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Background Symptoms, endoscopy, histology, and biomarkers are used to evaluate disease activity and response to therapy in ulcerative colitis (UC). Histologic disease activity may persist in ~25% of patients with normal-appearing endoscopic mucosa, and observational studies demonstrate an association between the achievement of histologic remission (vs endoscopic remission alone) and a lower risk of complications. These findings suggest that histologic remission may be a distinct treatment target. The aim of the VERDICT trial is to determine the optimal treatment target in UC to inform clinical practice and future drug development. Methods The primary objective of the multicentre, randomised, controlled VERDICT trial (Figure 1) is to determine whether a treatment target of corticosteroid (CS)-free symptomatic + endoscopic + histologic remission is superior to CS-free symptomatic remission alone in moderately to severely active UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2). Patients are randomised to 3 treatment targets (2:3:5 ratio): CS-free symptomatic remission (Mayo RBS = 0) (Group 1); CS-free endoscopic remission (MES ≤1) + symptomatic remission (Group 2); or CS-free histologic remission (Geboes score Results The primary efficacy outcome is the time from treatment target achievement to a UC-related complication, defined as a UC-related hospitalisation, colectomy, need for rescue therapy, or treatment-related or other complication. This composite outcome will be compared among treatment target Groups 1 and 3 using the Cox proportional hazard model analysis. The trial was initiated in September 2020, and 660 patients are planned for enrolment. Of these, ~50% are currently enrolled at 55 sites across 10 North American and European countries. Prespecified interim analyses will be conducted when the first 50 patients in each group reach weeks 16, 32, and 48. Conclusion The VERDICT trial in active UC is designed to determine the optimal treatment target to inform clinical practice, drug trials, and future evidence-based recommendations.

Background Intestinal and perianal fistulas and fissures are associated with significant morbidity and decreased quality of life in patients with Crohn’s disease (CD). We evaluated rates of fistula and fissure improvements with upadacitinib (UPA), an oral selective Janus kinase inhibitor, in patients with CD who had fistulas or fissures at baseline in phase 3 induction and maintenance trials. Methods In the U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836) phase 3 induction trials, patients with moderate-to-severe CD were randomized to UPA 45 mg once daily (QD) or placebo (PBO) for 12 weeks. Patients who achieved clinical response after 12 weeks of induction were eligible for U-ENDURE (NCT03345823) and rerandomized to UPA 30 mg QD, UPA 15 mg QD, or PBO for an additional 52 weeks of maintenance treatment. Fistula activity was assessed by presence of external openings and draining upon gentle compression. Presence of perianal fissures was also assessed. The proportion of patients with external closure of fistula openings, complete resolution of draining, and ≥ 50% reduction in draining was recorded at weeks 12 and 52. Endpoints were analyzed using non-responder imputation. Results Of 1021 enrolled patients, 143 patients had fistulas (124 [86.7%] perianal; 19 [13.3%] enterocutaneous) and 54 patients had perianal fissures at baseline. The proportion of patients who achieved external closure of fistula openings was higher with UPA vs PBO at week 12 (Fig 1A) and at week 52 (Fig 2A). The proportion of patients who achieved complete resolution of draining and ≥ 50% reduction in draining was higher with UPA vs PBO at week 12 (Fig 1B and 1C) and at week 52 (Fig 2B and 2C). A higher proportion of patients achieved complete resolution of fissures with UPA vs PBO at week 12 (Fig 1D) and at week 52 (Fig 2D). At weeks 12 and 52, a higher proportion of patients with fistulas treated with UPA vs PBO achieved clinical remission and endoscopic response (Fig 1E and 2E). Rates of adverse events (AEs), serious AEs, or AEs leading to study drug discontinuation were similar in UPA groups compared with PBO during the induction and maintenance periods. Rates of abscess formation were 1.8% with UPA 45 mg and 6.8% with PBO at week 12, and 3.0% with UPA 30 mg, 6.4% with UPA 15 mg, and 2.5% with PBO at week 52. Conclusion Among patients with CD complicated with fistulas and/or fissures at baseline, UPA treatment led to higher rates of external closure of fistula openings, resolution of draining, and healing of fissures, along with clinical remission and improvements in luminal disease compared with PBO. No new safety concerns were identified.

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.

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 An association between shorter disease duration and improved clinical efficacy has been shown in post hoc analyses of clinical trial data with biological therapies in Crohn’s disease (CD). The efficacy and safety of risankizumab (RZB) as induction and maintenance therapy have been recently reported. Here, the efficacy of RZB stratified by baseline CD duration is reported. Methods In ADVANCE (NCT03105128) and MOTIVATE (NCT03104413), patients with moderately to severely active CD received intravenous (IV) RZB induction therapy or placebo (PBO) for 12 weeks. Patients with clinical response to RZB IV induction were re-randomised in a 52-week maintenance study (FORTIFY, NCT03105102) to receive subcutaneous (SC) RZB or PBO (ie, withdrawal). For this post-hoc analysis, patient subgroups were stratified by years of CD duration at baseline (< 2, 2–5, > 5–10, and > 10 years). Induction analyses focused on patients who received RZB 600 mg IV or PBO for 12 weeks. As all patients who entered maintenance responded to RZB IV induction, maintenance analyses were limited to those patients who responded to induction and then received RZB 360 mg SC for 52 weeks. Clinical and endoscopic outcomes were evaluated using nonresponder imputation incorporating multiple imputation to handle missing data due to impact of the COVID-19 pandemic. Safety was assessed throughout the studies. Results The induction and maintenance analyses included 527 patients who received RZB 600 mg IV and 141 patients who received RZB 360 mg SC, respectively. At the end of induction (week 12), patients with CD duration of < 2 years achieved higher rates of endoscopic outcomes with IV RZB induction vs patients with longer durations of disease (Figure 1), and regardless of baseline CD duration, greater proportions of RZB-treated patients achieved clinical remission (defined by stool frequency and abdominal pain), endoscopic response, endoscopic remission, and ulcer-free endoscopy vs PBO (P ≤ .05). Clinical remission rates at week 12 were numerically higher in patients with CD duration of < 5 years vs > 5 years (Figure 1). Similar results for improved clinical and endoscopic outcomes associated with shorter disease duration were observed at week 52 with RZB 360 mg SC maintenance treatment (Figure 2). RZB was well tolerated with lower rates of serious adverse events and serious infections vs PBO in induction, across CD duration subgroups. Conclusion RZB induction and maintenance therapy was effective and well tolerated with a safety profile generally similar across CD duration subgroups. Achievement of clinical and endoscopic endpoints were higher in patients with shorter duration of CD, suggesting that earlier introduction of RZB therapy may lead to improved outcomes.

Background Breastmilk (BM) is a complex fluid that contributes to shaping the immune system of the offspring. BM composition depends on stage of lactation, maternal health status and diet, environment, and genetics. Limited data exists on the composition of the BM from women with IBD and its potential impact on the newborn’s microbiome composition. Methods The MECONIUM (Exploring MEChanisms Of disease traNsmission In Utero through the Microbiome) study is a prospective cohort study including pregnant women with IBD, pregnant healthy control (HC), and their offspring. BM samples were collected 2 weeks post-delivery. Stool samples from the offspring were collected throughout the first 3 years of life and used to assess faecal calprotectin (fCal) and gut microbiota composition (16S). Targeted proteomics of the BM samples was performed with the Olink inflammation panel (92 protein biomarkers). Correlations between specific proteins in the BM, fCal and 16S were assessed using non-parametric tests. Multiple testing correction was performed with false discovery rate (FDR). MaAsLin2 R package was used for multivariate testing. Results 236 BM samples were analysed: 174 from HC, 37 Crohn’s disease (CD), 25 ulcerative colitis (UC). Thymic stromal lymphopoietin (TSLP), a cytokine with an important role in the maturation of T cells, was significantly lower in BM of women with IBD vs HC (FDR p=0.0017). The levels of TSLP in the BM of the mothers correlated negatively with infant fCal at year1 (rho=-0.20, p=0.01), and with the relative abundance of Cronobacter (MaAsLin2 FDR 0.1) of the offspring at month 1. Chemokine (C-C motif) ligand 20 (CCL20), which acts in chemotaxis of dendritic cells and T-cells and B-cells, was also significantly lower in women with CD vs HC (FDR 0.013) and in women with CD vs UC (p=0.014). Matrix metalloproteinase-1 (MMP-1), a collagenase involved in the breakdown of extracellular matrix, was also lower in BM of women with CD (p=0.009) and a negative correlation was observed between the levels of MMP1 and fCal at 3 months and 1 year (rho=-0.20 and -0.18, p=0.01 and 0.02, respectively). Osteoprotegerin (OPG), higher in BM of women with UC (p=0.018), was positively correlated with Streptococcus (MaAsLin2 FDR p=0.2) and negatively correlated with Bacteroides and Parabacteroides (MaAsLin2 FDR p=0.03 and 0.1) in the offspring at month 1. Conclusion The proteomic profile of BM of women with IBD is distinct from that of women without IBD. BM composition may influence offspring’s’ gut microbiome signatures and fCal level at different timepoints. These findings suggest that BM composition may impact the offspring’s intestinal immune system maturation and microbiome development, and warrant further research.

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 Treatment of perianal fistulizing Crohn’s disease (PFCD) is a major unmet need. Filgotinib (FIL) is a once-daily, oral, preferential Janus kinase 1 inhibitor in development for the treatment of inflammatory bowel diseases. The efficacy and safety of FIL for the treatment of PFCD was evaluated in the phase 2, double-blind, randomized, placebo (PBO)-controlled DIVERGENCE 2 study (NCT03077412). Methods Patients (18–75 years old) with PFCD (documented diagnosis of CD for at least 3 months and 1–3 external openings [EOs] with drainage [spontaneous or on compression] for ≥ 4 weeks before screening) previously treated with antibiotics, immunomodulators and/or tumour necrosis factor inhibitors (TNFi) were randomized (2:2:1) to receive FIL 200 mg, FIL 100 mg or PBO once daily for up to 24 weeks. Active luminal CD was permitted providing that the Crohn’s Disease Activity Index score was ≤ 300 at screening. The primary endpoint was combined fistula response (reduction of ≥ 1 from baseline in the number of draining EOs determined by investigator assessment and no fluid collections > 1 cm on centrally read pelvic magnetic resonance imaging [MRI]) at Week 24. Combined fistula remission (closure of all draining EOs present at baseline and no fluid collections > 1 cm) at Week 24 was a key secondary endpoint. The study was not powered for statistical comparisons and was prematurely terminated owing to low recruitment rates during the COVID-19 pandemic. Results Baseline characteristics were broadly similar across the treatment groups (Table 1). Overall, 91.2% of patients had complex perianal fistulae and TNFi treatment had previously failed in 64.9% of patients. A lower proportion of patients randomized to receive FIL 200 mg discontinued the study compared with those who received PBO (Table 2). The proportion of patients who achieved a combined fistula response at Week 24 was numerically higher in the FIL 200 mg group (47.1%; 90% confidence interval [CI]: 26.0–68.9) than in the PBO group (25.0%; 90% CI: 7.2–52.7) (Figure 1), with similar results observed for combined fistula remission (FIL 200 mg [47.1%; CI: 26.0–68.9] versus PBO [16.7%; CI: 3.0–43.8]) (Figure 2). Treatment-emergent severe adverse events were highest in the FIL 200 mg group (Table 2). Adverse event rates were otherwise similar across treatment groups. Conclusion In this phase 2 study, numerically higher fistula response and remission rates were observed after 24 weeks of treatment with FIL 200 mg versus PBO in patients with active PFCD and a history of multiple medical treatment failures. FIL was well tolerated overall. Further studies of FIL for the treatment of PFCD are warranted.

Background Pouchitis occurs in up to 80% of patients with ulcerative colitis (UC) after total proctocolectomy (TPC) with ileal pouch anal anastomosis (IPAA). The pathogenesis of pouchitis is unclear, but is thought to involve a complex interaction between the microbiome and mucosal immune system. To examine the underlying pathophysiological mechanisms of pouchitis, the present study aims to simultaneously define immuno-histological and microbial parameters associated with different pouch phenotypes. Methods Endoscopic biopsies from the pre-pouch ileum (PI) and the pouch body (PB) were obtained from 51 subjects age>18 who underwent TPC with IPAA, n=48 for UC and n=3 for familial adenomatous polyposis (FAP). Mucosal mononuclear cells (MMC) were isolated from the intra-epithelial compartment (IEC) and lamina propria (LP) and examined for lymphoid, myeloid and innate immune subsets by multiparameter flow-cytometry (FC). Histological sections were examined by two pathologists, blinded to clinical identifiers and scored for inflammatory parameters that included neutrophilic activity, lymphoplasmacytic infiltration, eosinophilia, villous atrophy and submucosal fibrosis. Metagenomic sequencing of stool was performed and analyzed for microbial beta and alpha diversity. Results IPAA subjects were classified into the following phenotypes: normal pouch (NP) n=15 (29.4%), acute pouchitis (AP) n=9 (17.6%), chronic antibiotic dependent pouchitis (CADP) n=9 (17.6%), Crohn’s disease like pouch inflammation (CDLPI) n=15 (29.4%), and FAP NP n=3 (5.9%). Among subjects with NP, the PB had a higher frequency of naïve-CD4+ and CD8+ T cells, central memory- CD4+ T cells, and naïve B cells and a lower frequency of homeostatic IELs relative to the PI (Fig. 1A). Immune remodeling of the PB was further confirmed on histology that demonstrated increased lymphoid aggregates and decreased IELs. Subjects with CDLPI had significantly higher levels of inflammation, chronicity, and lymphoid aggregates but decreased IELs in the PI than NP or AP patients (Fig. 1B and 1C). In contrast to immune parameters, the composition of the microbiota in non-inflamed UC pouches was more similar to inflamed UC pouches than to FAP pouches. Alpha diversity and genus relative abundance differences between UC and FAP pouch stool samples were not statistically significant (Fig. 1D). Conclusion CDLPI represents a distinct entity of pouchitis that is associated with heightened levels of chronic inflammation relative to AP despite similarities in microbiota.

Background Mucosal healing, evaluated by a combination of endoscopic and histologic examinations, is a desired outcome in ulcerative colitis (UC), but few long-term or open-label extension (OLE) studies of UC treatments have assessed these outcomes. In the phase 3 True North (TN) study, ozanimod 0.92 mg once daily demonstrated efficacy and safety for up to 52 weeks in patients with moderately to severely active UC. The current analysis evaluated long-term endoscopic and histologic endpoints in patients who reinitiated ozanimod after experiencing disease relapse when rerandomised to placebo during the TN maintenance period (MP). Methods Responders to ozanimod 10-week induction therapy were rerandomised 1:1 to ozanimod (n=230) or placebo (n=227); this OLE interim analysis (data cutoff: 10 January 2022, the point at which the OLE Week 94 disposition is available for patients) included all patients who relapsed on placebo during the MP and reinitiated ozanimod in the OLE. Endpoints included percentages of patients with endoscopic improvement (endoscopic subscore of ≤1 point), histologic remission (Geboes index score Results Seventy-seven (34%) patients rerandomised to placebo experienced a disease relapse in the TN MP. Median time to relapse was 12.7 weeks. At data cutoff, all 77 patients had either completed OLE Week 94 (51.9%) or discontinued treatment. At OLE Week 46, endoscopic improvement, histologic remission, and mucosal healing were achieved by 50%, 56%, and 42% of patients, respectively (OC analysis). Proportions with these endpoints further increased to 60%, 68%, and 48%, respectively, by OLE Week 94. Per NRI analysis, endoscopic improvement, histologic remission, and mucosal healing at OLE Weeks 46 and 94 were observed in 30% and 27%, 31% and 25%, and 23% and 17% of patients, respectively (Figure). Furthermore, 52% of patients with endoscopic improvement at OLE Week 46, 58% of patients with histologic remission at OLE Week 46, and 44% of patients with mucosal healing at OLE Week 46 continued to sustain the respective endpoints at OLE Week 94 with another year of ozanimod treatment. Conclusion In patients who experienced disease relapse after rerandomisation to placebo, reinitiation of ozanimod was associated with recapture of response and long-term endoscopic and histologic benefits, including histologic remission and mucosal healing. These data suggest that patients who experience disease relapse when ozanimod is temporarily discontinued may benefit from resumption of ozanimod treatment.

Background Vedolizumab (VDZ) is a frontline drug for Ulcerative colitis (UC) and Crohn’s disease (CD) that targets integrin α4β7, a gut-homing receptor. Despite significant use, the mechanism(s) of action (MOA) of VDZ remain unclear. Methods Peripheral blood mononuclear cells (PBMC) from UC patients (n=43) and paired intestinal biopsies in a subset (n=12) were examined at week 0 (pre-infusion) and 14, by multiparameter flow cytometry (FC). TNF inhibitor (TNFi)-treated UC patients served as controls. Drug MOA was further examined in detail in murine models using single-cell RNA-seq, FC, conventional and immunofluorescent microscopy (IF). Photoconvertible (Kikumi) mice were used to study cellular trafficking after anti-α4β7 (DATK32) antibody (mAb) administration. Two distinct UC cohorts (n=42 and n=21 respectively) were used to correlate GI immune alterations following VDZ with mucosal healing. Results A significant decrease of colonic and ileal naïve B and T cells was noted in VDZ- but not in TNFi-treated patients (Fig 1A), while total T cell-frequencies were unchanged. Circulating gut-homing plasmablasts (β7+) were significantly decreased post-VDZ. Peyer’s patches (PP) in anti-α4β7-treated mice showed a rapid loss of cellularity associated with decreased follicular naïve B cells (Fig 1B). Single-cell RNA-seq also demonstrated a significant loss of follicular B cells, including a unique population of epithelium-associated B cells following anti-α4β7 mAb. In Kikumi mice, anti-α4β7 mAb impaired non-photoconverted follicular B cells and T cells into photoconverted PPs (Fig 1C) demonstrating that loss of PP cellularity was due to impaired cellular ingress. In VDZ-treated (but not TNFi-treated) UC patients, lymphoid aggregate (LA) size was significantly reduced in treatment responders compared to non-responders (defined by absence of histological inflammation). A distinct validation cohort further confirmed that reduced lymphoid aggregate size was associated with response to VDZ-therapy (Fig 1D). Conclusion VDZ is associated with impaired ingress of naïve B and T cells, resulting in attrition of intestinal LA. Reduced LA size is associated with VDZ response. Immune inductive site targeting represents a novel MOA of VDZ in patients with UC.

Background Upadacitinib (UPA), an oral, selective JAK inhibitor demonstrated superior efficacy for clinical remission compared with placebo (PBO) and an acceptable safety profile in patients with moderately to severely active Crohn’s disease (CD) in 2 phase 3 induction trials, U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836).1-2 There remains an unmet need for therapies that provide rapid symptom relief in ambulatory patients with moderate to severe CD experiencing disease flares. This sub-analysis evaluated the efficacy of UPA 45 mg once daily (UPA45) on early symptomatic improvement for the first 15 days of treatment, using pooled data from U-EXCEL and U-EXCEED. Methods U-EXCEL and U-EXCEED were multicentre, double-blind, PBO-controlled trials that enrolled patients who had average daily very soft or liquid stool frequency (SF) ≥4 and/or abdominal pain score (APS) ≥2 at baseline, plus a Simple Endoscopic Score for CD ≥6 (≥ 4 for patients with isolated ileal disease), excluding the narrowing component. Patients (n=1021) were randomized (2:1 ratio) to receive UPA45 (n=674) or PBO (n=347) for 12 weeks. First dose of study drug was administered on day 1. Improvement in daily symptoms of SF and APS, in addition to time to first achievement of daily SF/APS clinical remission were assessed. Results Patients treated with UPA45 experienced a significant improvement in daily symptoms compared with PBO-treated patients, simultaneously achieving SF < 3 and APS ≤ 1 beginning at day 3 (9.6% UPA vs. 5.8% PBO) (P≤0.05, Figure 1A). Difference from PBO was maintained through day 15 (P≤0.05), except for day 4 (P=0.0518). Similar results were found when evaluating each symptom separately, with a higher proportion of patients who received UPA45 achieving either SF < 3, beginning at day 5 (31.6% UPA vs. 23.1% PBO, Figure 1B). UPA-treat patients attained significance for APS ≤ 1 beginning at day 6 (49.1% UPA vs. 39.3% PBO, Figure 1C), compared with patients that received PBO. Differences from PBO were sustained through day 15 for either symptom (P≤0.01 for both endpoints). A greater proportion of patients receiving UPA45 also demonstrated at least a 60% decrease in SF by day 5, compared to PBO, which was maintained through day 15 (P≤0.01, Figure 1D). Patients treated with UPA45 achieved daily SF/APS clinical remission significantly earlier than PBO-treated patients (median time to clinical remission: 13 days UPA45 vs 32 days PBO; P Conclusion Patients who received UPA 45 mg once daily significantly improved daily symptoms of diarrhea or abdominal pain within the first week of treatment and achieved daily clinical remission faster than PBO-treated patients, providing rapid symptom relief.

Background Early treatment of Crohn’s disease (CD) often involves biologics such as anti-tumor necrosis factor (anti-TNF) agents. Ileocecal resection (ICR), while a therapeutic option in early CD, is generally reserved for complicated CD or when medical treatment fails. We aimed to compare long-term outcomes of ICR and anti-TNF therapy as index treatment for ileocecal CD, initiated within one year of diagnosis, in the Danish nationwide cohort. Methods Using cross-linked nationwide registers, we identified all individuals who lived in Denmark and were diagnosed with ileal CD between 2003 and 2018. We included individuals who underwent ICR or received anti-TNF drugs as index treatment for ileocecal CD within one year of diagnosis. We excluded patients who did not have pathology information confirming disease in the ileocecal region. The primary outcome was a composite of CD-related hospitalization, systemic corticosteroid exposure, CD-related surgery, and perianal CD diagnosis. We conducted Cox proportional hazards regression analyses to compare outcomes in the two groups after adjusting for potential confounders. We also determined the proportion of individuals initiated on immunomodulator (IMM), anti-TNF, or no therapy at 5 years after ICR. Results Of the 16,443 individuals diagnosed with ileocecal CD between 2003 and 2018, 581 (3.5%) and 698 (4.2%) individuals with confirmed disease in the ileocecal region underwent ICR and received anti-TNF as the index treatment, respectively. The composite outcome occurred in 273 individuals (IR 110.3/100,0 person years (PY)) in the ICR group and in 318 individuals (IR 201.9/100,0 PY) in the anti-TNF group. The risk of the composite outcome was 33% lower in the ICR group compared to the anti-TNF group (aHR 0.67; 95% CI 0.54, 0.83), after adjusting for demographic and clinical variables. On analysis of individual outcomes, ICR was associated with reduced risk of systemic corticosteroid exposure and CD-related surgery, but not CD-related hospitalization or perianal CD diagnosis. Of individuals who underwent ICR, the proportion that was initiated on IMM, anti-TNF treatment or no treatment at 5 years of follow up was 47.5%, 17.1%, and 50.3%, respectively. Conclusion These data support the role of ICR as an index treatment for ileocecal CD and challenge the current paradigm of reserving surgery for complicated CD refractory or intolerant to medications. Further studies will help identify characteristics of individuals who needed no treatment after ICR.

Background Prior exposure to biologics can influence response to subsequent lines of advanced therapies. Previous analyses showed that patients who did not achieve clinical response following 10 weeks of ozanimod treatment in the phase 3 True North (TN) study benefited from extended induction with open-label ozanimod in the TN open-label extension (OLE) study. As the impact of prior biologic exposure on outcomes with extended induction is unknown, the aim of this analysis was to evaluate that question. Methods Clinical nonresponders to ozanimod at TN Week (W) 10 entered the OLE (data cutoff: January 10, 2022, at which point the disposition was available until OLE W94 for all patients). Data were analysed in patients with and without prior biologic exposure at baseline. Disease activity was assessed at TN W0 (baseline) and at W10 (OLE entry). Symptomatic clinical response and remission were evaluated through OLE W94, and multiple clinical, endoscopic, and histologic endpoints were evaluated at OLE W46 and W94 using observed case (OC) and nonresponder imputation (NRI) analyses. Results A total of 220 patients with prior biologic information entered the OLE after not achieving clinical response at TN W10 (biologic-naive, n=122; biologic-experienced, n=98). Disease activity at baseline was generally consistent between biologic-naive and experienced patients. About half of the ozanimod W10 nonresponders in both groups achieved symptomatic clinical response by OLE W5, with a higher proportion of biologic-naive patients maintaining response until OLE W94 in both OC and NRI analyses (Figure 1). Higher proportions of biologic-naive patients also sustained symptomatic clinical remission until OLE W94 in both OC and NRI analyses. In OC analysis, a higher proportion of biologic-naive patients achieved all clinical, endoscopic, and histologic endpoints at OLE W46 compared with biologic-experienced patients; by OLE W94, however, the proportions of patients who achieved all clinical, endoscopic, and histologic endpoints were generally consistent, regardless of prior biologic exposure (Figure 2). As expected, a smaller proportion of patients achieved the efficacy endpoints in the NRI analysis, with proportions being higher in biologic-naive patients; response rates were sustained between OLE W46 and W94 in each group. Conclusion Both biologic-naive and -experienced clinical nonresponders to ozanimod at the end of induction demonstrated response to extended induction with ozanimod. Delayed response was durable for up to 2 years of continuous ozanimod treatment in both groups, with higher proportions achieved in biologic-naive patients.

Background The optimal treatment target for ulcerative colitis (UC) is uncertain. The VERDICT trial in moderate to severe UC aims to determine if a treatment target of corticosteroid (CS)-free symptomatic + endoscopic + histologic remission is superior to CS-free symptomatic remission alone. Trial progress and the study cohort to date are described herein. Methods Our aim is to enrol 660 patients with moderately to severely active UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2). Patients are randomised to 3 treatment targets (2:3:5 ratio): CS-free symptomatic remission (Mayo RBS = 0) (Group 1); CS-free endoscopic remission (MES ≤1) + symptomatic remission (Group 2); or CS-free histologic remission (Geboes score Results As of 2 November 2022, 331 patients were enrolled at 55 sites across 10 North American and European countries. Mean (SD) baseline characteristics (Table) include a UC duration of 8.6 (8.3) years, Mayo Clinic score of 8.7 (1.7), C-reactive protein level of 13.3 (15.6) mg/dL, and a faecal calprotectin level of 1462.3 (1481.3) mg/kg. At baseline, 52% (172/331) and 11% (37/331) of patients were receiving concomitant CS and immunosuppressives, respectively, and 14% (47/331) had current/prior exposure to tumour necrosis factor antagonists. Most patients (85%) were receiving nonbiologic therapy. Of all randomised patients, 43/69 (Group 1), 65/98 (Group 2), and 115/164 patients (Group 3) have reached week 16; and 28 (65%), 25 (39%), and 42 (37%) met their target, respectively. After a median of 35 weeks (IQR 18-53), a total of 30 (Group 1), 32 (Group 2), and 50 patients (Group 3) have met their target and will be followed to relapse or study termination. The serious adverse event rate (8%; 36/483) was similar across groups. Conclusion VERDICT has randomised ~50% of its target enrolment. Enrolled patients represent a typical moderate to severe UC population and are primarily bionaive and receiving early VDZ initiation. Early results suggest the feasibility of achieving each treatment target, specifically histologic remission, and are consistent with expected values. No new VDZ safety signals were identified. Completion of enrolment is anticipated in late 2023.

Background CD is classically seen as a progressive disease leading to bowel damage and disability. Disability has been proposed by the Spirit-IOIBD consensus1 as an endpoint in disease modification trials. However, there is a paucity of data regarding disability in CD patients at diagnosis. Methods The “Crohn′s Disease Cohort Study” (CROCO) is an ongoing prospective cohort aiming to study the longitudinal evolution of bowel damage and disability following diagnosis of CD. All patients are included within 12 months following CD diagnosis and will be followed over 5 years with serial assessments of bowel damage and disability. At recruitment patients completed an IBD disability score questionnaire (DS),2 comprising several domains: mobility, self-care, major daily life activities, gastrointestinal-related problems, mental health and interaction with the environment. We here describe the baseline DS and its association with disease features, disease activity score (Harvey-Bradshaw Index), and biomarkers of disease activity, on the first patients recruited into CROCO. Results Ninety-four patients were recruited, of which 66 filled at least 80% of the questions in the DS questionnaire; of those 55% were male and median age at diagnosis was 30.6 [IQR 24.2;38.8]. The baseline visit occurred at a median time of 6 months [IQR 2.6;9.2] after CD diagnosis. Ileal involvement (L1/L3) was reported in 82% of patients; 68% had B1 phenotype, and 26% presented extra-intestinal manifestations. Overall, 32% of patients had been hospitalised, and 6% had a history of CD-related surgery. Regarding medication [from diagnosis to baseline], 55% received steroids, 56% immunosuppressants, and 65% Anti-TNF therapy. The median DS was 79 [IQR 67;108.2] (range: 49;198); only 2 patients (3%) patients presented DS>162 (the central value of the DS), indicating no or mild disability. No correlations were found between clinical or analytical biomarkers of disease activity at the time of recruitment (Table 1). Associations between disease features and DS are displayed in Table 2. A history of CD-related hospitalisation was associated with a significantly higher DS (103 [IQR 79;157] versus 76.5 [65.5;97], p=0.013). No other associations were observed. Conclusion In a cohort of newly diagnosed CD patients, disability was mostly mild and independent of disease activity, disease location or behaviour; around 1/3 required hospitalisation within the first year of diagnosis, which was associated with increased disability. These data add to the growing concept that newly diagnosed disease represents a window of opportunity for intervention.

Background In the phase 3 True North (TN) study, ozanimod (OZA) 0.92 mg once daily showed efficacy and safety for up to 52 weeks in patients (pts) with moderately to severely active ulcerative colitis, and is approved for adults in the EU, US, and other countries for this indication. This analysis (data cutoff: 10 January 2022) evaluated the impact of prior biologic exposure on the long-term durability of response in pts who experienced disease relapse while on placebo (PBO) during the TN maintenance period (MP) and then recaptured response to OZA during the TN open-label extension (OLE). Methods Responders to OZA 10-week induction therapy who were biologic-naive or exposed to prior biologics at baseline were rerandomised 1:1 to OZA (n=230) or PBO (n=227) during the TN MP. Pts who relapsed while on PBO subsequently entered the OLE and reinitiated open-label OZA in this interim OLE analysis. Symptomatic, clinical, endoscopic, and histologic endpoints were evaluated by observed case (OC) and nonresponder imputation (NRI) analyses. Results This analysis included 38 biologic-naive and 38 biologic-exposed pts who entered the OLE after disease relapse on PBO (median time to relapse, 13.1 and 11.2 weeks, respectively). Symptomatic clinical response based on NRI was achieved by 26/38 (68.4%) of biologic-naive and 20/38 (52.6%) of biologic-exposed pts 5 weeks after restarting OZA in the OLE. Symptomatic clinical response by OC analysis at OLE Week 5 was achieved in 72.2% (26/36) and 55.6% (20/36) of biologic-naive and -exposed pts, respectively. Although a greater proportion of biologic-naive vs -exposed pts completed OLE Week 94 (65.8% vs 39.5%), OC rates of symptomatic clinical response at OLE Week 94 were similar (biologic-naive: 95.0% [19/20] vs biologic-exposed: 100.0% [13/13]). Key clinical, endoscopic, and histologic endpoints are shown in Fig 1. Durability of response between OLE Weeks 46 and 94 was similar in biologic-naive (40%–56%) vs -exposed pts (50%–67%) but varied depending on endpoints (NRI analysis). Reductions in mean [SD] total Mayo score were similar and sustained through OLE Week 94 in biologic-naive and -exposed pts (OLE Week 0: 8.9 [1.8] and 9.3 [1.6], respectively; OLE Week 46: 2.3 [1.7] and 4.2 [2.6], respectively; OLE Week 94: 2.6 [2.0] and 2.6 [1.4], respectively) (Fig 2). Conclusion In pts who lost clinical response after OZA treatment withdrawal, symptomatic clinical response was recaptured within 5 weeks of OZA reinitiation in the majority of pts, and clinical benefit was maintained for up to 94 weeks (extent of current analysis) in biologic-naive and -exposed pts. This suggests that in clinical practice, pts who experience a disease relapse after temporarily holding OZA may benefit from resumption of OZA.

Background There is increasing evidence of a pre-clinical phase of inflammatory bowel disease (IBD), but its length and progression with time is not well characterized. We here identified the use of any prescription medications within a decade prior to IBD diagnosis and compared their use in a matched population of individuals without IBD. Methods We harnessed the cross-linked nationwide Danish health registers to identify all individuals with incident IBD in Denmark from 2005 to 2018. Individuals with IBD were matched one to ten to individuals without IBD on age, sex, municipality of residence, and year of IBD diagnosis. Next, we examined their use of any prescription medication within the decade leading to IBD diagnosis or matching date. Prescription histories were compared and examined according to the WHO classification of medication by anatomical main group and therapeutical subgroup. Results We compared 29,219 individuals with IBD to 292,190 individuals without IBD. Up to a decade prior to IBD diagnosis, the IBD population had a significantly higher use of medications across all organ systems than the matched population. Medication use was more abundant in the IBD population at ten years before diagnosis/matching (p-value Conclusion There is an increased use of a broad range of medications a decade before diagnosis of IBD. These findings further suggest a long pre-diagnostic phase of IBD, association of IBD with other immune-mediated diseases, and that IBD could be a multiorgan disease to a much larger extent than hitherto established. The long pre-diagnostic period is a window of opportunity for earlier detection, diagnosis, and intervention of IBD.

Background Ozanimod is approved in the EU, US, and other countries for treatment of moderately to severely active ulcerative colitis (UC) in adults. In the phase 3 True North (TN) study, ozanimod 0.92 mg once daily demonstrated efficacy and safety for up to 52 weeks in patients (pts) with moderately to severely active UC. This open-label extension (OLE) analysis evaluated the long-term durability of ozanimod based on symptomatic and clinical endpoints in pts who experienced disease relapse while on placebo during the TN maintenance period (MP) and then recaptured response to ozanimod during the OLE. Methods Responders to ozanimod 10-week induction therapy were rerandomised 1:1 to ozanimod (n=230) or placebo (n=227); this OLE interim analysis (data cutoff: January 10, 2022, at which point the OLE Week 94 disposition was available for pts) included all pts who relapsed on placebo during the MP and reinitiated ozanimod in the OLE. Endpoints included symptomatic response and remission, clinical response and clinical remission (which include endoscopy subscores), and corticosteroid (CS)-free remission (clinical remission while off CS for ≥12 weeks) evaluated using observed case (OC) and nonresponder imputation (NRI) analyses, and mean total Mayo score over time. Results A total of 77/227 pts (34%) rerandomised to placebo during MP experienced a relapse after a median of 12.7 weeks and all entered the OLE. Symptomatic response was achieved by 46/73 (63%) pts 5 weeks after restarting ozanimod in the OLE (NRI analysis: 60% at OLE Week 5) and in 32/33 (97%) by OLE Week 94 in the OC analysis. Symptomatic remission was also achieved by OLE Week 5 by 24/73 (33%) pts. Sustained efficacy of ozanimod reinitiation was also demonstrated comparing OLE Weeks 46 and 94 across clinical endpoints by OC analysis (clinical response, 76% and 86%; clinical remission, 44% and 59%; CS-free remission, 37% and 52%) and NRI analysis (clinical response, 42% and 31%; clinical remission, 25% and 22%; CS-free remission, 21% and 20%) (Figure 1). In addition, 56.3%, 52.6%, and 50% of pts who experienced clinical response, clinical remission, and CS-free remission, respectively, at OLE Week 46 continued to sustain these endpoints at OLE Week 94. Reductions in mean total Mayo score at OLE Week 46 were also sustained through OLE Week 94 (Figure 2). Conclusion Response to ozanimod was regained after temporary therapy discontinuation for most pts, and this response was durable for up to 2 years as demonstrated by both symptomatic and clinical endpoints in this interim analysis from the TN OLE study. These results suggest that pts who experienced disease relapse after temporarily holding ozanimod in clinical practice may benefit from resumption of ozanimod.

Background Ozanimod is approved in the EU, US, and other countries for the treatment of moderately to severely active ulcerative colitis in adults. In the phase 3, 52-week, double-blind True North (TN) study, Week 10 clinical nonresponders to ozanimod could enter the open-label extension (OLE) to continue treatment. Previous analysis showed that approximately 50% of Week 10 nonresponders achieved symptomatic clinical response with extended induction during the OLE in as early as 5 weeks. The current analysis evaluated long-term clinical and symptomatic endpoints up to 2 years in this delayed responder subgroup. Methods Efficacy data were analysed for TN Week 10 ozanimod nonresponders who subsequently received open-label ozanimod in the OLE, both by whole subgroup and original study arms (double-blind [Cohort 1] and open-label ozanimod [Cohort 2]) (data cutoff: January 10, 2022). Endpoints included symptomatic clinical response, symptomatic clinical remission, total Mayo score, clinical response, clinical remission, and corticosteroid (CS)-free remission up to OLE Week 94 (104 weeks of continuous ozanimod treatment). Data were evaluated using observed case (OC) and nonresponder imputation (NRI) analyses. Results A total of 226 nonresponders at TN Week 10 entered the OLE (Cohort 1, n=150; Cohort 2, n=76). Males comprised 67% of this subgroup, and mean (SD) age was 39.6 (13.6) years. Symptomatic clinical response (Figure 1), symptomatic clinical remission, and reduction in partial Mayo scores were observed as early as OLE Week 5 and were maintained through OLE Week 94. Minimal change in total Mayo score was observed from TN Week 0 (baseline) to TN Week 10 (OLE Week 0), but significant reductions from baseline occurred by OLE Week 46 (–4.2 [2.7]) and OLE Week 94 (–5.3 [2.6]). Overall, 62% of patients achieved clinical response, 26% achieved clinical remission, and 24% achieved CS-free remission at OLE Week 46; these increased to 74%, 35%, and 33%, respectively, by OLE Week 94 in the OC analysis (Figure 2). Data were similar between Cohorts 1 and 2. Conclusion Symptomatic response in ozanimod nonresponders was observed as early as 5 weeks after extended induction with ozanimod. Delayed response to ozanimod was maintained for up to 2 years as demonstrated by both symptomatic and objective endpoints. Even in those with delayed initial response, efficacy of ozanimod was durable.

Background Ozanimod, a novel oral therapeutic option for patients with moderately to severely active ulcerative colitis, demonstrated significant improvements in clinical, endoscopic, and histologic endpoints in the phase 3, 52-week, double-blind True North (TN) study. Approximately one-third of the patients did not achieve clinical response to ozanimod after 10 weeks of TN induction therapy. However, a delayed response was observed in a subset of these nonresponders upon extended induction with ozanimod. The present analysis evaluated ozanimod efficacy on endoscopic and histologic endpoints in these delayed responders in the TN open-label extension (OLE) study. Methods Data were analysed for the overall delayed responder population and separately for the blinded (Cohort 1) and open-label (Cohort 2) cohorts (data cutoff: 10 January 2022, the point at which patient disposition was available for all patients up to OLE Week 94). Endpoints included endoscopic improvement (defined as an endoscopy subscore of ≤1 point), histologic remission (defined as Geboes index score Results A total of 226 patients (Cohort 1, n=150; Cohort 2, n=76) were nonresponders at Week 10 and entered the OLE (67% male; mean [standard deviation] age, 39.6 [13.6] years). At OLE entry, 24% of patients had moderate disease (Mayo endoscopic score [MES]=2) and 73% had severe disease (MES=3). Approximately half of these patients achieved symptomatic clinical response as early as 5 weeks of ozanimod open-label treatment. In OC analysis at OLE Week 46, 30% of patients achieved endoscopic improvement, 42% achieved histologic remission, and 24% achieved mucosal healing that further increased to 48%, 48%, and 39%, respectively, by OLE Week 94 (Figure 1A). In NRI analysis, the following patient proportions were observed at OLE Weeks 46 and 94: 18% and 19% (endoscopic improvement), 22% and 14% (histologic remission), and 13% and 11% (mucosal healing) (Figure 1B). Data were generally similar in Cohorts 1 and 2. Conclusion Delayed responders to ozanimod achieved and maintained mucosal healing over 2 years of continuous ozanimod treatment. Ozanimod treatment resulted in the healing of intestinal mucosal lesions, even in patients with moderate to severe disease who may have an initial delayed response to ozanimod.

Background NLRX1 is a mitochondrial membrane protein whose activation reduces oxidative stress and decreases effector cell differentiation and cytokine release. NX-13 is a first-in-class, orally active, gut selective NLRX1 agonist with low systemic exposure. In preclinical studies of IBD, NX-13 effectively reduced inflammatory responses and disease severity. A phase 1a study (healthy subjects) showed NX-13 to be well tolerated with low systemic drug exposure suggesting a gut-selective drug delivery. We report the results of a phase 1b study in patients with Ulcerative colitis (UC) on the safety, target engagement and clinical efficacy of NX-13. Methods In this double-blind trial, 36 patients with active UC (Total Mayo Score [MCS] 4-10; Mayo endoscopic subscore [MES] 2-3) were randomly assigned to NX-13 250mg Immediate Release (IR), 500mg IR, 500mg Modified Release (MR) or Placebo to be taken QD for 4 weeks (safety visit at week 5). Biologic exposed patients, stable 5’ASAs dose and corticosteroids (oral ≤20mg/day prednisone or equivalent) were permitted. IV or topical corticosteroids use was prohibited. Primary endpoints were safety and pharmacokinetic (PK) analysis. The study was not powered for clinical efficacy, however MCS, histopathologic Geboes score, and NLRX1, cytokine, and gene expression were obtained at baseline and day 28 in exploratory analyses (Table 1). Results During the 5-week observation period, no serious adverse events (AEs) were reported. All AEs were classified as mild or moderate and were most common in the 500mg MR group. One patient was withdrawn before week 5 due to a flare of UC. IR dose plasma PK levels peaked at 1hour, while the MR dose was absorbed later and maintained a low exposure longer. Qualitative immunohistochemical analysis showed target engagement as indicated by increase of NLRX1 at all doses. Symptomatic efficacy was seen in 8/11 patients in the 250mg group with a PRO (RB+SF) score of 0 at week 4. The decrease in MCS was 2.1-3.4 in the NX-13 arms vs 1 point with placebo (Fig 1A) while clinical response rates ranged from 27-72% amongst the active arms with no placebo responders, though no dose-response relationship was observed (Fig 1B). Endoscopic response ranged from 27-40% (Fig 1C), with 5/32 dosed patients being in endoscopic remission. Histologic remission largely paralleled endoscopic response and cytokine and mRNA levels support target engagement. Conclusion In patients with active UC, NX-13 was well-tolerated and target engagement was achieved. The exploratory efficacy endpoints indicated rapid clinical, endoscopic, and histologic improvement at week 4, relative to placebo. This novel mechanism of action will be further evaluated in a phase 2 study.

Background CT-P13 subcutaneous (SC) infliximab formulation was developed to provide patients with a convenient option for treatment. Previous studies have shown efficacy and safety of CT-P13 SC comparable to CT-P13 intravenous (IV) in inflammatory bowel disease (IBD)1 and rheumatoid arthritis2. This study aimed to demonstrate superiority of CT-P13 SC over placebo in maintenance therapy after induction therapy of CT-P13 IV in patients with ulcerative colitis (UC). Methods Patients with moderately to severely active UC (modified Mayo score 5 to 9 with endoscopic subscore of ≥ 2 points) were enrolled LIBERTY-UC (NCT04205643) and treated with open label CT-P13 IV 5 mg/kg at Weeks 0, 2 and 6 as induction therapy. At Week 10, patients who had a clinical response, defined as decrease in modified Mayo score from baseline of at least 2 points and at least 30%, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1 point, were randomised in a 2:1 ratio to receive either CT-P13 SC 120 mg (CT-P13 SC) or placebo SC arms every 2 weeks up to Week 54. The primary endpoint was clinical remission at Week 54. The key secondary endpoints of clinical response, endoscopic-histologic mucosal improvement, and corticosteroid-free remission were assessed at Week 54. Safety was evaluated up to Week 54. Results A total of 548 patients were enrolled. Among them, 438 patients (79.9%) responded to CT-P13 IV induction dosing and were randomised (294 in CT-P13 SC arm and 144 in placebo arm, respectively) at Week 10. The rate of clinical remission at Week 54 was significantly greater in CT P13 SC (43.2%) compared to placebo (20.8%) (P The safety profile during maintenance phase was generally comparable between CT-P13 SC and placebo arms (table 2). No deaths were reported. Conclusion CT-P13 SC was more effective than placebo for clinical remission, clinical response, endoscopic histologic mucosal improvement, and corticosteroid-free remission at Week 54 in patients with moderately to severely active UC. No new safety concerns were identified. These results demonstrate that the CT-P13 SC provides both a robust clinical benefit and the convenience of SC administration to patient with moderately to severely active UC. 1 Schreiber et al., 2021. Gastroenterology 2021;160:2340–23 2 Westhovens et al., 2020. Rheumatology 2020;00:1

Background Clinical understanding of different disease courses in response to targeted therapies in ulcerative colitis (UC) is lacking. Symptom load over time can help to define different trajectories leading to outcome measures at week 52. This post hoc analysis from the GEMINI 1 study of vedolizumab (VDZ) vs placebo for the treatment of moderately to severely active UC1 aimed to define different clinical patterns of response that led to Week 52 endoscopic remission based on daily collection of symptom data: rectal bleeding (RB) and stool frequency (SF). Methods RB and SF data, each scored 0 to 3, were extracted from the diary cards of patients who were treated with VDZ up to Week 50, had clinical outcome assessed at Week 52 and had sufficient diary data. From the daily scores, six different daily symptom score rules comprising RB alone or various combinations of RB and SF (Table 1) were derived. Each of the six symptom score rules was then accrued over the time to derive cumulative symptom scores (area under the curve [AUC]). The AUCs at Weeks 6, 10, 14 and 22 for each rule were evaluated for sensitivity and specificity to predict endoscopic remission at Week 52, which was defined as Mayo endoscopic subscore of ≤1 point. Results Of the 895 pts included in the GEMINI 1 study, 217 pts were treated with VDZ, had sufficient RB and SF data and Week 52 outcome data. Of these, 157 (72.4%) achieved endoscopic remission at Week 52. Rule 4, with a score of 0 if both RB=0 and SF≤1 or 1 if not, was consistently better at predicting response at Week 52, i.e., had largest area under the receiver-operator characteristic (ROC) curve (Week 10 and Week 14 shown in Table 2). Area under ROC curve for Rule 4 was 0.7317 (0.6578, 0.8057) and 0.7534 (0.6810, 0.8258) at Week 10 and Week 14, respectively (Fig 1). Rule 4 had better predictive performance than the use of RB Mayo score (RB1) alone or the simple dichotomization (RB2, 0 if RB≤1, 1 if RB >1) [Table 2]. AUCs for Rule 4 differed between pts with vs without endoscopic remission at Week 52, with differences evident as early as Week 10: median AUC=41 for pts with endoscopic remission vs 70 for pts without (Fig 2). Conclusion The daily collection of RB and SF symptoms during the first weeks of therapy with VDZ identifies patients with a high likelihood for endoscopic emission at Week 52. Early clinical symptom change is a simple method for tight monitoring of patients with UC. The identification of preferential responder populations in which marked reduction of suffering are combined with hard endpoints could help in establishing treatment optimization algorithms for targeted therapies. References: 1. Feagan BG et al. (2013) N Engl J Med 369:699–710

Background The perturbation of the symbiotic relationship between microbes and the intestinal immune system contributes to Inflammatory Bowel Disease (IBD) development even years before diagnosis. However, the causes underlying the loss of gut microbial equilibrium (dysbiosis) associated with inflammation still remain unknow. The host glycocalyx (repertoire of glycans/sugar-chains at the surface of gut mucosa) constitutes a major biological interface between gut mucosa and microorganisms1. In this study we aimed to evaluate whether and how an altered host glycome perturbs microbiome composition associated with dysbiosis and initiation of intestinal inflammation. Methods We have modulated the glycosylation profile at the level of gut mucosa using specific glycoengineered mouse models (KO) that exhibit specific alterations (deficiencies) in glycosylation composition. Colitis was induced using DSS and microbiome analysis was performed by 16S rDNA sequencing both in WT and KO mice. The mucosa glyco-immunoprofile was characterized. Results We first demonstrated in different glycoengineered mice that changes in the composition of glycans at gut mucosa resulted in dysbiosis characterized by a significant decrease in beneficial members of the Firmicutes phylum compared with WT mice. These mice with deficiency in mucosa glycosylation exhibited a higher susceptibility to colitis2. Then, and to determine the causal effect of mucosa glycosylation-induced microbiota modulation, we co-housed KO and WT mice. After 5 weeks of cohousing with WT mice, the KO mice exhibited a much less severe colitis and an increased proportion of bacteria from Firmicutes phylum compared to single housed KO mice. Inferred metagenomics analysis further revealed an alteration of the glycosylation biosynthetic pathway that was apparently shared and gained upon co-housing the KO mice with WT. The analysis of colonic inflammatory infiltrate from cohoused KO mice showed an increased expression of IL17 and IL22 production in gut mucosa, at baseline and before DSS. This pinpoints a potential protective effect of the enhancement of glycosylation biosynthesis (through microbiome sharing with WT) for preventing dysbiosis and dysregulation of gut immune response. Conclusion In this study, we demonstrate that changes in composition of glycans at the gut mucosa level is associated with dysbiosis and susceptibility to colitis. These results illustrate the relevance of the gut glycome in shaping the gut microbiota, highlighting its role in maintaining a homeostatic crosstalk between the microbiome and host immunity. This study was funded by ECCO Pioneer Award. 1. Verhelst, Gastroenterology 2020. PMID: 31626754 2. Dias et al PNAS 2018 PMID: 29720442

Background Acute Severe Ulcerative Colitis (ASUC) may occur in up to 25% of patients with UC during their disease course. Despite intensive in-hospital management, some patients still require colectomy. We aimed to define the mucosal immune phenotypes related to ASUC that associate with treatment-outcomes. Methods Adult patients with ASUC (defined by Truelove and Witts criteria), (n=32) were recruited. UC patients (mild-moderate disease) (n=31) and normal volunteers (NV) (n=27) served as controls. Gastrointestinal (GI) biopsies from the left colon were analyzed by multiparameter flow cytometry (FC) for myeloid cells (classical and non-classical monocytes, dendritic cells), lymphoid cells (T cells, B cells) and innate (Natural Killer) cells. Therapeutic non-response was defined as surgery within 3 months of admission. Results Six of the ASUC patients (18.8%) required colectomy during index admission and 8 (25%) within 3 months of admission, i.e. non-responders. Only 14/32(44%) patients were bio naïve on admission. Clinical parameters significantly associated with treatment non-response included lower hemoglobin and albumin levels (Fig. 1A). Significantly higher frequency of classical (CD14+) and non-classical (CD16+) monocytes as well as proliferating CD4+ and CD8+ cells were seen in ASUC compared to NV and UC patients with Mayo 1, 2, 3 inflammation (Fig. 1B). Furthermore, ASUC patients who were non-responsive to medical treatment had higher frequencies of CD14+ monocytes and proliferating (Ki67+) CD4+ T cells in the colon compared to medical treatment responders (Fig 1C). Conclusion High frequencies of CD14+ monocytes and proliferating CD4+ T cells in the colon represent distinct immune signatures that relate to ASUC outcomes. Clinical trials targeting adverse clinical and immune phenotype-associated ASUC patients with combination therapies are warranted.

Background There is an increasing incidence of inflammatory bowel disease (IBD) for which environmental factors are suspected. Antibiotics have been associated with development of IBD in earlier generations, but their influence on IBD risk across the ages is uncertain. We assessed the changing impact of antibiotic exposure, including dose response, timing, and antibiotic class, on the risk of IBD in all individuals ≥10 years-old. Methods Using Denmark nationwide registries, a population-based cohort of residents ≥10 years-of-age was established between 2000 and 2018. Incidence rate ratios (IRRs) for IBD following antibiotic exposure were calculated using Poisson regression, with adjustment for concomitant PPI, antiviral and antifungal use. Results There were a total of 6,104,245 individuals, resulting in 87,112,328 person-years of follow-up, 36,017 new cases of ulcerative colitis (UC) and 16,881 new cases of Crohn’s disease (CD). Antibiotic exposure was associated with an increased risk of IBD as compared with no antibiotic exposure for all age groups, though was greatest among individuals aged 40-60 years-old and ≥ 60 years-old (10-40 years-old, IRR 1.28, 95%CI 1.25-1.32; age 40-60 years-old, IRR 1.48, 95%CI 1.43-1.54; age ≥ 60 years-old, IRR 1.47, 95%CI 1.42-1.53). When assessing the number of antibiotic courses received, each subsequent course added additional risk, leading to a positive dose response relationship for all age groups: increase in IRR per antibiotic course was 1.11 (95% CI 1.10-1.12), 1.15 (95% CI 1.14-1.16), and 1.14 (95% CI 1.13-1.15) for individuals aged 10-40 years, 40-60 years, and ≥60 years, with similar results seen for both UC and CD. The highest risk of developing IBD was observed 1-2 years after antibiotic exposure, and after use of antibiotic classes often prescribed to treat gastrointestinal pathogens. Nitrofurantoin, which has minimal impact on the intestinal microbiome, was not associated with risk of IBD across all age groups (age 10-40 years IRR 1.11, 95%CI 0.88-1.38; age 40-60 years IRR 1.22 (95%CI 0.95-1.53); age ≥60 years IRR 0.93, 95%CI 0.79-1.07). Conclusion Our results demonstrate a positive dose response, highlighting the strong association between antibiotic exposure and the development IBD, particularly among adults forty years and older. This risk was highest in the years immediately following antibiotic use, persisted across antibiotic classes impacting the gastrointestinal microbiome, and was associated with the development of both UC and CD. Thus, antibiotic stewardship may be important not only to limit the development of multidrug resistant organisms, but also to reduce the risk of IBD, particularly among older adults.

Background There are increasing data on changes in intestinal inflammation and microbiome diversity during pregnancy in women with inflammatory bowel disease (IBD) with implications towards individual and offspring immune function. However, differences in intestinal inflammation, as measured by fecal calprotectin (FC) and microbial a-diversity, in consecutive pregnancies are not known. Methods We prospectively enrolled a cohort of women, 37 with IBD and 39 without IBD, during two consecutive pregnancies, and their offspring. We collected serial stool samples and clinical data, and measured FC and bacterial abundance during each trimester of each pregnancy. We further performed correlation analysis between FC in consecutive pregnancies and between microbial a-diversity in consecutive pregnancies among women with and without IBD. Results Compared to healthy controls, IBD pregnancies had significantly lower gestational age at birth and higher frequency of Cesarean section. Mode of delivery, the status of Group B Streptococcus (GBS) infection and GBS infection prophylaxis were significantly associated with the pregnancy order in both IBD and controls (Table). Furthermore, we observed strong correlations of FC (r=0.56, p-value=0.093) and microbial alpha-diversity assessed as operational taxonomic unit (OTU) richness (r=0.88, p=0.0087) between paired consecutive pregnancies in women with IBD, but not in those without IBD (Figure). There were no differences in microbial alpha-diversity using the Shannon and Simpson indices when comparing consecutive pregnancies of women with and without IBD. Conclusion In this study, we demonstrate that intestinal inflammation and microbiome diversity are more conserved in consecutive pregnancies of women with IBD compared to healthy controls. These findings may have implications towards understanding the impact of pregnancy on host-microbiome interactions in IBD as well as the potential impact on offspring health.

Background In Crohn’s disease (CD), biologics can induce mucosal healing and stable remission. After reaching this target, treatment de-escalation could be considered but the risk of relapse needs to be estimated. Current biomarkers used to predict relapse (C-reactive protein: CRP, faecal calprotectin) offer a limited prognostic capacity. Furthermore, they only monitor inflammation while we recently highlighted various and distinct pathological processes associated with the risk of short-term (6 months) relapse in CD patients stopping infliximab. Herein, the aim of our study was to further characterise this distinction. Methods Serum abundance of 92 proteins were measured by proximity extension assay (immune response panel, Olink) at baseline of the STORI cohort (infliximab diScon-Tinuation in CrOhn’s disease patients in stable Remission on combined therapy with Immunosuppressors, n=102). Association of markers with the risk of relapse was determined by univariable Cox model in stratified (relapse 6 months) and non-stratified datasets. Study of protein characteristics and enrichment analyses were performed to find biological patterns differentiating short-term from mid/long-term relapsers. To evaluate the predictive capacity of markers, we combined them systematically by pairs (‘AND’ or ‘OR’ logical operators) and used log-rank statistics with false discovery rate (FDR) correction (Benjamini-Hochberg). Results The risk of mid/long-term relapse was associated with a decreased circulating level of anti-inflammatory effectors while the risk of short-term relapse was associated with an increased circulating level of pro-inflammatory effectors (Fig. 1A, 1B). The risk associated with the downstream signalling of cytokine and pattern recognition receptors showed an opposite pattern in the short-term versus mid/long-term relapsers (Fig. 1D, 1E). The risk of short-term relapse was characterised by a perturbed circulating level of proteins inducing tolerance and immunity in antigen presenting cells (Fig. 2A, 2B). The risk of mid/long-term relapse was characterised by an increased circulating level of proteins promoting lymphocyte tolerance (Fig. 2D, 2E) and a decreased circulating level of cellular junction proteins (Fig. 3). We found 1223 (short-term relapse dataset), 233 (mid/long-term relapse dataset) and 101 (non-stratified dataset) novel marker combinations with FDR Conclusion In CD patients stopping infliximab, blood proteins linked to immunoregulation or cellular junctions support the distinct profiles of short-term and mid/long-term relapsers. These proteins showed a capacity to predict the relapse.

Background Corticosteroids (CSs) can induce clinical remission of Crohn’s disease (CD), but long-term use is associated with serious side effects. In the GEMINI 2 trial, a greater proportion of patients with moderately to severely active CD treated with vedolizumab (VDZ) maintenance therapy achieved CS-free remission at week 52 compared with placebo (PBO).1 Response to VDZ is influenced by prior exposure to anti-TNF therapy. In this post hoc exploratory analysis of GEMINI 2, we investigated the impact of VDZ maintenance therapy on use of CSs stratified by prior anti-TNF therapy failure status and baseline disease activity (moderate or severe). Methods In GEMINI 2, patients who responded to VDZ induction therapy at week 6 were re-randomized to receive VDZ or PBO every 4 or 8 weeks and began a prespecified CS tapering regimen (Figure 1).1 In patients receiving CSs at baseline, we measured change in CS dose from baseline to week 52 , proportion of patients with CS dose ≤ 7.5 mg/day, and proportion of patients with ≥ 90 or ≥ 180 consecutive CS-free days at week 52. Analyses were conducted overall and stratified by prior anti-TNF therapy failure status, baseline Crohn’s Disease Activity Index (CDAI) score (moderate: ≤ 330, severe: > 330), and the composite of both measures. Results In the overall population, a greater proportion of patients treated with VDZ (67.7%) vs PBO (61.5%) had their CS dose reduced from baseline. This trend was also observed among patients with no prior anti-TNF therapy failure, with a baseline CDAI score ≤ 330, and with no prior anti-TNF therapy failure and a baseline CDAI score ≤ 330 (Figure 2). Similarly, numerically higher proportions of patients treated with VDZ vs PBO received a CS dose of ≤ 7.5 mg/day in the overall population and in subgroups with no prior anti-TNF therapy failure, with baseline CDAI score ≤ 330, and with no prior anti-TNF therapy failure and a baseline CDAI score ≤ 330 (Figure 3). Overall, 35.2% and 32.7% of patients receiving VDZ had ≥ 90 and ≥ 180 consecutive CS-free days, respectively, compared with 28.0% and 22.0% of those receiving PBO. The proportion of patients with ≥ 180 consecutive CS-free days was numerically higher for the VDZ group vs the PBO group, regardless of prior anti-TNF therapy failure status or baseline CDAI score. Conclusion VDZ maintenance therapy was associated with more successful CS withdrawal than PBO, particularly in patients with no prior anti-TNF therapy failure and moderate disease activity. Interpretation of these results is limited by the exploratory nature of the analyses, small sample sizes and different initiation weeks for CS tapering per patient. Reference

Background Previous retrospective studies have demonstrated that patients with inflammatory bowel disease (IBD) exposed to anti-TNF and/or immunomodulators (IMM) following a diagnosis of cancer were not at an increased risk of new or recurrent cancer compared with those unexposed to these agents. Prospective studies are lacking and little is known about cancer risk with ustekinumab and vedolizumab. The SAPPHIRE Registry was developed to prospectively examine whether patients with IBD and a history of cancer subsequently exposed to immunosuppressive IBD therapies are at greater risk of new or recurrent cancer compared with those not exposed to immunosuppression. Methods We are longitudinally following patients with IBD and a histologically confirmed first cancer within the last five years from 8 centres affiliated with the New York Crohn’s and Colitis Organization (NYCCO) between 2017 and 2019. Patients receiving chemotherapy or radiation at enrolment, a first cancer more than 5 years prior to study entry, or recurrent cancer within the last 5 years are excluded. Cancers are categorised into luminal gastrointestinal (GI), hematologic, dermatologic, and other solid malignancies. Our primary outcome is the development of new or recurrent cancer stratified by immunosuppression exposure. Results We identified 170 patients with IBD and a history of a first cancer within the last 5 years (Table 1). The average age at IBD diagnosis was 36 years; average age at cancer diagnosis was 54 years. Patients were 49% male, 91% white, and 39% former smokers. Prior cancers were solid (78; 46%), GI (23; 14%), dermatologic (59; 35%), and hematologic (12; 7%) malignancies. Following a diagnosis of cancer, patients were exposed to IMM (38; 22%), anti-TNF (45; 26%), vedolizumab (41; 23%), ustekinumab (17; 10%), or no immunosuppression (33; 19%; Table 2). During follow-up, 13 (8%) patients developed 14 subsequent cancers (6 new, 8 recurrent) comprising 6 (43%) solid, 1 (7%) gastrointestinal, and 7 (50%) dermatologic malignancies. Compared to patients not exposed to immunosuppression, exposure to an IMM (RR 4.94, 95% CI 0.50, 48.6) or a biologic (RR 3.53, 95% CI 0.71, 17.5) was not associated with an increased risk of new or recurrent cancer. However, exposure to combination therapy with an IMM and a biologic (RR 6.81, 95% CI 1.40, 33.2) was associated with an increased risk in this small sample. Conclusion In this ongoing prospective study, exposure to immunosuppressive IBD monotherapies in patients with IBD and a recent history of cancer has so far conferred no increased risk of new or recurrent cancer. Continued enrolment will enable a more refined estimate of the safety of combination therapies.

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

Background The optimal endoscopic target in early Crohn’s disease (CD) that limits long-term disease complications is unknown. Methods We analysed medical records from patients who had follow-up data since the end of CALM. Patients with Crohn’s disease endoscopic index of severity (CDEIS) scores at the end of CALM were included. The primary outcome was a composite of major adverse outcomes reflecting CD progression: new internal fistula/abscess, stricture, perianal fistula/abscess, CD hospitalisation, or CD surgery since the end of CALM. We compared median CDEIS and per cent improvement from baseline CDEIS. Youden index analysis was used to identify optimal CDEIS cut-off score associated with CD progression. Kaplan–Meier and Cox regression methods were used to compare rates of progression by different CDEIS targets. Multivariable models were adjusted for age, prior surgery, and stricturing behaviour. Results 110 patients with median age 28 (IQR 22–38) years, disease duration 0.2 (0.1–0.5) years, and median follow up of 3.1 (1.9–4.4) years were included. Eleven per cent had a history of stricture, 5.5% history of surgery, and 52% were originally in the tight control arm of the CALM study. Median CDEIS score at end of CALM was 3 (0–5.4) and 32 (29%) patients had disease progression. Baseline median CDEIS score was similar between those with and without progression [10.9 (7.5–15.5) vs. 11.9 (8–17.5)]. Median CDEIS score at the end of CALM was higher among those with progression [1.3 (0–5.1) vs. 4.9 (3–9.1), p < 0.001)]. Patients within higher quartiles of CDEIS score had higher rates of progression over time (Figure 1). Patients without disease progression had a greater median decrease in CDEIS score from baseline to end of CALM [90% (60–100%) vs. 50% (30–80%), p < 0.001]. The optimal CDEIS score cut-off was 2 with sensitivity 84%, specificity 60% and NPV 90% for progression. Patients with CDEIS ≤ 2 had less progression over time compared with patients with > 50% improvement from baseline CDEIS (not reaching CDEIS ≤ 2) and those not meeting either endpoint (Figure 2). On adjusted analysis, CDEIS score ≤ 2 was associated with a decreased risk of progression (aHR 0.23, 95% CI 0.09–0.56). Conclusion In early CD, a CDEIS score ≤ 2 is optimal cut-off associated with a lower risk of disease progression.

Background Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Safety and efficacy of tofacitinib in patients with UC were evaluated in two Phase 3 induction studies (OCTAVE Induction 1 and 2; NCT01465763, NCT01458951), a 52-week, Phase 3 maintenance study (OCTAVE Sustain, NCT01458574) [1], and an ongoing, open-label, long-term extension study (NCT01470612) [2]. We evaluated the impact of disease duration on tofacitinib efficacy in the OCTAVE trials. Methods Patients received tofacitinib 10 mg twice daily (BID) or placebo in OCTAVE Induction 1 and 2, and responders at Week 8 were eligible to receive tofacitinib 5 or 10 mg BID or placebo during OCTAVE Sustain (final efficacy assessment at Week 52). Non-responders from OCTAVE Induction 1 and 2 and completers/treatment failures from OCTAVE Sustain could enter the OLE study. In the OLE study, patients who did not show clinical response to 8 weeks of tofacitinib 10 mg BID in OCTAVE Induction 1 and 2 (induction non-responders [IndNR]) received an additional 8 weeks of tofacitinib 10 mg BID; all patients underwent endoscopy at Month 2 (data as of Sep 2018). Patients were stratified by UC disease duration (6 years) at OCTAVE Induction 1 and 2 baseline (ie prior to study treatment). Associations between disease duration category and efficacy endpoints were assessed using the Cochran-Mantel–Haenszel Chi-square test. Results Among patients who received tofacitinib 10 mg BID in OCTAVE Induction 1 and 2, remission and mucosal healing rates at Week 8 were numerically higher in those with shorter disease duration than those with longer disease duration, but associations were not statistically significant (Table). Clinical response rates were similar across disease duration categories. At Week 52 of OCTAVE sustain, remission and mucosal healing rates were highest in patients with the shortest disease duration ( Conclusion In general, disease duration did not impact tofacitinib efficacy. Patients diagnosed with UC References

Background Upadacitinib (UPA), an oral, reversible JAK inhibitor engineered for increased selectivity for JAK1 over JAK2, JAK3, or tyrosine kinase 2 (TYK2), 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 trials, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026). This analysis evaluated the efficacy of UPA on early symptomatic improvement for the first 14 days, using pooled data from U-ACHIEVE Induction and U-ACCOMPLISH. Methods U-ACHIEVE and U-ACCOMPLISH were multicentre, double-blind, PBO-controlled trials that enrolled patients who have had moderately to severely UC with an Adapted Mayo Score of 5 to 9 points and centrally reviewed endoscopy subscore of 2 to 3. A total of 998 patients were randomized to receive UPA 45mg once daily (QD) (n=658) or PBO (n=328) for 8 weeks (wks) in a 2:1 ratio. First dose of study drug was administered on Day 0. Improvement in symptoms including stool frequency subscore (SFS), rectal bleeding subscore (RBS), abdominal pain, and bowel urgency were analysed from daily symptom diary data. Multivariate regression analysis was used to determine if early changes in UC symptoms could be used to evaluate a potential correlation with patients’ likelihood of achieving clinical response or clinical remission per Adapted Mayo score at the end of induction. Results Baseline characteristics were similar between both treatment groups. Patients treated with UPA 45 mg QD experienced significant improvement in daily symptoms, with significantly more subjects achieving SFS≤1 (p Conclusion UPA 45 mg QD significantly improved UC symptoms as early as day 1, providing patients with rapid symptom relief. Patients who achieved early symptom improvement were more likely to attain clinical remission or clinical response at week 8. [Clinicaltrials.gov, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026)]

Background According to the hygiene hypothesis, exposure to parasites may promote immune tolerance and protect against inflammatory bowel disease (IBD). The early life period, considered to extend from prenatal life to up to 5 years of age, is important towards immune maturation; exposures during this period are especially relevant towards IBD risk. We examined the impact of exposure to mebendazole, a broad-spectrum anthelminthic agent, during childhood and adolescence, on the risk of IBD, ulcerative colitis (UC) and Crohn’s disease (CD). Methods We used prospectively collected historical data of all individuals born in Denmark between 1995 and 2018 from national registers to conduct a population-based cohort study. Using the National Prescription Register, we identified mebendazole exposure at Results Of 1,520,290 individuals in the cohort, 615,794 had childhood mebendazole exposure. 1,555 and 1,499 individuals were subsequently diagnosed with pediatric- and adult-onset IBD, respectively. On multivariable analysis, mebendazole exposure at Table: Crude and adjusted estimates for outcome with exposure to mebendazole in early life ( Figure: Cumulative incidence curves for (a) ulcerative colitis and (b) Crohn’s disease Conclusion Early life, but not later in childhood or adolescence, mebendazole exposure is associated with increase in the risk of adult-onset UC. Mebendazole exposure does not impact pediatric-onset IBD risk or CD risk. These findings emphasize the importance of early-life exposures in shaping the risk of IBD later in life, may indicate differences between UC and CD risk factors and pathways, and may call for re-evaluation of risks and benefits of large-scale helminth eradication programs.

Background Ozanimod was approved by the FDA to treat patients (pts) with moderately to severely active Ulcerative Colitis (UC) based on the results from the 52-week (wk) phase 3 True North (TN) study. We sought to evaluate long-term efficacy and safety of ozanimod. Methods We examined data from an interim analysis of pts in the TN parent study who entered the ongoing TN open-label extension (OLE). Pts entered the TN OLE from the phase 3 TN study if they were non-responders at the end of induction, lost response during maintenance, or completed maintenance treatment, or from the phase 2 Touchstone OLE if they remained at study closure and received once-daily oral ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg). Clinical remission, clinical response, endoscopic improvement, and corticosteroid (CS)-free remission were evaluated at Wks 46, 94, and 142 in the TN OLE for all pts who entered the OLE from the TN parent study, and in the subset of pts in clinical response at the OLE entry. The data were analysed in the intent-to-treat population using observed cases (OC), which used the number of pts remaining in the study at the corresponding time point, and non-responder imputation (NRI), which used the number of pts remaining in the study at the corresponding time point and those who withdrew before the time point but would have reached the time point if they had stayed. Treatment-emergent adverse events were evaluated from the pooled phase 2 and phase 3 UC studies. Results A total of 823 pts from TN entered the TN OLE; as of the cut-off date (Sept 30, 2020), 64% completed Wk 46, 34% completed Wk 94, and 14% completed Wk 142 of the OLE. The most common reason for discontinuation was lack of efficacy (21%). Baseline demographics were similar as in the TN study. A total of 261 pts were in clinical response at the time of OLE entry. OC analyses showed that the percentage of pts achieving clinical remission, clinical response, endoscopic improvement, and CS-free remission was maintained over time (Table). Efficacy in the responders was higher compared to the total population and was comparable within the endpoints at Wks 46 and 94. Using the more conservative NRI analysis, the proportion of pts achieving each endpoint was lower than in the OC; however, after 94 wks of OLE treatment, 34% of all pts and 55% of the responders still maintained clinical response. No new safety signals were seen with longer-term ozanimod use in the 1158 pts in the pooled population. Conclusion UC pts from the phase 3 TN study demonstrated maintenance of response with long-term ozanimod treatment. These data reflect approximately 2 years of additional ozanimod treatment, with no new safety signals identified.

Background EIMs are common in patients with UC and are associated with impaired quality of life. This analysis evaluated the impact of treatment with the selective Janus kinase 1 inhibitor UPA on EIMs in patients with moderate-to-severe UC. Methods Data were included from two induction studies (U-ACHIEVE Induction [NCT02819635] and U-ACCOMPLISH [NCT03653026]) and a maintenance study (U-ACHIEVE Maintenance). Patients with moderate-to-severe UC were randomised 2:1 to 8 weeks’ induction treatment with UPA 45 mg once daily (QD) or placebo. Patients with a clinical response to induction were re-randomised (1:1:1) to 52 weeks’ maintenance treatment with UPA 15 mg or 30 mg QD, or placebo. The presence of EIMs (peripheral arthropathy, axial arthropathy, episcleritis, uveitis, iritis, erythema nodosum, pyoderma gangrenosum, Sweet’s syndrome, oral aphthous ulcers, primary sclerosing cholangitis, autoimmune hepatitis, venous thromboembolism, chronic obstructive pulmonary disease, bronchiectasis, nephrolithiasis and anaemia) was captured in the EIM form at the start of induction (baseline) and at every visit up to Week 52. The induction study results were pooled for analysis. Results At baseline, 25.0% and 26.5% of patients in the UPA 45 mg QD and placebo induction groups had ≥1 EIM, while 24.3%, 26.6% and 24.8% of patients randomised to maintenance treatment with UPA 15 mg QD, UPA 30 mg QD or placebo, respectively, had ≥1 EIM (Table 1). The most common EIMs at baseline were anaemia, peripheral arthropathy and axial arthropathy; all other EIMs were reported in Conclusion UPA treatment is effective in resolving EIMs in patients with UC. EIM symptom resolution was improved versus placebo following induction treatment with UPA 45 mg and after maintenance treatment with UPA 15 or 30 mg, with the 30 mg dose providing statistically significant improvements versus placebo.

Background Control of endoscopic inflammation like endoscopic remission is an important treatment target in Crohn’s disease (CD), as suggested in the STRIDE II guidelines. This study evaluated the relationship of early improvement in endoscopic outcomes on hospitalisation and surgery rates at, 52 wks in patients with CD treated with risankizumab (RZB). Methods This post-hoc analysis uses data from three double-blind, randomised Phase, 3 induction (ADVANCE and MOTIVATE) and maintenance (FORTIFY) trials evaluating the efficacy and safety of RZB in patients with moderate to severe CD. Patients who responded to, 12-wk induction therapy with RZB IV (600 mg or, 1200mg) in ADVANCE or MOTIVATE and received up to, 52 wks of maintenance therapy with RZB SC (180 mg or, 360 mg) in FORTIFY were analysed. Incidence rates (events/100 person-years) of CD-related hospitalisation, CD-related surgery (surgical procedures due to adverse events or complications related to CD), all-cause hospitalisation, and all-cause surgery were evaluated from the beginning of maintenance to wk, 52 and compared between patients who achieved endoscopic outcomes at end of induction (wk, 12) and those who did not. Endoscopic response, endoscopic remission and ulcer-free endoscopy (absence of ulceration) were defined using the Simple Endoscopic Score for CD (SES-CD) (Figure, 1–3), as scored by a blinded central reviewer. Results A total of, 298 patients were included in the analyses. Patients who achieved endoscopic response (n=121) at wk, 12 had a significantly reduced incidence rate of CD-related hospitalisation, CD-related surgery, and all-cause hospitalisation by wk, 52 compared to those who did not achieve an endoscopic response (n=177) at wk, 12 (Figure, 1). Additionally, patients who achieved endoscopic remission at wk, 12 (n=83) had a significantly reduced incidence rate of CD-related hospitalisation, CD-related surgery, and all-cause hospitalisation by wk, 52, compared to those not achieving endoscopic remission at wk, 12 (n=215) (Figure, 2). Though not statistically significant, numerically lower rates of all-cause surgery were observed for patients who achieved endoscopic remission or endoscopic response at wk, 12. Significantly lower rates of CD-related hospitalisation, CD-related surgery, all-cause hospitalisation, and all-cause surgery by wk, 52 were observed among patients who achieved ulcer-free endoscopy (absence of ulceration) (n=70) vs those who did not (n=228) at wk, 12 (Figure 3). Conclusion Early improvement of endoscopic outcomes at wk, 12 is associated with significant reductions in hospitalisations and surgeries through, 52 wks for patients receiving RZB therapy.

Background Coronavirus disease 2019 (COVID-19) tends to cause mild disease in children, although severe disease occurs rarely. Children with inflammatory bowel disease (IBD) often receive immunosuppressive medications that may increase risk of infectious complications. Little is known about the severity of breakthrough infection after COVID-19 vaccination in children with IBD. We describe COVID-19 outcomes among children with IBD, including those with breakthrough infection. Methods The Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) is a database created to evaluate COVID-19 outcomes in IBD patients. We included children (age ≤18) from the SECURE-IBD database through November 17th, 2021. We used descriptive statistics to summarize demographic/disease characteristics of the study population, both overall and stratified by hospitalization status, and performed bivariate comparisons. We reported demographic and clinical details of patients requiring an intensive care unit stay and those with breakthrough infection (defined as ≥1 COVID-19 vaccination prior to infection), respectively. Results We analyzed 606 pediatric IBD COVID-19 cases from 37 countries. The most common IBD medications were tumor necrosis factor (TNF) antagonist monotherapy (48%) and sulfasalazine/mesalamine (20%). Most patients (85%) had no non-IBD comorbidities. No patients died, and 28 children (5%) were hospitalized. Factors associated with hospitalization included non-IBD comorbid conditions (43% hospitalized vs 13% not; p Conclusion We found that children with IBD have a relatively low risk of severe COVID-19 outcomes. Among children with IBD who developed COVID-19 after vaccination, the majority were on immunosuppressants and had mild disease that did not require hospitalization. These data may reassure families and providers of children with IBD during the COVID-19 pandemic and support public health recommendations for COVID-19 vaccination among eligible children with IBD.

Background Current endoscopic scoring indices such as the Simple Endoscopic Score for Crohn’s Disease (SES-CD) quantify the degree of mucosal inflammation in Crohn’s disease (CD) but lack prognostic potential. The Modified Multiplier of the Simple Endoscopic Score for Crohn’s Disease (MM-SES-CD) is an internally validated endoscopic scoring tool that quantifies the endoscopic burden of CD and can be accessed online (https://www.mcmasteribd.com/mm-ses-cd).1 This analysis aims to establish thresholds of the MM-SES-CD that classify CD endoscopic burden into inactive or very mild disease, mild, moderate, and severe disease based on the probability of achieving endoscopic remission (ER) on active therapy at one-year. Methods This post-hoc analysis included pooled data from three CD clinical trials (n=350 patients, baseline SES-CD ≥3 with confirmed ulceration). Maximum Youden Index calculations were used to determine thresholds for severity. Chi-square tests of trend were used to compare achievement of ER between severity categories, and Kaplan-Meier survival curve analysis was used to compare time to clinical remission (CR). Results Table 1 demonstrates the baseline characteristics of the 350 participants included in this analysis. MM-SES-CD severity categories were established as inactive or very mild (score Conclusion We have established numerical cut-offs of the MM-SES-CD that categorize endoscopic disease severity and are prognostic for one-year ER and CR. These cut-offs could help ensure adequate balance between study arms (e.g. in prevalence of mild or moderate endoscopic disease) and identify patients with severe endoscopic disease and low probability of achieving ER. Reference 1. Predicting endoscopic remission in Crohn’s disease by the modified multiplier SES-CD (MM-SES-CD). Gut, 2021: p. gutjnl-2020–323799.

Background IBD patients on immune-modulatory therapies are considered high-risk for SARS-CoV-2 infection. Direct comparisons of serological responses to SARS-CoV-2 infection in IBD patients across different continents and medications are lacking. We performed SARS-CoV-2 sero-surveillance of IBD patients prior to vaccination at seven large tertiary centres in Asia, Europe, and North America. Methods Clinical data and sera were collected from, 2,213 IBD patients receiving routine care at institutions in Belgium, Canada, Hong Kong, India, Japan, the United Kingdom, and the United States between, 26 May, 2020 and, 24 September, 2021 (Table, 1). Sera were taken prior to vaccination. Clinical data were collected through patient questionnaires and medical records. Antibody reactivity to the SARS-CoV-2 spike protein was assessed using the Roche SARS-CoV-2 anti-spike total antibody and/or Siemens Healthineers COV2T anti-spike total antibody assays, which showed, 99.4% concordance. Univariate analysis was performed to evaluate association between individual variables and sero-status. Results The pre-vaccination seroprevalence of antibodies to SARS-CoV-2 in IBD patient varied widely according to location from, 0% in Hong Kong to, 57.9% in New Delhi, India (p Conclusion We confirm in diverse poulations that exposure to biologics or immunomodulators, type of disease, and smoking status are associated with seroprevalence and antibody levels. We show for the first time the dominant influence of geographical location on sero-status in these patients. These observations should be considered as we look towards post-vaccination data to help stratify patients for clinical guidelines on SARS-CoV-2 vaccination.

Background Upadacitinib (UPA) is an oral, once-daily (QD), selective Janus kinase inhibitor that has demonstrated efficacy in the induction and maintenance treatment of Ulcerative Colitis (UC). This analysis aimed to assess the impact of baseline UC characteristics on clinical outcomes following UPA therapy. Methods Patients (pts) with moderately to severely active UC who had failed conventional or biological treatment were enrolled in two randomised, double-blind (DB), placebo (PBO)-controlled, Phase 3, 8-week induction studies of UPA 45 mg QD vs PBO. Pts achieving a clinical response (decrease from baseline in Adapted Mayo score ≥2 points and ≥30% from baseline, plus a decrease in rectal bleeding score [RBS] ≥1 or an absolute RBS ≤1) at Week (Wk) 8 entered a 52-week, randomised, DB, PBO-controlled, Phase 3 maintenance study, and received UPA 15 mg QD, UPA 30 mg QD, or PBO. The primary efficacy endpoint was clinical remission per Adapted Mayo score at Wk 8 (induction) and at Wk 52 (maintenance). Pre-specified (PS) and post hoc (PH) analyses were conducted by baseline disease activity (full Mayo score ≤9 or >9) (PS), extent (PS), duration (5–10, >10 years [yrs]) (PH), and high-sensitivity C-reactive protein (hs-CRP) level (≤5 or >5 mg/L) (PH). Results 988 pts were included in the induction studies, and 451 in the maintenance study. The treatment difference between UPA 45 mg QD and PBO excluded zero for all subgroups at Wk 8 (Figure 1). Wk 8 remission rates were lower for full Mayo score >9 vs ≤9, and for CRP >5 vs ≤5 mg/dL, with minimal effects of disease extent or duration. Wk 52 maintenance of remission rates were greater with UPA 15 mg and 30 mg QD vs PBO (16–44% and 30–50% difference, respectively), and with UPA 30 vs UPA 15 mg QD. This incremental benefit of the 30 mg dose was greater in pts with severely (full Mayo score >9) vs moderately active disease (Figure 2); 15 mg and 30 mg demonstrated similar efficacy in pts with Mayo score 5 mg/L. Conclusion UPA 45 mg QD is an effective induction treatment for UC, regardless of baseline disease characteristics. Both 15 and 30 mg UPA doses are effective maintenance regimens, regardless of baseline disease characteristics. However, the 30 mg dose shows a trend towards increased benefit vs 15 mg in pts with Mayo score >9 and extensive disease. This analysis suggests that while UPA 15 mg may be most appropriate for patients with UC with a low inflammatory burden (per full Mayo score and extent), the 30 mg dose may be more appropriate for those with a high one.

Background Mitigating the burden of inflammatory bowel disease (IBD) in Western countries requires understanding how its epidemiology is evolving. We conducted a temporal analysis of the epidemiology of IBD between 1995 and 2018 in the Danish nationwide cohort. Methods We used the Danish Civil Registration System (CRS) to obtain demographic information on all residents in Denmark between January 1, 1995 and December 31, 2018. We obtained information on Crohn’s disease (CD) and ulcerative colitis (UC) diagnosis from the National Patient Registry (NPR) using International Classification of Disease 8/10 codes. IBD diagnosis was defined as having at least two CD- or UC-related registrations within a two-year period and the date of the first IBD-related registration was considered as the date of diagnosis. We estimated overall and annual incidence rates and prevalence of CD and UC standardized with respect to age and sex. Results 52,407 individuals met the criteria for IBD diagnosis in the period 1995–2018, of which 17,355 (33%) were diagnosed with CD and 35,052 (67%) were diagnosed with UC. The median age at diagnosis (IQR) for CD and UC was 34 (22, 53) and 43 (29, 60) years, respectively. 9,745 (56.2%) and 18,332 (52.3%) individuals with CD and UC, respectively, were of female sex. During the study period, 1995–2018, the overall incidence rate (95% CI) rose from 9.2 (8.4, 10) per 100,000 person years (PY) to 18 (16.8, 19) per 100,000 PY for CD, corresponding to a 94.9% increase, and from 21.1 (19.9, 22.4) per 100,000 PY to 28.4 (27, 29.8) per 100,000 PY for UC, corresponding to a 34.1% increase. The incidence rates of CD and UC increased for all age groups, at different rates, highest for CD in age group 15–39 years (Figure). While CD incidence was consistently higher in women, increase in CD and UC incidence was comparable between both sexes. The prevalence of IBD also increased from 1995–2018 (225.6% and 218.4% for CD and UC, respectively) with the greatest increase in UC prevalence among individuals older than 40 years of age (248.4%). Conclusion The epidemiology of IBD has shifted in the last 20 years with a still increasing incidence of CD and UC in young adults, and a sharply increased prevalence in older age groups, especially for UC. These findings have implications towards understanding environmental shifts associated with this evolution as well as preparing for management of an aging IBD population.

Background The efficacy and safety of risankizumab (RZB) as induction and maintenance therapy for patients with moderately to severely active Crohn’s disease (CD) has been documented. Steroid-free clinical remission is an important additional treatment goal in CD. The efficacy of RZB by baseline steroid use during induction and steroid-free outcomes during maintenance was examined. Methods In ADVANCE (NCT03105128) and MOTIVATE (NCT03104413), patients with moderately to severely active CD received intravenous (IV) RZB induction therapy or placebo (PBO) for 12 weeks. Patients with clinical response to RZB were re-randomised in a 52-week maintenance study (FORTIFY; NCT03105102) to subcutaneous (SC) RZB or PBO (ie, withdrawal). Patients receiving steroids (maximum prednisone or equivalent ≤ 20 mg/day; budesonide ≤ 9 mg/day) at baseline of the induction studies maintained stable doses for the 12-week study duration. A mandatory steroid taper per protocol was initiated at the beginning of maintenance for patients receiving steroids during induction. Patients losing clinical response (per investigator assessment) after initiation of taper could have their steroid dose increased up to the induction baseline dose. This analysis included patients who received RZB 600 mg IV in ADVANCE or MOTIVATE and patients who received RZB 360 mg SC in FORTIFY. Endpoints reported included clinical remission (defined by CD Activity Index [CDAI] or stool frequency/abdominal pain score [SF/APS] criteria) at week 12 of induction by baseline steroid use, steroid-free clinical remission (CDAI or SF/APS), steroid-free endoscopic response, and steroid-free endoscopic remission at week 52 of maintenance. Steroid discontinuation rates over 52 weeks of maintenance were also assessed. Results Induction of clinical remission at week 12 with RZB 600 mg IV in ADVANCE or MOTIVATE was independent from baseline steroid use (Figure 1).Clinical remission rates (CDAI or SF/APS) at week 12 were similar for patients using steroids vs those who were not (33.8%–42.0% vs 34.9%–46.6%; Figure 1). Steroid use decreased over time in FORTIFY, with a greater proportion of patients receiving RZB 360 mg SC discontinuing steroids at week 52 vs withdrawal (PBO SC; Figure 2A). Rates of steroid-free clinical remission (P ≤ .012), steroid-free endoscopic response (P < .001), and steroid-free endoscopic remission (P < .001) were significantly higher with RZB 360 mg SC vs withdrawal (PBO SC) at week 52 of maintenance (Figure 2B–2C). Conclusion Efficacy of RZB induction therapy was independent of baseline steroid use. RZB maintenance promotes high rates of steroid-free clinical and endoscopic outcomes, demonstrating a benefit of RZB treatment in CD.