Latiglutenase Protects the Mucosa and Attenuates Symptom Severity in Patients With Celiac Disease Exposed to a Gluten Challenge.

BACKGROUND & AIMS: Gluten ingestion in patients with celiac disease can lead to gastrointestinal symptoms and small intestinal mucosal injury. METHODS: This gluten challenge phase 2 trial was double blind and placebo controlled, and it assessed the efficacy and safety of a 1200-mg dose of IMGX003 in patients with celiac disease exposed to 2 g of gluten per day for 6 weeks. The change in the ratio of villus height to crypt depth was the primary endpoint. Secondary endpoints included density of intraepithelial lymphocytes and symptom severity. These endpoints were evaluated by analysis of covariance. Additional endpoints included serology and gluten-immunogenic peptides in urine. RESULTS: Fifty patients were randomized, and 43 patients completed the study (IMGX003, n = 21; placebo, n = 22). The mean change in the ratio of villus height to crypt depth (primary endpoint) for IMGX003 vs placebo was -0.04 vs -0.35 (P = .057). The mean change in the density of intraepithelial lymphocytes (secondary endpoint) for IMGX003 vs placebo was 9.8 vs 24.8 cells/mm epithelium (P = .018). The mean change (worsening) in symptom severity in relative units (secondary endpoint) for IMGX003 vs placebo was 0.22 vs 1.63 (abdominal pain, P = .231), 0.96 vs 3.29 (bloating, P = .204), and 0.02 vs 3.20 (tiredness, P = .113). The 3 × 2-week trend line significance values for these symptoms, respectively, were P = .014, .030, and .002. CONCLUSIONS: IMGX003 reduced gluten-induced intestinal mucosal damage and symptom severity. (ClinicalTrials.gov, Number: NCT03585478).

Vulvar Crohn's Disease: Clinical Features and Outcomes.

INTRODUCTION: Vulvar involvement is a rare complication of Crohn's disease (CD). The optimal treatment of vulvar CD is unknown. METHODS: We conducted a 25-year retrospective cohort study of vulvar CD from 3 referral centers. Clinical features and outcomes were studied. RESULTS: Fifty patients were identified. The most common vulvar symptoms were pain (74%), edema (60%), ulcerations (46%), nodules (36%), and abscess (34%). Medical management leading to symptomatic improvement varied, and 5 patients ultimately required surgery. DISCUSSION: Vulvar CD manifests with a broad spectrum of symptoms. Aggressive medical management was frequently effective, although surgery was required in 10% of cases.

A 1-Year Cross-sectional Inflammatory Bowel Disease Surveillance Colonoscopy Cohort Comparing High-definition White Light Endoscopy and Chromoendoscopy.

BACKGROUND: We sought to compare the dysplasia detection rate of high-definition white light endoscopy (HDWLE) with that of chromoendoscopy in patients with long-standing inflammatory bowel disease (IBD). METHODS: This is a retrospective observational cohort of patients with IBD who underwent surveillance colonoscopy between October 1, 2016 and September 30, 2017. We assessed the association between dysplasia detection and multiple variables. RESULTS: A total of 808 unique colonoscopies were performed, of which 150 (18.6%) included chromoendoscopy. Primary sclerosing cholangitis was a comorbid diagnosis in 24.5% of patients. The performing endoscopist was an IBD specialist with 37.1% of patients and had >10 years' experience with 64.9% of patients. Prior dysplasia had been seen in 245 (30.3%) patients: 102 (68.0%) and 143 (22.0%) among patients who had chromoendoscopy and HDWLE, respectively. Dysplasia in polyps was found in 129 procedures (15.1%). Among patients who had chromoendoscopy and HDWLE, polypoid dysplasia was identified in 50 (33.0%) and 79 (12.0%) patients, respectively, P < 0.01. Dysplasia in random biopsies was found in 39 patients (4.8%): 15 (10%) who had chromoendoscopy and 24 (3.6%) who had HDWLE (P < 0.001). On multivariate analysis, patient and disease characteristics significantly associated with an increased odds for polypoid dysplasia included older age at diagnosis (odds ratio [OR] = 1.3 per 10 years; 95% confidence interval [CI], 1.07-1.60), having an IBD physician endoscopist (OR = 1.6; 95% CI, 1.01-2.67), having an endoscopist with less than 10 years' experience (OR = 1.8; 95% CI (1.16-2.89), and prior random dysplasia (OR = 4.2; 95% CI (1.93-9.17). Concomitant primary sclerosing cholangitis was significantly associated with random dysplasia (OR = 2.3; 95% CI, 1.02-5.07). After multivariate analysis adjusting for these variables, chromoendoscopy was no more likely to identify dysplasia than was HDWLE. CONCLUSIONS: Chromoendoscopy and HDWLE had a similar diagnostic yield for dysplasia detection in patients with chronic IBD-colitis after adjusting for multiple known risk factors.

Combination Biologic Therapy in Inflammatory Bowel Disease: Experience From a Tertiary Care Center.

The global incidence of inflammatory bowel disease (IBD) has increased considerably during the past few decades.1 IBDs, composed of Crohn's disease (CD) and ulcerative colitis (UC), are characterized by heterogeneous presentation and widely variable clinical course. The therapeutic goals are to induce and maintain remission. Despite the current treatments available, many patients do not achieve this goal.

Certolizumab Trough Levels and Antibodies in Crohn Disease: A Single-Center Experience.

Background: Certolizumab pegol (CZP) has been successfully used for the treatment of Crohn disease (CD); however, real-world data regarding the utility of CZP trough levels (CTLs) are lacking. We aimed to correlate CTL with CD outcomes and to determine frequency of CZP antibodies. Methods: Retrospective evaluation of all CD patients on maintenance CZP with CTL obtained between 2016 and 2019. Outcomes included: median CTL, presence of anti-CZP antibodies, biochemical response (BR), clinical response (CR), radiologic response (RR), radiologic healing (RH), and mucosal healing (MH). Results: Seventy-seven CD patients were included. Median CTL was 18.9 µg/mL (interquartile range, 7.6-35.4). Twenty-three patients (27.3%) had positive antibody levels, with lower median CTL compared to patients with no antibodies (0.0 vs 29.8; P < 0.0001). Median CTL levels were higher in patients with vs without CR (30.4 vs 10.3 µg/mL; P = 0.0015) and RR (29.6 vs 5.8 µg/mL; P = 0.006). CZP dosing at least every 2 weeks was associated with higher odds of achieving MH (odds ratio, 3.2; 95% confidence interval, 1.03-9.97). CTL resulted in change in clinical management in 62.7% of cases and presence of CMZ antibodies was associated with an odds ratio of 5.83 (95% confidence interval, 1.57-21.73) of change in management. Receiver operating characteristic curve and quartile analysis suggested that CTL >19 µg/mL is associated with increased rates of CR and RR. Conclusions: Higher CTL was significantly associated with CR and RR. The rate of CZP antibodies was 27.3%. Our data suggest maintenance CTL of ≥19 µg/mL should be achieved in order to optimize outcomes in clinical practice.

The Combination of Patient-Reported Clinical Symptoms and an Endoscopic Score Correlates Well with Health-Related Quality of Life in Patients with Ulcerative Colitis.

BACKGROUND AND AIMS: Patient-reported outcomes (PROs) will become increasingly important as primary endpoints in future clinical trials. We aimed to evaluate the relationship between health-related quality of life (HRQoL) and the combination of patient-reported clinical symptoms (ClinPRO2) and Mayo endoscopic subscore (MES) in patients with ulcerative colitis (UC). METHODS: We conducted a prospective cross-sectional study of 90 consecutive UC patients who were scheduled for sigmoidoscopy or colonoscopy. All patients completed the following questionnaires: (1) self-rated rectal bleeding and stool frequency (ClinPRO2); (2) Short Inflammatory Bowel Disease Questionnaire (SIBDQ); (3) European Quality of Life 5-Dimensions 3-Level (EQ5D3L); (4) Work Productivity and Activity Impairment questionnaire (WPAI); (5) Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); and (6) Hospital Anxiety and Depression Scale (HADS). The endoscopic images were graded according to the MES. "No symptoms" was defined as a symptom score of 0, and "mucosal healing" was defined as MES score of 0-1. Correlations between the combined ClinPRO2 and MES with HRQoL were assessed using Spearman's correlation coefficients. RESULTS: The combination of the ClinPRO2 and MES was well correlated to SIBDQ (r = -0.70), EQ5D3L (r = -0.51), WPAI (r = 0.62), FACIT-F (r = -0.58), and HADS-depression (r = 0.45). SIBDQ scores had strong correlations with FACIT-F (r = 0.86), WPAI (r = -0.80), and HADS-depression (r = -0.75) (p < 0.05 for all correlations). Patients with no symptoms reported the greatest all HRQoL scores. CONCLUSIONS: In patients with ulcerative colitis, the combination of a ClinPRO2 and the MES had good correlation with the SIBDQ. In addition, SIBDQ was well correlated to the various HRQoL.

Narrow band imaging evaluation of duodenal villi in patients with and without celiac disease: A prospective study.

BACKGROUND: Duodenal biopsies are commonly obtained during esophagogastroduodenoscopy (EGD) but are very often histopathologically normal. Therefore, a more strategic method for evaluating the duodenal mucosa and avoiding unnecessary biopsies is needed. AIM: To examine the clinical utility of narrow band imaging (NBI) for evaluating duodenal villous morphology. METHODS: We performed a prospective cohort study of adult patients at Mayo Clinic Rochester from 2013-2014 who were referred for EGD with duodenal biopsies. A staff endoscopist scored, in real-time, the NBI-based appearance of duodenal villi into one of three categories (normal, partial villous atrophy, or complete villous atrophy), captured ≥ 2 representative duodenal NBI images, and obtained mucosal biopsies therein. Images were then scored by an advanced endoscopist and gastroenterology fellow, and biopsies (gold standard) by a pathologist, in a masked fashion using the same three-category classification. Performing endoscopist, advanced endoscopist, and fellow NBI scores were compared to histopathology to calculate performance characteristics [sensitivity, specificity, positive and negative, negative predictive value (NPV), and accuracy]. Inter-rater agreement was assessed with Cohen's kappa. RESULTS: 112 patients were included. The most common referring indications were dyspepsia (47%), nausea (23%), and suspected celiac disease (14%). Duodenal histopathology scores were: 84% normal, 11% partial atrophy, and 5% complete atrophy. Performing endoscopist NBI scores were 79% normal, 14% partial atrophy, and 6% complete atrophy compared to 91%, 5%, and 4% and 70%, 24%, and 6% for advanced endoscopist and fellow, respectively. NBI performed favorably for all raters, with a notably high (92%-100%) NPV. NBI score agreement was best between performing endoscopist and fellow (κ = 0.65). CONCLUSION: NBI facilitates accurate, non-invasive evaluation of duodenal villi. Its high NPV renders it especially useful for foregoing biopsies of histopathologically normal duodenal mucosa.

Mechanisms of Disease: Inflammatory Bowel Diseases.

Inflammatory bowel diseases (IBDs), represented by Crohn disease and ulcerative colitis, are associated with major morbidity in Western countries and with increasing incidence in the developing world. Although analysis of the genome of patients with IBD, especially through genome-wide association studies, has unraveled multiple pathways involved in IBD pathogenesis, only part of IBD heritability has been explained by genetic studies. This finding has revealed that environmental factors also play a major role in promoting intestinal inflammation, mostly through their effects in the composition of the microbiome. However, in order for microbial dysbiosis to result in uncontrolled intestinal inflammation, the intestinal barrier formed by intestinal epithelial cells and the innate immune system should also be compromised. Finally, activation of the immune system depends on the working balance between effector and regulatory cells present in the intestinal mucosa, which have also been found to be dysregulated in this patient population. Therefore, IBD pathogenesis is a result of the interplay of genetic susceptibility and environmental impact on the microbiome that through a weakened intestinal barrier will lead to inappropriate intestinal immune activation. In this article, we will review the mechanisms proposed to cause IBD from the genetic, environmental, intestinal barrier, and immunologic perspectives.

Vedolizumab Drug Level Correlation With Clinical Remission, Biomarker Normalization, and Mucosal Healing in Inflammatory Bowel Disease.

BACKGROUND/AIMS: The clinical utility of vedolizumab (VDZ) trough levels (VTLs) in inflammatory bowel disease (IBD) is not well defined. The aims of this study are to determine the median VTLs and frequency of detected antibodies, the correlation of VTLs with C-reactive protein (CRP) and mucosal healing (MH), and the change in clinical management based on VTLs. METHODS: A cross-sectional study of IBD patients treated with VDZ with VTLs checked between July 1, 2016, and March 1, 2017, was conducted. Mucosal healing was defined as absence of mucosal ulcers in Crohn's disease (CD) and Mayo endoscopic score ≤1 for ulcerative colitis (UC). Normal CRP was defined as ≤8 mg/L. RESULTS: A total of 171 patients (62% CD, 31% UC, 7% indeterminate colitis) were included. Median VTLs was 15.3 ug/mL (range, 0-60), and 1 patient had detectable antibodies to VDZ. Patients with a normal CRP had a median VTLs of 17.3 ug/mL vs 10.7 ug/mL in high CRP patients (P = 0.046). This was noted in CD (20.3 vs 10.4 ug/mL; P = 0.005) but not in UC patients (14.4 vs 20.8; P = 0.72). Mucosal healing was achieved in 35% of patients (37 of 105); among these, median VTLs was 13.7 ug/mL vs 16.1 ug/mL in patients who did not achieve MH (P = 0.64). Vedolizumab trough levels resulted in a change in clinical management in 73%. CONCLUSIONS: Our cohort showed a low rate of immunogenicity to VDZ and an association between VTLs and CRP in CD but not in UC patients. No relationship between VTLs and MH was detected. Vedolizumab trough level measurements altered management in approximately three fourths of patients.

Phenotype and Clinical Course of Inflammatory Bowel Disease With Co-existent Celiac Disease.

BACKGROUND AND AIMS: Inflammatory bowel diseases, principally Crohn's disease and ulcerative colitis, and celiac disease are among the most common immune-mediated gastrointestinal diseases. We aim to elucidate the clinical course and outcomes of patients with concomitant inflammatory bowel disease and celiac disease, a unique population that remains scarcely studied to date. METHODS: A retrospective matched case-control study of adults with co-existent inflammatory bowel disease [IBD] and celiac disease was performed at a tertiary referral institution in North America. Logistic regression and Kaplan-Meier curves compared disease characteristics and clinical outcomes of the two groups. RESULTS: A total of 342 inflammatory bowel disease patients were included in this study, of whom 114 had co-existent celiac disease and 228 did not. Patients with co-existent inflammatory bowel disease and celiac disease had higher rates of primary sclerosing cholangitis [19.3% vs 5.7%; odds ratio, 4.4; 95% confidence interval, 2.1-9.4; p <0.001], extensive ulcerative colitis [78.1% vs 59.0%; odds ratio, 2.8; 95% confidence interval, 1.5-5.5; p =0.002], and family history of celiac disease [10.5% vs 3.5%; odds ratio 3.2; 95% confidence interval, 1.3-8.2; p =0.01], compared with patients without concomitant celiac disease. CONCLUSIONS: Patients with inflammatory bowel disease with concomitant celiac disease have unique phenotypic features compared with non-celiac inflammatory bowel disease, with higher risks for colitis-related hospitalisations, extensive colitis, and primary sclerosing cholangitis. Increased recognition of co-existent IBD and celiac disease can prompt clinicians to investigate for concomitant disease sooner, particularly in patients with seemingly refractory disease.

Outcomes of Treatment for Latent Tuberculosis Infection in Patients With Inflammatory Bowel Disease Receiving Biologic Therapy.

Background: Treatment for latent tuberculosis infection (LTBI) is of particular concern in patients with inflammatory bowel disease (IBD) initiating biologic therapies to prevent tuberculosis (TB) reactivation. This study aimed to evaluate the effectiveness of LTBI treatment in IBD patients receiving biologic therapy. Methods: There was a retrospective review of all IBD patients diagnosed with LTBI following a tuberculin skin test (TST) and/or interferon gamma release assay (IGRA) and who received biologic therapy between 2002 and 2016. The primary outcome was tuberculosis reactivation after completion of LTBI treatment. Results: Three-hundred twenty-nine IBD patients were identified, and 35 (27 Crohn's disease; 8 ulcerative colitis) met the study inclusion criteria. The mean age was 38.3 years, and 68.6% were male. The most common LTBI treatment regimen was isoniazid (INH) for 9 months (74%). Biologic therapies used were infliximab (40%), adalimumab (29%), vedolizumab (20%), and certolizumab pegol (11%). Combination therapy with an immunomodulator was administered in 57% of cases. The median time from initiation of LTBI treatment to biologics was 43 days. The mean duration of follow-up was 2.9 years. The estimated median annual risk of TB reactivation without treatment was 0.52% by a prediction formula. Only 1 patient taking adalimumab monotherapy developed reactivation of TB several years after completing 6 months of isoniazid therapy. The estimated TB reactivation rate was 0.98 cases per 100 patient-years of follow-up in our cohort. Conclusions: Treatment for LTBI in patients with IBD treated with biologics is effective but does not eliminate the risk of reactivation. 10.1093/ibd/izy133_video1izy133.video15776720675001.

Clinical Benefit of Capsule Endoscopy in Crohn's Disease: Impact on Patient Management and Prevalence of Proximal Small Bowel Involvement.

Background: Ileocolonoscopy and computed tomography (CT) or magnetic resonance (MR) enterography (CTE/MRE) are utilized to evaluate patients with small bowel (SB) Crohn's disease (CD). The purpose of our study was to estimate the impact of capsule endoscopy (CE) on patient management after clinical assessment, ileocolonoscopy, and CTE/MRE. Methods: We prospectively analyzed 50 adult CD patients without strictures at clinically indicated ileocolonoscopy and CTE/MRE exams. Providers completed pre- and post-CE clinical management questionnaires. Pre-CE questionnaire assessed likelihood of active SBCD and management plan using a 5-point level of confidence (LOC) scales. Post-CE questionnaire assessed alteration in management plans and contribution of CE findings to these changes. A change of ≥2 on LOC scale was considered clinically meaningful. Results: Of the 50 patients evaluated (60% females), median age was 38 years, median disease duration was 3 years, and median Crohn's Disease Activity Index (CDAI) score was 238 points. All CTE/MRE studies were negative for proximal disease. CE detected proximal disease in 14 patients (28%) with a median Lewis score of 215 points. CE findings altered management in 17 cases (34%). The most frequent provider-perceived benefits of CE were addition of new medication (29%) and exclusion of active SB mucosal disease (24%). Conclusion: CE is a safe imaging modality that alters clinical management in patients with established SBCD by adding incremental information not available at ileocolonoscopy and cross-sectional enterography.

Concurrent Sweet's syndrome and myopericarditis following mesalamine therapy.

Mesalamine, or 5-aminosalicylic acid, is a frequently used medication for the treatment of inflammatory bowel disease (IBD). We report the case of a 40-year-old woman recently diagnosed with IBD and started on mesalamine, who presented with new onset tender skin lesions 3 days following medication administration. One day following the onset of skin lesions, the patient developed acute chest pain, shortness of breath, ECG changes, troponemia, C-reactive protein elevation and pericardial enhancement on cardiac MRI consistent with myopericarditis. Subsequent skin biopsy confirmed the diagnosis of Sweet's syndrome. On cessation of the drug, both the skin lesions and the cardiac symptoms resolved in combination with anti-inflammatory therapy. While mesalamine has been previously associated with myocarditis and pericarditis, to our knowledge this is the first case of coexisting Sweet's syndrome with myopericarditis in the context of mesalamine therapy.

Targeting Specific Immunologic Pathways in Crohn's Disease.

Understanding the immunologic pathways in intestinal inflammation is crucial for the development of new therapies that can maximize patient response and minimize toxicity. Targeting integrins and cytokines is intended to control leukocyte migration to effector sites or inhibit the action of proinflammatory cytokines. New approaches to preventing leukocyte migration may target integrin receptors expressed on the intestinal vascular endothelium. The interleukin (IL)-12/IL-23 pathway has been a therapeutic target of interest in controlling active Crohn's disease (CD). New therapeutic approaches in CD may involve the enhancement of anti-inflammatory cytokine pathways and modulation of cellular responses and intranuclear signals associated with intestinal inflammation.

Inflammatory Bowel Disease: Updates on Molecular Targets for Biologics.

Therapy for inflammatory bowel disease (IBD) has changed, with several new agents being evaluated. The era of anti-tumor necrosis factor (anti-TNF) antibody therapy saw remarkable progress in IBD therapy. Some patients, however, do not respond to anti-TNF treatment, or their response decreases over time. This phenomenon highlights the need to identify new molecular targets for therapy in IBD. The targets of new therapeutic molecules in IBD must aim to restore immune dysregulation by the inhibition of proinflammatory cytokines (TNF-α, interleukin [IL]-6, IL-13, IL-17, IL-18, and IL-21) and augmentation of the effect of anti-inflammatory cytokines (IL-10, IL-11, and transforming growth factor ß) and to pursue new anti-inflammatory targets, such as regulatory T-cell therapy, Smad7 antisense, Janus-activated kinase inhibition, Toll-like receptor stimulation, leukocyte adhesion, and blockade of T-cell homing via integrins and mucosal addressin cellular adhesion molecule-1. In addition, potential molecular targets could restore mucosal barrier function and stimulate mucosal healing. Despite these potential targets, the value and clinical significance of most new molecules remain unclear, and clinical efficacy and safety must be better defined before their implementation in clinical practice. This article aims to review the promising and emerging molecular targets that could be clinically meaningful for novel therapeutic approaches.

Aberrant function of myeloid-derived suppressor cells (MDSCs) in experimental colitis and in inflammatory bowel disease (IBD) immune responses.

BACKGROUND AND AIMS: Myeloid-derived suppressor cells (MDSCs) encompass a novel population of suppressor cells and a potential candidate for cell-based therapies in inflammatory diseases. Herein, we investigated their immunomodulatory properties in experimental inflammatory colitis and T cell-mediated immune responses in inflammatory bowel disease (IBD) patients. METHODS: MDSCs (defined as CD14-HLA-DR-/lowCD33+CD15+) numbers were determined in peripheral blood (PB) from IBD patients. PB MDSC function was assessed in vitro. Experimental colitis was induced upon 2,4,6-trinitrobenzene sulfonic acid (TNBS) treatment and MDSCs were characterized by flow cytometry. The in vivo suppressive potential of bone marrow (BM)-derived MDSCs (BM-MDSCs) was tested by using both depleting and adoptive transfer strategies. RESULTS: MDSCs were enriched in the periphery of IBD patients during active disease. TNBS colitis induced amplification of MDSCs, particularly of the granulocytic (Ly6G+) subset during the effector phase of disease. Of interest, BM-MDSCs potently suppressed CD4+ T cell responses under steady state but failed to control colitis-associated immune responses in vivo. Mechanistically, under the colonic inflammatory milieu MDSCs switched phenotype (decreased proportion of Gr1high and increased numbers of Gr1low) and downregulated CCAAT/enhancer-binding protein beta (CEBPß) expression, a critical transcription factor for the suppressive function of MDSCs. In accordance with the murine data, human CD33 + CD15+ MDSCs from peripheral blood of IBD patients not only failed to suppress autologous T cell responses but instead enhanced T cell proliferation in vitro. CONCLUSIONS: Our findings demonstrate an aberrant function of MDSCs in experimental inflammatory colitis and in IBD-associated immune responses in vitro. Delineation of the mechanisms that underlie the loss of MDSCs function in IBD may provide novel therapeutic targets.

The Role of the Histone Methyltransferase Enhancer of Zeste Homolog 2 (EZH2) in the Pathobiological Mechanisms Underlying Inflammatory Bowel Disease (IBD).

Regulatory T (Treg) cells expressing the transcription factor FOXP3 play a pivotal role in maintaining immunologic self-tolerance. We and others have shown previously that EZH2 is recruited to the FOXP3 promoter and its targets in Treg cells. To further address the role for EZH2 in Treg cellular function, we have now generated mice that lack EZH2 specifically in Treg cells (EZH2Δ/ΔFOXP3+). We find that EZH2 deficiency in FOXP3+ T cells results in lethal multiorgan autoimmunity. We further demonstrate that EZH2Δ/ΔFOXP3+ T cells lack a regulatory phenotype in vitro and secrete proinflammatory cytokines. Of special interest, EZH2Δ/ΔFOXP3+ mice develop spontaneous inflammatory bowel disease. Guided by these results, we assessed the FOXP3 and EZH2 gene networks by RNA sequencing in isolated intestinal CD4+ T cells from patients with Crohn's disease. Gene network analysis demonstrates that these CD4+ T cells display a Th1/Th17-like phenotype with an enrichment of gene targets shared by FOXP3 and EZH2. Combined, these results suggest that the inflammatory milieu found in Crohn's disease could lead to or result from deregulation of FOXP3/EZH2-enforced T cell gene networks contributing to the underlying intestinal inflammation.

A case report of sevelamer-associated recto-sigmoid ulcers.

BACKGROUND: Optimal phosphorous control is an important aspect of the care of patients with end-stage renal disease, and phosphate binders are usually needed. CASE PRESENTATION: A 74-year-old woman with end-stage renal disease on maintenance hemodialysis presented to the emergency room with abdominal discomfort, rectal pain, and blood-tinged stools. Initial concern was for a rectal carcinoma, based on the symptoms and imaging in initial computerized tomography of the abdomen showing rectal wall thickening, and her clinical presentation. She had been treated with the phosphate binder sevelamer for two months. In this case report, we explore the unique features of sevelamer-associated recto-sigmoid ulcers which led to her symptoms. CONCLUSION: Sevelamer is widely used in chronic kidney disease and end-stage renal disease patients with hyperphosphatemia. It is a crosslinked polymeric amine that binds phosphates and bile acids; it is not systemically absorbed. To the authors' knowledge, this is the first reported case of recto-sigmoid ulcers associated with use of this phosphate binder. Nephrologists, pathologists, and gastroenterology sub-specialists should be aware of this recently-reported entity in patients on sevelamer with suggestive symptoms, as this medication is widely used in renal patients.

Krüppel-like factor KLF10 deficiency predisposes to colitis through colonic macrophage dysregulation.

Krüppel-like factor (KLF)-10 is an important transcriptional regulator of TGF-ß1 signaling in both CD8(+) and CD4(+) T lymphocytes. In the present study, we demonstrate a novel role for KLF10 in the regulation of TGFßRII expression with functional relevance in macrophage differentiation and activation. We first show that transfer of KLF10(-/-) bone marrow-derived macrophages into wild-type (WT) mice leads to exacerbation of experimental colitis. At the cell biological level, using two phenotypic strategies, we show that KLF10-deficient mice have an altered colonic macrophage phenotype with higher frequency of proinflammatory LyC6(+)MHCII(+) cells and a reciprocal decrease of the anti-inflammatory LyC6(-)MHCII(+) subset. Additionally, the anti-inflammatory CD11b(+)CX3CR1(hi) subset of colonic macrophages is significantly decreased in KLF10(-/-) compared with WT mice under inflammatory conditions. Molecularly, CD11b(+) colonic macrophages from KLF10(-/-) mice exhibit a proinflammatory cytokine profile with increased production of TNF-α and lower production of IL-10 in response to LPS stimulation. Because KLF10 is a transcription factor, we explored how this protein may regulate macrophage function. Consequently, we analyzed the expression of TGFßRII expression in colonic macrophages and found that, in the absence of KLF10, macrophages express lower levels of TGFßRII and display an attenuated Smad-2 phosphorylation following TGF-ß1 stimulation. We further show that KLF10 directly binds to the TGFßRII promoter in macrophages, leading to enhanced gene expression through histone H3 acetylation. Collectively, our data reveal a critical role for KLF10 in the epigenetic regulation of TGFßRII expression in macrophages and the acquisition of a "regulatory" phenotype that contributes to intestinal mucosal homeostasis.