Rationale Asthma is characterized by chronic inflammation;inhaled corticosteroids (ICS) are the preferred antiinflammatory treatment at all severity levels. Velsecorat, a once-daily inhaled non-steroidal selective glucocorticoid receptor (GR) modulator potentially has an improved risk-benefit profile compared to ICS. The aim of this Phase 1 study (AMBER, NCT03976869) was to establish the pharmacokinetic (PK) and pharmacodynamic (PD) profile of velsecorat in adolescents to enable inclusion of this population in phase 3 studies. Necessitating long site visits, PK studies are challenging to conduct in adolescents, disrupt patient school attendance and interfere with the daily lives of the patients' families. In AMBER, we revolutionized the conduct of this type of study by bringing the study directly to the patient's home (Figure 1). Methods This open-label, multi-center study enrolled 36 adolescents (12-17 years) with Global Initiative for Asthma (GINA) step 2 asthma. After a 2-3-week washout of asthma controller, patients received 360μg velsecorat inhaled once-daily for two weeks, with short acting β-agonists allowed as rescue medication. The primary objective was to determine steady state PK;key secondary endpoints were safety and change from baseline in;trough FEV1, plasma cortisol, and asthma control as measured by the asthma control questionnaire-5 (ACQ-5). Study site visits were combined with telemedicine and home nursing visits, as well as collection of daily dairy data via smartphone app. Results Following administration of velsecorat, individual steady state exposure parameters in patients aged 12-14 and 15-17 years were within the same range. Change from baseline in adjusted mean plasma cortisol levels, mean ACQ-5 scores and mean Day15 FEV1 were limited and not clinically significant. Velsecorat was well tolerated, and no new safety concerns were identified. During the COVID-19 pandemic, patient recruitment was accelerated, highlighting that the decentralized design of AMBER, was more suitable for social distancing practices than the traditional site-centric trial model. Participant and caregiver surveys administered at study end revealed that most participants were willing to participate in similar decentralized trials in the future. Conclusions Overall, the results support the advancement of velsecorat into phase 3 studies including adolescents. AMBER offered a convenient and patient-centric study experience for adolescents and their families during the pandemic. Decentralized studies has the potential to become a new standard by offering a flexible convenient, safe and patient-friendly study format for an adolescent population, as shown by the high recruitment and retention rate during the peak of the COVID-19 pandemic.

Background: A complex interplay of genetic and environmental factors are implicated in the pathogenesis of ulcerative colitis (UC), resulting in an abnormal immune response and subsequent destruction of the colonic epithelium. The Icelandic population has a restricted gene pool with extensive medical records in combination with one of the highest incidence of UC in the world [1]. We aimed to assess the exomic genetic data and colonic transcriptomics of patients with UC and healthy controls to identify novel deleterious mutations and its influence on the colonic mucosa. Methods: We performed exome sequencing and whole genome wide microarray analysis on macroscopically normal colonic mucosa from patients with a histological diagnosis of UC and healthy patients with no family history of UC undergoing colonoscopy. Gene-ontology analysis was used to identify common processes and pathways differentially expressed in diseased tissue. Exon sequencing screening for rare or novel mutations was performed on both cohorts. Results: Non-inflamed colonic tissue from UC patients demonstrated significant alteration in the transcriptomic profile when compared with control tissue. Over 2,000 genes were differentially expressed in the rectum. Gene-ontology analysis identified up-regulation in genes associated with cell cycle and protein metabolism in patients with UC. Exome sequencing identified 2 missense mutations in thiopurine S-methytransferase (TPMT) in 7/13 of the UC biopsies compared to 1/14 controls. The mutations identified are known to result in a loss of enzyme function leading to high levels of toxic metabolites from thiopurine analogues, which cause liver toxicity and bone marrow suppression. [2] This variant seems to be significantly more prevalent in this population. We identified 2 significant possibly damaging mutations which have influence on rectal gene expression. Table 1. Significantly enriched deleterious mutations in the Icelandic UC cohort with corresponding allele frequency from EXAC and UCLex variant databases The mutations correspond with differential expression of SPOP with TPMT variant and DUOXA2 and DUOX2 with SLC26A3 variant. Conclusions: Rectal mucosal samples from UC patients show an elevation in cell cycle activity and protein metabolism. The perceived increase in the TPMT variant would suggest screening of the UC population to avoid the serious toxicity associated with thiopurine analogue therapy. Significantly enriched deleterious mutations in the UC cohort, also have an influence on rectal gene expression of DUOXA2, DUOX2 and SPOP. References: [1] Bjornsson, S et al. (2015). Incidence of inflammatory bowel disease in Iceland 1995–2009. A nationwide population-based study, Scand. J. Gastroenterolgy, 5521, 1–8 [2] Roberts, R.L. & Barclay, M.L, (2015). Update on thiopurine pharmacogenetics in inflammatory bowel disease, Pharmacogenomics, 16, 891–903

Background and AimsThe EpiCom study and inception cohort was initiated in 2010 in 31 centers from 14 Western and 8 Eastern European countries, covering a 10.1million person background population. Our aim was to investigate whether there is a difference between Eastern and Western Europe in health care and education of patients with inflammatory bowel disease (IBD).MethodsA quality of care (QoC) questionnaire was developed in the EpiCom group consisting of 16 questions covering 5 items: time interval between the onset of symptoms and diagnosis, information, education, empathy and access to health care providers.ResultsOf 1,515 patients, 947 (217 east/730 west) answered the QoC questionnaire. Only 23% of all patients had knowledge about IBD before diagnosis. In Eastern Europe, significantly more patients searched out information about IBD themselves (77% vs. 68%, p<0.05), the main source was the Internet (92% vs. 88% p=0.23). In Western Europe, significantly more patients were educated by nurses (19% vs. 1%, p<0.05), while in Eastern Europe, gastroenterologists were easier to contact (80% vs. 68%, p<0.05).ConclusionHealth care differed significantly between Eastern and Western Europe in all items, but satisfaction rates were high in both geographic regions. Because of the low awareness and the rising incidence of IBD, general information should be the focus of patient organizations and medical societies. In Western Europe IBD nurses play a very important role in reducing the burden of patient management.

Background & AimsHealth-related quality of life (HRQoL) is impaired in patients with Inflammatory Bowel Disease (IBD). The aim was prospectively to assess and validate the pattern of HRQoL in an unselected, population-based inception cohort of IBD patients from Eastern and Western Europe.MethodsThe EpiCom inception cohort consists of 1560 IBD patients from 31 European centres covering a background population of approximately 10.1million. Patients answered the disease specific Short Inflammatory Bowel Disease Questionnaire (SIBDQ) and generic Short Form 12 (SF-12) questionnaire at diagnosis and after one year of follow-up.ResultsIn total, 1079 patients were included in this study. Crohn's disease (CD) patients mean SIBDQ scores improved from 45.3 to 55.3 in Eastern Europe and from 44.9 to 53.6 in Western Europe. SIBDQ scores for ulcerative colitis (UC) patients improved from 44.9 to 57.4 and from 48.8 to 55.7, respectively. UC patients needing surgery or biologicals had lower SIBDQ scores before and after compared to the rest, while biological therapy improved SIBDQ scores in CD. CD and UC patients in both regions improved all SF-12 scores. Only Eastern European UC patients achieved SF-12 summary scores equal to or above the normal population.ConclusionMedical and surgical treatment improved HRQoL during the first year of disease. The majority of IBD patients in both Eastern and Western Europe reported a positive perception of disease-specific but not generic HRQoL. Biological therapy improved HRQoL in CD patients, while UC patients in need of surgery or biological therapy experienced lower perceptions of HRQoL than the rest.

OBJECTIVE:The incidence of inflammatory bowel disease (IBD) is increasing in Eastern Europe. The reasons for these changes remain unknown. The aim of this study was to investigate whether an East-West gradient in the incidence of IBD in Europe exists. DESIGN:A prospective, uniformly diagnosed, population based inception cohort of IBD patients in 31 centres from 14 Western and eight Eastern European countries covering a total background population of approximately 10.1 million people was created. One-third of the centres had previous experience with inception cohorts. Patients were entered into a low cost, web based epidemiological database, making participation possible regardless of socioeconomic status and prior experience. RESULTS:1515 patients aged 15 years or older were included, of whom 535 (35%) were diagnosed with Crohn's disease (CD), 813 (54%) with ulcerative colitis (UC) and 167 (11%) with IBD unclassified (IBDU). The overall incidence rate ratios in all Western European centres were 1.9 (95% CI 1.5 to 2.4) for CD and 2.1 (95% CI 1.8 to 2.6) for UC compared with Eastern European centres. The median crude annual incidence rates per 100,000 in 2010 for CD were 6.5 (range 0-10.7) in Western European centres and 3.1 (range 0.4-11.5) in Eastern European centres, for UC 10.8 (range 2.9-31.5) and 4.1 (range 2.4-10.3), respectively, and for IBDU 1.9 (range 0-39.4) and 0 (range 0-1.2), respectively. In Western Europe, 92% of CD, 78% of UC and 74% of IBDU patients had a colonoscopy performed as the diagnostic procedure compared with 90%, 100% and 96%, respectively, in Eastern Europe. 8% of CD and 1% of UC patients in both regions underwent surgery within the first 3 months of the onset of disease. 7% of CD patients and 3% of UC patients from Western Europe received biological treatment as rescue therapy. Of all European CD patients, 20% received only 5-aminosalicylates as induction therapy. CONCLUSIONS:An East-West gradient in IBD incidence exists in Europe. Among this inception cohort--including indolent and aggressive cases--international guidelines for diagnosis and initial treatment are not being followed uniformly by physicians.

Background and AimsThe incidence of inflammatory bowel disease (IBD) is increasing in Eastern Europe possibly due to changes in environmental factors towards a more “westernised” standard of living. The aim of this study was to investigate differences in exposure to environmental factors prior to diagnosis in Eastern and Western European IBD patients.MethodsThe EpiCom cohort is a population-based, prospective inception cohort of 1560 unselected IBD patients from 31 European countries covering a background population of 10.1million. At the time of diagnosis patients were asked to complete an 87-item questionnaire concerning environmental factors.ResultsA total of 1182 patients (76%) answered the questionnaire, 444 (38%) had Crohn's disease (CD), 627 (53%) ulcerative colitis (UC), and 111 (9%) IBD unclassified. No geographic differences regarding smoking status, caffeine intake, use of oral contraceptives, or number of first-degree relatives with IBD were found. Sugar intake was higher in CD and UC patients from Eastern Europe than in Western Europe while fibre intake was lower (p<0.01). Daily consumption of fast food as well as appendectomy before the age of 20 was more frequent in Eastern European than in Western European UC patients (p<0.01). Eastern European CD and UC patients had received more vaccinations and experienced fewer childhood infections than Western European patients (p<0.01).ConclusionsIn this European population-based inception cohort of unselected IBD patients, Eastern and Western European patients differed in environmental factors prior to diagnosis. Eastern European patients exhibited higher occurrences of suspected risk factors for IBD included in the Western lifestyle.

Einleitung: PSC-Patienten mit erhöhten IgG4 Serumspiegeln (PSC-IgG4+) zeigen nach neueren US- amerikanischen Studien einen aggressiveren Verlauf als Patienten mit „klassischer“ PSC ohne erhöhte IgG4 Serumspiegel. Vergleichbare europäische Daten existieren bisher nicht.

BACKGROUND:Gut-directed hypnotherapy is an effective treatment option for irritable bowel syndrome (IBS). However, clinical observations suggest that patient satisfaction with hypnotherapy is not always associated with improvement in IBS symptoms.METHODS:We evaluated 83 patients with IBS treated with gut-directed hypnotherapy (1 h week(-1), 12 weeks). After the treatment period, patients reported their satisfaction with the treatment (ranging from 1 = not at all satisfied, to 5 = very satisfied) and completed questionnaires to assess IBS symptom severity, quality of life, cognitive function, sense of coherence, depression, and anxiety before and after treatment.KEY RESULTS:After hypnotherapy improved IBS symptom severity, quality of life, cognitive function, and anxiety were seen. Thirty patients (36%) were very satisfied with the treatment and 57 (69%) patients scored 4 or 5 on the patient satisfaction scale. Patient satisfaction was associated with less severe IBS symptoms and better quality of life after the treatment. In a multiple linear regression analysis, only the quality of life domain sexual relations was independently associated with patient satisfaction after hypnotherapy, explaining 22% of the variance. Using 25% reduction of IBS symptom severity to define an IBS symptom responder, 52% of the responders were very satisfied with hypnotherapy, but this was also true for 31% in the non-responder group.CONCLUSIONS & INFERENCES:Patient satisfaction with gut-directed hypnotherapy in IBS is associated with improvement of quality of life and gastrointestinal (GI) symptoms. However, other factors unrelated to GI symptoms also seems to be of importance for patient satisfaction, as a substantial proportion of patients without GI symptom improvement were also very satisfied with this treatment option.

Drug-induced liver injury (DILI) is the most frequent reason cited for the withdrawal of approved drugs from the market and accounts for up to 15% of the cases of acute liver failure. Investigators around the globe have begun to identify and study patients with DILI; several large registries and tissue banks are being established. In order to gain the maximum scientific benefit from these efforts, the definitions and terminology related to the clinical phenotypes of DILI must be harmonized. For this purpose, an international DILI Expert Working Group of clinicians and scientists reviewed current DILI terminology and diagnostic criteria so as to develop more uniform criteria that would define and characterize the spectrum of clinical syndromes that constitute DILI. Consensus was established with respect to the threshold criteria for definition of a case as being DILI, the pattern of liver injury, causality assessment, severity, and chronicity. Consensus was also reached on approaches to characterizing DILI in the setting of chronic liver diseases, including autoimmune hepatitis (AIH).

Aliment Pharmacol Ther 2010; 32: 1154–1162SummaryBackground Reliable epidemiological data for portal vein thrombosis are lacking.Aims To investigate the incidence, prevalence and survival rates for patients with portal vein thrombosis.Methods Retrospective multicentre study of all patients registered with the diagnosis of portal vein thrombosis between 1995 and 2004.Results A total of 173 patients (median age 57 years, 93 men) with portal vein thrombosis were identified and followed up for a median of 2.5 years (range 0–9.7). The mean age‐standardized incidence and prevalence rates were 0.7 per 100 000 per year and 3.7 per 100 000 inhabitants, respectively. Liver disease was present in 70 patients (40%), malignancy in 27%, thrombophilic factors in 22% and myeloproliferative disorders in 11%. Two or more risk factors were identified in 80 patients (46%). At diagnosis, 65% were put on anticoagulant therapy. Thrombolysis, TIPS, surgical shunting and liver transplantation were performed in 6, 3, 2 and 8 patients, respectively. The overall survival at 1 year and 5 years was 69% and 54%. In the absence of malignancy and cirrhosis, the survival was 92% and 76%, respectively.Conclusions The incidence and prevalence rates of portal vein thrombosis were 0.7 per 100 000 inhabitants per year and 3.7 per 100 000 inhabitants, respectively. Concurrent prothrombotic risk factors are common. The prognosis is variable and highly dependent on underlying disease.

The editorial team of Digestive Diseases and Sciences (DDS) wishes to acknowledge the critically important role played by the individuals whose names appear in the following list of reviewers for calendar year 2008. Manuscript reviews by these clinical and research scientists, as well as by members of the editorial board, are the cornerstone of the journal and are vital to maintaining and improving the quality of DDS. Reviewers’ generosity with both expertise and time has allowed the editorial team to improve DDS’s review turnaround (from submission to first decision) from 58 days in 2007 to the current average of 28 days.

not found in the control group.All R341H variants (8 in patients and 3 in controls) associated with the previously-described intronic K8 IVS7+10delC deletion.Keratin variants did not associate with the presence of anti-mitochondrial antibodies but there was a trend for association with liver disease severity (10.3% amino acid altering variants in Ludwig stages III/IV versus 4.3% in stages I/II).Conclusion: A significant frequency of K8/K18/K19 variants is found in association with PBC in an Italian cohort of patients, which suggests that K8/ K18/K19 variants may predispose to PBC in some patients. .

SummaryBackground There is currently no treatment available to manage acute pain attacks in IBS patients regardless of subtype.Aims To evaluate efficacy and safety of the GLP‐1 analogue ROSE‐010 in patients with irritable bowel syndrome (IBS) through a randomized, double‐blind, placebo‐controlled study.Methods Eligible patients (n = 166) meeting Rome II criteria were randomly assigned to receive single subcutaneous injections of ROSE‐010 100 μg, 300 μg and placebo in a cross‐over design. Safety was assessed from spontaneously reported adverse events and measurement of vital signs. Patient‐rated pain relief and intensity were measured on a 100‐mm visual analogue scale. The primary efficacy variable was proportion of patients with >50% maximum total pain relief response from 10 to 60 min after treatment. Secondary endpoints included the maximum summed pain intensity difference, time to meaningful pain relief and patient ratings of satisfaction with treatment.Results Twice as many patients were responders in the primary efficacy endpoint after both ROSE‐010 injections compared to placebo (24%P = 0.011, 23%P = 0.005, and 12% after 300 μg, 100 μg and placebo injections, respectively). Similar results were obtained for the proportion of patients with total pain intensity response. Times to meaningful and total pain relief were shorter for both doses of ROSE‐010 compared with placebo. Compared with placebo, more patients (P < 0.05) were satisfied with ROSE‐010 and considered ROSE‐010 better than previous IBS medications used.Conclusion ROSE‐010 was well tolerated and provided fast and effective relief of acute pain attacks on demand in IBS patients.

Wei G, Bergquist A, Broome U, Lindgren S, Wallerstedt S, Almer S, Sangfelt P, Danielsson A, Sandber-Gertzen H, Loof L, Prytz H, Bjomsson E (Sahlgrenska University Hospital, Gothenburg; Karolinska University Hospital, Huddinge, Stockholm; University Hospital MAS, Malmo; University Hospital, Linkoping; University Hospital, Uppsala; University Hospital, Umea; University Hospital, Orebro; Central Hospital, Vasteras; and University Hospital, Lund; Sweden). Acute liver failure in Sweden: etiology and outcome. J Intern Med 2007; 262: 393-401.Objective. To determine the causes and outcome of all patients with acute liver failure (ALF) in Sweden 1994-2003 and study the diagnostic accuracy of King's College Hospital (KCH) criteria and the model for end-stage liver disease (MELD) score with transplant-free deaths as a positive outcome.Research design and methods. Adult patients in Sweden with international normalized ratio (INR) of >= 1.5 due to severe liver injury with and without encephalopathy at admission between 1994-2003 were included.Results. A total of 279 patients were identified. The most common cause of ALF were acetaminophen toxicity in 42% and other drugs in 15%. In 31 cases (11%) no definite etiology could be established. The KCH criteria had a positive-predictive value (PPV) of 67%, negative-predictive value (NPV) of 84% in the acetaminophen group. Positive-predictive value and negative-predictive value of KCH criteria in the nonacetammophen group were 54% and 63% respectively. MELD score > 30 had a positive-predictive value of 21%, negative-predictive value of 94% in the acetaminophen group. The corresponding figures for the nonacetaminophen group were 64% and 76% respectively.Conclusions. Acetaminophen toxicity was the most common cause in unselected patients with ALF in Sweden. KCH criteria had a high NPV in the acetaminophen group, and in combination with MELD score < 30 predicts a good prognosis in acetaminophen patients without transplantation.

BACKGROUND:In chronic heart failure (CHF) it has been proposed that a dysfunction of the gastrointestinal barrier could lead to translocation of endotoxin into the systemic circulation. A secondary inflammatory reaction, observed as increased levels of cytokines, could negatively affect cardiac function. The aims of this paper were therefore to determine whether patients with CHF have a disturbed mucosal barrier and whether it was possible to detect endotoxin in venous blood. METHODS:Nineteen stable patients with CHF (New York Heart Association II-III, EF40% and earlier hospitalisation for heart failure) were investigated. Twenty healthy subjects (HS group) and 25 patients, who were admitted for bone marrow transplantation (BMT group), served as controls. Gastrointestinal permeability was assessed by a (51)Cr-EDTA absorption test. RESULTS:Eleven patients with and eight without peripheral oedema were included. Median age was 76.5 years. Intestinal permeability was 1.82+/-1.96% in the CHF patients and 1.54+/-.59% and 1.9+/-.9% in HS and BMT groups, respectively (p=0.4 and p=0.7, CHF vs HS and BMT, respectively). No difference was found between patients with and without oedema and endotoxins were below the detection limit in all patients. DISCUSSION:This study does not support the hypothesis that patients with CHF have a dysfunctional gastrointestinal barrier, at least as assessed by the (51)Cr-EDTA resorbtion test.