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Munch A.,Linköping University | Aust D.,University Hospital | Bohr J.,Örebro University | Bonderup O.,Regional Hospital Silkeborg | And 7 more authors.
Journal of Crohn's and Colitis | Year: 2012

Microscopic colitis (MC) is an inflammatory bowel disease presenting with chronic, non-bloody watery diarrhoea and few or no endoscopic abnormalities. The histological examination reveals mainly two subtypes of MC, lymphocytic or collagenous colitis. Despite the fact that the incidence in MC has been rising over the last decades, research has been sparse and our knowledge about MC remains limited. Specialists in the field have initiated the European Microscopic Colitis Group (EMCG) with the primary goal to create awareness on MC. The EMCG is furthermore a forum with the intention to promote clinical and basic research. In this article statements and comments are given that all members of the EMCG have considered being of importance for a better understanding of MC. The paper focuses on the newest updates in epidemiology, symptoms and diagnostic criteria, pathophysiology and highlights some unsolved problems. Moreover, a new treatment algorithm is proposed on the basis of new evidence from well-designed, randomized control trials. © 2012 European Crohn's and Colitis Organisation.


Munch A.,Linköping University | Bohr J.,Örebro University | Miehlke S.,Center for Digestive Disease | Benoni C.,Skåne University Hospital | And 19 more authors.
Gut | Year: 2016

Objective: This 1-year study aimed to assess low-dose budesonide therapy for maintenance of clinical remission in patients with collagenous colitis. Design: A prospective, randomised, placebo-controlled study beginning with an 8-week open-label induction phase in which patients with histologically confirmed active collagenous colitis received budesonide (Budenofalk, 9 mg/day initially, tapered to 4.5 mg/day), after which 92 patients in clinical remission were randomised to budesonide (mean dose 4.5 mg/day; Budenofalk 3 mg capsules, two or one capsule on alternate days) or placebo in a 12-month double-blind phase with 6 months treatment-free follow-up. Primary endpoint was clinical remission throughout the double-blind phase. Results: Clinical remission during open-label treatment was achieved by 84.5% (93/110 patients). The median timetoremissionwas10.5days(95%CI(9.0to 14.0 days)). The maintenance of clinical remission at 1 year was achieved by 61.4% (27/44 patients) in the budesonide group versus 16.7% (8/48 patients) receiving placebo (treatment difference 44.5% in favour of budesonide; 95% CI (26.9% to 62.7%), p<0.001). Health-related quality of life was maintained during the 12-month double-blind phase in budesonide-treated patients. During treatment-free follow-up, 82.1% (23/28 patients) formerly receiving budesonide relapsed after study drug discontinuation. Low-dose budesonide over 1 year resulted in few suspected adverse drug reactions (7/44 patients), all non-serious. Conclusions: Budesonide at a mean dose of 4.5 mg/day maintained clinical remission for at least 1 year in the majority of patients with collagenous colitis and preserved health-related quality of life without safety concerns. Treatment extension with low-dose budesonide beyond 1 year may be beneficial given the high relapse rate after budesonide discontinuation. Trial registration numbers: http://www.clinicaltrials.gov (NCT01278082) and http://www.clinicaltrialsregister.eu (EudraCT: 2007-001315-31). © 2015, BMJ Publishing Group. All rights reserved.


PubMed | Amager Hospital, Dr Falk Pharma GmbH, Regional Hospital, Lund University and 9 more.
Type: Clinical Trial, Phase III | Journal: Gut | Year: 2015

This 1-year study aimed to assess low-dose budesonide therapy for maintenance of clinical remission in patients with collagenous colitis.A prospective, randomised, placebo-controlled study beginning with an 8-week open-label induction phase in which patients with histologically confirmed active collagenous colitis received budesonide (Budenofalk, 9mg/day initially, tapered to 4.5mg/day), after which 92 patients in clinical remission were randomised to budesonide (mean dose 4.5mg/day; Budenofalk 3 mg capsules, two or one capsule on alternate days) or placebo in a 12-month double-blind phase with 6months treatment-free follow-up. Primary endpoint was clinical remission throughout the double-blind phase.Clinical remission during open-label treatment was achieved by 84.5% (93/110 patients). The median time to remission was 10.5days (95% CI (9.0 to 14.0days)). The maintenance of clinical remission at 1year was achieved by 61.4% (27/44 patients) in the budesonide group versus 16.7% (8/48 patients) receiving placebo (treatment difference 44.5% in favour of budesonide; 95% CI (26.9% to 62.7%), p<0.001). Health-related quality of life was maintained during the 12-month double-blind phase in budesonide-treated patients. During treatment-free follow-up, 82.1% (23/28 patients) formerly receiving budesonide relapsed after study drug discontinuation. Low-dose budesonide over 1year resulted in few suspected adverse drug reactions (7/44 patients), all non-serious.Budesonide at a mean dose of 4.5mg/day maintained clinical remission for at least 1year in the majority of patients with collagenous colitis and preserved health-related quality of life without safety concerns. Treatment extension with low-dose budesonide beyond 1year may be beneficial given the high relapse rate after budesonide discontinuation.http://www.clinicaltrials.gov (NCT01278082) and http://www.clinicaltrialsregister.eu (EudraCT: 2007-001315-31).


Singh V.K.,Johns Hopkins University | Moran R.A.,Johns Hopkins University | Afghani E.,Center for Digestive Disease | De-Madaria E.,Hospital General Universitario Of Alicante
Expert Review of Gastroenterology and Hepatology | Year: 2015

The medical treatment of acute pancreatitis continues to focus on supportive care, including fluid therapy, nutrition, and antibiotics, all of which will be critically reviewed. Pharmacologic agents that were previously studied were found to be ineffective likely due to a combination of their targets and flaws in trial design. Potential future pharmacologic agents, particularly those that target intracellular calcium signaling, as well as considerations for trial design will be discussed. As the incidence of acute pancreatitis continues to increase, greater efforts will be needed to prevent hospitalization, readmission and excessive imaging in order to reduce overall healthcare costs. Primary prevention continues to focus on post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis and secondary prevention on cholecystectomy for biliary pancreatitis as well as alcohol and smoking abstinence. ©2015 Informa UK Ltd.


Wallace K.,Medical University of South Carolina | Brandt H.M.,University of South Carolina | Bearden J.D.,Gibbs Cancer Center and Research Institute | Blankenship B.F.,Medical University of South Carolina | And 14 more authors.
Digestive Diseases and Sciences | Year: 2016

Background: Compared to whites, blacks have higher colorectal cancer incidence and mortality rates and are at greater risk for early-onset disease. The reasons for this racial disparity are poorly understood, but one contributing factor could be differences in access to high-quality screening and medical care. Aims: The present study was carried out to assess whether a racial difference in prevalence of large bowel polyps persists within a poor and uninsured population (n = 233, 124 blacks, 91 whites, 18 other) undergoing screening colonoscopy. Methods: Eligible patients were uninsured, asymptomatic, had no personal history of colorectal neoplasia, and were between the ages 45–64 years (blacks) or 50–64 years (whites, other). We examined the prevalence of any adenoma (conventional, serrated) and then difference in adenoma/polyp type by race and age categories. Results: Prevalence for ≥1 adenoma was 37 % (95 % CI 31–43 %) for all races combined and 36 % in blacks <50 years, 38 % in blacks ≥50 years, and 35 % in whites. When stratified by race, blacks had a higher prevalence of large conventional proximal neoplasia (8 %) compared to whites (2 %) (p value = 0.06) but a lower prevalence of any serrated-like (blacks 18 %, whites 32 %; p value = 0.02) and sessile serrated adenomas/polyps (blacks 2 %, whites 8 % Chi-square p value; p = 0.05). Conclusions: Within this uninsured population, the overall prevalence of adenomas was high and nearly equal by race, but the racial differences observed between serrated and conventional polyp types emphasize the importance of taking polyp type into account in future research on this topic. © 2015, Springer Science+Business Media New York.


Kono S.,Tokyo Medical University | Gotoda T.,Tokyo Medical University | Yoshida S.,Aomori Prefectural Central Hospital | Oda I.,National Cancer Center Hospital | And 6 more authors.
World Journal of Gastroenterology | Year: 2015

AIM: To assess the diagnostic concordance between endoscopic and histological atrophy in the United Kingdom and Japan. METHODS: Using published data, a total of 252 patients, 126 in the United Kingdom and 126 in Japan, aged 20 to 80 years, were evaluated. The extent of endoscopic atrophy was classified into five subgroups according to a modified Kimura-Takemoto classification system and was compared with histological findings of atrophy at five biopsy sites according to the updated Sydney system. RESULTS: The strength of agreement of the extent of atrophy between histology and visual endoscopic inspection showed good reproducibility, with a weighted kappa value of 0.76 (P < 0.001). Multivariate analysis showed that three factors were associated with decreased concordance: Japanese ethnicity [odds ratio (OR) 0.22, 95% confidence interval (CI) 0.11-0.43], older age (OR = 0.32, 95%CI: 0.16-0.66) and endoscopic atrophy (OR = 0.10, 95%CI: 0.03-0.36). The strength of agreement between endoscopic and histological atrophy, assessed by cancer risk-oriented grading, was reproducible, with a kappa value of 0.81 (95%CI: 0.75-0.87). Only nine patients (3.6%) were endoscopically underdiagnosed with antral predominant rather than extensive atrophy and were considered false negatives. CONCLUSION: Endoscopic grading can predict histological atrophy with few false negatives, indicating that precancerous conditions can be identified during screening endoscopy, particularly in patients in western countries. © 2015 Baishideng Publishing Group Inc. All rights reserved.


Schurich A.,University College London | Khanna P.,University College London | Lopes A.R.,University College London | Han K.J.,University College London | And 7 more authors.
Hepatology | Year: 2011

An excess of coinhibitory signals has been proposed to drive the T-cell exhaustion characteristic of persistent viral infections. In this study we examined the contribution of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) to CD8 T cell tolerance in chronic hepatitis B virus (HBV) infection (CHB). CD8 T cells in patients with CHB have an increased propensity to express the coinhibitory receptor CTLA-4 and this correlates with viral load. CTLA-4 is up-regulated on those HBV-specific CD8 T cells with the highest levels of the proapoptotic protein Bim, which we have previously shown mediates their premature attrition; abrogation of CTLA-4-mediated coinhibition can reduce Bim expression. Longitudinal study of CHB patients beginning antiviral therapy reveals that HBV DNA suppression induces transient reconstitution of HBV-specific CD8 T cells but does not reprogram their CTLA-4 hiBim hi tolerogenic phenotype. Blocking CTLA-4 is able to increase the expansion of interferon gamma (IFN-γ)-producing HBV-specific CD8 T cells in both the peripheral and intrahepatic compartments. The rescue of anti-HBV responses by either CTLA-4 or PD-L1 blockade is nonredundant. Conclusion: CTLA-4 is expressed by HBV-specific CD8 T cells with high levels of Bim and helps to drive this proapoptotic phenotype. CTLA-4 blockade could form one arm of a therapeutic approach to modulate the diverse patterns of coregulation of T-cell exhaustion in this heterogeneous disease. © 2011 American Association for the Study of Liver Diseases.


Schurich A.,University College London | Pallett L.J.,University College London | Lubowiecki M.,University College London | Singh H.D.,University College London | And 6 more authors.
PLoS Pathogens | Year: 2013

Optimal immune activation of naïve CD8 T cells requires signal 1 mediated by the T cell receptor, signal 2 mediated by co-stimulation and signal 3 provided by pro-inflammatory cytokines. However, the potential for signal 3 cytokines to rescue anti-viral responses in functionally exhausted T cells has not been defined. We investigated the effect of using third signal cytokines IL-12 or IFN-α to rescue the exhausted CD8 T cell response characteristic of patients persistently infected with hepatitis B virus (HBV). We found that IL-12, but not IFN-α, potently augmented the capacity of HBV-specific CD8 T cells to produce effector cytokines upon stimulation by cognate antigen. Functional recovery mediated by IL-12 was accompanied by down-modulation of the hallmark inhibitory receptor PD-1 and an increase in the transcription factor T-bet. PD-1 down-regulation was observed in HBV but not CMV-specific T cells, in line with our finding that the highly functional CMV response was not further enhanced by IL-12. IL-12 enhanced a number of characteristics of HBV-specific T cells important for viral control: cytotoxicity, polyfunctionality and multispecificity. Furthermore, IL-12 significantly decreased the pro-apoptotic molecule Bim, which is capable of mediating premature attrition of HBV-specific CD8 T cells. Combining IL-12 with blockade of the PD-1 pathway further increased CD8 functionality in the majority of patients. These data provide new insights into the distinct signalling requirements of exhausted T cells and the potential to recover responses optimised to control persistent viral infections. © 2013 Schurich et al.


Peppa D.,University College London | Micco L.,University College London | Javaid A.,Center for Digestive Disease | Kennedy P.T.F.,University College London | And 9 more authors.
PLoS Pathogens | Year: 2010

NK cells are enriched in the liver, constituting around a third of intrahepatic lymphocytes. We have previously demonstrated that they upregulate the death ligand TRAIL in patients with chronic hepatitis B virus infection (CHB), allowing them to kill hepatocytes bearing TRAIL receptors. In this study we investigated whether, in addition to their pathogenic role, NK cells have antiviral potential in CHB. We characterised NK cell subsets and effector function in 64 patients with CHB compared to 31 healthy controls. We found that, in contrast to their upregulated TRAIL expression and maintenance of cytolytic function, NK cells had a markedly impaired capacity to produce IFN-c in CHB. This functional dichotomy of NK cells could be recapitulated in vitro by exposure to the immunosuppressive cytokine IL-10, which was induced in patients with active CHB. IL-10 selectively suppressed NK cell IFN-c production without altering cytotoxicity or death ligand expression. Potent antiviral therapy reduced TRAIL-expressing CD56bright NK cells, consistent with the reduction in liver inflammation it induced; however, it was not able to normalise IL-10 levels or the capacity of NK cells to produce the antiviral cytokine IFN-c. Blockade of IL-10 +/2 TGF-b restored the capacity of NK cells from both the periphery and liver of patients with CHB to produce IFN-c, thereby enhancing their non-cytolytic antiviral capacity. In conclusion, NK cells may be driven to a state of partial functional tolerance by the immunosuppressive cytokine environment in CHB. Their defective capacity to produce the antiviral cytokine IFN-c persists in patients on antiviral therapy but can be corrected in vitro by IL-10+/2 TGF-b blockade. ©2010 Peppa et al.

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