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Background Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). Etrasimod reversibly sequesters specific lymphocyte subsets in lymph nodes, reducing circulating lymphocytes and resulting in fewer immune cells available to traffic to the gastrointestinal tract. To better understand how etrasimod reduces inflammation in UC, the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials included a per protocol exploratory immunophenotyping biomarker analysis in fixed-formalin paraffin-embedded (FFPE) colon biopsies. Methods In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). Characterization of immune cell types in colon biopsies were assessed at baseline, week 12, and week 52 (ELEVATE UC 52 only) by Epiontis ID, an epigenetic immune monitoring method. Biomarker levels for each lymphocyte subset were evaluated between responders vs nonresponders, defined by achievement of clinical efficacy criteria within each treatment group, using t-tests and nominal P values. Results Colon biopsies were collected and analysed from 276 subjects in ELEVATE UC 52 (179 etrasimod, 97 PBO) and 150 subjects in ELEVATE UC 12 (97 etrasimod, 53 PBO). Etrasimod induced significant changes from baseline (nominal P value Conclusion In this per protocol exploratory analysis of two independent phase 3 trials, etrasimod induced changes from baseline in colonic tissue T- and B-cell subsets in subjects with UC, with nominally significant reductions observed in those who met response criteria. The reduction in activated immune cells in colonic tissue in responders suggests etrasimod induces a reduction in local inflammation that could contribute to remission. These findings are the first to report changes to immune cell subsets in colonic tissue in response to a S1P receptor modulator.

Background Crohn’s disease (CD) is characterized by chronic inflammation that can discontinuously affect any segment of the gastrointestinal tract. New findings concerning clinical behaviour, epidemiology, genetics, and gut microbiota suggest that CD in the ileum (iCD) and the colon (cCD) should be considered as two distinct subtypes of IBD. As systemic immune cell signatures differ between CD and UC, we propose a similar strategy for the differentiation between iCD and cCD. The aim of this study is to analyse and compare peripheral blood mononuclear cell (PBMC) subsets of iCD and cCD patients. For a robust analysis of the peripheral immune compartment in inflammatory bowel diseases (IBD), PBMC subsets of ileocolonic CD (icCD), ulcerative colitis (UC) and healthy controls (HC) were included as well. Methods In this study a total of 50 adults, 10 subjects per subgroup – iCD, cCD, icCD, UC and HC – were included. From each individual, both naïve and PMA/Ionomycin stimulated samples were stained for phenotypic and functional characterization using mass cytometry. For data analysis pre-gating was performed in Cytobank followed by debarcoding, compensation, normalization, clustering, and analysis on differential abundances edge R (DA_edgeR) and differential states limma (DS_limma) with CATALYST in R. Results FlowSOM allowed us to cluster CD45+ PBMCs of all samples into 16 major cell subtypes as visualized via UMAP (Fig. 1). DA testing showed significant differences between iCD and cCD, iCD and icCD but not cCD and icCD (Fig 2). Significantly different abundances among CD subgroups and HC included cluster 1 CD33+ myeloid cells, 7 CD45RO+ CD16+ cells, 8 CD11b+ cells, 9 CD4+ IL7R+ T cells and 12 CD27+ CD38+ CD45RA+ B cells (Fig. 3). When focussing on differences between iCD, cCD and icCD, DS testing revealed significantly higher IFNgamma and TNFalpha production in cluster 9 (CD4+ IL7R+ T cells), 15 (CD8+ T cells) and 16 (CD8+ CD45RO+ T cells) in iCD compared to icCD. Moreover, cluster 9 showed significantly higher levels of IFNgamma in iCD compared to cCD, and for TNFalpha cluster 16 revealed significantly higher levels in cCD compared to icCD (Fig. 4). Fig. 1 UMAP clustering of stimulated cells. Fig. 2 Differential analysis of stimulated samples with DA_edgeR and DS_limma. Fig. 3 Relative population abundances with DA_edge R testing. Fig. 4 Relative state marker abundance within clusters with DS_limma testing. Conclusion Deep phenotyping of the peripheral immune cell compartment in CD might serve as a confirmatory marker for disease location and therefore as predictor of clinical behaviour.

Background Patients suffering from IBD frequently suffer from chronic visceral pain, severely affecting quality of life. To better understand factors impacting pain signaling by enteric nervous system (ENS) neuronal cells, we analyzed the infiltration of the myenteric plexus (MP) of the ENS by inflammatory cell populations. In detail, we characterized (i) the immune cell populations infiltrating the MP, (ii) neurotransmitter expression by MP cells and (iii) neuronal cell survival of MP in Crohn’s disease (CD) and ulcerative colitis (UC). Methods We included 12 UC and nine CD patients that received colectomies or ileocecal resections, respectively, and 10 control patients with surgeries for non-inflammatory reasons. FFPE material was used for immunohistochemistry analysis of the MP. Immunostaining was performed for the detection of ENS neurons (beta-III tubulin, PGP9.5), for T-cells (CD3, CD4, CD8 and FOXP3), for B-cells (CD20), for monocytes (CD68, CD163) and apoptosis (Annexin V) and the neurotransmitters CGRP and substance P. Intraganglionic and periganglionic immune cell populations were determined by conventional LSM confocal microscopy. Results CD3+ and CD8+ intraganglionic T-cells for CD (CD3+: 1.7 ± 0.6 cells/10.000 µm²; CD8+: 4.8 ± 1.1 cells/10.000 µm²) were found to be increased compared to control patients (CD3+: 0.2 ± 0.1 cells/10.000 µm², p=0.04; CD8+: 0.4 ± 0.2 cells/10.000 µm², p=0.006), Figure 1. CD20+ B-cells and CD68+ monocytes were significantly increased in CD MP as well (CD20+ B-cells in CD: 0.8 cells/10.000 µm², CD20+ B-cells in controls: 0 cells/10.000 µm, p=0.02), CD68+ monocytes in CD: 12.3 cells/10.000 µm², CD68+ monocytes in controls: 3.5 cells/10.000 µm², p=0.001). CD8+ cytotoxic T-cells infiltrating the periganglionic area of the MP were significantly increased for UC. 1.6-fold increased expression of the neurotransmitter CGRP were detected for UC MP, p=0.01. Substance P was found to be 0.7-fold reduced for CD MP, p=0.01. MP-cell survival (Annexin V) was found to be reduced for UC MP, p=0.048. Figure 2 shows representative neurotransmitter immunostainings in two patients per condition. Conclusion In conclusion, MP immune cell infiltrations in CD are comprised of CD3+, CD8+ T-cells as well as CD68+ monocytes and CD20+ B-cells. Specifically periganglionically, CD8+ T-cells are found in UC. The expression of the neurotransmitter CGRP is increased in CD-MPs whereas levels of substance P are reduced in UC MP. UC-affected MPs revealed higher levels of apoptosis.

Background Mirikizumab [(miri), a p19-directed IL-23 antibody] has been shown to be effective in patients with moderately to severely active ulcerative colitis (UC) in Phase 3, randomised, double-blind, placebo-controlled trials (LUCENT-1 NCT03518086; LUCENT-2 NCT03524092).1 Given the importance of understanding treat-to-target strategies, the relationship between improved histologic and endoscopic endpoints and improvement of the inflammatory biomarkers faecal calprotectin (fCal) and C-reactive protein (CRP) was studied within miri-treated patients enrolled in the programme. Methods This analysis focused on miri-treated patients (n=868) from the induction study receiving intravenous (IV) every 4 weeks (Q4W) until week (W)12 and miri induction responders at week W12, who were rerandomised for the maintenance period, receiving subcutaneous miri (n=365) Q4W up to W52. The relationship between achieving histologic-endoscopic mucosal improvement (HEMI), histologic-endoscopic mucosal remission (HEMR) (definitions in Tables) and improvement of fCal (≤250µg/g) and CRP (≤6mg/L) levels at W12 and W52 was explored using Fisher’s exact tests. Results At W12, a significantly higher percentage of miri-treated patients achieving HEMI (n=235/868) had normalised fCal and CRP values (76.2% and 88.5%), compared to miri-treated patients who did not achieve HEMI (n=633/868) (21.8% and 72.7%, both p At W52, a significantly higher percentage of the miri induction responder patients rerandomised to miri achieving HEMI (174/365) had normalised fCal and CRP values (74.1% and 87.9%), compared to patients not achieving HEMI (191/365) (32.5% and 61.3%; both p Conclusion At both W12 and W52, patients treated with miri who achieved HEMI or HEMR showed statistically significant improvements in fCal and CRP levels. This suggests that CRP and fCal may be useful markers of histology and endoscopy outcomes after induction and maintenance with miri. 1.Magro et al., MP245 Efficacy of mirikizumab in resolving active histologic inflammation in Ulcerative Colitis in Lucent-1 induction and Lucent-2 maintenance trials (2022), UEG Week Moderated Posters. United European Gastroenterol J, 10: 185-472.

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

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 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 Durable treatment effectiveness is an important consideration in the long-term management of patients with Crohn’s disease (CD) receiving biologic therapy. The aim of this analysis was to evaluate rates of failure and dose modification for biologic treatment over time in patients with CD using data from a large long-term observational study evaluating secondary outcomes in patients initiating treatment on vedolizumab (VDZ) and other biologics. Methods We analysed data from a multicentre, prospective, observational, post-authorisation safety study (PASS; NCT02674308, EUPAS6469) following VDZ or other biologic treatment cohorts under routine standard of care. Longitudinal data on treatment failure (including biologic discontinuation†, IBD non-surgical hospitalization, primary IBD surgery and corticosteroid initiation) up to 36 months and dose modification at any time during the study were analysed in biologic-naïve and biologic-experienced patients with CD in the treatment cohorts. Results The cohort comprised 1338 biologic-naïve patients (pts) (VDZ, n=312; other biologics, n=1026) and 1543 biologic-experienced pts (VDZ, n=829; other biologics, n=714). Baseline pt characteristics (Table 1) were broadly similar across different treatment cohorts, although there were some notable differences with respect to fistulising disease and age at CD diagnosis. Treatment failure rates for biologic-naïve and biologic-experienced pts cumulatively over time at specific time points are shown in Table 2. The proportion of pts continuing biologic treatment with dose modification at any time during the study period for biologic-naïve pts was 13/312 (4.2%) in VDZ-treated pts vs 502/1026 (48.9%) in the group treated with other biologics and 34/829 (4.1%) vs 433/714 (60.6%), respectively for biologic-experienced pts. Conclusion This large observational study reported rates of treatment failure, hospitalization, and IBD-related surgeries during long-term follow-up of biologic-naïve and biologic-experienced pts with CD. Dose modification occurred less frequently in biologic-naïve and biologic-experienced pts treated with VDZ compared with pts receiving other biologic treatments during the study.

Background Hospitalisations and surgeries are a major driver of health resource utilisation increasing disease burden on patients (pts) with ulcerative colitis (UC) and Crohn’s disease (CD). This analysis aimed to evaluate the number of hospitalisations and surgeries among pts with UC and CD initiating vedolizumab (VDZ) or other biologic treatment, as a marker for disease modification and health resource utilisation. Methods Secondary outcome data from a multicentre, observational, prospective, cohort post-authorisation safety study (PASS; NCT02674308) of biologic-naïve pts with UC or CD initiating VDZ or other biologic treatment were utilised. Pts received treatment under routine standard of care with clinical decisions at the discretion of treating physicians, and so treatment could be modified or changed without the need to withdraw from the study. Inflammatory bowel disease (IBD)-related hospitalisation rate and occurrences of IBD-related surgeries were assessed in pts initiating VDZ and other biologic. Time to first hospitalisation and surgery was also assessed. Results In total, 1149 pts with UC (556 initiating VDZ, 593 initiating other biologics) and 1338 pts with CD (312 initiating VDZ, 1026 other biologics) were included in this analysis. Baseline characteristics are displayed in Table 1. VDZ-treated pts with UC had fewer IBD-related hospitalisations (12.9% vs 25.0%; risk ratio [RR] 0.52 [95% CI 0.40, 0.67]) and IBD-related surgeries (4.3% vs 10.1%; RR 0.43 [0.27, 0.68]) than those treated with other biologics (Table 2). With regard to surgical procedures, VDZ-treated pts with UC had fewer total colectomies (RR 0.40 [0.20, 0.80]), colectomy (RR 0.32 [0.13, 0.79]) and other IBD-related surgeries (RR 0.37 [0.17, 0.78]). Among pts with CD, those treated with VDZ had fewer IBD-related hospitalisations (19.2% vs 26.4%; RR 0.73 [0.57, 0.93]) and IBD-related surgeries (7.1% vs 13.8%; RR 0.51 [0.33, 0.78]) than those treated with other biologics (Table 2). Pts with UC treated with VDZ had a longer time to event of first IBD-related hospitalisation and primary and secondary IBD-related surgery (in pts without history of IBD-related surgery at baseline) than pts treated with other biologics (Table 3). Conclusion In this large multinational, observational study, fewer biologic-naïve pts with UC or CD on VDZ treatment had hospitalisations and IBD-related surgeries than pts on other biologics. These real-world data suggest VDZ as a first line biologic treatment may contribute to modifying the course of IBD over time. Further research into the role of additional factors associated with differences in biologic treatments shown here is warranted.

Background Inflammatory bowel disease (IBD) patients pose a lifelong risk of developing colitis-associated carcinoma (CAC). Current understanding and mechanisms of CAC development stem from murine CAC models while studies on human CAC carcinogenesis are scarce. Thus, we aimed to understand CAC carcinogenesis, using human samples from patients suffering from Crohn′s disease (CD), CD-associated CAC (CD-CAC), ulcerative colitis (UC), and UC-associated CAC (UC-CAC) and further validated the findings in vitro. Methods We obtained FFPE specimens from 40 patients that suffered from either one of the IBDs or CACs and furthermore inflammation-free healthy controls (10 patients per group). These samples were micro-dissected, followed by RNA isolation and Nanostring gene expression analysis. Our data revealed a strong upregulation of SPP1 (Secreted Phosphoprotein-1) gene encoding for osteopontin (OPN) upon comparing heathy controls to IBD and to CAC. We then used in vitro-models to elucidate the mechanism of OPN-induced carcinogenesis. We stimulated intestinal epithelial cell lines HT-29/B6 and T84 cells with rhOPN (recombinant human OPN), following bulk RNAseq. We validated the findings using Seahorse assay for analysis of mitochondrial respiration (determining oxygen consumption rate, OCR). Western phospho-blots were done to unravel signal transduction events. Results Nanostring gene expression data revealed the following: (i) SPP1 gene encoding for OPN and epithelial-to-mesenchymal (EMT) transcription factors fibronectin-1 (FN1) and ZEB1 were strongly upregulated in UC-CAC and CD-CAC patients when compared to UC and CD. (ii) IL17-pathway genes were significantly downregulated in UC-CAC patients. (iii) Tight junction and polarity genes were altered in both UC-CAC and CD-CAC patients. rhOPN stimulation in vitro to HT29/B6 and T84 cells excluded OPN as the trigger of EMT but uncovered upregulated mitochondrial respiratory chain genes as a potential trigger for tumour cell proliferation. Validation of RNAseq findings by Seahorse assay revealed that after sequential injections of oligomycin, FCCP, rotenone and antimycin A both, HT-29/B6 and T84 cells, had higher basal and maximal OCRs in response to rhOPN (Fig. 1). T84, but not HT-29/B6 cells also showed an upregulated ATP production in response to rhOPN. Conclusion SPP1 expression correlates with CAC carcinogenesis. Putative underlying pathways rather include modulation of mitochondrial respiratory chain activity by differential gene expression than induction of EMT.

Background Vedolizumab (VDZ) is a gut-selective humanised monoclonal anti-α4β7 integrin antibody for treatment of UC and CD. This post-authorization safety study (PASS) compared long-term safety in patients (pts) treated with VDZ or other biologics for UC or CD. Methods This was a prospective, observational, multicentre, cohort study in pts with UC or CD starting treatment with VDZ or other biologics (NCT02674308, EUPAS6469). Pts were biologic naïve (VDZ=35%, Other biologic=65%) or had prior exposure to biologics other than VDZ and were followed for up to 7 yrs. Pts were treated under usual standard of care as directed by their physician with no discontinuation from the study due to physician-directed treatment changes. The primary safety outcome was serious infections and was compared between cohorts using a Cox proportional hazards model adjusted by propensity score (with other biologics as reference). Secondary safety outcomes were adverse events (AE) of special interest (AESI) as listed in Tables 2 and 3. Results In total, 5208 patients were enrolled across 21 countries between Mar 2015 and Jul 2019. The full analysis set comprised 5008 pts (VDZ=2502; other biologic=2506) and mean (SD) study duration was 37.4 (14.1) months. Consistent with the observational nature of the study and the current standard of care, the baseline characteristics in the two cohorts were imbalanced (Table 1). The overall treatment-emergent Adverse Event (AE) rate was 61.3% (VDZ) and 59.5% (other biologic), with serious AEs in 27.5% (VDZ) and 25.7% (other biologic), respectively. In UC pts, the incidence rate (IR) of serious infections were: 0.014 (95% CI: 0.010, 0.019) [VDZ] and 0.015 (0.010, 0.023) [other biologic], with a hazard ratio (HR) of 1.018 (0.931, 1.114), p=0.70 (Table 2). In CD pts, corresponding findings were 0.012 (95% CI: 0.008, 0.017) [VDZ] and 0.006 (95% CI: 0.004, 0.009) [other biologic] with HR of 1.035 (0.959, 1.117), p=0.38 (Table 3). The incidence of primary and secondary safety outcomes is reported in Table 2 for UC and Table 3 for CD. There were no safety issues relating to pregnancy and no cases of PML observed. There were 19 deaths in the VDZ cohort (1 case of pneumonia deemed as treatment-related); and 13 deaths in the other biologic cohort, 2 cases deemed treatment-related (one case septic shock and pneumonia; one case non-small cell lung cancer). Clinical outcomes and quality of life (QoL) measures were comparable between cohorts. Conclusion In this long-term, prospective, real-world observational study of a large multinational population under routine standard of care there was no new safety signal identified in relation to VDZ. Results are consistent with the known safety profile of VDZ.

Background Crohn’s disease (CD) is a chronic inflammatory condition that can affect all parts of the intestine. Commonly, there is inflammation in the terminal ileum. An intestinal barrier consisting of epithelial cells covered by a mucus layer is on the one hand preventing pathogen invasion while on the other hand allowing the uptake of nutrients. However, despite the significance of the terminal ileum in CD, little is known about the mucus composition and viscoelastic properties in the terminal ileum. In our study, we wanted to do a comprehensive analysis of the mucus in the terminal ileum of CD patients compared to healthy controls. Thus, we aspire to gain a better understanding of the role of mucus and biophysical and biochemical triggers contained in the mucus layer during the course of ileal inflammation. Methods During colonoscopy, native mucus and saline washes containing mucus as well as biopsies from the terminal ileum of 33 CD patients and 25 healthy controls were collected. The disease course and dietary habits of all patients and healthy controls were recorded. Samples were treated according to protocol for different types of analysis such as rheology, proteomics, metabolomics, and microbiome. Furthermore, human intestinal organoids were generated from the biopsies. Additionally, we analysed bulk RNA sequencing data from intestinal mucosal biopsies of a cohort of 128 patients, consisting of non-IBD individuals and CD patients. Results We here present preliminary data for the different types of analyses. Regarding the viscoelastic properties, preliminary rheology data suggests that there is no major difference between CD patients and healthy controls. As for proteomics, the first cohort is currently being analysed. Concerning the microbiome, we could show that saline washes containing mucus are more suitable than biopsies for analysing bacterial as well as host DNA. Although not statistically significant, healthy controls showed a tendency for higher alpha- diversity in microbiota. Also there were some differences in the taxonomy. Intestinal organoids were grown as cultures. In the end, the results of the analyses mentioned above will be interpreted together with the clinical data. Concerning the gene expression, we found that 12 mucin and mucin-like genes were expressed both in colon and ileum tissue. Interestingly, a subset of CD patients showed a de-novo expression of MUC5AC, MUC6, MUCL1 and MUCL3 in the ileum. Conclusion All in all, in our multidisciplinary study we hope to achieve a thorough analysis of the mucus layer in the terminal ileum, thus gaining new insight into the pathogenetic mechanisms in intestinal inflammation that could prospectively be used for therapeutic means.

Background Ulcerative colitis (UC) is marked by impaired mucosal homeostasis with predominance of intestinal effector T cells and insufficient expansion of mucosal regulatory T cells (Tregs), thereby providing a scientific rationale for Treg-based immunotherapy in UC. Methods We developed a protocol to generate large numbers of autologous CD25+ cells under aegis of IL-2, rapamycin and anti-CD3/anti-CD28 expander beads ex vivo from CD25+ precursors derived from peripheral blood cells, intended for clinical use under good manufacturing practice (GMP) conditions. We initiated a single-centre, open-label, fast-track dose-escalation, phase-1 clinical trial with a single adoptive transfer of autologous ex vivo expanded CD4+CD25+CD127−/lo Tregs in patients with refractory UC. The primary objective of the trial was to define safety and the maximum tolerable dose of a single intravenous administration of autologous expanded Tregs according to the fast-track dosing principle. Adoptive transfer was escalated from the starting dose of 0.5×106 Tregs/kg body weight to the next dose level (1×106, 2×106, 5×106 and 10×106 Tregs/kg body weight) in each consecutive patient, respectively, if no dose-limiting toxicity occurred. We here report interim study data of the first 8 patients that received Treg transfer and were followed up over 12 weeks. There were no changes in concomitant medication during the study period. Results The 8 patients received 0.5 x106 (n=1), 1×106 (n=1), 2×106 (n=1), 2.8x106 (n=1), 5×106 (n=1) and 10×106 (n=3) Treg/kg body weight, respectively. The patients did not show any dose-limiting toxicity and there were no adverse events related to Treg transfer. 87.5% (7/8) of patients had previously received treatment with at least 2 different substance classes of advanced therapies, such as biologics and JAK inhibitors and the mean Mayo Score (MS) at baseline was 9.1±1.6. The mean modified MS (mMS) dropped significantly from 6.6±1.2 at baseline to 4.5±2.2 at week 4 (p=0.006) and 4.6±2.0 at week 12 (p=0.01). There was reduction of mean faecal Calprotectin levels from 1708±397 µg/g at baseline, to 1411±471 µg/g at week 4 and 919±332 µg/g at week 12. Clinical response was reached by 62.5% (5/8) of patients at week 4 and also week 12. Clinical response predominantly occurred in patients receiving the highest number of 10×106 Tregs/kg body weight. Clinical remission was achieved by 12.5% (1/8) of patients at week 4 and also week 12. Conclusion Autologous regulatory T cell transfer was well tolerated up to the maximal tested dose of 10×106 Tregs/kg body weight. Study results suggest that adoptively transferred polyclonal Tregs might be effective in refractory ulcerative colitis, warranting further clinical studies.

Background Infections are an important safety concern in patients with IBD and may be due to its therapies, such as corticosteroids. Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). The biologic effect of etrasimod leads to selective and reversible lymphocyte retention in lymph nodes with a decrease in peripheral lymphocyte count. We report the infection events from the phase 3 ELEVATE programme. Methods Infection events were evaluated in the pivotal UC pooled safety analyses set comprising two phase 3 studies: ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369). Subjects (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). We report the n (%) and exposure-adjusted incidence rate (EAIR) of infections including serious infections, severe infections, opportunistic infections (including tuberculosis), and herpes infections. Infections were considered adverse events of special interest (AESI) if they were severe (≥ CTCAE Grade 3), were opportunistic infections, or were herpes zoster or herpes simplex infections. Results From the pooled ELEVATE UC 12 and ELEVATE UC 52 trials, 527 subjects received ≥1 dose of etrasimod 2 mg (265.6 subject-years of exposure) and 260 subjects were randomised to PBO (103.0 subject-years of exposure). Infections were similar between treatment groups (etrasimod: 99 [18.8%], EAIR=0.41; PBO: 46 [17.7%], EAIR=0.52). The most frequent infections in both groups were COVID-19, urinary tract infections, and nasopharyngitis (Table 1). Serious infections occurred in 3 (0.6%) subjects in the etrasimod arm (EAIR=0.01) and 5 (1.9%) in PBO arm (EAIR=0.05). Two cases of herpes zoster were reported in each treatment group (etrasimod: 0.4%, EAIR Conclusion In these trials, etrasimod-treated subjects reported no increase in infections relative to PBO. Serious infections and herpes zoster were more commonly reported in the PBO-treated group. Longer-term follow-up data from the ongoing 5-year open-label extension will further characterize the etrasimod safety profile.

Background Upadacitinib (UPA) is an oral selective Janus kinase inhibitor with demonstrated efficacy in induction and maintenance treatment of Crohn’s disease (CD). This post hoc analysis assessed the efficacy of UPA in patients with CD by baseline (BL) disease severity. Methods In the U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836) induction studies, patients with moderate-to-severe CD and intolerance/inadequate response to biologic therapy (both studies) and/or conventional therapy (U-EXCEL) received UPA 45 mg once daily (QD) or placebo (PBO) for 12 weeks. Patients who achieved clinical response to UPA induction were re-randomised in a maintenance study (U-ENDURE, NCT03345823) to receive UPA 15 mg QD, UPA 30 mg QD, or PBO for 52 weeks. Clinical remission and endoscopic response were evaluated in subgroups stratified by BL disease characteristics: Crohn’s Disease Activity Index (CDAI), very soft/liquid stool frequency (SF), abdominal pain score (APS), and Simple Endoscopic Score for CD (SES-CD). Patients from the U-EXCEL and U-EXCEED studies were pooled for analysis. Results Among 1021 patients with moderate-to-severe CD (UPA 45 mg, n=674; PBO, n=347), week 12 clinical remission and endoscopic response rates were significantly higher for patients receiving UPA 45 mg vs PBO regardless of BL disease severity (nominal P Conclusion UPA induction and maintenance therapy improved clinical and endoscopic outcomes vs PBO in patients with moderate-to-severe CD, across levels of disease severity. Data for the small subgroup of patients with SES-CD Reference: 1. Atreya R, et al.Curr Res Pharmacol Drug Discov. 2022;3:100097.

Background Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator (S1P1,4,5) in development for the treatment of moderately to severely active ulcerative colitis (UC). To better understand how etrasimod reduces inflammation and induces clinical remission, the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials included a per protocol exploratory analysis of peripheral blood inflammatory proteomics, the results of which are presented here. Methods In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). Plasma was collected at baseline and week 12 for both trials and week 52 for ELEVATE UC 52. Characterization of plasma inflammatory protein abundance and changes in abundance over time were assessed by proximity extension assay using the Olink Target 96 Inflammation panel. Normalized protein expression and change from baseline by visit were summarized by descriptive statistics; fold changes in Olink measurements were expressed as log2. Results Plasma samples were collected and analysed from 238 patients in ELEVATE UC 52 (162 etrasimod, 76 PBO) and 163 patients in ELEVATE UC 12 (108 etrasimod, 55 PBO). While no meaningful changes in protein biomarkers were observed over time in PBO-treated patients, factors modulated by etrasimod included those associated with tissue remodelling (MMP-1, MMP-10), T-cell response (CD5, CD6, CD8A, TNFRSF9), chemotaxis (CCL11, CCL19, CCL28, CX3CL1), and pleiotropic cytokine response (IL-7, IL-17A, IL-10, OSM), with a high degree of overlap and consistency in trends between the two trials (Figure 1). Etrasimod induced statistically significant reductions in circulating inflammatory proteins including IL-17A and OSM at week 12, and these remained decreased at week 52. Decreases in IL-17A and OSM at weeks 12 and 52 correlated with efficacy outcome measures across various clinical subgroups in responders vs nonresponders (Table 1). Conclusion In this per protocol exploratory analysis of two independent phase 3 randomised controlled trials, etrasimod induced consistent, statistically significant changes in circulating inflammatory proteins involved in tissue remodelling, T-cell response, chemotaxis, and cytokine response, including IL-17A and OSM. The reduction in activated immune cells in the peripheral blood of responders suggests etrasimod induces a reduction in inflammation that could contribute to remission.

Background The interleukin 36 (IL-36) family consists of three agonists (IL-36α, IL-36β, IL-36γ), that activate the NF-κB pathway and lead to the production of pro-inflammatory cytokines and the natural antagonist (IL-36RA), which inhibits IL-36 signaling. While it is known that IL-36 signaling is important in the skin, it has been only recently reported that IL-36 might play an important role in maintaining gut homeostasis and in the development of fibrosis (Scheibe et al., 2019). Here, we aim to understand how IL-36RA mutations contribute to development and maintenance of intestinal inflammation in Crohn’s disease. Methods By whole-exome sequencing (WES) and subsequently targeted Sanger sequencing we identified a Crohn’s disease (CD) patient with a heterozygous missense mutation in IL-36RA (p.Ser113Leu). To understand how the mutation affects immune cells composition and function, we characterized peripheral blood mononuclear cells (PBMCs) of the patient by mass cytometry and measured cytokine levels in the serum by ELISA. In an available WES dataset of 177 CD patients, 47 ulcerative colitis (UC) patients and 34 healthy donors (HD), we searched for additional patients with IL-36RA mutations. Finally, we overexpressed the identified IL-36RA mutations in HEK cells and produced mutated recombinant proteins to study the effect of the mutations on protein expression and function. Results Our IL-36RA mutation-carrying patient presented with a severe course of Crohn’s disease and consecutive of fibrosis, which was resistant to all commonly used treatment options. In the patient, we detected increased levels of IL-36RA, IL-18 and IL-23 in the serum and an increased frequency of TH17 cells in the blood. These findings could hint towards an over-activation of the IL-36 signaling pathway in the IL-36RA mutated patient. In the available WES data, we identified two more CD patients with IL-36RA mutations (p.Leu133Ile, p.Pro76Leu), indicating that IL-36RA mutations are enriched in CD patients. By overexpressing the three identified mutations in HEK cells, we could demonstrate that two mutations (p.Ser113Leu and p.Pro76Leu) lead to a reduced protein expression. Also, our current data shows that the p.Ser113Leu mutant has a reduced capacity to antagonize IL-36 stimulation. However, further testing is required for the two other IL-36RA mutants. Conclusion Our data suggests that IL-36RA mutations are enriched in Crohn’s disease patients and should be considered as a possible cause for therapy-refractory and fibrotic Crohn’s disease.

Background Mucosal healing (MH) is considered an important treatment target for patients (pts) with moderate to severe Crohn’s disease (CD). The aim of this analysis was to evaluate rates of MH achieved during treatment with vedolizumab (VDZ) or other biologics in pts with CD who underwent endoscopic assessments during routine clinical practice in a long-term observational study across a number of multinational study centres. Methods Data were analysed from a long-term prospective, multicentre, post-authorization safety study (PASS; NCT02674308, EUPAS6469) cohort of pts with CD. This secondary outcome was evaluated in pts initiating treatment with VDZ or other biologics, including infliximab, adalimumab and ustekinumab. Pts received treatment under routine standard of care with clinical decisions at the discretion of treating physicians, treatment could be modified or changed without the need to withdraw from the study. For pts with available endoscopy data, rates of MH (simple endoscopy score [SES-CD] ≤ 2) at baseline and 12-months were compared in biologic-naïve or biologic-experienced pts treated with VDZ versus other biologics. Results MH was analysed in pts with CD who had endoscopic assessment. In those pts who were biologic-naïve and had baseline endoscopy (VDZ n=76, other biologics n=239), MH rates at baseline were 11.8% (9/76) versus 12.1% (29/239), respectively. After 12-months’ treatment, MH rates in biologic-naïve pts who had endoscopy data at month 12 (VDZ n=48, other biologics n=108) were 70.8% (34/48) in VDZ-treated pts versus 60.2% (65/108) in pts treated with other biologics (Table 1). In pts who received biologic treatment prior to study entry (biologic-experienced) and had baseline endoscopy (VDZ n=151, other biologic n=146), MH rates at baseline were 11.9% (18/151) versus 16.4% (24/146), and 51.1% (45/88) versus 31.4% (27/86) after 12 months of treatment in the VDZ and other biologic cohorts, respectively. Conclusion These real-world data from a multinational observational study show that VDZ was effective at achieving MH, particularly as a first-line biologic treatment, and also in biologic-experienced pts.

Background Approximately one third of IBD patients show a primary non-response to anti-TNF therapy. An individualized treatment approach requires clinical predictors. Our previous study showed that LPS-stimulated TNF production can be used to predict response to infliximab in Crohn′s Disease patients. The expression of the myeloid receptor TREM1 is also known as a potential predictive marker for anti-TNF therapy response. The aim of this study is to compare these two predictors for response to adalimumab. Methods In this prospective observational study 24 adults with Crohn′s Disease starting adalimumab treatment were included. Disease activity was assessed clinically (Harvey-Bradshaw-Index (HBI)), through lab results (leukocytes, C-reactive protein, calprotectin) and per ultrasound (Limberg-Score) at the time point of adalimumab induction, after 6 and 12 weeks. TNF-production of LPS-stimulated peripheral blood mononuclear cells was measured via ELISA at the baseline. The expression of TREM1 and its soluble isoform TREM1sv was quantified from whole blood RNA via qPCR. Primary endpoints were clinical response after week 6 and 12. Response was defined as a decrease in HBI ≥2, remission as HBI Results Of 24 recruited patients 18 have currently reached week 12. 5 patients have not reached remission within 6 weeks, 4 have not reached remission within 12 weeks. TNF production and TREM1 expression differed among patients at baseline. After definition of a cut-off value 6 low-TNF-producers, 8 low-TREM1-producers and 7 low-TREM1sv-producers could be identified. Three out of 6 low-TNF-producers were in non-remission after 6 weeks compared to 2 out of 12 high-TNF-producers (p=0.1366). Five out of 8 low-TREM1-producers were in non-remission after 6 weeks compared to 0 out of 9 high-TREM1-producers (p=0.0048, 1 missing value). Four out of 7 low-TREM1sv-producers were in non-remission after 6 weeks compared to 1 out of 10 high-TREM1sv-producers (p=0.0488, 1 missing value). Figure 1) Remission after 6 weeks of adalimumab treatment - low vs. high TNF Figure 2) Remission after 6 weeks of adalimumab treatment - low vs. high TREM1 Figure 3) Remission after 6 weeks of adalimumab treatment - low vs. high TREM1sv Conclusion Low TREM1 and TREM1sv expression seem to be stronger predictors for non-remission after 6 weeks of adalimumab treatment compared to TNF-production. These results are to be validated with increased patient numbers.

Background The efficacy of risankizumab (RZB), an interleukin 23 p19 inhibitor, in patients with Crohn’s disease (CD) has been reported. Normalisation of high-sensitivity C-reactive protein (hs-CRP) and faecal calprotectin (FCP) are intermediate treatment targets in CD. Here, we evaluated changes in these objective inflammatory biomarkers and clinical outcomes with RZB treatment. Methods In 2 phase 3, randomised, double-blind studies (ADVANCE, NCT03105128; MOTIVATE, NCT03104413), patients with moderately to severely active CD received 12-week intravenous (IV) RZB induction therapy or placebo (PBO). Patients with clinical response to RZB IV induction were rerandomised in a 52-week maintenance study (FORTIFY, NCT03105102) to receive subcutaneous (SC) RZB or PBO (ie, RZB withdrawal). Induction analyses included patients who received either 600 mg RZB IV or PBO for 12 weeks. Maintenance analyses included patients who received 360 mg RZB SC every 8 weeks or withdrawal (PBO SC) for 52 weeks. Outcomes assessed were normalisation of hs-CRP and FCP concentrations at week 12 of induction and at week 52 of maintenance in patients with elevated biomarkers at baseline (hs-CRP > 5 mg/L and/or FCP > 250 μg/g), clinical biomarker response (defined as enhanced clinical response [≥ 60% average daily stool frequency (SF) decrease and/or ≥ 35% average daily abdominal pain score (APS) decrease] and ≥ 50% reduction in hs-CRP or FCP), and clinical biomarker remission (defined as clinical remission per CD Activity Index or SF/APS criteria and normal hs-CRP or FCP) during maintenance treatment. Nonresponder imputation was used for missing data. Results Greater proportions of patients receiving RZB vs PBO achieved normalisation of hs-CRP and FCP at the end of the 12-week induction period and the 52-week maintenance period (P < .0001 for all; Table). Among patients with clinical response to RZB IV induction and entered maintenance, rates of clinical biomarker response were maintained through week 52 in patients receiving 360 mg RZB SC and declined over time among patients in the withdrawal (PBO SC) arm (Figure A). Rates of clinical biomarker remission increased over time in patients receiving 360 mg RZB SC. At week 52, clinical remission and normalisation of hs-CRP or FCP was achieved by 41% of patients receiving RZB vs 28%–29% of patients in the withdrawal (PBO SC) arm (Figure B-C). The safety profile of RZB in CD was previously reported. Conclusion Normalisation of objective biomarkers of inflammation in CD was achieved with RZB induction and maintenance therapy. Improvements in both clinical outcomes and biomarker levels were sustained with continuous RZB maintenance therapy and decreased over time in patients discontinuing RZB.

Background Ozanimod, a sphingosine 1-phosphate (S1P) receptor modulator selectively targeting S1P1 and S1P5, is approved in the US for the treatment of moderately to severely active ulcerative colitis (UC). In the pivotal phase 3 True North randomised controlled trial in moderate-to-severe UC, significantly more patients (pts) achieved clinical response and remission with ozanimod vs placebo (PBO) at week (wk) 10 of the induction period. Here, we report the rapidity of ozanimod-induced symptomatic response and remission in pts from True North (NCT02435992). Methods In True North, pts were randomised to once-daily ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or PBO (Cohort 1) or received open-label ozanimod (Cohort 2) during induction. This analysis evaluated symptomatic response (defined as ≥1 point and ≥30% decrease from baseline in adapted partial Mayo score and ≥1 point decrease from baseline in rectal bleeding score [RBS] or absolute RBS ≤1) and symptomatic remission (defined as RBS of 0 and stool frequency score [SFS] ≤1 point and ≥1 point decrease from baseline at each study visit from wk 2 through 10. Results During induction, 645 pts were randomised to ozanimod (n=429) or PBO (n=216) in Cohort 1, and 367 pts received open-label ozanimod in Cohort 2. Baseline demographics and clinical characteristics were well balanced across groups. Differences in symptomatic response were observed between ozanimod and PBO recipients in Cohort 1 as early as 2 wk after ozanimod initiation (1 wk post-titration) for the overall population (36.1% vs 26.4%; difference: 9.6% [95% CI, 2.1–17.0]; Figure 1) and tumour necrosis factor inhibitor (TNFi)-naïve pts (38.5%, n=301 vs 29.1%, n=151; difference: 9.4% [95% CI, 0.2–18.5]), and as early as 4 wk for TNFi-exposed pts (42.2%, n=128 vs 27.7%, n=65; difference: 15.8% [95% CI, 1.8–29.8]). Differences in symptomatic remission were observed between ozanimod and PBO recipients in Cohort 1 as early as 5 wk after ozanimod initiation (4 wk post-titration) for the overall population (26.3% vs 16.7%; difference: 8.6% [95% CI, 1.8–15.4] Figure 2), as early as 4 wk for TNFi-naïve pts (27.2% vs 17.9%; difference: 9.4% [95% CI, 1.5–17.4]), and as early as 8 wk for TNFi-exposed pts (22.7% vs 12.3%; difference: 11.7% [95% CI, 1.3–22.1]). Rates of symptomatic response and remission in pts receiving open-label ozanimod (Cohort 2) were similar to those in pts receiving randomised ozanimod (Cohort 1). Conclusion In the overall population, ozanimod was associated with higher rates of symptomatic response and remission vs PBO as early as 2 and 5 wk, respectively, after treatment initiation. Both clinical endpoints were more rapidly achieved in TNFi-naïve vs TNFi-exposed pts.

Background The interleukin 36 (IL-36) family consists of three agonists (IL-36α, IL-36β, IL-36γ), which activate the NF-κB pathway and lead to the production of pro-inflammatory cytokines and the natural antagonist (IL-36RA), which inhibits IL-36 signaling. While it is known that IL-36 signaling is important in the skin, it has been only recently reported that IL-36 might play an important role in maintaining gut homeostasis and in the development of fibrosis (Scheibe et al., 2019). However, it is not clear how IL-36 signaling contributes to the development of intestinal inflammation and which cell types are involved in this process. To shed more light on the role of IL-36 in intestinal inflammation, we took the opportunity to perform an in-depth characterization of a Crohn’s disease patient with a mutation in IL36RA and identify cell subsets responding to IL-36 stimulation. Methods By whole exome-sequencing of EDTA blood we identified in a Crohn’s disease patient a heterozygous mutation in IL36RA (p.Ser113Leu), which we confirmed by Sanger sequencing. By ELISA, we quantified IL-36RA serum levels in comparison to other Crohn’s disease (CD) patients and healthy donors (HD). Finally, we stimulated peripheral blood mononuclear cells (PBMCs) of the IL-36RA patient, CD patients, and HDs with ionomycin/PMA, LPS or IL-36α and performed deep immune profiling by mass cytometry with 35 markers. Results Our IL36RA mutation carrying patient presented with a severe course of Crohn’s disease and consecutive of fibrosis, which was resistant to all commonly used treatment options. As an individual treatment, autologous stem cell transplantation was performed, but did not lead to long-term improvement in symptoms. By ELISA, we found strongly elevated IL-36RA levels in the serum of our patient compared to CDs and HDs. Mass cytometry analysis revealed that the IL36RA mutation does not lead to major shifts in the immune cell composition of the blood, as the frequencies of B, T, NK, and myeloid cells in PBMCs of our patient were comparable to those in HDs and CDs. Furthermore, our data revealed that IL-36α stimulation mainly induced TNFα and IL-6 expression in myeloid cells as well as IFNγ expression in NK cells but did not affect T and B cells. Conclusion Our data is the first description of a Crohn’s disease patient with an IL36RA mutation and indicate that defects in IL-36 signaling should be considered as a possible cause for therapy-refractory and fibrotic Crohn’s disease. Furthermore, we identified NK cells and myeloid cells as main responders to IL-36α stimulation. As next step, we plan to use recombinant produced, mutant IL-36RA in in-vitro assays with immune cells and fibroblasts to study the effect of the mutation on the IL-36RA function in more depth.

Background Patients with ulcerative colitis (UC) and patients with multiple sclerosis (MS) have an elevated risk of developing herpes zoster (HZ), caused by reactivation of latent varicella zoster virus (VZV). Increased incidence of HZ has been reported with sphingosine, 1-phosphatase (S1P) receptor modulators. This analysis examined the number of patients who failed screening due to a lack of demonstrated VZV immunity and the incidence of HZ from completed phase, 3 ozanimod clinical trials. Methods Safety results were included from True North (52-week trial) in patients with UC, and SUNBEAM (12-month trial), and RADIANCE (24-month trial) in patients with MS. All patients were required to have had a positive VZV IgG antibody status or completed VZV vaccination ≥30 days prior to randomization based on known effects of S1P modulators. Patients with a negative VZV antibody titer could choose to receive the VZV vaccination to qualify for the trial. Number of pre-screen failures because of lack of demonstrated immunity, occurrence of HZ, and association between HZ cases and lymphopenia were analyzed. Results Of, 1831 patients with UC screened for VZV immunity, 104 (5.7%) failed screening due to lack of documentation of VZV antibody or VZV vaccination ≥30 days before randomization;, 22% (23/104) subsequently received varicella vaccination and were rescreened and enrolled. Of, 3332 MS patients tested for VZV immunity, 309 (9.3%) tested negative and, 32% (98/309) of these patients were vaccinated prior to randomization. In the UC and MS trials, the incidence of HZ cases was low in ozanimod-treated patients (8 cases [1.0%] and, 5 cases [0.6%], respectively; Table, 1). All cases were distributed across a single dermatome, did not result in a complication of HZ, and were treated with oral antivirals while patients remained on ozanimod. None of the patients discontinued ozanimod because of HZ and none of the HZ cases were associated with grade, 4 lymphopenia (defined as an absolute lymphocyte count Conclusion In the ozanimod phase, 3 UC and MS trials, 5%–10% of patients screened did not have demonstrated VZV immunity;, 22%–32% of these patients received varicella vaccination, were rescreened and enrolled. The overall HZ incidence in clinical trials was low (≤1% of patients), all cases were distributed across a single dermatome, and no serious or complicated cases occurred in ozanimod-treated patients with VZV immunity. Additional studies are warranted to evaluate the incidence of HZ in clinical practice.

Background In Crohn’s disease, hyperplastic mesenteric adipose tissue wrapping around inflamed small intestinal segments is a pathognomonic finding. Factors secreted by this so-called creeping fat can influence immune cells and affect disease severity in animal models. However, data on the interactions of adipose tissue and the intestinal epithelium are still sparse and derive almost exclusively from cell lines and animal models. Therefore, we employed primary human intestinal organoid culture and primary human adipose tissue explants to elucidate the role of adipose tissue-derived factors on the epithelium. Methods Creeping fat and unaffected mesenteric adipose tissue from a Crohn’s disease patient was used to produce adipose tissue-conditioned medium (ATcM). ATcM or control medium was added to growth medium (contains Wnt3a) and differentiation medium (Wnt3a removal) during primary human ileum-derived organoid culture. We analysed organoid morphology, proliferation, and phenotype by light microscopy, live cell imaging, resazurin viability assay, and reverse transcription quantitative polymerase chain reaction (RT-qPCR). Results In the presence of ATcM, differentiation of organoids was accompanied by a subtle and only transient delay in the development of morphologic signs of differentiation, namely organoid budding and darkness. In line, RT-qPCR at day 4 showed high expression of the differentiation markers MUC2 and ALPI in ATcM as well as in control conditions. In stem cell-enhancing growth medium, however, ATcM from both unaffected mesenteric adipose tissue and creeping fat induced a profound alteration of organoid morphology, perfectly reflecting so-called spheroids. Additionally, this ATcM-treated organoids were larger than the control, which corresponded with increased proliferation as measured by resazurin assay. This stem-like phenotype was further confirmed by a reduced expression of the differentiation markers MUC2 and ALPI in ATcM-treated organoids compared to the control. Conclusion Overall, our data suggest that factors from human mesenteric adipose tissue have profound effects on intestinal epithelial stem cells, while differentiated cells appear less affected. In the stem cell niche, they promote stem cell proliferation and inhibit differentiation. In Crohn’s disease, factors released from creeping fat could thus play a significant role in the pathophysiology, e.g. by enhancing epithelial regeneration via a promotion of stem cell proliferation.

Recent observational studies document that non-adherence to mesalamine therapy during remission is frequent. We aimed to investigate patient impact of patient education using objective assessments of adherence.A 14-month randomised, prospective clinical trial of adherence to mesalamine was conducted in 248 patients with ulcerative colitis [UC], Colitis Activity Index [CAI] ≤ 9, receiving standard care [n = 122] versus a standardised patient education programme [n = 126]. Primary endpoint was adherence at all visits (5-aminosalicylic acid [5-ASA] urine levels). Secondary endpoints included quality of life (inflammatory bowel disease questionnaise [IBDQ]), disease activity, partial adherence, and self-assessment of adherence.Patient allocation was well balanced. Baseline non-adherence was high in quiescent/mildly active UC [52.4%] without difference between the groups (52.4% of patients in the education group versus 52.5% in the standard care group [p = 0.99]). No difference between the intervention group and standard care was seen in IBDQ, partial adherence, self-assessment of adherence, or therapy satisfaction at all visits. We suggest a model in which individual risks for non-adherence are driven by patients with young age, short disease duration, and low education levels.Non-adherence is frequent in a population with quiescent/mildly active UC. Although more than 25% of the population was not in remission at the various time points, no relationship between disease activity and adherence was seen over the 14-month observation period. Physicians should maximise their efforts to motivate high-risk patients for adherence. Future trials should use objective exposure assessments to examine the impact of continuous education and consultations on the background of individual risks to develop non-adherence.

Young adults suffering from chronic diseases represent a critical subgroup of patients that after reaching legal age have to be transferred to the colleagues from adult medicine. Thus in this patient group two evident problems come together: first, the adolescence phase that presents a challenge for any young adult and second, the transition to the novel structure and environment of adult medicine. It has been recognized for Germany that there are significant deficits for this transition phase. These deficits have already been addressed by other countries through the introduction of so-called transition clinics. In this article, we will summarize the challenges of this transition phase and the resulting points and needs that will have to be addressed by a structured program for transition. As an example, the Berliner TransitionsProgramm (BTP) will be presented where a framework structure is provided that allows for the transition of various chronic diseases. The BTP accompanies the transition process for a two-year time period by providing a framework structure consisting of transition consultations, a transition booklet, a structured summary of the previous disease course as well as a case manager who assures that the included patients stay within the program and do not get lost to assure treatment continuity. In addition, the program succeeded, at least from some insurance companies, in obtaining financial reimbursement for this time-consuming effort. Thus in our view, the BTP functions as role model for transition medicine in Germany.

Background Nowadays patients with haemophilia survive longer due to improvements in haemophilia care. It has been hypothesized that the bleeding type and frequency may vary with age and are influenced by co-morbidities and co-medication in elderly patients. Objectives To investigate a large group of patients older than 60 years of age with haemophilia concerning haemophilia treatment, bleeding pattern changes, co-morbidities, co-medication, bleeding sites and patient mortality. Methods A retrospective multi-centre data collection study was initiated on behalf of the German, Austrian and Swiss Society of Thrombosis and Haemostasis Research (GTH). Parameters of interest were investigated over the 5 years prior to study entry. Results A total of 185 haemophilia patients (mean age, 69.0±7.0 years, 29% with severe haemophilia) were included in the study. Regular prophylaxis was performed in 30% of the patients with severe haemophilia. In total, the annual bleeding rate was 2.49 and in patients with severe haemophilia 5.61, mostly caused by joint bleeds. Hypertension was the most common co-morbidity, but it occurred significantly less frequently than in an age-matched general population older than 70 years; 12% of the patients suffered from ischaemic heart disease, and 13% of the patients received anticoagulant or antiplatelet therapy. Within the observation period, 17% of the patients with severe haemophilia developed a higher frequency of bleeding symptoms, which was significantly associated with the use of antiplatelet or anticoagulant drugs. Conclusions The most common co-morbidity of the patient population was hypertension, a considerable part had ischemic heart disease and antiplatelet or anticoagulant drugs.

Background A complex interplay of innate and adaptive immune cells maintains intestinal homeostasis. In inflammatory bowel disease (IBD), the fragile balance between regulatory and inflammatory cell subsets breaks down. The latter are recruited to the gut where they sustain intestinal inflammation and lead to tissue destruction. Due to re-circulation and gut-homing processes, the circulating immune cell compartment experiences profound changes that reflect disease activity. Meanwhile, single-cell techniques like mass cytometry have become a powerful technology to shed a light on the heterogeneity and dynamics of immune cells. As obtaining intestinal biopsies from inflamed gut is invasive and poses patients at risk, diagnostics and therapy monitoring from ‘liquid biopsies’ would be a great advance. A deeper understanding of the circulating immune cell landscape in IBD pre- and post-treatment could significantly contribute to IBD patient management by early prediction of therapy response. Methods Whole blood from 24 IBD patients—including 16 ulcerative colitis (UC) and 6 Crohn’s disease (CD) patients before treatment—and 18 age- and sex-matched healthy donors (HDs) was incubated with proteomic stabiliser and frozen. Upon thawing, cell suspensions were Palladium barcoded, stained with a 37-marker panel and acquired on a Helios mass cytometer. The generated dataset was normalised, de-barcoded and subsequently analysed. Results Using dimensionality reduction and neural-network-based algorithms, we faithfully identified different circulating immune subsets in healthy donors and IBD patients. Our preliminary analysis revealed altered myeloid cell populations, like neutrophils and macrophages, in IBD patients. In line with an activation of the innate immune system, we observed a considerable increase in the neutrophil compartment compared with healthy donors. Moreover, patterns of marker expression within different subsets showed substantial differences between healthy donors, CD and UC patients. Conclusion Here, we show a mass cytometry panel that identifies the circulating immune cell landscape and shows major differences between healthy donors, CD and UC patients.

After the expiry date of the patent protection for Infliximab in 2013, the biosimilar CT‑P13 was approved for indications in Crohn's disease and ulcerative colitis in adults as well as in children. The approval has been based on two randomized clinical studies indicating equivalence for the biosimilar with regard to pharmacokinetics, efficacy, as well as side-effects. The clinical experience since, in addition to multiple non-randomized studies, indicate a comparable efficacy and immunogenicity of the Infliximab biosimilar CT-P13 in inflammatory bowel disease. Thus, the introduction of the biosimilar as primary therapy seems to be justified. Tight monitoring of the safety of biosimilars with regard to efficacy and side effects has to be ensured.

Chronisch-entzundliche Darmerkrankungen weisen eine zunehmende Inzidenz auf und betreffen meist jungere Menschen in kritischen Lebensphasen. Eine fruhe Diagnosestellung sowie eine daraus resultierende schnelle und effiziente Therapieeinleitung sind daher essenziell. In Deutschland hat sich hier das akzelerierte „Step-up“-Vorgehen durchgesetzt, eine schnelle Therapieeskalation bei fehlendem Ansprechen mit fruher Einleitung einer immunsuppressiven Therapie. Trotz neuer Therapiestrategien fehlen fur eine Subgruppe von Patienten weitere medikamentose Optionen. Zukunftig konnten fur diese Subgruppe die Adhasionsmolekulantikorper eine neue Therapiemoglichkeit darstellen. Um jedoch primar eine individuelle Therapieplanung zu ermoglichen, ist die Identifizierung von Pradiktoren, die den weiteren Krankheitsverlauf zuverlassig vorhersagen, unabdingbar. Sollten sich die Transkriptomdaten der CD8+-T-Zellen prospektiv bestatigen, steht hier in absehbarer Zukunft ein wichtiger Biomarker zur Verfugung.

Background: Case-control studies suggest that patients with allergic diseases have a lower risk of developing glioma but not meningioma or schwannoma. However, those data can be differen ...

In sugar industries where growers and millers are independent economic entities, payment systems aim at sharing the annual sugar industry revenue. Payment systems are designed to create incentives to improve milling performance, cane yield and quality. Like most revenue sharing agreements, they tend to be a contentious issue between growers and millers. As far as quality is concerned, they are often based on complex and sophisticated formulae, and may be difficult for stakeholders to understand. In some industries, although modifying the payment system can be the key to increasing industry profitability, mistrust between growers and millers can hamper such improvements. The situation is currently exacerbated by the development of sugarcane co-products, such as ethanol, electricity or by-products for niche markets, which can generate higher profits than sugar, thus calling for a rethink of payment systems. This paper presents a decision support approach to assess new cane payment systems while increasing the transparency of revenue sharing and the effects of quality incentives on income. It is based on a decision support system called PEMPA, which helps to assess the impact of new cane payment systems on growers' incomes and on revenue sharing between stakeholders. Simulations were performed to assess the situation of 3800 growers who supply two mills on Reunion Island. Results showed that both individual incomes and collective revenue could be increased by adopting a new payment system based on a relative formula. The simulation approach could facilitate understanding and implementation of the payment formula. PEMPA is now available as freeware for testing in different settings, especially for multiple-purpose sugarcane.

Summary. On-demand or prophylactic home-treatment is currently the treatment of choice for haemophilia patients. To allow physicians to monitor the amount of factor concentrates administered, the patients document each factor injection in a paper-diary. Nevertheless, because of the fact that most patients visit their physicians only two to four times a year, there could be considerable delay in detecting medication problems. The aim of this pilot study was to assess whether an electronic documentation tool could successfully replace traditional paper-diaries for haemophilia A patients and enable the physician to have a timely overview of the patient’s treatment. An electronic, hand-held documentation tool, Haemoassist™, was developed. In this study, patients using prophylaxis and on-demand therapies documented their factor consumption both electronically and on paper-diaries. Documentations were compared and descriptively evaluated. Patients also completed a survey to evaluate the feasibility and gather their opinions on the Haemoassist™ system. Ten patients from two haemophilia treatment centres in Germany submitted a total of 548 records via hand-held device during the observation period, from March 2006 to February 2007. Comparison of electronic and paper-based records showed differing responses among patients with some patients entering more electronic and some others more paper-based documentations. In the questionnaires on feasibility and usefulness of Haemoassist™, three patients preferred the electronic tool, two patients wanted to continue using paper-based diaries, and one had no preference. The study shows that an electronic documentation system is feasible for haemophilia patients and provides the physician with the opportunity to more closely monitor patients. However, not all patients seem to be qualified for using an electronic tool, and the tool has to run reliably without major errors for ensuring reliability and acceptability. In the future, Haemoassist™ might support quality assurance in haemophilia treatment and improve guidance in the home-care setting.

BACKGROUND AND METHODS: A single centre study including 52 German patients aged ≥16 years with severe haemophilia A was performed to compare the amount of clotting factor and outcome between on-demand therapy (26 patients) and continuous prophylaxis (26 patients) over 1 year. RESULTS: Prophylaxis reduced the number of bleeds significantly. Compared to on-demand treatment (20.5 ± 3.0 bleeds/year/patient), under prophylaxis 7.8 ± 1.3 bleeds/year/patient were observed. Joint bleeds were reduced from 12.2 ± 1.5 to 4.7 ± 1.0/year/ patient. In the on-demand group 38% of the patients suffered from more than 2 bleeds/month, whereas in the prophylaxis group no patient was found with more than 2 bleeds/month. Mean annual factor VIII (FVIII) consumption increased from 767 ± 110 IU/kg body weight under on-demand treatment to 2,841 ± 341 IU/kg body weight under continuous prophylaxis, displaying a nearly fourfold increase in FVIII consumption. Furthermore, prophylaxis implies a more than four-fold increase in treatment days which escalated from a mean weekly injection rate of 0.56 ± 0.08 FVIII injections/week when bleeds were treated on demand to 2.52 ± 0.30 FVIII injections/week during prophylaxis. CONCLUSION: Even though the results reflect a benefit also for prophylactically treated patients regarding their bleeding frequency, one has to take into account a substantial increase of the costs for coagulation concentrates when all patients with severe haemophilia A switch to continuous prophylaxis.

The medical use of cannabis is discussed in gastroenterology for inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), and chronic pancreatitis.A systematic literature search until March 2015 was performed in the databases Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, www.cannabis-med.org , and clinicaltrials.gov. Randomized controlled trials (RCT) investigating herbal cannabis and/or pharmaceutical cannabinoids in IBD, IBS, or chronic pancreatitis with a study duration of ≥ 4 weeks and a sample size of at least n = 10 per study arm were identified. Clinical outcomes comprised efficacy (pain, nausea, appetite/weight, diarrhea, health-related quality of life, and remission rates for IBD), tolerability (drop-out rate due to side effects), and safety (severe side effects). Methodology quality of RCTs was evaluated with the Cochrane Risk of Bias Tool.Only one RCT treating 21 patients with Crohn's disease and herbal cannabis was identified. The study revealed no significant differences of remission rate because of low statistical power. However, there was a clear tendency for less abdominal pain and improved appetite with medical cannabis. The methodological risk of the study was high. Furthermore, results of two RCTs investigating synthetic cannabis in IBD and chronic pancreatitis, respectively, have not yet been released. No RCT for IBS was found. Several case reports described cannabis-induced acute pancreatitis.Cannabis may be useful for symptom relief in Crohn's disease such as pain, nausea, and loss of appetite. However, studies with high methodological quality, sufficient sample size, and study duration are mandatory to determine potential therapeutic effects and risks of cannabis in gastroenterology. Currently, use of tetrahydrocannabinol to alleviate symptoms such as pain and appetite loss in Crohn's disease should only be considered in individual patients after failure of established medical therapies and only after careful risk-benefit assessment.