bluuebunny/crossref_metadata_2025 huggingface dataset:
OP29 Peripheral blood DNA methylation biomarkers accurately predict clinical- and endoscopic response to vedolizumab in a real-life cohort of Crohn’s Disease patients
Authors: Joustra V , Hageman I , Li Yim A , Levin E , Satsangi J , Adams A , De Jonge W , Henneman P , D’Haens G
Published: January 2022

Background

Despite the proven efficacy of vedolizumab (VDZ), only 29% and 36% of the Crohn’s disease (CD) patients present corticosteroid-free clinical- and endoscopic remission, respectively. Therefore, predictive biomarkers for treatment success would be of extreme value. Previous studies have identified aberrant DNA methylation associated with CD-specific phenotypes, suggesting that the methylome may be useful for classification and prediction of VDZ treatment response. Here, we sought to identify such DNA methylation biomarkers that can predict clinical- and endoscopic response to VDZ in CD patients.

Methods

We prospectively recruited adult CD patients that initiated VDZ treatment following a baseline colonoscopy in two cohorts: a discovery and validation cohort. Peripheral blood DNA methylation profiles were measured prior to treatment (T1), and after a median of 22 weeks (T2) using the Illumina Infinium HumanMethylation EPIC BeadChip array. Response (R) was defined as the strict combination of endoscopic- (≥50% reduction in SES-CD score) and steroid-free clinical response (≥3 point drop in HBI and HBI ≤4 AND no systemic steroids) and/or biochemical response (≥50% reduction in C-reactive protein (CRP) and fecal calprotectin or a CRP ≤5 g/mL and fecal calprotectin ≤250 µg/g). Twenty-one patients had deep remission (DR), defined as a combined endoscopic- (SES-CD≤2) and steroid-free clinical remission (HBI ≤4, no systemic steroids). Biomarker identification and classification analyses were performed using stability selection gradient boosting.

Results

In total, 64 CD patients were enrolled (discovery 16R/14NR and validation 20R/14NR). Both cohorts were comparable for age, sex and smoking status. Forty-nine (77%) patients had previously failed an anti-TNF agent. All patients had measurable serum vedolizumab concentration at T2 (median 14.5 (6.9 – 21.3) µg/mL). Through classification analysis at T1, we were capable of discriminating R from NR with high predictive performance (25 CpGs, AUC 0.88, F1-score of 0.84, PPV of 0.91 and NPV of 0.85). When analysing the methylome of patients in deep remission, we identified 23 CpGs with high predictive performance upon independent validation (F1-score 0.80, PPV of 0.71 and NPV of 0.86). Investigating the CpGs of interest implicated genes involved in endothelial cell-cell adhesion and integrin dependent T-cell homing, corroborating VDZ’s mode of action.

Conclusion

We demonstrate two novel 25- and 23-feature panels of epigenetic biomarkers that accurately predict response or deep remission to vedolizumab respectively. Similar analyses on infliximab, adalimumab and ustekinumab are currently ongoing as part of the EPIC-CD study.
OP33 Effect of upadacitinib (UPA) treatment on extraintestinal manifestations (EIMs) in patients with moderate-to-severe Ulcerative Colitis (UC): Results from the UPA Phase 3 programme
Authors: Colombel J F , Cao Q , Ghosh S , Reinisch W , Zhou W , Ilo D , Shu L , Yao X , Rubin D T
Published: January 2022

Background

EIMs are common in patients with UC and are associated with impaired quality of life. This analysis evaluated the impact of treatment with the selective Janus kinase 1 inhibitor UPA on EIMs in patients with moderate-to-severe UC.

Methods

Data were included from two induction studies (U-ACHIEVE Induction [NCT02819635] and U-ACCOMPLISH [NCT03653026]) and a maintenance study (U-ACHIEVE Maintenance). Patients with moderate-to-severe UC were randomised 2:1 to 8 weeks’ induction treatment with UPA 45 mg once daily (QD) or placebo. Patients with a clinical response to induction were re-randomised (1:1:1) to 52 weeks’ maintenance treatment with UPA 15 mg or 30 mg QD, or placebo. The presence of EIMs (peripheral arthropathy, axial arthropathy, episcleritis, uveitis, iritis, erythema nodosum, pyoderma gangrenosum, Sweet’s syndrome, oral aphthous ulcers, primary sclerosing cholangitis, autoimmune hepatitis, venous thromboembolism, chronic obstructive pulmonary disease, bronchiectasis, nephrolithiasis and anaemia) was captured in the EIM form at the start of induction (baseline) and at every visit up to Week 52. The induction study results were pooled for analysis.

Results

At baseline, 25.0% and 26.5% of patients in the UPA 45 mg QD and placebo induction groups had ≥1 EIM, while 24.3%, 26.6% and 24.8% of patients randomised to maintenance treatment with UPA 15 mg QD, UPA 30 mg QD or placebo, respectively, had ≥1 EIM (Table 1). The most common EIMs at baseline were anaemia, peripheral arthropathy and axial arthropathy; all other EIMs were reported in <2% of patients (Table 1). The proportion of patients reporting resolution of any EIM, arthropathy (peripheral and axial) and anaemia at Week 8 was numerically greater with UPA 45 mg QD than placebo in the induction studies (Figure 1A). Resolution at Week 52 of any EIM in patients with ≥1 EIM at baseline was significantly increased with UPA 30 mg QD (p<0.001), and numerically greater with UPA 15 mg QD, versus placebo (Figure 1B). In patients with arthropathy (peripheral or axial) at baseline, the proportion achieving resolution of arthropathy (peripheral and axial) at Week 52 was significantly increased with UPA 30 mg QD (p=0.010), and numerically higher with UPA 15 mg QD, versus placebo (Figure 1B). The same was true of anaemia resolution in patients with anaemia at baseline (p=0.019 for UPA 30 mg QD versus placebo; Figure 1B).

Conclusion

UPA treatment is effective in resolving EIMs in patients with UC. EIM symptom resolution was improved versus placebo following induction treatment with UPA 45 mg and after maintenance treatment with UPA 15 or 30 mg, with the 30 mg dose providing statistically significant improvements versus placebo.
DOP05 Morbid obesity, a new susceptibility factor for developing Inflammatory Bowel Disease. Results of a population-based study
Authors: Canete Pizarro F C , Vela E , Calafat M , Clèries M , Mañosa M , Domènech E
Published: January 2022

Background

Some genetic polymorphisms (present in less than 30% of patients) and environmental factors, such as tobacco exposure, have been identified to increase the susceptibility for developing inflammatory bowel disease (IBD), but it is suspected that there may be other still unknown environmental or epidemiological factors. In this sense, some studies suggested an increased incidence of IBD in individuals undergoing bariatric surgery (BS) for morbid obesity (MO). We aimed to assess whether BS or MO are associated with an increased risk of developing IBD.

Methods

All individuals resident in Catalonia (7.7 million inhabitants in 2021) with a diagnosis of obesity or MO within the period 2005–2020 were identified from the Catalan Public Health System Database. Children under the age of 18 and those diagnosed with IBD prior to the diagnosis of obesity or MO were excluded. Individuals BS and those with a new diagnosis of IBD were identified, and the likelihood of developing IBD was analyzed by Kaplan-Meier survival analysis. A Cox regression multivariable analysis was performed to assess independent risk factors for the development of IBD, Crohn’s disease (CD) and ulcerative colitis (UC).

Results

Three cohorts were identified: 94,473 individuals with MO; 1,009,256 with obesity; and 14,698 who underwent BS during the study period. A total of 4,277 new diagnoses of IBD were identified, of which 78 among individuals who underwent BS prior to IBD diagnosis (0.84 cases per 1000 person-years), 409 among individuals with OM but without BS (0.90 cases per 1000 person-years), and 3,790 in obese individuals (0.60 cases per 1000 person-years). The likelihood of developing IBD was significantly higher in patients with MO as compared with obese patients (HR 1.46; 95%CI 1.32–1.62). These differences were maintained when the likelihood of developing CD or UC were assessed separately. In the multivariable logistic regression analysis, MO (HR 1,68; CI95% 1.41–1.99), female gender (HR 1.17; 95%CI 1.05–1.31) and active smoking (HR 1.62; 95%CI 1.43–1.84) were associated with an increased risk of CD. In UC, MO (HR 1,36; 95%CI 1.19–1.55) and BS (HR 2.62; 95%CI 1.34–2.11) were independent risk factors, whereas female gender (HR 0.86; 95%CI 0.79–0.93) was an independent protective factor.

Conclusion

MO is an independent risk factor for the development of IBD, for both CD and UC, whereas BS seems to increase the risk only for UC.
DOP06 Antibiotics as a risk factor for older onset IBD: A population-based cohort study
Authors: Faye A , Allin K , Iversen A , Agrawal M , Faith J , Colombel J F , Jess T
Published: January 2022

Background

Older adults are the fastest growing subpopulation of patients with IBD, with approximately 15% diagnosed after 60 years-of-age. Moreover, environmental exposures are thought to play a significant role in the development of older-onset IBD, given the lower genetic risk. Antibiotics have been associated with development of IBD in earlier generations, but the impact on IBD risk in older adults is uncertain. In this population-based cohort study, we assessed the impact of cumulative antibiotic use, the timing of antibiotic use, and the association between specific antibiotic classes and the development of older-onset IBD.

Methods

Using Denmark nationwide registries, a cohort of residents ≥60 years-of-age was established between 2000–2018. Information on exposure to antibiotics was retrieved from the Danish National Prescription Register. The number of courses of antibiotics (overall and specific classes) was considered a time-varying variable. The outcome, IBD, was identified based on ICD-10 codes in the Danish National Patient Register. Incidence rate ratios (IRRs) for IBD according to antibiotic use 1 to 5 years prior to IBD diagnosis were calculated by log-linear Poisson regression, and adjusted for age, sex, and calendar period.

Results

There were a total of 2,327,796 individuals aged 60 to 90 years included in the cohort, resulting in 22,670,484 person-years of follow-up. There were 10,773 new cases of ulcerative colitis (UC) and 3,825 new cases of Crohn’s disease (CD). Overall, any antibiotic use was associated with an IRR for the development of IBD (IRR 1.64, 95%CI 1.58–1.71), with a positive dose response observed (1 course of antibiotics IRR 1.27 95%CI 1.21–1.33; 2 courses IRR 1.54 95%CI 1.46–1.63; 3 courses IRR 1.66 95%CI 1.67–1.77; 4 courses IRR 1.96 95%CI 1.83–2.09; 5+ courses IRR 2.35, 95%CI 2.24–2.47). A higher IRR was noted between the timeframe of 1–2 years before diagnosis (IRR 1.87, 95%CI 1.79–1.94) as compared to 2–5 years before diagnosis (IRR 1.42, 95%CI 1.36–1.48). Additionally, all antibiotic classes were associated with the development of IBD, including those not used to treat gastrointestinal infections. Antibiotics with the highest IRR were fluoroquinolones (IRR 2.27, 95%CI 2.08–2.48), nitroimidazoles (IRR 2.21, 95%CI 1.95–2.50), and macrolides (IRR 1.74, 95%CI 1.64–1.84). All results remained statistically significant when stratifying by UC and CD, with effect estimates slightly higher for CD as compared to UC.

Conclusion

Use of antibiotics, regardless of class studied, was associated with an increased risk of older-onset IBD. This risk was highest one to two years prior to diagnosis, but persisted even prior to that, suggesting a link between overall antibiotic use and development of older-onset IBD.
DOP17 Evaluating segmental healing with the modified Mayo endoscopic score (MMES) has a clear additional value in predicting long-term outcome in patients with Ulcerative Colitis: Results from a prospective cohort study
Authors: Lenfant M , Verstockt B , Sabino J , Vermeire S , Ferrante M
Published: January 2022

Background

Most endoscopic scoring systems (including the Mayo endoscopic subscore, MES) do not consider the extent of inflammation and can therefore not pick up segmental endoscopic improvement. The modified Mayo endoscopic score (MMES) was developed to overcome this limitation. We examined the predictive value of the MMES in addition to the MES on long-term clinical outcome in ulcerative colitis (UC).

Methods

Between 2014 and 2017, patients initiating biologic therapy for active UC (baseline MES ≥2) were recruited. Patients without assessment of the upper margin of inflammation or with a clinical follow-up <12 months were excluded. We conducted a clinical and endoscopic assessment at baseline and week 8 (adalimumab, ADM) or 14 (golimumab, GOL; infliximab, IFX; vedolizumab, VDZ). Clinical response was defined as a decrease in the adapted Mayo score (excluding physician global assessment) with ≥2 points and ≥30%, plus a decrease in rectal bleeding score ≥1 or an absolute rectal bleeding score ≤1. We classified patients by evolution of endoscopic activity at week 8/14 in group A (endoscopic healing, MES ≤1), group B (segmental healing, MES >1 but decrease in MMES ≥30%) and group C (MES >1 and no drop in MMES ≥30%). Clinical relapse-free, discontinuation-free and colectomy-free survival was estimated by Kaplan-Meier analysis with log-rank test.

Results

A total of 150 UC patients were included (52% male, median age 42 years, median disease duration 7 years) with a median (IQR) follow-up of 61 (48–68) months. An anti-TNF was initiated in 74 (35 IFX, 23 ADM, 16 GOL), and VDZ in 76 patients. A significant reduction in MES and MMES was observed at week 8/14 (cf. table). In group A 67/69 (97%) patients achieved clinical response compared to 15/27 (55%) in group B and 11/54 (20%) in group C. During follow-up 60/93 (65%) patients maintained clinical response, 83/150 (55%) patients discontinued treatment due to primary non-response or loss of response and 33/150 (22%) patients underwent colectomy. The ΔMMES demonstrated to be of additional predictive value: there was a significant difference between groups B and C regarding clinical relapse, drug persistence and need for colectomy (cf. figure).

Conclusion

Although MES ≤1 remains the best predictor of long-term outcome, the MMES - identifying a subgroup with a segmental endoscopic response - demonstrated a clear additional value predicting long-term outcome in UC. These promising results merit inclusion of the MMES in future clinical trials.

Table

The MMES is calculated by multiplying the Mayo endoscopic subscore for the different colon segments with the maximal extent of inflammation (in decimeters) divided by the number of segments with active inflammation (Lobatón T, et al. JCC 2015; 9:846–52.)

Figure
DOP31 Efficacy and safety of bone marrow-derived mesenchymal stem cells in refractory perianal fistulae in Crohn’s Disease: Results from a prospective monocentric study
Authors: Reenaers Dr C , Vieujean S , Coimbra C , Gillard R , Meunier P , Boutaffala L , Louis E
Published: January 2022

Background

Anoperianal lesions affect up to 30% of patients with Crohn’s disease (CD). Long-term fistula healing is challenging with conventional biotherapies. Although recent studies demonstrated the efficacy of local injections of adipose tissue-derived stem cells with 50 % of fistulae closure without abscess at one year, this treatment is not available in routine.

The primary aim of this study was to evaluate the safety and the feasibility of the injection of bone marrow-derived mesenchymal stem cells isolated and prepared in a local university laboratory of cell therapy for perianal fistulizing CD. The second aim was to evaluate the efficacy of this treatment and his impact on the quality of life of the patients.

Methods

A prospective observational study was performed in the CHU of Liège from October 2019 till October 2021. All CD patients with perianal fistula and seton placement for at least 6 months were eligible. PRO, clinical examination, CRP, fecal calprotectine, CDAI, Short health scale (SHS) and MRI were performed at weeks 0, 12 and 48. PDAI was calculated at inclusion and at Week 48. Efficacy was defined as closure of all treated external openings at clinical examination without abscess at MRI.

Results

Sixteen patients with a median age of 49 years old and a median duration of perianal CD of 8 years were included. Eleven (69%) patients were on anti-TNF. CDAI and PDAI at inclusion were 97,5 ± 48,8 et 5 ± 4,4 respectively. Four (25%) patients reported adverse events the week after the injection (local pain 3/16, mild bleeding 1/16), all of them quickly resolutive. Ten (63%) and 8 (50%) patients had a closure of all the external opening at week 12 and 48 respectively. Five out of 6 patients with 2 external openings had at least 1 opening closed at Week 48. One abscess was observed during the follow-up. The median PDAI was numerically lower at the end of the study (3 versus 5 at the inclusion). The quality of life improved with a regression of the SHS from 10 to 7.5 at the end of the follow-up. At MRI, MAGNIFI-CD score and Van Assche index were similar for each patients at the inclusion and at the end of the study.

Conclusion

Injection of locally prepared bone marrow-derived mesenchymal stem cells seems safe and effective in refractory perianal fistulae in Crohn’s disease with 50% of closure at 1 year. The treatment is associated with an improvement of the perianal activity scores and the quality of life scores but not with the MRI scores.
DOP36 Efficacy and safety of vedolizumab in patients with chronic active pouchitis refractory to anti-TNF therapy: Results of a retrospective multicenter study
Authors: Sallette M , Bouhnik Y , Nachury M , Bellanger C , Laharie D , Amiot A , Peyrin-Biroulet L , Roblin X , Altwegg R , Buisson A , Reenaers C , Bouguen G , Vuitton L , Bourreille A , Gilletta C , Serrero M , Hébuterne X , Filippi J
Published: January 2022

Background

Total coloproctectomy with ileoanal anastomosis (IAA) is the procedure of choice for patients with treatment-resistant ulcerative colitis (UC). It is most often curative, but can be complicated by pouchitis in 30% of cases, which becomes chronic in 10% of patients. Its treatment is not codified after failure of conventional treatments and a first line of anti-TNF. The objective of our study was to determine the efficacy and safety of vedolizumab (VDZ) in patients with anti-TNF refractory chronic pouchitis.

Methods

This was a retrospective, multicenter study conducted in 17 hospital centers. Patients were selected from July 2019 to January 2021. All patients had chronic pouchitis refractory to a first line of anti-TNF. We evaluated clinical, endoscopic and biological characteristics at initiation of VDZ therapy, at week (W) 10 as well as at W52. The primary objective of the study was to assess clinical response (improvement ≥ 50% in stool frequency and rectal bleeding) at W52. Secondary objectives were to assess clinical response and remission (absence of symptom) at W10, endoscopic response (improvement ≥ 50% of endoscopic lesions) and remission (mucosal healing) at W10 and 52. Adverse events were also collected.

Results

Forty-nine patients were included in the study (23 women, 26 men, mean age 48 years). Thirty-one patients (63%) had received only one line of biologic.

Forty-four (90%) patients had endoscopic evaluation before initiation of VDZ, and 25 (51%) patients at W10 and 52. CRP was assessed in all patients at baseline, 43 (88%) patients at W10, and 33 (67%) patients at W52.At W10, 17 (34%) patients were clinically responders without corticosteroids, of whom 3 (6%) were in remission; among the 25 patients evaluated, endoscopic response was obtanine in 5 (20%) patients and endoscopic remission in 11 (44%) patients. At W52, 22 (44%) patients were clinically responders, 12 (24%) of whom were in remission; endoscopic response was obtained in 15 (60%) patients and endoscopic remission in 5 (20%) patients.

Although there was a trend for CRP to decrease during follow-up (17.3 mg/L at inclusion vs. 7.9 mg/L at W52) in the responder group, there was no significant difference between this subgroup and the non-responder patients at W52. Eight patients (16%) had adverse events, leading to discontinuation of treatment in three of them.

Optimization of VDZ at W10 was the only factor predicting nonresponse at W52: 40% in the non-responder group vs 8% in the responder group (p=0.05).

At 1 year, 69% of patients were continuing treatment.

Conclusion

This retrospective multicenter study shows that VDZ is a therapeutic option that may be considered in the treatment of chronic pouchitis refractory to anti-TNF.
DOP41 Efficacy and safety of extended induction treatment with upadacitinib 45 mg once daily followed by maintenance upadacitinib 15 or 30 mg once daily in patients with moderately to severely active Ulcerative Colitis
Authors: Vermeire S , Danese S , Zhou W , Klaff J , Ilo D , Yao X , Levy G , Higgins P D R , Loftus E V , Panaccione R
Published: January 2022

Background

Upadacitinib (UPA), a selective and reversible Janus kinase inhibitor, has been shown to be safe and effective when administered at a dose of 45 mg once daily (QD) as 8-week induction therapy in moderate-to-severe Ulcerative Colitis (UC). This analysis evaluated outcomes following extended induction (45 mg QD for 16 weeks) followed by maintenance (15 or 30 mg QD) treatment with UPA in patients with UC who did not achieve a clinical response after 8 weeks’ induction.

Methods

Patients with moderate-to-severe UC who failed to achieve a clinical response (Adapted Mayo score decrease of ≥2 points and ≥30% from baseline, plus ≥1-point decrease in rectal bleeding score [RBS] or absolute RBS ≤1) to 8 weeks’ induction treatment with UPA 45 mg QD in the U-ACHIEVE Induction (NCT02819635) or U-ACCOMPLISH (NCT03653026) studies, continued to receive UPA 45 mg QD in an 8-week open-label extension. Responders at the end of the open-label extension entered the U-ACHIEVE Maintenance study and were randomised 1:1 to UPA 15 mg or 30 mg QD for 52 weeks. The efficacy endpoints were evaluated at Week 16 for the induction studies and at Week 52 for the maintenance study.

Results

In total, 125 patients who failed to achieve a clinical response after 8 weeks’ induction treatment received open-label UPA 45 mg for a further 8 weeks. Of these patients, 48.3% achieved a clinical response at Week 16 and were re-randomised to UPA 15 or 30 mg in U-ACHIEVE Maintenance. Among 16-week responders who entered the maintenance study, clinical remission, maintenance of clinical response, and endoscopic improvement, respectively, at Week 52 were achieved in 33.3% versus 19.0%, 66.7% versus 35.7%, and 37.5% versus 23.8% of those who received UPA 30 versus UPA 15 mg QD as maintenance treatment (Table 1). Adverse events of special interest were reported infrequently in the two maintenance treatment groups (Table 2).

Conclusion

In this analysis, prolonged induction treatment for a total of 16 weeks was beneficial in almost half of UC patients who failed to achieve a clinical response after 8 weeks’ induction with UPA 45 mg. The benefit of maintenance therapy in these delayed responders was further demonstrated, with UPA 30 mg providing greater benefit than UPA 15 mg QD.
DOP43 Rapidity of ozanimod-induced symptomatic response and remission in patients with moderately to severely active Ulcerative Colitis: Results from the induction period of True North
Authors: Siegmund B , Axelrad J , Pondel M , Osterman M T , Ahmad H A , Memaj A , Regueiro M , Armuzzi A , Afzali A
Published: January 2022

Background

Ozanimod, a sphingosine 1-phosphate (S1P) receptor modulator selectively targeting S1P1 and S1P5, is approved in the US for the treatment of moderately to severely active ulcerative colitis (UC). In the pivotal phase 3 True North randomised controlled trial in moderate-to-severe UC, significantly more patients (pts) achieved clinical response and remission with ozanimod vs placebo (PBO) at week (wk) 10 of the induction period. Here, we report the rapidity of ozanimod-induced symptomatic response and remission in pts from True North (NCT02435992).

Methods

In True North, pts were randomised to once-daily ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or PBO (Cohort 1) or received open-label ozanimod (Cohort 2) during induction. This analysis evaluated symptomatic response (defined as ≥1 point and ≥30% decrease from baseline in adapted partial Mayo score and ≥1 point decrease from baseline in rectal bleeding score [RBS] or absolute RBS ≤1) and symptomatic remission (defined as RBS of 0 and stool frequency score [SFS] ≤1 point and ≥1 point decrease from baseline at each study visit from wk 2 through 10.

Results

During induction, 645 pts were randomised to ozanimod (n=429) or PBO (n=216) in Cohort 1, and 367 pts received open-label ozanimod in Cohort 2. Baseline demographics and clinical characteristics were well balanced across groups. Differences in symptomatic response were observed between ozanimod and PBO recipients in Cohort 1 as early as 2 wk after ozanimod initiation (1 wk post-titration) for the overall population (36.1% vs 26.4%; difference: 9.6% [95% CI, 2.1–17.0]; Figure 1) and tumour necrosis factor inhibitor (TNFi)-naïve pts (38.5%, n=301 vs 29.1%, n=151; difference: 9.4% [95% CI, 0.2–18.5]), and as early as 4 wk for TNFi-exposed pts (42.2%, n=128 vs 27.7%, n=65; difference: 15.8% [95% CI, 1.8–29.8]). Differences in symptomatic remission were observed between ozanimod and PBO recipients in Cohort 1 as early as 5 wk after ozanimod initiation (4 wk post-titration) for the overall population (26.3% vs 16.7%; difference: 8.6% [95% CI, 1.8–15.4] Figure 2), as early as 4 wk for TNFi-naïve pts (27.2% vs 17.9%; difference: 9.4% [95% CI, 1.5–17.4]), and as early as 8 wk for TNFi-exposed pts (22.7% vs 12.3%; difference: 11.7% [95% CI, 1.3–22.1]). Rates of symptomatic response and remission in pts receiving open-label ozanimod (Cohort 2) were similar to those in pts receiving randomised ozanimod (Cohort 1).

Conclusion

In the overall population, ozanimod was associated with higher rates of symptomatic response and remission vs PBO as early as 2 and 5 wk, respectively, after treatment initiation. Both clinical endpoints were more rapidly achieved in TNFi-naïve vs TNFi-exposed pts.
DOP45 Long-term cardiac safety of ozanimod in phase 3 clinical program of Ulcerative Colitis and relapsing multiple sclerosis
Authors: Armuzzi A , Cross R K , Lichtenstein G , Calkwood J , Pai A , Pondel M , Ahmad H A , Charles L , Elegbe A , Petersen A , Sheffield J K , Javed A , Hou J , Regueiro M , Wolf D C , Long M
Published: January 2022

Background

Sphingosine-1-phosphate (S1P) receptor modulators may be associated with bradycardia and atrioventricular conduction delays. A previous analysis demonstrated first-dose ozanimod had minimal effects on cardiac function, including in patients (pts) with a known history of cardiovascular disease. This analysis evaluated long-term cardiac safety following continuous ozanimod treatment from the phase 3 ulcerative colitis (UC) True North trial and multiple sclerosis (MS) 12-mo SUNBEAM and 24-mo RADIANCE trials.

Methods

Ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg)–treated pts from True North and pooled SUNBEAM/RADIANCE trials were included. In True North, pts in Cohort 1 received double-blind ozanimod or placebo and pts in Cohort 2 received open-label ozanimod in the induction period; in the maintenance period, pts with clinical response to ozanimod at 10 weeks were rerandomized to double-blind ozanimod or placebo. In True North, ECGs were monitored at screening, day 1, wk-10, and wk-52; heart rate (HR) was monitored at every visit. In the MS trials, ECGs were monitored at screening, baseline, day 15, and end of treatment (EOT); HR was monitored similarly at the beginning, then every 3 mo until EOT. Cardiac-related treatment-emergent AEs (TEAEs) were reported.

Results

In the UC trial, continuous ozanimod treatment was not associated with any clinically significant changes in HR or ECG. The incidence of cardiac-related TEAEs with ozanimod during induction in Cohorts 1 and 2 was low (Table). In maintenance, cardiac-related TEAEs were reported in 1.3% (3/230) of pts in the continuous ozanimod group (Table); incidence was numerically higher in ozanimod pts with (2 of 57 pts [3.5%]) versus without (1 of 173 pts [0.6%]) prior history of cardiovascular disease. Cardiac-related serious AEs (SAEs) were uncommon (angina pectoris, coronary artery stenosis, pericarditis in 1 patient each). In the pooled MS studies, no clinically significant HR or ECG changes were associated with chronic treatment up to mo 24. The incidence of cardiac-related TEAEs was low with ozanimod (Table); incidence was similar among pts with (6 of 171 pts [3.5%]) versus without (24 of 711 pts [3.4%]) prior history of cardiovascular disease. Two of 882 patients experienced cardiac-related SAEs resulting in hospitalization with ozanimod in the MS studies (asymptomatic sinus bradycardia [HR 44 bpm] and symptomatic supraventricular tachycardia).

Conclusion

Ozanimod had a manageable long-term cardiac safety profile with a low incidence of bradycardia and few serious long-term cardiac safety findings in the phase 3 UC and MS ozanimod trials.
DOP47 Identification and characterization of T-cell receptor sequences associated with Crohn’s Disease
Authors: Pesesky M , Carty C L , Singh N , Le Bourhis L , Rosati E , Bokemeyer B , Schreiber S , Görg S , Gittelman R M , Dines J N , Kaplan I M , Zahid H J , Baldo L , Snyder T M , Robins H S , Franke A , Allez M
Published: January 2022

Background

T cells, as part of the adaptive immune system, are a significant driver of inflammation in Crohn’s disease (CD), yet specific T-cell targets are largely unknown. Genetic factors contribute to a small portion of CD risk including several HLA alleles, such as DRB1*07:01 and HLA-DRB1*01:03, associated with CD. The involvement of HLAs suggests that studying specific T cells could lead to new insights into CD development and progression. In this study, we use established immunoSEQ® technology to profile T-cell receptors (TCRs) and identify TCRs associated with CD and CD characteristics.

Methods

We analyzed TCRs from blood of 1,738 CD cases and 4,970 healthy controls. TCRs that were statistically enriched in cases, but not healthy controls (p <0.001), were termed Enhanced Sequences (ES) associated with CD. An independent cohort of 434 CD cases was used for validation. We inferred associations between the ES and 145 common HLA alleles using data from a separate, HLA-typed dataset. We defined ES clusters by correlating TCRs with single amino acid substitutions.

Results

We identified 1,121 CD-associated ES in the exploratory cohort. These were also enriched in CD cases in our validation cohort (Fig 1A). Using intestinal tissue samples from a subset of cases, we found that a median of 14% ES from individual cases were shared between blood and tissue samples (Fig. 1B). ES breadth (ES diversity relative to total TCR diversity) was significantly associated with history of CD-related surgery (Fig 1C, p < 1x10-15), with stricturing or fistulizing phenotypes (Fig 1D, p < 1x10-5 for B1 versus B2 or B3), and with ileal or ileocolonic location (Fig 1E, p < 1x10-7 for L2 versus L1 or L3).

We found that 202 ES formed clusters of similar sequences consisting of 2–23 members (Fig. 2A). We confidently (p < 0.0001) associated 398 ES to a specific HLA allele (Fig 2B), including 134 of the ES assigned to clusters (Fig 2A). Some clusters, including the largest, had no members that could be assigned to an HLA allele, raising the possibility that these ES clusters bind non-canonical HLAs.

Conclusion

Our discovery set of public TCRs associated with CD indicates that the immune system of CD patients responds to a consistent set of antigens. Importantly, CD ES were present in both tissue and blood, demonstrating that evaluating TCRs in blood may be a surrogate of TCRs in tissue. The HLA allele associations of these ES potentially point to new risk factors and disease insights, such as the involvement of DP and DQ alleles. The association of ES frequency with CD characteristics strongly suggested that further examination of these TCRs may impact CD patient care and advance understanding of the pathophysiology of the disease.
DOP55 Long-term outcomes after histologic-endoscopic mucosal healing: Results from the UNIFI study in Ulcerative Colitis
Authors: Leong R , Sands B , Peyrin-Biroulet L , Marano C , Miao Y , Izanec J , Feagan B , Rubin D
Published: January 2022

Background

In the UNIFI study of ustekinumab (UST) in ulcerative colitis (UC), patients who achieved histo-endoscopic mucosal healing (HEMH; ie, both histologic and endoscopic improvement of mucosa) after induction had higher clinical remission and corticosteroid-free clinical remission rates through 1 year than those who achieved either histologic or endoscopic improvement alone.1 Here, we report the effect of achieving HEMH after induction on long-term symptomatic outcomes through 3 years.

Methods

Patients who were in clinical response after 8 wks of IV induction with UST 130mg or ~6mg/kg (wk 8 responders) were randomized to maintenance treatment with SC UST 90mg q12w or q8w on entry into maintenance. Those who were not in clinical response to the initial UST dose at wk8 but achieved response at wk16 after receiving a single SC dose of UST 90mg at wk8 (wk16 responders) entered maintenance receiving SC 90mg q8w. After 44 wks of maintenance treatment, patients were given the option to continue in the long-term extension. HEMH was defined as achieving both endoscopic improvement (Mayo endoscopy subscore ≤1) and histologic improvement (neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue; based on the Geboes score). Patients with insufficient data for histologic evaluation at the end of induction were excluded. Symptomatic remission was defined as a Mayo stool frequency subscore of 0 or 1 and a Mayo rectal bleeding subscore of 0.

Results

Of the 438 patients who were wk8 or wk16 responders to UST induction and received UST maintenance, 116 (26.5%) achieved HEMH after induction, 30 (6.8%) achieved endoscopic improvement without histologic improvement (EI), and 106 (24.2%) achieved histologic improvement without endoscopic improvement (HI). Patients who achieved HEMH after induction had higher symptomatic remission and corticosteroid-free symptomatic remission rates at wks92 and 152 than those with EI or HI; the differences were statistically significantly greater at wk152, while they were only numerically greater at wk92 (Table). The differences were primarily driven by patients with HEMH after induction being more likely to maintain symptomatic remission between wks92 and 152, than those with EI or HI alone. Symptomatic remission and corticosteroid-free remission rates decreased between wks92 and 152 in patients with EI or HI only.

Conclusion

Patients with UC who achieved HEMH after induction with UST were more likely to maintain symptomatic remission and corticosteroid-free symptomatic remission between 2 and 3 years of maintenance treatment than those who achieved EI or HI alone.

Reference

1. K Li, et al. Poster 1008. Presented at UEGW 2019. October 22, 2019. Barcelona, Spain.
DOP74 Comparative effectiveness of vedolizumab and ustekinumab in Crohn’s Disease patients who failed anti-TNF treatment: Interrogating 1019 patients from the UK IBD BioResource
Authors: Desoki R , Balendran K , Kapizioni C , Shawky R , Parkes M , Raine T
Published: January 2022

Background

Ustekinumab (UST) and vedolizumab (VDZ) are widely used to treat patients with Crohn’s disease (CD). However, limited data exist regarding comparative effectiveness of these agents for patients with CD who have failed anti-TNF treatment. We aimed to compare the efficacy of UST and VDZ utilizing the largest cohort of CD patients who failed anti-TNF in real world clinical practice.

Methods

We conducted a retrospective cohort analysis using data retrieved from the UK IBD BioResource, capturing 34,148 subjects. We identified patients with CD, who failed anti-TNF and were subsequently treated with UST or VDZ as second or third-line therapy. Inverse probability of treatment weighting (IPTW) was used to balance groups using a propensity score-weighting approach accounting for baseline patient or disease related characteristics. Persistence on therapy with clinician assessment of treatment success, without the need for treatment change or surgery was used to estimate the response to treatment. We compared treatment survival curves before and after IPTW and used a log rank test for differences between groups

Results

654 CD patients received VDZ, either as second line (51%) or third line (49%) therapy. 365 patients received UST, 52% as a second line and 48% as a third line therapy. All patients received either infliximab or adalimumab as first and/or second biologic therapy. Baseline characteristics are detailed in table 1. Following IPTW, variables were well balanced. Patients receiving VDZ showed similar rates of treatment success compared to UST as second- and third-line biologic agent after anti TNF failure (before IPTW adjustment, log rank p 0.241; after IPTW, log rank p 0.154). Outcomes for UST were similar between 2nd and 3rd line usage (p 0.81), but outcomes for VDZ were significantly worse when used 3rd line compared to 2nd line (p <0.0001).Subgroup analysis of unadjusted survival data showed significantly better outcomes for patients with ileal disease distributiontreated with UST compared to VDZ (p=0.043) but no significant differences in outcomes for subgroups with colonic or ileocolonic disease.We estimate persistence on UST and VDZ to be 67%, 54%, 49% and 49% at 1, 2, 3 and 5 years respectively.

Conclusion

Using data from a multi-institutional cohort of patients with CD with larger number of participants and longer follow-up than previous cohorts, we demonstrate no difference between UST and VDZ used as second and/or third line biologic therapy, after anti-TNF failure. Subgroup analysis reveals some patient characteristics predictive of differential treatment response.
DOP76 Real-world multicenter comparison of effectiveness between tofacitinib and vedolizumab in patients with Ulcerative Colitis after failure to at least one anti-TNF agent
Authors: Buisson A , Nachury M , Fumery M , Guilmoteau T , Leclerc E , Altwegg R , Serrero M , Mathieu N , Treton X , Vuitton L , Pereira B , Amiot A , Bouguen G
Published: January 2022

Background

Several therapeutic options are now available in ulcerative colitis after anti-TNF failure, but no data compared hitherto tofacitinib and vedolizumab.

We compared the effectiveness of tofacitinib and vedolizumab in UC patients with prior exposure ≥ 1 anti-TNF.

Methods

In this multicentre retrospective study, we consecutively included all adult UC patients with partial Mayo score > 2, with ≥ 1 prior anti-TNF agent and started either tofacitinib (10mg b.i.d ± decreased to 5 mg b.i.d from week 8 (W8)) or vedolizumab (300 mg IV at W0-W2-W6 -W14 [± additional W10]) between January 2019 and June 2021.

The primary endpoint was corticosteroid-free clinical remission or CFREM (partial Mayo score ≤ 2) at W16. Secondary endpoints were endoscopic improvement (CFREM + endoscopic Mayo score ≤ 1) and mucosal healing (CFREM + endoscopic and histological remission defined as Nancy index ≤ 1).

All the comparisons were performed using propensity score analyses (inverse probability of treatment weighting) adjusted on gender, smoking, UC duration and extent, number of prior biologics or prior primary failure to biologics, concomitant 5-ASA, steroids or immunosuppressive agents, and disease severity.

Results

Overall, 400 patients will be included. Among the 200 first patients, 87 and 112 received tofacitinib and vedolizumab, respectively (one missing patient). Except for more pancolitis (54.0% vs 38.4%, p=0.028), less immunosuppressive therapies (4.6% vs 27.7%, p < 0.001), and higher rate of prior exposure ≥ 2 biologics (87.4% vs 37.5%, p < 0.001) in tofacitinib arm, baseline characteristics were similar across the two groups including concomitant 5-ASA (10.3% vs 18.8%) and steroids (23.0% vs 31.2%). Vedolizumab infusion at W10 was performed in 34.3% while 42.5% received tofacitinib 10 mg b.i.d until W16.

CFREM was achieved in 54.2% and 42.5% in tofacitinib and vedolizumab, respectively p=0.089). The rate of CFREM at W16 was 57.4% vs 51.1% (p=0.77) after one biologic, 55.4% vs 41.8% (p=0.61) after 2 biologics, 56.9% vs 6.3% (p=0.007) after at least 3 biologics, and 59.0% vs 33.3% (p=0.17) in the subgroup with partial Mayo score ≥ 6, in tofacitinib and vedolizumab groups, respectively.

Tofacitinib was more effective than vedolizumab to achieve CFREM at W16 in patients with primary failure to at least biologic (71.6% vs 30.8%, p=0.049).

Among 177 patients, endoscopic improvement was higher in patients treated with tofacitinib (33.6 % vs 7.1%, p=0.048). Mucosal healing was observed in 6.4% vs 3.8% in tofacitinib and vedolizumab arms, respectively (p=0.27).

Conclusion

Tofacitinib and vedolizumab are effective after failure to anti-TNF agents. Tofacitinib seems to be more effective in case of primary failure to biologics and multiple therapeutic failure.
DOP81 Baseline whole-blood gene expression of TREM1 does not predict clinical or endoscopic outcomes following adalimumab treatment in patients with Ulcerative Colitis or Crohn’s Disease in the SERENE studies
Authors: Verstockt B , Al Mahi N , Pivorunas V , Smaoui N , Guay H , Kennedy N A , Hanauer S B , Ferrante M , Panés J , Vermeire S
Published: January 2022

Background

Conflicting evidence exists regarding whether low baseline Triggering Receptor Expressed on Myeloid cells (TREM)1 whole-blood gene expression predicts response or non-response to anti-tumour necrosis factor agents in patients with Ulcerative Colitis (UC) or Crohn’s Disease (CD). This study investigated whether baseline TREM1 expression predicted outcomes following adalimumab treatment in patients with UC or CD in the SERENE Phase 3 studies.

Methods

The SERENE studies (SERENE-UC, NCT02065622; and SERENE-CD, NCT02065570) compared a higher adalimumab induction dosing regimen versus the standard regimen in patients with UC or CD. Whole-blood TREM1 expression was analysed by RNA sequencing in patients who received standard-dose adalimumab and had clinical and endoscopic outcomes at Week 8 or 52 in SERENE-UC (n=95 for Week 8 and n=70 for Week 52 outcomes), or Week 12 or 56 in SERENE-CD (n=106 for all Week 12 outcomes; n=48 for clinical and n=50 for endoscopic outcomes at Week 56). Outcome definitions are summarised in Table 1. A 2-sample t-test was used to compare baseline TREM1 gene expression (log2 counts per million) in clinical or endoscopic remitters or responders versus non-remitters or non-responders at Weeks 8 and 52 (SERENE-UC) or Weeks 12 and 56 (SERENE-CD).

Results

In SERENE-UC, baseline TREM1 expression did not predict clinical remission at Week 8 (Figure 1a; p=0.7942) and was only weakly predictive of clinical remission at Week 52 (Figure 1b; p=0.04997). Further, it was not predictive of clinical response at Week 8 or Week 52, nor of endoscopic remission or endoscopic response (Figure 1c) at Week 8 (p>0.05 in all cases), although a weak correlation was observed with both endoscopic remission (p=0.0484) and endoscopic response (p=0.01162; Figure 1d) at Week 52. In SERENE-CD, baseline TREM1 expression was not linked to endoscopic or clinical outcomes at either Week 12 or Week 56 (p>0.05 in all cases; Figure 2a–d). Stratification by adalimumab quartiles did not increase the ability of baseline TREM1 expression to predict clinical outcomes in either study. Of note, a highly positive correlation was observed between baseline TREM1 expression and neutrophils in endoscopic responders and non-responders in both studies. Regardless of clinical or endoscopic response or non-response, TREM1 expression decreased over time following adalimumab treatment. All results obtained with standard-dose adalimumab were replicated with the higher dose (data not shown).

Conclusion

The findings of this study suggest that baseline whole-blood TREM1 gene expression is not a robust predictor of clinical or endoscopic outcomes following adalimumab treatment in patients with UC or CD.
DOP83 Normalisation of biomarkers and improvement in clinical outcomes in patients with Crohn’s Disease treated with risankizumab in the phase 3 ADVANCE, MOTIVATE, and FORTIFY studies
Authors: Atreya R , Feagan B , Shchukina O , Jairath V , Rieder F , Hisamatsu T , Siegmund B , Rizzo J , Kligys K , Neimark E , Song A , Zambrano J , Mallick M , Cheng E , Armuzzi A
Published: January 2022

Background

The efficacy of risankizumab (RZB), an interleukin 23 p19 inhibitor, in patients with Crohn’s disease (CD) has been reported. Normalisation of high-sensitivity C-reactive protein (hs-CRP) and faecal calprotectin (FCP) are intermediate treatment targets in CD. Here, we evaluated changes in these objective inflammatory biomarkers and clinical outcomes with RZB treatment.

Methods

In 2 phase 3, randomised, double-blind studies (ADVANCE, NCT03105128; MOTIVATE, NCT03104413), patients with moderately to severely active CD received 12-week intravenous (IV) RZB induction therapy or placebo (PBO). Patients with clinical response to RZB IV induction were rerandomised in a 52-week maintenance study (FORTIFY, NCT03105102) to receive subcutaneous (SC) RZB or PBO (ie, RZB withdrawal). Induction analyses included patients who received either 600 mg RZB IV or PBO for 12 weeks. Maintenance analyses included patients who received 360 mg RZB SC every 8 weeks or withdrawal (PBO SC) for 52 weeks. Outcomes assessed were normalisation of hs-CRP and FCP concentrations at week 12 of induction and at week 52 of maintenance in patients with elevated biomarkers at baseline (hs-CRP > 5 mg/L and/or FCP > 250 μg/g), clinical biomarker response (defined as enhanced clinical response [≥ 60% average daily stool frequency (SF) decrease and/or ≥ 35% average daily abdominal pain score (APS) decrease] and ≥ 50% reduction in hs-CRP or FCP), and clinical biomarker remission (defined as clinical remission per CD Activity Index or SF/APS criteria and normal hs-CRP or FCP) during maintenance treatment. Nonresponder imputation was used for missing data.

Results

Greater proportions of patients receiving RZB vs PBO achieved normalisation of hs-CRP and FCP at the end of the 12-week induction period and the 52-week maintenance period (P < .0001 for all; Table). Among patients with clinical response to RZB IV induction and entered maintenance, rates of clinical biomarker response were maintained through week 52 in patients receiving 360 mg RZB SC and declined over time among patients in the withdrawal (PBO SC) arm (Figure A). Rates of clinical biomarker remission increased over time in patients receiving 360 mg RZB SC. At week 52, clinical remission and normalisation of hs-CRP or FCP was achieved by 41% of patients receiving RZB vs 28%–29% of patients in the withdrawal (PBO SC) arm (Figure B-C). The safety profile of RZB in CD was previously reported.

Conclusion

Normalisation of objective biomarkers of inflammation in CD was achieved with RZB induction and maintenance therapy. Improvements in both clinical outcomes and biomarker levels were sustained with continuous RZB maintenance therapy and decreased over time in patients discontinuing RZB.