BACKGROUND:Real-world evidence studies of ustekinumab (UST) in ulcerative colitis (UC) are needed because randomized controlled trials do not represent unselected patient populations in everyday clinical practice. Patients with UC were recruited when starting biologic therapy for the first time or switching to a new biologic therapy. This study assessed the effectiveness of maintenance therapy with UST in comparison to anti-TNF or vedolizumab (VDZ) at 12 months. METHODS:Between 2020 and 2022, 507 UC patients starting biologic therapy for the first time or switching to a new biologic therapy were enrolled at 34 inflammatory bowel disease (IBD)-specialized centers in Germany. After excluding patients receiving other biologics or small molecules, as well as those with stomas or missing outcomes, the final sample consisted of 476 patients. The outcomes were clinical response, clinical remission (CR), and steroid-free remission. Propensity score (PS) adjustment with inverse probability of treatment weighting was used to reduce the effect of confounding due to physician selection of therapy. RESULTS:A total of 476 patients with UC were included in the analysis (UST: 147, anti-TNF: 168, VDZ: 161). Treatment persistence over 12 months differed significantly (P < .001) between UST (93.9%), VDZ (87.0%), and anti-TNF (75.0%). The PS-weighted effectiveness of UST in the mITT analysis at month 12 was not significantly different from anti-TNF or VDZ (CR: UST 26.9%, anti-TNF 34.7%, VDZ 40.9%; P = .063). CONCLUSIONS:In the prospective RUN-UC study with PS-weighted groups, UST showed higher treatment persistence but no significant difference in maintenance effectiveness compared to anti-TNF or VDZ in UC.

Purpose The clinical course of ulcerative colitis (UC) is highly heterogeneous, with 20 to 30% of patients experiencing chronic disease activity requiring immunosuppressive or biologic therapies. The aim of this study was to identify predictors for a complicated disease course in an inception cohort of patients with UC. Methods EPICOL was a prospective, observational, inception cohort (UC diagnosis, ≤ 6 months) study in 311 patients with UC who were naive to immunosuppressants (IS)/biologics. A complicated course of disease was defined as the need for IS and/or biologic treatment (here therapy with a TNF-α antagonist) and/or UC-related hospitalisation. Patients were followed up for 24 months. Results Of the 307 out of 311 participants (4 patients did not meet the inclusion criteria “confirmed diagnosis of active UC within the last 6 months” ( n = 2) and “immunosuppressive-naïve” ( n = 2), analysis population), 209 (68.1%) versus 98 (31.9%) had an uncomplicated versus a complicated disease course, respectively. In a multivariate regression analysis, prior use of corticosteroids and prior anaemia were associated with a significantly increased risk for a complicated disease course (2.3- and 1.9-fold increase, respectively; p < 0.001 and p = 0.002). Based on these parameters, a risk model for patient stratification was developed. Conclusion Our study identifies anaemia and an early need for corticosteroids as predictors for a complicated course of disease in an inception cohort of patients with UC. By determining these parameters in routine clinical practice, our results may support the identification of patients who might benefit from early escalation of therapy.

Corrected by:Aktualisierte S3-Leitlinie Colitis ulcerosaZ Gastroenterol 2019; 57(11): e1-e1DOI: 10.1055/a-1108-3778

ZUSAMMENFASSUNGSicherung der Diagnose und Objektivierung des entzündlichen Schadens chronisch-entzündlicher Darmerkrankungen sind Kernelemente bei Erstdiagnose und für die Verlaufsbeurteilung. Neben dem Goldstandard der Endoskopie nehmen konsequent wiederholbare, nicht-invasive Verfahren wie das fäkale Calprotectin und der Darmultraschall zentrale Rollen ein, um das Therapieergebnis langfristig zu optimieren, Komplikationen zu verhindern und teils erhebliche Kosten sinnvoll einzusetzen.

The aim of our study was to identify clinical parameters in recently diagnosed Crohn’s disease (CD) patients for prediction of their disease course. EPIC (Early Predictive parameters of Immunosuppressive therapy in Crohn’s disease) is a prospective, observational study in 341 patients with a recent CD diagnosis (≤ 6 months), and naïve to immunosuppressants (IS) and anti-tumor necrosis factor α (TNF) agents. Patient characteristics were documented up to 2 years. In line with national and international guidelines, a complicated disease course was defined as need for immunosuppressants and/or anti-TNF agents, and CD-related hospitalization with or without immunosuppressants and/or anti-TNF agents. A total of 212 CD patients were analyzed of whom 57 (27%) had an uncomplicated disease within 24 months, while 155 (73%) had a complicated disease course: need for IS and/or anti-TNF agents (N = 115), CD-related hospitalization with or without IS/anti-TNF agents (N = 40). Identified risk predictors for a complicated disease were as follows: age at onset < 40 years (OR 2.3; 95% CI 1.2–4.5), anemia (OR 2.1; 95% CI 1.1–4.2), and treatment with systemic corticosteroids at first flare (OR 2.2; 95% CI 1.1–4.7). These three parameters were used to develop a risk model allowing prediction of the future disease course. Our three-parameter model enables an assessment of each CD patient’s risk to develop a complicated disease course. Due to the easy accessibility of these parameters, this model can be utilized in daily clinical care to assist selecting the initial treatment for each individual patient.

Die neue S3-Leitlinie Colitis stellt aktuelle und evidenzbasierte Empfehlungen zur Behandlung der Colitis ulcerosa zur Verfügung. Sie ersetzt damit die Vorläuferversion von 2011. Neben den neuesten Erkenntnissen zu Diagnostik und Therapie werden insbesondere infektiologische Probleme, chirurgische und Ernährungsmaßnahmen aufgegriffen. Unter der Federführung der DGVS wurde die Leitlinie gemeinsam mit 10 weiteren Fachgesellschaften und Patientenvertretern erarbeitet mit dem Ziel, eine optimale interdisziplinäre Versorgung der Patienten zu gewährleisten.

Background and Objectives The transmembrane heparan sulphate proteoglycan syndecan-4 (Scd4) has been implicated in cell-matrix adhesion, cell migration, differentiation, proliferation and plays an important role during inflammation in rheumatoid arthritis. Scd4 is a mediator and modulator of inflammatory signals, upon its binding of cytokines Scd4 acts either as a decoy receptor or through the initiation of Scd-dependend signalling, followed by the formation of a Scd4 complex. Cartilage damage is decreased in sdc4-deficient mice, but osteopontin-mediated liver damage is increased. Because of these dual effects we investigate the impact of sdc4 in murine experimental colitis. Materials and Methods We performed DSS-induced colitis in Scd4-/- and C57BL/6 WT mice. We used weight loss, colon length and histological scoring of colonic modifications to measure the course of colitis. Scd4-/- and WT mice were orally gavaged with 5 × 108 colony-forming units (CFU) of invasive bacterium Citrobacter rhodentium (C. rhodentium). The changes of body weight and faecal excretion of C. rhodentium were monitored for 21 days followed by evaluation of histological changes after infection. The permeability of the colon was examined in vitro by infection of colon samples from Scd4-/- and C57BL/6 WT mice with C. rhodentium. The migration behaviour of endothelial human cells (T-84) and scd4-siRNA T-84 knockdown cells was analysed by scratch assay. Results DSS-treated Scd4-/- mice lost dramatically more body weight compared to the WT mice and the histological damage according to the Dieleman-Score was markedly increased. At day 19 of post infection the clearance of C. rhodentium in Scd4-/- mice was markedly prolonged. In vitro infection of colon samples from Scd4-/- mice with C. rhodentium revealed a higher permeability for the bacterium compared to WT colon samples. The knockdown of Scd4 in human endothelial T-84 cells leads to delayed cell migration. Conclusions Like in inflammatory liver damage, Scd4 appears to play an important role in colitis and exerts protective effects in intestinal inflammation. The Scd4 deficiency leads to a higher permeability of the colon to C. rhodentium and a delayed cell migration. Further analysis are needed to explore the mechanisms of Sdc4-signalling in colitis.

In patients with inflammatory bowel disease (IBD) and in murine IBD models, mucosal disease activity is routinely assessed by endoscopy and histologic evaluation. This information is valuable for monitoring treatment response, with mucosal healing being a major treatment goal. The aim of this study was to evaluate the translational potential of noninvasive 18F-FDG PET/CT for the assessment of mucosal damage in murine dextran sodium sulfate (DSS) colitis and human IBD. Methods: After induction of DSS colitis, 18F-FDG uptake was serially assessed from colonic volumes of interest defined on PET/CT scans and intraindividually correlated to histologic findings and to infiltrating cell types. In addition, 18F-FDG PET/CT scans of 25 Crohn disease patients were analyzed, and colonic 18F-FDG uptake was correlated to endoscopically assessed damage. Results: At days 4 and 7 after DSS induction, colonic 18F-FDG uptake was significantly increased, with a distinct peak in the medial colon. 18F-FDG uptake strongly correlated with histologic epithelial damage. Additionally, 18F-FDG uptake increased in the bone marrow in the course of the disease, correlating with an increase in intestinal 18F-FDG uptake. Histology and fluorescence-activated cell sorting analysis of the bone marrow of DSS mice revealed an increased number of immature neutrophils, whereas mucosal polymerase chain reaction suggested a correlation of 18F-FDG uptake to T cell infiltration. In accordance with the results of 18F-FDG PET/CT in DSS colitis, an increased 18F-FDG uptake was found in 87% of deep mucosal ulcerations in IBD patients, whereas mild endoscopic lesions were detected only by 18F-FDG PET/CT in about 50% of patients assessed. Conclusion:18F-FDG PET/CT is a noninvasive method for evaluation of both experimental colitis and Crohn disease patients and thereby offers promising translational potential.

The role of cytomegalovirus (CMV) infection in the pathogenesis and exacerbation of Inflammatory Bowel Disease (IBD) has been unresolved. Typically, the CMV genome remains dormant in infected cells, but a breakdown of immune surveillance can lead to re-activation of viral replication in the gut mucosa, which is not necessarily associated with viremia or changes in antibody titers. We hypothesized that the detection of CMV-specific CD8 effector T cells should permit the distinction between dormant and active CMV infection. As CD8 effector T cells, unlike memory CD8 T cells, have perforin (PFN) and granzyme B (GzB) preformed in their cytoplasmic granules, we employed single cell resolution ELISPOT assays to measure the CMV antigen-triggered release of these molecules by CD8 T cells isolated from subjects with IBD, and age-matched healthy controls. The frequencies of CMV-specific (GzB) and PFN-producing CD8 T cells were increased in IBD patients compared to healthy controls. Furthermore, the increased CMV reactivity was associated with active IBD disease and with longer disease duration. Notably, PCR on serum frequently failed to detect CMV DNA during flares. The data show that during active IBD there is a flare of CD8 T cell activity against CMV in a substantial proportion of IBD patients, suggesting CMV reactivation that serum PCR does not detect. While it remains open whether CMV reactivation is a cause or consequence of IBD, our data suggest that monitoring CMV antigen-specific effector CD8 T cells with GzB and PFN ELISPOT analysis can provide novel insights into the role of CMV infection in IBD. Additionally, our data have implications for the fields of transplantation, HIV, cancer, and autoimmune diseases, in all of which patient care critically depends on sensitive and reliable detection of a reactivation of CMV infection.

Treatment options for inflammatory bowel disease (IBD) are incompletely helpful, and surgery is often needed. One promising class of future therapeutic agents for IBD is melanocortin-related peptides, which exhibit potent immunomodulatory effects. We investigated KdPT, a tripeptide derivative of the C-terminus of α-melanocyte-stimulating hormone, as an anti-inflammatory small molecule in vivo and in vitro. Intestinal inflammation was studied after oral administration of dextran sodium sulfate and in IL-10 gene-deficient mice. The effects of KdPT on key colonic epithelial cell functions were studied in vitro and in vivo by evaluating proliferation, wound healing, transepithelial resistance, and expression of tight junction proteins. Melanin assays were performed to determine the melanotropic effects of KdPT. KdPT-treated animals showed markedly reduced severity of inflammation in both colitis models. In colonic epithelial cells, KdPT increased proliferation, accelerated closure of wounds, and improved transepithelial electrical resistance after stimulation with interferon-γ/tumor necrosis factor-α. Moreover, treatment with KdPT also prevented the loss of tight junction protein expression and improved barrier function in vivo. KdPT acted independently of IL-1 receptor type I in vivo and did not affect melanogenesis in vitro. KdPT is capable of attenuating the course of experimental colitis in different models and maintains epithelial cell function. Furthermore, KdPT does not induce pigmentation, emphasizing the potential of this small molecule for the future treatment of IBD.

Aim: Recent research has shown a crucial role of mesenchymal cell expressed Melanocortin-1-receptor (MC1R) in experimental colitis. The aim of this study was to evaluate therapeutic effects of MC1Rs main ligand, alpha-Melanocyte-stimulating hormone (α-MSH) or its C-terminal tripeptide KPV in intestinal inflammation in vivo and in intestinal epithelial cells in vitro. Methods: Antiinflammatory activity of KPV was analyzed in two murine models of IBD, DSS- and CD45RBhigh-transfercolitis. To further characterize this effect we tested the influence of α-MSH on secretion of IL-8 in intestinal epithelial cells. Results: In DSS-colitis, treatment with KPV lead to significantly reduced weight loss and tissue myeloperoxidase activity. Histologically, markedly reduced inflammatory infiltrates were seen in colonic tissue. In the CD45RBhigh-transfercolitis model KPV-treated animals regained body weight, while control mice continuously lost weight. In vitro MC1R was found to be expressed by various intestinal epithelial cell lines allowing its ligand α-MSH/KPV to bind to those epithelial cells leading to a marked decrease of cytokine-induced IL-8 secretion in these cells. Conclusions: The melanocortin-derived tripeptide KPV showed significant antiinflammatory effects in two murine models of colitis potentially through downregulation of epithelial expressed chemokines such as IL-8.