Inflammatory Bowel Disease Events Research Articles

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.

The JAK-Inhibitor Tofacitinib Rescues Human Intestinal Epithelial Cells and Colonoids from Cytokine-Induced Barrier Dysfunction.

Alterations to epithelial tight junctions can compromise the ability of the epithelium to act as a barrier between luminal contents and the underlying tissues, thereby increasing intestinal permeability, an early critical event in inflammatory bowel disease (IBD). Tofacitinib (Xeljanz), an orally administered pan-Janus kinase (JAK) inhibitor, was recently approved for the treatment of moderate to severe ulcerative colitis. Nevertheless, the effects of tofacitinib on intestinal epithelial cell functions are largely unknown. The aim of this study was to determine if JAK inhibition by tofacitinib can rescue cytokine-induced barrier dysfunction in intestinal epithelial cells (IECs). T84 IECs were used to evaluate the effects of tofacitinib on JAK-signal transducer and activator of transcription (STAT) activation, barrier permeability, and expression and localization of tight junction proteins. The impact of tofacitinib on claudin-2 promoter activity was assessed in HT-29 IECs. Tofacitinib rescue of barrier function was also tested in human colonic stem cell-derived organoids. Pretreatment with tofacitinib prevented IFN-γ-induced decreases in transepithelial electrical resistance (TER) and increases in 4 kDa FITC-dextran permeability (FD4), partly due to claudin-2 transcriptional regulation and restriction of ZO-1 rearrangement at tight junctions. Although tofacitinib administered after IFN-γ challenge only partially normalized TER and claudin-2 levels, FD4 permeability and ZO-1 localization were fully recovered. The IFN-γ-induced FD4 permeability in primary human colonoids was fully rescued by tofacitinib. These data suggest differential therapeutic efficacy of tofacitinib in the rescue of pore vs leak-tight junction barrier defects and indicate a potential contribution of improved epithelial barrier function to the beneficial effects of tofacitinib in IBD patients.

Incidence rates of inflammatory bowel disease in patients with psoriasis, psoriatic arthritis and ankylosing spondylitis treated with secukinumab: a retrospective analysis of pooled data from 21 clinical trials

ObjectivesHere, we present the reported incidence rates of inflammatory bowel disease (IBD) in patients receiving treatment with secukinumab for psoriasis (PsO), psoriatic arthritis (PsA) or ankylosing spondylitis (AS), in a...

Inflammatory bowel disease events after exposure to the interleukin-17 inhibitors ixekizumab and secukinumab: A report from the RADAR (Research on Adverse Drug Events and Reports) project

Inflammatory bowel disease events after exposure to the interleukin-17 inhibitors ixekizumab and secukinumab: A report from the RADAR (Research on Adverse Drug Events and Reports) project

Inflammatory bowel disease events after exposure to interleukin 17 inhibitors secukinumab and ixekizumab: Postmarketing analysis from the RADAR (“Research on Adverse Drug events And Reports”) program

Inflammatory bowel disease events after exposure to interleukin 17 inhibitors secukinumab and ixekizumab: Postmarketing analysis from the RADAR (“Research on Adverse Drug events And Reports”) program

Higher Infliximab Levels Are Not Associated With an Increase in Adverse Events in Inflammatory Bowel Disease.

Patients requiring optimization of therapy for suboptimal response and/or targeting more robust outcomes may eventually reach high serum levels. Data evaluating the relationship between infliximab concentration and toxicity are limited. The aim of this study was to evaluate the frequency of adverse events (AEs) in inflammatory bowel disease (IBD) patients with infliximab higher-range (HR) and lower-range (LR) trough levels. We performed a retrospective analysis of 180 patients with at least 1 measurement of serum infliximab from 2012 to 2016. The cohort was divided according to an infliximab level cutoff of 15 µg/mL (HR and LR). The primary outcome was frequency of AEs, including infections, dermatological manifestations, and infusion reactions, between the 2 groups. The secondary outcomes included frequencies of all AEs (dermatological manifestations, infusion reactions, autoimmune reactions, and opportunistic and serious infections) in both groups. AEs were also compared against observed infliximab level quartiles using logistic regression analysis. A total of 53 AEs in 47 patients were reported in the overall cohort. In the LR group, there were 36 AEs recorded in 30 patients, whereas in the HR group, 17 AEs were experienced by 17 patients. Patients with HR levels did not have a higher prevalence of infections in comparison with patients with LR levels (12.2% vs 18.8%; P = 0.3). Stratification of infliximab levels by quartiles showed a comparable frequency of infection. Our findings indicate that higher infliximab serum concentrations are not associated with a higher frequency of infections.

Steroid but not Biological Therapy Elevates the risk of Venous Thromboembolic Events in Inflammatory Bowel Disease: A Meta-Analysis.

Inflammatory bowel disease [IBD] is associated with a 1.5- to 3-fold increased risk of venous thromboembolism [VTE] events. The aim of this study was to determine the risk of VTE in IBD as a complication of systemic corticosteroids and anti-tumour necrosis factor alpha [TNFα] therapies. A systematic review and meta-analysis was conducted, which conforms to the Preferred Reporting Items for Systematic Reviews and Meta-analyses [PRISMA] statement. PubMed, EMBASE, Cochrane Library and Web of Science were searched for English-language studies published from inception inclusive of 15 April 2017. The population-intervention-comparison-outcome [PICO] format and statistically the random-effects and fixed-effect models were used to compare VTE risk during steroid and anti-TNFα treatment. Quality of the included studies was assessed using the Newcastle-Ottawa scale. The PROSPERO registration number is 42017070084. We identified 817 records, of which eight observational studies, involving 58518 IBD patients, were eligible for quantitative synthesis. In total, 3260 thromboembolic events occurred. Systemic corticosteroids were associated with a significantly higher rate of VTE complication in IBD patients as compared to IBD patients without steroid medication (odds ratio [OR]: 2.202; 95% confidence interval [CI]: 1.698-2.856, p < 0.001). In contrast, treatment with anti-TNFα agents resulted in a 5-fold decreased risk of VTE compared to steroid medication [OR: 0.267; 95% CI: 0.106-0.674, p = 0.005]. VTE risk should be carefully assessed and considered when deciding between anti-TNFα and steroids in the management of severe flare-ups. Thromboprophylaxis guidelines should be followed, no matter the therapy choice.

Incidence of Inflammatory Bowel Disease Events in Adalimumab Clinical Trials Across Indications

Abstract Not Available Disclosures: Study supported by AbbVie.

Abstract TP182: Risk of Acute Ischemic Stroke Increases During Severe Flares of Inflammatory Bowel Disease

Introduction: Flares of inflammatory bowel disease (IBD) have been associated with venous thromboembolism, and recent studies suggest an association between IBD and myocardial infarction. The association between IBD flares and cerebral thrombotic disease is less clear. We therefore sought to evaluate the risk of cerebral venous and arterial stroke during IBD flares. Hypothesis: IBD flares are associated with an increased risk of a cerebral thrombotic event. Methods: We used data on all admissions at nonfederal acute care hospitals in California, Florida, and New York to identify patients with a primary ICD-9-CM diagnosis code for ulcerative colitis or Crohn’s disease between 2005 and 2012. Patients with a documented abdominal surgery during the index hospitalization were excluded. An IBD flare was defined as a period of 120 days from the start of the index IBD-related hospitalization. Our outcomes were ischemic stroke and cerebral venous sinus thrombosis. We used a self-controlled case series design in which we compared the risk of a thrombotic event in the 120 days after hospitalization versus the risk during the 120 days prior to hospitalization. Results: We identified 31,993 patients with IBD, of whom 98 (0.31%) developed ischemic stroke. As compared with the control period preceding the index hospitalization, the risk of stroke was significantly elevated during the 120 days after IBD-related hospitalization (incidence rate ratio [IRR] 2.0; 95% confidence interval [CI] 1.3-3.0). In subgroup analyses, this elevated risk was apparent only in the 16,280 patients older than the median age of 44 years (IRR 1.9; 95% CI, 1.27-2.95), and not in the 15,713 patients younger than 44 years of age, among whom we identified only one stroke. We found only one patient with a documented venous sinus thrombosis and thus could not estimate the risk associated with an IBD flare. Conclusion: We found an association between IBD-related hospitalization and the risk of ischemic stroke in older patients. These results build on recent studies suggesting an association between IBD and the risk of arterial thrombotic events. Further research is needed to better define the association between IBD and cerebrovascular events, especially rare events such as cerebral sinus thrombosis.

Thromboembolic events in patients with inflammatory bowel disease.

Background/Aims:Inflammatory bowel disease (ulcerative colitis and Crohn's disease) is characterized by a chronic inflammatory condition, and is accompanied by abnormalities in coagulation and a hyper-coagulable state. This study was conducted to examine the risk factors for developing Thromboembolic Events in Inflammatory Bowel Disease (IBD) in a population with prevalent consanguinity.Patients and Methods:Patients with a definitive diagnosis of IBD who were seen in the gastroenterology clinic of King Khalid University Hospital (Riyadh, Saudi Arabia) from 2010- to 2012, were asked to participate in this prospective cohort study, and were followed for one 1 year. Data was collected using specifically designed case report forms (CRF) by trained research personnel.Results:A total of 100 Saudi patients with IBD were studied. There were 51 (51%) women and the mean ± standard deviation (SD) age of the group was 31.24 ± 10.78 years. Those with Crohn's disease constituted 72% of the patients, and 28% had ulcerative colitis. Eight patients (8%) had at least one Thrombotic Event ([six deep venous thrombosis (DVT), and two pulmonary embolism (PE)]. Family history of deep venous thrombosis was present in 5%, and family history of pulmonary embolism (PE) in 4% of the patients. After adjusting for age and gender, a family history of Thrombotic event was identified as to be the only statistically significant predictor of thrombosis in IBD patients (RR = 9.22, 95% CI: 2.10--40.43).Conclusion:In a population with high consanguinity, Thromboembolic events (DVT and PE) had a prevalence of 8% among IBD patients, positive family history of pulmonary embolism was a predictor of thrombosis. Further studies are needed to explore the role of genetic factors in this population.

Rates of serious infections, opportunistic infections, inflammatory bowel disease, and malignancies in subjects receiving etanercept vs. controls from clinical trials in ankylosing spondylitis: a pooled analysis

Objectives: Therapies involving anti-tumour necrosis factor are associated with increased risk of serious infections, opportunistic infections, and some types of malignancies in subjects with rheumatic diseases. However, limited data have been collected for subjects with ankylosing spondylitis (AS). The aim of this retrospective analysis of all sponsor-conducted trials was to examine the rates of serious infections, inflammatory bowel disease (IBD), malignancies, and non-malignant skin cancers during treatment in subjects with AS.Method: Data from five randomized controlled trials (one sulfasalazine-controlled, four placebo-controlled) and four open-label studies evaluating etanercept were pooled for analyses. All randomized subjects who received at least one dose of treatment were included in the study.Results: Analyses included 1323 subjects (> 1500 subject-years of treatment). Rate ratios of serious infections and IBD events for etanercept vs. placebo/sulfasalazine during the double-blind studies were 2.19 [95% confidence interval (CI) 0.22–107.79] and 1.09 (95% CI 0.06–64.56), respectively. There were no reports of opportunistic infections. Using the Surveillance, Epidemiology and End Results database, the standardized incidence ratio for malignancies was 1.47 (95% CI 0.54–3.21).Conclusions: These data suggest that etanercept is well tolerated in subjects with AS. Despite the large number of patients, the 95% CI data all cross 1.0, limiting possible conclusions. No new safety signals were observed.

P8: Dietary nitrite induces TFF3 and attenuates inflammation in experimental colitis

Nitric oxide (NO) and its derivative nitrite NO 2 - have evolved as important mediators in the prevention of gastrointestinal diseases. A central event in inflammatory bowel disease is the disruption of the mucosal homeostasis. Trefoil peptides (TFFs) are emerging as key mediators in the defense and repair of the gastrointestinal mucosa as they play a key role in epithelial restitution, the initial step in the wound healing process. Here we examined the anti-inflammatory effects of dietary NO 2 - and the potential role of TFFs in a model of ulcerative colitis: the dextran sulfate sodium (DSS) model. Balb/c mice were treated with DSS (2%, drinking water) in the presence of sodium nitrite (1 mg/kg, drinking water), or with 2.5% DSS for 3 days prior to administration of sodium nitrite. At the end of the experiment (7–10 days) the extent of inflammation was measured by the colon length, the disease activity index (DAI), and colonic expression of the intestinal trefoil factor (TFF3). In addition, colon epithelial cells (SW480) were treated with increasing doses of Na NO 2 - (1μM-1 mM), and the mRNA levels of TFF3 were evaluated. Finally, the effect of Na NO 2 - (1 μM−1 mM) was also analyzed in an in vitro wound healing assay (SW480 cells, 0–48 h). DSS groups (2% and 2.5%) developed colitis as evident by a marked reduction in colon length as well as an increase in DAI, compared to the control groups. In both groups nitrite reduced DAI score but the prevention of the decrease in colon length was only significant with 2% of DSS. The colonic levels of TFF3 increased in the presence of 2% DSS but decreased with 2.5% DSS administration. NO 2 - treatment increased TFF3 levels in both groups, but the effect was higher with 2% DSS. A dose-dependent response in mRNA expression of TFF3 was observed in SW480 cells after NO 2 - treatment; where a maximum increase in the expression was reached with 1–10 μM of nitrite. Interestingly, these results mirrored those obtained in the epithelial wound healing model in which nitrite increased the speed of repair. In conclusion, our results show that the dietary administration of nitrite reduces inflammation and improves clinical symptoms in DSS-induced colitis. This protection may involve regulation of the epithelial restitution process, as indicated by the increase in the healing process and the expression of TFF3 by dietary concentrations of nitrite. Disclosure Nothing to disclose.

Dysplastic Lesions in Inflammatory Bowel Disease: Molecular Pathogenesis to Morphology

Context.-Inflammatory bowel disease (IBD) is a long-standing chronic active inflammatory process in the bowel with increased risk for the development of colorectal carcinoma. Several molecular events involved in chronic active inflammatory processes contribute to multistage progression of human cancer development, including reactive oxygen and nitrogen species, aberrant arachidonic acid metabolites and cytokines/growth factors, and immune dysfunction. These molecular events in IBD lead to genetic abnormality and promote aberrant cell proliferation, which further lead to epithelial changes encompassing a broad spectrum from inflammation-induced hyperplasia to dysplasia. Objective.-To review the (1) epidemiologic and molecular pathogenesis of the risk for colorectal cancer in IBD, (2) morphologic characterization, biomarker(s), and classification of dysplastic lesions, and (3) clinical management of dysplastic lesions arising in IBD. Data Sources.-The different IBD-related dysplastic lesions are illustrated by using morphology in conjunction with molecular pathways, and the "field cancerization" theory and its potential significance are discussed with a review of the literature. Conclusions.-Patients with IBD are at increased risk of developing colorectal cancer. The risk of developing carcinoma is related to the extent/duration/activity of the patient's disease. There is no consensus regarding the extent of carcinoma risk associated with IBD; however, all would agree that patients with IBD represent a group at significant risk for developing carcinoma and as such, warrant adequate surveillance and prevention. With better screening modalities and detection/characterization of dysplastic lesions, IBD-associated serrated lesions, and "field cancerization," we will improve our understanding of and approach to risk stratification.

Establishment of a novel extracorporeal bowel model to study luminal approaches to treat inflammatory bowel disease

SUMMARYWe have established an extracorporeal bowel model system for the analysis of early events in inflammatory bowel disease (IBD) and therapeutic applications. This model consists of an intestinal segment that is cannulated and perfused in situ, allowing the investigation of cellular responses of apical mucosa cells on luminal applied substances. Short-term treatment with iodoacetamide mimicked experimental intestinal inflammation in IBD, as indicated by histological alterations such as hemorrhage, hyperemia and loss of regular crypt architecture, as well as enhanced expression of cytokines (e.g. IL-6, IL-10 and MCP-1) compared with control segments perfused with media. Perfusion of therapeutic agents (e.g. dexamethasone or Mutaflor) in the small intestine segment significantly reduced the features of early inflammation that are induced by iodoacetamide. Moreover, similar data were obtained for Resormin®, a montmorillonite-illite mixed-layer mineral (smectite), indicating that smectites might be a newly identified therapeutic option for IBD. In summary, this model could provide novel insights into epithelial injury as well as genesis of IBD and, therefore, be useful in testing the therapeutic potential of compounds for IBD therapy.

Dietary Conjugated Linoleic Acid Activates PPARγ and the Intestinal Trefoil Factor in SW480 Cells and Mice with Dextran Sulfate Sodium-Induced Colitis1–3

A central event in inflammatory bowel disease is the disruption of the mucosal homeostasis. Trefoil peptides [(TFF)] are emerging as key mediators in the defense and repair of the gastrointestinal mucosa. Here, we demonstrate induction of TFF by CLA with therapeutic antiinflammatory effects in a mouse model of inflammatory bowel disease. SW480 cells were treated with linoleic acid or CLA (0–2.5 μ mol/L) in the absence or presence of the PPARγ inhibitor GW9662. Cells treated with CLA showed an upregulation of the intestinal trefoil factor, which was prevented by pretreatment with GW9662. Dextran sulfate sodium (2%) was used to induce colitis in mice and they were simultaneously fed with a standard or a CLA-supplemented (100 mg · kg -1 · d -1 ) diet for 7 d. The CLA-enriched diet prevented the colon shortening induced by DSS and markedly reduced the disease activity index and the colonic expression of inducible NO synthase and NF-κB. Immunohistochemistry revealed an increase in PPARγ and TFF3 expression after CLA administration. Altogether, these results indicate that dietary CLA protects against DSS-induced colitis in a process involving induction of PPARγ and TFF3.

Bilateral Hand Necrosis in Undiagnosed Ulcerative Colitis

Purpose: Thromboembolic disease is a common extra-intestinal manifestation of inflammatory bowel disease (IBD) associated with significant morbidity. Here in we present a case of bilateral hand necrosis in a patient with undiagnosed ulcerative colitis. Case: A 63-year-old male presents with severe bilateral hand pain. He had noted darkening and subsequently necrosis of his fingertips which progressed proximally over a two month period. Investigations were non-revealing for vasculitis, cryoglobulinemia, or other rheumatological state. A hypercoagulable workup was non-revealing. Amputation of his left hand was performed and pathology revealed vaso-occlusive disease with diffuse thrombi in superficial and deep small and large vessels without evidence of vasculitis. A DVT of his left lower extremity had been diagnosed 4 months prior to his presentation and he had been on therapeutic anticoagulation with Coumadin®. He reported frequent diarrhea over the preceding five years. He had no family history of IBD. He had never had a colonoscopy. CT of his abdomen and pelvis revealed diffuse colonic wall thickening. An IBD-7 serology was consistent with ulcerative colitis. A colonoscopy revealed pan-ulceration starting in his rectum. Biopsies from colon showed crypt abscesses without evidence of microthrombi. Patient eventually succumbed to hospital acquired pneumonia. Discussion: A variety of host factors may contribute to the hypercoagulability and thromboembolic events associated with IBD. The most common thromboembolic events in IBD result in deep venous thrombosis and pulmonary embolisms. Above we report a unique case of microthrombi to hand vasculature associated with ulcerative colitis. It is known that chronic gut inflammation alters microvascular hemodynamics and cell-signaling. Also a variety of factors including thrombocytosis, high levels of clotting factors V, VIII, fibrinogen, accelerated thromboplastin generation, anti-thrombin III deficiency, decreased protein C and S, elevated anticardiolipin antibodies, and elevated homocystein levels contribute to thromboembolic events. However, such as in the case presented, no single consistent coagulation abnormality is typically identified. The immense morbidity associated with extra-intestinal manifestations of IBD is highlighted in this case.Figure: Patient's right hand.

Inflammatory bowel disease and thrombosis.

Inflammatory Bowel Disease (IBD) is a group of chronic and relapsing inflammatory disorders of the gastrointestinalsystem. In these cases, findings are detected in extraintestinal systems also. There is a tendency for thrombotic eventsin IBD, as in the other inflammatory processes. The pathogenesis of this thrombotic tendency is multidimensional,including lack of natural anticoagulants, prothrombotic media induced via the inflammatory process, long-termsedentary life style, steroid use, surgery, and catheter placement. The aim of this review was to highlight the positiverelationship between IBD and thrombotic events, and the proper treatment of at-risk patients.

Risk Factors for Cardiovascular Events in Inflammatory Bowel Disease

1Department of Clinical Medicine, Trinity Centre for Health Science, Adelaide and Meath Hospital, Dublin, Ireland Correspondence: Maria O'Sullivan, BSc, PhD, Department of Clinical Medicine, Trinity College Dublin Centre for Health Sciences, Adelaide and Meath Hospital, Dublin 24, Ireland. E-mail: [email protected] This letter underwent AJG editorial review.

Influence of NFκB inhibitors on IL-1β-induced chemokine CXCL8 and -10 expression levels in intestinal epithelial cell lines: glucocorticoid ineffectiveness and paradoxical effect of PDTC

PurposeActivation of intestinal epithelial cell (IEC) nuclear factor κB (NFκB) and the consequent chemokine upregulation are crucial events in inflammatory bowel disease (IBD) pathogenesis. Not much is known about the consequences of NFκB inhibition in terms of chemokine expression in intestinal cells. Therefore, we aimed to evaluate the efficacy of compounds known to disrupt the NFκB pathway on NFκB transcriptional activity and CXCL8 and CXCL10 gene expression in intestinal cell lines.MethodsThe influence of NFκB inhibitors (dexamethasone, pyrrolidine dithiocarbamate (PDTC) and BAY 11-7082) on IL-1β-induced NFκB transcriptional activity was investigated by transient transfection of Caco-2 cells with an NFκB-secreted alkaline phosphatase reporter plasmid. Il-1β stimulated CXCL8 and CXCL10 mRNA and protein expression and was studied in Caco-2 and HT29 cells in the presence and absence of the NFκB inhibitors by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent serologic assay, respectively. To reveal alternative signalling cascades, experiments were also performed in the presence of the p38MAPK inhibitor SB 203580 and the ERK inhibitor PD 98059.ResultsDexamethasone did not downregulate chemokine expression sufficiently, probably due to a lack of glucocorticoid receptors in these cells. While BAY11-7082 inhibited chemokine expression, PDTC led to a paradoxical upregulation of CXCL8 in Caco-2 cells, which could be prevented by inhibition of p38MAPK.ConclusionThese data explain the frequent unresponsiveness of IBD to glucocorticoid treatment and suggest that alternative NFκB inhibition in IECs might be of use in IBD therapy. Drug development based on measuring anti-NFκB activity might be misleading and should therefore also include studies on relevant gene products.

Cover Picture: Eur. J. Immunol. 5/09

AbstractThe cover image depicts human intestinal microvascular endothelial cells stained for ICAM‐1 after in vitro stimulation with the pro‐inflammatory cytokine TNF‐α. The image was taken from a recently‐published article by Scaldaferri et al. (Eur. J. Immunol. 2009. 39: 290–300), in which the authors demonstrate that stimulation with TNF‐α up‐regulates ICAM‐1 expression in human intestinal microvascular endothelial cells leading to increased recruitment of lymphocytes in the gut, a key pathogenic event in inflammatory bowel disease.