Management of colorectal neoplasia in IBD patients: current practice and future perspectives.

Inflammatory bowel disease (IBD) patients are at increased risk of developing colorectal neoplasia (CRN). In this review, we aim to provide an up-to-date overview and future perspectives on CRN management in IBD. Advances in endoscopic surveillance and resection techniques have resulted in a shift towards endoscopic management of neoplastic lesions in place of surgery. Endoscopic treatment is recommended for all CRN if complete resection is feasible. Standard (cold snare) polypectomy, endoscopic mucosal resection and endoscopic submucosal dissection should be performed depending on lesion complexity (size, delineation, morphology, surface architecture, submucosal fibrosis/invasion) to maximize the likelihood of complete resection. If complete resection is not feasible, surgical treatment options should be discussed by a multidisciplinary team. While (sub)total and proctocolectomy play an important role in management of endoscopically unresectable CRN, partial colectomy may be considered in a subgroup of patients in endoscopic remission with limited disease extent without other CRN risk factors. High synchronous and metachronous CRN rates warrant careful mucosal visualization with shortened intervals for at least 5 years after treatment of CRN.

Interobserver agreement of current and new proposed endoscopic scores for postoperative recurrence in Crohn's disease.

BACKGROUND AND AIMS: The modified Rutgeerts' score (mRS) is widely used for the assessment of endoscopic postoperative recurrence (ePOR) in Crohn's disease (CD) after ileocolic resection to guide therapeutic decisions. To improve the validity and prognostic value of this endoscopic assessment, two new scores have been proposed. This study assessed the interobserver agreement of the current (mRS) and new endoscopic scores for ePOR in CD. METHODS: Sixteen Dutch academic and non-academic IBD specialists assessed endoscopic videos (n=71) of postoperative CD patients (n=66) retrieved from nine Dutch centers. Each video was assessed for the degree of inflammation by four gastroenterologists using the mRS and the new proposed endoscopic score: REMIND score (separate score of anastomosis and neoterminal ileum) and updated Rutgeerts score (assessment of lesions at the anastomotic line, ileal inlet, ileal body and neoterminal ileum). In addition, lesions at the ileal body, ileal inlet, neoterminal ileum, colonic and/or ileal blind loop were separately assessed. Interobserver agreement was assessed using Fleiss' weighted kappa. RESULTS: Fleiss' weighted kappa for the mRS was 0.67 (95% confidence interval [CI] 0.59-0.74). The weighted kappa for the REMIND score was 0.73 (95% CI 0.65-0.80) for lesions in the neoterminal ileum and 0.46 (95% CI 0.35-0.58) for anastomotic lesions. The weighted kappa for the updated Rutgeerts' score was 0.69 (95% CI 0.62-0.77). The weighted kappa for lesions in the ileal body, ileal inlet, neoterminal ileum, colonic and ileal blind loop was 0.61 (95% CI 0.49-0.73), 0.63 (95% CI 0.54-0.72), 0.61 (95% CI 0.49-0.74), 0.83 (95% CI 0.62-1.00) and 0.68 (95% CI 0.46-0.89). CONCLUSION: The interobserver agreement of the mRS is substantial. Similarly, the interobserver agreement is substantial for the updated Rutgeerts' score. According to the REMIND score, the interobserver agreement was substantial for lesions in the neoterminal ileum, whereas only moderate for anastomotic lesions. Since therapeutic decisions in clinical practice are based on these assessments and these scores are used as outcome measure in clinical studies, further improvement of the interobserver agreement is essential.

SARS-CoV-2 breakthrough infections after COVID-19 vaccination in patients with inflammatory bowel disease: a systematic review and meta-analysis.

Background: Patients with inflammatory bowel disease (IBD) have an attenuated serologic response to COVID-19 vaccination. It is unclear whether an impaired immune response in vaccinated IBD patients impacts the susceptibility to SARS-CoV-2 infection and occurrence of severe COVID-19. Objectives: To evaluate SARS-CoV-2 breakthrough infection rates and the disease course of COVID-19 in vaccinated IBD patients. Design: A systematic literature search and meta-analysis was performed. Data sources and methods: The search was performed in Embase, Medline, Web of Science Core Collection, Cochrane Central Register of Controlled Trials and CINAHIL. The articles were independently screened and selected by two reviewers. A random-effects model was used to calculate the pooled relative risk for breakthrough infections in vaccinated IBD patients and controls. Results: A total of 16 studies were included, with study periods ranging from January 2020 to October 2021 and follow-up time from 3 weeks to 6 months. The breakthrough infection rates range from 0 to 37.4% in vaccinated IBD patients. The disease course of COVID-19 was generally mild, with low hospitalization and mortality rates (0-8.7% and 0-4.3%, respectively). Vaccinated IBD patients had a significantly lower relative risk of breakthrough infection rate compared to unvaccinated controls (risk ratio: 0.07, 95% CI: 0.03-0.18). No difference was observed between IBD patients and non-IBD controls, and between partially and fully vaccinated IBD patients. The impact of immunosuppressive therapy on breakthrough infection rates differs between studies. Most studies showed no impact from immunosuppressive treatment, anti-tumour necrosis factor alpha or corticosteroids and other biologics; one study reported higher rates for patients treated with infliximab versus vedolizumab. Conclusion: Vaccination is effective to prevent COVID-19 infections in patients with IBD. Breakthrough infections do occur, but the disease course is generally mild. Available data seem to suggest a declining trend of breakthrough infections during calendar time. Registration: The protocol was published in the PROSPERO database (CRD42021292853).

Endoscopic and surgical treatment outcomes of colitis-associated advanced colorectal neoplasia: a multicenter cohort study.

BACKGROUND: Inflammatory bowel disease (IBD) patients are at increased risk of advanced neoplasia (high-grade dysplasia or colorectal cancer). The authors aimed to (1) assess synchronous and metachronous neoplasia following (sub)total or proctocolectomy, partial colectomy or endoscopic resection for advanced neoplasia in IBD, and (2) identify factors associated with treatment choice. MATERIAL AND METHODS: In this retrospective multicenter cohort study, the authors used the Dutch nationwide pathology databank (PALGA) to identify patients diagnosed with IBD and colonic advanced neoplasia (AN) between 1991 and 2020 in seven hospitals in the Netherlands. Logistic and Fine & Gray's subdistribution hazard models were used to assess adjusted subdistribution hazard ratios for metachronous neoplasia and associations with treatment choice. RESULTS: The authors included 189 patients (high-grade dysplasia n =81; colorectal cancer n =108). Patients were treated with proctocolectomy ( n =33), (sub)total colectomy ( n =45), partial colectomy ( n =56) and endoscopic resection ( n =38). Partial colectomy was more frequently performed in patients with limited disease and older age, with similar patient characteristics between Crohn's disease and ulcerative colitis. Synchronous neoplasia was found in 43 patients (25.0%; (sub)total or proctocolectomy n =22, partial colectomy n =8, endoscopic resection n =13). The authors found a metachronous neoplasia rate of 6.1, 11.5 and 13.7 per 100 patient-years after (sub)total colectomy, partial colectomy and endoscopic resection, respectively. Endoscopic resection, but not partial colectomy, was associated with an increased metachronous neoplasia risk (adjusted subdistribution hazard ratios 4.16, 95% CI 1.64-10.54, P <0.01) compared with (sub)total colectomy. CONCLUSION: After confounder adjustment, partial colectomy yielded a similar metachronous neoplasia risk compared to (sub)total colectomy. High metachronous neoplasia rates after endoscopic resection underline the importance of strict subsequent endoscopic surveillance.

Clonal Patterns Between Pouch Neoplasia and Prior Colorectal Neoplasia in Inflammatory Bowel Disease Patients: An Exploratory Cohort Study.

Prior colorectal neoplasia is the strongest predictor of pouch neoplasia in inflammatory bowel disease, but the underlying mechanism is unknown. We observed clonality between colorectal and pouch neoplasia in 30% of patients, indicating that most pouch neoplasia develops clonally independent from prior colorectal lesions.

Longitudinal Fecal Calprotectin Profiles Characterize Disease Course Heterogeneity in Crohn's Disease.

BACKGROUND AND AIMS: The progressive nature of Crohn's disease is highly variable and hard to predict. In addition, symptoms correlate poorly with mucosal inflammation. There is therefore an urgent need to better characterize the heterogeneity of disease trajectories in Crohn's disease by utilizing objective markers of inflammation. We aimed to better understand this heterogeneity by clustering Crohn's disease patients with similar longitudinal fecal calprotectin profiles. METHODS: We performed a retrospective cohort study at the Edinburgh IBD Unit, a tertiary referral center, and used latent class mixed models to cluster Crohn's disease subjects using fecal calprotectin observed within 5 years of diagnosis. Information criteria, alluvial plots, and cluster trajectories were used to decide the optimal number of clusters. Chi-square test, Fisher's exact test, and analysis of variance were used to test for associations with variables commonly assessed at diagnosis. RESULTS: Our study cohort comprised 356 patients with newly diagnosed Crohn's disease and 2856 fecal calprotectin measurements taken within 5 years of diagnosis (median 7 per subject). Four distinct clusters were identified by characteristic calprotectin profiles: a cluster with consistently high fecal calprotectin and 3 clusters characterized by different downward longitudinal trends. Cluster membership was significantly associated with smoking (P = .015), upper gastrointestinal involvement (P < .001), and early biologic therapy (P < .001). CONCLUSIONS: Our analysis demonstrates a novel approach to characterizing the heterogeneity of Crohn's disease by using fecal calprotectin. The group profiles do not simply reflect different treatment regimens and do not mirror classical disease progression endpoints.

Multiple infliximab biosimilar switches appear to be safe and effective in a real-world inflammatory bowel disease cohort.

BACKGROUND: Switching from originator infliximab (IFX) to biosimilar IFX is effective and safe. However, data on multiple switching are scarce. The Edinburgh inflammatory bowel disease (IBD) unit has undertaken three switch programmes: (1) Remicade to CT-P13 (2016), (2) CT-P13 to SB2 (2020), and (3) SB2 to CT-P13 (2021). OBJECTIVE: The primary endpoint of this study was to assess CT-P13 persistence following switch from SB2. Secondary endpoints included persistence stratified by the number of biosimilar switches (single, double and triple), effectiveness and safety. METHODS: We performed a prospective, observational, cohort study. All adult IBD patients on IFX biosimilar SB2 underwent an elective switch to CT-P13. Patients were reviewed in a virtual biologic clinic with protocol driven collection of clinical disease activity, C-reactive protein (CRP), faecal calprotectin (FC), IFX trough/antibody levels, and drug survival. RESULTS: 297 patients (CD n = 196 [66%], ulcerative colitis/inflammatory bowel disease unclassified n = 101, [34%]) were switched (followed-up: 7.5 months [6.8-8.1]). This was the third, second and first IFX switch for 67/297 (22.5%), 138/297 (46.5%) and 92/297 (31%) of the cohort respectively. 90.6% of patients remained on IFX during follow-up. The number of switches was not independently associated with IFX persistence after adjusting for confounders. Clinical (p = 0.77), biochemical (CRP ≤5 mg/ml; p = 0.75) and faecal biomarker (FC<250 µg/g; p = 0.63) remission were comparable at baseline, week 12 and week 24. CONCLUSION: Multiple successive switches from IFX originator to biosimilars are effective and safe in patients with IBD, irrespective of the number of IFX switches.

Rates, predictive factors and effectiveness of ustekinumab intensification to 4- or 6-weekly intervals in Crohn's disease.

BACKGROUND: The UNITI trial reports efficacy of ustekinumab (UST) dose intensification in Crohn's disease (CD) from 12- to 8-weekly, but not 4-weekly. We aimed 1) to assess the cumulative incidence of UST dose intensification to 4- or 6-weekly, 2) to identify factors associated with dose intensification, and 3) to assess the effectiveness of this strategy. METHODS: We performed a retrospective, observational cohort study in NHS Lothian including all UST treated CD patients (2015-2020). RESULTS: 163 CD patients were treated with UST (median follow-up: 20.3 months [13.4-38.4]), of whom 55 (33.7%) underwent dose intensification to 4-weekly (n = 50, 30.7%) or 6-weekly (n = 5, 3.1%). After 1 year 29.9% were dose intensified. Prior exposure to both anti-TNF and vedolizumab (HR 9.5; 1.3-70.9), and concomitant steroid use at UST start (HR 1.8; 1.0-3.1) were associated with dose intensification. Following dose intensification, 62.6% patients (29/55) remained on UST beyond 1 year. Corticosteroid-free clinical remission was achieved in 27% at week 16 and 29.6% at last follow-up. CONCLUSION: One third of CD patients treated with UST underwent dose intensification to a 4- or 6-weekly interval within the first year. Patients who failed both anti-TNF and vedolizumab, or required steroids at initiation were more likely to dose intensify.

Systematic Review and Meta-analysis: Loss of Response and Need for Dose Escalation of Infliximab and Adalimumab in Ulcerative Colitis.

BACKGROUND: Loss of response to infliximab or adalimumab in ulcerative colitis occurs frequently, and dose escalation may aid in regaining clinical benefit. This study aimed to systematically assess the annual loss of response and dose escalation rates for infliximab and adalimumab in ulcerative colitis. METHODS: A systematic search was conducted from August 1999 to July 2021 for studies reporting loss of response and dose escalation during infliximab and/or adalimumab use in ulcerative colitis patients with primary response. Annual loss of response, dose escalation rates, and clinical benefit after dose escalation were calculated. Subgroup analyses were performed for studies with 1-year follow-up or less. RESULTS: We included 50 unique studies assessing loss of response (infliximab, n = 24; adalimumab, n = 21) or dose escalation (infliximab, n = 21; adalimumab, n = 16). The pooled annual loss of response for infliximab was 10.1% (95% confidence interval [CI], 7.1-14.3) and 13.6% (95% CI, 9.3-19.9) for studies with 1-year follow-up. The pooled annual loss of response for adalimumab was 13.4% (95% CI, 8.2-21.8) and 23.3% (95% CI, 15.4-35.1) for studies with 1-year follow-up. Annual pooled dose escalation rates were 13.8% (95% CI, 8.7-21.7) for infliximab and 21.3% (95% CI, 14.4-31.3) for adalimumab, regaining clinical benefit in 72.4% and 52.3%, respectively. CONCLUSIONS: Annual loss of response was 10% for infliximab and 13% for adalimumab, with higher rates during the first year. Annual dose escalation rates were 14% (infliximab) and 21% (adalimumab), with clinical benefit in 72% and 52%, respectively. Uniform definitions are needed to facilitate more robust evaluations.

Annual loss of response in ulcerative colitis was 10% for infliximab and 13% for adalimumab, with higher rates during the first year. Annual dose escalation was higher than loss of response, with clinical benefit for 72% (infliximab) and 52% (adalimumab).

Significant Differences in IBD Care and Education across Europe: Results of the Pan-European VIPER Survey.

BACKGROUND: Inflammatory bowel disease (IBD) care and education might differ around Europe. Therefore, we conducted this European Variation In IBD PracticE suRvey (VIPER) to investigate potential differences between countries. METHODS: This trainee-initiated survey, run through SurveyMonkey®, consisted of 47 questions inquiring basic demographics, IBD training, and clinical care. Results were compared according to gross domestic product (GDP) per capita, for which countries were divided into 2 groups (low/high income, according to the World Bank). RESULTS: The online survey was completed by 1,285 participants from 40 European countries, with a majority of specialists (65.3%) working in academic institutions (50.4%). Significant differences in IBD-specific training (55.9% vs. 38.4%), as well as availability of IBD units (58.4% vs. 39.7%) and multidisciplinary meetings (73.2% vs. 40.1%), were observed between respondees from high and low GDP countries (p < 0.0001). In high GDP countries, IBD nurses are more common (85.9% vs. 36.0%), also mirrored by more nurse-led IBD clinics (40.6% vs. 13.7%; p < 0.0001). IBD dieticians (33.4% vs. 16.5%) and psychologists (16.8% vs. 7.5%) are mainly present in high GDP countries (p < 0.0001). In the current COVID era, telemedicine is available in 73.2% versus 54.1% of the high/low GDP countries, respectively (p < 0.0001). Treat-to-target approaches are implemented everywhere (85.0%), though access to biologicals and small molecules differs significantly. CONCLUSION: Much variability in IBD practice exists across Europe, with marked differences between high and low GDP countries. Further work is required to help address some of these inequalities, aiming to improve and standardize IBD care and training across Europe.

Quality of Surveillance Impacts the Colitis-Associated Advanced Neoplasia Risk: A Multicenter Case-Control Study.

BACKGROUND AND AIMS: Although colorectal cancer (CRC) surveillance is embedded in clinical inflammatory bowel disease (IBD) practice, a subset of patients still develops advanced neoplasia (AN) (high-grade dysplasia [HGD] and/or CRC). We aimed to assess the impact of surveillance quality on AN risk in IBD. METHODS: In this multicenter case-control study, we searched the Dutch nationwide pathology databank to identify IBD cases with AN and controls with indefinite or low-grade dysplasia. The surveillance colonoscopy preceding the index lesion (first indefinite for dysplasia [IND]/low-grade dysplasia [LGD] or AN) was used to assess the impact of surveillance quality. We assessed intervals, bowel preparation, cecal intubation, and absence of inflammation as primary quality indicators. In addition, we assessed chromoendoscopy, endoscopist expertise, hospital setting, and biopsy strategy. Associations of quality indicators with AN risk were determined with multivariable logistic regression analyses with Firth's correction. RESULTS: We included 137 cases and 138 controls. Delayed intervals (58.2% vs 39.6%) and active inflammation (65.3% vs 41.8%) were frequently present in cases and controls and were associated with AN (delayed interval: adjusted odds ratio [aOR], 2.00; 95% confidence interval [CI], 1.07-3.81; P = .03; active inflammation: aOR, 2.46; 95% CI, 1.33-4.61; P < .01). Surveillance compliant with primary quality indicators was associated with a reduced AN risk (aOR, 0.43; 95% CI, 0.22-0.91; P = .03), similar to chromoendoscopy (OR, 0.11; 95% CI, 0.01-0.89; P = .01). Other indicators were not significantly associated with AN. CONCLUSIONS: Surveillance compliant with primary quality indicators is associated with a reduced colitis-associated AN risk. Delayed surveillance intervals and active inflammation were associated with an increased AN risk. This underlines the importance of procedural quality, including endoscopic remission to optimize the effectiveness of endoscopic surveillance.

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.

BACKGROUND: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD). AIM: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab. RESULTS: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure. CONCLUSION: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure.

Increased Colorectal Neoplasia Risk in Patients with Inflammatory Bowel Disease and Serrated Polyps with Dysplasia.

BACKGROUND: The impact of serrated polyps on the advanced colorectal neoplasia (CRN) risk in inflammatory bowel disease (IBD) patients is unknown. Serrated polyps are histologically categorized as hyperplastic polyps (HPs), sessile serrated lesions (SSLs), and traditional serrated adenomas (TSAs). AIMS: We aimed (1) to characterize the serrated polyps in IBD patients, (2) to identify factors associated with the presence of serrated polyps in IBD, and (3) to assess the CRN risk in IBD patients with serrated polyps. METHODS: We established a retrospective cohort of IBD patients with and without colonic serrated polyps. Cox-regression analysis with time-dependent variables was used to compare advanced CRN risk in IBD patients with and without serrated polyps. RESULTS: Of the 621 enrolled IBD patients, 198 had a serrated polyp (92 HPs, 88 SSLs without dysplasia, 13 SSLs with dysplasia, and 5 TSAs). Independent factors associated with serrated polyps were ulcerative colitis (UC) (odds ratio (OR) 1.77, 95% confidence interval (CI) 1.19-2.62, p = 0.005), male gender (OR 1.63, 95% CI 1.11-2.40, p = 0.013), and older age (per year increase, OR 1.06, 95%CI 1.05-1.08, p < 0.001). TSAs and SSLs with dysplasia were risk factors for subsequent advanced CRN (HR 13.51, 95% CI 3.11-58.68, p < 0.001), while HPs (HR 1.98, 95% CI 0.46-8.60, p = 0.36) and SSLs without dysplasia (HR 0.87, 95% CI 0.11-6.88, p-0.89) did not impact the subsequent advanced CRN risk. CONCLUSIONS: UC, male gender and older age were associated with the presence of serrated polyps. The majority of serrated polyps (91%) were HPs and SSL without dysplasia and did not affect the CRC risk. However TSAs and SSLs with dysplasia, representing a small subgroup of serrated polyps (9%), were associated with subsequent advanced CRN.

Patterns of emergency admission for IBD patients over the last 10 years in Lothian, Scotland: a retrospective prevalent cohort analysis.

OBJECTIVE: It is unclear how the compounding prevalence of inflammatory bowel disease (IBD) has translated into the causes and rates of hospitalisation, particularly in an era of increased biologic prescribing. We aimed to analyse these trends in a population-based IBD cohort over the last 10 years. DESIGN: The Lothian IBD registry is a complete, validated, prevalent database of IBD patients in NHS Lothian, Scotland. ICD-10 coding of hospital discharge letters from all IBD patient admissions to secondary care between 1 January 2010 and 31 December 2019 was interrogated for admission cause, with linkage to local/national data sets on death and prescribed drugs. RESULTS: Fifty-seven per cent (4673/8211) of all IBD patients were admitted to secondary care for >24 h between 1 January 2010 and 31 December 2019. In patients <40 years, IBD was the commonest reason for admission (38% of admissions), whereas infection was the most common cause in those >60 years (19% of admissions). Three per cent (243/8211) of IBD patients accounted for 50% of the total IBD bed-days over the study period. Age-standardised IBD admission rates fell from 39.4 to 25.5 admissions per 100,000 population between 2010 and 2019, an average annual percentage reduction of 3% (95% CI -4.5% to -2.1%, p < 0.0001). Non-IBD admission rates were unchanged overall (145-137 per 100,000 population) and specifically for serious (hospitalisation) and severe (ITU admission or death) infection over the same period. CONCLUSION: Despite compounding prevalence and increased biologic use, IBD admission rates are falling. The cause of admission varies with age, with infection the predominant cause in older patients.

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

BACKGROUND AND AIMS: Infliximab attenuates serological responses to SARS-CoV-2 infection. Whether this is a class effect, or if anti-tumour necrosis factor [anti-TNF] level influences serological responses, remains unknown. METHODS: Seroprevalence and the magnitude of SARS-CoV-2 nucleocapsid antibody responses were measured in surplus serum from 11 422 (53.3% [6084] male; median age 36.8 years) patients with immune-mediated inflammatory diseases, stored at six therapeutic drug monitoring laboratories between January 29 and September 30, 2020. Data were linked to nationally held SARS-CoV-2 PCR results to July 11, 2021. RESULTS: Rates of PCR-confirmed SARS-CoV-2 infection were similar across treatment groups. Seroprevalence rates were lower in infliximab- and adalimumab- than vedolizumab-treated patients (infliximab: 3.0% [178/5893], adalimumab: 3.0% [152/5074], vedolizumab: 6.7% [25/375], p = 0.003). The magnitude of SARS-CoV-2 reactivity was similar in infliximab- vs adalimumab-treated patients (median 4.30 cut-off index [COI] [1.94-9.96] vs 5.02 [2.18-18.70], p = 0.164), but higher in vedolizumab-treated patients (median 21.60 COI [4.39-68.10, p < 0.004). Compared to patients with detectable infliximab and adalimumab drug levels, patients with undetectable drug levels [<0.8 mg/L] were more likely to be seropositive for SARS-CoV-2 antibodies. One-third of patients who had PCR testing prior to antibody testing failed to seroconvert, all were treated with anti-TNF. Subsequent positive PCR-confirmed SARS-CoV-2 was seen in 7.9% [12/152] of patients after a median time of 183.5 days [129.8-235.3], without differences between drugs. CONCLUSION: Anti-TNF treatment is associated with lower SARS-CoV-2 nucleocapsid seroprevalence and antibody reactivity when compared to vedolizumab-treated patients. Higher seropositivity rates in patients with undetectable anti-TNF levels support a causal relationship, although confounding factors, such as combination therapy with a immunomodulator, may have influenced the results.

Gastroenteropancreatic Neuroendocrine Neoplasms in Patients with Inflammatory Bowel Disease: An ECCO CONFER Multicentre Case Series.

BACKGROUND: Gastroenteropancreatic neuroendocrine neoplasms [GEP-NENs] have rarely been reported in association with inflammatory bowel diseases [IBDs]. METHODS: An ECCO COllaborative Network For Exceptionally Rare case reports project [ECCO-CONFER] collects cases of GEP-NENs diagnosed in patients with IBD. RESULTS: GEP-NEN was diagnosed in 100 IBD patients; 61% female, 55% Crohn's disease, median age 48 years (interquartile range [IQR] 38-59]). The most common location was the appendix [39%] followed by the colon [22%]. Comprehensive IBD-related data were available for 50 individuals with a median follow-up of 30 months [IQR 11-70] following NEN diagnosis. Median duration of IBD at NEN diagnosis was 84 months [IQR 10-151], and in 18% of cases NEN and IBD were diagnosed concomitantly. At diagnosis, 20/50 were stage-I [T1N0M0], and 28/50 were graded G1 [ki67 ≤2%]. Incidental diagnosis of NEN and concomitantly IBD diagnosis were associated with an earlier NEN stage [p = 0.01 and p = 0.02, respectively]. Exposure to immunomodulatory or biologic therapy was not associated with advanced NEN stage or grade. Primary GEP-NEN were more frequently found in the segment affected by IBD [62% vs 38%]. At the last follow-up data, 47/50 patients were alive, and only two deaths were related to NEN. CONCLUSIONS: In the largest case series to date, prognosis of patients with GEP-NEN and IBD seems favourable. Incidental NEN diagnosis correlates with an earlier NEN stage, and IBD-related therapies are probably independent of NEN stage and grade. The association of GEP-NEN location and the segment affected by IBD may suggest a possible role of inflammation in NEN tumorigenesis.

Effectiveness and Safety of Adalimumab Biosimilar SB5 in Inflammatory Bowel Disease: Outcomes in Originator to SB5 Switch, Double Biosimilar Switch and Bio-Naïve SB5 Observational Cohorts.

BACKGROUND AND AIMS: Multiple adalimumab [ADA] biosimilars are now approved for use in inflammatory bowel disease [IBD]; however, effectiveness and safety data remain scarce. We aimed to investigate long-term outcomes of the ADA biosimilar SB5 in IBD patients following a switch from the ADA originator [SB5-switch cohort] or after start of SB5 [SB5-start cohort]. METHODS: We performed an observational cohort study in a tertiary IBD referral centre. All IBD patients treated with Humira underwent an elective switch to SB5. We identified all these patients in a biological prescription database that prospectively registered all ADA start and stop dates including brand names. Data on IBD phenotype, C-reactive protein [CRP], drug persistence, ADA drug and antibody levels, and faecal calprotectin were collected. RESULTS: In total, 481 patients were treated with SB5, 256 in the SB5-switch cohort (median follow-up: 13.7 months [IQR 8.6-15.2]) and 225 in the SB5-start cohort [median follow-up: 8.3 months [4.2-12.8]). Of the SB5-switch cohort, 70.8% remained on SB5 beyond 1 year; 90/256 discontinued SB5, mainly due to adverse events [46/90] or secondary loss of response [37/90]. In the SB5-start cohort, 81/225 discontinued SB5, resulting in SB5-drug persistence of 60.3% beyond 1 year. No differences in clinical remission [p = 0.53], CRP [p = 0.80], faecal calprotectin [p = 0.40] and ADA trough levels [p = 0.55] were found between baseline, week 26 and week 52 following switch. Injection site pain was the most frequently reported adverse event. CONCLUSION: Switching from ADA originator to SB5 appeared effective and safe in this study with over 12 months of follow-up.

Real-world experience with tofacitinib in ulcerative colitis: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Tofacitinib is a Janus kinase inhibitor (JAKi) recently approved for the treatment of moderate to severe ulcerative colitis (UC) based on robust efficacy and safety data derived from OCTAVE clinical trials. Evidence on the outcomes of tofacitinib therapy in real-world UC patients is needed, as a number of these patients would be deemed ineligible for clinical trials. We have therefore summarised data derived from observational, real-world evidence (RWE) studies on the effectiveness and safety of tofacitinib in moderate to severe UC patients. METHODS: We searched the PubMed, EMBASE, Scopus, Web of Science and Cochrane databases for observational studies on the use of tofacitinib in UC patients, published between 30 May 2018 and 24 January 2021. Pooled induction (8-14 weeks) and maintenance (16-26 weeks) clinical response and remission rates were calculated, as well as the proportion of reported adverse events using random effects models. RESULTS: Nine studies were included, comprising 830 patients, of which 81% were previously treated with anti-tumour necrosis factor (TNF) and 57% with vedolizumab. Induction of clinical response and remission were achieved in 51% (95% confidence interval, 41-60%) and 37% (26-45%) of patients, after a median follow-up of 8 weeks. At the end of a median follow-up of 24 weeks, maintenance of clinical response and remission were met in 40% (31-50%) and 29% (23-36%) of patients, respectively. Thirty-two percent of the patients had at least one adverse event, the most commonly reported being mild infection (13%) and worsening of UC, requiring colectomy (13%). A third of the patients (35%) discontinued tofacitinib, most frequently due to primary non-response (51%). CONCLUSION: Tofacitinib is a safe and effective therapy in real-world UC patients, as previously reported by clinical trials.

Clinical Outcomes of Covid-19 in Patients With Inflammatory Bowel Disease: A Nationwide Cohort Study.

BACKGROUND AND AIMS: The COVID-19 risk and disease course in inflammatory bowel disease [IBD] patients remains uncertain. Therefore, we aimed to assess the clinical presentation, disease course, and outcomes of COVID-19 in IBD patients. Second, we determined COVID-19 incidences in IBD patients and compared this with the general population. METHODS: We conducted a multicentre, nationwide IBD cohort study in The Netherlands and identified patients with COVID-19. First, we assessed the COVID-19 disease course and outcomes. Second, we compared COVID-19 incidences between our IBD study cohort and the general Dutch population. RESULTS: We established an IBD cohort of 34 763 patients. COVID-19 was diagnosed in 100/34 763 patients [0.29%]; 20/100 of these patients [20%] had severe COVID-19 defined as admission to the intensive care unit, mechanical ventilation, and/or death. Hospitalisation occurred in 59/100 [59.0%] patients and 13/100 [13.0%] died. All patients who died had comorbidities and all but one were ≥65 years old. In line, we identified ≥1 comorbidity as an independent risk factor for hospitalisation (odds ratio [OR] 4.20, 95% confidence interval [CI] 1.58-11.17,; p = 0.004). Incidences of COVID-19 between the IBD study cohort and the general population were comparable (287.6 [95% CI 236.6-349.7] versus 333.0 [95% CI 329.3-336.7] per 100000 patients, respectively; p = 0.15). CONCLUSIONS: Of 100 cases with IBD and COVID-19, 20% developed severe COVID-19, 59% were hospitalised and 13% died. A comparable COVID-19 risk was found between the IBD cohort [100/34 763 = 0.29%] and the general Dutch population. The presence of ≥1 comorbidities was an independent risk factor for hospitalisation due to COVID-19.