bluuebunny/crossref_metadata_2025 huggingface dataset:
Negative evidence for a role of APH1B T27I variant in Alzheimer’s disease
Authors: Zhang Xulun , Zhang Can , Prokopenko Dmitry , Liang Yingxia , Han Weinong , Tanzi Rudolph E , Sisodia Sangram S
Published: January 2020

γ-secretase is a macromolecular complex that catalyzes intramembranous hydrolysis of more than 100 membrane-bound substrates. The complex is composed of presenilin (PS1 or PS2), anterior pharynx defect-1 (APH-1), nicastrin (NCT) and PEN-2 and early-onset; autosomal dominant forms of Alzheimer’s disease (AD) are caused by inheritance of mutations of PS. No mutations in genes encoding NCT, or PEN-2 have been identified to date that cause AD. In this regard, a large genetic meta-analysis of four cohorts consisting of more than 600 000 individuals identified a common missense variant, rs117618017 in the APH1B gene that results in a T27I mutation, as a novel genome-wide significant locus. In order to confirm the findings that rs117618017 is associated with risk of AD, we performed a genetic screen from deep whole genome sequencing of the large NIMH family-based Alzheimer’s Disease (AD) dataset. In parallel, we sought to uncover potential molecular mechanism(s) by which APH-1B T27I might be associated with AD by generating stable HEK293 cell lines, wherein endogenous APH-1A and APH-1B expression was silenced and into which either the wild type APH-1B or the APH-1B T27I variant was stably expressed. We then tested the impact of expressing either the wild type APH-1B or the APH-1B T27I variant on γ-secretase processing of human APP, the murine Notch derivative mNΔE and human neuregulin-1. We now report that we fail to confirm the association of rs1047552 with AD in our cohort and that cells expressing the APH-1B T27I variant show no discernable impact on the γ-secretase processing of established substrates compared with cells expressing wild-type APH-1B.
P097 FAVORABLE SAFETY PROFILE FOR AMISELIMOD, A SELECTIVE S1P RECEPTOR MODULATOR, IN CROHN’S DISEASE
Authors: D’Haens Geert R A M , Slatkin Neal , Israel Robert , Heimanson Zeev
Published: January 2020

Background

Sphingosine 1-phosphate (S1P) receptor modulators are being developed to treat autoimmune-mediated diseases, including ulcerative colitis (UC) and Crohn’s disease (CD). Amiselimod (AMS), a second-generation S1P receptor modulator, was developed to reduce bradycardia associated with other S1P receptor modulators, including fingolimod.

Methods

This multicenter, randomized, double-blind, parallel group, placebo (PBO)-controlled (DBPC) phase 2a clinical trial in adults with moderate to severe active CD evaluated the safety and efficacy of oral AMS 0.4 mg/d for 14 wks, followed by open-label extension (OLE) of AMS for ≤36 wks. Patients were required to have used corticosteroids, immunosuppressants, or anti-TNF-α agents for CD treatment. The primary efficacy endpoint was a 100-point drop at wk 12 in the Crohn’s Disease Activity Index.

Results

Of the 78 patients randomized 1:1 to receive AMS (n=40) or PBO (n=38), 78% [n=61] completed the DBPC phase. Of those continuing into the OLE, 26 (AMS/AMS [n=14]; PBO/AMS [n=12]) completed it. AMS 0.4 mg for 12 wks did not have a significant effect on clinical disease activity (CDA) in CD. At least 1 treatment-related adverse event (TRAE) was reported by 31% receiving AMS and 24% receiving PBO; the most frequently reported TREAs for AMS were skin and subcutaneous tissue disorders (10%), infections and infestations, musculoskeletal and connective tissue disorders, nervous system disorders, and cardiac disorders (all 8%). Five serious AEs (SAEs) led to treatment discontinuation (1 in the PBO group; 4 in the AMS group). In the OLE, more PBO/AMS patients (40%) vs AMS/AMS (33%) reported TRAEs; most frequent TRAEs for AMS/AMS were blood and lymphatic system disorders (14%) and investigations (14%). Of 13 SAEs reported by 9 patients, 2 treatment-related SAEs (1 in the PBO/AMS group) led to treatment discontinuation. In the DBPC study, cardiac disorders, all mild, were reported in 3 in the AMS group vs 1 in the PBO group; in the OLE, cardiac disorders were reported by 1 in the AMS group and 1 in the PBO group. There were no clinically significant reports of bradycardia, ventricular tachycardia, or atrioventricular block in the AMS group in either study. In the DBPC study, macular edema (ME) was confirmed in 1 AMS patient (mild/nonserious); none were reported in the OLE. There were no deaths, opportunistic infections, clinically significant negative laboratory or abnormal ECG findings after AMS treatment.

Conclusions

Oral AMS 0.4 mg was generally well tolerated, with no new safety concerns identified. Other than 1 patient with mild ME, there were no other findings related to the known AMS risk profile. While AMS did not have an effect on CDA in previously treated CD, this favorable safety profile, including no clinically significant reports of bradycardia, is promising for treatment of other autoimmune-mediated diseases, including UC.
P098 FROM OLD BUMP TO BONE INFECTION: A CASE OF BRODIE’S ABSCESS IN A CROHN’S PATIENT
Authors: Marston John , Chapman J C , Hamer Diana
Published: January 2020

Introduction

Brodie’s abscess is an uncommon variant of subacute osteomyelitis leading to a contained infectious focus within a bone. It classically occurs in young people with a history of trauma to the affected bone. We present a case of a Brodie’s abscess in a 52-year-old Crohn’s patient on dual immunosuppressive therapy.

Case Description

A 52 year old man with Crohn’s disease managed with adalimumab and methotrexate presented to an orthopedist with worsening left hip and thigh pain and fevers over the week prior. He reported a remote sports-related injury to the same region with mild pain intermittently over the subsequent years. MRI of the left pelvis showed an enhancing lesion of the anterior superior iliac spine with cortical erosion. He was admitted and started on broad spectrum antibiotics, and his immunosuppressive agents were held. CT-guided biopsy of the lesion returned as abscess, and culture of the lesion grew methicillin-sensitive staphylococcus aureus. The abscess was debrided in the OR and he completed a 6-week course of culture-guided antibiotic therapy.

Discussion

To our knowledge this is the first reported case of Brodie’s abscess associated with Crohn’s disease and dual immunosuppressive therapy. Opportunistic pathogens are most often associated with anti-TNFα therapy, though there is also evidence other bacterial infections are more frequent in these patients, particularly salmonellosis, listeriosis, and pneumococcal disease. Patients on anti-TNFα therapy appear to be at highest risk for serious infections in the first six months after initiation, but it is unclear if there is a persistent or cumulative risk with long-term therapy. The underlying mechanism of immunosuppression in anti-TNFα therapy is thought to be multifactorial, impacting both innate and adaptive immunity. Data suggests increased risk of infection in rheumatoid arthritis patients taking methotrexate. Only observational data exists regarding infection risk in Crohn’s patients on methotrexate, but it is reasonable to infer that it may have played a role in our patient’s presentation. Bone trauma seems to be associated with the development of Brodie’s abscess, and our patient reported a long history of chronic left hip and thigh pain due to a remote sports-related injury to that region. The source of his infection was most likely transient bacteremia, which seeded this nidus in his anterior superior iliac spine. While causation cannot be determined, this interesting case serves as reminder to prescribers of dual immunosuppressive therapy to be cognizant of infectious complications outside of those commonly attributed.
P099 LEUKOCYTOCLASTIC VASCULITIS AFTER USTEKINUMAB INDUCTION IN CROHN’S DISEASE: A CASE SERIES AND SYSTEMATIC REVIEW
Authors: Chugh Rishika , Proctor Deborah , Little Alicia , Myung Peggy , Imaeda Suguru , Al-Bawardy Badr
Published: January 2020

Ustekinumab (UST) is an effective treatment for Crohn’s disease (CD). Here we present two cases of leukocytoclastic vasculitis (LCV) in CD patients after UST induction therapy with a review of the literature.

Patient #1: A 26 year old woman with a 14 year history of Crohn’s ileocolitis. She was previously treated with 6-mercaptopurine, infliximab, and vedolizumab without durable response. She ultimately underwent a left hemicolectomy due to development of a sigmoid stricture and was started on UST postoperatively. Thirty-six days after her initial UST intravenous (IV) infusion of 390 milligrams (mg) she developed new partially blanching, erythematous, non-tender, non-pruritic macules and papules over the right medial thigh, which later evolved into palpable purpura involving both lower extremities (Figure 1A). She reported no gastrointestinal (GI) or other symptoms. White blood cell (WBC) count and metabolic panel were normal. Antinuclear antibody (ANA) titer was 1:80. Perinuclear pattern antineutrophil cytoplasmic antibodies (p-ANCA) were positive. C-reactive protein (CRP) was elevated to 41.5 mg/liter (L). One lesion was biopsied, and pathology findings were consistent with LCV (Figure 1B). She was started on colchicine 0.6 mg daily with improvement in her rash and has received her second dose of UST without further complications.

Patient #2: A 29 year old woman with a 6 year history of Crohn’s ileocolitis. Her prior treatments include budesonide, mesalamine, and infliximab. While on infliximab, she developed jejunal and ileal ulcers on video capsule endoscopy. Infliximab was discontinued, and UST was started. Three months following initial IV induction therapy of UST, she developed pink purpuric papules and hemorrhagic vesicles involving her bilateral shins, dorsal feet, calves, and bilateral extensor forearms. The appearance of the rash was consistent with LCV (Figure 2). She was started on prednisone at 60 mg daily for 1 week with taper resulting in complete resolution of her rash. UST was continued with no recurrence. WBC count and metabolic panel were normal. ANCA was negative, and ANA titer was 1:80. CRP was elevated to 13.2 mg/L.

Literature review revealed only one prior published case report of a patient with inflammatory bowel disease developing LCV after administration of UST. In this case, UST was discontinued since re-administration caused the rash to return. Here we have two patients who developed LCV soon after initiating UST therapy, although after treatment with prednisone/colchicine, there was no recurrence with continuing UST. It is possible to develop LCV in association with CD alone; however, these patients had longstanding disease without occurrence of LCV until being started on UST. Moreover, patient #1, was in remission from a Crohn’s disease standpoint at the time of UST initiation and onset of the rash.
P100 REAL-WORLD COMPARISON OF ARTHRALGIAS WITH INFLIXIMAB VS. VEDOLIZUMAB IN THE TREATMENT OF BIO-NAIVE INFLAMMATORY BOWEL DISEASE
Authors: Ritter Timothy , Fourment Chris , Kuten Samantha , Van Anglen Lucinda
Published: January 2020

Background

Both infliximab (IFX) and vedolizumab (VDZ) are approved for the treatment of inflammatory bowel disease (IBD) in adults. VDZ is gut-specific and thought to be less effective in controlling extraintestinal manifestations than IFX. The purpose of this study was to compare the incidence and timing of arthralgias between IFX and VDZ.

Methods

We performed a retrospective cohort study of bio-naïve adult patients treated with IFX or VDZ for ulcerative colitis (UC) or Crohn’s disease (CD) at a large multicenter gastroenterology private practice. Patients were case-matched 1:1 based on age, gender, diagnosis, and baseline disease severity using the partial Mayo (pMayo) for UC and the modified Harvey-Bradshaw Index (mHBI) for CD. Arthralgias were captured out to 12 months of therapy and classified as pre-existing or new-onset based on time to occurrence. Those with pre-existing arthralgias were excluded from new-onset arthralgias analyses. Rates of arthralgias and time to new-onset arthralgias were compared between IFX and VDZ patients.

Results

A total of 77 IFX (58 UC, 19 CD) and 77 VDZ (58 UC, 19 CD) case-matched pairs were generated. Baseline demographics were similar between IFX and VDZ groups: mean age 45±16.9 vs 46±16.2, male gender 60% vs 61%. Rates of pre-existing arthralgias were 13/77 (17%) and 12/77 (16%) in IFX and VDZ cohorts (p=0.83), respectively. Resolution of pre-existing arthralgias was also similar between groups (6/13 vs 7/12, p=0.70). Of the remaining 64 IFX and 65 VDZ patients without arthralgias at baseline, 16 (25%) IFX patients and 17 (26%) VDZ patients experienced new-onset arthralgias (p=1.0). Median time to new-onset arthralgias was 5.0 (IQR 3.4–7.0) months in IFX patients, compared to 3.3 (IQR 1.4–5.3) months in VDZ patients (p=0.15). While VDZ patients appeared to develop new-onset arthralgias earlier, this was not significant (p=0.20) [Figure 1]. Of note, two IFX patients discontinued therapy due to suspected drug-induced lupus with arthralgias; there were no VDZ discontinuations due to arthralgias.

Conclusions

Our data suggests that resolution of pre-existing arthralgias and new-onset arthralgias are similar, despite the gut selectivity of VDZ compared to IFX. Additionally, there was no difference in overall time to new-onset arthralgias. These data need to be verified in a larger cohort.
P153 MET642, AN ORAL FXR AGONIST, IMPROVES COLITIS INDUCED BY ADOPTIVE T-CELL TRANSFER
Authors: Liu Xueqing , O’Connell Robert , Bendele Alison , Walker Melissa , Ohlsen Connor , Govek Steve , Nagasawa Johnny , Douglas Karensa , Milik Angelica , Lu Nhin , Qian Jing , Ortiz Alvaro , Chai Pauline , Zook Douglas , Lee Kyoung-Jin , Smith Nicholas , Wagner Brandee , Song Ken
Published: January 2020

Introduction

Farnesoid X receptor (FXR) is a ligand-activated nuclear hormone receptor expressed in the gastrointestinal tract, with high expression levels in the intestinal epithelium. Previously we have shown that FXR agonists with sustained activity decreased colitis in multiple chronic IBD models (i.e. Adoptive transfer colitis, Mdr1a-/- colitis, and SAMP1/YitFc ileitis). Because FXR agonists are dosed orally and do not have systemic immunosuppressive properties, they represent a novel and differentiated therapeutic approach for IBD. MET642 is an optimized, potent non-bile acid FXR agonist with sustained FXR activation. In this study, we examined the efficacy of MET642 in therapeutic treatment mode in adoptive T-cell transfer model.

Methods

Colitis was induced by transplanting CD4+CD45RBhi T-cells to recipient C.B-17 SCID mice. Body weights were monitored throughout study duration. Staring 21 days after T-cell transfer, mice were treated with vehicle (n=10), MET642 (0.1, 0.3 or 1 mg/kg p.o., daily, n=10), or anti-IL-12p40 (neutralizing both IL-12 and IL-23, 0.5mg/mouse, i.p., weekly, n=5) for 4 weeks. Terminal endpoints included colon weight to length ratio (W/L), colon histopathology and gene expression. Histopathology scores were determined for inflammation, erosion, gland loss and hyperplasia, each with a score of 0–5, and cumulative sum score of 0–20.

Results

CD4+CD45RBhi T-cell transfer led to a significant reduction in body weight and increase in colon W/L ratio; both were reversed by MET642 and anti-IL-12p40. All dose levels of MET642 significantly improved the histopathology sum score relative to vehicle treatment, with maximal efficacy reached at 0.3mg/kg. Similar to anti-IL-12p40, MET642 showed improvements across all individual histopathology endpoints. Gene expression analysis suggests FXR activation increases anti-microbial activity, improves gut barrier and transporter function, and suppresses inflammation.

Conclusion

MET642, an oral once daily FXR agonist, significantly improved colitis in the adoptive T-cell transfer model. Activation of FXR by MET642 potentially promotes pathways of gut anti-microbial function, barrier function, and suppression of inflammation. These findings support further development of MET642 as a novel oral therapeutic for treating IBD.
P094 A COMPARISON OF EXERCISE MEASURES AMONG ADULTS WITH INFLAMMATORY BOWEL DISEASE
Authors: Davis Suja , Melendez Carlos , Crane Patricia , Long Millie
Published: January 2020

Background

Individuals with IBD, comprised of Crohn’s disease (CD) and Ulcerative Colitis (UC), often have ongoing gastrointestinal symptoms that limit their ability to exercise. Importantly, exercise can help to maintain remission in individuals with IBD. Other positive health outcomes of exercise include improvement in quality of life, social and psychological well-being, weight maintenance, bone health, fatigue management and maintaining muscle mass and function. Unfortunately, many of the tools used to measure exercise are burdensome for clinical utility or are not applicable to the IBD population. The purpose of this secondary analysis was to determine if one question related to physical activity would capture exercise in adults with either UC or CD and those with active or inactive disease.

Methods

This study is a cross-sectional study using the data obtained from IBD Partners, an internet-based longitudinal cohort of adults ≥ 18 year of age living with IBD. This secondary analysis includes only those participants without a current ostomy or pouch, who completed demographic information, disease activity and exercise characteristics. Disease activity was measured via the simple clinical colitis activity index (SCCAI) for UC and the short Crohn’s disease activity index (sCDAI) for CD. Exercise was measured via the Godin Leisure -Time Activity Index (GLTA) questionnaire that assessed type of exercise and intensity for the past seven days. A separate measurement of physical activity included a single question: “How often did you participate in 1 or more physical activities of 20–30 minutes’ duration per session during your leisure time within the past 6 months?” measured via a 6-point ordered category item.

Results

A total of 8327 patients with IBD were included. Most (63%) of the participants had CD, and 54% were in remission. Majority of the participants were physically active based on GLTA scores (49.7%), and one question physical activity scores (62%; combined scores of 5 & 6). Polychoric correlation coefficient was computed, with a strong correlation between GLTA and the one question (r = 0.74, p < 0.001). Ordinal regression analysis between the one physical activity question and IBD type (UC vs CD) yielded higher odds of physical activity with UC (Odds ratio (OR)=1.2, 95% CI [1.11 -1.31], p < 0.0001). Similar results were noted with ordinal regression analysis between GLTA scores and UC;(OR=1.2, 95% CI [1.09 -1.3], p < 0.0001).

Conclusions

Both GLTA and the single question of physical activity were highly correlated. The ordinal regression results were comparable for both measures. Adoption of the single physical activity question may adequately reflect exercise status in IBD patients and reduce burden for clinical use. Further longitudinal studies are need to support the use of one question in measuring exercise in those with IBD.
P061 VALUE OF US AND MRE IMAGES IN THE DIAGNOSTICS OF ACTIVE CROHN’S DISEASE IN CHILDREN
Authors: Zbroja Monika , Cyranka Weronika , Kuczynska Maryla , Piekarska Monika , Siejka Karolina , Nowakowska Malgorzata , Grzegorczyk Magdalena , Brodzisz Agnieszka , Wozniak Magdalena Maria
Published: January 2020

Introduction

Crohn’s disease is classified as chronic inflammatory bowel disease.

The incidence of it in Europe ranges from 1 to almost 11.4 per 100,000 population per year. Ultrasound and magnetic resonance enterography examinations play an important role in imaging diagnostics of inflammatory bowel lesions. They allow for recognising and monitoring changes during therapy as well as assessing complications such as fistula or abscess.

Materials and Methods

36 children were included in the study: 16 boys and 20 girls with an active phase of Crohn’s disease. Each patient underwent intestinal ultrasound examination with a high frequency 7–12 Mhz linear probe and MRE with intravenous administration of a contrast agent.

Results

All patients showed a significant correlation between ultrasound and MRE. In the US examination all children had thickened, low echogenic wall showing varying degrees of vascular flow signals. Additionally, in 8 patients Bauhin’ valve edema was visible. In 16 children, inflammatory infiltration of the periintestinal fat around the affected segment of the intestine was found. In all patients a mesenteric lymphadenopathy in the short axis of 10-15mm was visible. MRE confirmed the presence of the confirmed ideal lesions and Bauhin’ valve edema in all 36 children. In addition, in 4 patients small intestine fistulas were found whereas abscess was observed in another 4 patients. In contrast-enhanced images, a vivid enhancement of the affected bowel section was revealed and in 10 children inflammatory reactions of peri-intestinal fat was demonstrated.

Conclusion

US and MRE are reliable tools in diagnosis of enteric inflammatory disease of the small intestine, evaluation of disease activity and assessment of potential complications. They are complementary elements in diagnostics of Crohn’s disease.
P125 COMPLICATIONS FOLLOWING OUTPATIENT COLONOSCOPY IN INFLAMMATORY BOWEL DISEASE (IBD) PATIENTS
Authors: Chu Daniel , Chen Po-Hung , Brant Steven , Miller Steven , Turner Natasha , Hutfless Susan
Published: January 2020

Inflammatory Bowel Disease (IBD) patients have frequent complications after surgical procedures. Inflammation, immunosuppression and other factors that are more common in Crohn’s disease (CD) and ulcerative colitis (UC) may play a role in increasing their complication risk profile. IBD patients also undergo colonoscopy procedures more frequently than the general population. We aimed to identify risks of complications during or within 7 days of colonoscopy in IBD patients.

Methods: Colonoscopy procedures performed between January 2016 through March 2019 in an outpatient setting (hospital or ambulatory surgical center) were identified from the United States Medicare fee-for-service claims. All Medicare beneficiaries were eligible. Colonoscopy was identified using the Healthcare Common Procedure Coding System (HCPCS) codes (‘45378’ through ‘45393’ and ‘45398’). A patient was considered to have Crohn’s disease (CD) if ICD-10-CM code K50.x was recorded; Ulcerative Colitis (UC) if ICD-10-CM code K51.x was recorded; and IBD if either was recorded on the date of the procedure. Complications recorded during the procedure included intestinal perforation (K63.1), gastrointestinal hemorrhage (K92.2), and “other post-procedural complications of the digestive system” (K91), including, but not limited to, post-gastrectomy syndrome, malabsorption, and intestinal obstruction. We examined these complications in procedures performed on IBD patients compared to the general population using logistic regression. We accounted for age, sex, race, year of colonoscopy, comorbidity score, and procedure discontinuation (identified by HCPCS modifier) in the analysis. A random effect for patient was included in the model to account for multiple procedures performed in the same patient during the study period, restricting patients from contributing multiple procedures.

Results: There were 3,181,759 eligible procedures. There were 26,583 (0.84%) colonoscopy procedures in CD patients and 50,708 (1.59%) in UC patients. After accounting for other risk factors, CD and UC were more likely to have intestinal perforation than the non-IBD population (CD OR=2.7, 95% CI: 1.1–6.5; UC=OR 1.9, 95% CI 0.9–4.1), with CD having a statistically significant increase. Women were at greater risk for perforations (OR=1.3; 95% CI: 1.0–1.7). Conversely, IBD patients were less likely than non-IBD patients to have a complication recorded as “other” (CD OR=0.5; 95% CI: 0.2–0.9; UC OR=0.5; 95% CI:0.3–0.8). Older age at colonoscopy (OR=1.02, 95% CI 1.01–1.03), six or more comorbidities (OR=1.9, 95% CI: 1.5–2.3) and procedure discontinuation (OR=2.0, 95% CI 1.2–3.4) were associated with complications regardless of IBD status.

Conclusion: IBD was associated with higher risk of perforation, and lower risk of other postprocedural complications in outpatient colonoscopy procedures.
4 TOTAL ABDOMINAL COLECTOMIES WITH PROCTECTOMY ARE ASSOCIATED WITH HIGHER 30-DAY READMISSION RATES IN CHILDREN WITH ULCERATIVE COLITIS
Authors: Egberg Matthew , Phillips Michael , Kappelman Michael
Published: January 2020

Background

Hospital readmissions are frequent and expensive. Thirty-day readmission rates for adult patients undergoing colectomy are as high as 25%, with inflammatory bowel disease (IBD) being a major risk factor for readmission. We sought to 1) determine the 30-day readmission rate for pediatric patients with ulcerative colitis (UC) undergoing total abdominal colectomy (TAC) between 2012 and 2017 using a national pediatric surgical database and 2) identify risk factors for unplanned readmission in this population.

Methods

We used the National Surgical Quality Improvement Program-Pediatrics (NSQIP-P) to identify pediatric UC patients undergoing a TAC between 2012 and 2017. The NSQIP-P is a national, multi-center effort by the American College of Surgeons to improve surgical care through standardized collection of patient-level data and longitudinal 30-day monitoring of patients following surgery. We identified patient and procedural data from the index hospitalization and used logistic regression to identify risk factors for 30-day readmission rates, adjusting for confounding factors.

Results

We identified 489 pediatric UC TAC hospitalizations between 2012 and 2017. Among these, 19% were readmitted unexpectedly to the hospital within 30-days of discharge. Patient demographics and preoperative lab values (hematocrit, albumin) were not associated with risk of readmission. However, TAC procedures that included a proctectomy were at a 2-fold (95% CI, 1.2–3.8) higher risk of 30-day readmission than staged procedures after adjusting for patient demographics, index admission length of stay, operative time, pediatric surgeon, and laparoscopic versus open approach.

Conclusion

Nearly 20% of annual pediatric UC hospitalizations involving a colectomy result in an unplanned readmission within 30 days of hospital discharge. Notably, TAC procedures that included a proctectomy had significantly higher rates of readmission than those not including a proctectomy. These results can inform risk management strategies aimed at reducing morbidity and hospital readmissions for children with UC.
P150 ENHANCING EPITHELIAL BARRIER FUNCTION WITH NOVEL E-CADHERIN ACTIVATING MONOCLONAL ANTIBODIES REDUCES INFLAMMATORY BOWEL DISEASE PROGRESSION IN MOUSE MODELS
Authors: Bandyopadhyay Chirosree , Schecterson Leslayann , Gumbiner Barry
Published: January 2020

Deficits in gastrointestinal (GI) epithelial barrier function play important roles in the pathogenesis of Inflammatory Bowel Disease (IBD). The CDH1 gene encoding E-cadherin, a key component of the epithelial junctional complex, is associated with Ulcerative Colitis (UC), and perhaps Crohn’s disease (CD). E-cadherin is the principle adhesive component of the adherens junction, and it regulates paracellular permeability by facilitating the formation of tight junctions and organizing the entire epithelial junction complex. We have identified monoclonal antibodies (mAbs) that bind to E-cadherin and activate adhesion in a variety of epithelial cells. In this study, we aim to test the hypothesis that strengthening E-cadherin adhesion with activating mAbs will enhance barrier function and decrease progression of IBD while maintaining mucosal health and homeostasis. Mouse mAbs to E-cadherin have been tested in vivo using the IL10-knock out mouse and adoptive T cell transfer model of colitis with similar histological evaluation. Transfer of CD4+CD45Rb high T cells from donor to immunocompromised mice produced typical histologic lesions for the adoptive transfer model including inflammation of the mucosa/submucosa, crypt damage, erosions, edema, and epithelial hyperplasia. E-Cadherin activating mAb (r56.4) treatment reduced total colitis score, mucosal hyperplasia, inflammation, gland loss scores, and neutrophilic infiltration in CD45Rb high T cell recipient mice compared to control E-cad mAb (r19.1–10) treatment. In IL10 KO BL6 mouse model of colitis, average lesion severity scores were lower in the r56.4 treatment group in comparison to the r19.1–10 treatment group for all the histological hallmarks of colitis. Further studies are in progress to investigate the therapeutic potential of E-Cadherin mAbs in the rescue of inflammation in pre-clinical mouse models of colitis.
P158 LOSS OF AUTOTAXIN ALTERS INNATE AND ADAPTIVE IMMUNE MECHANISM AND PROMOTES SPONTANEOUS COLITIS IN IL10-KO MICE
Authors: Kim Su Jin , Howe Cody , Mitchell Jonathon , Im Eunok , Rhee Sang
Published: January 2020

Background & Aims

Autotaxin (Atx) is a secreted enzyme converting lysophosphatidylcholine (LPC) and sphingosyl-phosphorylcholine into lysophosphatidic acid and sphingosine 1-phosphate, respectively. Given the high affinity of LPC to cholesterol and the enrichment of cholesterol and sphingolipids in lipid rafts wherein LPS sensor Toll-like receptor 4 (TLR4) and its co-receptor CD14 reside, we hypothesized that Atx deficiency inhibits TLR4-mediated innate and adaptive immunity; thereby, accelerating the susceptibility to microbe-induced intestinal inflammation.

Method

We generated myeloid cell lineage-restricted Atx-knockout (ko) mice (AtxdME/dME) to study TLR4-mediated immune and inflammatory responses and investigated LPS-receptor complex formation through fluorescence resonance energy transfer technique, confocal microscopy, and flow cytometry. Lamina propria CD4+ T cells and bacterial load in the intestinal mucosa were examined. An impact of Atx deficiency in inflammatory bowel diseases (IBD) was investigated using AtxdME/dME;Il10-/- mice that have both Atx-deletion in myeloid cells and a global Il10 deletion. We examined the serum samples from IBD patients.

Results

With peritoneal macrophages from AtxdME/dME mice, we identified that Atx-ko disrupted the integrity of lipid rafts at the plasma membrane, resulting in the inhibition of TLR4 complex formation. Accordingly, the recruitment of adaptor molecules to TLR4 was suppressed, and TLR4-mediated responses were substantially reduced in Atx-ko macrophages. TLR4-induced innate immunity such as phagocytosis was attenuated in Atx-ko macrophages. The activation of CD4+ effector T cells and regulatory T cells was diminished in the lamina propria lymphocytes of AtxdME/dME mice compared to that of Atx+/+ littermates. Consequently, AtxdME/dME mice had a higher bacterial prevalence in the intestinal mucosa compared to controls. Just like the notion that commensal microbes translocated from the lumen into the intestinal mucosa can elicit spontaneous colitis in Il10-/- mice, combining AtxdME/dME with Il10-/- mice (AtxdME/dME; Il10-/-) did accelerate spontaneous colitis development. AtxdME/dME; Il10-/- mice had gross inflammation occurring throughout the colon, massive neutrophil infiltration and necrosis in the colonic mucosa, and increased mortality (Log-rank P=0.0046), while Atx+/+;Il10-/- littermates are normal. Notably, ATX serum protein level was lower in UC (n=26) and CD (n=34) patients compared to the level in normal subjects (n=26) (P<0.001), indicating an association of reduced ATX levels with the intestinal inflammation.

Conclusions

Collectively, we found that Atx deficiency suppresses TLR4-mediated innate and adaptive immune mechanisms; thereby accelerating the susceptibility to microbe-induced gut inflammation.
P159 PHENOTYPIC CHARACTERIZATION OF INFLAMMATORY BOWEL DISEASE BIOPSIES REVEAL THAT MAST CELLS ARE SIGNIFICANTLY ELEVATED AND ACTIVATED IN PATIENTS WITH ULCERATIVE COLITIS
Authors: Youngblood Bradford , Davis Tina , Schanin Julia , Butuci Melina , Brock Emily , Singh Bhupinder , Rasmussen Henrik , Holman Amy , Drake Richard , Peterson Kathryn , Flynn Ann
Published: January 2020

Rationale

Accumulation and activation of mast cells and eosinophils have been implicated in the pathogenesis of several chronic inflammatory gastrointestinal (GI) diseases, including eosinophilic gastrointestinal diseases (EGIDs) and inflammatory bowel disease (IBD). Despite the strong association of mast cell and eosinophil numbers and activation with the pathogenesis of IBD, no further characterization of these cells has been performed. Current treatment options for IBD include aminosalicylates, antibiotics, immunomodulators, biologic agents and small molecules. These therapies are only moderately effective. A significant proportion of patients fail to respond, do not fully respond, or lose response over time. Therefore, there is significant need for more selective and effective therapy options. Siglec-8 is an inhibitory receptor selectively expressed on human eosinophils and mast cells and represents a novel target for the treatment of IBD with the anti-Siglec-8 mAb, antolimab (AK002). We aimed to quantify and evaluate the activation state of mast cells and eosinophils in colonic tissue from IBD or non-diseased patients. In addition, we quantified the production of TNFa from human colon tissue mast cells and evaluated the inhibitory activity of antolimab (AK002) on these cells.

Methods

Single-cell suspensions were prepared by enzymatic digestion of fresh colonic biopsies from patients clinically diagnosed with IBD (n=29) or non-diseased control tissues (n=16). Multi-color flow cytometry was performed to identify major immune cell populations and evaluate the activation state of mast cells and eosinophils. Mast cells were FACS-sorted from human colon tissue to evaluate cytokine production and inhibitory activity of antolimab.

Results

The percentage of mast cells and the expression of the mast cell degranulation marker CD107a were significantly increased in ulcerative colitis (UC) patient biopsy tissue compared to Crohn’s disease (CD) and non-diseased colonic tissue (Figure 1A and B). Furthermore, FACS-sorted mast cells from human colon tissue produced significant quantities of TNFa that was reduced after ex vivo antolimab treatment. Colonic tissue eosinophils were also elevated in a subset of UC and CD patient biopsies, and all UC and CD tissue eosinophils displayed increased expression of the activation marker CD11b compared to control colonic tissue.

Conclusions

Mast cells and eosinophils may play a significant role in driving the pathogenesis of ulcerative colitis through the production of inflammatory mediators. The high expression of Siglec-8 and the inhibitory activity against mast cells suggests that antibodies that target this receptor, such as antolimab (AK002) represent a potential novel approach for the treatment of IBD.
P141 GREEN TEA POLYPHENOL EPIGALLOCATECHIN-3-GALLATE DIFFERENTIALLY MODULATES ENDOPLASMIC RETICULUM STRESS-MEDIATED WOUND HEALING PROCESS IN SUBEPITHELIAL MYOFIBROBLASTS
Authors: Li Chao , Kuemmerle John
Published: January 2020

Epigallocatechin-3-gallate (EGCG) has multifaceted roles in the preclinical treatment of diseases including liver and lung fibrosis. EGCG has also been tested with fewer reported side effects than therapeutic drugs. Previously we showed that increase in endoplasmic reticulum (ER) stress response in subepithelial myofibroblasts (SEMF) contributes to activation of TGF-β1 and resultant intestinal fibrosis in patients with fibrostenotic Crohn’s disease. Moreover, different migratory potential of myofibroblasts isolated from inflamed, fibrostenotic, or fistulized Crohn’s disease mucosa could be an explanation for impaired or excess wound healing and subsequently for fistula or fibrosis in patients with Crohn’s disease. To investigate the effect of EGCG on ER stress-mediated wound healing process, SEMF were isolated from normal ileum and affected ileum in the same patient with Crohn’s disease. Cells were cultured and treated with EGCG (10 μg/ml), AG1024 (a tyrosine kinase inhibitor, 6 μM), U1026 (an ERK inhibitor, 6 μM), LY294002 (a PI3K inhibitor, 10 μM), SB202190 (a p38 inhibitor, 50 nM), 4-PBA (a chemical chaperone, 10 μg/ml), and MG132 (a NF-KB inhibitor, 3 μM) for 2 hours in serum free medium. Cell lysates were obtained for Western blot analysis. An ER stress agonist tunicamycin (5 μg/ml) was incubated with SEMF for different time points. Wound healing assay was used in a cell monolayer, capturing the images at the beginning and at regular intervals during cell migration to close the wound, and comparing the images to quantify the migratory potential of the cells. In vivo effect of EGCG was tested in a murine TNBS colitis model and observed by Storz Coloview standard operating procedures. Here we showed that EGCG further decreased endogenous GRP78 protein expression by 18∼29±1.5% in SEMF compared to that treated with different inhibitors targeting other non-ER stress signals. EGCG prevented tunicamycin-induced migratory potential of SEMF isolated from normal ileum by 40±2.5%, 65±3.3% after 48 and 72 hours, as well as cell proliferation by 85±3.3%, 120±6.1% after 48 and 72 hours, respectively. Moreover, EGCG also further decreased cell migratory potential of SEMF isolated from affected ileum by 15±1.2% and 50±1.8% compared to the control group after 48 and 72 hours, respectively. Coloview showed that EGCG decreased inflammatory activity in the mice colon compared to TNBS colitis group after 8-week treatment. Ongoing study includes methylene blue staining of the colonic mucosa during endoscopy, endoscopic scoring of inflammation activity, and trichrome staining of collagen production in a colonic biopsy. Taken together, EGCG alleviates ER Stress response, leads to greater inhibition of migratory potential of SEMF, and decreases TGF-β1 and collagen productions, which is the major molecular feature of fibrosis.
P076 TRANSFERABLE IMMUNE REACTIVE MICROBIOTA DETERMINE CLINICAL AND IMMUNOLOGIC OUTCOME OF FECAL MICROBIOTA TRANSPLANTATION FOR ULCERATIVE COLITIS
Authors: Lima Svetlana , Gogokhia Lasha , Viladomiu Monica , Crawford Carl , Jacob Vinita , Scherl Ellen , Rosenthal Melissa , Brown Su-Ellen , Hambor John , Longman Randy
Published: January 2020

Background

Biologic therapy has significantly improved treatment for UC, but nearly two-thirds of patients attenuate response. Additional therapeutic modalities are therefore needed to address the underlying pathophysiology of UC. Fecal microbiota transplant (FMT) is an emerging therapy for the treatment of UC, but several randomized controlled trials have shown variable efficacy of FMT, and the microbial mechanisms responsible for clinical response are not well understood. Therefore, using samples from our pilot FMT study (Jacob, V, et al Inflamm. Bowel Dis. 2017), we aim to identify the core transferable microbiota (CTM) in UC patients responsive to FMT therapy and to define the therapeutic mechanism of these strains in pre-clinical models.

Methods

IBD disease activity scores were used to define clinical response. Metagenomic sequencing of donor, recipient, and 4 week post-FMT fecal samples was performed to define the CTM. Strain level transferability was defined using StrainFinder. To define the transferable immune-reactive microbiota (TIM), IgA-seq was performed on donor, recipient, and 4 week post-FMT fecal samples. TIM strains were isolated from fecal samples and gnotobiotic mouse models were used to evaluate their impact on mucosal immunity and mouse models of colitis.

Results

Here, we defined a CTM associated with clinical response to FMT for UC. Strain level tracking of the CTM confirmed that clinical response correlated with strain transferability. In addition, we defined a core TIM by IgA-seq that correlated with clinical response. In humanized mouse models, these TIM were found to induce IgA in a T cell independent manner. Colonization of germ-free mice with a core TIM strain of Odoribacter induced IL-10-dependent, RORgt+/Foxp3+ iTreg cells and reduced the severity of transfer T cell colitis in mono-colonized RAG-/- mice.

Conclusion

Our data highlight an immune-reactive, core transferable microbiota in responders to FMT for UC. Using pre-clinical mouse models of colitis, we define the mechanistic impact of these TIM in shaping mucosal immunity and guiding the response to UC. This work provides a framework for rational selection of TIM for microbial-therapy in IBD.
P118 CONTENT VALIDITY OF THE SUBCUTANEOUS ADMINISTRATION ASSESSMENT QUESTIONNAIRE (SQAAQ) IN ADULT AND ADOLESCENT PATIENTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS
Authors: Naegeli April , Hunter Theresa , Delbecque Laure , Karn Hayley , Skalicky Anne
Published: January 2020

Background

Subcutaneous (SC) delivery of biologic therapies is typically self-administered via a prefilled syringe or an auto-injector. Auto-injector devices are designed to offer a more convenient and more consistent administration of the drug product. The Subcutaneous Administration Assessment Questionnaire (SQAAQ) is a novel, 12-item, self-administered questionnaire that assesses ease of use of SC delivery devices and patient confidence while using the device to administer an injection of drug. This study aimed to establish evidence of the content validity of the SQAAQ among patients with moderate to severe ulcerative colitis (UC).

Methods

A cross-sectional, US-based, qualitative study using a semi-structured discussion guide was conducted using online focus groups and one-on-one telephone interviews among adolescent (12–17 years (yrs)) and adult (18 yrs+) participants with diagnosis of moderate-to-severely active UC recruited from clinical sites and patient panels. Cognitive debriefing of the SQAAQ instructions, items, recall period, scoring algorithm, and response options was conducted to assess understanding and interpretation of the items. The SQAAQ instructs patients to evaluate the questions based on “to what extent do you agree that the device you just used has these features” on a 7-point Likert scale ranging from “strongly disagree” to “strongly agree”.

Results

Thirty-one patients (n=27, 87% focus group; n=4, 13% telephone) participated in an interview. The majority were female (n=23, 74%); non-Hispanic or Latino (n=28, 90%); and White (n=22, 71%). Twelve (39%) were ≥18 yrs; 8 (26%) were 15–17 yrs; and 11 (35%) were 12–14-yrs. Administration of current medication use included: 48% on intravenous, 36% on SC, and 16% on oral. Adult and adolescent participants found the SQAAQ to be relevant, straight-forward, and easy to understand. Participants described the questionnaire as being ‘clear’, ‘detailed’, and felt as if the questionnaire included all the necessary items. All participants described the response options as ‘good’ and that they were able to select a response from a range of options. None of the participants had suggestions for changes to the response options. The confirmed conceptual framework (see Figure) for the SQAAQ depicts the 12 item concepts within 4 domains: ease of use (n=6 items), injection convenience (n=3 items), injection self-efficacy (n=2 items), and perceived self-efficacy (n=3 items).

Conclusion

Patient feedback confirms content validity of the SQAAQ and provides strong evidence that the concepts included in the SQAAQ are important to and well-understood by adults and adolescents with UC.
P017 INFLAMMATORY BOWEL DISEASE: YOUTH BELIEFS AND BARRIERS TO TRANSITION
Authors: Beeson Erynn , MacKay Heather , Beard Jacklyn Stellway , Paternostro Jennifer , Lin Henry , Harris Michael
Published: January 2020

Introduction

Transitioning from pediatric to adult care remains a vulnerable time for all youth, especially those with inflammatory bowel disease (IBD). While the medical community recognizes this, it is still an understudied phenomenon and youth often become lost in transition. Our mixed methods study is unique in that it comprehensively assesses youth/caregiver understanding and priorities through interviews and surveys surrounding the transition process for youth with IBD.

Methods

This is a prospective chart review. English speaking youth with IBD ages 12–25 and their caregivers at a tertiary care center were given the Transition Barriers and Beliefs scale (TBAB). Data were analyzed by descriptive statistics and frequencies. A subgroup of youth/caregiver dyads from the above sample were asked a semi-structured set of questions. The answers were audio recorded and transcribed.

Results

70% of caregivers reported they are not discussing transition with their youth.

74% of caregivers and 70% of youth reported that no provider initiated a transition discussion.

40% of youth older than 16 reported providers initiated a transition discussion.

25% of youth and 33% of caregivers expressed concern over transition.

90% of caregivers reported there was no transition plan regardless of age.

53% of youth and 73% of caregivers believed that similar support services are offered in adult care.

Caregivers and youth shared similar priorities to discuss prior to transition, the most important being insurance.

Caregivers and youth both overwhelmingly prefer information be relayed face-face.

Youth and caregivers agreed providers should begin talking about transition at age 16–17, seeing the provider alone at 17–18, and transitioning at 18.

Conclusion

Discussion around transition in IBD care is not happening at home or with providers. Accordingly, most youth and their families have no plan for this process. Our data agree with other research indicating that youth and their caregivers view transition more as an event and less as a process (e.g., transition discussions and transfer to adult care around the same age 17 to 18). This is highlighted by the finding that youth/caregiver dyads reported that seeing the physician alone should happen just before transition. As a whole, our data indicate that youth and their families are underprepared to transition care, with a majority expressing the expectation that similar support services will be offered in adult care. This leaves them vulnerable to a lapse in medical care, unmanaged flares, and negative consequences of drug holidays. Interestingly, youth and their families are worried about the transition from pediatric to adult IBD care and are interested in receiving this information in person, reinforcing that this information should be incorporated into routine care and is best received from their IBD providers.