake of screening nationally remains under 60%. We aimed to see whether circulating plasma miRNAs can be used to screen for patients with colorectal polyps, adenomas, or both. METHODS: Blood samples were taken from patients from the Bowel Cancer Screening Programme (asymptomatic but faecal occult blood testing [FOBt] positive). Plasma RNA was extracted, target miRNAs (19a, 98, 146b, 186, 191, 222*, 331-5p, 452, 625, 664, 1247) were identified on pooled case miRNA assay cards, and miRNA fraction was quantified by quantitative RT-PCR assay. Results were compared with endoscopy reports and with histology of any polyps identified and removed. Analysis was done with Excel (2011) and SPSS (version 20) software. FINDINGS: 210 patients were included (117 with polyps, 12 with cancer, 81 healthy controls [FOBt positive]). The miRNA panel showed significant differences in expression (on t testing) for patients compared with controls for those with polyps, cancer, or both (miR-19a, p=0·0184; miR-98, p=0·0206; miR-146b, p=0·0029; miR-186, p=0·0006; miR-62,5 p=0·0008), polyps (miR-19a, p=0·0233; miR-98, p=0·0224; miR-146b, p=0·003; miR-186, p=0·0004; miR-625, p=0·001), adenomas (miR-19a, p=0·0339; miR-98, p=0·0266; miR-146b, p=0·0045; miR-186, p=0·0008; miR-625, p=0·0049), multiple adenomas (both sides of colon; miR-146b, p=0·0194; miR-186, p=0·0226; miR-625, p=0·0013), and right-sided adenomas (miR-98, p=0·031; miR-146b, p=0·0076; miR-186, p=0·0041; miR-331-5p, p=0·0142; miR-625, p=0·0049). Receiver operating characteristic analysis showed sensitivity of 60% or more, and specificity of 86% or more for men with polyps, men with adenomas, all patients with haemorrhoids or diverticulosis and polyps, and all patients with haemorrhoids or diverticulosis and adenomas. INTERPRETATION: The target miRNAs that we identified showed significant differences in expression levels for patients with polyps and patients with adenomas from controls. Use of this panel has potential as a screening test. FUNDING: Bowel Disease Research Foundation.

Correlation of caecal intubation rate to volume: colonoscopists should undertake at least 120 procedures per year.

INTRODUCTION: The measurement of the quality of colonoscopy has been in the vanguard of quality improvement. The Joint Advisory Group on Gastrointestinal endoscopy (JAG) has issued guidance for practitioners to achieve caecal intubation rates (CIR) of ≥90% and to undertake ≥100 colonoscopies per annum. The British Society of Gastroenterology National Colonoscopy Audit published in 2012-2013 demonstrated a combined CIR of 92.3%. In 2012, we published data from 16 064 colonoscopies showing a combined CIR of 90.57%-both meeting JAG's standard. Analysis of our audit looked at the relationship of volume and outcome. CIR of operators performing ≥100 procedures per annum was 91.76%; those performing <100 was 87.77%. The 2-year data we collected involved 120+ operators. This provided an opportunity to study the correlation between volume and CIR in detail. METHODS: We analysed 129 operator records who had undertaken 20-399 procedures per annum (total 12 594). Each operator's volume was plotted against CIR as individuals and groups of operators undertaking a similar annual volume. 9859 procedures (78.3%) were performed by operators undertaking 20-199 procedures per annum (120 operators); this subgroup was further analysed. RESULTS: When plotting individuals and groups of individuals who have undertaken a similar annual volume against CIR, the trend-lines cross a 90% CIR at a volume of 120-125 procedures. The subgroup analysis showed the trend-line crossing at 110-120 procedures. CONCLUSIONS: This detailed analysis of 12 594 colonoscopies over 2 years suggests that JAG should advise operators to undertake ≥120 procedures per annum to support the quality standard for CIR of ≥90%.