Vedolizumab Treatment Research Articles

Clinical Analysis of Salvage Treatment of Glucocorticoid Resistant Graft-Versus-Host Disease with Vedolizumab in Children

To investigate the efficacy and safety of VDZ (Vedolizumab) in the salvage treatment of glucocorticoid resistance to gastrointestinal graft-versus-host disease (GR-GI GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children. The clinical data of 5 patients with refractory GI GVHD who received allo-HSCT in Wuhan Children's Hospital from December 2020 to December 2021 were retrospectively analyzed with VDZ salvage therapy. Among the 5 children with refractory GI GVHD, there were 1 male and 4 female, including 2 cases of extremely severe aplastic anemia, 1 case of acute myeloid leukemia (M2, high-risk), 1 case of fanconi anemia and 1 case of myelodysplastic syndrome. The median age of transplant recipients was 54.4 (12-164) months. The median treatment time from transplantation to VDZ was 1.4 (0.6-6.8) months. On average, 3.5 (2-5) doses of VDZ were received. After receiving treatment, 2 patients achieved a complete response (CR), 2 patients achieved a very good partial response (VGPR), 1 patient was non-responsive (NR) after a short-term partial response (PR). Compared with that before VDZ treatment, the amount of diarrhea, stool color, blood and traits of the children after medication were effectively improved. The median follow-up time was 9.3 (7.23-12.83) months. No disseminated or severe bacterial/fungal infections occurred during VDZ treatment and follow-up, and 2 children died of leukemia recurrence and pulmonary bronchiolitis obliterans. VDZ salvage treatment of refractory GI GVHD in children has obvious short-term efficacy and good safety.

Short-term efficacy and safety of vedolizumab in patients with inflammatory bowel disease

Objective: To evaluate the short-term efficacy and safety of vedolizumab in patients with inflammatory bowel disease (IBD). Methods: Patients with moderate and severe active IBD at the first use of vedolizumab from May 1 to October 31, 2021 were retrospectively enrolled. Then the clinical characteristics, and the efficacy and safety of vedolizumab were evaluated. Meanwhile, the clinical response rate, biological response rate and endoscopic response rate were calculated. Multivariate analysis was used to evaluate the independent influencing factors of short-term clinical efficacy and safety. Results: A total of 78 patients (44 males and 34 females) with IBD were enrolled, with a mean age of (40.5±11.9) years. The clinical remission rate, clinical response rate, biological remission rate, biological response rate and endoscopic remission rate was 60.3% (47/78), 85.9% (67/78), 70.5% (55/78), 43.6% (34/78) and 47.0% (31/66) respectively after 14 weeks of treatment. Body mass index (BMI) ≥ 18.5 kg/m2 (HR=5.04, 95%CI: 1.50-16.91, P=0.009) and biological remission at 6 weeks of treatment (HR=15.22, 95%CI: 3.16-73.38, P=0.001) were predictors of endoscopic remission at 14 weeks of treatment. Adverse reactions occurred in 57 patients, with an incidence of 73.1%. The main manifestations were liver and kidney damage (37.2%) and infection (26.9%). Conclusions: More than half of patients with moderate and severe active IBD can achieve clinical remission after 14 weeks of vedolizumab treatment. Baseline BMI level and biological remission at 6 weeks of treatment are predictors of mucosal healing at 14 weeks. The incidence of adverse reactions is not low, although serious adverse reactions are rare in short-term treatment.

Vedolizumab‐related agranulocytosis with Epstein‐Barr virus esophagitis: A case report

AbstractVedolizumab has a good safety profile for the treatment of inflammatory bowel disease. Agranulocytosis is a rare but fatal condition. Although many drugs are considered to have a high risk of agranulocytosis, no previous study has mentioned vedolizumab. A 71‐year‐old female with Sjogren's syndrome received vedolizumab treatment for moderate to severe ulcerative colitis. Her symptoms improved; however, leukopenia was noted after the first dose. Four days after the second dose, she complained of oral and chest pain. Agranulocytosis, oral candidiasis, and Epstein‐Barr virus esophagitis with ulceration were noted. After granulocyte‐colony stimulating factor treatment, the white blood cell count returned to normal and the esophageal ulcers healed. Vedolizumab is a very safe gut‐selective biologic agent, but it also carries the risk of agranulocytosis.

Vedolizumab for pediatric patients with gastrointestinal acute graft-versus-host-disease.

Vedolizumab, an anti-α4β7 integrin monoclonal antibody, impairs homing of T-cells to the gastrointestinal (GI) endothelium and acts as a gut-selective anti-inflammatory agent. Recent reports of the efficacy of vedolizumab in treating lower GI acute graft-versus-host disease (aGVHD) are promising, but experience in children is scarce. We present a cohort of 13 pediatric patients who were treated with vedolizumab for GI aGVHD. Ten of the patients were treated for steroid-refractory disease, out of which, six suffered from severe (stage 3 or 4) GI disease before the first dose of vedolizumab. In the other three patients, vedolizumab was introduced early in the disease course. Median time between GI GVHD onset to vedolizumab treatment was 23 days (range 7-59 days), with a median of 3 doses (range 1-5) per patient. GI GVHD staging was evaluated at various time points after the first vedolizumab dose, showing improvement in nine of the 13 patients. After a median follow-up time of 13 months (range 6-34 months), eight patients completely recovered, two had ongoing chronic colitis, and threepatients died. During the vedolizumab treatment period, 38 infectious episodes were noted, most of them GI related. The unique activity profile of vedolizumab makes it an appealing treatment option for lower GI aGVHD, but caution for concurrent infections is warranted.

Outcomes, dosing, and predictors of vedolizumab treatment in children with inflammatory bowel disease (VEDOKIDS): a prospective, multicentre cohort study

Scarce data are available on the use of vedolizumab in children with inflammatory bowel disease (IBD). We aimed to evaluate the safety, effectiveness, and dosing of vedolizumab to induce remission of IBD. VEDOKIDS was a paediatric, multicentre, prospective cohort study done in 17 centres in six countries. We report the 14-week outcomes as the first analyses of the planned 3-year follow-up of the VEDOKIDS cohort. Children (aged 0-18 years) with IBD who had commenced vedolizumab were followed up at baseline and at 2, 6, and 14 weeks. Children were managed according to local prescribing practices without standardisation of dosing or criteria for escalation, but the study protocol suggested dosing of 177 mg/m2 body surface area (up to 300 mg maximum). The primary outcome was steroid-free and exclusive enteral nutrition-free remission at 14 weeks, analysed according to the intention-to-treat principle. Serum samples were taken for analysis of drug concentration and faecal calprotectin at baseline, and at 2, 6, and 14 weeks. Adverse events were recorded in real time and classified as severe or non-severe and related or unrelated to vedolizumab. This study is registered with ClinicalTrials.gov, NCT02862132. Between May 19, 2016, and April 1, 2022, 142 children (76 [54%] girls and 66 [46%] boys; mean age 13·6 years [SD 3·6]) were enrolled. 65 (46%) children had Crohn's disease, 68 (48%) had ulcerative colitis, and nine (6%) had unclassified IBD (those with unclassified IBD were analysed with the ulcerative colitis group). 32 (42% [95% CI 30-54]) of 77 children with ulcerative colitis and 21 (32% [23-45]) of 65 children with Crohn's disease were in steroid-free and exclusive enteral nutrition-free remission at 14 weeks. Median drug concentrations at week 14 were higher in children with ulcerative colitis than in those with Crohn's disease (11·5 μg/mL [IQR 5·5-18·1] vs 5·9 μg/mL [3·0-12·7]; p=0·006). In children who weighed less than 30 kg, the optimal drug concentration associated with steroid-free and exclusive enteral nutrition-free clinical remission was 7 μg/mL at week 14 (area under the curve 0·69 [95% CI 0·41-0·98]), corresponding to a dose of 200 mg/m2 body surface area or 10 mg/kg. 32 (23%) of 142 children reported at least one adverse event, the most common were headache (five [4%]), myalgia (four [3%]), and fever (three [2%]). None of the adverse events were classified as severe, and only two (1%) patients discontinued treatment due to adverse events. Vedolizumab showed good safety and effectiveness at inducing remission in children with IBD at 14 weeks, especially those with ulcerative colitis. Vedolizumab should be considered in children when other approved drug interventions for IBD are unsuccessful. In children who weigh less than 30 kg, vedolizumab should be dosed by the child's body surface area (200 mg/m2) or weight (10 mg/kg). The European Crohn's and Colitis Organization, the European Society for Paediatric Gastroenterology Hepatology and Nutrition, and Takeda.

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.

S983 Baseline Demographics and Disease Characteristics of Patients With Ulcerative Colitis Who Responded to Vedolizumab at Week 6

S983 Baseline Demographics and Disease Characteristics of Patients With Ulcerative Colitis Who Responded to Vedolizumab at Week 6

Transcriptional Behavior of Regulatory T Cells Predicts IBD Patient Responses to Vedolizumab Therapy.

Inflammatory bowel disease (IBD) involves chronic T cell-mediated inflammatory responses. Vedolizumab (VDZ), a monoclonal antibody against α4β7 integrin, inhibits lymphocyte extravasation into intestinal mucosae and is effective in ulcerative colitis (UC) and Crohn's disease (CD). We sought to identify immune cell phenotypic and gene expression signatures that related to response to VDZ. Peripheral blood (PBMC) and lamina propria mononuclear cells (LPMCs) were analyzed by flow cytometry and Cytofkit. Sorted CD4 + memory (Tmem) or regulatory T (Treg) cells from PBMC and LPMC were analyzed by RNA sequencing (RNA-seq). Clinical response (≥2-point drop in partial Mayo scores [UC] or Harvey-Bradshaw index [CD]) was assessed 14 to 22 weeks after VDZ initiation. Machine-learning models were used to infer combinatorial traits that predicted response to VDZ. Seventy-one patients were enrolled: 37 received VDZ and 21 patients remained on VDZ >2 years. Fourteen of 37 patients (38%; 8 UC, 6 CD) responded to VDZ. Immune cell phenotypes and CD4 + Tmem and Treg transcriptional behaviors were most divergent between the ileum and colon, irrespective of IBD subtype or inflammation status. Vedolizumab treatment had the greatest impact on Treg metabolic pathways, and response was associated with increased expression of genes involved in oxidative phosphorylation. The strongest clinical predictor of VDZ efficacy was concurrent use of thiopurines. Mucosal tissues offered the greatest number of response-predictive biomarkers, whereas PBMC Treg-expressed genes were the best predictors in combinatorial models of response. Mucosal and peripheral blood immune cell phenotypes and transcriptional profiles can inform VDZ efficacy and inform new opportunities for combination therapies.

Mucosal Eosinophil Abundance in Non-Inflamed Colonic Tissue Is Associated with Response to Vedolizumab Induction Therapy in Inflammatory Bowel Disease.

Vedolizumab is used as a treatment for patients with inflammatory bowel disease (IBD), but induction therapy leads to clinical response and remission in approximately 55% and 30% of patients with IBD, respectively. In this study, we aimed to explore the predictive value of mucosal eosinophils and serum eotaxin-1 regarding response to vedolizumab induction therapy. Eighty-four (84) patients with IBD (37 Crohn’s disease [CD], 47 ulcerative colitis [UC]) were included. For 24 patients with IBD, histopathology was assessed for eosinophil counts in non-inflamed colonic tissue prior to vedolizumab treatment. For 64 patients with IBD, serum eotaxin-1 levels were quantified prior to (baseline) and during vedolizumab treatment. Serum samples of 100 patients with IBD (34 CD, 66 UC) from the GEMINI 1 and 2 trials were used for external validation. Baseline mucosal eosinophil numbers in non-inflamed colonic tissue were significantly higher in responders to vedolizumab induction therapy when compared to primary non-responders (69 [34–138] vs. 24 [18–28] eosinophils/high-power field, respectively, p < 0.01). Baseline serum eotaxin-1 levels in the discovery cohort were significantly elevated in responders, compared to primary non-responders (0.33 [0.23–0.44] vs. 0.20 [0.16–0.29] ng/mL, p < 0.01). Prediction models based on mucosal eosinophil counts and serum eotaxin-1 showed an area under the curve (AUC) of 0.90 and 0.79, respectively. However, the predictive capacity of baseline serum eotaxin-1 levels could not be validated in the GEMINI cohort. Mucosal eosinophil abundance in non-inflamed colonic tissue was associated with response to vedolizumab induction therapy in patients with IBD. Future studies are warranted to further validate the potential value of mucosal eosinophils and serum eotaxin-1 as biomarkers for response to vedolizumab therapy.

Effects of Different Biological Therapies on S1/S2 Antibody Response to SARS-CoV-2 Vaccination in a Cohort of Patients with Inflammatory Bowel Disease.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has affected the entire planet. The objectives of our study were to compare responses to the vaccine (Pfizer-Biontech COMIRNATY) in a population of patients with intestinal bowel syndrome undergoing different biological therapies or conventional therapy. The study recruited 390 patients who received the first vaccination dose during the dedicated vaccination campaign for inflammatory bowel disease (IBD) patients. The inclusion criteria were a diagnosis of CD or UC and complete vaccination with the Pfizer–BioNTech COVID-19 (Comirnaty) vaccine. The exclusion criteria were other significant diseases or important therapies under way or contraindications to vaccination according to the European drug surveillance recommendations. Linear rank models were run to assess the association between the different therapies and S1/S2 antibodies at three different times. The models showed that in patients with IBD receiving Vedolizumab a significant increase in mean IgG levels was observed, independently of other therapies and confounding factors (β: 57.45, 95% CI 19.62 to 19.00). This study confirmed the complete antibody response to vaccination against COVID-19 in patients with IBD undergoing biological therapy—particularly Vedolizumab treatment—but also a reduced immune response due to concomitant steroid therapy.

Memory T Cell Subpopulations as Early Predictors of Remission to Vedolizumab in Ulcerative Colitis.

BackgroundVedolizumab is a humanized monoclonal antibody targeting the α4β7 integrin used for the treatment of ulcerative colitis. Few biomarkers related to vedolizumab response have been identified. The aim of this work was to assess whether baseline circulating CD4+ and CD8+ memory T-lymphocyte subpopulations could help to identify patients with response to vedolizumab treatment in ulcerative colitis.MethodsProspective pilot study in 15 patients with active ulcerative colitis and previous failure to anti-TNFα starting vedolizumab treatment. Peripheral blood samples were obtained before the first dose of vedolizumab and at week 6 and 14 of treatment. Clinical remission was defined as a Mayo Clinic partial score of ≤2 points without any concomitant dose of steroids. Biochemical remission or endoscopic improvement was defined as fecal calprotectin <250 mcg/g or Mayo endoscopic subscore ≤1.ResultsAt week 14, nine patients achieved clinical remission and eight patients achieved biochemical remission or endoscopic improvement. Patients in clinical remission presented higher baseline CD8 α4β7+ memory T cells concentration when compared with patients with no remission. In addition, patients with biochemical remission or endoscopic improvement at week 14 presented higher baseline concentration of CD8 α4β7+ memory T cells. No differences were identified according to flare severity, extent of disease or type of anti-TNFα failure. There were no significant differences regarding changes in T cell subsets during vedolizumab induction.ConclusionCD8+ α4β7+ memory T cells before starting vedolizumab therapy could be an early predictor of remission in ulcerative colitis patients and therefore help to select a subset of responders.

Superior Effectiveness of Tofacitinib Compared to Vedolizumab in Anti-TNF-experienced Ulcerative Colitis Patients: A Nationwide Dutch Registry Study

Clinicians face difficulty in when and in what order to position biologics and Janus kinase inhibitors in patients with anti-tumor necrosis factor-alpha (TNF) refractory ulcerative colitis (UC). We aimed to compare the effectiveness and safety of vedolizumab and tofacitinib in anti-TNF-exposed patients with UC in our prospective nationwide Initiative on Crohn and Colitis Registry. Patients with UC who failed anti-TNF treatment and initiated vedolizumab or tofacitinib treatment were identified in the Initiative on Crohn and Colitis Registry in the Netherlands. We selected patients with both clinical as well as biochemical or endoscopic disease activity at initiation of therapy. Patients previously treated with vedolizumab or tofacitinib were excluded. Corticosteroid-free clinical remission (Simple Clinical Colitis Activity Index ≤2), biochemical remission (C-reactive protein ≤5 mg/L or fecal calprotectin ≤250 μg/g), and safety outcomes were compared after 52 weeks of treatment. Inverse propensity score-weighted comparison was used to adjust for confounding and selection bias. Overall, 83 vedolizumab- and 65 tofacitinib-treated patients were included. Propensity score-weighted analysis showed that tofacitinib-treated patients were more likely to achieve corticosteroid-free clinical remission and biochemical remission at weeks 12, 24, and 52 compared with vedolizumab-treated patients (odds ratio [OR], 6.33; 95% confidence interval [CI], 3.81-10.50; P < .01; OR, 3.02; 95% CI, 1.89-4.84; P < .01; and OR, 1.86; 95% CI, 1.15-2.99; P= .01; and OR, 3.27; 95% CI, 1.96-5.45; P < .01; OR, 1.87; 95% CI, 1.14-3.07; P= .01; and OR, 1.81; 95% CI, 1.06-3.09; P= .03, respectively). There was no difference in infection rate or severe adverse events. Tofacitinib was associated with superior effectiveness outcomes compared with vedolizumab in anti-TNF-experienced patients with UC along with comparable safety outcomes.

Real-world multicentre observational study including population pharmacokinetic modelling to evaluate the exposure-response relationship of vedolizumab in inflammatory bowel disease: ERELATE Study.

ERELATE was a phase 4, multinational, retrospective, observational study. To evaluate the relationship between intravenous vedolizumab exposure and treatment outcomes over 52 weeks in adults with ulcerative colitis (UC) or Crohn's disease (CD). Real-world data from patients with UC or CD treated with intravenous vedolizumab in nine centres in six countries were collected retrospectively. Treatment outcomes were collected at Weeks 14, 26 and 52. An established population pharmacokinetic model (incorporating observed vedolizumab concentrations based on a Bayesian approach) was used to predict individual vedolizumab exposure. Vedolizumab exposure-response relationship was evaluated overall, by indication and based on baseline characteristics. The study population (n= 695; UC, n= 304; CD, n= 391) had a median age of 39 years; 47.9% were male and 86.9% had prior tumour necrosis factor antagonist exposure. By Week 14, clinical, endoscopic, deep (clinical plus endoscopic) and biologic remission was achieved by 47.3%, 59.6%, 30.7% and 19.0% of patients respectively. Higher vedolizumab trough concentration early in treatment was consistently associated with clinical remission at later time points. Clinical remission at Week 14 and Week 52 was associated with Week 6 trough concentrations of ≥31.0 and ≥32.0μg/ml respectively. Importantly, multivariable analysis identified baseline clearance as the only exposure measure predictive of clinical and deep remission at Week 52. In this real-world study, a positive exposure-response relationship was observed for vedolizumab. Vedolizumab concentration during induction may be an important predictor of short- and long-term outcomes, and similarly, vedolizumab baseline clearance may be an important predictor of remission.

Real-world data on switching from intravenous to subcutaneous vedolizumab treatment in patients with inflammatory bowel disease.

SummaryBackground and AimsVedolizumab is a gut‐selective treatment approved for Crohn’s disease (CD) and ulcerative colitis (UC). Recently, a subcutaneous formulation of vedolizumab was approved. The aims of this study were to evaluate efficacy, safety, pharmacokinetics, patient experience and costs following a switch from intravenous to subcutaneous vedolizumab treatment.MethodsPatients were switched from intravenous to subcutaneous vedolizumab maintenance treatment and followed prospectively for 6 months and a subgroup for 12 months. The primary endpoint was change in faecal calprotectin levels. Furthermore, we evaluated clinical disease activity, remission rates, plasma CRP, drug persistence, adverse events, local injection reactions, serum drug concentrations, patient satisfaction, quality‐of‐life and treatment costs.ResultsEighty‐nine patients were included (48 CD; 41 UC). Faecal calprotectin decreased significantly in CD but not in UC. Clinical indices, remission rates, plasma CRP levels and quality‐of‐life scores remained unchanged. Patients that had been on standard compared to optimised IV vedolizumab dosing displayed similar outcomes on standard SC dosing. Drug persistence at 6 and 12 months was 95.5% and 88.5%, respectively. Frequencies of adverse events were similar before and after the switch. No serious adverse events occurred. Transient severe local injection reactions were experienced by 1.2% of patients. Median vedolizumab trough levels were 2.3 times higher on subcutaneous compared to intravenous treatment. Patient satisfaction was generally high. Annualised treatment costs were reduced by 15% following the switch.ConclusionsThe switch from intravenous to subcutaneous vedolizumab could be done with preserved therapeutic effectiveness, safety, high patient satisfaction and low discontinuation rate, at a reduced cost.

Real-world characteristics, treatment experiences and corticosteroid utilisation of patients treated with tofacitinib for moderate to severe ulcerative colitis

BackgroundTofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. We aimed to describe the real-world treatment experience and corticosteroid utilisation of patients treated with tofacitinib in a US claims database.MethodsPatients with a UC diagnosis who initiated tofacitinib, vedolizumab or tumour necrosis factor inhibitor (TNFi) treatment between May 2018 and July 2019 were identified from the Optum Research Database. Demographic and clinical characteristics of patients who initiated tofacitinib, vedolizumab or TNFi were described. Oral corticosteroid use prior to and following tofacitinib initiation was evaluated. Tofacitinib adherence (proportion of days covered) and continuation was assessed for 6 months following initiation. Analyses were descriptive and stratified by prior biologic use (naïve, 1 or ≥ 2; minimum of 12 months prior to tofacitinib initiation).ResultsAmong patients initiating tofacitinib (N = 225), mean age was 45.6 (SD 16.5) years and 50.2% were female. Of these, 43 (19.1%) patients were biologic-naïve and 182 (80.9%) had prior biologic use (92 [40.9%], 1 prior biologic; 90 [40.0%], ≥ 2 prior biologics). Among patients with 1 prior biologic, 82.6% were previously treated with a TNFi. Among patients with ≥ 2 prior biologics, 54.4% were previously treated with vedolizumab and a TNFi, 16.7% with two TNFi and 28.9% with ≥ 3 prior biologics. In the 6 months prior to tofacitinib initiation, 65.8% of patients had received oral corticosteroids (74.4%, 60.9% and 66.7% for biologic-naïve, 1 and ≥ 2 prior biologics, respectively). The proportion of patients with ongoing oral corticosteroid use 3–6 months after tofacitinib initiation decreased to 13.3% (9.3%, 18.5% and 10.0% for biologic-naïve, 1 and ≥ 2 prior biologics, respectively), and 19.6% of patients discontinued oral corticosteroid use during the 6 months after tofacitinib initiation. Overall, tofacitinib adherence, as determined by the mean proportion of days covered during the 6-month follow-up, was 0.7 (median 0.8). During the 6-month follow-up, 84.9% of patients continued tofacitinib.ConclusionsAmong patients with UC initiating tofacitinib, the majority had prior biologic use. Tofacitinib adherence was high, discontinuation was low and oral corticosteroid utilisation decreased irrespective of prior biologic use. Further research with longer follow-up and a larger sample size is required.

MAdCAM-1 Costimulates T Cells through Integrin α4β7 to Cause Gene Expression Events Resembling Costimulation through CD28.

Successful treatment of inflammatory bowel disease (IBD) with the anti-integrin α4β7 mAb vedolizumab suggests that interaction of this integrin with addressin mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is central to IBD pathogenesis. Although this was presumed to be due to an inhibition of lymphocyte trafficking to the gut, as has been observed in animal models, we report no depletion of CD4 T cells from the colonic mucosa as a consequence of vedolizumab treatment in humans, regardless of efficacy. Likewise, no upregulation of alternative trafficking mechanisms was observed as a consequence of therapy to suggest that this homeostasis is maintained in patients by a mechanistic escape from inhibition. Instead, we explore a role for MAdCAM-integrin interaction as a gut-specific costimulatory signal, demonstrating that it can replace CD28 ligation to activate human T cells in vitro. This activation through integrin α4β7 is mediated through the gut-restricted molecule MAdCAM-1, and it cannot be replicated by matrix molecules or proteins that bind other integrins. A detailed analysis of mRNA expression by human T cell subsets following suboptimal TCR stimulation in the presence or absence of CD28 versus MAdCAM-1 costimulation reveals marked similarity in the effect that these two signals have upon T cells, with temporal or quantitative differences detected in the expression of cytokines associated with Th17 cells or pyogenic inflammation. Thus, we describe an alternative costimulatory pathway for T cells in the intestine, through ligation of integrin α4β7 by MAdCAM-1, which may explain the therapeutic efficacy of vedolizumab and have implications concerning the treatment of IBD.

A165 VEDOLIZUMAB IS AN OPTION TO TREAT MICROSCOPIC COLITIS IN PATIENTS DEPENDENT ON ORAL STEROIDS OR HAVE FAILED A BIOLOGIC: A MULTICENTRE CANADIAN CASE SERIES

BackgroundMicroscopic colitis (MC) is an inflammatory bowel condition demonstrating normal mucosa on endoscopy, with evidence of inflammation and lymphocytosis on pathologic analysis of biopsies. The pathophysiology for this disease is largely unknown, and evidence for its management in cases refractory to oral steroids or after failing a biologic is sparse. Vedolizumab, an integrin receptor antagonist, has been used in a handful of persons with MC with limited literature.AimsReview literature on the use of Vedolizumab in treatment of MC. Present 7 cases of MC where Vedoluzimab was used to manage patients refractory to therapy (either steroid dependent, or failing biologic therapy).MethodsPatients with MC managed with Vedolizumab were identified by soliciting practicing Gastroenterologists within Winnipeg at 3 health centres. A chart review was conducted to obtain pertinent information including patient demographics, symptoms, and medications previously trialed.ResultsReview of literature revealed 3 case reports, and 4 case series reporting on the use of Vedolizumab in MC. We identified 7 cases; 6 female, and a mean age at diagnosis of 50.7. Histologies included 3 lymphocytic, 2 collagenous, 1 developed from lymphocytic to collagenous over time, and 1 with evidence of both. 4 patients were on a biologic prior to initiating Vedolizumab with a mean duration of therapy of 24.25 months. Indications for initiating Vedolizumab included: 3 with steroid dependency, 3 Infliximab failures, and 1 with Adalimumab-associated hepatotoxicity. Mean disease duration prior to initiating Vedolizumab was 112.7 months. Number of stools pre-Vedolizumab were: 1–3 = 0, 4–6 = 2, 7–9 = 2, >/=10 = 3, compared to >6 months post-Vedolizumab: 1–3 = 5, 4–6 = 1, 7–9 = 1, >/=10 = 0. Symptoms pre-Vedolizumab compared to >6 months post-Vedolizumab included: 4 with urgency pre-Vedolizumab versus 1, 3 had incontinence versus 0, and 4 had nocturnal symptoms versus 0. Use of alternative medications included anti-diarrheals, oral 5-aminosalicylic acid, and immunomodulators. On average, patients tried 7.6 different treatments prior to starting Vedolizumab. 1 case is considered to have failed Vedolizumab due to increasing symptoms.ConclusionsThis multicentre case series is the first in Canada to assess patient characteristics and symptoms before and after Vedolizumab induction in persons with MC who are either steroid dependent or have failed a biologic. Our results demonstrate an overall improvement in symptoms when assessed >6 months after induction therapy. This review was limited in not having a symptom inventory/severity index completed at each clinic visit, resulting in a number of difficult-to-compare and incomplete data points.Funding AgenciesNone

Evaluation of Natural Language Processing for the Identification of Crohn Disease-Related Variables in Spanish Electronic Health Records: A Validation Study for the PREMONITION-CD Project.

BackgroundThe exploration of clinically relevant information in the free text of electronic health records (EHRs) holds the potential to positively impact clinical practice as well as knowledge regarding Crohn disease (CD), an inflammatory bowel disease that may affect any segment of the gastrointestinal tract. The EHRead technology, a clinical natural language processing (cNLP) system, was designed to detect and extract clinical information from narratives in the clinical notes contained in EHRs.ObjectiveThe aim of this study is to validate the performance of the EHRead technology in identifying information of patients with CD.MethodsWe used the EHRead technology to explore and extract CD-related clinical information from EHRs. To validate this tool, we compared the output of the EHRead technology with a manually curated gold standard to assess the quality of our cNLP system in detecting records containing any reference to CD and its related variables.ResultsThe validation metrics for the main variable (CD) were a precision of 0.88, a recall of 0.98, and an F1 score of 0.93. Regarding the secondary variables, we obtained a precision of 0.91, a recall of 0.71, and an F1 score of 0.80 for CD flare, while for the variable vedolizumab (treatment), a precision, recall, and F1 score of 0.86, 0.94, and 0.90 were obtained, respectively.ConclusionsThis evaluation demonstrates the ability of the EHRead technology to identify patients with CD and their related variables from the free text of EHRs. To the best of our knowledge, this study is the first to use a cNLP system for the identification of CD in EHRs written in Spanish.

Vedolizumab for perianal fistulizing Crohn's disease: systematic review and meta-analysis.

Background/AimsPerianal fistulas are a debilitating manifestation of Crohn’s disease (CD). Despite the advent of anti-tumor necrosis factor (anti-TNF) therapy, the medical management of fistulizing CD continues to be challenged by unmet needs. We conducted a systematic review and meta-analysis of the effectiveness of vedolizumab for the management of perianal fistulizing CD.MethodsA search of PubMed, EMBASE and the Cochrane Library was performed from inception to June 2020 for studies reporting rates of perianal fistula healing in CD patients treated with vedolizumab. The primary outcome of interest was complete healing of perianal fistulas and the secondary outcome was partial healing. The pooled fistula healing rates with 95% confidence intervals (CI) were calculated utilizing a random effects model.ResultsA total of 74 studies were initially identified, 4 of which met the inclusion criteria. A total of 198 patients with active perianal fistulas were included, 87% of whom had failed previous anti-TNF therapy. The pooled complete healing rate was 27.6% (95% CI, 18.9%–37.3%) with moderate heterogeneity (I2=49.4%) and the pooled partial healing rate was 34.9% (95% CI, 23.2%–47.7%) with high heterogeneity (I2=67.1%).ConclusionsIn a meta-analysis of 4 studies that included 198 patients with perianal fistulizing CD, the majority of whom had failed previous anti-TNF therapy, vedolizumab treatment led to healing of perianal fistulas in nearly one-third of the patients. The lack of high-quality data and significant study heterogeneity underscores the need for future prospective studies of fistula healing in patients receiving anti-integrin therapy.

EARLY VERSUS DELAYED INITIATION OF VEDOLIZUMAB IN ULCERATIVE COLITIS: TREATMENT RESPONSE IN THE REAL WORLD (RALEE)

Abstract BACKGROUND Pivotal trials in ulcerative colitis (UC) have indicated that earlier intervention with a biologic is associated with greater likelihood of treatment response. However, in real-world clinical practice, patients with newly diagnosed UC are often prescribed conventional therapies, such as immunomodulators (IM), corticosteroids (CS), and/or 5-aminosalicylates (5-ASA) before biologic treatment, which may result in suboptimal clinical outcomes and high costs. RALEE is an observational study investigating the impact of early versus delayed initiation of vedolizumab (VDZ) on clinical and economic outcomes in patients with inflammatory bowel disease, using administrative data sets. Here, we report the impact on treatment response in patients with UC. METHODS Using the MarketScan Commercial Claims and Encounters database and the MarketScan Medicare Supplemental database, we identified adult patients diagnosed with UC between 2017 and 2018 who had ≥ 1 claim for VDZ and continuous enrollment for ≥ 12 months before and after their initial UC diagnosis. Patients were excluded if they received VDZ, anti-tumor necrosis factor therapy, or other biologic therapy in the 12 months before their initial UC diagnosis. Five post-diagnosis treatment pathways were predefined: (1) EARLY VDZ, VDZ within 30 days of initial UC diagnosis; (2) DELAYED VDZ 1, IM (not 5-ASA) before VDZ; (3) DELAYED VDZ 2, CS with IM before VDZ; (4) DELAYED VDZ 3, 5-ASA with CS before VDZ; or (5) DELAYED VDZ 4, 5-ASA with CS and IM before VDZ. Response was defined as no occurrence of the following events within 60 days after VDZ initiation: new concomitant use of CS, inflammatory bowel disease-related surgery, increased administration of VDZ, VDZ treatment discontinuation, or treatment switch. Response was evaluated with logistic regression (backwards selection) with EARLY VDZ as the reference group. RESULTS We identified 136,315 patients with UC, of whom 1,342 received VDZ and met the selection criteria. The median age of patients was 43 years; 51.0% of patients were male and 96.4% were commercially insured. The proportion of patients with response to VDZ was higher for EARLY VDZ (88.8%) than any of the DELAYED VDZ treatment pathways (70.1–79.8%) (Figure 1). Delayed initiation of VDZ (DELAYED VDZ 1, 2, and 4) was associated with a significantly lower likelihood of response than EARLY VDZ (Figure 2). CONCLUSION This analysis demonstrates that patients with UC are more likely to respond to therapy if initiated on VDZ within 30 days of diagnosis than if initiation is delayed by use of IM, CS, and/or 5-ASA. These findings are consistent with clinical guidelines that recommend use of VDZ for induction of remission in patients with moderately to severely active UC. Further analyses of remission, healthcare resource utilization, and associated direct medical costs are underway.