TNF Promoter Hypomethylation Is Associated With Mucosal Inflammation in IBD and Anti-TNF Response.

Background and Aims: Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions influenced heavily by environmental factors. DNA methylation is a form of epigenetic regulation linking environmental stimuli to gene expression changes and inflammation. Here, we investigated how DNA methylation of the tumor necrosis factor (TNF) promoter differs between inflamed and uninflamed mucosa of IBD patients, including anti-TNF responders and nonresponders. Methods: We obtained mucosal biopsies from 200 participants (133 IBDs and 67 controls) and analyzed TNF promoter methylation using bisulfite sequencing, comparing inflamed with uninflamed segments, in addition to paired inflamed/uninflamed samples from individual patients. We conducted similar analyses on purified intestinal epithelial cells from bowel resections. We also compared TNF methylation levels of inflamed and uninflamed mucosa from a separate cohort of 15 anti-TNF responders and 17 nonresponders. Finally, we sequenced DNA methyltransferase genes to identify rare variants in IBD patients and functionally tested them using rescue experiments in a zebrafish genetic model of DNA methylation deficiency. Results: TNF promoter methylation levels were decreased in inflamed mucosa of IBD patients and correlated with disease severity. Isolated intestinal epithelial cells from inflamed tissue showed proportional decreases in TNF methylation. Anti-TNF nonresponders showed lower levels of TNF methylation than responders in uninflamed mucosa. Our sequencing analysis revealed 2 missense variants in DNA methyltransferase 1, 1 of which had reduced function in vivo. Conclusion: Our study reveals an association of TNF promoter hypomethylation with mucosal inflammation, suggesting that IBD patients may be particularly sensitive to inflammatory environmental insults affecting DNA methylation. Together, our analyses indicate that TNF promoter methylation analysis may aid in the characterization of IBD status and evaluation of anti-TNF therapy response.

Increased Activity of MAPKAPK2 within Mesenchymal Cells as a Target for Inflammation-Associated Fibrosis in Crohn's Disease.

BACKGROUND: Mesenchymal stromal cells are suggested to play a critical role in Crohn's disease [CD]-associated fibrosis. MAPKAPK2 [MK2] has emerged as a potential therapeutic target to reduce inflammation in CD. However, the cell-specific pattern of phospho-MK2 activation and its role in CD-associated fibrosis are unknown. The objectives of this study were to evaluate cell-specific changes in MK2 activity between predominantly inflammatory CD vs CD with fibrotic complications and define the role of stromal cell-specific MK2 activation in CD-associated fibrosis. METHODS: CD tissue, CD tissue-derived mesenchymal stromal cells known as myo-/fibroblasts [CD-MFs], and fibroblast-specific MK2 conditional knockout [KO] mice were used. RESULTS: In the inflamed area of predominantly inflammatory CD, high MK2 activity was equally distributed between mesenchymal and haematopoietic cells. By contrast, in CD with fibrotic complications, high MK2 activity was mostly associated with mesenchymal stromal cells. Using ex vivo CD tissue explants and an IL-10KO murine colitis model, we demonstrated that pro-fibrotic responses are significantly reduced by treatment with the MK2 inhibitor PF-3644022. Inhibition of MK2 activity in primary cultures of CD-MFs significantly reduced basal and TGF-ß1-induced profibrotic responses. Using fibroblast-specific MK2 knockout mice in chronic dextran saline sulphate colitis, we demonstrated that fibroblast intrinsic MK2 signalling is among the key processes involved in the chronic inflammation-induced profibrotic responses. CONCLUSIONS: Our data suggest that activation of MK2 within fibroblasts contributes to the chronic inflammation-induced fibrosis in CD and that targeting MK2 has potential for the development of novel therapeutic approaches for fibrosis in CD.

Incidence of retained biopsy specimens after esophagogastroduodenoscopy and colonoscopy.

Background and study aims In gastrointestinal endoscopy, biopsies must transit through the accessory channel and cap, presenting an opportunity for loss of tissue. We sought to determine the incidence of specimen retention in the accessory channel or cap and identify procedure characteristics associated with specimen retention. Patients and methods After completion of standard endoscopic procedures in which biopsies were obtained, the biopsy cap and accessory channel were inspected, brushed, and irrigated for any retained biopsy specimens according to a standard protocol. For controls, the same protocol was applied to procedures in which biopsies were not obtained. Specimen bottles from the recovery protocol were sent for pathological examination regardless of whether any visible tissue was present. Results A total of 216 outpatient procedures were included: 55 esophagogastroduodenoscopies (EGDs) and 50 colonoscopies in which biopsies were obtained and 56 EGDs and 55 colonoscopies in the control group. Retained specimens were found in either the cap or channel in 50 of 105 (48%). In 20 of 105 (19%), retained specimens were found just in the cap, in six of 105 (5.7%), retained specimens were found just in the channel, while in 24 of 105 (23%), retained specimens were found in both the cap and channel. Retained specimens were more likely to be found in EGDs compared to colonoscopies (58% vs. 36%, P = 0.031). No retained specimens were found in the control group. Conclusions Retained specimens are startingly common in standard gastrointestinal endoscopic procedures and could potentially change diagnoses and management. Quality improvement measures should be instituted to monitor prevalence of retained biopsies and methods to prevent them should be developed.

Etrolizumab as induction and maintenance therapy in patients with moderately to severely active Crohn's disease (BERGAMOT): a randomised, placebo-controlled, double-blind, phase 3 trial.

BACKGROUND: Etrolizumab is a gut-targeted anti-ß7 monoclonal antibody targeting α4ß7 and αEß7 integrins. We aimed to compare the safety and efficacy of two doses of etrolizumab with placebo in patients with Crohn's disease. METHODS: BERGAMOT was a randomised, placebo-controlled, double-blind, phase 3 study done at 326 treatment centres worldwide. We included patients aged 18-80 years with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] score of 220-480, and a mean daily stool frequency score of ≥6 or a mean daily stool frequency score of >3, and a mean daily abdominal pain score of >1, as well as the presence of active inflammation on screening ileocolonoscopy) who had intolerance, inadequate response, or no response to one or more of corticosteroids, immunosuppressants, or anti-TNF therapy within the past 5 years. BERGAMOT consisted of three induction cohorts (a placebo-controlled, double-blind exploratory cohort [cohort 1]; an active treatment cohort not containing a placebo control [cohort 2]; and a placebo-controlled, double-blind pivotal cohort [cohort 3]) and one maintenance cohort. In induction cohort 3, during the 14-week induction, patients were randomly assigned (2:3:3) to receive matched placebo, 105 mg etrolizumab subcutaneously every 4 weeks (at weeks 0, 4, 8, and 12) or 210 mg etrolizumab subcutaneously (at weeks 0, 2, 4, 8, and 12), stratified by concomitant treatment with oral corticosteroids, concomitant treatment with immunosuppressants, baseline disease activity, and previous exposure to anti-TNF therapy. To preserve masking, all patients received two injections at weeks 0, 4, 8, and 12 and one injection at week 2. Week 14 etrolizumab responders from all cohorts were re-randomly assigned (1:1) to receive 105 mg etrolizumab (etrolizumab maintenance group) or placebo (placebo maintenance group) every 4 weeks for 52 weeks; patients in the induction placebo group underwent a sham re-randomisation to preserve masking. During maintenance, randomisation was stratified by CDAI remission status, concomitant treatment with oral corticosteroids, induction dose regimen, and previous exposure to anti-TNF therapy. All participants and study site personnel were masked to treatment assignment for both induction and maintenance. Co-primary induction endpoints at week 14 (placebo vs 210 mg etrolizumab) were clinical remission (mean stool frequency ≤3 and mean abdominal pain ≤1, with no worsening) and endoscopic improvement (≥50% reduction in Simple Endoscopic Score for Crohn's Disease [SES-CD]). Co-primary maintenance endpoints at week 66 (placebo vs etrolizumab) were clinical remission and endoscopic improvement. Efficacy was analysed using a modified intention-to-treat (mITT) population, defined as all randomised patients who received at least one dose of study drug (induction) and as all patients re-randomised into maintenance who received at least one dose of study drug in the maintenance phase (maintenance). Safety analyses included all patients who received at least one dose of study drug. Maintenance safety analyses include all adverse events occurring in both induction and maintenance. This trial is registered with ClinicalTrials.gov, NCT02394028, and is closed to recruitment. FINDINGS: Between March 20, 2015, and Sept 7, 2021, 385 patients (209 [54%] male and 326 [85%] white) were randomly assigned in induction cohort 3 to receive placebo (n=97), 105 mg etrolizumab (n=143), or 210 mg etrolizumab (n=145). 487 patients had a CDAI-70 response in any of the induction cohorts and were enrolled into the maintenance cohort, of whom 434 had a response to etrolizumab and were randomly assigned to placebo (n=217) or 105 mg etrolizumab (n=217). At week 14, 48 (33%) of 145 patients in the 210 mg induction etrolizumab group versus 28 (29%) of 96 patients in the placebo induction group were in clinical remission (adjusted treatment difference 3·8% [95% CI -8·3 to 15·3]; p=0·52), and 40 (27%) versus 21 (22%) showed endoscopic improvement (5·8% [-5·4 to 17·1]; p=0·32). At week 66, a significantly higher proportion of patients receiving etrolizumab than those receiving placebo had clinical remission (76 [35%] of 217 vs 52 [24%] of 217; adjusted treatment difference 11·3% [95% CI 2·7-19·7]; p=0·0088) and endoscopic improvement (51 [24%] vs 26 [12%]; 11·5% [4·1-18·8]; p=0·0026). Similar proportions of patients reported one or more adverse events during induction (95 [66%] of 143 in the 105 mg etrolizumab group, 85 [59%] of 145 in the 210 mg etrolizumab group, and 51 [53%] of 96 in the placebo group) and maintenance (189 [87%] of 217 in the etrolizumab group and 190 [88%] of 217 in the placebo group). During induction, the most common treatment-related adverse events were injection site erythema (six [4%] of 143 in the 105 mg etrolizumab group, four [3%] of 145 in the 210 mg etrolizumab group, and none of 96 in the placebo group), and arthralgia (two [1%], one [1%], and four [4%]). In the maintenance cohort, the most common treatment-related adverse events were injection site erythema (six [3%] of 217 in the etrolizumab group vs 14 [6%] of 217 in the placebo: group), arthralgia (five [2%] vs eight [4%]), and headache (five [2%] vs seven [3%]). The most common serious adverse event was exacerbation of Crohn's disease (14 [6%] of 217 patients taking placebo and four [2%] of 217 patients taking 105 mg etrolizumab in the maintenance cohort). INTERPRETATION: A significantly higher proportion of patients with moderately to severely active Crohn's disease achieved clinical remission and endoscopic improvement with etrolizumab than placebo during maintenance, but not during induction. FUNDING: F Hoffmann-La Roche.

Metabolic targeting of NRF2 potentiates the efficacy of the TRAP1 inhibitor G-TPP through reduction of ROS detoxification in colorectal cancer.

Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial homolog of HSP90 chaperones. It plays an important role in protection against oxidative stress and apoptosis by regulating reactive oxidative species (ROS). To further elucidate the mechanistic role of TRAP1 in regulating tumor cell survival, we used gamitrinib-triphenylphosphonium (G-TPP) to inhibit TRAP1 signaling pathways in colon cancer. Inhibition of TRAP1 by G-TPP disrupted redox homeostasis and induced cell death. However, colon cancers show a wide range of responses to G-TPP treatment through the induction of variable ER stress responses and ROS accumulation. Interestingly, a strong inverse correlation was observed between the expression of TRAP1 and antioxidant genes in colon tumor tissues using the GSE106582 database. Using a luciferase reporter assay, we detected increased transcriptional activation of antioxidant response elements (AREs) in G-TPP-treated DLD1 and RKO cells but not in SW48 cells. We found that G-TPP induced upregulation of GRP78, CHOP and PARP cleavage in G-TPP-sensitive cells (SW48). In contrast, G-TPP treatment of G-TPP-resistant cells (DLD1 and RKO) resulted in excessive activation of the antioxidant gene NRF2, leading to ROS detoxification and improved cell survival. The NRF2 target genes HO1 and NQO1 were upregulated in G-TPP-treated DLD1 cells, making the cells more resistant to G-TPP treatment. Furthermore, treatment with both a NRF2 inhibitor and a TRAP1 inhibitor led to excessive ROS production and exacerbated G-TPP-induced cell death in G-TPP-resistant cells. Taken together, dual targeting of TRAP1 and NRF2 may potentially overcome colon cancer resistance by raising cellular ROS levels above the cytotoxic threshold.

Proactive infliximab optimisation using a pharmacokinetic dashboard versus standard of care in patients with Crohn's disease: study protocol for a randomised, controlled, multicentre, open-label study (the OPTIMIZE trial).

INTRODUCTION: Preliminary data indicates that proactive therapeutic drug monitoring (TDM) is associated with better outcomes compared with empiric dose escalation and/or reactive TDM, and that pharmacokinetic (PK) modelling can improve the precision of individual dosing schedules in Crohn's disease (CD). However, there are no data regarding the utility of a proactive TDM combined PK-dashboard starting early during the induction phase, when disease activity and drug clearance are greatest. The aim of this randomised, controlled, multicentre, open-label trial is to evaluate the efficacy and safety of a proactive TDM combined PK dashboard-driven infliximab dosing compared with standard of care (SOC) dosing in patients with moderately to severely active CD. METHODS AND ANALYSIS: Eligible adolescent and adult (aged ≥16-80 years) patients with moderately to severely active CD will be randomised 1:1 to receive either infliximab monotherapy with proactive TDM using a PK dashboard (iDose, Projections Research) or SOC infliximab therapy, with or without a concomitant immunomodulator (IMM) (thiopurine or methotrexate) at the discretion of the investigator. The primary outcome of the study is the proportion of subjects with sustained corticosteroid-free clinical remission and no need for rescue therapy from week 14 throughout week 52. Rescue therapy is defined as any IFX dose escalation other than what is forecasted by iDose either done empirically or based on reactive TDM; addition of an IMM after week 2; reintroduction of corticosteroids after initial tapering; switch to another biologic or need for CD-related surgery. The secondary outcomes will include both efficacy and safety end points, such as endoscopic and biological remission, durability of response and CD-related surgery and hospitalisation. ETHICS AND DISSEMINATION: The protocol has been approved by the Institutional Review Board Committee of the Beth Israel Deaconess Medical Center (IRB#:2021P000391). Results will be disseminated in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER: NCT04835506.

Biodiversity influences the effects of oil disturbance on coastal ecosystems.

Biodiversity can enhance the response of ecosystems to disturbance. However, whether diversity can reduce the ecological effect of human-induced novel and extreme disturbances is unclear. In April 2010, the Deepwater Horizon (DwH) platform exploded, allowing an uncontrolled release of crude oil into the northern Gulf of Mexico. Initial surveys following the spill found that ecological impacts on coastal ecosystems varied greatly across habitat-type and trophic group; however, to date, few studies have tested the influence of local biodiversity on these responses. We used a meta-analytic approach to synthesize the results of 5 mesocosm studies that included 10 independent oil experiments and 5 independent oil + dispersant experiments. We tested whether biodiversity increased the resistance and/or resilience of coastal ecosystems to oil disturbance and whether a biodiversity effect depended on the type of diversity present (taxonomic or genetic) and/or the response type measured (population, community, or ecosystem level). We found that diversity can influence the effects of oiling, but the direction and magnitude of this diversity effect varied. Diversity reduced the negative impact of oiling for within-trophic-level responses and tended to be stronger for taxonomic than genetic diversity. Further, diversity effects were largely driven by the presence of highly resistant or quick to recover taxa and genotypes, consistent with the insurance hypothesis. However, we found no effect of diversity on the response to the combination of oil and dispersant exposure. We conclude that areas of low biodiversity may be particularly vulnerable to future oil disturbances and provide insight into the benefit of incorporating multiple measures of diversity in restoration projects and management decisions.

A Randomized Trial Comparing the Specific Carbohydrate Diet to a Mediterranean Diet in Adults With Crohn's Disease.

BACKGROUND & AIMS: This study compared the effectiveness of the Specific Carbohydrate Diet (SCD) to the Mediterranean diet (MD) as treatment for Crohn's disease (CD) with mild to moderate symptoms. METHODS: Adult patients with CD and with mild-to-moderate symptoms were randomly assigned 1:1 to consume the MD or SCD for 12 weeks. For the first 6 weeks, participants received prepared meals and snacks according to their assigned diet. After 6 weeks, participants were instructed to follow the diet independently. The primary outcome was symptomatic remission at week 6. Key secondary outcomes at week 6 included fecal calprotectin (FC) response (FC <250 µg/g and reduction by >50% among those with baseline FC >250 µg/g) and C-reactive protein (CRP) response (high-sensitivity CRP <5 mg/L and >50% reduction from baseline among those with high-sensitivity CRP >5 mg/L). RESULTS: The study randomized 194 patients, and 191 were included in the efficacy analyses. The percentage of participants who achieved symptomatic remission at week 6 was not superior with the SCD (SCD, 46.5%; MD, 43.5%; P = .77). FC response was achieved in 8 of 23 participants (34.8%) with the SCD and in 4 of 13 participants (30.8%) with the MD (P = .83). CRP response was achieved in 2 of 37 participants (5.4%) with the SCD and in 1 of 28 participants (3.6%) with the MD (P = .68). CONCLUSIONS: The SCD was not superior to the MD to achieve symptomatic remission, FC response, and CRP response. CRP response was uncommon. Given these results, the greater ease of following the MD and other health benefits associated with the MD, the MD may be preferred to the SCD for most patients with CD with mild to moderate symptoms. ClinicalTrials.gov Identifier: NCT03058679.

Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.

Disturbance-driven changes to northern Gulf of Mexico nekton communities following the Deepwater Horizon oil spill.

The 2010 Deepwater Horizon (DwH) oil spill in the Gulf of Mexico discharged ~3.19 million barrels of oil into Gulf waters, making it one of the largest marine disasters in history in terms of volume. We report on the results of a study to assess oil impacts to coastal fishes and invertebrates. Using two-decades of fisheries-independent data in coastal Alabama and Mississippi, we document variability following both natural and anthropogenic disturbances from two periods pre-DwH (1997-2001 and 2007-2009), one intra-spill period for acute DwH effects (2010-2012) and one period post-spill for chronic, longer-term impacts (2014-2017). Results indicated significant changes to community structure, relative abundance, and diversity in the intra-spill period. Causation for changes is confounded by variables such as behavioral emigration, altered freshwater inflow, death of consumers, and the mandated fishery closure. Results highlight the need for long-term, comprehensive monitoring/observing systems to provide adequate background for assessing future disturbances.

Expansion of Bacteriophages Is Linked to Aggravated Intestinal Inflammation and Colitis.

Bacteriophages are the most abundant members of the microbiota and have the potential to shape gut bacterial communities. Changes to bacteriophage composition are associated with disease, but how phages impact mammalian health remains unclear. We noted an induction of host immunity when experimentally treating bacterially driven cancer, leading us to test whether bacteriophages alter immune responses. Treating germ-free mice with bacteriophages leads to immune cell expansion in the gut. Lactobacillus, Escherichia, and Bacteroides bacteriophages and phage DNA stimulated IFN-γ via the nucleotide-sensing receptor TLR9. The resultant immune responses were both phage and bacteria specific. Additionally, increasing bacteriophage levels exacerbated colitis via TLR9 and IFN-γ. Similarly, ulcerative colitis (UC) patients responsive to fecal microbiota transplantation (FMT) have reduced phages compared to non-responders, and mucosal IFN-γ positively correlates with bacteriophage levels. Bacteriophages from active UC patients induced more IFN-γ compared to healthy individuals. Collectively, these results indicate that bacteriophages can alter mucosal immunity to impact mammalian health.

Family History Associates With Increased Risk of Colorectal Cancer in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Individuals with inflammatory bowel diseases (IBDs) have an increased risk of developing colorectal cancer (CRC). Although family history of CRC is a well-established risk factor in healthy individuals, its role in patients with IBD is less clear. We aimed to estimate the risk of CRC in a cohort of patients with IBD from Utah and the significance of family history of CRC in a first-degree relative (FDR). METHODS: We identified Utah residents with IBD, using the Intermountain Healthcare and University of Utah Health Sciences databases, from January 1, 1996, through December 31, 2011. CRCs were identified using the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. CRC incidence was compared with that of the state population by standardized incidence ratios (SIRs). RESULTS: A cohort of 9505 individuals with IBD was identified and 101 developed CRC during the study period. The SIR for CRC in patients with Crohn's disease was 3.4 (95% CI, 2.3-4.4), and in patients with ulcerative colitis was 5.2 (95% CI, 3.9-6.6). Patients with IBD and a concurrent diagnosis of primary sclerosing cholangitis had the greatest risk of CRC (SIR, 14.8; 95% CI, 8.3-21.2). A history of CRC in a FDR was associated with a nearly 8-fold increase in risk of CRC in patients with IBD (SIR, 7.9; 95% CI, 1.6-14.3), compared with the state population. CONCLUSIONS: Patients with IBD have a 3- to 5-fold increase in risk of CRC, and those with CRC in a FDR have an almost 8-fold increase in risk. Family history may act as a simple measure to identify individuals with IBD at highest risk for CRC and indicates the need for enhanced surveillance in this population.

CMV Disease in IBD: Comparison of Diagnostic Tests and Correlation with Disease Outcome.

Background: Significance of cytomegalovirus (CMV) in inflammatory bowel disease (IBD) is unclear due to pathobiology, numerous CMV tests, and disparate treatment outcomes. Methods: Retrospective chart review was done on patients with positive qualitative CMV tissue polymerase chain reaction (PCR) from 2005-2013 at a tertiary referral hospital. Frequency of PCR+, hematoxylin and eosin staining(HE)+, histopathology and immunohistochemistry (IHC)+ was assessed. IHC was assessed on a sample of PCR- tissues. Surgery rates were correlated with CMV testing and treatment. Results: PCR was done on 310 samples from 180 patients. Thirty-seven samples were PCR+ (51.4% PCR+ only, 35.1% IHC/PCR+, 13.5% HE/IHC/PCR+). The H&E frequently failed to detect CMV identified on extensive IHC. Of 13 PCR- samples tested with IHC, 100% were negative. Twenty-five patients were CMV+ (40% PCR+, 40% IHC/PCR+, 20% HE/IHC/PCR+). Surgery rates increased with number of positive tests: 60% in IHC/PCR+ and 80% in HE/IHC/PCR+, compared to 26.8% in PCR- or PCR+ (P = 0.03, P = 0.02, respectively). There were 20/25 PCR+ patients who received CMV treatment. Surgery occurred in 80% of HE+ patients despite treatment and 100% of IHC+ patients without treatment. Conclusions: Rates of CMV+ testing and surgical risk varied by test modality. PCR+ results were most frequent but alone did not detect clinically significant CMV. HE+ testing was least frequent and associated with highest surgical rate, despite treatment. CMV treatment may benefit IHC+ patients most, supporting immunostaining as optimal diagnostic test for clinically significant CMV in IBD. In PCR+ samples, HE frequently did not detect CMV identified on extensive IHC. In PCR- samples, data suggest IHC is likely negative. Consider using qualitative PCR to guide extensive immunostaining.

Chromoendoscopy for Dysplasia Surveillance in Inflammatory Bowel Disease.

Long-standing ulcerative colitis (UC) and extensive Crohn's colitis confer increased risk for development of colorectal cancer. Screening and surveillance colonoscopy programs aim to identify, resect, or detect dysplasia or colorectal cancer. Dysplastic lesions can be removed by endoscopic resection and patients with unresectable lesions can be referred for colectomy at an earlier stage, with the goal of reducing overall morbidity and mortality from colorectal cancer. Surveillance colonoscopy for patients with inflammatory bowel disease (IBD) is endorsed by multiple specialty societies. High-definition endoscopy systems provide improved image resolution, and application of dilute indigo carmine or methylene blue for chromoendoscopy can provide increased contrast. International specialty society guidelines differ in their recommendations regarding use of chromoendoscopy for dysplasia surveillance, with some guidelines advocating a risk-stratified surveillance strategy. In this review, we discuss chromoendoscopy technique, training, implementation, yield as compared with standard-definition and high-definition white light colonoscopy, and positioning of this technique in clinical practice.

Colorectal Cancer in Inflammatory Bowel Diseases: A Population-Based Study in Utah.

BACKGROUND AND AIMS: The molecular, endoscopic, and histological features of IBD-associated CRC differ from sporadic CRC. The objective of this study was to describe the prevalence, clinical features, and prognosis of IBD-associated CRC compared to patients with sporadic CRC in a US statewide population-based cohort. METHODS: All newly diagnosed cases of CRC between 1996 and 2011 were obtained from Utah Cancer Registry. IBD was identified using a previously validated algorithm, from statewide databases of Intermountain Healthcare, University of Utah Health Sciences, and the Utah Population Database. Logistic regression was performed to identify risk factors associated with IBD-associated cancer and Cox regression for differences in survival. RESULTS: Among 12,578 patients diagnosed with CRC, 101 (0.8%) had a prior history of IBD (61 ulcerative colitis and 40 Crohn's disease). The mean age at CRC diagnosis was greater for patients without IBD than those with IBD (67.1 vs 52.8 years, P < 0.001). Individuals with IBD-associated CRC were more likely to be men (odds ratio [OR] 1.90, 95% CI 1.23-2.92), aged less than 65 years (OR 6.77, 95% CI 4.06-11.27), and have CRC located in the proximal colon (OR 2.79, 95% CI 1.85-4.20) than those with sporadic CRC. Nearly 20% of the IBD-associated CRCs had evidence of primary sclerosing cholangitis. After adjustment for age, gender, and stage at diagnosis, the excess hazard of death after CRC diagnosis was 1.7 times higher in IBD than in non-IBD patients (95% CI 1.27-2.33). CONCLUSIONS: The features of patients with CRC and IBD differ significantly from those without IBD and may be associated with increased mortality.

Update on the Diagnosis and Management of Colon Ischemia.

OPINION STATEMENT: Colonic ischemia is the most common ischemic disorder of the gastrointestinal tract. The condition occurs more commonly in women, and risk increases with advancing age. Presenting symptoms include abdominal pain, bowel urgency, and passage of bloody diarrhea; however, nearly one half of patients do not present with this classic triad of symptoms. Abdominal pain without bloody diarrhea or non-bloody diarrhea should raise concern for an isolated right colon pattern of ischemia. An isolated right colon distribution is associated with more severe outcomes, including need for surgical intervention and increased mortality. Patients that present with symptoms concerning for ischemia should undergo computed tomography (CT) scan of the abdomen and pelvis with oral and IV contrast and laboratory testing. Colonoscopy should be performed in patients without evidence of peritonitis. Medical history should be obtained to identify possible etiologies of ischemia. Thrombophilia workup should be considered in young patients and those with recurrent ischemia, but is not required universally. In cases of isolated right colon ischemia, evaluation of the mesenteric vasculature is particularly important, for exclusion of concurrent acute mesenteric ischemia. Treatment of ischemic colitis is supportive in less severe cases, with intravenous fluids and bowel rest. Broad-spectrum antibiotics should be initiated, and surgical consultation should be obtained in cases of severe disease, pancolonic ischemia, and isolated right colonic ischemia. Surgery should be performed for peritonitis, hemodynamic instability, or failure of non-operative management. This article will review colonic ischemia diagnosis, evaluation, and treatment.

Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci. METHODS: We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the United States; additional controls were collected from 4 other Immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease, 361 with ulcerative colitis, 62 with IBD type unknown, and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed. RESULTS: The strongest associations were observed between ulcerative colitis and HLA rs9271366 (P = 7.5 × 10(-6)), Crohn's disease and 5p13.1 rs4286721 (P = 3.5 × 10(-6)), and IBD and KAT2A rs730086 (P = 2.3 × 10(-6)). Additional suggestive associations (P < 4.2 × 10(-5)) were observed between Crohn's disease and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P < 3.1 × 10(-4)) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P < 3.9 × 10(-4)) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2-15q23, and 16p12.2-16p12.1. Network analyses showed significant enrichment (false discovery rate <1 × 10(-5)) in genes that encode members of the JAK-STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles. CONCLUSIONS: In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we also found evidence for variants and loci not previously associated with IBD. The complex genetic factors that determine risk for or protection against IBD in different populations require further study.

Human Placenta-derived Cells (PDA-001) for the Treatment of Moderate-to-severe Crohn's Disease: A Phase 1b/2a Study.

BACKGROUND: PDA-001 (cenplacel-L), a preparation of placenta-derived mesenchymal-like adherent cells with immunomodulatory effects, previously demonstrated safety and tolerability in an open-label Crohn's disease (CD) study. The current phase 1b/2a study evaluated the safety and efficacy of PDA-001 in subjects with moderate-to-severe CD. METHODS: Subjects had active inflammation on colonoscopy or elevated fecal calprotectin and inadequate response to conventional therapy. Concomitant therapy with stable doses of immunomodulators and/or biologics was permitted. Subjects received 8 units of PDA-001 (1.5 × 10 cells per unit) in the phase 1b open-label study. In the phase 2a double-blind study, subjects were randomly assigned placebo, 1 unit, or 4 units of PDA-001 (2 infusions 1 wk apart). The primary endpoint was induction of clinical response (≥100 points and/or 25% decrease in Crohn's Disease Activity Index) at 4 and 6 weeks. RESULTS: Fifty subjects were enrolled (safety analysis, 50 subjects; efficacy analysis, 48 subjects). Four subjects received 8 units of PDA-001 (phase 1b study); 46 subjects were subsequently randomized to 1 or 4 units of PDA-001 or placebo (phase 2a study). The primary endpoint was achieved in 10/28 (36%) of PDA-001 subjects compared with placebo (0%, P = 0.026). Clinical remission was achieved in 4/28 (14%) of PDA-001 subjects compared with placebo (0%, P = 0.3). One treatment-related serious adverse event occurred (systemic hypersensitivity reaction at 8 units). In the phase 2a study, serious adverse events occurred in 9/28 (32%) of PDA-001 subjects and 1/16 (7%) of placebo subjects. CONCLUSIONS: A 2-infusion regimen of PDA-001 induced clinical response in subjects with moderate-to-severe CD. Additional studies are warranted.

Briakinumab for treatment of Crohn's disease: results of a randomized trial.

BACKGROUND: This study assessed the efficacy and safety of briakinumab, a human anti-IL-12/23p40 monoclonal antibody, compared with placebo for the induction and maintenance of remission in patients with moderately to severely active Crohn's disease. METHODS: In this phase 2b, multicenter, double-blind, parallel group study, 246 patients stratified by prior tumor necrosis factor-antagonist use and response, were randomized (1:1:1:3) to 4 intravenous induction regimens: placebo, 200, 400, or 700 mg briakinumab, at weeks 0/4/8. At week 12, responders in the placebo or 400-mg induction groups entered the maintenance phase with the same regimen, whereas responders in the 700-mg induction group were rerandomized (1:1:1) to receive placebo, 200, or 700 mg briakinumab at weeks 12/16/20. At week 24, patients in remission stopped receiving study drug (withdrawal phase) until relapse. Patients experiencing relapse, nonresponders, and nonremitters could enter the open-label phase. RESULTS: The primary end point of clinical remission at week 6 was not met. There were numerically greater rates of remission and response at 6, 12, or 24 weeks in patients treated with briakinumab. The safety and tolerability profile of briakinumab was similar in the induction and maintenance phases of the trial. CONCLUSIONS: Briakinumab showed a similar safety and tolerability profile to placebo in the induction and maintenance phases, and comparable rates of serious adverse events, adverse events leading to discontinuation, and malignancy. These data provide support for the potential efficacy of briakinumab and other IL-12/23 inhibitors in the treatment of moderate-to-severe Crohn's disease.