Pentacyclic triterpenes modulate farnesoid X receptor expression in colonic epithelial cells: Implications for colonic secretory function.

The nuclear bile acid receptor, farnesoid X receptor (FXR), is an important regulator of intestinal and metabolic function. Previous studies suggest that pentacyclic triterpenes (PCTs), a class of plant-derived bioactive phytochemical, can modulate FXR activity and may therefore offer therapeutic benefits. Here, we investigated the effects of a prototypical PCT, hederagenin (HG), on FXR expression, activity, and antisecretory actions in colonic epithelial cells. T84 cells and murine enteroid-derived monolayers were employed to assess HG effects on FXR expression and activity in colonic epithelia. We measured mRNA levels by qRT-PCR and protein by ELISA and immunoblotting. Transepithelial Cl- secretion was assessed as changes in short circuit current in Ussing chambers. We determined HG treatment (5-10 µM) alone did not induce FXR activation but significantly increased expression of the receptor, both in T84 cells and murine enteroid-derived monolayers. This effect was accompanied by enhanced FXR activity, as assessed by FGF-15/19 induction in response to the synthetic, GW4064, or natural FXR agonist, chenodeoxycholic acid. Effects of HG on FXR expression and activity were mimicked by another PCT, oleanolic acid. Furthermore, we found FXR-induced downregulation of cystic fibrosis transmembrane conductance regulator Cl- channels and inhibition of transepithelial Cl- secretion were enhanced in HG-treated cells. These data demonstrate that dietary PCTs have the capacity to modulate FXR expression, activity, and antisecretory actions in colonic epithelial cells. Based on these data, we propose that plants rich in PCTs, or extracts thereof, have excellent potential for development as a new class of "FXR-targeted nutraceuticals".

A systematic review of the effect of structured exercise on inflammation and body composition in inflammatory bowel disease.

PURPOSE: Given the substantial risk of treatment failure in inflammatory bowel disease (IBD), adjuvant therapies may play a role in disease management. We aim to carry out a systematic review to examine the effects of structured exercise on the inflammatory response in patients with IBD. Our secondary aim is to examine the effect of structured exercise programmes on body composition given both an increase in visceral obesity and the presence of sarcopenia have deleterious effects on outcomes in IBD. METHODS: A systematic review was carried out following the Methodological Expectations of Cochrane Intervention Reviews (MECIR) manual and the Cochrane Handbook for Systematic Reviews of Interventions. Title/Abstract and MeSH Terms were used to search for relevant studies. RESULTS: In total, 1516 records were screened for eligibility, and 148 records were reviewed for eligibility, of which 16 were included and a further 7 studies were identified from hand searching references. Four studies included body composition outcomes, and 14 studies reviewed the inflammatory response to exercise. CONCLUSION: Further studies of adequate duration are required to include patients with more active disease to demonstrate an inflammatory response to exercise. Body composition measurements including muscle mass and visceral adiposity may play a key role in response to medical therapy in IBD and should be included as exploratory outcomes in future studies. A meta-analysis was not carried out due to the significant heterogeneity amongst studies.

Visceral adiposity and inflammatory bowel disease.

BACKGROUND: Rates of obesity are increasing worldwide, as is the incidence of inflammatory bowel disease (IBD). Obesity is now considered an inflammatory state. Visceral adiposity in particular may be associated with a more severe inflammatory phenotype in IBD. AIM: The aim of this review article is to summarise the current literature on the association between visceral adiposity and outcomes in inflammatory bowel disease METHODS: To collect relevant articles, PubMed/MEDLINE and Embase searches were performed using Boolean search phrases. Grey literature and manual searches were also performed. Abstracts were selected by two independent reviewers based on pre-determined criteria. Full text articles were reviewed, and data extracted and assessed. RESULTS: One hundred twenty-seven abstracts were obtained through the initial search, with 85 abstracts reviewed and 22 full text articles included. Characteristics are included in Table 1. Most of these were retrospective studies and of moderate or weak quality. Studies suggested visceral fat content is higher in Crohn's disease than in healthy controls. Visceral adiposity was associated with an increased risk of complex Crohn's disease phenotype (OR 26.1 95% CI 2-75.4; p = 0.02). Post-operative recurrence was higher in patients with higher visceral fat indices (RR 2.1; CI 1.5-3; p = 0.012). There were conflicting data regarding the effect of visceral adiposity on post-operative complications and the efficacy of medical therapy. Table 1 Study characteristics Author Year Country Study type Study numbers Control group Disease type Methodology e.g. CT Body composition measurements Results Argeny [24] 2018 Austria Retrospective cohort N = 95 N/A Crohn's disease CT; L3 level Visceral fat area (cm2) Visceral fat index (VFA/m2) No association between VFA or VFI and short-term post-operative outcomes Bryant [30] 2018 Australia Prospective cohort N = 110 N/A Crohn's disease and UC DXA Visceral adipose tissue (VAT) (cm3) Visceral adipose tissue (grams) VAT/height index (cm3/m2) VAT:subcutaneous adipose tissue ratio Fat mass index (kg/m2) VAT and VHI increased significantly over 24 months Bryant [13] 2018 Australia Prospective cohort N = 72 N/A Crohn's disease; female DXA Visceral adipose tissue (VAT) (cm3) Visceral adipose tissue (grams) VAT/height index (cm3/m2) VAT:subcutaneous adipose tissue ratio VAT:SAT positively associated with stricturing disease Adiposity not associated with fistulising disease phenotype VAT:SAT significantly associated with faecal calprotectin in L3 phenotype VAT:SAT significantly negatively associated with VHI and QoL over 24 months Buning [25] 2015 Germany Case control N = 50 N = 19 healthy controls Crohn's disease MRI US VAT Thickness of abdominal fat Distance to posterior wall of aorta Area of inferior part of perirenal fat VAT accumulation was higher in CD patients vs healthy controls VAT and VAT/fat mass ratio higher in patients in short-term remission vs long-term remission VAT/FM higher in stricturing/fistulising disease vs inflammatory subtype No association between VAT/FM and CDAI, HBI or anti-TNF treatment Connolly [26] 2014 US Retrospective cohort N = 143 N/A Crohn's disease CT (L1-L5 level) Visceral/intra-abdominal adiposity (VA) Subcutaneous adiposity (SA) VA not associated with post-operative morbidity Decreased SA and increased visceral/subcutaneous ratio were predictive of post-op complications. (p = 0.02; p < 0.001) Cravo [27] 2017 Portugal Retrospective cohort N = 71 N/A Crohn's disease CT (L3 level) Smooth muscle area (cm2) Visceral fat area (cm2) Subcutaneous fat area (cm2) Visceral fat index Muscle radiation attenuation L2 phenotype associated with lower muscle attenuation and higher visceral fat index (non-significant) B2/B3/surgery - significantly lower muscle attenuation. VFI associated with increased risk of complicated phenotype. (OR 26.1; 95% CI 1-75; p = 0.02) Ding [17] 2016 US Retrospective cohort N = 164 N/A Crohn's disease CT (L3 level) Visceral fat area (cm2) Subcutaneous fat area Total fat area Visceral obesity associated with longer duration of surgery, increased intra-operative blood loss and longer length of bowel resected Higher complication rates in patients with visceral obesity (p < 0.001) VFA independent risk factor of adverse post-op outcomes Ding [14] 2017 Retrospective cohort N = 106 N/A Crohn's disease CT (L3 level) Visceral fat area Subcutaneous fat area Skeletal muscle area Skeletal muscle index Visceral obesity and myopenic obesity not significantly associated with risk of primary non-response Body composition factors not associated with secondary loss of response Erhayiem [18] 2011 UK Retrospective cohort N = 50 N/A Crohn's disease CT (L4 level) Mesenteric fat index (visceral:subcutaneous area ratio)N = 50 Mesenteric fat index was significantly higher in complicated Crohn's disease. ROC analysis for MFI in identifying complicated Crohn's disease: AUC = 0.95 (95% CI 0.89-1.0) Feng [28] 2018 China Retrospective cohort N = 80 Non-IBD GI patients Crohn's disease CT-energy spectral Visceral fat area (cm2) Subcutaneous fat area (cm2) Mesenteric fat index No significant difference in VFA between Crohn's disease cohort and control group. (p = 0.669). ROC analysis: detection of disease based on VFA and MFI: AUC 0.776 Sensitivity 77.5% Specificity 67.5% Hafraoui [16] 1998 France/Belgium Prospective N = 43 Healthy volunteers n = 13 Intestinal resection n = 9 Crohn's disease MRI (umbilicus) Total abdominal fat (cm2) Intra-abdominal fat (cm2) Subcutaneous fat (cm2) Ratio of intra-abdominal:total fat area was significantly higher in patients with Crohn's vs controls. (p = 0.012) No correlation between abdominal fat tissue and disease activity, duration or steroid therapy Holt [29] 2017 Australia/New Zealand RCT N = 44 N = 11 placebo group Crohn's disease CT/MRI (L3, L4-5 levels) Visceral adipose tissue area Subcutaneous adipose tissue area Skeletal muscle area Visceral adipose tissue/height index VHI > 1.5 times gender mean was specific for endoscopic recurrence (100%) with sensitivity of 29%. PPV = 1 (0.59-1.00) There was no significant difference in disease activity at 18 months post-resection based on VHI > 1.5 gender mean Li [31] 2015 China Retrospective cohort N = 72 N/A Crohn's disease CT (umbilicus) Visceral fat area (cm2) Subcutaneous fat area (cm2) Mesenteric fat index Post-op recurrence was more frequent with high VFA values. (p = 0.019) VFA and MFI were independent risk factors for post-operative recurrence. (p = 0.013 and p = 0.028, respectively) High VFA and high MFI were significantly higher in patients with endoscopic activity (p = 0.023) Liu [32] 2016 Retrospective case-control N = 59 N = 30 (< 15% increase VFA) IBD with IPAA CT (L3) Visceral fat area Subcutaneous fat area No difference in pouchitis, pouch sinus formation and composite adverse pouch outcomes between the 2 groups with and without VFA increase > 15%. Excessive VAT gain was an independent risk factor for the composite adverse pouch outcomes. (OR 12.6 (95% CI 1.19-133.5) Magro [33] 2018 Brazil Cross-sectional study N = 78 N = 28 Health control Crohn's disease DEXA Fat and lean masses Visceral fat (kg) Visceral fat/BMI Visceral fat per %body fat VF was higher in Crohn's disease group (p = 0.004) compared to controls Parmentier-Decrucq [34] 2009 Prospective study N = 132 N/A Crohn's disease MRI Subcutaneous fat Visceral fat Total abdominal fat increased 18% in Crohn's disease patients treated with infliximab induction therapy Shen [35] 2018 China Retrospective N = 97 N/A Crohn's disease CT (umbilicus) Subcutaneous fat area Visceral fat area Mesenteric fat index VFA and MFI were significantly lower in patients with mucosal healing (post-infliximab). (p < 0.0001) SFA was not significantly different VFA correlated with CDAI (p < 0.001) and was an independent predictive factor for mucosal healing Stidham [15] 2015 Retrospective N = 269 N/A Crohn's disease CT(T10-L5) Subcutaneous fat volume Visceral fat volume No significant difference in visceral fat volume between patients with surgical complications Thiberge [36] 2018 France Retrospective N = 149 N/A Crohn's disease CT (L3 level) Skeletal muscle index Visceral adiposity index Subcutaneous adiposity index SAI and VAI were significantly lower in patients who underwent surgery or who died in 6 months post-CT(p = 0.009 and p < 0.001) VanDerSloot [37] 2017 Cohort study N/A Crohn's disease CT (T11-S5) Visceral adipose tissue volume Non-significant trend toward increased risk of surgery and penetrating disease with increasing VAT Wei [38] 2018 China Retrospective N = 86 N/A IBD post-resection CT (L3 level) Visceral adipose volume Subcutaneous adipose volume Increased visceral:subcutaneous fat ratio was associated with increased procalcitonin levels on post-op days 1, 3 and 5 Yadav [39] 2017 India Prospective N = 97 N/A IBD CT (L4 level) Visceral fat area Subcutaneous fat area No statistically significant correlation between visceral fat and disease behaviour in Crohn's disease N/A not applicable, VFA visceral fat area, VFI visceral fat index, VAT visceral adipose tissue, VHI visceral adipose tissue to height index, SAT subcutaneous adipose tissue, DXA dual-energy X-ray absorptiometry, CT computer tomography, MRI magnetic resonance imaging, US ultrasound, CDAI Crohn's disease activity index, HBI Harvey-Bradshaw Index, anti-TNF anti-tumour necrosis factor, SA subcutaneous adiposity, ROC receiver operating curve, AUC area under the curve, MFI mesenteric fat index, SAI subcutaneous adiposity index, PPV positive predictive value CONCLUSION: Visceral adiposity appears to be increased in Crohn's disease with some evidence that it is also associated with more complex disease phenotypes. There is also a signal that post-operative recurrence rates are affected by increasing mesenteric adiposity. There is a relative lack of data in UC patients and furtherhigh-quality studies are necessary to elucidate the relationship between visceral adiposity and IBD and the implications for patient outcomes.

The optimal management of anti-drug antibodies to infliximab and identification of anti-drug antibody values for clinical outcomes in patients with inflammatory bowel disease.

PURPOSE: Secondary loss of response (LOR) to infliximab (IFX) commonly occurs. One cause is the development of anti-drug antibodies (ADAs). Evidence regarding the optimal management of ADAs is lacking. We aim to identify the best practice of management of ADAs to IFX to avoid discontinuation of therapy and to determine specific ADA cut-off values to determine pre-specified clinical outcomes. METHODS: This is a 3-year study of patients receiving IFX who developed ADAs > 8µg/ml. We reviewed the management strategies and subsequent outcomes in patients who developed ADAs. RESULTS: A total of 132 patients are included. Baseline characteristics include 54% male patients and mean age of 39.4 years. Fifty-two percent (n = 69) of patients discontinued IFX following the development of ADAs, 33.3% (n = 44) sited as secondary to LOR. Both an increase in IFX and adjustments to combination therapy were associated with lower rates of discontinuation of IFX vs no intervention (p value < 0.001, p value < 0.001). An increase in IFX resulted in a significant difference in ADAs/IFX trough levels pre- and post-intervention (p value < 0.001, p value = 0.032). ROC curve analysis yielded significant cut-off values for ADAs and treatment failure (ADA >16µg/ml, AUC 0.642, p value 0.003), steroid use (ADA >19 µg/ml, AUC 0.61, p value 0.048) development of infusion reactions (ADA> 37 µg/ml, AUC 0.68, p value 0.045) and switch to another biologic (ADA >45 µg/ml, AUC 0.739, p value <0.001). CONCLUSION: Both escalation of IFX and combination therapy resulted in lower rates of LOR. ROC curve analysis identified significant cut-off values for ADA trough levels and important clinical outcomes.

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.

Meta-analysis of Histological Margin Positivity in the Prediction of Recurrence After Crohn's Resection.

BACKGROUND: Despite significant advances in the medical management of Crohn's disease, many patients will require intestinal resection during their lifetime. It is disappointing that many will also develop disease recurrence. OBJECTIVES: The current study utilizes meta-analytical techniques to determine the effect of positive histological margins at the time of index resection on disease recurrence. DATA SOURCES: Embase, Medline, PubMed, PubMed Central, and Cochrane databases were searched using a Boolean search algorithm for articles published up to August 2017. STUDY SELECTION: Meta-analysis was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. MAIN OUTCOME MEASURES: Databases were searched for studies reporting the outcomes for patients with Crohn's disease undergoing primary resection that correlated resection margin status with disease recurrence. Results were reported as pooled ORs with 95% CI. RESULTS: A total of 176 citations were reviewed; 18 studies comprising 1833 patients were ultimately included in the analysis, with a mean rate of histopathological margin positivity of 41.7 ± 17.4% and a pooled mean follow-up of 69 ± 39 months. Histopathological margin positivity was associated with a higher rate of overall recurrence (OR, 1.7; 95% CI, 1.3-2.1; p < 0.001), clinical recurrence (OR, 1.7; 95% CI, 1.0-2.8; p = 0.04), and anastomotic recurrence (OR, 1.6; 95% CI, 1.0-2.3; p = 0.03). In studies reporting plexitis specifically at the resection margin, there was an increase in recurrence (OR, 2.3; 95% CI, 1.1-4.9; p = 0.02). LIMITATIONS: The definitions of histological margin positivity and postoperative recurrence vary between the studies and follow-up durations vary. CONCLUSIONS: The presence of involved histological margins at the time of index resection in Crohn's disease is associated with recurrence, and plexitis shows promise as a marker of more aggressive disease. Further studies with homogeneity of histopathological and recurrence reporting are required.

Inflammatory Bowel Disease Provoked by Etanercept: Report of 443 Possible Cases Combined from an IBD Referral Center and the FDA.

BACKGROUND: Anti-TNF therapies have revolutionized the treatment of autoimmune inflammatory conditions. Paradoxical treatment with these agents is associated with the development of de novo autoimmune diseases. Less well recognized is the provocation of de novo IBD by these agents. Etanercept is not effective for the treatment of inflammatory bowel disease and may be more often reported with the development of Crohn's disease or ulcerative colitis. AIM: This study assessed the association of new onset IBD in patients with receiving etanercept. METHODS: The Brigham and Women's (BWH) patient database and the FDA Adverse Event Reporting System were searched for cases of IBD reported with etanercept. RESULTS: A total of 443 cases were identified: 5 pts at BWH (3 CD, 2 UC) and 438 (294 CD, 144 UC) reported to the FDA. Data which were most complete were pooled from 49 patients. NSAID use was reported in 43 % and combination with methotrexate in 29 %. Etanercept was discontinued in 34 pts and 19 required treatment with a different anti-TNF agent. Eight patients had resolution of GI symptoms on discontinuation of etanercept. Therapy was continued in three patients in response to 5-ASA therapy. CONCLUSION: Development of IBD should be suspected in patients receiving etanercept who develop GI symptoms. This phenomenon appears more commonly associated with initiation of CD. The clinical phenotype appears indistinguishable from usual patterns of IBD. Unlike other autoimmune phenomenon associated with anti-TNF therapy, IBD often does not resolve when the agent is discontinued. This tentative association requires further investigation.

Optimizing Biologic Agents in Ulcerative Colitis and Crohn's Disease.

The goals of therapy in inflammatory bowel disease (IBD) are the induction and maintenance of clinical and biological remission. Mucosal healing is desirable to prevent complications and reduce the need for surgery, hospitalizations, and steroid exposure. Therapeutic monoclonal antibodies (biologic agents) have revolutionized the treatment of IBD. The initial magnitude of the clinical/biologic response to these agents has been associated with a number of underlying phenotypic features in the recipient. In addition, the durability of the initial response often declines over time. This can occur due to low drug serum drug levels, anti-drug antibodies, and a shift to alternative inflammatory pathways. This review discusses strategies that may optimize the initial response to biologics and sustain this to improve patient outcomes.

Inflammatory Bowel Disease Increases Risk of Adverse Pregnancy Outcomes: A Meta-Analysis.

BACKGROUND: Inflammatory bowel disease may place women at greater risk of adverse pregnancy outcomes. AIM: To examine the association between inflammatory bowel disease and adverse pregnancy outcomes: preterm birth, small for gestational age (SGA) birth weight, congenital anomalies, and stillbirth. METHODS: We searched PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov for studies published from January 1980 through February 2014 and reference lists of relevant studies. We reviewed 1748 citations and identified studies evaluating outcomes of pregnancies complicated by inflammatory bowel disease. Selected studies evaluated one or more of the outcomes of interest, were in English, and gave sufficient details to perform meta-analysis. Three investigators independently reviewed articles for inclusion; discordant decisions were resolved by team review and consensus. Twenty-three studies that included 15,007 women with inflammatory bowel disease (5449 Crohn's, 6559 ulcerative colitis) and 4,614,271 controls met selection criteria. Random-effects analytical methods were used to generate pooled odds ratios. RESULTS: We found an increased odds of the outcomes studied among women with inflammatory bowel disease compared with non-diseased controls: 1.85 for preterm birth (22 studies; 95 % confidence interval [CI] 1.67-2.05), 1.36 for SGA birth weight (13 studies; 95 % CI 1.16-1.60), 1.57 for stillbirth (10 studies; 95 % CI 1.03-2.38), and 1.29 for congenital anomalies (11 studies; 95 % CI 1.05-1.58). The latter result, however, may be unreliable secondary to publication bias. CONCLUSION: Inflammatory bowel disease may increase the odds of adverse pregnancy outcomes.

Mortality in inflammatory bowel disease patients under 65 years of age.

OBJECTIVE: To assess mortality in inflammatory bowel disease (IBD) patients under 65 years of age and to identify the factors related to death in this age group. METHODS. We studied 2570 IBD patients who were diagnosed as having disease before 65 years of age and attended a single tertiary referral center area between 1983 and 2012. Follow-up was censored at 65 years. The causes of death were determined from death certificates obtained from the Irish registry office of births, marriages and deaths. Observed all-cause survival was compared with expected survival of persons of the same age and sex in the general population. Expected survival was obtained from national life tables produced by the central statistics office. Survival estimates were calculated for disease type, disease site, gender, the presence of primary sclerosing cholangitis (PSC), immunomodulator use, biologic therapy use, presence of fistulating disease and prior surgery. RESULTS: Fifty-two deaths were reported in the population younger than 65 years, of which 41 were IBD related. We found little difference in survival in the first 25 years of follow-up, but relative survival decreased in both the Crohn's disease (CD) and ulcerative colitis (UC) cohort thereafter, so that 30-year mortality was excessive in both groups. An adjusted multivariate regression analysis of patients with CD identified PSC as the only predictor of premature mortality (p = 0.003). PSC was also identified as the only independent predictor of mortality in UC patients (p = 0.03). CONCLUSIONS: The presence of PSC poses the greatest risk for mortality in both UC and CD.

Microscopic colitis: clinical characteristics, treatment and outcomes in an Irish population.

BACKGROUND AND AIMS: Many aspects of microscopic colitis remain poorly understood. Our aim was to report a single centre experience with this condition. METHODS: Two hundred and twenty-two patients (52 male, 170 female; median age 64 years; range 32-90) diagnosed between 1993 and 2010 were studied. Medical notes were reviewed, and data on age, gender, clinical features, history of autoimmune diseases, medication use, cigarette smoking, histology and outcome were collected. RESULTS: There were 99 cases of lymphocytic and 123 of collagenous colitis. Diarrhoea was almost invariably present (98 %) while abdominal pain (24 %), weight loss (10 %), faecal incontinence (8 %) and blood PR (5 %) were also described. Twenty-eight percent had concomitant autoimmune diseases, most commonly coeliac disease. Patients were taking a variety of medications at diagnosis thought to be associated with microscopic colitis including NSAIDs (22 %), aspirin (19 %), statins (15 %), proton pump inhibitors (19 %) and SSRIs (10 %) at diagnosis. Prior to the widespread use of budesonide in our institution, 33 % of patients required two or more medications during therapy compared to 15 % following the introduction of budesonide (p = 0.001). Thirty-eight percent of patients achieved spontaneous remission with either no treatment or simple anti-diarrhoeals. Using a multivariate model, the only factor associated with spontaneous remission was male gender (RR 1.9; 95 % CI 1.0-3.6; p = 0.04). Two patients had refractory microscopic colitis; one required a colectomy while a more recent case has responded to anti-TNFα therapy. CONCLUSION: Microscopic colitis is predominantly a benign and self-limiting disorder. The introduction of budesonide has revolutionised treatment of this lesser studied inflammatory bowel disease.

Environmental triggers for IBD.

The fundamental elucidation of how environmental influences provoke the initiation of disease as well as flares of inflammatory bowel disease (IBD) remains incomplete. The current understanding of these diseases suggests that ulcerative colitis (UC) and Crohn's disease (CD) result from poorly defined interactions between genetic and environmental factors which culminate in the pathologic effects and clinical manifestations of these diseases. The genetic variant appears not sufficient itself to lead to the development of the clinical disease, but likely must combine with the environmental factors. The intestinal microbiome is pivotal to IBD development. A greater understanding of the contribution of these factors to dysbiosis is critical, and we aspire to restoring a healthy microbiome to treat flares and ideally prevent the development of IBD and its complications. This article aims to place the environmental influences in the context of their potential contribution to the development of the pathophysiology of IBD.

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.

Primary sclerosing cholangitis and disease distribution in inflammatory bowel disease.

BACKGROUND & AIMS: The relationship between site of intestinal inflammation and primary sclerosing cholangitis (PSC) development in inflammatory bowel disease (IBD) has not been studied extensively, but may be important in understanding the pathogenesis of PSC. We aimed to determine patterns of disease distribution in IBD patients with and without PSC. METHODS: We performed a 2-part study involving the following: (1) 2754 IBD patients and (2) 82 separate PSC patients attending the Irish National Liver Transplant Unit. RESULTS: Fifty-nine of 2708 (2.2%) IBD patients had PSC. In ulcerative colitis patients, PSC incidence increased with increasing colonic involvement (P = .001) and was relatively rare in those without total colitis. Thirteen Crohn's disease patients had PSC, none with isolated small-bowel disease had PSC (P = .03). In study 2, the majority of ulcerative colitis patients with PSC had total colitis, whereas the remainder had disease extending at least to the left colon. In addition, all 10 PSC patients with Crohn's disease had colonic involvement. CONCLUSIONS: An inflamed colon, but not small bowel, is important in PSC development and it is possible that bacterial translocation and subsequent portal bacteremia is important in PSC development in IBD.

"Role of exercise in preventing and restoring gut dysbiosis in patients with inflammatory bowel disease": A letter to the editor.

Exercise-induced changes of the microbiome in inflammatory bowel diseases (IBD) is a promising field of research with the potential for personalized exercise regimes as a promising therapeutic adjunct for restoring gut dysbiosis and additionally for regulating immunometabolic pathways in the management of IBD patients. Structured exercise programmes in IBD patients of at least of 12 wk duration are more likely to result in disease-altering changes in the gut microbiome and to harness potential anti-inflammatory effects through these changes along with immunometabolic pathways.

Isavuconazole Treatment of Spinal Cord Invasive Aspergillosis Guided by Cerebrospinal Fluid (1,3)-ß-d-Glucan Levels in a Patient with Low Interferon-Gamma and Ulcerative Colitis.

This case highlights the use of (1,3)-beta-d glucan to direct treatment of a cervical spinal cord Aspergillus fumigatus infection in a 22-year-old woman immunocompromised due to steroid and anti-TNF therapy in the context of ulcerative colitis and interferon gamma deficiency. A 4-year treatment course requiring neurosurgical intervention on four occasions and prolonged antifungal therapy, including isavuconazole, resulted in clinical cure with a corresponding decrease in CSF beta-d-glucan to <30 pg/mL. Serum and CSF galactomannan levels were not elevated at any point during the clinical course.

Assessment of the value of gastroenterologists' activity in the outpatient setting: applying the "Moneyball" approach to clinical care.

BACKGROUND: With the emergence of alternative payment systems replacing the traditional funding models, the value of physician activity is scrutinized more closely. Attempts have been made to quantify the value of endoscopists' activity; there is little in the medical literature describing gastroenterologists' value in the outpatient setting. AIMS: To characterize the value of clinical activity of gastroenterologists in the outpatient setting. METHODS: The value of clinical activity of ten gastroenterologists in an academic medical center was estimated. Value was defined as Q (quality of clinical care) divided by TA (duration of outpatient visit adjusted for complexity level); TA served as a surrogate measure of the cost of the clinician's services. Medical records of each patient's clinical visit were reviewed and graded independently by three staff gastroenterologists; each reviewer was blinded to the identity of the physician and to other reviewers' scores. RESULTS: Over consecutive weeks, the clinical records of 307 patients who were seen by ten gastroenterologists were reviewed and graded for quality (Q) and complexity (C); the duration of each visit (T) was recorded. Each physician saw a mean of 31 patients; mean physician value varied from 0.28 to 0.87. More senior physicians demonstrated higher levels of value. CONCLUSION: Measurement of the value of clinical activity represents an important component of gastroenterologists' performance. There was a threefold variation among physician levels of value with more experienced clinicians demonstrating higher value levels. Further studies will be required to more clearly define valid metrics for physician value.

Measuring the value of endoscopic retrograde cholangiopancreatography activity: an opportunity to stratify endoscopists on the basis of their value.

INTRODUCTION: As finite healthcare resources come under pressure, the value of physician activity is assuming increasing importance. The value in healthcare can be defined as patient health outcomes achieved per monetary unit spent. Even though some attempts have been made to quantify the value of clinician activity, there is little in the medical literature describing the importance of endoscopists' activity. This study aimed to characterize the value of endoscopic retrograde cholangiopancreatography (ERCP) performance of five gastroenterologists. PATIENTS AND METHODS: We carried out a retrospective-prospective cohort study using the databases of patients undergoing ERCP between September 2014 and March 2017. We collected data from 1070 patients who underwent ERCP comparing value among the ERCPists at index ERCP. Procedure value was calculated using the formula Q/(T/C), where Q is the quality of procedure, T is the duration of procedure and C is the adjusted for complexity level. Quality and complexity were derived on a 1-4 Likert scale on the basis of American Society for Gastrointestinal Endoscopy criteria; time was recorded (in min) from intubation to extubation. Endoscopist time calculated from procedure time was considered a surrogate marker of cost as individual components of procedure cost were not itemized. RESULTS: In total, 590 procedures were analysed: 465 retrospectively over 24 months and 125 prospectively over 6 months. There was a 32% variation in the value of endoscopist activity in a more substantial retrospective cohort, with an even more considerable 73% variation in a smaller prospective arm. CONCLUSION: In an analysis of greater than 1000 ERCPs by a small cohort of experienced ERCPists, there was a wide variation in the value of endoscopist activity. Although the precision of estimating procedural costs needs further refinement, these findings show the ability to stratify ERCPists on the basis of the value their activity. As healthcare costs are scrutinized more closely, such value measurements are likely to become more relevant.

Protocol for a multicentred randomised controlled trial investigating the use of personalised golimumab dosing tailored to inflammatory load in ulcerative colitis: the GOAL-ARC study (GLM dose Optimisation to Adequate Levels to Achieve Response in Colitis) led by the INITIAtive group (NCT 0268772).

INTRODUCTION: Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD), often leading to an impaired quality of life in affected patients. Current treatment modalities include antitumour necrosis factor (anti-TNF) monoclonal antibodies (mABs) including infliximab, adalimumab and golimumab (GLM). Several recent retrospective and prospective studies have demonstrated that fixed dosing schedules of anti-TNF agents often fails to consistently achieve adequate circulating therapeutic drug levels (DL) with consequent risk of immunogenicity treatment failure and potential risk of hospitalisation and colectomy in patients with UC.The design of GLM dose Optimisation to Adequate Levels to Achieve Response in Colitis aims to address the impact of dose escalation of GLM immediately following induction and during the subsequent maintenance phase in response to suboptimal DL or persisting inflammatory burden as represented by raised faecal calprotectin (FCP). AIM: The primary aim of the study is to ascertain if monitoring of FCP and DL of GLM to guide dose optimisation (during maintenance) improves rates of patient continuous clinical response and reduces disease activity in UC. METHODS AND ANALYSIS: A randomised, multicentred two-arm trial studying the effect of dose optimisation of GLM based on FCP and DL versus treatment as per SMPC. Eligible patients will be randomised in a 1:1 ratio to 1 of 2 treatment groups and shall be treated over a period of 46 weeks. ETHICS AND DISSEMINATION: The study protocol was approved by the Research Ethics committee of St. Vincent's University Hospital. The results will be published in a peer-reviewed journal and shared with the worldwide medical community. TRIAL REGISTRATION NUMBERS: EudraCT number: 2015-004724-62; Clinicaltrials.gov Identifier: NCT0268772; Pre-results.