Collagenous Colitis Research Articles

Isolated Collagenous Duodenitis: A Rare Cause of Malabsorption

Collagenous gastroenteritides are uncommon disorders with distinct histopathology, characterized by subepithelial collagen deposition. We describe collagenous duodenitis in an adult male with six months of weight loss. Collagenous duodenitis in the absence of collagenous colitis is rare, with less than 120 reported cases, and can lead to malnutrition and death if untreated. A 49 year old Caucasian male with hypertension and history of stage I testicular seminoma presented with a 70lb weight loss over 6 months, and intermittent melena and hematochezia for 2 months. His hemoglobin was 12g/dL with Hct of 36.5; AST was 118 U/L, ALT 27 U/L, and alkaline phosphatase 241 U/L. Prealbumin was 11.9 mg/dL. Examination revealed active bowel sounds but nontender, nondistended abdomen. Stool was heme positive. Computed tomography demonstrated asymmetric nodular thickening of the rectal wall 7cm above the anal verge concerning for possible mass. No adenopathy or retroperitoneal mass was identified. Pantoprazole twice daily was started. Esophagogastroduodenoscopy found diffuse, moderately scalloped mucosa at the 2nd and 3rd portions of the duodenum. Tissue transglutaminase IgA was normal, with elevated total serum IgA. Duodenal histopathology revealed a sub-epithelial collagen band 25μm in thickness with preserved villous architecture consistent with collagenous duodenitis. Colonoscopy showed sigmoid diverticulosis and colonic polyps, which were resected. Surrounding non-adenomatous tissue showed no features of collagenous colitis. The patient's hemoglobin remained stable; he was discharged on daily pantoprazole with plans for outpatient follow up. Collagenous duodenitis is often described as sharing histopathologic features of collagenous sprue. However, our patient had collagen banding with preserved duodenal villous architecture in the absence of celiac disease. Pathogenesis is thought to be secondary to immune/autoimmune inflammation from unknown luminal antigens, and collagenous duodenitis has been associated with T cell lymphoma. Left untreated, patients often have progressive malnutrition, which can lead to death. Various therapies have been trialed, including corticosteroids, H2 blockers, PPI therapy, hypoallergenic diets, and tumor necrosis factor inhibitors with varying results. Physicians should consider collagenous gastroenteritides in the differential in a patient presenting with malabsorption.

Spontaneous Tear After Insufflation: A Unique Finding of Collagenous Colitis

Spontaneous Tear After Insufflation: A Unique Finding of Collagenous Colitis

Luminal Clinical

<b>Luminal Clinical</b>

Interventions for treating lymphocytic colitis.

Lymphocytic colitis is a cause of chronic diarrhea. Therapy is based mainly on case series and uncontrolled trials, or by extrapolation of data for treating collagenous colitis, a related disorder. This review was performed to identify therapies for lymphocytic colitis that have been proven in randomized controlled trials.To determine effective treatments for patients with clinically active lymphocytic colitis.The MEDLINE, PUBMED and EMBASE databases were searched using the search criteria "microscopic colitis" or "lymphocytic colitis" and "treatment" or "therapy" or "management" to identify relevant papers published between 1970 and September 2006. Manual searches from the references of identified papers and relevant review papers were performed. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. Finally, the Cochrane Central Register of Controlled Trials and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register was searched for other studies.A single randomized trial published in abstract form only which studied bismuth subsalicylate was identified, and included only 5 patients with lymphocytic colitis (and 9 with collagenous colitis).Data were extracted independently by each author onto 2x2 tables (treatment versus placebo and response versus no response). For therapies assessed in one trial only, P values were derived using the chi-square test.There were 5 patients with lymphocytic colitis in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks vs. placebo). Although all three patients on active drug experienced clinical improvement compared to none of the placebo group, there were no statistically significant differences in clinical (P = 0.10) or histological (P = 0.71) improvement.A single trial studying bismuth subsalicylate as therapy for lymphocytic colitis suggests that it may be beneficial. However, it included only 5 patients and no firm conclusions can be made from such a small trial. Larger trials studying treatments for lymphocytic colitis are warranted.

Prevalence, Pathogenesis, Diagnosis, and Management of Microscopic Colitis.

Microscopic colitis (MC), which is comprised of lymphocytic colitis and collagenous colitis, is a clinicopathological diagnosis that is commonly encountered in clinical practice during the evaluation and management of chronic diarrhea. With an incidence approaching the incidence of inflammatory bowel disease, physician awareness is necessary, as diagnostic delays result in a poor quality of life and increased health care costs. The physician faces multiple challenges in the diagnosis and management of MC, as these patients frequently relapse after successful treatment. This review article outlines the risk factors associated with MC, the clinical presentation, diagnosis and histologic findings, as well as a proposed treatment algorithm. Prospective studies are required to better understand the natural history and to develop validated histologic endpoints that may be used as end points in future clinical trials and serve to guide patient management.

Abstract 3772: A multi-scale survey to assess the impact of inflammatory diseases of the abdominal cavity and prostate cancer severity

Abstract Introduction and Objectives: Prostate cancer (PCa) is the most common cancer detected in men (181,000 annual cases), and nearly 26,000 American men die each year due to PCa and related complications. Reports have shown that PCa is more aggressive when its comorbid with inflammatory diseases. However, the correlations and risks attributed to inflammatory diseases of the abdominal cavity and oncophenotypes are not known. Methods: To investigate how inflammatory pathways and PCa genes induce aggressive oncophenotypes in the setting of PCa, we have compiled a multiscale survey that includes data from surgical observations, inflammatory phenotypes, clinical registries, biomarkers and mouse models. We applied an integrative informatics approach with experimental validation to understand the associations between inflammatory diseases (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, indeterminate colitis, ischemic colitis, diverticulitis, hernia, etc.) and PCa. Results: We found distinct patterns of shared molecular features—gene sets, pathways, and networks—and comorbidities across inflammatory disease and PCa. For example, we found that diverticulitis tend to increase inflammation in the abdominal cavity and could potentially lead to aggressive prostate oncophenotypes. To test abdominal inflammation and PCa correlation, we induced inflammation in a mouse model of hiatus hernia, which resulted in an increase in the expression of the combined markers of inflammation and PCa (TGFB, TNFA, and IL6). Evaluation of pathology stage, Gleason scores and physical attributes of previous inflammation observed during robotic prostatectomy surgery also reveals trend towards aggressive tumor characteristics with an increase in inflammation. Gene-set overlap analyses showed that several inflammatory disease and prostate cancer genes share genetic modules. Conclusion: Collectively, our findings provide the first set of computational, experimental and clinical evidence to recommend clinicians to evaluate the impact of inflammatory disease induced oncophenotypes in patients with PCa. Given that 1.3 million patients undergo prostate-specific antigen (PSA)-triggered invasive trans-rectal biopsy, the present findings in combination with PSA could facilitate the identification patient subset with aggressive cancer. Stratifying patients at risk for prostate cancer who are undergoing surgical interventions of abdominal cavity for inflammation diseases could also evaluate other non-surgical or therapeutic strategies. Funding acknowledgements: AKT is supported by grants from Prostate Cancer Foundation and Deane Prostate Health. JT is supported by grants from National Cancer Institute NCI-U54-CA189201-02, National Center for Advancing Translational Sciences NCATS-UL1TR000067 and Clinical and Translational Science Award (CTSA). Note: This abstract was not presented at the meeting. Citation Format: Khader Shameer, Kamlesh Kumar Yadav, Li Li, Shalini S. Yadav, Benjamin Glicksberg, Irtaza Khan, Kipp W. Johnson, Marcus A. Badgeley, Cordelia Elaiho, Ben Readhead, Brian A. Kidd, Andrew Kasarskis, Joel T. Dudley, Ashutosh K. Tewari. A multi-scale survey to assess the impact of inflammatory diseases of the abdominal cavity and prostate cancer severity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3772. doi:10.1158/1538-7445.AM2017-3772

Microscopic Colitis Evolved Into Inflammatory Bowel Diseases Is Characterized by Increased Th1/Tc1 Cells in Colonic Mucosal Lamina Propria.

An association between microscopic colitis (MC), i.e., lymphocytic colitis (LC) and collagenous colitis (CC), and inflammatory bowel diseases (IBD) has been noticed. A subset of MC cases may evolve into IBD, and IBD in remission may present as MC in a histologic pattern. Moreover, MC and IBD may coexist in different regions of the bowel. A link between MC and IBD in their pathogenesis is, therefore, suggested. Abnormal mucosal immunity is likely the key. We reviewed 2324 MC cases in Calgary over 14years and identified 20 cases evolved into IBD (IBD transformers). 13 of them were further investigated for colonic mucosal lamina propria mononuclear cells (LPMNCs), as opposed to 22 cases whose MC resolved. On their index colonic biopsy immunohistochemistry was performed to detect major T cell subsets characterized by key cytokines and master transcription factors (IFNγ and T-bet for Th1/Tc1, GATA-3 for Th2/Tc2, IL-17 and RORc for Th17/Tc17, FoxP3 for Treg/Tcreg) as well as TNFα+ cells (partly representing Th1). LPMNCs positive for each marker were counted (average number per high-power field). IBD transformers had increased IFNγ+, T-bet+, TNF-α+, and GATA-3+ LPMNCs compared to the MC-resolved cases. The LC-to-IBD subgroup had increased IFNγ+ and GATA-3+ cells compared to the LC-resolved subgroup. The CC-to-IBD subgroup had increased T-bet+, TNF-α+, and GATA-3+ cells compared to the CC-resolved subgroup. Among MC-resolved patients, more TNF-α+ and RORc+ cells were seen in LC than in CC. Th1/Tc1- and TNFα-producing cells, and likely a subset of Th2/Tc2 cells as well, may be involved in the MC-to-IBD transformation.

Macroscopic findings, incidence and characteristics of microscopic colitis in a large cohort of patients from the United Kingdom

Objective: Microscopic colitis (MC) is classically associated with normal or near-normal endoscopic appearances. However, non-specific macroscopic findings have been described, the importance of biopsy location for confirming a diagnosis of MC is unclear, and reported incidence data from the United Kingdom are limited. This study was designed to assess macroscopic features, incidence, demographics, and location and positivity of biopsy samples in MC.Materials and methods: Retrospective, cross-sectional study of individuals with newly diagnosed MC.Results: From 2010 to 2015, 540 cases of MC were reported. Macroscopic findings occurred in 16.5% (n = 89) cases, with trends towards increased frequency of ulceration or linear scarring in collagenous colitis (CC). The mean incidence of MC was 11.3 per 100,000 population/year, including 291 (53.9%) with CC (incidence 6.1 per 100,000/year), 203 (37.6%) with lymphocytic colitis (incidence 4.2 per 100,000/year) and 46 (8.5%) with MC, not otherwise specified. Most individuals were female (70.2%). Common features in patients with MC included symptom duration <6 months, weight loss, abdominal pain and use of proton pump inhibitors, statins, or non-steroidal anti-inflammatory drugs. In individuals with right- and left-sided biopsies taken, 98.2% had diagnostic features in both. However, rectal biopsies were only positive in 88.7%.Conclusions: One in six patients with MC demonstrated distinct macroscopic findings at colonoscopy. Our data confirm a female preponderance in MC, a relatively short symptom duration and use of certain drugs as common features. Both right- and left-sided biopsies were frequently positive, suggesting flexible sigmoidoscopy and biopsy could confirm a diagnosis in certain individuals.

Biomarkers and Microscopic Colitis: An Unmet Need in Clinical Practice.

One of the most common causes of chronic diarrhea is ascribed to microscopic colitis (MC). MC is classified in subtypes: collagenous colitis (CC) and lymphocytic colitis (LC). Patients with MC report watery, non-bloody diarrhea of chronic course, abdominal pain, weight loss, and fatigue that may impair patient’s health-related quality of life. A greater awareness, and concomitantly an increasing number of diagnoses over the last years, has demonstrated that the incidence and prevalence of MC are on the rise. To date, colonoscopy with histological analysis on multiple biopsies collected along the colon represents the unique accepted procedure used to assess the diagnosis of active MC and to evaluate the response to medical therapy. Therefore, the emerging need for less-invasive procedures that are also rapid, convenient, standardized, and reproducible, has encouraged scientists to turn their attention to the identification of inflammatory markers and other molecules in blood or feces and within the colonic tissue that can confirm a MC diagnosis. This review gives an update on the biomarkers that are potentially available for the identification of inflammatory activity, related to CC and LC.

Immune modulator therapy for microscopic colitis in a case series of 73 patients.

Microscopic colitis (MC) is a common cause of chronic diarrhoea. Various treatment options have been described, but there are limited data describing outcomes of corticosteroid-sparing treatments. To evaluate the outcomes of patients with active MC treated with immune modulators. All patients seen at Mayo Clinic, Rochester between January 1, 1997 and November 30, 2016 with a histological diagnosis of MC were identified. Patients treated with an immune modulator of interest were selected and clinical outcomes recorded. Seventy-three MC patients (50 collagenous colitis and 23 lymphocytic colitis) with a median disease duration of 24 months (range, 7-60) were included. The indications for treatment were budesonide-refractoriness in 66%, budesonide dependence in 29%, and budesonide intolerance in 5%. Median age was 51.8 years (range, 43.4-63.1) and 61 (84%) were female. Thiopurines were used in 49 patients (67%) for a median of 4 months (range, 1.5-15). Complete and partial response occurred in 43% and 22% respectively. Adverse effects resulting in therapy cessation occurred in 17 patients (35%). Twelve patients (16%) were treated with methotrexate for a median of 14 months (3-18.8). Complete and partial response occurred in 58% and 17%, respectively. Anti-TNF therapy was used in 10 patients (14%) for a median of 4 months (range, 2.3-5.5). Complete response occurred in four patients and partial response in four patients. The majority of patients with active MC responded to thiopurines, methotrexate, or anti-TNF therapy. Larger controlled studies are required to confirm the efficacy and safety of these medications in MC.

Collagenous colitis: Requirement for high-dose budesonide as maintenance treatment

BackgroundControlled studies show high efficacy of budesonide in inducing short-term clinical remission in collagenous colitis (CC), but relapses are common after its withdrawal. AimTo evaluate the need for high-dose budesonide (≥6mg/d) to maintain clinical remission in CC. MethodsAnalysis of a multicentre retrospective cohort of 75 patients with CC (62.3±1.5years; 85% women) treated with budesonide in a clinical practice setting between 2013 and 2015. Frequency of budesonide (9mg/d) refractoriness and safety, and the need for high-dose budesonide to maintain clinical remission, were evaluated. Drugs used as budesonide-sparing, including azathioprine and mercaptopurine, were recorded. Logistic regression analysis was performed to evaluate the risk factors associated with the need for high-dose budesonide (≥6mg/d) to maintain clinical remission. ResultsBudesonide induced clinical remission in 92% of patients, with good tolerance. Fourteen of 68 patients (21%; 95% CI, 13–32%) needed high-dose budesonide to maintain remission. Only intake of NSAIDs at diagnosis (OR, 8.6; 95% CI, 1.6–44) was associated with the need for high-dose budesonide in the multivariate analysis. Treatmentwith thiopurines was effective in 5 out of 6 patients (83%; 95% CI, 44–97%), allowing for withdrawal from or a dose decrease of budesonide. ConclusionsOne fifth of CC patients, especially those with NSAID intake at diagnosis, require high-dose budesonide (≥6mg/d) to maintain clinical remission. In this setting, thiopurines might be effective as budesonide-sparing drugs.

53 Long term follow up of microscopic colitis

Background Microscopic colitis (MC) has been increasingly diagnosed in recent years. The two main variants are lymphocytic colitis (LC) and collagenous colitis (CC). Aim To evaluate the long term natural history and follow-up of patients diagnosed with MC. Method Patients diagnosed with MC were identified from the histopathology department database in our institution. Clinical details were obtained through a combination of chart review and follow up telephone interview. Results Conclusions MC is commonly associated with other autoimmune conditions. A significant proportion of patients had no follow-up/did not seek follow-up which raises the possibility that their symptoms were not problematic. Further follow-up of patients with MC is necessary to gain better insight into the natural history of this condition.

332i - Immunochip Analysis Revealed HLA Mechanism in Collagenous Colitis and Overlapping Genes with Immunomediated Diseases

332i - Immunochip Analysis Revealed HLA Mechanism in Collagenous Colitis and Overlapping Genes with Immunomediated Diseases

Su1985 - Gene Expression Profiles in Collagenous Colitis

Su1985 - Gene Expression Profiles in Collagenous Colitis

Over 90% of cases of Microscopic Colitis can be diagnosed by performing a short colonoscopy

To determinate the topographical distribution of key diagnostic histological features of lymphocytic colitis (LC) and collagenous colitis (CC) and to establish what correlations may exist between the histological findings and the causes and severity of MC. Patients with MC were included in a prospective multicentre French study from September 2010 to October 2012. MC was diagnosed by performing total colonoscopy with multiple biopsies of the rectum and colon collected in separate jars and analyzed separately for each site (descending and sigmoid colon, transverse colon, ascending colon). CC was defined as a subepithelial collagen layer>10μm thick and LC as an intraepithelial lymphocyte (IEL) count>20 lymphocytes per 100 epithelial cells without any associated thickening of the subepithelial collagen. Ninety-five patients, 69 with LC 26 and with CC, were included in the analysis. The sensitivity of the biopsies for diagnosing MC was maximum in the transverse colon and minimum in the rectum. Rectal and left colonic biopsies resulted in the diagnosis of CC and CL in 93% and 94% of cases, respectively. All the remaining cases of MC were diagnosed by performing additional biopsies beyond the splenic flexure. In patients with LC, a higher rate of IELs was associated with the absence of abdominal pain (P=0.01) and a shorter duration of diarrhea (P=0.001). In patients with CC, a lower level of collagen thickness in the basement membrane was associated with the presence of an autoimmune disease (P=0.02). More than 90% of cases of microscopic colitis were diagnosed in this study by performing rectal and left colonic biopsies.

Advances for improved diagnosis of microscopic colitis in patients with chronic diarrhoea

Microscopic colitis is a generic term that includes 2 main forms, collagenous colitis and lymphocytic colitis, and describes a form of inflammatory bowel disease with a chronic and relapsing course. The incidence of microscopic colitis is between 2 and 8 times higher in women than in men, although age, more than sex, increases the risk of collagenous colitis (odds ratio [OR] 8.3 for age ≥65 vs. <65 and OR 2.8 for women). The main symptom is chronic non-bloody watery diarrhoea. Other common symptoms include abdominal pain (50%-70%), with the result that many patients with microscopic colitis meet criteria for irritable bowel syndrome. Colonoscopy with multiple colonic biopsies is currently recommended, as histological changes are the main characteristic feature. The colonic mucosa is macroscopically normal, although certain minimal endoscopic abnormalities have been described.

P720 Use of proton pump inhibitors associated with a markedly increased risk of microscopic colitis

Background: Microscopic colitis (MC) is a chronic inflammatory bowel disease with unknown etiology. Proton pump inhibitor (PPI) use has been consistently linked to an increased risk of MC. The specific role of the different classes of PPI is unknown. Based on the nationwide Danish registries we explored the association between MC and use of PPI and in addition the effect of different classes of PPIs and dose-dependency. Secondly we explored the effect of concomitant use of PPI and NSAID. Methods: In a ten-year period (January 2004 to December 2013) we identified 10652 patients with a first-time recorded diagnosis of MC including 6254 (59%) with collagenous colitis (CC) and 4398 (41%) with lymphocytic colitis (LC). MC cases were identified via the Danish Pathology Registry. For each MC case, we sampled 10 population controls. Information on PPI use was obtained from the Danish Prescription Register. The analysis conformed to a case-control design, estimating the odds ratio (OR) for the association between PPI use and the risk MC using conditional logistic regression, while adjusting for potential confounders. Results: We found strong associations between current PPI use and both CC (adjusted OR [aOR] 8.75; 95% CI: 8.12–9.43) and LC (aOR 5.03; 95% CI: 4.61–5.49). This association was seen across all individual PPIs, however, the strongest association was seen with current use of lansoprazole, for both CC (aOR 20.10; 95% CI: 18.05–22.37) and LC (aOR 7.70; 95% CI: 6.79–8.73). When considering timing, ORs were highest for current use of PPI, while the association quickly diminished when considering recent or past exposure. When analyzing the prescribed strength of PPI, we found no apparent dose-response pattern. The use of NSAID was associated with a modest increased risk of CC (aOR 1.70; 95% CI: 1.55–1.87). However, the combination of NSAID and PPI and was associated with a higher risk for CC (aOR 9.72; 95% CI: 8.65–10.92) compared to the use of one of the drugs alone. Conclusions: In a large comprehensive case-control study based on nationwide Danish registries we found an increased risk of MC associated with the use of PPI and especially an increased risk with the use of lanzoprazole. The combination of NSAID and PPI and was associated with a high risk for CC.

P048 Decreased expression of aquaporins in colonic biopsies from collagenous colitis patients. A novel diarrhoeal pathomechanism?

P048 Decreased expression of aquaporins in colonic biopsies from collagenous colitis patients. A novel diarrhoeal pathomechanism?

Drug Exposure and the Risk of Microscopic Colitis: A Critical Update.

A variety of luminal antigens, including a wide range of drugs, have been associated with the still little-known pathophysiology of microscopic colitis (MC), with variable evidence suggesting causality. This article aims to review the aspects related to drugs as potential triggers of MC; to discuss the most commonly identified associations between drugs and MC; and to analyze the limitations of the studies currently available. A literature search was performed in PubMed combining the search terms ‘drug exposure’, ‘drug consumption’, and ‘risk factors’ with ‘microscopic colitis’, ‘lymphocytic colitis’, and ‘collagenous colitis’, with no language restrictions. Reference lists of retrieved documents were also reviewed. A handful of case–control studies have demonstrated significant associations between some commonly used drugs and a higher risk of developing MC. No universally accepted criteria for establishing cause–effect relationships in adverse reactions to drugs are available, but several methods that can be applied to MC, can provide degrees of the likelihood of an association. A high probability imputation in the development of MC as a drug adverse effect has only been demonstrated for individual cases by applying chronological (challenge, de-challenge, and relapse with re-challenge) and semiological criteria. Several case–control studies have shown significant associations between exposure to drugs and MC, but the variability in their design, the reference populations used, and the definitions for drug exposure considered require specific analyses. It can be concluded that drug exposure and MC as a likely cause–effect relationship has only been described for a handful of drugs and in individual cases.

Reduced IL-37 Production Increases Spontaneous Chemokine Expressions in Colon Epithelial Cells

Background and AimMicroscopic colitis, comprising collagenous colitis and lymphocytic colitis, is a common cause of chronic diarrhea. Previously, we showed enhanced chemokine productions in microscopic colitis patients, indicating dysregulated immune cell chemotaxis in the immunopathogenesis. We also showed decreased mRNA of IL-37, mainly regarded as an anti-inflammatory cytokine, in the colonic mucosa of these patients, potentially an important factor for the chronicity of the colitis. Our aim in this study was to understand the possible role of IL-37 in chemokine production using a cell line model.MethodsA colon epithelial cell line, T84, was stimulated with the TLR5 ligand flagellin. IL-37 protein production was reduced 20% using the CRISPR/Cas9 system, and the changes in chemokine mRNA and protein expressions were compared to cells transfected with empty plasmid.ResultsThe 20% reduction in IL-37 protein levels spontaneously increased CCL5, CXCL8, CXCL10, and CXCL11 mRNA and protein expressions. CCL2 mRNA and protein levels were enhanced upon TLR5 stimulation. CCL3, CCL20, and CX3CL1 mRNA expressions were increased either spontaneously or following TLR5 stimulation, whereas CCL4 and CCL22 mRNA expressions were significantly decreased.ConclusionsEven a minor decrease in the ability of colon epithelial cells to produce IL-37 results in altered chemokine expression, mainly an increase in the production of several chemokines. Our results indicate that a decreased IL-37 expression by colon epithelial cells may be an important factor for increasing the recruitment of immune cells and subsequently developing microscopic colitis.