Amar S. Naik

Vitamin D deficiency in patients with inflammatory bowel disease: association with disease activity and quality of life.

BACKGROUND Vitamin D deficiency is common in inflammatory bowel disease (IBD). The aim of the study was to determine the prevalence and predictors of vitamin D deficiency in an IBD cohort. It was hypothesized that vitamin D deficiency is associated with increased disease activity and lower health-related quality of life (HRQOL). METHODS This was a retrospective cohort study. Harvey-Bradshaw index and ulcerative colitis disease activity index were used to assess disease activity. Short Inflammatory Bowel Disease Questionnaire scores were used to assess HRQOL. Multivariate logistic regression was used to identify independent predictors of vitamin D deficiency and its association with disease activity and HRQOL. RESULTS The study included 504 IBD patients (403 Crohns disease [CD] and 101 ulcerative colitis [UC]) who had a mean disease duration of 15.5 years in CD patients and 10.9 years in UC patients; 49.8% were vitamin D deficient, with 10.9% having severe deficiency. Vitamin D deficiency was associated with older age (P = .004) and older age at diagnosis (P = .03). Vitamin D deficiency was associated with lower HRQOL (regression coefficient -2.21, 95% confidence interval [CI], -4.10 to -0.33) in CD but not UC (regression coefficient 0.41, 95% CI, -2.91 to 3.73). Vitamin D deficiency was also associated with increased disease activity in CD (regression coefficient 1.07, 95% CI, 0.43 to 1.71). CONCLUSIONS Vitamin D deficiency is common in IBD and is independently associated with lower HRQOL and greater disease activity in CD. There is a need for prospective studies to assess this correlation and examine the impact of vitamin D supplementation on disease course.

QuantiFERON TB gold testing for tuberculosis screening in an inflammatory bowel disease cohort in the United States.

Background: Reactivation of latent Mycobacterium tuberculosis (TB) is a rare, yet devastating infectious complication associated with anti‐tumor necrosis factor alpha (TNF‐&agr;) therapy. We evaluated the performance of the QuantiFERON TB Gold test (QFT‐G) for TB screening in a cohort of inflammatory bowel disease (IBD) patients in the United States. Methods: We performed a retrospective, observational study of patients initiated and/or maintained on an anti‐TNF‐&agr; agent in a single IBD referral center and recorded the frequency and the test results of QFT‐G testing and the rate of TB reactivation. Results: 512 QFT‐G tests were done in 340 patients. Five patients (1.5%) had a positive, nine (2.7%) indeterminate, and 326 patients (95.8%) had a negative QFT‐G. After a mean follow‐up of 17 months there was one case of TB reactivation (0.3%). The use of immunosuppressive therapy or anti‐TNF therapy at the time of testing did not affect the results of the QFT‐G testing. Test–retest had substantial concordance (&kgr; = 0.72). 25% of patients (n = 85) had TST testing. Concordance between the TST and QFT‐G was found to be moderate (&kgr; = 0.4152, P = 0.0041). Conclusions: Most patients with negative QFT‐G tolerated anti‐TNF therapy with no evidence of TB reactivation. Concomitant use of immunosuppressive therapy or anti‐TNF did not seem to affect QFT‐G results. One patient had an indeterminate QFT‐G while on infliximab and later developed miliary TB. Concordance with TST is moderate. (Inflamm Bowel Dis 2011;)

Does primary sclerosing cholangitis impact quality of life in patients with inflammatory bowel disease

Background: Impairment of health‐related quality of life (HRQoL) is an important concern in inflammatory bowel disease (IBD; ulcerative colitis [UC], Crohns disease [CD]). Between 2%–10% of patients with IBD have primary sclerosing cholangitis (PSC). There has been limited examination of the disease‐specific HRQoL in this population compared to non‐PSC IBD controls. Methods: This was a retrospective, case–control study performed at a tertiary referral center. Cases comprised 26 patients with a known diagnosis of PSC and IBD (17 UC, 9 CD). Three random controls were selected for each case after matching for IBD type, gender, age, and duration of disease. Disease‐specific HRQoL was measured using the Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Disease activity for CD was measured using the Harvey–Bradshaw index (HB) and using the UC activity index for UC. Independent predictors of HRQoL were identified. Results: There was no significant difference in the age, gender distribution, or disease duration between PSC‐IBD and controls. There was no difference in use of immunomodulators or biologics between the 2 groups. Mean SIBDQ score was comparable between PSC‐IBD patients (54.5) and controls (54.1), both for UC and CD. Likewise, the disease activity scores were also similar (2.8 versus 3.1, P = 0.35). On multivariate analysis, higher disease activity score (−1.33, 95% confidence interval [CI] 95% CI −1.85 to −0.82) and shorter disease duration were predictive of lower HRQoL. Coexisting PSC did not influence IBD‐related HRQoL. There was a higher proportion of permanent work disability in PSC‐IBD (7.7%) compared to controls (0%). Conclusions: PSC does not seem to influence disease‐specific HRQoL in our patients with IBD but is associated with a higher rate of work disability. (Inflamm Bowel Dis 2010)

Initial Vancomycin Monotherapy is Associated With Higher Rates of Subsequent Clostridium difficile Infection in Inflammatory Bowel Disease Population

BACKGROUND: Screening and treatment for latent tuberculosis (TB) before the use of antiTNF therapy has decreased the risk of active TB. In Spain, which has a high prevalence of TB, the recommended TB screening according to national guidelines includes 2-step tuberculin skin test (TST) and chest X-ray. No data are available on the risk of developing a positive response in serial TST in inflammatory bowel disease (IBD) patients receiving long-term infliximab therapy whose initial 2-step TST was negative. The aim of this study was to determine the likelihood of detecting latent TB by the positive conversion of serial TST in a cohort of IBD patients treated with infliximab. The outcome of patients with positive conversion in the TST was also investigated. METHODS: This prospective single-center study included all consecutive IBD patients with negative 2-step TST before starting infliximab treatment. TST was positive if induration was ≥5 mm in first test or the induration was ≥5 mm in the second test (if the first TST was <5mm but provided a booster effect). We performed annual serial TST in all patients. Patients with a positive result in any serial TST were treatedwith a complete therapeutic regimen for latent TBwhile continuing on infliximab. These patients were followed to assess clinical outcomes. RESULTS: Sixty two patients (mean age 41 years, 39% male) with either Crohns disease (n=33) or ulcerative colitis (n=29) were enrolled. Eight patients had a positive TST during follow-up (mean TST induration 13 mm, range 9-20 mm). At one year, positive conversion had occurred in 5/62 (8.1%; 95% CI: 2.7-17.8) patients. At two and three years, 2/27 (7.4%; 95% CI: 0.9-24.2) patients and 1/ 11 (9.1%; 95% CI: 0.2-41.2) patients had a positive TST, respectively. The cumulative two year risk of positive conversion of TST was 7/32 (21.8%; 95% CI: 6-37.8) patients. The patients with positive conversion of TST received a 9month course of isoniazid and continued with infliximab therapy. An occupational exposure to TB was identified in only 1/8 patients. After a median of 16 months (range 3-30 months) follow-up, none of the patients with positive conversion of TST had clinical or radiological signs of active TB. CONCLUSION: Patients with IBD treated with infliximab were at high risk of conversion in the serial TST, even when the initial 2-step TST was negative. Although the exact significance of these positive conversions is not well known, annual TST is advisable as false negative responses to latent TB or new TB contacts are possible in IBD patients receiving long-term infliximab therapy, especially in countries with a high prevalence of TB.

Impact of pregnancy on health-related quality of life of patients with inflammatory bowel disease

To examine the impact of pregnancy on health‐related quality of life (HRQoL) of women with inflammatory bowel disease (IBD).

Tu1282 Azothioprine or 6-Mercaptopurnine Dose Does Not Effect Serum Infliximab Level or Rate of Antibody to Infliximab Formation

Background: Combined immunomodulator (IMM) and biologic therapy is superior to either therapy alone in inflammatory bowel disease (IBD) patients. This is thought to be a result of increased serum infliximab (IFX) level and decreased rates of antibody to infliximab (ATI) formation in combination therapy patients. A previous study did not show an association of IMM dose to serum IFX levels or ATI formation; rather only 6 TG levels were predictive of IFX levels and ATI formation. Our aim was to determine if IMM dose influenced IFX level and ATI formation in a larger IBD cohort. Methods: This was a retrospective analysis at a single tertiary care IBD center. Patients with a history of IFX use for IBD who had serum IFX levels tested using Prometheus serum IFX/ATI assay were included in the study. Demographic information, disease type, SIBDQ score, IBD activity score, IBD duration to PROMETHEUS date, IFX duration, IMM type, IMM daily dose, IMM mg/kg dose, and albumin closest to IFX test were recorded. Serum IFX levels did not follow a normal distribution so data was divided into quartiles for analysis: low/undetected IFX 19.55 ug/mL. Results: Overall, 269 patients were included. There was no significant difference in demographic or disease characteristics between serum IFX quartiles (table 1). There were 99 AZA/6MP users with average weight-based dose 0.95 mg/kg (range 0.2-2.4 mg/kg). The low/undetectable IFX quartile had a larger percentage of patients not using IMMs, compared to other quartiles (p=0.01). AZA/6MP users were in higher proportion in therapeutic and high/medium high groups than in low/undetected group (p=0.05). Also, MTX users were in a greater proportion in higher IFX level quartiles (p=0.04). There was no difference in AZA/6MP daily dose or weight based (mg/kg) dose between quartiles (p=0.49 and p=0.73). Regression analysis of AZA dose showed no correlation with serum infliximab levels (p= 0.88). Patients on any dose of IMM were less likely to develop ATI than patients not on IMM (10 % vs. 24%; p=0.03). The greatest proportion of patients with ATI were in the low/undetectable IFX quartile (p =0.001). Serum albumin levels were similar among serum IFX level quartiles (p=0.07) but showed a very weak correlation with serum IFX levels (cor= 0.13, p=0.048) (table 2). Conclusions: Our study found that IBD patients on any dose of IMM are less likely to have a low serum IFX level or develop ATI than those not on IMM therapy. Our trial confirms a prior studys results that IMM dose does not affect IFX level or ATI formation rates. These findings suggest that even low dose concomitant IMM therapy may be effective at maintaining adequate serum IFX levels and preventing ATI development. Table 1

Endoscopic suturing of esophageal stent into skin flap after laryngectomy

A 75-year-old woman had received a diagnosis of oropharyngeal cancer in 2009. It was treated with concurrent chemoradiation in 2009. In 2010 there was a recurrence of the cancer, which was treated with total laryngectomy and reconstruction with skin flap. In 2016, a large tracheoesophageal fistula, over 25 mm in diameter, developed. As a result, the patient had recurrent aspiration pneumonia despite receiving no food or intake by mouth. The patient was not a candidate for surgical correction after being evaluated by 2 different surgeons. They both thought that the patient was not healthy enough for a surgical repair of the fistula and requested a novel attempt at endoscopic therapy. An 18-mm by 8-cm fully covered metal stent was placed across the fistula. After stent placement, there was no further leakage through the fistula, no recurrent aspiration pneumonia, and no foreign-body sensation problems. A decision was made to endoscopically suture the stent in place through the skin flap to

839 Development of Irritable Bowel Syndrome Symptoms in Quiescent Inflammatory Bowel Disease: Significant Association With Presence of Psychiatric Illness and Early Onset IBD

genome-wide association study (GWAS) using Illumina OmniExpress, comparing patients with and without perianal disease (n=780). Serum was analyzed by ELISA for anti-Saccharomyces cerevisiae (ASCA), anti-outer membrane porin C (anti-OmpC), anti-Cbir1, and antiPseudomonas fluorescens (anti-I2). Data analysis was undertaken using univariate logistic regression for clinical and serologic data (statistical significance at p ,0.001). Multivariate regression was used for GWAS data, with principal components/disease location as covariates. We report single nucleotide polymorphisms (SNPs) that reached p=10E-6. Results: Perianal disease was documented in 35% (n=297). Perianal disease was associated with colonic and ileocolonic disease locations (p,0.0001), as well as with upper GI (p=0.0006) and rectal disease (p,0.0001). Anti-OmpC was significantly more prevalent among individuals with perianal disease (p, 0.0001). Two statistically significant SNPs were identified. One was a SNP at chromosome 8q24 (rs6470545, p=9x10E-6), which is 200 kilobases upstream from the proto-oncogene MYC, and near a colon cancer locus (rs6983267) known to control MYC expression. Three nearby SNPs (rs10091329, rs6470537, rs6470552) in close linkage disequilibrium (r2 .0.8) had p-values of 10E-5. Another SNP on chromosome 8 in a gene desert was also associated with perianal disease (rs10092418, p=8x10E-6). Conclusions: We report novel genetic and serologic associations with perianal disease in a large cohort of Crohns disease patients. The association between perianal disease and a locus near MYC, which encodes a transcription factor with broad activity in cell proliferation, apoptosis, and differentiation, suggests novelmechanisms in the development of perianal disease. Replication will be important to confirm findings and direct further investigation into this unique Crohns disease phenotype. *Dr. Weizman and Dr. Murdoch contributed equally to this study.

Sa2064 Probiotics Associated With Higher Rates of Subsequent Clostridium difficile Infection in Inflammatory Bowel Disease Population

Introduction:There has been an increased rate of Clostridium difficile infection (CDI) with disproportionately higher impact on the inflammatory bowel disease (IBD) populationCrohns disease (CD) and Ulcerative Colitis (UC). Treatment protocol has traditionally consisted of vancomycin or metronidazole. The outcome of probiotic treatment in this unique population is not defined. We sought to evaluate the impact of probiotics on rates of subsequent CDI and disease course. Methods:This was a retrospective observational study of all IBD pts followed at a single IBD center with CDI confirmed by suggestive gastrointestinal symptoms and either positive toxin A/B ELISA stool test or nucleic acid amplification stool test (NAAT). Pt demographics and disease characteristics were collected. We evaluated the performance of probiotics used by assessing rate of subsequent CDI over the following year. Probiotic used was Florajen (reported to have 20 billion live, freeze dried, human source strains of lactobacillus acidophilus). IBD clinical course the year following CDI was evaluated using inflammatory markers, corticosteroid usage, and disease related complications including hospitalizations and surgeries. Results:There were 101 IBD (62 CD, 39 UC) pts who had CDI confirmed (35 inpts and 66 outpts). 31 IBD pts (20 CD, 11 UC) with CDI were in the probiotic group (P) and 70 IBD pts (42 CD and 28 UC) were in the control group (C). There was no difference in disease duration, IBD maintenance therapy, disease type/ behavior between these groups. Initial antibiotic therapy used for treatment of CDI was metronidazole (M) in 48 pts, vancomycin (V) in 38 pts and combination of metronidazole + vancomycin (M+V) in 15 pts. The rate of subsequent CDI (>1) over the following year was 39% (12/31pts) in P group and 16% (11/70pts) in the C group (p=0.01). Probiotic treatment rates were 15% (7/48) in the M group, 42% (16/38) in the V group, and 53% (8/15) in the M+V group. There was a higher rate of probiotic treatment in the V group compared with the M group (42% vs 15%; p=0.04) and in the M+V group compared with the M group (15% vs 53%; p=0.002). There was no difference in probiotic use between V andM+V groups (42% vs 53%; p=0.46). Recurrence rate was not affected by IBDmaintenance therapy (biologic/immunomodulator or both). Antibiotic used in initial CDI had no impact on rate of hospitalizations, IBD related surgeries or mean ESR and CRP values over the following year. Conclusions:In our cohort, use of lactobacillus acidophilus single strain probiotic during initial CDI was associated with higher rates of subsequent CDI. Probiotic usage was higher in the CDI treatment groups with vancomycin alone and in combination with metronidazole. Further studies are necessary to define appropriate roles for probiotic strains in combination with antibiotics for preventing CDI recurrence.

Mo1728 Increased Rate of Non Melanoma Skin Cancer Detection With Screening Skin Exam in Inflammatory Bowel Disease: Is it Time to Recommend Routine Dermatology Care?

Background: Tuberculosis (TB) is a recognized risk in patients with Inflammatory Bowel Disease (IBD), especially given the therapeutic use of anti-TNF agents in the last decade. This large database study sought to determine if the risk of TB has increased since the introduction of biologic therapies for the treatment of IBD. Patients/Methods: Linked records of statistical abstracts for all hospital admissions in the Oxford region from 1963 to 1998 (ORLS1 database), Oxford region from 1998-2008 (ORLS2) and subsequently all of England from 1998-2008 (HES database), were used to identify hospital admissions for those patients who had a diagnosis of TB following an admission for IBD. Rates and rate-ratios (RR) of TB infection were determined in Crohns disease and ulcerative colitis, compared to a nonIBD reference cohort (minimum matching ratio 30:1). TB rates were stratified by age, sex, district and index year of IBD hospitalization for the combined cohort. This was used to determine stratum-standardized rates for each group. Results: 18/4884 Crohns disease (CD) and 13/6768 ulcerative colitis (UC) patients had TB in ORLS 1. 10/5438 CD and 7/7842 UC patients had TB in ORLS2. 172/103285 CD and 124/143253 UC patients had TB in the HES database, giving a 10-year average annual incidence rate for hospitalized CD and UC patients of 38.7 and 15.6 per 100000 pt.yr, respectively (England, 1998-2008). RR for Tuberculosis in hospitalized CD patients, compared with the reference cohort, was significantly elevated in all three databases, though slightly higher in ORLS1 compared with ORLS2 and HES (5.35 vs 3.06 vs 3.85). RR for TB in UC patients was only significantly elevated in the HES database, with little variation in RR across the three database populations. Conclusions: We report the highest incidence rates of TB, compared with existing literature, potentially reflecting the higher disease burden of hospitalized IBD patients. Compared to relatively healthy hospitalized controls, Crohns disease is associated with a 3 to 5-fold higher risk of TB, while UC exhibits a 2-fold higher risk. Comparing the periods before and after the introduction of anti-TNF agents for IBD, TB rates appear to have dropped. Strict attention must be paid to the risk of TB infection in hospitalized IBD patients.