Multiomics-empowered Deep Phenotyping of Ulcerative Colitis Identifies Biomarker Signatures Reporting Functional Remission States.

INTRODUCTION: Ulcerative colitis [UC] is a chronic disease with rising incidence and unclear aetiology. Deep molecular phenotyping by multiomics analyses may provide novel insights into disease processes and characteristic features of remission states. METHODS: UC pathomechanisms were assessed by proteome profiling of human tissue specimens, obtained from five distinct colon locations for each of the 12 patients included in the study. Systemic disease-associated alterations were evaluated thanks to a cross-sectional setting of mass spectrometry-based multiomics analyses comprising proteins, metabolites, and eicosanoids of plasma obtained from UC patients during acute episodes and upon remission, in comparison with healthy controls. RESULTS: Tissue proteome profiling indicated colitis-associated activation of neutrophils, macrophages, B and T cells, fibroblasts, endothelial cells and platelets, and hypoxic stress, and suggested a general downregulation of mitochondrial proteins accompanying the establishment of apparent wound healing-promoting activities including scar formation. Whereas pro-inflammatory proteins were apparently upregulated by immune cells, the colitis-associated epithelial cells, fibroblasts, endothelial cells, and platelets seemed to predominantly contribute anti-inflammatory and wound healing-promoting proteins. Blood plasma proteomics indicated chronic inflammation and platelet activation, whereas plasma metabolomics identified disease-associated deregulations of gut and gut microbiome-derived metabolites. Upon remission several, but not all, molecular candidate biomarker levels recovered back to normal. CONCLUSION: The findings may indicate that microvascular damage and platelet deregulation hardly resolve upon remission, but apparently persist as disease-associated molecular signatures. This study presents local and systemic molecular alterations integrated in a model for UC pathomechanisms, potentially supporting the assessment of disease and remission states in UC patients.

Inflammatory Bowel Disease and Risk of Major Bleeding During Anticoagulation for Venous Thromboembolism.

BACKGROUND: Little is known about the bleeding risk in patients with inflammatory bowel disease (IBD) and venous thromboembolism (VTE) treated with anticoagulation. Our aim was to elucidate the rate of major bleeding (MB) events in a well-defined cohort of patients with IBD during anticoagulation after VTE. METHODS: This study is a retrospective follow-up analysis of a multicenter cohort study investigating the incidence and recurrence rate of VTE in IBD. Data on MB and IBD- and VTE-related parameters were collected via telephone interview and chart review. The objective of the study was to evaluate the impact of anticoagulation for VTE on the risk of MB by comparing time periods with anticoagulation vs those without anticoagulation. A random-effects Poisson regression model was used. RESULTS: We included 107 patients (52 women, 40 with ulcerative colitis, 64 with Crohn disease, and 3 with unclassified IBD) in the study. The overall observation time was 388 patient-years with and 1445 patient-years without anticoagulation. In total, 23 MB events were registered in 21 patients, among whom 13 MB events occurred without anticoagulation and 10 occurred with anticoagulation. No fatal bleeding during anticoagulation was registered. The incidence rate for MB events was 2.6/100 patient-years during periods exposed to anticoagulation and 0.9/100 patient-years during the unexposed time. Exposure to anticoagulation (adjusted incidence rate ratio, 3.7; 95% confidence interval, 1.5-9.0; P = 0.003) and ulcerative colitis (adjusted incidence rate ratio, 3.5; 95% confidence interval, 1.5-8.1; P = 0.003) were independent risk factors for MB events. CONCLUSION: The risk of major but not fatal bleeding is increased in patients with IBD during anticoagulation. Our findings indicate that this risk may be outweighed by the high VTE recurrence rate in patients with IBD.

Use of complementary and alternative medicine and low quality of life associate with the need for psychological and psychotherapeutic interventions in inflammatory bowel disease.

INTRODUCTION: Patients with inflammatory bowel disease (IBD) suffer from various symptoms, impairing their quality of life and often affecting psychosocial issues. This may lead to the need for additional psychological care. This study investigated patients' subjective need for integrated psychosomatic support and psychotherapy and indicators for it. MATERIALS AND METHODS: This is a cross-sectional multicentre study in Austrian IBD patients who were in routine care at 18 IBD outpatient clinics. Patients filled in an anonymous, validated questionnaire (Assessment of the Demand for Additional Psychological Treatment Questionnaire [ADAPT]) assessing the need for psychological care. The ADAPT gives two separate scores: the need for integrated psychosomatic support and for psychotherapy. In addition, health-related quality of life and the use of complementary and alternative medicine as well as clinical and socio-demographic variables were queried. Multivariable regression analysis was performed to estimate the effect of the previously mentioned variables on the need for additional psychological care. RESULTS: Of 1286 patients, 29.7% expressed a need for additional psychological care, 19.6% expressed a need for integrated psychosomatic support and 20.2% expressed a need for psychotherapy. In the multivariable analysis, the two strongest indicators for the need for both types of psychological care were the use of complementary and alternative medicine (for integrated psychosomatic support: odds ratio = 1.64, 95% confidence interval 1.13-2.39, p = 0.010; for psychotherapy: odds ratio = 1.74, 95% confidence interval 1.20-2.53, p = 0.004), and a low health-related quality of life score (for integrated psychosomatic support: odds ratio = 0.95, 95% confidence interval 0.94-0.96, p < 0.001; for psychotherapy: odds ratio = 0.96, 95% confidence interval 0.94-0.97, p < 0.001). DISCUSSION: About 30% of the Austrian IBD patients expressed a need for integrated psychosomatic support and/or psychotherapy. The most important indicators for this need were the use of complementary and alternative medicine and low quality of life.

Prevalence and indicators of use of complementary and alternative medicine in Austrian patients with inflammatory bowel disease.

OBJECTIVE: Complementary and alternative medicine (CAM) seems to be frequently used among patients with inflammatory bowel disease (IBD). We aimed to determine the prevalence and indicators of CAM use in Austrian IBD patients. METHODS: In a multicentre cross-sectional study, adult patients with IBD attending 18 Austrian outpatient clinics completed a multi-item questionnaire that recorded use of CAM as well as medical and socioeconomic characteristics. Patients were recruited between June 2014 and June 2015. The study outcome was the prevalence of CAM use and its socioeconomic and disease-related associations. RESULTS: A total of 1286 patients (Crohn's disease 830, ulcerative colitis 435, IBD unclassified 21; females 651) with a median age of 40 years (interquartile range 31-52 years) and a median disease duration of 10 years (4-18 years) were analysed. The prevalence of previous and/or current CAM use was 50.7%, with similar results for Crohn's disease and ulcerative colitis. In the multivariable analysis, female gender and a university education were independent socioeconomic indicators of CAM use. IBD-related indicators were longer duration of the disease and previous and/or current treatment with steroids and TNF-α inhibitors. CONCLUSION: CAM use for IBD is frequent in Austrian IBD patients and associated with female gender, higher educational level of university degree, longer duration of the disease, and treatment with steroids and TNF-α inhibitors.

Diagnostic delay in patients with inflammatory bowel disease in Austria.

BACKGROUND: Delayed diagnosis seems to be common in inflammatory bowel diseases (IBD). The study was carried out to investigate the diagnostic delay and associated risk factors in Austrian IBD patients. METHODS: In a multicenter cross-sectional study adult patients with IBD attending 18 Austrian outpatient clinics completed a multi-item questionnaire that recorded medical and socioeconomic characteristics. The study outcome was diagnostic delay defined as the period from symptom onset to diagnosis of IBD. RESULTS: A total of 1286 patients (Crohn's disease 830, ulcerative colitis 435, inflammatory bowel disease unclassified 21; females 651) with a median age of 40 years (interquartile range 31-52 years) and a median disease duration of 10 years (4-18 years) were analyzed. The median diagnostic delay was 6 months (2-23 months) in Crohn's disease and 3 months (1-10 months) in ulcerative colitis (p < 0.001). In the multivariable regression analysis Crohn's disease, greater age at diagnosis and a high educational level (compared to middle degree level) were independently associated with longer diagnostic delay. CONCLUSION: The diagnostic delay was longer in Crohn's disease than in ulcerative colitis patients and was associated with greater age at diagnosis and a higher educational level.

Clinical presentation of venous thromboembolism in inflammatory bowel disease.

BACKGROUND AND AIMS: Patients with inflammatory bowel disease (IBD) are at increased risk of venous thromboembolism (VTE), but data on frequency, site of thrombosis and risk factors are limited. We sought to determine prevalence, incidence as well as location and clinical features of first VTE among IBD patients. METHODS: We evaluated a cohort of 2811 IBD patients for a history of symptomatic, objectively confirmed first VTE, recruited from 14 referral centers. Patients with VTE before IBD diagnosis or cancer were excluded. Incidence rates were calculated based on person-years from IBD diagnosis to first VTE or end of follow-up, respectively. RESULTS: 2784 patients (total observation time 24,778 person-years) were analyzed. Overall, of 157 IBD patients with a history of VTE, 142 (90.4%) had deep vein thrombosis (DVT) and/or pulmonary embolism (PE), whereas 15 (9.6%) had cerebral, portal, mesenteric, splenic or internal jugular vein thrombosis. The prevalence and incidence rate of all VTE was 5.6% and 6.3 per 1000 person years, respectively. Patients with VTE were older at IBD diagnosis than those without VTE (34.4±14.8years vs 32.1±14.4years, p=0.045), but did not differ regarding sex, underlying IBD and disease duration. 121 (77.1%) VTE were unprovoked, 122 (77.7%) occurred in outpatients and 78 (60.9%) in patients with active disease. Medication at first VTE included corticosteroids (42.3%), thiopurines (21.2%), and infliximab (0.7%). CONCLUSION: VTE is frequent in IBD patients. Most of them are unprovoked and occur in outpatients. DVT and PE are most common and unusual sites of thrombosis are rare.

Inflammatory bowel disease is a risk factor for recurrent venous thromboembolism.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) are at increased risk of a first venous thromboembolism (VTE), yet their risk of recurrent VTE is unknown. We performed a cohort study to determine the risk for recurrent VTE among patients with IBD compared with subjects without IBD. METHODS: We assessed 2811 patients with IBD for a history of VTE, recruited from outpatient clinics at 14 referral centers (June 2006-December 2008). Patients with VTE before a diagnosis of IBD or those not confirmed to have VTE, cancer, or a VTE other than deep vein thrombosis or pulmonary embolism, were excluded. Recurrence rates were compared with 1255 prospectively followed patients without IBD that had a first unprovoked VTE (not triggered by trauma, surgery, or pregnancy). The primary end point was symptomatic, objectively confirmed, recurrent VTE after discontinuation of anticoagulation therapy after a first VTE. RESULTS: Overall, of 116 IBD patients who had a history of first VTE, 86 were unprovoked. The probability of recurrence 5 years after discontinuation of anticoagulation therapy was higher among patients with IBD than patients without IBD (33.4%; 95% confidence interval [CI]: 21.8-45.0 vs 21.7%; 95% CI: 18.8-24.6; P = .01). After adjustment for potential confounders, IBD was an independent risk factor of recurrence (hazard ratio = 2.5; 95% CI: 1.4-4.2; P = .001). CONCLUSIONS: Patients with IBD are at an increased risk of recurrent VTE compared to patients without IBD.

A systematic survey evaluating 6-thioguanine-related hepatotoxicity in patients with inflammatory bowel disease.

OBJECTIVE: Drug-induced liver injury was recently reported as a major complication leading to hepatic nodular regenerative hyperplasia (NRH) in patients with inflammatory bowel disease (IBD) and 6-thioguanine (6-TG) therapy. The aim of the study was to evaluate the prevalence of 6-TG-related hepatotoxicity in a large multi-centered IBD population by means of a systematic online survey. METHODS: Clinical and laboratory data, imaging techniques (sonography, CT, MRI) and histology of liver biopsies were surveyed in IBD patients treated with 6-TG. The decision on whether liver imaging and/or liver biopsy were performed was exclusively at the discretion of the investigator. RESULTS: 6-TG use was fully documented in 296 patients (median treatment duration 56 weeks, range < 1-207). Laboratory signs of drug-induced liver injury were found in 43 patients (14.5%). Liver imaging revealed pathologic results in 68/176 patients (38.6%). Liver biopsy was performed in a subset of 60 patients; using silver-reticulin staining (n = 59), NRH was considered in 16 patients (27.1%). Age was the only independent, albeit weak, risk factor for development of NRH. CONCLUSION: This large online survey confirms the strong association between 6-TG treatment and the significant risk of development of NRH in patients with IBD. The definitive diagnosis of NRH depends solely upon liver biopsy.