Eosinophil infiltration in the upper gastrointestinal tract of patients with bronchial asthma.

BACKGROUND: Eosinophilic esophagitis (EoE) is related to allergic diseases such as bronchial asthma (BA), atopic dermatitis, and allergic rhinitis. The aim of this study was to examine the eosinophil infiltration in the upper gastrointestinal (GI) tract in patients with BA using esophagogastroduodenoscopy. METHODS: Patients with BA who had upper GI tract symptoms were enrolled. Patients who received systemically administered steroids were excluded. Eosinophil infiltrations in the esophagus, stomach, and duodenum were examined with regard to the endoscopic findings and pathological findings of biopsy specimens (UMIN000010132). RESULTS: Ninety patients were enrolled from October in 2012 to September in 2014. Thirty-six were male, 54 were female, and the mean age was 57.5 years. Eighty-one (90%) used inhaled corticosteroids. Fourteen patients (15.6%) had reflux esophagitis, 8 of whom had grade A and 6 had grade B. No patient with EoE was observed. One female patient who had marked eosinophil infiltration in the esophagus, stomach, and duodenum was diagnosed as having eosinophilic gastroenteritis, but endoscopy showed only mucosal edema in the antrum. Another female patient who had marked eosinophil infiltration in the esophagus, stomach, and duodenum was diagnosed as having eosinophilic granulomatosis with polyangiitis, and endoscopy showed erosions in the antrum and the duodenum. Three patients had eosinophil infiltration in the stomach, but none of them had severe symptoms. CONCLUSIONS: Patients with asthma who had upper gastrointestinal symptoms rarely had eosinophilic gastrointestinal disorders. Biopsy specimens are of high importance in the diagnosis of eosinophilic gastrointestinal disorders even if there is no remarkable endoscopic finding.

Early intervention with adalimumab may contribute to favorable clinical efficacy in patients with Crohn's disease.

BACKGROUND: We evaluated the clinical efficacy of adalimumab (ADA) for Crohn's disease (CD) and analyzed predictive factors for clinical remission and long-term prognosis. METHODS: We retrospectively reviewed the medical records of 45 patients treated with ADA for CD at Keio University Hospital between October 2010 and March 2014. Clinical remission was defined as a Harvey-Bradshaw index of ≤4. RESULTS: Twenty-eight of 45 patients (62.2%) achieved clinical remission at week 4. Among these 28 patients, 18 patients (64.3%) maintained clinical remission at week 26, and among these, 16 patients (88.9%) maintained clinical remission at week 52. Absence of a history of bowel resection and absence of prior anti-tumor necrosis factor (anti-TNF) therapy were significant predictive factors for clinical remission at week 4 upon multivariate logistic regression analyses. Younger age and a disease duration of ≤3 years correlated with clinical remission at week 26 upon univariate analyses. Patients without a history of bowel resection showed significantly better long-term prognosis than those with a history of bowel resection (p = 0.01). None of the patients contracted a serious infectious disease. CONCLUSIONS: Younger age, shorter duration of disease, being naive to anti-TNF antagonists, and absence of a history of bowel resection were associated with the efficacy of ADA in CD patients.

Risk and management of intra-abdominal abscess in Crohn's disease treated with infliximab.

BACKGROUND AND AIMS: Infliximab (IFX) is a monoclonal antibody used to treat patients with Crohn's disease (CD). Intra-abdominal abscess formation is a major complication of CD with negative effects on patient prognosis. We have analyzed risk factors for abscess formation in CD patients treated with IFX. METHODS: CD patients who received IFX between January 2000 and April 2011 at Keio University Hospital were analyzed retrospectively. Risk factors for abscess formation were assessed by univariate and multivariate logistic regression analyses. RESULTS: Intra-abdominal abscess was seen in 15 of 258 patients. Univariate analyses showed serum C-reactive protein (CRP) concentration at 14 weeks after initiation of IFX (p = 0.021), serum albumin concentration at week 0 (p = 0.022) and week 14 (p = 0.004), the presence of anal lesions (p = 0.036), progression of intestine deformation (p = 0.015) and early loss of response to IFX (p < 0.0001) to be risk factors. Multivariate analysis showed that CRP concentration at 14 weeks [odds ratio (OR) 1.361] and loss of IFX response within 6 months (OR 5.361) were independent risk factors. CONCLUSIONS: Abscess formation should be suspected in patients with symptoms of CD recurrence during IFX therapy. Uncontrolled CRP concentration and early loss of response to IFX are risk factors.

Modified bowel preparation regimen for use in second-generation colon capsule endoscopy in patients with ulcerative colitis.

BACKGROUND AND AIM: We have reported that second-generation colon capsule endoscopy (CCE-2) might be feasible for assessing the severity of mucosal inflammation in ulcerative colitis (UC). However, because of the low rate (69%) of complete evaluation of the colon and owing to inadequate cleansing. We believe that the method of bowel preparation could be improved by reducing volume. In the present study, we attempted to improve the colon-cleansing regimen in order to optimize the usefulness of CCE-2 in the management of UC patients. METHODS: Twenty patients with histologically confirmed UC were enrolled. Patients took a maximum 2.2 L lavage solution (polyethylene glycol solution and magnesium citrate) in two or three divided doses. To assess the effectiveness of the modified bowel preparation regimen, we evaluated the rate of total colonobservation, the effectiveness of bowel cleansing, andinterobserver agreement in assessing UC disease activity. We used a four-point grading scale (poor, fair, good, and excellent) for evaluating the quality of bowel cleansing. Matts' endoscopic score was used to evaluate disease activity. RESULTS: The rate of total colon observation was 85%, and 15 patients (75%) excreted the CCE-2 within 8 h. The proportion of excellent plus good cleansing was approximately 60%. There was a substantial interobserver agreement (κ = 0.777) in assessment of overall cleansing, which was still substantial at the fair cleansing level (κ = 0.700). CONCLUSION: Using CCE-2, the modified bowel preparation regimen, with reduced volume has the potential to succeed in the evaluation of mucosal severity in UC.

Mucosal CXCR4+ IgG plasma cells contribute to the pathogenesis of human ulcerative colitis through FcγR-mediated CD14 macrophage activation.

BACKGROUND: Chronic inflammation characterised by IgG-producing plasma cell infiltration of colonic mucosa is a histological hallmark of ulcerative colitis (UC); however, whether its function is pathogenic or protective remains unclear. OBJECTIVE: To explore the contribution of intestinal IgG plasma cells to UC pathogenesis. METHODS: We isolated lamina propria mononuclear cells (LPMCs) from intestinal mucosa of UC patients and analysed the characteristics of intestinal plasma cells (expression profiles of differentiation molecules and chemokine receptors). We investigated the involvement of IgG-immune complex (IC)-Fc gamma receptor (FcγR) signalling in intestinal inflammation by examining the cytokine production by LPMCs in response to IgG-IC stimulation. RESULTS: IgG plasma cells that were markedly increased in number in the inflamed mucosa of UC patients showed a distinct expression profile (CD19(+)CD27(low), CCR10(low)CXCR4(high)) compared with IgA plasma cells (CD19(+/-)CD27(high), CCR10(high)CXCR4(-/low)). In vitro IgG-IC stimulation activated intestinal CD14 macrophages that were increased in number in the inflamed mucosa of UC patients via FcγRI and FcγRII, and induced the extensive production of pro-inflammatory cytokines such as tumour necrosis factor (TNF) and interleukin-1ß (IL-1ß), comparable to the effect of commensal bacteria stimulation. Co-stimulation with IgG-IC and commensal bacteria increased TNF and IL-1ß production more than stimulation with the latter alone. Furthermore, IgG-IC notably up-regulated the expression of TL1A, whereas commensal bacteria specifically induced IL-23. CONCLUSIONS: Collectively, these results demonstrate a novel aspect of UC pathogenesis in which unique IgG plasma cells infiltrate the inflamed mucosa via CXCR4, and critically influence UC pathogenesis by exacerbating mucosal inflammation through the activation of 'pathogenic' intestinal CD14 macrophages via IgG-IC-FcγR signalling.

TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease.

Bile acids (BAs) play important roles not only in lipid metabolism, but also in signal transduction. TGR5, a transmembrane receptor of BAs, is an immunomodulative factor, but its detailed mechanism remains unclear. Here, we aimed to delineate how BAs operate in immunological responses via the TGR5 pathway in human mononuclear cell lineages. We examined TGR5 expression in human peripheral blood monocytes, several types of in vitro differentiated macrophages (Mϕs) and dendritic cells. Mϕs differentiated with macrophage colony-stimulating factor and interferon-γ (Mγ-Mϕs), which are similar to the human intestinal lamina propria CD14(+) Mϕs that contribute to Crohn's disease (CD) pathogenesis by production of pro-inflammatory cytokines, highly expressed TGR5 compared with any other type of differentiated Mϕ and dendritic cells. We also showed that a TGR5 agonist and two types of BAs, deoxycholic acid and lithocholic acid, could inhibit tumour necrosis factor-α production in Mγ-Mϕs stimulated by commensal bacterial antigen or lipopolysaccharide. This inhibitory effect was mediated by the TGR5-cAMP pathway to induce phosphorylation of c-Fos that regulated nuclear factor-κB p65 activation. Next, we analysed TGR5 levels in lamina propria mononuclear cells (LPMCs) obtained from the intestinal mucosa of patients with CD. Compared with non-inflammatory bowel disease, inflamed CD LPMCs contained more TGR5 transcripts. Among LPMCs, isolated CD14(+) intestinal Mϕs from patients with CD expressed TGR5. In isolated intestinal CD14(+) Mϕs, a TGR5 agonist could inhibit tumour necrosis factor-α production. These results indicate that TGR5 signalling may have the potential to modulate immune responses in inflammatory bowel disease.

Activated hepatic stellate cells mediate the differentiation of macrophages.

AIM: Liver macrophages play integral roles in both the progression and resolution of hepatic inflammation and fibrosis, comprising opposing functions that largely coincide with the activation state of nearby hepatic stellate cells (HSC). While cross-talk between HSC and macrophages may be essential at various stages of inflammation and fibrogenesis, many facets of this interaction have yet to be thoroughly explored. Here, we examine the potential roles of HSC-derived signaling molecules as mediators of liver macrophage differentiation. METHODS: Human peripheral blood mononuclear cells (PBMC) were differentiated to macrophages in the presence or absence of cultured HSC-derived conditioned media. The phenotype of resulting macrophages was characterized by examination of cell surface marker expression, antigen-presenting capabilities and cytokine secretion. RESULTS: Conditioned media from activated human HSC promoted the differentiation of a unique set of macrophages that differed in morphology and function from both classical (M1) and alternative (M2) macrophages, expressing increased levels of CD14 and CD16, as well as a distinct interleukin (IL)-6(high) /IL-10(low) /transforming growth factor (TGF)-ß(high) expression profile. These macrophages expressed high levels of CD206, CD209, CD80 and human leukocyte antigen DR, though no significant increases in antigen presentation were apparent. HSC-derived macrophages exhibited specific activation of p38 mitogen-activated protein kinase, and inhibition of this activation by p38 inhibitors during differentiation effectively reversed increases in IL-6 and TGF-ß. CONCLUSION: The present results suggest that HSC-derived signaling molecules promote differentiation of liver macrophages with both pro-inflammatory and profibrotic functions. Furthermore, these effects appear to be mediated, at least partially, in a p38-dependent manner.

Applicability of second-generation colon capsule endoscope to ulcerative colitis: a clinical feasibility study.

BACKGROUND AND AIM: Colon capsule endoscopy has already been used for colon visualization and detection of polyps but its applicability to inflammatory bowel disease is still unconfirmed. The aim of this study was to assess the feasibility of evaluating the severity of mucosal inflammation in patients with ulcerative colitis (UC) using a second-generation colon capsule endoscope (CCE-2). METHODS: Forty patients with histological confirmed diagnosis of UC were enrolled. Low-volume (2 L) polyethylene glycol solution with prokinetics (mosapride citrate and metoclopramide) regimen was used for the bowel preparation. In Phase 1, consisting of 10 patients, to confirm appropriate CCE-2 bowel preparation for UC. In Phase 2, consisting of 30 patients, CCE-2 was performed with a fixed bowel preparation regimen. CCE-2 findings were recorded for 8 h starting from capsule ingestion and conventional colonoscopy was subsequently performed on the same day. CCE-2 procedure completion rate and the colon cleansing level with a 4-point grading scale (poor, fair, good, and excellent) were evaluated in Phase 2. Correlations between Matts endoscopic scores as judged by CCE-2 and conventional colonoscopy were calculated. RESULTS: CCE-2 procedure was completed within 8 h in 69% of the patients. The proportion of patients with good or excellent cleansing level was below 50%. However, Matts endoscopic scores determined by CCE-2 showed a strong correlation with scores obtained by conventional colonoscopy (average ρ = 0.797). CONCLUSIONS: Although modifications in bowel preparation are needed, CCE-2 might be feasible for assessing the severity of mucosal inflammation in patients with UC.

Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway.

Dendritic cells (DCs) are known as antigen-presenting cells and play a central role in both innate and acquired immunity. Peripheral blood monocytes give rise to resident and recruited DCs in lymph nodes and non-lymphoid tissues. The ligands of nuclear hormone receptors can modulate DC differentiation and so influence various biological functions of DCs. The role of bile acids (BAs) as signalling molecules has recently become apparent, but the functional role of BAs in DC differentiation has not yet been elucidated. We show that DCs derived from human peripheral blood monocytes cultured with a BA produce lower levels of interleukin-12 (IL-12) and tumour necrosis factor-α in response to stimulation with commensal bacterial antigens. Stimulation through the nuclear receptor farnesoid X (FXR) did not affect the differentiation of DCs. However, DCs differentiated with the specific agonist for TGR5, a transmembrane BA receptor, showed an IL-12 hypo-producing phenotype. Expression of TGR5 could only be identified in monocytes and was rapidly down-regulated during monocyte differentiation to DCs. Stimulation with 8-bromoadenosine-cyclic AMP (8-Br-cAMP), which acts downstream of TGR5 signalling, also promoted differentiation into IL-12 hypo-producing DCs. These results indicate that BAs induce the differentiation of IL-12 hypo-producing DCs from monocytes via the TGR5-cAMP pathway.

Small-Bowel Lesions in Patients Taking Direct Oral Anticoagulants Detected Using Capsule Endoscopy.

METHODS: This study was a prospective, open-label, nonblinded, multicenter, and observational study. From September 2013 to March 2017, patients taking DOACs were enrolled. Patients underwent VCE. The type and location of small-bowel lesions were registered. Also, (1) the proportion of lesions detected between types of DOAC was evaluated and (2) the hemoglobin (Hb) and serum ferritin levels were compared between patients with and without small-bowel lesions. RESULTS: 33 patients were enrolled, but 4 patients withdrew their consent, and VCE was performed on 29 patients. Eight, 13, and 8 patients received dabigatran, rivaroxaban, and apixaban, respectively. Small-bowel transit was complete in 27 of 29 patients (93.1%). Small-bowel lesions were detected in 23 (79.3%), redness in 12 (41.4%), erosions in 14 (48.3%), and angioectasia in 3 (10.3%) patients, and 6 patients (20.7%) had no abnormalities. Redness and erosions were detected in the upper, middle, or lower portions, but erosions tended to be less frequent in the middle portion (p = 0.25, 0.06). Angioectasia was not detected in the lower portion. No patients had active bleeding. The findings did not differ according to the drug. The relationships between the endoscopic findings and the Hb and serum ferritin levels were not significant. CONCLUSION: Many patients taking DOACs had small-bowel lesions; however, most lesions were relatively mild. Observing small-bowel lesions over longer periods may be necessary in patients taking DOACs. This trial is registered with UMIN000011527.

The impact of visceral adipose tissue as best predictor for difficult colonoscopy and the clinical utility of a long small-caliber scope as rescue.

BACKGROUND: There have been many reports about a variety of factors associated with incomplete colonoscopy or difficult colonoscopy with long cecal intubation time (CIT). The aim of this retrospective study was to analyze the factors related to difficult colonoscopy under conscious sedation and demonstrate the clinical utility of a small-caliber scope as rescue by using the data from a large number of subjects who underwent health check-ups. METHODS: Consecutive 1036 cases over a 12-month period (April 2015 to March 2016) were enrolled and 619 subjects were divided into two groups: Easy colonoscopy (CS) Group (CIT ≤ 10 min); Difficult CS Group (CIT > 10 min or incomplete colonoscopy by a standard scope). The two groups were compared by subjects and colonoscopy characteristics with univariate analysis followed by multivariate logistic regression analysis. Reasons for incomplete colonoscopy were also assessed. RESULTS: Cecal intubation rate increased from 97.9% to 99.9% (1007/1008) by the rescue scope. Main reasons for incomplete colonoscopy were tortuosity in the left hemicolon (38%), redundancy in the right hemicolon (29%), pain (19%) and fixation (14%). Moreover, 95% (20/21) of rescue colonoscopies were completed without additional sedation. Higher BMI (21 kg/m2 ≤ BMI) and intermediate visceral adipose tissue (VAT) (75 cm2 ≤ VAT < 150 cm2) were significantly associated with easy CS (80.7% vs 19.3%, P = 0.004; 56.3% vs 43.7%, P = 0.001) by univariate analysis. Age, gender, and VAT, not BMI, were independently associated with difficult colonoscopy by multivariate analysis (OR (95% CI), P: 0.964 (0.942, 0.985), 0.001; 1.845 (1.101, 3.091), 0.020; 2.347 (1.395, 3.951), 0.001). Subgroup analysis by gender also showed VAT as the best predictor for both genders. CONCLUSION: Difficult colonoscopy was significantly associated with advancing age, female gender and, lower (< 75 cm2) or higher (150 cm2 ≤) VAT. These subjects may benefit from having complete and more comfortable colonoscopy examinations by using the small-caliber scope rather than the standard scope.

Polyp detection rate in transverse and sigmoid colon significantly increases with longer withdrawal time during screening colonoscopy.

BACKGROUND: The guidelines for colonoscopy present withdrawal time (WT) and adenoma detection rate (ADR) as the quality indicator. The purpose of this retrospective study is to analyze the predicting factors with polyp detection rate (PDR) as a surrogate for ADR by using comprehensive health checkup data, and assess the correlation between PDR per each colonic segment and WT, and factors influencing WT. METHODS: One thousand and thirty six consecutive health checkup cases from April 2015 to March 2016 were enrolled in this study, and 880 subjects who undertook colonoscopy without polyp removal or biopsy were divided into the two groups (polyp not detected group vs polyp detected group). The two groups were compared by subjects and clinical characteristics with univariate analysis followed by multivariate analysis. Colonoscopies with longer WT (≥ 6 min) and those with shorter WT (< 6 min) were compared by PDR per each colonic segment, and also by subjects and clinical characteristics. RESULTS: A total of 1009 subjects included two incomplete colonoscopies (CIR, 99.9%) and overall PDR was 35.8%. A multiple logistic regression model demonstrated that age, gender, and WT were significantly related factors for polyp detection (odds ratio, 1.036; 1.771; 1.217). PDR showed a linear increase as WT increased from 3 min to 9 min (r = 0.989, p = 0.000) and PDR with long WT group was higher than that with short WT group per each colonic segment, significantly in transverse (2.3 times, p = 0.004) and sigmoid colon (2.1 times, p = 0.001). Not only bowel preparation quality but also insertion difficulty evaluated by endoscopist were significant factors relating with WT (odds ratio, 3.811; 1.679). CONCLUSION: This study suggests that endoscopists should be recommended to take more time up to 9 min of WT to observe transverse and sigmoid colon, especially when they feel no difficulty during scope insertion.

Irritable bowel syndrome evaluation using computed tomography colonography.

AIM: To evaluate the morphology of the colon in patients with irritable bowel syndrome (IBS) by using computed tomography colonography (CTC). METHODS: Twelve patients with diarrhea type IBS (IBS-D), 13 patients with constipation type IBS (IBS-C), 12 patients with functional constipation (FC) and 14 control patients underwent colonoscopy following CTC. The lengths of the rectosigmoid colon, transverse colon and the total colon were measured. The diameters of the rectum, sigmoid colon, descending colon, transverse colon, and ascending colon were measured. RESULTS: The mean length of the total colon was 156.5 cm in group C, 158.9 cm in group IBS-D, 172.0 cm in group IBS-C, and 188.8 cm in group FC. The total colon in group FC was significantly longer than that in group C (P < 0.05). The mean length of the rectosigmoid colon was 56.2 cm, 55.9 cm, 63.6cm, and 77.4 cm (NS). The mean length of the transverse colon was 49.9 cm, 43.1 cm, 57.0 cm, and 55.0 cm. The transverse colon in group IBS-D was significantly shorter than that in group IBS-C (P < 0.01) and that in group FC (P = 0.02). The mean diameter of the sigmoid colon was 4.0 cm, 3.3 cm, 4.2 cm, and 4.3 cm (NS). The mean diameter of the descending colon was 3.6 cm, 3.1 cm, 3.8 cm, and 4.3 cm. The descending colon diameter in group IBS-D was significantly less than that in group IBS-C (P = 0.03) and that in group FC (P < 0.001). The descending colon diameter in group FC was significantly greater than that in group C (P = 0.04). The mean diameter of the transverse colon was 4.4 cm, 3.3 cm, 4.2 cm, and 5.0 cm (NS). CONCLUSION: CT colonography might contribute the clarification of subtypes of IBS.

Pyogenic granuloma of the ileum diagnosed by double-balloon enteroscopy.

A pyogenic granuloma (PG) is a capillary hemangioma that usually occurs on the skin or in the oral cavity; it is rarely observed in the gastrointestinal tract. We herein describe a case of a 86-year-old woman who presented with anemia. Esophagogastroduodenoscopy and colonoscopy did not reveal any significant bleeding focus, but capsule endoscopy revealed a bleeding focus in the small intestine. We performed double-balloon enteroscopy and identified a 7-mm-diameter, reddish, subpedunculated, hemispheric polyp with a smooth surface in the small intestine, approximately 100 cm from the ileocecal valve. The polyp was surgically removed, and the histological findings were consistent with a diagnosis of PG.

Immune aspects of the pathogenesis of inflammatory bowel disease.

Although the precise etiologies of inflammatory bowel disease (IBD) (ulcerative colitis and Crohn's disease) remain obscure, several reports have indicated that dysfunction of the mucosal immune system plays an important role in its pathogenesis. Recent progress with genome-wide association studies has identified many IBD susceptibility genes. In individuals with genetic risk, abnormal interactions between the host immune system and gut flora, and dysregulation of cellular responses such as autophagy and ER stress, induce an abnormal host immune response in the gut resulting in intestinal inflammation. Research progress animal models in IBD, and in human IBD, has identified several key molecules in IBD pathogenesis such as TNFα and adhesion molecules, and molecular targeting therapies based on these molecules have been developed. Here, we review immunological aspects in IBD pathogenesis and the development of immunoregulatory therapy.

Role of enhanced visibility in evaluating polyposis syndromes using a newly developed contrast image capsule endoscope.

BACKGROUND/AIMS: A flexible spectral imaging color enhancement system was installed in new capsule software for video capsule endoscopy. Contrast image capsule endoscopy (CICE) is a novel technology using light-emitting diodes selected for the main absorption range of hemoglobin. We assessed the feasibility and diagnostic effi cacy for small bowel surveillance in patients with polyposis syndromes. METHODS: Six patients with polyposis syndromes, four with familial adenomatous polyposis and one each with Cowden syndrome (CS) and Cronkhite-Canada syndrome (CCS) were examined using CICE. We conducted three evaluations to assess the effect on the numbers of the detected polyps; compare polyp diagnostic rates between adenoma and hamartoma; and assess polyp visibility. RESULTS: The numbers of detected polyps and diagnostic accuracy did not differ signifi cantly between pre-contrast and contrast images. However, 50% of the adenomatous polyps displayed enhanced visibility on contrast images. CICE contrast images exhibited clearly demarcated lesions and improved the visibility of minute structures of adenomatous polyps. Hamartomatous polyp micro-structures in patients with CS and CCS were more clearly visualized on contrast than pre-contrast images. CONCLUSIONS: CICE is an effective tool for enhancing the visibility of polyps in patients with polyposis syndrome.