BACKGROUND & AIMS:Secondary loss of response to ustekinumab is observed in patients with Crohn's disease (CD). Multiple dose-intensification regimens have been proposed. We aimed to test prospectively 2 different dose-intensification regimens with ustekinumab in patients with CD experiencing secondary loss of response. METHODS:This was an investigator-initiated, multicenter, randomized, placebo-controlled trial conducted at 15 hospitals in Belgium. Eligible patients were adults with CD treated with ustekinumab on maintenance dosing of 90 mg subcutaneous every 8 weeks and experiencing a secondary loss of response (Patient-Reported Outcomes 2: abdominal pain score >1 and liquid or very soft stool frequency >3 and an objective documentation of disease). Patients were randomized 1:1 to receiving a single intravenous reinduction with ustekinumab ≈6 mg/kg followed by either subcutaneous ustekinumab 90 mg every 4 weeks or every 8 weeks until week 48. The primary endpoint was the proportion of patients with steroid-free clinical remission at week 48, defined as Patient-Reported Outcomes 2 remission: (abdominal pain ≤ 1 and stool frequency ≤3) and fecal calprotectin <250 μg/g and no steroids in the 90 days before week 48. RESULTS:Between March 2020 and October 2023, 108 patients were randomized. Steroid-free clinical remission at week 48 was reached in 15% vs 19% of patients in the every 4 weeks vs the every 8 weeks group (difference 4%; P = 0.5). Serious adverse events occurred in 17% vs 13% of patients. CONCLUSIONS:In patients with CD and secondary loss of response to ustekinumab, dose intensification with a single intravenous administration and followed by 4 weekly subcutaneous dosing of ustekinumab was not more effective than 1 intravenous administration followed by 8 weekly subcutaneous dosing of ustekinumab. (ClinicalTrials.gov, Number: NCT04245215).

Abstract Topic Esophageal Cancer: Barrett‘s Esophagus: High-Grade Dysplasia and Early Invasive Cancer Background In many European countries, esophageal adenocarcinoma (EAC) incidence is increasing [1]. Barrett’s esophagus(BE), strongly associated with EAC, can progress via dysplasia to early and invasive adenocarcinoma [2]. Endoscopic treatment is the mainstay for early mucosal cancer (T1a/b) but requires intense post-treatment surveillance [3]. This results in overtreatment in most, and undertreatment in only a subset of patients [4]. The ENDEAVOR consortium, with over 10 partners from 8 European countries, will execute a 5-year project to develop a risk stratification model guiding treatment and surveillance. Below, preliminary results from the pilot study. Methods A total of 60 patients with BE and a visible lesion on endoscopy will be included in this study. Patients will be evaluated for endoscopic resection, with ablation therapy as needed. Forceps biopsies, brush biopsies and blood samples are taken before and after endoscopic resection. From these samples, clonal diversity measurements for HER-2, cMYC and CEP-17 are determined. Using these results, a determination of low or high clonal diversity is made. The degree of clonal diversity will be correlated to histopathological risk factors (lymphovascular invasion, differentiation grade, invasion depth) and recurrence events. Results Ongoing recruitment is at 33 patients. The population includes 6,1% female gender, mean age 67,27 (SD 10,42) and mean BMI 27,93 (SD 5,91). Median BE segment length is C1M3, 39,3% short-segment Barrett (<3cm maximum extent), and hernia diaphragmatica was present in 46,4% of patients. Paris classification lesion types consisted of Is (7; 20,59%), IIa (15; 44,12%), IIb (6; 17,65%), IIc (4; 11,76%). There were no Ip or III lesions included so far, 2 lesions (5,88%) were not classifiable. Of the 26 endoscopic resections performed so far, en bloc resection was performed in 23/26 procedures (88,46%). Histopathology staging has been obtained for 18 specimens, of which 9 were T0 (60%), 8 were T1a (33,33%) and 1 was T1b (6,67%) (see Table 1). In the 14 patients that have undergone endoscopy after endoscopic resection, There have been no recurrences registered so far, with average follow-up time after endoscopic resection of 3,54 months. Conclusion Our population includes an important number of patients with short-segment BE. With ongoing discussion about the surveillance intervals for short-segment BE, future data on recurrence rates in this subgroup will prove valuable. Continued follow-up to detect recurrences and biomarker analysis is being conducted.

Abstract Background In Crohn’s disease (CD), an exposure-response relationship exists for ustekinumab, with higher serum levels associated with better outcomes. Although several retrospective and observational studies demonstrate dose-escalation of ustekinumab can be effective in case of secondary loss of response (LOR), prospective placebo-controlled data are lacking. The aim of the REScUE study (NCT04245215) was to investigate the effect of 2 different re-induction regimens with ustekinumab on clinical, endoscopic, biological and pharmacological outcomes in patients with CD. Methods This Belgian multicentre prospective double-blind randomized placebo-controlled trial included adult patients with CD treated with ustekinumab who presented with secondary LOR to ustekinumab after documented primary response. Secondary LOR was defined by PRO-2 (AP> 1 AND SF> 3) and confirmed by either an elevated biomarker (CRP >5 mg/L or faecal calprotectin >250 µg/mg) or endoscopic signs of inflammation. All patients received a single IV re-induction with ustekinumab (≈6mg/kg) and were then randomized 1:1 to blinded maintenance ustekinumab 90 mg SC Q4W (intervention) or 90 mg SC Q8W (control) for 48 weeks. Primary endpoint was proportion of patients with steroid-free clinical remission (definition in fig 1) at week 48, with missing data were handled using non-responder imputation. Results In total, 132 patients were screened, and 108 patients were included: 67% female, median [IQR] age 41 [32-54] year, median disease duration 14 [7-22] years. Prior anti-TNF exposure was reported in 92% of patients, while ustekinumab was the first-line advanced treatment in 7% of patients. The primary endpoint of steroid-free clinical remission at week 48 was achieved by 9/54 (17%) patients in the q4w regimen vs 8/54 (16%) in the q8w regimen (p=0.96) (fig 1). Endoscopic remission (SES-CD <3) was achieved in 5/54 (10%) vs 3/54 (6%) (p=0.52), endoscopic response (≥50% decrease in SES-CD from baseline) was achieved in 11/54 (22%) vs 6/54 (12%) (p=0.23) and 0.52biomarker remission was achieved in 20/54 (38%) vs 13/54 (26%) (p=0.19) in the q4w regimen vs the q8w regimen, respectively. Time to first clinical remission was similar between groups (fig 2). Association with ustekinumab serum levels will be reported. No new safety signals were observed. Conclusion In patients with CD experiencing secondary LOR to ustekinumab, dose optimization with a single IV re-induction followed by intensified maintenance dosing (90 mg SC q4W) was not superior to a single IV re-induction followed by conventional maintenance dosing (90 mg SC q8W) in achieving steroid-free clinical remission. The secondary endpoints were numerically higher but not significant in the intensified regimen.

BACKGROUND AND AIMS:Mucosal healing is considered a key therapeutic endpoint in inflammatory bowel diseases (IBD) and comprises endoscopic improvement of inflammation without taking barrier healing into account. Mucins are critical components of the mucosal barrier function that give rise to structurally diverse isoforms. Unraveling disease-associated mucin isoforms that could act as an indication for barrier function would greatly enhance IBD management. METHODS:We present the intestinal mucin RNA isoform landscape in IBD and control patients using a targeted mucin isoform sequencing approach on a discovery cohort (n = 106). Random Forest modeling (n = 1683 samples) with external validation (n = 130 samples) identified unique mucin RNA isoform panels that accurately stratified IBD patients in multiple subpopulations based on inflammation, IBD subtype (Crohn's disease [CD], ulcerative colitis [UC]), and anatomical location of the intestinal tract (i.e. ileum, proximal colon, distal colon, and rectum). RESULTS:Particularly, the mucin RNA isoform panels obtained from the inflamed UC and CD distal colon showed high performance in distinguishing inflamed biopsies from their control counterparts (AUC of 93.3% and 91.1% in the training, 95.0% and 96.0% in the test, and 89.5% and 78.3% in the external validation datasets, respectively). Furthermore, the differentially expressed MUC4 (PB.1238.363), MUC5AC (PB.2811.15), MUC16 (ENST00000397910.8), and MUC1 (ENST00000462317.5 and ENST00000620103.4) RNA isoforms frequently occurred throughout the different panels highlighting their role in IBD pathogenesis. CONCLUSIONS:We unveiled region-specific mucin RNA isoform panels capturing the heterogeneity of the IBD patient population and showing great potential to indicate barrier function in IBD patients.

Abstract Background Mucosal healing is considered as a key therapeutic endpoint in inflammatory bowel diseases (IBD) and comprises endoscopic improvement of inflammation without taking barrier healing into account. Mucins are critical components of the intestinal mucosal barrier function that give rise to structurally diverse isoforms. In a recent study, we demonstrated that intestinal region-specific mucin RNA isoform expression captured the heterogeneity of the IBD patient population and showed great potential to indicate barrier function enhancing IBD management [1]. Given that epithelial cells can enter the bloodstream because of epithelial barrier injury upon inflammation, we further investigated whether intestinal-type mucin RNA isoforms have the potential as non-invasive biomarkers for IBD disease monitoring. Methods Using bulk RNA sequencing data (Illumina) mapped to our recently designed mucin RNA isoform landscape [1], we assessed mucin RNA isoform expression in the blood from 45 IBD patients (22 UC, 23 CD) and 19 controls and correlated the data to clinical outcome parameters (i.e. endoscopic activity (Mayo or SES-CD), inflamed intestinal region, histological activity (Geboes score), C-reactive protein level). Additionally, random forest-based feature selection, using a publicly available dataset (PRJNA774251), was carried out to select peripheral mucin RNA isoforms that accurately stratified UC patients (n=79) from controls (n=209). Results Overall, expression of MUC1, MUC4, MUC6, MUC12, MUC12-AS1, MUC16, MUC20, MUC20P1, and MUC20-OT1 mRNA was identified in the blood of IBD and control patients, with MUC1, MUC20 and MUC20-OT1 being abundantly present in both cohorts. At mucin RNA isoform level, 50 originated from the intestinal mucin RNA isoform landscape [1] with RNA isoforms derived from MUC20 and MUC20-OT1 classified as the top 10 most predominantly expressed isoforms. Interestingly, expression of several MUC20-OT1 RNA isoforms was decreased in UC or CD patients with moderate to severe inflammation compared to controls (Figure 1). In addition, four MUC20-OT1 isoforms and two MUC20 were correlated to the endoscopic inflammation score. Feature selection based on random forest modeling to distinguish UC patients with moderate to severe inflammation from controls unveiled a panel of 5 mucin RNA isoforms (MUC6 (ENST00000421673.7), MUC20-OT1(ENST00000429897.5), MUC4(ENST00000467235.1), MUC20-OT1(ENST00000626852.2) and MUC5AC(PB.2811.15); area under the curve of 75.7% (train set) and 60.3% (test set); Figure 2). Conclusion Peripheral blood mucin RNA isoform expression can be monitored in IBD patients, with MUC20-OT1 RNA isoforms as potential non-invasive biomarkers for intestinal barrier dysfunction. References [1]Arras, W., Breugelmans, T., Oosterlinck, B., De Man, J. G., Malhotra-Kumar, S., Abrams, S., ... & Smet, A. (2024). The intestinal mucin isoform landscape reveals region-specific biomarker panels for inflammatory bowel disease patient stratification. Journal of Crohn’s and Colitis, jjae155.

Aims The treatment of gallstones consists of an endoscopic retrograde cholangiopancreatography (ERCP) to extract choledocholithiasis (CDL) and a cholecystectomy (CCE) to prevent disease recurrence. Amongst the most feared and frequent complications of performing an ERCP is a post-ERCP pancreatitis (PEP). In this study, we compared a single step CCE+ERCP via rendez-vous technique to a two-step procedure to assess the risk of PEP.The treatment of gallstones consists of an endoscopic retrograde cholangiopancreatography (ERCP) to extract choledocholithiasis (CDL) and a cholecystectomy (CCE) to prevent disease recurrence. Amongst the most feared and frequent complications of performing an ERCP is a post-ERCP pancreatitis (PEP). In this study, we compared a single step CCE+ERCP via rendez-vous technique to a two-step procedure to assess the risk of PEP.

Background:Helicobacter pylori (Hp) infection predisposes to malignant and non-malignant diseases warranting eradication. In Belgium, resistance rates for clarithromycin demonstrate regional variations making the use of standard triple therapy (STT) borderline acceptable. According to a recent Belgian survey, STT and bismuth-based quadruple therapy (BQT), are equally frequent prescribed as first line treatment for treatment naïve Hp positive patients. This study aims to evaluate the eradication rates (ER) of BQT versus STT. Methods:Multicentre, non-blinded randomized, prospective study comparing ER in treatment-naïve Hp positive patients. ER were compared by intention to treat (ITT) and per protocol (PP) analysis. Results:Overall 250 patients were included (STT 126, BQT 124). Seventeen patients were lost to follow-up (6,8%). No significant difference in ER between BQT and STT was observed in ITT (73% vs 68%, p= 0,54) neither in PP analysis (81% vs 75%, p= 0,33). Side effects and endoscopic findings were comparable between groups. Post-hoc analysis showed no differences according to gender or site allocation. Conclusion:The numerical advantage of BQT did not translate in a significant improvement of ER when compared with STT. These results question the cost-effectiveness of BQT, while confirming the suboptimal eradication rates on STT. A nationwide monitoring of resistance patterns, maximal investments in treatment adherence as well as a detailed follow-up of the changing treatment landscape are mandatory to continuously optimise Hp ER in Belgium.

We report the case of a 59-year-old patient with a history of peripheral T-cell lymphoma, not otherwise specified (PTCLNOS) presenting with profuse diarrhea 3 months after completing lymphoma treatment. After exhaustive workup a recurrence of the peripheral T-cell lymphoma in the gastrointestinal tract was diagnosed. Predominant gastrointestinal recurrence is a unique presentation of relapse of PTCL-NOS. To the best of our knowledge, no other case reports have covered predominant gastrointestinal recurrence of PTCL-NOS so far. (Acta gastroenterol. belg., 2024, 87, 527-530).

Abstract Mucosal barrier dysfunction and aberrant mucin expression are major hallmarks in the pathophysiology of IBD. Mucins are highly polymorphic, and the presence of genetic differences can alter gene expression, resulting in several mRNA isoforms via alternative splicing. While most isoforms encode similar biological functions, others alter protein function, potentially resulting in progression towards disease. Currently, little attention has been given to the importance of mucin mRNA isoforms in IBD. The aim of our study is to investigate the potential of mucin mRNA isoforms as novel biomarkers for the evaluation of IBD activity and subtypes. To obtain this goal, RNA was extracted from colonic and terminal ileal biopsies of IBD patients that underwent an endoscopy at the Antwerp University Hospital (UZA). Additionally, patients without a history of IBD undergoing an endoscopy due to a positive iFOBT which show no endoscopic abnormalities, were included as controls. Library preparation was performed with the PacBio Iso-Seq multiplex protocol adapted for targeted transcriptome sequencing. Targeted capture was accomplished by using a custom-designed pool of probes, developed for the capture of all mucin gene transcripts. Samples were sequenced on the PacBio Sequel platform at the University of Antwerp. The data was analyzed by using the isoseq3-pipeline and additional filtering with SQANTI3 was performed. In total 106 biopsies were sequenced on the PacBio platform. The resulting intestinal mucin transcriptome was merged with the human reference transcriptome. On this combined mucin transcriptome Illumina bulk RNA sequencing data from over 2000 intestinal biopsies (GEO dataset GSE193677) were mapped to determine mucin isoform expression. An external dataset (GEO dataset GSE165512) was used for additional validation. A classification random forest was trained on this data to distinguish inflamed IBD from non-inflamed control patients based on the mucin isoform expression alone. The model performed well on train and test datasets but decreased in the external validation (Table 1). Dividing the samples based on disease phenotype greatly increases performance on the external validation dataset (Table 1). When only training on ileal biopsies, the model proved to be excellent in distinguishing Crohn’s disease patients from controls (Table 1). Classification of inflamed ulcerative colitis from control patients based on only the biopsies from the distal colon was similar to the latter (Table 1). Our machine learning model was able to distinguish Crohn’s disease from control patients and ulcerative colitis from control patients based on mucin mRNA isoform expression. In addition, our data suggests that the mucin isoform expression may vary between different regions within the colon. Table 1 Area under the receiver operator curve (AUCROC) from a random forest classifier trained on mucin isoform expression of inflamed biopsies of IBD and non-inflamed control patients.

Background and aims:adenoma detection rate is a well known quality parameter for colonoscopy. However recently other quality parameters have emerged. We wanted to evaluate the histology of the resected polyps, different quality indicators of colonoscopy and post colonoscopy colorectal cancer (PCCRC) in Belgium and analyzed data about colonoscopies performed between 2008-2015.Methods:Reimbursement data on colorectal related medical procedures from the Intermutualistic Agency were linked with data on clinical and pathological staging of colorectal cancer and with histologic data of resected polyps available at the Belgian Cancer Registry over a period covering 8 years (2008-2015).Results:298,246 polyps were resected in 294,923 colonoscopies, of which 275,182 were adenomas (92 %) and 13,616 were SSLs (4%). There was a significant but small correlation between the different quality parameters and PCCRC. Post colonoscopy colorectal cancer rate after 3 years was 7.29 %. There were marked geographic differences in Belgium concerning adenoma detection rate, sessile adenoma detection rate and post colonoscopy colorectal cancer.Conclusion:Most resected polyps were adenomas, only a small percentage involved sessile serrated lesions. There was a significant correlation between adenoma detection rate and other quality parameters, and a small but significant correlation between PCCRC and the different quality parameters. The lowest post colonoscopy colorectal cancer rate was reached with an ADR of 31.4 % and a SSL-DR of 1.2 %.

The European Society of Gastrointestinal Endoscopy and United European Gastroenterology have defined performance measures for upper and lower gastrointestinal, pancreaticobiliary, and small-bowel endoscopy. Quality indicators to guide endoscopists in the growing field of advanced endoscopy are also underway. We propose that equal attention is given to developing the entire advanced endoscopy team and not the individual endoscopist alone.We suggest that the practice of teams intending to deliver high quality advanced endoscopy is underpinned by six crucial principles concerning: selection, acceptance, complications, reconnaissance, envelopment, and documentation (SACRED).

Acute pancreatitis can be complicated with necrosis of the pancreatic or peripancreatic tissue. This necrosis can become liquified and form a well-defined wall (walled-off necrosis or WON) and can become infected and form abscesses. Necrotizing soft tissue infections are rare infections of the deep tissue and subcutaneous fat and are mostly caused by trauma or perforated visceral organs. They can, however, rarely be caused by infected retroperitoneal collections. To date only 3 case reports have been published of a necrotizing soft tissue infection complicating a necrotizing pancreatitis. Both acute, complicated pancreatitis and necrotizing soft tissue infections carry a high mortality and morbidity rate with surgery being the mainstay therapy for the latter, often leaving the patient disfigured. We report the case of a 62-year-old man presenting to the emergency department with a painful and erythematous rash of the upper leg as complication of an acute necrotizing pancreatitis.

Patient inclusion and study design The PROVE-IBD study is a prospective multicentre observational study. The study cohort (n=71) consisted of 44 patients with moderate-to-severe UC and 27 patients with moderate-to-severe CD, who initiated vedolizumab as part of their conventional treatment plan and fulfilling the national reimbursement criteria (which entails previous failure of immunosuppressants). Active CD was defined by a Harvey-Bradshaw Index (HBI) score higher than 4 together with a C-reactive protein (CRP) level higher than 10 mg/l or fecal calprotectin higher than 250 μg/g or presence of ulcers during endoscopy. Active UC was defined as a total Mayo score higher than 7. All subjects were at least 18 years of age at the initiation of vedolizumab therapy. Exclusion criteria were unclassified IBD, previous treatment with anti-adhesion molecules and subtotal colectomy or proctocolectomy prior to vedolizumab initiation. The concomitant use of thiopurines or steroids was allowed in case of a stable dose for at least 4 and 2 weeks, respectively, however the use of steroids was tapered at week 10 to assure that the response defined at week 14 could be attributed to vedolizumab treatment. According to the treatment guidelines, patients received 300 mg intravenous vedolizumab at weeks 0, 2 and 6, while CD patients received an additional dose at week 10. Some patients did not follow the full treatment plan due to the development of complications during the induction phase. Data obtained from these patients were included using the last observation carried forward method.

Dose intensification of vedolizumab (VDZ) for moderate‐to‐severe ulcerative colitis (UC) and Crohn's disease (CD) may be effective in patients losing response. We aimed to assess the clinical and pharmacokinetic effect of VDZ dose intensification.

Abstract Background Patients with inflammatory bowel diseases (IBD) are at increased risk of dysplasia and colitis-associated cancer (CAC). The presentation of (pre)neoplastic lesions (low-grade dysplasia (LGD), high-grade dysplasia (HGD) or colorectal cancer (CRC) is reported to vary depending if the lesions are located inside disease area (IDA) or outside diseased area (ODA). The primary aim was to analyse the characteristics and prognostic of IDA compared with ODA neoplastic lesions in a large cohort of IBD patients. Methods We performed a multicentre retrospective pathological data collection from 7 tertiary referral regional or academic IBD centres in Belgium. Clinical, endoscopic and pathological data were retrieved through retrospective electronic chart review. From the IBD pathology databases, 1183 colorectal lesions were identified in 541 IBD patients: 415 developed dysplasia (77%) and 126 CRC (23%) during their follow-up. Biopsies and surgical specimen were centrally reviewed by an expert IBD pathologist to confirm the diagnosis of dysplasia and/or CRC. Results Demographic and clinical variables of the study population are summarised in Table 1. More patients with IDA lesions had HGD (9%) or CAC (27%) during their follow-up compared with the group of patients with ODA lesions (3% of HGD and 11% of CRC) (p < 0,0001). Mortality was higher in patients with IDA than in those with ODA lesions (p < 0.05). When comparing IBD patients with IDA lesions and CAC (=111) to those with ODA lesions and sporadic CRC (n = 15), median age at IBD diagnosis was lower (29 (IQR:22–49) vs. 41(IQR:28–54) years; p = 0.0001). Characteristics of the 1183 neoplastic lesions are summarised in Table 2. IDA lesions were more frequently non-visible, non-polypoid and ≥ 1 cm than ODA lesions (p < 0.0001). ODA sporadic CRC was more frequently located in the right colon compared with IDA CAC (5/16 (31%) vs. 21/133 (16%), p < 0.01). Conclusion Neoplastic lesions outside the diseased area were more likely to be visible, polypoid, < 1cm, in the right colon and diagnosed at endoscopy than inside disease area lesions. A lower prevalence of HGD and Cancer were reported with neoplastic lesions outside the diseased area.

Few data are available regarding the combination of biological therapies (anti-TNF, anti-integrin, anti-interleukins (IL4, 12/23, 17A, 23)) or with a small molecule in patients with IBD. We here report the safety and efficacy of combining these drugs through a national retrospective multicenter case series. Cases were extracted from local databases within the last 3 years. Combined therapy was defined as the concomitant use for a minimum of 1 day of 2 biologics or 1 biologic with a small molecule. Patients’ demographics, disease’ characteristics and types of combined therapies were recorded. Safety was defined as the occurrence of any serious adverse event (SAE): serious infection, opportunistic infection, any hospitalisation, cancer and death, whereas the efficacy of combination was clinically appreciated by physicians. From 8 centres, 23 combined therapies were observed in 19 IBD patients (74% Crohn’s disease, 21% ulcerative colitis and 5% IBD type unclassified). Median age at combination was 43.0 years ([IQR]: 31.5–59.0). Seventeen patients presented with a minimum of 1 concomitant IMID (ankylosing spondylitis (n = 11), psoriasis or psoriatic arthritis (n = 5) and other conditions (n = 5)). Reasons for starting a combination were active IBD (57%), another active IMID (30%) or both (13%). Anti-TNF and anti-integrin were combined in 11 cases, anti-TNF and anti-ILs in 5, anti-integrin and anti-ILs in 4 and other combinations in 3 (anti-TNF+rituximab+methotrexate; anti-IL4+anti-IL12/23; anti-IL12/23+methotrexate+leflunomide). The median duration of combined therapies was 5 months ([IQR]: 2–9). During 15.8 patients/years of combined therapy, 11 adverse events (AE) including 9 SAE were recorded in 8 patients. Eight infections were reported with various combinations: anti-TNF and anti-IL in 4 cases, anti-TNF and anti-integrin in 3 and anti-TNF+rituximab+methotrexate in 1. Two infections (both anti-TNF+ anti-integrin) were graded severe leading to hospitalisation, 6 were graded mild or moderate. Cancer and death were not observed. After combined therapy, IBD disease activity was clinically improved in 44% and remained stable in 50% of patients, whereas clinical improvement of IMID was observed in 25% of patients. Overall, the combination of treatments was withdrawn due to ineffectiveness or serious adverse events in 39% and 4%, respectively. In our experience, the combination of biologics in patients with IBD ±. another IMID was associated with short term increased efficacy in almost half of patients but also with a risk of infections in one third. No new safety signals were observed in this difficult to treat patients but extensive data are urgently needed.

BACKGROUND AND AIMS:There is evidence for a disturbed intestinal barrier function in inflammatory bowel diseases [IBD] but the underlying mechanisms are unclear. Because mucins represent the major components of the mucus barrier and disturbed mucin expression is reported in the colon of IBD patients, we studied the association between mucin expression, inflammation and intestinal permeability in experimental colitis.METHODS:We quantified 4-kDa FITC-dextran intestinal permeability and the expression of cytokines, mucins, junctional and polarity proteins at dedicated time points in the adoptive T cell transfer and dextran sodium sulfate [DSS]-induced colitis models. Mucin expression was also validated in biopsies from IBD patients.RESULTS:In both animal models, the course of colitis was associated with increased interleukin-1β [IL-1β] and tumour necrosis factor-α [TNF-α] expression and increased Muc1 and Muc13 expression. In the T cell transfer model, a gradually increasing Muc1 expression coincided with gradually increasing 4-kDa FITC-dextran intestinal permeability and correlated with enhanced IL-1β expression. In the DSS model, Muc13 expression coincided with rapidly increased 4-kDa FITC-dextran intestinal permeability and correlated with TNF-α and Muc1 overexpression. Moreover, a significant association was observed between Muc1, Cldn1, Ocln, Par3 and aPKCζ expression in the T cell transfer model and between Muc13, Cldn1, Jam2, Tjp2, aPkcζ, Crb3 and Scrib expression in the DSS model. Additionally, MUC1 and MUC13 expression was upregulated in inflamed mucosa of IBD patients.CONCLUSIONS:Aberrantly expressed MUC1 and MUC13 might be involved in intestinal barrier dysfunction upon inflammation by affecting junctional and cell polarity proteins, indicating their potential as therapeutic targets in IBD.

Tofacitinib, an oral small molecule Janus kinase inhibitor, has been approved in 2018 for the treatment of moderate to severe ulcerative colitis (UC) in Europe. We report on real-world short-term efficacy and safety data from a multicenter Belgium refractory cohort of UC patients with prior exposure to both anti-TNFα and vedolizumab. This is an observational, national, retrospective multicentre study including all UC active patients started on tofacitinib (10 mg BID) from 25 centres in Belgium between November 2018 and August 2019. Prospectively collected data were retrospectively analysed according to intention to treat. Primary endpoints were clinical and endoscopic response and remission rates at weeks 8 and 16. Clinical response and remission were defined as a reduction in the Modified Clinical Mayo score (rectal bleeding, stool frequency) of ≥2 and ≤1, respectively. Endoscopic response and remission were defined as a reduction in Endoscopic Mayo score of ≥1 and ≤1, respectively. Complete endoscopic remission was defined as an Endoscopic Mayo score of 0. Descriptive statistics and Wilcoxon signed-rank test were calculated using Medcal 19.1. Demographic and baseline data of the 70 included patients are presented in Table 1. Of note is that nearly all patients were refractory to at least one anti-TNF and vedolizumab. Median follow-up was 16 weeks (IQR 13–26). Fifty-four per cent (38/70) of patients required prolonged induction at 10mg BID. Clinical evaluation was available in all patients at week 8 and 49 patients at week 16, while endoscopic data were available in 52 patients and 42 at weeks 8 and 16, respectively. Clinical response and remission, and endoscopic response and remission at weeks 8 and 16 are presented in Figures 1 and 2. Fifty per cent (21/42) of the patients under steroids at baseline could have stopped steroids at 16 weeks. Median baseline Modified Mayo score (rectal bleeding, stool frequency and endoscopy) decreased from 7 (IQR 5–8) to 4 (IQR 2–7) after 8 weeks (n = 49) (p < 0.0001), and down to 2 (IQR 1–5) at week 16 (n = 40) (p < 0.0001). Median CRP significantly decreased from baseline (5.3 mg/l, IQR [1.9–16.8]) to 1 mg/l at week 8 (IQR 0.5–6.2) (n = 49) (p = 0.003). Tofacitinib was well tolerated with only 1 reported case of single dermatome herpes zoster and no case of venous thromboembolism. Tofacitinib very effectively induced short-term clinical and endoscopic response and remission even in a refractory cohort of patients with UC in a real-world clinical setting. During this short-term follow-up, tofacitinib was well tolerated with respect to adverse events.