bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP53 Long-term Efficacy and Safety of Risankizumab in Patients With Moderate to Severe Crohn's Disease up to 3 Years of Treatment: Results From the FORTIFY Open-Label Long-term Extension
Authors: Ferrante M , Panaccione R , Colombel J F , Dubinsky M , Hisamatsu T , Lindsay J O , Song A , Neimark E , Zhang Y , Kligys K , Crowley J , Duan W R , D’Haens G 
Published: January 2024

Abstract

Background
The ongoing FORTIFY maintenance open-label extension (OLE) substudy evaluates the long-term efficacy and safety of risankizumab (RZB), a p19 interleukin-23 inhibitor, for treatment of moderate to severe Crohn’s disease (CD). Here, we report 2-year results of FORTIFY OLE.

Methods
The FORTIFY (NCT03105102) OLE enrolled patients (pts) who completed 52-wks maintenance dosing in the FORTIFY substudies or RZB phase 2 OLE.1,2 All pts received 180 mg subcutaneous (SC) RZB every 8 wks (Q8w), starting at wk56, except for pts who had prior rescue therapy (single 1200mg intravenous [IV] RZB dose then 360mg SC Q8w) who continued 360mg SC Q8w in the OLE. Pts with inadequate response (increased symptoms plus objective marker of inflammation) during the OLE could receive rescue therapy as described above. Pooled data from both treatment groups (RZB 180 mg & 360 mg SC) were assessed. Clinical outcomes were evaluated every 24 wks (endpoint definitions in Figure footnote). Endoscopy was performed every 96 wks. Results are reported as observed. Efficacy data for pts receiving rescue therapy in the OLE were included up to rescue initiation. Safety was assessed through the cutoff date of 05MAR2023. As this trial is ongoing, most patients have not reached the wk152 study visit. Any treatment-emergent adverse events (TEAEs) reported on or after the first dose in the OLE were analysed.

Results
As of the cutoff date, 1147 pts entered the OLE, of which 203 (17.6%) pts received rescue therapy during the OLE. Clinical response and remission rates were generally maintained with RZB from wks 56 to 152 (CD activity index [CDAI] clinical response, 85.8% to 86.5%, respectively; enhanced clinical response, 88.6% to 89.2%; CDAI clinical remission, 68.5% to 77.6%; stool frequency/abdominal pain score clinical remission, 64.4% to 71.0%) (Figure). At wks 56 and 152, respectively, rates of endoscopic response were 53.4% and 74.2%, endoscopic remission were 37.5%, and 58.9%, and ulcer-free endoscopy were 31.0% and 50.0%. There were no new trends for exposure-adjusted rates of TEAEs, and rates of adjudicated major cardiovascular adverse events, malignancies, serious infections and hepatic events remained stable with no new safety risks identified. There were no events of active tuberculosis, serious hypersensitivity, or adjudicated anaphylactic reaction. Three deaths occurred during the OLE (see Table footnote), all assessed by investigators as unrelated to study drug.

Conclusion
Pts receiving long-term RZB maintenance therapy in FORTIFY demonstrated sustained clinical and endoscopic efficacy with at least 3 years of treatment. The safety profile is consistent and supports long-term RZB treatment.
1doi: 10.1093/ecco-jcc/jjab093
2doi: 10.1016/S0140-6736(22)00466-4.
DOP63 Mortality in Pediatric-onset Immune-Mediated Inflammatory Disease – A Nationwide Study
Authors: Malham M , Jansson S , Ingels H A S , Jørgensen M H , Roed N , Wewer A V , Fox M P 
Published: January 2024

Abstract

Background
Patients with pediatric-onset immune-mediated inflammatory diseases (pIMID) show more aggressive phenotypes compared to patients diagnosed as adults. Despite this, data on mortality is extrapolated from patients diagnosed in adulthood, which might underestimate the actual risk. We aim to estimate the effect of pIMID compared to reference individuals from the general population on the long-term risk of all-cause mortality.

Methods
A population-based cohort study using the nationwide Danish health care registers. We included all patients diagnosed with pIMID in Denmark from 1980 to 2018 and matched them to up to ten reference individuals from the general population (with no recorded IMID) based on sex, age at diagnosis, and area of residence. Exposure was pIMID, defined as ICD codes indicative of autoimmune hepatitis, primary sclerosing cholangitis, Crohn’s disease, ulcerative colitis, juvenile idiopathic arthritis, system lupus erythematosus, or vasculitis registered before age 18.
The primary outcome was all-cause mortality. The secondary outcome was cause-specific mortality. Cox survival analysis was used to estimate hazard ratios (HR) and Aalen survival analysis to estimate rate differences with corresponding 95% confidence intervals (CI) adjusted for the year of diagnosis and family income.
Denmark has universal free health care, and health care data can be accessed through the nationwide health registers, continuously updated since 1980.

Results
We included 11,581 individuals diagnosed with pIMID, and 99,665 matched reference individuals, accounting for 1,371,994 person-years of follow-up. Median age at pIMID diagnosis was 12.6 years (IQR: 7.9 – 15.9). During follow-up, 152 pIMID patients and 316 reference individuals died, resulting in an all-cause mortality adjusted HR (aHR) of 3.8 (95% confidence interval [CI]: 3.1-4.7) compared to reference individuals without pIMID. This corresponded to 7.8 (95%CI: 6.1-9.5) additional deaths per 10,000 person-years. The strongest associations were found for gastrointestinal disorders (aHR 22.8 [95%CI: 9.6-64.1]), gastrointestinal cancers (aHR 19.2 [95%CI: 5.0-74.2]), and lymphoproliferative diseases (aHR 6.8 [95%CI: 2.8-16.8]). The aHR of suicide was 2.9 (95%CI: 1.6-5.0).

Conclusion
Patients diagnosed with pIMID have a four-fold increased risk of mortality when followed into adulthood. This underlines the severe disease course of pIMID and highlights the need for lifelong multidisciplinary care.
DOP70 Prevalence and severity of bowel urgency in Crohn’s Disease: Results from the Communicating Needs and Features of IBD Experience (CONFIDE) Survey
Authors: Dubinsky M C , Gibble T , Travis S , Panaccione R , Hibi T , Bleakman A P , Panni T , Kayhan C , Favia A D , Atkinson C , Schreiber S , Rubin D T 
Published: January 2024

Abstract

Background
Bowel urgency (BU) affects patients with Crohn’s disease (CD); however, its prevalence and severity are unclear. Here, data from Communicating Needs and Features of IBD Experiences (CONFIDE) study were used to understand the burden and impact of BU among patients with moderate-to-severe CD.

Methods
CONFIDE is an online, quantitative, cross-sectional survey exploring the experiences and impact of symptoms on patients with CD or ulcerative colitis in Europe (France, Germany, Italy, Spain, and UK), United States (US) and Japan. Criteria based on previous treatment, steroid use, and/or hospitalization defined moderate-to-severe CD. Patients were asked about bowel movement deferral time with response options ranging from able to wait ≥15 minutes (mins) to sometimes unable to make it to the bathroom in time. Patients currently experiencing BU (in last month) rated BU severity in the last 3 days using the Urgency Numeric Rating Scale (NRS, 0-10), a content-validated patient-reported instrument. CD data from Europe and US are presented here using descriptive statistics.

Results
Surveys were completed by 547 European (male [M]=55.4%, mean age 38 years) and 215 US (M=54.9%, mean age 40.9 years) patients with CD. Current BU (over the past month) was reported by 38% of patients in Europe and 42.3% in US. More than one-third of all patients in both Europe and US reported that over the last 3 days, they needed to get to the bathroom within 5 mins, and 1.8% European and 2.8% US patients were sometimes unable to make it to the bathroom in time. Among patients who reported currently experiencing BU, 46% reported the need to get to the bathroom within 5 mins and 3% reported sometimes being unable to make it to the bathroom in time in both Europe and US. Shorter deferral times were reported by those with higher mean Urgency NRS scores (Table). Mean (SD) Urgency NRS scores in patients with a deferral time &lt;5 mins vs those with a deferral time &gt;5 mins were 7.0 (1.7) vs 6.5 (2.1) among European and 7.3 (1.5) vs 6.7 (1.9) among the US patients. Most European and US patients reported experiencing BU, BU-related accidents, and/or wearing diaper/pad/other protection due to fear/anticipation of BU-related accidents at least once a month in past 3 months (Figure).

Conclusion
Patients with moderate-to-severe CD reported similar experiences of BU in the Europe and US, with most patients reporting currently experiencing BU and wearing diaper/pad/protection due to fear of BU-related accidents at least once a month. Patients currently experiencing BU had short deferral times, often having to reach the bathroom in ≤5 mins. Given the substantial burden and impact, BU should be considered when assessing patients with CD.
P016 Reduction of mucosal (active) eosinophils, B cells and T cells after vedolizumab therapy in patients with ulcerative colitis
Authors: Jacobs I , Cremer J , Ferrante M , Sabino J , Vermeire S , Breynaert C , Vanuytsel T , Verstockt B 
Published: January 2024

Abstract

Background
Patients with ulcerative colitis (UC) are often treated with biological therapies or small molecules. Knowledge about the impact of these therapies on the intestinal and peripheral blood immune cell composition is scarce. Therefore, we investigated how advanced therapies modulate immune cell distribution in UC patients.

Methods
We included 30 UC patients (53% male, median age 42 years) who started a biological or small molecule. Before the first drug administration, mucosal colonic biopsies and a peripheral blood sample were obtained. At the end of induction, colonic biopsies and peripheral blood were sampled again. Patients starting adalimumab (n=2), infliximab (n=3), vedolizumab (n=11), ustekinumab (n=6), ozanimod (n=2) and the JAK inhibitors filgotinib (n=3) and tofacitinib (n=3) were included. Endoscopic improvement was defined as a Mayo endoscopic subscore of 0-1 at the end of induction. From the biopsies, a single-cell suspension was made. Intestinal and circulating immune cells were characterized via flow cytometry. Statistical analysis was performed using a paired t-test.

Results
Independent of the mechanism of action (MOA), patients responding to therapy showed a decrease of colonic granulocytes (neutrophils (p&lt;0.0001) (Figure 1A), basophils (p&lt;0.0001) (Figure 1B) and eosinophils (p=0.008) (Figure 1C)), active eosinophils (p=0.002) (Figure 1D)), B cells (p=0.05) (Figure 1E), regulatory T cells (p&lt;0.0001) (Figure 1F) and T helper (Th) 2 cells (p=0.02) (Figure 1G), balanced with an increase of Th1 cells (p=0.03) (Figure 1H). In peripheral blood, eosinophils increased in patients not responding to therapy (p=0.05) (Figure 1I). Furthermore, we observed that only patients starting vedolizumab (n=11) showed a decrease in colonic eosinophils (p=0.02) (Figure 1J), active eosinophils (p=0.002) (Figure 1K), B cells (p=0.03) (Figure 1L) and T cells (p=0.004) (Figure 1M). Considering only non-vedolizumab patients (n=19), we did not observe this effect.

Conclusion
UC patients responding to advanced therapies showed a different intestinal immune cell distribution compared to non-responders, regardless of MOA. Vedolizumab therapy furthermore decreased several mucosal immune cell subsets that migrate to the gut through α4β7-MAdCAM-1 binding. While the effect of vedolizumab on B cells and T cells was previously described, we have now potentially identified an additional eosinophil-reducing effect in the colon.
P028 A pathogenic role of activated mucosal-associated invariant T cells in an animal model of Inflammatory Bowel Disease
Authors: Yasutomi Y , Chiba A , Haga K , Murayama G , Makiyama A , Kuga T , Nagahara A , Nagaishi T , Miyake S 
Published: January 2024

Abstract

Background
It is known that the mucosal-associated invariant T (MAIT) cells are the innate-like T cells that are restricted by the major histocompatibility complex-related molecule 1 (MR1), and that these cells express a semi-invariant T cell receptor. We have previously reported that the activation status of the circulating MAIT cells in patients with Ulcerative Colitis (UC) is associated with disease activity, and these cells infiltrate the inflamed colonic mucosa. These findings imply that MAIT cells are involved in the pathogenesis of Inflammatory Bowel Disease (IBD). However, the role of MAIT cells in the setting of IBD has not been revealed. Therefore, we investigated the role of MAIT cells in an animal model of UC.

Methods
To this end, we utilized MR1 deficient mice (MR1-/-), which lack MAIT cells, and isobutyl 6-formyl pterin (i6-FP), which is a synthetic antagonistic MR1 ligand. MR1-/- on the C57BL/6 background, their littermate wild-type controls, and C57BL/6 mice were sensitized by rectal administration of oxazolone to induce colitis. These were then administered an oral i6-FP. Splenocytes (SPL) and colonic lamina propria lymphocytes (LPL) were isolated from mice receiving i6-FP to measure cytokine production. MR1-/-, i6-FP-treated mice and their controls were orally administered FITC-dextran to analyze intestinal permeability. The peripheral blood mononuclear cells (PBMC) from the patients with UC were also isolated to study the effect of i6-FP on cytokine production by MAIT cells.

Results
MR1 deficiency or i6-FP treatment resulted in reduced severity of oxazolone-induced colitis. Mice treated with i6-FP resulted in reduced MAIT cell production of pro-inflammatory cytokines such as IFN-g and TNF in both SPL and colonic LPL. Similar results were also observed in PBMC isolated from the patients with UC when incubated with i6-FP. Although MR1 deficiency resulted in increased intestinal permeability, i6-FP administration did not affect gut integrity in mice.

Conclusion
The current studies indicate that MAIT cells have a pathogenic role in colitis and suppressing activation of these cells may reduce the severity of colitis without affecting gut integrity. Thus, MAIT cells may be potential therapeutic targets for IBD including UC.
P048 Identification of IL36RN missense mutations in Crohn’s disease patients as a potentially new drug target for treating rare patients with over-activation of the IL36 signaling cascade
Authors: Hecker J , Saurenbach J , Letizia M ,   T. TRR241 IBDome Consortium, Löscher B S , Franke A , Koop K , Neufert C , Schütz A , Siegmund B , Weidinger C 
Published: January 2024

Abstract

Background
The interleukin 36 (IL-36) family includes the agonists IL-36α, IL-36β, IL-36γ, which activate the NF-κB pathway and the natural antagonist IL-36RA, which inhibits IL-36 signaling. While missense mutations in the gene encoding IL-36RA (IL36RN) are associated with severe skin inflammation, their role in Crohn’s disease (CD) is currently unknown. Therefore, we here investigated if IL36RN mutations contribute to inflammation in CD and whether IL-36 signaling might represent a potential drug target for personalized therapy.

Methods
Mutations in IL36RN were identified by whole exome sequencing (WES) followed by targeted Sanger sequencing. Peripheral blood mononuclear cells (PBMCs) of affected patients were analyzed by mass cytometry and serum cytokines were measured by ELISA. Identified IL36RN mutations were characterized by overexpression experiments and functional assays. Clinical and molecular responses of one IL-36RN mutant patient to combined treatment with spesolimab and certolizumab pegol was assessed by fecal calprotectin, endoscopy, RNA sequencing and mass cytometry at week 0 and 12 of treatment.

Results
In a cohort of 47 ulcerative colitis patients, 177 CD patients and 34 healthy controls, we identified 3 CD patients with heterozygous missense mutations in IL36RN (IL-36RA S113L, IL-36RA P76L and IL-36RA L133I). In the patient carrying the IL-36RA S113L variant, we detected elevated serum levels of IL-18 and IL-23, as well as an increased frequency of TH17 cells in PBMCs, suggesting an overactivation of the IL-36 pathway. Overexpression experiments showed that IL-36RA S113L causes decreased expression of IL-36RA, resulting in increased IL-36 signaling. The patient was therefore treated with 1200 mg of the IL-36R blocking antibody spesolimab every 4 weeks and 200 mg of certolizumab pegol biweekly on the basis of an Out Of Scope request. This approach resulted in reduced intestinal inflammation and a reduction in the frequency of pro-inflammatory myeloid cells in PBMCs.

Conclusion
In this study, we show that pathogenic IL36RN mutations are present in a subset of CD patients and that blocking IL-36 signaling may represent a personalized therapeutic approach for this rare subset of patients in whom conventional biologic therapies have failed.

Disclaimer
Boehringer Ingelheim was given the opportunity to review the abstract for medical and scientific accuracy as well as intellectual property considerations in relation to the potential mention of BI substances. Boehringer Ingelheim had no role in the design, analysis or interpretation of the results in this study. Spesolimab was made available on the basis of an out of scope request. Boehringer Ingelheim was given the opportunity to review this abstract as a courtesy.
P144 Modulation of Immunometabolism via NLRX1 or PLXDC2: Novel Bimodal Mechanisms for the Treatment of Inflammatory Bowel Diseases
Authors: Danese S , Colombel J F , Rieder F , Peyrin-Biroulet L , Siegmund B , Vermeire S , Dubinsky M , Schreiber S , Yarur A , Panaccione R , Feagan B , Mosig R , Cataldi F , Verstockt B 
Published: January 2024

Abstract

Background
Immunometabolism exerts a bimodal action at the interface of extracellular immune response and intracellular metabolism. It controls both intracellular processes and extracellular inflammatory responses by regulating both cellular energy supply & demands, factors that determine how a cell responds to the extracellular signals. Hence, immunometabolic pathways represent an attractive target as a gate of entry & checkpoint for the inflammatory cascade. Nucleotide-binding oligomerization domain, Leucine Rich repeat containing X1 (NLRX1) & PLeXin Domain-Containing protein 2 (PLXDC2) have been identified in immunometabolic pathways for multiple cell types in immune mediated inflammatory diseases (IMIDs) and inflammatory bowel diseases (IBD)2,3. The goal of this analysis was to compare these two key immunometabolic pathways.

Methods
For both programs, in vitro murine T cell & macrophage differentiation & in vivo mouse dextran sodium sulfate (DSS) colitis models, gene expression, metabolic profiles & cytokine expression were assessed.

Results
NX-13, a novel NLRX1 agonist, resulted in regulation of cellular metabolism: activation of mitochondrial genes such as mt-nd3 & odgh, and concomitant down-regulation of glucose uptake by murine T cells (Fig1A). Simultaneously, NLRX1 stabilization by NX-13 increased antioxidant enzyme expression & reduced reactive oxygen species in T cells. NX-13 specifically reduced effector T cell differentiation (Fig1B) & inflammatory cytokine expression, while Treg differentiation was increased. Ultimately, these bimodal effects converge to dampened colitis severity scores in acute DSS colitis (Fig1C). PLXDC2 activation by LABP-69 directly reduced glycolysis, reflected by decreased extracellular acidification & oxygen consumption in bone marrow-derived macrophages (BMDM) stimulated with lipopolysaccharide (LPS, Fig1D). LABP-69 also reduced superoxide levels in BMDM. Of note, PLXDC2 activation downregulated cellular expression of the inflammatory cytokines TNFα & IFNγ by T cells (Fig1E). The PLXDC2 agonist PX-04 decreased inflammation in acute DSS colitis in mice as shown by disease activity score (Fig1F).

Conclusion
Agents targeting immunometabolism demonstrate a novel, innovative concept with potential therapeutic applicability in IBD & other IMID. NLRX1 & PLXDC2 represent distinct pathways that modulate the intracellular metabolic state simultaneously with extracellular inflammation and hence can be targeted to break the inflammatory cascade to stop chronic inflammation. These bimodal MOAs will be studied further to understand how they may synergistically address multiple aspects of chronic immune diseases such as IBD.
1Chi Cell Mol Immunol (19)
2Leber et al. J Immunol 203(12)
3Tubau-Juni et al. J Immunol 206(Supp)
P196 Pregnancy and perinatal outcomes of Inflammatory Bowel Disease mothers in Taiwan - a nationwide health and welfare databases analysis
Authors: Wu H Y , Chen C N , Weng M T , Huang C B , Tsao P N , Wei S C 
Published: January 2024

Abstract

Background
The incidence of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), has exhibited a consistent rise in recent years across Asia and Taiwan. Existing literature suggests that women with IBD may experience suboptimal perinatal outcomes. However, the specific relationship between IBD in pregnant Taiwanese women and the subsequent health outcomes of their newborns remains unclear. This study aims to meticulously examine the association between maternal IBD and perinatal outcomes using extensive and representative health databases in Taiwan.

Methods
We utilized four large national representative health and welfare databases: 1) Maternal and Child Health Database, 2) Birth Certificate Database, 3) National Health Insurance Database, and 4) Catastrophic Illness Database. Data spanning from 2004 to 2018 were linked using encrypted personal IDs to establish a birth cohort during this period. Mothers identified with a registered IBD diagnosis (CD: ICD 9=555, ICD 10= K50.00-K50.919; UC: ICD 9=556.0-556.6 and 556.8-556.9, ICD 10= K51.00-K51.919) in the Catastrophic Illness Database were defined as cases, with a comparison group of healthy pregnant women matched 1:10 in the same birth year and maternal age. Statistical analyses were done by chi-square tests and conditional logistic regression models.

Results
Among the 3,059,647 births between 2004 and 2018, 146 newborns (126 UC; 20 CD) were born by mothers with a registered IBD diagnosis (Figure 1). No statistically significant differences were observed in stillbirth, preterm birth, cesarean delivery, low birth weight, small-for-gestational-age (SGA), large-for-gestational-age (LGA), and low Apgar scores when compared to the 1,460 matched healthy mothers (Table 1). The only significant difference was observed in the incidence of hypertensive disorders of pregnancy, with a lower prevalence in the IBD group compared to the control group (4.1% vs. 13.6%; p=0.001). Multivariate conditional logistic regression analysis disclosed no significant differences in the aforementioned perinatal outcomes. Subgroup analysis demonstrated that no difference was noted between the CD and UC groups.

Conclusion
Through this comprehensive analysis of long-term health and welfare databases in Taiwan, we found comparable perinatal outcomes between women with IBD and matched healthy women. The birth outcomes are also improved compared with previous studies. This may be associated with advancements in medical management for IBD in recent years. Further research is needed to explore the long-term neurodevelopmental outcomes of these newborns.