Comprehensive Association Analyses of Extraintestinal Manifestations in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) frequently develop extraintestinal manifestations (EIMs) that contribute substantially to morbidity. We assembled the largest multicohort data set to date to investigate the clinical, serologic, and genetic factors associated with EIM complications in IBD. METHODS: Data were available in 12,083 unrelated European ancestry IBD cases with presence or absence of EIMs (eg, ankylosing spondylitis [ankylosing spondylitis and sacroiliitis], primary sclerosing cholangitis [PSC], peripheral arthritis, and skin and ocular manifestations) across 4 cohorts (Cedars-Sinai Medical Center, National Institute for Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium, Sinai Helmsley Alliance for Research Excellence Consortium, and Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease cohort). Clinical and serologic parameters were analyzed by means of univariable and multivariable regression analyses using a mixed-effects model. Within-case logistic regression was performed to assess genetic associations. RESULTS: Most EIMs occurred more commonly in female subjects (overall EIM: P = 9.0E-05, odds ratio [OR], 1.2; 95% CI, 1.1-1.4), with CD (especially colonic disease location; P = 9.8E-09, OR, 1.7; 95% CI, 1.4-2.0), and in subjects who required surgery (both CD and UC; P = 3.6E-19, OR, 1.7; 95% CI, 1.5-1.9). Smoking increased risk of EIMs except for PSC, where there was a "protective" effect. Multiple serologic associations were observed, including with PSC (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-flagellin) and any EIM (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-Pseudomonas fluorescens-associated sequence). We identified genome-wide significant associations within major histocompatibility complex (ankylosing spondylitis and sacroiliitis, P = 1.4E-15; OR, 2.5; 95% CI, 2.0-3.1; PSC, P = 2.7E-10; OR, 2.8; 95% CI, 2.0-3.8; ocular, P = 2E-08, OR, 3.6; 95% CI, 2.3-5.6; and overall EIM, P = 8.4E-09; OR, 2.2; 95% CI, 1.7-2.9) and CPEB4 (skin, P = 2.7E-08; OR, 1.5; 95% CI, 1.3-1.8). Genetic associations implicated tumor necrosis factor, JAK-STAT, and IL6 as potential targets for EIMs. Contrary to previous reports, only 2% of our subjects had multiple EIMs and most co-occurrences were negatively correlated. CONCLUSIONS: We have identified demographic, clinical, and genetic associations with EIMs that revealed underlying mechanisms and implicated novel and existing drug targets-important steps toward a more personalized approach to IBD management.

A Rare Case of Left Hemicolectomy Masking the Signs and Symptoms of Underlying Hirschsprung's Disease in an Adult.

Hirschsprung's disease (HD) is a congenital gastrointestinal condition characterized by the lack of ganglion cells within the submucosal and myenteric nervous plexuses in the large intestine. This results in a dysfunctional segment of the large colon, resulting in symptoms such as failure to pass meconium, constipation, and dilated loops of the bowel. The vast majority of patients are diagnosed during the neonatal period, but a handful can be diagnosed later into childhood and adolescence. A rare subset is diagnosed during adulthood, in which the section of the aganglionic colon is minimal yet symptomatic. We report the case of a 54-year-old female presenting with dilated loops of bowel and a remote history of severe constipation, recurrent bowel obstructions, previous left hemicolectomy, and an improvement of symptoms following the procedure. Upon further workup, she was diagnosed with HD, raising the question of whether there should be increased testing for this condition in adults. This case can serve as an example of the need for a more in-depth workup of severe constipation in adults, as the finding for HD in adults is rare but still possible.

Hypoalbuminemia and Bandemia Predict Failure of Infliximab Rescue Therapy in Acute Severe Ulcerative Colitis.

BACKGROUND AND AIMS: Infliximab rescue therapy is effective in patients with corticosteroid refractory acute severe ulcerative colitis, but predictors of response remain poorly understood. We aimed to identify predictors of colectomy in this high-risk patient population. METHODS: Patients hospitalized with acute severe ulcerative colitis who received infliximab after failing intravenous corticosteroid therapy between July 2012 and June 2017 were retrospectively identified. Stepwise regression with backward elimination was used to identify predictors of colectomy at 90 days and 1 year. Ninety-day and 1-year colectomy rates were compared between the patients who received 5 mg/kg and 10 mg/kg IFX rescue dose. RESULTS: Sixty-three patients met the eligibility criteria. Twenty-nine patients received 5 mg/kg, and 34 received 10 mg/kg infliximab dose. Serum albumin on admission (OR 0.10; p = 0.04) and band neutrophil percentage at the time of infliximab administration (OR 1.21; p = 0.02) were independent predictors of 90-day colectomy. A combination of serum albumin ≤ 2.5 g/dl and band neutrophil count ≥ 13% had a 100% positive predictive value for 90-day colectomy. Unadjusted 90-day and 1-year colectomy rates were similar in the 5 mg/kg and 10 mg/kg infliximab groups. After adjusting for confounding factors, 10 mg/kg infliximab dose was potentially protective for 90-day (OR 0.07; p = 0.06) but not for 1-year colectomy (OR 0.19; p = 0.16). CONCLUSIONS: Bandemia and low serum albumin are independent predictors of failure of infliximab rescue therapy in acute severe ulcerative colitis. Serum albumin ≤ 2.5 g/dl and band neutrophil count ≥ 13% had a 100% positive predictive value for 90-day colectomy.

Electronic patient agenda forms: comparing agreement between the reason for specialty consultation reported by referring providers and patients.

OBJECTIVE: Little is known about the agreement between referring providers' reason for specialty evaluation and patients' understanding of why they are referred for consultation. Here, we compared the reason for consult (RFC) documented by referring providers during usual care vs. the perceived RFC independently reported by patients through an e-portal just prior to the specialist visit. METHODS: We performed an observational study among patients referred for gastrointestinal (GI) evaluation. Patients referred to the specialty clinic submitted their self-reported RFC using an online patient agenda form prior to their visit. Therefore, each participant had a referring provider- and patient-documented RFC. Blinded physicians reviewed the RFCs in random order using a priori coding criteria. We then compared whether the provider and patient RFC pairs were concordant (i.e., ≥1 clinical topic[s] in the RFCs matched). RESULTS: Sixty patients completed the e-portal prior to their visit, leading to 60 provider-patient RFC pairs. The RFC pairs were concordant in only 52% of cases. CONCLUSIONS: There is poor agreement between referring providers' reason for GI referral and patients' understanding of why they are visiting the clinic. Future research examining whether electronic patient agenda forms impact diagnostic and management precision, patient satisfaction, and healthcare utilization is warranted.

Genetic associations with adverse events from anti-tumor necrosis factor therapy in inflammatory bowel disease patients.

AIM: To study the type and frequency of adverse events associated with anti-tumor necrosis factor (TNF) therapy and evaluate for any serologic and genetic associations. METHODS: This study was a retrospective review of patients attending the inflammatory bowel disease (IBD) centers at Cedars-Sinai IBD Center from 2005-2016. Adverse events were identified via chart review. IBD serologies were measured by ELISA. DNA samples were genotyped at Cedars-Sinai using Illumina Infinium Immunochipv1 array per manufacturer's protocol. SNPs underwent methodological review and were evaluated using several SNP statistic parameters to ensure optimal allele-calling. Standard and rigorous QC criteria were applied to the genetic data, which was generated using immunochip. Genetic association was assessed by logistic regression after correcting for population structure. RESULTS: Altogether we identified 1258 IBD subjects exposed to anti-TNF agents in whom Immunochip data were available. 269/1258 patients (21%) were found to have adverse events to an anti-TNF-α agent that required the therapy to be discontinued. 25% of women compared to 17% of men experienced an adverse event. All adverse events resolved after discontinuing the anti-TNF agent. In total: n = 66 (5%) infusion reactions; n = 49 (4%) allergic/serum sickness reactions; n = 19 (1.5%) lupus-like reactions, n = 52 (4%) rash, n = 18 (1.4%) infections. In Crohn's disease, IgA ASCA (P = 0.04) and IgG-ASCA (P = 0.02) levels were also lower in patients with any adverse events, and anti-I2 level in ulcerative colitis was significantly associated with infusion reactions (P = 0.008). The logistic regression/human annotation and network analyses performed on the Immunochip data implicated the following five signaling pathways: JAK-STAT (Janus Kinase-signal transducer and activator of transcription), measles, IBD, cytokine-cytokine receptor interaction, and toxoplasmosis for any adverse event. CONCLUSION: Our study shows 1 in 5 IBD patients experience an adverse event to anti-TNF therapy with novel serologic, genetic , and pathways associations.

CSA13 inhibits colitis-associated intestinal fibrosis via a formyl peptide receptor like-1 mediated HMG-CoA reductase pathway.

Many Crohn's disease (CD) patients develop intestinal strictures, which are difficult to prevent and treat. Cationic steroid antimicrobial 13 (CSA13) shares cationic nature and antimicrobial function with antimicrobial peptide cathelicidin. As many functions of cathelicidin are mediated through formyl peptide receptor-like 1 (FPRL1), we hypothesize that CSA13 mediates anti-fibrogenic effects via FPRL1. Human intestinal biopsies were used in clinical data analysis. Chronic trinitrobenzene sulfonic acid (TNBS) colitis-associated intestinal fibrosis mouse model with the administration of CSA13 was used. Colonic FPRL1 mRNA expression was positively correlated with the histology scores of inflammatory bowel disease patients. In CD patients, colonic FPRL1 mRNA was positively correlated with intestinal stricture. CSA13 administration ameliorated intestinal fibrosis without influencing intestinal microbiota. Inhibition of FPRL1, but not suppression of intestinal microbiota, reversed these protective effects of CSA13. Metabolomic analysis indicated increased fecal mevalonate levels in the TNBS-treated mice, which were reduced by the CSA13 administration. CSA13 inhibited colonic HMG-CoA reductase activity in an FPRL1-dependent manner. Mevalonate reversed the anti-fibrogenic effect of CSA13. The increased colonic FPRL1 expression is associated with severe mucosal disease activity and intestinal stricture. CSA13 inhibits intestinal fibrosis via FPRL1-dependent modulation of HMG-CoA reductase pathway.

Statins and pancreatic cancer.

Pancreatic cancer remains among the most lethal cancers, despite ongoing advances in treatment for all stages of the disease. Disease prevention represents another opportunity to improve patient outcome, with metabolic syndrome and its components, such as diabetes, obesity and dyslipidemia, having been recognized as modifiable risk factors for pancreatic cancer. In addition, statins have been shown to potentially reduce pancreatic cancer risk and to improve survival in patients with a combination of metabolic syndrome and pancreatic cancer. Furthermore, preclinical studies have demonstrated that statins exhibit antitumor effects in pancreatic cancer cell lines in vitro and animal models in vivo, in addition to delaying the progression of pancreatic intraepithelial neoplasia to pancreatic ductal adenocarcinoma (PDAC) and inhibiting PDAC formation in conditional K-Ras mutant mice. The mechanisms by which statins produce anticancer effects remain poorly understood, although appear to involve inhibition of the mevalonate/cholesterol synthesis pathway, thus blocking the synthesis of intermediates important for prenylation and activation of the Ras/mitogen-activated protein kinase 1 signaling pathway. Furthermore, statins have been identified to modulate the phosphoinositide 3-kinase/Akt serine/threonine kinase 1 and inflammation signaling pathways, and to alter the expression of genes involved in lipid metabolism, which are important for PDAC growth and proliferation. In addition, statins have been demonstrated to exhibit further antitumor mechanisms in a number of other cancer types, which are beyond the scope of the present review. In the present review, current evidence highlighting the potential of statins as chemopreventive agents in pancreatic cancer is presented, and the antitumor mechanisms of statins elucidated thus far in this disease are discussed.

Outcomes with Anti-Tumour Necrosis Factor-Alpha Therapy and Serology in Patients with Denovo Crohn's Disease After Ileal Pouch Anal Anastomosis.

BACKGROUND AND AIMS: A subset of patients who undergo ileal pouch-anal anastomosis [IPAA] for ulcerative colitis [UC] will later be diagnosed with denovo Crohn's disease [CD]. These patients have a higher risk of pouch failure. In this study we evaluated inflammatory bowel disease [IBD] serology in patients with denovo CD and examined the success of anti-tumour necrosis factor-alpha [anti-TNFα] therapy in preventing ileostomy in denovo CD patients who failed anti-TNFα therapy before IPAA. METHODS: A prospectively maintained database of patients undergoing IPAA was reviewed to identify patients who developed denovo CD [defined as small bowel inflammation above the pouch inlet or pouch fistula/perianal disease appearing more than 3 months after stoma closure]. Clinical characteristics and IBD serology were analysed. Treatment failure was defined as pouch failure requiring ileostomy or pouchectomy. RESULTS: Of 350 patients included in the study, 92 [26%] patients developed denovo CD. Significantly more denovo CD patients had anti-I2 positivity postoperatively versus preoperatively [p = 0.007]. Anti-TNFα therapy successfully treated denovo CD in 28 out of 38 [74%] patients. Out of 17 patients with denovo CD who had failed to respond to anti-TNFα agents before surgery and were treated with anti-TNFα therapy after surgery, 12 [71%] patients responded to treatment. CONCLUSIONS: I2 serology may possibly help identify patients who have developed or are at risk for developing denovo CD. Anti-TNFα therapy for denovo CD after IPAA can help prevent permanent ileostomy in almost 75% of cases, even in patients who previously failed anti-TNFα treatment before surgery.

Nonbloody Diarrhea but Not Significant Weight Loss at Diagnosis Is Associated with the Development of Denovo Crohn's Disease After Ileal Pouch-anal Anastomosis for Ulcerative Colitis.

BACKGROUND: Denovo Crohn's disease (CD) develops in 5% to 10% of patients after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) leading to increased morbidity and rates of pouch failure. Initial nonbloody diarrhea and weight loss at diagnosis are independent risk factors for a change in diagnosis from UC to CD in nonsurgical patients. We investigated whether these features were risk factors for denovo CD in a longitudinal cohort of patients with UC undergoing IPAA. METHODS: Prospective profiles of patients with UC undergoing IPAA followed over a 22-year period by 1 surgeon were analyzed. Denovo CD was diagnosed when mucosal inflammation (5 or more ulcers) involved the small bowel mucosa proximal to the ileal pouch any time after surgery and/or when a pouch fistula or other perianal complication developed more than 3 months after ileostomy closure. Patients with inflammatory bowel disease unclassified, acute pouchitis, chronic pouchitis, and those lost to follow-up were excluded from analysis. Cox regression analysis was performed for statistical significance. RESULTS: Of the 199 study patients included in the analysis, denovo CD developed in 42 patients (21%). Patients who developed denovo CD had an increased incidence of nonbloody diarrhea (n = 12; 29%) compared with patients who had no evidence of pouch inflammation (n = 25; 16%) (P = 0.03). In contrast, the incidence of weight loss was not significantly increased in patients with denovo CD (n = 7; 17%) compared with patients who never had pouch inflammation (n = 16; 10%) (P = 0.12). CONCLUSIONS: Initial nonbloody diarrhea is associated with denovo CD after IPAA. This association warrants close consideration before surgery.

Hepatitis B: Working Towards a Cure.

First-line oral therapies for hepatitis B are effective at viral suppression, and treatment can lead to biochemical improvement and histologic regression. Unfortunately, recommended endpoints of treatment such as HBeAg loss and seroconversion may not be durable, with high rates of seroreversion, requiring monitoring, and unfortunately, low rates of  HBsAg loss/seroconversion. Additionally, meeting these endpoints requires years or even indefinite administration, leading to concerns regarding cost, side effects, and high rates of nonadherence. This article will review defined endpoints of therapy and their durability, the risks of long-term therapy, and the evolving new therapies aimed at a viral cure.

Diabetes, pancreatic cancer, and metformin therapy.

Pancreatic cancer carries a poor prognosis as most patients present with advanced disease and preferred chemotherapy regimens offer only modest effects on survival. Risk factors include smoking, obesity, heavy alcohol, and chronic pancreatitis. Pancreatic cancer has a complex relationship with diabetes, as diabetes can be both a risk factor for pancreatic cancer and a result of pancreatic cancer. Insulin, insulin-like growth factor-1 (IGF-1), and certain hormones play an important role in promoting neoplasia in diabetics. Metformin appears to reduce risk for pancreatic cancer and improve survival in diabetics with pancreatic cancer primarily by decreasing insulin/IGF signaling, disrupting mitochondrial respiration, and inhibiting the mammalian target of rapamycin (mTOR) pathway. Other potential anti-tumorigenic effects of metformin include the ability to downregulate specificity protein transcription factors and associated genes, alter microRNAs, decrease cancer stem cell proliferation, and reduce DNA damage and inflammation. Here, we review the most recent knowledge on risk factors and treatment of pancreatic cancer and the relationship between diabetes, pancreatic cancer, and metformin as a potential therapy.