Inflammatory Bowel Disease Subgroups Research Articles

P140 Serum Metabolomic Biomarkers Can Identify and Characterize Associated Subtypes and Phenotypes in Inflammatory Bowel Disease

Abstract Background Metabolomics is increasingly recognized for uncovering pathophysiology and identifying diagnostic and prognostic biomarkers in inflammatory bowel disease (IBD). This study focuses on exploring comprehensive serum metabolomic profiles and corresponding specific metabolic pathways, in order to differentiate IBD patients from healthy individuals and to accurately identify IBD subtypes (Crohn's disease [CD], ulcerative colitis [UC]) through serum biomarkers with high patient acceptability. Methods Serum samples with matched clinical metadata were comprehensively collected from patients with IBD at Kyung Hee University Hospital, Seoul, Korea. Corresponding samples from normal controls (NCs) were obtained for comparison. Untargeted profiling was performed with Gas Chromatography-Time-Of-Flight-Mass Spectrometry, and targeted profiling of bile acids and tryptophan used Liquid Chromatography-Triple Quadrupole-Mass Spectrometry. The identification of distinct metabolites and potential biomarkers was achieved through extensive univariate and multivariate statistical analyses. Receiver operating characteristic (ROC) curves and metabolic pathway analyses were also conducted. Results A total of 346 subjects were analyzed, comprising 258 IBD patients (134 with CD and 124 with UC) and 88 NCs, Table 1. The patients with IBD were clearly clustered from the NCs, while IBD subgroups were not clearly separated from each other in the nontargeted profiling. Tryptophan and indole-3-acetic acid were elevated in both patients with CD and UC, while kynurenine and indole-3-propionic acid increased only in CD. Conversely, patients with UC had lower levels of indole-3-acetic acid, serotonin, and acetylcholine compared to CD. The ratio of primary and secondary bile acids was also significantly decreased in both patient groups compare with NCs. The ROC curves (Figure 1A) showed good discriminatory power for NCs vs CD (AUC:0.9738), NCs vs UC (AUC:0.9887), and UC vs CD (AUC:0.7140). Pathway analysis of the identified metabolites showed a sustained change in glyoxylate and dicarboxylate metabolism/alanine, aspartate and glutamate metabolism/glycine, serine and threonine metabolism associated with all comparisons (NCs vs UC, NCs vs CD, UC vs CD). Beta-alanine, arginine, and proline metabolism were linked to IBD compared to NCs. Glycerolipid metabolism distinctly differed between UC and CD (Figure 1B-1D). Network analysis revealed associations between metabolomic markers and specific clinical phenotypes of IBD subtypes. Conclusion This study demonstrates that serum metabolomic biomarkers are novel and effective tools for diagnosing IBD, as well as for identifying and characterizing its subtypes and associated phenotypes.

P1045 Comparative Efficacy of Fecal Microbiota Transplantation for Clostridioides Difficile Infection in Patients with and without Inflammatory Bowel Disease: A Retrospective Cohort Study

Abstract Background Clostridioides difficile infection (CDI) significantly exacerbates and worsens the prognosis of inflammatory bowel disease (IBD). While fecal microbiota transplantation (FMT) is recognized as a safe and efficacious therapy for patients battling recurrent or refractory CDI, but comparative studies focusing on the success rates in IBD and non-IBD patients remain scarce. Our study aims to shed light on this gap in knowledge. Methods In this retrospective cohort study conducted at Chang Gung Memorial Hospital between April 2019 and February 2023, patients undergoing FMT via colonoscopy for recurrent or refractory CDI were enrolled. Participants were categorized into IBD and non-IBD groups based on their underlying conditions. We compared baseline characteristics and clinical outcomes at one-month and one-year follow-up intervals. CDI diagnosis was confirmed through positive CD toxin A/B genes and associated clinical symptoms. Donor specimens were sourced from Chang Gung Microbiota Therapy Center's fecal bank. Results Our study included 88 patients who received FMT, comprising 30 in the IBD group and 58 in the non-IBD group. The indications were recurrent CDI in 31 patients, refractory CDI in 54, and both conditions in 3 patients. Among the IBD subgroup, 20 patients had ulcerative colitis, and 10 had Crohn's disease. In the baseline comparison, the IBD group was significantly younger (mean±SD, 45.23±16.45 years vs. 61.90±24.40 years, P = 0.001) and had fewer comorbidities such as hypertension (10.0% vs. 55.2%, P < 0.001), diabetes mellitus (6.7% vs. 31.0%, P = 0.014), and cancer (3.3% vs. 31.0%, P = 0.012) than the non-IBD group. Additionally, the IBD group had less prior Fidaxomin use (6.9% vs. 26.3%, P = 0.021) and fewer HMG-CoA reductase inhibitor users (0.0% vs. 15.5%, P = 0.025). Post-FMT, IBD severity indices showed significant improvement at one month. The mean partial Mayo score in the IBD group decreased by 2.9 points, the endoscopic Mayo subscore decreased by 0.7 points, and the Crohn’s Disease Activity Index decreased by 79.98 points. At this time, the IBD group showed a similar percentage of negative CDI toxin A/B tests (83.3% vs. 63.8%, P = 0.174) but had lower clinical remission rates (79.5% vs. 96.5%, P = 0.006) compared to the non-IBD group. However, at the one-year follow-up, the eradication rate (94.4% vs. 73.9%, P = 0.112) and clinical remission rate (84.2% vs. 90.3%, P = 0.661) were comparable between both groups. No safety issues or adverse effects were reported in any of the patients. Conclusion FMT demonstrates safety and efficacy in treating recurrent or refractory CDI in both IBD and non-IBD patients, also aiding in mitigating IBD-associated inflammation.

Evaluation of Lipid Profile Changes In Patients With Inflammatory Bowel Disease: A Single Center Experience

Introduction: Inflammatory Bowel Disease (IBD) encompasses chronic inflammatory disorders of the gastrointestinal tract, including Crohn's disease and ulcerative colitis. While initially considered a localized disorder, IBD has emerged as a systemic disease with a growing recognition of its potential impact on lipid metabolism and cardiovascular health. This study aims to comprehensively investigate lipid profiles and dyslipidemia prevalence among IBD patients, shedding light on potential associations with disease characteristics. Materials and Methods: A single-center cross-sectional observational study was conducted on 707 IBD patients between December 2007 and February 2021. Inclusion criteria comprised confirmed IBD diagnosis, age 18-65, and informed consent. Demographic data, medical history, anthropometric measurements, and fasting blood samples for lipid profile analysis were collected. Lipid profiles included total cholesterol, high-density lipoprotein cholesterol (HDL-C), lowdensity lipoprotein cholesterol (LDL-C), and triglycerides. Statistical analyses, including t-tests, chi-square tests, and multivariate regression, explored associations. Results: This study reveals a high prevalence of dyslipidemia in IBD patients (58%), surpassing the general population. Notably, male IBD patients displayed significantly higher levels of total cholesterol, LDL-C, and triglycerides than their counterparts in the general male population. Differences in HDL-C levels were also observed. There were no significant variations in lipid profiles between Crohn's disease and ulcerative colitis patients within the IBD subgroup. Conclusion: The findings underscore the importance of regular lipid profile assessments in clinical management, particularly for male IBD patients. The significantly elevated prevalence of dyslipidemia in this population implies a potential influence of IBD on lipid metabolism and cardiovascular risk. Further research is needed to elucidate mechanisms and potential therapeutic interventions. Addressing dyslipidemia among IBD patients holds promise for reducing cardiovascular risk and enhancing overall health outcomes in this complex patient group.

Serum and Urine Metabolomic Profiling of Newly Diagnosed Treatment-Naïve Inflammatory Bowel Disease Patients.

Inflammatory bowel disease (IBD) is a prevalent chronic noncurable disease associated with profound metabolic changes. The discovery of novel molecular indicators for unraveling IBD etiopathogenesis and the diagnosis and prognosis of IBD is therefore pivotal. We sought to determine the distinctive metabolic signatures from the different IBD subgroups before treatment initiation. Serum and urine samples from newly diagnosed treatment-naïve IBD patients and age and sex-matched healthy control (HC) individuals were investigated using proton nuclear magnetic resonance spectroscopy. Metabolic differences were identified based on univariate and multivariate statistical analyses. A total of 137 Crohn's disease patients, 202 ulcerative colitis patients, and 338 HC individuals were included. In the IBD cohort, several distinguishable metabolites were detected within each subgroup comparison. Most of the differences revealed alterations in energy and amino acid metabolism in IBD patients, with an increased demand of the body for energy mainly through the ketone bodies. As compared with HC individuals, differences in metabolites were more marked and numerous in Crohn's disease than in ulcerative colitis patients, and in serum than in urine. In addition, clustering analysis revealed 3 distinct patient profiles with notable differences among them based on the analysis of their clinical, anthropometric, and metabolomic variables. However, relevant phenotypical differences were not found among these 3 clusters. This study highlights the molecular alterations present within the different subgroups of newly diagnosed treatment-naïve IBD patients. The metabolomic profile of these patients may provide further understanding of pathogenic mechanisms of IBD subgroups. Serum metabotype seemed to be especially sensitive to the onset of IBD.

An online survey among US patients with immune-mediated conditions: Attitudes about biosimilars.

BACKGROUND: Few surveys about biosimilars have been conducted among US patients. OBJECTIVE: To evaluate attitudes about biosimilars among patients with rheumatoid arthritis (RA), psoriasis and/or psoriatic arthritis (PsO/A), and/or inflammatory bowel disease (IBD). METHODS: WebMD, LLC fielded a 16-item online survey to members of the US Dynata consumer panel meeting these criteria: aged 18 years or older; self-reported specialist diagnosis of RA, PsO/A, or IBD of at least 1 year; and not currently receiving an infliximab biosimilar. A quota of 500 was set, stratified by region and condition. The survey was exempt by the institutional review board, exploratory, and not registered. RESULTS: Overall, 44% (n = 221) of patients were on a biologic; 56% (n = 279) were not on a biologic (40% [n = 199] were biologic naive and 16% [n = 80] used biologics in the past). Among all patients, 66% were unaware of biosimilars and 24% were aware (10% unsure). After being shown the US Food and Drug Administration definition of a biosimilar, main concerns were side effects (59%), long-term safety (50%), and not knowing a lot (46%). Among current users, 43% would switch to a biosimilar and 26% would not (32% unsure). Of those unwilling to switch, 51% were concerned about side effects, 42% about financial support, and 40% about efficacy. When those not on a biologic were asked if their doctor prescribed an original anti-tumor necrosis factor α but their insurance required its biosimilar, 49% would switch and 8% would not (43% unsure). 51% of patients surveyed thought pharmacist-level substitution of an interchangeable biosimilar was acceptable with notification. Survey findings were consistent among the RA, PsO/A, and IBD subgroups. CONCLUSIONS: Although two-thirds of patients surveyed were unaware of biosimilars, the majority were potentially receptive to biosimilar treatment after being provided with the definition of a biosimilar. Patients expressed a desire to know more about biosimilars in general, how they compare with original biologics, their benefits, and cost. DISCLOSURES: This study was funded by Boehringer Ingelheim Pharmaceuticals Inc. (BIPI). WebMD, LLC, fielded the survey. BIPI was given the opportunity to review the article for medical and scientific accuracy and intellectual property considerations. Dr Gibofsky is a consultant/advisor for AbbVie Inc., Biosplice Therapeutics, Lilly, Novartis Pharmaceuticals Corporation, and Pfizer Inc., and he is on the speakers' bureau for AbbVie Inc., Amgen, Lilly, and Pfizer Inc., and has stock ownership in AbbVie Inc., Amgen, Bristol-Myers Squibb Company, Horizon Pharma plc, and Pfizer Inc. Dr Peyrin-Biroulet reports that he has received personal consulting fees from Merck Sharp & Dohme, AbbVie, Janssen, Takeda, Celltrion, Pfizer, Bristol-Myers Squibb Company, Pharmacosmos, Shire, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, UCB-Pharma, Hospira, BIPI, and Lilly. Dr McCabe is an employee of BIPI. Dr McGrath was an employee of BIPI at the time the survey was conducted. Mr Jacobson, Mr Franklin, and Ms O'Hara-Levi report no disclosures.

Comparison of depression and anxiety in inflammatory bowel patients treated with anti-TNF or immune modulators

The aim of this study was to investigate patients diagnosed with inflammatory bowel disease (IBD), the effects of drug groups used in the treatment of inflammatory bowel disease on depression and anxiety. This study was a single-center prospective study involving 94 patients with inflammatory bowel disease, 51 of whom had ulcerative colitis (UC) and 43 had Crohn's disease (CD). Harvey-Bradshaw activity scores for CD and Mayo Clinic activation scores for UC were calculated. Depression and anxiety data were collected with the Beck Depression Inventory and Beck Anxiety Inventory. The mean age for UC and CD were 40.25 ± 14 and 38.9 ± 13.8 years, respectively. There was a positive correlation between disease activation and depression and anxiety levels in both IBD subgroups (p<0.05). All patients included in the study were compared in terms of depression and anxiety levels before and after treatment, and a statistically significant improvement was found with the remission of both ulcerative colitis and Crohn's disease (p<0.001). There was a significant difference in depression and anxiety levels before and after treatment according to treatment options (p<0.001). There is a positive relationship between the disease activation score and the level of depression and anxiety in IBD. Immunosuppressive and immunomodulatory drugs used in the treatment of IBD may also improve the parameters of depression and anxiety in this disease.

P817 Symptoms of COVID-19 in Patients with Immune Mediated Inflammatory Diseases

Abstract Background Pandemic situation of the novel coronavirus disease (COVID-19) represents a challenging condition with a plethora of aspects. Symptoms of patients with immune mediated inflammatory diseases (IMID) such as inflammatory bowel disease (IBD) and different rheumatic diseases are not well described. Methods We conducted a prospective questionnaire-based study (04/2022 – 10/2022) at our university medical center. Outward patients over the age of 18 years were screened. Participating patients reported about their individual COVID-19 history during pandemic′s course. Results In the end, 156 patients were willing to participate. Vast majority of the cohort had an established diagnosis of inflammatory bowel disease (117 [75%] vs. 39 [25%] patients with rheumatic disease). Eightyone patients (51%) self-reported about their COVID-19 infection. Diagnosis had usually been established by positive PCR. In general, courses of infection were mild: Only two patients (2% of patients with reported COVID-19) were hospitalized due to COVID-19 with one of the two needing intensive care. Asymptomatic COVID-19 had been described by 7 persons (9% of patients with reported COVID-19). Acute COVID-19 was accompanied by fatigue/tiredness in 58 persons (72% of patients with COVID-19) as most frequent symptom. Other complaints were common cold (55 patients = 68%), cough (51 patients = 63%), headache (44 patients = 54%) and fever (35 patients = 43%). Joint respectively muscle pain was a symptom of eight respectively nine patients with rheumatic IMID (=33%/38% of 24 self-reported COVID-19). Five rheumatic patients (21%) presented diarrhea as complaint due to COVID-19. In the IBD subgroup 15 patients (27% of 57 self-reported COVID-19) had this complaint. Painful joints were mentioned in 23 IBD patients (41%). Aching muscles occurred in 19 IBD patients (34%). Conclusion Discrimination between symptoms of COVID-19 in contrast to chronic IMID condition can be difficult as complaints might be overlapping.

Prevalence of Zinc Deficiency in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

Malabsorptive disorders are closely associated with micronutrient deficiencies. In inflammatory bowel disease (IBD), trace element deficiencies pose a clinical burden from disease onset throughout its course, contributing to morbidity and poor quality of life. We aimed to conduct a systematic review and meta-analysis of the prevalence of zinc deficiency in IBD. Literature screening was performed on six electronic databases until 1 May 2022. Two independent investigators assessed the 152 retrieved articles for inclusion criteria, met by only nine, that included 17 prevalence entries for Crohn’s disease (CD) (n = 9) and ulcerative colitis (UC) (n = 8). No exclusion criteria were applied to language, deficiency cut-offs, population age, general health status, country, or study setting (cohort or cross-sectional). The prevalence of zinc deficiency in blood was scored positive if due to a single disease, not cumulative factors. Zinc deficiency prevalence across selected studies showed higher values in CD than in UC. Pooled analyses by the IBD subgroup showed a total population of 1677 with CD, for an overall mean zinc deficiency prevalence of 54% and 95% confidence intervals (CI) ranging from 0.51 to 0.56, versus 41% (95%CI 0.38–0.45) in the UC population (n = 806). The overall prevalence at meta-analysis was estimated at 50% (95%CI 0.48–0.52), but with high heterogeneity, I2 = 96%. The funnel plot analysis failed to show any evidence of publication bias. The risk of bias across selected studies was moderate to low. In IBD contexts, one of two patients suffers from zinc deficiency. Mismanagement of micronutrient deficiencies plays a role in inflammation trajectories and related cross-pathways. Clinicians in the field are advised to list zinc among trace elements to be monitored in serum.

Evaluation of insulin resistance and beta cell activity in patients with inflammatory bowel disease.

Insulin resistance is an important risk factor for developing metabolic syndromes that cause morbidity diseases such as diabetes and cardiovascular diseases. Interestingly, in chronic inflammatory diseases, some inflammatory mediators can play, either directly or indirectly, a pivot role in the development of insulin resistance. This can be considered as an additional factor causing increased mortality and morbidity in these patients. In this paper, we want to investigate and compare the insulin resistance status in patients with Inflammatory Bowel Disease (IBD) and healthy control, as well as different stages of patients with Ulcerative colitis (UC) and Crohn's Disease (CD). A total of 180 patients were enrolled in this study; while 95 patients had inflammatory bowel disease [Crohn's Disease (n): 47, Ulcerative colitis (n): 48], 85 people were healthy controls. Insulin resistance status was evaluated with the HOMA-IR (hemostasis model of assessment of insulin resistance) index. p < 0.05 was accepted as significant. The mean HOMA-IR levels were found to be similar for both IBD and control, and Crohn's disease and control (p = 0.174, p = 0.96, respectively); but the mean HOMA-IR score in ulcerative colitis, one of the IBD subgroups, was significantly higher than the control group (p < 0.039). This study clearly showed that insulin resistance is increased in ulcerative colitis. Consequently, patients with ulcerative colitis should be followed and closely monitored for developing insulin resistance, metabolic syndromes, diabetes, and cardiovascular diseases. Consequently, all of them can cause an additional risk of morbidity and mortality in these patients.

Precision Medicine in Inflammatory Bowel Diseases: Challenges and Considerations for the Path Forward

Precision Medicine in Inflammatory Bowel Diseases: Challenges and Considerations for the Path Forward

COMPARING THE GUT METABOLOMIC PROFILES IN HISPANIC AND NON-HISPANIC PEDIATRIC ULCERATIVE COLITIS PATIENTS

Abstract BACKGROUND Diagnosis of ulcerative colitis (UC), a subgroup of inflammatory bowel disease (IBD), is frequently overlooked among the Hispanic population. Although previously thought to impact predominantly white populations, epidemiological studies have shown an increased incidence of UC among Hispanics. Other studies have also noted variations in disease phenotype when comparing Hispanic UC patients to non-Hispanic patients. These variations could be linked to differences in the gut microbiome and shifts in the metabolomic profile. This study aims to compare the profiles of Hispanic UC patients to those of non-Hispanic whites. METHODS Participants aged 7-21 with mild to moderate UC were enrolled at Children’s Hospital of Los Angeles. Eighteen Hispanic and forty non-Hispanic patients were included in this analysis. Metabolite profiling yielded 230 known metabolites. Independent sample T-tests were used to identify significant differences (p&amp;lt;0.05) in metabolites between Hispanic and non-Hispanic UC samples. The average for each metabolite was calculated in Hispanic, non-Hispanic, and healthy patients. Averages were then compared and used to define metabolites as enhanced or diminished. RESULTS 66 metabolites were found to be significantly different between Hispanic and non-Hispanic UC patients. When comparing the profiles of Hispanic to that of non-Hispanic patients, 2 metabolites were enhanced and 64 were diminished. The two enhanced metabolites included 1-monostearin and 1-monopalmitin. Figure 1 depicts the top 10 most diminished metabolites in Hispanic patients compared to non-Hispanic patients. These 10 metabolites were amino acids, amino acid degradation products, and one polyol compound. DISCUSSION This study found a significant difference in the metabolomic profiles of Hispanic UC patients compared to non-Hispanics. This difference could suggest a relationship between ethnicity and the gut’s metabolomic profile. Most notably, Hispanic patients were found to have diminished levels of nearly all significantly different metabolites when compared to non-Hispanic patients. This includes protective fatty acids, amino acids, and amino acid degradation byproducts. Increased deficits of protective anti-inflammatory mediators can be linked to increased risk of severe disease among Hispanic UC patients. These findings support the need for therapeutics targeting specific metabolite deficiencies within Hispanic UC patients.

COMPARING THE GUT METABOLOMIC PROFILES IN HISPANIC AND NON-HISPANIC PEDIATRIC ULCERATIVE COLITIS PATIENTS

Diagnosis of ulcerative colitis (UC), a subgroup of inflammatory bowel disease (IBD), is frequently overlooked among the Hispanic population. Although previously thought to impact predominantly white populations, epidemiological studies have shown an increased incidence of UC among Hispanics. Other studies have also noted variations in disease phenotype when comparing Hispanic UC patients to non-Hispanic patients. These variations could be linked to differences in the gut microbiome and shifts in the metabolomic profile.

Cytokine profile in serum and gingival crevicular fluid of children with inflammatory bowel disease: A case-control study.

To evaluate the cytokine profile in gingival crevicular fluid (GCF) and serum of pediatric inflammatory bowel disease (IBD) patients and determine the cluster patterns of cytokines. Fifty IBD patients and 21 systemically healthy children were enrolled in the study. The GCF samples were collected from the participants during periodontal examination and periodontal indices were recorded. Based on activity indexes and response to conventional treatment, patients with IBD were further categorized into subgroups as: remission, active disease, and treatment-resistant. Serum samples were obtained from IBD patients to determine serum levels of cytokines. The levels of pro- (interleukin (IL)-1β, IL-12, IL-21, IL-22, IL-23, IL-17A, IL-17F) and anti-inflammatory (IL-4, IL-10) cytokines in serum and GCF were measured using Enzyme-linked Immunosorbent Assay (ELISA) kits. Among 50 IBD patients, 58% were in remission, 20% had active disease, and 22% were defined as treatment-resistant. The severity of gingival inflammation measured by the criteria of Löe had increasing trends in IBD patients with active disease and treatment resistance. GCF IL-1β level was lower and GCF IL-4 and GCF IL-23 levels were higher in IBD patients compared to healthy controls. In the active disease group, more cytokine clusters occurred compared to the control group and other IBD subgroups, as explained by increased cytokine-cytokine interactions. Considering the increased complexity of cytokine interactions and the increased severity of gingival inflammation in patients with active disease, it can be concluded that disease activity might have an impact on gingival inflammation in pediatric patients with IBD.

704 Inflammatory bowel disease and the impact on rates of chorioamnionitis, sepsis, and severe maternal morbidity

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), affects thousands of women during reproductive years. Previous studies described an increased risk of adverse perinatal outcomes with IBD; however, the impact of IBD on obstetric-related infection and severe maternal morbidity remains unclear. Our objective was to evaluate the association between IBD in pregnancy and chorioamnionitis, maternal sepsis, and severe maternal morbidity (SMM). This cohort study used linked delivery hospitalization discharge and vital record data from births in California between 2007-2012. We identified IBD cases using a composite of ICD-9 codes representing CD, UC, and IBD-unclassified (IBD-U). The primary outcomes were chorioamnionitis, sepsis, and SMM (composite measure from the CDC) during delivery hospitalization. Multivariable logistic regression modeling was used to evaluate associations, adjusting for age, parity, education, insurance and group B streptococcus (GBS) colonization. Models were then stratified by IBD subgroup. Secondary outcomes included other perinatal complications assessed using chi-square tests. IBD prevalence was 9.5 per 10,000 births (n=2,338 of 2,461,143) among women giving birth in California. A higher proportion of IBD patients were older and had private insurance compared with patients without IBD (Table 1). IBD was associated with increased odds of chorioamnionitis (aOR 1.5; 95% CI: 1.2, 1.8), sepsis (aOR 14.7; 95% CI: 8.6, 25.3), and SMM (aOR 3.3; 95% CI: 2.7, 4.1). Cesarean birth, preterm birth, low birthweight, and NICU admission were also more common in IBD patients (all p<0.01) (Table 2). Our study found IBD was associated with increased chorioamnionitis, sepsis, and SMM during delivery hospitalization, extending prior research on obstetric related outcomes. Future studies, with emphasis on antenatal optimization of IBD and sepsis risk factors, are key in improving pregnancy outcomes for persons with IBD.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Molecular Genetic Architecture of Monogenic Pediatric IBD Differs from Complex Pediatric and Adult IBD.

Inflammatory bowel disease (IBD) manifests as a complex disease resulting from gene–environment interactions or as a monogenic disease resulting from deleterious mutations. While monogenic IBD is predominantly pediatric, only one-quarter of complex IBD is pediatric. In this study, we were the first to systematically compare genetic architecture between monogenic and complex pediatric and adult IBD on genetic and molecular pathway levels. Genes reported as causal for monogenic pediatric IBD and related syndromes and as risk factors for pediatric and adult complex IBD were analyzed using CytoScape and ClueGO software tools to elucidate significantly enriched Gene Ontology (GO) terms. Despite the small overlap (seven genes) between monogenic IBD genes (85) and complex IBD loci (240), GO analysis revealed several enriched GO terms shared between subgroups (13.9%). Terms Th17 cell differentiation and Jak/STAT signaling were enriched in both monogenic and complex IBD subgroups. However, primary immunodeficiency and B-cell receptor signaling pathway were specifically enriched only for pediatric subgroups, confirming existing clinical observations and experimental evidence of primary immunodeficiency in pediatric IBD patients. In addition, comparative analysis identified patients below 6 years of age to significantly differ from complex pediatric and adult IBD and could be considered a separate entity.

S2307 COVID-19 in a Patient on Dual Biologic Therapy for Inflammatory Bowel Disease

INTRODUCTION: Preliminary data suggest that dual biologic therapy might be effective and safe in a subgroup of inflammatory bowel disease (IBD) patients. However, the safety and outcomes of dual biologic therapy in IBD with Coronavirus Disease 19 (COVID-19) is unknown. Here, we present a case of a Crohn’s disease (CD) patient on adalimumab (ADA) and ustekinumab (UST) combination therapy who developed COVID-19. CASE DESCRIPTION/METHODS: This is a 24-year-old man with fibrostenotic Crohn’s ileocolitis diagnosed at age 9. He had a secondary loss of response to infliximab despite dose escalation to 10 mg/kg in combination with methotrexate (MTX). He was then transitioned to ADA and dose was escalated to 40 mg weekly with MTX (subsequently self-discontinued MTX). He achieved clinical response but not remission with ADA. Magnetic resonance enterography showed active inflammation in the terminal ileum, distal sigmoid colon, and rectum (Image 1). A colonoscopy showed ulcerated and polypoid mucosa in the terminal ileum and at the ileocecal valve with narrowing and patchy, mild pan-colonic inflammation (Image 2A/B). ADA level was 17 mcg/mL without antibodies. Switching to a different biologic was recommended. The patient was hesitant about discontinuing ADA due to symptomatic improvement. After discussion of risks and benefits, it was decided to bridge with UST and continue ADA with a plan to eventually discontinue ADA if remission was achieved. He received standard intravenous UST loading followed by 90 mg subcutaneously every 8 weeks. Five months later, he tested positive for COVID-19 due to exposure to an infected individual. He was asymptomatic from a respiratory standpoint and his gastrointestinal (GI) symptoms were at baseline. He received a dose of UST 1 day prior to COVID-19 testing and last ADA was 1 week prior to testing. ADA was held and resumed 2 weeks after as he remained without fever, respiratory symptoms or new onset GI symptoms at 2 and 6 weeks after testing positive for COVID-19. DISCUSSION: This case describes a favorable outcome of a CD patient who tested positive for COVID-19 while on ADA and UST. Multiple series have demonstrated that biologic monotherapy is not associated with poor outcomes in COVID-19 infected IBD patients. Instead, corticosteroids, advanced age and co-morbidities are predictors of adverse outcomes. However, more data is needed on the safety of combination biologic therapy in the COVID-19 era.Image 1.: Magnetic resonance enterography (coronal T1 weighted image) showing wall thickening, edema and hyperenhancement involving the terminal ileum over a length of approximately 20 cm with associated vascular engorgement is present.Image 2.: Colonoscopy images showing polypoid stenotic ileoceal valve (A) and the terminal ileum showing ulcerations (B).

S0810 Dual Biologic Therapy for the Treatment of Severe/Refractory Inflammatory Bowel Disease: Intravenous Immunoglobulin in Combination With Standard Biologic Agents

INTRODUCTION: Despite improved therapeutic options, a subgroup of Inflammatory Bowel Disease (IBD) patients follow a severe/refractory disease trajectory. Intravenous immunoglobulin (IVIG) is a biologic agent, derived from pooled human plasma, used to treat severe inflammation (i.e. vasculitis, dermatomyositis, etc.) which has been explored as a potential therapy for refractory IBD. However, the use of dual biologic therapy, with IVIG and a second standard biologic agent for IBD treatment has not been described. We report our institutional experience with dual biologic therapy; IVIG treatment with standard biologic therapy in refractory IBD. METHODS: We analyzed a prospective registry of consented IBD patients followed at a tertiary-center to identify Crohn’s disease (CD) or Ulcerative Colitis (UC) patients that received IVIG therapy for refractory disease. Patients that received IVIG for other conditions were excluded. Clinic visits, endoscopic reports and medication exposure before and after IVIG were collected. Harvey-Bradshaw index (HBI) for CD and Ulcerative Colitis Activity Index (UCAI) for UC were utilized to assess the disease course. Quality of life was characterized using the Short Inflammatory Bowel Disease Questionnaire (SIBDQ). RESULTS: Among 25 IBD patients (median age 43 yrs, median disease duration 14 yrs, CD 20, females 21), 14 received a combination of IVIG with a 2nd biologic agent (Table 1). Among 19 patients who had active disease before IVIG initiation, 6 (31.6%) achieved remission, 5 of them in combination with second biologic agent. The median improvement in HBI score was 2 (0–3) and in UCAI was 6 (2–10), while the median SIBDQ improvement was 2.5 (1–13). In 6 patients, CRP levels normalized. Furthermore, among 17 patients who were on systemic steroids before IVIG, 3 transitioned to topical steroids, 3 reduced the dosage and 2 patients completely tapered off steroids. In addition, 15 patients reported that IVIG therapy was helpful while 9 patients demonstrated marked improvement endoscopically. Finally, regarding side effects, 7 patients reported headache, 2 nausea, 1 emesis, 1 abdominal pain while 1 patient required hospitalization because of hives and shortness of breath after IVIG infusion. CONCLUSION: Dual biologic therapy using IVIG in combination with standard biologic agents is safe and effective in IBD patients with refractory disease. Further investigation is warranted to define the optimal use of IVIG alone or in combination with biologic agents in refractory IBD.Table 1Figure 1.: The effect of IVIG therapy in averages HBI and UCAI scores when used as monotherapy or in combination with another biologic agent.

Serum IgG4 Subclass Deficiency Defines a Distinct, Commonly Encountered, Severe Inflammatory Bowel Disease Subtype.

Immunoglobulin G subclass 4 (IgG4) is hypothesized to play an immunomodulatory role, downregulating humoral immune responses. The role of this anti-inflammatory molecule in inflammatory bowel disease (IBD) has not been fully characterized. We sought to define alterations in serum IgG4 in patients with IBD and their association with multiyear disease severity. We analyzed metadata derived from curated electronic health records from consented patients with IBD prospectively followed at a tertiary center over a 10-year time period. Patients with IBD with IgG4 serum levels available formed the study population. Demographics and multiyear clinical data were collected and analyzed. We stratified patients with IBD with low, normal, or high serum IgG4 levels. We found IgG4 characterized in 1193 patients with IBD and low IgG4 levels in 233 patients (20%) and elevated IgG4 levels in 61 patients (5%). An IgG4 deficiency did not significantly correlate with other antibody deficiencies. In a multiple Poisson regression analysis, low IgG4 was associated with more years on biologic agents (P = 0.002) and steroids (P = 0.049) and more hospital admissions (P < 0.001), clinic visits (P = 0.010), outpatient antibiotic prescriptions (P < 0.001), and CD-related surgeries (P = 0.011) during the study period after controlling for certain confounders. Elevated IgG4 was only associated with primary sclerosing cholangitis (P = 0.011). A cohort of patients with IgG4-deficient severe IBD received intravenous Ig replacement therapy, which benefited and was continued in 10 out of 11 individuals. An IgG4 subclass deficiency, distinct from other antibody deficiencies, occurred commonly in a referral IBD population and was associated with multiple markers of disease severity. This is the first association of IgG4 subclass deficiency with an inflammatory disease process. Further work is needed to define the mechanistic role of IgG4 deficiency in this severe IBD subgroup.

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Exhaled Breath Analysis for Assessment of IBD (Inflammatory Bowel Disease) Based on Electronic Nose System

Introduction The diagnosis and differentiation of IBD (Inflammatory Bowel Disease) lacks a single gold standard. IBD commonly suffers from a delay in time from first occurrence of symptoms to diagnosis, especially in young patients with ileal disease, which hinders our ability to alter the progression of disease. Also, once the diagnosis of IBD is made its sub categorization into CD (Crohn’s Disease) or UC (ulcerative colitis) is critical for determining the optimal treatment strategy. It is important to identify at risk population that could benefit from a therapeutic approach [1]. Metabolomics studies have recently enter the field of IBD. A variety of studies have been conducted to be significantly different between CD, UC and heathy controls [2]. Limitation for use of metabolomics markers would be too time-consuming and expensive for assessment of IBD or invasive testing in cases. An ideal approach regarding IBD assessment is that breath metabolome offers great potential with simply, easy to use, non-invasive, cheap, rapid and reproducible [3]. An electronic nose system, which is an instrument comprises an array of chemical sensors with partial specificity and an appropriate pattern recognition system capable of recognition simple or complex odors [4], has been suggested a potential alternative as a novel approach for breath analytic technique.In this presentation, we introduce exhaled breath analysis for assessment of IBD from controls and CD from UC using an electronic nose system incorporating a solid-phase micro extraction (SPME) technique. Method We have been developed an electronic nose system composed one chip type array of chemical sensors, chamber, data acquisition system with microprocessor, and sampling system for SPME fiber operation for non-invasive heath care monitoring. The 2x4 sensor array in the system consisted of three oxides of SnO2, NiO2, and In2O3 using Au, Pt, and Pd as catalyst and fabricated on one chip by glancing angle deposition method [5]. A chamber was used to maintain the stable operating temperature of sensor array, and SPME fiber used transferring of exhaled breath samples for measurement. Figure 1 is shown electronic nose system which has been used for experimental work in the hospital. The collection of exhaled breath for IBD patients (23 CD, 32 UC) and 15 controls was carried out using tedlar bag in connection with mouthpiece having a saliva trap to prevent humidity. The SPME fiber coated 85μm Polyacrylate was inserted into the tedlar bag and exposed to the collected breath at an ambient temperature. The system exposed the fiber to the heated sensor array desorbing the volatile off the fiber directly onto the sensors in the chamber. The collection and measurement of expiration were conducted in a hospital after approval of the IRB (Institutional Review Board) at Dongsan Medical Center, Deagu, Korea. Results and Conclusions The primary result for collected data from electronic nose system is shown at Figure 2 using Linear Discriminant Analysis (LDA) algorithm. As shown in Figure 2, IBD patients and controls are distinguished, especially IBD subgroup between CD and UC is well separated each other. However, some samples from UC subgroup are mixed with controls. In this study, we implemented an electric nose system by fabricating a one chip sensors array incorporating SPME sampling technique. Throughout the experimental result, we investigate the possibility of classification between IBD including 2 subgroup discrimination and controls. However, we need more research to improve discrimination regarding UC and controls following by optimal VOCs markers between UC and control including instrument control.