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Background: 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., Methods: 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., Results: 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., Conclusions: 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., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Given the rising prevalence of diabetes mellitus (DM) and the limited data on its effect on the course of inflammatory bowel disease (IBD), we characterized multiyear patterns of disease severity in a cohort of IBD patients with coexistent DM., Methods: Data of consented IBD patients followed prospectively in a natural history registry at a tertiary center between 2009 and 2017 were analyzed. Patients with ≥3 years of clinical follow-up were included. Patients identified with a diagnosis of DM were compared with 400 consecutive IBD controls without a diagnosis of DM, no laboratory evidence of hyperglycemia, and no history of antihyperglycemic treatment., Results: Out of 2810 IBD patients, 141 (5%) had DM (IBD DM; 44% ulcerative colitis, 56% Crohn's disease, 48.2% female). IBD DM had higher use of 5-aminosalicylic acid (5ASA) agents (P = 0.04), narcotics (P < 0.001), and antibiotics (P = 0.007) but not immunomodulators and/or biologics compared with IBD controls. When analyzing biomarkers of severity, IBD DM demonstrated higher frequencies of elevated C-reactive protein (CRP; P = 0.006), elevated erythrocyte sedimentation rate (ESR; P = 0.001), eosinophilia (P = 0.004), monocytosis (P = 0.02), and hypoalbuminemia (P = 0.001). IBD DM had worse quality of life (mean Short Inflammatory Bowel Disease Questionnaire; P < 0.001). IBD DM had increased health care utilization compared with controls (emergency room usage P = 0.008, hospitalizations P < 0.001, gastroenterology clinic visits P < 0.001, and median annual charges P < 0.001). Among IBD DM patients, the use of immunomodulators and/or biologics was not associated with further complications as measured by antibiotic use or hospitalizations., Conclusions: This study of a large IBD cohort suggests that DM in IBD may be associated with increased disease severity and that there may be room for increasing use of highly effective immunomodulator and/or biologic agents in this group., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Chronic idiopathic inflammatory bowel disease (IBD) is a significant risk factor for the development of intestinal adenocarcinoma. The underlying molecular alterations in IBD-associated intestinal adenocarcinoma remain largely unknown., Methods: We compared the clinicopathologic and molecular features of 35 patients with 47 IBD-associated intestinal adenocarcinomas with a consecutive series of 451 patients with sporadic colorectal carcinoma identified at our institution and published data on sporadic colorectal carcinoma., Results: c-MYC amplification was the most frequent molecular alteration identified in 33% of IBD-associated intestinal adenocarcinoma that is a significantly higher frequency than in sporadic colorectal carcinoma (8%) (P = 0.0001). Compared to sporadic colorectal carcinoma, IBD-associated intestinal adenocarcinomas more frequently demonstrated mucinous differentiation (60% vs 25%, P < 0.001) and signet ring cell differentiation (28% vs 4%, P < 0.001). Mucinous and signet ring cell differentiation were significantly associated with the presence of c-MYC amplification (both with P < 0.05). HER2 positivity (11%), KRAS exon 2 or 3 mutation (10%), and IDH1 mutation (7%) were less commonly observed in IBD-associated intestinal adenocarcinoma. There was an association between poor survival and HER2 status with 3 of 4 patients having HER2-positive adenocarcinoma dead of disease at last clinical follow-up; however, no statistically significant survival effect was identified for any of the molecular alterations identified., Conclusions: We demonstrate that IBD-associated intestinal adenocarcinomas have a high frequency of c-MYC amplification that is associated with mucinous and signet ring cell differentiation. Many of the identified molecular alterations have potential therapeutic relevance, including HER2 amplification, IDH1 mutation, and low frequency KRAS mutation.

Background: We undertook a study to test the hypothesis that inflammation alters peripheral sensory mechanisms, thereby contributing to chronic abdominal pain in ulcerative colitis (UC)., Methods: Patients with UC and healthy individuals rated abdominal pain using a visual analog scale and completed surveys describing anxiety or depression (Hospital Anxiety and Depression Score) and gastrointestinal symptoms (Rome III questionnaire). Patient age, sex, and severity of inflammation were determined. Rectal biopsies were processed using immunohistochemical techniques to assess nerve fiber density and real-time PCR to determine transcript expression of neurotrophins (nerve growth factor, glial cell-derived neurotrophic factor, artemin, neurturin), ion channels (transient receptor potential vanilloid type 1, transient receptor potential ankyrin 1) and inflammatory mediators (tumor necrosis factor-α, interleukin [IL]-1β, IL-6, IL-10, IL-17)., Results: A total of 77 patients with UC (27 female, 50 male) and 21 controls (10 female, 11 male) were enrolled. Patients with UC with pain had significantly higher depression scores than controls and patients with UC without pain (P < 0.05). There was no correlation between any of the inflammatory markers and pain scores. Visual analog scale pain scores significantly correlated with younger age, higher depression scores, increased expression of neurturin and decreased expression of transient receptor potential ankyrin 1 in the mucosa. Mucosal nerve fiber density did not correlate with any measures of inflammation or pain. Only higher depression scores independently predicted pain in UC (r > 0.5)., Conclusions: We did not observe changes in mucosal innervation and did not see a significant relationship between nerve fiber density, inflammatory mediators, neurotrophic factors, or mucosal ion channel expression and pain. In contrast, the importance of depression as the only independent predictor of pain ratings mirrors functional disorders, where central processes significantly contribute to symptom development and/or perpetuation.

Background: Managing patients with inflammatory bowel disease requires multidisciplinary coordination. Technological advances have enhanced access to care for patients and improved physician interactions. The primary aim of our project was to convene diverse institutions and specialties through a multisite virtual conferencing platform to discuss complex patient management., Methods: The case conference is designed to include multiple institutions to exchange ideas, review evidence-based data, and provide input on the management of patients with Crohn's disease and ulcerative colitis. Technology is supplied and coordinated by an information technology specialist and Chorus Call, Inc., an international teleconferencing service provider. The Inflammatory Bowel Disease Live Interinstitutional Interdisciplinary Videoconference Education (IBD LIVE) initiative is accredited by the University of Pittsburgh Medical Center (UPMC) Center for Continuing Education in the Health Sciences for 1 AMA PRA Category 1 Credit per weekly session., Results: IBD LIVE began in 2009 comprising only adult gastroenterology and pediatric gastroenterology from UPMC Presbyterian and Children's Hospitals. Participation steadily increased from 5 sites in 2010 to 11 sites in 2014. Maximum attendance for a single conference was 73 participants with a median of 48. The Continuing Medical Education scores (1 = worst to 5 = best) have a high median overall score (4.6, range 3.2-5.0) with positive responses with regard to the degree to which the conference changed practice., Conclusions: IBD LIVE has been successful and continues to grow. Implementation of the Crohn's and Colitis Foundation of America Virtual Preceptor Program using the IBD LIVE platform will provide expanded national physician access to this professional education activity.

Background: The distribution of IgG4 plasma cells in colonic mucosa, its significance, and relation to disease activity in patients with inflammatory bowel disease (IBD) is unclear. We systematically evaluated IgG4 cell distribution in colonic mucosal biopsies of patients with IBD and correlated histological findings with disease pattern and mucosal inflammation., Methods: We reviewed clinical records and pathology specimens of 54 randomly selected patients with IBD (13 Crohn's colitis: 7 active, 6 inactive; 18 ulcerative colitis [UC]: 10 active, 8 inactive; 23 UC with primary sclerosing cholangitis: 11 active colitis, 12 inactive colitis), and 11 controls (3 nonspecific diarrhea, 8 collagenous/lymphocytic colitis) who had colonoscopy and biopsies performed at our institution from April 2003 to July 2010. Immunostains for IgG4 were performed on archived rectal biopsies. Presence of >10 IgG4 cells per high-power field (×40 field) on microscopic evaluation was considered significant., Results: Overall, significant IgG4 plasma cell infiltration was seen in 24% of patients compared with none of the controls (P = 0.05). Within IBD groups, significant infiltration was limited to patients with UC with active colitis (30%), primary sclerosing cholangitis with inactive (25%) and active (64%) colitis. In contrast, patients with Crohn's colitis, UC with inactive colitis, and controls had rare IgG4 plasma cells. No correlation was observed between the number of IgG4 cells and degree of active inflammation. In 4 patients with UC and primary sclerosing cholangitis who had more than 1 colonoscopy and biopsies, the number of IgG4 cells fluctuated without correlation with colonic disease activity., Conclusions: IgG4 plasma cells are significantly increased in a subset of patients with IBD suggesting the possibility of a B-cell-mediated mechanism in these patients.