AGA Clinical Practice Update on Diet and Nutritional Therapies in Patients With Inflammatory Bowel Disease: Expert Review.

DESCRIPTION: Diet plays a critical role in human health, but especially for patients with inflammatory bowel disease (IBD). Guidance about diet for patients with IBD are often controversial and a source of uncertainty for many physicians and patients. The role of diet has been investigated as a risk factor for IBD etiopathogenesis and as a therapy for active disease. Dietary restrictions, along with the clinical complications of IBD, can result in malnutrition, an underrecognized condition among this patient population. The aim of this American Gastroenterological Association (AGA) Clinical Practice Update (CPU) is to provide best practice advice statements, primarily to clinical gastroenterologists, covering the topics of diet and nutritional therapies in the management of IBD, while emphasizing identification and treatment of malnutrition in these patients. We provide guidance for tailored dietary approaches during IBD remission, active disease, and intestinal failure. A healthy Mediterranean diet will benefit patients with IBD, but may require accommodations for food texture in the setting of intestinal strictures or obstructions. New data in Crohn's disease supports the use of enteral liquid nutrition to help induce remission and correct malnutrition in patients heading for surgery. Parenteral nutrition plays a critical role in patients with IBD facing acute and/or chronic intestinal failure. Registered dietitians are an essential part of the interdisciplinary team approach for optimal nutrition assessment and management in the patient population with IBD. METHODS: This expert review was commissioned and approved by the AGA Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the CPU Committee and external peer review through standard procedures of Gastroenterology. The best practice advice statements were drawn from reviewing existing literature combined with expert opinion to provide practical advice on the role of diet and nutritional therapies in patients with IBD. Because this was not a systematic review, formal rating of the quality of evidence or strength of the presented considerations was not performed. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Unless there is a contraindication, all patients with IBD should be advised to follow a Mediterranean diet rich in a variety of fresh fruits and vegetables, monounsaturated fats, complex carbohydrates, and lean proteins and low in ultraprocessed foods, added sugar, and salt for their overall health and general well-being. No diet has consistently been found to decrease the rate of flares in adults with IBD. A diet low in red and processed meat may reduce ulcerative colitis flares, but has not been found to reduce relapse in Crohn's disease. BEST PRACTICE ADVICE 2: Patients with IBD who have symptomatic intestinal strictures may not tolerate fibrous, plant-based foods (ie, raw fruits and vegetables) due to their texture. An emphasis on careful chewing and cooking and processing of fruits and vegetables to a soft, less fibrinous consistency may help patients with IBD who have concomitant intestinal strictures incorporate a wider variety of plant-based foods and fiber in their diets. BEST PRACTICE ADVICE 3: Exclusive enteral nutrition using liquid nutrition formulations is an effective therapy for induction of clinical remission and endoscopic response in Crohn's disease, with stronger evidence in children than adults. Exclusive enteral nutrition may be considered as a steroid-sparing bridge therapy for patients with Crohn's disease. BEST PRACTICE ADVICE 4: Crohn's disease exclusion diet, a type of partial enteral nutrition therapy, may be an effective therapy for induction of clinical remission and endoscopic response in mild to moderate Crohn's disease of relatively short duration. BEST PRACTICE ADVICE 5: Exclusive enteral nutrition may be an effective therapy in malnourished patients before undergoing elective surgery for Crohn's disease to optimize nutritional status and reduce postoperative complications. BEST PRACTICE ADVICE 6: In patients with IBD who have an intra-abdominal abscess and/or phlegmonous inflammation that limits ability to achieve optimal nutrition via the digestive tract, short-term parenteral nutrition may be used to provide bowel rest in the preoperative phase to decrease infection and inflammation as a bridge to definitive surgical management and to optimize surgical outcomes. BEST PRACTICE ADVICE 7: We suggest the use of parenteral nutrition for high-output gastrointestinal fistula, prolonged ileus, short bowel syndrome, and for patients with IBD with severe malnutrition when oral and enteral nutrition has been trialed and failed or when enteral access is not feasible or contraindicated. BEST PRACTICE ADVICE 8: In patients with IBD and short bowel syndrome, long-term parenteral nutrition should be transitioned to customized hydration management (ie, intravenous electrolyte support and/or oral rehydration solutions) and oral intake whenever possible to decrease the risk of developing long-term complications. Treatment with glucagon-like peptide-2 agonists can facilitate this transition. BEST PRACTICE ADVICE 9: All patients with IBD warrant regular screening for malnutrition by their provider by means of assessing signs and symptoms, including unintended weight loss, edema and fluid retention, and fat and muscle mass loss. When observed, more complete evaluation for malnutrition by a registered dietitian is indicated. Serum proteins are no longer recommended for the identification and diagnosis of malnutrition due to their lack of specificity for nutritional status and high sensitivity to inflammation. BEST PRACTICE ADVICE 10: All patients with IBD should be monitored for vitamin D and iron deficiency. Patients with extensive ileal disease or prior ileal surgery (resection or ileal pouch) should be monitored for vitamin B12 deficiency. BEST PRACTICE ADVICE 11: All outpatients and inpatients with complicated IBD warrant co-management with a registered dietitian, especially those who have malnutrition, short bowel syndrome, enterocutaneous fistula, and/or are requiring more complex nutrition therapies (eg, parenteral nutrition, enteral nutrition, or exclusive enteral nutrition), or those on a Crohn's disease exclusion diet. We suggest that all newly diagnosed patients with IBD have access to a registered dietitian. BEST PRACTICE ADVICE 12: Breastfeeding is associated with a lower risk for diagnosis of IBD during childhood. A healthy, balanced, Mediterranean diet rich in a variety of fruits and vegetables and decreased intake of ultraprocessed foods have been associated with a lower risk of developing IBD.

Peripheral Blood Monocytosis Is Associated With Long-Term Disease Severity in Pediatric-Onset Inflammatory Bowel Disease.

OBJECTIVES: Peripheral blood monocytosis (PBM) is a marker of increased disease severity in adults with inflammatory bowel diseases (IBDs). We sought to determine whether PBM serves as a prognostic biomarker in patients with pediatric-onset IBD for a more aggressive long-term disease course when followed into adulthood. METHODS: Patients with pediatric-onset inflammatory bowel disease were identified within an adult tertiary care center, within a consented, prospectively collected natural history disease registry, to compare clinical outcomes between patients with and without PBM from the years 2009 to 2019. Patients demonstrating elevation in PBM at any time defined membership and long-term clinical trajectories were compared with pediatric-onset patients without PBM. RESULTS: A total of 581 patients with IBD, diagnosed by 18 years of age, were identified for inclusion, of which 440 patients were diagnosed with Crohn disease and 141 with ulcerative colitis. Monocytosis was detected by complete blood cell counts in 40.1% of patients. PBM was associated with steroid and biologic exposure, number of IBD-related surgeries, and increased health care utilization. Multivariate logistic regression analyses, accounting for elevation of inflammatory markers and other values associated with acute disease activity as well as steroid use, showed persistently increased odds of biologic exposure, emergency department visits, and hospitalizations, but not surgeries, after detection of monocytosis. CONCLUSIONS: Within patients with pediatric-onset IBD, the sub-cohort with PBM had associated worse clinical outcomes and other markers of increased disease severity.

Nightshade Vegetables: A Dietary Trigger for Worsening Inflammatory Bowel Disease and Irritable Bowel Syndrome?

The Solanaceae family of plants, commonly known as Nightshade vegetables or Nightshades, contains a diverse range of crops of over 2000 members with significant culinary, economic, and cultural importance. Familiar edible Nightshades include tomatoes, peppers, eggplants, and white potatoes. Many pharmacologically active compounds used in traditional medicine, including atropine and hyoscyamine, are derived from Nightshades. In addition to these beneficial pharmacologic agents, Nightshade-derived glycoalkaloid compounds, a key defense mechanism against predation, have been shown to disrupt intestinal epithelium and to potentially activate mast cells in the gut mucosa, leading to adverse symptoms in humans. There is a new appreciation that mast cell activation is an allergic inflammatory mechanism contributing both to pain in irritable bowel syndrome (IBS) and to gut inflammation in inflammatory bowel disease (IBD). Given their ubiquity in Western diets and their shared glycoalkaloid active compounds, edible Nightshades are attracting new interest as a potential trigger for worsening gut symptoms in functional and inflammatory gastrointestinal disorders. Here, we review the limited existing literature on the adverse effects of Nightshade consumption, including the effects of Nightshade-derived glycoalkaloids on IBD gut inflammation, and the under-recognized contribution of Nightshades to food allergies and allergic cross-reactivity. We then highlight new evidence on the contributions of mast cell activation to GI disorder pathogenesis, including potential linkages between Nightshade antigens, intestinal mast cells, and GI dysfunction in IBS and IBD.

Histone deacetylase inhibitors (HDACi) increase expression of KCa2.3 (SK3) in primary microvascular endothelial cells.

The small conductance calcium-activated potassium channel (KCa2.3) has long been recognized for its role in mediating vasorelaxation through the endothelium-derived hyperpolarization (EDH) response. Histone deacetylases (HDACs) have been implicated as potential modulators of blood pressure and histone deacetylase inhibitors (HDACi) are being explored as therapeutics for hypertension. Herein, we show that HDACi increase KCa2.3 expression when heterologously expressed in HEK cells and endogenously expressed in primary cultures of human umbilical vein endothelial cells (HUVECs) and human intestinal microvascular endothelial cells (HIMECs). When primary endothelial cells were exposed to HDACi, KCa2.3 transcripts, subunits, and functional current are increased. Quantitative RT-PCR (qPCR) demonstrated increased KCa2.3 mRNA following HDACi, confirming transcriptional regulation of KCa2.3 by HDACs. By using pharmacological agents selective for different classes of HDACs, we discriminated between cytoplasmic and epigenetic modulation of KCa2.3. Biochemical analysis revealed an association between the cytoplasmic HDAC6 and KCa2.3 in immunoprecipitation studies. Specifically inhibiting HDAC6 increases expression of KCa2.3. In addition to increasing the expression of KCa2.3, we show that nonspecific inhibition of HDACs causes an increase in the expression of the molecular chaperone Hsp70 in endothelial cells. When Hsp70 is inhibited in the presence of HDACi, the magnitude of the increase in KCa2.3 expression is diminished. Finally, we show a slower rate of endocytosis of KCa2.3 as a result of exposure of primary endothelial cells to HDACi. These data provide the first demonstrated approach to increase KCa2.3 channel number in endothelial cells and may partially account for the mechanism by which HDACi induce vasorelaxation.

Brief Behavioral Therapy and Bupropion for Sleep and Fatigue in Young Adults With Crohn's Disease: An Exploratory Open Trial Study.

BACKGROUND/AIMS: Sleep disturbances and fatigue are common symptoms amongst patients with Crohn's disease (CD). The aim of this study was to test the feasibility and effects of a pragmatic, stepped-care intervention for the treatment of poor sleep quality and fatigue in adolescents and young adults with CD. METHODS: This study is a two-phase open trial exploring interventions for sleep and fatigue. After the initial comprehensive assessment which included quantitative measures and an interview to evaluate sleep and physical and mental health, the 12-week intervention consisted of two sequential steps: 1) a brief behavioral therapy for sleep in inflammatory bowel disease (IBD) (BBTS-I; 4 weeks) and 2) adding the psychotropic medication, bupropion sustained release (BUP-SR; 8 weeks), for the subset of subjects continuing to experience fatigue. RESULTS: 232 CD patients (median age=24, median sex=female) were approached over 18 months, of whom 112 screened positive on the Pittsburgh Sleep Quality Index (PSQI) and multi-dimensional fatigue inventory (MFI), with 68 CD patients completing the more comprehensive baseline assessment. Of the 68 patients, 52 participated in Phase I of the BBTS-I intervention. Following 4-weeks of the BBTS-I, there were significant improvements in sleep quality (p < .001) and fatigue (p < .001). As part of Phase II, of the 52 patients who met fatigue threshold criteria, 33 patients participated in the BUP-SR+BBTS-I arm while 19 participated in the BBTS-I only intervention group. After 8 weeks of Phase II, both intervention groups saw significant further improvement in sleep, fatigue, anxiety and depressive symptoms, but without significant differences between the two intervention groups. CONCLUSIONS: A stepped-care approach shows that we can improve sleep disturbance with BBTS-I in CD patients, but fatigue only partially improves. For a subset of patients who chose to add BUP-SR to their behavioral therapy, fatigue improves further but not to a statistically significant effect compared to behavioral therapy alone.

An Expert Opinion/Approach: Clinical Presentations, Diagnostic Considerations, and Therapeutic Options for Gastrointestinal Manifestations of Common Variable Immune Deficiency.

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. It is characterized by impaired B-cell differentiation. Although patients can be diagnosed with CVID anytime during their lifetime, most patients have symptoms for 5-9 years before their diagnosis. The diagnosis of CVID starts with a detailed history focusing on the infectious and noninfectious manifestations of the disease. In patients who are suspected to experience CVID, quantitative immunoglobulins (Ig) should be checked to confirm the diagnosis. IgG should be at least 2 times less than the age-specific SD along with either a low IgA or IgM and with evidence of impaired vaccine response. CVID is usually associated with infectious and/or noninfectious conditions, the latter of which can be inflammatory, autoimmune, lymphoproliferative, or malignant, among other manifestations. Ig therapy has positively affected the disease course of patients with infectious complications but has limited effect on the noninfectious manifestations because the noninfectious complications are related to immune dysregulation involving B cells and T cells rather than primarily due to antibody deficiency. When the gastrointestinal (GI) system is involved, patients with CVID may display signs and symptoms that mimic several GI conditions such as celiac disease, pernicious anemia, or inflammatory bowel diseases. The inflammatory bowel disease-like condition is usually treated with steroids, 5-aminosalicylates, thiopurines, or biologic agents to control the inflammation. In this review, the clinical presentations, diagnostic considerations, and therapeutic options for GI manifestations of CVID will be discussed to facilitate the individualized management of these often-complex patients.

Should high-fiber diets be recommended for patients with inflammatory bowel disease?

PURPOSE OF REVIEW: Dietary fiber intake in IBD patients has oftentimes generated conflicting data and clinical recommendations. This review aims to unify apparently conflicting lines of evidence regarding dietary fiber intake in IBD patients by highlighting new information from natural history studies and prospective clinical trials. RECENT FINDINGS: IBD patients have lower dietary fiber intake than the general population as well as national guideline recommendations. Patients report short-term benefits from fiber avoidance. Low fiber and low FODMAP diets are associated with lower fecal microbiota abundance and essential nutrient intake. There is emerging evidence suggesting that IBD patients may be able to increase dietary fiber intake with short-term benefit and good tolerability, particularly when fiber is introduced during clinical remission. Current societal recommendations do not favor withholding dietary fiber during long-term IBD management. The long-term impact of increased dietary fiber on IBD clinical outcomes remains unanswered. SUMMARY: Dietary fiber intake is not necessarily contraindicated in IBD patients.

Tofacitinib inhibits inflammatory cytokines from ulcerative colitis and healthy mucosal explants and is associated with pSTAT1/3 reduction in T-cells.

Poor translatability of animal disease models has hampered the development of new inflammatory bowel disorder (IBD) therapeutics. We describe a preclinical, ex vivo system using freshly obtained and well-characterized human colorectal tissue from patients with ulcerative colitis (UC) and healthy control (HC) participants to test potential therapeutics for efficacy and target engagement, using the JAK/STAT inhibitor tofacitinib (TOFA) as a model therapeutic. Colorectal biopsies from HC participants and patients with UC were cultured and stimulated with multiple mitogens ± TOFA. Soluble biomarkers were detected using a 29-analyte multiplex ELISA. Target engagement in CD3+CD4+ and CD3+CD8+ T-cells was determined by flow cytometry in peripheral blood mononuclear cells (PBMCs) and isolated mucosal mononuclear cells (MMCs) following the activation of STAT1/3 phosphorylation. Data were analyzed using linear mixed-effects modeling, t test, and analysis of variance. Biomarker selection was performed using penalized and Bayesian logistic regression modeling, with results visualized using uniform manifold approximation and projection. Under baseline conditions, 27 of 29 biomarkers from patients with UC were increased versus HC participants. Explant stimulation increased biomarker release magnitude, expanding the dynamic range for efficacy and target engagement studies. Logistic regression analyses identified the most representative UC baseline and stimulated biomarkers. TOFA inhibited biomarkers dependent on JAK/STAT signaling. STAT1/3 phosphorylation in T-cells revealed compartmental differences between PBMCs and MMCs. Immunogen stimulation increases biomarker release in similar patterns for HC participants and patients with UC, while enhancing the dynamic range for pharmacological effects. This work demonstrates the power of ex vivo human colorectal tissue as preclinical tools for evaluating target engagement and downstream effects of new IBD therapeutic agents.NEW & NOTEWORTHY Using colorectal biopsy material from healthy volunteers and patients with clinically defined IBD supports translational research by informing the evaluation of therapeutic efficacy and target engagement for the development of new therapeutic entities. Combining experimental readouts from intact and dissociated tissue enhances our understanding of the tissue-resident immune system that contribute to disease pathology. Bayesian logistic regression modeling is an effective tool for predicting ex vivo explant biomarker release patterns.

Altered Expression of the Epithelial Mucin MUC1 Accompanies Endoscopic Recurrence of Postoperative Crohn's Disease.

BACKGROUND: MUC1-glycoprotein is expressed at low levels and in fully glycosylated form on epithelial cells. Inflammation causes MUC1 overexpression and hypoglycosylation. We hypothesized that overexpression of hypoglycosylated MUC1 would be found in postoperative Crohn's disease (CD) recurrence and could be considered an additional biomarker of recurrence severity. METHODS: We examined archived neo-terminal ileum biopsies from patients with prior ileocecal resection who had postoperative endoscopic assessment of CD recurrence and given a Rutgeerts ileal recurrence score. Consecutive tissue sections were stained using 2 different anti-MUC1 antibodies, HMPV that recognizes all forms of MUC1 and 4H5 that recognizes only inflammation-associated hypoglycosylated MUC1. RESULTS: A total of 71 postoperative CD patients were evaluated. There was significant increase in MUC1 expression of both glycosylated/normal (P<0.0001) and hypoglycosylated/abnormal (P<0.0001) forms in patients with severe endoscopic CD recurrence (i3+i4), ileal score i2, compared with patients in endoscopic remission (i0+i1). Results were similar regardless of anti-TNF-α use. Although MUC1 expression and Rutgeerts scores were in agreement when characterizing the majority of cases, there were a few exceptions where MUC1 expression was characteristic of more severe recurrence than implied by Rutgeerts score. CONCLUSIONS: MUC1 is overexpressed and hypoglycosylated in neo-terminal ileum tissue of patients with postoperative CD recurrence. Increased levels are associated with more severe endoscopic recurrence scores, and this is not influenced by anti-TNF-α use. Discrepancies found between Rutgeerts scores and MUC1 expression suggest that addition of MUC1 as a biomarker of severity of postoperative CD recurrence may improve categorization of recurrence status and consequently treatment decisions.

AGA Technical Review on the Management of Mild-to-Moderate Ulcerative Colitis.

Most patients with ulcerative colitis (UC) have mild-to-moderate disease activity, with low risk of colectomy, and are managed by primary care physicians or gastroenterologists. Optimal management of these patients decreases the risk of relapse and proximal disease extension, and may prevent disease progression, complications, and need for immunosuppressive therapy. With several medications (eg, sulfasalazine, diazo-bonded 5-aminosalicylates [ASA], mesalamines, and corticosteroids, including budesonide) and complex dosing formulations, regimens, and routes, to treat a disease with variable anatomic extent, there is considerable practice variability in the management of patients with mild-moderate UC. Hence, the American Gastroenterological Association prioritized clinical guidelines on this topic. To inform clinical guidelines, this technical review was developed in accordance with the Grading of Recommendations Assessment, Development and Evaluation framework for interventional studies. Focused questions included the following: (1) comparative effectiveness and tolerability of different oral 5-ASA therapies (sulfalsalazine vs diazo-bonded 5-ASAs vs mesalamine; low- (<2 g) vs standard (2-3 g/d) vs high-dose (>3 g/d) mesalamine); (2) comparison of different dosing regimens (once-daily vs multiple times per day dosing) and routes (oral vs rectal vs both oral and rectal); (3) role of oral budesonide in patients mild-moderate UC; (4) comparative effectiveness and tolerability of rectal 5-ASA and corticosteroid formulations in patients with distal colitis; and (5) role of alternative therapies like probiotics, curcumin, and fecal microbiota transplantation in the management of mild-moderate UC.

Complete Resolution of Mucosal Neutrophils Associates With Improved Long-Term Clinical Outcomes of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: We investigated correlations between histologic features of the colonic mucosa in patients with ulcerative colitis (UC) and clinical outcomes during a 3-year follow-up period. METHODS: We obtained baseline biopsies from all colorectal segments (n = 889) from 281 patients with UC enrolled in a prospective study at a single center from 2009 through 2013. Biopsies were assessed in a blinded manner using validated histologic scoring systems (the Geboes score, Nancy histopathologic index, and Robarts histopathologic index). Clinical, endoscopic, and histologic data were collected and tested for correlations with systemic corticosteroid use, hospitalization, and colectomy within 3 years of the index colonoscopy. RESULTS: We found histologic evidence of UC activity (Geboes score ≥ 2B.1) in biopsies from 182 patients (65%) and endoscopic evidence of UC activity in 149 patients (53%) (substantial agreement, κ = 0.60). Histologic features of UC activity were associated with increased rates of systemic corticosteroid use, colectomy, and hospitalization in the entire cohort (P < .05 for all) and associated with increased rates of systemic corticosteroid use in an analysis limited to patients in endoscopic remission (P < .001). In patients in endoscopic remission, only histologic activity was independently associated with use of systemic corticosteroids (multivariate odds ratio, 6.34; 95% CI, 2.20-18.28; P = .001). Similar results were seen when the entire cohort was analyzed. Compared with patients without histologic evidence of UC activity, patients with only a small number of mucosal neutrophils still had higher rates of systemic corticosteroid use (P < .001). CONCLUSIONS: Histologic evidence of UC activity, including small numbers of neutrophils in the colonic mucosa, is the only factor independently associated with use of systemic corticosteroids. Complete resolution of neutrophil-associated inflammation should be a target for treatment of UC.

Predictors of Suicidal Ideation Among IBD Outpatients.

BACKGROUND: Suicidal ideation (SI) is understudied in inflammatory bowel diseases (IBD). We aim to determine SI rates among IBD outpatients and to evaluate predictors of SI. MATERIALS AND METHODS: This is a prospective observational study of consecutive adult IBD outpatients over 18 months. Patients were screened for depression and SI using patient health questionnaire (PHQ-9). Demographic data were obtained from electronic medical record. Regression modeling was used for predictor analyses. RESULTS: In total, 71 of consecutive 1352 IBD outpatients had SI. Significant correlations between SI and depression severity, tricyclic antidepressants (TCA), IBD-related quality of life, and low vitamin D levels were seen. Univariate regression showed that depression severity, TCA use, and quality of life predicted SI. Multivariate regression showed depression severity (ß=0.46; P=0.002) and TCA use (ß=0.31; P=0.012) made unique contributions. CONCLUSIONS: SI is associated with depressive severity and less directly with IBD activity. Low-dose TCA, often used for chronic abdominal pain, is also a risk factor. Identifying the subset of IBD patients most vulnerable to SI can facilitate proper referrals to behavioral services and prevent progression to completed suicides.

Epithelioid Granulomas Associate With Increased Severity and Progression of Crohn's Disease, Based on 6-Year Follow-Up.

BACKGROUND & AIMS: Epithelioid granulomas are characteristics of a subset of patients with Crohn's disease (CD), but their significance, with regard to disease progression and severity, is unclear. We investigated the relationship between granulomas and CD severity over a 6-year time period in a large cohort of patients. METHODS: We performed a retrospective study of patients with CD seen at the Inflammatory Bowel Disease Center at the University of Pittsburgh; data were collected from 2009 through 2014 and patients were assigned to groups with and without histologic evidence of granuloma. Demographic, clinical (including disease activity, quality of life, medication use, and healthcare utilization), and laboratory data were used in association and survival analyses. Differences between groups were evaluated using the Mann-Whitney U-test for continuous variables. RESULTS: Of 1466 patients with CD, granulomas were identified in 187 (12.8%). In the subset of patients who underwent surgery, 21.0% had granulomas. The presence of granuloma was associated with increased serum levels of c-reactive protein (odds ratio [OR], 2.9; 95% CI, 2.078-4.208; P < .0001), younger mean age at diagnosis (23.6 ± 11.3 years in patients with granulomas vs 27.9 ± 13.3 years in patients without; P = .0005), higher rates of stricturing or penetrating disease phenotype, higher rates of steroid and narcotic use, and higher healthcare utilization. Among patients that underwent surgery, the presence of granulomas was associated with need for repeat surgery during the 6-year observation period (OR, 2.5; 95% CI, 1.54-4.02; P = .0002). Infliximab use was associated with detection of granuloma in a significantly lower proportion of surgical specimens compared to patients who had not been treated with a biologic agent (OR, 0.22; 95 CI, 0.05-0.97; P = .03). CONCLUSIONS: Epithelioid granulomas develop in less than 13% of patients with CD, and are associated with a more aggressive disease phenotype. Patients who have undergone surgery for CD and have granulomas are at increased risk for repeat surgery within 6 years.

Ileocecal Anastomosis Type Significantly Influences Long-Term Functional Status, Quality of Life, and Healthcare Utilization in Postoperative Crohn's Disease Patients Independent of Inflammation Recurrence.

OBJECTIVES: Anastomotic reconstruction following intestinal resection in Crohn's disease (CD) may employ side-to-side anastomosis (STSA; anti-peristaltic orientation) or end-to-end anastomosis (ETEA). Our aim was to determine the impact of these two anastomotic techniques on long-term clinical status in postoperative CD patients. METHODS: We performed a comparative effectiveness study of prospectively collected observational data from consented CD patients undergoing their first or second ileocolonic bowel resection and re-anastomosis between 2008 and 2012, in order to assess the association between anastomosis type and 2-year postoperative quality of life (QoL), healthcare utilization, disease clinical or endoscopic recurrence, use of medications, and need for repeat resection. RESULTS: One hundred and twenty eight postoperative CD patients (60 STSA and 68 ETEA) were evaluated. At 2 years postoperatively, STSA patients had higher rates of emergency department visits (33.3% vs. 14.7%; P=0.01), hospitalizations (30% vs. 11.8%; P=0.01), and abdominal computed tomography scans (50% vs. 13.2%; P<0.001) with lower QoL (mean short inflammatory bowel disease questionnaire 47.9 vs. 53.4; P=0.007). There was no difference among the two groups in the 30 day surgical complications and 2-year patterns of disease activity, CD medication requirement, endoscopic recurrence, and need for new surgical management (all P > 0.05). CONCLUSIONS: At 2 years postoperatively, CD patients with ETEA demonstrated better QoL and less healthcare utilization compared with STSA, despite having similar patterns of disease recurrence and CD treatment. These findings suggest that surgical reconstruction of the bowel as an intact tube (ETEA) contribute to improved functional and clinical status in patients with CD.

Telephone Encounters Predict Future High Financial Expenditures in Inflammatory Bowel Disease Patients: A 3-Year Prospective Observational Study.

BACKGROUND: Telephone activity is essential in management of complex chronic diseases including inflammatory bowel disease (IBD). Telephone encounters logged in the electronic medical record have recently been proposed as a surrogate marker of disease activity and impending health care utilization; however, the association between telephone calls and financial expenditures has not been evaluated. STUDY: We performed a 3-year prospective observational study of telephone encounters logged at a tertiary referral IBD center. We analyzed patient demographics, disease characteristics, comorbidities, clinical activity, and health care financial charges by telephone encounter frequency. RESULTS: Eight hundred one patients met inclusion criteria (52.3% female; mean age, 44.1 y), accounted for 12,669 telephone encounters, and accrued $70,513,449 in charges over 3 years. High telephone encounter frequency was associated with female gender (P=0.003), anxiety/depression (P<0.001), and prior IBD surgery (P<0.001). High telephone encounter categories had significantly more hospitalizations (P<0.001), IBD surgery (P<0.001), worse quality of life (P<0.001), more corticosteroid (P<0.001), biological (P<0.001), and opiate prescriptions (P<0.001). High telephone encounter frequency patients amassed higher total available charges in each year (P<0.001) and over the 3 years (P<0.001). Telephone encounters in 2009 (P=0.02) and 2010 (P<0.001) were significantly associated with financial charges the following year after controlling for demographic, utilization, and medication covariates. CONCLUSIONS: Increased telephone encounters are associated with significantly higher health care utilization and financial expenditures. Increased call frequency is predictive of future health care spending. Telephone encounters are a useful tool to identify patients at risk of clinical deterioration and large financial expense.

Quality of Sleep and Coexistent Psychopathology Have Significant Impact on Fatigue Burden in Patients With Inflammatory Bowel Disease.

BACKGROUND: Fatigue is common in inflammatory bowel disease (IBD) patients and is associated with factors such as psychopathology, sleep quality, and disease activity. GOAL: To investigate the combined role of all the above factors in the burden of fatigue among IBD patients. STUDY: We conducted an observational study of adult patients enrolled in an IBD clinical research registry at a tertiary care clinic. Fatigue burden was defined by Item 1 of the Short-form IBD Questionnaire (SIBDQ), which is scored on a 7-point Likert scale. Crohn's disease (CD) and ulcerative colitis (UC) disease activity were measured with the Harvey-Bradshaw Index or the UC Activity Index, respectively. Labs were obtained to assess anemia, vitamin deficiencies, and inflammatory markers. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Use of psychotropic medications and narcotics was used as proxy measure of psychopathology and pain. RESULTS: Among 685 IBD patients enrolled in the registry, 631 (238 UC, 393 CD) had a complete SIBDQ. High fatigue burden was found in 57.5% of patients (64.4% CD, 46.2% UC). Fatigue burden was significantly associated with sleep disturbance (PSQI), SIBDQ, and disease activity. CD patients had more fatigue burden than UC patients. Multivariate regression showed that poor quality of life, sleep disturbance, and being on a psychotropic medication are significantly associated with fatigue burden for both UC and CD. CONCLUSION: Because fatigue is common in IBD patients, these findings suggest that attention to quality of sleep and psychopathology is as important as medical disease management.

Cost-Effectiveness of Melanoma Screening in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) patients are at increased risk of melanoma and non-melanoma skin cancers, and preventive care guidelines in IBD favor annual skin examinations. Here we estimate the cost-effectiveness of annual melanoma screening in IBD. METHODS: Melanoma screening was defined as receiving annual total body skin examinations starting at age 40 from a dermatologist. Screening was compared to US background total body skin examination rates performed by primary care practitioners. A Markov model was used to estimate intervention costs and effectiveness. Future costs and effectiveness were discounted at 3% per year over a lifetime horizon. Strategies were compared using a willingness-to-pay threshold of $100,000/quality-adjusted life year (QALY) gained. RESULTS: Annual melanoma screening cost an average of $1961 per patient, while no screening cost $81 per patient. Melanoma screening was more effective, gaining 9.2 QALYs per 1000 persons, at a cost of $203,400/QALY gained. Screening every other year was the preferred strategy, gaining 6.2 QALYs per 1000 persons and costing $143,959/QALY. One-way sensitivity analyses suggested the relative risk of melanoma in IBD, melanoma progression, and screening costs were most influential with clinically plausible variation, leading to scenarios costing < $100,000/QALY gained. Probabilistic sensitivity analyses suggested screening every other year was cost-effective in 17.4% of iterations. CONCLUSIONS: Screening for melanoma in IBD patients was effective but expensive. Screening every other year was the most cost-effective strategy. Studies to identify IBD patients at the highest risk of developing melanoma may assist in targeting a prevention program in the most cost-effective manner.

Low Rates of Dermatologic Care and Skin Cancer Screening Among Inflammatory Bowel Disease Patients.

BACKGROUND: Dermatologic manifestations of inflammatory bowel disease (IBD) are common, and certain IBD medications increase the risk of skin cancer. AIMS: To define the rates of care and factors associated with dermatologic utilization with a focus on skin cancer screening. METHODS: We utilized a prospective, natural history IBD research registry to evaluate all outpatient healthcare encounters from 2010 to 2016. Gastrointestinal, dermatologic and primary care visits per individual were identified. We calculated the proportion of patients obtaining care, categorized primary indications for dermatologic visits, determined the incidence of melanoma and non-melanoma skin cancers, and used logistic regression to determine factors associated with dermatology utilization. RESULTS: Of the 2127 IBD patients included, 452 (21.3%) utilized dermatology over the study period, and 55 (2.6%) had a total body skin examination at least once. The 452 patients incurred 1633 dermatology clinic visits, 278 dermatologic procedures, and 1108 dermatology telephone encounters. The most frequent indication was contact dermatitis or dermatitis. Factors associated with dermatology use were family history of skin cancer, employment, systemic steroids, longer disease duration, emergency room use, and the number of IBD-related clinic visits. Between 8.3 and 11% of IBD patients recommended for skin cancer screening visited dermatology each year, and the resulting incidence of non-melanoma skin cancer was 35.4/10,000 [95% CI 23.3-51.5] and melanoma was 6.56/10,000 [95% CI 2.1-15.3]. CONCLUSIONS: Less than one in ten IBD patients obtain dermatologic care. Given the increased risk of skin cancers among IBD patients, an emphasis on education, prevention, and screening merits attention.

Peripheral Eosinophilia in Patients With Inflammatory Bowel Disease Defines an Aggressive Disease Phenotype.

OBJECTIVES: Peripheral blood eosinophilia (PBE) in inflammatory bowel disease (IBD) is associated with ulcerative colitis (UC) and active disease. Little data exist on the long-term impact of PBE on disease course. We aimed to investigate the multi-year patterns of PBE and its impact on disease severity in a large IBD cohort. METHODS: We performed a registry analysis of a consented, prospective, natural history IBD cohort at a tertiary center from 2009 to 2014. Demographics, comorbidities, disease activity, healthcare utilization, and time to hospitalization or surgical resection of patients who displayed PBE were compared to patients without PBE. RESULTS: Of the 2,066 IBD patients, 19.2% developed PBE. PBE was significantly associated with UC (P<0.001), extensive colitis (P<0.001), and shorter disease duration (P=0.03). Over six years, PBE patients had more active disease (Harvey-Bradshaw Index P=0.001; ulcerative colitis activity index P<0.001), concurrent C-reactive protein elevation (P<0.001), healthcare utilization (hospitalization P<0.001, IBD surgery P<0.001), and more aggressive medical therapy (prednisone P<0.001, anti-TNF P<0.001). Patients with PBE had a significantly reduced time to hospitalization in both UC (P<0.001) and Crohn's disease (CD) (P<0.001) and reduced time to colectomy in UC (P=0.003). On multivariable modeling, PBE remained significantly associated with hospitalization and surgery in both CD and UC. New diagnosis of UC with PBE was associated with increased steroid (P=0.007) and anti-TNF (P=0.001) requirement. CONCLUSION: This multi-year study of a large IBD cohort suggests that peripheral blood eosinophilia represents a biomarker of a distinct IBD subgroup, with a unique inflammatory signature, and at risk for worse clinical outcomes.

Association of Vitamin D Level With Clinical Status in Inflammatory Bowel Disease: A 5-Year Longitudinal Study.

OBJECTIVES: Emerging data suggest that vitamin D has a significant role in inflammatory bowel disease (IBD). Prospective data evaluating the association of vitamin D serum status and disease course are lacking. We sought to determine the relationship between vitamin D status and clinical course of IBD over a multiyear time period. METHODS: IBD patients with up to 5-year follow-up from a longitudinal IBD natural history registry were included. Patients were categorized according to their mean serum 25-OH vitamin D level. IBD clinical status was approximated with patterns of medication use, health-care utilization, biochemical markers of inflammation (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)), pain and clinical disease activity scores, and health-related quality of life. RESULTS: A total of 965 IBD patients (61.9% Crohn's disease, 38.1% ulcerative colitis) formed the study population (mean age 44 years, 52.3% female). Among them, 29.9% had low mean vitamin D levels. Over the 5-year study period, subjects with low mean vitamin D required significantly more steroids, biologics, narcotics, computed tomography scans, emergency department visits, hospital admissions, and surgery compared with subjects with normal mean vitamin D levels (P<0.05). Moreover, subjects with low vitamin D levels had worse pain, disease activity scores, and quality of life (P<0.05). Finally, subjects who received vitamin D supplements had a significant reduction in their health-care utilization. CONCLUSIONS: Low vitamin D levels are common in IBD patients and are associated with higher morbidity and disease severity, signifying the potential importance of vitamin D monitoring and treatment.