Α4β7 Integrin Research Articles

DOP01 The effect of vedolizumab on CD8 T cell repertoire homogeneity and blood-gut trafficking in patients with inflammatory bowel disease

Abstract Background Inflammatory bowel disease (IBD) causes T cell to infiltrate intestinal mucosa, but the heterogeneity of these cells is not understood at a clonal level. The anti-integrin α4β7 agent vedolizumab is believed to treat IBD by blocking this T cell infiltration from blood. Methods To understand the clonal distribution of T cells in IBD and how this is affected by vedolizumab, we studyined the T cell receptor (TCR) repertoire in CD8+ T cell subsets sorted from blood samples and colon mucosal biopsies via FACS. Inflamed or uninflamed colon segments from 15 ulcerative colitis and 13 Crohn’s disease patients were compared to colon biopsies from 11 people without IBD. In peripheral blood, we profiled purified α4β7+, α4β7- effector/memory, CD45RA+ terminal effector/memory (TEMRA) CD8 T cells, and mucosal-associated invariant T (MAIT) cells. In a separate cohort of 13 IBD patients, samples were obtained before and during vedolizumab therapy to determine its effect on the diversity and overlap of the TCR repertoires of blood and colon CD8+ T cells. Results CD8 TCR diversity in the mucosa and peripheral blood did not correlate with inflammation. CD8 TCR repertoire overlap between any two anatomically distinct locations of a person’s colon was consistently high, though often lower between inflamed and uninflamed sites. Repertoire overlap was also seen between the colon and each peripheral blood subpopulation studied, with the highest overlap seen for integrin α4β7+ T cells and the lowest for MAIT cells. Inflamed tissue overlapped more than uninflamed with each blood subpopulation. Vedolizumab did not affect the overlap between colon CD8+ T cells and circulating α4β7+ CD8 T cells, nor their TCR diversity, regardless of treatment efficacy. Indeed, flow cytometry revealed no relative depletion of effector/memory T cells in the colons of vedolizumab recipients. Instead, vedolizumab caused the depletion of rare naïve mucosal T cells and dendritic cells (DC) from the colonic mucosa. Conclusion CD8 T cell clones are spread homogenously throughout the colon. Although TCR repertoire overlap is greater within than between inflamed and uninflamed colon segments, a similar diversity of TCRs in both argues against local clonal expansion being the main source of excess T cells in inflamed mucosa. Rather, our data reveal increased TCR overlap between blood and inflamed mucosa to support the significance of T cell trafficking in IBD pathogenesis, particularly concerning experienced α4β7+ T cell populations. However, we surprisingly found neither gross nor clonal evidence that blockade of this trafficking is the mechanism by which vedolizumab treats IBD, instead finding only naïve T cells and DC to be depleted from the colonic mucosa in response to vedolizumab.

P586 Vedolizumab in Mild to Moderate Crohn’s Disease Patients Naïve to Biological Therapy: a Multicentric Observational Study

Abstract Background Vedolizumab, a human monoclonal antibody that blocks integrin α4-β7, was approved for the management of Inflammatory Bowel Diseases. In real-world experience the number of patients using vedolizumab as first-line biological therapy was low, mainly in Crohn′s Disease (CD). This study aimed to evaluate the efficacy of vedolizumab exclusively in CD patients who were naïve to previous biologics, with mild to moderate disease. Additionally, we aimed to analyze the safety profile of vedolizumab, rates of mucosal healing, need for abdominal surgery and drug discontinuation over time in this specific population. Methods We performed a retrospective multicentric cohort study with patients with mild to moderate CD treated with VDZ who were naïve to previous biologics agents. These patients had clinical activity scores (Harvey-Bradshaw Index [HBI]) measured at baseline and weeks 12, 26, 52 as well as at the last follow-up. Clinical response was defined as a reduction ≥3 in HBI whereas clinical remission as HBI ≤4. Mucosal healing was defined as the complete absence of ulcers in control colonoscopies. Kaplan-Meier survival analysis was used to assess the persistence with vedolizumab over time. Results From a total of 72 patients (6 excluded) 53% (35/66) reached clinical remission at week 12. This percentage increased to 71.9% (46/64) at week 26, 88.1% (52/59) at week 52 and 81.8% (54/66) at the last follow-up visit. Clinical response was achieved in 72.7% (48/66), 92.2% (59/64), 95,1% (58/61) and 83.3% (55/66) in the same periods, respectively. Mucosal healing was achieved in 62.3% (33/57) of patients. Vedolizumab was well-tolerated and most adverse events were minor; 89.3% remained on vedolizumab after 52 weeks. During vedolizumab treatment, 3/66 patients underwent surgery. Conclusion Vedolizumab was effective in the management of patients with mild to moderate CD as first biological agent, with a remission rate of 88.1% after one year. Mucosal healing was observed in 62.3% of patients and major abdominal surgery was needed in only 4.5% of patients. This is one of the first international studies focused on the use of vedolizumab as a first-line biological treatment option in clinical practice in mild to moderate CD.

P102 A small molecule selective integrin α4β7 inhibitor demonstrates efficacy in a chronic model of Inflammatory Bowel Disease

Abstract Background Integrin α4β7 regulates the recruitment of T cells to intestinal mucosa through its interaction with mucosal addressin cell adhesion molecule (MAdCAM)-1. Disruption of this interaction has been clinically validated for the treatment of inflammatory bowel diseases (IBD) by the anti-α4β7 antibody vedolizumab. The current study was aimed at elucidating the preclinical efficacy of MT-103, a potent and selective small molecule α4β7 inhibitor in the clinically relevant CD4+CD45RBhi T cell transfer (TCT) colitis mouse model. Methods Mice were administered either MT-103 via subcutaneously implanted minipumps across 3 dose cohorts (3, 10, or 30 mg/ml), or an antibody specific for IL12p40 (25 mg/kg) or α4β7 (30 mg/kg), through intraperitoneal injections for 7 weeks. Colitis development was evaluated via readouts including body weights, gross colon weight by length ratios, colonic tissue gene expression, and histopathological scores. Results MT-103 significantly inhibited the development of colitis in mice at all 3 doses equivalently, as evident from significantly improved gross colon weight/length ratios in comparison to vehicle controls which presented with moderate-severe colitis (Figure 1A). MT-103 treatment also led to a significant protection from weight loss that occurred in vehicle-treated mice. Importantly, mice treated with MT-103 exhibited remarkably improved histopathology scores, including inflammation, hyperplasia, and gland loss compared to vehicle controls (Figure 1B). Furthermore, broad gene transcriptional analysis showed that MT-103 broadly suppressed pro-inflammatory pathways and processes within colonic tissues. Specifically, MT-103-induced downregulation of Ifng, Il17a, and Il1b, besides reduced Cd3 as a surrogate metric of T cell trafficking inhibition to the colon, and conversely enabled upregulation of anti-inflammatory cytokine Il10. The colitis-protective effects of MT-103 were equivalent, if not superior, to the saturating doses of α4β7 mAb or anti-IL12p40 mAb when compared to their respective vehicle controls. Conclusion Treatment with MT-103 protects from colitis by restoring colonic tissue homeostasis as measured by body fitness and an array of immunological and histopathological assessments. These proof-of-concept data demonstrate an α4β7-specific small molecule, MT-103, can occlude pathogenic T cells from initiating disease in a chronic IBD model, equivalent to an α4β7 blocking antibody.

P061 Response to anti-α4β7 therapy in Ulcerative colitis is associated with lymphoid aggregate attrition through impaired recruitment of naïve lymphocytes

Abstract Background Vedolizumab (VDZ) is a frontline drug for Ulcerative colitis (UC) and Crohn’s disease (CD) that targets integrin α4β7, a gut-homing receptor. Despite significant use, the mechanism(s) of action (MOA) of VDZ remain unclear. Methods Peripheral blood mononuclear cells (PBMC) from UC patients (n=43) and paired intestinal biopsies in a subset (n=12) were examined at week 0 (pre-infusion) and 14, by multiparameter flow cytometry (FC). TNF inhibitor (TNFi)-treated UC patients served as controls. Drug MOA was further examined in detail in murine models using single-cell RNA-seq, FC, conventional and immunofluorescent microscopy (IF). Photoconvertible (Kikumi) mice were used to study cellular trafficking after anti-α4β7 (DATK32) antibody (mAb) administration. Two distinct UC cohorts (n=42 and n=21 respectively) were used to correlate GI immune alterations following VDZ with mucosal healing. Results A significant decrease of colonic and ileal naïve B and T cells was noted in VDZ- but not in TNFi-treated patients (Fig 1A), while total T cell-frequencies were unchanged. Circulating gut-homing plasmablasts (β7+) were significantly decreased post-VDZ. Peyer’s patches (PP) in anti-α4β7-treated mice showed a rapid loss of cellularity associated with decreased follicular naïve B cells (Fig 1B). Single-cell RNA-seq also demonstrated a significant loss of follicular B cells, including a unique population of epithelium-associated B cells following anti-α4β7 mAb. In Kikumi mice, anti-α4β7 mAb impaired non-photoconverted follicular B cells and T cells into photoconverted PPs (Fig 1C) demonstrating that loss of PP cellularity was due to impaired cellular ingress. In VDZ-treated (but not TNFi-treated) UC patients, lymphoid aggregate (LA) size was significantly reduced in treatment responders compared to non-responders (defined by absence of histological inflammation). A distinct validation cohort further confirmed that reduced lymphoid aggregate size was associated with response to VDZ-therapy (Fig 1D). Conclusion VDZ is associated with impaired ingress of naïve B and T cells, resulting in attrition of intestinal LA. Reduced LA size is associated with VDZ response. Immune inductive site targeting represents a novel MOA of VDZ in patients with UC.

THE EFFECT OF VEDOLIZUMAB ON CD8 T CELL REPERTOIRE HOMOGENEITY AND BLOOD-GUT TRAFFICKING IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Abstract BACKGROUND Inflammatory bowel disease (IBD) causes T cell infiltration of the intestinal mucosa, but the heterogeneity of these cells is not understood at a clonal level. The drug vedolizumab is believed to treat IBD by blocking the entry of circulating integrin α4β7+ T cells into the intestinal mucosa. METHODS We sought to understand the clonal distribution of T cells in IBD and how this is affected by vedolizumab by studying the T cell receptor (TCR) repertoire in CD8+ T cell subsets sorted from blood samples and colon mucosal biopsies via FACS. Inflamed or uninflamed colon segments from 15 ulcerative colitis and 13 Crohn’s disease patients were compared to colon biopsies from 11 people without IBD. In peripheral blood, we profiled purified α4β7+, α4β7- effector/memory, CD45RA+ terminal effector/memory (TEMRA) CD8 T cells, and mucosal-associated invariant T (MAIT) cells. In a separate cohort of 13 IBD patients, samples were obtained before and during vedolizumab therapy to determine its effect on the diversity and overlap of the TCR repertoires of blood and colon CD8+ T cells. RESULTS CD8 TCR diversity in the mucosa and peripheral blood did not correlate with inflammation. Repertoire overlap between any two anatomically distinct locations of a person’s colon was consistently high, though often lower between inflamed and uninflamed sites. CD8 TCR repertoire overlap was also seen between the colon and each peripheral blood subpopulation studied, with the highest overlap seen for integrin α4β7+ T cells and the lowest for MAIT cells. Inflamed tissue overlapped more than uninflamed with each blood subpopulation. Surprisingly, vedolizumab did not affect the degree of overlap between colon CD8+ T cells and circulating α4β7+ CD8 T cells, nor their TCR diversity, regardless of treatment efficacy. Indeed, flow cytometry revealed no relative depletion of effector/memory T cells in the colons of vedolizumab recipients. Instead, vedolizumab caused the depletion of rare naïve mucosal T cells and dendritic cells (DC) from the colonic mucosa. CONCLUSIONS CD8 T cell clones are spread homogenously throughout the colon. Although TCR repertoire overlap is greater within than between inflamed and uninflamed colon segments, a similar diversity of TCRs in both argues against local clonal expansion being the main source of excess T cells in inflamed mucosa. Rather, our data reveal increased TCR overlap between blood and inflamed mucosa to support the significance of T cell trafficking in IBD pathogenesis, particularly concerning experienced α4β7+ T cell populations. However, we surprisingly found neither gross nor clonal evidence that blockade of this trafficking is the mechanism by which vedolizumab treats IBD, instead finding only naïve T cells and DC to be depleted from the colonic mucosa in response to vedolizumab.

ARTHRITIS AND ARTHRALGIA AS EXTRAINTESTINAL MANIFESTATIONS IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE TREATED WITH VEDOLIZUMAB: A META-ANALYSIS

Abstract BACKGROUND Vedolizumab is a humanized gut selective drug that specifically targets α4β7 integrin and has been used successfully in the treatment of Inflammatory Bowel Disease (IBD). Although Vedolizumab is an effective treatment for IBD and acts specifically on the gastrointestinal system, some studies have reported extraintestinal manifestations as adverse events. One of the most frequently reported non-infectious adverse events is articular manifestations. However, it is difficult to know for sure whether the joint symptoms are due to the vedolizumab adverse event or due to extraintestinal symptoms of the disease itself. AIMS This systematic review and meta-analysis aimed to assess the incidence of extraintestinal manifestations in patients receiving Vedolizumab and to investigate whether these adverse events are indeed drug-related. METHODS Pubmed, Cochrane, and Scopus were searched for randomized clinical trials reporting the incidence of articular events in patients with Crohn’s Disease or Ulcerative Colitis who were treated with Vedolizumab. The considered outcomes were new-onset or worsening of pre-existing joint manifestations. We used Revman to calculate the pooled incidence of the reported outcomes and their corresponding 95% confidence intervals (95% CI). RESULTS The search strategy yielded 4.206 articles. After removal of duplicates and screening of results, 4 randomized studies met the inclusion criteria (Figure 1). A total of 2.466 patients with moderately to severe IBD were included. Of those, 1822 were randomized to intervention group, with Vedolizumab administration, and 644 to placebo. In the intervention group, 232 patients developed arthritis or arthralgia of any kind, versus 66 patients of placebo group (95% CI 0.7%-1.3%; Figure 2). Of those patients, 73,8% and 33% had prior treatment with anti-TNF and immunomodulators, respectively. 63% and 15% also had prior anti-TNF and immunomodulators previous failure, respectively. CONCLUSION The meta-analysis presented above shows a result without statistical significance to say that vedolizumab is responsible for the manifestations previously described. Therefore, it is necessary to hypothesize that the new onset of worsening arthritis and arthralgia may be associated with the course of the disease itself, the body's response to the drugs or the exclusion of corticosteroids or anti-TNF from concomitant treatment with Vedolizumab. More studies with larger samples are needed, especially randomized clinical trials comparing Anti-TNF, corticosteroids and immunomodulators to assess the incidence of joint manifestations and even other rheumatologic manifestations in patients with Inflammatory Bowel Disease.

EFFICACY AND SAFETY OF VEDOLIZUMAB AND TUMOR NECROSIS FACTOR INHIBITORS IN THE TREATMENT OF STEROID-REFRACTORY MICROSCOPIC COLITIS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract BACKGROUND Tumor necrosis factor (TNF-α) inhibitors and the α4β7 integrin antagonist, vedolizumab have been investigated as a treatment option for patients with steroid-refractory microscopic colitis (MC) with controversial findings. AIMS To perform a systematic review and meta-analysis to evaluate the benefit of vedolizumab and TNF-α inhibitors in patients with steroid-refractory MC. METHODS Retrospective cohort studies and case series involving adult patients with steroid-refractory MC who either received vedolizumab, adalimumab, or infliximab were eligible for inclusion. Outcomes of interest included the rate of clinical remission at induction, clinical response, maintenance of remission, histologic remission, and overall medication related adverse effects. Pooled proportional meta-analyses were used to calculate the overall rates of the primary and secondary endpoints. Heterogeneity was assessed using the I2 statistic. Publication bias was assessed via visual inspection of the funnel plots and using Egger’s regression. All statistical analysis was performed in R using the metafor and meta packages. RESULTS A total of 14 retrospective case series/studies involving 164 patients were included. Pooled analysis showed a clinical remission rate of 63.5% (95% CI [0.483; 0.776], I2=43% P=0.08), 57.8% (95% CI [0.3895; 0.7571], I2=0%, P=0.7541), and 39.3% (95% CI [0.0814; 0.7492, I2=66%, P=0.02) for vedolizumab, infliximab, and adalimumab, respectively. The maintenance of remission rate was 60.5% (95% CI [0.2772; 0.8953], I2=67%, P=0.03), 45.3% (95% CI [0.1479; 0.7747], I2=0%, P=0.36) and 32.5% (95% CI [0.000; 0.8508], I2=53%, P=0.14) in patients who received vedolizumab, infliximab, and adalimumab, respectively. Rate of biologic-related adverse events warranting discontinuation of therapy was 12.2%, 32.9%, and 23.0% for the vedolizumab, infliximab, and adalimumab groups, respectively. CONCLUSION Vedolizumab and anti-TNF-α agents demonstrated a clinical benefit in the treatment of steroid-refractory MC and with a tolerable safety profile. Given the nature of included studies, superiority of either therapy could not be elucidated. Future randomized controlled trials are needed to standardize study protocols, compare vedolizumab with TNF-α inhibitors, and further examine data on patients’ quality of life. Forest plot showing the pooled clinical remission rate at induction in patients with steroid-refractory microscopic colitis receiving (A) vedolizumab or TNF inhibitors (B) Data summary of the meta-analyses of the studies investigating secondary endpoints in patients with refractory MC receiving either (A) vedolizumab or (B) TNF inhibitors ABBREVIATIONS MR, maintenance remission; CR, clinical response; HR, histologic remission; OAE, overall adverse effects.

Role of Integrins Involved in Mn2+-Dependent Adhesion to Fibronectin Peptide of Mastocytoma P-815 Cells and Peritoneal Mast Cells

Mn2+-dependent integrin-mediated adhesion to the extracellular matrix is extensively studied, however, its implication in mast cell biology remains unexplored. This study aims to investigate the role of Mn2+ in promoting adhesion in mouse mastocytoma P-815 cells (P-815) and peritoneal mast cells (PMC) to the Arg-Gly-Asp (RGD)-enriched fibronectin peptide (RGD matrix) within the culture medium. Our findings indicate that Mn2+ induces cell adhesion, with optimal results achieved when P-815 were exposed to 2 mM Mn2+ for 30 min at 37ºC, resulting in approximately 40% cell adhesion to the RGD matrix. The Mn2+-dependent P-815 adhesion was inhibited by anti-integrin α4, β1, and β3 subunit function-blocking antibodies, and by the integrin αIIbβ3 antagonist tirofiban, indicating the involvement of integrins α4β1 and αIIbβ3. Similarly, Mn2+-dependent PMC adhesion to the RGD matrix was inhibited by anti-integrin α4, α5, β1, β3, and β7 subunit function-blocking antibodies and tirofiban, demonstrating the involvement of integrins α4β1, α4β7, α5β1, and αIIbβ3. Integrins α4β1 and αIIbβ3 were consistently involved in Mn2+-induced adhesion reactions in both P-815 and PMC, while integrins α4β7 and α5β1 were specifically implicated in the response to PMC only. The addition of the actin inhibitor cytochalasin D, glycosylphosphatidylinositol-anchored protein (GPI-AP) cleaving enzyme phosphatidylinositol-specific phospholipase C, and the PKA inhibitor H-89 significantly reduced Mn2+-dependent P-815 adhesion to the RGD matrix. However, adding the myosin II inhibitor brebbistatin and the RhoA inhibitor Y27632 did not produce the same effect. Furthermore, cellular cholesterol removal with 6-O-α-maltosyl-β cyclodextrin significantly diminished Mn2+-dependent P-815 adhesion, concomitant with a decrease in the expression of integrin α4 and β1 subunits on the cell surface.

Pharmacological and Clinical data of oral alpha 4 integrin antagonist, Carotegrast methyl, CAROGRA®

Carotegrast-methyl (brand name: CAROGRA® Tablets) is a new chemical entity created by Ajinomoto Pharmaceuticals Co., Ltd. (currently EA Pharma Co., Ltd.) as an α4 integrin inhibitor. In vivo, it exerts an anti-inflammatory effect by inhibiting the functions of both α4β1 integrin and α4β7 integrin expressed on the surface of inflammatory cells such as lymphocytes. Under the joint development of EA Pharma Co., Ltd. and Kissei Pharmaceutical Co., Ltd., the efficacy and safety of carotegrast methyl were confirmed in patients with moderate active ulcerative colitis. Carotegrast-methyl, the Japan-originated, world-first orally available α4 integrin antagonist, was approved in March and launched in May 2022 in Japan. Patients who had inadequate response or intolerance to the basic treatment with 5-ASA preparations for ulcerative colitis, have widely desired an orally available treatment with the new mechanism of actions. Carotegrast methyl can be a treatment option that meets that unmet medical need and has the potential to greatly contribute to the treatment of ulcerative colitis based on the thorough practice of proper use. This article mainly introduces the pharmacological properties and clinical trial results of carotegrast methyl.

Pharmacokinetics and Safety of Vedolizumab Following Administration of a Single Intravenous Dose in Healthy Chinese Subjects.

Vedolizumab is a humanized monoclonal antibody, indicated for the treatment of moderately to severely active ulcerative colitis (UC) or Crohn's disease (CD), that specifically binds to the α4β7 integrin. The aim of this study was to assess the pharmacokinetics, safety, and tolerability of vedolizumab following a single intravenous (IV) infusion in healthy adult Chinese subjects. Sixteen participants received a single IV infusion of vedolizumab (300mg). Blood samples were collected to measure vedolizumab serum concentrations. The safety of all subjects was monitored. The pharmacokinetic analysis showed that vedolizumab reached the maximum observed serum concentration (Cmax) at approximately 1.32hours. The mean Cmax and area under the concentration-time curve from time 0 to time of the last quantifiable concentration (AUC0-t) and to infinity (AUC0-∞) were 137.25µg/mL, 2360days·µg/mL, and 2395days·µg/mL, respectively. The elimination of vedolizumab was relatively slow, with a mean terminal disposition phase half-life elimination (t1/2) of 20.23days. Six subjects were positive for anti-vedolizumab antibodies (AVAs) on day 106 and day 127. Finally, 4 out of 16 subjects (25.0%) had treatment-emergent adverse events (TEAEs), all of which were upper respiratory tract infections. Vedolizumab was well tolerated in healthy Chinese subjects when administered as a single-dose IV 300mg infusion. In this study, the rate of AVA positivity was 37.5%, which occurred near the end of the study; no significant differences in pharmacokinetic profiles were observed between the AVA-positive and AVA-negative groups. http://www.chinadrugtrials.org.cn : CTR20171528.

Localised Delivery of Macromolecules to the Large Intestine: Translation to Clinical Trials.

Oral administration of macromolecules aimed at systemic delivery has been at the forefront of pharmaceutical research for over 50 years. Yet, in terms of clinical translation for systemic delivery, output is limited to five US Food and Drug Administration (FDA)-approved oral peptide products to date, such are the hurdles. Somewhat neglected by comparison but with potentially lower delivery demands, the goal of local delivery of macromolecules directed mostly to the terminal ileum and colon to treat inflammatory bowel conditions has led to a range of macromolecules including gut-restricted peptides, fusion proteins, enzymes, antibodies, and antisense oligonucleotides that have reached clinical trials. While some of these trials reached primary endpoints, others are at early clinical stages, but it is likely that at least a few approvable products will emerge to supplement the current cohort of parenterally administered macromolecules and oral small molecules. The outstanding successes to date are the FDA approvals of two gut-restricted guanylate cyclase C-activating peptides to treat irritable bowel syndrome (constipated). Over-expressed targets for macromolecules in the gut wall of inflammatory bowel disease patients include α4β7 integrin, TNF-α, CD-3, ICAM-1, and SMAD-7, while reduced responses to IL-10 and melanocortin offer opportunities for macromolecular agonists. In this Leading Article, a landscape of locally delivered macromolecules to access the gut that have recently reached clinical trials is provided.

Expression and function of α4β7 integrin predict the success of vedolizumab treatment in inflammatory bowel disease

Inflammatory bowel diseases are medically intractable and require constant therapy in many cases. While a growing number of biologicals and small molecules is available for treatment, a substantial portion of patients experiences primary non-response to these compounds and head-to-head evidence for therapy selection is scarce. Thus, approaches to predict treatment success in individual patients are a huge unmet need.We had previously suggested that the expression and function of α4β7 integrin on T cells in the peripheral blood correlate to outcomes of therapy with the anti-α4β7 integrin antibody vedolizumab. Here, we conducted a translational multicenter trial to prospectively evaluate this hypothesis.In a cohort of 89 patients with inflammatory bowel disease undergoing regular therapy with vedolizumab, lower baseline expression of α4β7 was associated with short-term clinical response. Consistently, low α4β7 expression in patients achieving remission predicted sustained remission in week 30. Moreover, high dynamic adhesion of CD4+ T cells to MAdCAM-1 and high reduction of adhesion by vedolizumab in vitro at baseline were associated with clinical remission.These data substantiate the potential of α4β7 integrin function and expression to forecast outcomes of vedolizumab therapy. Further translational efforts are necessary to improve the performance of the assays and to implement the concept in clinical practice.

Korean clinical practice guidelines on biologics for moderate to severe Crohn's disease.

Crohn's disease (CD) is a relapsing and progressive condition characterized by diarrhea, abdominal pain, weight loss, and hematochezia that results in serious complications such as perforations, fistulas, and abscesses. Various medications, interventions, and surgical treatments have been used to treat CD. The Korean guidelines for CD management were distributed in 2012 and revised in 2017 by the Inflammatory Bowel Disease (IBD) Research Group of the Korean Association for the Study of Intestinal Diseases. Substantial progress in mucosal immunologic research has elucidated the pathophysiology of IBD, leading to development of biological agents for treatment of CD. The first developed biologic agent, tumor necrosis factor-α agents, were shown to be efficacious in CD, heralding a new era in management of CD. Subsequently, vedolizumab, a monoclonal antibody against integrin α4β7, and ustekinumab, a human monoclonal antibody that inhibits the common p40 subunit of interleukin-12 and interleukin-23, were both approved for clinical use and are efficacious and safe for both induction and maintenance of remission in moderate-to-severe CD patients. Moreover, a recent study showed the non-inferiority of CT-P13, an infliximab biosimilar, compared with infliximab in CD patients. The third Korean guidelines for CD management provide updated information regarding treatment of moderate-to-severe CD patients with biologic agents.

Etrolizumab as induction and maintenance therapy in patients with moderately to severely active Crohn's disease (BERGAMOT): a randomised, placebo-controlled, double-blind, phase 3 trial

Etrolizumab as induction and maintenance therapy in patients with moderately to severely active Crohn's disease (BERGAMOT): a randomised, placebo-controlled, double-blind, phase 3 trial

Efficacy and safety of vedolizumab for inflammatory bowel diseases: A systematic review and meta-analysis of randomized controlled trials.

Background:Vedolizumab is a humanized monoclonal antibody that inhibits gut-selective α4β7 integrins on the surface of leukocytes, preventing their trafficking into the gastrointestinal tract, and ultimately achieves the effect of suppressing intestinal inflammation. This study aimed to evaluate the efficacy and safety of vedolizumab in the treatment of inflammatory bowel disease.Methods:After a systematic review of relevant studies, the pooled relative risk (RR) and 95% confidence intervals (CIs) were calculated to evaluate the effect. Heterogeneity was explored using sensitivity analysis, univariate meta-regression, and subgroup analysis. Potential publication bias was evaluated using Egger test and trim-and-fill method.Results:Nine randomized controlled trials involving 4268 participants were included in the meta-analysis. During induction therapy, vedolizumab was more effective than placebo in treating active ulcerative colitis and Crohn disease in terms of clinical response (RR = 1.55, 95%CI: 1.35–1.78), clinical remission (RR = 1.90, 95%CI: 1.50–2.41), and mucosal healing (RR = 1.53, 95%CI: 1.21–1.95). A superior effect in terms of durable Clinical or Crohn disease Activity Index-100 response (RR = 1.65, 95%CI: 1.20–2.26), clinical remission (RR = 1.92, 95%CI: 1.48–2.50), and glucocorticoid-free remission (RR = 2.22, 95%CI: 1.71–2.90) was found during maintenance treatment. Vedolizumab was not associated with any adverse events and was as safe as placebo in terms of the risk of serious adverse reactions.Conclusions:Vedolizumab may be safe and effective as an induction and maintenance therapy for the treatment of inflammatory bowel disease; however, further studies are needed to validate this conclusion.

Use of Vedolizumab in Inflammatory Bowel Disease: A Single-Center Experience.

Vedolizumab, which is a monoclonal antibody that selectively binds to α4β7 integrin in the gastrointestinal system, may be an effective and safe treatment alternative in those with anti-tumor necrosis factor-resistant inflammatory bowel disease. Patients administered vedolizumab due to anti-tumor necrosis factor resistant or anti-tumor necrosis factor side effects between August 2017 and November 2020 were included in the study. Crohn's patients were evaluated using the Harvey-Bradshaw index and Simple Endoscopic Score for Crohn's Disease, whereas ulcerative colitis patients were evaluated with the Partial Mayo Score Index and Rachmilewitz score. All patients were followed up for 3 months and their blood samples were taken every 3 months. Hemoglobin, white blood cell, leukocyte, lymphocyte, and platelet counts of the patients were performed. Albumin, C-reactive protein, and erythrocye sedimentation rate values were recorded. The side effect profile for vedolizumab was evaluated for all patients. Among the side effects, arthralgia and flu-like symptoms were observed. A total of 48 patients (18 ulcerative colitis and 30 Crohn's disease) were included in the study. Vedolizumab therapy was initi- ated in the patients due to anti-tumor necrosis factor resistance (17 ulcerative colitis and 26 Crohn's disease) or anti-tumor necrosis factor side effects (1 ulcerative colitis and 4 Crohn's disease). A total of 30 (63%) patients, including 15 (83%) ulcerative colitis and 15 (50%) Crohn's disease, responded to treatment (both response and remission). The mean duration of response to treatment was 4.5 ± 1.5 months. A total of 20 (42%) patients in the vedolizumab therapy subgroup (10/10, ulcerative colitis/Crohn's disease) went into remission. The mean Harvey-Bradshaw Index value was 9.8 ± 2.8 in the Crohn's disease patients at the time of initial treatment. The mean Simple Endoscopic Score for Crohn's disease value was 11.2 ± 3.1 at the time of initial treatment. The mean Harvey-Bradshaw Index value was 6.5 ± 3.0 and the mean Simple Endoscopic Score for Crohn's disease value was 4.9 ± 3.6 at 6 months post-treatment. The mean Ulcerative Colitis Endoscopic Index (Rachmilewitz) value was 9.3 ± 1.2 at the time of initial treatment. In addition, the mean Partial Mayo Scoring Index was 6.4 ± 1.5 at the time of initial treatment. The mean Ulcerative Colitis Endoscopic Index (Rachmilewitz) value was 0 (0-6.0), and the mean Partial Mayo Scoring Index was 1.5 (0.3-4.0) at 6 months post-treatment. Vedolizumab therapy is effective in both induction and maintenance of remission in inflammatory bowel disease patients who are resistant to anti-tumor necrosis factor or who can not receive anti-tumor necrosis factor therapy due to side effects. No signifi- cant side effect was observed in the patients during follow-up.

S793 Full Target Engagement With Saturation of α4β7 Integrin Receptor Occupancy Resulting in Changes in Subset of Lymphocytes by MORF-057 Following 200 Mg Daily Dosing in Healthy Subjects

S793 Full Target Engagement With Saturation of α4β7 Integrin Receptor Occupancy Resulting in Changes in Subset of Lymphocytes by MORF-057 Following 200 Mg Daily Dosing in Healthy Subjects

S2763 Post-Transplant Lymphoproliferative Disorder Presenting as an Isolated Pre-Pouch Ileal Ulcer in a Liver Transplant Patient With Crohn’s Disease

Introduction: Post-transplant lymphoproliferative disorder (PTLD) can occur in solid organ and hematopoietic cell transplant recipients in the setting of chronic immunosuppression. It often results from Epstein-Barr virus (EBV) affected B-cell propagation. We present a case of PTLD in a liver transplant (LT) patient with Crohn’s disease (CD) on biologic therapy. Case Description/Methods: A 67-year-old male with primary sclerosing cholangitis (PSC) cirrhosis status post living donor LT in 2001 on tacrolimus, multiple skin cancers, recurrent PSC after transplant and pan-ulcerative colitis on sulfasalazine underwent total proctocolectomy with ileo-anal anastomosis in 2013 to 2014 for colonic dysplasia. In 2019, he was diagnosed with moderate-to-severe CD of the J-pouch and pre-pouch ileum, up to 50cm from the entry site. Vedolizumab (VDZ), an α4β7 integrin monoclonal antibody, was initiated with steroid-free clinical response on every four week dosing. Repeat pouchoscopy on VDZ showed pre-pouch ileitis up to 30cm and a large, isolated ulcer in the pre-pouch ileum, 10cm proximal to the ileitis (Figure). Biopsies revealed B-cell lymphoma, consistent with PTLD. Negative EBV-encoded RNA (EBER) in-situ hybridization suggested that this diagnosis was unrelated to EBV exposure. Positron emission tomography (PET) scan did not identify distant disease activity, and bone marrow biopsy was unremarkable. VDZ was stopped due to loss of response, budesonide resumed and R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) was subsequently initiated. Follow-up pouchoscopy showed lymphoma regression but persistent CD activity. Discussion: PTLD typically presents as extra-nodal masses involving the central nervous system, lungs, gastrointestinal tract, liver, skin or allograft within one year of transplant. Immunosuppression reduction is the cornerstone of management; however, more aggressive cases, as in our patient, require systemic therapy. This case highlights a unique presentation of PTLD as an isolated ileal ulcer in a CD patient 19 years post-LT. Interestingly, the ulcer did not appear endoscopically distinct from CD-related ulceration. Furthermore, while malignancy is a potential risk of certain treatments for inflammatory bowel disease (IBD), our patient had never received thiopurines or anti-tumor necrosis factor (TNF) agents, and VDZ has not been associated with an increased risk of B-cell lymphoma. He is currently stable on low dose tacrolimus and budesonide.Figure 1.: Isolated pre-pouch ileal ulcer.

S955 Effectiveness of Vedolizumab in Patients With Inflammatory Bowel Disease and Concomitant Primary Sclerosing Cholangitis

Introduction: Patients with concomitant primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) are known to have a unique clinical phenotype (PSC-IBD), including higher expression of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in both liver and intestinal tissues. MADCAM-1 interacts with α4β7 integrin to allow access of lymphocytes to the intestinal mucosa and is inhibited by vedolizumab (VDZ). Although VDZ has not been shown to slow progression of PSC, little is known about its impact in intestinal inflammation of PSC-IBD patients. We aimed to report the effectiveness of VDZ in controlling intestinal inflammation in a large PSC-IBD cohort. Methods: We conducted a retrospective review of patients with PSC-IBD treated with VDZ from January 2009 to January 2019. Demographic, clinical, endoscopic, and radiologic data were abstracted at baseline, and at 6 and 12 months after initiation of VDZ. Outcomes of interest included: clinical response, radiologic response and healing, endoscopic response, mucosal healing, and histologic healing. Results: A total of 108 patients with PSC-IBD treated with VDZ were identified. The majority were male (66%), with median age of 45 years (range, 19 -83). The most common IBD subtype was ulcerative colitis (UC) (61.1%), followed by Crohn’s disease (CD) (33.3%), and indeterminate colitis (5.6%). Median disease duration at the start of VDZ was 8 years (range, 0-50), with ileocolonic CD (85.3%) and pancolitis (92.2%) as the predominant disease locations. Over three quarters of the cohort (79.6%) had previously failed other biologic therapy (Table). VDZ was most often dosed every 8 weeks (73.1%) and the median duration of VDZ therapy was 17.5 months (range, 2-66). Clinical response was 72.6% at 6 months and 77.1% at 1 year. Among patients who had follow-up endoscopy, endoscopic response was noted in 47.1% and 58.1% of the cases at 6 months and 1 year, respectively. Radiologic response at 6 months and 1 year was 32.4% and 38.9%, respectively. Radiology healing at 6 months and 1 year was 16.2% and 18.2%, respectively. Histologic healing at 6 months was 6.7% and 18.8% at 1 year. Conclusion: VDZ is effective in the management of intestinal inflammation in patients with PSC-IBD, with clinical and endoscopic outcomes at 1-year follow-up comparable to currently available clinical trials in non-PSC patients. Further studies comparing outcomes of PSC-IBD patients on VDZ to other biologic therapies are needed. Table 1. - Patient Demographics and Vedolizumab Outcomes Patient demographics N = 108 Male, n (%) 72 (66.7) Median age, years (range) 45 (19-83) Median disease duration, years (range) 8 (0-50) Prior use of other biologics, n (%) 86 (79.6) Combination therapy while on VDZ, n (%) Thiopurine/6MP/azathioprine 18 (17.3) Methotrexate 1 (1.0) IBD Subtype, n (%) CD 36 (33.3) UC 66 (61.1) Indeterminate colitis 6 (5.6) CD Location, n (%) Terminal ileum 0/34 (0) Colon 4/34 (11.8) Ileocolonic 29/34 (85.3) Upper GI 1/34 (2.9) Perianal disease, n (%) 9 (8.8) CD phenotype, n (%) Inflammatory 16/36 (44.4) Stricturing 14/36 (38.9) Penetrating 6/36 (16.7) UC extension, n (%) Proctitis 3/64 (4.7) Left sided colitis 2/64 (3.1) Pancolitis 59/64 (92.2) Bowel resection before VDZ, n (%) 45 (55.6) History of liver transplant, n (%) 33 (30.6) VDZ outcomes N = (108) Median duration of therapy, months (range) 17.5 (2.0-66.0) Drug dose frequency, n (%) Every 8 weeks 79 (73.1) Every 6 weeks 7 (6.5) Every 4 weeks 22 (20.4) VDZ discontinued indefinitely, n (%) 46 (43.0) Clinical response at 6 months, n (%) 74/102 (72.6) Clinical response at 1 year, n (%) 64/83 (77.1) Endoscopic response at 6 months, n (%) 24/51 (47.1) Endoscopic healing at 6 months, n (%) 8/55 (14.5) Endoscopic response at 1 year, n (%) 25/43 (58.1) Endoscopic healing at 1 year, n (%) 12/46 (26.1) Radiologic response at 6 months, n (%) 11/34 (32.4) Radiologic healing at 6 months, n (%) 6/37 (16.2) Radiologic response at 1 year, n (%) 7/18 (38.9) Radiologic healing at 1 year, n (%) 4/22 (18.2) Histologic healing at 6 months, n (%) 3/45 (6.7) Histologic healing at 1 year, n (%) 9/48 (18.8) Colectomy on VDZ, n (%) 16/108 (15.0)

S751 The Vedolizumab Pregnancy Exposure Registry: An OTIS Pregnancy Study Update

Introduction: Vedolizumab is a gut-selective immunoglobulin (Ig) G1 monoclonal antibody that binds to α4β7 integrin; it is approved for the treatment of moderately to severely active Crohn’s disease (CD) and ulcerative colitis (UC) in the U.S. and elsewhere. Published studies on the effect of vedolizumab in human pregnancy are limited. Data from the ongoing Vedolizumab Pregnancy Exposure Registry (NCT02678052) in the U.S. and Canada have been collected by the MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (OTIS). This prospective observational pregnancy cohort study planned to enroll and analyze the outcomes of 100 vedolizumab-exposed (Vedo) participants compared to 100 disease-matched (DM) and 100 healthy comparison (HC) participants. Methods: Pregnant women treated with vedolizumab for UC or CD with at least one dose in the first trimester were enrolled in the Vedo group. Pregnant women with UC or CD but no exposure to vedolizumab were enrolled in the DM group. Pregnant women with no exposure to any biologic during pregnancy and not diagnosed with an auto-inflammatory or other exclusionary disease were enrolled in the HC group. Data were collected from telephone interviews and maternal and pediatric medical records; live-born children were followed to one year of age with a dysmorphological examination and developmental screening. The Short Quality of Life in Inflammatory Bowel Disease Questionnaire (SIBDQ) was administered to women with CD or UC. Results: Between December 2015 and March 2022, outcomes were collected for 301 women, 98 in the Vedo group, 104 in the DM group, and 99 in the HC group. SIBDQ mean scores were similar in the Vedo group, 5.8 (SD 1.0) and the DM group, 5.9 (SD 1.0). Preliminary descriptive outcome data are shown in Table. In the Vedo group 7.3% of pregnancies resulted in a fetus or infant with a major birth defect, compared to 7.8% in the DM group, and 4.7% in the HC group. No pattern of major birth defects was identified in the Vedo group. Conclusion: The proportion of pregnancies with vedolizumab exposure resulting in a major birth defect are similar to proportions in the disease comparison group, and did not represent a specific pattern. The Vedolizumab Pregnancy Exposure Registry is ongoing with formal statistical analysis planned once the study is completed in 2023. Table 1. - Pregnancy Outcomes in the Study Cohort Vedo-Total(N=98) DM-Total(N=104) HC-Total(N=99) Pregnancies ending with live born infant - n/N (%) 93/98 (94.9) 99/104 (95.2) 85/99 (85.9) Spontaneous abortion – N (Left Truncation Accounted Rate a ) 3 (8.7%) 3 (6.1%) 1 (6.4%) Termination - n/N (%) 0/98 (0.0) 0/104 (0.0) 0/99 (0.0) Stillbirth - n/N (%) 0/98 (0.0) 1/104 (1.0) 0/99 (0.0) Lost to follow-up (LTFU) - n/N (%) 2/98 (2.0) 1/104 (1.0) 13/99 (13.1) Preterm delivery – N (Rate b ) 13 (14.5%) 6 (6.1%) 6 (7.2%) Birth weight full term infants – mean g (SD) 3410.4 (436.7) 3428.8 (454.0) 3308.1 (432.3) Number of pregnancies with major birth defects among all pregnancies excluding LTFU – n/N’ (%) 7/96 (7.3) 8/103 (7.8) 4/86 (4.7) Serious infections in live born infants up to 1 year of age – n/N’(%) c 3/97 (3.1) 2/99 (2.0) 1/88 (1.1) Ages and Stages Screening at 1 year of age with concern – n/N’ (%) c 10/66 (15.2) 20/87 (23.0) 11/59 (18.6) aSpontaneous abortion rate computed using Fleming-Harrington estimate at 20 weeks' gestation, accounting for left truncation because women can enroll at various times in gestation;bComputed using Fleming-Harrington estimate at 37 weeks' gestation;cIncludes twins; % = (n/N') * 100. N' at each category: Number of pregnancies meeting the criteria specified in the row title.