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Background Subcutaneous (SC) formulations of infliximab (IFX) and vedolizumab (VDZ) were recently approved for maintenance treatment of patients with inflammatory bowel disease. However, further investigation is required to identify the patients most likely to benefit from intravenous (IV)-to-SC switch. We hypothesise that therapeutic drug monitoring (TDM) can guide the IV-to-SC switch. Methods Population pharmacokinetic (popPK) simulations were performed with previously published popPK models to explore the exposure profiles following various label and off-label IV-to-SC dosing scenarios (NONMEM 7.5).1-3 All virtual patients received IV IFX or VDZ at treatment weeks 0, 2, 6, 14, 22, and 30, and then switched to every two weeks (Q2W) or Q1W SC dosing. Results Following IV-to-SC switch according to label, the serum trough concentrations (Ctrough) will gradually increase over eight weeks (for IFX) and 16 weeks (for VDZ) before reaching the new steady state (SS) (Figure 1A-B). A linear relationship was observed between IV and SC Ctrough,ss for both drugs, allowing the prediction of SC Ctrough,ss hnbased on previous IV Ctrough,ss (Figure 1C-D). Administering the first SC dose four instead of eight weeks after the last IV dose will hit SS much faster (immediately for IFX and in two months for VDZ), thereby allowing earlier TDM and avoiding the risk of temporary underexposure (Figure 2). Patients on Q6W or Q8W IV infliximab can safely switch to Q2W SC infliximab without a meaningful decrease in Ctrough,ss, while patients on Q4W IV infliximab need Q1W SC infliximab (Figure 3A). Vedolizumab Ctrough,ss will always be maintained after switching to Q2W dosing (Figure 3B). While the Ctrough,ss target is easily maintained, it is more challenging to guarantee a stable eight-week averaged area under the concentration-time curve at SS (AUC8w,ss) upon switch. Surprisingly, switching to Q2W SC infliximab resulted in a lower AUC8w,ss than all possible IV infliximab dosing regimens used in clinical practice (Figure 3C). Only patients on Q4W IV vedolizumab should switch to Q1W SC dosing (Figure 3D). Depending on the belief whether it is Ctrough,ss or AUC that drives therapeutic response, patients who were on escalated IV dosing regimens may need Q1W SC to guarantee similar exposure before versus after switch (Table 1). Conclusion We performed popPK simulations to inform clinicians how to integrate TDM of IFX and VDZ into their clinical practice as a tool to monitor patients and guide decision-making on the optimal dosing strategy. REFERENCES: 1. EMA/CHMP/548703/2019. European Medicines Agency. 2019. 2. Rosario et al. Aliment Pharmacol Ther. 2015. 3. Rosario et al. J Crohns Colitis. 13, S357 (2019).

Introduction Access to surgical care for the transgender population has been a persistent challenge. Frequently cited barriers include long waiting lists, strict insurance prior authorization protocols, surgeon scarcity, financial cost, and social stigma. These issues have been magnified throughout the COVID-19 pandemic response, as the diversion of resources has led to the postponement of surgeries deemed “routine” or “non-essential.” Many medical societies and healthcare organizations have classified gender-affirming surgery (GAS) as such despite the World Professional Association for Transgender Health (WPATH) defining surgical care for gender dysphoric individuals as medical necessity. Unfortunately, delays in care for this population contribute to prolonged mental health distress. Another important barrier to access centers on the issue of surgical timing. Many patients cannot afford to postpone school and work obligations to undergo multiple surgeries each with long recovery times. Furthermore, staffing shortages nationwide have limited operating room (OR) availability. To respond to these issues, our center organized a multidisciplinary collaboration among various surgical subspecialties to perform simultaneous GASs (e.g., top and bottom surgeries). In this way, the patient can undergo multiple GASs in a single procedure, thus limiting anesthesia exposure, expediting postoperative recovery, improving patient satisfaction and maximizing limited healthcare resources. Objective To describe a multidisciplinary model for GAS involving simultaneous top and bottom surgery to improve access to care for the transgender population in a resource-limited environment. Methods Case report describing successful multidisciplinary surgical management of a transgender female desiring multiple simultaneous GAS. Results Patient is a 24-year-old active duty transgender female who met WPATH criteria for top and bottom surgery. She desired numerous procedures including simple orchiectomy, breast implants and facial feminization. Given our limited OR availability during COVID-19, the decision was made to perform all of these surgeries under the same anesthetic. She underwent breast augmentation and fat harvesting with plastic surgery, which was immediately followed by simultaneous simple orchiectomy by urology and facial feminizing surgery with otolaryngology. Total operative time was 8.3 hours. Patient was discharged on post-op day 1 and had an uneventful recovery without surgical or anesthetic complications. Conclusions Simultaneous GAS is an effective approach to improve access to care during the COVID-19 pandemic. A single anesthetic enables the patients to achieve their surgical goals sooner and to lessen their overall recovery time compared to staged procedures. Disclosure No

Background Sarcopenia (loss of skeletal muscle mass and/or strength) is a predictor of postoperative morbidity in various surgical populations. We evaluated the impact of sarcopenia in postoperative outcomes after intestinal surgery in patients with Crohn’s disease (CD) at a tertiary referral centre. Methods This is a retrospective analysis of all patients with CD undergoing intestinal surgery at our centre, between January 2013 and September 2019 with available abdominal computed tomography images within 90 days before surgery. The images were assessed for sarcopenia according EWGSOP2 criteria (Skeletal Muscle Index Results A total of 114 patients with Crohn’s disease were included (table 1 and 2). The prevalence of sarcopenia was 67.5%. Common intestinal procedures were ileocecal resections (49%), segmental small-bowel resections/stricturoplasty (6.1%), and colon resection (8.8%). Sarcopenic patients have more frequently penetrating phenotype than patients without sarcopenia (p=0.007). Body mass index and serum albumin levels were significantly lower (p Conclusion The prevalence of sarcopenia based on EWGSOP2 criteria is high in patients with CD requiring bowel resection. In this cohort, sarcopenia was not linked to higher rate of postoperative complications, although this might be explained by different surgical procedures and nutrition management before and after surgery for CD.

Background There is an ongoing debate whether the type of anastomosis following intestinal resection for Crohn’s disease (CD) can have an impact on complications and postoperative recurrence. The aim of the present study is to describe the outcome of side-to-side (S-S) versus end-to-end (E-E) anastomosis after ileocolic resection for CD. Methods A retrospective single center comparative study was conducted in consecutive CD patients who underwent primary ileocecal resection between 2005 and 2013. All patients underwent colonoscopy 6-months postoperatively to assess endoscopic recurrence, defined as modified Rutgeerts’ score >i2b. Surgical recurrence implied reoperation due to CD activity at the anastomotic site. Modified surgical recurrences was defined as the need for re-operation or balloon-dilation. Perioperative factors related to recurrence were evaluated. Results Of the128 patients included, 52 (40.6%) received an E-E anastomosis. Median follow-up was longer in the E-E group (8.62 vs 13.68 years, p Conclusion The type of anastomosis did not influence endoscopic recurrence and immediate postoperative disease complications. However, the wide diameter and the morphologic characteristic of the stapled S-S anastomosis result in a lower risk for balloon dilatation and surgical reintervention in the long-term.

Background An ileocolonic resection with ileocolonic anastomosis is often required in patients with Crohn’s disease (CD). Postoperative recurrence (POR) is common, with host-luminal interactions being implicated. However, these interactions are poorly understood. We aimed to obtain insights in the early mechanisms of POR CD focusing on sequencing-based gene networks in the mucosa. Methods We included 36 CD patients who underwent ileocolonic resection with ileocolonic anastomosis, and collected mucosal biopsies from the neoterminal ileum 6 months after surgery (Table 1). We defined POR by a Rutgeerts score ≥i2b at month 6, and compared this to complete absence of endoscopic activity (i0). All biopsies underwent single-end RNA sequencing (Illumina TruSeq Stranded mRNA). Gene co-expression network clusters were identified using weighted gene co-expression network analysis (R\WGCNA), were tested for correlation with the primary outcome POR and clinical factors, and multiple testing correction was applied (FDR Results WGCNA analysis identified 25 co-expression clusters, of which five correlated with the postoperative outcome (clusters V, VI, IX, XV, XXV) (Fig.1). All but cluster XXV were upregulated in POR, with a profound immune-related enrichment in cluster V and VI (eg. (a)granulocyte adhesion and diapedesis, and IL17 signalling); microRNA biogenesis (cluster IX) and wound healing and fibrosis signalling (cluster XV). Interestingly, one cluster (XXV) was inversely correlated with POR, and genes within this cluster were mainly involved in autophagy, ferroptosis and oxidative stress response. The main hub gene (r=0.95, FDR=8.17E-19) within this cluster XXV was GPX4 (Glutathione peroxidase 4), a negative regulator of ferroptosis. Moreover, after cellular deconvolution, we found a positive correlation between the epithelial gene enrichment signature and the expression of GPX4 (r=0.52, p=0.0011). Finally, the main upstream regulator of the genes within this cluster XXV was HNF4A, a transcription factor known to regulate ferroptotic response. Conclusion We identified a mucosal transcriptomic signature associated with postoperative CD recurrence. Both autophagy and ferroptosis were found to be key protective pathways for recurrence with GPX4 as central hub. Our results complement recent findings of impaired epithelial GPX4 activity in ileal CD lesions evoking an inflammatory response to dietary lipids (Mayr et al Nat Comm 2020).

Background The efficacy of faecal microbiota transplantation (FMT) in UC has been reported to be donor-, patient- and procedure-dependent (Rees et al., 2022). The RESTORE-UC trial [NCT03110289] aimed to improve the outcome of FMT in patients with active UC by donor preselection on microbiota level, a strict anaerobic preparation and repeated FMT administration. The trial was prematurely stopped for futility (Caenepeel et al., 2022). We investigated changes in resp. biopsy and faecal samples obtained host transcriptomics and microbiota profiles from baseline to primary endpoint (PE) at week 8 to understand reasons for the observed lack of efficacy. Methods Active UC patients (total Mayo score 4-10 with endoscopic sub-score ³2, n=72) were randomly allocated to receive 4 anaerobic-prepared superdonor (S) FMT or autologous (A) FMT. Primary endpoint was defined as steroid-free clinical remission (Total Mayo ≤ 2, with no sub-score >1). Host RNA extractions were performed from mucosal biopsies collected at week 0 (n=63) and 8 (n=54) using the Qiagen AllPrep DNA/RNA Mini kit, and sequenced using Illumina HiSeq4000. Sequencing data was further processed (read-count filtering, normalization) and further analyzed using DESeq2 package. Corresponding faecal samples (resp. n=62 and n=50) were submitted to DNA extractions using MagAttract PowerMicrobiome DNA/RNA kit on an automated extraction platform, followed by library prep and 16S rDNA-sequencing using Illumina MiSeq. The obtained sequences were subjected to the DADA2 pipeline in R and the Quantitative Microbial Composition (QMP) was quantified by flow cytometry. Results Eight responders were observed: 3 after S-FMT and 5 after A-FMT, as well as 58 non-responders considering the intention-to-treat population. Responders to FMT tended to cluster at baseline (adonis p=0.34) and PCA analysis on the top 500 mucosal genes with the highest variance (Fig.1), showed a significant host effect at week 8 between responders and non-responders (adonis p Conclusion A trend towards clustering of responders on host mRNA level and QMP was observed at baseline as well as at the primary endpoint, showing a potential role for pre-FMT patient selection by phenotype. Moreover, the dysbiotic enterotype Bacteroides-2 seems to be decreased after FMT. However, further analyses are mandatory to identify specific predictors of response and the origin of the microbiota shift.

Background Optimal management of perianal Crohn’s disease (pCD) consists of combined medical (preferentially anti-TNF) and surgical treatment. However, it is still unclear if this has improved outcomes. This study aimed to described outcome and prognosis of pCD patients at a referral center over almost two decades. Methods All pCD patients referred for active perianal fistulas between 2000-2018 at our center were considered eligible for this retrospective study. Patients were divided into two groups according to the date of pCD diagnosis: period A (2000-2006) and period B (2006-2018). The complement of Kaplan-Meier estimates were used to visualize the time since pCD diagnosis until temporary and definitive fecal diversion. Clinically important outcomes such as need for temporary or permanent fecal diversion, and factors associated to these outcomes were evaluated by Cox regressions models. Results A total of 336 patients with active pCD were identified. The mean interval between the diagnosis of CD and the perineal fistulizing disease was 4.9 years (+-7.64). Mean follow up was 10.83 years (SD ± 4.5). The two groups were similar for demographic and clinical characteristics, except for the cumulative exposure to biologicals prior to pCD diagnosis [27.8% vs 46.9% in period A and B, respectively (p Conclusion This retrospective analysis spanning almost twenty years shows that prognosis of CD patients affected by anal fistulas remains poor and has not much changed over time, despite the introduction of biologicals and new surgical techniques. The observed increase in definitive fecal diversion in more recent years can be partially explained by referral bias and/or a more aggressive clinical management of the most severe cases. Extraintestinal manifestations and synchronous complicated luminal disease increased the risk of definitive stoma in the long-term.

Background Up to 10% of patients with ulcerative colitis who undergo a proctocolectomy with ileal pouch-anal anastomosis, will develop chronic antibiotic refractory pouchitis (CARP). As there is a large unmet need in the management of these patients, we evaluated the efficacy and safety of induction and maintenance therapy with ustekinumab (UST). Methods We performed a prospective, multicentre, open-label study of patients with CARP (mPDAI ≥5 with an endoscopic subscore ≥2) . Patients received a weight-range-based infusion of UST at baseline (~6mg/kg) and subcutaneous injections of 90mg UST every 8 weeks thereafter until week 48. Patients underwent a pouchoscopy at baseline, week 16 and week 48, with assessment of the modified pouchitis disease activity index (mPDAI). The primary endpoint was the proportion of patients achieving steroid-free remission (mPDAI Results We enrolled 22 patients (59% male, median age 42.2 years, median time after surgery 8.2 years). Twelve (54.5%) patients had previously been treated with biologics for CARP (table 1). At week 16, steroid-free remission was achieved in 27.3% of patients. At week 48, steroid-free remission was achieved in 36.4% and response in 54.5% of patients. In the 14 patients continuing UST at week 48, a significant decrease in total mPDAI (4 (1.8-7.3) vs. 8 (8-10), p Conclusion In this open-label pilot study in patients with CARP, maintenance therapy with UST showed a clinical and endoscopic effect in half of the patients, but was not associated with changes in inflammatory biomarkers. These promising results warrant confirmation in a placebo-controlled study with UST for the treatment of CARP.

Background There is a growing consensus across stakeholders on the value of patient preference (PP) studies, as recognized by the European Medicines Agency and the European Network for Health Technology Assessment. This study aimed to develop a PP survey to quantitatively evaluate which characteristics are most important to inflammatory bowel disease (IBD) patients, so that the results can inform the medicinal product life cycle (MPLC). Methods Following the PREFER recommendations, a four-step approach was followed to develop the PP survey: 1) stated preference method selection, 2) attribute and level development, 3) survey implementation, and 4) survey piloting. Throughout the different steps of the survey development, an advisory board (AB) consisting out of patients, patient organizations, gastroenterologists, IBD nurses, and statisticians were consulted. Results First, a discrete choice experiment (DCE) was chosen as the preferred elicitation method because it allows to reach the objectives of the survey, namely to: 1) quantify the relative importance of different attributes, 2) elicit the trade-offs patients make, and 3) measure preference heterogeneity. Second, a scoping literature review of IBD clinical trials, available IBD treatments, and previously published preference studies was performed. Discussions on these characteristics with patients (n=11) during focus group discussions (FGDs) using the nominal group technique revealed the following patient prioritized characteristics: prevent surgery, long-term clinical remission, improved quality of life, occurrence of urgency, and improved labor rate. Based upon the results of the FGDs, a preliminary list of possible attributes for inclusion in the DCE was refined during AB meetings. This list was iteratively adapted until consensus was found on 14 attributes, their levels, and corresponding explanations (Figure 1). Third, the DCE survey was designed to include these 14 attributes using partial profiles next to measures about sociodemographic variables, health literacy, and treatment experience. Fourth, piloting the study with IBD patients (n=4) revealed that the survey was comprehensible, had a good flow, and contained graphics that supported the content. Only minor text edits were needed. Conclusion It is key to develop a PP survey in partnership with patients and other members of the AB. This survey will be rolled out across Europe in 11 different languages and will increase understanding of which treatment aspects are most important to IBD patients. These aspects should be included in drug development and evaluation so that the MPLC can be more patient-centered and future treatments will target aspects that are most important to IBD patients themselves.

Background At present, the significance of histologic remission in Crohn’s disease [CD] is unclear. One of the main reasons is the heterogeneous distribution of the lesions. This contrasts with ulcerative colitis, where histologic scoring systems have been applied with success on limited numbers of biopsies. We assessed the variability of histologic activity in paired same-segment biopsies from CD patients. Methods All CD patients undergoing ileocolonoscopy between January 2020 and July 2022 at our tertiary referral center were eligible for inclusion. Clinical data were retrospectively collected from medical records. Endoscopies were video-recorded and the Simple Endoscopic Score for Crohn’s Disease [SES-CD] was used to evaluate endoscopic activity. Paired biopsies were taken within the most affected area per segment, in accordance with ECCO guidelines. The Global Histology Activity Score (GHAS), the Geboes Score [GS], the Robart’s Histopathology Index [RHI] and the Nancy Histological Index [NHI] were determined for each biopsy by an experienced IBD pathologist [GDH] blinded to the endoscopic scores. The cut-off values for histologic remission were set at GHAS ≤4, GS Variability was assessed by intraclass correlation coefficient [ICC] and Kappa statistics. Association between histologic and endoscopic scores was studied with Spearman’s rank correlation coefficient. Results A total of 151 biopsy pairs from 128 patients were analysed. Patient characteristics are summarised in Table 1. Endoscopic activity was observed in 79% of segments. In patients with endoscopic remission, histologic activity (presence of neutrophils) was found in 29% of cases. There was a moderate association between the endoscopic and histologic assessment, with correlation levels ranging from 0.48 to 0.52 [p Histologic indices showed fair agreement between paired biopsies [Table 2]. Looking at the predefined cut-offs, moderate variability across the different histological scores was seen [Table 3]. When comparing biopsies from segments with endoscopic activity and those without, overall higher variability in active segments and substantial agreement in paired biopsies from inactive segments was observed [Table 4]. Conclusion The patchy nature of microscopic inflammation in CD is reflected in the histologic scores of paired same-segment biopsies, with only moderate agreement across histologic scoring indices, although lower variability was seen in biopsies from endoscopic inactive segments. Endoscopic activity only moderately reflects histological status. Multiple biopsies per segment are therefore needed for accurate histological evaluation, the optimal number necessary remains to be explored.

Background Extending the infliximab infusion interval has been attempted in patients with Crohn’s disease (CD) and ulcerative colitis (UC) who sustained treatment response following an earlier interval shortening. We aimed to identify predictors of sustained remission after infliximab interval extension. Methods: Data from 30 adult patients (17 CD, 13 UC), who underwent infliximab interval extension following earlier interval shortening, were collected from a single-centre database search. All patients were in steroid-free clinical (two-item patient-reported outcome [PRO2] ≤1 [UC] and ≤8 [CD]) and biological (C-reactive protein [CRP] Results In total, 37% of patients (n=11) remained relapse-free until one year after infliximab interval extension (Figure 1). A time-constant (exponential) hazard model proved best to describe the relapse data of patients with CD (Figure 2, Table 1). The Gompertz hazard model best described the data of patients with UC, with the relapse hazard risk increasing over time. Patients with CD had an overall higher relapse hazard risk than patients with UC. For patients with UC, the infliximab trough concentration was negatively related to the relapse hazard risk and was included in the model using a sigmoidal inhibitory Emax function. Also, in patients with UC, a higher infliximab clearance was associated with an increase in the relapse risk. The infliximab clearance was also a predictor of the relapse hazard risk, but its effect could not be precisely estimated. Conclusion Patients with CD had a higher relapse risk than patients with UC. Only in patients with UC, the hazard risk increased with time, but this risk was lower when the infliximab trough concentration increased. No exposure-response relationship was observed in patients with CD. Results of this exploratory analysis should be interpreted with care and prospective confirmation is awaited (MODIFI study; NCT04982172).2 1Kantasiripitak W. et al. CPT PSP. 2022 2Sheiner LB. et al. CPT. 1997

Background With the recent approval of ozanimod in ulcerative colitis (UC) and promising data of etrasimod, S1P receptor (S1PR) modulators are entering the therapeutic landscape. Besides differences in receptor selectivity (ozanimod S1PR1/5, etrasimod S1PR1/4/5), both compounds induce a drop in circulating B/T-lymphocytes, without affecting monocyte counts. This lymphocyte drop seems independent of treatment response, suggesting that other cell types – like monocytes, implicated in IBD pathogenesis - might contribute to efficacy. Furthermore, very little is known about the expression of S1PR on circulating lymphocytes/monocytes in the context of IBD. Methods Peripheral blood mononuclear cells were isolated from 135 IBD patients with active endoscopic disease (Table 1), and subsequently FACS sorted (CD14 monocytes and CD4 T-cells). RNA was extracted from lysed cells, and single-end sequenced using Illumina HiSeq4000. Results All S1PR were identified on both CD4 T-cells and monocytes, though with hardly any S1PR5 expression on circulating monocytes and hardly any S1PR3 expression on T-cells. Receptor expression on both monocytes and T-cells correlated significantly only for S1PR1 (r0.25, p=0.003) and S1PR4 (r 0.19, p=0.02). Circulating T-cells had substantial higher expression of S1PR1 (fold change [FC] 1092.0, p Conclusion Besides lymphocytes, monocytes do express S1PR in patients with IBD. The clinical consequences and the potential link with efficacy of S1PR modulators should therefore be further explored, especially given the heterogeneity of S1PR expression on circulating cells in IBD patients.

Background About one third of patients with Crohn’s disease (CD) develop strictures during their disease course requiring surgical resection. The immune landscape involved in this process is poorly understood. Therefore, we aimed to characterise the fibroblast phenotype, immune cells and their mediators involved in intestinal strictures. Methods We included 25 CD patients with stricturing disease in the terminal ileum (TI) and 10 controls with colorectal cancer (CRC), all undergoing an ileocolonic resection. Transmural samples from the resection specimen of the TI were obtained. Macroscopically, CD tissue was divided into unaffected, fibrostenotic and inflamed regions by an experienced histopathologist. Next, mucosa was separated from deeper layers, after which single cells were isolated and fluorescently stained for flow cytometry. Protein levels were determined via the MesoScale Discovery (MSD) platform in the corresponding samples. Comparisons between CRC controls and CD patients were performed via an unpaired t-test or Mann-Whitney analysis and corrected for multiple testing. Results An increase in active fibroblasts and decrease in inactive fibroblasts in the fibrotic and inflamed mucosa (p=0.0002 and p Conclusion The fibrotic and inflamed tissue of CD patients is characterized by increased activated eosinophils, Th2 and regulatory T cells and decreased Th1 cells, as well as many of their mediator cytokines. The current immunological characterisation can help to prioritise potential anti-fibrotic targets for stricturing CD.

Background Total colectomy for ulcerative colitis (UC) is associated with postoperative morbidity, including venous thromboembolism (VTE), in patients who already have a 2 to 4-fold risk for thromboembolic events. In light of recent concerns on increased major adverse events associated with JAK inhibitor exposure, we aimed to evaluate the postoperative VTE risk as well as other (non)infectious complications in UC patients undergoing colectomy after JAK inhibitor use. Methods This retrospective cohort study included all UC patients who underwent colectomy between 2013 and 2021 in our tertiary IBD center, and documented the 180-day postoperative non-infectious and infectious risks (table 1). Clinically relevant information included patient demographics, comorbidities, family history of IBD, personal history of VTE, intake of oral anticonception, smoking behaviour, disease characteristics including indication for colectomy, preoperative serum laboratory values, perioperative drug exposure (table 2) and surgical characteristics including low-molecular weight heparin (LMWH) prophylaxis (table 3). Results One-hundred seventy-nine UC patients (43.6% women, median [IQR] age 42.0 [28.5 – 56.2] years) underwent colectomy due to refractory disease (n=154) or suspected dysplasia or carcinoma (n=25). Forty-nine patients (27.4%) were operated urgently. In the twelve weeks prior to surgery, 55 (30.7%) patients had received anti-TNF agents, 40 (22.3%) anti-adhesion therapy, 16 (8.9%) anti-IL12/23, 2 (1.1%) investigational agents and 36 (20.1%) JAK inhibitors. Preoperatively, 27 patients (15.1%) were administered a moderate to high dose of systemic corticosteroids. All patients received antithrombotic prophylactic LMWH postoperatively, except for two patients who developed a gastrointestinal bleeding. During the 180-day postoperative period, a total of 3 patients (1.7%; mean age 51 years, 1 female) developed an intra-abdominal thrombosis, found by coincidence on CT scan. In all patients risk factors were identified, e.g. inflammatory state, cancer, high dose of corticosteroids. No VTE was seen in the patients who underwent colectomy while on JAK inhibitor. Only two out of 36 JAK inhibitor treated patients (5.6%) developed an infectious complication, while the overall risk of developing an infectious complication was 19.5%. Conclusion The overall risk for UC patients to develop VTE after colectomy is low with adequate antithrombotic prophylactic therapy. We did not observe any VTE in patients who were exposed to JAK inhibitors prior to surgery, nor did we see an increased risk on short-term infectious complications in this patient group. All patients who developed VTE despite LMWH had additional risk factors.

Background A better characterization of inflammatory bowel disease is needed. We previously developed a molecular classification tool for Crohn’s disease, based on a combination of metagenomics (dysbiosis score - MDI), transcriptomics (barrier integrity score - BIS, autophagy score – ATS, unfolded protein response score - UPRS), serum proteomics (inflammation score - IPS) and genetics (polygenic risk score - GRS)1. We here investigated if this score could also apply for ulcerative colitis (UC) and how the individual components correlate with clinical outcomes. Methods For a total of 173 UC patients and 181 controls (CO), we collected faecal and blood samples, as well as colon biopsies (Table). Faecal microbiota 16S-sequencing, intestinal RNA-sequencing, and serum proteomics (OLINK inflammatory panel) were performed. Using proteomics and RNA expression data, IPS, ATS, UPRS and BIS were calculated. MDI was calculated as previously described1. Based on these findings, patients were categorized into quartiles, ranging from Q1 (the least dysfunctional state) to Q4 (the most dysfunctional state). The individual scores were correlated with time to first biological or biological switch, as well as correlations with C-reactive protein (CRP), faecal calprotectin (FC), and the Montreal classification. The therapeutic value of MDI score was studied in a small dietary intervention pilot study (n=8)2. Results None of the individual components of the score were associated with disease extent. Patients diagnosed at a later age had increased ATS and BIS levels. BIS and UPRS showed a positive correlation with disease duration (r=0.36, r=0.54 respectively, p Conclusion In UC patients, we created a multifaceted scoring system to molecularly describe disease by the degree of dysbiosis, dysregulation of the immune proteome, and intestinal barrier integrity. We also demonstrated the dynamic of MDI of this score in relation to dietary intervention. Therefore, molecular profiling of patients may represent a new, individualized strategy to the management of UC. References: 1. OP30 ECCO 2020, JCC 14(Supplement_1):S028-S0302. 2. P767 ECCO 2017, JCC 11(suppl_1):S473-S473.

Background Four randomized controlled trials studying faecal microbiota transplantation (FMT) in active UC patients showed variable success rates. The efficacy of FMT appears to be influenced by various factors including donor- and procedure-specific characteristics. We hypothesized that the outcome of FMT in patients with active UC could be improved by donor preselection on microbiota level, by using a strict anaerobic approach, and by repeated FMT administration. Methods The RESTORE-UC trial (NCT03110289) was a national, multi-centric double-blind, sham-controlled randomized trial. Active UC patients (Total Mayo score 4–10 with endoscopic sub-score ≥2) were randomly allocated (1:1) to receive 4 anaerobic-prepared superdonor (S) FMT or autologous (A) FMT (Figure 1) by permutated blocks (2 and 4) and stratified for weight, concomitant steroid use, and therapy refractoriness. S-FMTs were selected after a rigorous screening excluding samples with Bacteroides2 enterotype, high abundances of Fusobacterium, Escherichia coli and Veillonella and the lowest microbial loads (Q1). A futility analysis after 66% (n=72) of inclusions was planned per protocol including a modified intention-to-treat (mITT) analysis using non-responder imputation (NRI) for patients receiving at least one FMT. The primary endpoint was steroid-free clinical remission (Total Mayo ≤ 2, with no sub-score >1) at week 8. Results Between March 2017–2021, 72 patients signed the ICF and 66 were randomly allocated to S-FMT (n=30) or A-FMT (n=36) and received at least one FMT. In the S-FMT and the A-FMT resp. 4 and 5 patients terminated the trial early due to worsening of colitis (4 in both arms) or FMT enema intolerance (1 A-FMT). They were included in the mITT analysis using NRI (Fig. 2). Both study arms were matched for baseline characteristics (Table 1), yet a trend (p= 0.066) towards higher concomitant biological use in the S-FMT arm was observed. After 66% of intended inclusions, the primary endpoint was reached in 3/30 (10%) S-FMT and 5/31 (13.9%) patients randomized to A-FMT (p=0.72). As the predefined minimum difference between both treatment arms was not attained, the study was stopped due to futility. The full set of endpoints are summarized in Table 2.Of note, no patients on concomitant biologicals reached the primary endpoint. There were 2 serious adverse events in the A-FMT arm: dysuria requiring hospitalization and worsening of UC requiring colectomy. Conclusion In this double-blind sham-controlled trial comparing repeated administrations of anaerobic-prepared S-FMT with A-FMT in patients with active UC, no significant difference in steroid-free remission rates at week 8 were observed. The FMT procedure was generally well tolerated, and no new safety signals were observed.

Background Up to 10% of ulcerative colitis patients who undergo a proctocolectomy with ileal pouch-anal anastomosis, will develop chronic antibiotic refractory pouchitis (CARP). As there is a large unmet need in the management of these patients, we evaluated the efficacy and safety of induction therapy with ustekinumab (UST) for this indication. Methods We performed a prospective, Belgian, multicentre, open-label study of patients with CARP. Patients received a weight-range-based infusion of UST at baseline (6mg/kg) and one subcutaneous injection of 90mg UST at week 8. The first 4 weeks, ciprofloxacin 500mg BID was added as bridging therapy, but need of antibiotics thereafter was regarded as treatment failure. Patients underwent pouchoscopy at baseline and week 16, with assessment of the modified pouchitis disease activity index (mPDAI). The primary endpoint was the proportion of patients achieving clinically relevant steroid-free remission (mPDAI Results We report the first 18 patients (56% male, median age 41.5 years, median time after surgery 11.2 years) who reached the primary endpoint assessment. Eleven (61.1%) patients had previously been treated with biologics (anti-TNF, n=8; vedolizumab, n=6; tofacitinib, n=1) for CARP (table 1). At week 16, clinically relevant steroid-free remission was reached in 27.8% and response in 50.0% of patients. A significant decrease in total mPDAI (8.0 (7.0–8.3) vs. 6.5 (3.8–9.0), p=0.04) and clinical subscore (3.0 (2.0–4.0) vs. 2.0 (1.0–3.3), p=0.04) but not endoscopic subscore (5.0 (4.0–6.0) vs. 4.0 (3.0–6.0), p=0.1) was observed at week 16 (figure 1). Faecal calprotectin (288.0 (154.8–634.8) vs. 145 (88.3–749.3) mg/kg, p=0.47) and CRP (4.8 (1.9–7.2) vs. 3.9 (1.9–8.9) mg/L, p=0.63) levels did however not decrease significantly (figure 2). Three serious adverse events (hospitalization for subobstruction, worsening pouchitis and choledocholithiasis) were recorded, but were not considered related to UST. Conclusion In this open-label pilot study in patients with CARP, induction therapy with UST showed a clinical effect in half of the patients, but was not associated with endoscopic improvement or changes in inflammatory biomarkers. Placebo-controlled studies are needed for further positioning UST in the treatment algorithm of CARP.

Background Several biologicals and small molecules have been added to the therapeutic arsenal of inflammatory bowel disease, which generated a wide interest in precision medicine. In this context, both clinical features and laboratory tests have shown some correlation with therapy outcome. Recently, an online clinical decision support tool1 (CDST) was built, using clinical and biochemical variables (e.g. disease location, prior anti-TNF exposure), to help physicians predict the outcome of various biological treatments in Crohn’s disease (CD). We sought to evaluate the predictive performance of this tool in patients with CD initiating ustekinumab (UST). Methods Baseline data were collected from consecutive CD patients who started UST IV induction followed by eight weekly UST 90 mg SC maintenance from December 2015 through March 2021 at our referral center. The probability of achieving clinical remission (low, intermediate, or high) was determined using the online CDST using patients’ data. Also, differences in rates of primary non-response and ustekinumab persistence were compared between CDST classifications. Primary non-response was defined as failing to attain endoscopic response (≥50% decrease in SES-CD) nor clinical response (a drop in the physician global assessment score or patients reported outcome), both assessed at month 6 after UST initiation. Finally, we studied the relation between the individual components used to construct the CDST and the three classifications in a univariate analysis. Results A total of 291 CD patients started UST, of whom 237 had objectively-assessed (CRP, fCal, symptoms or endoscopy) baseline disease activity. Using the CDST, the proportion of patients with “low”, “intermediate” or “high” probability to attain clinical remission were 11.8 % (n=28), 55.7 % (n=132) and 32.5 % (n=77), respectively. The CDST could not discriminate patients with primary non-response (p value = 0.18; Figure 1), nor identify trends in drug persistence (p value = 0.44; Figure 2). In the univariate analysis, 3 out of 9 components (active fistulizing disease, disease location and concomitant immunomodulatory use) were not significantly contributing to the CDST classification (Table 1). Conclusion The recently developed clinical decision support tool showed low performance in predicting short-term (primary clinical and endoscopic response) and long-term (drug persistence) real-life outcomes in CD patients starting UST. These findings underscore the necessity of incorporating molecular variables, in addition to clinical ones, to construct reliable and reproducible tools to predict therapeutic outcomes. 1. https://via.juxlyapps.com/pathway/archemedx/ibd-cdst/index.html#/disease-selection

Background Infliximab (IFX) de-escalation (i.e., extending the dosing interval and/or decreasing the dose) has been attempted in patients with inflammatory bowel disease (IBD) who sustained treatment response following an earlier IFX escalation. We aimed to identify predictors of sustained disease remission after IFX de-escalation. Methods Data of 30 adult patients (17 Crohn’s disease [CD], 13 ulcerative colitis [UC]), who underwent IFX de-escalation following earlier escalation, were retrospectively collected from a single-centre database search. All patients were in steroid-free clinical (two-item patient-reported outcome [PRO2] ≤1 [UC] and ≤8 [CD]) and biological (C-reactive protein Results The percentage of patients who sustained steroid-free clinical and biological remission gradually decreased over time to 57% at 180 days and 37% at 360 days (Fig 1). A lower baseline PRO2 was predictive for attaining the primary endpoint (P=0.039), regardless of IBD type. One unit increase in PRO2 increased the probability of losing remission by 17% (95% CI: 0.8%-36%). The IFX TC at baseline was similar between patients with and without sustained remission during the first year (median 6.8 [IQR 6.0–7.6] mg/L and 6.0 [5.1–9.2] mg/L, respectively; P>0.05). Throughout the study period, neither IFX TCs nor IFX CLs predicted attaining the primary endpoint (P >0.05). At the fifth infusion, patients who did not attain the secondary endpoint had a higher IFX CL (P=0.025), but the IFX TC was not different (Fig 2). In mGLM, the estimated IFX CL, but not the IFX TC itself, was identified as a predictor for attaining the secondary endpoint (P=0.016). A 0.1-unit increase in IFX CL (L/day) increased the probability of losing remission 3,227-fold. Conclusion Lower PRO2 at IFX de-escalation predicted a higher chance of sustained remission. Monitoring the IFX CL using a Bayesian forecasting software tool may provide more insight into disease activity than monitoring the IFX concentration as such. A prospective study is awaited to confirm our findings (MODIFI; NCT04982172). Reference 1. Dreesen BJCP. 2020

Background As therapeutic options in Crohn’s disease (CD) are growing, new challenges including choice of first line therapy arise. Both adalimumab (ADM) and ustekinumab (UST) are effective at inducing and maintaining endoscopic remission in moderate-to-severe CD. Recently, the SEAVUE trial (Sands et al. DDW, 2021) did not show a difference in (steroid-free) clinical remission nor endoscopic remission at week, 52 in biological-naive patients with moderate-to-severe CD. Our aim was to explore if these results withstand in a real world setting of biological-naive CD patients starting their first biological. Methods This retrospective cohort study included adult, biological-naive CD patients starting ADM or UST between, 2017–2020 in our tertiary referral centre. Patients were eligible for biological therapy as per reimbursement criteria and all had endoscopy-proven moderate-to-severe disease (at least one ulcer of any size) prior to start of therapy. ADM could be dose optimized. Clinical remission was defined as a Harvey-Bradshaw Index (HBI) Results A total of, 70 consecutive biological-naive CD patients were included (38 ADM, 32 UST) and prospectively followed for, 60 (33–104) weeks. Baseline characteristics were similar between both treatment groups (Table, 1). Median (IQR) time to endoscopy was comparable between both groups [ADM, 26 (23–33) vs. UST, 25 (24–45) weeks; p=0.38]. Clinical remission rates, only in patients with active clinical disease at baseline, at week, 26 (ADM:, 72% vs. UST:, 48%, p=0.09) and, 52 (ADM:, 62% vs. UST:, 35%, p=0.09) were numerically but not statistically different between groups. However, ADM was superior to UST in achieving endoscopic remission (61% vs., 31%, p=0.02) and improvement (74% vs., 47%, p=0.03) at week, 26–52. Fifteen (39%) patients in the ADM and, 6 (19%) in the UST group were on steroids at baseline. Numerical differences in steroid-free endoscopic remission (55% vs., 31%, p=0.06) and improvement (68% vs., 47%, p=0.09) rates were seen between ADM and UST at week, 26–52. Rates of treatment persistence were not significantly different between both treatment groups (p=0.31; Figure, 1). The number of adverse events was similar in both groups after one year of therapy (p=0.98). Conclusion In a real-world cohort of biological-naive CD patients, ADM seems superior to UST in achieving endoscopic remission and improvement, but no difference was seen in clinical remission at W26-52.

Background Small molecules are being added to the treatment armamentarium of ulcerative colitis (UC). In contrast to monoclonal antibodies, very little is known about their pharmacokinetic-pharmacodynamic profile. We therefore assessed pharmacokinetic-pharmacodynamic changes in Tofacitinib (TFC) treated UC patients, with a focus on STAT3 phosphorylation, as it has been proposed as a marker of efficacy. Methods Thirty UC patients initiating TFC therapy, 10mg BID were prospectively monitored (Table, 1). At week, 8, patients could de-escalate to, 5mg BID or maintain, 10mg BID depending on their response. Endoscopic assessment and sampling (colonic tissue and serum) was performed at baseline and, 8–16 weeks after TFC initiation. Endoscopic improvement was defined as Mayo endoscopic subscore, 0–1. TFC was extracted from tissue using acetonitrile, dried down and quantitated using mass spectrometry. Both total as well as phosphorylated STAT3 were measured in lysed tissue using specific antibodies with an ultrasensitive luminescent oxygen channelling assay. Results TFC tissue and serum concentrations correlated significantly (r=0.92, p Tofacitinib tissue (A) and serum (B) exposure at the end of high dose induction in relation to the achievement of endoscopic improvement at week, 16, defined by a Mayo endoscopic sub-score of, 0–1. Conclusion We could demonstrate for the first time a mucosal exposure-response relationship with TFC in UC patients. Additionally, pSTAT3/STAT3 ratio was identified as potential molecular marker to track response directly linked to the mode-of-action of TFC. Whether an increased local dose of TFC could result in better efficacy without compromising safety should be further explored.

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 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

Background Endoscopic post-operative recurrence (ePOR) is common following ileocecal resection (ICR) in patients with Crohn’s disease (CD), reaching up to, 70% at, 1-year. In clinical trials, prophylaxis with anti-TNF therapies demonstrated a decrease in ePOR to around, 20% at, 1-year. Here we aimed to compare the effectiveness of vedolizumab (VDZ) and ustekinumab (UST) to anti-TNFs for preventing ePOR after curative ICR in adults with CD in a real-world setting. Methods This was a retrospective multicenter study, assessing patients with CD >17years who underwent ICR between, 2015–2019, started prophylaxis within six months of surgery, and underwent an ileocolonoscopy ≥ four months after prophylaxis. ePOR (Rutgeerts score ≥ i2 or colonic-segmental-SES-CD≥6) was assessed at, 12, 24, 36-months periods post-surgery. Multivariate logistic regression was used to assess risk factors for ePOR, and IPTW was performed to compare the effectiveness between agents. Results Included, 297 patients [53.9% males, age-at-diagnosis, 24(19–32) years (median;IQR), age-at-ICR, 34(26–43)years (median;IQR), 18.5% current-smokers]. Of these, 17.2% had previous-ICR, 8.1% were biologic naïve, 65.7% anti-TNF experienced, and, 28.6% exposed to, 2 biologics. Overall, 224, 39 and, 34 patients received respectively anti-TNFs, VDZ or UST for prevention of POR. Patients on VDZ and UST were more likely to be biologic experienced or post previous-ICR. ePOR rates for the entire cohort, anti-TNF, VDZ and UST were:, 41.8%, 40.2%, 33%, and, 61.8% at, 12-months, 49.0%, 46.5%, 44.4%, and, 72.4% at, 24- months, and, 48.6%, 47.9%, 44.0% and, 62.5% at, 36-months, respectively. Risk factors for ePOR: past infliximab (Adj.OR =1.73 [95% CI:, 1.01–2.97], p=0.045) or adalimumab (Adj.OR = 2.32 [95% CI:, 1.35–4.01], p=0.002), and technical aspects of anastomosis. After controlling for the disparities between groups by the IPTW method risk of ePOR at, 12-months was comparable between patients on anti-TNFs vs VDZ or anti-TNFs vs UST. However, comparison between VDZ vs UST groups revealed that patients on UST were at a higher risk for ePOR at, 12-months (OR=3.75 [95% CI:, 1.33–10.6]), p=0.012. Conclusion Prevention of ePOR was successful in ~60% of patients at, 12-months period. Patients on prophylaxis VDZ or UST consisted of a distinct, more refractory group with higher rates of ePOR. Post-operative treatment with UST or VDZ resulted in a similar risk of ePOR when compared to post-operative prophylaxis with anti-TNF after controlling for disease severity.

Background Underexposure to IFX is a common cause of loss of response in patients with inflammatory bowel disease (IBD). To ensure adequate – but not unnecessarily high – exposure, we aimed to identify a precise and unbiased approach for model-based dosing of IFX in patients with IBD. Methods A retrospective study was performed using data from, 54 patients on IFX maintenance therapy. The predictive performance of, 18 published IFX population pharmacokinetic (popPK) models was evaluated using NONMEM (v7.5). A priori prediction (only based on covariates) and Bayesian forecasting (BF; also based on one to three consecutively measured IFX trough concentrations; TC-2, TC-1, and TC0) of the IFX TC+1 was evaluated (Fig, 1). The predictive performance of a single-model approach was compared with two automated multi-model approaches: a model selection algorithm (MSA) and a model averaging algorithm (MAA).1 Relative bias (rBias) and relative root mean square error (rRMSE) were used to determine bias and imprecision of the predicted versus observed TC+1. Clinical acceptability was defined as an rBias between ±20% with a, 95%CI including zero. The predicted and observed TC+1 were classified at, 5.0 mg/L TC target.2 Results Four models were selected based on their predictive performances and implemented in the TDMx software tool to support model-based IFX dosing in the forthcoming prospective MODIFI study (NCT04982172). A priori prediction of TC+1 was clinically unacceptable with both single- and multi-model approaches (rBias +30% to +97%, rRMSE, 107% to, 158%; Fig, 2A). Also, a priori prediction had the lowest classification accuracy (median, 59%, IQR, 59%-63%; Fig, 3A). Providing one IFX TC greatly improved predictive performance (rBias -10% to +15%, rRMSE, 30% to, 49%; Fig, 2B, 2C) and classification accuracy (TC-1: median, 70%, IQR, 63%-72%; TC0: median, 80%, IQR, 76%-84 %; Fig, 3B, 3C). More specifically, BF resulted in a significantly lower chance of a falsely predicted ≥5 mg/L TC+1 than a priori prediction (p Providing more than one previous TC improved predictive performances only marginally (data not shown). In general, MAA performed better than MSA. Conclusion Conclusion: A multi-model averaging approach provided more reliable Bayesian forecasts than the single-model approach. Adding one previous trough concentration in addition to covariate information sufficed to provide accurate and unbiased predictions of future exposure. Concentration data collected with a rapid assay may reduce the chance of performing unnecessary dose optimisation. Reference1. Uster D CPT,2021;2Vande Casteele N Gastroenterology,2017

Background Patients with immune-mediated inflammatory diseases (IMID) are at higher risk for infectious diseases. Despite this increased risk and the available guidelines1, we reported a sub-optimal vaccination rate of 27.4% of IMID patients in 2018. In the meantime, a vaccination module was introduced in the electronic patient health record of our hospital to accurately document and monitor vaccination status of patients. The impact of this new module on vaccination coverage was re-evaluated in the same IMID patients in 2021. Methods Between Aug and Oct 2021, the vaccination status of 1448 (out of the original 1488) IMID patients (44.8% male, median age 53.6 years) was collected (798 patients with IBD, 612 with rheumatological, and 38 with dermatological inflammatory conditions) and compared to that of 2018. The vaccination status was obtained mainly through the patients’ electronic medical records. Missing data were added after contacting patients or their general practitioner. Results From 2018 to 2021, the overall vaccination coverage of all IMID patients significantly increased from 27.4% to 51.9% (p The vaccination coverage in IBD patients increased significantly from 75.9% to 86.3% for influenza (p Similarly, the vaccination coverage significantly increased for rheumatology patients, namely from 69.3% to 78.3% for influenza (p For patients with dermatological inflammatory conditions, vaccination coverage significantly increased from 60.5% to 81.6% for pneumococci (p=0.031) and from 47.1% to 55.3% for hepatitis B (p=0.002) (Table 1). Conclusion The suboptimal vaccination rate measured in 2018 and the COVID-19 pandemic stressed the importance of vaccination recommendations to patients and healthcare professionals. We here show that the implementation of a vaccination tool integrated in the electronic medical record of patients is correlated with a significant increase in specific vaccination rates and also in the total amount of IMID patients that were fully vaccinated according to guidelines. Reference 1. Rahier JF, Magro F, Abreu C, et al. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis. 2014;8:443–468.

Background Ustekinumab (UST), an anti-IL12/23p40 monoclonal antibody, has been approved for treating Crohn’s disease (CD). As for all biologicals, efficacy is reduced in patients with previous anti-TNF exposure. We here sought to investigate whether UST outcomes and serum exposure are affected by UST positioning as first-, second-, or third-line biological treatment and type of previous biologicals (anti-TNF biologicals and vedolizumab [VDZ]). Methods Data on primary (non)-response, drug persistence and serum trough levels were collected from CD patients who started UST as a first-, second-, or third-line biological treatment from December 2015 through October 2020, allowing a follow-up of ≥12 months. Differences in rates of primary non-response (< 50% decrease in SES-CD and absence of any clinical improvement) after 6–12 months, and UST persistence were compared based on UST positioning and previous biologicals. Finally, we compared serum UST exposure profiles between groups. Results A total of 181 CD patients with active disease started UST as first- (n=41; 22.65%), second- (n=57, 31.5%) or third-line (n=83, 45.85%), respectively (Table 1). Of second-line UST starters, 52 (28.7%) patients were exposed to one anti-TNF biological and 5 (2.8%) to vedolizumab. Of third-line UST starters, 41 (22.65%) patients were exposed to both one anti-TNF and VDZ, while 42 (23.2%) were exposed to two anti-TNFs. Second-line UST starters with previous VDZ were excluded from further analysis due to small sample size (n=5). A gradual decrease in response rates (p=0.02; Figure 1) and drug persistence (p=0.03; Figure 2) was observed with increasing lines of biologicals given prior to start UST, with patients starting UST as third-line treatment after two anti-TNFs having the highest rates of primary non-response (43%) and the shortest drug persistence. This finding was paralleled by a progressive decrease in UST serum levels with increasing number of previous biologicals and number of previous anti-TNFs (Figure 3), in 71 patients of whom induction and maintenance UST serum levels were available. Conclusion Both short term response rates, as well as long term UST persistence rates, decreased with increasing lines of previous biological therapies. Patients exposed to two anti-TNFs had worse UST outcomes on short-term and long-term, and lower serum trough levels than patients who received only one or no anti-TNF biological before or prior VDZ exposure. These data help in positioning UST in CD and in framing the discussion with patients.

Background Immunomodulators (IMM) and Targeted Immune-Modulating Therapies (TIMT) such as anti-TNF, anti-interleukins and Janus Kinase inhibitors, for treatment of Immune Mediated Inflammatory diseases (IMID) could theoretically interfere with the cytokine storm and humoral immune response against COVID19 infection and vaccination. We investigate seroprevalence and evolution of SARS-CoV2 antibodies in relation to previous vaccination and/or exposure to COVID19 and ongoing IMID-treatment in a Belgian, real-life population of IMID patients. Methods A cross-disciplinary, prospective, observational cohort study was set up at two university hospitals. All patients with IMIDs of the gut (Crohn’s disease, ulcerative colitis), joints (rheumatoid, psoriatic or spondyloarthritis) and skin (psoriasis, hidradenitis suppurativa, atopic dermatitis) visiting the respective clinics were asked to participate. Patients had to fill out an electronic survey (REDCap®, based on WHO-ISARIC) and blood samples were drawn for serology testing (anti-Spike(S) and anti-viral Nucleocapsid(N) protein antibody IgG, Abbott). Results at baseline, prior to the national vaccination program and at 6 months follow-up are presented. R version 4.0.2 was used for statistical analyses. Results At baseline 2165 IMID patients consented to take part. In 3.2% SARS-CoV2 anti-N seroconversion was confirmed. Of the anti-N seroconverted patients 72.9% reported a positive PCR test prior to inclusion. At 6-months follow-up, data of 1853 IMID patients was collected. Of these, 81.7% were fully and 14.4% partially vaccinated. Seroconversion for anti-N antibodies was confirmed in 2.5% of all participants and seroconversion for anti-S antibodies in 90.8%. In 5.1% (61/1483) of fully vaccinated IMID patients no seroconversion in anti-N nor anti-S antibodies was found. Chi Square analyses show, at 6-months follow-up, no significant association between anti-S seroconversion rate and treatment with systemic steroids (RiskRatio 1.22, 95%CI 0.38–3.9, P=0.99), TIMT (RiskRatio 0.57, 95% CI 0.3–1.1, P=0.12), IMM (RiskRatio 1.65, 95% CI 0.85–3.19, P=0.19) or combination treatment IMM/TIMT (RiskRatio 1.60, 95% CI 0.75–3.4, P=0.32). Appearance of COVID19 symptoms followed the epidemiological curve in Belgium (Fig1). Conclusion In this real-life IMID cohort, the number of COVID19 cases confirmed by PCR prior to vaccination was low. Seroconversion rate for anti-N antibodies was lower at 6-months follow-up, suggesting decrease in antibody titre over time. Full COVID19 vaccination led to a high anti-S antibody seroconversion rate. Nonetheless, 5.1% of fully vaccinated patients showed no antibody seroconversion. So far, no significant association between anti-S antibody seroconversion and IMID treatment was noted.

Background Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease of the gut, characterized by multiple symptoms of which some cannot be successfully managed by existing conventional therapies. The use of complementary alternative medicines (CAMs) and CAM services among patients with chronic disorders including IBD has increased globally over the past several years (Rawsthorne Gut 2012; Weizman APT 2012). The main aims of this study were (a) to profile the use of CAMs and CAM services in a cohort of IBD patients being treated at a Belgian IBD referral center and (b) to identify the clinical and demographic factors associated with the use of CAMs. Methods An anonymized and customized Dutch version of the international questionnaire to measure the use of complementary and alternative medicine (I-CAM-Q – Quandt J Altern Complement Med 2009) was provided over an 8-week period spanning September and October 2021) to all IBD patients visiting the IBD outpatient clinic and infusion unit. Pearson’s Chi-square test was used to identify the relationships between clinical and demographic variables (age, gender, educational status) and CAM usage. Results From among the 410 IBD (144 UC, 253 CD) patients who responded to the survey, 173 (42.2%) were using CAMs or had used CAMs. A vast majority (79.8%) of the CAM using IBD patients reported the use of nature-based therapies (aloe vera, green tea, curcumin, cannabis, vitamin/mineral supplements and probiotics), a fifth of which was accounted for by Cannabis and its derivatives. This was followed by mind-body therapies (42.1%) (mindfulness, yoga, acupuncture, hypnotherapy, meditation). Two-thirds of patients (66.7%) mentioned to use CAMs for IBD-related symptoms. 125/173 of the CAM using IBD patients attributed the use of CAMs to their know-how about the potential of CAMs in ameliorating symptoms (32%), low efficacy or presence of adverse effects of conventional therapies (29.6%), minimize disease burden (28.8%) and avoiding surgery (7.2%). A vast majority (93.9%) of the CAM using IBD patients who responded to the query stated that consultation with their gastroenterologist would be beneficial to ascertain possible interference with their ongoing conventional therapy. Conclusion A significant proportion of IBD patients use CAMs to manage the complicated and often systemic symptoms of IBD. The most frequently used CAMs included nature-based therapies such followed by mind-body medicine. Given that CAMs are not officially regulated as medicinal therapies, their impact on conventional therapies is not entirely clear and should be further studied. Multi-center surveys profiling the use of CAMs in IBD patients as well as other chronic disorders are warranted.

Background In recent phase 3 trials, risankizumab (RZB), a humanised monoclonal IgG1 antibody targeting the interleukin 23 p19 subunit, proved to be superior to placebo in inducing and maintaining clinical remission and endoscopic response in patients with moderate-to-severe Crohn’s disease. In this study, we aimed to evaluate the effectiveness and safety of RZB in a real-world cohort of multi-refractory CD patients. Methods Adult CD patients from six Belgian IBD centres who initiated RZB prior to May 2021 as part of a medical need program were prospectively followed. Patients with an ostomy were excluded for the main analyses. The primary endpoint was steroid-free clinical remission at week 24 (average daily liquid stool frequency [SF] ≤2.8 and average abdominal pain [AP] score ≤1, both not worse than baseline). Secondary endpoints included clinical response, endoscopic remission, endoscopic response, biological remission, biological response, need for CD-related hospitalisation or surgery, and serious adverse events (definitions in Figure 1). Given that a follow-up endoscopy has not yet been performed in some patients, results are shown for both “all patients” (with non-responder imputation) and “as observed”. Results A total of 27 patients started RZB of whom 19 patients were eligible for this study with a minimal follow-up of 24 weeks (Table 1). Eight patients were excluded as they had an ostomy at time of RZB initiation. Eighteen patients (95%) had been exposed to more than 3 biologicals and 13 (68%) previously underwent a CD-related intestinal resection. By week 24, 7/19 (37%) and 7/19 (37%) patients achieved steroid-free clinical remission and endoscopic response, respectively (Figure 1). In the “as observed” analyses, these rates were 7/18 (39%) and 7/9 (78%), respectively (Figure 2). Five patients used concomitant steroids at baseline and were all able to stop it after a median of 10 weeks. Eventually, three patients had to be hospitalized for bowel resection (2 with placement of an ostomy) after a median of 24 weeks, two of them required earlier an emergent hospitalization due to flares of abdominal pain and bloody diarrhea. None of the patients experienced serious infections or intolerance. Based on physician global assessment, three out of eight patients with an ostomy did achieve clinical remission, and two other achieved clinical response. Endoscopic follow-up data were available in six patients, and three of them experienced endoscopic response. Conclusion In this real-world, multi-refractory cohort, clinical remission and endoscopic response were both observed by week 24 in more than one third of CD patients initiating RZB. RZB was well tolerated with no safety issues.

Background Therapeutic options in IBD are rapidly growing, causing new challenges including choice of first line therapy. Both adalimumab (ADM) and vedolizumab (VDZ) are effective at inducing and maintaining endoscopic remission in moderate-to-severe IBD. The VARSITY trial (Sands et al NEJM 2019) showed superiority of VDZ over ADM in achieving clinical remission and endoscopic improvement at W52 in UC patients. Our aim was to explore if these results withstand in a real world setting of UC patients, and if they are also valid in CD. Methods This retrospective cohort study included adult, biological-naive IBD patients starting ADM or VDZ between 2015-2019 in our referral IBD centre. Patients had moderate-to-severe disease (endoscopic Mayo sub score ≥ 2 for UC, presence of ulcerations for CD) prior to start of therapy. For UC, we assessed endoscopic remission (endoscopic Mayo sub score 0) and improvement (endoscopic Mayo sub score ≤ 1) at W52. For CD, we assessed endoscopic remission (absence of ulcerations) and improvement (markedly better endoscopy despite still presence of ulcerations) at weeks 26-52. Missing values were imputed as nonresponses for binary outcomes, and last-observation carried-forward was used for continuous outcomes. Results A total of 109 UC and 86 CD patients were included (Table 1). Endoscopic remission at W52 was significantly better for VDZ than ADM in UC (35% vs 15%, p=0.03), and also endoscopic improvement was numerically, yet not significantly, better for VDZ than ADM (56% vs 37%, p=0.08). At baseline, 23 UC patients (50%) in the ADM group and 40 (63%) in the VDZ group were on steroids. By W52, 83% and 78% (p=0.75) of UC patients respectively could discontinue steroids and steroid-free endoscopic remission was not different between groups (ADM: 22% vs VDZ: 23%, p=1.00). For CD patients, similar endoscopic remission (60% vs 48%, p=0.37) and improvement (77% vs 79%, p=1.00) rates at weeks 26-52 were seen between ADM and VDZ. Twenty-five (47%) CD patients in the ADM and 16 (48%) in the VDZ group were on steroids at baseline, and 88% of them in both groups could successfully stop steroids by W52. Again, no difference in steroid-free endoscopic remission was seen between ADM (56%) and VDZ (31%) treated CD patients (p=0.20). At the end of follow-up [81 (27-157) weeks], the rates of treatment persistence were significantly different between ADM and VDZ treatment groups in UC patients, though not in CD patients (Figure 1). Conclusion In a real-world cohort of bio-naive UC patients, VDZ was superior to ADM in achieving endoscopic remission at W52, while in bio-naive CD patients VDZ and ADM resulted in similar endoscopic outcomes.

Background Histologic healing is being proposed as new treatment target in ulcerative colitis (UC), and the concept of histo-endoscopic mucosal improvement was introduced in the UNIFI study with ustekinumab (UST) in moderate–to-severe UC. Very little is known about the Pk-PD relationship of ustekinumab in UC patients, and especially whether serum UST concentrations correlate well with colonic tissue drug exposure and with histologic healing. The aim of this study is to provide real-world data including histology, and to study UST serum concentrations and its relation to tissue levels and drug efficacy. Methods UC patients starting UST in standard dosage at our referral centre were prospectively followed by clinical and endoscopic assessments at week, 16 or week, 24, and colonic biopsies were taken for histopathologic scoring. Histologic remission was defined as Nancy histology index (NHI) of, 0. Other collected outcomes were clinical response, clinical remission, endoscopic improvement, endoscopic remission and mucosal healing (definitions in Figure, 1). Paired trough serum sample and colonic mucosal biopsy were collected for UST levels measurement using a CE marked in-house developed ELISA. Results A total of, 42 UC patients started ustekinumab between June, 2019 and May, 2021, allowing a follow-up of at least, 6 months (Table, 1). By week, 24, clinical response, clinical remission, endoscopic improvement, endoscopic remission, and mucosal healing were observed in, 31 (74%), 24 (57%), 22 (52%), 11 (26%) and, 10 (24%) patients, respectively (Figure, 1). Histologic remission was observed in, 19 (45%) patients, of whom, 10 and, 9 with endoscopic Mayo, 0 and, 1, respectively. Multivariate analysis identified clinical response at week, 8 as a predictor for histologic remission at week, 24 [OR, 8.84, p = 0.024], and inversely correlated with therapy discontinuation [OR, 0.10, p = 0.006]. A trend of higher UST serum trough levels was observed in patients achieving histologic and endoscopic outcomes in comparison with patients who did not reach these outcomes, with a significant statistical difference at week, 8 for endoscopic outcomes (Figure, 2). UST concentrations from paired serum and biopsy samples revealed a strong positive correlation (Spearman r=0.88, p1) (r=0.89, p Conclusion In this real-word cohort of UC patients initiating UST, more than a third of the patients achieved histologic remission. Serum UST levels were furthermore strongly correlated with tissue levels of UST. A drug exposure-response relationship was observed for histologic and endoscopic outcomes.

Background Perianal fistula can originate idiopathically (cryptoglandular fistula) or can be a representation of underlying Crohn’s disease (CD). In case of idiopathic fistula, the cryptoglandular theory suggests their development from the anal glands. In contrast, the pathophysiology of CD-related fistula is very poorly understood. Hence, we molecularly characterised and compared the fistula tract in both conditions. Methods We collected surgical biopsies from the fistula tract in 70 CD patients with active draining perianal fistula and in 12 patients with cryptoglandular non-CD related, active draining fistula, all requiring surgical examination under anaesthesia. RNA was sequenced using Illumina HiSeq4000, and these data were analysed through differential gene expression analysis (DESeq2). A false discovery rate (FDR) of 0.05 and a |log 2-fold change (log2FC)| >1 was considered significant. Pathway analysis was performed using IPA (Qiagen). In addition, cellular deconvolution methods (xCell) were applied to study the cellular composition. Results Gene expression analysis identified 1087 genes being differentially expressed between CD-related and cryptoglandular fistula (716 up, 371 down). Top differentially expressed genes encode proteins implicated in IBD pathogenesis including CARD18 (log2FC= 23.2, p=3.9E-21), BATF2 (log2FC=2.8, p=1.8E-8), ETV7 (log2FC=2.1, p=2.0E-7), DSG1 (log2FC=7.8, p=2.7E-6) and IL22RA1 (log2FC=5.3, p=4.6E-6). Additional pathway analysis highlighted various proinflammatory processes in CD fistula (as compared to cryptoglandular fistula), including upregulation of antigen presentation and Th1/Th2 activation (p Conclusion CD fistulas have a strong proinflammatory fingerprint, but seem to have lower wound healing capacity as compared to cryptoglandular fistula. An aggressive medical and surgical treatment is therefore required, including the search for novel, powerful anti-inflammatory and wound healing compounds.

Background Switching between biological therapies is frequently observed in the routine management of inflammatory bowel disease (IBD). Yet, it is unknown whether sequential use of biologicals affects safety such as serious infections and malignancies. We aimed to compare the occurrence of serious infections and malignancies in regards to the number and classes of biologicals to which patients were exposed. Methods This retrospective cohort study included all IBD patients exposed to commercially available biologicals from 1999 to 2019 in a tertiary referral centre. Follow-up started at initiation of first biological. Exclusion criteria included: patients Results In total 1374 patients were included (Figure 1). During a median (IQR) follow-up of 8 (4–13) years, 373 serious infections and 127 malignancies were reported in 245 (19%) and 92 (7%) patients, leading to an incidence rate of 2.2 and 0.8 per 100.000 patients per year, respectively. The number of serious infections was dependent on prior exposure to immunomodulators (IM, p = 0.001), the number of biologicals (p = 0.042) and the number of biological classes to which the patient was exposed (p = 0.004, overall test Poisson model p = 0.0001). The risk of serious infections increased when a patient was exposed to three or more different biologicals or two or more different classes of biologicals. The number of malignancies was also affected by the number of biologicals (p = 0.028) to which the patient was exposed, with a higher risk of developing a malignancy with exposure to an increasing number of biologicals (Figure 2 and 3). Cox regression for the time to develop a first or second malignancy was independent of exposure to IM, number of biologicals as well as number of different biological classes to which the patient was exposed. Median (IQR) time to develop a first or second malignancy after the start of the first biological was 6 (3–9) and 6 (4–12) years. Conclusion In this large single-centre cohort study spanning 20 years, the overall risk of serious infections and malignancies in patients exposed to biologicals remains low, yet the risk increased with more and sequential use of biologicals so close vigilance is needed.

Maintenance of blood DC homeostasis is essential to preventing autoimmunity while controlling chronic infection. However, the ability of bacteremic pathogens to directly regulate blood DC homeostasis has not been defined. One such bacteremic pathogen, Porphyromonas gingivalis, is shown by our group to survive within mDCs under aerobic conditions and therein, metastasize from its oral mucosal niche. This is accompanied by expansion of the blood mDC pool in vivo, independently of canonical DC poietins. We presently know little of how this bacteremic pathogen causes blood DC expansion and the pathophysiological significance. This work shows that optimum differentiation of MoDCs from primary human monocytes, with or without GM-CSF/IL-4, is dependent on infection with P. gingivalis strains expressing the DC-SIGN ligand mfa-1. DC differentiation is lost when DC-SIGN is blocked with its ligand HIV gp120 or knocked out by siRNA gene silencing. Thus, we have identified a novel, noncanonical pathway of DC differentiation. We term these PDDCs and show that PDDCs are bona fide DCs, based on phenotype and phagocytic activity when immature and the ability to up-regulate accessory molecules and stimulate allo-CD4+ T cell proliferation when matured. The latter is dependent on the P. gingivalis strain used to initially “educate” PDDCs. Moreover, we show that P. gingivalis-infected, conventional MoDCs become resistant to apoptosis and inflammatory pyroptosis, as determined by levels of Annexin V and caspase-8, -3/7, and -1. Taken together, we provide new insights into how a relatively asymptomatic bacteremia may influence immune homeostasis and promote chronic inflammation.