Abstract Background Differentiation of bowel wall changes between ischemia and other causes in CT imaging can prove challenging, particularly in colon wall. Therefore, measurement of relative colon wall attenuation and contrast uptake were evaluated for aiding in diagnosis of colon ischemia. Methods CTs with inquiry for bowel ischemia were retrospectively identified. Cases involving colon ischemia or colon wall changes of other etiologies were included. Three regions of interest (ROIs) were placed in representative areas of colon wall with and without evident changes, in arterial and venous phase images, respectively. Means of the ROIs were used to calculate the relative bowel enhancement between affected and unaffected wall in each contrast phase, as well as the contrast uptake of the wall between phases. Relative enhancement and contrast uptake were compared between patients with and without ischemia. A subset of cases was reanalyzed for intra- and inter-reader comparison. Results 31 patients with and 56 patients without ischemia were included. Relative enhancement of affected to unaffected colon wall was -51.2% in arterial phase and -44.6% in venous phase images for patients with ischemia. Relative enhancement was significantly higher in patients without ischemia at -0.5% in both phases ( p < 0.001). There was no significant difference in contrast uptake of affected bowel (40.6% vs. 39.8% respectively, p = 0.67). ROC curves revealed a maximum Youden-Index at a cut-off of -37.4% (AUC: 0.818) in arterial phase to differentiate between groups. Intra-reader comparison showed a good, and inter-reader a moderate, correlation in a subset. Conclusions Objective measurement of relative colon wall attenuation between affected and unaffected areas can be an additional imaging feature to aid in identifying ischemic colon.

Abstract Background Inflammatory bowel disease (IBD) is a chronic intestinal disorder characterized by relapse and remission. Dysregulated cytokine networks and excessive immune activation drive intestinal inflammation. Therapies targeting cytokines (e.g., TNF, IL-12/23) and immune cell trafficking (e.g., integrin inhibitors) have been effective. However, the impact of anti-integrin (vedolizumab) and anti-IL-12/23 (ustekinumab) therapies on systemic inflammation is poorly understood. This study compares serum proteome profiles of patients treated with vedolizumab or ustekinumab to elucidate their distinct effects on inflammatory pathways. Methods This study included patients with Crohn’s disease (CD), ulcerative colitis (UC), and age- and sex-matched healthy donors (HD), who received either ustekinumab or vedolizumab treatment. The ustekinumab cohort comprised 23 CD and 10 UC patients, while the vedolizumab cohort included 7 CD and 27 UC patients. Serum samples were collected from ustekinumab-treated patients at baseline (week 0) and 8 weeks post-treatment, and from vedolizumab-treated patients at baseline (week 0) and 6 weeks post-treatment. Additionally, serum samples were collected from 32 healthy donors. Proteomic analysis was performed using the Olink Inflammation Panel, measuring 92 inflammation-related proteins. Differential protein expression analysis was conducted to compare baseline and post-treatment samples within each cohort. Results Serum proteomic analysis using the Olink Inflammation panel revealed significant alterations in the levels of 15 proteins in IBD patients compared to healthy controls. Pro-inflammatory markers, including 4E-BP1, SIRT2 and TNF were significantly upregulated, indicating immune activation in IBD. Conversely, anti-inflammatory regulators, such as LIF-R and SCF, were significantly downregulated. Ustekinumab treatment led to upregulation of IL-12B and downregulation of 4E-BP1, SIRT2. Notably, IL-12B was upregulated in both CD and UC, while 4E-BP1 and SIRT2 were downregulated in CD (week 8 vs week 0). Conversely, vedolizumab treatment induced robust proteomic changes over time. Between week 0 and week 6, majority of proteins showed significant differential expression, more than the differences observed between IBD and HD groups. Conclusion Serum proteomic profiles of IBD patients differ from healthy donors. Ustekinumab induced minimal serum changes, indicating a limited systemic effect, while vedolizumab led to substantial proteomic shifts, suggesting broader modulation of inflammation. These distinct effects highlight the differing mechanisms of ustekinumab and vedolizumab on systemic inflammation in IBD, prompting further investigation to optimize therapeutic strategies.

Abstract Background The IL-36 signaling pathway has recently been identified as a key regulator of intestinal homeostasis and inflammation. However, the role of mutations in the IL-36R signaling pathway in the pathogenesis of inflammatory bowel disease remains unclear. Methods Mutations in the IL-36 receptor antagonist (IL-36RA, IL36RN) were identified in a cohort of 86 ulcerative colitis patients, 244 Crohn’s disease patients and 45 non-inflamed controls by whole exome sequencing followed by targeted Sanger sequencing. In-depth immune cell profiling of one IL36RN-mutated patient was performed using mass cytometry and multiplexed immunoassays. Overexpression experiments and functional assays characterized identified IL36RN mutations. Clinical and molecular responses of one IL36RN-mutated patient to a combined treatment with the IL-36R-blocking antibody spesolimab and the TNF-blocker certolizumab-pegol were assessed by fecal calprotectin, endoscopy, multiplexed immunoassays and mass cytometry. Results We identified four Crohn’s disease patients with heterozygous missense mutations in IL36RN. Experimental overexpression and functional assays demonstrated that two identified mutations resulted in a reduced protein expression of IL-36RA. In-depth immune profiling of one IL36RN-mutated patient revealed an increased response of PBMCs to IL-36 stimulation and elevated serum levels of IL-36-regulated cytokines. Administration of the IL-36R-blocking antibody spesolimab in combination with certolizumab-pegol over a period of 22 weeks to this patient resulted in a reduction of intestinal inflammation and alterations in immune cell composition and function. Conclusion Our findings indicate that pathogenic IL36RN mutations may contribute to the pathogenesis of Crohn’s disease in a subset of patients and that inhibiting IL-36 signaling in combination with TNF-blockade could offer a personalized therapeutic approach for these patients. Disclaimer Spesolimab was made available based on an out-of-scope request. Boehringer Ingelheim was given the opportunity to review this abstract as a courtesy. Boehringer Ingelheim had no role in the design, analysis or interpretation of the results in this study.

Ulcerative colitis (UC) is classified as a chronic inflammatory bowel disease (IBD) and can present in various degrees of severity. In addition to mild courses of the disease, such as uncomplicated proctitis, which can often be successfully treated with topical 5-ASA formulations, complicated courses can be observed, which can sometimes be life-threatening. Affected patients are often considerably burdened and often severely restricted in their quality of life, as they suffer from numerous, often bloody bowel movements, which are accompanied by abdominal cramps, urgency and sometimes even incontinence. In addition, many UC patients suffer from concomitant extraintestinal inflammatory manifestations including skin manifestations like psoriasis, erythema nodosum or joint involvement such as spondylarthritis. For many years, steroids and conventional immunosuppressants such as azathioprine were the only treatment options available. Twenty years ago, the approval of the first anti-TNF antibody, Infliximab, marked a significant turning point in IBD therapy. Despite the continuous progress in drug therapy, the rates of primary and/or secondary treatment failure are still considerable. With this in mind, a large number of additional substances have been developed and approved for the treatment of UC in the recent years. In addition to TNF antibodies and their biosimilars, the anti-integrin vedolizumab, various Janus kinase (JAK) inhibitors, an interleukin (IL)-12/-23p40 antibody, various IL-23p19 antibodies and sphingosine-1-phosphate receptor (S1PR) modulators have broadened the therapeutic landscape and found their way into the clinical treatment of UC patients. In this article we will discuss case-based decision paths for the selection of fitting anti-inflammatory treatments in UC patients and summarize the principles of the different therapeutic strategies for UC.

BACKGROUND:Reproduction is a fundamental aspect of life. This study aimed to provide an international overview of gastroenterologists' approaches to managing inflammatory bowel disease (IBD) during preconception, pregnancy, lactation, and postpartum. METHODS:An anonymous 75-question survey was distributed to gastroenterologists in 36 countries, including European countries, the United States of America, Latin American countries, Australia, and New Zealand, focusing on clinical practices for managing pregnancy and breastfeeding in IBD patients. RESULTS:A total of 856 gastroenterologists participated, 61% were IBD specialists. In pregnant patients in remission, participants stated they would discontinue IBD therapy as follows: 19% for thiopurines, 41% for anti-TNF, 37% for vedolizumab, 31% for ustekinumab, and 96% for small molecules. Many gastroenterologists avoided initiating oral or rectal budesonide, anti-TNF, vedolizumab, or ustekinumab during disease flares. Despite existing safety concerns, one-third of gastroenterologists reported initiating thiopurines to manage disease flares during pregnancy. Only 50% of gastroenterologists had specialized follow-up programs for pregnant patients with IBD in remission. Thirteen percent of gastroenterologists believed that all drugs were safe during breastfeeding. For vaccinations, about 20% advised against non-live vaccines, and 50% avoided live-vaccines during the first 12 months for infants exposed to anti-TNF in utero. Few gastroenterologists had referral pathways to IBD-specialized obstetricians or paediatricians. CONCLUSION:Our international survey suggests that management of IBD during pregnancy, lactation, and postpartum remains suboptimal, even among gastroenterologists specifically dedicated to IBD. Urgent educational efforts are needed to address these issues and improve care.

Abstract Background Mirikizumab, a humanized IgG4 monoclonal antibody binding subunit p19 of interleukin 23, has been approved for the therapy of ulcerative colitis since May 2023. Phase 3 studies showed significant efficacy in both inducing and sustaining clinical remission in patients with moderate to severe active ulcerative colitis. Methods All patients with active ulcerative colitis who began induction therapy with Mirikizumab at our outpatient clinic between July 2023 and June 2024 were analyzed retrospectively with a follow-up period until October 2024. Patients with prednisolone therapy exceeding 20 mg, loperamide intake or deviation of standard clinical application period were excluded. The primary endpoints were defined as achieving clinical remission following the completion of intravenous induction (at weeks 12, 16 or 24) and the maintenance of clinical remission at any time between week 8 and week 49 following the initiation of subcutaneous application. Secondary endpoints included rates of clinical remission and relapse in patients previously treated with Ustekinumab, a monoclonal antibody targeting the p40 subunit of interleukin-12 and -23. Results A total of 40 patients started Mirikizumab induction therapy, with 23 meeting the inclusion criteria. Seventeen patients were observed in the maintenance period. After completion of induction, 20 out of 23 patients (87.0%) achieved clinical remission. Among these, 12 (60.0%) had previously been treated with Ustekinumab. During the maintenance period, 6 out of 17 patients (35.3%) experienced a relapse, of whom 5 (83.3%) had prior therapy with Ustekinumab. Within the Ustekinumab subgroup, 5 out of 10 patients (50.0%) suffered relapse after initially achieving clinical remission. Conclusion Mirikizumab is an effective therapy in patients with active ulcerative colitis, including those who had a prior loss of response to Ustekinumab therapy. Patients with prior Ustekinumab therapy exhibited a higher rate of relapse during the maintenance phase.

Ulcerative colitis (UC) is classified as a chronic inflammatory bowel disease (IBD) and can present in various degrees of severity. In addition to mild courses of the disease, such as uncomplicated proctitis, which can often be successfully treated with topical 5-ASA formulations, complicated courses can be observed, which can sometimes be life-threatening. Affected patients are often considerably burdened and often severely restricted in their quality of life, as they suffer from numerous, often bloody bowel movements, which are accompanied by abdominal cramps, urgency and sometimes even incontinence. In addition, many UC patients suffer from concomitant extraintestinal inflammatory manifestations including skin manifestations like psoriasis, erythema nodosum or joint involvement such as spondylarthritis. For many years, steroids and conventional immunosuppressants such as azathioprine were the only treatment options available. Twenty years ago, the approval of the first anti-TNF antibody, Infliximab, marked a significant turning point in IBD therapy. Despite the continuous progress in drug therapy, the rates of primary and/or secondary treatment failure are still considerable. With this in mind, a large number of additional substances have been developed and approved for the treatment of UC in the recent years. In addition to TNF antibodies and their biosimilars, the anti-integrin vedolizumab, various Janus kinase (JAK) inhibitors, an interleukin (IL)-12/-23p40 antibody, various IL-23p19 antibodies and sphingosine-1-phosphate receptor (S1PR) modulators have broadened the therapeutic landscape and found their way into the clinical treatment of UC patients. In this article we will discuss case-based decision paths for the selection of fitting anti-inflammatory treatments in UC patients and summarize the principles of the different therapeutic strategies for UC.

The IL-36 signaling pathway has recently been identified as a key regulator of intestinal homeostasis and inflammation. However, the role of mutations in the IL-36R signaling pathway in the pathogenesis of inflammatory bowel disease remains unclear. We here identified four Crohn’s disease patients with heterozygous missense mutations in the IL-36 receptor antagonist ( IL36RN , IL-36RA). Experimental overexpression and functional assays demonstrated that two identified mutations resulted in reduced expression of IL-36RA. In-depth immune profiling of one IL36RN -mutated patient revealed an increased response of PBMCs to IL-36 stimulation and elevated serum levels of IL-36-regulated cytokines. Administration of the IL-36R-blocking antibody spesolimab to this patient resulted in a reduction of intestinal inflammation and alterations in immune cell composition and function. Our findings indicate that pathogenic IL36RN mutations may contribute to the pathogenesis of Crohn’s disease in a subset of patients and that inhibiting IL-36 signaling could offer a personalized therapeutic approach for these patients.

Abstract Background Failure to respond to the anti-α4β7 integrin therapy, vedolizumab, is observed in a subset of inflammatory bowel disease (IBD) patients, potentially linked to distinct T cell activation profiles. This study aims to characterize the transcriptional and phenotypic features of circulating memory CD4⁺ T cells in vedolizumab non-responders and their association with treatment resistance. Methods We performed multidimensional flow cytometry and single-cell RNA sequencing to analyze IBD patients' circulating memory CD4⁺ T cell compartment, comparing pre- and post-treatment peripheral blood samples from vedolizumab responders and non-responders. Proteogenomic analysis and TCR repertoire profiling of CD4⁺ T cells were conducted using matched peripheral blood samples. Flow cytometry characterized T cell subsets based on surface markers, migration receptors, transcription factors, and cytokine expression, focusing on differences in activation and migration profiles. Results Ki67⁺ cells were enriched in the memory CD4⁺ T cell population of vedolizumab non-responders in both UC and CD, confirmed by two independent cohorts. TCR repertoire analysis showed increased diversity in memory CD4⁺ T cells post-treatment. Single-cell sequencing and proteomics revealed these Ki67⁺ cells had a high activation and proliferation profile (HLA-DR, CD40LG, MKI67) with reduced IL7R and SELL expression. They displayed elevated integrins (α4, β1, β7) and gut-homing receptors (CXCR3, CCR6). Upregulated T-bet, EOMES, and RORγt and increased IL-17A, indicated a pro-inflammatory Th1/Th17 phenotype in non-responders. Conclusion Ki67⁺ memory CD4⁺ T cells are significantly enriched in the peripheral blood of vedolizumab non-responders, displaying a distinct transcriptional and phenotypic profile characterized by Th1/Th17 polarization, high integrin α4β1 expression, and enhanced gut-homing capacity. These findings indicate that proliferating effector memory CD4⁺ T cells could contribute to therapy resistance in IBD, emphasizing the need for alternative therapeutic strategies targeting these cells in anti-α4β7 integrin therapy non-responders.

Abstract Background Reproduction is an essential part of life. Our aim was to obtain a global perspective on IBD management by gastroenterologists (GIs) during preconception, pregnancy, lactation and neonatal period. Methods An anonymous survey (75 questions) was developed to investigate different aspects of clinical practice concerning the management of pregnancy and breastfeeding in patients with IBD. A national representative from each European country, USA, Latin America, Australia and New Zealand was selected to distribute the survey among their GI colleagues who treat patients with IBD (irrespectively of their experience). Results A total of 856 GIs from 36 countries participated in the survey. Among the participants, 63% had over a decade of experience as GIs, and 61% identified themselves as IBD specialist (IBDologists). The most relevant survey results and sub-analyses based on expertise are presented in tables 1 and 2. In the management of pregnant patients in remission, treatment discontinuation occurred either consistently or occasionally as follows: 20% thiopurines, 37% vedolizumab, 31% ustekinumab, and 96% small molecules. Notably, 13% did not always discontinue small molecules in patients contemplating pregnancy. Safety was the main reason for discontinuing IBD therapy during pregnancy. Contrary to the recommendations in clinical practice guidelines, many GIs avoid starting oral or rectal budesonide, anti-TNF, vedolizumab or ustekinumab during a disease flare. Further, a third of GIs would start thiopurines for a flare during pregnancy. Moreover, 13% will never perform a colonoscopy in a pregnant patient to guide decision making. Half of GIs implemented a dedicated outpatient follow-up program for pregnant patients in remission, with 87% enrolling all pregnant patients in this program. Concerning breastfeeding, 14% believed that all drugs can be used while breastfeeding. Regarding offspring’s vaccination, about 20% recommend against the administration of non-live vaccines and only 50% recommended avoiding live vaccines during the first 12 months for children exposed to anti-TNF in-utero. Among those GIs who recommended delaying vaccines in such cases, only 41% recommended testing the infant for detectable anti-TNF levels if live vaccines were required. Among the surveyed GIs, only a minority had a referral obstetrician, and only 35% referred patients with active or complicated IBD, while 45% had a referral paediatrician with expertise in IBD. Conclusion The management of IBD during pregnancy, lactation, and neonatal period is notably suboptimal, even among GIs specifically dedicated to IBD. It is crucial to address this current need and implement urgent educational measures in this area.

ABSTRACT Despite the success of biological therapies in inflammatory bowel disease (IBD), patient management remains challenging due to a lack of therapy response predictors. Here we prospectively sampled two cohorts of IBD patient cohorts receiving the anti-integrin α4β7 antibody vedolizumab. Samples were subjected to mass cytometry, single-cell RNA sequencing, single-cell V(D)J sequencing, serum proteomics, and multidimensional flow cytometry to comprehensively assess vedolizumab-induced immunological changes in the peripheral blood and their potential associations with treatment response. Vedolizumab induced changes in the abundance of both circulating innate and adaptive immune cell compartments and modified the T cell receptor diversity of circulating gut-homing CD4 + memory T cells. Through integration of multimodal parameters and machine learning, we identify that pretreatment activated proliferating CD4 + memory T cell abundance is associated with treatment failure, independent of clinical variables, thereby providing a reliable predictive classifier with significant implications for the personalized management of IBD patients.

Abstract Background Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). We present data from the ELEVATE UC 52 and ELEVATE UC 12 phase 3 clinical trials1 assessing etrasimod efficacy and safety in patients (pts) who were biologic/Janus kinase inhibitor (JAKi)-naïve and previously took 5-aminosalicylic acid (5-ASA) and/or thiopurines. Methods In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), eligible pts were randomised 2:1 to etrasimod 2 mg once daily or placebo (PBO). Pts in this post hoc analysis were naïve to prior biologic and/or JAKi treatments, and included regardless of prior/concomitant corticosteroids (CS). Pts in Cohort A were previously exposed to or currently taking 5-ASA, but naïve to prior thiopurines; pts in Cohort B were previously exposed to a thiopurine with/without prior/concomitant 5-ASA. Efficacy endpoints included clinical remission and endoscopic improvement (Weeks [Wks] 12 and 52), CS-free remission and sustained clinical remission (Wk 52) and symptomatic response (Wks 2, 4, 8 and 12). Data up to Wk 12 were pooled from both trials; Wk 52 data were from ELEVATE UC 52. Safety was assessed up to 52 wks. Results In Cohort A, 135 and 62 pts were randomised to etrasimod and PBO, respectively; more pts in the etrasimod vs PBO arm achieved clinical remission (Wks 12 and 52), endoscopic improvement (Wks 12 and 52), CS-free remission (Wk 52) and sustained clinical remission (Wk 52; all p<0.05; Figure 1A). In Cohort B, 69 and 35 pts were randomised to etrasimod and PBO, respectively; significantly more pts in the etrasimod vs PBO arm achieved clinical remission and endoscopic improvement (Wk 12) and sustained remission (Wk 52; all p<0.05; Figure 1B). In both cohorts, numerical differences in the etrasimod vs PBO arm in pts achieving symptomatic response were seen starting at Week 2. In both cohorts, safety findings were consistent with the overall population, with no increases in incidence rates of serious AEs or serious infections in the etrasimod vs PBO arm. Conclusion This post hoc analysis further characterises the efficacy and safety of etrasimod as a first-line advanced treatment after conventional 5-ASA and/or thiopurine therapy, and is consistent with previous results in the cohort of pts naïve to biologic/JAKi which showed greater treatment effects than in pts experienced with advanced treatments.2 Limitations included post hoc analysis and small cohort sample sizes. References 1. Sandborn WJ et al. Lancet 2023; 401: 1159–1171. 2. Feagan B et al. United European Gastroenterol J 2022; 10: 388–389.

Die Erstdiagnose einer chronisch entzündlichen Darmerkrankung (CED) erfolgt oft im jungen Erwachsenenalter. Für viele Patientinnen spielen daher Familienplanung und Schwangerschaft eine zentrale Rolle. Die European Crohn's and Colitis Organization (ECCO) hat 2022 eine neue Leitlinie zu Kinderwunsch, Schwangerschaft und Stillzeit herausgegeben 1. In diesem Beitrag gehen wir auf die neuen Aspekte in Bezug auf Schwangerschaft bei Morbus Crohn ein.

Inflammatory bowel disease (IBD) is often diagnosed in young adults. Starting a family is an important step in life and can be further complicated by Crohn's disease. Therefore, family planning should be discussed with every patient early in the disease course. Counseling about the importance of disease remission and the safety of IBD medication during pregnancy can ameliorate the pregnancy outcome. Active disease during pregnancy can lead to adverse pregnancy outcomes such as preterm birth and low birthweight. To maintain disease remission most therapies should be continued despite the wish to have children. Only a few substances currently used to treat Crohn's disease are contraindicated during pregnancy and should be stopped before conception. This includes Januskinase (JAK)-inhibitors and Methotrexate. Biologics including anti-TNF-therapy, anti-IL-12/anti-IL-23 and anti-integrin therapies should be continued during pregnancy.