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There are tremendous challenges in meeting the 17 sustainable development goals (SDGs) of Agenda 2030. A collaborative search for solutions is needed to tackle the complex and novel problems at the crux of these challenges. This requires local governments and companies to join forces with other stakeholders. This collaboration usually takes the form of new Public-Private partnerships (PPPs) in emerging innovation ecosystems focused on the SDGs. These ecosystems are integrated through relational business models – multisided platforms with heterogeneous stakeholders and multidimensional utilities. Using the newly developed stakeholder resource-based view (SRBV), we have identified some characteristics of these business models and their complex relational governance. We recognize that a lot of work is still needed to define the right governance for PPPs.

A conversation with Joan E. Ricart – Interviewed by Christian Nielsen

Efficiency has been defined in at least two different ways: in terms of the refinement of existing products, processes or capabilities (static efficiency) or the development of new ones (dynamic efficiency). This paper analyzes the organizational trade-off between these two forms of efficiency. It shows that there is a tendency towards extremes, and that the irreversibility of efficiency orientations tends to tip the balance to be struck between static and dynamic efficiency toward the latter. The paper also advances hypotheses about the industry, business and corporate factors that mediate between the choice of a particular efficiency orientation and organizational performance. [ABSTRACT FROM AUTHOR]

Introduction: Crohn's disease (CD) varies by location, potentially affecting therapy efficacy and surgery risk, although research on this topic is conflicting. This study aims to investigate the independent association between CD location and therapeutic patterns., Methods: We analyzed patients with CD diagnosed from January 2005 to May 2023 registered in the nationwide ENEIDA registry. A univariate Cox regression analysis assessed the association of disease location with biologic use and persistence (with treatment discontinuation as a failure event), as well as the use of intestinal resections. A multivariate model was constructed to evaluate the independent association of disease location with therapeutic patterns, controlling for potential confounders such as sex, age at inclusion and diagnosis, disease duration and behavior, previous surgery or biological therapy, extraintestinal manifestations, and perianal disease., Results: The study included 17,292 patients with a median follow-up period of 6 years (interquartile range 2-10 years). Ileocolonic location was associated with a higher biologic use than colonic location (hazard ratio [HR] 1.30, 95% confidence interval [CI] 1.22-1.38) and ileal disease (HR 1.21, 95% CI 1.16-1.27), independently predicting biologic use (P < 0.001). Ileal location was associated with a lower biologic persistence than ileocolonic location (HR 1.14, 95% CI 1.07-1.21) and colonic disease (HR 1.10, 95% CI 1.01-1.20), independently predicting biologic persistence (P = 0.019). Ileal disease was associated with a higher likelihood of intestinal resections than colonic (HR 2.82, 95% CI 2.45-3.25) and ileocolonic location (HR 1.13, 95% CI 1.05-1.22), independently predicting the use of surgery (P < 0.001)., Discussion: CD location with ileal predominance is associated with a distinct therapeutic pattern, including higher biologic use, lower treatment persistence, and increased rates of intestinal resections., (Copyright © 2024 by The American College of Gastroenterology.)

Background & Aims: The impact of patient sex on the presentation of inflammatory bowel disease (IBD) has been poorly evaluated. Our aims were to assess potential disparities in IBD phenotype and progression between sexes., Methods: We performed an observational multicenter study that included patients with Crohn's disease (CD) or ulcerative colitis from the Spanish Estudio Nacional en Enfermedad Inflamatoria intestinal sobre Determinantes genéticos y Ambientales registry. Data extraction was conducted in July 2021., Results: A total of 51,595 patients with IBD were included, 52% were males and 25,947 had CD. The median follow-up period after diagnosis was 9 years in males and 10 years in females. In CD, female sex was an independent risk factor for medium disease onset (age, 17-40 y) (relative risk ratio, 1.45; 95% CI, 1.31-1.62), later disease onset (age, >40 y) (relative risk ratio, 1.55; 95% CI, 1.38-1.73), exclusive colonic involvement (odds ratio, 1.24; 95% CI, 1.14-1.34), inflammatory behavior (odds ratio, 1.14; 95% CI, 1.07-1.21), and extraintestinal manifestations (odds ratio, 1.48; 95% CI, 1.38-1.59). However, female sex was a protective factor for upper gastrointestinal involvement (odds ratio, 0.84; 95% CI, 0.79-0.90), penetrating behavior (odds ratio, 0.76; 95% CI, 0.70-0.82), perianal disease (odds ratio, 0.77; 95% CI, 0.71-0.82), and complications (odds ratio, 0.73; 95% CI, 0.66-0.80). In ulcerative colitis, female sex was an independent risk factor for extraintestinal manifestations (odds ratio, 1.48; 95% CI, 1.26-1.61). However, female sex was an independent protective factor for disease onset from age 40 onward (relative risk ratio, 0.76; 95% CI, 0.66-0.87), left-sided colonic involvement (relative risk ratio, 0.72; 95% CI, 0.67-0.78), extensive colonic involvement (relative risk ratio, 0.59; 95% CI, 0.55-0.64), and abdominal surgery (odds ratio, 0.78; 95% CI, 0.69-0.88)., Conclusions: There is sexual dimorphism in IBD. The patient's sex should be taken into account in the clinical management of the disease., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Familial inflammatory bowel disease (IBD) history is a controversial prognostic factor in IBD. We aimed to evaluate the impact of a familial history of IBD on the use of medical and surgical treatments in the biological era., Methods: Patients included in the prospectively maintained ENEIDA database and diagnosed with IBD after 2005 were included. Familial forms were defined as those cases with at least one first-degree relative diagnosed with IBD. Disease phenotype, the use of biological agents, or surgical treatments were the main outcomes., Results: A total of 5263 patients [2627 Crohn's disease (CD); 2636 ulcerative colitis (UC)] were included, with a median follow-up of 31 months. Of these, 507 (10%) corresponded to familial forms. No clinical differences were observed between familial and sporadic IBD forms except a lower age at IBD diagnosis and a higher rate of males in familial forms of UC. In CD, the proportions of patients treated with thiopurines (54.4% vs 46.7%; P = .015) and survival time free of thiopurines (P = .009) were lower in familial forms. No differences were found regarding the use of biological agents. Concerning surgery, a higher rate of intestinal resections was observed in sporadic CD (14.8% vs 9.9%, P = .027). No differences were observed in UC., Conclusions: In the era of biological therapies, familial and sporadic forms of IBD show similar phenotypes and are managed medically in a similar way; whether these is due to lack of phenotypical differences or an effect of biological therapies is uncertain. What is already known on this topic: IBD's etiopathogenesis points to an interaction between environmental and genetic factors, being familial history a controversial prognostic factor. Biological agents use and need for surgery regarding familial or sporadic forms of IBDs present conflicting results. What this study adds: Familial and sporadic forms of IBD have similar phenotypes and are managed medically and surgically in a similar way. How this study might affect research, practice or policy: Familial aggregation should not be considered a factor associated with more aggressive disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of Fellowship of Postgraduate Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: It is uncertain whether ulcerative colitis leads to accumulated bowel damage on cross-sectional image. We aimed to characterise bowel damage in patients with ulcerative colitis using magnetic resonance imaging [MRI], and to determine its relation with duration of disease and the impact on patients' quality of life., Methods: In this prospective study, patients with ulcerative colitis [UC] in endoscopic remission underwent MRI without bowel cleansing, and completed quality-of-life questionnaires. Participants' magnetic resonance findings were analysed considering normal values and thresholds determined in controls with no history of inflammatory bowel disease [n=40], and in patients with Crohn's disease with no history of colonic involvement [n = 12]. Subjects with UC were stratified according to disease duration [< 7 years vs 7‒14 years vs > 14 years]., Results: We analysed 41 subjects with ulcerative colitis [20 women; Mayo endoscopic subscore 0 in 38 [92.7%] and 1 in three [7.3%]]. Paired segment-by-segment comparison of magnetic resonance findings in colonic segments documented as being affected by ulcerative colitis versus controls showed that patients with ulcerative colitis had decreased cross-sectional area [p ≤ 0.0034] and perimeter [p ≤ 0.0005] and increased wall thickness [p = 0.026] in all segments. Colon damage, defined as wall thickness ≥ 3 mm, was seen in 22 [53.7%] patients. Colon damage was not associated with disease duration or quality of life., Conclusions: Morphological abnormalities in the colon were highly prevalent in patients with ulcerative colitis in the absence of inflammation. Structural bowel damage was not associated with disease duration or quality of life., (© 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.)

Background and Aim: Autologous haematopoietic stem cell transplantation [AHSCT] is a therapeutic option for refractory Crohn's disease [CD]. However, high adverse event rates related to chemotherapy toxicity and immunosuppression limit its applicability. This study aims to evaluate AHSCT's safety and efficacy using a cyclophosphamide [Cy]-free mobilisation regimen., Methods: A prospective, observational study included 14 refractory CD patients undergoing AHSCT between June 2017 and October 2022. The protocol involved outpatient mobilisation with G-CSF 12-16 μg/kg/daily for 5 days, and optional Plerixafor 240 μg/d [1-2 doses] if the CD34 + cell count target was unmet. Standard conditioning with Cy and anti-thymocyte globulin was administered. Clinical, endoscopic, and radiological assessments were conducted at baseline and during follow-up., Results: All patients achieved successful outpatient mobilisation [seven patients needed Plerixafor] and underwent transplantation. Median follow-up was 106 weeks (interquartile range [IQR] 52-348). No mobilisation-related serious adverse events [SAEs] or CD worsening occurred. Clinical and endoscopic remission rates were 71% and 41.7% at 26 weeks, 64% and 25% at 52 weeks, and 71% and 16.7% at the last follow-up, respectively. The percentage of patients who restarted CD therapy for clinical relapse and/or endoscopic/radiological activity was 14% at 26 weeks, 57% at 52 weeks, and 86% at the last follow-up, respectively. Peripheral blood cell populations and antibody levels post-AHSCT were comparable to Cy-based mobilisation., Conclusions: Cy-free mobilisation is safe and feasible in refractory CD patients undergoing AHSCT. Although relapse occurs in a significant proportion of patients, clinical and endoscopic responses are achieved upon CD-specific therapy reintroduction., (© 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.)

Background: We aimed to (1) analyze the applicability of the updated Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) recommendations in real-world clinical practice, (2) identify barriers to their implementation, and (3) propose practical measures to overcome these obstacles., Methods: This qualitative study was based on a survey, a literature review, and expert opinions. Nine inflammatory bowel disease (IBD) experts identified 7 areas likely to be controversial or potential implementation barriers in daily clinical practice: endoscopy, histology, ultrasound, quality of life, biomarkers, symptom control, and patient-reported outcomes (PROs). Based on this, a survey was carried out among educational course participants. The experts discussed the literature review and survey results and proposed several statements and practical actions., Results: A total of 55 gastroenterologists answered the survey. The reported difficulty level in reaching STRIDE-II treatment goals in clinical practice was high. Only 22% of participants performed clinical remission assessments using clinical indexes and PROs. Seventy percent of responders did not use fecal calprotectin cutoffs and considered changes from the previous levels instead. Mucosal healing as a long-term therapeutic goal was considered necessary to be individualized in specific patient subgroups (eg, elderly/fragile patients, multiple treatment failures, and last-line therapies). Other barriers, like the lack of access to imaging techniques or insufficient knowledge and skills among healthcare professionals, were detected. The experts suggested adding less stringent treatment goals and measurements, patient stratification, local adaptations, educational activities, and research., Conclusions: STRIDE-II recommendations face various implementation barriers needing careful evaluation in order to enhance their adoption in clinical practice, and ultimately improve outcomes in IBD patients., Competing Interests: ER has received support for congress and conference attendance, speaker fees, research support, or consulting fees from MSD, Abbvie, Ferring, Janssen, Otsuka, Pfizer, Takeda, Faes Farma, Galapagos, Kern Pharma, Lilly, and Fresenius-Kabi. DG has received support for congress and conference attendance, speaker fees, or consulting fees from MSD, Abbvie, Ferring, Janssen, Adacyte, Pfizer, Takeda, Faes Farma, Galapagos, Kern Pharma, Lilly, and Fresenius-Kabi. I M-J has been a speaker, consultant, and advisory member for or has received research funding from Abbvie, Amgen, Chiesi, Dr. Falk Pharma, Faes Farma, Ferring, Fresenius, Galapagos, Gebro Pharma, Janssen, Kern Pharma, Lilly, MSD, Otsuka Pharmaceutical, Pfizer, Sandoz, Shire Pharmaceuticals, Takeda, Tillotts Pharma, and Vifor Pharma. LM has been a speaker, consultant, or advisory member for or has received unrestricted grants from MSD, Abbvie, Takeda, Janssen, Pfizer, Biogen, Galapagos, Kern Pharma, Lilly Otsuka Pharmaceuticals, Tillotts, Dr. Falk Pharma, Ferring, Medtronic, and General Electric. DC has been a speaker, consultant, or advisory member for or has received unrestricted grants from Abbvie, Dr Falk Pharma, Faes, Ferring, Galapagos, Johnson & Johnson, Kern Pharma, Lilly, MSD, Pfizer, Takeda, and Tillots. The rest of the authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn's & Colitis Foundation.)

Background: Ulcerative proctitis (UP) can have a milder, less aggressive course than left-sided colitis or extensive colitis. Therefore, immunosuppressants tend to be used less in patients with this condition. Evidence, however, is scarce because these patients are excluded from randomised controlled clinical trials. Our aim was to describe the characteristics of patients with refractory UP and their disease-related complications, and to identify the need for immunosuppressive therapies., Methods: We identified patients with UP from the prospective ENEIDA registry sponsored by the GETECCU. We evaluated socio-demographic data and complications associated with immunosuppression. We defined immunosuppression as the use of immunomodulators, biologics and/or small molecules. We used logistic regression to identify factors associated with immunosuppressive therapy., Results: From a total of 34,716 patients with ulcerative colitis, we identified 6281 (18.1%) with UP; mean ± SD age 53 ± 15 years, average disease duration of 12 ± 9 years. Immunosuppression was prescribed in 11% of patients, 4.2% needed one biologic agent and 1% needed two; 2% of patients required hospitalisation, and 0.5% underwent panproctocolectomy or subtotal colectomy. We identified 0.2% colorectal tumours and 5% extracolonic tumours. Patients with polyarthritis (OR 3.56, 95% CI 1.86-6.69; p < 0.001) required immunosuppressants., Conclusions: Among patients with refractory UP, 11% required immunosuppressant therapy, and 4.2% required at least one biologic agent., (© 2024 John Wiley & Sons Ltd.)

Background and Aims: Switching from the intravenous to the subcutaneous biosimilar infliximab (SC-IFX) has been shown to safely maintain clinical remission and increase drug levels in patients with Crohn's disease (CD) and ulcerative colitis (UC). The aim of this study was to evaluate long-term outcomes after switching from intravenous IFX (IV-IFX) to SC-IFX, the drug concentration thresholds for maintaining remission and other predictors for loss of response after the switch., Methods: Multicenter observational study involving CD and UC patients who were in clinical remission for at least 24 weeks and scheduled to switch from IV-IFX to SC-IFX., Results: Two hundred and twenty patients were included [74 UC (34%) and 146 (66%) CD]. IV-IFX was administered for 52.5 months [range 25-89]. Pre-switch, 106 (49%) patients were receiving intensified IV-IFX. While SC-IFX levels significantly increased following the switch from IV to SC-IFX, clinical parameters, C-reactive protein and faecal calprotectin remained unchanged during follow-up. SC-IFX levels were significantly higher between patients receiving the standard IV-IFX dose than those with the intensified dose. Immunomodulator therapy at baseline and perianal disease had no effect on IFX trough levels, whereas higher body mass index was associated with increased levels. The suggested optimal SC-IFX cut-off concentration for clinical and biochemical remission based on ROC analysis was 12.2 μg/mL (AUC: 0.62) at week 12 and 13.2 μg/mL (AUC: 0.57) at week 52. Drug persistence was 92% at week 52, with a good safety profile., Conclusion: Switching from IV-IFX to SC-IFX safely maintains long-term remission in patients with CD and UC. In maintenance, the optimal cut-off point associated with remission was 12-13 μg/mL., (© 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.)

Background and Objectives: Combination therapy with an immunomodulator (IMM) and an anti-TNF is commonly recommended in Crohn's disease (CD) and ulcerative colitis (UC) patients. However, little is known about relapse rates after therapeutic de-escalation. This study aimed to evaluate the risk of relapse in a cohort of UC and CD patients with long-standing clinical remission after discontinuation of IMM or anti-TNF and to identify predictive factors for relapse., Methods: This retrospective study included patients with UC or CD on combination therapy and clinical remission for at least 6 months. IMM or anti-TNF was stopped upon physician decision. Primary objective was to evaluate the relapse rates after discontinuation of IMM or anti-TNF and to analyze predictors of relapse., Results: The study included 88 patients, 48 patients (54.5%) discontinued IMM and 40 (45.5%) anti-TNF. During follow-up, relapse rates were 16.7% and 52.5% in the IMM discontinuation group and anti-TNF discontinuation group, respectively (p<0.001). Multivariate analysis showed that anti-TNF discontinuation (HR=3.01; 95% CI=1.22-7.43) and ileal CD location (HR=2.36; 95% CI=1.02-5.47) were predictive factors for relapse while inflammatory CD phenotype was a protective factor (HR=0.32; 95% CI=0.11-0.90). Reintroduction of anti-TNF upon relapse was effective and safe., Conclusion: Anti-TNF discontinuation led to significantly higher relapse rates compared to IMM discontinuation in UC and CD patients on combination therapy. Anti-TNF discontinuation and ileal CD location were identified as predictive factors for relapse while inflammatory CD phenotype was a protective factor. Retreatment after anti-TNF discontinuation was effective and safe., (Copyright © 2023 Elsevier España, S.L.U. All rights reserved.)

Background and Aims: Magnetic resonance enterography (MRE) depicts transmural changes in response to biological treatment for Crohn's disease (CD); however, the long-term prognostic significance of these findings is unknown. The primary objective of this study was to identify findings on MRE 46 weeks after initiating biological treatment that predict adverse long-term outcomes., Methods: Patients with CD underwent MRE 46 weeks after initiating biological treatment and were prospectively followed for 2 years. A logistic regression analysis was performed to assess the prognostic value of different radiologic findings for various predefined adverse outcomes., Results: Of the 89 patients included, 46 (51.7%) had ≥1 adverse outcome during follow-up: 40 (44.9%) had clinical recurrence; 18 (20.2%) required surgery, 8 (9%) endoscopic balloon dilation, 12 (13.5%) hospitalization and 7 (7.8%) required corticosteroids. In the multivariate analysis, persistence of severe lesions (MaRIA ≥11) in any intestinal segment was associated with an increased risk of surgery [OR 11.6 (1.5-92.4)], of surgery and/or endoscopic balloon dilation [OR 6.3 (1.3-30.2)], and of clinical relapse [OR 4.6 (1.6-13.9)]. Penetrating lesions were associated with surgery [OR 3.4 (1.2-9.9)]. Creeping fat with hospitalization [OR 5.1 (1.1-25.0)] and corticosteroids requirement [OR 16.0 (1.2-210.0)]. The presence of complications (stricturing and/or penetrating lesions) was associated with having ≥1 adverse outcome [OR 3.35 (1.3-8.5)]., Conclusion: MRE findings at week-46 after initiating biological therapy can predict long-term adverse outcomes in CD. Therapeutic intervention may be required in patients with persistence of severe inflammatory lesions, CD-associated complications, or creeping fat., (© 2024 John Wiley & Sons Ltd.)

Markers that allow for the selection of tailored treatments for individual patients with inflammatory bowel diseases (IBD) are yet to be identified. Our aim was to describe trends in real-life treatment usage. For this purpose, patients from the ENEIDA registry who received their first targeted IBD treatment (biologics or tofacitinib) between 2015 and 2021 were included. A subsequent analysis with Machine Learning models was performed. The study included 10,009 patients [71% with Crohn's disease (CD) and 29% with ulcerative colitis (UC)]. In CD, anti-TNF (predominantly adalimumab) were the main agents in the 1st line of treatment (LoT), although their use declined over time. In UC, anti-TNF (mainly infliximab) use was predominant in 1st LoT, remaining stable over time. Ustekinumab and vedolizumab were the most prescribed drugs in 2nd and 3rd LoT in CD and UC, respectively. Overall, the use of biosimilars increased over time. Machine Learning failed to identify a model capable of predicting treatment patterns. In conclusion, drug positioning is different in CD and UC. Anti-TNF were the most used drugs in IBD 1st LoT, being adalimumab predominant in CD and infliximab in UC. Ustekinumab and vedolizumab have gained importance in CD and UC, respectively. The approval of biosimilars had a significant impact on treatment.

The treatment of inflammatory bowel disease has undergone a significant transformation following the introduction of biologic drugs. Thanks to these drugs, treatment goals have evolved from clinical response and remission to more ambitious objectives, such as endoscopic or radiologic remission. However, even though biologics are highly effective, a significant percentage of patients will not achieve an initial response or may lose it over time. We know that there is a direct relationship between the trough concentrations of the biologic and its therapeutic efficacy, with more demanding therapeutic goals requiring higher drug levels, and inadequate exposure being common. Therapeutic drug monitoring of biologic medications, along with pharmacokinetic models, provides us with the possibility of offering a personalized approach to treatment for patients with IBD. Over the past few years, relevant information has accumulated regarding its utility during or after induction, as well as in the maintenance of biologic treatment, in reactive or proactive strategies, and prior to withdrawal or treatment de-escalation. The aim of this document is to establish recommendations regarding the utility of therapeutic drug monitoring of biologics in patients with inflammatory bowel disease, in different clinical practice scenarios, and to identify areas where its utility is evident, promising, or controversial., (Copyright © 2024 The Author(s). Publicado por Elsevier España, S.L.U. All rights reserved.)

Aims: Methotrexate (MTX) is used to induce and maintain remission in patients with steroid-dependent Crohn's disease (CD). Despite its proven efficacy, its use is limited due to associated adverse events. Polymorphisms involving folate pathway genes might influence MTX efficacy and toxicity. We aimed to assess the impact of certain polymorphisms on the therapeutic outcomes of MTX in CD., Methods: Patients with CD who exclusively followed MTX monotherapy and fulfilled inclusion criteria were identified from the GETECCU ENEIDA registry. Variants of ATIC, DHFR, MTHFR, SLC19A1, ABCB1 and ABCC3 genes were analysed and their association with efficacy and toxicity was assessed., Results: A total of 129 patients were included in the analysis. MTX was used at a median weekly dose of 25 mg (interquartile range, 15-25 mg) and a median time of 14 months (interquartile range, 4-52 months). Thirty-seven percent of the patients achieved disease remission with MTX monotherapy, while 34% were nonresponders (MTX failure). MTX-related toxicity occurred in 40 patients (30%), leading to MTX discontinuation in 19%. DHFR rs408626 (odds ratio [OR] 3.12, 95% confidence interval [CI] 1.22-7.69; P = .017) and MTHFR rs1801133 (OR 2.86, 95% CI 1.23-6.68; P = .015) variants, and smoking (OR 2.61, 95% CI 1.12-6.05; P = .026) were associated with a higher risk of MTX failure. Additionally, the MTHFR rs1801131 variant was associated with a higher risk of MTX-related adverse effects (OR 2.78, 95% CI 1.26-6.13, P = .011)., Conclusion: Our study shows that variants of MTHFR and DHFR genes may be associated with MTX efficacy and adverse events in patients with CD., (© 2024 British Pharmacological Society.)

Purpose: Currently, 15% of gynaecological and 9% of haematological malignancies are diagnosed before the age of 40. The increased survival rates of cancer patients who are candidates for gonadotoxic treatments, the delay in childbearing to older ages, and the optimization of in vitro fertilisation techniques have all contributed to an increased interest in fertility preservation (FP) treatments. This study reviews the experience of the Fertility Preservation Programme (FPP) of a tertiary public hospital with a multidisciplinary approach., Methods: This retrospective study included all the available (FP) treatments, performed in patients of childbearing age between 2006 and 2022., Results: 1556 patients were referred to the FPP: 332 oocyte vitrification cycles, 115 ovarian cortex cryopreservation with 11 orthotopic autotransplantations, 175 gonadotropin-releasing hormone (GnRH) agonist treatments, 109 fertility-sparing treatments for gynaecological cancer, and 576 sperm cryopreservation were performed. Malignancy was the main indication for FP (the main indications being breast cancer in women and haematological malignancies in men), although non-oncological pathologies, such as endometriosis and autoimmune diseases, have increased in recent years. Currently, the most widely used FP technique is oocyte vitrification, the increase of which has been associated with a decrease in the use of cortex CP and GnRH agonists., Conclusions: The increase in FP treatment reflects the implementation of reproductive counselling in oncology programmes. A multidisciplinary approach in a tertiary public hospital allows individualised FP treatment for each patient. In recent years, there has been a change in trend with the introduction of new indications for FP and a change in techniques due to their optimisation., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Circular RNAs (circRNAs) are covalently closed non-coding RNAs lacking the 5' cap and the poly-A tail. Nevertheless, it has been demonstrated that certain circRNAs can undergo active translation. Therefore, aberrantly expressed circRNAs in human cancers could be an unexplored source of tumor-specific antigens, potentially mediating anti-tumor T cell responses. This study presents an immunopeptidomics workflow with a specific focus on generating a circRNA-specific protein fasta reference. The main goal of this workflow is to streamline the process of identifying and validating human leukocyte antigen (HLA) bound peptides potentially originating from circRNAs. We increase the analytical stringency of our workflow by retaining peptides identified independently by two mass spectrometry search engines and/or by applying a group-specific FDR for canonical-derived and circRNA-derived peptides. A subset of circRNA-derived peptides specifically encoded by the region spanning the back-splice junction (BSJ) are validated with targeted MS, and with direct Sanger sequencing of the respective source transcripts. Our workflow identifies 54 unique BSJ-spanning circRNA-derived peptides in the immunopeptidome of melanoma and lung cancer samples. Our approach enlarges the catalog of source proteins that can be explored for immunotherapy., (© 2024. The Author(s).)

Autoimmune diseases (ADs) are characterized by loss of immune tolerance, high chronicity, with substantial morbidity and mortality, despite conventional immunosuppression (IS) or targeted disease modifying therapies (DMTs), which usually require repeated administration. Recently, novel cellular therapies (CT), including mesenchymal stromal cells (MSC), Chimeric Antigen Receptors T cells (CART) and regulatory T cells (Tregs), have been successfully adopted in ADs. An international expert panel of the European Society for Blood and Marrow Transplantation and the International Society for the Cell and Gene Therapy, reviewed all available evidence, based on the current literature and expert practices, on use of MSC, CART and Tregs, in AD patients with rheumatological, neurological, and gastroenterological indications. Expert-based consensus and recommendations for best practice and quality of patient care were developed to support clinicians, scientists, and their multidisciplinary teams, as well as patients and care providers and will be regularly updated., Competing Interests: RG discloses speaking honoraria from Biotest, Pfizer, Medac, Neovii and Magenta. TA received study support from Amgen, Janssen and honoraria from Neovii, GSK, Astra-Zeneca, Abbvie. FM received honoraria & travel support from BMS, Janssen, Gilead, Miltenyi, Novartis, Astra-Zeneca, Biontech, received research support from Gilead, and discloses advisory board from Biontech. JAS discloses consultancy for Vertex, Medac and Jazz, and advisory board from Kiadis. PA discloses study support by NIHR, payment for expert testimony by Pinsent Mason and Bugge Valentin and consulting to Cellerys AG. RS discloses speaking honoraria from Novartis and Gilead. CCL received travel support for attending meeting by Gilead and discloses consultancy for Nektar Therapeutics and Gilead. FSG received study support from Novartis and Gilead, speaking honoraria from Astra-Zeneca and travel support from Abbvie, Gilead and Pierre-Fabre. FO discloses speaking honoraria from Takeda, Medac, Kyowa Kirin, Menarini-Stemline, and travel support from Medac, Jazz and Janssen. JOL received study support from Abbvie, Gilead, Takeda, consultancy & honoraria from AbbVie, BMS, Celgene, Celtrion, Engytix, Ferring, Galapagos, Gilead, GSK, Janssen, Lilly, MSD, Pfizer, Shire, Takeda, travel support by Abbvie, Takeda, Celltrion. AM received study support from Kyverna, Miltenyi and honoraria from Miltenyi, and participated to advisory board from Century Therapeutics. RC discloses speaking honoraria from GSK, AstraZeneca, Werfen, Rubió, Eli-Lilly, Pfizer. IYA discloses speaking honoraria from Kite, Novartis and BMS. None of the mentioned conflicts of interest were related to financing of the content of this manuscript. The remaining authors have nothing to declare., (© 2024 The Author(s).)

Background: Both vedolizumab and ustekinumab are approved for the management of Crohn's disease [CD]. Data on which one would be the most beneficial option when anti-tumour necrosis factor [anti-TNF] agents fail are limited., Aims: To compare the durability, effectiveness, and safety of vedolizumab and ustekinumab after anti-TNF failure or intolerance in CD., Methods: CD patients from the ENEIDA registry who received vedolizumab or ustekinumab after anti-TNF failure or intolerance were included. Durability and effectiveness were evaluated in both the short and the long term. Effectiveness was defined according to the Harvey-Bradshaw index [HBI]. The safety profile was compared between the two treatments. The propensity score was calculated by the inverse probability weighting method to balance confounder factors., Results: A total of 835 patients from 30 centres were included, 207 treated with vedolizumab and 628 with ustekinumab. Dose intensification was performed in 295 patients. Vedolizumab [vs ustekinumab] was associated with a higher risk of treatment discontinuation (hazard ratio [HR] 2.55, 95% confidence interval [CI]: 2.02-3.21), adjusted by corticosteroids at baseline [HR 1.27; 95% CI: 1.00-1.62], moderate-severe activity in HBI [HR 1.79; 95% CI: 1.20-2.48], and high levels of C-reactive protein at baseline [HR 1.06; 95% CI: 1.02-1.10]. The inverse probability weighting method confirmed these results. Clinical response, remission, and corticosteroid-free clinical remission were higher with ustekinumab than with vedolizumab. Both drugs had a low risk of adverse events with no differences between them., Conclusion: In CD patients who have failed anti-TNF agents, ustekinumab seems to be superior to vedolizumab in terms of durability and effectiveness in clinical practice. The safety profile is good and similar for both treatments., (© 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.)

Background: Despite research, there are still controversial areas in the management of Crohn's disease (CD)., Objective: To establish practical recommendations on using anti-tumour necrosis factor (TNF) drugs in patients with moderate-to-severe CD., Methods: Clinical controversies in the management of CD using anti-TNF therapies were identified. A comprehensive literature review was performed, and a national survey was launched to examine current clinical practices when using anti-TNF therapies. Their results were discussed by expert gastroenterologists within a nominal group meeting, and a set of statements was proposed and tested in a Delphi process., Results: Qualitative study. The survey and Delphi process were sent to 244 CD-treating physicians (response rate: 58%). A total of 14 statements were generated. All but two achieved agreement. These statements cover: (1) use of first-line non-anti-TNF biological therapy; (2) role of HLA-DQA1*05 in daily practice; (3) attitudes in primary non-response and loss of response to anti-TNF therapy due to immunogenicity; (4) use of ustekinumab or vedolizumab if a change in action mechanism is warranted; (5) anti-TNF drug level monitoring; (6) combined therapy with an immunomodulator., Conclusion: This document sought to pull together the best evidence, experts' opinions, and treating physicians' attitudes when using anti-TNF therapies in patients with CD., Competing Interests: Competing interests: IM-J has served as a speaker, consultant, or advisory member for or has received unrestricted grants from Dr Falk Pharma, Galapagos, Tillotts, Otsuka, Sandoz, MSD, AbbVie, Takeda, Janssen, Pfizer, Amgen, Kern Pharma, and Ferring. GB has served as a speaker, consultant, or advisory member for or has received unrestricted grants from AbbVie, Takeda, Janssen, Pfizer, Galapagos, Kern Pharma, Tillotts, and Ferring. ER has served as a speaker, consultant, or advisory member for or has received research funding from MSD, AbbVie, Takeda, Janssen, Galapagos, Fresenius Kabi, Pfizer, Amgen, Kern Pharma, and Ferring. YG-L has served as a speaker, consultant, or advisory member for or has received unrestricted grants from MSD, AbbVie, Takeda, Janssen, Pfizer, Amgen, Kern Pharma, and Ferring. LM has served as a speaker, consultant or advisory member for or has received unrestricted grants from MSD, AbbVie, Takeda, Janssen, Pfizer, Biogen, Galapagos, Kern Pharma, Tillotts, Dr Falk Pharma, Ferring, Medtronic, and General Electric. DG has served as a speaker, consultant, or advisory member for or has received unrestricted grants from AbbVie, Takeda, Janssen, Pfizer, Biogen, Adacyte, Sandoz, and Ferring. DC has served as a speaker, consultant, or advisory member for or has received unrestricted grants from AbbVie, Takeda, Janssen, Pfizer, Adacyte, Galapagos, Fresenius-Kabi, and Ferring. FM has served as a speaker, consultant, or advisory member for or has received unrestricted grants from AbbVie, Takeda, Janssen, Pfizer, and Ferring. DC has served as a speaker, consultant or advisory member for or has received unrestricted grants from AbbVie, Fresenius-Kabi, Ferring, Galapagos, Gilead, Janssen, Kern, MSD, Pfizer, and Takeda., (© 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.)

BACKGROUND. New biologic agents for Crohn disease (CD) create a need for noninvasive disease markers. DWI may assess bowel inflammation without contrast agents. OBJECTIVE. The purpose of this study was to evaluate ADC values for identifying bowel inflammation and therapeutic response in patients with CD treated with biologic therapy. METHODS. This study entailed post hoc analysis of prospective trial data. Analysis included 89 patients (median age, 37 years; 49 women, 40 men) with CD treated by biologic therapy who underwent MR enterography (MRE) at baseline and 46 weeks after therapy, from March 2013 to April 2021; 43 patients underwent ileocolonoscopy at both time points. Analysis was conducted at the level of small-bowel and colorectal segments (586 segments analyzed). MR index of activity (MaRIA) score and presence of endoscopic ulcers were determined at both time points. One observer measured bowel wall ADC. Diagnostic performance was evaluated. Dichotomous ADC assessments used a threshold of 1301 × 10 -6 mm 2 /s based on initial ROC analysis; dichotomous MaRIA score assessments used a threshold of 11 (moderate to severe inflammation). A second observer repeated ADC measurements in 15 patients. RESULTS. At baseline, ADC had AUC of 0.92, sensitivity of 78.6%, specificity of 91.4%, and accuracy of 88.2% for detecting segments with MaRIA score 11 or greater. At baseline, AUC for detecting endoscopic ulcers was 0.96 for MaRIA score versus 0.87 for ADC ( p < .001); sensitivity, specificity, and accuracy were 70.8%, 90.2%, and 85.1% for ADC and 86.2%, 96.2%, and 93.6% for MaRIA score. At follow-up, ADC had AUC of 0.87, sensitivity of 75.4%, specificity of 83.6%, and accuracy of 80.0% for detecting improvement in MaRIA score to less than 11. At follow-up, AUC for detecting endoscopic ulcer healing was 0.94 for MaRIA score versus 0.84 for ADC ( p = .01); sensitivity, specificity, and accuracy were 70.7%, 95.8%, and 84.4% for ADC and 90.2%, 100.0%, and 95.6% for MaRIA score. Interobserver agreement for ADC, based on intraclass correlation coefficient, was 0.70 at baseline and 0.65 at follow-up. CONCLUSION. The findings do not support use of ADC rather than MaRIA scores for detecting biologic therapy response. CLINICAL IMPACT. ADC may have an adjunct role in assessing bowel inflammation in CD, but showed limited performance for detecting biologic therapy response.

Ulcerative colitis and Crohn's disease are chronic inflammatory intestinal diseases with perplexing heterogeneity in disease manifestation and response to treatment. While the molecular basis for this heterogeneity remains uncharacterized, single-cell technologies allow us to explore the transcriptional states within tissues at an unprecedented resolution which could further understanding of these complex diseases. Here, we apply single-cell RNA-sequencing to human inflamed intestine and show that the largest differences among patients are present within the myeloid compartment including macrophages and neutrophils. Using spatial transcriptomics in human tissue at single-cell resolution (CosMx Spatial Molecular Imaging) we spatially localize each of the macrophage and neutrophil subsets identified by single-cell RNA-sequencing and unravel further macrophage diversity based on their tissue localization. Finally, single-cell RNA-sequencing combined with single-cell spatial analysis reveals a strong communication network involving macrophages and inflammatory fibroblasts. Our data sheds light on the cellular complexity of these diseases and points towards the myeloid and stromal compartments as important cellular subsets for understanding patient-to-patient heterogeneity., (© 2023. The Author(s).)

(1) Background: Transition is a planned movement of paediatric patients to adult healthcare systems, and its implementation is not yet established in all inflammatory bowel disease (IBD) units. The aim of the study was to evaluate the impact of transition on IBD outcomes. (2) Methods: Multicentre, retrospective and observational study of IBD paediatric patients transferred to an adult IBD unit between 2017-2020. Two groups were compared: transition (≥1 joint visit involving the gastroenterologist, the paediatrician, a programme coordinator, the parents and the patient) and no-transition. Outcomes within one year after transfer were analysed. The main variable was poor clinical outcome (IBD flare, hospitalisation, surgery or any change in the treatment because of a flare). Predictive factors of poor clinical outcome were identified with multivariable analysis. (3) Results: A total of 278 patients from 34 Spanish hospitals were included. One hundred eighty-five patients (67%) from twenty-two hospitals (65%) performed a structured transition. Eighty-nine patients had poor clinical outcome at one year after transfer: 27% in the transition and 43% in the no-transition group ( p = 0.005). One year after transfer, no-transition patients were more likely to have a flare (36% vs. 22%; p = 0.018) and reported more hospitalisations (10% vs. 3%; p = 0.025). The lack of transition, as well as parameters at transfer, including IBD activity, body mass index < 18.5 and corticosteroid treatment, were associated with poor clinical outcome. One patient in the transition group (0.4%) was lost to follow-up. (4) Conclusion: Transition care programmes improve patients' outcomes after the transfer from paediatric to adult IBD units. Active IBD at transfer impairs outcomes.

Introduction: The prevalence of penetrating complications in Crohn's disease (CD) increases progressively over time, but evidence on the medical treatment in this setting is limited. The aim of this study was to evaluate the effectiveness of biologic agents in CD complicated with internal fistulizing disease., Methods: Adult patients with CD-related fistulae who received at least 1 biologic agent for this condition from the prospectively maintained ENEIDA registry were included. Exclusion criteria involved those receiving biologics for perianal disease, enterocutaneous, rectovaginal, anastomotic, or peristomal fistulae. The primary end point was fistula-related surgery. Predictive factors associated with surgery and fistula closure were evaluated by multivariate logistic regression and survival analyses., Results: A total of 760 patients from 53 hospitals (673 receiving anti-tumor necrosis factors, 69 ustekinumab, and 18 vedolizumab) were included. After a median follow-up of 56 months (interquartile range, 26-102 months), 240 patients required surgery, with surgery rates of 32%, 41%, and 24% among those under anti-tumor necrosis factor, vedolizumab, or ustekinumab, respectively. Fistula closure was observed in 24% of patients. Older patients, ileocolonic disease, entero-urinary fistulae, or an intestinal stricture distal to the origin of the fistula were associated with a higher risk of surgery, whereas nonsmokers and combination therapy with an immunomodulator reduced this risk., Discussion: Biologic therapy is beneficial in approximately three-quarters of patients with fistulizing CD, achieving fistula closure in 24%. However, around one-third still undergo surgery due to refractory disease. Some patient- and lesion-related factors can identify patients who will obtain more benefit from these drugs., (Copyright © 2023 by The American College of Gastroenterology.)

Background: Motorized Spiral Enteroscopy (MSE) reduces procedure time and increases insertion depth into the small bowel; however, there is scarce evidence on factors affecting MSE efficacy., Aims: To evaluate diagnostic yield and adverse events of MSE including patients with prior major abdominal surgery., Methods: A prospective observational study was conducted on patients undergoing MSE from June 2019 to December 2021. Demographic characteristics, procedure time, depth of maximum insertion (DMI), technical success, diagnostic yield, and adverse events were collected., Results: Seventy-four anterograde (54.4%) and 62 retrograde (45.6%) enteroscopies were performed in 117 patients (64 males, median age 67 years). Fifty patients (42.7%) had prior major abdominal surgery. Technical success was 91.9% for anterograde and 90.3% for retrograde route. Diagnostic yield was 71.6% and 61.3%, respectively. The median DMI was 415 cm (264-585) for anterograde and 120 cm (37-225) for retrograde enteroscopy. In patients with prior major abdominal surgery, MSE showed significantly longer small bowel insertion time (38 vs 29 min, p = 0.004), with similar diagnostic yield (61 vs 71.4%, p = 0.201) and DMI (315 vs 204 cm, p = 0.226). The overall adverse event rate was 10.3% (SAE 1.5%), with no differences related to prior abdominal surgery (p = 0.598). Patients with prior surgeries directly involving the gastrointestinal tract showed lower DMI (189 vs 374 cm, p = 0.019) with equal exploration time (37.5 vs 38 min, p = 0.642) compared to those with other abdominal surgeries., Conclusions: MSE is effective and safe in patients with major abdominal surgery, although longer procedure times were observed. A lower depth of insertion was detected in patients with gastrointestinal surgery., (© 2022. The Author(s).)

Ulcerative colitis (UC) is a chronic inflammatory disease with a high impact. In order to improve patient outcomes, the clinician-patient relationship in daily practice is critical. Clinical guidelines provide a framework for UC diagnosis and treatment. However, standard procedures and the medical content focused upon medical consultations in UC patients has not yet been defined. Moreover, UC is a complex disease, given that patient characteristics and patient needs have been proven to vary during clinical consultation since establishing the diagnosis and upon the course of the disease. In this article, we have discussed the key elements and specific objectives to consider in medical consultation, such as diagnosis, first visits, follow-up visits, active disease patients, patients on topical therapies, new treatment initiation, refractory patients, extra-intestinal manifestations, as well as challenging situations. The key elements have been mentioned to comprise effective communication techniques, motivational interviewing (MI), as well as information and educational aspects, or organizational issues. The key elements to be implemented in daily practice were reported to comprise several general principles like duly prepared consultations, in addition to honesty and empathy with patients, as well as effective communication techniques, MI, information and educational points, or organizational issues. The role of other healthcare professionals such as specialized nurses, psychologists, or the use of checklists was also discussed and commented on., Competing Interests: Conflict-of-interest statement: Fortes P and Cábez A are employees of Pfizer (Spain). González-Lama Y, Casellas F, and Ricart E have received consultancy fees from Pfizer S.L.U. for their work in this project but have no other relevant financial relationships to disclose. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in this manuscript apart from those disclosed. González-Lama Y received research funding from AbbVie, Ferring, MSD, Takeda, Janssen, and Pfizer; speaker fees from AbbVie, Ferring, Gebro, Takeda, and Janssen. Casellas F received research funding from AbbVie, Ferring, MSD, Shire, Takeda, Zambon and Pfizer; speaker fees from AbbVie, Chiesi, Ferring, Gebro, MSD, Shire, Takeda, and Zambon., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background and Aims: Clinical trials and real-life studies with ustekinumab in Crohn's disease [CD] have revealed a good efficacy and safety profile. However, these data are scarcely available in elderly patients. Therefore, we aim to assess the effectiveness and safety of ustekinumab in elderly patients with CD., Methods: Elderly patients [>60 years old] from the prospectively maintained ENEIDA registry treated with ustekinumab due to CD were included. Every patient was matched with two controls under 60 years of age, according to anti-tumour necrosis factor use and smoking habit. Values for the Harvey-Bradshaw Index [HBI], endoscopic activity, C-reactive protein [CRP] and faecal calprotectin [FC] were recorded at baseline and at weeks 16, 32 and 54., Results: In total, 648 patients were included, 212 of whom were elderly. Effectiveness was similar between young and elderly patients during the follow-up. Steroid-free remission was similar at week 16 [54.6 vs 51.4%, p = 0.20], 32 [53.0% vs 54.5%, p = 0.26] and 54 [57.8% vs 51.1%, p = 0.21]. Persistence of ustekinumab as maintenance therapy was similar in both age groups [log-rank test; p = 0.91]. There was no difference in the rate of adverse effects [14.2% vs 11.2%, p = 0.350], including severe infections [7.1% vs 7.3%, p = 1.00], except for the occurrence of de novo neoplasms, which was higher in older patients [0.7% vs 4.3%, p = 0.003]., Conclusions: Ustekinumab is as effective in elderly patients with CD as it is in non-elderly patients. The safety profile also seems to be similar except for a higher rate of de novo neoplasms, probably related to the age of the elderly patients., (© The Author(s) 2022. 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.)

(1) Scant information is available concerning the characteristics that may favour the acquisition of COVID-19 in patients with inflammatory bowel disease (IBD). Therefore, the aim of this study was to assess these differences between infected and noninfected patients with IBD. (2) This nationwide case−control study evaluated patients with inflammatory bowel disease with COVID-19 (cases) and without COVID-19 (controls) during the period March−July 2020 included in the ENEIDA of GETECCU. (3) A total of 496 cases and 964 controls from 73 Spanish centres were included. No differences were found in the basal characteristics between cases and controls. Cases had higher comorbidity Charlson scores (24% vs. 19%; p = 0.02) and occupational risk (28% vs. 10.5%; p < 0.0001) more frequently than did controls. Lockdown was the only protective measure against COVID-19 (50% vs. 70%; p < 0.0001). No differences were found in the use of systemic steroids, immunosuppressants or biologics between cases and controls. Cases were more often treated with 5-aminosalicylates (42% vs. 34%; p = 0.003). Having a moderate Charlson score (OR: 2.7; 95%CI: 1.3−5.9), occupational risk (OR: 2.9; 95%CI: 1.8−4.4) and the use of 5-aminosalicylates (OR: 1.7; 95%CI: 1.2−2.5) were factors for COVID-19. The strict lockdown was the only protective factor (OR: 0.1; 95%CI: 0.09−0.2). (4) Comorbidities and occupational exposure are the most relevant factors for COVID-19 in patients with IBD. The risk of COVID-19 seems not to be increased by immunosuppressants or biologics, with a potential effect of 5-aminosalicylates, which should be investigated further and interpreted with caution.

Chronic gut inflammation in Crohn’s disease (CD) is associated with an increase in oxidative stress and an imbalance of antioxidant enzymes. We have previously shown that catalase (CAT) activity is permanently inhibited by CD. The purpose of the study was to determine whether there is any relationship between the single nucleotide polymorphisms (SNPs) in the CAT enzyme and the potential risk of CD associated with high levels of oxidative stress. Additionally, we used protein and regulation analyses to determine what causes long-term CAT inhibition in peripheral white mononuclear cells (PWMCs) in both active and inactive CD. We first used a retrospective cohort of 598 patients with CD and 625 age-matched healthy controls (ENEIDA registry) for the genotype analysis. A second human cohort was used to study the functional and regulatory mechanisms of CAT in CD. We isolated PWMCs from CD patients at the onset of the disease (naïve CD patients). In the genotype-association SNP analysis, the CAT SNPs rs1001179, rs475043, and rs525938 showed a significant association with CD (p < 0.001). Smoking CD patients with the CAT SNP rs475043 A/G genotype had significantly more often penetrating disease (p = 0.009). The gene expression and protein levels of CAT were permanently reduced in the active and inactive CD patients. The inhibition of CAT activity in the PWMCs of the CD patients was related to a low concentration of CAT protein caused by the downregulation of CAT-gene transcription. Our study suggests an association between CAT SNPs and the risk of CD that may explain permanent CAT inhibition in CD patients together with low CAT gene and protein expression.

Patients with inflammatory bowel disease (IBD) may require different immunosuppressive treatments throughout their illness. It is essential to assess the immunization status of patients at diagnosis or, if this is not possible, at least before the beginning of immunosuppressive therapy and, subsequently, administering the appropriate vaccines. Therefore, the aim of this work is to establish clear and concise recommendations on vaccination in patients with IBD in the different settings of our clinical practice including vaccination in children, during pregnancy, breastfeeding or on trips. This consensus document emphasises the differences between inactivated and attenuated vaccines and the different degrees of immunosuppression and correlates them with the administration of both mandatory and optional vaccines recommended to our patients with IBD. Finally, as a summary, 17 recommendations are established based on the available scientific evidence and expert opinion. A multidisciplinary team with extensive experience in IBD and vaccination, made up of specialists in gastroenterology, paediatrics, nursing and pharmacy, has participated in the preparation of these recommendations of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis., (Copyright © 2022 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Crohn's disease (CD) is a chronic inflammatory bowel disorder that progresses to bowel damage (BD) over time. An image-based index, the Lémann index (LI), has been developed to measure cumulative BD., Aim: To characterize the long-term progression of BD in CD based on changes in the LI and to determine risk factors for long-term progression., Methods: This was a single-center longitudinal cohort study. Patients who had participated in prospective studies on the accuracy of magnetic resonance imaging using endoscopy as a gold standard and who had a follow-up of at least 5 years were re-evaluated after 5-12 years., Results: Seventy-two patients were included. LI increased in 38 patients (52.8%), remained unchanged in 9 patients (12.5%), and decreased in 25 patients (34.7%). The small bowel score and surgery subscale significantly increased ( P = 0.002 and P = 0.001, respectively), whereas the fistulizing subscale significantly decreased ( P = 0.001). Baseline parameters associated with BD progression were ileal location ( P = 0.026), CD phenotype [stricturing, fistulizing, or both ( P = 0.007, P = 0.006, and P = 0.035, respectively)], disease duration > 10 years ( P = 0.019), and baseline LI stricturing score ( P = 0.049). No correlation was observed between BD progression and baseline clinical activity, biological markers, or severity of endoscopic lesions., Conclusion: BD, as assessed by the LI, progressed in half of the patients with CD over a period of 5-12 years. The main determinants of BD progression were ileal location, stricturing/fistulizing phenotype, and disease duration., Competing Interests: Conflict-of-interest statement: Dr. Rimola reports grants from Abbvie, personal fees from Alimentiv, personal fees from Janssen, personal fees from Takeda, non-financial support from Gilead and from Agumab during the conduct of the study., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) resulting from the interaction of multiple environmental, genetic and immunological factors. CD5 and CD6 are paralogs encoding lymphocyte co-receptors involved in fine-tuning intracellular signals delivered upon antigen-specific recognition, microbial pattern recognition and cell adhesion. While CD5 and CD6 expression and variation is known to influence some immune-mediated inflammatory disorders, their role in IBD remains unclear. To this end, Cd5 - and Cd6 -deficient mice were subjected to dextran sulfate sodium (DSS)-induced colitis, the most widely used experimental animal model of IBD. The two mouse lines showed opposite results regarding body weight loss and disease activity index (DAI) changes following DSS-induced colitis, thus supporting Cd5 and Cd6 expression involvement in the pathophysiology of this experimental IBD model. Furthermore, DNA samples from IBD patients of the ENEIDA registry were used to test association of CD5 (rs2241002 and rs2229177) and CD6 (rs17824933, rs11230563, and rs12360861) single nucleotide polymorphisms with susceptibility and clinical parameters of CD (n=1352) and UC (n=1013). Generalized linear regression analyses showed association of CD5 variation with CD ileal location (rs2241002 CC ) and requirement of biological therapies (rs2241002 C -rs2229177 T haplotype), and with poor UC prognosis (rs2241002 T -rs2229177 T haplotype). Regarding CD6 , association was observed with CD ileal location (rs17824933 G ) and poor prognosis (rs12360861 G ), and with left-sided or extensive UC, and absence of ankylosing spondylitis in IBD (rs17824933 G ). The present experimental and genetic evidence support a role for CD5 and CD6 expression and variation in IBD's clinical manifestations and therapeutic requirements, providing insight into its pathophysiology and broadening the relevance of both immunomodulatory receptors in immune-mediated disorders., Competing Interests: FL is founder and ad-honorem scientific advisor of Sepsia Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Casadó-Llombart, Velasco-de Andrés, Català, Leyton-Pereira, Gutiérrez-Cózar, Suárez, Armiger, Carreras, Esteller, Ricart, Ordás, Gisbert, Chaparro, Esteve, Márquez, Busquets, Iglesias, García-Planella, Martín-Arranz, Lohmann, Ayata, Niess, Engel, Panés, Salas, Domènech, Lozano and ENEIDA Project of GETECCU.)

(1) Background: Fecal calprotectin (FC) correlates well with colonic inflammatory activity of Crohn’s disease (CD); data about relation of FC and small bowel (SB) lesions are still contradictory. The main aim was to analyze the relationship between FC levels and SB inflammatory activity in patients with established or suspected Crohn’s disease, assessed by small bowel capsule endoscopy (SBCE) or magnetic resonance enterography (MRE). (2) Methods: Two cohorts of patients were included: 1. Prospective data were collected from patients with established or suspected CD who underwent SBCE and FC (Cohort A); 2. A retrospective cohort of patients who underwent MRE and FC determination (Cohort B). Different cutoffs for FC were tested in both cohorts. (3) Results: 83 patients were included and 66 were finally analyzed. A total of 69.6% had SB lesions seen by SBCE (n = 25) or MRE (n = 21). FC mean levels were 605.74 + 607.07 μg/g (IQ range: 99.00−878.75), being significantly higher in patients with SB lesions compared to patients without lesions (735.91 + 639.70 μg/g (IQ range: 107.75−1366.25) vs. 306.35 + 395.26 μg/g (IQ range: 78.25−411.0), p < 0.005). For cohort A, 25 out of 35 patients had SB lesions and a significant correlation between Lewis Score and FC levels was achieved (R2: 0.34; p = 0.04). FC sensitivity (S), specificity (E), positive predictive value (PPV), and negative predictive values (NPV) for predicting SB lesions were 80%, 50%, 80%, and 50%, respectively, for FC > 100 µg/g. For cohort B, inflammatory SB activity, measured by MaRIA score, was detected in 21 out of 31 patients (67.7%). Patients with positive findings in MRE had significantly higher values of FC than those with no lesions (944.9 + 672.1 µg/g vs. 221 + 212.2 µg/g, p < 0.05). S, E, PPV, and NPV of FC were 89%, 50%, 77.2%, and 71.4% for FC levels > 100 µg/g. The higher sensitivity and specificity of the FC levels for the detection of SB lesions with SBCE and MRE was obtained for an FC cutoff >265 μg/g and >430 μg/g, respectively. (4) Conclusions: FC has a good correlation with the presence of SB lesions, assessed by SBCE and MRE, in patients with established or suspected Crohn’s disease. However, the ideal cutoff is here proven to be higher than previously reported. Multicenter and large prospective studies are needed in order to establish definitive FC cutoff levels.

Background and Aims: Immunomediated adverse events [IAEs] are the most frequently reported infliximab [IFX]-related adverse events. Combination therapy may reduce their incidence, although this strategy is not recommended in elderly patients. We aimed to compare the rates of IFX-related IAEs and loss of response [LOR] in elderly and younger patients., Methods: Adult patients in the ENEIDA registry who had received a first course of IFX therapy were identified and grouped into two cohorts regarding age at the beginning of treatment [over 60 years and between 18 and 50 years]. The rates of IAEs and LOR were compared., Results: In total, 939 patients [12%] who started IFX over 60 years of age and 6844 [88%] below 50 years of age were included. Elderly patients presented a higher proportion of AEs related to IFX [23.2% vs 19%; p = 0.002], infections [7.1% vs 4.3%; p < 0.001] and neoplasms [2.2% vs 0.5%; p < 0.001]. In contrast, the rates of IAEs [14.8% vs 14.8%; p = 0.999], infusion reactions [8.1% vs 8.1%; p = 0.989], late hypersensitivity [1.3% vs 1.2%; p = 0.895], paradoxical psoriasis [1% vs 1.5%; p = 0.187] and drug-induced lupus erythematosus [0.6% vs 0.7%; p = 0.947] were similar in elderly and younger patients. LOR rates were also similar between the two groups [20.5% vs 19.3%; p = 0.438]. In the logistic regression analysis, IFX monotherapy, extraintestinal manifestations and female gender were the only risk factors for IAEs, whereas IFX monotherapy, extraintestinal manifestations and Crohn's disease were risk factors for LOR., Conclusions: Elderly patients with inflammatory bowel disease have a similar risk of developing IFX-related IAEs and LOR to that of younger patients., (© The Author(s) 2021. 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.)

(1) Aims: Patients receiving antitumor necrosis factor (anti-TNF) therapy are at risk of developing tuberculosis (TB), usually due to the reactivation of a latent TB infection (LTBI). LTBI screening and treatment decreases the risk of TB. This study evaluated the diagnostic performance of different LTBI screening strategies in patients with inflammatory bowel disease (IBD). (2) Methods: Patients in the Spanish ENEIDA registry with IBD screened for LTBI between January 2003 and January 2018 were included. The diagnostic yield of different strategies (dual screening with tuberculin skin test [TST] and interferon-ץ-release assay [IGRA], two-step TST, and early screening performed at least 12 months before starting biological treatment) was analyzed. (3) Results: Out of 7594 screened patients, 1445 (19%; 95% CI 18−20%) had LTBI. Immunomodulator (IMM) treatment at screening decreased the probability of detecting LTBI (20% vs. 17%, p = 0.001). Regarding screening strategies, LTBI was more frequently diagnosed by dual screening than by a single screening strategy (IGRA, OR 0.60; 95% CI 0.50−0.73, p < 0.001; TST, OR 0.76; 95% CI 0.66−0.88, p < 0.001). Two-step TST increased the diagnostic yield of a single TST by 24%. More cases of LTBI were diagnosed by early screening than by routine screening before starting anti-TNF agents (21% [95% CI 20−22%] vs. 14% [95% CI 13−16%], p < 0.001). The highest diagnostic performance for LTBI (29%) was obtained by combining early and TST/IGRA dual screening strategies in patients without IMM. (4): Conclusions: Both early screening and TST/IGRA dual screening strategies significantly increased diagnostic performance for LTBI in patients with IBD, with optimal performance achieved when they are used together in the absence of IMM.

Introduction: Colorectal cancer (CRC) is a potentially life-threatening complication of long-standing ulcerative colitis (UC). MicroRNAs (miRNA) are epigenetic regulators that have been involved in the development of UC-associated CRC. However, their role as potential mucosal biomarkers of neoplastic progression has not been adequately studied., Methods: In this study, we analyzed the expression of 96 preselected miRNAs in human formalin-fixed and paraffin-embedded tissue of 52 case biopsies (20 normal mucosa, 20 dysplasia, and 12 UC-associated CRCs) and 50 control biopsies (10 normal mucosa, 21 sporadic adenomas, and 19 sporadic CRCs) by using Custom TaqMan Array Cards. For validation of deregulated miRNAs, we performed individual quantitative real-time polymerase chain reaction in an independent cohort of 50 cases (13 normal mucosa, 25 dysplasia, and 12 UC-associated CRCs) and 46 controls (7 normal mucosa, 19 sporadic adenomas, and 20 sporadic CRCs)., Results: Sixty-four miRNAs were found to be differentially deregulated in the UC-associated CRC sequence. Eight of these miRNAs were chosen for further validation. We confirmed miR-31, -106a, and -135b to be significantly deregulated between normal mucosa and dysplasia, as well as across the UC-associated CRC sequence (all P < 0.01). Notably, these miRNAs also confirmed to have a significant differential expression compared with sporadic CRC (all P < 0.05)., Discussion: UC-associated and sporadic CRCs have distinct miRNA expression patterns, and some miRNAs indicate early neoplastic progression., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Objectives: Patients with Crohn's disease (CD) require multiple assessments with magnetic resonance enterography (MRE) from a young age. Standard MRE protocols for CD include contrast-enhanced sequences. Gadolinium deposits in brain tissue suggest avoiding gadolinium could benefit patients with CD. This study aimed to compare the accuracy of the simplified Magnetic Resonance Index of Activity (sMaRIA) calculated with and without contrast-enhanced sequences in determining the response to biologic drugs in patients with CD., Methods: This post hoc analysis of a prospective study included patients with CD with endoscopic ulceration in ≥ 1 intestinal segment starting biologic drug therapy. Two blinded radiologists used the sMaRIA to score images obtained at baseline and week 46 of treatment first using only unenhanced sequences (T2-sMaRIA) and 1 month later using both unenhanced and enhanced images (CE-sMaRIA). We calculated the rates of agreement between T2-sMaRIA, CE-sMaRIA, and ileocolonoscopy for different conceptualizations of therapeutic response., Results: A total of 46 patients (median age, 36 years [IQR: 28-47]) were included. Agreement with ileocolonoscopy was similar for CE-sMaRIA and T2-sMaRIA in identifying ulcer healing (kappa = 0.74 [0.55-0.93] and 0.70 [0.5-0.9], respectively), treatment response (kappa = 0.53 [0.28-0.79] and 0.44 [0.17 - 0.71]), and remission (kappa = 0.48 [0.22-0.73] and 0.43 [0.17-0.69]). The standardized effect size was moderate for both CE-sMaRIA = 0.63 [0.41-0.85] p < 0.001 and T2-sMaRIA = 0.58 [0.36-0.80] p < 0.001., Conclusions: sMaRIA with and without contrast-enhanced images accurately classified the response according to different therapeutic endpoints determined by ileocolonoscopy., Key Points: • The simplified Magnetic Resonance Index of Activity is accurate for the assessment of Crohn's disease activity, severity, and therapeutic response, using four dichotomic components that can be evaluated without the need of using contrast-enhanced sequences, representing a practical and safety advantage, but concerns have been expressed as to whether the lack of contrast sequences may compromise precision. • The simplified Magnetic Resonance Index of Activity can assess the response to biologic therapy in patients with Crohn's disease without the need for intravenous contrast agents obtaining comparable results without and with contrast-enhanced sequences. • Avoiding intravenous contrast agents could reduce the duration of the MRE examination and its cost and would increase the acceptance and safety of MRE in clinical research in patients with Crohn's disease., (© 2021. The Author(s), under exclusive licence to European Society of Radiology.)