bluuebunny/crossref_metadata_2025 huggingface dataset:
OP08 The effects of maintenance therapy with upadacitinib on abdominal pain, bowel urgency, and fatigue in patients with moderately to severely active Ulcerative Colitis: Phase 3 U-ACHIEVE maintenance results
Authors: Danese S , Tran J , D’Haens G , Rubin D T , Aoyama N , Zhou W , James B , Yao X , SanchezGonzalez Y , Panaccione R
Published: January 2022

Background

Abdominal pain (AP), bowel urgency (BU), and fatigue are debilitating symptoms that reduce quality of life in patients with active ulcerative colitis (UC). Results from two Phase 3 induction trials (U-ACHIEVE induction [NCT02819635] and U-ACCOMPLISH [NCT03653026]) showed significant improvements in AP, BU, and fatigue following induction with upadacitinib (UPA) in patients with active UC who had previously failed conventional or biologic therapy. We evaluated the effects of 52-week UPA maintenance treatment on AP, BU, and fatigue in patients who achieved a clinical response after induction.

Methods

Four hundred fifty-one patients who achieved a clinical response after 8 weeks of induction with UPA 45 mg once daily (QD) were enrolled in the U-ACHIEVE maintenance study and were re-randomised 1:1:1 to UPA 15 mg QD (n=148), UPA 30 mg QD (n=154), or placebo (PBO) QD (n=149). Endpoints in this analysis were the percentage of patients who reported no AP or no BU at Weeks 0, 4, 8, 20, 28, 36 and 52, respectively, and the change in Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT–F) from induction baseline to Weeks 0 and 52 in the maintenance study. Patients recorded AP and BU daily via an electronic, handheld device. Lastly, the percentage of patients reporting a clinically meaningful within person change (MWPC), defined as ≥5-point increase in FACIT-F score from induction baseline, and normalization of fatigue, defined as a FACIT-F score >40 points, were determined at Weeks 0 and 52.

Results

Significantly more patients reported no AP at Week 8 for UPA 15 mg vs PBO (60.8% vs 48.3%, p<0.05, Figure 1) and at Week 12 for UPA 30 mg vs PBO (59.7% vs 43.6%, p<0.01); significant differences were maintained through Week 52 (15 mg: 45.9%; 30 mg: 55.3% vs PBO: 20.8%, p<0.001). For no BU reported, significant differences vs PBO were observed with UPA 30 mg at Week 4 (68.8% vs 54.4%, p<0.05, Figure 2) and with UPA 15 mg at Week 8 (64.9% vs 49.7%, p<0.01) and were maintained through Week 52 (15 mg: 56.1%; 30 mg: 63.6% vs PBO: 17.4%, p<0.001). A significantly greater percentage of patients achieved MWPC in FACIT-F with both UPA 15 mg (55.4%) and UPA 30 mg (58.8%) compared with PBO (35.1%; p<0.001) at Week 52. In addition, a greater percentage of UPA-treated patients achieved normalization of fatigue (52.0% and 55.7% for UPA 15 mg and UPA 30 mg, respectively) vs PBO (35.7%) at Week 52 (p<0.01).

Conclusion

In patients with moderately to severely active UC who responded to UPA 45 mg induction treatment, significant and clinically meaningful improvements in patient-reported AP, BU, and fatigue achieved during induction were sustained through 52 weeks of UPA 15 mg or 30 mg maintenance treatment.
OP10 Comparative efficacy of biologics for endoscopic healing of the ileum and colon in Crohn’s Disease
Authors: Narula N , Wong E , Dulai P , Marshall J , Jairath V , Reinisch W
Published: January 2022

Background

We compared the efficacy of adalimumab, infliximab, ustekinumab, and vedolizumab for achieving endoscopic healing (EH) in the ileum and colon after one-year of therapy in Crohn’s disease (CD).

Methods

A pooled analysis of patient-level data from 344 patients with CD from four clinical trial programs was performed. Patients who received continuous adalimumab, infliximab, ustekinumab, or vedolizumab throughout the trial and had at least one ileocolonic segment with a Simple Endoscopic Score for CD (SES-CD) ≥ 3 at enrolment were included. Proportions of patients achieving one-year endoscopic healing (EH), defined as SES-CD of 0, using each of four biologics were compared. Multivariate logistic regression was used to model the relationship between individual biologics and one-year outcomes, adjusted for potential confounders of EH, including disease duration, concomitant corticosteroid use, and prior anti-TNF failure.

Results

Compared to vedolizumab [10/77 (13%)], both infliximab [29/79 (36.7%), aOR: 3.27 (95% CI: 1.34–8.01), p<0.001] and adalimumab [12/40 (30%), aOR: 3.01 (95% CI: 1.10–8.21), p=0.032] were superior for achieving one-year EH of the ileum among patients with ileal involvement at baseline. No difference was observed between ustekinumab [5/22 (22.7%)] and vedolizumab [aOR: 2.75 (95% CI: 0.76–9.91), p=0.123]. In biologic-naïve patients, ustekinumab, adalimumab, and infliximab were superior to vedolizumab for achieving one-year EH of the ileum. For colonic disease, in comparison to ustekinumab [9/31 (29.0%), adalimumab [30/48 (62.5%), aOR: 4.04 (95% CI: 1.88–8.71), p<0.001] and infliximab (55/105 (52.4%), aOR: 2.02 (95% CI: 1.03–3.99), p=0.041] were superior for one-year EH in the colon among patients with colonic involvements at baseline. No difference was seen between vedolizumab [26/87 (29.9%)] and ustekinumab [aOR: 1.01 (95% CI: 0.39–2.59), p=0.987]. Similar differences were noted among biologic-naïve patients.

Conclusion

In this post-hoc analysis of pivotal clinical trials, TNFα antagonists were generally superior to vedolizumab and ustekinumab for achieving EH of the ileum and colon in patients with CD. However, among biologic-naïve patients, ustekinumab, adalimumab, and infliximab were superior to vedolizumab for attaining one-year EH of the ileum.
DOP03 The use and efficacy of biological therapies 2010–2020 for Inflammatory Bowel Disease in a Danish tertiary centre
Authors: Wewer M D , Arp L , Melek S , Oluf Krautwald F , Vind I , Pedersen G , Nielsen A M , Kiszka-Kanowitz M , Boysen T , Theede K , Nordgaard-Lassen I , Bendtsen F , Burisch J
Published: January 2022

Background

Direct health care costs have shifted towards drug-related expenditures in patients with inflammatory bowel disease (IBD). Frequently, patients will have to switch to a second- or third-line biological therapy due to no response or loss of response. The aim of this study was to describe the use and efficacy of biological therapy in a tertiary centre during a 10-year period and investigate the need for surgery.

Methods

The study population consisted of all bio-naïve IBD patients who initiated biological therapy between January 1, 2010 and February 19, 2020 at the Gastro unit, Hvidovre Hospital, Denmark. The electronic medical records were reviewed, and data were systematically registered. Failure of the biological therapy as no response and loss of response was defined by the need for surgery, steroid or shift in biological therapy.

Results

The study population consisted of 291 (46.9%) patients with ulcerative colitis (UC), 327 (52.7%) with Crohn’s disease (CD) and 3 with (0.5%) IBD Unclassified (IBDU), who initiated biological therapy with a median follow-up of 3 (IQR=2–5) years from initiation of therapy. The annual number of patients who initiated biological therapy was increasing throughout the study period.

Most patients (457, 73.6%) received one biological drug, 126 (20.3%) received two, and 38 (6.1%) received three or more different types of biological drugs during the study period. Systemic steroid was required in 99 patients (15.9%) and the 5-year surgery-free survival was 76.5% (120 patients with surgery). 302 patients (54.3%) had effect of the first biological therapy at one year follow-up.

In multivariate Cox-regression analyses, concurrent treatment with thiopurines decreased the risk of failure of the first biological therapy in UC patients (hazard ratio (HR) 0.745, 95% CI: 0.559–0.992) but not in CD patients (HR 0.969, 95% CI: 0.722–1.300). Male gender decreased the risk of failure (HR: 0.677, 95% CI: 0.505–0.908) while higher age at initiation of biological therapy increased the risk (HR: 1.0152, 95% CI: 1.004–1.027) in CD patients. These factors had no impact in UC patients. Prior surgery, disease duration and location were not associated with increased risk of failure of first biological therapy.

Conclusion

In conclusion, an increasing number of IBD patients received biological therapy during the 10-year period at our tertiary centre. A considerable part of IBD patients in biological therapy will require surgery, additional steroids, or second line biological therapy. Our findings suggest a beneficial role of thiopurine in combination with biological therapy. Improved identification of patients not responding to first line biological therapy is of great importance.
DOP11 Early intestinal ultrasound predicts endoscopic response to anti-inflammatory treatment and shows drug-specific response to biologicals and tofacitinib in Ulcerative Colitis
Authors: de Voogd F , Bots S , Van Wassenaer E , De Jong M , Pruijt M , Löwenberg M , D’Haens G , Gecse K
Published: January 2022

Background

Objective evaluation of treatment response is the gold standard in ulcerative colitis (UC). In this setting, intestinal ultrasound (IUS) is a non-invasive alternative to endoscopy. Recent studies showed change in IUS parameters after treatment initiation but studies with an endoscopic reference standard are scarce. The aim of this study was to evaluate early change of IUS parameters and determine cut-off values for endoscopic endpoints in UC patients starting anti-inflammatory treatment.

Methods

In this longitudinal prospective study consecutive patients with moderate-severe UC (baseline endoscopic Mayo score (EMS)≥2) starting an anti-inflammatory treatment were included. Clinical scores, biochemical parameters and IUS parameters were collected at baseline, after 2 (T1), 6 (T2) and 8–26 weeks (T3) around time of the second sigmoidoscopy/colonoscopy. IUS parameters were measured as previously established1. Endoscopic remission (ER) and mucosal healing (MH) were evaluated in the sigmoid and defined as EMS=0 and EMS≤1, respectively. The ultrasonographist and endoscopist were blinded for the outcomes of endoscopy and IUS, respectively.

Results

51 consecutive patients were included (Table 1) of whom 31 underwent a second endoscopy (MH: n=15 (45%), ER: n=9 (27%)). Two additional patients underwent colectomy and were considered non-responders. 18 patients did not undergo second endoscopy due to the COVID-19 pandemic (n=2), refusal (n=5), loss to follow-up (n=1) or treatment escalation because of clinical deterioration confirmed by IUS and biomarkers before second endoscopy was performed (n=10). Bowel wall thickness (BWT) was significantly lower from T2 onwards in patients reaching MH (p=0.026) and ER (p=0.002) at T3 (Fig 1). A significant decrease in BWT was already visible at T1 in patients receiving infliximab (p=0.001) or tofacitinib (p=0.007), but not in patients treated with vedolizumab (p=0.11) (Fig 2). Most accurate BWT cut-off values at T3 to determine MH and ER were 3.52 mm (AUROC: 0.95, 95% CI: 0.86–1.00, p<0.0001, sens: 91%, spec: 91%) and 2.98 mm (AUROC: 0.94, 95% CI: 0.85–1.00, p=0.001, sens: 87%, spec: 100%), respectively. Other IUS parameters at T3 did not improve association with MH or ER. IUS parameters at T2 that predict MH and ER are demonstrated in Table 2.

Table 1

Fig 1

Fig 2

Table 2

Conclusion

BWT and Colour Doppler Signal 6 weeks after start of treatment are associated with and could predict MH and ER. In addition, treatment response patterns at IUS are drug-specific. Furthermore, we have provided accurate BWT cut-off values for endoscopic outcomes. In a point-of-care setting, (early) treatment evaluation with IUS could guide treatment decision in UC in order to optimize treatment response.

Reference

1. Bots et al, JCC, 2021
DOP18 Advanced optical diagnosis technology for assessment of endoscopic and histological remission in Ulcerative Colitis: A systematic review and meta-analysis
Authors: Nardone O M , Snir Y , Hodson J , Cannatelli R , Labarile N , Siau K , Hassan C , Yanai H , Dotan I , Ghosh S , Iacucci M
Published: January 2022

Background

Advanced endoscopic technologies led to significant progress in the definition of endoscopic remission of ulcerative colitis (UC), and correlate better with histological changes, compared to standard endoscopy. However, whilst studies have assessed the diagnostic accuracy of endoscope technologies individually, there is current limited data comparing between technologies. As such, we aimed to compare the correlations between endoscopy and histology disease activity scores across endoscope technologies

Methods

We searched PubMed and Embase in January 2021 for eligible studies reporting the correlation between endoscopy and histology activity scores in UC. Studies were grouped by endoscope technology as standard-definition white light (SD-WLE), high-definition white light (HD-WLE), or electronic virtual chromoendoscopy (VCE), and comparisons made between these groups

Results

A total of N=27 studies were identified, of which N=12 were included in a meta-analysis of correlations between endoscopic and histological activity scores. Combining these returned a pooled correlation coefficient (rho) for the SD-WLE group of 0.61, which did not differ significantly from HD-WLE (rho: 0.79, p=0.140) or VCE (rho: 0.70, p=0.471) [Fig 1a]. In addition, N=4 studies reported the accuracy of endoscopic activity scores on WLE and VCE to diagnose histological remission. Pooling these found significantly higher accuracy for VCE, compared to WLE (risk ratio: 1.13, 95% CI: 1.07–1.19, p<0.001).[Fig 1b]

Conclusion

Activity scores assessed using endoscopy are strongly correlated with activity on histology. VCE appears to have better accuracy for the diagnosis of histological remission in UC, compared to WLE.
DOP28 Venous thromboembolism following discharge from hospital in patients admitted for Inflammatory Bowel Disease
Authors: Harvey P , Coupland B , Mytton J , Trudgill N , De Silva S
Published: January 2022

Background

Patients admitted to hospital with active Inflammatory bowel disease(IBD) are at increased risk of thromboembolism. Surgical specialties have demonstrated benefits of thromboembolism prophylaxis after hospital discharge in high risk groups.

This study aims to identify IBD patients at increased risk and develop a scoring system to recognise them.

Methods

Hospital episode statistics data was used to identify all patients admitted for IBD emergently or electively for surgery. All Patients with a thromboembolism within 90 days of hospital discharge were identified. A multilevel logistic regression model was used to identify patient and admission level factors associated with increased risk of thromboembolism. A scoring system to identify higher risk patients was constructed based on this model. Score performance was assessed using bootstrapped data.

Results

201,779 admissions in 101,966 patients were included. The rate of thromboembolism within 90 days was 17.24 per 1000 patient years at risk. This was highest in patients admitted as an emergency undergoing surgery (36.91) followed by emergency admission without surgery (15.63) and elective admission for surgery (15.60). The rate of thromboembolism between 180 and 270 days following discharge was 0.84, 1.59 and 1.70 per 1000 patient years at risk respectively.

Regression analysis demonstrated that female gender (OR 0.65(95%CI 0.53–0.80),p<0.001), increasing age (49–60 years,(4.73(3.40–6.58),p<0.001), increasing length of stay; 5–7 days (1.77(1.27–2.46),p=0.001), 7–10 days (1.91(1.40–2.60),p<0.001), >10 days (4.04(2.98–5.46),p<0.001), increasing number of prior admissions for IBD in preceding 3 months; 1 (1.36(1.11–1.68),p=0.004), 2 (1.66(1.23–2.22),p=0.001), >2 (2.32(1.67–3.21),p<0.001), Ulcerative Colitis (1.46(1.19–1.79),p<0.001) and admission type compared to Elective surgery (Emergency admission including surgery (1.64(1.15–2.33),p=0.006)), (Emergency admission not including surgery(1.57(1.07–2.32), p=0.023)) were statistically significant associations.

In the scoring system, a score >=9 gave a positive predictive value of 1%. The AUC was 0.71(95%CI 0.69–0.72)

Conclusion

Patients admitted to hospital have ongoing increased risk of thromboembolism in the 90 day period following discharge. Risk was increased in patients with prolonged length of stay, increasing age, male gender or admitted as an emergency requiring surgery. Higher risk patients were identifiable by a scoring system.
DOP37 Efficacy and safety of filgotinib in patients with Ulcerative Colitis stratified by age: Post hoc analysis of the phase 2b/3 SELECTION and SELECTIONLTE studies
Authors: Schreiber S , Loftus E V , Maaser C , Danese S , Rudolph C , Jongen R , De Haas A , Oortwijn A , Vermeire S
Published: January 2022

Background

With a growing prevalence of inflammatory bowel disease (IBD) in elderly patients, there is a clinical requirement to understand the impact of treatment in this population.1 Filgotinib (FIL) is an oral Janus kinase 1 preferential inhibitor. This post hoc analysis of data collected in the phase 2b/3 SELECTION programme evaluated the efficacy and safety of FIL in patients with ulcerative colitis (UC) stratified by age.

Methods

The SELECTION programme includes two Induction Studies, a Maintenance Study (NCT02914522) and a long-term extension (LTE) study (NCT02914535). Adults aged 18–75 years with moderately to severely active UC were randomized 2:2:1 to receive FIL 200 mg or 100 mg or placebo once daily for 11 weeks. Responders at week 10 were re-randomized 2:1 to continue assigned FIL treatment or placebo from week 11–58. In LTE, patients with disease worsening and those completing week 58 continued assigned treatment before receiving open-label FIL. We assessed the efficacy and safety of FIL at any dose in the overall cohort of SELECTION and LTE, stratified into five age groups: <30, ≥30–<40, ≥40–<50, ≥50–<60 and ≥60 years. Clinical remission was evaluated at week 10 and pMCS remission was assessed at week 10, 58 and LTE weeks 2, 4, 12 and 24. Exposure-adjusted incidence rates (EAIRs) were calculated for adverse events (AEs). A data cut-off of 28 February 2020 was used.

Results

Baseline disease activity and previous and concomitant treatments were comparable across age groups in each treatment arm. While there were fewer patients in the ≥60 years group, patient distribution was similar in all other age groups. FIL induced clinical (~16%) and pMCS (~36%) remission in similar proportions of patients across all age groups at week 10 (Figure 1). At week 58, pMCS remission was achieved in ~53% of FIL-treated patients across age groups (Figure 2). In LTE, the proportion of FIL-treated patients in pMCS remission generally increased with time and remained similar across all age groups (Figure 3). FIL-treated patients aged ≥60 years had higher EAIRs of any AE, infections, herpes zoster, malignancies, NMSC and MACE than younger patients (Table). One thromboembolic event occurred in a FIL-treated patient aged <30 years. Three deaths related to cardiovascular disease occurred in FIL-treated patients aged ≥50 years.

Conclusion

These findings suggest FIL is efficacious in inducing and maintaining symptomatic remission and could have an acceptable safety profile in adults with UC of all ages, including ≥60 years old. Age-related increases in incidences of certain AEs might be expected in patients with IBD; however, the number of patients ≥60 years limits comparison of these data with reported rates.

Reference

1Zammarchi et al. BMC Gastroenterol 2020;20;147
DOP44 Long-term use of ozanimod in patients with moderately to severely active Ulcerative Colitis
Authors: Danese S , Colombel J F , Ponich T , Jovanovic I , Bossuyt P , Longman R , Alekseeva O , Petersen A , Chitkara D , Marta C , Charles L , Rubin D T , Afzali A , Loftus E V , Wolf D C
Published: January 2022

Background

Ozanimod was approved by the FDA to treat patients (pts) with moderately to severely active Ulcerative Colitis (UC) based on the results from the 52-week (wk) phase 3 True North (TN) study. We sought to evaluate long-term efficacy and safety of ozanimod.

Methods

We examined data from an interim analysis of pts in the TN parent study who entered the ongoing TN open-label extension (OLE). Pts entered the TN OLE from the phase 3 TN study if they were non-responders at the end of induction, lost response during maintenance, or completed maintenance treatment, or from the phase 2 Touchstone OLE if they remained at study closure and received once-daily oral ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg). Clinical remission, clinical response, endoscopic improvement, and corticosteroid (CS)-free remission were evaluated at Wks 46, 94, and 142 in the TN OLE for all pts who entered the OLE from the TN parent study, and in the subset of pts in clinical response at the OLE entry. The data were analysed in the intent-to-treat population using observed cases (OC), which used the number of pts remaining in the study at the corresponding time point, and non-responder imputation (NRI), which used the number of pts remaining in the study at the corresponding time point and those who withdrew before the time point but would have reached the time point if they had stayed. Treatment-emergent adverse events were evaluated from the pooled phase 2 and phase 3 UC studies.

Results

A total of 823 pts from TN entered the TN OLE; as of the cut-off date (Sept 30, 2020), 64% completed Wk 46, 34% completed Wk 94, and 14% completed Wk 142 of the OLE. The most common reason for discontinuation was lack of efficacy (21%). Baseline demographics were similar as in the TN study. A total of 261 pts were in clinical response at the time of OLE entry. OC analyses showed that the percentage of pts achieving clinical remission, clinical response, endoscopic improvement, and CS-free remission was maintained over time (Table). Efficacy in the responders was higher compared to the total population and was comparable within the endpoints at Wks 46 and 94. Using the more conservative NRI analysis, the proportion of pts achieving each endpoint was lower than in the OC; however, after 94 wks of OLE treatment, 34% of all pts and 55% of the responders still maintained clinical response. No new safety signals were seen with longer-term ozanimod use in the 1158 pts in the pooled population.

Conclusion

UC pts from the phase 3 TN study demonstrated maintenance of response with long-term ozanimod treatment. These data reflect approximately 2 years of additional ozanimod treatment, with no new safety signals identified.
DOP58 An artificial intelligence–driven scoring system to measure histological disease activity in Ulcerative Colitis
Authors: Peyrin-Biroulet L , Adsul S , Dehmeshki J , Kubassova O
Published: January 2022

Background

Histological remission is increasingly regarded as an important and deep therapeutic target for ulcerative colitis (UC). Assessment and scoring of histological images is a tedious procedure, that can be imprecise and prone to inter- and intra-observer variability. Therefore, a need exists for an automated method that is accurate, reproducible and reliable. This study aimed to investigate whether an artificial intelligence (AI) system developed using image processing and machine learning algorithms could measure histological disease activity based on the Nancy index.

Methods

A total of 200 histological images of patients with UC from a database at University Hospital, Vandoeuvre-lès-Nancy, France were used for this study. The novel AI system was used to fully characterise histological images and automatically measure Nancy index. The in-house AI algorithm was developed using state-of-the-art image processing and machine learning algorithms based on deep learning and feature extraction. The cell regions of each image, followed by Nancy index, were manually annotated and measured independently by 3 histopathologists. Manual and AI-automated measurements of Nancy index score were done and assessed using the intraclass correlation coefficient (ICC).

Results

The 200-image dataset was divided into 2 groups (80% was used for training and 20% for testing). ICC statistical analyses were performed to evaluate AI tool and used as a reference to calculate the accuracy (Table 1). The average ICC amongst the histopathologists was 89.33 and average ICC between histopathologists and AI tool was 87.20. Despite the small number of image data, the AI tool was found to be highly correlated with histopathologists.

Conclusion

The high correlation of performance of the AI method suggested promising potential for IBD clinical applications. A standardised and validated histological AI-driven scoring system can potentially be used in daily IBD practice to eliminate the subjectivity of the pathologists and assess the disease severity for treatment decision.
DOP66 Disease course of Ulcerative proctitis in children: A population based study on behalf of the SIGENP IBD Group
Authors: Martinelli M , Fedele F , Romano C , Aloi M , Lionetti P , Alvisi P , Panceri R , Bramuzzo M , Illiceto M , Bosa L , Norsa L , Pastore M , Graziano F , Arrigo S , Felici E , Gatti S , Fuoti M , Strisciuglio C , Dipasquale V , D’Arcangelo G , Scarallo L , Labriola F , Miele E
Published: January 2022

Background

Ulcerative proctitis (UP), defined as a colonic location limited to the rectum, is a poorly investigated condition in children, usually considered as a minor form of Ulcerative Colitis (UC). The aim of the present study was to compare the disease course of paediatric patients affected by UP at diagnosis with the other UC locations.

Methods

This multicentre retrospective observational study has been carried out starting from the data prospectively registered in the IBD Registry of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP). Seventeen IBD referral centres adhering to the registry were included in the study. Patients age 0 to 18 years, who were diagnosed with UC according to the Porto criteria starting from January 1, 2009, to May 1st, 2021 were identified. Only children with a minimum follow-up of 12 months were included in the study. Once enrolled, children were subsequently divided in two groups based on Paris classification: group 1 (E1) and group 2 (E2, E3 and E4).

Results

Eight-hundred-eighty-five children were finally included in the study (median age at diagnosis: 11.2 years, range: 0–18 years; M/F: 434/451), of whom 176 (19.8%) belonging to group 1 and 709 (80.1%) to group 2. The median age at diagnosis was significantly higher in group 1 when compared to group 2 [11.9 (0–18) versus 11 (0–18) years, respectively; (p<0.001)]. At diagnosis, the induction therapy was significantly different with 68 (39.5%) patients of group 1 undergoing steroid therapy versus 505 (71.2%) of group 2 (p<0.001) and 79 (41.9%) of group 1 practising only mesalamine respect to 186 (26.2%) of group 2 (p<0.001). A higher number of children from group 2 started immunosuppressive or biologic therapy as maintenance therapy at diagnosis [Group 1: 11 (6.2%) versus 173 (24.4%), respectively; (p<0.001)]. The median follow-up of our cohort was 4.5 years (range 1–13 years). At the last follow-up, 67/176 (38%) children with UP showed an extension of their disease location without significant difference when compared to group 2 [265 (37.5%); p=0.9], while 81 (45%) children from Group 1 were under immunosuppressive or biologic therapy versus 566 (79.8%) from group 2 (p<0.001). Five children (3%) of Group 1 underwent colectomy during the follow up versus 45 (6.9%) of Group 2 (p=0.06).

Conclusion

UP is a frequent location of paediatric onset UC and the risk of endoscopic extension of proctitis is similar to the more extensive forms. A considerable number of patients with UP required immunosuppressive or biologic therapy during the follow-up and no significant difference was observed in terms of surgery. Overall, UP cannot be considered as a minor form of UC.
DOP67 First-line infliximab is cost-effective compared to conventional treatment in paediatric Crohn’s Disease – Results from the TISKids study
Authors: Vuijk S , Jongsma M , Hoeven B , Cozijnsen M , van Pieterson M , de Meij T , Norbruis O , Groeneweg M , Wolters V , van Wering H , Hummel T , Stapelbroek J , van der Feen C , van Rheenen P , van Wijk M , Teklenburg S , Poleij M , Escher J , de Ridder L
Published: January 2022

Background

First-line infliximab (FL-IFX) induction treatment combined with azathioprine (AZA) is more effective to achieve clinical remission without treatment escalation at week 52 compared to conventional induction treatment (CONV) (Exclusive Enteral Nutrition or prednisone) combined with AZA in children with moderate-to-severe Crohn’s disease (CD). FL-IFX may lead to higher treatment costs compared to conventional treatment. However, data on cost-effectiveness of FL-IFX in children with CD is still limited. Therefore, our aim is to investigate the cost-effectiveness of FL-IFX in comparison with CONV. We hypothesized that cost effectiveness of FL-IFX is comparable to CONV in children with newly diagnosed moderate-to-severe CD in the first two years after treatment.

Methods

We included patients from the TISKids international randomized controlled trial in which children with moderate-to-severe CD were treated with either FL-IFX (Inflectra, biosimilar of IFX) or CONV.(1) Patients included outside of the Netherlands (n=6) or patients with serious comorbidity besides CD were excluded from this analysis (n=2). Data on healthcare consumption and costs were obtained per hospital for all included patients until week 104. Direct health-related costs were collected, including hospital visits, drug costs, laboratory tests, endoscopies and surgeries. The effectiveness of treatment was assessed by mean weighted paediatric CD activity index (wPCDAI) and faecal calprotectin (fcal) levels (µg/g) measured over time until week 104. This analysis was performed by a mixed model. Moreover, time to additional anti-tumor necrosis factor-α (anti-TNF) treatment up to 104 weeks after inclusion was assessed.

Results

In this analysis, 89 patients were included, 44 in the FL-IFX group and 45 in the conventional treatment group. There were no significant differences between the two groups at baseline. Interestingly, the mean costs were similar for FL-IFX (€34,783) and CONV (€34,923) after two years, p=0.97 (Figure 1). Mean fcal levels were lower for FL-IFX compared to CONV over two years (416 vs. 625, p=0.03). The mean wPCDAI scores over two years were numerically lower for FL-IFX compared to CONV (5.95 vs. 10.34, p=0.01), but this difference became smaller over time. Furthermore, the time to (re)start anti-TNF treatment was significantly longer in the FL-IFX group (median 68 weeks) compared to the conventional treatment group (median 32 weeks) (p=0.02) (Figure 2).

Conclusion

Treatment with FL-IFX is cost-effective compared to conventional treatment in the first two years after diagnosis in children with moderate-to-severe CD.

Reference

1. Jongsma MME et al. Gut. 2020 Dec 31; DOI: 10.1136/gutjnl-2020–322339. / PMID: 33384335
DOP71 Low occurrence of colectomy with long-term (up to 4 years) golimumab treatment in patients with moderate-to-severe active Ulcerative Colitis: Data from the PURSUIT maintenance and long-term extension studies
Authors: Weinstein C L , Meehan A G , Lin J , Govoni M , Qureshi Z P
Published: January 2022

Background

In a previous real-world study of long-term (up to 4 years) treatment with golimumab (GLM) in ulcerative colitis (UC), patients reported a low overall colectomy incidence (5.8%).1 This analysis evaluates the incidence of colectomy among patients with moderate-to-severe active UC in the PURSUIT-maintenance (-M)2 and long-term extension (-LTE)3 studies.

Methods

Eligible PURSUIT-M trial participants completed a 6-week GLM induction trial without requiring colectomy.4,5 Responders to GLM induction were randomised 1:1:1 to GLM 50 mg, 100 mg, or placebo (PBO) maintenance for up to 1 year, administered every 4 weeks (q4w). Nonresponders to GLM or PBO induction received GLM 100 mg; responders to PBO induction received PBO (each administered q4w for up to 1 year). Participants experiencing loss of clinical response during maintenance were eligible for one treatment intensification (switch from PBO to GLM 100 mg, or GLM dose increase). Participants who completed PURSUIT-M were eligible to continue their treatment in the 3-year PURSUIT-LTE study. Colectomy (total or partial) was a prespecified outcome in PURSUIT-M; serious adverse event narratives and safety summaries were also examined for reports of colectomy (total or partial). For PURSUIT-LTE, serious adverse event narratives and safety summaries were examined for reports of colectomy (total or partial). The reasons for colectomy were not collected systematically in PURSUIT-M or -LTE. Descriptive information on colectomies was assessed and reported.

Results

A total of 60 (4.9%) colectomies were reported among the 1228 patients who enrolled in the 1-year PURSUIT-M study, including 672 participants who continued into the 3-year LTE study. The table shows the distribution of colectomies by study phase, induction responder status, initial treatment assignment, and treatment prior to colectomy. The colectomy rate during the 3-year extension was lower than that observed during the maintenance phase of the study [1.3% (9/672) compared to 4.2% (51/1228)].

Conclusion

Consistent with previously reported data, this retrospective evaluation of colectomy data from the PURSUIT-M and -LTE studies in patients with moderate-to-severe active UC demonstrated a low occurrence of colectomy with long-term (up to 4 years) GLM treatment. The limited number of colectomies observed in the LTE study occurred predominantly in patients with more severe disease at baseline (induction non-responders) who had been receiving GLM 100 mg.

References

1. Iborra M, et al. SciRep. 2020;10:17774

2. Sandborn WJ, et al. Gastroenterol. 2014;146:96–109

3. Reinisch W, et al. J Crohn’s Col. 2018;12:1053–1066

4. Sandborn WJ, et al. Gastroenterol. 2014;146:85–95

5. Rutgeerts P, et al. Aliment Pharmacol Ther. 2015;42:504–514
DOP73 A comparative efficacy and safety analysis of subcutaneous infliximab and vedolizumab in patients with Crohn’s Disease and Ulcerative Colitis
Authors: Peyrin-Biroulet L , Arkkila P , Armuzzi A , Atreya R , Danese S , Ferrante M , Guardiola J , Jahnsen J , Louis E , Lukáš M , Reinisch W , Roblin X , Smith P J , Kwon T S , Kim J Y , Yoon S W , Kim D H
Published: January 2022

Background

CT-P13 is the first and only subcutaneous (SC) formulation of infliximab (IFX) which received EMA approval in July 2020 for the treatment of Crohn’s disease (CD) and ulcerative colitis (UC). This study compares efficacy and safety between IFX SC and vedolizumab (VDZ) in moderate-to-severe CD or UC patients using data from the pivotal study of IFX SC, VISIBLE 2 and recently presented systematic literature review and meta-analysis [1].

Methods

This comparative study analyses 7 randomised controlled trials. The IFX SC trial (NCT02883452) was compared with the VDZ trials including GEMINI II, GEMINI III, VISIBLE 2 for CD and GEMINI I, VISIBLE 1, and VARSITY for UC. VISIBLE 2 was added in this analysis as it was published after the presented meta-analysis. In all studied VDZ trials, only responders at week 6 continued to receive maintenance treatment except VARSITY trial, which followed a treat-through design.

Crohn’s Disease Activity Index (CDAI)-70, CDAI-100 response and clinical remission for CD, and clinical response, clinical remission, and mucosal healing for UC at week 6 (induction) and 1 year (week 50–54, maintenance) were compared between IFX SC and VDZ for evaluating efficacy. Discontinuation due to lack of efficacy and safety profiles over 1 year were also assessed.

Results

In the patients with CD, IFX yielded significantly better efficacy results in the induction phase compared to VDZ with non-overlapping 95% confidential interval while IFX SC displayed better results, although statistically non-significant during the maintenance phase (Table 1). In UC, similar efficacy was shown between the treatments during both induction and maintenance phase (Table 2). The proportion of patients discontinued due to lack of efficacy was significantly higher in VDZ compared to IFX SC in both CD (IFX SC 5% and VDZ 32%) and UC (IFX SC 3% and VDZ 15%) over 1 year (Tables 1,2).

The safety profiles were generally comparable between IFX SC and VDZ. Similar proportion of patients experienced serious adverse event (9% and 14% in CD; 12% and 11% in UC in IFX SC and VDZ). The proportion of patients experiencing serious infection between the treatments was also similar in both CD and UC (Tables 3,4).

Conclusion

Better efficacy was shown in IFX SC compared to VDZ in CD, while a similar efficacy was shown in UC. A significantly higher proportion of patients were discontinued due to lack of efficacy in VDZ compared to that of IFX SC over 1 year. Safety profiles over 1 year were generally comparable between IFX SC and VDZ in both indications.

Reference

1. Peyrin-Biroulet, L. (2021). P0414 Efficacy and safety of infliximab and vedolizumab in patients with inflammatory bowel diseases: a systematic review and meta-analysis. Poster presented at: 2021 UEG Week.
DOP89 Infliximab and ustekinumab clearance during induction predicts post-induction endoscopic outcomes in patients with Crohn’s Disease
Authors: Wang Z , Kantasiripitak W , Verstockt B , João S , Ferrante M , Declerck P , D’Haens G , Laharie D , Vermeire S , Dreesen E
Published: January 2022

Background

Monitoring of monoclonal antibody clearance has been hypothesised to be an appealing approach for predicting treatment outcomes in patients with inflammatory bowel diseases. We aimed to investigate the benefits of monitoring infliximab and ustekinumab clearance in patients with Crohn’s disease (CD) based on data from clinical trials.

Methods

Data were obtained from patients with moderate-to-severe CD starting infliximab (n=108)1 or ustekinumab (n=80)2 therapy. Endoscopic remission (CD Endoscopic Index of Severity <3) and endoscopic response (≥50% decrease from baseline in simple endoscopic score for CD) were assessed at week (w)12 and w24 of infliximab and ustekinumab therapy, respectively. A priori prediction (based on covariate data only; at w0) and a posteriori prediction (Bayesian forecasting using measured drug concentrations; during treatment) were performed using previously built population pharmacokinetic models (NONMEM 7.5).3,4 Covariates of fecal calprotectin, albumin, CD activity index, and antibodies towards infliximab (ATIs) were used to estimate infliximab clearance. Albumin and body weight were used to estimate ustekinumab clearance.

Results

Patients achieving endoscopic remission at w12 had significantly lower infliximab clearance and higher infliximab serum concentration at w2 and w6 of treatment (P <0.05, Table 1). Patients achieving endoscopic response at w24 had significantly lower ustekinumab clearance at w4 and w8, as well as a significantly larger reduction in clearance relative to w0 (P <0.05, Table 1). However, ustekinumab serum concentrations at w4 and w8 were similar between patients with and without endoscopic response (P >0.2, Table 1).

Most patients with an early increase in infliximab clearance (16/22; 73%) and ustekinumab clearance (27/29; 93%) did not reach the endoscopic endpoint (P <0.05; Table 2). However, a decrease in clearance was no guarantee for endoscopic remission during infliximab therapy (false predictive rate 46%) and response during ustekinumab therapy (false predictive rate 69%).

The infliximab clearance after start of induction therapy (at w2 and w6) was significantly higher in patients who developed ATIs during induction therapy (Figure 1).

Conclusion

Lower infliximab and ustekinumab clearance (absolute as well as relative to w0) early during induction predict more favourable endoscopic outcomes. In patients treated with ustekinumab, clearance monitoring may better predict endoscopic response at w24 as compared to standard therapeutic drug monitoring.

References1. D’Haens et al.Gastroenterology 2018

2. Verstockt et al. J Crohns Colitis 20193. Dreesen et al. Br J Clin Pharmacol 20214. Wang et al. Br J Clin Pharmacol 2021.
DOP90 Efficacy of the treat-to-target approach in modifying disease course with ustekinumab in patients with moderate-to-severe Crohn’s Disease: Results from the STARDUST trial
Authors: Peyrin-Biroulet L , Vermeire S , D’Haens G R , Panés J , Dignass A , Magro F , Le Bars M , Lahaye M , Nazar M , Ni L , Bravatà I , Lavie F , Daperno M , Lukáš M , Armuzzi A , Löwenberg M , Gaya D R , Danese S
Published: January 2022

Background

STARDUST is a phase 3b randomized trial comparing two therapeutic strategies with ustekinumab (UST) in patients (pts) with Crohn’s disease (CD): treat-to-target (T2T) using early endoscopic assessment vs standard of care (SoC). Results from the Week (W)48 and long-term extension (LTE) (W48 to W104) were published previously.1,2 Here we explore the efficacy of the T2T approach in modifying disease course with UST by analyzing time-to-disease modifying (DM) event up to W104.

Methods

Adult pts with moderate–severe active CD, received iv, weight-based UST ~6mg/kg at W0; then sc UST 90mg at W8. At W16, pts with ≥70-point reduction in CD Activity Index were randomized 1:1 to either T2T or SoC and received sc UST 90mg, every 12W/8W (up to 4W in the T2T arm), as per the protocol. From W48, eligible pts could continue to receive sc UST up to W104 with further protocol-guided dose adjustment. DM events were recorded through W48 and W104 starting at randomization, and time-to-event analysis was performed for pts in both arms. DM events are represented by combined bowel damage events (defined as the development of new strictures/fistulae or the occurrence of an intra-abdominal abscess) or CD-related hospitalizations or surgeries based on the adverse event analysis. Time-to-first bowel damage event, CD-related surgery, hospitalization, hospitalization or surgery was analyzed separately; Kaplan–Meier (K–M) curves with corresponding hazard ratios (HRs) and 95% confidence intervals (CIs) are shown here.

Results

Of 440 pts randomized to either T2T or SoC at W16, 74 discontinued before W48. Of the remaining 366 pts completing W48, 43 discontinued and did not enter LTE. At W48, 323 pts entered LTE; 20.1% of these pts discontinued before completing W104. HRs (95% CI) for time-to-first DM event from randomization through W48 and W104 are shown in Table 1, suggesting a numeric benefit in favour of the T2T arm. The separation of the K–M curves for time-to-first DM event between the two arms was apparent at W48 and continued up to W104, without significant difference (Figure 1a and b).

Conclusion

In STARDUST, with UST, starting at W48, numerically less DM events were observed in the T2T arm, mainly driven by the lower number of CD-related hospitalizations and bowel damage events, potentially linked to numerically higher proportion of endoscopic responders at W48.1 These results advocate for an optimized T2T approach using strictly defined targets like endoscopic response, on top of clinical and biomarkers, to facilitate decision making in clinical practice.

References

1. Danese S, et al. United European Gastroenterol J. 2020;8:1264–1265 (Abstract LB11).

2. Peyrin-Biroulet L, et al. United European Gastroenterol J. 2021;9 (Suppl 1).
P001 Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on the IL23/IFNg axis
Authors: Lo J , Cozzetto D , Madgwick M , Sieh J Y X S , Olbei M , Alexander J L , Miguens Blanco J , Kudo H , Ibraheim H , Liu Z , Castro Seoane R , Goldin R , Marchesi J , Korcsmaros T , Lord G , Powell N
Published: January 2022

Background

Immune checkpoint inhibitors (CPI) have revolutionised cancer treatment, with previously untreatable disease now amenable to potential cure. Combination regimens of anti-CTLA4 and anti-PD-1 show enhanced efficacy but are prone to off target immune-mediated tissue injury, particularly at the barrier surfaces. CPI-induced colitis is a common a serious complication.

Methods

To probe the impact of immune checkpoints on intestinal homeostasis mice were challenged with combination anti-CTLA4 and anti-PD-1 immunotherapy, manipulation of the intestinal microbiota and antibody blockade/depletion studies. Colonic immune responses were profiled using RNA-sequencing, including high-resolution single cell analyses, and flow cytometry.

Results

CPI colitis was dependent on the composition of the intestinal microbiota and was characterized by remodelling of mucosal lymphocytes with induction of polyfunctional lymphocyte responses characterized by expression of interferon-g (IFNg), other pro-inflammatory cytokines/chemokines (Il22, Il17a Ccl3, Ccl4 and Ccl9) and cytotoxicity molecules (Gzmb, Gzma, Prf1, Nkg7). In comparison with mucosal lymphocytes in the steady state, polyfunctional lymphocytes from both CD4+ and CD8+ lineages upregulated costimulatory molecules and checkpoint molecules in CPI-colitis, indicating that these cells are usually very tightly regulated. CPI-colitis was attenuated following depletion of effector lymphocytes or following blockade of the IL23/IFNg axis.

Conclusion

This study provides new mechanistic insights into CPI-colitis, identifying polyfunctional, cytotoxic lymphocytes as key mediators of disease. Therapeutic targeting of their effector response or regulatory networks, including the IL23/IFNg axis holds the key to preventing and reversing CPI-colitis.
P008 Modulation of Wnt signaling via a Wnt mimetic improved epithelial healing without causing hyperplasia in a mouse colitis model
Authors: Lu C , Xie L , Shah D , Newman M , Baribault H , Yeh W C , Li Y
Published: January 2022

Background

Disruption of the colon epithelial barrier is a characteristic of ulcerative colitis (UC), allowing luminal microbes to come into contact with intestinal immune cells resulting in inflammation. All approved UC treatments are anti-inflammatory drugs and because they do not directly heal the epithelial barrier, the intestinal immune system continues to be exposed to gut microbes, resulting in low remission rates. Physiological Wnt signaling is fundamental to intestine epithelial homeostasis and renewal. Modulation of Wnt signaling might present an opportunity to achieve histological remission, which is associated with an improved clinical course, in UC. Previously, in vivo overexpression or administration of exogenous R-Spondin (RSPO), which amplifies Wnt signaling by increasing the amount of Wnt receptors on the cell surface, was reported to show effects on the intestine epithelium and helped regenerate intestine epithelium in various injury models. However, RSPO was also reported, to induce hyperplasia in normal intestine epithelium. Wnt signaling may also be modulated with recently developed Wnt mimetics which mimic endogenous Wnt proteins and activate downstream β-catenin signaling upon engaging with receptors of Wnts. The objective of the current study was to compare the effect of these two approaches in an acute DSS model.

Methods

Utilizing a mouse acute DSS colitis model, we compared the epithelial healing effects of a Surrozen proprietary Wnt mimetic, R2M3-26, RSPO2, and combination treatments of R2M3-26 and RSPO2. Animals received 4% (wt/vol) dextran sulfate sodium (DSS) in drinking water for 7 days followed by 1% DSS in drinking water from day 8. Protein treatments began on day 4. Disease activity, body weight (BW), fecal score, and occult blood were measured daily. Animals were terminated on day 10 for colon and small intestine histology as well as a serum cytokine panel.

Results

DSS damage to the colon epithelium was visible by H&E stain at day 4 and day 7 and continued to progress. We observed reduced mRNA expression of Wnt target genes and Wnt ligands in the colon, suggesting compromised Wnt signaling in the tissue. R2M3-26, RSPO2, and the combination treatments were efficacious in improving Disease Activity Index (DAI) and reducing serum cytokine levels. However, both RSPO treatments and combination treatments caused hyperproliferation of epithelium in the small intestine and the colon, consistent with what was reported in normal mice.

Conclusion

The Surrozen Wnt mimetic, R2M3-26, repaired the DSS damaged colon epithelium without causing hyperproliferation of epithelial cells in the intestine, making it a potential therapeutic platform for IBD.