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Bile acids are endogenous ligands of nuclear receptors pregnane X (PXR) and farnesoid X (FXR). PXR and FXR regulate pathways that are impaired in inflammatory bowel disease (IBD). Decreases in PXR and FXR activity are documented in IBD; however reasons for this are unknown. We aimed to assess the effect of Crohn’s disease (CD) on the plasma bile acid composition in vivo and the resultant impact on PXR and FXR activation. A cross-sectional study evaluated the plasma concentrations of 12 bile acids in addition to 4β-hydroxycholesterol (4βOHC), an in vivo probe of the PXR target-gene cytochrome 3A4 (CYP3A4) and the FXR target-gene, fibroblast growth factor (FGF) 19 in individuals with (n = 74) and without (n = 71) CD. An in vitro model was used to assess the impact of CD-specific changes in the plasma bile acid composition on PXR and FXR activation. Decreases in glycochenodeoxycholic acid, taurocholic acid and lithocholic acid were seen in CD with increases in glycodeoxycholic acid and glycocholic acid relative to the total plasma bile acid profile. In vitro , increasing concentrations of bile acids applied in the same ratio as seen in the study cohorts resulted in decreased activation of both PXR and FXR in the CD model. In vivo , plasma 4βOHC (CD = 18.68 ng/ml ± 13.02 ng/ml, non-CD = 46.38 ng/ml ± 40.70 ng/ml, p ≤ 0.0001) and FGF19 (CD = 0.276 pg/L ± 0.189 pg/L, non-CD = 0.485 pg/L ± 0.42 pg/L, p = 0.0002) concentrations were lower in CD versus controls. Ultimately, CD-specific changes in the plasma bile acid composition lead to reduced activation of FXR and PXR target genes in vitro and in vivo .

Endoscopy under propofol sedation has become a routine procedure. Given the number of Canadians undergoing an endoscopy annually, as well as the pervasive use of cannabis by many patients, understanding the effect of cannabis use on the propofol dose at endoscopy is highly relevant. We aimed to evaluate the association between cannabis exposure and the propofol dose needed to achieve adequate sedation at endoscopy. A case-control study of individuals undergoing endoscopy was conducted at a single outpatient endoscopy clinic in London, Ontario between 2014 and 2017. Cases included all individuals with any self-reported cannabis exposure, while controls included all individuals without any self-reported history of cannabis use. Dose of propofol administered by a single anesthetist was collected on each subject as well as additional demographic and procedure-related covariates. Three hundred and eighteen participants were included (cases, n = 151; controls, n = 167). Cannabis exposure was associated with an increase in propofol dose (cases 0.33 mg/kg/minute ±0.24; controls, 0.18 mg/kg/minute ±0.11; p<0.0001). Cannabis exposure remained an independent predictor of propofol dose on multivariate linear regression accounting for other important covariates (p<0.0001). Daily cannabis users required a higher propofol dose than weekly or monthly users. Three procedural sedation-related complications occurred in the cannabis-exposed group, while none occurred in the unexposed group. Our data suggest that cannabis use is significantly associated with the quantity of propofol needed for sedation at endoscopy. Further study is needed to better understand the molecular basis for this possible drug-drug interaction.

The interleukin-6 family cytokine, oncostatin-M (OSM) has been associated with response to tumor necrosis factor-α antagonists (anti-TNFs) in small cohorts of patients with inflammatory bowel disease (IBD). We aimed to evaluate the association between plasma OSM concentrations and response to anti-TNFs (infliximab and adalimumab) in both ulcerative colitis (UC) and Crohn’s disease (CD). A retrospective cohort study was conducted in patients with IBD with a history of anti-TNF exposure. Blood samples, collected prior to anti-TNF exposure, were analyzed by enzyme-linked immunosorbent assay for the presence and quantity of OSM. Clinical remission was assessed at 1-year post anti-TNF exposure in addition to the occurrence of surgery, hospitalization, corticosteroid use, and adverse drug events. Lastly the threshold OSM plasma concentration associated with anti-TNF non-response was assessed by receiver operator characteristic (ROC) curve analysis. Patients with IBD (CD, n = 82; UC, n = 40) were assessed. In both UC and CD, mean pre-treatment OSM concentrations were significantly lower in those who achieved clinical remission at 1-year (p < 0.0001). A threshold plasma OSM concentration of 168.7 pg/ml and 233.6 pg/ml respectively separated those who achieved clinical remission at 1-year on an anti-TNF from those who did not in CD and UC respectively (CD: area under the receiver operator characteristic curve, AUROC = 0.880, 95% CI 0.79–0.96; UC: AUROC = 0.938, 95% CI 0.87–1.00). High OSM concentrations were associated with anti-TNF discontinuation and use of rescue steroids in CD and UC. High pre-treatment OSM concentrations identify IBD patients at-risk of anti-TNF non-response at 1-year as well as other deleterious clinical outcomes.

BackgroundLimited data suggest that non-melanoma skin cancer (NMSC) risk is higher in patients with inflammatory bowel disease (IBD) particularly in those on a tumor necrosis factor-α antagonist (TNF antagonist). It remains unknown whether TNF antagonist exposure alters the clinical course of NMSC in patients with IBD or if this therapy should be discontinued.AimsTo assess the impact of TNF antagonist exposure on NMSC severity, recurrence and need for ancillary treatments.MethodsPatients with IBD seen at London Health Sciences Centre, London, Canada were assessed for a history of NMSC and pre-diagnosis TNF antagonist exposure. NMSC severity (low risk and high risk), ancillary NMSC therapies, including chemo or radiotherapy, and changes to IBD therapy were assessed.ResultsEleven of 472 patients with IBD reviewed were diagnosed with NMSC. Sixty-four percent (7/11) were on a TNF antagonist at the time of NMSC diagnosis. All patients with TNF antagonist exposure, (7/7) presented with a high-risk lesion based on National Comprehensive Cancer Network (NCCN) clinical practice guidelines. The incidence of positive margins was 42.9% (3/7) and 14.3% (1/7) required ancillary therapy. No metastatic disease was seen. TNF antagonist therapy was discontinued in a single patient due to NMSC diagnosis. Recurrent NMSC lesions were not seen in any of the TNF antagonist exposed patients.ConclusionsIn this case series, TNF antagonist exposure may be associated with a severe NMSC clinical course. Larger studies are needed to confirm whether TNF antagonist discontinuation should be considered in the setting of NMSC diagnosis in IBD.

Pyoderma gangrenosum is an uncommon neutrophilic dermatosis that is highly associated with pathergy in the setting of trauma or surgery, systemic disease, or may be idiopathic. Herein, we present the case of a 68-year-old female with ulcerative colitis who underwent a subtotal colectomy with an end-ileostomy and presented post-operatively with large, multifocal pyoderma gangrenosum at two abdominal sites. She was managed with intralesional triamcinolone injections and high-dose systemic steroids and was transitioned to IV infliximab. Our case report illustrates the role of infliximab in the treatment of complicated multifocal pyoderma gangrenosum and contemplates the impact of systemic infliximab exposure.

The farnesoid X receptor (FXR) is implicated in Crohn's disease (CD) pathogenesis. It is unclear how genetic variation in FXR impacts CD severity versus genetic variation in nuclear receptors such as pregnane X receptor (PXR) and the multi-drug resistance protein 1 (MDR1, ABCB1). To evaluate FXR-1G  >  T as a genomic biomarker of severity in CD and propose a plausible molecular mechanism. A retrospective study (n = 542) was conducted in a Canadian cohort of CD patients. Genotypic analysis ( FXR-1G  >  T , MDR1 3435C  >  T and PXR -25385C  >  T ) as well as determination of the FXR downstream product, fibroblast growth factor (FGF) 19 was performed. Primary outcomes included risk and time to first CD-related surgery. The effect of estrogen on wild type and variant FXR activity was assessed in HepG2 cells. The FXR-1GT genotype was associated with the risk of (odds ratio, OR = 3.34, 95% CI = 1.58–7.05, p  = 0.002) and earlier progression to surgery (hazard ratio, HR = 3.00, 95% CI = 1.86–4.83, p  < 0.0001) in CD. Female carriers of the FXR-1GT genotype had the greatest risk of surgery (OR = 14.87 95% CI = 4.22–52.38, p  < 0.0001) and early progression to surgery (HR = 6.28, 95% CI = 3.62–10.90, p  < 0.0001). Women carriers of FXR-1GT polymorphism had a three-fold lower FGF19 plasma concentration versus women with FXR-1GG genotype ( p  < 0.0001). In HepG2 cells cotransfected with estrogen receptor (ER) and FXR, presence of estradiol further attenuated variant FXR activity. MDR1 and PXR genotypes were not associated with surgical risk. Unlike MDR1 and PXR , FXR-1GT genetic variation is associated with earlier and more frequent surgery in women with CD. This may be through ER-mediated attenuation of FXR activation.

Background The threshold concentration of infliximab during maintenance therapy has not been well-defined in relation to histologic remission. The aim of the study is to dentify the maintenance-phase infliximab concentration associated with histologic remission in inflammatory bowel disease patients (IBD). Methods A prospective cohort study was carried out in 104 IBD patients seen at a tertiary care centre in London, Canada. Infliximab trough concentrations were collected during the maintenance phase of treatment and compared between participants with and without evidence of histologic remission. Participants were additionally evaluated for sustained histologic remission, and relapse to active disease. Results Participants in histologic remission attained higher mean concentrations of infliximab during the maintenance phase (10.34 ± 0.69 μg/ml) compared to those with persistent disease activity (6.23 ± 0.67 μg/ml, p-value < 0.0001). Additionally, during the maintenance phase, sustained histologic remission was also associated with a higher mean concentration of infliximab (10.81 ± 5.46 μg/ml) compared to those who relapsed to active disease (5.68 ± 3.70, p < 0.001). Overall, participants with a mean infliximab trough concentration greater than 8ug/ml were more likely to have histologic remission (area under the receiver operating characteristic curve, AUROC = 0.72, 95%CI = 0.65–0.84, p < 0.0001) and sustained histologic remission (AUC = 0.77, 95%CI = 0.63–0.91, p = 0.002). Conclusion Maintenance-phase infliximab trough concentrations greater than 8 μg/ml, which is higher than the currently recommended target concentration, are highly associated with histologic remission and sustained histologic remission.

Background. Candida glabrata (C. glabrata) has become a recognized pathogen in fungal esophagitis. A proportion of these isolates are azole-resistant which may have treatment implications. Variability in the prevalence of this organism exists in the limited data available. Objective. To determine the incidence of C. glabrata esophagitis in a North American hospital setting and to highlight factors that may predispose patients to this condition. Methods. Patient charts were collected from January 1, 2009 to July 30, 2011. Any charts of patients identified as having esophagitis with a positive fungal culture were reviewed for the species of Candida and the presence of factors that would predispose them to esophageal candidiasis. Results. The prevalence of Candida esophagitis based on culture was 2.2% (37 subjects). C. glabrata was the 2nd most prevalent pathogen identified (24.3% or 9 subjects). Of the C. glabrata cohort, all patients had at least one factor predisposing them to candidiasis. Conclusion. C. glabrata esophagitis makes up a large portion of the candidal esophagitis seen in hospital. C. glabrata infections were associated with at least one risk factor for candidal infection. Given its resistance to azole-based therapy, this may have treatment implications for how candidal esophagitis is approached by the clinician.

Abstract Background We aimed to determine the correlation between tissue and plasma infliximab concentrations in an outpatient ulcerative colitis (UC) cohort based on histologic disease activity in addition to their relationship with long-term clinical outcomes. We assessed intraparticipant variability in infliximab concentrations between adjacent intestinal samples and the correlation between disease activity and tumor necrosis factor-α (TNF-α). Methods A prospective cohort study was conducted in participants with UC receiving infliximab. Blood and 2 sigmoid colon biopsies were obtained at the index colonoscopy for infliximab and TNF-α quantification. Histological disease activity was assessed. Participants were followed for 2 years for the occurrence of hospitalization, surgery, disease relapse, and infliximab discontinuation. Results A positive correlation was observed between mean plasma and uninflamed tissue infliximab concentrations only (Rs = 0.75, P = .0071). Lower mean tissue infliximab concentrations correlated with a shorter time to disease relapse vs those with higher mean tissue concentrations (Rs = 0.77, P = .032). This was not seen when using plasma infliximab concentrations. Additionally, no significant intraparticipant variability of infliximab concentrations was observed for all participants independent of disease activity. Neither plasma nor tissue TNF-α correlated with disease activity. Conclusions These findings support data generated in patients with Crohn’s disease: plasma infliximab concentrations are reflective of infliximab exposure in tissue in the UC patient in remission, but not for those with active disease. Increasing tissue concentrations in the noninflamed tissues may improve durability of infliximab. Neither plasma nor tissue TNF-α appear to correlate with UC disease activity. Larger follow-up studies would be of benefit. Lay Summary Plasma infliximab concentrations are reflective of infliximab exposure in tissue in the UC patient in remission, but not for those with active disease. Increasing tissue concentrations in the noninflamed tissues may improve durability of infliximab.