Genetic biomarkers of methotrexate response and safety in Crohn's disease: Data from the Spanish ENEIDA registry.

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.

Comparison of green solvents for the revalorization of orange by-products: Carotenoid extraction and in vitro antioxidant activity.

Orange peels contain a considerable number of bioactive compounds such as carotenoids, that can be used as ingredients in high-value products. The aim of this study was to compare orange peel extracts obtained with different green solvents (vegetable oils, fatty acids, and deep eutectic solvents (DES)). In addition, the chemical characterization of a new hydrophobic DES formed by octanoic acid and l-proline (C8:Pro) was performed. The extracts were compared in terms of carotenoid extraction, antioxidant activity by three methods, color, and environmental impact. The results confirmed that the mixture of C8:Pro is a DES and showed the highest carotenoid extraction (46.01 µg/g) compared to hexane (39.28 µg/g). The antioxidant activity was also the highest in C8:Pro (2438.8 µM TE/mL). Finally, two assessment models were used to evaluate the greenness and sustainability of the proposed extractions. These results demonstrated the potential use of orange peels in the circular economy and industry.

Serum and Urine Metabolomic Profiling of Newly Diagnosed Treatment-Naïve Inflammatory Bowel Disease Patients.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a prevalent chronic noncurable disease associated with profound metabolic changes. The discovery of novel molecular indicators for unraveling IBD etiopathogenesis and the diagnosis and prognosis of IBD is therefore pivotal. We sought to determine the distinctive metabolic signatures from the different IBD subgroups before treatment initiation. METHODS: Serum and urine samples from newly diagnosed treatment-naïve IBD patients and age and sex-matched healthy control (HC) individuals were investigated using proton nuclear magnetic resonance spectroscopy. Metabolic differences were identified based on univariate and multivariate statistical analyses. RESULTS: A total of 137 Crohn's disease patients, 202 ulcerative colitis patients, and 338 HC individuals were included. In the IBD cohort, several distinguishable metabolites were detected within each subgroup comparison. Most of the differences revealed alterations in energy and amino acid metabolism in IBD patients, with an increased demand of the body for energy mainly through the ketone bodies. As compared with HC individuals, differences in metabolites were more marked and numerous in Crohn's disease than in ulcerative colitis patients, and in serum than in urine. In addition, clustering analysis revealed 3 distinct patient profiles with notable differences among them based on the analysis of their clinical, anthropometric, and metabolomic variables. However, relevant phenotypical differences were not found among these 3 clusters. CONCLUSIONS: This study highlights the molecular alterations present within the different subgroups of newly diagnosed treatment-naïve IBD patients. The metabolomic profile of these patients may provide further understanding of pathogenic mechanisms of IBD subgroups. Serum metabotype seemed to be especially sensitive to the onset of IBD.

A Population-Based Cross-Sectional Study of Paediatric Coeliac Disease in Catalonia Showed a Downward Trend in Prevalence Compared to the Previous Decade.

(1) Background: Previous studies showed an increased prevalence and incidence of coeliac disease (CD) over time. The objective is to ascertain whether the CD prevalence in Catalonia (a region of Southern Europe) among children aged 1-5 is as high as previously found in 2004-2009; (2) Methods: From 2013 to 2019, 3659 subjects aged 1-5 years were recruited following the previously used methodology. Factors with a potential impact on CD prevalence were investigated; (3) Results: In 2013-2019, 43/3659 subjects had positive serology, giving a standardised seroprevalence of 12.55/1000 (95% CI: 8.92; 17.40), compared to 23.62 (13.21; 39.40) in 2004-2007. The biopsy-proven crude prevalence was 7.92/1000 (95% CI: 5.50; 11.30), and the crude prevalence based on ESPGHAN criteria was 8.74/1000 (95% CI: 6.20-12.30). In contrast to 2004-2009, we did not find differences in the seroprevalence rates between 1 and 2 years vs. 3 and 4 years of age (age percentage of change -7.0 (-29.5; 22.8) vs. -45.3 (-67.5; -8.0)). Rotavirus vaccination was the most remarkable potential protective factor (48% vs. 9% in 2004-2009; p < 0.0001), but not the time of gluten introduction. (4) Conclusion: The present study did not confirm a worldwide CD prevalence increase and emphasizes the need to perform prevalence studies over time using the same methodology in the same geographical areas.

Macrophage and neutrophil heterogeneity at single-cell spatial resolution in human inflammatory bowel disease.

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.

Green Assessment of Phenolic Acid Composition and Antioxidant Capacity of Advanced Potato Mutant Lines through UPLC-qTOF-MS/MS Quantification.

Potatoes are one of the most consumed crops worldwide. They contain a high amount of bioactive compounds such as phenolic compounds and vitamins with important antioxidant activities, which makes this crop of high biological value for human health. The goal of this research was to biochemically evaluate polyphenol levels and antioxidant capacities in parent and control genotypes compared to advanced mutant potato lines in the M1V8 generation. This will reveal the genetic changes that result from induced mutagenesis. The quantified compounds and the evaluated antioxidant activity boost the health benefits of consuming the improved mutant potatoes. In the present study, the phenolic composition and antioxidant activity of eighteen mutant and initial potato genotypes were analyzed by UPLC-qTOF-MS/MS and the ORAC method, respectively. In each of the hybrid combinations, mutant lines with an improved phenolic compound profile were observed. Representative samples from the third hybrid combination had notable increases in phenolic compound concentrations, as well as the presence of metabolites not found in the parental lines. With one exception, the remaining nine mutants showed significantly higher antioxidant capacities. The results will be used in future potato breeding programs, with participation of the valuable mutant lines containing new phenolic substances not present in the initial genotypes.

Persistent villous atrophy predicts development of complications and mortality in adult patients with coeliac disease: a multicentre longitudinal cohort study and development of a score to identify high-risk patients.

OBJECTIVE: Persistent villous atrophy (pVA) in coeliac disease (CD) despite a gluten-free diet (GFD) has unclear meaning. We aimed to (i) study the relationship between pVA and long-term outcomes and (ii) develop a score to identify patients at risk of pVA. DESIGN: This is a multicentre retrospective-prospective study consisting of a study cohort (cohort 1) and an external validation cohort (cohort 2) of patients with biopsy-proven CD diagnosed between 2000 and 2021. Cohort 1 was used to (i) compare long-term outcomes between patients with and without pVA (Marsh ≥3a) at follow-up biopsy and (ii) to develop a score to evaluate the risk of pVA, which was validated in cohort 2. RESULTS: Of 2211 patients, 694 (31%) underwent follow-up duodenal biopsy and were included in the study cohort (491F, 44±16 years). 157/694 (23%) had pVA. Risk of complications (HR 9.53, 95% CI 4.77 to 19.04, p<0.001) and mortality (HR 2.93, 95% CI 1.43 to 6.02, p<0.01) were increased in patients with pVA. A 5-point score was developed and externally validated (receiver operating characteristic area under the curve 0.78, 95% CI 0.68 to 0.89) to stratify patients by risk of pVA: low (0-1 points, 5% pVA), intermediate (2 points, 16% pVA) and high (3-5 points, 73% pVA). Predictors for pVA used in the score were age at diagnosis ≥45 years (OR 2.01, 95% CI 1.21 to 3.34, p<0.01), classical pattern of CD (OR 2.14, 95% CI 1.28 to 3.58, p<0.01), lack of clinical response to GFD (OR 2.40, 95% CI 1.43 to 4.01, p<0.001) and poor GFD adherence (OR 48.9, 95% CI 26.1 to 91.8, p<0.001). CONCLUSIONS: Risk of complications and mortality were increased in patients with pVA. We developed a score to identify patients at risk of pVA and in need of histological reassessment and closer follow-up.

Endoscopic treatment (endoscopic balloon dilation/self-expandable metal stent) vs surgical resection for the treatment of de novo stenosis in Crohn's disease (ENDOCIR study): an open-label, multicentre, randomized trial.

BACKGROUND: Stenosis is one of the most common complications in patients with Crohn's disease (CD). Endoscopic balloon dilation (EBD) is the treatment of choice for a short stenosis adjacent to the anastomosis from previous surgery. Self-expandable metal stents (SEMS) may be a suitable treatment option for longer stenoses. To date, however, there is no scientific evidence as to whether endoscopic (EBD/SEMS) or surgical treatment is the best approach for de novo or primary stenoses that are less than 10 cm in length. METHODS/DESIGN: Exploratory study as "proof-of-concept", multicentre, open-label, randomized trial of the treatment of de novo stenosis in the CD; endoscopic treatment (EBD/SEMS) vs surgical resection (SR). The type of endoscopic treatment will initially be with EDB; if a therapeutic failure occurs, then a SEMS will be placed. We estimate 2 years of recruitment and 1 year of follow-up for the assessment of quality of life, costs, complications, and clinical recurrence. After the end of the study, patients will be followed up for 3 years to re-evaluate the variables over the long term. Forty patients with de novo stenosis in CD will be recruited from 15 hospitals in Spain and will be randomly assigned to the endoscopic or surgical treatment groups. The primary aim will be the evaluation of the patient quality of life at 1 year follow-up (% of patients with an increase of 30 points in the 32-item Inflammatory Bowel Disease Questionnaire (IBDQ-32). The secondary aim will be evaluation of the clinical recurrence rate, complications, and costs of both treatments at 1-year follow-up. DISCUSSION: The ENDOCIR trial has been designed to determine whether an endoscopic or surgical approach is therapeutically superior in the treatment of de novo stenosis in CD. TRIAL REGISTRATION: ClinicalTrials.gov NCT04330846. Registered on 1 April 1 2020. https://clinicaltrials.gov/ct2/home.

Effectiveness and Safety of Ustekinumab in Elderly Patients with Crohn's Disease: Real World Evidence From the ENEIDA Registry.

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 Genetic Diversity and Dysfunctionality of Catalase Associated with a Worse Outcome in Crohn's Disease.

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.

Experimental and genetic evidence for the impact of CD5 and CD6 expression and variation in inflammatory bowel disease.

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 (rs2241002CC) and requirement of biological therapies (rs2241002C-rs2229177T haplotype), and with poor UC prognosis (rs2241002T-rs2229177T haplotype). Regarding CD6, association was observed with CD ileal location (rs17824933G) and poor prognosis (rs12360861G), and with left-sided or extensive UC, and absence of ankylosing spondylitis in IBD (rs17824933G). 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.

Mucosal Interleukin-10 depletion in steroid-refractory Crohn's disease patients.

BACKGROUND: Previous studies suggested that Interleukin-10 (IL-10) depletion in Crohn's disease (CD) could predict outcome. AIM: To determine IL-10 in blood and at different intestinal locations in patients with active CD and to assess its potential prognostic capacity to identify aggressive CD. METHODS: Twenty-three patients with CD were included. Ulcerative colitis (UC), infectious colitis and healthy individuals acted as controls. Serum and mucosal samples were taken at baseline and 1 month after steroid initiation in CD patients. Patients were classified according to steroid response. Control samples were obtained from different intestinal locations. IL-10 expression was measured with real-time polymerase chain reaction, immunofluorescence (intestine) and ELISA (serum, biopsy cultures' supernatants and tissue homogenates). RESULTS: CD and UC showed an increase in IL-10 messenger RNA (mRNA) versus controls (p < .0001) in mucosa, whereas IL-10 protein secretion was increased in all types of intestinal inflammation (p < .001). No differences in IL-10 mRNA were found in CD at baseline regarding steroid response, but levels decreased in non-responders versus responders (p = .027) and were restored with rescue therapy. Serum IL-10 was increased in steroid-refractory CD at baseline and after treatment. CONCLUSIONS: Abnormal IL-10 levels in refractory patients in both mucosa and blood have physiopathological relevance and may have potential clinical applications.

Sustainable Development and Storage Stability of Orange By-Products Extract Using Natural Deep Eutectic Solvents.

The citrus industry produces large amounts of waste rich in bioactive compounds that have important effects on human health. Their extraction was performed using organic solvents, and a greener alternative to those solvents are natural deep eutectic solvents (NADES). The present study aimed to obtain and optimize extracts rich in polyphenols and flavonoids from orange peels using NADES and monitor polyphenol stability in the extracts for 30 days. The software COSMOtherm (conductor-like screening model) was used to screen fourteen NADES. The most promising solvents were lactic acid:glucose (LA:Glu) with an extraction yield of 1932 ± 7.83 mgGAE/100 gdw for TPC (total polyphenol content) and 82.7 ± 3.0 mg/100 gdw for TFC (total flavonoid content) and in the case of L-proline:malic acid (LP:MA) was 2164 ± 5.17 mgGAE/100 gdw for TPC and 97.0 ± 1.65 mg/100 gdw for TFC. The extraction process using LA:Glu and LP:MA was optimized, and the results showed that the selected variables (%NADES, solid:liquid ratio, and extraction time) had a significant influence on the extraction of TPC and TFC. Results showed that NADES improve the stability of TPC. These findings revealed that NADES are efficient for the extraction of bioactive compounds from orange by-products, and these extracts can represent an alternative for the food industry to enrich food products with natural ingredients.

Performance of Screening Strategies for Latent Tuberculosis Infection in Patients with Inflammatory Bowel Disease: Results from the ENEIDA Registry of GETECCU.

(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-×¥-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.

Self-expandable metal stents versus endoscopic balloon dilation for the treatment of strictures in Crohn's disease (ProtDilat study): an open-label, multicentre, randomised trial.

BACKGROUND: Endoscopic balloon dilation (EBD) is the established endoscopic treatment for short strictures in Crohn's disease. Fully covered self-expandable metal stents (FCSEMS) have been used for endoscopic treatment of patients for whom EBD was unsuccessful. We aimed to determine the efficacy and safety of the two endoscopic treatments in patients with Crohn's disease with stenosis and compare the mean cost of both treatments. METHODS: This multicentre, open-label, randomised trial was done in 19 tertiary and secondary hospitals in Spain. Patients with Crohn's disease with obstructive symptoms and predominantly fibrotic strictures of less than 10 cm in length were eligible for inclusion. We excluded patients with stenosis treated with SEMS or EBD in the previous year and stenosis not accessible to a colonoscope. Patients were randomly assigned (1:1) to receive either EBD (EBD group) or FCSEMS (FCSEMS group) using a digital en-block randomisation system (block size of four). In the EBD group, dilation was done with a CRE Boston Scientific (Marlborough, MA, USA) pneumatic balloon with the diameter set at the discretion of the endoscopist; a maximum of two sessions of dilation were allowed with a minimum interval of 15-30 days between them. In the FCSEMS group, a 20 mm diameter Taewoong (Gimpo-si, South Korea) fully covered metal stent was placed; stent length was set at the discretion of the endoscopist. The primary outcome was to assess the efficacy of the endoscopic treatment, defined by the proportion of patients free of a new therapeutic intervention (EBD, FCSEMS, or surgery) due to symptomatic recurrence at 1 year of follow-up. Patients were analysed according to the intention-to-treat principle. Adverse events were recorded for all the patients; events were considered associated to be with the procedure when a causal association was possible, probable, or definite. This trial is registered with ClinicalTrials.gov, NCT02395354. FINDINGS: From Aug 28, 2013, to Oct 9, 2017, we assessed the eligibility of 99 patients, of whom 19 (19%) patients were excluded. Thus, 80 (81%) patients were randomly assigned to treatment: 39 (49%) patients to the FCSEMS group and 41 (51%) patients to the EBD group. 33 (80%) of 41 patients in the EBD group and 20 (51%) of 39 patients in the FCSEMS group were free of a new therapeutic intervention at 1 year (odds ratio [OR] 3·9 [95% CI 1·4-10·6]; p=0·0061). Two (3%) of 80 patients had severe adverse events (one [2%] patient in the EBD group and one [3%] patient in the FCSEMS group); both patients had perforations. INTERPRETATION: EBD is more effective than FCSEMS for Crohn's disease strictures, with a good safety profile for both treatments. FUNDING: Spanish National Institute of Health, Foundation of Spanish Society of Digestive Endoscopy, Catalan Society of Gastroenterology, and Taweoong.

Usefulness of endoscopic ultrasound in patients with minilithiasis and/or biliary sludge as a cause of symptoms of probable biliary origin after cholecystectomy.

INTRODUCTION: Endoscopic ultrasound (EUS) is a more sensitive technique than transabdominal ultrasound for the diagnosis of gallstones. This greater sensitivity, especially in the diagnosis of microlithiasis/biliary sludge, facilitates the indication of cholecystectomy in patients with symptoms of probable biliary origin but may result in over-indication of this surgery. OBJECTIVES: Evaluate the role of EUS in the diagnosis of minilithiasis/biliary sludge in patients with digestive symptoms of probable biliary origin by resolving the symptoms after cholecystectomy. Analyse factors related to the remission of symptoms following cholecystectomy. PATIENTS AND METHODS: Retrospective, longitudinal, single-centre study based on a prospective database of 1.121 patients undergoing EUS. Seventy-four patients were identified as meeting inclusion-exclusion criteria (diagnosed with minilithiasis/sludge by EUS after presenting digestive symptoms of probable biliary origin without a history of complicated cholelithiasis). A telephone questionnaire for symptoms was conducted with cholecystectomized patients. Factors related to a good response were analysed with logistic regression analysis. RESULTS: Of the 74 patients, 50 were cholecystectomized (67.5%), mean age 49 years (SEM 2.26) (41 women). Seventy percent of patients (35/50) presented remission of symptoms with median follow-up 353.5 days (95% CI, 270-632.2). The only variable associated with remission of symptoms was the presence of typical biliary colic with an OR of 7.8 (95% CI, 1.8-34; p=0.006). No complications associated with EUS were recorded. One patient (2%) suffered haemoperitoneum and 18% (9/50) suffered diarrhoea following cholecystectomy. CONCLUSIONS: EUS is a very useful technique for the indication of cholecystectomy in patients with minilithiasis/sludge and typical symptoms of biliary colic.

Rapidity of clinical response to adalimumab and improvement of quality of life in luminal Crohn's disease: RAPIDA study.

OBJECTIVE: No studies evaluating the rapidity of response to biological therapies are available for Crohn's disease (CD). The aim of this study was to evaluate rapidity of onset of clinical response and impact on quality of life (QoL) of adalimumab therapy in adult anti-TNF-naïve patients with moderately-to-severely active CD. PATIENTS AND METHODS: RAPIDA was an open-label, single-arm, prospective, multicenter clinical trial. Adult patients with moderately-to-severely active luminal CD, anti-TNF-naïve, and unresponsive to conventional therapy were treated with adalimumab. Clinical disease activity, QoL and inflammatory biomarkers were measured at day 4, and weeks 1, 2, 4, and 12 after treatment initiation. RESULTS: Eighty-six patients were included in the intention-to-treat (ITT) analyses. Clinical disease activity was reduced from a median of 9.0 points to 6.0 points at day 4. Clinical response (≥ 3-point reduction in the Harvey-Bradshaw Index, HBI) was achieved by 61.6% (d4) and 75.6% (w1) of patients in the ITT population (median 2.5 days) and with non-responder imputation (NRI), by 55.8% and 53.4%, respectively. The proportion of patients in clinical remission (HBI<5) at weeks 2 and 4 in the ITT population was 54.7% and 62.8%, respectively (median 7.0 days), and 38.4% and 45.3% in the NRI population. All QoL scores significantly improved and inflammatory biomarkers significantly decreased from day 4 onwards (p<0.0001). CONCLUSION: Rapid clinical response and remission, improvement in QoL and fatigue, and a reduction of inflammatory biomarkers were achieved with adalimumab as early as day 4 in adult anti-TNF-naïve patients with moderately-to-severely active CD.

Risk of Immunomediated Adverse Events and Loss of Response to Infliximab in Elderly Patients with Inflammatory Bowel Disease: A Cohort Study of the ENEIDA Registry.

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.

Influenza vaccination coverage and factors associated with severe laboratory-confirmed influenza-related illness in patients receiving care at a tertiary hospital in Catalonia (Spain) during the 2018-2019 epidemic season.

INTRODUCTION: Influenza vaccination rates in risk groups remain suboptimal. Evidence supporting a significant association between influenza vaccination and severe illness is limited. METHODS: We retrospectively analyzed the epidemiological characteristics of out- and inpatients with laboratory-confirmed influenza infection attended during the 2018-19 epidemic season. Influenza vaccination coverage by indication was analyzed. Logistic regression was used to compare the odds of vaccination between severe and non-severe influenza-positive patients. Severe cases were defined as presenting pneumonia, admission to critical care units and/or death. RESULTS: The overall vaccination coverage among influenza-positive patients was 30.4%. In subjects with ≥ 1 indication for vaccination, the vaccination coverage was 42.4%. By indication, coverage rates were: 52.5% in patients aged ≥ 59 years, 42.2% in obese patients, 29.2% in immunosuppressed subjects and 6.5% in pregnant women. In patients with underlying chronic diseases, a higher coverage was found in patients with cognitive impairment (77%), muscular dystrophy (63.6%) and renal disease (60.4%). The multivariate logistic regression model showed severe influenza-related illness was associated with a lack of influenza vaccination before seeking care during the 2018-2019 season [0.59 (95%CI 0.36-0.97); p = 0.038], older age [1.01 (95%CI 1.00-1.02); p = 0.009] and current or former smoking status [1.63 (95%CI 0.84-3.18) and 2.03 (95%CI 1.16-3.57); p = 0.031], adjusted by underlying disease. CONCLUSION: Adjusting by age, smoking status and underlying disease, a moderate association between the influenza vaccine and severe laboratory-confirmed influenza-related illness was found in an epidemic season in which there was matching between the vaccine and circulating strains. Protection against complications, especially in older subjects and in those with underlying disease is postulated as one of the strengths of annual influenza vaccination. However, influenza vaccination is a pending issue in these groups, especially in pregnant women and obese people. To avoid suboptimal vaccination coverages, health professionals should recommend the seasonal influenza vaccination according to the annual instructions of the health authorities.