| 1. |
- Carstens, Adam, 1975-, et al.
(författare)
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The Gut Microbiota in Collagenous Colitis Shares Characteristics With Inflammatory Bowel Disease-Associated Dysbiosis
- 2019
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Ingår i: Clinical and Translational Gastroenterology. - : Nature Publishing Group. - 2155-384X. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: In inflammatory bowel disease (IBD), an aberrant immune response to gut microbiota is important, but the role of the microbiota in collagenous colitis (CC) is largely unknown. We aimed to characterize the microbiota of patients with CC compared with that of healthy control and patients with IBD.METHODS: Fecal samples were collected from patients with CC (n = 29), age- and sex-matched healthy controls (n = 29), patients with Crohn's disease (n = 32), and patients with ulcerative colitis (n = 32). Sequence data were obtained by 454 sequencing of 16S rRNA gene amplicons, and the obtained sequences were subsequently taxonomically classified.RESULTS: Analysis of similarity statistics showed a segregation between patients with CC and healthy controls with increasing taxonomic resolution, becoming significant comparing operational taxonomic unit data (P = 0.006). CC had a lower abundance of 10 different taxa. Taxa-specific analyses revealed a consistent lower abundance of several operational taxonomic units belonging to the Ruminococcaceae family in patients with CC, q < 0.05 after false discovery rate correction. Loss of these taxa was seen in patients with CC with active disease and/or corticosteroid treatment only and resembled the findings in patients with IBD.DISCUSSION: CC is associated with a specific fecal microbiome seen primarily in patients with active disease or ongoing corticosteroid treatment, whereas the microbiome of CC patients in remission resembled that of healthy controls. Notably, the shift in key taxa, including the Ruminococcaceae family, was also observed in IBD. There may be common mechanisms in the pathogenesis of CC and IBD.
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| 2. |
- Miehlke, Stephan, et al.
(författare)
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European guidelines on microscopic colitis : United European Gastroenterology (UEG) and European Microscopic Colitis Group (EMCG) statements and recommendations
- 2021
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Ingår i: United European Gastroenterology journal. - : Sage Publications. - 2050-6406 .- 2050-6414. ; 9:1, s. 13-37
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Forskningsöversikt (refereegranskat)abstract
- Introduction: Microscopic colitis is a chronic inflammatory bowel disease characterised by normal or almost normal endoscopic appearance of the colon, chronic watery, non-bloody diarrhoea and distinct histological abnormalities, which identify three histological subtypes, the collagenous colitis, the lymphocytic colitis and the incomplete microscopic colitis. With ongoing uncertainties and new developments in the clinical management of microscopic colitis, there is a need for evidence-based guidelines to improve the medical care of patients suffering from this disorder.Methods: Guidelines were developed by members from the European Microscopic Colitis Group and United European Gastroenterology in accordance with the Appraisal of Guidelines for Research and Evaluation II instrument. Following a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the certainty of the evidence. Statements and recommendations were developed by working groups consisting of gastroenterologists, pathologists and basic scientists, and voted upon using the Delphi method.Results: These guidelines provide information on epidemiology and risk factors of microscopic colitis, as well as evidence-based statements and recommendations on diagnostic criteria and treatment options, including oral budesonide, bile acid binders, immunomodulators and biologics. Recommendations on the clinical management of microscopic colitis are provided based on evidence, expert opinion and best clinical practice.Conclusion: These guidelines may support clinicians worldwide to improve the clinical management of patients with microscopic colitis.
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| 3. |
- Olsen, Laerke Müller, et al.
(författare)
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Histological disease activity in patients with microscopic colitis is not related to clinical disease activity or long-term prognosis
- 2021
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Ingår i: Alimentary Pharmacology and Therapeutics. - Chichester, United Kingdom : Wiley-Blackwell. - 0269-2813 .- 1365-2036. ; 54:1, s. 43-52
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Tidskriftsartikel (refereegranskat)abstract
- Background Microscopic colitis (MC) is a common cause of chronic watery diarrhea. Biopsies with characteristic histological features are crucial for establishing the diagnosis. The two main subtypes are collagenous colitis (CC) and lymphocytic colitis (LC) but incomplete forms exist. The disease course remains unpredictable varying from spontaneous remission to a relapsing course.Aim To identify possible histological predictors of course of disease.Methods Sixty patients from the European prospective MC registry (PRO-MC Collaboration) were included. Digitised histological slides stained with CD3 and Van Gieson were available for all patients. Total cell density and proportion of CD3 positive lymphocytes in lamina propria and surface epithelium were estimated by automated image analysis, and measurement of the subepithelial collagenous band was performed. Histopathological features were correlated to the number of daily stools and daily watery stools at time of endoscopy and at baseline as well as the clinical disease course (quiescent, achieved remission after treatment, relapsing or chronic active) at 1-year follow-up.Results Neither total cell density in lamina propria, proportion of CD3 positive lymphocytes in lamina propria or surface epithelium, or thickness of collagenous band showed significant correlation to the number of daily stools or daily watery stools at any point of time. None of the assessed histological parameters at initial diagnosis were able to predict clinical disease course at 1-year follow-up.Conclusions Our data indicate that the evaluated histological parameters were neither markers of disease activity at the time of diagnosis nor predictors of disease course.
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| 4. |
- Amcoff, Karin, 1975-, et al.
(författare)
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Concordance in Anti-OmpC and Anti-I2 Indicate the Influence of Genetic Predisposition : Results of a European Study of Twins with Crohn's Disease
- 2016
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Ingår i: Journal of Crohn's & Colitis. - Oxford, United Kingdom : Oxford University Press. - 1873-9946 .- 1876-4479. ; 10:6, s. 695-702
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: An adaptive immunological response to microbial antigens has been observed in Crohn's disease (CD). Intriguingly, this serological response precedes the diagnosis in some patients and has also been observed in healthy relatives. We aimed to determine whether genetic factors are implicated in this response in a CD twin cohort.Methods: In total, 82 twin pairs (Leuven n = 13, Maastricht n = 8, Örebro n = 61) took part: 81 pairs with CD (concordant monozygotic n = 16, discordant monozygotic n = 22, concordant dizygotic n = 3, discordant dizygotic n = 40) and 1 monozygotic pair with both CD and ulcerative colitis. Serology for Pseudomonas fluorescens-related protein (anti-I2), Escherichia coli outer membrane porin C (anti-OmpC), CBir1flagellin (anti-CBir1) and antibodies to oligomannan (anti-Saccharomyces cerevisiae antibody [ASCA]) was determined by standardized enzyme-linked immunoassay.Results: All markers were more often present in CD twins than in their healthy twin siblings. Using the intraclass correlation coefficient (ICC), agreements in concentrations of anti-OmpC and anti-I2 were observed in discordant monozygotic but not in discordant dizygotic twin pairs with CD (anti-OmpC, ICC 0.80 and -0.02, respectively) and (anti-I2, ICC 0.56 and 0.05, respectively). In contrast, no agreements were found in anti-CBir, immunoglobulin (Ig) G ASCA and ASCA IgA.Conclusions: We show that anti-I2 and anti-CBir1 statuses have specificity for CD and confirm previous reported specificities for anti-OmpC and ASCA. Based on quantitative analyses and observed ICCs, genetics seems to predispose to the anti-OmpC and anti-I2 response but less to ASCA and anti-CBir1 responses.
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| 5. |
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| 6. |
- Bohr, Johan
(författare)
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Collagenous colitis : A study of epidemiology, etiology, clinical features and treatment
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Collagenous colitis (CC) is characterised clinically by chronic watery diarrhoea and histopathologically by an increased submucosal collagen layer. An epidemiologic study of CC during 1984 to 1993 showed a female:male ratio of 9:1. The median age at diagnosis was 64 (28-78) years. The prevalence was 15.7/105 on December 31, 1993, and the mean annual incidence was 1.8/1()5 inhabitants. Age specific incidence showed a peak of 14.6/105 in females 70-79 years old, which approaches the incidence for ulcerative colitis in the same age group. Faecal stream diversion in 9 patients with severe, medically intractable CC induced histologic and clinical remission. This observation indicates that a noxious agent in the faecal stream constitutes an etiologic factor in CC. Faecal stream diversimi offers a treatment alternative in patients with severe CC who do not respond to medical treatment. Sera from 38 patients with CC and matched controls were analysed for specific autoantibodies, immunoglobulins and complement. The mean value of I gM was significantly increased in patients; 2.5 g!L compared to 1.4 gn ... in controls (p=0.002). ANA and pANCA occurred more frequently in patients, although the difference did not reach statistical significance. The result.;; of all other immunoglobulins, complement factors, and specific antiboctles were similar in patients and controls. The findingsof an increased IgM level in patients, might give some support to a hypothesis of autoimmunity in CC. The ANA- and pANCA positive patients could constitute a subpopulation among CC patients. Procollagen III propeptide (P-III-NP) is a product of collagen Ill metabolism. No significant difference between the serum level of P-III-NP in 38 patients (3.8±2.0 P-g!L) and 38 matched controls (3.7±1.3 ~g!L) was found, and P-III-NP did not correlate to clinical activity. There was a significant correlation, however, between P-III-NP and age in both patients and controls. The study showed that colonoscopy is still required to diagnose CC and cam~-9t be replaced, at present, by a simple blood test. A register of patients with CC was set up at the Örebro Medical Center Hospital. Twenty five Swedish hospitals contributed with patient records to this register which comprised of data from 163 patients. Data showed that CC usually followed a chronic intermittent benign course. The onset was sudden in up to 42% of the patients. The most common symptoms were chronic watery diarrhoea, sometimes nocturnal, abdominal pain and weight loss. Routine laboratory data were most often normaL Evaluation of the treatment showed a response rate of 59% for sulphasalazine, and 40% respectively SO% for olsalazine and mesalazine. Prednisolone was effective in about 80% of the patients, but the required dosage was often high, and the effect not sustained after withdrawal. Metronidazole, erythromycin and penicillin had response rates from 55% to 100%. Cholestyramine and loperamide offer treatmentalternatives of which about two thirds of the patients benefit.
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| 7. |
- Bohr, Johan, 1957-, et al.
(författare)
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Diagnosis and management of microscopic colitis : Current perspectives
- 2014
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Ingår i: Clinical and Experimental Gastroenterology. - Macclesfield, United Kingdom : Dove Medical Press Ltd.(Dovepress). - 1178-7023. ; 7, s. 273-284
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Forskningsöversikt (refereegranskat)abstract
- Collagenous colitis and lymphocytic colitis, together constituting microscopic colitis, are common causes of chronic diarrhea. They are characterized clinically by chronic nonbloody diarrhea and a macroscopically normal colonic mucosa where characteristic histopathological findings are seen. Previously considered rare, they now have emerged as common disorders that need to be considered in the investigation of the patient with chronic diarrhea. The annual incidence of each disorder is five to ten per 100,000 inhabitants, with a peak incidence in 60- to 70-year-old individuals and a predominance of female patients in collagenous colitis. The etiology and pathophysiology are not well understood, and the current view suggests an uncontrolled mucosal immune reaction to various luminal agents in predisposed individuals. Clinical symptoms comprise chronic diarrhea, abdominal pain, fatigue, weight loss, and fecal incontinence that may impair the patient's health-related quality of life. An association is reported with other autoimmune disorders, such as celiac disease, thyroid disorders, diabetes mellitus, and arthritis. The best-documented treatment, both short-term and long-term, is budesonide, which induces clinical remission in up to 80% of patients after 8 weeks' treatment. However, after successful budesonide therapy is ended, recurrence of clinical symptoms is common, and the best possible long-term management deserves further study. The long-term prognosis is good, and the risk of complications, including colonic cancer, is low. We present an update of the epidemiology, pathogenesis, diagnosis, and management of microscopic colitis.
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| 8. |
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| 9. |
- Bohr, Johan
(författare)
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Mikroskopisk kolit
- 2008. - 1
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Ingår i: Medicinska mag- och tarmsjukdomar. - Lund : Studentlitteratur. - 9789144017112 ; , s. 351-357
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 10. |
- Bohr, Johan, et al.
(författare)
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Mikroskopisk kolit hos äkta makar
- 2008
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Ingår i: Gastrokuriren. ; 13:30, s. PO-09
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 11. |
- Borro, Bruno C., et al.
(författare)
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Microfluidics-based self-assembly of peptide-loaded microgels : Effect of three dimensional (3D) printed micromixer design
- 2019
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Ingår i: Journal of Colloid and Interface Science. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0021-9797 .- 1095-7103. ; 538, s. 559-568
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Tidskriftsartikel (refereegranskat)abstract
- In an effort to contribute to research in scalable production systems for polymeric delivery systems loaded with antimicrobial peptides (AMPS), we here investigate effects of hydrodynamic flow conditions on microfluidic particle generation. For this purpose, rapid prototyping using 3D printing was applied to prepare micromixers with three different geometric designs, which were used to prepare Ca2+-crosslinked alginate microgels loaded with the AMP polymyxin B in a continuous process. Based on fluid dynamic simulations, the hydrodynamic flow patterns in the micromixers were designed to be either (i) turbulent with chaotic disruption, (ii) laminar with convective mixing, or (iii) convective with microvortex formation. The physicochemical properties of the microgels prepared with these micromixers were characterized by photon correlation spectroscopy, laser-Doppler micro-electrophoresis, smallangle x-ray scattering, and ellipsometry. The particle size and compactness were found to depend on the micromixer geometry: From such studies, particle size and compactness were found to depend on micromixer geometry, the smallest and most compact particles were obtained by preparation involving microvortex flows, while larger and more diffuse microgels were formed upon laminar mixing. Polymyxin B was found to be localized in the particle interior and to cause particle growth with increasing peptide loading. Ca2+-induced cross-linking of alginate, in turn, results in particle contraction. The peptide encapsulation efficiency was found to be higher than 80% for all investigated micromixer designs; the highest encapsulation efficiency observed for the smallest particles generated by microvortexmediated self-assembly. Ellipsometry results for surface-immobilized microgels, as well as results on peptide encapsulation, demonstrated electrolyte-induced peptide release. Taken together, these findings demonstrate that rapid prototyping of microfluidics using 3D-printed micromixers offers promises for continuous manufacturing of AMP-loaded microgels. Although the micromixer combining turbulent flow and microvortexes was demonstrated to be the most efficient, all three micromixer designs were found to mediate self-assembly of small microgels displaying efficient peptide encapsulation. This demonstrates the robustness of employing 3D-printed micromixers for microfluidic assembly of AMP-loaded microgels during continuous production.
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| 12. |
- Colombo, Stefano, et al.
(författare)
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Transforming nanomedicine manufacturing toward Quality by Design and microfluidics
- 2018
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Ingår i: Advanced Drug Delivery Reviews. - : Elsevier. - 0169-409X .- 1872-8294. ; 128, s. 115-131
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Forskningsöversikt (refereegranskat)abstract
- Nanopharmaceuticals aim at translating the unique features of nano-scale materials into therapeutic products and consequently their development relies critically on the progression in manufacturing technology to allow scalable processes complying with process economy and quality assurance. The relatively high failure rate in translational nanopharmaceutical research and development, with respect to new products on the market, is at least partly due to immature bottom-up manufacturing development and resulting sub-optimal control of quality attributes in nanopharmaceuticals. Recently, quality-oriented manufacturing of pharmaceuticals has undergone an unprecedented change toward process and product development interaction. In this context, Quality by Design (QbD) aims to integrate product and process development resulting in an increased number of product applications to regulatory agencies and stronger proprietary defense strategies of process-based products. Although QbD can be applied to essentially any production approach, microfluidic production offers particular opportunities for QbD-based manufacturing of nanopharmaceuticals. Microfluidics provides unique design flexibility, process control and parameter predictability, and also offers ample opportunities for modular production setups, allowing process feedback for continuously operating production and process control. The present review aims at outlining emerging opportunities in the synergistic implementation of QbD strategies and microfluidic production in contemporary development and manufacturing of nanopharmaceuticals. In doi ng so, aspects of design and development, but also technology management, are reviewed, as is the strategic role of these tools for aligning nanopharmaceutical innovation, development, and advanced industrialization in the broader pharmaceutical field. (C) 2018 Elsevier B.V. All rights reserved.
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| 13. |
- Edling, Lars, et al.
(författare)
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Celiac disease and giardiasis : a case report
- 2012
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Ingår i: European Journal of Gastroenterology and Hepathology. - : Lippincott Williams & Wilkins. - 0954-691X .- 1473-5687. ; 24:8, s. 984-987
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Tidskriftsartikel (refereegranskat)abstract
- When investigating a patient with suspected celiac disease (CD), several other conditions must be considered, including potential infection with Giardia lamblia. Although giardiasis is rare, its histopathological and serological picture may resemble that of CD. We report the case of a young man with diabetes mellitus and a family history of CD referred to our hospital because of diarrhoea and weight loss. Investigation showed, among other factors, partial villous atrophy in duodenal biopsies and elevated immunoglobulin A antitissue transglutaminase antibodies. The patient was diagnosed with CD and recommended a gluten-free diet. At the same time, faecal tests were conducted, indicating the presence of G. lamblia. The patient was treated and improved, even after discontinuing the gluten-free diet. Subsequent follow-up after 6 months showed total regression of mucosal histopathology and a normal antitissue transglutaminase antibodies level. Eur J Gastroenterol Hepatol 24:984-987 (c) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
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| 14. |
- Fransén, Karin, 1973-, et al.
(författare)
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Polymorphism in the retinoic acid metabolizing enzyme CYP26B1 and the development of Crohn's disease
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:8, s. e72739-
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Tidskriftsartikel (refereegranskat)abstract
- Several studies suggest that Vitamin A may be involved in the pathogenesis of inflammatory bowel disease (IBD), but the mechanism is still unknown. Cytochrome P450 26 B1 (CYP26B1) is involved in the degradation of retinoic acid and the polymorphism rs2241057 has an elevated catabolic function of retinoic acid, why we hypothesized that the rs2241057 polymorphism may affect the risk of Crohn's disease (CD) and Ulcerative Colitis (UC). DNA from 1378 IBD patients, divided into 871 patients with CD and 507 with UC, and 1205 healthy controls collected at Örebro University Hospital and Karolinska University Hospital were analyzed for the CYP26B1 rs2241057 polymorphism with TaqMan® SNP Genotyping Assay followed by allelic discrimination analysis. A higher frequency of patients homozygous for the major (T) allele was associated with CD but not UC compared to the frequency found in healthy controls. A significant association between the major allele and non-stricturing, non-penetrating phenotype was evident for CD. However, the observed associations reached borderline significance only, after correcting for multiple testing. We suggest that homozygous carriers of the major (T) allele, relative to homozygous carriers of the minor (C) allele, of the CYP26B1 polymorphism rs2241057 may have an increased risk for the development of CD, which possibly may be due to elevated levels of retinoic acid. Our data may support the role of Vitamin A in the pathophysiology of CD, but the exact mechanisms remain to be elucidated.
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| 15. |
- Gunaltay, Sezin, 1986-, et al.
(författare)
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Clinical and immunologic effects of faecal microbiota transplantation in a patient with collagenous colitis
- 2017
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Ingår i: World Journal of Gastroenterology. - : Baishideng Publishing Group Co. - 1007-9327 .- 2219-2840. ; 23:7, s. 1319-1324
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Tidskriftsartikel (refereegranskat)abstract
- One to six percent of patients with microscopic colitis are refractory to medical treatment. The effect of faecal microbiota transplantation (FMT) in active collagenous colitis (CC) has, to the best of our knowledge, never been reported before. Here, we report the effect of repeated FMT in a patient with CC. The patient presented with severe symptoms including profuse diarrhea and profound weight loss. Although she responded to budesonide in the beginning, she became gradually refractory to medical treatment, and was therefore treated with FMT. The patient remained in remission for 11 mo after the third faecal transplantation. The immunomodulatory effect of the therapy was evaluated using flow cytometry, which showed alterations in the profile of intraepithelial and lamina propria lymphocyte subsets after the second transplantation. Our observations indicate that FMT can have an effect in CC, which support the hypothesis that luminal factors, influencing the intestinal microbiota, are involved in the pathogenesis of CC.
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| 16. |
- Günaltay, Sezin, 1986-, et al.
(författare)
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Differential expression of interleukin-1/Toll-like receptor signaling regulators in microscopic and ulcerative colitis
- 2014
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Ingår i: World Journal of Gastroenterology. - : WJG Press. - 1007-9327 .- 2219-2840. ; 20:34, s. 12249-12259
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To investigate Toll-like receptor (TLR) signaling regulators in microscopic and ulcerative colitis patients.METHODS: Total RNA and microRNA were isolated from fresh frozen colonic biopsies of non-inflamed controls and patients with active or in-remission collagenous colitis (CC), lymphocytic colitis (LC), or ulcerative colitis (UC). We compared expressions of interleukin-1 receptor-associated kinase (IRAK)-2, IRAK-M, interleukin (IL)-37, microRNA (miR)-146a, miR-155, and miR-21 using quantitative real time reverse transcription polymerase chain reaction.RESULTS: IRAK-M expression was increased in LC patients with active disease in histopathological remission (LC-HR; P = 0.02) and UC patients (P = 0.01), but no differences in IRAK-2 expression were detected compared to controls. miR-146a, -155 and -21 expressions were increased in LC-HR (P = 0.04, 0.07, and 0.004) and UC (P = 0.02, 0.04 and 0.03) patients. miR-146a and miR-21 expressions were significantly enhanced in UC patients compared to UC remission (UC-R; P = 0.01 and 0.04). Likewise, active CC patients showed significantly increased expression of miR-155 (P = 0.003) and miR-21 (P = 0.006). IL-37 expression was decreased in both CC (P = 0.03) and LC (P = 0.04) patients with a similar trend in UC patients but not statistically significant, whilst it was increased in UC-R patients compared to controls (P = 0.02) and active UC (P = 0.001).CONCLUSION: The identification of differentially expressed miRNAs, IL-37, and IRAK-M suggests different pathophysiologic mechanisms in various disease stages in LC, CC, and UC. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.
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| 17. |
- Gunaltay, Sezin, 1986-, et al.
(författare)
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Enhanced levels of chemokines and their receptors in the colon of microscopic colitis patients indicate mixed immune cell recruitment
- 2015
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Ingår i: Mediators of Inflammation. - : Hindawi Limited. - 0962-9351 .- 1466-1861.
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Tidskriftsartikel (refereegranskat)abstract
- Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC), is a common cause of chronic diarrhea. Various immune cell infiltrations in the epithelium and lamina propria are seen in MC immunopathology. We compared gene and protein expressions of different immune cell attracting chemokines and their receptors in colon biopsies from MC patients in active disease or histopathological remission (CC/LC-HR) with controls, using qRT-PCR and Luminex, respectively. CC and LC patients with active disease demonstrated a mixed chemokine profile with significantly enhanced gene and/or protein expressions of the chemokines CCL2, CCL3, CCL4, CCL5, CCL7, CCL22, CXCL8, CXCL9, CXCL10, CXCL11, and CX(3)CL1 and the receptors CCR2, CCR3, CCR4, CXCR1, CXCR2, and CX(3)CR1. Enhanced chemokine/chemokine receptor gene and protein levels in LC-HR patients were similar to LC patients, whereas CC-HR patients demonstrated almost normalized levels. These findings expand the current understanding of the involvement of various immune cells in MC immunopathology and endorse chemokines as potential diagnostic markers as well as therapeutic candidates. Moreover, this study further supports the hypothesis that CC and LC are two different entities due to differences in their immunoregulatory responses.
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| 18. |
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| 19. |
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| 20. |
- Gunaltay, Sezin, 1986-, et al.
(författare)
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Oligoclonal T-cell Receptor Repertoire in Colonic Biopsies of Patients with Microscopic Colitis and Ulcerative Colitis
- 2017
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Ingår i: Inflammatory Bowel Diseases. - : Lippincott Williams & Wilkins. - 1078-0998 .- 1536-4844. ; 23:6, s. 932-945
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Tidskriftsartikel (refereegranskat)abstract
- Background: Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC), is a type of variation of inflammatory bowel diseases. Local T-cell infiltration in the mucosa plays a major role in MC immunopathology.Methods: To understand diversity and clonality of infiltrating T cells, we analyzed the T-cell receptor beta (TCR beta) chains in colonic biopsies of MC, ulcerative colitis (UC), and their remission counterparts (CC/LC-HR [histological remission] or UC-R [remission]) compared with patients with non-inflamed colons using next-generation sequencing.Results: Compared with controls and patients with CC, patients with LC had significantly lower diversity with significantly lower evenness and richness in TCRVb-Jb gene segments. Similarly, patients with LC-HR had lower diversity because of significantly lower TCRVb-Jb clone richness. Patients with UC and UC-R showed significantly higher diversity and richness. Univariate and multivariate analyses were performed to identify TCRVb-Jb gene segments differentiating disease types from controls or their remission counterparts. Patients with LC were discriminated from controls by 12 clones and from patients with CC by 8 clones. Neither univariate nor multivariate analyses showed significance for patients with CC or CC-HR compared with controls. Patients with UC and UC-R had 16 and 14 discriminating clones, respectively, compared with controls.Conclusions: Altogether, patients with MC and UC showed an oligoclonal TCRb distribution. TCRVb-Jb clone types and their diversity were distinctive between patients with CC and LC, as well as for patients with UC, suggesting different pathophysiological mechanisms according to disease type and stage. This study suggests that CC and LC are different entities because of differences in immunoregulatory responses, as mirrored by their T-cell repertoire.
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| 21. |
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| 22. |
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| 23. |
- Göranzon, C., et al.
(författare)
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Immunohistochemical characterization of lymphocytes in microscopic colitis
- 2013
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Ingår i: Journal of Crohn's and Colitis. - : Elsevier. - 1197-4982 .- 1873-9946. ; 7:10, s. e434-e442
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Microscopic colitis (MC), encompassing the subgroups collagenous colitis (CC) and lymphocytic colitis (LC), is characterized by macroscopically normal or near-normal colonic mucosa, and an increased number of intraepithelial lymphocytes (IELs) and mononuclear cell infiltration in the underlying lamina propria (LP), in addition to an increased collagen layer in CC. This study aimed to characterize the inflammatory cells involved in mucosal inflammation, using immunohistochemistry.Methods Paraffin-embedded biopsies from 23 untreated patients with MC (CC = 13, LC = 10) and 17 controls were stained with antibodies against CD3, CD4, CD8, CD20, CD30, Foxp3, CD45RO and Ki67. Computerized image analysis was used to calculate areas of stained lymphocytes in the surface and crypt epithelia as well as in the LP.Results In CC and LC, an increase of predominantly CD8+ lymphocytes was seen in both the epithelium and the lamina propria, whereas a decreased amount of CD4+ lymphocytes was found in the lamina propria. CD45RO+ and Foxp3+ cells were more abundant in all areas in both patient groups compared to controls, as were CD20+ areas, although more scarce. Ki67+ areas were only more abundant in the epithelium, whereas CD30+ areas were more abundant in the lamina propria of both patient groups compared to controls.Conclusions This study confirms an increased amount of CD8+ lymphocytes in the epithelium. Lymphocytic proliferation and activation markers were more abundant, whereas a decreased amount of CD4+ lymphocytes was seen in the LP. Further studies are needed to reveal the underlying mechanism(s).
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| 24. |
- Hjortswang, Henrik, et al.
(författare)
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Defining Clinical Criteria for Clinical Remission and Disease Activity in Collagenous Colitis
- 2009
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Ingår i: Inflammatory Bowel Diseases. - : Oxford University Press (OUP). - 1536-4844 .- 1078-0998. ; 15:12, s. 1875-1881
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Tidskriftsartikel (refereegranskat)abstract
- Background: Collagenous colitis is a chronic inflammatory bowel disease accompanied mainly by nonbloody diarrhea. The objectives of treatment are to alleviate the symptoms and minimize the deleterious effects on health-related quality of life (HRQOL). There is still no generally accepted clinical definition of remission or relapse. The purpose of this study was to analyze the impact of bowel symptoms on HRQOL and accordingly suggest criteria for remission and disease activity based on impact of patient symptoms on HRQOL. Methods: The design was a cross-sectional postal survey of 116 patients with collagenous colitis. The main outcome measures were 4 HRQOL questionnaires: the Short Health Scale, the Inflammatory Bowel Disease Questionnaire, the Rating Form of IBD Patient Concerns, and the Psychological General Well-Being Index, and a 1-week symptom diary recording number of stools/day and number of watery stools/day. Results: Severity of bowel symptoms had a deleterious impact on patients' HRQOL. Patients with a mean of >= 3 stools/day or a mean of >= 1 watery stool/day had a significantly impaired HRQOL compared to those with <3 stools/day and < 1 watery stool/day. Conclusions: We propose that clinical remission in collagenous colitis is defined as a mean of <3 stools/day and a mean of < 1 watery stool per clay and disease activity to be a daily mean of >= 3 stools or a mean of >= 1 watery stool.
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| 25. |
- Hjortswang, Henrik, et al.
(författare)
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Health-related quality of life is impaired in active collagenous colitis
- 2011
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Ingår i: Digestive and Liver Disease. - : Elsevier BV. - 1590-8658 .- 1878-3562. ; 43:2, s. 102-109
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The characteristic clinical symptoms of collagenous colitis are non-bloody diarrhoea, urgency and abdominal pain. Treatment is aimed at reducing the symptom burden and the disease impact on patients' health-related quality of life. The objective of this study was to analyse health-related quality of life in patients with collagenous colitis. Methods: In a cross-sectional, postal HRQL survey, 116 patients with collagenous colitis at four Swedish hospitals completed four health-related quality of life questionnaires, two disease-specific (Inflammatory Bowel Disease Questionnaire and Rating Form of IBD Patient Concerns), and two generic (Short Form 36, SF-36, and Psychological General Well-Being, PGWB), and a one-week symptom diary. Demographic and disease-related data were collected. Results for the collagenous colitis population were compared with a background population controlled for age and gender (n = 8931). Results: Compared with a Swedish background population, patients with collagenous colitis scored significantly worse in all Short Form 36 dimensions (p < 0.01), except physical function. Patients with active disease scored worse health-related quality of life than patients in remission. Co-existing disease had an impact on health-related quality of life measured with the generic measures. Lower education level and shorter disease duration were associated with decreased well-being. Conclusion: Health-related quality of life was impaired in patients with collagenous colitis compared with a background population. Disease activity is the most important factor associated with impairment of health-related quality of life. Patients in remission have a health-related quality of life similar to a background population. (C) 2010 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
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| 26. |
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| 27. |
- Holster, Savanne, et al.
(författare)
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Faecal microbiota transfer in patients with microscopic colitis : a pilot study in collagenous colitis
- 2020
-
Ingår i: Scandinavian Journal of Gastroenterology. - : Taylor & Francis. - 0036-5521 .- 1502-7708. ; 55:12, s. 1454-1466
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Faecal microbiota transfer (FMT) consists of the infusion of donor faecal material into the intestine of patients with the aim to restore a disturbed gut microbiota. Methods: In this pilot study (NCT03275467), the effect of three repeated FMTs (day 0, two weeks, four weeks) was studied and followed up for six months in nine collagenous colitis (CC) patients, using two stool donors. Results: Five patients had an active disease at the time of baseline sampling. The primary endpoint (remission at six weeks, defined as <3 stools whereof <1 watery stool per day) was achieved by two of these patients, and by one at eight weeks. Overall, in all nine patients, FMT did not result in a significant reduction of watery stools, assessed by daily diary. However, diarrhoea (assessed by gastrointestinal symptom rating scale) was significantly improved at four (p = .038) and eight weeks (p = .038), indigestion at eight (p = .045) and 12 weeks (p = .006), disease-related worries at four (p = .027) and eight weeks (p = .027), and quality of life at six months (p = .009). FMT resulted in an increased number of lamina propria lymphocytes, possibly indicating an initial mucosal immune activation. No serious adverse events, no systemic effects, and no changes in faecal calprotectin and psychological symptoms were observed. Conclusions: FMT is able to improve symptoms in a yet undefined subset of CC patients. Further studies could help to characterise this subset and to understand if these results can be generalised to all microscopic colitis patients.
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| 28. |
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| 29. |
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| 30. |
- Kumawat, Ashok Kumar, 1982-
(författare)
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Adaptive immune response in the intestinal mucosa of microscopic colitis patients
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Microscopic colitis (MC) is a chronic diarrhoeal disease of unknown aetiology, comprising collagenous colitis (CC) and lymphocytic colitis (LC). The nature of the adaptive local immune responses in the mucosa of MC patients is however far from elucidated. The present study investigates phenotypic and functional characteristics of the adaptive local immune responses in the colonic mucosa of these patients.Our immunohistochemistry and flow cytometry studies (Paper I & II) demonstrated increased frequencies of CD8+ T cells in the colonic epithelium and lamina propria of both LC and CC patients compared to controls, whereas the frequencies of CD4+ T cells were unaltered or reduced. Our flow cytometry data revealed increased local activation of both CD4+ and CD8+ T cells in the lamina propria as well as the intraepithelial compartment of CC and LC patients compared to controls, demonstrated as increased proportions of these cells expressing the active/memory marker CD45RO and the proliferation marker Ki67.Analysis of recent thymic emigrants by measuring T cell receptor excision circle (TREC) levels in the colonic mucosa of CC and LC patients revealed reduced TRECs levels in these patients compared to controls (Paper III). These results suggests that the observed increased numbers of T cells in the mucosa of CC and LC patients is due to the expansion of local resident T cells rather than direct recruitment of recent thymic emigrants to the mucosa.Molecular analysis of T helper (Th) cell and cytotoxic T lymphocyte (Tc) mucosal cytokines at messenger and protein levels in the colonic biopsies from CC and LC patients demonstrated a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile and revealed significant differences in the mucosal cytokine levels in CC and LC patients compared to controls (Paper IV).Finally, we have set up an in vitro model to investigate how the colonic milieu affects the activation and differentiation of T lymphocytes (Paper V). Our preliminary data indicate increased production of both pro inflammatory and antiinflammatory cytokines by peripheral blood T cells in the presence of soluble factors from the inflamed colonic mucosa of CC patients compared to controls.
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| 31. |
- Kumawat, Ashok Kumar, et al.
(författare)
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An in vitro model for analysis of the impact of the colonic milieu in collagenous colitis patients on peripheral T lymphocyte activation and differentiation
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Soluble factors released by intestinal mucosal cells contribute to immune homeostasis in the gut. This is the first study to investigate the role of soluble factors from the intestinal mucosa of collagenous colitis (CC) patients in the regulation of effector T cells using a novel system that mimics the in vivo exposure of newly recruited peripheral blood T cells to soluble factors derived from the colonic milieu of normal individuals and inflamed CC patient mucosa.Methods: Denuded biopsies (DNB) and isolated lamina propria mononuclear cells (LPMCs) from mucosal biopsies from CC patients and non-inflamed controls were cultured to collect conditioned medium (CM). Enriched peripheral blood CD4+ T cells from healthy donors were polyclonally activated in the absence or presence of CM from CC patients and controls. Proliferation, as well as secretion of IL-1β IL-4, IL-6, IL-10, IL-17A, IFN-γ and TNF-α was analysed the latter with Luminex® analysis.Results: Peripheral CD4+ T cells exposed to CM from the colonic mucosa demonstrated reduced proliferation. This inhibition was less pronounced with DNB-CM derived from CC patients compared to non-inflamed control mucosa. In contrast, LPMC-CM from non-inflamed controls inhibited T-cell proliferation less than LPMC-CM from CC patients. Both DNB-CM and LPMC-CM from CC patients induced more or less increased production of the proinflammatory cytokines IFN-γ, IL-17A, IL-6 and TNF-α as well as the anti-inflammatory cytokines IL-4 and IL-10 from peripheral CD4+ T cells compared to non-inflamed controls. In contrast, IL-1β production by peripheral T cells showed mixed results – it was either increased or reduced in the presence of both DNB and LPMC-CM from CC patients compared to noninflamed controls with different blood donors and different concentrations.Conclusion: Our preliminary data indicates reduced inhibition of proliferation of peripheral CD4+ T cells in the presence of mucosa-derived soluble factors from CC patients compared to controls. In addition, increased production of both inflammatory and anti-inflammatory cytokines by peripheral CD4+ T cells was recorded in the presence of soluble factors from the colonic mucosa of CC patients compared to controls. This model can be valuable in evaluating the effect(s) of existing and new drugs on T cell differentiation in the intestinal mucosa.
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| 32. |
- Kumawat, Ashok Kumar, 1982-, et al.
(författare)
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An In Vitro Model to Evaluate the Impact of the Soluble Factors from the Colonic Mucosa of Collagenous Colitis Patients on T Cells : Enhanced Production of IL-17A and IL-10 from Peripheral CD4(+) T Cells
- 2014
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Ingår i: Mediators of Inflammation. - New York, USA : Hindawi Publishing Corporation. - 0962-9351 .- 1466-1861.
-
Tidskriftsartikel (refereegranskat)abstract
- Soluble factors from intestinal mucosal cells contribute to immune homeostasis in the gut. We have established an in vitro model to investigate the regulatory role of soluble factors from inflamed intestinal mucosa of collagenous colitis (CC) patients in the differentiation of T cells. Peripheral blood CD4(+) T cells from healthy donors were polyclonally activated in the presence of conditioned medium (CM) generated from denuded biopsies (DNB) or isolated lamina propria mononuclear cells (LPMCs) from mucosal biopsies from CC patients compared to noninflamed controls, to determine proliferation and secretion of cytokines involved in T-cell differentiation. Compared to controls, we observed significantly increased production of the proinflammatory cytokines IFN-gamma, IL-17A, IL-6, and IL-1 beta and the anti-inflammatory cytokines IL-4 and IL-10 in the presence of CC-DNB-CM. The most pronounced effect of CC-LPMC-CM on peripheral CD4(+) T cells was a trend towards increased production of IL-17A and IL-10. A trend towards reduced inhibition of T-cell proliferation was noted in the presence of CC-DNB-CM. In conclusion, our in vitro model reveals implications of soluble factors from CC colonic mucosa on peripheral T cells, enhancing their production of both pro-and anti-inflammatory cytokines.
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| 33. |
- Kumawat, Ashok Kumar, 1982-, et al.
(författare)
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Microscopic colitis patients demonstrate a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile
- 2013
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Ingår i: Molecular Immunology. - : Elsevier BV. - 0161-5890 .- 1872-9142. ; 55:3-4, s. 355-364
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Tidskriftsartikel (refereegranskat)abstract
- Background:Microscopic colitis (MC) is a chronic inflammatory bowel disorder of unknown aetiology comprising collagenous colitis (CC) and lymphocytic colitis (LC). Data on the local cytokine profile in MC is limited. This study investigated the T helper (Th) cell and cytotoxic T lymphocyte (CTL) mucosal cytokine profile at messenger and protein levels in MC patients.Methods:Mucosal biopsies from CC (n = 10), LC (n = 5), and CC or LC patients in histopathological remission (CC-HR, n = 4), (LC-HR, n = 6), ulcerative colitis (UC, n = 3) and controls (n = 10) were analysed by real-time PCR and Luminex for expression/production of IL-1 beta, -4, -5, -6, -10, -12, -17, -21, -22, -23, IFN-gamma, TNF-alpha, T-bet and RORC2.Results:Mucosal mRNA but not protein levels of IFN-gamma and IL-12 were significantly up regulated in CC, LC as well as UC patients compared to controls. Transcription of the Th1 transcription factor T-bet was significantly enhanced in CC but not LC patients. mRNA levels for IL-17A, IL-21, IL-22 and IL-6 were significantly up regulated in CC and LC patients compared to controls, albeit less than in UC patients. Significantly enhanced IL-21 protein levels were noted in both CC and LC patients. IL-6 protein and IL-1 beta mRNA levels were increased in CC and UC but not LC patients. Increased mucosal mRNA levels of IFN-gamma, IL-21 and IL-22 were correlated with higher clinical activity, recorded as the number of bowel movements per day, in MC patients.Although at lower magnitude, IL-23A mRNA was upregulated in CC and LC, whereas TNF-alpha protein was increased in CC, LC as well as in UC patients.Neither mRNA nor protein levels of IL-4, IL-5 or IL-10 were significantly changed in any of the colitis groups. LC-HR and especially CC-HR patients had normalized mRNA and protein levels of the above cytokines compared to LC and CC patients. No significant differences were found between LC and CC in cytokine expression/production.Conclusion:LC and CC patients demonstrate a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile.
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| 34. |
- Kumawat, Ashok Kumar, et al.
(författare)
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Microscopic colitis patients have increased frequencies of Ki67+proliferating and CD45RO+ active/memory CD8+ and CD4+8+ mucosal T cells
- 2013
-
Ingår i: Journal of Crohn's & Colitis. - Oxford, United Kingdom : Oxford University Press. - 1873-9946 .- 1876-4479. ; 7:9, s. 694-705
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Tidskriftsartikel (refereegranskat)abstract
- Background: Collagenous colitis (CC) and lymphocytic colitis (LC) are chronic inflammatory bowel disorders of unknown etiology. This study investigated phenotypic characteristics of the mucosal lymphocytes in CC and LC.Methods: Lamina propria and intraepithelial lymphocytes (LPLs, IELs) isolated from mucosal biopsies from CC (n = 7), LC (n = 6), as well as LC or CC patients in histopathological remission, (LC-HR) (n = 6) and CC-HR (n = 4) and non-inflamed controls (n = 10) were phenotypically characterized by four-color flow cytometry.Results: The proportions of CD8+ IELs were increased in CC and LC (p < 0.01) compared to controls. Increased proportions of CD45RO+CD8+ IELs and LPLs were observed in LC and even more in CC patients (p < 0.01). Both CC (p < 0.05) and LC patients had elevated proportions of CD4+8+ IELs and LPLs compared to controls. The proportions of CD45RO+ cells were increased in CD4+8+ IELs and LPLs (p < 0.05) in CC and LC patients compared to controls. Both CC (p < 0.05) and LC patients had higher proportions of Ki67+CD8+ IELs and LPLs compared to controls.In contrast, decreased proportions of CD4+ LPLs were observed in CC and LC as well as CD4+ IELs in LC compared to controls. Increased proportions of Ki67+CD4+ IELs and LPLs (p < 0.05) were observed in CC and LC patients. CC-HR but not LC-HR patients demonstrated normalized proportions of both IELs and LPLs compared to CC and LC patients respectively.Conclusion: LC and CC patients have differences in mucosal lymphocyte subsets, with increased proportions of Ki67+ and CD45RO+ CD8+ and CD4+8+ mucosal T cells.
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| 35. |
- Kumawat, Ashok Kumar, 1982-, et al.
(författare)
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Reduced T cell receptor excision circle levels in the colonic mucosa of microscopic colitis patients indicate local proliferation rather than homing of peripheral lymphocytes to the inflamed mucosa
- 2013
-
Ingår i: BioMed Research International. - New York, USA : Hindawi Publishing Corporation. - 2314-6133 .- 2314-6141.
-
Tidskriftsartikel (refereegranskat)abstract
- Dysregulated T cell responses in the intestine may lead to chronic bowel inflammation such as collagenous colitis (CC) and lymphocytic colitis (LC), together known as microscopic colitis (MC). Having demonstrated increased local T cell responses in the intestinal mucosa of MC patients, we investigated the recent thymic emigrants by measuring T cell receptor excision circle (TREC) levels in the colonic biopsies from CC (n = 8), LC (n = 5), and CC or LC patients in histopathological remission (CC-HR, n = 3) (LC-HR, n = 6), non-inflamed diarrhoea patients (n = 17), and controls (n = 10) by real-time PCR. We observed lower median TREC levels in both CC and LC patients as well as in LC-HR patients compared to controls. In contrast to MC patients, non-inflamed diarrhoea patients presented with enhanced TREC levels compared to controls. None of the recorded differences did, however, reach statistical significance. A trend towards increased relative expression of CD3 was noted in all MC subgroups examined and reached statistical significance in LC patients compared to controls. In conclusion, reduced TRECs level in the colonic mucosa, together with our previously demonstrated enhanced expression of Ki67(+) T cells, suggests local expansion of resident T lymphocytes in the inflamed mucosa of MC patients.
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| 36. |
- Kumawat, Ashok Kumar, et al.
(författare)
-
Reduced T cell receptor excision circle (TREC) levels in the colonic mucosa of microscopic colitis patients indicate local proliferation rather than homing of peripheral lymphocytes to the inflamed mucosa
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Aims: Dysregulated T cell responses in the intestine may lead to chronic bowel inflammation such as collagenous colitis (CC) and lymphocytic colitis (LC), together known as microscopic colitis (MC). Having demonstrated increased local T cell responses in the intestinal mucosa of MC patients, we investigated the recent thymic emigrants by measuring T cell receptor excision circle (TREC) levels in the colonic mucosa of CC and LC patients.Methods: Mucosal biopsies from CC (n=8), LC (n=5), and CC or LC patients in histopathological remission, (CC-HR, n=3), (LC-HR, n=6), non-inflamed diarrhoea patients (n=17) and controls (n=10) were analysed for TRECs expression by real time PCR.Results: The median TREC levels were lower in both CC and LC patients as well as in LCHR patients compared to controls. In contrast to MC patients, non-inflamed diarrhoea patients presented with enhanced TREC levels compared to controls. None of the recorded differences did however reach statistical significance. No differences were observed in median TREC levels in either CC-HR or LC-HR patients compared to active CC and LC patients. A trend towards increased relative expression of CD3 was noted in all MC subgroups examined; and reached statistical significance in LC patients compared to controls. LC patients had ignificantly increased CD3 mRNA levels also compared to CC, CC-HR, LC-HR and non-inflamed iarrhoea patients.Conclusions: Reduced TRECs level in the colonic mucosa, together with our previously demonstrated enhanced expression of Ki67+ T cells, suggest local expansion of resident T lymphocytes in the inflamed mucosa of MC patients.
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| 37. |
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| 38. |
- Larsson, Johanna K, et al.
(författare)
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Cancer Risk in Collagenous Colitis
- 2019
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Ingår i: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 8:11
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Tidskriftsartikel (refereegranskat)abstract
- Data on malignancy in patients with collagenous colitis (CC) is scarce. We aimed to determine the incidence of cancers in patients with CC. In a two-stages, observational study, data on cancers in patients diagnosed with CC during 2000-2015, were collected from two cohorts. The risk was calculated according to the age-standardized rate for the first cohort and according to the standardized incidence ratio for the second cohort. The first cohort comprised 738 patients (394 from Scotland and 344 from Sweden; mean age 71 +/- 11 and 66 +/- 13 years, respectively). The incidence rates for lung cancer (RR 3.9, p = 0.001), bladder cancer (RR 9.2, p = 0.019), and non-melanoma skin cancer (NMSC) (RR 15, p = 0.001) were increased. As the majority of NMSC cases (15/16) came from Sweden, a second Swedish cohort, comprising 1141 patients (863 women, mean age 65 years, range 20-95 years) was collected. There were 93 cancer cases (besides NMSC). The risk for colon cancer was decreased (SIR 0.23, p= 0.0087). The risk for cutaneous squamous cell carcinoma was instead markedly increased (SIR 3.27, p = 0.001).
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| 39. |
- Lushnikova, Alexandra, et al.
(författare)
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Altered levels of immune checkpoint molecules in colon biopsies and sera from microscopic colitis and ulcerative colitis patients compared to controls
- 2021
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Ingår i: Journal of Immunology. - : American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 206:Suppl.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Microscopic colitis (MC), comprising lymphocytic colitis (LC) and collagenous colitis (CC), is an inflammatory bowel disorder. MC patients have a lower risk of developing colorectal cancer (CRC) than ulcerative colitis (UC) patients. We hypothesize that the immune response in MC is geared more towards immune surveillance of tumor cells than that of UC, which instead contributes to inflammation-associated CRC.Methods: Using Luminex, protein levels of 14 immune checkpoints (TIM-3, CD28, CD137, CD27, CD152, HVEM, IDO, LAG-3, BTLA, GITR, CD80, PD-1, PD-L1, PD-L2) in protein lysates from colon biopsies (controls, n = 9; diarrhea controls, n = 7; LC, n = 14; CC, n = 15; UC, n = 17) were analyzed. Soluble checkpoints were analyzed in serum (23 controls, 17 LC, 36 CC and 2 UC).Results: In patients with active LC and CC, CD137, IDO, and CD80 levels were increased compared with one or both control groups. CD152 and PD-1 levels were increased in patients with active CC compared with both control groups. In patients with active UC, levels of CD137, CD152, BTLA, PD-1, and PD-L2 were increased compared with both control groups, IDO levels were increased compared with controls, and CD80 levels were raised compared with diarrhea controls.In sera, CD27, IDO, CD80, PD-1, and PD-L2 levels were decreased in LC patients compared to controls.Conclusions: Increased levels of immune checkpoint molecules in colon biopsies from UC and MC patients are likely a sign of inflammation and may indicate what kind of homeostatic feed-back mechanisms are active to balance inflammation. Lowered concentrations of soluble immune checkpoint molecules in sera from patients with LC indicate a different level of homeostatic balance systemically in LC patients versus controls.
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| 40. |
- Lushnikova, Alexandra, et al.
(författare)
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Patients With Microscopic Colitis Have Altered Levels of Inhibitory and Stimulatory Biomarkers in Colon Biopsies and Sera Compared to Non-inflamed Controls
- 2021
-
Ingår i: Frontiers in Medicine. - Lausanne, Switzerland : Frontiers Media S.A.. - 2296-858X. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Microscopic colitis (MC) is an inflammatory bowel condition with two subtypes, lymphocytic colitis (LC) and collagenous colitis (CC). Unlike patients with ulcerative colitis (UC) and non-inflamed individuals, MC patients have reduced risk of developing colorectal cancer, possibly due to increased immune surveillance in MC patients.Aim: To examine differences in levels of immunomodulatory molecules, including those involved in immune checkpoint mechanisms, in sera from patients with MC and in colonic biopsies from patients with MC and UC compared with controls.Methods: Using Luminex, 23 analytes (4-1BB, 4-1BBL, APRIL, BAFF, BTLA, CD27, CD28, CD80, CTLA-4, E-cadherin, Galectin-3, GITR, HVEM, IDO, IL-2Rα, LAG-3, MICA, MICB, PD-1, PD-L1, PD-L2, sCD40L and TIM-3) were studied in serum from patients with active MC (n = 35) and controls (n = 23), and in colonic biopsies from patients with active LC (n = 9), active CC (n = 16) and MC in histological remission (LC n = 6, CC n = 6), active UC (n = 15) and UC in remission (n = 12) and controls (n = 58).Results: In serum, IDO, PD-1, TIM-3, 4-1BB, CD27, and CD80 were decreased whereas 4-1BBL and IL-2Rα were increased in MC patients compared with controls. In contrast, in biopsies, levels of PD-L2 and 4-1BB were increased in MC and UC patients with active disease. Furthermore, in biopsies from CC and UC but not LC patients with active disease, CTLA-4, PD-1, APRIL, BAFF, and IL-2Rα were increased compared with controls. PD-L1 was increased in CC but not UC or LC patients. CD27 and TIM-3 were decreased in biopsies from MC patients in comparison to controls whereas levels of MICB were decreased in patients with active UC compared with controls.Conclusions: Compared with non-inflamed controls, levels of soluble and membrane-bound immunomodulatory molecules were systemically and locally altered in MC and UC patients, with most analytes being decreased in serum but enhanced in colonic biopsies. These findings contribute to knowledge about checkpoint molecules and their role as biomarkers in MC and may also contribute to knowledge about possible mechanisms behind the seemingly protective effects of MC against colorectal cancer.
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| 41. |
- Münch, Andreas, et al.
(författare)
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Budesonide as induction therapy for incomplete microscopic colitis : A randomised, placebo-controlled multicentre trial
- 2021
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Ingår i: United European Gastroenterology journal. - : Sage Publications. - 2050-6406 .- 2050-6414. ; 9:7, s. 837-847
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Incomplete microscopic colitis (MCi) is a subtype of microscopic colitis (MC). Budesonide is recommended as a first-line treatment for MC. However, randomised trials on efficacy of treatment in MCi are missing. We therefore performed a randomised, placebo-controlled trial to evaluate budesonide as induction therapy for MCi.Methods: Patients with active MCi were randomly assigned to either budesonide 9 mg once daily or placebo for 8 weeks in a double-blind, double-dummy design. The primary endpoint was clinical remission, defined as a mean of <3 stools/day and a mean of <1 watery stool/day in the 7 days before week 8.Results: Due to insufficient patient recruitment, the trial was discontinued prematurely. The intention-to-treat analysis included 44 patients (21 budesonide and 23 placebo). The primary endpoint of clinical remission at week 8 was obtained by 71.4% on budesonide and 43.5% on placebo (p = 0.0582). All clinical secondary endpoints were in favour of budesonide. Budesonide decreased the number of soft or watery stools (16.3 vs. 7.7, p = 0.0186) and improved health-related quality of life for all four dimensions of the short health scale. Adverse events with a suspected relation to study drug were reported in one patient in the budesonide group and two patients in the placebo group. Neither serious nor severe adverse events occurred during the double-blind phase.Conclusions: Budesonide decreased the frequency of soft or watery stools and improved the patients' quality of life significantly in MCi, but the primary endpoint was not met due to the low sample size (type 2 error). Budesonide was safe and well tolerated during the 8-weeks treatment course.
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| 42. |
- Munch, Andreas, et al.
(författare)
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Lack of effect of methotrexate in budesonide-refractory collagenous colitis
- 2013
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Ingår i: Clinical and Experimental Gastroenterology. - : Dove Medical Press. - 1178-7023. ; 6, s. 149-152
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:In most cases, collagenous colitis can be treated effectively with budesonide. However, some patients develop side effects or have chronic symptoms refractory to budesonide. This paper reports an open case series of patients intolerant or refractory to budesonide who were treated with methotrexate (MTX).METHODS AND PATIENTS:Nine patients (seven women) with a median (range) age of 62 (44-77) years were studied. Bowel movements were registered during 1 week prior to baseline and after 6 and 12 weeks' treatment, enabling calculation of the mean bowel movements/day. All patients underwent colonoscopy with biopsies before inclusion to confirm diagnosis. Open treatment with MTX was given 15 mg subcutaneously weekly for 6 weeks and was increased to 25 mg for a further 6 weeks if symptoms were unresponsive to the first 6 weeks' treatment. The endpoint was clinical remission, which was defined as a mean <3 stools/day and mean <1 watery stool/day/week at Week 12. The Short Health Scale was used at baseline and Week 12 to assess health-related quality of life.RESULTS:Five patients fulfilled the treatment according to the protocol and four patients discontinued the study after 3-6 weeks because of adverse events. No patient achieved clinical remission at Week 12. The mean stool frequency/day at baseline was 6.0 stools/day, thereof 5.4 watery stools/day and after 12 weeks treatment 6.4 stools/day, thereof 5.7 watery/day. No patient appreciated an improvement of health-related quality of life.CONCLUSION:Short-term treatment with MTX had no clinical effect in collagenous colitis patients intolerant or refractory to budesonide. Alternative therapies should be investigated in these patients.
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| 43. |
- Münch, Andreas, et al.
(författare)
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Low-dose budesonide for maintenance of clinical remission in collagenous colitis : a randomised, placebo-controlled, 12-month trial
- 2016
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Ingår i: Gut. - : BMJ Publishing Group. - 0017-5749 .- 1468-3288. ; 65:1, s. 47-56
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Tidskriftsartikel (refereegranskat)abstract
- 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 time to remission was 10.5 days (95% CI (9.0 to 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.
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| 44. |
- Münch, Andreas, et al.
(författare)
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Microscopic colitis : Current status, present and future challenges Statements of the European Microscopic Colitis Group
- 2012
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Ingår i: Journal of Crohn's & Colitis. - Amsterdam, Netherlands : Elsevier. - 1873-9946 .- 1876-4479. ; 6:9, s. 932-945
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 45. |
- Münch, Andreas, et al.
(författare)
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Smoking Status Influences Clinical Outcome in Collagenous Colitis
- 2016
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Ingår i: Journal of Crohn's & Colitis. - Oxford, United Kingdom : Oxford University Press. - 1873-9946 .- 1876-4479. ; 10:4, s. 449-454
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Tidskriftsartikel (refereegranskat)abstract
- Background: The relationship between clinical and histological parameters in collagenous colitis (CC) is poorly understood. Smoking is a risk factor for CC, whereas its impact on clinical activity and outcome is not well known.Methods: In a post hoc analysis of pooled data from two randomized controlled trials we assessed the association between demographic data (gender, age, smoking habits, family history of inflammatory bowel disease), clinical variables (duration of symptoms, mean number of stools/watery stools per day, abdominal pain, clinical remission) and histological data (thickness of the collagen band, inflammation of the lamina propria, total numbers of intraepithelial lymphocytes, degeneration). Moreover, we analysed the predictive value of baseline parameters for clinical outcome in a logistic regression model.Results: Pooled data were available from 202 patients with active CC, of whom 36% were current smokers, 29% former smokers and 35% non-smokers. Smoking status was associated with decreased ability to achieve clinical remission (current smokers vs non-smokers: odds ratio [OR] 0.31, 95% confidence interval [CI] 0.10-0.98, p = 0.045; former smokers vs non-smokers: OR 0.19, 95% CI 0.05-0.73, p = 0.016). Current smokers had an increased mean number of watery stools at baseline compared with non-smokers (p = 0.051) and increased mean number of watery stools per se was associated with decreased likelihood of obtaining clinical remission (OR 0.63, 95% CI 0.47-0.86, p = 0.003). Patient characteristics and histology at baseline had no association with clinical parameters and no predictive value for clinical outcome.Conclusion: Smoking worsens clinical symptoms in CC and is associated with an increased number of watery stools and decreased likelihood of achieving clinical remission. There is no significant association between histology and clinical data.
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- Nyhlin, Nils, 1971-, et al.
(författare)
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Long-term prognosis of clinical symptoms and health-related quality of life in microscopic colitis : a case-control study
- 2014
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Ingår i: Alimentary Pharmacology and Therapeutics. - Hoboken : Wiley-Blackwell. - 0269-2813 .- 1365-2036. ; 39:9, s. 963-972
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Tidskriftsartikel (refereegranskat)abstract
- Background: Microscopic colitis, comprising collagenous colitis (CC) and lymphocytic colitis (LC), is a common cause of chronic diarrhoea. The long-term prognosis is not well described.Aim: To study outcome of symptoms and health-related quality of life (HRQoL).Methods: A case-control study using a postal questionnaire with three population-based controls per patient matched for age, sex and municipality. HRQoL was assessed by the Short Health Scale (SHS). Patients in clinical remission, defined as a mean of <3 stools/day, were evaluated separately (CC; n=72, LC; n=60).Results: The study included 212 patients and 627 matched controls. Median disease duration was 5.9 (range 0.5-27) years and 6.4 (0.3-14.8) years for CC and LC respectively. Abdominal pain, fatigue, arthralgia, myalgia, faecal incontinence and nocturnal defecation were significantly more prevalent in CC patients compared with controls. These differences persisted in CC patients in clinical remission with respect to abdominal pain (36% vs. 21%), fatigue (54% vs. 34%), arthralgia (61% vs. 41%) and myalgia (53% vs. 37%). In LC patients, abdominal pain, fatigue, faecal incontinence and nocturnal defecation were more prevalent compared with controls. In LC patients in clinical remission, fatigue was more prevalent compared with controls (54% vs. 37%). These differences were statistically significant (P<0.05). All four HRQoL dimensions (symptom burden, social function, disease-related worry, general well-being) were impaired in patients with active CC and LC.Conclusions: Although considered to be in clinical remission, patients with microscopic colitis suffer from persisting symptoms such as abdominal pain, fatigue, arthralgia or myalgia several years after diagnosis.
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| 49. |
- Nyhlin, Nils, et al.
(författare)
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Microscopic colitis : a common and an easily overlooked cause of chronic diarrhoea
- 2008
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Ingår i: European journal of internal medicine. - Amsterdam : Elsevier. - 0953-6205 .- 1879-0828. ; 19:3, s. 181-186
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Forskningsöversikt (refereegranskat)abstract
- Microscopic colitis, comprising collagenous colitis and lymphocytic colitis, is characterised clinically by chronic watery diarrhoea, a macroscopically normal colonic mucosa where diagnostic histopathological features are seen on microscopic examination. The annual incidence of each disorder is 4–6/100,000 inhabitants, with a peak incidence in 60–70 year old individuals and a noticeable female predominance in collagenous colitis. The aetiology is unknown. Abdominal pain, weight loss, fatigue, and faecal incontinence are common symptoms in addition to chronic diarrhoea that impair the health-related quality of life of the patient. There is an association to other autoimmune disorders such as celiac disease, diabetes mellitus, thyroid disorders and arthritis. Budesonide is the best-documented short-term treatment, but the optimal long-term strategy needs further study. The long-term prognosis is good and the risk of complications including colonic cancer is low.
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