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Dysregulation at the intestinal epithelial barrier is a driver of inflammatory bowel disease (IBD). However, the molecular mechanisms of barrier failure are not well understood. Here, we demonstrate dysregulated mitochondrial fusion in intestinal epithelial cells (IECs) of patients with IBD and show that impaired fusion is sufficient to drive chronic intestinal inflammation. We found reduced expression of mitochondrial fusion-related genes, such as the dynamin-related guanosine triphosphatase (GTPase) optic atrophy 1 ( OPA1 ), and fragmented mitochondrial networks in crypt IECs of patients with IBD. Mice with Opa1 deficiency in the gut epithelium ( Opa1 i∆IEC ) spontaneously developed chronic intestinal inflammation with mucosal ulcerations and immune cell infiltration. Intestinal inflammation in Opa1 i∆IEC mice was driven by microbial translocation and associated with epithelial progenitor cell death and gut barrier dysfunction. Opa1 -deficient epithelial cells and human organoids exposed to a pharmacological OPA1 inhibitor showed disruption of the mitochondrial network with mitochondrial fragmentation and changes in mitochondrial size, ultrastructure, and function, resembling changes observed in patient samples. Pharmacological inhibition of the GTPase dynamin-1-like protein in organoids derived from Opa1 i∆IEC mice partially reverted this phenotype. Together, our data demonstrate a role for epithelial OPA1 in regulating intestinal immune homeostasis and epithelial barrier function. Our data provide a mechanistic explanation for the observed mitochondrial dysfunction in IBD and identify mitochondrial fusion as a potential therapeutic target in this disease.

The intestinal epithelium forms the boundary between the intestinal immune system in the lamina propria and the outside world, the intestinal lumen, which contains a diverse array of microbial and environmental antigens. Composed of specialized cells, this epithelial monolayer has an exceptional turnover rate. Differentiated epithelial cells are released into the intestinal lumen within a few days, at the villus tip, a process that requires strict regulation. Dysfunction of the epithelial barrier increases the intestinal permeability and paves the way for luminal antigens to pass into the intestinal serosa. Stem cells at the bottom of Lieberkühn crypts provide a constant supply of mature epithelial cells. Differentiated intestinal epithelial cells exhibit a diverse array of mechanisms that enable communication with surrounding cells, fortification against microorganisms, and orchestration of nutrient absorption and hormonal balance. Furthermore, tight junctions regulate paracellular permeability properties, and their disruption can lead to an impairment of the intestinal barrier, allowing inflammation to develop or further progress. Intestinal epithelial cells provide a communication platform through which they maintain homeostasis with a spectrum of entities including immune cells, neuronal cells, and connective tissue cells. This homeostasis can be disrupted in disease, such as inflammatory bowel disease. Patients suffering from inflammatory bowel disease show an impaired gut barrier, dysregulated cellular communication, and aberrant proliferation and demise of cells. This review summarizes the individual cellular and molecular mechanisms pivotal for upholding the integrity of the intestinal epithelial barrier and shows how these can be disrupted in diseases, such as inflammatory bowel disease., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Mirikizumab, a humanised monoclonal antibody that inhibits IL-23p19, is effective in moderate-to-severe ulcerative colitis. We aimed to evaluate the efficacy and safety of mirikizumab in patients with moderately-to-severely active Crohn's disease., Methods: VIVID-1 was a global phase 3, randomised, double-blind, double-dummy, placebo-controlled and active-controlled, treat-through study. The study enrolled adult patients at 324 sites (hospitals or medical centres, clinical practices, and clinical research sites) in 33 countries across Europe, Asia, North America, Central America, South America, and Australia. Adult patients with moderately-to-severely active Crohn's disease and previous inadequate response, loss of response, or intolerance to one or more approved biological therapies or conventional therapies were randomly assigned 6:3:2 to receive mirikizumab 900 mg intravenously at weeks 0, 4, and 8, then 300 mg subcutaneously every 4 weeks from weeks 12 to 52; ustekinumab about 6 mg/kg intravenously at week 0, then 90 mg subcutaneously every 8 weeks from weeks 8 to 52; or placebo. The coprimary endpoints assessing superiority of mirikizumab over placebo were composite endpoints: patient-reported outcome (PRO) clinical response at week 12 and endoscopic response at week 52 (endoscopic response-composite), and PRO clinical response at week 12 and Crohn's Disease Activity Index (CDAI) clinical remission at week 52 (CDAI clinical remission-composite). The adjusted risk differences were calculated, and the comparison was performed by the Cochran-Mantel-Haenszel test. Non-responder imputation was used. VIVID-1 was registered on ClinicalTrials.gov, NCT03926130, and is now complete., Findings: Between July 23, 2019, and Aug 23, 2023, 1150 patients were randomly assigned and received study treatment (safety population); 1065 patients were included in the efficacy population and received mirikizumab (n=579), ustekinumab (n=287), or placebo (n=199). Both coprimary endpoints were met: endoscopic response-composite was reached in 220 (38·0%) of 579 patients on mirikizumab versus 18 (9·0%) of 199 on placebo (99·5% CI 20·6-36·8; p<0·0001); CDAI clinical remission-composite was reached in 263 (45·4%) of 579 patients on mirikizumab versus 39 (19·6%) of 199 patients on placebo (99·5% CI 15·9-35·6; p<0·0001). The incidence rates of overall adverse events and discontinuations in patients treated with mirikizumab were lower compared with placebo. The most common adverse event across the three groups was COVID-19. Serious adverse events were reported in 65 (10·3%) of 630 patients on mirikizumab, 33 (10·7%) of 309 patients on ustekinumab, and 36 (17·1%) of 211 patients on placebo. There were three deaths during VIVID-1, one in the ustekinumab group, and two in the placebo group, including one in a placebo non-responder who switched to mirikizumab after week 12. None of the deaths were considered related to the study drug. The safety of mirikizumab in Crohn's disease was consistent with its known favourable profile., Interpretation: Mirikizumab was safe and effective as induction and maintenance treatment for patients with moderately-to-severely active Crohn's disease who had intolerance, inadequate response, or loss of response to standard therapy., Funding: Eli Lilly and Company., Competing Interests: Declaration of interests MF has received research grants from AbbVie, Biogen, Janssen, Pfizer, Takeda, and Viatris; consultancy fees from AbbVie, AgomAb Therapeutics, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Janssen-Cilag, MRM Health, MSD, Pfizer, Takeda, and ThermoFisher; and speakers fees from AbbVie, Biogen, Boehringer Ingelheim, Falk, Ferring, Janssen-Cilag, MSD, Pfizer, Takeda, Truvion Healthcare, and Viatris. GD'H has served as adviser or speaker for Abbvie, Alimentiv, Amgen, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Ferring, Eli Lilly, Engene, Galapagos, GlaxoSmithKline, Immunic, Index Pharmaceuticals, Johnson and Johnson, Merck, Polpharm, Prometheus biosciences, Prometheus Laboratories, Procise Diagnostics, Protagonist, Sandoz, Takeda, Tillotts, and Ventyx. VJ has received consulting or advisory board fees from AbbVie, Alimentiv, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, AstraZeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead, Innomar, JAMP Pharma Group, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, SCOPE, Second Genome, Sorriso, Takeda, TD Securities, Teva, Topivert, Ventyx, and Vividion; and speaker's fees from AbbVie, Ferring, Bristol Myers Squibb, Galapagos, Janssen Pfizer Shire, Takeda, and Fresenius Kabi. SD has received consulting fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, Union Chimique Belge, Vial, and Vifor; has received lecture fees from AbbVie, Amgen, Ferring Pharmaceuticals, Gilead, Janssen, Mylan, Pfizer, and Takeda. MC provided educational activities for AbbVie, China Medical System, IPSEN, Janssen, and Takeda; served on an advisory board for Boehringer Ingelheim and Janssen; and has received support for clinical research from Janssen and Takeda. SG has speaking commitments with AbbVie, Takeda, Janssen, Pfizer, Gilead, Galapagos, Ferring, Eli Lilly and Company, and Celltrion; serves on the drug monitoring committees with Janssen; and serves on advisory committees with Janssen, AbbVie, Takeda, Gilead, Galapagos, Eli Lilly and Company, Pfizer, Celltrion, and Ferring; serves on steering committees with Janssen, Bristol Myers Squibb, and AbbVie. TH has a joint research agreement from Kissei Pharmaceutical and EA Pharma; has received research grants from AbbVie, Daiichi Sankyo, EA Pharma, JIMRO, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, Boston Scientific, and Zeria Pharmaceutical; and has received consulting and lecture fees from AbbVie, EA Pharma, Gilead Sciences, Janssen Pharmaceuticals, JIMRO, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical, Pfizer, Kissei Pharmaceutical, and Takeda. JK has received research grants from AbbVie, Egis, Janssen, Nestlé, Nutricia, and Takeda; has received honoraria from AbbVie, Egis, Janssen, Nestlé, Nutricia, and Takeda; and has received consulting fees from AbbVie, Egis, Janssen, Nestlé, Nutricia, and Takeda. BS has served as a consultant for AbbVie, Abivax, Arena, Bristol Myers Squibb, Boehringer, CED Service, Celgene, CT Scout, Endpoint Health, Falk, Forga Software, Galapagos, Janssen, Lilly, Materia Prima, Pfizer, Takeda, Pharma Insight, Predictimmune, and PsiCro; has received speaker fees for AbbVie, BMS, CED Service, Chiesi, Falk, Ferring, Gilead, Janssen, Lilly, Materia Prima, Takeda, and Pfizer; and has received grant support from Arena and Pfizer (served as representative of the Charité). SMB, WC, FD, EH, ZL, MUL, NM, MP, and HC are employees and stockholders of Eli Lilly and Company. BES reports consulting fees from AbbVie, Alimentiv, Amgen, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Morphic Therapeutics, MRM Health, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Sun Pharma, Surrozen, Target RWE, Teva, TLL Pharmaceutical, and Ventyx Biosciences; consulting and speaking fees from Abivax; consulting and speaking fees and other support from Lilly; research grants, consulting and speaking fees, and other support from Bristol Myers Squibb, Janssen, Pfizer, and Takeda; research grants and consulting fees from Theravance Biopharma; and stock options from Ventyx Biopharma., (Copyright © 2024 Elsevier Ltd. 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Thin film interference is integral to modern photonics, e.g., allowing for precise design of high performance optical filters, photovoltaics and light-emitting devices. However, interference inevitably leads to a generally undesired change of spectral characteristics with angle. Here, we introduce a strategy to overcome this fundamental limit in optics by utilizing and tuning the exciton-polariton modes arising in ultra-strongly coupled microcavities. We demonstrate optical filters with narrow pass bands that shift by less than their half width (< 15 nm) even at extreme angles. By expanding this strategy to strong coupling with the photonic sidebands of dielectric multilayer stacks, we also obtain filters with high extinction ratios and up to 98% peak transmission. Finally, we apply this approach in flexible filters, organic photodiodes, and polarization-sensitive filtering. These results illustrate how strong coupling provides additional degrees of freedom in thin film optics that will enable exciting new applications in micro-optics, sensing, and biophotonics., Competing Interests: Competing interests: A.M. and M.C.G. are inventors of two pending patent applications (application numbers DE102020125597 and DE102024109482.6) filed by the University of Cologne on polariton-based filters. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Background & Aims: In Crohn's disease, wrapping of mesenteric fat around the bowel wall, so-called "creeping fat," is highly associated with strictures. The strongest contributor to luminal narrowing in strictures is a thickening of the human intestinal muscularis propria (MP). We investigated creeping fat-derived factors and their effect on mechanisms of human intestinal MP smooth muscle cell (HIMC) hyperplasia., Methods: Free fatty acids (FFAs) in creeping fat or noncreeping mesenteric fat organ cultures were measured via lipidomic mass spectrometry. Primary HIMCs were exposed to FFAs and cell proliferation was assessed. Intracellular FFA metabolism pathways and reactive oxygen species were functionally evaluated. Muscle thickness was investigated in dextran sodium sulfate colitis with small molecule inhibition of FFA transport and a novel fat deletion mouse model., Results: Subserosal creeping fat is associated with a markedly thickened MP. Experimental deletion of mesenteric fat (FAT-ATTAC [fat apoptosis through targeted activation of caspase 8] mouse) reduced MP thickness. Human creeping fat-conditioned medium strongly up-regulated HIMC proliferation. Creeping fat released higher amounts of 5 long-chain FFAs, including palmitate. Inhibition of HIMC long-chain FFA metabolism or FFA uptake into mitochondria through carnitine palmitoyltransferase-1 reduced the palmitate-induced HIMC proliferation. Blockade of conversion of palmitate into phospholipids reduced HIMC proliferation. Prophylactic inhibition of carnitine palmitoyltransferase-1 in experimental dextran sodium sulfate colitis did not ameliorate inflammation, but reduced MP thickness., Conclusions: Creeping fat-released long-chain FFAs induce a selective proliferative response by HIMC. These results point to creeping fat as a novel contributor to stricture formation in Crohn's disease., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Normalization of high-sensitivity C-reactive protein [hs-CRP] and fecal calprotectin [FCP] are suggested Crohn's disease [CD] intermediate treatment targets. This analysis evaluates achievement of biomarker normalization and the relationship between improvements in biomarker concentrations and clinical and endoscopic outcomes among patients treated with risankizumab., Methods: This post hoc analysis included patients with moderately to severely active CD and elevated baseline hs-CRP [> 5 mg/L] or FCP [> 250 µg/g] concentrations from the 12-week ADVANCE and MOTIVATE induction studies, and the 52-week FORTIFY maintenance study. We assessed the proportion of patients achieving biomarker normalization, defined as hs-CRP ≤ 5 mg/L and FCP ≤ 250 µg/g, and the association between achieving biomarker normalization and improved clinical and endoscopic outcomes., Results: Among 748 patients with elevated baseline hs-CRP or FCP concentrations, higher proportions of patients treated with risankizumab vs placebo achieved normalization of hs-CRP [week 12: placebo, 17.5%; risankizumab 600 mg, 48.5%; week 52: placebo, 29.5%; risankizumab 180 mg, 45.2%; risankizumab 360 mg, 40.8%] and FCP [week 12: placebo, 9.1%; risankizumab 600 mg, 26.0%; week 52: placebo, 28.0%; risankizumab 180 mg, 43.0%; risankizumab 360 mg, 44.0%; nominal p < 0.05 vs placebo for all comparisons]. Achievement of both clinical or endoscopic outcomes and improvement of biomarker concentrations occurred at higher rates among patients treated with risankizumab vs placebo, regardless of prior exposure to biologic therapies., Conclusions: Risankizumab treatment led to sustained normalization of inflammatory biomarkers with improved clinical and endoscopic results., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background: Quality of life research with respect to patient reported outcomes (PROs) other than pain has not yet been conducted in the field of Diffuse Sclerosing Osteomyelitis. This cross-sectional study aims to investigate changes in quality of life regarding 34 subjective parameters in patients with diffuse sclerosing osteomyelitis after intravenous Ibandronic acid administration (6mg)., Material and Methods: 15 patients (11 female, 4 male) with diffuse sclerosing osteomyelitis (DSO) treated with 6mg of Ibandronic acid completed the standardized questionnaires (EORTC QLQ-C30, EORTC QLQ-H&N35, OHIP-G 14) considering quality of life before and two weeks after infusion., Results: All 15 patients reported a significantly improved quality of life after administration of Ibandronate. Patients reported improvements in oral health associated quality of life as well as reduction of pain and intake of analgesics. In addition patients reported a significant improvement in fatigue, sexuality, social interactions, emotional, cognitive and role functioning. Furthermore patients reported an improvement in mouth opening, weight loss and loss of appetite as well as a reduction of speech and swallowing problems. Moreover, insomnia occurred less frequently after bisphosphonate infusions., Conclusions: The study evaluates patients subjectively benefit from a standardized Ibandronic acid regimen. A significantly improved quality of life after administration of Ibandronate was observed in all 15 patients.

Background & Aims: Primary sclerosing cholangitis (PSC), often associated with inflammatory bowel disease (IBD), presents a multifactorial etiology involving genetic, immunologic, and environmental factors. Gut dysbiosis and bacterial translocation have been implicated in PSC-IBD, yet the precise mechanisms underlying their pathogenesis remain elusive. Here, we describe the role of gut pathobionts in promoting liver inflammation and fibrosis due to the release of bacterial outer membrane vesicles (OMVs)., Methods: Preclinical mouse models in addition to ductal organoids were used to acquire mechanistic data. A proof-of-concept study including serum and liver biopsies of a patient cohort of PSC (n = 22), PSC-IBD (n = 45), and control individuals (n = 27) was performed to detect OMVs in the systemic circulation and liver., Results: In both preclinical model systems and in patients with PSC-IBD, the translocation of OMVs to the liver correlated with enhanced bacterial sensing and accumulation of the NLRP3 inflammasome. Using ductal organoids, we were able to precisely attribute the pro-inflammatory and pro-fibrogenic properties of OMVs to signaling pathways dependent on Toll-like receptor 4 and NLRP3-gasdermin-D. The immunostimulatory potential of OMVs could be confirmed in macrophages and hepatic stellate cells. Furthermore, when we administered gut pathobiont-derived OMVs to Mdr2 -/- mice, we observed a significant enhancement in liver inflammation and fibrosis. In a translational approach, we substantiated the presence of OMVs in the systemic circulation and hepatic regions of severe fibrosis using a PSC-IBD patient cohort., Conclusions: This study demonstrates the contribution of gut pathobionts in releasing OMVs that traverse the mucosal barrier and, thus, promote liver inflammation and fibrosis in PSC-IBD. OMVs might represent a critical new environmental factor that interacts with other disease factors to cause inflammation and thus define potential new targets for fibrosis therapy., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Despite the success of biological therapies in treating inflammatory bowel disease, managing patients remains challenging due to the absence of reliable predictors of therapy response., Methods: In this study, we prospectively sampled 2 cohorts of patients with inflammatory bowel disease receiving the anti-integrin α4β7 antibody vedolizumab. Samples were subjected to mass cytometry; single-cell RNA sequencing; single-cell B and T cell receptor sequencing (BCR/TCR-seq); serum proteomics; and multiparametric flow cytometry to comprehensively assess vedolizumab-induced immunologic changes in the peripheral blood and their potential associations with treatment response., Results: Vedolizumab treatment led to substantial alterations in the abundance of circulating immune cell lineages and modified the T-cell receptor diversity of gut-homing CD4 + memory T cells. Through integration of multimodal parameters and machine learning, we identified a significant increase in proliferating CD4 + memory T cells among nonresponders before treatment compared with responders. This predictive T-cell signature demonstrated an activated T-helper 1/T-helper 17 cell phenotype and exhibited elevated levels of integrin α4β1, potentially making these cells less susceptible to direct targeting by vedolizumab., Conclusions: These findings provide a reliable predictive classifier with significant implications for personalized inflammatory bowel disease management., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Infections are a safety concern in patients with ulcerative colitis [UC]. Etrasimod is an oral, once daily [QD], selective sphingosine 1-phosphate [S1P]1,4,5 receptor modulator for the treatment of moderately to severely active UC. It leads to selective and reversible lymphocyte sequestration and partial peripheral lymphocyte count decrease. We report infection events from the phase 3 ELEVATE programme., Methods: Proportions, incidence rates [IRs; per 100 patient-years], and descriptive analyses of all serious, severe, herpes zoster and opportunistic infections are reported in the Pivotal UC cohort [ELEVATE UC 52 and ELEVATE UC 12]. Cox regression models evaluated potential baseline risk factors., Results: In this analysis [n = 787], proportions [IRs] of all infection events were similar for patients receiving etrasimod 2 mg QD (18.8% [41.1]) or placebo (17.7% [49.0]). Serious infections occurred in three [0.6%] and five [1.9%] patients receiving etrasimod and placebo, respectively. Two herpes zoster events were reported in each group [etrasimod: 0.4%; placebo: 0.8%], all localised and non-serious. One opportunistic infection event was reported in each group. No patient with an absolute lymphocyte count [ALC] < 0.2 × 109/L reported serious/severe or opportunistic infections; no baseline risk factors were identified for such events. No deaths occurred., Conclusions: Patients receiving etrasimod demonstrated no increased risk of infection. The incidence of serious infections and herpes zoster was similar in each group. Among patients receiving etrasimod, no association between ALC < 0.5 × 109/L and infection events was observed. Longer-term follow-up will further characterise the etrasimod safety profile. Clinicaltrials.gov: NCT03945188; NCT03996369., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background and Aims: Standardising health outcome measurements supports delivery of care and enables data-driven learning systems and secondary data use for research. As part of the Health Outcomes Observatory [H2O] initiative, and building on existing knowledge, a core outcome set [COS] for inflammatory bowel diseases [IBD] was defined through an international modified Delphi method., Methods: Stakeholders rated 90 variables on a 9-point importance scale twice, allowing score modification based on feedback displayed per stakeholder group. Two consecutive consensus meetings were held to discuss results and formulate recommendations for measurement in clinical practice. Variables scoring 7 or higher by ≥80% of the participants, or based on consensus meeting agreement, were included in the final set., Results: In total, 136 stakeholders (45 IBD patients [advocates], 74 health care professionals/researchers, 13 industry representatives, and four regulators) from 20 different countries participated. The final set includes 18 case-mix variables, three biomarkers [haemoglobin to detect anaemia, C-reactive protein and faecal calprotectin to detect inflammation] for completeness, and 28 outcomes (including 16 patient-reported outcomes [PROs] and one patient-reported experience). The PRO-2 and IBD-Control questionnaires were recommended to collect disease-specific PROs at every contact with an IBD practitioner, and the Subjective Health Experience model questionnaire, PROMIS Global Health and Self-Efficacy short form, to collect generic PROs annually., Conclusions: A COS for IBD, including a recommendation for use in clinical practice, was defined. Implementation of this set will start in Vienna, Berlin, Barcelona, Leuven, and Rotterdam, empowering patients to better manage their care. Additional centres will follow worldwide., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Spondyloarthritis (SpA) is a term to describe a group of chronic inflammatory rheumatic diseases, which have common pathophysiological, genetic, and clinical features. Under the umbrella term SpA, two main groups are subsumed: axial SpA (radiographic axSpA and non-radiographic axSpA) and peripheral SpA (with the leading representative being psoriatic arthritis (PsA) but also arthritis associated with inflammatory bowel disease (IBD), reactive arthritis, and undifferentiated pSpA). The key clinical symptom in axSpA is chronic back pain, typically with inflammatory characteristics, which starts in early adulthood, while the leading clinical manifestations of peripheral SpA (pSpA) are arthritis, enthesitis, and/or dactylitis. Furthermore, extra-musculoskeletal manifestations (EMMs) (acute anterior uveitis, psoriasis, and IBD) can accompany axial or peripheral symptoms. All these factors need to be taken into account when making treatment decisions in SpA patients. Despite the major advances in the treatment landscape over the past two decades with the introduction of biological disease-modifying anti-rheumatic drugs (bDMARDs) and most recently targeted synthetic DMARDs (tsDMARDs), a relevant proportion of patients still does not achieve the desired state of remission (=absence of disease activity). With this implementation of new treatment modalities, clinicians now have more choices to make in the treatment algorithms. However, despite generalized treatment recommendations, all factors need to be carefully considered when deciding on the optimal treatment strategy for an individual patient in clinical practice, aiming at an important first step towards personalized treatment strategies in SpA. In this narrative review, we focus on the efficacy of approved and emerging treatment options in axSpA and PsA as the main representative of pSpA and discuss their selective effect on the different manifestations associated with SpA to provide guidance on drivers of treatment decisions in specific situations., Competing Interests: Declaration of competing interest TID: has nothing to disclose. FP: received grants and personal fees from Novartis, Eli Lilly, and UCB and personal fees from AbbVie, AMGEN, BMS, Celgene, Galapagos, Janssen, Hexal, Medscape, MSD, Pfizer and Roche outside the presented work. KG: received grants or contracts from Bristol Myers Squibb; received consulting fees from Abbvie, Lilly, Almirall, Janssen, Boehringer Ingelheim, Pfizer, Bristol Myers Squibb, and UCB; received payment /honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from Abbvie Allergan Alimera Bayer Novartis Pfizer Roche Santen Thea; received support for attending meetings and/or travel from Abbvie, Almirall, BMS, and Lilly. UP: received grants or contracts from EU, BMBF; received consulting fees from Affibody, Alcon, Allergan, Janssen, Novartis, Panoptes, Pfizer, Roche, Thea, Lilly, Pfizer, Santen. Holds patents EP 19732357.9, PCT/EP2019/066419, PCT/J/2020–570,837.BS: received grants or contracts from Pfizer; received consulting fees from Abbvie, Abivax, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Endpoint Health, Falk Pharma, Galapagos, Gilead, Janssen, Landos, Lilly, Pfizer, and Takeda; received payment /honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from Abbvie, BMS, CED Service GmbH, Eli Lilly, Falk Pharma, Ferring, Galapagos, Janssen, Lilly, Pfizer, and Takeda.DP: received consulting fees from AbbVie, Biocad, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, MSD, Moonlake, Novartis, Pfizer, Samsung Bioepis and UCB; received payment /honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, MSD, Medscape, Novartis, Peervoice, Pfizer and UCB., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Importance: The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown., Objective: To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis., Design, Setting, and Participants: Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab., Interventions: For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks., Main Outcomes and Measures: The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial., Results: Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P < .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P < .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups., Conclusion and Relevance: Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up., Trial Registration: ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135.

Background and Aims: Fistula formation is a major complication in Crohn's disease [CD] and the role of the immune cell compartment remains to be elucidated. Thus, we compared the immune cell compartment of CD fistula to inflammatory CD colitis using imaging mass cytometry [IMC] and immunofluorescence., Methods: A 36-marker panel including structural, functional, and lineage markers for use in IMC was established. This panel was applied to analyse paraffin-embedded CD fistula tract [n = 11], CD colitis [n = 10], and colon samples from non-inflamed controls [n = 12]. Computational methods for cell segmentation, dimensionality reduction, and cell type clustering were used to define cell populations for cell frequency, marker distribution, and spatial neighbourhood analysis. Multiplex immunofluorescence was used for higher resolution spatial analysis., Results: Analysis of cell frequencies in CD fistulas compared to CD colitis and control colonic samples revealed a significant increase in neutrophils, effector cytotoxic T cells, and inflammatory macrophages in CD fistula samples, whereas regulatory T cells were decreased. Neutrophils in CD fistula expressed significantly more matrix metalloproteinase 9 [MMP9], correlating with extracellular matrix remodelling. Neighbourhood analysis revealed a strong association between MMP9+ neutrophils and effector cytotoxic T cells in both CD fistulas and colitis., Conclusions: This study presents the first highly multiplexed single cell analysis of the immune cell compartment of CD fistulas and their spatial context. It links immune cell dynamics, particularly MMP9+ neutrophils, to extracellular matrix remodelling in CD fistulas, offering insights into the complex network of cellular interactions and potential therapeutic targets for CD complications., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

As a promising candidate to drive low-power, off-grid applications, organic indoor photovoltaics are beginning to attract research and commercial attention. In organic photovoltaic devices, charge transport layers are often used to promote the extraction of majority carriers, while blocking minority carriers. They can however be a source of device degradation and introduce additional complexity to the fabrication of the device stack. Here, a simplified, yet performant indoor OPV architecture is demonstrated with extended absorber thickness and without electron transport layer (ETL). We show that the diminished impact of the ETL on indoor OPV results from a drastically reduced surface recombination in thick absorber devices. However, the ETL remains important under strong, outdoor illumination, since in that case the reduced surface recombination is overwhelmed by bulk recombination. The proposed simplified device architecture with thick absorber (>500 nm) has great potential in large-scale production of indoor OPV.

Background: Early diagnosis is key to prevent bowel damage in inflammatory bowel disease (IBD). Risk factor analyses linked with delayed diagnosis in European IBD patients are scarce and no data in German IBD patients exists., Aim: To identify risk factors leading to prolonged diagnostic time in a German IBD cohort., Methods: Between 2012 and 2022, 430 IBD patients from four Berlin hospitals were enrolled in a prospective study and asked to complete a 16-item questionnaire to determine features of the path leading to IBD diagnosis. Total diagnostic time was defined as the time from symptom onset to consulting a physician (patient waiting time) and from first consultation to IBD diagnosis (physician diagnostic time). Univariate and multivariate analyses were performed to identify risk factors for each time period., Results: The total diagnostic time was significantly longer in Crohn's disease (CD) compared to ulcerative colitis (UC) patients (12.0 vs 4.0 mo; P < 0.001), mainly due to increased physician diagnostic time (5.5 vs 1.0 mo; P < 0.001). In a multivariate analysis, the predominant symptoms diarrhea ( P = 0.012) and skin lesions ( P = 0.028) as well as performed gastroscopy ( P = 0.042) were associated with longer physician diagnostic time in CD patients. In UC, fever was correlated ( P = 0.020) with shorter physician diagnostic time, while fatigue ( P = 0.011) and positive family history ( P = 0.046) were correlated with longer physician diagnostic time., Conclusion: We demonstrated that CD patients compared to UC are at risk of long diagnostic delay. Future efforts should focus on shortening the diagnostic delay for a better outcome in these patients., Competing Interests: Conflict-of-interest statement: All authors declare that they have no conflicts of interest related to this paper., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Janus kinase (JAK) inhibitors and sphingosine 1 phosphate (S1P) receptor modulators are small molecule drugs (SMDs) approved for IBD treatment. Their use in clinical practice might be limited due to cardiovascular concerns. We aimed to provide guidance on risk assessment, monitoring, and management strategies, aiming to minimize potential cardiovascular risks of SMDs and to facilitate an adequate shared decision-making. A systematic literature search was conducted, and proposed statements were prepared. A virtual consensus meeting was held, in which eleven IBD physicians and two cardiovascular specialists from ten countries attended. Proposed statements were voted upon in an anonymous manner. Agreement was defined as at least 75 % of participants voting as 'agree' with each statement. Consensus was reached for eighteen statements. Available evidence does not show a higher risk of cardiovascular events with JAK inhibitors in the overall IBD population, although it might be increased in patients with an unfavorable cardiovascular profile. S1P receptor modulators may be associated with a risk of bradycardia, atrioventricular blocks, and hypertension. Cardiovascular risk stratification should be done before initiation of SMDs. Although the risk of cardiovascular events in patients with IBD on SMDs appears to be low overall, caution should still be taken in certain scenarios., Competing Interests: Conflict of Interest PAO declares no conflict of interest. AD reports fees for participation in clinical trials, review activities such as data monitoring boards, statistical analysis, and end point committees from Abivax, AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb/Celgene, Dr Falk Foundation, Galapagos, Gilead, Janssen, and Pfizer; consultancy fees from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Celltrion, Dr Falk Foundation, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Roche/Genentech, Sandoz/Hexal, Takeda, Tillotts, and Vifor Pharma; payment from lectures including service on speakers bureaus from AbbVie, Biogen, CED Service GmbH, Celltrion, Falk Foundation, Ferring, Galapagos, Gilead, High5MD, Janssen, Materia Prima, MedToday, MSD, Pfizer, Streamed-Up, Takeda, Tillotts, and Vifor Pharma; payment for manuscript preparation from Falk Foundation, Takeda, Thieme, and UniMed Verlag. MCD has received consulting fees from AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Pfizer Inc, Prometheus Laboratories, Takeda, and UCB. GP declares no conflict of interest. PGK: speaking and consultancy honorarium from Abbvie, Janssen, Pfizer and Takeda; Scientific grants from Pfizer and Takeda. ID has served as a speaker, consultant, or advisory board member for Takeda, Janssen, AbbVie, Pfizer, Eli-Lilly, Ferring, Roche/Genentech, Cambridge Healthcare, Celgene/BMS, Falk Pharma, Ierative Scopes, Rafa Laboratories, Neopharm, Arena, Gilead, Galapagos, Celltrion, Sublimity, Sandoz, Abbott, and Athos Therapeutics. TK has served as a speaker, a consultant or an advisory board member for AbbVie, Alfresa Pharma, Bristol Myers Squibb, Celltrion, Covidien, EA Pharma, Eisai, Eli Lilly, Ferring Pharmaceuticals, Gilead Sciences, Janssen, JIMRO, Kyorin Pharmaceutical, Kissei, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Sekisui Medical, Takeda Pharmaceutical, Zeria Pharmaceutical, and received research funding from AbbVie, Alfresa Pharma, EA Pharma, Gilead, Kyorin Pharmaceutical, Mochida Pharmaceutical, Nippon Kayaku, Otsuka Holdings, Pfizer, Sekisui Medical, Takeda Pharmaceutical, Zeria Pharmaceutical. SG reports research grants from GSK, Abbvie; Drug Monitoring Committee from Janssen, Steering Committees from BMS, Receptos, Janssen, Abbvie, Gilead, Galapagos; Lecture fees from Takeda, Pfizer, Janssen, Abbvie, BMS, Galapagos, Gilead, Celltrion and consulting fees from Abbvie, Janssen, Takeda, Pfizer, Galapagos, Celltrion, Ferring. FM has served as a speaker and received honoraria from Abbvie, Arena, Biogen, Bristol-Myers Squibb, Falk, Ferring, Hospira, Janssen, Laboratórios Vitoria, Pfizer, Lilly, Merck Sharp & Dohme, Sandoz, Takeda, UCB, and Vifor. JRFN declares no conflict of interest. BS has consulted for AbbVie, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Endpoint Health, Falk Pharma, Galapagos, Janssen, Landos, Lilly, Pfizer, Prometheus, and Takeda; has received speaker fees from AbbVie, CED Service GmbH, Falk Pharma, Ferring, Janssen, Novartis, Pfizer, and Takeda, and has received funding from Pfizer. SD has served as a speaker, consultant, and advisory board member for Schering-Plough, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson & Johnson, Millenium Takeda, MSD, NikkisoEurope GmbH, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, UCB Pharma, and Vifor. LPB reports personal fees from Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillots, Celltrion, Takeda, Pfizer, Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Inotrem, Al-lergan, MSD, Roche, Arena, Gilead, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, OSE Immunotherapeutics, Enthera, Theravance, Pandion Therapeutics, Gossamer Bio, Viatris, Thermo Fisher; grants from AbbVie, MSD, Takeda, Fresenius Kabi; and has stock options in CTMA., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Die Übersicht über die Interessenkonflikte der Autorinnen und Autoren sind im Leitlinienreport veröffentlicht.

Background: While standard clinical magnetic resonance (MR) enterography can detect inflammatory bowel disease, it is of limited value in deciding between medical versus surgical treatment. Alternatively, intestinal MR elastography has the potential to contribute additional information to therapeutic decision-making; however, the influence of bowel distension by oral contrast agent on viscoelastic tissue properties remains elusive. Therefore, we aimed to investigate the influence of oral contrast agent-induced bowel distension on the viscoelastic properties of the terminal ileum in healthy volunteers., Methods: In this prospective pilot study, 20 healthy volunteers (33.2±8.2 years; 10 men, 10 women) underwent multifrequency MR elastography using a single-shot spin-echo echo planar imaging sequence at 1.5 Tesla and drive frequencies of 40, 50, 60 and 70 Hz. Maps of shear wave speed ( c in ms -1 ) and loss angle ( φ in rad), representing stiffness and viscous properties, respectively, were generated using tomoelastography data processing. The volunteers were scanned before and after ingestion of 1,000 mL of 2% mannitol solution as oral contrast agent., Results: There was no significant difference in terminal ileum biomechanical properties before vs. after ingestion of an oral contrast agent (mean c : 1.47±0.24 vs. 1.40±0.25 ms -1 with P=0.37; mean φ : 0.70±0.12 rad vs. 0.68±0.12 rad with P=0.61). Moreover, there was no statistically significant correlation between MR elastography parameters before and after the ingestion of oral contrast ( c : r =0.22, P=0.36; φ : r =0.24, P=0.30)., Conclusions: The results of this study suggest that bowel distension for intestinal MR elastography has no systematic effect on the biomechanical tissue properties of the terminal ileum determined by MR elastography. Therefore, future study protocols appear feasible with or without oral contrast agents., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-101/coif). B.S., A.A.K., B.H., J.B., I.S., and R.R. report that this study was funded by the German Research Foundation. B.H. is Grant recipient from Abbott, AbbVie, Ablative Solutions, Accovion, Achogen Inc., Actelion Pharmaceuticals, ADIR, Aesculap, Agios Pharmaceuticals, INC., AGO, Arbeitsgemeinschaft industrieller Forschungsvereinigungen, Arbeitsgemeinschaft internistische Onkologie, Aktionsbündnis Partnersicherheit e.V., Alexion Pharmaceuticals, Amgen, AO Foundation, Aravive, Arena Pharmaceuticals, ARMO Biosciences, Inc., Array Biopharma Inc., Art photonics GmbH Berlin, ASAS, Ascelia Pharma AB, Ascendis, Advanced sleep research, Astrellas, AstraZeneca, August Research OOF, Sofia, BG, BARD, Basiliea, Bayer Healthcare, Bayer Schering Pharma, Bayer Vital, BBraun, BerGenBioASA, Berlin-Brandenburger Centrum für regenerative Therapie, Berliner Krebsgesellschaft, Biontech Mainz, BioNTech SE, Biotronik, Bioven, BMBF, BMS, Boehring Ingelheimer, Boston Biomedical Inc., Boston Scientific Medizintechnik GmbH, BRACCO Group, Brahms GmbH, Brainsgate, Bistol-Myers Squibb, Calithera Biosciences UK, Cantargia AB, Medicon Village, Cascadian Therapeutics, Inc., Celgene, CELLACT Pharma, Celldex Therapeutics, Cellestia Biotech AG CH, CeloNova BioSciences, and Charité research organization GmbH. B.S. has served as consultant for Abbvie, Abivax, BMS, Boehringer, CED Service GmbH, Endpoint Health, Falk, Galapagos, Janssen, Lilly, Pfizer, Takeda, and Predictimmune; he received speaker fees from: AbbVie, BMS, CED Service GmbH, Falk, Ferring, Galapagos, Janssen, Lilly, Materia Prima, Takeda, Pfizer and grant support by Arena/Pfizer (served as representative of the Charité). The other authors have no conflicts of interest to declare., (2024 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Fibrostenosis of the small bowel is common in patients with Crohn's disease. No consensus recommendations on definition, diagnosis and management in clinical practice are currently available. In this Consensus Statement, we present a clinical practice RAND/UCLA appropriateness study on the definition, diagnosis and clinical management of fibrostenosing Crohn's disease. It was conducted by a panel of 28 global experts and one patient representative. Following a systematic literature review, 526 candidate items grouped into 136 questions were generated and subsequently evaluated for appropriateness. Strictures are best defined as wall thickening, luminal narrowing and prestenotic dilation. Cross-sectional imaging is required for accurate diagnosis of fibrostenosing Crohn's disease, and it is recommended before making treatment decisions. It should also assess the degree of inflammation in the bowel wall. Multiple options for medical anti-inflammatory, endoscopic and surgical therapies were suggested, including follow-up strategies following therapy. This Consensus Statement supports clinical practice through providing guidance on definitions, diagnosis and therapeutic management of patients with fibrostenosing small bowel Crohn's disease., (© 2024. Springer Nature Limited.)

Crohn's disease (CD) is an inflammatory bowel disease that can affect any part of the gastrointestinal tract, frequently involving the terminal ileum. While colonic mucus alterations in CD patients have been described, terminal ileal mucus and its mechanobiological properties have been neglected. Our study is the first of its kind to decipher the viscoelastic and network properties of ileal mucus. With that aim, oscillatory rheological shear measurements based on an airway mucus protocol that was thoroughly validated for ileal mucus were performed. Our pilot study analyzed terminal ileum mucus from controls (n = 14) and CD patients (n = 14). Mucus network structure was visualized by scanning electron microscopy. Interestingly, a statistically significant increase in viscoelasticity as well as a decrease in mesh size was observed in ileal mucus from CD patients compared to controls. Furthermore, rheological data were analyzed in relation to study participants' clinical characteristics, revealing a noteworthy trend between non-smokers and smokers. In conclusion, this study provides the first data on the viscoelastic properties and structure of human ileal mucus in the healthy state and Crohn's disease, demonstrating significant alterations between groups and highlighting the need for further research on mucus and its effect on the underlying epithelial barrier., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The efficacy and safety of risankizumab as compared with ustekinumab in patients with Crohn's disease are unknown., Methods: In this phase 3b, multicenter, open-label, randomized, controlled trial with blinded assessment of end points, patients with moderate-to-severe Crohn's disease who had had an inadequate response to anti-tumor necrosis factor (TNF) therapy or unacceptable side effects with such therapy were randomly assigned to receive risankizumab or ustekinumab at standard doses for 48 weeks. The two primary end points, which were tested sequentially, were clinical remission at week 24 (defined as a Crohn's Disease Activity Index score of <150 [range, 0 to 600, with higher scores indicating more severe disease activity]), which was analyzed in the first 50% of patients to complete the week 24 visit, with a noninferiority margin of 10 percentage points; and endoscopic remission at week 48 (defined as a score of ≤4, a decrease of ≥2 points from baseline, and no subscore >1 in any individual variable on the Simple Endoscopic Score for Crohn's Disease [range, 0 to 56, with higher scores indicating more severe disease]), which was analyzed for superiority in 100% of the patients. Safety was assessed in all patients who received at least one dose of risankizumab or ustekinumab., Results: In the full intention-to-treat population for the efficacy analysis, 230 of 255 patients (90.2%) who received risankizumab and 193 of 265 patients (72.8%) who received ustekinumab completed all the assigned treatments. Both primary end points were met; risankizumab was noninferior to ustekinumab with respect to clinical remission at week 24 (58.6% vs. 39.5%; adjusted difference, 18.4 percentage points; 95% confidence interval [CI], 6.6 to 30.3) and superior to ustekinumab with respect to endoscopic remission at week 48 (31.8% vs. 16.2%; adjusted difference, 15.6 percentage points; 95% CI, 8.4 to 22.9; P<0.001). The incidence of adverse events appeared to be similar in the two groups., Conclusions: In this head-to-head clinical trial of risankizumab and ustekinumab involving patients with moderate-to-severe Crohn's disease who had had unacceptable side effects with anti-TNF therapy or an inadequate response to such therapy, risankizumab was noninferior to ustekinumab with respect to clinical remission at week 24 and superior with respect to endoscopic remission at week 48. (Funded by AbbVie; ClinicalTrials.gov number, NCT04524611.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Ozanimod, approved for the treatment of moderately to severely active ulcerative colitis (UC) and relapsing multiple sclerosis (RMS), is a weak in vitro monoamine oxidase B (MAO-B) inhibitor. MAO-B inhibitors can cause serotonin accumulation with concomitant use of selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs). We evaluated the incidence of treatment-emergent adverse events (TEAEs) potentially associated with serotonin accumulation during ozanimod and concomitant SSRI/SNRI use in this post hoc analysis of pooled UC studies and the open-label extension RMS DAYBREAK., Methods: Data for ozanimod 0.92 mg from pooled UC studies (n = 1158; cutoff: January 10, 2022) and RMS DAYBREAK (n = 2257; cutoff: February 1, 2022) were analyzed. Concomitant SSRI/SNRI use was allowed in the UC (n = 67) and RMS (n = 274) studies. A narrow Medical Dictionary for Regulatory Activities search ("serotonin syndrome," "neuroleptic malignant syndrome," and "malignant hyperthermia") and a broad search including terms potentially associated with serotonin accumulation were conducted. The percentages of patients with TEAEs in both searches were analyzed by concomitant SSRI/SNRI use when the TEAE occurred., Results: No patients had TEAEs matching the narrow search criteria. No differences were observed in the percentages of patients with ≥1 TEAE matching the broad search regardless of SSRI/SNRI use in UC (with: 25.4% [n = 17 of 67]; without: 15.0% [n = 164 of 1091]) and RMS (with: 12.4% [n = 34 of 274]; without: 15.6% [n = 310 of 1982]) studies., Conclusions: No evidence of increased TEAEs potentially associated with serotonin accumulation was observed with concurrent use of ozanimod and SSRIs/SNRIs., Clinical Trial Registration: NCT01647516, NCT02531126, NCT02435992, NCT02576717., (© 2024 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Background: An estimated 20% of patients with oral and oropharyngeal squamous cell carcinoma (OOSCC) have micrometastases (Mi) or isolated tumor cells (ITC) in the cervical lymph nodes that evade detection by standard histological evaluation of lymph node sections. Lymph node Mi and ITC could be one reason for regional recurrence after neck dissection. The aim of this study was to review the existing data regarding the impact of Mi on the survival of patients with OOSCC., Methods: PubMed and the Cochrane Library were searched for articles reporting the impact of Mi and ITC on patient survival. Two authors independently assessed the methodological quality of retrieved studies using the Downs and Black index. Data were also extracted on study type, number of included patients, mode of histological analysis, statistical analysis, and prognostic impact., Results: Sixteen articles with a total of 2064 patients were included in the review. Among the 16 included studies, eight revealed a statistically significant impact of Mi on at least one endpoint in the Kaplan-Meier and/or multivariate analysis. Three studies regarded Mi as Ma, while five studies found no impact of Mi on survival. Only one study demonstrated an impact of ITC on patient's prognosis in the univariate but not in the multivariate analysis., Conclusion: The majority of cases included in the review were patients with oral cancer. The findings provide low-certainty evidence that Mi negatively impacts survival. Data on ITC were scarcer, so no conclusions can be drawn about their effect on survival. The lower threshold to discriminate between Mi and ITC should be defined for OOSCC since the existing thresholds are based on data from different tumors. The histological, immunohistological, and anatomical characteristics of Mi and ITC in OOSCC as well as the effect of radiotherapy on Mi should be further investigated separately for oral and oropharyngeal carcinomas., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The luminal surface of the intestinal epithelium is protected by a vital mucus layer, which is essential for lubrication, hydration, and fostering symbiotic bacterial relationships. Replicating and studying this complex mucus structure in vitro presents considerable challenges. To address this, we developed a hydrogel-integrated millifluidic tissue chamber capable of applying precise apical shear stress to intestinal models cultured on flat or 3D structured hydrogel scaffolds with adjustable stiffness. The chamber is designed to accommodate nine hydrogel scaffolds, 3D-printed as flat disks with a storage modulus matching the physiological range of intestinal tissue stiffness (~3.7 kPa) from bioactive decellularized and methacrylated small intestinal submucosa (dSIS-MA). Computational fluid dynamics simulations were conducted to confirm a laminar flow profile for both flat and 3D villi-comprising scaffolds in the physiologically relevant regime. The system was initially validated with HT29-MTX seeded hydrogel scaffolds, demonstrating accelerated differentiation, increased mucus production, and enhanced 3D organization under shear stress. These characteristic intestinal tissue features are essential for advanced in vitro models as they critically contribute to a functional barrier. Subsequently, the chamber was challenged with human intestinal stem cells (ISCs) from the terminal ileum. Our findings indicate that biomimicking hydrogel scaffolds, in combination with physiological shear stress, promote multi-lineage differentiation, as evidenced by a gene and protein expression analysis of basic markers and the 3D structural organization of ISCs in the absence of chemical differentiation triggers. The quantitative analysis of the alkaline phosphatase (ALP) activity and secreted mucus demonstrates the functional differentiation of the cells into enterocyte and goblet cell lineages. The millifluidic system, which has been developed and optimized for performance and cost efficiency, enables the creation and modulation of advanced intestinal models under biomimicking conditions, including tunable matrix stiffness and varying fluid shear stresses. Moreover, the readily accessible and scalable mucus-producing cellular tissue models permit comprehensive mucus analysis and the investigation of pathogen interactions and penetration, thereby offering the potential to advance our understanding of intestinal mucus in health and disease.

Background: Biomarkers offer potential alternatives to endoscopies in monitoring ulcerative colitis (UC) progression and therapeutic response. This post hoc analysis of the ELEVATE UC clinical program assessed potential predictive values of fecal calprotectin (fCAL) and high-sensitivity C-reactive protein (hsCRP) as biomarkers and associated responses to etrasimod, an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active UC, in 2 phase 3 clinical trials., Methods: In ELEVATE UC 52 and ELEVATE UC 12, patients were randomized 2:1 to 2 mg of etrasimod once daily or placebo for 52 or 12 weeks, respectively. Fecal calprotectin/hsCRP differences between responders and nonresponders for efficacy end points (clinical remission, clinical response, endoscopic improvement-histologic remission [EIHR]) were assessed by Wilcoxon P-values. Sensitivity and specificity were presented as receiver operating characteristics (ROC) curves with area under the curve (AUC)., Results: In ELEVATE UC 52 and ELEVATE UC 12, 289 and 238 patients received etrasimod and 144 and 116 received placebo, respectively. Baseline fCAL/hsCRP concentrations were generally balanced. Both trials had lower week-12 median fCAL levels in week-12 responders vs nonresponders receiving etrasimod for clinical remission, clinical response, and EIHR (all P < .001), with similar trends for hsCRP levels (all P < .01). For etrasimod, AUCs for fCAL/hsCRP and EIHR were 0.85/0.74 (week 12; ELEVATE UC 52), 0.83/0.69 (week 52; ELEVATE UC 52), and 0.80/0.65 (week 12; ELEVATE UC 12)., Conclusions: Fecal calprotectin/hsCRP levels decreased with etrasimod treatment; ROC analyses indicated a prognostic correlation between fCAL changes during induction and short-/long-term treatment response., (© 2024 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

The concept of disease clearance has been proposed as a potential target in ulcerative colitis (UC). We conducted a systematic review to investigate the role of disease clearance, defined as a composite outcome including simultaneous clinical, endoscopic, and histologic remission of disease in the management of patients with UC. Based on the literature data, statements regarding disease clearance were developed and voted on by the members of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) according to a Delphi methodology. A definition of disease clearance was proposed to standardize its use in clinical practice and clinical trials and to provide practical recommendations for its implementation as a therapeutic target in UC., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Aims: NX-13 activation of NLRX1 reduces intracellular reactive oxygen species and decreases inflammation in animal models of colitis. A phase 1a trial demonstrated a gut-selective pharmacokinetic profile with good tolerability. This phase Ib study aimed to evaluate the safety, tolerability, and pharmacokinetics of NX-13 in patients with active ulcerative colitis [UC]., Methods: We conducted a multicentre, randomized, double-blind, placebo-controlled trial of NX-13 in patients with active UC. Patients with a Mayo Clinic Score of 4-10 were randomly assigned [3:3:3:1 ratio] to three NX-13 oral dose groups (250 mg immediate release [IR], 500 mg IR, or 500 mg delayed release [DR], or placebo) once daily for 4 weeks. Safety and pharmacokinetics were the primary and secondary objectives, respectively., Results: Thirty-eight patients [11 females] were recruited and randomized to placebo [five], NX-13 250 mg IR [11], NX-13 500 mg IR [11], or NX-13 500 mg DR [11] and received at least one dose. There were no serious adverse events or deaths during the trial. One patient [500 mg DR, 1/11] withdrew due to worsening of UC and a second [500 mg IR, 1/11] on the last day of treatment after a panic attack associated with atrial fibrillation. In the efficacy population [36 patients], clinical improvement in rectal bleeding and stool frequency scores relative to placebo were seen as early as week 2 and endoscopic response was seen at week 4., Conclusions: NX-13 was generally safe and well tolerated with early signs of rapid symptom and endoscopic improvement. This novel mechanism of action warrants further investigation. ClinicalTrials.gov: NCT04862741., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

The COVID-19 pandemic has posed a major challenge to healthcare systems globally. Millions of people have been infected, and millions of deaths have been reported worldwide. Glucocorticoids have attracted worldwide attention for their potential efficacy in the treatment of COVID-19. Various glucocorticoids with different dosages and treatment durations have been studied in patients with different severities, with a suitable dosage and treatment duration not yet defined. This study aimed to investigate whether in-hospital survival differs between critically ill patients treated with low-dose glucocorticoids, high-dose glucocorticoids or no glucocorticoids. All critically ill patients admitted to the intensive care unit of the Charité Hospital-Universitätsmedizin Berlin between February 2020 and December 2021 with COVID-19 pneumonia receiving supplemental oxygen were eligible to participate in this multicenter real-world data study. Patients were retrospectively assigned to one of three groups: the high corticosteroid dose (HighC) group (receiving 6 mg parenteral dexamethasone or an equivalent corticosteroid dosage for ten days), the low corticosteroid dose (LowC) group (receiving less than 6 mg parenteral dexamethasone or an equivalent corticosteroid dosage for ten days), or the no corticosteroid (NoC) group. Overall survival and risk effects were compared among groups within the total observation period, as well as at 35 days after the onset of COVID-19 symptoms. Adjusted multivariable Cox proportional hazard regression analysis was performed to compare the risk of death between the treatment groups. Out of 1561 critically ill COVID-19 patients, 1014 were included in the baseline analysis. In the survival study, 1009 patients were assigned to the NoC (n = 346), HighC (n = 552), or LowC group (n = 111). The baseline characteristics were balanced between groups, except for age, BMI, APACHE II score, SOFA and SAPS II. While the 35-day survival did not show any differences, a landmark analysis of the patients surviving beyond 35 days revealed differences between groups. The restricted mean survival time was 112 days in the LowC group [95% CI: 97 - 128], 133 days in the HighC group [95% CI: 124 - 141] and 144 days in the NoC group [95% CI: 121 - 167]. The multivariable-adjusted Cox proportional hazard analysis indicated that, regardless of age, sex, health status or invasive oxygenation, a low-dose treatment increased the hazard of death of critically ill COVID-19 patients by a factor of 2.09 ([95% CI: 0.99, 4.4], p = 0.05) and a high-dose corticosteroid treatment increased the risk by a factor of 1.07 ([95% CI: 0.53, 2.15], p = 0.85) compared to no treatment with glucocorticoids. The analysis reveals that corticosteroid treatment does not influence the survival of critically ill COVID-19 patients in the intensive care unit within 35 days. Our evaluations further suggest that regardless of ventilation status, the decision-making process for administering corticosteroid therapy should account for the individual severity of the illness., (© 2024. The Author(s).)

Competing Interests: Die Übersicht über die Interessenkonflikte der Autorinnen und Autoren sind im Leitlinienreport veröffentlicht.

Introduction: Whether inpatients with inflammatory bowel disease (IBD) are reimbursed in a cost-covering manner in German hospitals has not yet been investigated. In this context, the present study analyses the reimbursement situation (cost-revenue comparison) of IBD in German hospitals with regard to the complexity of the disease and the type of care., Methods: For this retrospective study, anonymized case data, including cost data from the InEK calculation (§ 21-4 KHEntgG) of the DRG project of the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS) from 2019, were available. 3385 cases with IBD the as main diagnosis from 49 hospitals were analyzed. To investigate the impact of disease complexity on reimbursement, different variables were analyzed, including gastroenterological complications, infections, the reason for admission, and additional charges. To investigate possible center effects, hospitals were grouped by type of care, mostly defined by the number of beds., Results: The present study shows that all types of care can be classified as not cost-covering on average. The under-recovery is, on average, 10% (296 € absolute under-recovery) and varies between the types of care. Cases with higher complexity show a higher cost under-recovery than cases with lower complexity. At the DRG level, the analyzed costs of the three most common IBD DRGs for inlier patients are higher than the InEK costs; however, the difference is not significant. Nonetheless, cases with the admission reason transfer of specific DRGs bear significantly higher costs., Discussion: Our results show that CED is not reimbursed in a cost-covering manner. This is due to inadequate reimbursement for gastroenterological complications, infections, specific procedures, and emergency and transfer cases. Transfer cases bear significantly higher costs., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Competing Interests: SS received investigator-initiated study grants from AbbVie, Janssen, Takeda, Tillots Pharma, and Biogen; consulting fees from Takeda, AbbVie, Merck, Ferring, Pharmacocosmos, Warner Chilcott, Janssen, Falk Pharma, Biohit, TriGenix, Celgene, Tillots Pharma, Eli Lilly, Bristol Myers Squibb, and Amgen; speaker honoraria from AbbVie, Takeda, Celltrion, Pfizer, Biogen, AbbVie, Janssen, Merck, Warner Chilcott, and Falk Pharma Janssen; and is chair for the Research Committee of the British Society of Gastroenterology, chair for the Clincom Committee of the European Crohn's and Colitis Organisation, and co-director of Research for the South Asian IBD Alliance. BS received research grants from Pfizer and Arena; consulting fees from AbbVie, Abivax, Arena, Bristol Myers Squibb, Boehringer, CED Service, Celgene, CT Scout, Endpoint Health, Falk, Forga Software, Galapagos, Janssen, Lilly, Materia Prima, Pfizer, Takeda, Pharma Insight, Predictimmune, and PsiCro; speaker honoraria from AbbVie, Bristol Myers Squibb, CED Service, Chiesi, Falk, Ferring, Gilead, Janssen, Lilly, Materia Prima, Takeda, and Pfizer; and is President of the European Crohn's and Colitis Organisation. DPBM received consulting fees from Prometheus Biosciences, Merck, Prometheus Labs, Takeda, and Palisade Bio; has patents pending for Prometheus Biosciences and Cedars-Sinai Medical Center; holds share options for Prometheus Biosciences; and participated in the data monitoring boards of Prometheus Biosciences and Takeda. CJvdW is treasurer for the European Crohn's and Colitis Organisation. All other authors declare no competing interests. FT is an IBD patient advocate and founder of IBD Ethiopia.

Background and Aims: The Pharmacovigilance Risk Assessment Committee (PRAC) proposed measures to address severe side effects linked to Janus kinase inhibitors (JAKi) in immune-mediated inflammatory diseases (IMID). Use of these medications in individuals aged 65 and older, those at high cardiovascular risk, active or former long-term smokers, and those with increased cancer risk should be considered only if no alternatives exist. Caution is advised when administering JAKi to patients at risk of venous thromboembolism. We aim to implement recommendations from regulatory guidelines based on areas of uncertainty identified., Methods: A two-round modified Research and Development/University of California Los Angeles appropriateness methodology study was conducted. A panel of 21 gastroenterologists, dermatologists and rheumatologists used a 9-point Likert scale to rate the appropriateness of administering a JAKi for each proposed clinical scenario. Scores for appropriateness were categorized as appropriate, uncertain, or inappropriate. Two rounds were performed, each with online surveys and a virtual meeting to enable discussion and rating of each best practice., Results: Round 1 involved participants rating JAKi appropriateness and suggesting descriptors to reduce uncertainty. Survey results were discussed in a virtual meeting, identifying areas of disagreement. In round 2, participants rated their agreement with descriptors from round 1, and the level of uncertainty and disagreement reduced. Age flexibility is recommended in the absence of other risk factors. Active counseling on modifiable risks (e.g., overweight, mild hyperlipidemia and hypertension) and smoking cessation is advised. Uncertainty persists regarding cancer risk due to various factors., Conclusions: We outlined regulatory guidance without a personalized evaluation of the patient's risk profile might lead to uncertainty and become an arid technicality. Therefore, we identified gaps and implemented PRAC recommendations to help health professionals in clinical practice., Competing Interests: Declaration of Competing Interest Virginia Solitano and Magnus Petersen declare no conflict of interest. Paola Facheris has served as consultant for Eli Lilly. Ferdinando D'Amico has served as a speaker for Sandoz, Janssen, Galapagos, and Omega Pharma. He has also served as advisory board member for Abbvie, Ferring, Galapagos, and Nestlè. Michela Ortoncelli has declared no conflicts of interest. Daniel Aletaha received grants from AbbVie, Amgen, Galapagos, Eli Lilly and Sanofi, and honoraria (speaker's bureau, consultancy) from AbbVie, Amgen, Galapagos, Eli Lilly, Janssen, Merck, Novartis, Pfizer and Sandoz and is a member of the ARD Editorial Board. Pablo A. Olivera received consulting fees from Abbvie, Takeda, and Janssen and lecture fees from Takeda and Janssen. Thomas Bieber was speaker or consultant or Investigator for AbbVie, Affibody, Allmiral, AnaptysBio, Arena, Asana Biosciences, ASLAN pharma, Bayer Health, BioVerSys, Böhringer-Ingelheim, Bristol-Myers Squibb, Connect Pharma, Dermavant, Domain Therapeutics, EQRx, Eli Lilly and Company, Galderma, Glenmark, GSK, Incyte, Innovaderm, IQVIA, Janssen, Kirin, Kymab, LEO, LG Chem, L'Oréal, MSD, Novartis, Numab, OM-Pharma, Pfizer, Pierre Fabre, Q32bio, RAPT, Sanofi/Regeneron, UCB. He is founder and chairman of the board of the non-profit biotech “Davos Biosciences”. Sofia Ramiro research grants and/or consultancy fees: AbbVie, Eli Lilly, Janseen, Galapagos, MSD, Novartis, Pfizer, UCB, Sanofi. Subrata Ghosh declares receiving consulting fees from Pfizer, Janssen, AbbVie, Takeda, Bristol Myers Squibb, Receptos, Celgene, Gilead, Eli Lilly, and Boehringer Ingelheim, and speaker fees from AbbVie, Janssen, Takeda, Ferring, Pfizer, Shield, and Falk Pharma outside of the submitted work. Maria Antonietta D'Agostino reports speaker or consultant fees from Novartis, BMS, Janssen,Pfizer, Amgen, Galapagos, AbbVie, UCB, and Eli Lilly. PC reports research grants from UCB, MSD and Pfizer; speaker fees or consultant fees from Pfizer, MSD, Novartis, Bristol Myers Squibb, AbbVie, UCB, Eli Lilly, Gilead and Celgene Corporation. Britta Siegmund has served as consultant for Abbvie, Abivax, Arena, BMS, Boehringer, CED Service GmbH, Celgene, CT Scout, Endpoint Health, Falk, Forga Software, Galapagos, Janssen, Lilly, Materia Prima, Pfizer, Takeda, Pharma Insight, Predictimmune, PsiCro; Speaker fees: AbbVie, BMS, CED Service GmbH, Chiesi, Falk, Ferring, Gilead, Janssen, Lilly, Materia Prima, Takeda, Pfizer and grant support by Arena/Pfizer (served as representative of the Charité). Isabelle Chary-Valckenaere received consulting fees from Abbvie, BMS, Galapagos, Lilly, Novartis, Pfizer, UCB. Ailsa Hart has served as consultant, advisory board member or speaker for AbbVie, Arena, Atlantic, Bristol-Myers Squibb, Celgene, Celltrion, Falk, Galapogos, Lilly, Janssen, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Shire and Takeda. She also serves on the Global Steering Committee for Genentech. Lorenzo Dagna Lorenzo Dagna received consultation honoraria from Abbvie, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Galapagos, GlaxoSmithKline, Janssen, Kiniksa Pharmaceuticals, Novartis, Pfizer, Sanofi-Genzyme, SOBI, and Vifor outside of the current work. Fernando Magro has served as a speaker and received honoraria from Merck Sharp & Dohme, Abbvie, Vifor, Falk, Laboratorios Vitoria, Ferring, Hospira, and Biogen. Renaud Felten has been a consultant for Amgen, BMS, Galapagos, GSK, Janssen-Cilag, Lilly, Medac, MSD, Nordic, Novartis, Pfizer, Sanofi, UCB. Paulo Kotze has received honoraria from AbbVie, Ferring, Janssen, Pfizer, and Takeda as a speaker and member of advisory boards. He also received scientific research grants from Pfizer and Takeda. Vipul Jairath has received consultancy/advisory board fees from AbbVie, Alimentiv Inc., Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Reistone Biopharma, Roche, Sandoz, Second Genome, Takeda, Teva, Topivert, Ventyx, and Vividion; and speaker's fees from, Abbvie, Ferring, Galapagos, Janssen Pfizer Shire, Takeda, and Fresenius Kabi. Antonio Costanzo has served as an advisory board member, consultant and has received fees and speaker's honoraria or has participated in clinical trials for Abbvie, Almirall, Biogen, LEO Pharma, Lilly, Janssen, Novartis, Pfizer, Sanofi Genzyme and UCB-Pharma. Lars Erik Kristensen has received fees for participation in speakers bureaus, research grants and consultancy fees from Pfizer, AbbVie, Amgen, Galapagos, UCB, Celgene, BMS, MSD, Novartis, Eli Lilly and Janssen Pharmaceuticals. Laurent Peyrin Biroulet has served as a speaker, consultant, and advisory board member for Merck, Abbvie, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Hospira/Pfizer, Celltrion, Takeda, Biogaran, Boerhinger Ingelheim, Lilly, HAC Pharma, Index Pharmaceuticals, Amgen, Sandoz, Forward Pharma GmbH, Celgene, Biogen, Lycera, Samsung Bioepis, and Theravance. Silvio Danese has served as a speaker, consultant, and advisory board member for Schering-Plough, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson and Johnson, Millenium Takeda, MSD, Nikkiso Europe GmbH, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, UCB Pharma, and Vifor., (Copyright © 2023. Published by Elsevier B.V.)

Seeds of "sweet lupins" have been playing an increasing role in the food industry. Lupin proteins may be used for producing a variety of foods, including pasta, bread, cookies, dairy products, and coffee substitutes. In a small percentage of the population, lupin consumption may elicit allergic reactions, either due to primary sensitization to lupin or due to cross-allergy with other legumes. Thus, lupin has to be declared on commercial food products according to EU food regulations. In this study, we investigated the influence of roasting seeds of the L. angustifolius cultivar "Boregine" on the detectability of lupin by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), ELISAs, LC-MS/MS, and real-time PCR. Seeds were roasted by fluidized bed roasting, and samples were drawn at seed surface temperatures ranging from 98 °C to 242 °C. With increasing roasting temperature, the extractability of proteins and DNA decreased. In addition, roasting resulted in lower detectability of lupin proteins by ELISAs and LC-MS/MS and lower detectability of DNA by real-time PCR. Our results suggest reduced allergenicity of roasted lupin seeds used for the production of "lupin coffee"; however, this has to be confirmed in in vivo studies.

Background and Aims: Pain is a cardinal symptom in inflammatory bowel disease [IBD]. An important structure in the transduction of pain signalling is the myenteric plexus [MP]. Nevertheless, IBD-associated infiltration of the MP by immune cells lacks in-depth characterisation. Herein, we decipher intra- and periganglionic immune cell infiltrations in Crohn´s disease [CD] and ulcerative colitis [UC] and provide a comparison with murine models of colitis., Methods: Full wall specimens of surgical colon resections served to examine immune cell populations by either conventional immuno-histochemistry or immunofluorescence followed by either bright field or confocal microscopy. Results were compared with equivalent examinations in various murine models of intestinal inflammation., Results: Whereas the MP morphology was not significantly altered in IBD, we identified intraganglionic IBD-specific B cell- and monocyte-dominant cell infiltrations in CD. In contrast, UC-MPs were infiltrated by CD8+ T cells and revealed a higher extent of ganglionic cell apoptosis. With regard to the murine models of intestinal inflammation, the chronic dextran sulphate sodium [DSS]-induced colitis model reflected CD [and to a lesser extent UC] best, as it also showed increased monocytic infiltration as well as a modest B cell and CD8+ T cell infiltration., Conclusions: In CD, MPs were infiltrated by B cells and monocytes. In UC, mostly CD8+ cytotoxic T cells were found. The chronic DSS-induced colitis in the mouse model reflected best the MP-immune cell infiltrations representative for IBD., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Objective: We sought to investigate the role of interleukin (IL)-20 in IBD and experimental colitis., Design: Experimental colitis was induced in mice deficient in components of the IL-20 and signal transducer and activator of transcription (STAT)2 signalling pathways. In vivo imaging, high-resolution mini-endoscopy and histology were used to assess intestinal inflammation. We further used RNA-sequencing (RNA-Seq), RNAScope and Gene Ontology analysis, western blot analysis and co-immunoprecipitation, confocal microscopy and intestinal epithelial cell (IEC)-derived three-dimensional organoids to investigate the underlying molecular mechanisms. Results were validated using samples from patients with IBD and non-IBD control subjects by a combination of RNA-Seq, organoids and immunostainings., Results: In IBD, IL20 levels were induced during remission and were significantly higher in antitumour necrosis factor responders versus non-responders. IL-20RA and IL-20RB were present on IECs from patients with IBD and IL-20-induced STAT3 and suppressed interferon (IFN)-STAT2 signalling in these cells. In IBD, experimental dextran sulfate sodium (DSS)-induced colitis and mucosal healing, IECs were the main producers of IL-20. Compared with wildtype controls, Il20 -/- , Il20ra -/- and Il20rb -/- mice were more susceptible to experimental DSS-induced colitis. IL-20 deficiency was associated with increased IFN/STAT2 activity in mice and IFN/STAT2-induced necroptotic cell death in IEC-derived organoids could be markedly blocked by IL-20. Moreover, newly generated Stat2 ΔIEC mice, lacking STAT2 in IECs, were less susceptible to experimental colitis compared with wildtype controls and the administration of IL-20 suppressed colitis activity in wildtype animals., Conclusion: IL-20 controls colitis and mucosal healing by interfering with the IFN/STAT2 death signalling pathway in IECs. These results indicate new directions for suppressing gut inflammation by modulating IL-20-controlled STAT2 signals., Competing Interests: Competing interests: MFN has served as an advisor for Pentax, Giuliani, PPM, BMS, Janssen, MSD, Takeda and Boehringer. MFN has served as an Associate Editor of the journal/Editorial Board Member. BS has served as consultant for AbbVie, Arena, BMS, Boehringer, Celgene, Falk, Galapagos, Janssen, Lilly, Pfizer, Prometheus and Takeda and received speaker’s fees from AbbVie, CED Service, Falk, Ferring, Janssen, Novartis, Pfizer, Takeda (served as representative of the Charité). All other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Spondyloarthritis (SpA) is a group of immune-mediated diseases highly concomitant with nonmusculoskeletal inflammatory disorders, such as acute anterior uveitis (AAU) and Crohn's disease (CD). The gut microbiome represents a promising avenue to elucidate shared and distinct underlying pathophysiology., Methods: We performed 16S ribosomal RNA sequencing on stool samples of 277 patients (72 CD, 103 AAU, and 102 SpA) included in the German Spondyloarthritis Inception Cohort and 62 back pain controls without any inflammatory disorder. Discriminatory statistical methods were used to disentangle microbial disease signals from one another and a wide range of potential confounders. Patients were naive to or had not received treatment with biological disease-modifying antirheumatic drugs (DMARDs) for >3 months before enrollment, providing a better approximation of a true baseline disease signal., Results: We identified a shared, immune-mediated disease signal represented by low abundances of Lachnospiraceae taxa relative to controls, most notably Fusicatenibacter, which was most abundant in controls receiving nonsteroidal antiinflammatory drug monotherapy and implied to partially mediate higher serum C-reactive protein. Patients with SpA showed an enrichment of Collinsella, whereas human leukocyte antigen (HLA)-B27+ individuals displayed enriched Faecalibacterium. CD patients had higher abundances of a Ruminococcus taxon, and previous conventional/synthetic DMARD therapy was associated with increased Akkermansia., Conclusion: Our work supports the existence of a common gut dysbiosis in SpA and related inflammatory pathologies. We reveal shared and disease-specific microbial associations and suggest potential mediators of disease activity. Validation studies are needed to clarify the role of Fusicatenibacter in gut-joint inflammation, and metagenomic resolution is needed to understand the relationship between Faecalibacterium commensals and HLA-B27., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

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., Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: nein; Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an im Bereich der Medizin aktiven Firma: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an zu Sponsoren dieser Fortbildung bzw. durch die Fortbildung in ihren Geschäftsinteressen berührten Firma: nein Erklärung zu nichtfinanziellen Interessen ES: Beirat DCCV (Deutsche Crohn und Colitis Vereinigung) Mitgliedschaft DGVS, ECCO, DGIM ES served as consultant for Janssen, Taked as speaker for AbbVie, BMS, CED Service GmbH, Falk, Ferring,Janssen, Lilly,Takeda, BS: Beirat DCCV (Deutsche Crohn und Colitis Vereinigung) Mitgliedschaft DGVS, ECCO (President), DGIM BS served as consultant for Abbvie, Abivax, Arena, BMS, Boehringer, CED Service GmbH, Celgene, CT Scout, Endpoint Health, Falk, Forga Software, Galapagos, Janssen, Lilly, Materia Prima, Pfizer, Takeda, Pharma Insight, Predictimmune, PsiCro and as speaker for AbbVie, BMS, CED Service GmbH, Chiesi, Falk, Ferring, Gilead, Janssen, Lilly, Materia Prima, Takeda, Pfizer and grant support by Arena/Pfizer (in all functions as representative of Charité)., (Thieme. All rights reserved.)

Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: nein; Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an im Bereich der Medizin aktiven Firma: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an zu Sponsoren dieser Fortbildung bzw. durch die Fortbildung in ihren Geschäftsinteressen berührten Firma: nein Erklärung zu nichtfinanziellen Interessen ES: Beirat DCCV (Deutsche Crohn und Colitis Vereinigung) Mitgliedschaft DGVS, ECCO, DGIM ES served as consultant for Janssen, Taked as speaker for AbbVie, BMS, CED Service GmbH, Falk, Ferring,Janssen, Lilly,Takeda, BS: Beirat DCCV (Deutsche Crohn und Colitis Vereinigung) Mitgliedschaft DGVS, ECCO (President), DGIM BS served as consultant for Abbvie, Abivax, Arena, BMS, Boehringer, CED Service GmbH, Celgene, CT Scout, Endpoint Health, Falk, Forga Software, Galapagos, Janssen, Lilly, Materia Prima, Pfizer, Takeda, Pharma Insight, Predictimmune, PsiCro and as speaker for AbbVie, BMS, CED Service GmbH, Chiesi, Falk, Ferring, Gilead, Janssen, Lilly, Materia Prima, Takeda, Pfizer and grant support by Arena/Pfizer (in all functions as representative of Charité).

Gut microbiota-derived metabolites play a pivotal role in the maintenance of intestinal immune homeostasis. Here, we demonstrate that the human commensal Clostridium sporogenes possesses a specific metabolic fingerprint, consisting predominantly of the tryptophan catabolite indole-3-propionic acid (IPA), the branched-chain acids (BCFAs) isobutyrate and isovalerate and the short-chain fatty acids (SCFAs) acetate and propionate. Mono-colonization of germ-free mice with C. sporogenes (CS mice) affected colonic mucosal immune cell phenotypes, including up-regulation of Il22 gene expression, and increased abundance of transcriptionally active colonic tuft cells and Foxp3 + regulatory T cells (Tregs). In DSS-induced colitis, conventional mice suffered severe inflammation accompanied by loss of colonic crypts. These symptoms were absent in CS mice. In conventional, but not CS mice, bulk RNAseq analysis of the colon revealed an increase in inflammatory and Th17-related gene signatures. C. sporogenes -derived IPA reduced IL-17A protein expression by suppressing mTOR activity and by altering ribosome-related pathways in Th17 cells. Additionally, BCFAs and SCFAs generated by C. sporogenes enhanced the activity of Tregs and increased the production of IL-22, which led to protection from colitis. Collectively, we identified C. sporogenes as a therapeutically relevant probiotic bacterium that might be employed in patients with inflammatory bowel disease (IBD).

Background and Aims: The anti-MAdCAM-1 antibody ontamalimab demonstrated efficacy in a phase II trial in ulcerative colitis and results of early terminated phase III trials are pending, but its precise mechanisms of action are still unclear. Thus, we explored the mechanisms of action of ontamalimab and compared it to the anti-α4β7 antibody vedolizumab., Methods: We studied MAdCAM-1 expression with RNA sequencing and immunohistochemistry. The mechanisms of action of ontamalimab were assessed with fluorescence microscopy, dynamic adhesion and rolling assays. We performed in vivo cell trafficking studies in mice and compared ontamalimab and vedolizumab surrogate [-s] antibodies in experimental models of colitis and wound healing. We analysed immune cell infiltration under anti-MAdCAM-1 and anti-α4β7 treatment by single-cell transcriptomics and studied compensatory trafficking pathways., Results: MAdCAM-1 expression was increased in active inflammatory bowel disease. Binding of ontamalimab to MAdCAM-1 induced the internalization of the complex. Functionally, ontamalimab blocked T cell adhesion similar to vedolizumab, but also inhibited L-selectin-dependent rolling of innate and adaptive immune cells. Despite conserved mechanisms in mice, the impact of ontamalimab-s and vedolizumab-s on experimental colitis and wound healing was similar. Single-cell RNA sequencing demonstrated enrichment of ontamalimab-s-treated lamina propria cells in specific clusters, and in vitro experiments indicated that redundant adhesion pathways are active in these cells., Conclusions: Ontamalimab has unique and broader mechanisms of action compared to vedolizumab. However, this seems to be compensated for by redundant cell trafficking circuits and leads to similar preclinical efficacy of anti-α4β7 and anti-MAdCAM-1 treatment. These results will be important for the interpretation of pending phase III data., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aberrant CD4 + T cell reactivity against intestinal microorganisms is considered to drive mucosal inflammation in inflammatory bowel diseases. The disease-relevant microbial species and the corresponding microorganism-specific, pathogenic T cell phenotypes remain largely unknown. In the present study, we identified common gut commensal and food-derived yeasts, as direct activators of altered CD4 + T cell reactions in patients with Crohn's disease (CD). Yeast-responsive CD4 + T cells in CD display a cytotoxic T helper cell (T H 1 cell) phenotype and show selective expansion of T cell clones that are highly cross-reactive to several commensal, as well as food-derived, fungal species. This indicates cross-reactive T cell selection by repeated encounter with conserved fungal antigens in the context of chronic intestinal disease. Our results highlighted a role of yeasts as drivers of aberrant CD4 + T cell reactivity in patients with CD and suggest that both gut-resident fungal commensals and daily dietary intake of yeasts might contribute to chronic activation of inflammatory CD4 + T cell responses in patients with CD., (© 2023. The Author(s).)

Background: Although there is growing evidence that functional involvement and structural changes of mesenteric adipose tissue (MAT) influence the course of Crohn's disease (CD), its viscoelastic properties remain elusive. Therefore, we aimed to investigate the viscoelastic properties of MAT in CD using magnetic resonance elastography (MRE), providing reference values for CD diagnosis., Methods: In this prospective proof-of-concept study, 31 subjects (CD: n=11; healthy controls: n=20) were consecutively enrolled in a specialized care center for inflammatory bowel diseases (tertiary/quaternary care). Inclusion criteria for the CD patients were a clinically and endoscopically established diagnosis of CD based on the clinical record, absence of other concurrent bowel diseases, scheduled surgery for the following day, and age of at least 18 years. Diagnoses were confirmed by histological analysis of the resected bowel the day after MRE. Subjects were investigated using MRE at 1.5-T with frequencies of 40-70 Hz. To retrieve shear wave speed (SWS), volumes of interest (VOIs) in MAT were drawn adjacent to CD lesions (MAT CD ) and on the opposite side without adjacent bowel lesions in patients (MAT CD&#95;Opp ) and controls (MAT CTRL ). The presented study is not registered in the clinical trial platform., Results: A statistically significant decrease in mean SWS of 7% was found for MAT CD&#95;Opp vs. MAT CTRL (0.76±0.05 vs. 0.82±0.04 m/s, P=0.012), whereas there was a nonsignificant trend with an 8% increase for MAT CD vs. MAT CD&#95;Opp (0.82±0.07 vs. 0.76±0.05 m/s, P=0.098) and no difference for MAT CD vs. MAT CTRL . Preliminary area under the receiver operating characteristic curve (AUC) analysis showed diagnostic accuracy in detecting CD to be excellent for SWS of MAT CD&#95;Opp [AUC =0.82; 95% confidence interval (CI): 0.64-0.96] but poor for SWS of MAT CD (AUC =0.52; 95% CI: 0.34-0.73)., Conclusions: This study demonstrates the feasibility of MRE of MAT and presents preliminary reference values for CD patients and healthy controls. Our results motivate further studies for the biophysical characterization of MAT in inflammatory bowel disease., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-41/coif). BH, IS, PA, AAK, and BS report that this study was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation): SFB 1340/1 “Matrix in Vision” project number 372486779; IS reports that this study was funded by GRK 2260 BIOQIC; RR reports that this study was funded by RE 4161/2-1; AAK, CW, and BS report that this study was funded by SFB-TR 241 “IEC in IBD”. RR is a participant of the BIH-Charité Digital Clinician Scientist Program funded by Charité – Universitätsmedizin Berlin, Berlin Institute of Health and the DFG. BS has received grant money from Pfizer, consultancy fees from Abbvie, Arena Pharma, Boehringer, BMS, Celgene, CT-Scout, Galapagos, Gilead, Janssen, Lilly, Pfizer, PredictImmune, PsiCro, and honoraria for lectures, presentations from Abbvie, CED Service GmbH, CHiesi, Galapagos, Falk Foundation, Forga Software, IBD passport, Janssen, Materia Prima, Pfizer, Lilly (all payments were made to Charité). BH is a grant recipient for the Department of Radiology from Abbott, AbbVie, Ablative Solutions, Accovion, Achogen Inc., Actelion Pharmaceuticals, ADIR, Aesculap, Agios Pharmaceuticals, Inc., AGO, Arbeitsgemeinschaft Industrieller Forschungsvereinigungen (AIF), Arbeitsgemeinschaft Internistische Onkologie (AIO), Aktionsbündnis Partnersicherheit e.V., Alexion Pharmaceuticals, Amgen, AO Foundation, Aravive, Arena Pharmaceuticals, ARMO Biosciences, Inc., Array Biopharma Inc., Art Photonics GmbH Berlin, ASAS, Ascelia Pharma AB, Ascendis, ASR Advanced Sleep Research, Astrellas, AstraZeneca, August Research OOF, Sofia, BG, BARD, Basiliea, Bayer Healthcare, Bayer Schering Pharma, Bayer Vital, BBraun, BerGenBioASA, Berlin-Brandenburger Centrum für Regenerative Therapie (BCRT), Berliner Krebsgesellschaft, Biontech Mainz, BioNTech SE, Biotronik, Bioven, BMBF, BMS, Boehring Ingelheimer, Boston Biomedical Inc., Boston Scientific Medizintechnik GmbH, BRACCO Group, Brahms GmbH, Brainsgate, Bistol-Myers Squibb, Calithera Biosciences UK, Cantargia AB, Medicon Village, Cascadian Therapeutics, Inc., Celgene, CELLACT Pharma, Celldex Therapeutics, Cellestia Biotech AG CH, CeloNova BioSciences, Charité Research Organization GmbH, Chiltern, Clovis Oncology, Inc., Covance, CRO Charité, CTI Ulm, CUBIST, CureVac AG, Tübingen, Curis, Daiichi Sankyo, Dartmouth College, Hanover, NH, USA, DC Devices, Inc. USA, Delcath Systems, Dermira Inc., Deutsche Krebshilfe, Deutsche Rheuma Liga, DZ-Deutsche Diabetes Forschungsgesellschaft e.V., Deutsches Zentrum für Luft- und Raumfahrt e.V., DFG, Dr. Falk Pharma GmbH, DSM Nutritional Products AG, Dt. Gesellschaft für Muskuloskelettale Radiologie, Dt. Stiftung für Herzforschung, Dynavax, Aisai Ltd., European Knowledge Centre, Mosquito Way, Hatfield, Eli Lilly and Company Ltd., EORTC, Episurf Medical, Epizyme, Inc., Essex Pharma, EU Programmes, European Society of Gastrointestinal and Abdominal Radiology, Euroscreen S.A., F20 Biotech GmbH, Ferring Pharmaceuticals A/S, Fibrex Medical Inc., Focused Ultrasound Surgery Foundation, Fraunhofer Gesellschaft, GALA Therapeutics, US, Galena Biopharma, Galmed Research and Development Ltd., Ganymed, GBG Forschungs GmbH, GE, Gentech. Inc., Genmab A/S, Genzyme Europe B.V., GETNE (Grupo Espanol de Tumores Neuroendocrinos), Gilead Sciences, Inc., Glaxo Smith Kline, Glycotype GmbH Berlin, Goethe Uni Frankfurt, Guerbet, Guidant Europe NV, Halozyme, Hans-Böckler-Stiftung, Hewlett Packard GmbH, Holaira Inc., Horizon Therapeutics Ireland, ICON (CRO), Idera Pharmaceuticals, Inc., Ignyta, Inc., Immunomedics Inc., Immunocore, Inari Medical Europe GmbH Basel, Incyte, INC Research, Innate Pharma, InSightec Ltd., Inspiremd, InVentiv Health Clinical UK Ltd., Inventivhealth, IO Biotech ApS Copenhagen, IOMEDICO, IONIS, IPSEN Pharma, IQVIA ISA Therapeutics, Isis Pharmaceuticals Inc., ITM Solucin GmbH, Jansen-Cilag GmbH, Kantar Health GmbH (CRO), Kartos Therapeutics, Inc., Karyopharm Therapeutics, Inc., Kendle/MorphoSys AG, Kite Pharma, Kli Fo Berlin Mitte, Kura Oncology, Labcorb, La Roche, Land Berlin, Lilly GmbH, Lion Biotechnology, Lombard Medical, Loxo Oncology, Inc., LSK BioPartners, USA, Lundbeck GmbH, LUX Biosciences, LYSARC, MacroGenics, MagForce, MedImmune Inc., MedImmune Limited, Medpace, Medpace Germany GmbH (CRO), MedPass (CRO), Medtronic, Medtraveo GmbH, Merck, Merrimack Pharmaceuticals Inc., MeVis Medical Solutions AG, Millenium Pharmaceuticals Inc., Miltenyi Biomedicine GmbH, Bergisch Gladbach, miRagen Boukider, Mologen, Monika Kutzner Stiftung, MophoSys AG, MSD Sharp, Nektar Therapeutics, NeoVacs SA, Netzwerkverbund Radiologie, Neurocrine Biosciences Inc., US, Newlink Genetics Corporation, Nexus Oncology, NIH, NOGGO Berlin, Nord-Ostddeutsche Gesellschaft e.V., Novartis, Novocure, Nuvisan, Ockham oncology, Odonate Therapeutics San Diego, OHIRC Kanada, Oppilan Pharma Ltd., London, Orion Corporation Orion Pharma, OSE Immunotherapeutics, Parexel CRO Service, Pentixal Pharma GmbH Perceptive, Pfizer GmbH, PharmaCept GmbH, Pharma Mar, Pharmaceutical Reseach Associates GmbH (PRA), Pharmacyclics Inc., Philipps, Philogen s.p.a. Siena, Pliant Therapeutics San Francisco, PIQUR Therapeutics Ltd., Pluristem, PneuRX.Inc., Portola Pharmaceuticals, PPD (CRO), PRaint, Precision GmbH, Premier-Research, Priovant Therapeutics USA, Provectus Biopharmaceuticals, Inc., Psi-Cro, Pulmonx International Sarl, Quintiles GmbH, Radiobotics ApS, Regeneraon Pharmaceuticals Inc., Replimune, Respicardia, Rhythm Pharmaceuticals, Inc. Boston USA, Roche, Salix Pharmaceuticals Inc., Samsung, Sanofi, Sanofis-Aventis S.A., Sarepta Therapeutics, Cambridge, US, Saving Patient’s Lives Medical B.V., Schumacher GmbH, Seagen, Seattle Genetics, Servier (CRO), SGS Life Science Sercives (CRO), Shape Memorial Midical Inc., USA, Shire Human Genetic Therapies, Siemens, Silena Therapeutics, SIRTEX Medical Europe GmbH, SOTIO Biotech, Boston, Spectranetics GmbH, Spectrum Pharmaceuticals, Stiftung Charite/BIH, St. Jude Medical, Stiftung Wolfgang Schulze, Syneos Health UK, Ltd., Symphogen, Taiho Oncology, Inc., Taiho Pharmaceutical Co., Target Pharma Solutions Inc., TauRx Therapeutics Ltd., Terumo Medical Corporation, Tesaro, Tetec-Ag, TEVA, Theorem, Theradex, Theravance, Threshold Pharmaceuticals Inc., TNS Healthcare GmbH, Toshiba, UCB Pharma, Ulrich GmbH Ulm, Uni Jena, Uni München, Uni Tübingen, Vaccibody A.S., VDI/VDE, Vertex Pharmaceuticals Incorporated, Viridian Therapeutics, US, Virtualscopis LLC, Winicker-Norimed, Wyeth Pharma, Xcovery Holding Company, and Zukunftsfond Berlin (TSB) outside the presented study. The other authors have no conflicts of interest to declare., (2023 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Competing Interests: Die Übersicht über die Interessenkonflikte der Autorinnen und Autoren sind im Leitlinienreport veröffentlicht.

Background: It is known that various chronic pain conditions lead to maladaptive changes in the central nervous system. Endometriosis is frequently associated with chronic pelvic pain (CPP). Its sufficient treatment remains a clinical challenge. Transcranial direct current stimulation (tDCS) has been shown to be a powerful method to reduce chronic pain. Therefore, this study aimed to investigate pain reduction via anodal tDCS in patients with endometriosis and CPP., Methods: This clinical phase II, placebo-controlled, randomized, parallel-design study included 36 patients with endometriosis and CPP. All patients had CPP, defined as a score of ≥3/10 on the visual analog scale for ≥3 months in the prior 6 months. Anodal or placebo tDCS (18 patients per arm) was applied over the primary motor cortex for 10 days. The primary outcome measure was the pressure pain threshold (objective pain measure), and secondary outcomes were the numerical rating scale score (subjective pain measure), Von Frey monofilaments, and disease- and pain-related questionnaires. Data were collected at baseline, after the 10-day stimulation, and at a follow-up session, which took place 1 week after the tDCS had ended. Statistical analyses were performed with analyses of variance and t tests., Results: Significant decreased pain perception in both pain measurements (pressure pain threshold and numerical rating scale score) was found for the active tDCS group compared with the placebo group. This proof-of-concept study shows that tDCS is a helpful supporting pain therapy for patients with endometriosis and CPP. Moreover, further analyses revealed that 1 week after the stimulation had ended, pain reduction as indexed by pressure pain threshold remained significantly decreased, which indicates possible long-term analgesic effects., Conclusion: The present study provides evidence that tDCS is an effective therapy for pain reduction in endometriosis-associated CPP. The results support the notion that CPP is developed and maintained in the central nervous system, making a multimodal pain therapy necessary., Trial Registration: www.ClinicalTrials.gov ID: NCT05231239., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

To demonstrate and analyze the specific T-cell response following barrier disruption and antigen translocation, circulating food antigen-specific effector T-cells isolated from peripheral blood were analyzed in patients suffering from celiac disease (CeD) as well as inflammatory bowel disease (IBD). We applied the antigen-reactive T-cell enrichment (ARTE) technique allowing for phenotypical and functional flow cytometric analyses of rare nutritional antigen-specific T-cells, including the celiac disease-causing gliadin (gluten). For CeD, patient groups, including treatment-refractory cases, differ significantly from healthy controls. Even symptom-free patients on a gluten-free diet were distinguishable from healthy controls, without being previously challenged with gluten. Moreover, frequency and phenotype of nutritional antigen-specific T-cells of IBD patients directly correlated to the presence of small intestinal inflammation. Specifically, the frequency of antigen specific T-cells as well as pro-inflammatory cytokines was increased in patients with active CeD or Crohn's disease, respectively. These results suggest active small intestinal inflammation as key for the development of a peripheral food antigen-specific T-cell response in Crohn's disease and celiac disease.