The role of MRI in perianal fistulizing disease: diagnostic imaging and classification systems to monitor disease activity.

Perianal fistulizing disease, commonly associated with Crohn's disease, poses significant diagnostic and therapeutic challenges due to its complex anatomy and high recurrence rates. Radiological imaging plays a pivotal role in the accurate diagnosis, classification, and management of this condition. This article reviews the current radiological modalities employed in the evaluation of perianal fistulizing disease, including magnetic resonance imaging (MRI), endoanal ultrasound, and computed tomography (CT). MRI, recognized as the gold standard, offers superior soft tissue contrast and multiplanar capabilities, facilitating detailed assessment of fistula tracts and associated abscesses. CT, although less detailed than MRI, remains valuable in acute settings for detecting abscesses and guiding drainage procedures. This article discusses the advantages and limitations of each modality, highlights the importance of standardized imaging protocols, and underscores the need for interdisciplinary collaboration in the management of perianal fistulizing disease. Future directions include advancements in imaging techniques and the integration of artificial intelligence to enhance diagnostic accuracy and treatment outcomes.

Patients with immune mediated inflammatory diseases are insufficiently protected against vaccine-preventable infections.

BACKGROUND: Patients with Immune Mediated Inflammatory Diseases (IMIDs) using immunosuppressive therapy are at increased risk of infections, including vaccine-preventable infections. In this study, we aimed to evaluate whether patients with IMIDs on systemic immunosuppressive therapy are vaccinated according to current guidelines. METHODS: A survey was sent out, between August 2022 and March 2023, to all patients with IMIDs that visited the departments of dermatology, rheumatology and gastroenterology at an academic and regional hospital in Rotterdam, the Netherlands. Patient-reported vaccination status was compared to the Dutch guidelines on vaccinations in patients with chronic inflammatory diseases. RESULTS: A total of 1,905/5,987 patients responded to the survey (response rate 32%). After exclusion of patients without systemic immunosuppressive medication, the study population comprised 1,390 patients, median age 56 years (IQR 42-66) and 41% male. Most patients (92%) had been vaccinated according to the Dutch National Immunization Program. Before starting immunosuppressive therapy, 2% of the patients who were still considered at risk according to the Dutch guideline were vaccinated for measles, and 4% for diphtheria/tetanus/polio (DT-IPV). Additionally, 62% of patients received an annual influenza vaccine, 16% received a five-yearly pneumococcal vaccine, and 91% were fully vaccinated against COVID-19. CONCLUSION: Patients with IMIDs on immunosuppressive therapy are not vaccinated in accordance with the guidelines. Implementation strategies to improve the vaccination rates for patients with IMIDs should specifically focus on vaccinating against measles and diphtheria/tetanus/polio, and periodic vaccination against pneumococcal and influenza infections.

Systematic review: Patient-related, microbial, surgical, and histopathological risk factors for endoscopic post-operative recurrence in patients with Crohn's disease.

BACKGROUND: Risk stratification for endoscopic post-operative recurrence (ePOR) in Crohn's disease (CD) is required to identify patients who would benefit most from initiation of prophylactic medication and intensive monitoring of recurrence. AIMS: To assess the current evidence on patient-related, microbial, surgical and histopathological risk factors for ePOR in patients with CD after ileocolic (re-)resection. METHODS: Multiple online databases (Embase, MEDLINE, Web of Science and Cochrane Library) were searched up to March 2024. Studies with reported associations of patient-related, microbial, surgical and/or histopathological factors for ePOR (i.e., Rutgeerts' score ≥i2 or modified Rutgeerts' score ≥i2a) were included. The risk of bias was assessed with the Newcastle-Ottawa Scale for observational cohort studies and case-control studies. RESULTS: In total, 47 studies were included (four RCTs, 29 cohort studies, 12 case-control studies, one cross-sectional study and one individual participant data meta-analysis) including 6006 patients (median sample size 87 patients [interquartile range 46-170]). Risk of bias assessment revealed a poor quality in 41% of the studies. An association was reported in multiple studies of ePOR with active smoking at and post-surgery, male sex and prior bowel resection. A heterogeneous association with ePOR was reported for other risk factors included in the current guidelines (penetrating disease, perianal disease, younger age, extensive small bowel disease and presence of granulomas in the resection specimen or myenteric plexitis in the resection margin), and other patient-related, microbial, surgical and histopathological factors. CONCLUSION: Risk factors for ePOR in international guidelines are not consistently reported as risk factors in current literature except for active smoking and prior bowel resection. To develop evidence-based, personalised strategies, large prospective studies are warranted to identify risk factors for ePOR. Validation studies of promising (bio)markers are also required.

Non-stem cell lineages as an alternative origin of intestinal tumorigenesis in the context of inflammation.

According to conventional views, colon cancer originates from stem cells. However, inflammation, a key risk factor for colon cancer, has been shown to suppress intestinal stemness. Here, we used Paneth cells as a model to assess the capacity of differentiated lineages to trigger tumorigenesis in the context of inflammation in mice. Upon inflammation, Paneth cell-specific Apc mutations led to intestinal tumors reminiscent not only of those arising in patients with inflammatory bowel disease, but also of a larger fraction of human sporadic colon cancers. The latter is possibly because of the inflammatory consequences of western-style dietary habits, a major colon cancer risk factor. Machine learning methods designed to predict the cell-of-origin of cancer from patient-derived tumor samples confirmed that, in a substantial fraction of sporadic cases, the origins of colon cancer reside in secretory lineages and not in stem cells.

A Prediction Model for Successful Increase of Adalimumab Dose Intervals in Patients with Crohn's Disease: Secondary Analysis of the Pragmatic Open-Label Randomised Controlled Non-inferiority LADI Trial.

BACKGROUND: In the pragmatic open-label randomised controlled non-inferiority LADI trial we showed that increasing adalimumab (ADA) dose intervals was non-inferior to conventional dosing for persistent flares in patients with Crohn's disease (CD) in clinical and biochemical remission. AIMS: To develop a prediction model to identify patients who can successfully increase their ADA dose interval based on secondary analysis of trial data. METHODS: Patients in the intervention group of the LADI trial increased ADA intervals to 3 and then to 4 weeks. The dose interval increase was defined as successful when patients had no persistent flare (> 8 weeks), no intervention-related severe adverse events, no rescue medication use during the study, and were on an increased dose interval while in clinical and biochemical remission at week 48. Prediction models were based on logistic regression with relaxed LASSO. Models were internally validated using bootstrap optimism correction. RESULTS: We included 109 patients, of which 60.6% successfully increased their dose interval. Patients that were active smokers (odds ratio [OR] 0.90), had previous CD-related intra-abdominal surgeries (OR 0.85), proximal small bowel disease (OR 0.92), an increased Harvey-Bradshaw Index (OR 0.99) or increased faecal calprotectin (OR 0.997) were less likely to successfully increase their dose interval. The model had fair discriminative ability (AUC = 0.63) and net benefit analysis showed that the model could be used to select patients who could increase their dose interval. CONCLUSION: The final prediction model seems promising to select patients who could successfully increase their ADA dose interval. The model should be validated externally before it may be applied in clinical practice. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT03172377.

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, 2 new scores have been proposed. This study assessed the interobserver agreement of the current score (mRS) and the new endoscopic score for ePOR in CD. METHODS: Sixteen Dutch academic and nonacademic inflammatory bowel disease specialists assessed endoscopic videos (n = 71) of postoperative CD patients (n = 66) retrieved from 9 Dutch centers. Each video was assessed for degree of inflammation by 4 gastroenterologists using the mRS and the new proposed endoscopic score: the REMIND score (separate score of anastomosis and neoterminal ileum) and the 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, and colonic and/or ileal blind loop were separately assessed. Interobserver agreement was assessed by using Fleiss' weighted kappa. RESULTS: Fleiss' weighted kappa for the mRS was .67 (95% confidence interval [CI], .59-.74). The weighted kappa for the REMIND score was .73 (95% CI, .65-.80) for lesions in the neoterminal ileum and .46 (95% CI, .35-.58) for anastomotic lesions. The weighted kappa for the updated Rutgeerts score was .69 (95% CI, .62-.77). The weighted kappa for lesions in the ileal body, ileal inlet, neoterminal ileum, and colonic and ileal blind loop was .61 (95% CI, .49-.73), .63 (95% CI, .54-.72), .61 (95% CI, .49-.74), .83 (95% CI, .62-1.00) and .68 (95% CI, .46-.89), respectively. CONCLUSIONS: 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, although only moderate for anastomotic lesions. Because 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.

Covered versus bare-metal stenting of the mesenteric arteries in patients with chronic mesenteric ischaemia (CoBaGI): a multicentre, patient-blinded and investigator-blinded, randomised controlled trial.

BACKGROUND: Mesenteric artery stenting with a bare-metal stent is the current treatment for atherosclerotic chronic mesenteric ischaemia. Long-term patency of bare-metal stents is unsatisfactory due to in-stent intimal hyperplasia. Use of covered stents might improve long-term patency. We aimed to compare the patency of covered stents and bare-metal stents in patients with chronic mesenteric ischaemia. METHODS: We conducted a multicentre, patient-blinded and investigator-blinded, randomised controlled trial including patients with chronic mesenteric ischaemia undergoing mesenteric artery stenting. Six centres in the Netherlands participated in this study, including two national chronic mesenteric ischaemia expert centres. Patients aged 18 years or older were eligible for inclusion when an endovascular mesenteric artery revascularisation was scheduled and a consensus diagnosis of chronic mesenteric ischaemia was made by a multidisciplinary team of gastroenterologists, interventional radiologists, and vascular surgeons. Exclusion criteria were stenosis length of 25 mm or greater, stenosis caused by median arcuate ligament syndrome or vasculitis, contraindication for CT angiography, or previous target vessel revascularisation. Digital 1:1 block randomisation with block sizes of four or six and stratification by inclusion centre was used to allocate patients to undergo stenting with bare-metal stents or covered stents at the start of the procedure. Patients, physicians performing follow-up, investigators, and radiologists were masked to treatment allocation. Interventionalists performing the procedure were not masked. The primary study outcome was the primary patency of covered stents and bare-metal stents at 24 months of follow-up, evaluated in the modified intention-to-treat population, in which stents with missing data for the outcome were excluded. Loss of primary patency was defined as the performance of a re-intervention to preserve patency, or 75% or greater luminal surface area reduction of the target vessel. CT angiography was performed at 6 months, 12 months, and 24 months post intervention to assess patency. The study is registered with ClinicalTrials.gov (NCT02428582) and is complete. FINDINGS: Between April 6, 2015, and March 11, 2019, 158 eligible patients underwent mesenteric artery stenting procedures, of whom 94 patients (with 128 stents) provided consent and were included in the study. 47 patients (62 stents) were assigned to the covered stents group (median age 69·0 years [IQR 63·0-76·5], 28 [60%] female) and 47 patients (66 stents) were assigned to the bare-metal stents group (median age 70·0 years [63·5-76·5], 33 [70%] female). At 24 months, the primary patency of covered stents (42 [81%] of 52 stents) was superior to that of bare-metal stents (26 [49%] of 53; odds ratio [OR] 4·4 [95% CI 1·8-10·5]; p<0·0001). A procedure-related adverse event occurred in 17 (36%) of 47 patients in the covered stents group versus nine (19%) of 47 in the bare-metal stent group (OR 2·4 [95% CI 0·9-6·3]; p=0·065). Most adverse events were related to the access site, including haematoma (five [11%] in the covered stents group vs six [13%] in the bare-metal stents group), pseudoaneurysm (five [11%] vs two [4%]), radial artery thrombosis (one [2%] vs none), and intravascular closure device (none vs one [2%]). Six (13%) patients in the covered stent group versus one (2%) in the bare-metal stent group had procedure-related adverse events not related to the access site, including stent luxation (three [6%] vs none), major bleeding (two (4%) vs none), mesenteric artery perforation (one [2%] vs one [2%]), mesenteric artery dissection (one [2%] vs one [2%]), and death (one [2%] vs none). INTERPRETATION: The findings of this trial support the use of covered stents for mesenteric artery stenting in patients with chronic mesenteric ischaemia. FUNDING: Atrium Maquet Getinge Group.

Prognostic Value of the Modified Rutgeerts Score for Long-Term Outcomes After Primary Ileocecal Resection in Crohn's Disease.

INTRODUCTION: The prognostic value of the modified Rutgeerts score (mRS) in patients with Crohn's disease (CD) needs to be further elucidated. This study assessed the prognostic value of the mRS for long-term outcomes after primary ileocecal resection in patients with CD. METHODS: Patients with CD after primary ileocecal resection with an available mRS at first postoperative ileocolonoscopy (index mRS) were retrospectively included. The primary outcome was surgical recurrence. Secondary outcomes were clinical recurrence and progression to severe endoscopic recurrence (≥i3). Cox proportional hazard models were used to assess the association between index mRS and outcomes. RESULTS: Six hundred fifty-two patients were included (mean follow-up: 6.4 years, SD: 4.6). Surgical recurrence rates were 7.7%, 5.3%, 12.9%, 19.1%, 28.8%, 47.8% for index mRS i0, i1, i2a, i2b, i3, and i4, respectively. Clinical recurrence occurred in 42.2% (i0), 53.7% (i1), 58.5% (i2a), 80.2% (i2b), 79.4% (i3), and 95.3% (i4) of patients. Progression to severe endoscopic recurrence occurred in 21.1% (i0), 33.9% (i1), 26.8% (i2a), and 33.3% (i2b) of patients. An index mRS of i2b (adjusted hazard ratio [aHR] 3.0; 1.5-5.6), i3 (aHR 4.0; 2.0-7.9) and i4 (aHR 8.0; 4.0-16.0) were associated with surgical recurrence. An index mRS of i1 (aHR 1.7; 1.2-2.4), i2a (aHR 1.7; 1.2-2.4), i2b (aHR 4.4; 3.2-6.0), i3 (aHR 3.6; 2.5-5.2), and i4 (aHR 7.3; 4.8-10.9) were associated with clinical recurrence. An index mRS of i1 (aHR 2.0; 1.1-3.7) or i2b (aHR 2.5; 1.4-4.6) was associated with progression to severe endoscopic recurrence. DISCUSSION: The increasing mRS corresponds closely with the risk of surgical and clinical recurrence. An index mRS ≥ i2b is associated with surgical recurrence, an index mRS ≥ i1 is associated with clinical recurrence, and i1 or i2b with progression to severe endoscopic recurrence. These results support tight monitoring of disease activity and treatment optimization in patients with ileal lesions and a more conservative management in patients with anastomotic lesions.

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.

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.

Mpox virus infection and drug treatment modelled in human skin organoids.

Mpox virus (MPXV) primarily infects human skin to cause lesions. Currently, robust models that recapitulate skin infection by MPXV are lacking. Here we demonstrate that human induced pluripotent stem cell-derived skin organoids are susceptible to MPXV infection and support infectious virus production. Keratinocytes, the predominant cell type of the skin epithelium, effectively support MPXV infection. Using transmission electron microscopy, we visualized the four stages of intracellular virus particle assembly: crescent formation, immature virions, mature virions and wrapped virions. Transcriptional analysis showed that MPXV infection rewires the host transcriptome and triggers abundant expression of viral transcripts. Early treatment with the antiviral drug tecovirimat effectively inhibits infectious virus production and prevents host transcriptome rewiring. Delayed treatment with tecovirimat also inhibits infectious MPXV particle production, albeit to a lesser extent. This study establishes human skin organoids as a robust experimental model for studying MPXV infection, mapping virus-host interactions and testing therapeutics.

Scoping review on health-related physical fitness in patients with inflammatory bowel disease: Assessment, interventions, and future directions.

BACKGROUND: Reaching the Selecting Therapeutic Targets in Inflammatory Bowel Disease-II (STRIDE-II) therapeutic targets for inflammatory bowel disease (IBD) requires an interdisciplinary approach. Lifestyle interventions focusing on enhancing and preserving health-related physical fitness (HRPF) may aid in improving subjective health, decreasing disability, or even controlling inflammation. However, ambiguity remains about the status and impact of HRPF (i.e. body composition, cardiorespiratory fitness, muscular strength, muscular endurance, and flexibility) in IBD patients, hindering the development of physical activity and physical exercise training guidelines. AIM: To review HRPF components in IBD patients and the impact of physical activity and physical exercise training interventions on HRPF. METHODS: A systematic search in multiple databases was conducted for original studies that included patients with IBD, assessed one or more HRPF components, and/or evaluated physical activity or physical exercise training interventions. RESULTS: Sixty-eight articles were included. No study examined the complete concept of HRPF, and considerable heterogeneity existed in assessment methods, with frequent use of non-validated tests. According to studies that used gold standard tests, cardiorespiratory fitness seemed to be reduced, but findings on muscular strength and endurance were inconsistent. A limited number of studies that evaluated physical activity or physical exercise training interventions reported effects on HRPF, overall showing a positive impact. CONCLUSION: We performed a scoping review using a systematic and iterative approach to identify and synthesize an emerging body of literature on health-related physical fitness in patients with IBD, highlighting several research gaps and opportunities for future research. Findings of this review revealed a gap in the literature regarding the accurate assessment of HRPF in patients with IBD and highlighted important methodological limitations of studies that evaluated physical activity or physical exercise training interventions. This scoping review is a step towards performing studies and systematic reviews in the future, which was not possible at present given the heterogeneity in endpoints and designs of the available studies on this topic. Future well-designed studies are required to determine the optimal training paradigm for improving HRPF in patients with IBD before guidelines can be developed and integrated into the therapeutic strategy.

Impact of timing of primary ileocecal resection on prognosis in patients with Crohn's disease.

BACKGROUND: The advantage of early ileocecal resection after Crohn's disease diagnosis is a matter of debate. This study aims to assess the timing of ileocecal resection on prognosis, after correction for possible confounders. METHODS: Patients with Crohn's disease with primary ileocecal resection between 2000 and 2019 were included in a retrospective multicentre cohort. The primary endpoint was endoscopic recurrence (Rutgeerts score ≥i2b) within 18 months. Secondary endpoints were escalation of inflammatory bowel disease medication within 18 months and re-resection during follow-up. The association between timing of ileocecal resection and these endpoints was investigated using multivariable proportional hazard models, corrected for covariates including Montreal classification, postoperative prophylaxis, smoking, indication for surgery, medication before ileocecal resection, perianal fistulas, surgical approach, histology, length of resected segment and calendar year. RESULTS: In 822 patients ileocecal resection was performed after a median of 3.1 years (i.q.r. 0.7-8.0) after Crohn's disease diagnosis. The lowest incidence of endoscopic recurrence, escalation of inflammatory bowel disease medication and re-resection was observed for patients undergoing ileocecal resection shortly after diagnosis (0-1 months). After correction for covariates, patients with ileocecal resection at 0, 4 and 12 months after diagnosis had a cumulative incidence of 35 per cent, 48 per cent and 39 per cent for endoscopic recurrence, 20 per cent, 29 per cent and 28 per cent for escalation of inflammatory bowel disease medication and 20 per cent, 30 per cent and 34 per cent for re-resection, respectively. In the multivariable model ileocolonic disease (HR 1.39 (95 per cent c.i. 1.05 to 1.86)), microscopic inflammation of proximal and distal resection margins (HR 2.20 (95 per cent c.i. 1.21 to 3.87)) and postoperative prophylactic biological and immunomodulator (HR 0.16 (95 per cent c.i. 0.05 to 0.43)) were associated with endoscopic recurrence. CONCLUSION: The timing of ileocecal resection was not associated with a change of disease course; in the multivariable model, the postoperative recurrence was not affected by timing of ileocecal resection.

Combating pan-coronavirus infection by indomethacin through simultaneously inhibiting viral replication and inflammatory response.

Severe infections with coronaviruses are often accompanied with hyperinflammation, requiring therapeutic strategies to simultaneously tackle the virus and inflammation. By screening a safe-in-human broad-spectrum antiviral agents library, we identified that indomethacin can inhibit pan-coronavirus infection in human cell and airway organoids models. Combining indomethacin with oral antiviral drugs authorized for treating COVID-19 results in synergistic anti-coronavirus activity. Coincidentally, screening a library of FDA-approved drugs identified indomethacin as the most potent potentiator of interferon response through increasing STAT1 phosphorylation. Combining indomethacin with interferon-alpha exerted synergistic antiviral effects against multiple coronaviruses. The anti-coronavirus activity of indomethacin is associated with activating interferon response. In a co-culture system of lung epithelial cells with macrophages, indomethacin inhibited both viral replication and inflammatory response. Collectively, indomethacin is a pan-coronavirus inhibitor that can simultaneously inhibit virus-triggered inflammatory response. The therapeutic potential of indomethacin can be further augmented by combining it with oral antiviral drugs or interferon-alpha.

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).

Seasonal coronavirus infections trigger NLRP3 inflammasome activation in macrophages but is therapeutically targetable.

Seasonal coronaviruses widely circulate in the global population, and severe complications can occur in specific vulnerable populations. Little is known on their pathogenic mechanisms and no approved treatment is available. Here, we present anecdotal evidence that the level of IL-1ß, a hallmark of inflammasome activation, appears elevated in a subset of seasonal coronavirus infected patients. We found that cultured human macrophages support the full life cycle of three cultivatable seasonal coronaviruses. Their infections effectively activate NLRP3 inflammasome activation through TLR4 ligation and NF-κB activation. This activation can be attenuated by specific pharmacological inhibitors and clinically used medications including dexamethasone and flufenamic acid. Interestingly, combination of antiviral and anti-inflammatory drugs simultaneously inhibit seasonal coronavirus-triggered inflammatory response and viral replication. Collectively, these findings show that the TLR4/NF-κB/NLRP3 axis drives seasonal coronavirus triggered-inflammatory response, which in turn represents a viable therapeutic target.

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.

Cost-Effectiveness Analysis of Increased Adalimumab Dose Intervals in Crohn's Disease Patients in Stable Remission: The Randomized Controlled LADI Trial.

BACKGROUND AND AIMS: We aimed to assess cost-effectiveness of increasing adalimumab dose intervals compared to the conventional dosing interval in patients with Crohn's disease [CD] in stable clinical and biochemical remission. DESIGN: We conducted a pragmatic, open-label, randomized controlled non-inferiority trial, comparing increased adalimumab intervals with the 2-weekly interval in adult CD patients in clinical remission. Quality of life was measured with the EQ-5D-5L. Costs were measured from a societal perspective. Results are shown as differences and incremental net monetary benefit [iNMB] at relevant willingness to accept [WTA] levels. RESULTS: We randomized 174 patients to the intervention [n = 113] and control [n = 61] groups. No difference was found in utility (difference: -0.017, 95% confidence interval [-0.044; 0.004]) and total costs (-€943, [-€2226; €1367]) over the 48-week study period between the two groups. Medication costs per patient were lower (-€2545, [-€2780; -€2192]) in the intervention group, but non-medication healthcare (+€474, [+€149; +€952]) and patient costs (+€365 [+€92; €1058]) were higher. Cost-utility analysis showed that the iNMB was €594 [-€2099; €2050], €69 [-€2908; €1965] and -€455 [-€4,096; €1984] at WTA levels of €20 000, €50 000 and €80 000, respectively. Increasing adalimumab dose intervals was more likely to be cost-effective at WTA levels below €53 960 per quality-adjusted life year. Above €53 960 continuing the conventional dose interval was more likely to be cost-effective. CONCLUSION: When the loss of a quality-adjusted life year is valued at less than €53 960, increasing the adalimumab dose interval is a cost-effective strategy in CD patients in stable clinical and biochemical remission. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT03172377.

Immunosuppressants exert differential effects on pan-coronavirus infection and distinct combinatory antiviral activity with molnupiravir and nirmatrelvir.

BACKGROUND: Immunocompromised populations, such as organ transplant recipients and patients with inflammatory bowel disease (IBD) receiving immunosuppressive/immunomodulatory medications, may be more susceptible to coronavirus infections. However, little is known about how immunosuppressants affect coronavirus replication and their combinational effects with antiviral drugs. OBJECTIVE: This study aims to profile the effects of immunosuppressants and the combination of immunosuppressants with oral antiviral drugs molnupiravir and nirmatrelvir on pan-coronavirus infection in cell and human airway organoids (hAOs) culture models. METHODS: Different coronaviruses (including wild type, delta and omicron variants of SARS-CoV-2, and NL63, 229E and OC43 seasonal coronaviruses) were used in lung cell lines and hAOs models. The effects of immunosuppressants were tested. RESULTS: Dexamethasone and 5-aminosalicylic acid moderately stimulated the replication of different coronaviruses. Mycophenolic acid (MPA), 6-thioguanine (6-TG), tofacitinib and filgotinib treatment dose-dependently inhibited viral replication of all tested coronaviruses in both cell lines and hAOs. The half maximum effective concentration (EC50) of tofacitinib against SARS-CoV-2 was 0.62 µM and the half maximum cytotoxic concentration (CC50) was above 30 µM, which resulted in a selective index (SI) of about 50. The anti-coronavirus effect of the JAK inhibitors tofacitinib and filgotinib is dependent on the inhibition of STAT3 phosphorylation. Combinations of MPA, 6-TG, tofacitinib, and filgotinib with the oral antiviral drugs molnupiravir or nirmatrelvir exerted an additive or synergistic antiviral activity. CONCLUSIONS: Different immunosuppressants have distinct effects on coronavirus replication, with 6-TG, MPA, tofacitinib and filgotinib possessing pan-coronavirus antiviral activity. The combinations of MPA, 6-TG, tofacitinib and filgotinib with antiviral drugs exerted an additive or synergistic antiviral activity. Thus, these findings provide an important reference for optimal management of immunocompromised patients infected with coronaviruses.

Results of the Eighth Scientific Workshop of ECCO: Prevention and Treatment of Postoperative Recurrence in Patients With Crohn's Disease Undergoing an Ileocolonic Resection With Ileocolonic Anastomosis.

Despite the introduction of biological therapies, an ileocolonic resection is often required in patients with Crohn's disease [CD]. Unfortunately, surgery is not curative, as many patients will develop postoperative recurrence [POR], eventually leading to further bowel damage and a decreased quality of life. The 8th Scientific Workshop of ECCO reviewed the available scientific data on both prevention and treatment of POR in patients with CD undergoing an ileocolonic resection, dealing with conventional and biological therapies, as well as non-medical interventions, including endoscopic and surgical approaches in case of POR. Based on the available data, an algorithm for the postoperative management in daily clinical practice was developed.