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BACKGROUND: Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis. METHODS: In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (modified Mayo score [MMS]; 4-6 vs 7-9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively. FINDINGS: Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients vs ten [7%] of 135 patients; p

Introduction Thromboembolic events (TEs) are associated with considerable costs. However, there is a paucity of evidence quantifying the economic burden associated with TEs among patients with immune-mediated diseases (IMDs). Methods This retrospective cohort study used the IBM MarketScan® Commercial and Medicare Supplemental Claims databases (2014–2018). Commercially insured adults with IMDs were classified into two cohorts based on diagnosis of TEs (deep vein thrombosis, pulmonary embolism, ischemic stroke, myocardial infarction). Patients in the TE cohort were matched on type of IMD, age, sex, and year of diagnosis to patients in the no TE cohort. In the TE cohort, the index date was the date of first TE following first IMD diagnosis. In the no TE cohort, the index date was assigned so the duration from first IMD diagnosis to index date matched the duration for the corresponding patient in the TE cohort. All-cause total healthcare costs were compared between cohorts in the 30-day and 1-year periods following the index date (inclusive). Unadjusted comparisons were conducted using Wilcoxon signed-rank tests. Adjusted results were estimated using generalized estimating equations with robust sandwich estimator. Results Overall, 9681 matched patients were included in each cohort (mean age 61.1 years; 63.7% female). The TE cohort had higher proportions of comorbidities than the no TE cohort (Charlson Comorbidity Index [1.5 vs. 0.9]; p

Introduction Inflammatory bowel disease (IBD) is associated with greater risk of thromboembolic events (TEs) due to the link between systemic inflammation and hypercoagulability. This study assessed the rates of TEs among patients with IBD versus patients without immune-mediated disease (IMD) and the cost of TEs among patients with IBD in the United States. Methods This study used the IBM MarketScan® Commercial and Medicare Supplemental Databases (2014–2018). To assess the incremental rates of TEs (deep vein thrombosis [DVT], pulmonary embolism [PE], ischemic stroke [IS], myocardial infarction [MI]), patients with IBD were matched to patients without IMD. Unadjusted and adjusted incidence rate ratios (IRRs) of TEs were used to compare cohorts. To assess the cost of TEs, patients with IBD with TEs were matched to patients with IBD without TEs. Costs were assessed 30 days and 1 year post index date. Results There were 34,687 matched pairs included in the rates of TE analyses. Compared to patients without IMD, patients with IBD had greater rates of DVT (adjusted IRR [95% confidence interval] 2.44 [2.00, 2.99]; p

Background Clinical and molecular subcategories of inflammatory bowel disease (IBD) are needed to discover mechanisms of disease and predictors of response and disease relapse. We aimed to develop a study of a prospective adult research cohort with IBD (SPARC IBD) including longitudinal clinical and patient-reported data and biosamples. Methods We established a cohort of adults with IBD from a geographically diverse sample of patients across the United States with standardized data and biosample collection methods and sample processing techniques. At enrollment and at time of lower endoscopy, patient-reported outcomes (PRO), clinical data, and endoscopy scoring indices are captured. Patient-reported outcomes are collected quarterly. The quality of clinical data entry after the first year of the study was assessed. Results Through January 2020, 3029 patients were enrolled in SPARC, of whom 66.1% have Crohn’s disease (CD), 32.2% have ulcerative colitis (UC), and 1.7% have IBD-unclassified. Among patients enrolled, 990 underwent colonoscopy. Remission rates were 63.9% in the CD group and 80.6% in the UC group. In the quality study of the cohort, there was 96% agreement on year of diagnosis and 97% agreement on IBD subtype. There was 91% overall agreement describing UC extent as left-sided vs extensive or pancolitis. The overall agreement for CD behavior was 83%. Conclusion The SPARC IBD is an ongoing large prospective cohort with longitudinal standardized collection of clinical data, biosamples, and PROs representing a unique resource aimed to drive discovery of clinical and molecular markers that will meet the needs of precision medicine in IBD.

Introduction A potentially elevated risk for pulmonary thrombosis with Janus kinase inhibitors (JAKinibs) was identified, as well as an increased risk for portal vein thrombosis, in ruxolitinib patients. Consequently, the objective of this investigation was to repeat a comprehensive analysis of the US FDA’s Adverse Event Reporting System (FAERS) database to assess postmarketing reporting rates of thromboembolic events (TEs) in patients treated with JAKinibs. Methods FAERS data (1 January 2010 to 30 September 2019) were searched for reports of all FDA-approved JAKinibs across all indications. For each drug–adverse drug reaction (ADR) pair, the reporting odds ratio (ROR) [two-sided 95% confidence interval (CI)] and empirical Bayesian geometric mean (EBGM) [one-sided 95% lower bound] were calculated to detect drug–ADR pairs with higher-than-expected reporting rates within the FAERS. Significance was declared when both lower 95% CI bounds were > 1. Results Significantly elevated reporting rates of pulmonary thrombosis were evident with tofacitinib (ROR 2.36 [1.69–3.31]; EBGM 2.01 [1.53]), as was pulmonary embolism with baricitinib (ROR 12.23 [8.35–17.89]; EBGM 7.72 [3.82]) and portal vein thrombosis with ruxolitinib (ROR 4.16 [2.70–6.40]; EBGM 4.52 [3.11]). Deep vein thrombosis reports were increased with baricitinib (ROR 14.84 [9.64–22.84]; EBGM 9.49 [5.91]), as was thrombosis with ruxolitinib (ROR 1.40 [1.20–1.63]; EBGM 1.72 [1.52]). The relationship between the time of treatment initiation and event occurrence indicated that time to events occurred randomly. Conclusions This study found significant reporting rates for TEs in patients treated with JAKinibs across brands and indications, providing additional evidence that JAKinibs may be contraindicated in patients at risk of TEs. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01082-y.

Background and Aims This study aimed to compare real-world clinical effectiveness and safety of vedolizumab, an α4β7-integrin inhibitor, and anti-tumour necrosis factor-α [anti-TNFα] agents in biologic-naïve ulcerative colitis [UC] and Crohn’s disease [CD] patients. Methods This was a 24-month retrospective medical chart study in adult UC and CD patients treated with vedolizumab or anti-TNFα in Canada, Greece and the USA. Inverse probability weighting was used to account for differences between groups. Primary outcomes were cumulative rates of clinical effectiveness [clinical response, clinical remission, mucosal healing] and incidence rates of serious adverse events [SAEs] and serious infections [SIs]. Secondary outcomes included cumulative rates of treatment persistence [patients who did not discontinue index treatment during follow-up] and dose escalation and incidence rates of disease exacerbations and disease-related surgeries. Adjusted analyses were performed using inverse probability weighting. Results A total of 1095 patients [604 UC, 491 CD] were included. By 24 months, rates of clinical effectiveness were similar between groups, but incidence rates of SAEs (hazard ratio [HR] = 0.42 [0.28–0.62]) and SIs (HR = 0.40 [0.19–0.85]) were significantly lower in vedolizumab vs anti-TNFα patients. Rates of treatment persistence [p < 0.01] by 24 months were higher in vedolizumab patients with UC. Incidence rates of disease exacerbations were lower in vedolizumab patients with UC (HR = 0.58 [0.45–0.76]). Other outcomes did not significantly differ between groups. Conclusion In this real-world setting, first-line biologic therapy in biologic-naïve patients with UC and CD demonstrated that vedolizumab and anti-TNFα treatments were equally effective at controlling disease symptoms, but vedolizumab has a more favourable safety profile.

BACKGROUND: ERELATE was a phase 4, multinational, retrospective, observational study. AIM: 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). METHODS: 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. RESULTS: 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 ≥32.0 μg/ml respectively. Importantly, multivariable analysis identified baseline clearance as the only exposure measure predictive of clinical and deep remission at Week 52. CONCLUSIONS: 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. ispartof: ALIMENTARY PHARMACOLOGY & THERAPEUTICS vol:56 issue:3 pages:463-476 ispartof: location:England status: published

BackgroundInfliximab is an efficacious therapy for inflammatory bowel disease and may play a role in management of some extraintestinal manifestations. While higher trough levels of infliximab are associated with higher rates of disease remission, the association between trough levels of infliximab and arthralgia activity characterised as an extraintestinal manifestation has yet to be defined.ObjectiveWe aimed to assess the association between serum trough levels of infliximab and peripheral arthralgia activity in patients with inflammatory bowel disease.DesignIn this cross-sectional study, we identified patients with inflammatory bowel disease on infliximab therapy with known history of arthralgias attributed to an extraintestinal manifestation. Collected variables included disease phenotype, medications (such as thiopurines or methotrexate), Harvey Bradshaw Index, partial Mayo score, C reactive protein, trough levels of infliximab and anti-infliximab antibodies. The primary outcome was active patient-reported arthralgia.ResultsOut of 267 patients included, 65 (24.4%) had active arthralgias at the time the trough level of infliximab was measured. No significant differences in trough levels were seen between those patients with and without arthralgias. Patients on combination therapy with methotrexate or thiopurines or those with detectable anti-infliximab antibodies were not more likely to have inactive arthralgias (OR 0.99, 95% CI 0.57 to 1.74, p=0.99 and OR 1.94, 95% CI 0.9 to 4.1, p=0.09, respectively).ConclusionsThis study suggests that although therapeutic drug monitoring of infliximab can have a role in the management of Crohn’s disease and ulcerative colitis, it does not seem to be useful in managing arthralgias associated with inflammatory bowel disease.

Introduction: Despite the introduction of novel therapies and treatment strategies for ulcerative colitis (UC), many patients develop acute, severe episodes, warranting prompt care and aggressive management. There is a significant unmet need to improve outcomes in these patients. Clinicians must be able to identify those that will have worse prognosis and plan an aggressive therapy with an early/proactive adjustments in management if needed.Areas covered: The aim of this review is to evaluate the most recent evidence on the assessment and management of patients with acute severe ulcerative colitis. We searched the mainstream literature search engines for the most recent evidence on diagnosis and management of acute UC.Expert Opinion: The approach to patients with severe UC includes clinical and endoscopic assessment of disease severity and ruling out over-infections. While intravenous corticosteroids remain the first line therapy for acute severe colitis, many patients do not respond and require escalation to calcineurin inhibitors or infliximab, and may ultimately require colectomy. Even though several novel therapies are available or in development, their role in acute severe episodes of colitis is unknown.

BACKGROUND: A significant number of patients receiving therapy with anti-tumor necrosis factor (TNF) agents for Crohn’s disease (CD) experience primary or secondary non-response. The aim of this study was to assess if patients with non-response to anti-TNF agents have increased expression of alternative cytokine pathways. METHODS: We designed a prospective, cross-sectional study that included patients with CD receiving anti-TNF undergoing colonoscopy with adequate serum trough drug levels (≥8 μg/mL) and without anti-drug antibodies. Inflammatory cytokines and cell adhesions markers measured included intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), interleukin-(IL) 8, IL-1β and IL-6. The primary outcome was the presence of active endoscopic inflammation defined as the presence of at least one ulceration ≥5 mm. RESULTS: 47 patients were included. Patients with active inflammation had significantly higher levels of ICAM-1 and IL-1β when compared to those without intestinal inflammation (45.9 vs. 35.8 ng/mL, p

Background and Aims Therapeutic drug monitoring (TDM) with measurement of serum drug and antidrug antibody concentrations is used to optimize tumor necrosis factor antagonists (anti-TNF). The endoscopic healing index (EHI) is a validated serum-based assay to measure mucosal inflammation in adults with Crohn disease (CD). Our objectives were to evaluate the relationship between EHI and TDM results and to determine the anti-TNF concentration range associated with EHI Methods Adult and pediatric patients with CD (N = 1731) were selected retrospectively from a clinical laboratory cohort. Patients were selected if they had an ICD-10 code for CD and if results for EHI and TDM were available within 30 days of each other. The relationship between EHI and TDM results was examined and the anti-TNF concentration range associated with EHI 50 was evaluated. Results Median anti-TNF concentration was higher in patients with EHI 50 for infliximab (N = 796): 11.1 vs 3.4 µg/mL and for adalimumab (N = 935): 9.2 vs 5.0 µg/mL (P < 0.0001 both drugs). Patients with antibodies to infliximab (12.8%) or adalimumab (14.9%) had lower anti-TNF concentrations (P < 0.001 both drugs) and higher EHI (P < 0.01 both drugs). The concentration range for infliximab: 5–15 µg/mL (5–9 µg/mL in pediatric patients) and for adalimumab: 5–10 µg/mL (8 µg/mL in pediatric patients) best discriminated EHI 50. Conclusions We report the anti-TNF concentration range associated with EHI

A multidisciplinary panel of physicians was convened to gain understanding of the relationship between thromboembolic events (TEs) and immune-mediated diseases (IMDs). The primary objective of the panel was to assess areas of consensus on the IMD most prone to TE as well as modifiable and unmodifiable factors that might exacerbate or mitigate the risk of TEs.Thirteen nationally recognized physicians were selected based on their contributions to guidelines, publications and patient care. The modified Delphi panel consisted of four rounds of engagement: (1) a semi-structured interview, (2) an expert panel questionnaire, (3) an in-person panel discussion, and (4) a consensus statement survey.Ulcerative colitis and Crohn's disease were identified as two of four IMDs with the highest TE risk. Consensus was reached on several non-modifiable and modifiable characteristics of high-risk. Approaches to reduce TE incidence were identified such as altering treatment, requiring the monitoring of patients for TEs and modifying patient behaviors. Janus kinase inhibitors and corticosteroids were identified as therapies that required further evaluation given their potential TE risk.The panel reached a consensus that several IMDs are at an elevated risk of TEs. Physicians are unable to control most patient level risk factors but can control the therapies being used. Consequently, physicians should consider the specific IMD, be aware of TE risk factors, and take into account risk factors in selecting the therapies to optimally manage their conditions and to reduce the risk of TEs in this population.

PURPOSE This study assessed the association between thromboembolic events (TEs) and immune-mediated diseases (IMDs) and characterized the risk profile of TEs among patients with IMDs. METHODS An administrative claims database (2014-2018) was used to identify adults with ≥2 diagnoses on different dates for ≥1 IMD (IMD cohort; ankylosing spondylitis, atopic dermatitis, inflammatory bowel disease, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and systemic lupus erythematosus); patients without an IMD diagnosis were assigned to the non-IMD cohort. Patients in the IMD cohort were matched 1:1 to patients in the non-IMD cohort on age, sex, and index date. Incremental risk of TE (ie, deep vein thrombosis [DVT], pulmonary embolism [PE], myocardial infarction [MI], and ischemic stroke [IS]) was assessed using adjusted incidence rate ratios (aIRRs) to control for covariates in both cohorts. Risk factors for TEs were assessed in the IMD cohort and included age, female sex, comorbidities, baseline TEs, non-IMD treatments, and IMD treatments. FINDINGS A total of 182,431 patients were included in each cohort (mean age, [51.3] years; 64.3% female). A higher proportion of patients in the IMD cohort versus the non-IMD cohort had ≥1 baseline TE (4.1% vs 2.7%; P < 0.0001). The IMD cohort had a 1.80 (95% CI, 1.68-1.92; P < 0.0001) times higher rate of TEs versus patients in the non-IMD cohort. After adjustments, patients in the IMD cohort had a 1.49 (95% CI, 1.40-1.59; P < 0.0001) times higher rate of TEs versus patients in the non-IMD cohort. Similar results were observed across individual TEs (DVT: aIRR = 1.78; PE: aIRR = 1.66; MI: aIRR = 1.17; IS: aIRR = 1.35; all P < 0.05). Risk factor profiles varied by TE. The greatest risk factor was respective TE during baseline (eg, patients with baseline DVT had 41.1 times the rate of DVT during the study period vs patients without baseline DVT; P < 0.001). Comorbidities, such as cardiovascular diseases, type 2 diabetes, and peripheral vascular disease, were associated with increased rates of MI (IRR = 2.60, 1.30, and 1.54, respectively; all P < 0.05) and IS (IRR = 1.53, 1.54, and 1.24, respectively; all P < 0.05). Janus kinase inhibitors were associated with an increased rate of PE (IRR = 2.52; P < 0.05) and nonsignificant, numerically higher rates of DVT (IRR = 1.23; P = NS) and IS (IRR = 1.82; P = NS). Sphingosine 1-phosphate receptor modulators were associated with decreased rates of TEs (DVT: IRR = 0.61, P = NS; PE: IRR = 0.30, P = NS; MI: IRR = 0.54, P = NS; IS: IRR = 0.33, P < 0.05). IMPLICATIONS The risk of TEs was higher among patients with IMD versus patients without IMD; several factors may affect this risk.

Background: Combining biologics and small molecules could potentially overcome the plateau of drug efficacy in inflammatory bowel disease (IBD). We conducted a systematic review and meta-analysis (SRMA) to assess the safety and effectiveness of dual biologic therapy (DBT) or small molecule combined with a biologic therapy (SBT) in IBD patients. Methods: MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Database of Systematic Reviews and Clinical trials.gov were reviewed from inception to Nov 3, 2020. Studies with two or more IBD patients on DBT or SBT were included while single-case reports were excluded. The main outcome was safety assessed as pooled rates of adverse events (AEs) and serious AEs (SAEs) for each combination category. Effectiveness was reported as pooled rates of clinical, endoscopic and/or radiographic response and remission. Random-effects modeling was performed for between-study heterogeneity using the I² statistic. The SRMA was registered with PROSPERO (CRD4202018361). Findings: Of the 3,688 publications identified, 13 studies involving 266 patients on seven different combinations were included. Median number of prior biologics ranged from 0-4, and median duration of follow-up was 16-68 weeks. Most common DBT and SBT were vedolizumab (VDZ) with anti-Tumour Necrosis Factor (aTNF, n=56) or tofacitinib (Tofa, n=57), respectively. Pooled rates of SAE for these were 9·6% (95% CI, 1·5 – 21·4; 8 studies; I2 0%) for VDZ-aTNF and 1·0% (95% CI, 0·0 – 7·6; 5 studies; I2 0%) for Tofa-VDZ. Pooled clinical remission rates for these were 55·1% (95% CI, 19·6 – 88·5; 8 studies; 53 TTs; I2 81%) for VDZ-aTNF and 47·8% (95% CI, 19·0 – 77·4; 5 studies; 49 TTs; I2 69%) for Tofa-VDZ. No new safety signal was reported for any combination. There was considerable heterogeneity across studies (I2, 0 to 87%). Interpretation: DBT or SBT appears to be generally safe and effective in IBD patients with conclusions on effectiveness limited by between-study heterogeneity. This data needs to be confirmed in prospective studies. Registration: The SRMA was registered with PROSPERO (CRD4202018361). Funding Statement: None. Declaration of Interests: Kindra Clark-Snustad: Dr. Clark-Snustad reports personal fees from BMS, personal fees from Pfizer, outside the submitted work; Anish Patel: Dr. Patel reports personal fees from JANSSEN, personal fees from TAKEDA, personal fees from ABBVIE, outside the submitted work; Andres Yarur: Dr. Yarur reports personal fees from Takeda, personal fees from Prometheus Bioscience, personal fees from Arena Pharmaceutical, personal fees from Bristol Myers Squibb, during the conduct of the study; Benjamin L. Cohen: Dr. Cohen reports personal fees from Abbvie, personal fees and nonfinancial support from Pfizer, personal fees from Bristol Myers Squibb, personal fees from Janssen, personal fees from Target RWE, personal fees from Sublimity Therapeutics, outside the submitted work; Matthew A. Ciorba: Dr. Ciorba reports grants and personal fees from Pfizer, grants and personal fees from Takeda, outside the submitted work; Scott D. Lee MD: Dr. Lee reports grants and personal fees from Abbvie, grants and personal fees from UCB, grants and personal fees from JANSSEN, grants and personal fees from TAKEDA, grants from BMS, grants from ABGENOMICS, grants and personal fees from ELI LILLY, grants from ARENA, outside the submitted work; Edward V. Loftus, Jr.: Dr. Loftus reports grants and personal fees from AbbVie, personal fees from Allergan, grants and personal fees from Amgen, personal fees from Arena, personal fees from Boehringer Ingelheim, grants and personal fees from Bristol-Myers Squibb, personal fees from Calibr, grants and personal fees from Celgene, personal fees from Celltrion Healthcare, personal fees from Eli Lilly, grants and personal fees from Genentech, grants and personal fees from Gilead, personal fees from Iterative Scopes, grants and personal fees from Janssen, personal fees from Ono Pharma, grants and personal fees from Pfizer, grants from Receptos, grants from Robarts Clinical Trials, personal fees from Sun Pharma, grants and personal fees from Takeda, grants from Theravance, grants and personal fees from UCB, outside the submitted work; David Fudman: Dr. Fudman reports personal fees from Pfizer, outside the submitted work; Bincy P. Abraham: Dr. Abraham reports personal fees from Abbvie, personal fees from Ferring, grants and personal fees from Takeda, personal fees from Janssen, personal fees from Pfizer, personal fees from Medtronics, personal fees from Samsung bioepis, personal fees from Bristol-Myers Squibb, outside the submitted work; Jean-Frederic Colombel: Dr. Colombel reports grants and personal fees from Abbvie, personal fees from Amgen, personal fees from Allergan, personal fees from Arena Phramaceuticals, personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers-Squibb, personal fees from Celgene Corporation, personal fees from Celltrion, personal fees from Eli Lilly, personal fees from Enterome, personal fees from Ferring Phramaceuticals, personal fees from Genentech, personal fees from Gilead, personal fees from Iterative Scopes, personal fees from Ipsen, personal fees from Immunic, personal fees from Imtbio, personal fees from Inotrem, grants and personal fees from Janssen Pharmaceuticals, personal fees from Landos, personal fees from Limmatech, personal fees from Medimmune, personal fees from Merck, personal fees from Novartis, personal fees from OMass, personal fees from Otsuka, personal fees from Pfizer, personal fees from Shire, grants and personal fees from Takeda, personal fees from Tigenix, personal fees from VielaBio, outside the submitted work; Parakkal Deepak: Dr. Deepak reports personal fees from Janssen, personal fees from Pfizer, personal fees from Prometheus Biosciences, other from Boehringer Ingelheim, personal fees from Arena Pharmaceuticals, grants from Takeda Pharmaceuticals, grants from Arena Pharmaceuticals, grants from Bristol Myers Squibb-Celgene, grants from Boehringer Ingelheim, outside the submitted work; All other authors declare no competing interests.

Serum vedolizumab concentrations are associated with clinical response although, it is unknown if vedolizumab concentrations predict response to dose escalation. The aim of this study was to identify if vedolizumab trough concentrations predicted the response to vedolizumab dose escalation. We assessed a retrospective cohort of patients on maintenance vedolizumab dosing at five tertiary care centers with vedolizumab trough concentrations. Multivariate logistic regression was used to control for potential confounders of association of vedolizumab concentration and clinical status. Those who underwent a dose escalation were further examined to assess if vedolizumab trough concentration predicted the subsequent response. One hundred ninety-two patients were included. On multivariate analysis, vedolizumab trough concentration (p = 0.03) and the use of immunomodulator (p = 0.006) were associated with clinical remission. Receiver operator curve analysis identified a cut off of 7.4 &mu, g/mL for clinical remission. Of the fifty-eight patients with dose escalated, 74% of those with a vedolizumab concentration &lt, 7.4 &mu, g/mL responded versus 52% of those with a vedolizumab trough concentration &ge, g/mL (p = 0.08). After adjustment for relevant confounders, the odds ratio for response with vedolizumab concentration &lt, g/mL was 3.7 (95% CI, 1.1&ndash, 13, p = 0.04). Vedolizumab trough concentration are associated with clinical status and can identify individuals likely to respond to dose escalation. However, a substantial portion of patients above the identified cut off still had a positive response. Vedolizumab trough concentration is a potentially helpful factor in determining the need for dose escalation in patients losing response.

The safety and efficacy of tofacitinib in Crohn's disease (CD) has been studied in 2 phase II trials in patients with moderate-to-severe CD with no new safety signals observed, but no significant difference from placebo in the primary efficacy endpoint of clinical response.1-3 However, post hoc analyses and smaller studies have observed clinical and biologic response to tofacitinib in patients with CD.2,4,5 There is a paucity of real-world effectiveness and safety data for tofacitinib in non-Food and Drug Administration label usage in patients with CD and patients with inflammatory bowel disease-unclassified (IBD-U).

Background & Aims Adverse events (AEs) including reactivation of herpes zoster (HZ) and venous thromboembolism (VTE) have been reported from clinical trials of tofacitinib in ulcerative colitis (UC). We investigated the incidence rates of AEs in a real-world study of UC patients given tofacitinib. Methods We collected data from 260 patients with UC in the Tofacitinib Real-world Outcomes in Patients with ulceratIve colitis and Crohn’s disease consortium study, performed at 6 medical centers in the United States. Patients were followed up for a median of 6 months (interquartile range, 2.7–11.5 mo). AEs were captured using a standardized data collection instrument before study initiation and at weeks 8, 16, 26, 39, and 52. Serious AEs were defined as life-threatening or resulting in a hospitalization, disability, or discontinuation of therapy. Logistic regression was performed to examine risk factors for AEs. Results AEs occurred in 41 patients (15.7%); most were infections (N = 13; 5.0%). The incidence rate of any AE was 27.2 (95% CI, 24.4–30.7 per 100 patient-years of follow-up evaluation). Fifteen were serious AEs (36.6% of AEs), and tofacitinib was discontinued for 12 patients (4.6% of cohort). The incidence rates of serious AEs was 10.0 (95% CI, 8.9–11.2 per 100 patient-years of follow-up evaluation). Five patients developed HZ infection and 2 developed VTE (all receiving 10 mg tofacitinib, twice per day). Conclusions Real-world safety signals for tofacitinib are similar to those for clinical trials, with AEs reported from almost 16% of patients. HZ infection and VTE occurred in patients receiving 10 mg tofacitinib twice per day. These results support dose de-escalation after induction therapy, to reduce the risk of AEs.

Background and Aims Vedolizumab is an anti-α4β7 biologic approved for ulcerative colitis [UC] and Crohn’s disease [CD]. We aimed to examine the association of maintenance vedolizumab concentrations with remission. Methods We performed a cross-sectional multi-centre study of inflammatory bowel disease [IBD] patients on maintenance vedolizumab. A homogeneous mobility shift assay [HMSA] was used to determine trough serum concentrations of vedolizumab and anti-drug antibodies [ATVs]. The primary outcome was corticosteroid-free clinical and biochemical remission defined as a composite of clinical remission, normalized C-reactive protein [CRP] and no corticosteroid use in 4 weeks. Secondary outcomes included corticosteroid-free endoscopic and deep remission. Vedolizumab concentrations were compared between patients in remission and with active disease. Logistic regression, adjusting for confounders, assessed the association between concentrations and remission. Results In total, 258 IBD patients were included [55% CD and 45% UC]. Patients in clinical and biochemical remission had significantly higher vedolizumab concentrations [12.7 µg/mL vs 10.1 µg/mL, p = 0.002]. Concentrations were also higher among patients in endoscopic and deep remission [14.2 µg/mL vs 8.5 µg/mL, p = 0.003 and 14.8 µg/mL vs 10.1 µg/mL, p = 0.01, respectively]. After controlling for potential confounders, IBD patients with vedolizumab concentrations >11.5 µg/mL were nearly 2.4 times more likely to be in corticosteroid-free clinical and biochemical remission. Only 1.6% of patients had ATVs. Conclusions In a large real-world cohort of vedolizumab maintenance concentrations, IBD patients with remission defined by objective measures [CRP and endoscopy] had significantly higher trough vedolizumab concentrations and immunogenicity was uncommon.

Background and Aims Intestinal biopsy sampling during IBD trials represents a valuable adjunct strategy for understanding drug responses at the tissue level. Given the length and distinctive embryonic origins of the proximal and distal colon, we investigated whether inherent regional differences of immune cell composition could introduce confounders when sampling different disease stages, or pre/post drug administration. Here, we capitalise on novel mass cytometry technology to perform deep immunophenotyping of distinct healthy colonic segments, using the limited numbers of biopsies that can be harvested from patients. Methods Biopsies [2.8 mm] were collected from the caecum, transverse colon, descending colon, and rectum of normal volunteers. Intestinal leukocytes were isolated, stained with a panel of 37 antibodies, and mass cytometry data acquired. Results Site-specific patterns of leukocyte localisation were observed. The proximal colon featured increased CD8+ T cells [particularly resident memory], monocytes, and CD19+ B cells. Conversely, the distal colon and rectum tissues exhibited enrichment for CD4+ T cells and antibody-secreting cells. The transverse colon displayed increased abundance of both γδ T cells and NK cells. Subsets of leukocyte lineages also displayed gradients of expression along the colon length. Conclusions Our results show an inherent regional immune cell variation within colonic segments, indicating that regional mucosal signatures must be considered when assessing disease stages or the prospective effects of trial drugs on leukocyte subsets. Precise protocols for intestinal sampling must be implemented to allow for the proper interpretation of potential differences observed within leukocyte lineages present in the colonic lamina propria.

Background Evidence suggests that early treatment (Tx) with biologic agents in Crohn’s disease improves long-term clinical outcomes. However, there is less evidence in ulcerative colitis (UC), and data comparing early Tx with first-line biologic vedolizumab (VDZ) to anti-tumour necrosis factor (anti-TNF) in real-world settings is needed. This study compared the clinical effectiveness and safety of UC patients who initiated VDZ or an anti-TNF as a first-line biologic within 2 years following diagnosis. Methods This was a real-world, multi-country, retrospective chart review study in Canada, Greece and the United States where biologic-naïve UC patients (≥18 years old) were treated with VDZ or an anti-TNF (adalimumab, infliximab, golimumab) agent within 2 years following diagnosis (initiated Tx May 2014–March 2018). Clinical effectiveness and safety data were collected from Tx initiation to earliest of chart abstraction date, death, or 6 months post-Tx discontinuation (Canada only). Tx persistence was defined as the duration of time from treatment initiation to discontinuation. Analyses of cumulative rates of Tx persistence, clinical response, clinical remission and mucosal healing over 24 months were estimated using Kaplan–Meier analyses. Clinical response, remission and mucosal healing were assessed using pre-defined hierarchical algorithms of standard disease measures reported in the medical records. Analyses of incidence rates (per 100 person-years [PYs]) of disease exacerbations, disease-related surgeries, serious adverse events (SAEs) and serious infections (SIs) were performed. Adjusted analyses used inverse probability weighting to balance cohorts. Results This analysis included 176 UC patients (VDZ: 86; anti-TNF: 90) from 37 sites. Mean (SD) age at index date: VDZ, 41.4 (18.9); anti-TNF, 36.8 (15.6) years (p = 0.20) and the proportion male: VDZ, 58.1%; anti-TNF, 56.7% (p = 0.84). At 12 months, 72.9% and 58.1% continued VDZ and anti-TNF respectively (p = 0.03) (Figure 1A). Though there were no differences in clinical response, clinical remission or mucosal healing between VDZ and anti-TNF groups; VDZ patients were significantly less likely to experience disease exacerbations (HR = 0.47 [95% CI: 0.32–0.69]) and SAEs (HR = 0.37 [95% CI: 0.19–0.72]) (Figure 2). Adjusted outcomes (Figures 1C and D, and 2B) were similar to unadjusted outcomes. Conclusion EVOLVE is one of the first studies that compared early VDZ Tx to early anti-TNF Tx in biologic-naïve UC patients. Results showed VDZ was associated with higher persistence, lower likelihood of experiencing disease exacerbations and a more favourable safety profile. Thus, in early UC, Tx with VDZ may improve long-term clinical outcomes. Sample size limitations warrant further study.

Background Pivotal trials have shown that ustekinumab (UST) is effective in ulcerative colitis (UC). However, the population included in these trials do not always represent the cohort of patients treated in the “real world”. In this study, we aimed to describe the effectiveness and safety of UST in a clinical cohort of patients with UC Methods We performed a multi-center cohort study and included patients with active UC starting UST. Variables collected included demographics, previous and current UC medications, disease activity (measured using partial and endoscopic Mayo score [PMS and EMS]) at 8 weeks, 6 months and end of follow-up. We also abstracted UST drug level and anti-UST antibodies (AUA), albumin and C-reactive protein levels. Primary outcomes were clinical response at week 8 defined as a reduction of 3 points in the PMS or PMS Results Ninety-five patients were included with a median age of 42 years (IQR:32-57) and 53 (56%) were female. Median follow-up was 5 months (IQR:2.2-7.4). Only 4 (4.3%) were naïve to biologics or tofacitinib and 62 (66%) had previous exposure to at least 2 other biologics. No variables were found to be associated with response at week 8 (Figure 2). Those patients who responded at week 8 had higher median albumin levels vs those who did not (median of 4.4 [IQR: 4.1-4.6] vs 4.1 g/dL [IQR:3.8-4.3]; p=0.02). There were no differences in baseline CRP levels (1mg/dL [IQR:0.6-2.8] vs 0.6 mg/dL [0.3-1.5]; p=0.06). Among the 33 patients who had follow-up endoscopic assessment, 7 (21.2%) had achieved endoscopic remission and 4 (12%) achieved histologic remission. Median UST level was 4.1 mcg/ml (IQR:2.5-5.1) and no patients had detectable AUA. Five patients underwent colectomy (5.3%). Only 6 patients (6.6%) presented with an AE (all minor that included, rash, headaches, arthralgias and infection). Conclusion In a population enriched with refractory UC, UST was well tolerated and induce response and remission in a significant number of patients. The rate of response was lower in obese patients and those with extensive colitis but was not associated with previous exposure to biologics and/or tofacitinib. Larger studies with a longer follow-up are warranted. Figure 1: Rates of clinical response and remission in patients with UC receiving ustekinumab Figure 2: Association between several baseline characteristics and response to ustekinumab in UC

Background Patients with inflammatory bowel diseases (IBD) have lower bone mineral density (BMD). However, BMD does not reflect bone micro-structure/geometry, nor indicates the intrinsic properties of bone tissue. The trabecular bone score (TBS) delivers an indirect measurement of bone microarchitecture and predicts fracture risk independent of bone density. The aim of this study was to assess if patients with IBD present with lower TBS vs a healthy control (HC) population and to identify variables associated with lower TBS. Methods This prospective cohort study included patients with active Crohn’s disease (CD) or ulcerative colitis (UC) and a matched HC group. Patients with ostomies, short gut or known endocrine co-morbidities associated with low BMD, patients with osteoporosis on pharmacologic therapy were excluded. L1-L4 TBS and BMD parameters were determined by dual-energy X-ray absorptiometry (DXA) using a GE Lunar iDXA scan and TBS iNsight™ and GE enCORE™. Other collected variables included demographics, disease phenotype, laboratories (25-OH vitamin D [25OHD] and parathyroid hormone levels [PTH]), disease activity (c-reactive protein [CRP], simple endoscopic score [SES-CD] in CD, and endoscopic Mayo score [EMS] in UC). IBD severity was stratified based on endoscopy: mild (EMS=1 in UC or SES-CD=3–6), moderate (EMS=2 or SES-CD=7–15) and severe (EMS=3 or SES-CD>15). The primary outcome was the L1-L4 TBS. Secondary outcomes were left total and neck femoral BMD and the L1-L4 region BMD. Results A total of 141 patients were included (115 IBD and 26 HC). Patients with IBD had significantly lower TBS, femoral and L1-L4 BMD and Z-Scores when compared to controls (Figure 1). Endoscopic disease activity was not associated with TBS (Figure 2) or total/neck femur and L1-L4 BMD and Z-scores (p>0.05 for all). When stratifying levels by 25OHD quartiles, patients with 25OHD ≥28 ng/mL (the highest 50th percentile of the study population) had significantly higher TBS Z-scores when compared to those with 25OHD ≤28 ng/mL (0.3 [-0.2 – 1.1] vs -0.1 [-1.1 – 0.5], p=0.002). No associations were seen between TBS Z-scores and use of steroids, gender, type of IBD (UC vs CD), smoking status or when comparing females 50 years or older vs the rest of the group (p>0.05 for all). Moreover, there were no differences in TBS between patients who did or did not engage in resistance exercises (p=0.22) and/or regular aerobic exercises (RAPA ≥6) (p=0.84). Conclusion Patients with IBD present with lower TBS Z-scores when compared to HC and there is no correlation with disease activity. The only variable associated with lower TBS was a 25OHD FIGURE 1 FIGURE 2

Background Previously, we identified subsets of biologic-naïve patients (pts) with Crohn’s disease (CD) from the EVOLVE study who had higher rates of clinical remission (CR) [Fig 1] when initiating vedolizumab (VDZ) vs anti-TNFα treatment, using prediction models based on multiple baseline characteristics.1,2 To aid use in practice, we investigated whether these subsets could be identified using simpler rules based on fewer baseline characteristics. Methods Using data from EVOLVE, we used recursive partitioning and regression tree (RPART) classification to predict membership in the previously identified higher CR subsets for VDZ. The RPART algorithm repeatedly splits data, based on baseline predictors (demographics, prior treatments, clinical characteristics at treatment initiation, Charlson comorbidity index, prior extraintestinal manifestations [EIMs], and prior healthcare resource use). At each split, the predictor and its value as chosen by the algorithm to split the data were those that maximized the number of pts classified correctly. Simplified rules were developed from the resulting RPART decision trees. Analyses of the treatment effect of VDZ vs anti-TNFα were conducted in the subsets of pts identified by each rule. Results Pts with data on CR and candidate predictors were included (VDZ [n=195]; anti-TNFα [n=245]). Three simplified rules (A, B, & C) were identified (Table 1). Pt characteristics included in the rules (exacerbation ongoing at treatment initiation, no emergency department/emergency room (ED/ER) visits prior to treatment initiation, no fistulae at most recent assessment prior to treatment initiation, pre-initiation disease behaviour) were among the main predictors of CR in VDZ pts identified previously. Pts identified by Rule A comprised 32% of the EVOLVE population, and were those who 1) had an exacerbation ongoing at index, 2) did not have ED/ER visits prior to initiation and 3) had pre-initiation disease behaviour classified as other than stricturing with/without perianal disease. Among these pts, median time to CR for VDZ and anti-TNFα pts were 6.7 and 18.1 months, respectively (unadjusted log-rank p Conclusion Simple rules were developed to identify biologic-naïve, CD pts in whom VDZ initiation appeared to have a larger effect on CR relative to anti-TNFα initiation. Validation of these rules in other data sources is important to confirm these findings; if validated, these simplified rules can inform targeting of treatment and optimization of outcomes for pts with CD treated with VDZ.

Background Blocking of lymphocyte trafficking to bile ducts is a potential mechanism to alter the disease course of patients with primary sclerosing cholangitis (PSC). Aim To describe the effect of the α4 β7 integrin antibody, vedolizumab, on liver biochemistry and disease activity in patients with PSC and inflammatory bowel disease (IBD). Methods This is a retrospective multi-centre study of adult patients with a diagnosis of both IBD and PSC. The primary outcome was change in serum alkaline phosphatase level at weeks 14 and 30. Secondary outcomes included changes in other liver biochemistries and in clinical outcomes for the bowel disease. A safety analysis for adverse events was performed. Results Thirty-four patients (16 Crohn's disease, 18 ulcerative colitis) were included. Nine (26%) had a history of liver transplant. Median follow-up on vedolizumab was 9 months (IQR: 7-16). There was no overall change in serum alkaline phosphatase level with vedolizumab therapy (median 268 [IQR: 105-551] IU/L at baseline versus 249 [IQR: 183-634] IU/L, P = 0.99 at week 30). No significant changes in other liver biochemistries or the Mayo PSC Risk Score were demonstrated at week 30. Clinical remission was achieved at week 30 in 55% of Crohn's disease and 29% of ulcerative colitis patients. Seven (21%) patients ceased vedolizumab; six patients stopped therapy due to persistent IBD activity and one for worsening of liver biochemistries. Conclusion Vedolizumab treatment in patients with PSC and IBD did not improve liver biochemistry but was associated with improvement in bowel disease and a favourable safety profile.

SummaryBackground Infliximab has been found to be efficacious in the treatment of fistulas in the setting of Crohn's disease, even though some patients do not benefit from therapy. Aim To assess the correlation between perianal fistula healing and trough levels of infliximab. Methods In this cross-sectional study, we identified patients with Crohn's disease who had perianal fistulas and were treated with infliximab for at least 24 weeks. We excluded patients who underwent a faecal diversion procedure or proctectomy. Predictive variables included demographics, disease phenotype, disease activity, infliximab levels, anti-infliximab antibodies. The primary outcome was fistula healing defined as the absence of drainage. The secondary outcome was complete fistula closure and mucosal healing. Results 117 patients were included. Patients with fistula healing had significantly higher median serum infliximab levels when compared to those with active fistulas [15.8 vs. 4.4 μg/mL, respectively (P

Background Serum amyloid A (SAA) is an acute-phase protein, but its role as a biomarker of disease activity in Crohn's disease is unclear. The aim of the study was to assess the correlation between SAA, inflammatory cytokines, and mucosal inflammation in patients with Crohn's disease and to investigate whether this marker might be useful in patients who do not have elevated C-reactive protein (CRP) levels despite having active disease. Methods Cross-sectional study including patients with Crohn's disease who underwent colonoscopies for assessment of disease activity. Predictive variables were recorded at the time of the procedure and included demographics, phenotype of disease, medications, and collection of serum for cytokine analysis (SAA, CRP, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and interleukins 8, 1β, and 6). The primary outcome was the presence of mucosal healing (MH) (absence of macroscopic and microscopic inflammation). Results Ninety-four patients were included. Sixty-eight (72.3%) had not achieved MH. SAA, CRP, intercellular adhesion molecule, and interleukin-6 levels were significantly lower in those patients with MH. SAA was the only test that performed well in the sensitivity/specificity analysis (receiver operating characteristic: 0.81, P = 0.046). A high SAA was able to identify 70% of the patients with a normal CRP but active inflammation. Conclusions High circulating SAA levels can correlate with lack of MH and may be used as a surrogate marker for disease activity, even in those patients in whom CRP levels do not correlate with disease activity.