Thiopurines and the Risk of Cancer in Patients With Inflammatory Bowel Disease and Reference Individuals Without Inflammatory Bowel Disease - A Danish Nationwide Cohort Study (1996-2018).

BACKGROUND & AIMS: Thiopurine therapy is a cornerstone in the treatment of inflammatory bowel disease (IBD). We aimed to assess the effect of thiopurines on cancer risk in IBD according to drug exposure and age. METHODS: Danish national registers were used to identify incident IBD patients, exposure to drugs, and status of cancers, in 1996 to 2018. Cox regressions were used to compare cancer risks in IBD and non-IBD individuals and to assess IBD patients' cumulative drug exposure and the association to first cancer, excluding non-melanoma skin cancer. RESULTS: We followed 43,419 patients with IBD for a median of 8.2 years (interquartile range, 3.7-14.2 years) after IBD diagnosis. Cancer was reported in 3128 (7.2%) patients with IBD. The risk of cancer was increased in patients with IBD in all age categories compared with non-IBD individuals (<50 years: adjusted hazard ratio [aHR], 1.59; 95% confidence interval [CI], 1.43-1.77; 50-65 years: aHR, 1.31; 95% CI, 1.19-1.44; and >65 years: aHR, 1.14; 95% CI, 1.05-1.24). Monotherapy and combination therapy were associated with cancer (aHR, 1.36; 95% CI,1.17-1.57) and (aHR, 2.49; 95% CI, 1.64-3.78), respectively compared with unexposed patients with IBD. Among elderly patients (>65 years), the aHR was 2.79 (95% CI, 1.24-6.28) in those receiving combination therapy. In patients discontinuing thiopurines, aHRs returned to the level of unexposed (aHR, 0.89; 95% CI, 0.78-1.01). The aHR was positively associated with cumulative thiopurine exposure and in patients with >5 years of exposure, reaching an aHR of 1.36 (95% CI, 1.15-1.61). CONCLUSIONS: Thiopurines were associated with increased hazard of cancer, especially when used in combination therapy in the elderly. The hazard increased by 36% when patients were exposed to thiopurines for more than 5 years. Reassuringly, the hazard returned to baseline after discontinuation of thiopurines.

Patients with autoimmune liver disease have glucose disturbances that mechanistically differ from steatotic liver disease.

Autoimmune liver diseases are associated with an increased risk of diabetes, yet the underlying mechanisms remain unknown. In this cross-sectional study, we investigated the glucose-regulatory disturbances in patients with autoimmune hepatitis (AIH, n = 19), primary biliary cholangitis (PBC, n = 15), and primary sclerosing cholangitis (PSC, n = 6). Healthy individuals (n = 24) and patients with metabolic dysfunction-associated steatotic liver disease (MASLD, n = 18) were included as controls. Blood samples were collected during a 120-min oral glucose tolerance test. We measured the concentrations of glucose, C-peptide, insulin, glucagon, and the two incretin hormones, glucose insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We calculated the homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin resistance (Matsuda index), insulin clearance, and insulinogenic index. All patient groups had increased fasting plasma glucose and impaired glucose responses compared with healthy controls. Beta-cell secretion was increased in AIH, PBC, and MASLD but not in PSC. Patients with AIH and MASLD had hyperglucagonemia and hepatic, as well as peripheral, insulin resistance and decreased insulin clearance, resulting in hyperinsulinemia. Patients with autoimmune liver disease had an increased GIP response, and those with AIH or PBC had an increased GLP-1 response. Our data demonstrate that the mechanism underlying glucose disturbances in patients with autoimmune liver disease differs from that underlying MASLD, including compensatory incretin responses in patients with autoimmune liver disease. Our results suggest that glucose disturbances are present at an early stage of the disease.NEW & NOTEWORTHY Patients with autoimmune liver disease but without overt diabetes display glucose disturbances early on in their disease course. We identified pathophysiological traits specific to these patients including altered incretin responses.

Peripheral Joint and Enthesis Involvement in Patients With Newly Diagnosed Inflammatory Bowel Disease: Symptoms, and Clinical and Ultrasound Findings - A Population-Based Cohort Study.

OBJECTIVES: Musculoskeletal [MSK] manifestations in patients with inflammatory bowel disease [IBD] are common and associated with poorer outcomes. Hence, early detection is important to optimally tailor treatment. We aimed to determine the prevalence and distribution of inflammatory lesions in peripheral joints and entheses in newly diagnosed IBD patients. DESIGN: Patients with newly diagnosed IBD from a prospective population-based inception cohort were consecutively included. Data on MSK symptoms were collected by questionnaires and by structured rheumatological interview. Peripheral joints and entheses were assessed clinically and by ultrasound [US], using standardized definitions. RESULTS: Of 110 included patients (mean age: 42 years, 40% male, 70 with ulcerative colitis [UC], 40 with Crohn's disease [CD]), a history of ≥1 peripheral musculoskeletal symptom was reported by 49%. Clinical examination revealed peripheral MSK manifestations in 56 [52.3%] patients; 29 [27.1%] had ≥1 tender and/or swollen joints and 49 [45.8%] ≥1 tender entheses. Small peripheral joints were predominantly affected. US found inflammation in ≥1 joint or enthesis in 52 [49.5 %] patients; 29 [27.4 %] had US synovitis in ≥1 joint, while 36 [34%] had US enthesitis. Fibromyalgia classification criteria were fulfilled in seven [7.9%] patients. There was no difference in clinical or US findings between patients with UC and CD, nor between patients with active and inactive IBD. CONCLUSION: Half of the patients with newly diagnosed IBD had inflammation in their peripheral joints and/or entheses, documented by rheumatological clinical and US evaluations. This indicates a need for multidisciplinary collaboration to ensure an optimal therapeutic strategy for suppressing inflammation in all disease domains.

Neprilysin activity is increased in metabolic dysfunction-associated steatotic liver disease and normalizes after bariatric surgery or GLP-1 therapy.

Inhibitors of neprilysin improve glycemia in patients with heart failure and type 2 diabetes (T2D). The effect of weight loss by diet, surgery, or pharmacotherapy on neprilysin activity (NEPa) is unknown. We investigated circulating NEPa and neprilysin protein concentrations in obesity, T2D, metabolic dysfunction-associated steatotic liver disease (MASLD), and following bariatric surgery, or GLP-1-receptor-agonist therapy. NEPa, but not neprilysin protein, was enhanced in obesity, T2D, and MASLD. Notably, MASLD associated with NEPa independently of BMI and HbA1c. NEPa decreased after bariatric surgery with a concurrent increase in OGTT-stimulated GLP-1. Diet-induced weight loss did not affect NEPa, but individuals randomized to 52-week weight maintenance with liraglutide (1.2 mg/day) decreased NEPa, consistent with another study following 6-week liraglutide (3 mg/day). A 90-min GLP-1 infusion did not alter NEPa. Thus, MASLD may drive exaggerated NEPa, and lowered NEPa following bariatric surgery or liraglutide therapy may contribute to the reported improved cardiometabolic effects.

Disease Activity Patterns of Inflammatory Bowel Disease-A Danish Nationwide Cohort Study 1995-2018.

BACKGROUND AND AIMS: Few studies have assessed the contemporary patterns of disease activity in patients with inflammatory bowel disease [IBD]. We aimed to describe the disease patterns and their long-term outcomes. METHODS: All Danish individuals with IBD between 1995 and 2018 were identified using information about IBD-related hospitalizations, surgeries and redeemed prescriptions. The disease activity patterns for 5- and 10-year periods were assessed. RESULTS: In incident patients with Crohn's disease [CD], severe disease activity occurred in the year of diagnosis in 80% of patients; for ulcerative colitis [UC] this figure was 75%, in addition to 3.4% of UC patients who underwent a colectomy within the first year. After 20 years of disease, the proportion of CD and UC patients in remission increased to 89% and 72%, respectively. The proportion of prevalent patients in remission each year was stable, despite the introduction of biological therapies. A decreasing activity pattern was the most common in both CD and UC patients [both 45%]. The distribution of the disease activity patterns was seen to be stable over time. A quiescent disease pattern was accompanied by a significantly higher risk of intestinal cancer [HR: 3.37, 95% CI: 1.23-9.19] for CD patients, according to a Cox proportional hazards model. In UC patients, increasing disease activity [HR: 0.67, 95% CI: 0.31-1.48] was associated with an increased risk of intestinal cancer. CONCLUSIONS: We report the distribution of disease patterns among IBD patients. Patients with quiescent CD, as well as UC patients with chronic continuous or increasing activity, were at increased risk of developing intestinal cancer.

Biomarkers reflecting pericellular fibrosis improve together with liver histology after bariatric surgery in early non-alcoholic fatty liver disease.

AIM: Non-invasive tests for non-alcoholic fatty liver disease (NAFLD) are needed for assessing disease stage, prognosis and treatment efficacy. Extracellular matrix biomarkers, such as PRO-C3, are useful as biomarkers of advanced liver fibrosis. However, non-invasive biomarkers of early-stage NAFLD, characterized by pericellular fibrosis, are lacking. Here, we measured serological biomarkers of type IV and VIII collagens reflecting the remodeling of the pericellular basement membrane to explore the effect of bariatric surgery on pericellular fibrosis in patients with early NAFLD. METHODS: Seventy patients with severe obesity underwent bariatric surgery. The cohort consisted of 61 % females who had a mean age of 44. Patients had a median NAFLD activity score of 3 and mild-to-moderate fibrosis F0 (3 %), F1 (86 %), and F2 (11 %). Blood samples were taken at baseline, three, six and 12 months after surgery. At 12 months, 40 patients had a follow-up liver biopsy. The biomarkers PRO-C3, PRO-C4, C4M, and PRO-C8 were measured using indirect competitive ELISAs. RESULTS: Twelve months after surgery patients had significantly lower levels of ALT, GGT, HbA1c, fasting glucose, and CRP. The pericellular fibrosis biomarkers, C4M, PRO-C4, and PRO-C8 decreased by 24 %, 18 % and 44 %, respectively (p < 0.0001), while the interstitial matrix fibrosis marker PRO-C3 remained unchanged. Furthermore, baseline C4M was associated with histologically assessed hepatocyte ballooning and lobular inflammation in patients with (p = 0.032) and without (p = 0.032) steatosis, respectively. CONCLUSION: Biomarkers of pericellular fibrosis decrease in early-stage NAFLD after patients undergo bariatric surgery and potentially reflect an improvement in liver histology.

Single-cell transcriptome and cell type-specific molecular pathways of human non-alcoholic steatohepatitis.

The aim of this study is to characterize cell type-specific transcriptional signatures in non-alcoholic steatohepatitis (NASH) to improve our understanding of the disease. We performed single-cell RNA sequencing on liver biopsies from 10 patients with NASH. We applied weighted gene co-expression network analysis and validated our findings using a publicly available RNA sequencing data set derived from 160 patients with non-alcoholic fatty liver disease (NAFLD) and 24 controls with normal liver histology. Our study provides a comprehensive single-cell analysis of NASH pathology in humans, describing 19,627 single-cell transcriptomes from biopsy-proven NASH patients. Our data suggest that the previous notion of "NASH-associated macrophages" can be explained by an up-regulation of normally existing subpopulations of liver macrophages. Similarly, we describe two distinct populations of activated hepatic stellate cells, associated with the level of fibrosis. Finally, we find that the expression of several circulating markers of NAFLD are co-regulated in hepatocytes together with predicted effector genes from NAFLD genome-wide association studies (GWAS), coupled to abnormalities in the complement system. In sum, our single-cell transcriptomic data set provides insights into novel cell type-specific and general biological processes associated with inflammation and fibrosis, emphasizing the importance of studying cell type-specific biological processes in human NASH.

High Accuracy in Classifying Endoscopic Severity in Ulcerative Colitis Using Convolutional Neural Network.

INTRODUCTION: The evaluation of endoscopic disease severity is a crucial component in managing patients with ulcerative colitis (UC). However, endoscopic assessment suffers from substantial intraobserver and interobserver variations, limiting the reliability of individual assessments. Therefore, we aimed to develop a deep learning model capable of distinguishing active from healed mucosa and differentiating between different endoscopic disease severity degrees. METHODS: One thousand four hundred eighty-four unique endoscopic images from 467 patients were extracted for classification. Two experts classified all images independently of one another according to the Mayo endoscopic subscore (MES). In cases of disagreement, a third expert classified the images. Different convolutional neural networks were considered for automatically classifying UC severity. Five-fold cross-validation was used to develop and select the final model. Afterward, unseen test data sets were used for model evaluation. RESULTS: In the most challenging task-distinguishing between all categories of MES-our final model achieved a test accuracy of 0.84. When evaluating this model on the binary tasks of distinguishing MES 0 vs 1-3 and 0-1 vs 2-3, it achieved accuracies of 0.94 and 0.93 and areas under the receiver operating characteristic curves of 0.997 and 0.998, respectively. DISCUSSION: We have developed a highly accurate, new, automated way of evaluating endoscopic images from patients with UC. We have demonstrated how our deep learning model is capable of distinguishing between all 4 MES levels of activity. This new automated approach may optimize and standardize the evaluation of disease severity measured by the MES across centers no matter the level of medical expertise.

Influence of NAFLD and bariatric surgery on hepatic and adipose tissue mitochondrial biogenesis and respiration.

Impaired mitochondrial oxidative phosphorylation (OXPHOS) in liver tissue has been hypothesised to contribute to the development of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease (NAFLD). It is unknown whether OXPHOS capacities in human visceral (VAT) and subcutaneous adipose tissue (SAT) associate with NAFLD severity and how hepatic OXPHOS responds to improvement in NAFLD. In biopsies sampled from 62 patients with obesity undergoing bariatric surgery and nine control subjects without obesity we demonstrate that OXPHOS is reduced in VAT and SAT while increased in the liver in patients with obesity when compared with control subjects without obesity, but this was independent of NAFLD severity. In repeat liver biopsy sampling in 21 patients with obesity 12 months after bariatric surgery we found increased hepatic OXPHOS capacity and mitochondrial DNA/nuclear DNA content compared with baseline. In this work we show that obesity has an opposing association with mitochondrial respiration in adipose- and liver tissue with no overall association with NAFLD severity, however, bariatric surgery increases hepatic OXPHOS and mitochondrial biogenesis.

Inflammatory Bowel Diseases Affect the Phenotype and Disease Course of Coexisting Immune-Mediated Inflammatory Diseases: A Systematic Review With Meta-Analysis.

BACKGROUND: It is unclear whether inflammatory bowel diseases (IBDs) affect the phenotype and severity of co-occurring immune-mediated inflammatory diseases (IMIDs). We aimed to investigate the characteristics of IMIDs in relation to co-occurring IBD. METHODS: We conducted a systematic review of Medline and EMBASE databases from inception to September 2020. We identified studies reporting the phenotype, severity, or disease course of IMIDs among patients with or without co-occurring IBD. A meta-analysis was conducted using random effects models. RESULTS: The electronic search yielded 13 220 studies that we narrowed down to 73 eligible studies for full-text review, including 42 on primary sclerosing cholangitis, 12 on axial spondyloarthropathies, and 8 studies on psoriasis. In primary sclerosing cholangitis, IBD was associated with less frequent involvement of extrahepatic bile ducts (risk ratio [RR], 0.50; 95% confidence interval [CI], 0.33-0.75), longer liver transplantation-free survival (hazard ratio, 0.70; 95% CI, 0.60-0.82), and no increased risk of cholangiocarcinoma (RR, 0.88; 95% CI, 0.59-1.31). Patients with axial spondyloarthropathies and co-occurring IBD were characterized by an increased risk of dactylitis (RR, 2.06; 95% CI, 1.24-3.42), a lower Bath Ankylosing Spondylitis Radiology Index (mean difference [MD] = -2.28; 95% CI, -3.26 to -1.30), and better Schober's test results (MD = 1.07; 95% CI, 0.64-1.49). Psoriasis and co-occurring IBD was associated with reduced disease severity (RR, 1.41; 95% CI, 1.02-1.96) and less frequent presentation in nails (RR, 0.14; 95% CI, 0.05-0.42), with no apparent impact on psoriatic arthritis (RR, 0.94; 95% CI, 0.27-3.31). CONCLUSIONS: This systematic review with meta-analysis found IBD is associated with a distinct disease phenotype among the IMIDs investigated. Our findings emphasize the importance of multidisciplinary approaches to patients with co-occurring IMIDs and IBD.

This systematic review with meta-analysis of 73 studies demonstrates that the presence of inflammatory bowel diseases is associated with a milder phenotype and better prognosis of co-occurring immune-mediated inflammatory diseases.

Determination of hepatic clearance by derivations of the indocyanine green retention test in cirrhosis.

BACKGROUND AND AIM: The study was undertaken in order to compare single injection indocyanine green (ICG)-clearances with the steady-state ICG-clearance (ICGCl ) in patients with cirrhosis in order to assess the most accurate estimate for ICG-clearance and to relate the ICG-clearances to established indicators of liver dysfunction. METHODS: Thirty-eight patients (male 29) with cirrhosis (Child-Turcotte class A 8, class B 21, and class C 9) were studied during a hemodynamic investigation. A single injection of ICG was followed by blood samples for 5, 10, 15, and 20 min. The dose/plasma area clearance (ClA ) and plasma volume · initial slope clearance (ClPV ) were determined and compared with the steady-state infusion/plasma concentration ratio clearance (ICGCl ). RESULTS: The ClA (310; 214; 502 mL/min) and ClPV (294; 164; 481 mL/min) correlated closely with ICGCl (243; 120; 383 mL/min [median; interquartile range], R = 0.95-0.98, P < 0.000), but were significantly higher than ICGCl (P < 0.001). All three clearance measures correlated significantly with biochemical and hemodynamic variables of liver dysfunction (P < 0.05-0.000). All three ICG-clearances showed significantly lower values in patients with ascites compared to those without, and lower ICG-clearance values were present in patients with esophageal varices compared to those without (P < 0.05-0.002). CONCLUSION: Single injection markers (ClA and ClPV ) of the steady-state ICG-clearance as derived from the ICG-retention curve and the plasma volume correlate with ICGCl and established variables of portal hypertension and liver cell bile excretory dysfunction. Therefore, these markers can safely replace the more costly ICGCl .

The Use and Efficacy of Biological Therapies for Inflammatory Bowel Disease in a Danish Tertiary Centre 2010-2020.

Background: Patients with inflammatory bowel disease (IBD) who receive biologicals frequently experience lack or loss of response. Our aim was to describe the use and efficacy of biological therapy in a tertiary IBD center. Methods: We included all bio-naive IBD patients who initiated biological therapy between 2010 and 2020 at our centre. Their medical records were reviewed. Results: The population consisted of 327 Crohn's disease (CD) patients, 291 ulcerative colitis (UC) patients, and 3 patients with IBD unclassified (IBDU). The median follow-up was 3 years (interquartile range = 2-5) after initiating therapy. The annual number of patients initiating biological therapy rose from 29 (2010) to 85 (2019). Most patients (457, 73.6%) received 1 biological drug; 164 (26.4%) patients received 2 or more biologicals. Primary lack of response was observed in 36.4% (106/291) and 17.4% (57/327) of UC and CD patients; loss of response was observed in 27.1% (79/291) and 31.5% (103/327) of UC and CD patients, respectively. The 5-year surgery rates were 26.6% and 20.4% in UC and CD patients, respectively. Multivariate Cox regression showed that treatment with thiopurine reduced the likelihood of needing to switch biological therapy, requiring surgery or corticosteroids in UC patients (HR: 0.745, 95% CI: 0.559-0.993), but not in CD patients (HR: 0.996, 95% CI: 0.736-1.349). Conclusions: The annual number of IBD patients initiated on biological therapy increased considerably between 2010 and 2020. One-quarter of these patients required surgery after 5 years. Our findings suggest a beneficial effect of concurrent thiopurines for UC patients receiving biologicals, but this was not found for CD patients. This effect in UC patients was not observed when we included patients initiating thiopurines up to 6 months after the introduction of biological therapy.

Vedolizumab as the first line of biologic therapy for ulcerative colitis and Crohn's disease - a systematic review with meta-analysis.

BACKGROUND: The efficacy and safety of vedolizumab in bio-naïve patients with ulcerative colitis (UC) and Crohn's disease (CD) remain unknown. AIMS: To perform a meta-analysis regarding vedolizumab as first line of biological therapy for UC or CD. METHODS: A systematic review of Medline, EMBASE, and Cochrane databases per December 2020 was undertaken. Meta-analysis was conducted using random-effects models. RESULTS: This systematic review identified 79 eligible studies with 4,520 and 3,494 bio-naïve patients with UC and CD, respectively, and 8,105 and 11,140 bio-exposed patients. Among bio-naïve patients with UC, a total of 40.0% (95%CI 27.0-54.0, I2=86%) and 63.9% (95%CI 47.0-79.2, I2=36%) achieved clinical remission at weeks 14 and 52, respectively. The corresponding rates in CD were 54.0% (95%CI 42.0-66.0, I2=23%), and 61.7% (95%CI 55.2-68.1, I2=0%). Bio-naïvety was associated with a higher probability of clinical remission at week 52 in UC (relative risk (RR)=1.32 (95%CI 1.14-1.53)), while this was only apparent until week 26 in CD (RR=1.60 (95%CI 1.30-1.95)). Finally, bio-naïve UC patients had a lower risk of serious adverse events (RR=0.29 (95%CI 0.09-0.95)). CONCLUSION: Vedolizumab was found to have a favorable efficacy and safety profile in bio-naïve patients with UC and CD. The findings have implications in the management of IBD.

Effects of Roux-en-Y Gastric Bypass and Sleeve Gastrectomy on Non-Alcoholic Fatty Liver Disease: A 12-Month Follow-Up Study with Paired Liver Biopsies.

Roux-en-Y gastric bypass (RYGB) improves, and can sometimes resolve, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) but data based on histological assessment for the efficacy of sleeve gastrectomy (SG) in resolving NAFLD are sparse. Consequently, we aimed to compare the efficacy of RYGB vs. SG on NAFLD 12 months after surgery. In a prospective cohort study, 40 patients with obesity underwent bariatric surgery (16 RYGB and 24 SG). During surgery, a liver biopsy was taken and repeated 12 months later. NAFLD severity was evaluated using the NAFLD Activity Score (NAS) and Kleiner Fibrosis score. RYGB and SG patients were comparable at baseline. Mean (standard deviation, SD) NAS was 3.3 (0.9) in RYGB and 3.1 (1.4) in SG (p = 0.560) with similar degrees of steatosis, inflammation, and ballooning. Two RYGB patients, and six SG patients, had NASH (p = 0.439). Twelve months after surgery, NAS was significantly and comparably (p = 0.241) reduced in both RYGB (-3.00 (95% CI -3.79--2.21), p < 0.001) and SG (-2.25 (95% CI -2.92--1.59), p < 0.001) patients. RYGB patients had significantly more reduced (p = 0.007) liver steatosis (-0.91 (95% CI -1.47--1.2) than SG patients (-0.33 (95% CI -0.54--0.13) and greater improvement in the plasma lipid profile. Fibrosis declined non-significantly. NASH was resolved in seven of eight patients without a worsening of their fibrosis. RYGB and SG have similar beneficial effects on NAS and NASH without the worsening of fibrosis. RYGB is associated with a more pronounced reduction in liver steatosis.

Progressive alcohol-related liver fibrosis is characterised by imbalanced collagen formation and degradation.

BACKGROUND: Liver fibrosis accumulation is considered a turnover disease, with formation exceeding degradation, although this hypothesis has never been tested in humans. AIMS: To investigate extracellular matrix (ECM) remodelling in a biopsy-controlled study of alcohol-related liver disease (ALD) patients. METHODS: We evaluated the relationship between formation and degradation of four collagens as a function of histological fibrosis, inflammation and steatosis in 281 patients with ALD and 50 matched healthy controls. Post hoc, we tested the findings in a cohort of patients with alcohol-related cirrhosis and assessed the collagens' prognostic accuracy. We assessed the fibrillar collagens type III (PRO-C3/C3M) and V (PRO-C5/C5M), the basement membrane collagen IV (PRO-C4/C4M), and the microfilament interface collagen VI (PRO-C6/C6M). RESULTS: Mean age was 54 ± 6 years, 74% male, fibrosis stage F0/1/2/3/4 = 33/98/84/18/48. Compared to controls, patients with ALD had higher levels of type III collagen formation and degradation, with the highest concentrations in those with cirrhosis (PRO-C3 = 8.2 ± 1.7 ng/mL in controls, 14.6 ± 13.5 in ALD, 34.8 ± 23.1 in cirrhosis; C3M 7.4 ± 1.9 in controls, 9.3 ± 4.4 in ALD, 14.0 ± 5 in cirrhosis). ECM remodelling became increasingly imbalanced in higher stages of liver fibrosis, with formation progressively superseding degradation. This was particularly pronounced for type III collagen. We observed similar imbalance for inflammatory severity, but not steatosis. CONCLUSIONS: ALD is characterised by both elevated collagen formation and degradation, which becomes increasingly imbalanced with more severe disease. Net increase in fibrillar collagens contributes to fibrosis progression. This has important implications for monitoring and very early identification of patients at highest risk of progressing to cirrhosis.

Systematic review and meta-analysis: the impact of co-occurring immune-mediated inflammatory diseases on the disease localization and behavior of Crohn's disease.

BACKGROUND: Patients with Crohn's disease (CD) are at increased risk of co-occurring immune-mediated inflammatory diseases (IMIDs). As discrepancy exists regarding the phenotypic presentation of CD among patients with such co-occurring IMIDs, we aimed to conduct a systematic review with meta-analysis characterizing the phenotype of CD among this subgroup of patients. METHODS: PubMed, Embase, and Scopus were searched from their earliest records to October 2019 for studies reporting the behavior and localization of CD according to the Vienna or Montreal Classifications and CD-related surgery in patients with co-occurring IMIDs. These studies were the subject of a random effect meta-analysis. RESULTS: After reviewing 24,413 studies, we identified a total of 23 studies comprising 1572 and 35,043 CD patients with and without co-occurring IMIDs, respectively, that fulfilled our inclusion criteria. Overall, patients with co-occurring IMIDs were more likely to have upper gastrointestinal inflammation than were patients without co-occurring IMIDs [relative risk (RR) = 1.49 (95% confidence interval (CI) 1.09-2.04), p = 0.01, I 2 = 7%]. In addition, presence of primary sclerosing cholangitis (PSC) was associated with a lower occurrence of ileal affection [RR = 0.44 (95% CI 0.24-0.81), p < 0.01, I 2 = 32%], increased occurrence of colonic affection [RR = 1.78 (95% CI 1.33-2.38), p < 0.01, I 2 = 32%] and an increased likelihood of non-stricturing and non-penetrating behavior [RR = 1.43 (95% CI 0.97-2.11), p = 0.07, I 2 = 86%]. The latter reached significance when cumulating different IMIDs [RR = 1.30 (95% CI 1.09-1.55), p < 0.01, I 2 = 88%]. CD patients with PSC also underwent fewer CD-related surgeries [RR = 0.55 (95% CI 0.34-0.88), p = 0.01, I 2 = 0%], irrespective of CD location or behavior. CONCLUSION: This study emphasizes that CD patients with co-existing PSC are likely to have a unique inflammatory distribution primarily confined to the colon, while patients with IMIDs in general have higher likelihood of affection of upper gastrointestinal tract and a non-stricturing and non-penetrating behavior. As such a phenotype of CD is typically associated with a milder disease course; future studies are needed to confirm these results.

Vedolizumab as first-line biological therapy in elderly patients and those with contraindications for anti-TNF therapy: a real-world, nationwide cohort of patients with inflammatory bowel diseases.

BACKGROUND: Data from real-life populations about vedolizumab as first-line biological therapy for ulcerative colitis (UC) and Crohn's disease (CD) are emerging. OBJECTIVE: To investigate the efficacy and safety of vedolizumab in bio-naïve patients with UC and CD. METHODS: A Danish nationwide cohort study was conducted between November 2014 and November 2019. Primary outcomes were clinical remission, steroid-free clinical remission, and sustained clinical remission from weeks 14 through 52. RESULTS: The study included 56 patients (UC:31, CD:25) who initiated treatment with vedolizumab mainly because of contraindications to anti-TNFs, of whom 54.8 and 24.0%, respectively received systemic steroids at the initiation. Rates of clinical remission at weeks 6, 14, and 52 were 32.0, 48.0, and 40.0%, respectively, in UC, and 36.8, 36.8, and 47.4% in CD. Steroid-free clinical remission at week 52 was achieved among 36.0 and 47.4% of UC and CD patients, while sustained clinical remission was achieved in 32.0 and 36.8%. Lack of remission was associated with being female (68.8 vs. 11.1%, p = .01) in UC and non-structuring, non-penetrating behavior in CD (90.0 vs. 44.4%, p = .03); however, this was not confirmed in multivariate analysis. Discontinuation due to primary non-response occurred in 20.0 and 5.3% of UC and CD patients, respectively, while rates of secondary loss of response were 12.0 and 5.3% after 52 weeks of follow-up. Vedolizumab was well-tolerated as only one UC patient experienced a serious adverse event. CONCLUSION: Vedolizumab is effective in the achievement of short-term, long-term, and steroid-free clinical remission in bio-naïve UC and CD patients.

Using MR elastography to assess portal hypertension and response to beta-blockers in patients with cirrhosis.

BACKGROUND: MR elastography can determine organ-related stiffness, which reflects the degree of fibrosis. Liver stiffness increases in cirrhosis, and stiffness increases further post-prandially due to increased portal blood in-flow. Non-selective beta-blockers (NSBB) reduce the portal venous inflow, but their effect on liver and spleen stiffness are disputed. AIMS: To assess whether MR elastography of the liver or spleen reflects the severity of cirrhosis, whether treatment with NSBB changes liver and spleen stiffness and whether changes in stiffness can predict the effect of NSBB on portal pressure. METHODS: Fifty-two patients with cirrhosis underwent liver vein catheterization and two-dimensional (2D) MR elastography on separate days. Thirty-six of the patients had a hepatic venous pressure gradient (HVPG) of ≥12 mmHg and were tested prior to, and after, intravenous infusion of NSBB using HVPG measurement and MR elastography. RESULTS: HVPG showed a strong, positive, linear relationship with liver stiffness (r2  = 0.92; P < .001) and spleen stiffness (r2  = 0.94; P < .001). The cut-off points for identifying patients with a HVPG ≥ 12 mmHg were 7.7 kPa for liver stiffness (sensitivity 0.78, specificity 0.64) and 10.5 kPa for spleen stiffness (sensitivity 0.8, specificity 0.79). Intravenous administration of NSBB significantly decreased spleen stiffness by 6.9% (CI: 3.5-10.4, P < .001), but NSBB had no consistent effect on liver stiffness. However, changes in spleen stiffness were not related to the HVPG response (P = .75). CONCLUSIONS: Two-dimensional MR elastographic estimation of liver or spleen stiffness reflects the degree of portal hypertension in patients with liver cirrhosis, but changes in stiffness after NSBB do not predict the effect on HVPG.

Short and long-term effectiveness and safety of vedolizumab in treatment-refractory patients with ulcerative colitis and Crohn's disease - a real-world two-center cohort study.

OBJECTIVES: Real-world data about sustained clinical remission (SCR) and treatment optimization with vedolizumab for ulcerative colitis (UC) and Crohn's disease (CD) are scarce. We aimed to investigate the short and long-term effectiveness and safety of vedolizumab in a real-world cohort in Denmark. METHODS: A retrospective two-center cohort study was conducted between November 2014 and November 2019 with the primary outcomes of clinical remission (CR) at weeks 14, 30, 52 and 104 and SCR defined as CR at week 14 through week 52. RESULTS: The study included 182 patients (UC: 97, CD: 85), all previously exposed to at least one biological therapy. Rates of CR at weeks 14, 30, 52 and 104 were 36.6, 35.1, 34.0 and 27.8%, respectively, in UC, and 31.7, 30.1, 26.5 and 22.4% in CD. SCR was achieved in 19.6 and 20.0%, respectively. In UC and CD, optional dosing of vedolizumab at week 10 (odds ratio [OR] = 0.23 (95% confidence interval [CI], 0.03-1.17), and OR = 0.68 (95% CI, 0.22-2.04)), as well as increase of frequency (OR = .26 (95% CI, 0.01-2.86), and OR = 0.19 (95% CI, 0.01-1.45)), were not associated with CR at week 52. Furthermore, combination treatment with azathioprine was not associated with long-term outcomes. However, dose intensification of vedolizumab successfully restored CR in 65.2 and 57.1% of patients with UC and CD experiencing loss of response. CONCLUSIONS: Vedolizumab is effective in achieving and restoring short and long-term CR and SCR in patients with treatment-refractory UC and CD. This study emphasizes that supplementary dosing at week 10, and simultaneous treatment with azathioprine, did not improve long-term outcomes.

The Psychometric Hepatic Encephalopathy Syndrome score does not correlate with blood ammonia, endotoxins or markers of inflammation in patients with cirrhosis.

BACKGROUND: The pathogenesis of hepatic encephalopathy (HE) remains unclear but impaired clearance of gut-derived neurotoxins and increased systemic inflammation are thought to play key roles. The diagnosis is based on detection of neurophysiological and neuropsychometric abnormalities. The Psychometric Hepatic Encephalopathy Score (PHES) have been found to correlate with markers of systematic inflammation including interleukin 6, C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α). This study explores the associations between the PHES score and systemic inflammation, endotoxins and disease severity using baseline data from a trial involving patients with cirrhosis and minimal or no HE (NCT01769040). METHODS: Arterial blood was obtained during hepatic vein catheterization, from 54 patients [median age 55 (range, 33-70) years; 83% men] with decompensated but stable cirrhosis. None had clinical evidence of HE but 34 (55.6%) had an abnormal PHES score indicating the presence of minimal HE. Relationships were sought between the PHES score and markers of systemic inflammation, high sensitivity-CRP, cytokines (SDF-1α, TGF-b1, IP-10, IL-6, 10 and 18, and TNF-α; lipopolysaccharide (LPS), the lipopolysaccharide binding protein (LBP) and soluble CD14 (sCD14); and the blood ammonia. RESULTS: No significant relationships were found between the PHES score and any of the variables tested with the single exception of the correlation with serum IL-6 (r=-0.29, 95% confidence interval, -0.53 to -0.02, P=0.031). No independent predictors of the PHES score were identified in regression analyses. CONCLUSIONS: No predictive associations were identified between the PHES scores and circulating blood ammonia, endotoxins, or markers of systemic inflammation in this patient population.