Abstract Background Streamlining primary and secondary care pathways reduces the time-to-specialist IBD care. Prior to the COVID-19 pandemic, using an algorithm that screens endoscopy reports for probable IBD, we halved the time to IBD specialist review and treatment. Previous studies report that faecal immunochemical testing (FIT) could be used like calprotectin to test for suspected IBD. We sought to define the changing use of calprotectin and FIT prior to the diagnosis of IBD, and to determine whether their use influenced the time to secondary care treatment. Methods We conducted a retrospective observational cohort study of the time from endoscopic diagnosis of IBD to initiation of treatment. Demographics, stool testing, referral route, disease type, clinical review and treatment data were recorded from our electronic patient record. We sought factors associated with a delay in treatment defined as the upper quartile of time-to-treatment using logistic regression. Results Between 01/07/16 and 01/09/23 there were 805 new diagnoses of IBD (503 UC, 225 Crohn’s disease and 77 IBD-U). Monthly diagnosis rates were stable across the pandemic, except for March 2020 due to endoscopy unit closure. The median time from endoscopy to specialist review was 19.0 days (IQR7.0-44.0) and time to outpatient treatment 5.0 days (IQR 0.0-29.0 days). Overall, the use of pre-IBD diagnosis stool biomarkers has increased over time, but since 2020 there has been a progressive rise in FIT, and a decrease in calprotectin, testing (Fig 1). By 2023, people with a new diagnosis of IBD were more likely to have FIT than calprotectin testing. Whilst stool biomarker testing did not influence the time-to-IBD treatment, FIT testing was associated with a reduced delay from primary referral to endoscopy (OR 0.17 p=0.023). Factors associated with a delay in treatment were a diagnosis of Crohn’s disease versus UC/IBDU, having your index endoscopy undertake by a colorectal surgeon and being managed on a non-emergency pathway. IBD nurse contact prior to medical clinic review was associated with a significant reduction in delay to treatment (OR 0.55 p=0.003) Conclusion In the Southwest of the UK, pre-IBD diagnosis FIT, is now more common than pre-IBD diagnosis calprotectin testing. Factors linked to a delay in treatment were being diagnosed with Crohn’s disease versus UC/IBDU, having your index endoscopy undertaken by a colorectal surgeon and not specialist nurse or gastroenterologist and being managed on a non-emergency pathway. Further studies are needed to understand the influence of FIT versus calprotectin testing in the primary care diagnosis of IBD.

Abstract Background Antibody responses following SARS-CoV-2 infection or a single-dose of SARS-CoV-2 vaccine are impaired in patients with inflammatory bowel disease treated with anti-TNF compared to those treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody. Here we sought to determine if patients treated with infliximab have attenuated serological and T cell responses and an increased risk of breakthrough COVID-19 infection following primary SARS-CoV-2 vaccination. Methods Anti-spike (S) receptor binding domain (RBD) antibody concentration in 2306 infliximab-treated patients were compared to a cohort of 1045 vedolizumab-treated patients. Our primary outcome was anti-S RBD antibodies 2 to 10 weeks after a second dose of the BNT162b2 or ChAdOx1 nCoV-19 vaccines. Secondary outcomes were anti-spike T cell responses, durability of vaccine responses and risk of breakthrough infections following two doses of vaccine. Results Anti-S RBD antibody concentrations were lower in patients treated with infliximab than in those treated with vedolizumab, following a second dose of BNT162b2 (567.3 U/mL [6.1] vs 4601.1 U/mL [5.3], p <0.0001) and ChAdOx1 nCoV-19 (183.9 U/mL [5.0] vs 789.4 U/mL [3.5], p <0.0001) vaccines (Fig. 1). Vaccination with the BNT162b2 vaccine compared to the ChAdOx1 nCoV-19 was independently associated with a 3.7-fold [95% CI 3.30 – 4.13] higher anti-S RBD antibody concentration (p < 0.0001) (Fig. 2). There were no significant differences in the magnitude of anti-spike T cell responses observed in infliximab- compared with vedolizumab-treated patients after one or two doses of either vaccine. Antibody half-life was shorter in infliximab- than vedolizumab-treated patients following two-doses of BNT162b2 (4.0 weeks [95% CI 3.8 – 4.1] vs 7.2 weeks [95% CI 6.8 – 7.6]) and ChAdOx1 nCoV-19 (5.3 weeks [95% CI 5.1 – 5.5] vs 9.3 weeks [95% CI 8.5 – 10.2], p value < 0.0001). Breakthrough SARS-CoV-2 infections were more frequent (5.8% (202/3467) vs 3.9% (66/1691), p = 0.0032) and the time to breakthrough shorter in patients treated with infliximab than vedolizumab (p = 0.0023) (Fig. 3). Higher anti-S RBD antibody concentrations following a second dose of SARS-CoV-2 vaccine protected against breakthrough SARS-CoV-2 infection: overall, for every 10-fold rise in anti-S RBD antibody level we observed a 0.8-fold reduction in odds of breakthrough infection ([95% CI 0.70 – 0.99], p = 0.035). Conclusion Infliximab was associated with attenuated, less durable vaccine induced anti-S RBD antibody responses and a 50% increase in breakthrough SARS-CoV-2 infection. Further follow-up is required to assess whether third primary doses can mitigate the effects of infliximab on anti-S RBD antibody responses.

Abstract Background Given the existential threat from COVID-19 and the consequent restrictive public health measures it is perhaps unsurprising that SARS-CoV-2 infection has been linked to increases in rates of depression in the general population. Few studies, however have addressed anxiety and depression in patients with inflammatory bowel disease (IBD) during the COVID19 pandemic. We aimed to define, in patients with IBD treated with infliximab or vedolizumab and/or an immunomodulator, the prevalence, demographic and disease-related factors associated with depression and the effect of restrictive public health measures on rates of depression. Methods CLARITY IBD is a United Kingdom (UK) wide, multicentre, prospective observational cohort study investigating the impact of infliximab and vedolizumab and/or concomitant immunomodulators (thiopurines or methotrexate) on SARS-CoV-2 acquisition, illness, and immunity in patients with IBD. Patients were recruited between 22nd September and 23rd December 2020 and then assessed every 8 weeks. We measured depression using the 8-item Patient Health Questionnaire (PHQ-8). Secondary outcomes were anxiety and IBD-related quality of life assessed using the General Anxiety Disorder Assessment (GAD-7) and IBD-Control questionnaires, respectively. Multivariable logistic regression models were used to identify factors independently associated with depression at entry to the study. Baseline and paired responses during the third UK government’s stay-at-home lockdown order which commenced on the 4th January 2021 were compared using the Wilcoxon signed-rank test. Results The prevalence of depression at entry to the CLARITY study was 26% (1794/6933): 14% patients satisfied criteria for mild, 6% moderate and 5% severe depression. Depression scores were associated with anxiety (Spearman’s rho= 0.78, p<0.0001) and poorer IBD-Control-8 quality of life scores (Spearman’s rho=-0.67, p<0.0001). Multivariable analysis showed that vedolizumab (vs infliximab), steroid use, female sex, younger age, remaining at home, ulcerative colitis, comorbidity and higher income deprivation were associated with depression at entry to the study (Figure 1). Paired depression scores were unchanged between study entry and when assessed during the lockdown period (p=0.91). Conclusion Depression was negatively associated with infliximab therapy and was unchanged during the third UK stay-at-home lockdown. Longitudinal follow up in this cohort will allow us to determine whether COVID-19 vaccination influences depression and whether depression is linked to vaccine hesitancy or impaired serological responses to SARS-CoV-2 vaccination.

Abstract Background Anti-TNF (aTNF) treatment failure in patients with IBD is common. International guidelines recommend switching out of class when aTNF drug levels are therapeutic and within class with an immunomodulator when aTNF drug levels are suboptimal and associated with antibody development. We sought to define the: 1) risk of immunogenicity to a second aTNF stratified by immunogenicity to the first aTNF and 2) rates of drug persistence to a second aTNF in patients with pharmacodynamic or immunogenic failure of their first aTNF drug. Methods We performed a retrospective cohort study across 32 UK hospitals. 870 patients (444 male, 630 (72%) Crohn’s disease) who had both infliximab and adalimumab therapeutic drug monitoring performed by our service from May 2013 to November 2020 were identified. Drug and antibody levels were measured using the IDKmonitor® drug tolerant ELISA assays. Treatment failure included primary nonresponse, secondary loss of response, adverse drug reactions and IBD-related surgeries, and was identified by case note review. Immunogenic failure was defined as treatment failure with suboptimal drug levels (infliximab level <2 mg/L, adalimumab level <6 mg/L) with an antibody concentration ≥10 AU/ml. Pharmacodynamic failure was defined as treatment failure despite adequate drug levels. Results Patients who developed immunogenicity to adalimumab (first) were more likely to develop immunogenicity to infliximab (second) (63% vs 40%, p = 0.004), and patients who developed immunogenicity to infliximab (first) were more likely to develop immunogenicity to adalimumab (second) (33% vs 19%, p = 0.002) (Fig 1). Patients who developed: antibodies and undetectable drug, low drug levels, or low drug levels with immunogenicity to infliximab (first), were more likely to develop these outcomes to adalimumab (second) (all p<0.001). There was no difference in drug persistence to second aTNF in patients with pharmacodynamic and immunogenic treatment failure (Fig 2). In patients with immunogenic (but not pharmacodynamic) failure, commencing an immunomodulator at the time of switching to second aTNF drug was associated with longer drug persistence than in patients treated with an immunomodulator throughout or not all (Fig 3). Conclusion Immunogenicity to the first aTNF was associated with immunogenicity to the second aTNF, irrespective of drug sequence. Commencing an immunomodulator at the time of switching to second aTNF was associated with improved drug persistence in immunogenic, but not pharmacodynamic, failure. However, 50% of patients remained on second aTNF at 5 years in both groups, suggesting switching in-class may be appropriate irrespective of the cause of treatment failure to first aTNF.

Abstract Background Anti-TNF drugs increase the risk of serious respiratory infections and impair protective immunity following pneumococcal, influenza, and viral hepatitis vaccinations. Therefore, we sought to determine whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses following SARS-CoV-2 infection. Methods CLARITY IBD is a multicentre, prospective observational cohort study. Antibody responses in participants treated with infliximab were compared to a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody that is not associated with impaired vaccine responses or increased susceptibility to systemic infections. 6935 patients were recruited from 92 UK hospitals between 22nd September and 23rd December 2020. Nucleocapsid anti-SARS-CoV2 antibodies were measured using the Roche Elecsys assay. Clinical data and serum were collected every 8 weeks. Durability was defined as nonreduction in antibody level by at least 50% from baseline. Results At baseline, rates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab- than vedolizumab-treated patients (3.4% [161/4685], vs 6.0% [134/2250], p<0.0001). Multivariable logistic regression analyses confirmed that infliximab (vs vedolizumab; odds ratio [OR] 0.66 [95% CI 0.51–0.87], p=0.0027) and immunomodulator use (OR 0.70 [95% CI 0.53–0.92], p=0.012) were independently associated with lower seropositivity (Fig 1). In patients with confirmed SARS-CoV-2 infection seroconversion was observed in fewer infliximab- than vedolizumab-treated patients (48% [39/81], vs 83% [30/36], p=0.00044) and the magnitude of anti-SARS-CoV2 reactivity was lower (median 0.8 cut off index (COI) [0.2–5.6] vs 37.0 [15.2–76.1], p<0.0001). An initial increase in anti-SARS-Cov2 antibody reactivity was observed four weeks after a positive PCR test, in vedolizumab-(47.2 COI [IQR 24.1 - 113.0] vs 14.5 COI [IQR 0.4 – 30.7], p=0.0079), but not infliximab-treated patients (0.7 COI [IQR 0.2 - 7.5] vs 1.1 COI [IQR 0.4 - 4.5], p=0.70) (Fig 2). Antibody responses after an initial positive reading were also less durable in infliximab-treated patients (hazard ratio 5.15 [95%CI 2.95–9.00]; Fig 3), but durability was not influenced by immunomodulator use. Conclusion Seroprevalence, seroconversion in PCR-confirmed cases, and the magnitude and durability of anti-SARS-CoV2 antibodies were reduced in infliximab- compared with vedolizumab-treated patients. Serological testing and virus surveillance should be considered in patients treated with anti-TNF drugs to detect suboptimal vaccine responses, persistent infection, and viral evolution to inform public health policy.

Abstract Background Timely diagnosis of inflammatory bowel disease (IBD) is important because earlier use of biologic therapies leads to mucosal healing, a reduction in hospitalisations and surgeries and improvements in quality of life. In the United Kingdom, general practitioners refer patients with symptoms suggestive of IBD to colorectal surgeons, emergency department physicians, gastroenterologists or directly for a lower gastrointestinal endoscopy. Consequently, there is variation in the time from endoscopic diagnosis of IBD to specialist review. We created an electronic tool that screens all endoscopy reports for a new diagnosis of IBD. These cases are then reviewed in our weekly complex multidisciplinary team (MDT) meeting and new patients are allocated an IBD specialist. We sought to determine whether our new patient identifier reduced the time to clinical review by an IBD specialist and initiation of IBD treatment. Methods We designed a retrospective observational cohort study comparing time from endoscopic diagnosis of IBD to initiation of treatment and IBD specialist review. Outcomes were compared in the 18 months before and after the introduction, in January 2018, of our new IBD patient identifier. Demographic, endoscopic and treatment outcome data were recorded from our electronic patient record. Categorical and continuous variables were summarised as frequencies (%) and median [IQR] and compared with Fisher’s exact and Mann Whitney U tests respectively. Results Between the 1st January 2018 and 30th June 2019, 116 new patients diagnosed with IBD were identified and reviewed in our MDT meeting. In the preceding 18 months, 111 patients were diagnosed with IBD. There were no significant differences between groups according to sex, age, age at diagnosis, disease type, or phenotype according to the Montreal classification (Table 1). Both the median time from endoscopic diagnosis to treatment initiation (0 days [IQR 0 – 14.2] vs 14 days [IQR 0 – 31.6], p=0.007) and specialist clinic review (21 days [IQR 7 - 25] vs 48 days [IQR 34 – 63], p<0.0001) were shorter following the introduction of the new IBD patient identifier screening tool (Figure 1). Conclusion Systematic electronic screening of endoscopic reports linked to MDT review reduces the time to first treatment and specialist review in newly diagnosed patients with IBD.

Abstract Background Colonoscopic surveillance in inflammatory bowel disease (IBD) patients leads to earlier detection of colorectal cancer (CRC) and reduces CRC-associated deaths. However, adherence to international surveillance guidelines in practice is poor. Consequently, we hypothesised that patients with IBD-associated CRC had suboptimal endoscopic surveillance and conducted a root cause analysis of IBD-associated CRC diagnoses to identify the scale of missed surveillance opportunities. Methods We calculated the incidence of CRC in our IBD population between 1998 and 2019 by cross-referencing the hospital’s CRC and IBD databases. All cases were adjudicated by IBD specialists to determine eligibility for surveillance using guidelines contemporaneous to the time of CRC diagnosis. For all eligible patients, a root cause analysis was conducted to determine whether there were missed opportunities to detect CRC. Results Our search identified 94 patients with IBD and CRC. We excluded 16 patients diagnosed with IBD after the diagnosis of CRC. The overall incidence of IBD-associated CRC in East Devon from 1998 to 2019 was 0.17% per year (95% CI 0.14 %–0.18%) with no statistically significant change seen over time (R2= 0.15, p = 0.11). Fifty-one patients (65%) were male, the median age at diagnosis of CRC was 69 years (range 21–88) and the median duration of IBD prior to CRC diagnosis was 21 years (range 0–57). After adjudication, 42 (54%) patients were eligible for surveillance at the time of CRC diagnosis. Correctly timed surveillance colonoscopy identified 5/42 (12%) CRC cases, but failed to identify CRC in 6 (14%) patients with so-called interval cancers. Overdue surveillance colonoscopy identified a further 4/42 (10%) cases. Overall, 27/42 (64%) IBD-associated CRC cases were classified as having had missed opportunities for surveillance. Root cause analyses found that 10 (37%) patients had not been offered surveillance despite on-going secondary care follow-up. Four (15%) patients had a delayed diagnosis of CRC because of a failure to account for the adequacy of previous colonoscopic and histological findings. Thirteen patients were managed exclusively in primary care including 7 (26%) patients who had been discharged back to primary care without a plan for surveillance and 6 (22%) patients who were never known to secondary care. Conclusion Two-thirds of patients who were eligible for surveillance had a missed opportunity to diagnose CRC. In most cases, the patient was known to the secondary care IBD service but no recommendation for surveillance was made. There is a need to implement processes to facilitate identification and recall of patients eligible for surveillance across primary and secondary care.

Abstract Background Tofacitinib is a partially selective Janus kinase inhibitor that was approved for the treatment of refractory moderate to severe ulcerative colitis (UC) in 2018. We report the real-world clinical effectiveness and adverse effects of tofacitinib in UC. Methods We conducted a retrospective observational cohort study of tofacitinib-treated patients with UC between October 2018 to October 2019 from 4 UK centres. Disease activity was assessed using the Simple Clinical Colitis Activity Index (SCCAI) or Partial Mayo Score (PMS) depending on the study site. Response and remission were defined at week 8 and 26 as a reduction in SCCAI or PMS of ≥3, and SCCAI <3 or PMS <2, respectively. Corticosteroid-free remission was defined as remission with no corticosteroid use at the time of assessment irrespective of baseline corticosteroid status. Results We included 140 patients (65% M; median age 37y [range 16–81]) with a median disease duration of 5.5y (IQR 2.2–11.8). Forty-six per cent (65/140) were receiving corticosteroids at baseline and 83% (116/140) had previously received at least one biologic (62 anti-TNF, 4 vedolizumab, 50 both). Median (IQR) serum CRP and faecal calprotectin levels at baseline were 4 mg/l (1.6–15) and 540 µg/g (316–1175). Response and remission rates were 73% (81/111) and 56% (62/111) respectively at week 8 (median ΔSCCAI of −3 [IQR -6 to -1], median ΔPMS −4 [−6 to −1]) and 48% (39/82) and 39% (32/82) respectively at week 26 (median ΔSCCAI −3 [IQR −7 to –1], median ΔPMS −4 [−6 to –1]). Steroid-free remission was seen in 47% (52/111) and 37% (30/82) patients at week 8 and 26. Patients with response or remission had a significantly lower CRP (p = 0.02) but not calprotectin (p = 0.38) levels at baseline. Response and remission rates were no different stratified by prior biologic use (p = 0.56). Treatment was discontinued after a median of 3 months (IQR 2–4) in 43 patients: 32 with primary non-response, 9 loss of response and in 1 each because of an adverse drug reaction (headache) and patient choice. 7/17 patients had a clinical response to dose re-escalation following a loss of response on dose reduction. The median time to dose de-escalation was 67 (IQR 25–240) days. Seven patients were hospitalised and 5 underwent colectomy. Six serious infections were noted including 2 herpes zoster infections but there were no venous thromboembolic events. Median total cholesterol, low-density lipoprotein and high-density lipoprotein increased from 4.4 mmol/l (IQR 3.7–5.2), 2.47 (1.9–2.9) and 1.5 (1.1–1.9) to 4.8 mmol/l (4.1–6.0), 2.8 (2.13.5) and 1.7 (1.4–1.9) respectively after 8 weeks of tofacitinib. Conclusion Clinical effectiveness and side-effect profile of tofacitinib in UC in this multi-centre real-world cohort were similar to that reported in the pivotal OCTAVE clinical trials.

Background: Both non-interventional (NIC) and interventional cardiologists (IC) contribute to revascularisation decisions and perform diagnostic coronary angiography. Fractional flow reserve (FFR), an invasive pressure derived measurement, is considered the gold standard for assessing coronary stenosis severity to guide revascularisation. Objective(s): We sought to assess the diagnostic accuracy, correlation and management strategies between IC and NIC against FFR and the difference it makes to management. Method: Coronary angiograms of 111 patients performed at a tertiary institution were independently reviewed by two IC and two NIC at a separate cardiology institution. Reviewers recorded coronary percentage stenosis and recommendation for subsequent management: optimal medical therapy (OMT), percutaneous coronary intervention (PCI), coronary artery bypass surgery (CABG) or stress testing (ST). FFR values were then revealed and treatment change recorded. Results: Results are described as interventionists vs. non-interventionists: mean coronary stenosis was 50±18% vs. 52±19% (p=0.10); management by OMT, PCI, CABG or ST was 72%, 27%, 2%, 0% vs. 72%, 22%, 4%, 3% (p=0.02); with FFR values revealed, there was a significant change between groups of 77%, 18%, 5%, 0% vs. 74%, 18%, 8%, 0% (p=0.01). Diagnostic accuracy to predict an FFR positive lesion was similar between groups: Sensitivity 42%, Specificity 78%, Positive predictive value 39%, Negative predictive value 83%. Conclusion: The use of FFR significantly changes the overall management strategy regardless of being IC or NIC. This has important implications for reduced cost and long-term outcomes.

Transcatheter Aortic Valve Implantation (TAVI) is becoming the preferred intervention in managing symptomatic severe aortic stenosis (SAS) in patients at high risk for surgical Aortic Valve Replacement. We report an 83-year-old female who developed several periprocedural complications from elective TAVI that were managed collectively leading to a good outcome. She has symptomatic SAS (AVA 0.8cm2, MPG 61mmHg, Aortic DPI 0.23) on a background of ischaemic heart disease, obstructive sleep apnoea, insulin-dependent T2DM and obesity. During the TAVI, a 29mm Medtronic CoreValve was deployed but ‘popped up’. This required a snare to secure it and a second valve was successfully deployed. ProStar closure device was deployed in the RFA causing a leak in the femoral artery which was sealed with balloon inflation. Post-procedure, she developed complete heart block requiring a permanent pacemaker. She also developed a right femoral pseudoaneurysm whereby she became septic secondary to the infected pseudoaneurysm. Excision of her right common femoral artery mycotic aneurysm was performed and long-term intravenous flucoxacillin was commenced. Her groin wound was slow healing, leading to an ulcer formation. She underwent prolonged hospital rehabilitation with good results. TAVI may be seen as a panacea for SAS for what was until a recently a fatally progressive disease without surgery. But these patients often have a poor functional reserve and are prone to significant morbidity if any complication arises. This case illustrates the multiple cardiac and vascular complications that can result from TAVI. It emphasises the importance of a multi-disciplinary approach to appropriately select patients in whom possible morbidity may be avoided.