Pathologie multifactorielle, la maladie de Crohn pourrait être la conséquence de facteurs environnementaux, génétiques et impliquerait également une dérégulation de la réponse immunitaire vis-à-vis du microbiote intestinal. En effet, des variations qualitatives et quantitatives du microbiote intestinal ont pu être mises en évidence chez les patients atteints de cette pathologie. Dysbiose également observée dans le cancer colorectal dont le risque de développement est doublé chez les patients atteints de maladie de Crohn.Dans cette étude, nous nous sommes intéressés au rôle du récepteur de l’immunité innée NOD2, dont les polymorphismes génétiques prédisposent à la maladie de Crohn ainsi qu’à l’influence du microbiote intestinal dans l’établissement de colites et du cancer colorectal.Un modèle murin de colite chimique et de cancer associé à la colite (CAC) a permis de mettre en évidence une aggravation des signes cliniques de ces pathologies chez les animaux Nod2-/- et Rip2-/- en comparaison aux animaux sauvages suggérant un rôle protecteur de NOD2 et de son adaptateur protéique RIP2 dans la colite et à plus long terme dans la tumorigenèse.En vue de déterminer l’origine de ce sur-risque observé chez les animaux Nod2 ou Rip2-déficients nous avons tout d’abord vérifié le caractère transmissible de la colite. Des expériences de co-hébergement et d’adoption ont montré une transmission de la susceptibilité associée aux animaux déficients à des animaux sauvages de manière horizontale (par les congénères) et verticale (par la mère). Une analyse systématique du microbiote dans le modèle de CAC a mis en évidence une réduction de la diversité microbienne ainsi qu’une dysbiose chez les animaux Nod2-/- suggérant une implication de la flore dans l’établissement du sur-risque observé chez les animaux déficients. L’administration d’une antibiothérapie à large spectre a conforté cette hypothèse en réduisant la susceptibilité des animaux Nod2-/-. Une analyse transcriptionnelle a été réalisée afin d’établir les mécanismes moléculaires associés à la colite en réponse au microbiote et a permis de mettre en cause l’IL-6 ainsi que ses gènes cibles déjà décrits pour leur caractère pro-tumoral. Implication confirmée par inhibition de la voie IL-6 à l’aide d’un anticorps bloquant son récepteur capable de réduire la tumorigenèse. Enfin, la génération de souris axéniques Nod2-/- et leur recolonisation par une flore issue de souris sauvages a montré la possibilité d’inverser le sur-risque observé chez les Nod2-/-.Pour conclure, dans un contexte déficient pour Nod2, une réponse inflammatoire à l’encontre du microbiote intestinal dépendante de l’IL-6 favoriserait la mise en place d’une flore délétère qui prédisposerait à la colite et au CAC. Le caractère transmissible de cette flore représente en soi un outil pour l’étude des interactions avec le système immunitaire inné et adaptatif. Enfin, la mise en évidence de la ou des bactéries colitogènes ainsi que des mécanismes inflammatoires impliqués, permettra la mise au point de thérapies ciblées en vue de réduire la tumorigenèse associée à une inflammation persistante chez les patients atteints de la maladie de Crohn. / Crohn's disease is a multifactorial disease that could result from environmental factors, genetic factors and would also involved a dysregulation of the immune response against the intestinal microbiota. Indeed, qualitative and quantitative variations of the gut microbiota could be detected in Crohn’s patients or colorectal cancers patients. Moreover, risk of colorectal cancer development is two-fold increased in patients with Croh's disease.In this study, we focused on the role of innate immunity receptor Nod2, which polymorphisms predispose to Crohn's disease, and the influence of gut microbiota in the development of colitis and colorectal cancer.A chemical colitis model and chemical colitis associated cancer (CAC) in mouse highlighted an increased susceptibility of Nod2-/- and Rip2-/- animals compared to WT animals suggesting that NOD2 and its adaptor protein RIP2 can protect from colitis and tumorigenesis.To determine the origin of this increased risk observed in Nod2 or RIP2-deficient animals we first checked the transmissibility of colitis. Co-housing and cross-fostering experiments showed a transmission of susceptibility associated with deficient animals in WT animals horizontally (by congeners) and vertically (by mother). A systematic analysis of the microbiota in CAC model showed a reduction of microbial diversity and a dysbiosis in Nod2-/- animals suggesting an involvement of the flora in the establishment of the increased risk observed in deficient animals. Administration of a broad-spectrum antibiotherapy has confirmed this hypothesis by reducing the susceptibility of Nod2-/- animals. A transcriptional analysis was performed to determine the molecular mechanisms associated with colitis in response to microbiota and highlighted IL-6 and its target genes already described for theirs pro-tumoral effects. Involvement of IL-6 was confirmed by inhibition of IL-6 using an antibody blocking IL-6 receptor that can reduced tumorigenesis. Finally, the generation of germ free Nod2-deficient mice and recolonization by WT mice microbiota showed the ability to reverse the increased risk observed in Nod2-/- mice.Finally, in a context Nod2-deficient, an IL-6-dependent inflammatory response directed against intestinal microbiota, promote the establishment of pro-colitogenic microbiota and would predisposed to colitis and CAC. The transmissibility of this flora may be itself a tool to study interactions between innate and adaptive immune systems. Finally, identification of colitogenic bacteria and inflammatory mechanisms involved, will allow the development of therapies in order to reduce tumorigenesis associated with persistent inflammation in patients with Crohn disease.

Introduction: Inflammatory bowel disease is a common, complex relapsing disorder characterised by immune dysregulation, altered intestinal permeability and microbial insult. Limited knowledge is available regarding the metabolic changes observed during progression of the disease, and limited biomarkers of disease available that have been validated and shown to be of sound clinical value. Aim of Study: A two stage metabolomics approach was adopted to determine if metabolic signature profiles, could distinguish inflammatory bowel disease Crohn’s disease (CD) patients from ulcerative colitis (UC) patients and from healthy controls. Methods: A serum metabolomics approach was undertaken to define metabolic changes associated with UC and CD. Serum samples from a discovery study of 30 UC, 30 CD and 29 ethnically, age and gender matched controls were analysed by ultra-performance liquid chromatography mass spectrometry. A subsequent validation study was preformed using 28UC, 31CD, and 29 gender matched controls were also analysed using UPLC-MS.ResultsClasses of metabolites, identified as biologically interesting and at significantly different levels (p<0.05) in comparisons of control and CD and UC cohorts included: steroids and steroid derivatives, phosphocholine, Vitamin D metabolites, fatty acids and conjugates, glycerolipids, isoprenoids, amino acids, and phosphosphingolipids. There were fewer discriminatory metabolites differentiating the CD and UC cohorts. Conclusion: Serum Metabolomic profiling may represent a novel technology which could be used to distinguish individuals with CD from those with UC and healthy controls.

Orientador: Alba Regina Monteiro Souza Brito / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-26T17:16:46Z (GMT). No. of bitstreams: 1 Almeida_AnaCristinaAlvesde_D.pdf: 2447485 bytes, checksum: 029d5569d7c4d1eaaffa8f4a530937dd (MD5) Previous issue date: 2015 / Resumo: A Doença Inflamatória Intestinal (DII), que compreende a Doença de Crohn (DC) e a Retocolite Ulcerativa (RCU), é marcada por resposta inflamatória exacerbada a componentes da microbiota, com danos à mucosa do cólon. O tratamento de DII envolve drogas ineficazes para a remissão de todos os parâmetros da doença, com vários efeitos colaterais e custo elevado, o que motiva a busca de novos agentes terapêuticos. Sendo os produtos naturais uma importante fonte para desenvolvimento de medicamentos, buscou-se, nesse trabalho, avaliar o efeito do alcaloide índigo em modelos experimentais de colite. Inicialmente, foi avaliado o tratamento oral com índigo em colite aguda induzida por ácido trinitrobenzeno sulfônico (TNBS) em ratos HanUnib: WH (Wistar), um modelo experimental de DC. O tratamento com índigo resultou em redução da lesão macroscópica, medida através de escore, na dose de 3 mg/kg, e da área de lesão ulcerativa (doses 0,1; 3; 10 e 30 mg/kg). Apenas a administração da maior dose (30 mg/kg) evitou o aumento da razão peso/comprimento do cólon e não houve diminuição da diarreia e aderência do cólon, após tratamento com o alcaloide. Danos histológicos foram minimizados no cólon de animais tratados com índigo (3, 6 e 12 mg/kg). Como a lesão macroscópica por TNBS é bastante severa, a dose de 3 mg/kg, que reduziu tanto o índice (escore) quanto a área de lesão, foi selecionada para as análises posteriores. Nos ratos tratados com índigo (3 mg/kg), houve aumento na atividade da superóxido dismutase (SOD) e redução da atividade da glutationa peroxidase (GPx), redução dos níveis de peroxidação lipídica (LPO) e, parcialmente, de glutationa (GSH), sem alteração significativa na atividade da glutationa redutase (GR) e catalase (CAT). O tratamento com índigo (3 mg/kg) evitou aumento da expressão de ciclooxigenase 2 (COX-2), e não mostrou efeito significativo na expressão de fator nuclear de transcrição ?B (NF-?B) e na concentração de citocina anti-inflamatória interleucina 10 (IL-10). O segundo modelo experimental empregado neste trabalho foi a indução de colite aguda por dextrana sal sódico (DSS), em camundongos Unib: SW (Swiss), que apresenta similaridades com a RCU. A administração de índigo (3 mg/kg) não levou à redução significativa do índice de atividade da doença (DAI), o qual engloba alteração de peso corporal, presença de diarreia e sangue nas fezes; entretanto, foi eficaz em evitar o aumento da razão peso/comprimento do cólon. Em análise histológica, notou-se menor gravidade dos danos causados pelo DSS (aumento da parede do cólon, com infiltração celular na mucosa e submucosa, desorganização do epitélio). No cólon de animais tratados com índigo, observou-se aumento na atividade da SOD, não acompanhada de mudanças nos níveis de GSH e atividade da GPx, GR e CAT. O alcaloide inibiu aumento na concentração cólica da citocina IL-6, mas não da interleucina IL-1?. Em modelo experimental de colite crônica, com recidiva, associada a câncer de cólon por azoximetano e DSS (AOM/DSS) em camundongos Unib: SW (Swiss) machos, a administração de índigo reduziu a mortalidade, minimizou a perda de massa corporal dos animais e evitou o aumento da razão peso/comprimento do cólon. A substância teste, entretanto, não foi capaz de reduzir o DAI, nesse experimento, por não minimizar a perda de consistência e o aparecimento de sangue nas fezes. No modelo de colite crônica por AOM/DSS (9 semanas), animais sadios tratados com salina fisiológica (veículo) ou índigo (3 mg/kg) foram monitorados para análise de sinais de toxicidade do alcaloide, a partir dos parâmetros: mortalidade, evolução de peso corporal, consumo de ração, peso e avaliação macroscópica dos órgãos coração, pulmões, rins e fígado. Não foram encontrados indícios de toxicidade nos parâmetros avaliados, mas devido à mortalidade de 17 % dos camundongos tratados com índigo, foi realizado teste de toxicidade aguda de dose única. Após 14 dias da administração oral e intraperitoneal de índigo (1000 mg/kg), em camundongos Unib:SW (Swiss) machos e fêmeas, não foram observadas alterações na evolução de peso corporal, consumo de água e ração, peso de órgãos vitais, comportamento e sobrevivência dos animais. Em suma, o alcaloide índigo apresentou efeito anti-inflamatório em modelos de colite por TNBS, DSS e AOM/DSS. A redução do estresse oxidativo deve ter papel central na redução das lesões causadas pelo TNBS, enquanto que na colite por DSS, a regulação da IL-6 parece ser determinante para redução dos danos. Apesar de não minimizar todos os parâmetros de danos causados pela colite, o tratamento com índigo possibilitou que os animais ficassem, em geral, menos debilitados (evidenciado pelo maior peso e consumo de ração) que os animais não tratados / Abstract: Inflammatory Bowel diseases (IBD) are known as na exacerbated imune response within the intestinal tract, mainly the mucosa of the colon. The IBD treatment is rather ineffective, including various side effects and high costs. Thus, the research with active compounds may bring therapeutic alternatives for IBD. Since natural products have been a vast source for pharmacology, we decided to investigate the effect of Indigo alkaloid in experimental models of IBD. The oral administration of Indigo (3 mg/Kg) in trinitrobenzenesulphonic acid (TNBS) -induced colitis showed beneficial results in the macroscopic and microscopic lesions, without significant results in the other evaluated parameters (diarrhea and intestine adhesion). We observed a reduction in the sulfhydryl groups (GSH) and in the activity of Glutathione peroxidase (GPx), an increase in the activity of Superoxide Dismutase (SOD) and Lipid Peroxidation (LPO). The treatment with Indigo (3 mg/Kg) prevented an increase in the LPO levels, and partially, the reduction of GSH levels. Furthermore, Indigo inhibited the increase of Cycloxigenase 2 (COX-2) expression. In the Indigo-treated animals, the expression of the Nuclear Factor kB (NF-kB) and the concentration of interleukin 10 (IL-10) were kept at intermediary levels between the healthy group and the non-treated colitic group (Veículo + TNBS). In the Dextran Sodium Salt (DSS), Indigo showed no effect on the disease associated index (DAI), which includes body weight reduction, consistence and blood in feces. However, the 7-day oral treatment with Indigo was capable of avoiding the weight/length ratio of the colon, which is usually augmented in the intestinal inflammation. In the histological, we observed a thickening of the intestinal wall, with mucosal and submucosal cell infiltration, necrotic areas as well as epithelium disorganization in the DSS-induced inflammation. The treatment with Indigo showed less severe morphological lesions. In the Dss-induced colitis, IL-6 and IL-1? levels were higher in the negative control group (DSS), which was prevented with the treatment with Indigo. In the azoximethane/DSS-cancer associated recidive model of colitis, the administration of Indigo lowered the death rate, minimized the body weight loss and also prevented the increase in the wejght/length ratio of the colon. The test substance, however, was not capable of of reducing DAI in this model, since it didn't minimize the loss of consistence and neither the blood in feces. Animals treated with saline or Indigo for 9 weeks were used for the analyses of Indigo toxicity through the following parameters: body weight evolution, chaw consumption, organ weight and macroscopic evaluation (heart, kidneys, lung and liver). In this analysis, no signs of toxicity were found for this dose of Indigo. Although it did not enhance all the parameters studied in this model of colitis, we observed that the Indigo-treated animals were, in general, less debilitated than the non-treated ones. Other studies and parameters have to be performed for a better understanding of the alkaloid effects in the intestinal inflammation / Doutorado / Fármacos, Medicamentos e Insumos para Saúde / Doutora em Ciências

BACKGROUND: Pediatric patients with Inflammatory Bowel Disease (IBD) undergo costly and invasive investigations to diagnose and treat their chronic disease. To that end, it is important for researchers and physicians to continue to work to find novel tools to improve diagnosis and treatment processes. One of the main challenges is differentiating between the two main forms of IBD, Crohn disease (CD) and ulcerative colitis (UC). Physicians currently rely on a combination of endoscopic evaluations, mucosal biopsies, radiology studies, and biochemical testing to assess for the presence and extent of inflammation in the gastrointestinal (GI) tract. Serologic biomarkers can be useful to some extent, but changes in these markers do not typically reflect disease specific to the GI tract, or the state of inflammation related to a patient's IBD. In contrast, fecal biomarkers have the unique potential to provide specific information about inflammation in the GI tract. While serum antibody levels have been well studied for use in the diagnosis of patients with IBD, fecal antibody levels and anti-saccharomyces cerevisiae antibody (ASCA) in particular, have not been extensively evaluated. In this study, we will assess the dynamic range of fecal ASCA levels in acute and convalescent fecal samples collected from children and adolescents with CD and UC. METHODS: We recruited pediatric patients from inpatient and ambulatory settings at the Gastroenterology Program at Boston Children's Hospital. Patients had a diagnosis of either CD or UC. We collected baseline stool samples during a point of active disease, and follow-up samples three to six months later during a point of inactive disease. Samples were analyzed for fecal ASCA as well as lactoferrin (FLA), another marker of inflammation that can be measured in the stool. RESULTS: In patients with CD, fecal ASCA levels were significantly higher during active disease than during inactive disease. Additionally, fecal ASCA levels were higher in patients with CD than in patients with UC, regardless of disease activity. When compared to FLA, ASCA was shown to differentiate between CD and UC, with greater changes in the level of fecal ASCA (active - inactive) correlating with a diagnosis of CD. In patients with CD, FLA levels were significantly higher in the context of active disease than in inactive disease. However, FLA did not differentiate between CD and UC. CONCLUSIONS: Our results suggest that fecal ASCA may be a new marker of inflammation in the GI tract. Unlike FLA, changes in fecal ASCA levels appear more dynamic in patients with CD. Future studies are required to further demonstrate both how changes in fecal ASCA may help physicians distinguish between different forms of IBD as well as how measurement of fecal ASCA may help assess disease activity and response to therapy in patients with CD.

INTRODUCTION: The inflammation observed in patients with IBD can negatively impact the intake or absorption of vitamin D. This can increase the risk of disease relapse, impact patients’ quality of life, and increase the risk of IBD related surgeries. In addition to the traditional observation that vitamin D deficiency may be a comorbid manifestation of IBD, there is now growing evidence pointing to serum vitamin D levels as a pathogenic factor contributing to the initiation and propagation of mucosal inflammation in patients with IBD. It is well-established that variation in clinical practice leads to less optimal outcomes in any clinical setting. The relative scarcity of clinical and translational studies is even more pronounced in the pediatric population. OBJECTIVES: The primary objective of this study is to quantify the prevalence of clinician assessment of vitamin D levels in pediatric patients with IBD. We will also look at this behavior in subpopulations and compare their vitamin D status. It is secondary for this study to also describe variations in physician practices with respect to the testing and treatment of vitamin D deficiency at a single tertiary care IBD Center. METHODS: We conducted a retrospective cohort study on consecutive patients with UC, CD, and ID, that were followed in the ambulatory program in the Center for Inflammatory Bowel Disease at Boston Children’s Hospital from 1/1/2014 to 12/31/2014. We identified 498 patients and collected their demographic information, serologic testing, and physician prescribing behavior. RESULTS: Out of the entire population, 64% of the patients were vitamin D deficient (vitamin D level below 32 ng/ml). 24% of the patients received vitamin D supplementation. Vitamin D deficiency was less prevalent in patients with UC than those with CD, with an OR of 0.64 (95% CI 0.43-0.94). Out of the ones receiving supplementation, 37% of them were deficient. In terms of physician practice trends, 62% of the patients were not formally prescribed supplementation. 14.5% of those who were prescribed supplementation were receiving 50,000 IU weekly, and the rest receiving 400 – 2,000 IU daily. Patients with vitamin D levels below 20 ng/ml were more likely to receive the high dose vitamin D prescription (OR 11.5) than those with levels between 20 and 30 ng/ml (OR 5.7). CONCLUSIONS: Our study suggests that despite high prevalence of vitamin D deficiency in pediatric patients with IBD, there is a lack of consensus with respect to the assessment of vitamin D levels and consistency in prescribing vitamin D supplementation. With the potential role that vitamin D plays in IBD pathology and suggestions of the therapeutic effects of vitamin D supplementation, further studies are needed to explore this area.

INTRODUCTION: Anemia is a frequent complication in patients with inflammatory bowel disease (IBD). The inflammation observed in IBD negatively impact absorption of iron. This could lead to increased hospitalizations, affect growth and development, and decrease overall quality of life. This is especially pronounced in the pediatric population. The screening and treatment of iron deficiency anemia (IDA) varies between centers, and as a result, roughly 40-60% of pediatric IBD patients are iron deficient. OBJECTIVES: The objective of this study is to assess the efficacy and safety profile of intravenous and enteral iron therapy in a population of iron deficient patients with IBD. The secondary aim of this study is to determine if oral or intravenous iron therapy can improve hematologic and iron parameters. We will also examine the longitudinal changes in gastrointestinal (GI) symptoms and quality of life in patients receiving oral and intravenous iron supplementation. METHODS: We conducted a prospective cohort study in pediatric patients with IBD admitted to the inpatient GI service at Boston Children’s Hospital from 09/05/2017 to 03/05/2018. Forty-six IBD patients were screened, and twenty-nine (63%) were identified as iron deficient and were consented for data collection through chart review and administration of the IMPACT-III quality of life questionnaire. RESULTS: Out of the twenty-nine IBD patients, eighteen (62%) received intravenous iron, seven (24%) received oral iron, and four (14%) were untreated and served as controls. The mean change in hemoglobin in patients receiving parenteral, oral, or no iron therapy was 1.6g/dl±0.5, 1.1g/dl±0.4, and 0.2g/dl±0.5, respectively. The change in hemoglobin was significant between the parenteral and oral iron group (P<0.05). The mean change in health-related quality of life scores in patients receiving parenteral or oral iron therapy was 11.6±11.4 and 3.8l±7.5, respectively. CONCLUSION: Our study demonstrates that intravenous iron therapy was more efficacious than oral iron in improving hematologic and iron parameters in IBD patients. This improvement was concomitant with higher scores on the IMPACT-III quality of life questionnaire, suggesting that iron supplementation improves health-related quality of life in IBD patients with iron deficiency anemia.

Aim: VitaminD deficiency is a global health issue associated with increased health-care costs, and could play a role in the pathogenesis and management of inflammatory bowel disease. Prior studies show a high prevalence of vitaminD deficiency in veterans with inflammatory bowel disease. We aimed to examine the outcome differences in patients with inflammatory bowel disease, comparing treatment with ergocalciferol to cholecalciferol. Methods: A retrospective review of electronic medical records of patients with inflammatory bowel disease at a Veterans Affairs Medical Facility in the Southeastern United States was carried out. Those with at least one serum 25(OH) vitaminD level were included. Initial and follow-up vitamin D values were recorded. The type of vitaminD supplementation, whether cholecalciferol or ergocalciferol, was documented. Costs in the year after measurement of vitaminD were divided into separate inpatient and outpatient categories. Results: Veterans (n=108) with ulcerative colitis or Crohn's disease and an available 25(OH) vitaminD level were studied. There were differences in follow-up vitaminD levels; those who received weekly ergocalciferol had higher subsequent levels than those who received cholecalciferol, especially at a second follow up, although differences did not achieve statistical significance. However, those who received vitaminD3 were less likely to use laboratory, pharmacy, radiology and fee-based services, and had lower laboratory and pharmacy costs. Conclusions: Our data suggest that cholecalciferol replacement might improve outcomes to a greater extent than ergocalciferol, and might be better in limiting health-care costs and expenses in patients with inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) are known to have an increased propensity for thromboembolic events. Like any patient with a high risk of event recurrence, most of these patients can be managed successfully with long-term warfarin therapy. We present the case of a 66-year-old woman with Crohn's disease who, despite careful attention to the management of her international normalized ratio, developed a new deep vein thrombosis and required inferior vena cava filter placement in addition to ongoing warfarin therapy to prevent recurrent pulmonary emboli. This report serves as a reminder to physicians to have a low threshold for diagnosing thromboembolic events in patients with IBD, even if they are presumed to be adequately anticoagulated. Known and theoretical contributing factors to this increased clotting tendency are also reviewed.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18514号 / 医博第3934号 / 新制||医||1006(附属図書館) / 31400 / 京都大学大学院医学研究科医学専攻 / (主査)教授 上本 伸二, 教授 三森 経世, 教授 長田 重一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Despite advancements in the treatment of individuals with Inflammatory Bowel Disease (IBD), many patients will require the need to utilize biological therapies during their disease course. Moreover, some patients with IBD develop disease manifestations outside of the GI (gastrointestinal) tract termed extraintestinal manifestations (EIM). We sought to establish an association between prior EIM exposure and the sequential use of biological therapies in patients with IBD. A retrospective analysis of 555 patients with confirmed IBD and relevant EIM data was performed. EIM exposure was treated as both a dichotomized (ever, never) variable and a categorical (0, 1, 2 or more) variable in our analysis. Crude ratios were established using logistic regression and multinomial regression models. Bivariate analysis was used to test for significant confounding variables and significant confounders were included in the final multivariate regression model. We found female sex (p < 0.001), a disease duration of 13 years or longer (p = 0.001), and an ileocolonic disease location (p = 0.036) to be significantly associated with EIM exposure. We found that a disease duration of 13 years or longer (p = 0.037), diagnosis of Crohn’s Disease (CD) (p < 0.001), corticosteroid use (p < 0.001), and an ileocolonic disease location (p = 0.021) to be significantly associated with use of biologics. Our final adjusted model did not show statistical significance, but did notably indicate that individuals exposed to 2 or more EIM had 1.51 times the odds of progressing to biological therapy (95%CI: 0.67, 3.41; p = 0.32) compared to those patients with no EIM history. As a result, EIM exposure may be an indicator for high-risk IBD patients likely to require biological therapy, especially among particular groups. Our data emphasizes the need for further studies to characterize the association between EIM exposure and specific EIM with the utilization of biologics.