Inflammatory Bowel Disease Events Research Articles

Left middle cerebral artery and sigmoid sinuses thrombosis in a female patient with Crohn's disease

Introduction: Neurologic manifestations in patients with inflammatory bowel disease (IBD) appear to be more common than in the past. However, vascular events in IBD are still a rare presentation and were reported in few cases. Case presentation: A 48-year-old female patient known case of Crohn’s disease presented with sudden onset aphasia, headache, blurring of vision, and decreased level of consciousness for 2 hours. The patient looked ill, confused, agitated, and aphasic. Neurologic examination shows dysarthria and 0/5 power of the right upper and lower extremity. A brain CT without contrast was ordered and showed acute ischemic stroke. The patient received tPA (alteplase) immediately in the intensive care unit and was under observation. On admission, brain CT angiography, MRI, and MRV were performed, which showed middle cerebral artery and sigmoid sinuses thrombosis. The patient has undergone cerebral catheterization, and an MCA stent was inserted. Post catheterization, the patient’s right-sided extremity power was improved to 3/5. She was discharged from the hospital after 13 days in good general condition except for her expressive aphasia. Conclusion: To the best of our knowledge, here we report the first case presented with both; cerebral venous sinus thrombosis and cerebral arteries thrombosis in a patient with IBD. Clinicians must be considered ischemic stroke in any patients with IBD presented with acute neurological manifestation, and an urgent interventional approach must be performed.

Crosstalk between alternative splicing and inflammatory bowel disease: Basic mechanisms, biotechnological progresses and future perspectives.

Alternative splicing (AS) is an omnipresent regulatory mechanism of gene expression that enables the generation of diverse splice isoforms from a single gene. Recently, AS events have gained considerable momentum in the pathogenesis of inflammatory bowel disease (IBD). Our review has summarized the complex process of RNA splicing, and firstly highlighted the potential involved molecules that target aberrant splicing events in IBD. The quantitative transcriptome analyses such as microarrays, next-generation sequencing (NGS) for AS events in IBD have been also discussed. Available evidence suggests that some abnormal splicing RNAs can lead to multiple intestinal disorders during the onset of IBD as well as the progression to colitis-associated cancer (CAC), including gut microbiota perturbations, intestinal barrier dysfunctions, innate/adaptive immune dysregulations, pro-fibrosis activation and some other risk factors. Moreover, current data show that the advanced technologies, including microarrays and NGS, have been pioneeringly employed to screen the AS candidates and elucidate the potential regulatory mechanisms of IBD. Besides, other biotechnological progresses such as the applications of third-generation sequencing (TGS), single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST), will be desired with great expectations. To our knowledge, the current review is the first one to evaluate the potential regulatory mechanisms of AS events in IBD. The expanding list of aberrantly spliced genes in IBD along with the developed technologies provide us new clues to how IBD develops, and how these important AS events can be explored for future treatment.

S899 Predictors of Major Adverse Cardiac and Cerebrovascular Events in Inflammatory Bowel Disease Using Artificial Neural Network Analysis in a Nationally Representative US Cohort

S899 Predictors of Major Adverse Cardiac and Cerebrovascular Events in Inflammatory Bowel Disease Using Artificial Neural Network Analysis in a Nationally Representative US Cohort

Prior Authorizations Delay Therapy, Impact Decision-making, and Lead to Adverse Events in Inflammatory Bowel Disease: 2022 Provider Survey

Prior Authorizations Delay Therapy, Impact Decision-making, and Lead to Adverse Events in Inflammatory Bowel Disease: 2022 Provider Survey

IL-17 inhibitor-associated inflammatory bowel disease: A study based on literature and database analysis.

Objective: Few real-world studies have shown clear association between interleukin (IL)-17 inhibitors and inflammatory bowel disease (IBD) onset. This study investigated the reporting prevalence and evaluated the clinical features and management of IL-17 inhibitor-related IBD events. Methods: We used the US FDA Adverse Event Reporting System database and retrieved data, from 2015 to 2022, on IL-17 inhibitors to identify gastrointestinal inflammatory events and conduct disproportionality analyses by estimating the reporting odds ratios (RORs) and corresponding 95% confidence intervals (CIs). Furthermore, case reports and case series, from 2015 to 30 November 2022, on IBD induced by IL-17 inhibitors were collected for retrospective analysis. Results: A total of 388 cases of primary suspected IL-17 inhibitor-associated gastrointestinal events were reported (268 IBD and 120 colitis), including 348 cases involving secukinumab (SEC), 36 cases involving ixekizumab (IXE), and 4 cases involving brodalumab (BRO). Statistically significant reporting rates of total IBD events were observed for SEC and IXE (ROR = 2.13, 95% CI [1.96-2.30] and ROR = 2.79, 95% CI [2.39-3.27], respectively), whereas BRO did not trigger a safety signal. Twenty-nine studies, which included 34 cases, showed evidence of IBD, following SEC (79.4%) and IXE (20.6%) treatment. The median age was 42years; typical initial symptoms included diarrhea (90.9%), abdominal pain (57.6%), bloody diarrhea (51.5%), and fever (36.4%). The median time to onset of IBD symptoms was 2.9months. Some cases were accompanied by elevated white blood cell (WBC) count (87.5%), erythrocyte sedimentation rate (ESR; 85.7%), C-reactive protein (CRP; 100%), and fecal calprotectin (FC; 100%). Cessation of IL-17 inhibitors plus treatment with corticosteroids and TNF antagonists, as either monotherapy or in combination, could lead to complete clinical remission. The median time to remission after IL-17 inhibitor discontinuation was 4weeks. Conclusion: IL-17 inhibitor treatment is associated with exacerbation and new onset of IBD and colitis. Obtaining a detailed patient history before initiation of treatment and monitoring gastrointestinal symptoms and intestinal inflammatory biomarkers during IL-17 inhibitor treatment is important for safe use of these drugs.

A66 PROTON PUMP INHIBITORS AND THE RISK OF INFLAMMATORY BOWEL DISEASE: A REAL WORLD POPULATION-BASED COHORT STUDY

Abstract Background Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) are acid suppressant drugs indicated in highly prevalent conditions such as gastroesophageal reflux disease and peptic ulcer disease. A recent observational study reported an increased risk of inflammatory bowel disease (IBD) with the use of PPIs. However, this association may have been driven by certain methodological shortcomings, such as failure to properly account for protopathic bias, a conclusion-altering bias. Purpose To determine whether the use of PPIs compared with the use of H2RAs is associated with an increased risk of IBD. Method Using the longitudinal primary care records from the United Kingdom Clinical Practice Research Datalink database, we identified 1,498,416 initiators of PPIs and 322,474 initiators of H2RAs from January 1, 1990, through December 31, 2018, with follow-up until December 31, 2019. Standardized morbidity ratio weighted Cox proportional hazards models were used to estimate marginal hazard ratios (HRs) and 95% confidence intervals (CIs). Patients were analyzed according to the timing of the IBD events after treatment initiation (early versus late). In the early-event analysis, IBD events were assessed within the first two years of treatment initiation, an analysis subject to potential protopathic bias. In the late-event analysis, all exposures were lagged by two years to account for latency and minimize protopathic bias. Result(s) In the early-event analysis, the use of PPIs was associated with an increased risk of IBD within the first two years of treatment initiation, compared with H2RAs (HR: 1.39, 95% CI: 1.14-1.69). In contrast, the use of PPIs was not associated with an increased risk of IBD in the late-event analysis (HR: 1.05, 95% CI: 0.90 to 1.22). The results remained consistent in several sensitivity analyses. Image Conclusion(s) Compared with H2RAs, PPIs were not associated with an increased risk of IBD, after accounting for protopathic bias. Please acknowledge all funding agencies by checking the applicable boxes below CIHR Disclosure of Interest R. Yanofsky: None Declared, D. Abrahami Employee of: pfizer, R. Pradhan: None Declared, H. Yin: None Declared, E. McDonald: None Declared, A. Bitton Consultant of: Member of Advisory Boards for Abbie, Pfizer, Takeda, Jansen, and Merck, Speakers bureau of: Has received speaker fees for Abbie, Jansen, Takeda, and Pfizer, L. Azoulay Consultant of: Has received consults fees from Jansen, Pfizer, and Roche, Speakers bureau of: Has received speaker fees from Jansen, Pfizer, and Roche

Systematic Review and Meta-Analysis of Observational Studies on the Effectiveness and Safety of Ustekinumab among Patients with Inflammatory Bowel Disease in Eastern and Western Countries.

Ustekinumab (UST) is an IL12/23 inhibitor utilized for altering inflammatory responses in inflammatory bowel disease (IBD). Clinical trials and case reports suggested that the effectiveness and safety of UST may differ among IBD patients in Eastern and Western countries. However, related data have not been systematically reviewed and analyzed. This systematic review and meta-analysis of the safety and effectiveness of UST in IBD included relevant literature from the Medline and Embase databases. The main outcomes were clinical response, clinical remission, endoscopic response, endoscopic remission, and adverse events in IBD. We analyzed 49 real-world studies, most of which included patients with biological failure (89.1% CD and 97.1% UC). In UC patients, clinical remission rates were 34% at 12 weeks, 40% at 24 weeks, and 37% at 1 year. In CD patients, clinical remission rates were 46% at 12 weeks, 51% at 24 weeks, and 47% at 1 year. Clinical remission rates of CD patients were 40% at 12 weeks and 44% at 24 weeks in Western countries, versus 63% and 72% in Eastern countries, respectively. UST is an effective drug for IBD with a promising safety profile. Although no RCTs have been performed in Eastern countries, the effectiveness of UST on CD patients is not inferior to that in Western countries based on the existing data.

Akkermansia deficiency and mucin depletion are implicated in intestinal barrier dysfunction as earlier event in the development of inflammation in interleukin-10-deficient mice.

Dysbiosis and mucin depletion are related with intestinal barrier dysfunction and seems to be an early pathophysiological event in inflammatory bowel disease (IBD). The objective of this work is to study these parameters in the natural history of colitis in IL-10 deficient mice (IL-10-/-). Wild type (WT) and IL-10-/-. mice were followed until sacrifice at 3, 5, 10, 20, 57, and 70 weeks. Body weight, colonic weight/length ratio and in vivo intestinal permeability were registered. Expression of inflammatory and adhesion molecules in the colon was explored by qPCR as Mucin-2 (MUC-2) and molecules involved in goblet cell maturation Interleukin-18 (IL-18) and WAP Four-Disulfide Core Domain 2 (WFDC2), the endoplasmic reticulum stress markers X-box-binding protein (Xbp-1) and Reticulon-4B (RTN-4B). Bacterial composition in feces and colonic mucosa was determined by massive sequencing of the V3-V4 regions of 16S rDNA gene. IL-10-/- mice showed histological inflammation at weeks 20 and 57, but most notably the intestinal permeability was significantly higher from week 10. Concordantly, the number of goblet cells and expression of MUC-2, IL-18, WFDC2 and Xbp-1 were significantly lower in KO from week 10. Nevertheless, no significant differences were found in the mRNA expression of MUC-2 or Xbp-1 between both groups-derived colon organoids. Significant bacterial differences began at week 5, being the Akkermansia deficiency in KO the most relevant result. Gut microbiota alterations and mucin depletion are associated with early intestinal barrier dysfunction and precede overt gut inflammation in this animal model of IBD.

Occurrence of inflammatory bowel disease in patients with chronic inflammatory skin diseases: a cohort study: Classification: Epidemiology.

Several studies have linked various chronic inflammatory skin diseases (CISDs) with inflammatory bowel disease (IBD) in a range of data sources with mixed conclusions. We compared the incidence of IBD - ulcerative colitis (UC) and Crohn disease (CD) - in patients with a CISD vs. similar persons without a CISD. In this cohort study using nationwide, longitudinal, commercial insurance claims data from the USA, we identified adults and children who were seen by a dermatologist between 2004 and 2020, and diagnosed with either psoriasis, atopic dermatitis, alopecia areata, vitiligo or hidradenitis suppurativa. Comparator patients were identified through risk-set sampling; they were eligible if they were seen by a dermatologist at least twice and not diagnosed with a CISD. Patient follow-up lasted until either IBD diagnosis, death, disenrolment or end of data stream, whichever came first. IBD events, UC or CD, were identified via validated algorithms: hospitalization or diagnosis with endoscopic confirmation. Incidence rates were computed before and after adjustment via propensity-score decile stratification to account for IBD risk factors. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated to compare the incidence of IBD in CISD vs. non-CISD. We identified patients with atopic dermatitis (n = 123 614), psoriasis (n = 83 049), alopecia areata (n = 18 135), vitiligo (n = 9003) or hidradenitis suppurativa (n = 6806), and comparator patients without a CISD (n = 2 376 120). During a median follow-up time of 718 days, and after applying propensity-score adjustment for IBD risk factors, we observed increased risk of both UC (HRUC 2·30, 95% CI 1·61-3·28) and CD (HRCD 2·70, 1·69-4·32) in patients with hidradenitis suppurativa, an increased risk of CD (HRCD 1·23, 1·03-1·46) but not UC (HRUC 1·01, 0·89-1·14) in psoriasis, and no increased risk of IBD in atopic dermatitis (HRUC 1·02, 0·92-1·12; HRCD 1·08, 0·94-1·23), alopecia areata (HRUC 1·18, 0·89-1·56; HRCD 1·26, 0·86-1·86) or vitiligo (HRUC 1·14, 0·77-1·68; HRCD 1·45, 0·87-2·41). IBD was increased in patients with hidradenitis suppurativa. CD alone was increased in patients with psoriasis. Neither UC nor CD was increased in patients with atopic dermatitis, alopecia areata or vitiligo. What is already known about this topic? Several studies have linked various chronic inflammatory skin diseases (CISDs) with inflammatory bowel disease (IBD) utilizing a range of data sources, with mixed conclusions. What does this study add? This large-scale, claims-based cohort study expands current knowledge by providing background rates for IBD across multiple CISDs using consistent methods and within a single, nationally representative patient population. We observed a relative increased risk of IBD in patients with hidradenitis suppurativa, but the overall incidence rate difference of IBD was generally low. Crohn disease alone was significantly increased in patients with psoriasis, and neither ulcerative colitis nor Crohn disease was increased in patients with atopic dermatitis, vitiligo or alopecia areata.

Impact of BNT162b2 mRNA Vaccination on the Development of Short and Long-Term Vaccine-Related Adverse Events in Inflammatory Bowel Disease: A Multi-Center Prospective Study.

IntroductionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination has been effective in protecting against severe COVID-19 infections and related mortality. It is recommended for all individuals including patients with inflammatory bowel disease (IBD). However, safety data are lacking in this group of patients. Therefore, we aim to evaluate the short- and long-term vaccine related adverse events (AEs) in patients with IBD.MethodsThis is a prospective, observational cohort study investigating short- and long-term AEs related to the BNT162b2 vaccine in patients with IBD (study group) after the first and second dose compared to healthy participants (control group). Patients were recruited at the time of attendance to the clinic or infusion rooms. Short term (<3 weeks) localized and systemic AEs were assessed via questionnaire. Follow-up phone-based survey was made to collect data on long term (up to 24 weeks) AEs.ResultsA total of 408 patients answered the questionnaires, 204 patients in each group, the study and control group. No serious adverse events were reported in either the study or the control group after the first or the second dose. Participants in the control group reported more frequent pain at the injection site than those in the study group after the first dose [58 (57%) vs. 38 (37%) respectively, P = 0.005]. After the second dose, tiredness was reported more frequently in the control group [49 (48%)] compared to the study group [25 (24%) (P < 0.001)]. At 20–24 weeks post vaccination, 386 out of 408 (94.6%) patients were willing to participate in the follow-up phone based questionnaire [196 (96.1%) in the study group vs. 190 (93.1%) in the control group]. In both groups, none of the patients reported local, systemic, or severe adverse events (0 out of 386) at week 20–24 post second dose.ConclusionThe BNT162b2 vaccine is safe in patients with IBD. No severe or long-term adverse events were reported in our study. The frequency of local and systemic adverse events after the second dose was generally higher among healthy participants compared to patients with IBD. Further studies including a larger cohort with a longer follow-up duration are needed to assess for possible rare adverse events.

Safety of Ixekizumab in Adult Patients with Moderate-to-Severe Psoriasis: Data from 17 Clinical Trials with Over 18,000 Patient-Years of Exposure

IntroductionWe report a comprehensive summary of the safety outcomes in adult patients with moderate-to-severe psoriasis with up to 5 years of exposure to ixekizumab.MethodsLong-term safety of the IL-17A antagonist ixekizumab was assessed from 17 randomized trials. Treatment-emergent adverse events (TEAEs)-adjusted incidence rates (IRs) per 100 patient-years (PY) within 1-year time periods through 19 March 2021 were calculated for all patients treated with at least one dose of ixekizumab. Reported cases of major adverse cerebro-cardiovascular events (MACE) and inflammatory bowel disease (IBD) were adjudicated.ResultsA total of 6892 adult patients with a cumulative exposure of 18,025.7 PY were included. The IRs per 100 PY for any TEAE and serious adverse events (AEs) were 32.5 and 5.4. IR of discontinuation because of AE was 2.9. A total of 36 deaths were reported. IR of serious infections was low (1.3). There were no confirmed cases of reactivation of tuberculosis (TB). IR of Candida infections (IR 1.9) was low; most cases of Candida were localized, and no systemic cases were reported. IRs of injection site reactions and allergic/hypersensitivity were 5.9 and 5.6, respectively. No confirmed cases of anaphylaxis were observed. IRs were low for malignancies, depression, cytopenia, and MACE (all ≤ 1.2). IBD events were uncommon, although a total of 31 patients (IR 0.2) had confirmed IBD (ulcerative colitis, n = 18; Crohn disease, n = 13). Across safety topics, IRs decreased or remained constant over time.ConclusionsThe long-term safety profile for ixekizumab is consistent with that previously reported in patients with psoriasis. No new or unexpected safety events were detected.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-022-00743-9.

Lack of Monitoring Is Associated with Risk of Acute Kidney Events among Patients with Inflammatory Bowel Disease.

Background: Although the iatrogenic risk of kidney failure is infrequent with treatment for inflammatory bowel disease (IBD), the repercussions for the patient could be major. The aim of this study was to assess the incidence of kidney events in IBD and to examine the protective effect of kidney function monitoring. Methods: In the French National Health Insurance database, 94,363 patients had a diagnosis of IBD between January 2010 and December 2016. By using a survival model with time-dependent covariates, we analyzed the time from inclusion in this IBD cohort to the first hospitalization for acute kidney impairment (AKI) according to patient characteristics, comorbidities, IBD phenotype and presence of monitoring. Results: A total of 693 patients were hospitalized for AKI, with an incidence of 1.36/1000 person–years (95% confidence interval [CI] 1.26–1.47). The incidence of AKI was lower than those without 5-aminosalicylic acid (5-ASA) use. Patients with 5-ASA use rarely had any lack of monitoring as compared with those not under 5-ASA use (3% vs. 17%). On multivariate analysis, lack of monitoring was associated with a substantial risk of AKI (hazard ratio 3.96, 95% CI [3.20–4.90], p < 0.0001). Conclusions: Increased frequency of monitoring is essential to identify nephropathy at an early stage and avoid the progression to chronic kidney disease.

Safety of SARS-CoV-2 vaccination in patients with inflammatory bowel disease: A systematic review and meta-analysis.

IntroductionRisk of adverse effects and flare of inflammatory bowel disease (IBD) are frequently cited reasons for COVID-19 vaccine hesitancy.MethodsElectronic databases were searched to identify studies reporting the use of COVID-19 vaccine in IBD. We selected studies reporting the incidence of various adverse effects (local or systemic) and flares of IBD after COVID-19 vaccination. The pooled incidence rates for various adverse effects, stratified for the dose and the type of vaccine (adenoviral or mRNA) were estimated.ResultsNine studies (16 vaccination cohorts) were included. The pooled incidence rate of overall adverse events was 0.55 (95%CI, 0.45–0.64, I2= 95%). The pooled incidence rate of local adverse events was 0.64 (0.47–0.78, I2= 100%). The pooled incidence rates of fatigue, headache, myalgia, fever and chills were 0.30 (0.21–0.40, I2= 99%), 0.23 (0.17–0.30, I2= 99%), 0.18 (0.13–0.24, I2= 99%), 0.10 (0.06–0.17, I2= 98%) and 0.15 (0.06–0.3, I2= 86%), respectively. The pooled incidence rates of severe adverse events, adverse events requiring hospitalization and flares of IBD following COVID-19 vaccination were 0.02 (0.00–0.12, I2= 97%), 0.00 (0.00–0.01, I2= 27%) and 0.01 (0.01–0.03, I2= 45%), respectively.ConclusionCOVID-19 vaccination in patients with IBD appears to be safe with only mild adverse events. Flares of IBD and severe adverse events requiring hospitalization were infrequent.

P361 PREPARE-IBD: Physician Responses to disease Flares and Patient Adaptation in Relation to Events in Inflammatory Bowel Disease during the COVID-19 pandemic: A multicentre cohort analysis

BackgroundThe COVID-19 pandemic continues to pose complex problems across Europe and the world, with rising numbers of infections and the ongoing need for drastic public health interventions. This is difficult for patients with immune-mediated disorders like Inflammatory Bowel Disease (IBD), where immunosuppressive medications may affect susceptibility to serious infection. It was particularly challenging for physicians and patients during the first wave of the pandemic, when it was unclear whether anti-inflammatory flare treatment should be adapted to reduce infection risk, whilst trying to ensure symptomatic control and avoid admission to overwhelmed hospitals. Despite the development of various IBD / COVID-19 databases, the treatment adaptations and outcomes of patients experiencing IBD flares during the COVID-19 pandemic remain undefined. We aimed to compare IBD management and outcomes between pandemic and pre-pandemic cohorts.MethodsAn observational cohort study was performed, comprising patients who contacted IBD teams for a symptom flare between March – June, 2020 in, 60 National Health Service trusts in the United Kingdom. Data were compared to a pre-pandemic cohort after propensity-matching for age and disease severity. Statistical analyses were performed using R (version, 4.1.0, Vienna, Austria).ResultsIn total, 3728 patients in the pandemic (n=1864) and pre-pandemic (n=1864) cohorts were included. The principal findings were reduced systemic corticosteroid prescription during the pandemic in both Crohn’s disease (prednisolone: pandemic, 199/752, 26.5% vs, 263/708, 37.1%; p<0.001) and ulcerative colitis (UC) (prednisolone: pandemic, 372/1112, 33.5% vs, 470/1156, 40.7%, p<0.001), with increases in poorly bioavailable oral corticosteroids in Crohn’s (pandemic, 117/752, 15.6% vs, 48/708, 6.8%; p<0.001) and UC (pandemic, 131/1112, 11.8% vs, 60/1156, 5.2%; p<0.001). Ustekinumab (Crohn’s and UC) and vedolizumab (UC) treatment also significantly increased during the pandemic. Three-month steroid-free remission was similar in both Crohn’s (pandemic, 175/616, 28.4% vs, 195/608, 32.1%; p=0.17) and UC (pandemic, 312/858, 36.4% vs, 404/1006, 40.2%; p=0.095). The, 65 patients experiencing a flare and COVID-19 were more likely to have moderate-to-severely active disease at three months compared to those with a flare alone.ConclusionDespite several treatment adaptations during the pandemic, steroid-free outcomes were comparable to pre-pandemic levels, though patients with a flare and COVID-19 experienced worse outcomes. These findings have implications for IBD management during future waves or pandemics

Systematic Review and Meta-Analysis of Inflammatory Bowel Disease Adverse Events with Anti-Interleukin 17A Agents and Tumor Necrosis Factor Inhibitors in Rheumatic Disease and Skin Psoriasis.

IntroductionThe aim of this work is to perform a systematic review and meta-analysis of anti-tumor necrosis factor (anti-TNF) and anti-interleukin-17 (anti-IL-17) trials for spondyloarthritis, psoriatic arthritis, and psoriasis comparing rates of inflammatory bowel disease (IBD) events compared to placebo.MethodsMEDLINE, EMBASE, and The Cochrane Library were searched for double-blind, randomized placebo-controlled anti-TNF and anti-IL-17 trials of included diseases. Inflammatory bowel disease events from the RCT period were pooled and meta-analyzed using statistical methods suitable for low-event-rate meta-analysis (Peto’s, Mantel–Haenszel, hypergeometric-normal model, and Shuster-Guo-Skyler). When observed data were insufficient, we performed an exploratory sensitivity analysis to compare methods.ResultsWe identified 9551 original papers, and included 96 publications: 65 anti-TNF and 31 anti-IL-17 trials, containing 21 new and 12 flare IBD events in 28,209 participants. New IBD on anti-IL-17 occurred 0.23/100 patient-years (PY) in psoriasis, 0.61/100 PY in PsA and 1.63/100 PY in spondyloarthritis, rates similar to observational cohorts, and less commonly on anti-TNF (0/100 PY, 0/100 PY, 0.32/100 PY, respectively). No evidence of difference between groups was found, with wide CI from many pooled counts of zero, especially in placebo arms.ConclusionsIBD events were rare, occurring at rates similar to biologic-naive groups. We could not find statistically significant differences in risk of new or recurrent IBD between treatment and control groups using selected meta-analytical methods for low event rate scenarios. Meta-analyses of this topic require more IBD events, ideally without pooling heterogeneous groups. Larger, thoroughly reported trials with systematic and detailed safety reporting are required to improve risk estimation and to make accurate inferences.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00360-6.

Loss of PTPN2 in Intestinal Epithelial Cells Increases Invasion of Human Intestinal Epithelial Cells and Intestinal Permeability in Mice by Adherent‐invasive E. coli

Background : Alterations in epithelial tight junction proteins can compromise its ability to act as a barrier between luminal contents and underlying tissues, thereby increasing intestinal permeability, an early event in inflammatory bowel disease (IBD). Additionally, shifts in the gut microbiota and expansion of pathobionts such as adherent-invasive Escherichia coli (AIEC) are associated with the pathogenesis of IBD. Mice deficient in expression of the IBD gene candidate, Ptpn2,exhibit increased intestinal permeability and a pronounced expansion of a novel murine adherent-invasive Escherichia coli (mAIEC). This study aimed to investigate how PTPN2 expression in intestinal epithelial cells modifies mAIEC invasiveness and host-barrier properties after infection using in vitro and in vivo models. Methods First, we generated a fluorescent-tagged mAIEC strain — mAIECred. Caco-2BBe intestinal epithelial cells (IEC), stably expressing either scrambled shRNA or shRNA against Ptpn2, were infected with mAIECred. Tamoxifen-inducible, intestinal epithelial cell-specific knockout mice (Ptpn2∆IEC) and control littermates (Ptpn2fl/fl) were infected with either PBS, E. coli K12 or mAIECred. FITC-Dextran (FD4) and Rhodamine-Dextran (RD70) permeability probes were administered by oral-gavage. Post-necropsy, bacterial colonies were enumerated from mouse tissues. Results First we tested if PTPN2 deficiency in human IEC altered mAIECred invasion. Immunofluorescence showed that PTPN2 knockdown (KD) IECs exhibited increased bacterial invasion compared to control IECs (n=3). To confirm our results in an in vivo model, we infected Ptpn2∆IEC mice with either E. coli K12 or mAIECred or administered PBS as vehicle control. E. coli K12 increased FD4 but not RD70 permeability in Ptpn2∆IEC mice compared with Ptpn2fl/fl mice (P=0.0025; n=5-9) while mAIECred caused an even greater increase in FD4 permeability in Ptpn2∆IEC vs. Ptpn2fl/fl mice (P< 0.0001; n=6-9). Ptpn2∆IEC mice also exhibited higher mAIECred - but not K12 - bacterial load in distal colon tissue compared to Ptpn2fl/fl mice (P=0.038; n=9-12). As FD4 permeability was increased in Ptpn2∆IEC mice infected with K12 and mAIECred, we wanted to determine if this corresponded with changes in expression of relevant tight junction proteins. Western blot analysis from isolated IEC's revealed Ptpn2∆IEC mice infected with mAIECred had decreased E-cadherin (P=0.0142; n=4) and Occludin (P=0.0030; n=4). Conversely, we observed increased Claudin-2 in PBS and K12-infected Ptpn2∆IEC vs. Ptpn2fl/fl mice (P=0.015; n=4). mAIECred increased Claudin-2 levels above control(s) to comparable levels in Ptpn2fl/fl and Ptpn2∆IEC mice (P= 0.025; n=4). Conclusion Intestinal epithelial PTPN2 is critical in maintaining intestinal homeostasis by restricting bacterial invasion and preserving intestinal barrier function. Given that loss of PTPN2 in vivo also provokes expansion of AIEC, these studies indicate that PTPN2 is an important mediator of host-microbiome crosstalk.

Trends in Corticosteroid Use During the Era of Biologic Therapy: A Population-Based Analysis.

Corticosteroids are effective for inducing clinical remission in inflammatory bowel disease (IBD), but not for maintaining remission. Reducing corticosteroid use and dependence is an important treatment goal since their use is associated with adverse events. The extent to which the improvements in IBD therapy have led to less corticosteroid use in the modern era remains unclear. We used the University of Manitoba Inflammatory Bowel Disease Epidemiologic Database to assess the cumulative annual dosing of corticosteroids on a per-patient basis for all persons with IBD in the province of Manitoba between 1997 and 2017. Joinpoint analysis was used to assess for trends in corticosteroid use and to look at variation in the trends over time. The mean annual exposure to corticosteroids decreased from 419 mg/yr (1997) to 169 mg/yr (2017) for Crohn's disease (CD) (annual decline: 3.8% per year, 95% confidence interval 3.1-4.6) and from 380 to 240 mg/yr in ulcerative colitis (UC) (annual decline: 2.5% per year, 95% confidence interval 2.1-2.8). In CD, there was an acceleration in the rate of decline after 2007 (pre-2007, 1.9% decline per year; after 2007, 5.7% per year); there was no corresponding acceleration in the rate of decline in UC. Corticosteroid use has decreased in both CD and UC over the past 2 decades, becoming more pronounced after 2007 in CD. Potential explanations include introduction and increasing penetrance of biologic therapy in CD and greater awareness of corticosteroid-related adverse events in IBD. Further work is required understand the drivers of persistent corticosteroid use in IBD and how this can be further reduced.

Thromboembolic and atherosclerotic cardiovascular events in inflammatory bowel disease: epidemiology, pathogenesis and clinical management.

Inflammatory bowel disease (IBD) is associated with an increased risk of cardiovascular disease (CVD). The increased risk of CVD concerns an increased risk of venous thromboembolism (VTE), atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF), at corresponding relative risks of 2.5, 1.2 and 2.0, respectively, as compared with the general population. Especially young patients under the age of 40 years run a relatively high risk of these complications when compared with the general population. Chronic systemic inflammation causes a hypercoagulable state leading to the prothrombotic tendency characteristic of VTE, and accelerates all stages involved during atherogenesis in ASCVD. Increased awareness of VTE risk is warranted in patients with extensive colonic disease in both ulcerative colitis and Crohn’s disease, as well as during hospitalization, especially when patients are scheduled for surgery. Similarly, critical periods for ASCVD events are the 3 months prior to and 3 months after an IBD-related hospital admission. The increased ASCVD risk is not fully explained by an increased prevalence of traditional risk factors and includes pro-atherogenc lipid profiles with high levels of small dense low-density lipoprotein cholesterol particles and dysfunctional high-density lipoprotein cholesterol. Risk factors associated with HF are location and extent of inflammation, female sex, and age exceeding 40 years. A dose-dependent increase of overall CVD risk has been reported for corticosteroids. Immunomodulating maintenance therapy might reduce CVD risk in IBD, not only by a direct reduction of chronic systemic inflammation but possibly also by a direct effect of IBD medication on platelet aggregation, endothelial function and lipid and glucose metabolism. More data are needed to define these effects accurately. Despite accumulating evidence on the increased CVD risk in IBD, congruent recommendations to develop preventive strategies are lacking. This literature review provides an overview of current knowledge and identifies gaps in evidence regarding CVD risk in IBD, by discussing epidemiology, pathogenesis, and clinical management.

Neurological Adverse Effects Associated With Anti-tumor Necrosis Factor Alpha Antibodies in Pediatric Inflammatory Bowel Diseases.

Neurological adverse effects (NAEs) induced by biotherapies have been reported in the literature mainly in adult patients with inflammatory bowel disease (IBD), rheumatic diseases, or psoriasis. There are scant data in children. Aims of this study are to report and describe noninfective NAE associated with anti-TNFα antibodies in pediatric IBD, and to evaluate their incidence. We retrospectively collected all reports of NAE in pediatric IBD treated with anti-TNFα antibodies recorded in the French Pharmacovigilance Database. To estimate the national incidence of NAEs, we extrapolated data from the French regional inception population-based cohort EPIMAD. Between 2000 and 2018, 231 adverse events in pediatric IBD exposed to anti-TNFα antibodies were reported to this Database. Seventeen NAEs (7.36%) were collected: 8 severe NAE (1 demyelinating neuropathy, 1 optic neuritis, 1 acute transverse myelitis, 1 polyradiculoneuritis, 1 sensorineural hearing loss, 1 seizure, 1 stroke, and 1 glioma), 7 moderate NAE (headaches), and 2 neuropsychic events. The median delay between anti-TNFα start and NAE occurrence was 6 months (range: 13 days to 26 months). In 10 of 17 patients, anti-TNFα antibodies were stopped. Nine of 17 patients had a complete resolution (including 2 severe NAE) and 8 of 17 a partial resolution (including 6 severe NAE). We estimate the incidence of severe NAE in pediatric IBD treated with anti-TNFα antibodies at 1 case for 10,000 patients-year in France. NAE associated with anti-TNFα antibodies in pediatric IBD are rare. In severe NAE, we recommend to discontinue anti-TNFα therapy and to consider alternative treatment.

Thromboembolic events in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is associated with an increased risk of thromboembolic events (TEE) during outbreaks, increasing morbidity and mortality. The aim of our study was to specify the prevalence of TEE in IBD patients and to determine their epidemiological, clinical and evolutionary characteristics. This is a retrospective study collecting all patients with IBD, who had a thromboembolic complication confirmed by imagery, between January 2012 and December 2018. One hundred patients with IBD were diagnosed during the study period. A TEE occurred in 6 patients (5.9%). These patients had an average age of 41 years, divided into 4 women and 2 men. Five patients had Crohn's disease and one patient had ulcerative colitis. The IBD was active in all patients. Five patients were already hospitalized and under preventive heparin therapy. Patients had deep venous thrombosis of the lower limbs in 3 cases, associated with pulmonary embolism in 1 case, cerebral venous thrombosis in 2 cases and pulmonary embolism isolated in 1 case. Thrombophilia investigations were negative in all patients. Evolution under medical treatment was favorable in 4 patients and fatal in 2 patients. In our study, the prevalence of TEE in patients with IBD was 5.9%. Thrombosis occurred during the active phase of IBD in all cases.