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Background Intestinal fibrosis is a common complication of inflammatory bowel disease (IBD) with limited diagnostic modalities to detect and determine the degree of fibrosis. Fibroblast activation protein alpha (FAP) is a protein with both dipeptidyl peptidase and endopeptidase properties which is virtually absent in healthy tissues and has increased expression in chronic inflammatory and fibrotic diseases. In this study, we investigated the presence of FAP in intestinal fibrosis caused by Crohn’s disease (CD) and ulcerative colitis (UC). Methods For this study, transmural surgical resection specimens were retrieved from the Tytgat institute IBD biobank located at Amsterdam University Medical Center. IBD patients undergoing an ileocecal resection for stricturing CD or a subtotal colectomy for therapy-refractory disease, and patients undergoing a right-sided hemicolectomy or ileocecal resection for dysplasia or non-metastasized colorectal cancer (CRC), were included. All patients had an established diagnosis of (CD, UC, dysplasia or CRC) by previous endoscopy and biopsies and had provided informed consent prior to surgery. FAP protein and gene expression levels were determined using immunohistochemistry staining and quantitative polymerase chain reaction (qPCR). Mass cytometry was used to identify FAP–expressing cells. Results In total, 59 ileal and 35 colonic samples were stained and quantified to asses FAP expression (figure 1). A 1.7-fold and 1.9-fold increase of FAP protein expression was seen in inflamed (mean 22.3, p=0.0069); and stenotic (mean 25.5 p=0.0002) CD ileum compared to healthy non-IBD tissue (mean 13.1). Inflamed UC colon (mean 26.8, p = 0.0406) showed a 1.4-fold increase compared to healthy colon (mean 19.2). For the gene expression, 66 ileal and 42 colonic samples were processed and used for qPCR analysis. A 5-fold and 6.4-fold increase of FAP was found in inflamed (mean 0.011, p=0.0475) and stenotic (mean 0.014, p=0.0042) CD ileum, and a 1.7-fold increase was seen in inflamed UC colon (mean 0.278, p=0.0195) compared to controls (means: ileum 0.002; colon 0.165). Conclusion This is the first study reporting the potential of FAP as a fibrotic biomarker not only in stricturing CD, but also in therapy-refractory UC. Significantly increased FAP protein and gene expression is found in inflamed and stenotic ileum in CD and inflamed colon in UC. Additionally, CD90+GP38+ cells have been identified as the most present FAP expressing cells.

Background For patients living with inflammatory bowel diseases (IBD), the ultimate treatment goal is “normal life”. However, no patient-reported outcome measurement (PROM) exists to measure the level of life normality in IBD. We previously asked patients across the world (5 continents) to identify and rank-order items important to their “normal life”. The top-25 ranked items are being used for subsequent PROM development. In this study, we aimed to compare the perception of healthcare professionals (HCP) and patients with IBD on normal life. Methods IBD patients without an ostomy, pouch or significant comorbidities were interviewed in their mother tongue in 5 continents about “normal life” using a semi-structured interview guide. All items indicated as important were extracted from translated transcripts using directed content analysis (1) until saturation of items occurred. Categorisation was guided by the Wilson’s & Cleary’s Quality of Life model. (2) Second, in an online Delphi procedure, interviewed patients and HCP from each participating centre scored importance of each item on a 0-10 scale. Items scored 7 or higher by >75% were considered important to the respective group. Patient-ranked items were then presented to a patient focus group to clarify wording and merge similar items. Items merged in the patient focus group were merged similarly in HCP rankings. Third, HCP- and patient-rankings were compared. We compared top-25 items selected for PROM development and top-3 items per category. Results 45 CD and 40 UC patients spread over 6 countries were interviewed (median age 36, 56% male, 68% employed, median disease duration 7 years [IQR 4-15]) (table 1). Saturation occurred after 33 CD and 36 UC interviews, yielding 156 unique items. In the Delphi procedure, 54 patients considered 31 items important for normal life with IBD of which 25 remained after focus group discussion. 34 HCP (12 IBD nurses, 16 IBD gastroenterologists, 6 colorectal surgeons) considered 72 items important. Top-25 rankings overlapped in 15 items between patients and HCP, being 5 of 12 physical, 1 of 4 activities, 2 of 3 social, 4 of 11 psychological items and 3 of 5 circumstances (table 2). Top-3 rankings per category overlapped in 2 physical, 1 activities, 2 social, 1 psychological items and 2 circumstances (table 3). Conclusion We identified discrepancies in the perception of normal life with IBD between patients living with IBD and healthcare professionals (HCP). Of top-25 selected items for PROM development, 15 items overlapped between patients and HCP. Of top-3 items per category, the least overlap was seen in activities and psychological items. PROM development and international validation is ongoing.

Background Corticosteroids (CS) may be used for induction of remission in Crohn’s disease (CD); however, side effects, toxicities, and low rates of mucosal healing may limit their long-term use. Safety and efficacy of upadacitinib (UPA), an oral selective Janus kinase inhibitor, were evaluated among patients with CD receiving UPA with CS at baseline in phase 3 clinical trials. Methods In 2 phase 3 studies (U-EXCEL, NCT03345849; U-EXCEED, NCT03345836), patients with moderate-to-severe CD were randomized to 12-week induction with UPA 45 mg once daily (QD) or placebo (PBO). Patients who achieved clinical response to UPA 45 mg were rerandomized in U-ENDURE (NCT03345823) to UPA 30 mg QD, UPA 15 mg QD, or PBO for a 52-week maintenance period. Patients taking CS at baseline or week 0 of maintenance (end of induction) were included. A CS taper began at induction week 4 and continued during maintenance. Endpoints included the proportion of patients who discontinued CS use (CS-free) at week 12 or for ≥ 90 days prior to week 52, and achieved clinical remission by stool frequency/abdominal pain score or by Crohn’s Disease Activity Index (CDAI), enhanced clinical response, decrease of at least 100 points in CDAI from baseline, endoscopic remission, and endoscopic response at week 12 and week 52. CS daily dose (in prednisone equivalent doses) was recorded. Safety was assessed through induction and maintenance. Results Of 1021 patients evaluated, 358 (35.1%) were taking CS at baseline (mean daily prednisone equivalent dose, 23.0 mg). Greater changes from baseline in mean CS daily dose were observed with UPA vs PBO at induction week 12 (−17.3 mg vs −10.7 mg); these changes were sustained at maintenance week 52 (UPA 30 mg, −16.4 mg; UPA 15 mg, −17.4 mg; PBO, −14.7 mg). The proportion of patients who achieved a ≥ 50% reduction in CS daily dose was higher with UPA vs PBO at induction week 12 among patients taking CS at baseline (72.6% vs 48.4%) and at week 52 among patients taking CS at baseline or week 0 of maintenance (UPA 30 mg, 49.2%; UPA 15 mg, 44.4%; PBO, 11.1%). A significantly higher proportion of patients taking UPA vs PBO were CS-free and achieved clinical remission, clinical response, endoscopic response, and endoscopic remission at week 12 (Fig 1A) and week 52 (Fig 1B). Rates of adverse events (AEs), serious AEs, and discontinuation were comparable between groups (Table 1). Serious infections, opportunistic infections, and herpes zoster events were numerically higher with UPA vs PBO (Table 1). Conclusion Patients with CD taking CS were able to taper and discontinue their CS regimen and experience clinical and endoscopic improvements with UPA treatment during the induction and maintenance periods.

Background Abdominal pain (AP), bowel urgency (BU), stool frequency (SF), rectal bleeding (RB) and fatigue are debilitating symptoms that reduce quality of life in patients with ulcerative colitis (UC). Results from two Phase 3 induction trials and one maintenance trial (U-ACHIEVE [NCT02819635] and U-ACCOMPLISH [NCT03653026]) showed significant and clinically meaningful improvements in these symptoms following induction and maintenance treatment with upadacitinib (UPA) in patients with moderately to severely active UC. We evaluated the effects of 8-week UPA induction and 52-week UPA maintenance treatment on UC symptom resolution, defined as no BU, no AP, and symptomatic remission (no RB, SF≤1), and normalization of fatigue, defined as achievement of a Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT–F) score ≥ 40.1. Methods A total of 988 patients were randomized in the U-ACHIEVE and U-ACCOMPLISH induction studies to receive UPA 45 mg once daily (QD; n=660) or placebo (PBO) QD (n=328). Patients who achieved a clinical response after 8 weeks of induction (n=451) were enrolled in the U-ACHIEVE maintenance study and re-randomised 1:1:1 to UPA 15 mg QD (n=148), UPA 30 mg QD (n=154), or PBO QD (n=149). Symptom resolution was assessed at induction Weeks 0, 2, 4, 6, 8 and maintenance Weeks 0, 4, 8, 12, 20, 28, 36, 44, and 52. A more stringent assessment of symptom resolution and normalization of fatigue was conducted at Weeks 0, 2, and 8 of induction and Weeks 0 and 52 of maintenance. Results A higher percentage of patients achieved symptom resolution during induction treatment as early as Week 2 with UPA 45 mg vs PBO (11.1% vs 0.9%, p Conclusion Patients with moderately to severely active UC were more likely to achieve symptom resolution and normalization of fatigue during induction treatment with UPA compared to PBO, and these benefits were sustained during maintenance therapy.

Background Small bowel fibrostenotic strictures are common in patients with Crohn’s disease (CD). No global consensus recommendations on definitions, diagnosis and clinical management are available. Methods Several systematic reviews followed by a RAND/University of California Los Angeles appropriateness study on the definitions, diagnosis and clinical management of fibrostenosing CD in clinical practice were performed. A panel of 28 global experts and a patient representative were convened. They assessed a total of 152 candidate items. The items were subsequently evaluated for appropriateness. Results No accurate predictive biomarkers are available for naïve or anastomotic fibrostenosing strictures. Accurate diagnosis of fibrostenosing CD requires cross-sectional imaging which should evaluate bowel wall thickness, luminal narrowing and prestenotic dilatation. A potential inflammatory component should be assessed. Abdominal cross-sectional imaging was considered necessary prior to any treatment decision. The panel proposed an approach to medical, endoscopic, and surgical therapies (Figure 1 and Table 1). Technical characteristics for endoscopic balloon dilation and follow up strategies after successful dilation therapy were identified. Appropriateness, types and performance of different surgical approaches in various settings were evaluated. Conclusion This global consensus provides clinical guidance for the diagnostic and therapeutic management of patients with fibrostenotic CD.

Background In the risankizumab (RZB) phase 3 clinical programme, Crohn’s disease (CD) patients who responded to RZB intravenous (IV) induction were re-randomised to RZB or placebo (PBO) (withdrawal PBO subcutaneous [SC] in maintenance (FORTIFY), while responders to PBO induction continued receiving PBO. Patients in the withdrawal (PBO SC) arm of FORTIFY who received IV RZB induction achieved high rates of clinical response/remission at Week (Wk) 52 likely due to the prolonged PK/PD effect of RZB and robust efficacy during induction.1 Here, we describe disease activity outcomes in non-randomised patients who received PBO during both induction and maintenance. Methods: This post-hoc analysis included patients who received PBO IV in the induction study (ADVANCE or MOTIVATE), achieved clinical response (definition in Figure footnote) at Wk 12, and continued on PBO SC during FORTIFY.1,2 Subjective measures of disease activity (clinical remission [per CD Activity Index (CDAI)] and per stool frequency [SF] and abdominal pain score [APS], CDAI clinical response, and SF/APS enhanced clinical response), as well as objective measures of biomarkers (high sensitivity C-Reactive Protein and faecal calprotectin) levels and endoscopic outcomes (response, remission, and ulcer-free endoscopy), during FORTIFY were evaluated (endpoint definitions in Figure footnotes) at Wk 52. Biomarkers were additionally evaluated at induction baseline. For reference only, previously reported data from patients who were clinical responders to RZB IV induction and were re-randomised in FORTIFY are presented alongside data from the continuous PBO patients subgroup.1,2 Results In the 104 patients who received PBO during both induction and maintenance, clinical response and remission rates decreased steadily during FORTIFY (Figure), while biomarker levels were relatively unchanged from induction baseline to FORTIFY Wk 52. In contrast, a slower rate of loss of response per clinical response/remission and lower biomarker levels over time were observed in RZB IV induction responders re-randomised to PBO in FORTIFY. Although already low, endoscopic response rates in the continuous PBO group decreased from FORTIFY Wk 0 to Wk 52, whereas endoscopic remission and ulcer-free endoscopy rates remained unchanged. Conclusion The symptomatic improvement achieved in patients clinically responding to PBO during induction was not maintained with continued PBO treatment in maintenance, unlike that observed in patients withdrawn from RZB, underscoring the durability of RZB induction response.1 Most objective measures of disease activity in patients receiving continuous PBO were relatively unchanged over time, with biomarkers remaining elevated and endoscopic rates of response low.

Background Network meta-analysis (NMA) using randomised controlled trial (RCT) data can provide indirect evidence on comparative efficacy of various treatments.1 The NMA reported herein was conducted to evaluate infliximab (IFX) and vedolizumab (VDZ) comparative efficacy during maintenance treatment of moderate-to-severe Crohn’s disease (CD) and ulcerative colitis (UC), covering various dosing regimens and administration routes for each biologic. Methods Studies were identified by literature searches that included publications up to 1 November 2022. Parallel-group RCTs evaluating IFX or VDZ (intravenous [IV] or subcutaneous [SC]) for maintenance treatment of adult patients with moderate-to-severe CD or UC that reported clinical remission rates were included. Eligible studies treated patients for a minimum of 22 weeks, with follow-up of 30–60 weeks for maintenance. Clinical remission rates in tumour necrosis factor inhibitor (TNFi)-naïve patients from each study were analysed in a Bayesian NMA fixed-effect model. Results Overall, 13 RCTs were identified and included in the analysis (Table 1 for CD and Table 2 for UC). The difference in study design between IFX (treat-through) and VDZ (re-randomisation of induction responders only) was noted. A connected network of evidence could be generated using CD and UC studies (Figures 1A and 1B, respectively). In both CD and UC, IFX SC 120 mg had the highest odds ratio (95% confidence interval [CI]) vs. placebo for clinical remission during the maintenance phase (CD: 5.90 [1.90–18.2]; UC: 5.45 [1.94–15.3]), albeit with the CIs overlapping with the CIs of the other tested regimens (Figures 2A and 2B). In both CD and UC, IFX SC 120 mg ranked highest for clinical remission among the biological agents, dosing regimens, and routes of administration tested. Conclusion In both CD and UC, IFX SC showed a favourable efficacy profile for achieving clinical remission during maintenance treatment of TNFi-naïve adult patients, when compared with the other IFX IV or VDZ IV/SC regimens tested. References: 1 Rouse B et al., Intern Emerg Med 2017;12(1):103-111.

Background Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). Although ≈30% of UC patients initially present with isolated proctitis, most phase 3 trials of systemic therapies in UC excluded this subgroup. We report the efficacy and safety of etrasimod in subjects with isolated proctitis enrolled in the ELEVATE UC programme. Methods In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), subjects (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 comprised a 12-week induction period. Both trials allowed inclusion of subjects with isolated proctitis ( Results This analysis included 64 pooled subjects with isolated proctitis at week 12 (42 etrasimod, 22 PBO) and 36 subjects from UC 52 at week 52 (27 etrasimod, 9 PBO). Greater proportions (P Conclusion Efficacy and safety of etrasimod in subjects with isolated proctitis was consistent with the overall population of the ELEVATE programme.1 The analysis was performed on a small dataset and should be interpreted with caution but informs on the efficacy of etrasimod in a subpopulation of UC subjects commonly excluded from drug development trials. Reference: 1. Sandborn WJ, et al. Presented at: DDW 2022; May 24, 2022. Abstract 968a.

Environmental and lifestyle factors play an important role in the natural history of Crohn's disease and ulcerative colitis. A group of international experts from the International Organization for the Study of Inflammatory Bowel Diseases voted on a series of consensus statements to inform the management of inflammatory bowel disease (IBD). The recommendations include avoiding traditional cigarette smoking in patients with Crohn's disease or ulcerative colitis, screening for symptoms of depression, anxiety, and psychosocial stressors at diagnosis and during flares (with referral to mental health professionals when appropriate), and encouraging regular physical activity as tolerated. Patients using dietary approaches for treatment of their IBD should be encouraged to adopt diets that are best supported by evidence and involve monitoring for the objective resolution of inflammation. We recommend formal assessment for obesity and nutritional deficiencies, and patients should be encouraged to maintain a normal body-mass index. A shared decision-making approach to contraception should include the consideration of IBD-related factors, and risk factors for venous thromboembolism. Long-term or frequent use of high-dose non-steroidal anti-inflammatory drugs should be avoided. For primary prevention of disease in the offspring of patients with IBD, we recommend avoiding passive exposure to tobacco, using antibiotics judiciously, and considering breastfeeding when able.

Background To assess treatment response, objective measures are superior to clinical improvement in Crohn’s disease [CD]. Intestinal ultrasound [IUS] is an attractive, non-invasive alternative to endoscopy, demonstrating early transmural changes after treatment initiation. Therefore, we investigated IUS and contrast-enhanced ultrasound [CEUS] to predict [early] endoscopic treatment response. Methods Consecutive patients with endoscopically active CD, starting anti-TNFα therapy, were included. Clinical, biochemical, IUS, and CEUS parameters at baseline [T0], after 4–8 weeks [T1] and 12–34 weeks [T2] were collected. The most severely inflamed segment at endoscopy (highest segmental Simplified Endoscopic Score for Crohn’s Disease [SES-CD]) and IUS (highest segmental bowel wall thickness [BWT]) was identified. At T2, endoscopic response [decrease in SES-CD ≥ 50%] and remission [SES-CD = 0] were scored. Results A total of 40 patients were included: 14 reached endoscopic remission and 17 endoscopic response. At T1 (3.1 mm [1.9–4.2] vs 5.3 mm [3.8–6.9], p = 0.005) and T2 (2.0 mm [1.8–3.1] vs 5.1 [3.0–6.3] mm, p = 0.002) BWT was lower in patients with endoscopic remission. At T1 and T2, 18% (area under the receiver operating curve [AUROC]: 0.77; odds ratio [OR]: 10.80, p = 0.012) and 29% [AUROC: 0.833; OR: 37.50, p = 0.006] BWT decrease predicted endoscopic response, respectively. To determine endoscopic remission, BWT 3.2 mm was most accurate [AUROC: 0.94; OR: 39.42, p < 0.0001] at T2. In addition, absence of colour Doppler signal [OR: 13.76, p = 0.03] and the CEUS parameter wash-out rate [OR: 0.76, p = 0.019] improved the prediction model. Conclusions Reduction in BWT, already after 4–8 weeks of follow-up, predicted endoscopic response and remission. CEUS parameters were of limited value. Furthermore, we have provided accurate cut-offs for BWT reflecting endoscopic response and remission at different time points.

Background To date, the association between vedolizumab (VDZ) serum concentrations and histological remission in ulcerative colitis (UC) has not been studied prospectively. VDZ serum concentrations could potentially offer additional guidance for predicting histological remission. We studied the relationship between VDZ serum concentrations and histological remission in a prospective study. Methods LOVE-UC was a multicentre international (Belgium, the Netherlands, and Hungary) open label prospective study in patients with moderately to severely active UC treated with VDZ. VDZ serum concentrations were measured at trough prior to every infusion. Endoscopy was performed at baseline, week 26 and 52. Biopsies from the most severely affected area and endoscopy videos were scored by blinded central readers. Histological remission was defined as a Robarts Histopathology Index Results A total of 121 patients (61 male, 62 with prior exposure to tumour necrosis factor antagonists, mean total Mayo score at baseline of 9) received at least one infusion of VDZ. At week 26, 37.2% (45/121) patients were in histological remission, 38.8% (47/121) were in histological remission at week 52. The corresponding rates of combined histological and endoscopic remission were 19.8% (24/121) and 20.7% (25/121), respectively. Median VDZ serum concentrations were numerically higher at all time points in patients who achieved histological remission at week 26 than in those who did not (Table 1). Concentration thresholds (sensitivity, specificity, positive predictive value, negative predictive value, area under the receiver operating characteristic curve) of 32.5 mg/L (66%, 68%, 54%, 74%, 0.681) at week 6 and 12.5 mg/L (76%, 60%, 61%, 70%, 0.724) at week 22 were associated with histological remission at week 26. Higher proportions of patients achieved histological remission at week 26 in higher VDZ serum concentration quartiles (Figure 1). Conclusion VDZ serum concentrations were positively associated with histological remission in UC, although the predictive value of serum concentrations for subsequent histological remission was modest.

Background Corticosteroids are often used in Crohn’s disease (CD) to control inflammation. However, they are associated with adverse events; thus, achieving and maintaining remission without corticosteroids is a major treatment goal. GALAXI 1, a phase 2b, double-blind, placebo (PBO)-controlled study, evaluated efficacy and safety of guselkumab (GUS), a selective interleukin-23p19 subunit antagonist, in patients (pts) with moderately to severely active CD. Primary efficacy and safety data were presented previously. Here, we report corticosteroid-free clinical remission rates through Week (Wk) 48. Methods Pts with moderately to severely active CD were randomised in a treat-through design to GUS 200, 600, 1200mg; ustekinumab (UST) ~6mg/kg; or PBO intravenous (IV) induction followed by maintenance dosing (GUS 200mg IV-->GUS 100mg subcutaneous [SC] every 8 weeks [q8w], GUS 600mg IV-->GUS 200mg SC q4w, GUS 1200mg IV-->GUS 200mg SC q4w, UST ~6mg/kg IV-->UST 90mg SC q8w, PBO nonresponders-->UST ~6mg/kg IV-->UST 90mg SC q8w, PBO responders-->PBO SC q4w). Corticosteroid tapering was mandatory from Wk12 if medically feasible. Efficacy endpoints included corticosteroid-free CD Activity Index (CDAI) clinical remission ( Results At Wk48, 55.7-71.4% of pts in the GUS dose groups achieved corticosteroid-free CDAI clinical remission (Table 1). Similar rates were observed when the corticosteroid-free duration was ≥30 or ≥90 days before Wk48. Among pooled pts in CDAI clinical remission at Wk48 in the GUS groups, 115/120 (95.8%) were corticosteroid free. At Wk48, 49.2-68.3% of pts in the GUS dose groups achieved corticosteroid-free PRO-2 remission (Table 1). Among pooled pts in PRO-2 remission at Wk48 in the GUS groups, 105/110 (95.5%) were corticosteroid free. Outcomes in the reference UST group are shown in Table 1. Among pts in the GUS dose groups, 30.2-39.3% were using corticosteroids at Wk0 (median prednisone equivalent dose 20.0mg/d in each group); at Wk48, 60.0-78.9% of these pts met corticosteroid-free criteria (Table 2). Conclusion High rates of corticosteroid-free CDAI clinical and PRO-2 remission were achieved at Wk48 in the GUS dose groups. Among pts in clinical remission, most were corticosteroid free. Nearly all pts maintained corticosteroid-free CDAI clinical remission for ≥90 days. GUS IV induction followed by SC maintenance therapy also effectively reduced corticosteroid use at Wk48.

Background Endoscopic healing is an important treatment goal in Crohn’s disease (CD). Vedolizumab (VDZ) was shown to induce endoscopic healing after 6 months in a significantly greater proportion of pts with early CD than in those with late CD (>2 years)(UEGW 2022). We investigated whether further endoscopic healing could be attained with 6 more months of VDZ treatment in those pts with no SES-CD worsening at month 6 compared to baseline. Methods Pts in the LOVE-CD study received standard doses of VDZ and had ileocolonoscopies at baseline, w26 and 52. We studied the kinetics of endoscopic improvement during continued VDZ treatment. Endoscopies were scored by independent readers. So far, 157 pts completed the LOVE-CD trial with available central reading results. We here report the results of 76 pts (48%) who had stable endoscopic diseases or any degree of endoscopic improvement at w26 with 3 centrally read endoscopy scores (baseline, w26 and 52) available at present. VDZ serum conc were also measured and correlated to endoscopic improvement. Results We studied 76 pts (mean age 36.7, 51 (67%) female, median baseline SES-CD 10 (range 3-30) who reached w52 and had no SES-CD worsening at w26. We identified 3 endoscopic improvement patterns: 1) 24 pts (32%, 12 early, 12 late CD) with median baseline SES-CD 7.5 (range 3-21) had a SES-CD score of 0 at w26. Three of these pts had again mild lesions at w52 (SES-CD 1-4), the rest maintained SES-CD=0 at w52 (endoscopic healing); 2) 20 pts (26%, 6 early, 14 late CD) with median baseline SES-CD 8 (range 3-27) had a SES-CD of 1-3 at w26 (endoscopic remission defined as SES-CD4) with a drop to median SES-CD 7 (range 5-20) at w26 and further to median SES-CD 5 (range 0-15) at w52. Figure 1 shows the evolution of the SES-CD. The mean VDZ serum conc was (1) 19.36 mg/l at w26 and 22.23 mg/l at w52 in the group with endoscopic healing, (2) 19.52 mg/l at w26 and 21.69 mg/l at w52 in the group with endoscopic remission, and (3) 17.38 mg/l at w26 and 20.09 mg/l at w52 in the group without endoscopic healing or remission. Conclusion In this subset of LOVE-CD pts with endoscopic improvement or unchanged SES-CD at w26, the majority of pts (44/76) reached endoscopic remission (SES-CD

Background Up to 30% of Crohn's Disease (CD) patients suffer from perianal fistula creating a high disease burden. Treating CD fistula is challenging compared to cryptoglandular fistula, which have a significantly better wound healing response. Previous studies suggested epithelial to mesenchymal transition as an inducer of fistula formation, as markers were observed in fistula tracts. However, most studies compared CD fistula to normal mucosa, thus disregarding whether any observed difference was in fact a sign of healing (as CD fistula will have more active healing than uninjured mucosa) or a sign of pathology (as healing is not occurring effectively). Therefore, in this study we evaluated CD fistula, as well as both healthy mucosa (no active healing) and cryptoglandular fistula (effective healing) in order to determine the role of differences found. Methods Biopsies from the internal opening (n=20) of perianal fistula of CD patients were collected and compared to two publicly available datasets obtained from un-inflamed rectum (RISK cohort and GSE83245). In addition, curettage material of CD (n=54) and cryptoglandular fistula (n=15) was obtained. Expression profiling was performed using RNASeq. Results Comparing the mucosa at the internal opening of CD fistula to publicly available datasets of healthy rectum, 770 genes were differentially expressed. Pathway analysis revealed upregulation of proliferative and inflammatory processes, consistent with expected immune and wound healing responses. Interestingly, strongest upregulation was seen for processes of cornification and keratinization, including expression of IVL (involucrin) and FLGR2 (fillagrin2), involved in keratinocyte differentiation. To evaluate whether this was contributing to active wound healing or rather to persistent disease, we analyzed the actual tract in CD and cryptoglandular fistula. Strikingly, cornification and keratinization processes were more pronounced in cryptoglandular fistula, suggesting a role in effective healing rather than the persistent pathology seen in CD. Similar data was observed for TGFb, previously detected in CD fistula and thus considered a pathological contributor. While we confirm increased TGFb activity in CD fistula compared to normal mucosa, activity in cryptoglandular fistula tracts was higher than in CD fistula tracts. Again, this would suggest TGFb signaling as part of the wound healing response rather than part of the pathogenic mechanism. Conclusion Perianal fistulas show upregulation of keratinization and cornification pathways compared to healthy mucosa. Comparing CD and cryptoglandular fistula, we saw more cornification in the better healing cryptoglandular fistula, suggesting involvement in effective healing rather than pathology.

Background Vedolizumab (VDZ) is a monoclonal antibody directed against α4β7 integrin used to treat Crohn’s disease, which has proven to be efficacious in phase 3 clinical trials¹ and in real-world studies². However, there is a need for reliable biomarkers to predict whether an individual patient will respond to VDZ treatment. Glycosylation changes have been associated with CD, but have never been studied as potential predictors of remission to biological therapy³. A comparison of plasma N-glycan profiles between responders and non-responders to VDZ was used to detect potential biomarkers to response. Methods Plasma samples before (t1) and after (t2) initiation of vedolizumab treatment (mean follow up time at t2 215 ± 61 days) were taken from 58 patients with Crohn’s disease. They were analysed by high-performance liquid chromatography with mass spectrometry. Response to VDZ was assessed by a combination of clinical and endoscopic outcomes and was observed in 34 of 58 patients. 89 direct glycan traits met the criteria for quantification and were extracted from the data via LacyTools. Consequently, 21 derived glycan traits were calculated by combining direct traits with shared structural similarities. Correcting for age and sex, the direct and derived traits were tested across responses using logistic regression and cross-validation to determine which traits at t1 are predictive of response (p-value < 0.05) and traits at t2 are markers of response (p-value < 0.05). Results Two glycans, MAN6 (0.65 AUC) and FA2G2S2 (0.7 AUC) were higher in responders prior to treatment and moderate predictors of response, with no improvement in a combined model (figure 1A). Congruent to previous studies, galactosylation levels increased in responders after treatment. Overall, 17 direct traits and 4 derived traits were markers of response after treatment and collectively proved to be good predictors of response (0.80 AUC) (figure 1B). Conclusion This study has demonstrated multiple N-glycans are indicators of future response to VDZ treatment, with the potential to guide clinicians in determining the most appropriate form of treatment for individuals. These data require to be validated in the future; and to be assessed alongside other emerging biomarkers. References: 1 Sands BE, et al .2014 Sep;147(3):618-627.e3 2 Bressler B,et al.2021 Mar 30;15(10):1694–706. 3 Šimurina M, et al. 2018 Apr;154(5):1320-1333.e10

Background The efficacy and safety of mirikizumab (miri) for moderately to severely active ulcerative colitis (UC) was demonstrated in the Phase 3 LUCENT trials (LUCENT-1 and -2; NCT03518086, NCT03524092).1,2 Some patients may improve more slowly and require a prolonged course of induction before achieving clinical response. Therefore, we evaluated clinical response in patients who had not responded by the end of the 12-week(W) induction period and who received extended induction treatment for an additional 12W. Methods Patients not responding to intravenous (IV) administration of 300 mg miri every 4 weeks (Q4W) (n=272) at W12 (LUCENT-1), received extended 12-W induction treatment of open label 300 mg miri IV Q4W for 3 additional doses (LUCENT-2). Patients responding at W24 (n=144) of continuous IV treatment, entered open label maintenance and received 200 mg miri Q4W subcutaneously (SC) until W52. Key outcomes through 52W are reported (Definitions in Table). Results Among the 272 patients who failed to achieve a clinical response after 12W of induction treatment, 72.4% had a Mayo endoscopic subscore of 3, indicating severe disease. Of these patients, 146 (53.7%) achieved a clinical response and 31 (11.4%) achieved clinical remission at W24. Of the 144 responders at 24W entering the open label maintenance study, 52 (36.1%) patients achieved clinical remission, 104 (72.2%) achieved clinical response, 62 (43.1%) achieved endoscopic remission and 60 (41.7%) patients achieved histologic improvement at W52. Furthermore, for these patients, there was a 3.8 (±2.7) point reduction from baseline in bowel urgency (BU) severity and 58.8% achieved clinically meaningful improvement in BU (Table). Among these patients, 38.3% demonstrated treatment-emergent adverse events (TEAEs). Most TEAEs were mild (21.4%), while only 5.4% were serious. Overall, there was a 3.2% of discontinuation due to TEAEs. No new safety signals or deaths were reported. Conclusion Among patients who did not initially respond to induction treatment with miri at 12W, 3 additional miri induction doses induced clinical response and remission in patients, highlighting the potential benefit of extended induction treatment with miri in those patients with more severe inflammation at baseline. 1.D’Haens et al., OP26: Efficacy and safety of mirikizumab as induction therapy in patients with moderately to severely active Ulcerative Colitis: Results from the Phase 3 LUCENT-1 study, Crohn's and Colitis, Vol. 16, Iss. Supplement_1, Jan. 2022, i028–i029 2.Dubinsky et al., 867e: Efficacy and safety of mirikizumab as maintenance therapy in patients with moderately to severely active Ulcerative Colitis: Results from the Phase 3 Lucent-2 study, Gastroenterology, Vol. 162, Iss. 7, S-1393-94

Background Abdominal pain is a common occurrence for approximately 39% of patients with inflammatory bowel diseases in remission (quiescent IBD; qIBD). There is increasing evidence for a contributing role of the gastrointestinal fungal community (i.e., mycobiome) in relation to intestinal inflammation and irritable bowel syndrome (IBS). As such, abundance of Candida spp. and sub-species variation of Candida albicans were previously associated with IBD severity. In the current study, we aim to investigate mycobiome of patients with qIBD and qIBD with abdominal pain (qIBD–AP). Methods Patients with qIBD (defined as faecal calprotectin (FCP) ≤250 μg/g) with (n=91) or without (n=58) abdominal pain provided faecal samples. Abdominal pain was scored based on either the Irritable Bowel Syndrome Symptom Severity Scale (IBS–SSS) or Gastrointestinal Symptom Rating Score (GSRS) questionnaire. Faecal fungal communities were determined based on Internal Transcribed Spacer 1 (ITS1) sequencing. Cultivable yeasts from faecal samples were identified using Matrix Assisted Laser Deionization Time–of–Flight Mass Spectrometry. C. albicans strains (n=137 from 29 patients) were genotyped by ITS Sanger sequencing analysis and typing of seven microsatellite loci. Release of virulence-related enzymes (proteinase, phospholipase, lipase, esterase) by C. albicans was assessed through determination of precipitation zones on solid agar mediums containing enzyme-specific substrates. Results Descriptive mycobiota analysis revealed limited differences between compositions of qIBD and qIBD–AP patients, but a discriminative signature for abdominal pain was extracted using machine-based learning models. While ITS Sanger sequencing of faeces-derived C. albicans was insufficient to elucidate genetic variability, analysis of microsatellite loci revealed extensive variability and clustering into six clone clusters and a likely distinction between qIBD and qIBD-AP patients (Fig. 1). Phospholipase enzymatic activity of C. albicans strains correlated with GSRS–Abdominal Pain sub-score, as did proteinase activity with severity of abdominal pain according to the IBS–SSS (Fig. 2). Additionally, lipase activity inversely correlated with faecal calprotectin (Fig. 2). Conclusion The faecal gut mycobiome is associated with self–reported abdominal pain in patients with IBD in remission. This notion is based on both compositional and culture-dependent methods and specified clones of C. albicans may selectively contribute to abdominal pain for qIBD patients. This study opens further possibilities to investigate the role of faecal gut fungi in light of abdominal pain for qIBD-AP patients.

Background Perianal Crohn’s Disease (pCD) is a frequent and debilitating complication of Crohn’s Disease (CD). Magnetic Resonance Imaging (MRI) is the imaging modality for diagnosis, classification, and treatment monitoring in pCD. To evaluate treatment response, a validated radiological index is mandatory. Recently, the MAGNIFI-CD index has been developed. The aim of our study was to validate the MAGNIFI-CD index; evaluating reliability, responsiveness and accuracy. Methods At two tertiary IBD referral centers, patients (≥16yrs) with complex pCD that had pelvic MRI before and 3-24 months after medical and/or surgical treatment were included. Two independent, blinded abdominal radiologists randomly scored total MAGNIFI-CD and its separate items. Two clinicians scored clinical outcomes (remission, response, non-response) using the “fistula drainage assessment” (FDA). Interobserver agreement (ICCs or weighted K), responsiveness (according to FDA; Wilcoxon signed rank test), and test accuracy (ROC analyses for the follow-up (FU) MAGNIFI-CD) were determined. Youden indices (YI) were used to choose optimal cut-off values for the FDA categories. Results Sixty-seven patients (median age 30 [IQR 23-47], 51% female) were eligible with mean CD and pCD duration of 7.0 yrs (SD 8.7) and 3.7 yrs (SD 4.3), respectively. 44% was biological naïve, 9% had defunctioning ostomy and 20% had proctitis. Baseline MAGNIFI-CD was 18 [IQR 9–20]. MAGNIFI-CD had an almost perfect ICC of 0.88 (95%CI 0.78-0.92); reliability of the separate items was moderate to substantial. Between baseline and FU MAGNIFI-CD a significant decrease was observed in responders and remitters (p Conclusion The MAGNIFI-CD index is a reliable radiological index supported by an almost perfect agreement. Given the moderate agreement, the item “dominant feature” would need additional training or better definitions. The index shows a robust responsiveness to clinical change and does not improve significantly in non-responders. The MAGNIFI-CD seems to be an acceptable to excellent test to accurately determine response or remission. We suggest a cut-off value of ≤14 for response and ≤10 for remission at follow-up MAGNIFI-CD. These results support that the MAGNIFI-CD is suitable for treatment monitoring in clinical trials.

Background Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development to treat immune-mediated inflammatory disorders. CULTIVATE (NCT04173273) is a seamless phase 2/3 trial comprising 5 substudies designed to evaluate the efficacy, safety, and tolerability of etrasimod in subjects with moderately to severely active Crohn’s disease (CD). Here, we report the induction data from the first substudy (Substudy A). Methods Substudy A was a phase 2, randomised, double-blind study using a 14-week induction period followed by a 52-week extension period. Adults (18-80 years) with moderately to severely active CD and an inadequate response, loss of response to, or intolerance to ≥1 conventional or advanced treatments for CD were randomised 1:1 to once-daily etrasimod 2 mg or 3 mg. Subjects were stratified by baseline biologic failure status and oral corticosteroid use. The primary efficacy endpoint was achievement of endoscopic response (defined as endoscopic remission [SES-CD ≤4 and ≥2-point reduction from baseline with no subscore >1] or ≥50% decrease in SES-CD score) at week 14. Secondary/exploratory endpoints included achievement of endoscopic remission, clinical remission (CDAI Results Of 83 subjects randomised to etrasimod 2 mg or 3 mg, respectively, 32/42 (76.2%) and 36/41 (87.8%) completed week 14 (Table 1). Overall, 21.4% and 9.8% of subjects in the 2-mg and 3-mg groups, respectively, achieved the primary endpoint of endoscopic response, 14.3% and 7.3% achieved endoscopic remission, 31.0% and 43.9% achieved clinical remission, and 33.3% and 40.0% achieved IBDQ remission at week 14 (Figure 1). Most treatment-emergent AEs were mild or moderate, with more AEs reported in the 3-mg vs 2-mg group. The incidence of serious AEs (4.8% and 2.4%) and AEs leading to discontinuation (4.8% and 7.3%) was low in the 2-mg and 3-mg groups, respectively (Table 2). Two subjects in the 3-mg group experienced second degree atrioventricular block type 1 TEAEs (during 2-mg titration). Conclusion Data from this substudy of subjects with moderately to severely active CD suggest endoscopic and clinical improvement with both etrasimod 2 mg and 3 mg. However, the small sample size and lack of placebo arm limit the ability to draw conclusions about efficacy including comparison between the 2-mg vs 3-mg groups. Both doses were well tolerated and safety was consistent with other etrasimod clinical programmes. Data from the extension phase of Substudy A and the placebo-controlled, dose-ranging phase 2b Substudy 1 are forthcoming.

Background The clinical course of Crohn’s disease (CD) is associated with development of complications including strictures and penetrating lesions such as fistulas and abscesses. Close disease monitoring and optimizing therapy can prevent these complications. Intestinal ultrasound (IUS) is a non-invasive cross-sectional imaging method ideal for frequent assessment of disease activity and intra-abdominal complications. In this meta-analysis we provide an updated assessment of the diagnostic accuracy of IUS and its advanced modalities in the detection of intra-abdominal complications in CD compared to endoscopy, MRI/CT, surgery and pathology. Methods We conducted a literature search in Pubmed/MEDLINE and EMBASE databases from 01-01-1970 up to and including 17-10-2022 for studies describing diagnostic accuracy of IUS in adult patients with CD related intra-abdominal complications. Quality of the included studies was assessed with the QUADAS-2 tool. A univariate random-effects model was used to calculate the diagnostic test accuracy variables, including the log diagnostic odds ratio and area under the pooled ROC (AUC for SROC). All data were calculated with 95% confidence intervals (CIs). Chi-squared (χ²) test was used to assess study heterogeneity with p < 0.05 indicating significant heterogeneity. Funnel plots were created to assess publication bias. All meta-analysis were performed using the R-package mada. We calculated pooled sensitivity and specificity in Meta-DiSc. Results We identified 1506 studies of which 68 were used for the systematic review. Twenty-three studies with 3863 patients were included in this meta-analysis with an overall moderate to high risk of bias. In total 6 meta-analyses were performed, both for conventional IUS (B-mode) and oral contrast IUS (SICUS) for diagnosing CD-related complications. Pooled overall log diagnostic odds ratio for strictures, fistulas and inflammatory masses by B-mode IUS were 3.56 (2,90-4.21), 3.84 (3.28-4.41) and 3.97 (3.30-4.64) and the AUC were 0.926, 0.896 and 0.960 respectively. Pooled overall diagnostic odds ratio for the diagnosis of strictures, fistulas and inflammatory masses by SICUS were 4.51 (3.28-5.73), 4.80 (3.46-6.14) and 5.46 (3.61-7.30) and the AUC were 0.955, 0.982 and 0.985, respectively. Significant heterogeneity was seen between studies reporting data on diagnosing strictures by B-mode IUS. Conclusion These results indicate that IUS is an accurate tool for the diagnosis of intra-abdominal complications related to CD. IUS as a non-invasive, point-of-care modality is recommended as the first-line imaging tool if there is a suspicion of CD-related intra-abdominal complications.

Background The operating properties of histologic indices are poorly characterized in Crohn’s disease (CD) and no validated index exists. We assessed the reliability and responsiveness of histologic indices/items, developed an exploratory index, and compared different methods of scoring. Methods Using baseline and week 12 histologic image sets from the EXTEND placebo-controlled trial, blinded central readers scored 4 histologic indices (the Global Histologic Activity Score [GHAS], Geboes Score [GS], Robarts Histopathology Index [RHI], and Nancy Index [NHI]) and 3 additional novel items identified by an expert panel (mucin depletion, basal plasmacytosis, and pyloric gland metaplasia in the ileum). Reliability and responsiveness were evaluated for a global score (4 colonic segments + ileum), colonic score (4 colonic segments) and ileal score (ileum only) using the intraclass correlation coefficient (ICC) and area under the receiver operating curve (AUC), respectively. Change was defined using treatment assignment and improvement in histologic disease activity as measured on a 100-mm visual analogue scale (VAS) in responsiveness testing. Exploratory indices were developed using backward stepwise linear regression analysis. Candidate independent variables were items with an ICC ≥0.4 and AUC ≥0.56. The VAS served as the dependent variable. Results Paired histologic images were analysed from 55 subjects. Inter-rater reliability was substantial to almost perfect (ICC=0.73-0.85) and responsiveness was small to large (treatment assignment AUC=0.50-0.65; VAS AUC=0.71-0.94). The GHAS, GS, RHI, and NHI reached the minimum threshold for reliability (ICC ≥0.4) and responsiveness (AUC ≥0.56) regardless of whether the global and colonic scores were calculated using the worst affected segment, average of the included segments, or sum of the included segments (Table 1-3). Five items were tested as candidate predictors. Three exploratory indices were developed, each consisting of 3 items: a global index (neutrophils in the lamina propria, neutrophils in the epithelium, and erosion/ulceration), colonic index (chronic inflammatory infiltrate, neutrophils in the lamina propria, and erosion/ulceration) and ileal index (chronic inflammatory infiltrate, neutrophils in the epithelium, and erosion/ulceration). The novel indices highly correlated with the GHAS, GS, RHI, and NHI, with correlation coefficients ≥0.80 (Table 4). Conclusion The 4 existing indices were similarly reliable and responsive in measuring CD histologic activity, regardless of the method for calculating global and colonic scores and could be used in clinical trials. Attempts at novel index development did not offer benefit over current histologic indices.

Background Strictures develop in over half of Crohn’s Disease (CD) patients and can lead to complaints of bowel obstruction, requiring treatment. A study showed that strictures and pre-stricture small bowel (SB) have lower motility measured with cine-MRI, compared to normal bowel in CD. However, stricture motility has not been correlated with disease duration or Harvey Bradshaw Index (HBI). Investigating this correlation can provide insight in the physiologic behavior of a stricture in relation to the extent of bowel damage (disease duration) and clinical complaints (HBI). This could possibly support the clinician in treatment decisions. Our aim is to investigate correlations between stricture motility measured with cine-MRI and disease duration and HBI, respectively. Methods At a tertiary center CD patients (≥18yrs) with SB strictures were included. Patients fasted 4 hours, after which they drank 1600 mL (2.5%-mannitol-solution) in 60 minutes prior to 3T MRI. All underwent coronal dynamic 2D bFFE scans of the most stenotic SB and the pre-stenotic dilation if present, during a 20-second expiration breath-hold. Bowel motility was assessed with a validated displacement mapping technique (GIQuant, Entrolytics, Motilent, UK). Strictures (wall thickening >3mm and ≥50% luminal reduction) and pre-stenotic dilations (luminal diameter >3cm) were delineated on a reference image and motility was quantified on a motility map within these regions of interest (ROI), producing a single, numerical motility score (Arbitrary Units=AU). Stricture and pre-stenotic dilation motility scores are presented in medians [IQR]. Correlation was tested between stricture motility, disease duration and HBI by means of spearman’s rank correlation test. Results Twenty-two patients (55% male, age 37yrs [IQR 25-55], disease duration 7yrs[IQR 4-12]) were included. SB stricture motility was 57AU[IQR 48-71]. Pre-stenotic dilation motility (n=6) was 131AU[IQR 88-340]. Disease duration and stricture motility showed no correlation(r=0.2, p=0.4). HBI and stricture motility were inversely correlated(r=-0.6, p Conclusion We found an inverse correlation between SB stricture motility and HBI. No correlation was found between SB stricture motility and disease duration. The inverse correlation between HBI and stricture motility suggests that lower motility is associated with poorer clinical condition. This finding can possibly lead to earlier endoscopic or surgical intervention, since it indicates lower motility is associated with poorer clinical condition. Interestingly, we also measured higher pre-stenotic dilation motility compared to stricture motility, presumably a physiological response of the pre-stenotic dilation to the distal stricture and ongoing proximal peristalsis.

Background Crohn’s disease (CD) is a complex immune-mediated disease of the gastrointestinal tract where the gut microbiome plays an important role. Current biological treatment options in CD include the anti-TNFα agents adalimumab (ADA) and infliximab (IFX), vedolizumab (VDZ), and ustekinumab (USTE). Finding biomarkers to predict therapy response is still a clinical unmet need, as the majority of CD patients fail to reach endoscopic remission within 1 year of treatment. While the majority of studies focus on fecal samples, mucosa-adherent bacterial signature could bring forth stable biomarkers. In this study, we sought to identify signatures of the adherent microbiome in intestinal biopsies aimed at differentiating responders (R) from non-responders (NR), prior to the start of biological treatment. Methods We prospectively collected paired ileal and colonic biopsies (stored snapfrozen in -80 ºC) from adult CD patients scheduled to start anti-TNFα (IFX and ADA), VDZ and USTE treatment during baseline endoscopies. After 6-12 months of follow-up, patients were classified as either R or NR based on endoscopic response (≥50% reduction in SES-CD score) in combination with steroid-free clinical response (≥3 point drop in HBI or HBI ≤4) and/or biochemical response (≥50% reduction in C-reactive protein (CRP) and fecal calprotectin or a basal CRP ≤5 g/mL and fecal calprotectin ≤250 µg/g). Microbiome composition of the biopsies was determined using 16S RNA gene V3V4 amplicon sequencing. Results For the anti-TNFα cohort, we included in total 36 CD patients (21R and 18 NR), for VDZ cohort a total of 44 patients (28 R and 16 NR) and for USTE cohort a total of 40 patients (20R and 20 NR).When comparing α-diversity and β-diversity between R and NR, we did not find significant differences in ileal and colonic samples at baseline for the VDZ and USTE cohorts. Notable, for the anti-TNFα cohort (table 1), we obtained significant differences when comparing α-diversity (p=0.028) and β-diversity between R and NR. We demonstrated differences between colonic R and NR in taxa abundance for ASVs associated with the phyla Bacteroidetes, Firmicutes, Fusobacteria, Proteobacteria (figure 1). Furthermore, ASVs associated with Firmicutes, Bacteroidetes, Actinobacteria are different in abundance between ileal R and NR (figure 2). Figure 1: Differential taxa abundance colonic R vs NR anti-TNFα Figure 2: Differential taxa abundance ileal R vs NR anti-TNFα Figure 3: graphical summary Conclusion Here, we investigated the microbial signature of R and NR before the start of treatment of three separate cohorts and we demonstrated that the mucosa-associated microbiome differentiates R and NR to anti-TNFα therapy. Further analyses as part of the EPIC Pioneer study, are ongoing.

Background The efficacy and safety of risankizumab (RZB) in patients with Crohn’s disease (CD) has been demonstrated.1,2 We reported that an additional 12 weeks (ie, induction period 2) of RZB therapy could induce clinical response in patients with CD who did not achieve clinical response after an initial 12-week induction period.3 In this post hoc analysis, we report the proportion of patients who achieved clinical response over 24 weeks (initial and delayed responders to RZB induction therapy). Methods Data were pooled from the ADVANCE and MOTIVATE phase 3 RZB studies. Patients who had not achieved stool frequency (SF)/abdominal pain score (APS) clinical response (≥ 30% decrease in average daily SF and/or ≥ 30% decrease in average daily APS and both not worse than baseline) after an initial 12-week induction with intravenous (IV) RZB (600 mg or 1200 mg) at weeks 0, 4, and 8 were rerandomized 1:1:1 in induction period 2 to receive IV RZB 1200 mg (at weeks 12, 16, and 20) or subcutaneous (SC) RZB (180 mg or 360 mg at weeks 12 and 20) in a double-dummy–blinded fashion. In this post hoc analysis, efficacy was analysed in patients treated with either 600 mg RZB IV or placebo (PBO) for 12 weeks in the PBO-controlled induction period and patients who did not achieve clinical response with 600 mg RZB IV for 12 weeks and were rerandomized to 360 mg RZB SC every 8 weeks during induction period 2 (currently marketed RZB doses). SF/APS clinical response was assessed at week 12 for initial responders and at week 24 for delayed responders in induction period 2. Non-responder imputation with no special data handling for data missing due to COVID-19 was used. No multiplicity adjustment was performed. Results Of the 889 patients randomised to 600 mg IV RZB or PBO in the induction studies, 70.0% (369/527) in the RZB group compared with 45.6% (165/362) in the PBO group achieved SF/APS clinical response at week 12. Of the 47 patients who did not achieve initial clinical response to 600 mg IV RZB and received 360 mg SC in induction period 2, 32 (68.1%) achieved delayed SF/APS clinical response at week 24. The proportion of patients achieving SF/APS clinical response over 24 weeks (either initial or delayed responders) was 89.1% (401/450). The safety profile of RZB in patients with CD has been reported.1,2 Conclusion In patients with moderate-to-severe CD, RZB treatment leads to approximately 9 of 10 patients achieving either initial (600 mg IV) or delayed (600 mg IV followed by 360 mg SC) clinical response over 24 weeks. References: 1. D’Haens G, et al. Lancet. 2022; 399: 2015-30. 2. Ferrante M, Panaccione R, et al. Lancet. 2022; 399: 2031-46. 3. D’Haens G, et al. United European Gastroenterol J. 2021; 9(S8): 96-7.

Background Risankizumab (RZB), an anti-IL-23 p19 inhibitor, was well-tolerated and superior to placebo (PBO) in inducing clinical remission and endoscopic response in patients (pts) with moderate-to-severe Crohn’s disease (CD) in two phase 3 studies at 12 weeks. Aims FORTIFY (NCT03105102), was a 52-week (wk) phase 3 double-blind, re-randomized responder withdrawal study that evaluated the efficacy and safety of continuing RZB as subcutaneous (SC) maintenance therapy versus withdrawal to placebo in pts achieving induction response to RZB Methods Week 12 IV RZB responders were re-randomized 1:1:1 to: RZB SC 360mg (N=141), RZB 180mg (N=157), or PBO (withdrawal from IV RZB; N=164) every 8wks for 52wks. Co-primary endpoints were clinical remission (per CD Activity Index [CDAI] (US); or stool frequency/abdominal pain score [SF/APS] (OUS) and endoscopic response at wk52. Other clinical and endoscopic endpoints, inflammatory biomarkers, RZB serum levels, and safety were assessed over time. Results Rates of clinical remission (CDAI, SF/APS) and clinical response were similar for RZB and PBO groups through wk24, with rates lower for PBO thereafter. At wk52, clinical remission (CDAI, SF/APS) and endoscopic response rates were significantly higher with RZB 360mg than PBO ( P Conclusions In pts with moderate-to-severe CD, a robust pharmacodynamic effect on the IL-23 pathway after 12wks RZB IV induction was maintained with RZB SC maintenance therapy. The durability of RZB was demonstrated with high rates of efficacy over the 52-wk study. RZB was superior to PBO for achieving clinical remission and endoscopic response at wk52. Results for the more stringent endpoints (endoscopic remission\deep remission) and persistent improvements in inflammatory biomarkers are consistent with a dose response relationship. Continued RZB SC maintenance treatment was generally safe and well-tolerated. Funding Agencies AbbVie

Background While Vedolizumab (VDZ) is an established treatment for Crohn’s disease (CD), primary non-response is well-recognised – there is an urgent clinical need for biomarkers that predict response, before initiation of treatment. Metabolomic profiling is a rapidly growing field in biomarker discovery and can distinguish between active and quiescent inflammatory bowel diseases. Here, we sought to identify a metabolic signature able to predict response to VDZ. Methods Prospective serum samples from 62 CD patients before (baseline) and post-treatment follow-up (FU) (median 30 weeks, IQR 27–35) were analyzed. Patients were stratified into n=35 responders (R) and n=27 non-responders (NR) using endoscopic (≥50% reduction in SES-CD score), clinical (≥3 point drop in HBI or HBI ≤4, no systemic steroids), and/or biochemical assessments (≥50% reduction in C-reactive protein (CRP) and fecal calprotectin (fCal) or a basal CRP ≤5 g/mL and fecal calprotectin ≤250 µg/g). Untargeted metabolomic profiling was carried out using high-resolution nuclear magnetic resonance (NMR) spectroscopy. Significant differences in metabolite signatures were identified by orthogonal partial least squares discriminant analysis (OPLS-DA). Model accuracy (acc.) was assessed by external 10-fold cross-validation (CV), permutation testing, and validated on an independent test set. Results We first demonstrate that bowel preparation required for endoscopy had a significant impact on the serum metabolite profile (CV acc. 77±4%, acc. n=10 independent test set 80%, KS test p-value < 0.001) and samples taken from patients at colonoscopy were excluded from further analysis. This reduced the cohort size; 19 baseline (12R/7NR) and 25 FU (16R/9NR). No significant difference in baseline fCal or CRP was observed between R and NR (t-test p-value >0.05). The metabolite profiles at baseline and FU were indistinguishable (KS test p-value > 0.05) suggesting the metabolome was stable. However, high (>300 µg/g) fCal values were associated with elevated N-acetyl-glycoprotein (GlycA), a known inflammatory marker, elevated serum glucose along with decreased lipoprotein and lactate levels (CV acc. 74±3%, acc. n=10 independent test set 100%, KS test p-value < 0.001). This same metabolite signature predicts response (CV acc. 61±5%, acc. n=6 independent test set 83%, KS test p-value < 0.001) with responders exhibiting increased metabolic inflammation at baseline. Conclusion Here, we identify an inflammatory metabolic signature which predicts response to VDZ. Work to confirm these findings in a larger cohort and extend this method to investigate infliximab, adalimumab and ustekinumab treated patients, as part of the EPIC Pioneer study, is ongoing.

Background Abdominal pain (AP), bowel urgency (BU), and fatigue are debilitating symptoms that reduce quality of life in patients with active ulcerative colitis (UC). Results from two Phase 3 induction trials (U-ACHIEVE induction [NCT02819635] and U-ACCOMPLISH [NCT03653026]) showed significant improvements in AP, BU, and fatigue following induction with upadacitinib (UPA) in patients with active UC who had previously failed conventional or biologic therapy. We evaluated the effects of 52-week UPA maintenance treatment on AP, BU, and fatigue in patients who achieved a clinical response after induction. Methods Four hundred fifty-one patients who achieved a clinical response after 8 weeks of induction with UPA 45 mg once daily (QD) were enrolled in the U-ACHIEVE maintenance study and were re-randomised 1:1:1 to UPA 15 mg QD (n=148), UPA 30 mg QD (n=154), or placebo (PBO) QD (n=149). Endpoints in this analysis were the percentage of patients who reported no AP or no BU at Weeks 0, 4, 8, 20, 28, 36 and 52, respectively, and the change in Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT–F) from induction baseline to Weeks 0 and 52 in the maintenance study. Patients recorded AP and BU daily via an electronic, handheld device. Lastly, the percentage of patients reporting a clinically meaningful within person change (MWPC), defined as ≥5-point increase in FACIT-F score from induction baseline, and normalization of fatigue, defined as a FACIT-F score >40 points, were determined at Weeks 0 and 52. Results Significantly more patients reported no AP at Week 8 for UPA 15 mg vs PBO (60.8% vs 48.3%, p Conclusion In patients with moderately to severely active UC who responded to UPA 45 mg induction treatment, significant and clinically meaningful improvements in patient-reported AP, BU, and fatigue achieved during induction were sustained through 52 weeks of UPA 15 mg or 30 mg maintenance treatment.

Background Combination therapy with infliximab and anti-metabolites is an effective strategy for maintaining remission in patients with Crohn’s disease (CD); however, the implications of long-term combination therapy has led clinicians to consider discontinuing one of the two agents after sustained remission has been achieved. The SPARE investigators have addressed this in an unblinded clinical trial in which 211 patients were randomised to either continuation of combination therapy, withdrawal of infliximab, or withdrawal of antimetabolite therapy. Here, we aimed to determine whether nuclear magnetic resonance (NMR)-based metabolomics analysis of patient sera at baseline could determine which patients randomised to infliximab withdrawal would relapse over 2-years on anti-metabolite monotherapy. Methods The study cohort comprised patients randomised to infliximab cessation who had a serum aliquot available for analysis (n=63). All patients had been treated with a combination therapy of infliximab (IFX) and anti-metabolite >8 months and had been in sustained steroid-free remission >6 months. Disease relapse was defined by CDAI>250 (or between 150–250 with 70 points increase over two consecutive weeks) alongside serum CRP and faecal calprotectin levels. Untargeted metabolomic profiling was carried out using NMR spectroscopy. Key metabolites were identified by their variable importance in projection (VIP) score using orthogonal partial least squares discriminant analysis (OPLS-DA) with 10-fold cross-validation on independent data. Multiple logistic regression on the metabolites with highest VIP score was used to report a receiver operator characteristic (ROC) curve integral (AUC) value after collinear variables were removed. Results Of 63 patients, 21 (33%) relapsed. The mean time to relapse after infliximab discontinuation was 7.9 months. Four independent (multicollinearity R20.05, Pearson correlation). Patients who relapsed following infliximab discontinuation had significantly elevated serum acetoacetate and decreased alanine and glutamine levels (post-hoc students t-test, p Conclusion Here, we identify a panel of serum metabolites independent of baseline serum CRP, which predict high risk of disease relapse after infliximab discontinuation. These data may help in stratifying patients suitable for drug withdrawal, together with other clinical and multi-omic parameters.

Background Objective evaluation of treatment response is the gold standard in ulcerative colitis (UC). In this setting, intestinal ultrasound (IUS) is a non-invasive alternative to endoscopy. Recent studies showed change in IUS parameters after treatment initiation but studies with an endoscopic reference standard are scarce. The aim of this study was to evaluate early change of IUS parameters and determine cut-off values for endoscopic endpoints in UC patients starting anti-inflammatory treatment. Methods In this longitudinal prospective study consecutive patients with moderate-severe UC (baseline endoscopic Mayo score (EMS)≥2) starting an anti-inflammatory treatment were included. Clinical scores, biochemical parameters and IUS parameters were collected at baseline, after 2 (T1), 6 (T2) and 8–26 weeks (T3) around time of the second sigmoidoscopy/colonoscopy. IUS parameters were measured as previously established1. Endoscopic remission (ER) and mucosal healing (MH) were evaluated in the sigmoid and defined as EMS=0 and EMS≤1, respectively. The ultrasonographist and endoscopist were blinded for the outcomes of endoscopy and IUS, respectively. Results 51 consecutive patients were included (Table 1) of whom 31 underwent a second endoscopy (MH: n=15 (45%), ER: n=9 (27%)). Two additional patients underwent colectomy and were considered non-responders. 18 patients did not undergo second endoscopy due to the COVID-19 pandemic (n=2), refusal (n=5), loss to follow-up (n=1) or treatment escalation because of clinical deterioration confirmed by IUS and biomarkers before second endoscopy was performed (n=10). Bowel wall thickness (BWT) was significantly lower from T2 onwards in patients reaching MH (p=0.026) and ER (p=0.002) at T3 (Fig 1). A significant decrease in BWT was already visible at T1 in patients receiving infliximab (p=0.001) or tofacitinib (p=0.007), but not in patients treated with vedolizumab (p=0.11) (Fig 2). Most accurate BWT cut-off values at T3 to determine MH and ER were 3.52 mm (AUROC: 0.95, 95% CI: 0.86–1.00, p Table 1 Fig 1 Fig 2 Table 2 Conclusion BWT and Colour Doppler Signal 6 weeks after start of treatment are associated with and could predict MH and ER. In addition, treatment response patterns at IUS are drug-specific. Furthermore, we have provided accurate BWT cut-off values for endoscopic outcomes. In a point-of-care setting, (early) treatment evaluation with IUS could guide treatment decision in UC in order to optimize treatment response. Reference 1. Bots et al, JCC, 2021

Background In Phase 3 induction (LUCENT-1) and maintenance (LUCENT-2) studies, mirikizumab (miri), was well-tolerated and efficacious in patients with moderately to severely active ulcerative colitis (UC) who had an inadequate response, loss of response or intolerance to conventional or advanced therapy. This analysis evaluated clinical efficacy of miri compared to placebo (PBO) in induction and maintenance therapy based on number and types of prior targeted immune modulator (TIMs) failures, where TIMs include biologics (anti-TNFs, vedolizumab (VDZ)) and tofacitinib. Methods Patients were randomized at induction baseline to receive 3 intravenous doses of 300mg miri or PBO every 4 weeks (Q4W). Responders to miri induction at Week 12 were re-randomized to subcutaneous (SC) 200mg miri or PBO Q4W through W40 (52 weeks of continuous therapy). Endpoints evaluated were clinical remission, clinical response, symptomatic remission, and endoscopic remission at Week 12 of LUCENT-1, and clinical remission, corticosteroid (CS)-free remission, endoscopic remission, and histologic-endoscopic mucosal remission (HEMR) at Week 40 of LUCENT-2. Efficacy in the subgroup of patients who failed 0, 1, ≥2 prior TIMs, anti-TNFs, VDZ, or both anti-TNF and either VDZ or tofacitinib (anti-TNF+1) were assessed. There were not enough patients with prior tofacitinib failure alone for statistical significance analysis. Results At LUCENT-1 baseline, 58.8%, 21.1%, and 20.2% of patients failed 0, 1, and ≥ 2 prior TIMs, respectively. 36.3% failed anti-TNFs, 18.8% failed vedolizumab (VDZ), and 15.2% failed an anti-TNF +1 other TIM. At Week 12 of LUCENT-1 and Week 40 of LUCENT-2, a greater proportion of miri-treated patients achieved efficacy endpoints compared with placebo for all subgroups (Table 1). The treatment differences [95% CI] were significant for all subgroup analyses except for some subgroups from two endpoints: clinical remission at Week 12 of induction and HEMR at week 40 of maintenance (Figure 1). Three subgroups in the Week 12 clinical remission analysis did not achieve significant treatment differences: 1 prior TIM failure (6.5% [-2.9%, 15.8%]), ≥2 prior TIM failures (7.6% [-0.3%, 15.5%]), and anti-TNF failure (6.4% [-0.6%, 13.4%]). For the HEMR endpoint all subgroups achieved significant treatment differences except for the 1 prior TIM failure subgroup (15.3% [-1%, 31.6%]). Conclusion Regardless of the number and types of failed prior advanced therapies, mirikizumab is efficacious for both induction and maintenance therapy in patients with moderately to severely active UC.

Background Risankizumab (RZB), a p19-anti-interleukin-23 monoclonal antibody, has demonstrated efficacy as induction and maintenance therapy in patients with moderately to severely active Crohn’s disease (CD). This post hoc analysis evaluates the efficacy of induction and maintenance RZB therapy by baseline clinical, biochemical, and endoscopic disease severity. Methods In the ADVANCE (NCT03105128) and MOTIVATE (NCT03104413) studies, patients with moderately to severely active CD and intolerance/inadequate response to ≥ 1 biologic (both studies) and/or conventional therapy (ADVANCE) were randomized to receive intravenous (IV) RZB induction therapy or placebo (PBO) for 12 weeks. Patients achieving stool frequency and/or abdominal pain score clinical response to 12 weeks of induction therapy were rerandomized in the FORTIFY (NCT03105102) study to receive subcutaneous (SC) maintenance RZB (180 mg or 360 mg) or PBO (withdrawal). Clinical and endoscopic endpoints were evaluated by baseline disease characteristics (Crohn’s Disease Activity Index [CDAI: ≤ 300, > 300], highsensitivity C-reactive protein [hs-CRP: < 10 mg/L, ≥ 10 mg/L], and Simple Endoscopic Score for Crohn’s Disease [SES-CD: 6−15, > 15]). Induction analyses included patients who received RZB 600 mg or PBO; data from the ADVANCE and MOTIVATE studies were pooled. Nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used. Results The induction analysis included 527 patients who received RZB 600 mg IV and 362 patients who received PBO. Patients treated with RZB 600 mg IV achieved significantly higher response rates vs PBO at week 12, regardless of subgroup (P < .05 for all; Figure 1). In the maintenance study, patients treated with SC RZB continued to achieve higher response rates vs the PBO (withdrawal) group at week 52 regardless of subgroup (P was not < .05 for all; Figure 2). Improvements in clinical and endoscopic outcomes were generally observed from weeks 12 to 52 with RZB treatment across all subgroups. Response rates were generally similar across subgroups in both induction and maintenance studies; endoscopic remission and ulcer-free endoscopy (resolution of ulcer) rates were numerically lower for patients with increased inflammation (hs-CRP > 10 mg/mL) and higher endoscopic activity (SES-CD > 15). Conclusion RZB induction therapy resulted in higher response rates for clinical and endoscopic outcomes compared with PBO at week 12, regardless of baseline clinical, biochemical, and endoscopic disease severity. RZB also showed durable efficacy with continued RZB maintenance therapy, supporting the long-term use of RZB for patients across a range of baseline disease severity and activity.

Background Crohn’s disease (CD) is a chronic, immune-mediated inflammatory condition of the intestine, for which the majority of patients still needs to undergo surgical resection. Following the most common intervention ileocolonic resection, the vast majority of patients suffers from recurrence of CD in the neoterminal ileum. Endoscopic lesions usually precede symptoms in the first months after resection and predict the severity of the further disease course. No treatments have been approved for recurrence-prevention of CD. REPREVIO is a prospective placebo-controlled randomized trial investigating the preventive effect of vedolizumab, an anti-integrin antibody, on recurrence of CD. Methods Following ileocolonic resection, patients were treated with vedolizumab (300 mg IV at week 0,8,16 and 24) or PLC (1:1) at 12 sites in the Netherlands, France, Italy and Spain. Treatment was initiated within 4 weeks following ileocolonic resection with anastomosis. Six months following surgery, patients underwent ileocolonoscopy for assessment of recurrent lesions. Video recordings were centrally scored using the modified Rutgeerts’ score by 2 readers with adjudication in case of disagreement. The primary endpoint was endoscopic recurrence (ER) of CD (non-parametric); secondary endpoints were the proportion of patients with ER >i2a and clinical recurrence. Adverse events were recorded. Results 95 pts were screened and 80 randomized. All patients have reached month 6 and the videos are being analysed. We will receive the results of all statistical analysis in December, 2022. Conclusion The efficacy of vedolizumab postoperative recurrence-prevention treatment was studied in the REPREVIO study.

Background Chronic colonic inflammation in inflammatory bowel disease (IBD) patients increases the risk of colitis-associated cancer (CAC). Cancer development in CAC is different from that observed in sporadic colorectal cancer (CRC). Most studies have focused on the role of pro-inflammatory immune cell subsets in CAC, yet it is becoming increasingly clear that immunosuppression may also drive cancer progression. We hypothesize that emergence of immunosuppressive cell subsets as a result of chronic intestinal inflammation, dampens anti-tumor immune responses and accelerates the development of CAC. Methods To simulate cancer formation in the background of chronic inflammation, mice were treated with azoxymethane (AOM) followed by three cycles of dextran sodium sulphate (DSS). Apc Min/+ mice treated with AOM were used to model sporadic CRC. After 10 weeks, immune cells from the proximal and distal colonic lamina propria, mesenteric lymph nodes (MLNs) and tumors were obtained for microscopy analyses and processed to obtain single cell suspensions for flow cytometry. Immune cell populations were studied by conventional flow cytometry and immunofluorescence. Results We observed a significant increase in absolute numbers of PD1+CTLA4+TIM3+ ‘exhausted’ CD4+ T cells in the lamina propria from proximal colons in CAC mice as compared to sporadic CRC mice. Interestingly, these numbers showed a positive correlation with the inflammation score in AOM/DSS, demonstrating that chronic inflammation is associated with the emergence of ‘exhausted’ T cells. In addition, we observed a trend to higher numbers of M2-like (MHCII-CD206+) suppressive macrophages and CD4+FoxP3+ regulatory T cells (Tregs) in tumors from CAC mice compared to sporadic CRC. When analysing T cell immune responses in the MLNs, we found a significant decrease in the ratio IFNγ/IL10-producing CD8+ T cells in CAC mice as compared to CRC mice, suggesting a shift towards an anti-inflammatory T cell response in CAC. Conclusion In summary, suppressive immune cell subsets were increased in colonic mucosa and tumors from CAC mice as a result of chronic inflammation, which may be associated with the development of dysplasia. Further functional studies are necessary to prove the role of suppressive immune subsets in IBD-associated dysplasia- and carcinoma progression.

Background Infliximab (IFX) exposure is established predictive factor of pharmacokinetic (PK) origin in inflammatory bowel disease, and expert consensus is to achieve adequate exposure during induction (1). We evaluated the performance of a Bayesian PK tool in IBD patients starting IFX. Methods Trough IFX collected immediately before the third and fourth infusion (corresponding to week 6 and 14 on a standard dosing schedule, respectively) were evaluated from 307 IBD patients starting IFX and enrolled in three cohorts of IBD. The first cohort patients was adult CD enrolled in the TAILORIX trial (n=101, mean age [SEM]: 35.0±1.4 years, 60% female) (2), a second cohort was from the PRECISION trial (n=158, mean age 15.8±0.5, 75% CD, 46% female) (3) and a third cohort consisted of pediatric patients (n=45, mean age 13.2±0.5, 71% CD, 40% female). Forecasted IFX concentration at the 4th infusion were estimated using serum IFX, antibodies to IFX and albumin determined at the third infusion using population PK calculator with Bayesian prior. The outcome variable was a CRP-based clinical remission during follow-up with CRP levels below 3 mg/L in the absence of symptoms (corresponding to remission). Sustained CRP-based clinical remission status over the maintenance period was also calculated. Statistics consisted of Kaplan Meier analysis with calculation of Hazard ratio (HR), and logistic regression. Results IFX concentration above 15 µg/mL before the third infusion had shorter time to CRP-based clinical remission as compared to IBD with IFX concentration below 15 µg/mL (mean followup: 182±11 days). Measured IFX concentrations above 10 µg/mL before the 4th infusion were also associated with a higher rate and shorter time to remission (p Conclusion These data further support that IFX concentrations above recommended cutoffs are best to predict enhanced disease control. Patients presenting with low forecasted exposure may benefit from dose intensification sooner than the scheduled standard infusion. References: (1) Cheifetz AS et al. Am J Gastroenterol. 2021 116:2014-2025. (2) D’Haens G et al., Gastroenterology. 2018 154:1343-1351. (3) Dubinsky M et al. Inflamm Bowel Dis. 2022 28:1375-1385

Background The endoscopic healing index (EHI) is a novel multi-protein serum biomarker test developed and validated to assess endoscopic disease activity in patients with Crohn’s disease (CD). Evidence for the use of EHI to guide decision-making during infliximab (IFX) treatment remains scarce. Therefore, we aimed to characterise the relationships between IFX dose, serum IFX concentrations, EHI, and endoscopic remission (ER). Methods Data were obtained from 118 biologic naïve adult patients with CD enrolled in the phase 4 TAILORIX trial (EudraCT 2011 003038 14). All patients had confirmed active CD at baseline based on clinical, biological, and endoscopic criteria. IFX and EHI (scores ranging from 0–100) were measured using a homogenous mobility shift assay (HMSA) and immunoassay, respectively (Prometheus Laboratories). First, the previously published population pharmacokinetic (popPK) model of the TAILORIX study population was revisited to describe the HMSA data. The effect of EHI, faecal calprotectin (FC), C-reactive protein (CRP), and serum albumin (ALB) on IFX clearance was evaluated. Next, a minimal continuous-time Markov model was developed to describe the time course of EHI within patients. EHI was considered as a three-stage ordinal variable (scores 0–19, 20–49, and 50–100) with the lowest score stage (0–19) indicative of ER. The course-modifying effect of IFX on EHI was assessed. Finally, a generalised linear model was used to describe the relationship between EHI and the probability of attaining ER (Simple Endoscopic Score for CD [SES-CD] ≤2). The predictive ability of EHI for ER was compared with that of FC, CRP, ALB, and IFX using a receiver operating characteristic (ROC) curve analysis. Results The revisited two-compartment popPK model described the IFX data with adequate descriptive and predictive accuracies. EHI, FC, CRP, and ALB at week (w)0 were not found to explain interpatient variability in IFX clearance. In contrast, higher IFX at w14 was associated with a higher probability of achieving EHI Conclusion EHI, FC, ALB, and CRP at w0 should not be considered for a priori IFX dose optimisation. Nevertheless, a posteriori IFX dose optimisation (based on IFX concentrations measurements) towards a predefined IFX concentration at w14 may lead to lower post-induction EHI scores and thus improved ER rates. An IFX target of 10 mg/L at w14 is associated with four-fold higher normalisation of EHI as compared to the commonly used target of 5 mg/L.

Ozanimod, an oral sphingosine 1-phosphate receptor modulator currently approved for the treatment of moderately to severely active ulcerative colitis and relapsing multiple sclerosis, showed clinical, endoscopic, and histological benefit in the phase 2 STEPSTONE trial for Crohn's disease (CD). We aim to describe the trial design of the YELLOWSTONE phase 3 program evaluating the safety and efficacy of ozanimod in patients with moderately to severely active CD.The YELLOWSTONE program consists of phase 3, randomized, double-blind, placebo-controlled induction (NCT03440372 and NCT03440385) and maintenance (NCT03464097) trials and an open-label extension (OLE) study (NCT03467958). Patients with inadequate response or intolerance to ≥1 CD treatment are randomized to receive daily ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo for 12 weeks during induction. Those who respond to ozanimod are rerandomized to continue ozanimod or placebo maintenance therapy for 52 weeks. Patients who do not meet criteria for maintenance, experience relapse during maintenance, or complete maintenance or ≥ 1 year of STEPSTONE are eligible for open-label treatment for up to 234 weeks. Efficacy endpoints include clinical, endoscopic, and histologic outcomes.Expected 2023 (induction studies), 2024 (maintenance study), and 2026 (OLE).YELLOWSTONE will provide pivotal phase 3 data on the safety and efficacy of ozanimod in patients with moderately to severely active CD using state-of-the-art methods, including centrally read endoscopic and histologic measurements, along with subjective assessments of symptom control based on the Crohn's Disease Activity Index. These studies could enable approval of ozanimod as a new CD therapy.NCT03440372, NCT03440385, NCT03464097, NCT03467958.

Background Upadacitinib (UPA), an oral selective and reversible JAK inhibitor, demonstrated significantly greater efficacy compared with placebo (PBO) for induction of remission in patients with moderately to severely active ulcerative colitis (UC) in two phase 3 induction trials. Aims Evaluate safety and efficacy of 52 weeks of UPA 15 mg QD (UPA15) and 30mg QD (UPA30) compared to placebo in patients achieving clinical response following UPA 45 mg treatment in the induction trials. Methods The primary analysis (n=451) evaluated efficacy and safety of UPA15 and UPA30 compared to PBO as maintenance therapy. The primary endpoint was clinical remission via adapted Mayo score at wk 52. Ranked secondary endpoints included endoscopic improvement, maintenance of clinical remission, corticosteroid-free clinical remission, maintenance of endoscopic improvement, endoscopic remission, maintenance of clinical response and Histologic-endoscopic mucosal improvement (HEMI). Results Baseline characteristics were similar between all treatment groups. Both UPA15 and UPA30 met the primary endpoint, and all secondary endpoints. Significantly greater percentages of patients receiving UPA15 and UPA30 vs. PBO achieved clinical remission (42.3% and 51.7%, vs. 12.1%), endoscopic improvement (48.7% and 61.6%, vs. 14.5%), maintenance of clinical remission (59.2% and 69.7%, vs. 22.2%), corticosteroid-free clinical remission (57.1% and 68.0%, vs. 22.2%), maintenance of endoscopic improvement (61.6% and 69.5%, vs. 18.9%), endoscopic remission, (24.2% and 25.9%, vs. 5.6%) and HEMI (34.8% and 49.3%, vs. 11.8%) (p Conclusions In patients responding to UPA induction therapy, both UPA15 and UPA30 were safe and effective as maintenance treatment at 52 wk for all primary and secondary endpoints. Patients receiving UPA30 responded approximately 10% better for most endpoints compared to those receiving UPA15. Both doses were well-tolerated, with no new safety signals observed. Funding Agencies AbbVie

Background Increasing evidence suggests a role for the vermiform appendix in onset and relapse of ulcerative colitis (UC). Consequently, appendectomy is increasingly being seen as a potential alternative treatment. As a recent study suggests that patients with histological appendiceal inflammation are most likely to respond, pre-operative identification of ulcerative appendicitis could be beneficial1. Intestinal ultrasound (IUS) is increasingly utilized in the diagnosis and follow-up of patients with UC. The objective of this study was to characterize the appendix by IUS in UC patients with active and quiescent disease and healthy controls. Methods In this cross-sectional prospective observational cohort study, we performed appendiceal IUS on UC patients with active (A) disease (FCP>250 and SCCAI>5) and quiescent (Q) disease (FCP1000 examinations). Primary outcomes were signs of appendicitis on IUS, defined as a Results Out of 95 (A n=35, Q n=30, H n=30) included patients, the majority (n=58, 61.1%) had a visible appendix on IUS, which was similar among cohorts (p=0.56). The appendiceal diameter measured >6.0mm in a significantly higher proportion of active UC patients (A: 45.5%, Q: 5.6%, H: 0.0%, p=0.01). An increased diameter occurred irrespective of disease extent (42.9% of E1/E2 endoscopic active patients). Although the appendiceal diameter was higher for UC patients (Q-H p= 0.02, A-H p< 0.01), no significant difference between A and Q patients was found (p=0.15, Fig. 1). A higher proportion of UC patients had incompressibility when compared to healthy controls (Fig. 2a, p= 0.02). Hypervascularity was present in 54.5% of active UC (Fig. 2b, p= 0.02). Fig 1. Box plot of appendiceal diameter (mm) among cohorts Fig 2 (a, b). Bar charts of incompressibility (a) and hypervascularity (b) among cohorts a b Conclusion Appendiceal IUS was feasible in UC patients. Characteristics of appendiceal inflammation of IUS were reported for UC patients, as both the transverse appendiceal diameter and incompressibility rates were significantly higher in UC patients when compared to healthy controls. Correlating appendiceal IUS findings to histological inflammation could contribute to identifying UC patients most likely to benefit from appendectomy.

Background Tyrosine kinase 2 (TYK2) is an intracellular kinase that mediates the signalling of key cytokines involved in ulcerative colitis (UC) pathophysiology. Deucravacitinib (DEUC) is a novel, oral, selective TYK2 inhibitor that binds to the TYK2 regulatory domain. The safety and efficacy of DEUC were evaluated in patients (pts) with moderately-to-severely active UC. Methods LATTICE-UC (NCT03934216), a randomised, double-blind, placebo (PBO)-controlled, multicentre, Phase 2 trial, enrolled pts with moderately-to-severely active UC (modified Mayo score of 5 to 9 [endoscopic {ES} subscore ≥2, rectal bleeding {RB} subscore ≥1, stool frequency {SF} subscore ≥2) with inadequate response, loss of response, or intolerance to ≥1 conventional or biologic therapy. Pts were randomised 2:1 to oral DEUC 6 mg or PBO twice daily (BID) and stratified by baseline (BL) corticosteroid use and prior exposure to biologics. The primary endpoint was clinical remission (modified Mayo score with subscores of SF ≤1 with ≥1-point decrease from BL, RB=0, and ES ≤1 [modified, excludes friability]) at Week (Wk) 12; endoscopic response (ES ≤1) at Wk 12 was a secondary endpoint. Results Demographic and BL characteristics were generally similar across groups, except for BL disease activity as measured by the modified Mayo score and ES subscore. Most pts (63.4%) were biologic naïve, and 40.5% were receiving concomitant oral corticosteroids (Table 1). Of 131 pts randomised, 104 (79.4%) completed 12 wks of treatment (DEUC, 69/87 [79.3%]; PBO, 35/42 [83.3%]). At Wk 12, clinical remission rates were 14.8% and 16.3% in the DEUC and PBO arms, respectively, in the overall population (P=0.59); 14.0% and 25.9% in biologic-naïve pts; and 16.1% and 0.0% in biologic-experienced pts (Figure 1). At Wk 12, endoscopic response rates were 19.3% and 27.9% in the DEUC and PBO arms, respectively, in the overall population (P=0.88); 15.8% and 37.0% in biologic-naïve pts; and 25.8% and 12.5% in biologic-experienced pts (Figure 2). Pharmacodynamic data suggest insufficient inhibition of TYK2 pathways with DEUC 6 mg BID. Incidence of adverse events (AEs) was 70.1% in the DEUC arm and 47.6% with PBO; rates of serious AEs were 9.2% (n=8) and 4.8% (n=2), respectively. Rash, acne, and worsening of UC were the most common AEs in the DEUC arm. No meaningful changes from BL in mean values of laboratory parameters were observed with DEUC treatment. Conclusion This Phase 2 study of DEUC 6 mg BID in moderately-to-severely active UC did not meet its primary or secondary efficacy endpoints at Wk 12. In biologic-experienced pts, response rates were numerically higher with DEUC compared with PBO. The safety profile was consistent with DEUC trials in psoriasis and psoriatic arthritis.

Background Circulating serum proteins have provided insights into disease pathogenesis and are being used to identify prognostic, diagnostic and therapeutic biomarkers for chronic inflammatory diseases. With this pilot project, the Collaborative IBD Biomarker Research Initiative (COLLIBRI) consortium aimed to unravel disease heterogeneity in inflammatory bowel disease (IBD). Methods Serum samples were cross-sectionally obtained from 3,390 individuals (Crohn’s disease (CD), n=1815; ulcerative colitis (UC), n=1170; healthy, n=405) recruited at nine centres from Sweden and Belgium. Relative levels of 92 proteins were analysed using the Proseek Multiplex Inflammation I Probe kit 96x96 (Olink Proteomics, Uppsala, Sweden) and reported as arbitrary units, i.e., normalised protein expression on a log2 scale. Using a multivariate integrative approach, we identified protein signatures distinguishing CD and UC samples and attempted to identify clusters or subgroups within patients. Recruiting centre, cohort and batch information were considered for the integrative analysis. Optimisation was performed for identifying the number of components and features per component using 5-fold cross-validation and Leave-One-Group-Out-Cross-Validation, respectively. Information on transcriptional regulators was retrieved from the ReMap project using the orthogonal regulatory resource ChEA3. Results A panel of 8 proteins was identified which could segregate CD and UC patients (Figure 1). FGF19 exhibited a consistent trend of expression (downregulated in CD) across all batches of datasets. An integrated AUC of 72.5% was achieved across the different batches of samples used in the study with the highest AUC (79.2%, P-value 8.5e-07) being recorded for a single batch of samples (CD = 42, UC = 56). On a centre-specific dataset, the cross-centre integrated signature achieved an AUC of 75.1%. We identified three transcription factors (MEF2A, BATF, NFKB2), of which the two latter ones are known to modulate intestinal inflammation and which could potentially regulate the expression of at least half of the genes encoding the proteins in the predictive 8-protein panel. Conclusion We identified an integrated proteomic biomarker panel capable of separating CD and UC patients. Through further integration of confounder variables along with using other supervised and unsupervised approaches, subsequent analyses may further refine the molecular heterogeneity among CD and UC patients. Our results demonstrate the need for large datasets to identify relevant clusters of patients with IBD, since the diagnosis exhibits a high degree of clinical heterogeneity. *Equally contributed

Background The reliability and reproducibility of scoring endoscopic recurrence is of utmost importance because it generally determines initiating postoperative medical therapy and it is used as outcome parameter in clinical trials. Variability in endoscopic scoring may result in inappropriate therapeutic decisions and study conclusions. It is hypothesised that different types of anastomoses have an influence on scoring endoscopic recurrence using the Rutgeerts’ score. The aim of this study is to analyse to what extent the ulcerations are determined by the type of anastomosis and how it interferes with the scoring of Crohn’s recurrence. Methods This is a retrospective review of endoscopy videos to re-assess endoscopic recurrence. All videotapes of the ileocolonoscopy were blinded and scored by a trained gastroenterologist (MD) and a surgeon (WB). Videos were excluded if the quality of the video was low or if the anastomosis was not visualised properly. The primary outcome is the presence of ulcerations six months after surgery, on individual parts of the anastomosis: inverting stapled anastomosis (side to side conjunction) and everting type of junction (transection ends). In the latter group, at least one site – colon, ileum or both – was scored. Results Of 99 available endoscopy videos, eighty-nine eligible patients were included in this retrospective study for analysis. The inverting and everting stapled anastomosis were scored individually using the SES-CD. A SES-CD of zero was found in 21/89 (23.6%) of the inverting anastomoses versus 74/75 (98.67%) in the everting anastomoses. Conclusion This study demonstrated a significant difference in wound healing of the inverting anastomosis versus the everting anastomosis. Inverting anastomoses show ulcerations and a circular scar long after surgery irrespective of the presence of ulcerations of terminal ileum. A normal wound healing phenomena might mistakenly be seen for recurrent Crohns’ disease. Everting anastomosis, on the contrary, heal without residue.

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 Approximately 10% of ulcerative colitis (UC) patients undergoing ileal pouch-anal anastomosis (IPAA) are believed to develop ‘de novo Crohn’s disease’ (CD) of the pouch (1). Clear diagnostic criteria are lacking, but the diagnosis is mostly based on the development of fistula, strictures, treatment refractory disease, pre-pouch ileitis, or typical endoscopic findings fitting with CD, such as ulcers and patchy inflammation (1, 2). However, the findings on which this diagnosis is established may be caused by (unrecognized) surgical complications such as silent anastomotic leakage. It is important to distinguish these complications from what is truly a ‘de novo CD’ as treatment strategies differ in both groups. We aimed to investigate incidence rates and reasons for diagnosing CD of the pouch. Methods In total, 483 consecutive UC patients who underwent a proctocolectomy and IPAA in a tertiary IBD referral centre from January 1990 until December 2017 were retrospectively reviewed. Patients with a diagnosis ‘CD of the pouch’ were identified based on medical records, and could be based on either clinical, endoscopic, imaging and/or histological findings. Results Median follow-up time was 20 years (IQR 10 – 24). In 46 out of 483 patients (10%), de novo CD of the pouch was diagnosed, which was mostly based on endoscopic findings (29/46, 63%). Presence of pre-pouch ileitis was the most common reason to diagnose CD of the pouch, which was present in 18/29 patients (62%), followed by ulcerations in 6/29 (21%). On MRE, 19/46 (41%) patients had a fistula or sinus, 4/46 patients (9%) had a stricture (all proximal of the pouch). Interestingly, 12/46 patients (26%) never underwent cross sectional imaging after IPAA construction. Only ten patients (22%) showed histologic findings with a preference for CD in biopsies, revised colectomy specimen, and/or pouch excision specimen. Only two patients had granulomas, others showed signs of transmural inflammation, ulcerations or fibrosis. Other histologic findings were non-specific. Conclusion In our centre, 10% of patients were ‘diagnosed’ with de novo CD of the pouch. However, as confirmatory histological signs of CD were present in only 22%, chronic surgical complications as underlying cause might be of greater importance. It is advised to perform cross sectional imaging in every patient after a year after pouch construction to rule out silent leaks that might cause symptoms at a later stage mimicking Crohn’s disease, avoiding a diagnostic dilemma.

Background Despite the proven efficacy of vedolizumab (VDZ), only 29% and 36% of the Crohn’s disease (CD) patients present corticosteroid-free clinical- and endoscopic remission, respectively. Therefore, predictive biomarkers for treatment success would be of extreme value. Previous studies have identified aberrant DNA methylation associated with CD-specific phenotypes, suggesting that the methylome may be useful for classification and prediction of VDZ treatment response. Here, we sought to identify such DNA methylation biomarkers that can predict clinical- and endoscopic response to VDZ in CD patients. Methods We prospectively recruited adult CD patients that initiated VDZ treatment following a baseline colonoscopy in two cohorts: a discovery and validation cohort. Peripheral blood DNA methylation profiles were measured prior to treatment (T1), and after a median of 22 weeks (T2) using the Illumina Infinium HumanMethylation EPIC BeadChip array. Response (R) was defined as the strict combination of endoscopic- (≥50% reduction in SES-CD score) and steroid-free clinical response (≥3 point drop in HBI and HBI ≤4 AND no systemic steroids) and/or biochemical response (≥50% reduction in C-reactive protein (CRP) and fecal calprotectin or a CRP ≤5 g/mL and fecal calprotectin ≤250 µg/g). Twenty-one patients had deep remission (DR), defined as a combined endoscopic- (SES-CD≤2) and steroid-free clinical remission (HBI ≤4, no systemic steroids). Biomarker identification and classification analyses were performed using stability selection gradient boosting. Results In total, 64 CD patients were enrolled (discovery 16R/14NR and validation 20R/14NR). Both cohorts were comparable for age, sex and smoking status. Forty-nine (77%) patients had previously failed an anti-TNF agent. All patients had measurable serum vedolizumab concentration at T2 (median 14.5 (6.9 – 21.3) µg/mL). Through classification analysis at T1, we were capable of discriminating R from NR with high predictive performance (25 CpGs, AUC 0.88, F1-score of 0.84, PPV of 0.91 and NPV of 0.85). When analysing the methylome of patients in deep remission, we identified 23 CpGs with high predictive performance upon independent validation (F1-score 0.80, PPV of 0.71 and NPV of 0.86). Investigating the CpGs of interest implicated genes involved in endothelial cell-cell adhesion and integrin dependent T-cell homing, corroborating VDZ’s mode of action. Conclusion We demonstrate two novel 25- and 23-feature panels of epigenetic biomarkers that accurately predict response or deep remission to vedolizumab respectively. Similar analyses on infliximab, adalimumab and ustekinumab are currently ongoing as part of the EPIC-CD study.

Background Adalimumab (ADL) is a fully human monoclonal antibody against tumor necrosis factor that is approved for the management of inflammatory bowel disease (IBD). Therapeutic drug monitoring (TDM) of ADL is widely used to ensure adequate blood levels for maintenance of the clinical benefit. This study examined the clinical utility of a point of care (POC) ADL assay to facilitate TDM. Methods A fast ( Results A total of 84 IBD patients (LOR=37, No LOR= 47) were included in this study. Median ADL trough levels were lower in patients who experienced loss of response compared to patients who did not (median ADL 6.0 μg/mL vs 13. μg/mL, P < 0.001, figure 1). Area-Under-the-ROC Curve (AUC) value for loss of response was 0.822 (figure 2). Optimal ADL trough cut-off value was 8 μg/mL (Table 1). Figure 1. shows patients losing response to ADL had serum levels significantly lower than those maintaining response Figure 2. shows ROC curve analysis of the Procise ADL test for the detection of LOR Table 1. Showsclinical performance of Procise ADL for the detection of LOR at various ADL concentration Conclusion IBD patients in disease remission on maintenance ADL therapy with ADL levels below a cut-off 8.0 μg/mL had a 5.34 fold increased risk of LOR compared to those above 8.0 μg/mL. Identifying patients at high risk of LOR with a convenient POC format test enhances the clinical utility of TDM by enabling faster treatment adjustment.

Background In the assessment of treatment response in Crohn’s Disease (CD) objective measures are superior to clinical improvement. Intestinal ultrasound (IUS) is an emerging modality with high accuracy to detect CD disease activity. Less is known about early transmural changes at IUS in treatment follow-up. Therefore, we aimed to investigate conventional IUS and contrast-enhanced ultrasound (CEUS) parameters and how they are associated with endoscopic treatment response. Methods In this longitudinal prospective cohort study, consecutive patients with active CD according to the simplified endoscopic score (SES-CD≥3) starting anti-TNF-α treatment were included. We recorded clinical, biochemical, IUS and CEUS parameters at baseline (T0), after 4–8 weeks (T1) and at 12–34 weeks (T2). IUS parameters were scored as previously established1. The SES-CD was scored per segment by a gastroenterologist immediately after endoscopy. The bowel segment with highest SES-CD score and thickest wall on IUS was identified. At T2, endoscopic response (decrease SES-CD≥50%) and endoscopic remission (SES-CD=0) were scored per segment. IUS and CEUS were scored blindly by two readers using recorded videos. Results 40 patients were included (Table 1) with 23 completing follow-up. The other 17 patients had side-effects and stopped treatment (n=9), underwent bowel surgery (n=5) or were lost to follow-up (n=3). At T2, 14 reached endoscopic remission, 17 had endoscopic response. The absolute decrease in BWT at T1 and T2 paralleled endoscopic response (Figure 1). Decrease in BWT of 18% at T1 (Fig 2) predicted endoscopic response accurately (OR: 10.8, 95%CI: 1.7–69.0, p=0.012). For T2, 29% decrease in BWT (Fig 2) was most accurate to determine endoscopic response (OR: 37.5, 95%CI: 2.8–507.5, p=0.006). At T2, a BWT of 3.2 mm was most accurate (AUROC: 0.940, 95%CI: 0.862–1.000, p Conclusion Decrease of BWT 4–8 weeks after treatment initiation predicted endoscopic response later during follow-up. In addition, we have provided accurate cut-off values for (Δ)BWT associated with endoscopic response and remission at different time-points. CDS or WoR were both of additional value to determine endoscopic remission after 12–34 weeks. As CEUS is time consuming, CDS might be sufficient in the close follow-up of CD patients. Reference 1. Novak et al, JCC 2021

Background Monitoring of monoclonal antibody clearance has been hypothesised to be an appealing approach for predicting treatment outcomes in patients with inflammatory bowel diseases. We aimed to investigate the benefits of monitoring infliximab and ustekinumab clearance in patients with Crohn’s disease (CD) based on data from clinical trials. Methods Data were obtained from patients with moderate-to-severe CD starting infliximab (n=108)1 or ustekinumab (n=80)2 therapy. Endoscopic remission (CD Endoscopic Index of Severity Results Patients achieving endoscopic remission at w12 had significantly lower infliximab clearance and higher infliximab serum concentration at w2 and w6 of treatment (P 0.2, Table 1). Most patients with an early increase in infliximab clearance (16/22; 73%) and ustekinumab clearance (27/29; 93%) did not reach the endoscopic endpoint (P The infliximab clearance after start of induction therapy (at w2 and w6) was significantly higher in patients who developed ATIs during induction therapy (Figure 1). Conclusion Lower infliximab and ustekinumab clearance (absolute as well as relative to w0) early during induction predict more favourable endoscopic outcomes. In patients treated with ustekinumab, clearance monitoring may better predict endoscopic response at w24 as compared to standard therapeutic drug monitoring. References1. D’Haens et al.Gastroenterology 2018 2. Verstockt et al. J Crohns Colitis 20193. Dreesen et al. Br J Clin Pharmacol 20214. Wang et al. Br J Clin Pharmacol 2021.

Background Crohn’s disease (CD) is a complex disease where the gut microbiome plays an important role. One of the established treatments in CD is Vedolizumab (VDZ), an alpha(4)beta(7) integrin antibody. Finding biomarkers to predict therapy response is still a clinical unmet need, since this treatment has shown endoscopic remission in only a third of CD patients. Ananthakrishnan et al. demonstrated a strong relationship between microbial metagenomics signature and therapy response to VDZ in CD based on the metagenomics composition of baseline fecal samples. While the majority of studies focus on fecal samples, mucosa-adherent bacterial signature could bring forth stable biomarkers. In this study, we sought to identify the signature of the adherent microbiome in intestinal biopies to differentiate responders (R) from non-responders (NR) to VDZ treatment at baseline. Methods We prospectively collected ileal and colonic biopsies from adult CD patients scheduled to start VDZ treatment during baseline- and follow-up (FU) endoscopies. After median 27 weeks of follow-up, patients were classified as either R or NR based on endoscopic response (≥50% reduction in SES-CD score), steroid-free clinical response (≥3 point drop in HBI or HBI ≤4, no systemic steroids) and/or biochemical response (≥50% reduction in C-reactive protein (CRP) and fecal calprotectin or a basal CRP ≤5 g/mL and fecal calprotectin ≤250 µg/g). Microbiome composition of the biopsies was determined using 16S RNA gene V3V4 amplicon sequencing. We measured alpha and beta diversity using Wilcoxon and Adonis metrics. Results In total, 44 CD patients were included in the baseline cohort (28 R and 16 NR) and 53 CD patients were included in the follow up cohort (37 R and 20 NR), for which 21 patients overlap between baseline and follow up. When comparing alpha-diversity between R and NR, we did not find significant differences in ileal (Wilcoxon, p=0.78) and colonic (Wilcoxon, p=0.70) samples at baseline nor at follow up (ileal Wilcoxon, p=0. 27 and colonic Wilcoxon, p=0. 63). Next, comparing the beta-diversity, we demonstrated no significant differences between R and NR in ileal (baseline p=0.96, follow up p=0.11) and colonic (baseline p=0.11, follow up p=0.4). Microbiome profiles did show high inter-individual variation but were highly similar intra-individually both between body site and over time. Conclusion Here, we investigated the microbial signature of VDZ R and NR and demonstrated mucosa-associated microbiome is mostly stable after resolution/non-resolution of inflammation in CD and does not predict response to VDZ therapy. Further analyses on data of infliximab, adalimumab and ustekinumab treated patients, as part of the EPIC Pioneer study, are ongoing.

Background Subcutaneous (SC) formulation of vedolizumab (VDZ) is available for Crohn’s disease (CD) and ulcerative colitis (UC). We assessed the efficacy, safety, and pharmacokinetic (PK) profiles of patients with inflammatory bowel diseases (IBD) who switched from intravenous (IV) to SC VDZ treatment in two prospective, real world cohorts. Methods The primary cohort is an ongoing open-label, real life, prospective single centre cohort study. As a validation cohort, we used the Initiative on Crohn and Colitis (ICC) registry, a prospective, observational, nationwide registry including patients switching from IV to SC VDZ. In both cohorts, patients receiving IV VDZ maintenance for >4 months were offered to switch treatment to SC VDZ, 108 mg every 2 weeks. In the primary cohort, assessment of clinical, biochemical and PK parameters took place at baseline, at approximately 10 weeks following the switch and at the physician’s discretion thereafter. In the ICC cohort, follow up visits were at week 12 and 24. The primary endpoint was the proportion of patients discontinuing SC VDZ at week 24. Results In total, 78 (50 CD (64%) and 28 UC (36%)) and 54 patients (29 CD (54%) and 25 UC (46%)) were included in the primary and ICC cohort respectively (table 1). During follow up, 8 (10.3%) of the primary cohort and 6 (11.1%) patients of the ICC cohort stopped VDZ SC during follow-up time till week 24, after a median treatment duration of 18 (IQR=5–19) and 10 (IQR=7–15) weeks, respectively. Treatment withdrawal was most often caused by adverse events (AE), in total for 8 out of 132 patients (6%) (table 2). Four patients had loss of response to SC VDZ. Three of these patients had biochemical disease activity at initiation of SC therapy. Reported AEs included headache and injection related reactions. The median VDZ concentration increased from 11 ug/mL (IQR=9.4–20) to 28 ug/mL (IQR=24.3–31.2, p Conclusion The present abstract reports real world experience of switching IV to SC VDZ maintenance treatment in IBD patients in two observational Dutch cohorts. VDZ concentrations were significantly higher after the switch to SC VDZ. A switch from IV to SC VDZ appears to be effective and safe. However, a proportion of patients switched back to IV VDZ due to injection related AEs.