Development and Validation of a Test to Monitor Endoscopic Activity in Patients With Crohn's Disease Based on Serum Levels of Proteins.

BACKGROUND & AIMS: Noninvasive tests to measure endoscopic activity in patients with Crohn's disease (CD) have limitations. We aimed to develop a test to identify patients in remission, based on endoscopic analysis, and monitor CD activity based on serum levels of proteins. METHODS: We developed a test to measure 13 proteins in blood (ANG1, ANG2, CRP, SAA1, IL7, EMMPRIN, MMP1, MMP2, MMP3, MMP9, TGFA, CEACAM1, and VCAM1), called the endoscopic healing index [EHI], using samples from 278 patients with CD from a multinational training cohort. We validated the test using 2 independent cohorts of patients with CD: 116 biologic-naive patients with early-stage CD (validation cohort 1) and 195 biologic-exposed patients with chronic CD (validation cohort 2). The ability of the test to identify patients with active disease vs patients in remission (defined as a simple endoscopic score for CD of ≤2 and ≤1 in each segment, or a total CD endoscopic index of severity score <3) was assessed by using area under receiver operating characteristic curve (AUROC) analysis. The diagnostic accuracy of the test was compared with that of measurement of serum C-reactive protein (CRP) and fecal calprotectin. RESULTS: The EHI scores range from 0 to 100 units; higher scores indicate more severe CD activity, based on endoscopy findings. The EHI identified patients in remission with an AUROC of 0.962 in validation cohort 1 (95% confidence interval, 0.942-0.982) and an AUROC of 0.693 in validation cohort 2 (95% confidence interval, 0.619-0.767), regardless of CD location or phenotype. A cutoff value of 20 points identified patients in remission with the highest level of sensitivity (97.1% in validation cohort 1 and 83.2% in validation cohort 2), with specificity values of 69.0% and 36.6%, respectively. A cutoff value of 50 points identified patients in remission with the highest level of specificity (100% in validation cohort 1 and 87.8% in validation cohort 2), with sensitivity values of 37.3% and 30.0%, respectively. The EHI identified patients in remission with a significantly higher AUROC value than the test for CRP (0.876, P < .001 in validation cohort 1 and 0.624, P = .109 in validation cohort 2). In analysis of patients with available FC measurements, the AUROC value for the EHI did not differ significantly from that of measurement of FC (AUROC, 0.950 for EHI vs AUROC, 0.923 for FC; P = .147 in validation cohort 1 and AUROC, 0.803 for EHI vs AUROC, 0.854 for FC; P = .298 in validation cohort 2). CONCLUSIONS: We developed an index called the EHI to identify patients with CD in endoscopic remission based on blood levels of 13 proteins. The EHI identified patients with resolution of endoscopic disease activity, with good overall accuracy, although with variation between the 2 cohorts assessed. The EHI AUROC values were comparable to measurement of FC and higher than measurement of serum CRP. The test might be used in practice to assess endoscopic activity in patients with CD.

Irish data on the safety and efficacy of vedolizumab in the treatment of inflammatory bowel disease.

SUMMARY: This study reviews the safety and efficacy of treatment with vedolizumab for patients with inflammatory bowel disease across 9 Irish hospitals. It generates valuable and timely real-world data on treatment outcomes to add to the existing evidence base. Our population represents a refractory cohort with most patients previously exposed to at least one anti-TNFa agent and expressing an inflammatory phenotype. Results are reassuringly similar to larger international studies with additional insights into potential predictors of treatment response. This study further supports the safety and efficacy of vedolizumab in the treatment of inflammatory bowel disease. Key SummaryVedolizumab has growing real world data on its safety and efficacy in the treatment of IBD. Data on predictors of response are lacking. Studies such as VARSITY require new real-world data to help identify the place VDZ will occupy in the treatment algorithm for IBDThis study provides national Irish data on the safety and efficacy of VDZ in the treatment of IBD. It gives insight into various predictors of response for both UC and CD. It strengthens the available body of evidence on the use of VDZ and helps us determine its position on the treatment algorithm.

Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon.

Ward JB, Lajczak NK, Kelly OB, O'Dwyer AM, Giddam AK, Ní Gabhann J, Franco P, Tambuwala MM, Jefferies CA, Keely S, Roda A, Keely SJ. Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon. Am J Physiol Gastrointest Liver Physiol 312: G550-G558, 2017. First published March 30, 2017; doi:10.1152/ajpgi.00256.2016.-Inflammatory bowel diseases (IBD) comprise a group of common and debilitating chronic intestinal disorders for which currently available therapies are often unsatisfactory. The naturally occurring secondary bile acid, ursodeoxycholic acid (UDCA), has well-established anti-inflammatory and cytoprotective actions and may therefore be effective in treating IBD. We aimed to investigate regulation of colonic inflammatory responses by UDCA and to determine the potential impact of bacterial metabolism on its therapeutic actions. The anti-inflammatory efficacy of UDCA, a nonmetabolizable analog, 6α-methyl-UDCA (6-MUDCA), and its primary colonic metabolite lithocholic acid (LCA) was assessed in the murine dextran sodium sulfate (DSS) model of mucosal injury. The effects of bile acids on cytokine (TNF-α, IL-6, Il-1ß, and IFN-γ) release from cultured colonic epithelial cells and mouse colonic tissue in vivo were investigated. Luminal bile acids were measured by gas chromatography-mass spectrometry. UDCA attenuated release of proinflammatory cytokines from colonic epithelial cells in vitro and was protective against the development of colonic inflammation in vivo. In contrast, although 6-MUDCA mimicked the effects of UDCA on epithelial cytokine release in vitro, it was ineffective in preventing inflammation in the DSS model. In UDCA-treated mice, LCA became the most common colonic bile acid. Finally, LCA treatment more potently inhibited epithelial cytokine release and protected against DSS-induced mucosal inflammation than did UDCA. These studies identify a new role for the primary metabolite of UDCA, LCA, in preventing colonic inflammation and suggest that microbial metabolism of UDCA is necessary for the full expression of its protective actions.NEW & NOTEWORTHY On the basis of its cytoprotective and anti-inflammatory actions, the secondary bile acid ursodeoxycholic acid (UDCA) has well-established uses in both traditional and Western medicine. We identify a new role for the primary metabolite of UDCA, lithocholic acid, as a potent inhibitor of intestinal inflammatory responses, and we present data to suggest that microbial metabolism of UDCA is necessary for the full expression of its protective effects against colonic inflammation.

The Inappropriate Prescription of Oral Proton Pump Inhibitors in the Hospital Setting: A Prospective Cross-Sectional Study.

UNLABELLED: Proton pump inhibitors (PPIs) are used to treat upper gastrointestinal tract disorders. Their efficacy and perceived safety have led to widespread prescription. This is not without effect, in terms of adverse events and resource utilization. AIM: To prospectively assess oral PPI prescription in hospitalized patients. METHODS: PPI prescription in consecutive hospitalized patients was assessed. Indication and dose were assessed by patient interview and medical record review. Comparisons with current published prescribing guidelines were made. RESULTS: Four hundred and forty-seven patients were included. 57.5 % were prescribed PPIs. 26.8 % prescriptions were for inappropriate or unclear indications. 68.4 % were on higher doses than guidelines recommended, of which 41.6 % could have undergone dose reduction, and 26.5 % discontinued. In a multivariate analysis, age, gender, and length of stay had no association with PPI prescription. Although aspirin use was appropriately associated with PPI prescription (RR: 1.8, 95 % CI 1.127-3.69; p < 0.05), the PPI was often given at higher than recommended doses (p < 0.001). This may reflect older age and multiple risk factors in this subset. Surgical patients commenced more PPIs and at higher dosages (p < 0.001). Omeprazole and lansoprazole were most often inappropriately prescribed (p < 0.01, p < 0.001, respectively). CONCLUSION: Inappropriate PPI therapy is still a problem in hospitals, though it appears to be at a lower level compared with previous studies. Awareness of evidence-based guidelines and targeted medicine reconciliation strategies are essential for cost-effective and safe use of these medications.

Current and Future Perspectives on the Management of Helicobacter pylori: A Narrative Review.

The prevalence of Helicobacter pylori (H. pylori), a pathogen, has decreased globally in the last decade. To date, the management of H. pylori has focused on a reactive approach, whereby those diagnosed are treated with antimicrobials and acid suppression in combination. This review article provides an overview of the shift in the management of H. pylori from a reactive approach towards a proactive 'screen and treat' approach; the article reflects the current pharmacological landscape for H. pylori treatment by exploring similarities such as the first-line prescription of quadruple therapy in most countries and provides a summary table of the best practice guidance from Europe, Asia, and North America. It explores significant ongoing challenges in management, such as rising antimicrobial resistance rates, and explores a potential 'work smart' approach to antimicrobial susceptibility testing. We explore the role of registry databases in providing data on treatment efficacy and safety and how they can support a strategic approach to H. pylori treatment. We question if such a database's availability, update, and regular audit should serve as a key quality indicator in a population screening programme. Despite a call for vaccination against H. pylori and decades of research, not many have made it to a phase-three clinical trial. We explore the challenges that have complicated the development of such a vaccine, such as the genetic diversity of H. pylori, immunotolerance, and limitations of mouse models in research; we reflect on how these challenges are contributing to a low likelihood of having a vaccine in the short-medium term. Lastly, it explores the heterogeneity in research on probiotics and their role as an adjunct in the management of H. pylori.

Higher Ustekinumab Levels in Maintenance Therapy are Associated with Greater Mucosal Healing and Mucosal Response in Crohn's Disease: An Experience of 2 IBD Centers.

BACKGROUND: Ustekinumab (UST), a human monoclonal antibody that binds the p40 subunit of interleukin 12 (IL-12) and IL-23, is licensed for induction and maintenance therapy of moderate to severe inflammatory bowel disease (IBD). To date, there is limited data published on any potential association between ustekinumab serum trough levels and mucosal healing in order to guide treatment strategies and appropriate dosing. AIM: This study aims to identify a relationship between maintenance ustekinumab serum trough levels and mucosal healing and/or response in patients with Crohn's disease in an observational cohort study. METHODS: Ustekinumab serum trough levels and antibody titres were analyzed in patients on maintenance drug using an ELISA drug-tolerant assay. Mucosal response (MR) was defined as ≥50% reduction in fecal calprotectin level (FC) and/or ≥50% reduction in the Simple Endoscopic Score for Crohn's Disease (SES-CD score). Mucosal healing (MH) was defined as FC ≤150 µg/mL and/or global SES-CD score ≤5. Median trough levels were analyzed using the Kruskal-Wallis test, and logistic regression was used to determine sensitivity and specificity of levels predicting mucosal response. RESULTS: Forty-seven patients on maintenance ustekinumab for Crohn's disease were included in this study. The majority were female (66%), with a median age of 40 years (21-78 years). The majority of patients were biologic-experienced (89.4%, n = 42). Patients with histologically confirmed Crohn's disease represented 100% (n = 47) of the cohort. Over one-third of patients (n = 18, 38.3%) were on higher than standard dosing of 90 mg every 8 weeks. Patients with mucosal healing (n = 30) had significantly higher mean serum ustekinumab levels (5.7 µg/mL, SD 6.4) compared with those with no response (1.1 µg/mL, SD 0.52; n = 7, P < .0001). A serum ustekinumab trough level greater than 2.3 µg/mL was associated with MH, with a sensitivity of 100% and specificity of 90.6% (likelihood ratio 10.7). Similarly, for patients with MR (n = 40), we observed a higher mean serum ustekinumab trough level (5.1 µg/mL, SD 6.1) compared with those with no response (1.1 µg/mL, SD 0.52; n = 7, P < .0001). Furthermore, a serum ustekinumab trough level greater than 2.3 µg/mL was associated with a 10-fold increased likelihood of mucosal response vs mucosal nonresponse (sensitivity 100%, specificity 90.5%, likelihood ratio 10.5). CONCLUSION: This study demonstrates that higher ustekinumab serum trough levels are associated with a greater likelihood of achieving mucosal healing and mucosal response in patients with Crohn's disease regardless of prior biologic exposure. Further prospective studies are required to correlate target maintenance trough levels and the optimal time to dose-escalate in order to improve patient outcomes.

Ursodeoxycholic acid attenuates colonic epithelial secretory function.

Dihydroxy bile acids, such as chenodeoxycholic acid (CDCA), are well known to promote colonic fluid and electrolyte secretion, thereby causing diarrhoea associated with bile acid malabsorption. However, CDCA is rapidly metabolised by colonic bacteria to ursodeoxycholic acid (UDCA), the effects of which on epithelial transport are poorly characterised. Here, we investigated the role of UDCA in the regulation of colonic epithelial secretion. Cl(-) secretion was measured across voltage-clamped monolayers of T84 cells and muscle-stripped sections of mouse or human colon. Cell surface biotinylation was used to assess abundance/surface expression of transport proteins. Acute (15 min) treatment of T84 cells with bilateral UDCA attenuated Cl(-) secretory responses to the Ca(2+) and cAMP-dependent secretagogues carbachol (CCh) and forskolin (FSK) to 14.0 ± 3.8 and 40.2 ± 7.4% of controls, respectively (n = 18, P < 0.001). Investigation of the molecular targets involved revealed that UDCA acts by inhibiting Na(+)/K(+)-ATPase activity and basolateral K(+) channel currents, without altering their cell surface expression. In contrast, intraperitoneal administration of UDCA (25 mg kg(-1)) to mice enhanced agonist-induced colonic secretory responses, an effect we hypothesised to be due to bacterial metabolism of UDCA to lithocholic acid (LCA). Accordingly, LCA (50-200 µm) enhanced agonist-induced secretory responses in vitro and a metabolically stable UDCA analogue, 6α-methyl-UDCA, exerted anti-secretory actions in vitro and in vivo. In conclusion, UDCA exerts direct anti-secretory actions on colonic epithelial cells and metabolically stable derivatives of the bile acid may offer a new approach for treating intestinal diseases associated with diarrhoea.

Sociodemographic variables as predictors of adverse outcome in SARS-CoV-2 infection: an Irish hospital experience.

INTRODUCTION: Our hospital found itself at the epicentre of the Irish COVID-19 pandemic. We describe the organisational challenges faced in managing the surge and identified risk factors for mortality and ICU admission among hospitalised SARS-CoV-2-infected patients. METHODS: All hospitalised SARS-CoV-2 patients diagnosed between March 13 and May 1, 2020, were included. Demographic, referral, deprivation, ethnicity and clinical data were recorded. Multivariable regression, including age-adjusted hazard ratios (HR (95% CI), was used to explore risk factors associated with adverse outcomes. RESULTS: Of 257 inpatients, 174 were discharged (68%) and 39 died (15%) in hospital. Two hundred three (79%) patients presented from the community, 34 (13%) from care homes and 20 (8%) were existing inpatients. Forty-five percent of community patients were of a non-Irish White or Black, Asian or minority ethnic (BAME) population, including 34 Roma (13%) compared to 3% of care home and 5% of existing inpatients, (p < 0.001). Twenty-two patients were healthcare workers (9%). Of 31 patients (12%) requiring ICU admission, 18 were discharged (58%) and 7 died (23%). Being overweight/obese HR (95% CI) 3.09 (1.32, 7.23), p = 0.009; a care home resident 2.68 (1.24, 5.6), p = 0.012; socioeconomically deprived 1.05 (1.01, 1.09), p = 0.012; and older 1.04 (1.01, 1.06), p = 0.002 were significantly associated with death. Non-Irish White or BAME were not significantly associated with death 1.31 (0.28, 6.22), p = 0.63 but were significantly associated with ICU admission 4.38 (1.38, 14.2), p = 0.014 as was being overweight/obese 2.37 (1.37, 6.83), p = 0.01. CONCLUSION: The COVID-19 pandemic posed unprecedented organisational issues for our hospital resulting in the greatest surge in ICU capacity above baseline of any Irish hospital. Being overweight/obese, a care home resident, socioeconomically deprived and older were significantly associated with death, while ethnicity and being overweight/obese were significantly associated with ICU admission.

Differential miRNA Expression in Ileal and Colonic Tissues Reveals an Altered Immunoregulatory Molecular Profile in Individuals With Crohn's Disease versus Healthy Subjects.

BACKGROUND: MicroRNAs [miRNAs] are key modulators of gene expression in Crohn's disease [CD] and may drive tissue-specific molecular alterations underlying CD susceptibility. In this study, we analysed differential miRNA expression between CD and healthy subjects across ileal and colonic tissues. METHODS: A cohort of CD and healthy control [HC] subjects was recruited and clinical data collected. Endoscopically quiescent CD [CDq] was defined as inactive or mild by the Simple Endoscopic Score for CD. Total RNA was extracted from endoscopic biopsies taken from the terminal ileum and sigmoid colon. miRNA expression was quantified using NanoString Technologies. Statistical significance was assessed across biopsy site and diagnosis per miRNA, and corrected for multiple testing. RESULTS: In total, 23 CDq and 38 HC subjects were enrolled; 112 samples were included in the analysis, 51 from the ileum and 61 from the colon. We found 47 miRNAs differentially expressed by biopsy site in healthy tissue. Nine miRNAs were differentially expressed across HC and CDq, accounting for biopsy location. One of these, miR-223-3p, showed age and sex effects. We identified miRNA expression driven by diagnosis targeting genes involved in chemokine and cytokine signalling. miR-31-5p expression was driven by location and may be a biomarker for location subtypes in CD. CONCLUSIONS: We identified differentially expressed miRNAs in healthy ileal and colonic tissues. We discovered spatial miRNA expression patterns in CD and HC, suggesting site-specific regulation in subjects with no or minimal intestinal inflammation. These miRNAs target genes involved in immunoregulatory processes, suggesting a functional, tissue-specific role in CD.

Mucosa-Associated Microbiota in Ileoanal Pouches May Contribute to Clinical Symptoms, Particularly Stool Frequency, Independent of Endoscopic Disease Activity.

INTRODUCTION: Pouchitis is a common complication after ileal pouch-anal anastomosis (IPAA). However, there is a poor correlation between symptoms and endoscopic appearance of the pouch, and many patients can have debilitating symptoms in the absence of overt inflammation. It is unknown whether these clinical symptoms are independently associated with the microbiota. The objective of this work was to examine whether the individual clinical components of the pouch activity scoring systems are associated with specific microbiota. METHODS: Pouch biopsies from 233 patients (50% male, 100% IPAA/ulcerative colitis) post-IPAA were included. Clinical phenotyping was performed, and patients were classified using both clinical and endoscopic components of the Pouch Activity Scale. Scoring for symptoms examined 24-hour stool frequency, urgency, incontinence, and rectal bleeding as described by the Pouchitis Disease Activity Index Score. RESULTS: In the absence of inflammation, an increase in stool frequency reported over 24 hours was associated with a decrease in Bacteroidetes relative abundance, and this was the strongest association found. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis in inflamed groups showed that an increase in 24-hour stool frequency was associated with an increase in biofilm formation. DISCUSSION: These findings indicate that in patients with IPAA, the composition of mucosa-associated microbiota of the pouch may contribute to clinical symptoms, particularly stool frequency, independent of endoscopic disease activity.

The Prevalence and Clinical Associations of Subclinical Sacroiliitis in Inflammatory Bowel Disease.

BACKGROUND: Sacroiliitis, an inflammatory arthropathy associated with ankylosing spondylitis (AS), is found in patients with inflammatory bowel disease (IBD) but may go undiagnosed. The aims of this study were to assess prevalence of sacroiliitis in IBD and to determine association between clinical characteristics of IBD and sacroiliitis. METHODS: Inflammatory bowel disease patients undergoing abdomino-pelvic computed tomography (CT) for any indication (2006-2015) were identified. Using standardized CT scoring, sacroiliitis was confirmed. Two blinded readers used a standardised model where presence of ankylosis or erosion score >3 indicated sacroiliitis. Inflammatory bowel disease scoring was blinded to the presence of sacroiliitis. Demographics, IBD characteristics, clinical activity (Harvey Bradshaw Index >4, Mayo >2, as denoted by attending physician), endoscopic activity (Simple Endoscopic Score for Crohn's Disease >4/Mayo subscore >1), and arthritis/extraintestinal manifestations (EIMS) were recorded. Comparisons were made between those with/without sacroiliitis. RESULTS: Three hundred sixteen patients were included (50% male; 74% Crohn's disease [CD]). Computed tomography scoring identified 49 (16%) with sacroiliitis. Radiologists had reported sacroiliitis in 33% of these. Five patients had been to a spondylitis clinic. Thirty-three of 49 had abdominal x-rays; 64% of these fulfilled the imaging component of Modified New York criteria for AS. More than 5 sacroiliac erosions were associated with radiologist-reported sacroiliitis (P < 0.0001). There was no difference in prevalence between CD and ulcerative colitis. Sacroiliitis was associated with male sex (63.3% vs 47.9%; odds ratio [OR], 1.8; P = 0.04), known arthritis (41% vs 12%; OR, 4.7; P < 0.0001), pain as an IBD symptom (77.7% vs 56.9%; P = 0.03), and CD inflammatory phenotype (P = 0.01). Endoscopic activity, location, and extent were not associated. CONCLUSIONS: Sacroiliitis is underdiagnosed in IBD and is associated with male sex, arthritis, and inflammatory CD. Data support targeted screening in at-risk patients.

Fecal calprotectin correlates with active colonic inflammatory bowel disease but not with small intestinal Crohn's disease activity.

BACKGROUND: The utility of fecal calprotectin (FC) in small intestinal Crohn's disease (CD) is unclear. We examined how reliably FC reflects clinical and mucosal disease activity in small intestinal CD, colonic CD, and ulcerative colitis (UC). METHODS: A total of 72 Inflammatory Bowel Disease (IBD) patients (23 colonic CD, 14 isolated small intestinal CD, and 35 UC) were included. Clinical activity was assessed using the Harvey-Bradshaw Index (HBI) (CD) and Mayo score (UC). Inflammatory activity was assessed through ileocolonoscopy, cross-sectional imaging, C-reactive protein (CRP), and FC. Clinical activity was defined as HBI > 4 or Mayo clinical score ≥ 3. Endoscopy activity was defined as Mayo endoscopic subscore ≥ 1, SES-CD score ≥ 3, and Rutgeerts > i1. RESULTS: In UC, FC was correlated with the Mayo clinical score (P < 0.0001) and was highly correlated with the total Mayo score (P < 0.0001). A cut-off value of FC 100 µg/g provided sensitivity of 88% and specificity 100% for endoscopic activity. FC was lower for patients with endoscopic and clinical remission compared to active endoscopic disease (median 100 vs 1180 µg/g, P < 0.0001). In colonic CD, there was a significant correlation between FC and endoscopic activity (P < 0.001). For an FC cut-off value of 100 µg/g, sensitivity was 100%, and specificity was 67%. In contrast, for isolated small intestinal CD, there was no significant correlation between FC and objective disease activity measured by either endoscopy or imaging (AUC 0.52, P = 0.58). CONCLUSION: FC is reliable for the detection of colonic mucosal inflammation in both UC and CD but is less sensitive and reliable in the detection of small intestinal CD.

Differential Expression of microRNAs in Peripheral Blood Mononuclear Cells Identifies Autophagy and TGF-Beta-Related Signatures Aberrantly Expressed in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: MicroRNAs [miRNAs] have emerged as important regulators in inflammatory bowel disease [IBD]. This study investigated differential expression of miRNAs across clinical phenotypes in a well-characterized cohort of IBD patients and healthy controls [HCs]. METHODS: A cohort of Crohn's disease [CD] and ulcerative colitis [UC] patients and HCs was prospectively accrued. Total RNA was extracted from peripheral blood mononuclear cells for all subjects. miRNA expression was measured using NanoString technologies. The subjects were stratified according to disease activity and location. Statistical significance was assessed per miRNA across outcomes and corrected for multiple testing. miRNA regulation of transcription of important results was confirmed in vitro by a dual luciferase reporter assay and autophagy function was evaluated using immunofluorescence imaging of LC3 puncta in HeLa cells. RESULTS: In total, 120 subjects were enrolled. Seventy-four miRNAs were differentially expressed across CD, UC and HCs. Comparing quiescent CD [CDq] with HCs we found ten miRNAs upregulated in CDq. When comparing colonic CD [CCD] to UC, seven miRNAs were upregulated in CCD. The most differentially expressed miRNA in CCD vs UC was miR-874-3p, and we showed its possible utility as a biomarker of differential diagnosis. We showed miR-874-3p targets ATG16L1 and reduces its expression in vitro. An miR-874-3p mimic dysregulates autophagy by a reduction of LC3 in vitro. CONCLUSIONS: We identified unique miRNA signatures expressed in distinct IBD phenotypes. These associations highlight pathways dysregulated by aberrant miRNA expression, revealing possible mechanisms underlying the pathophysiology of IBD, but also suggest a cluster of miRNAs as readily accessible biomarkers to aid in differential diagnosis.

Therapeutic Drug Monitoring to Guide Infliximab Dose Adjustment is Associated with Better Endoscopic Outcomes than Clinical Decision Making Alone in Active Inflammatory Bowel Disease.

BACKGROUND: Adequate infliximab (IFX) levels are associated with favorable outcomes in inflammatory bowel disease. Using therapeutic drug monitoring (TDM) to guide dosing is cost effective and associated with clinical improvement, but effect on endoscopic outcomes remains unclear. METHODS: Primary responders to IFX who underwent dose escalation (2008-2014) were reviewed. Patients with active endoscopic disease were included. Two cohorts were examined: TDM-based decision to escalate (TDM) and clinical decision (non-TDM). Outcomes recorded at median 6 months after adjustment included endoscopic remission (Mayo <1, Simple Endoscopic Score for Crohn's Disease <3), C-reactive protein, and inflammatory bowel disease-specific health care utilization. Postadjustment IFX and antibodies to infliximab levels discriminant for endoscopic remission were determined. Multivariable regression evaluated independent predictors of remission. RESULTS: Of note, 312 dose optimizations were examined (149 TDM and 163 non-TDM). Clinically, groups were similar. Sixty-three percent TDM attained postadjustment endoscopic remission compared with 48% non-TDM (P < 0.05). Sixty-nine percentage TDM had significant clinical response (57% non-TDM [P < 0.01]); fewer were hospitalized (22% TDM versus 35% non-TDM, P = 0.025). Patients with ulcerative colitis had shorter time to escalation (10 versus 20 mo, P < 0.0001). Median IFX levels increased after escalation in TDM (1.5 [pre] and 11 µg/mL [post]; P < 0.0001) and were higher than non-TDM postadjustment levels (11 versus 6.5 µg/mL, P = 0.015). Postadjustment IFX >4.5 µg/mL (area under curve = 0.8; 95% confidence interval, 0.71-0.88) and antibodies to infliximab <3.3 U/mL (area under curve = 0.70; 95% confidence interval, 0.63-0.81) were associated with endoscopic remission. Multivariable analysis showed that IFX concentration (odds ratio 1.2 [95% confidence interval, 1.1-1.3]; P < 0.0001) remained an independent predictor of endoscopic remission. CONCLUSIONS: TDM before dose adjustment is associated with higher postadjustment levels and endoscopic remission.

Development of the Harvey-Bradshaw Index-pro (HBI-PRO) Score to Assess Endoscopic Disease Activity in Crohn's Disease.

BACKGROUND: There is a need for better, less-invasive disease activity indices that provide a representative assessment of endoscopic disease activity. We developed a new clinical score that incorporates the Harvey-Bradshaw index [HBI] with modified patient-reported outcomes [PROp] and physician [clinician]-reported outcomes [PROc] and assessed its ability to measure endosopic disease activity in ileocolonic Crohn's disease [CD]. METHODS: A cohort of 88 CD patients undergoing colonoscopy was accrued in a prospective fashion. In total, 48 of the subjects were CD cases and 40 had already undergone a post-operative ileocolonic resection [post-op CD]. Each patient underwent multiple, endoscopist-blinded assessments including: HBI score, a PROp question asking for patient perception of disease activity status, a PROc question for clinician perception of disease activity status and C-reactive protein [CRP]. Active endoscopic disease was defined as Simple Endoscopic Score for CD [SES-CD] ≥ 3 for CD subjects and Rutgeerts score > i1 for post-op CD subjects. RESULTS: Clinical remission as defined by the HBI did not accurately reflect endoscopic remission as defined by the SES-CD (area under the curve [AUC] = 0.54). Combining the HBI with PROp and PROc scores and then further adding CRP significantly improved the correlation with SES-CD [AUC = 0.78 and AUC = 0.88, respectively, p < 0.00001]. In post-op CD, HBI-defined remission also performed poorly against endoscopic remission defined by the Rutgeerts score [AUC = 0.52]. Combining HBI with PROp and the PROc scores and then further adding CRP did not significantly improve the model [AUC = 0.65 and AUC = 0.61, respectively, p = NS]. CONCLUSION: In CD, the HBI correlates poorly with endoscopic disease activity. However, the HBI-PRO score, which incorporated PROp, PROc, CRP and HBI, significantly improved its ability to predict endoscopic activity in ileocolonic CD without prior surgery.

Low Fecal Calprotectin Correlates with Histological Remission and Mucosal Healing in Ulcerative Colitis and Colonic Crohn's Disease.

BACKGROUND: Data regarding the correlation of histologic and endoscopic healing with fecal calprotectin (FC) are conflicting. We examined how FC levels correlate with histological and endoscopic remission in colonic inflammatory bowel disease. METHODS: Fifty-eight patients (23 with colonic Crohn's disease [CD] and 35 with ulcerative colitis [UC]) were included. Clinical activity was assessed by Harvey-Bradshaw index (CD) and Mayo score (UC). Inflammatory activity was assessed by ileocolonoscopy, C-reactive protein, and FC. Clinical remission was defined as Harvey-Bradshaw index ≤ 4 or Mayo score ≤ 2 and mucosal healing as Mayo endoscopic subscore = 0 (UC), and Simple Endoscopic Score-CD <3 (CD). Histologic activity was assessed in 27 patients (15 CD, 12 UC). Histological remission was defined as absence of active inflammation (Geboes score <3.1) and absence of basal plasmacytosis. RESULTS: In UC, FC correlated with clinical Mayo score (r = 0.63, P < 0.0001). This correlation was strengthened by adding the endoscopic subscore (r = 0.90, P < 0.0001). The endoscopic subscore also independently correlated with FC (r = 0.96, P < 0.0001). In Crohn's colitis, endoscopic activity correlated with FC (r = 0.61, P < 0.001). FC levels were lower overall for patients with endoscopic remission compared with active endoscopic disease (median 100 versus 1180 µg/g, P < 0.0001). FC also correlated with histological remission (Geboes score < 3.1) and absence of basal plasmacytosis in CD (r = 0.77, r = 0.80, respectively; P < 0.01). Area under the curve for FC as a predictor of histological remission (Geboes score <3.1) was 0.95 (95% CI, 0.82-1). CONCLUSIONS: Low FC correlates well with histological remission and mucosal healing in colonic inflammatory bowel disease and is thus a clinically useful surrogate for inflammatory activity.

Infliximab to Treat Refractory Inflammation After Pelvic Pouch Surgery for Ulcerative Colitis.

BACKGROUND: Inflammatory pouch complications refractory to first-line therapies remain problematic following ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC). We evaluated infliximab efficacy and associations with therapeutic response. METHODS: Data from individuals who underwent colectomy and IPAA for UC (2000-2014) were reviewed. Patients with chronic refractory pouchitis (CP) and Crohn's disease (CD)-like outcomes treated with infliximab were included. Pre-treatment parameters and response at median 8 (initial) and 48 weeks (sustained) were measured. Complete response was defined as symptomatic and endoscopic resolution with modified Pouchitis Disease Activity Index (mPDAI) <5. Partial response included mPDAI improvement >2. Serum was analysed for Anti-Saccharomyces cerevisiae antibodies (ASCA), anti-OmpC, anti-CBir1 and perinuclear Anti-Neutrophil Cytoplasmic Antibodies (pANCA). RESULTS: One hundred and fifty-two patients with CP or a CD-like phenotype were identified. Forty-two were treated with infliximab (33% male; age 32.6±2.6 years, 28.5% CD-like). Post-induction response was achieved in 74% (48% complete) and sustained response in 62.6% (29.6% complete). Mean mPDAI and C-reactive protein declined from 8.5±0.3 to 2±3.4 (p < 0.002) and from 29.48±6.2 to 5.76±1.6mg/L (p < 0.001), respectively. Female gender, smoking and presence of anti-CBir1 were associated with infliximab use (p < 0.01) but not response. Pre-treatment mPDAI <10 (p < 0.01), resolution of rectal bleeding (p < 0.001 ) and week 8 endoscopic activity were associated with sustained response (p = 0.04; odds ratio [OR] 2.2; 95% confidence interval [CI] 1.1-16.5]). More than 2 positive antimicrobial antibody titres were associated with non-response (p < 0.05), but did not retain significance in multivariate analysis (p = 0.197; OR 0.632; 95% CI 0.31-1.2). CONCLUSIONS: Infliximab can effectively treat inflammatory pouch complications. Pre-treatment mPDAI <10 and early endoscopy may identify responders.

Drug treatment of eosinophilic oesophagitis.

Eosinophilic oesophagitis is a clinicopathological disease characterized by oesophageal eosinophilia and gastrointestinal symptoms. Currently, the optimal treatment regimens remain unclear. The pathogenesis of eosinophilic oesophagitis appears to involve immune dysregulation, while acid reflux may have a secondary role; the mainstays in treatment are aimed principally at these dual processes. While a trial of a PPI is worthwhile it is likely that PPI therapy is treating concurrent acid reflux rather than true eosinophilic oesophagitis. Dietary elimination with elemental feed is safe but poorly tolerated. Swallowed topical steroids are the mainstay of commercially available therapies. Both fluticasone and budesonide have been proven to be beneficial both symptomatically and in reducing oesophageal eosinophil counts in the short and medium term. Basic studies have determined a role for IL-5 in oesophageal remodelling in eosinophilic esophagitis. Initial clinical studies have shown single or multiple infusions of monoclonal antibody to IL-5 to be well tolerated and to cause a long-term decrease in both peripheral and sputum eosinophil count in these eosinophil driven conditions. At present, swallowed corticosteroids are the mainstay of treatment for patients with eosinophilic oesophagitis in patients failing PPI therapy. Studies have been heterogenous in their diagnostic criteria for eosinophilic oesophagitis and in the definition of response to therapy, making comparison of results difficult.

Eosinophilic oesophagitis: an Irish experience.

INTRODUCTION: Eosinophilic oesophagitis is a recently recognized oesophageal disorder characterized by a combination of clinical and endoscopic features as well as the histological finding on oesophageal biopsy of greater than 15 eosinophils per high powered field. Recent reports suggest eosinophilic oesophagitis is increasing in incidence and this increase cannot be fully explained by increased recognition of the disorder. The aim of this retrospective study was to assess the incidence of eosinophilic oesophagitis within the catchment area of a tertiary referral hospital in southwest Dublin, Ireland. METHODS: The histopathology database at the Adelaide and Meath Hospital was used to identify all oesophageal biopsies obtained between January 2000 and July 2008 reported to show evidence of oesophagitis. Biopsy samples with greater than 15 eosinophils per high powered field in at least two fields were highlighted as possible eosinophilic oesophagitis. The oesophageal biopsies of patients identified in this way were reviewed by a histopathologist with a special expertise in gastroenterology for features suggestive of eosinophilic oesophagitis. RESULTS: Twenty-five thousand three hundred and sixty-five upper gastrointestinal endoscopies were performed between January 2000 and July 2008. A total of 11 072 sets of oesophageal biopsies were taken and 1364 (12.3%) of these revealed evidence of oesophagitis. Only 13 (0.1%) patients had oesophageal biopsies showing greater than 15 eosinophils per high powered field. The median age of this patient group was 23 years (interquartile range 10.5-50.5 years), with 46% of patients under 18 years at the time of diagnosis. The male to female ratio was 5.5 : 1 compared with 1.1 : 1 in the oesophagitis group as a whole, (P=0.002). There was no significant association between endoscopic findings or presenting complaints and the average number of eosinophils per high powered field. The average number of biopsies taken in patients with endoscopic findings suggestive of eosinophilic oesophagitis was 3.75 compared with 1 in patients without those features, (P=0.01). CONCLUSION: Our findings suggest that eosinophilic oesophagitis is a rare disorder predominantly affecting young men.