Daniel J. Stein

Medication Usage and the Risk of Neoplasia in Patients with Barrett's Esophagus

BACKGROUND & AIMS Experimental evidence indicates that proton pump inhibitors (PPIs), nonsteroidal anti-inflammatory drugs (NSAIDs)/aspirin, and statins can protect patients with Barretts esophagus (BE) from developing neoplasias. However, only limited data are available on chemoprevention in patients with BE. METHODS A retrospective observational study was performed using data from patients with documented BE. Prescription information was collected from pharmacy records. Cox regression analyses were performed to examine the association between prescriptions for PPIs, NSAIDs/aspirin, or statins and the risk of developing esophageal dysplasia or adenocarcinoma during follow-up (from 1982 to 2005). RESULTS We examined 344 patients diagnosed with BE (mean age 61 years, 90.4% Caucasian, 94.2% male). After BE diagnosis, 67.2% of the patients were prescribed PPIs for a mean duration of 5.1 years; 49.1% were prescribed NSAIDs for a mean duration of 3.6 years, and 25.3% were prescribed statins for a mean duration of 2.8 years. During 2620 patient-years, high grade dysplasia or esophageal adenocarcinoma developed in 33 patients. PPI treatment after BE diagnosis was associated with a reduced risk of high grade dysplasia or cancer; this association persisted after adjustment for gender, age, and the length of BE. NSAID and/or aspirin therapy were associated with a nonsignificant trend toward lower incidence of high grade dysplasia or esophageal cancer. CONCLUSIONS PPI therapy reduces the risk of neoplasms in patients with BE. NSAIDs/aspirin appear to reduce cancer risk whereas statin use is not significantly associated with the risk of neoplasia in patients with BE.

Higher infliximab trough levels are associated with perianal fistula healing in patients with Crohn's disease

Infliximab has been found to be efficacious in the treatment of fistulas in the setting of Crohns disease, even though some patients do not benefit from therapy.

Thalidomide inhibits inflammatory and angiogenic activation of human intestinal microvascular endothelial cells (HIMEC).

The glutamic acid derivative thalidomide is a transcriptional inhibitor of TNF-alpha but is also known to affect human blood vessels, which may underlie its teratogenicity. Thalidomide has been used in the treatment of refractory Crohns disease (CD), but the therapeutic mechanism is not defined. We examined the effect of thalidomide on primary cultures of human intestinal microvascular endothelial cells (HIMEC), the relevant endothelial cell population in inflammatory bowel disease (IBD), to determine its effect on endothelial activation, leukocyte interaction, and VEGF-induced angiogenesis. HIMEC cultures were pretreated with thalidomide before activation with either TNF-alpha/LPS or VEGF. A low-shear-stress flow adhesion assay with either U-937 or whole blood was used to assess HIMEC activation following TNF-alpha/LPS, and a Wrights stain identified adherent leukocytes. Expression of cell adhesion molecules (E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1) was assessed using radioimmunoassay. Effects of thalidomide on NF-kappaB activation, cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) expression in TNF-alpha/LPS-activated HIMEC were determined by RT-PCR and Western blotting. Thalidomide blocked adhesion of both U-937 and whole blood leukocytes by 50% in HIMEC, inhibiting binding of all classes of leukocytes. Thalidomide also blocked NF-kappaB and cell adhesion molecule expression in HIMEC. In marked contrast, thalidomide did not affect either iNOS or COX-2 expression, two key molecules that play a role in the downregulation of HIMEC activation. VEGF-induced HIMEC transmigration, growth, proliferation, tube formation, and Akt phosphorylation were significantly inhibited by thalidomide. In summary, thalidomide exerted a potent effect on HIMEC growth and activation, suggesting that it may also function via an endothelial mechanism in the treatment of CD.

Impact of prior irregular infliximab dosing on performance of long-term infliximab maintenance therapy in Crohn's disease†

Background: Infliximab is efficacious in the management of moderate to severe Crohns disease (CD). There are limited data regarding performance of infliximab in patients who require reinitiation of maintenance dosing following previous irregular exposure. Methods: This was a retrospective, observational study of CD patients treated with maintenance infliximab beyond 3 years. Maintenance infliximab infusion regimens were categorized as scheduled maintenance (SM) (maintenance infusions q ≤8 weeks after loading) or prior irregular (PI) (no loading, gap in therapy >8 weeks prior to or during maintenance therapy). We examined differences in need for medical and surgical hospitalizations as well as associated healthcare costs between the 2 groups. Results: In all, 104 CD patients met criteria for 3‐year maintenance infliximab treatment (SM n = 64; PI n = 40). The rates of CD‐related surgeries (60.9% and 55.0%, P = not significant [N.S.]) and medical hospitalizations (35.9% and 37.5%, P = N.S.) prior to infliximab initiation was similar between the 2 groups. However, the rate of medical (26.5% versus 47.5%, P = 0.035) and surgical hospitalizations (21.8% versus 48.7%, P = 0.009) were significantly lower in the SM compared to the PI group. During the third year of treatment the excess costs per patient for the PI group compared to the SM group amounted to

Association of Inflammatory Bowel Disease (IBD) with depressive symptoms in the United States population and independent predictors of depressive symptoms in an IBD population: a NHANES study

11,464 in spite of both cohorts being on SM therapy. Conclusions: Patients who begin and continue an uninterrupted maintenance dosing regimen had a lower incidence of hospitalization and surgery than those who received an irregular or interrupted regimen prior to beginning an SM regimen. (Inflamm Bowel Dis 2010)

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

Background/Aims There is a paucity of population-based studies on the association between inflammatory bowel disease (IBD) and depression in the U.S. population. We sought to study this association using the National Health and Nutrition Examination Survey (NHANES) database. Methods We used NHANES data from 2009 to 2010. Our study included 190,269,933 U.S. adults without IBD and 2,325,226 with IBD. We sought to determine whether IBD is an independent risk factor for depressive symptoms (DS) in the U.S. population and studied the independent predictors of DS in IBD population. Results DS was present in 49% of the IBD population versus 23% of the non-IBD population (p<0.001). During the multivariate analysis, we found that IBD was independently associated with DS in the U.S. population (p=0.002). The independent predictors of DS in the IBD population were older age (p=0.048) and divorced/separated/widowed status (p=0.005). There was nonsignificant increase in suicidal risk in IBD population with DS versus that in non-IBD population with DS (27% vs 12%, respectively, p=0.080). Only 36% of IBD individuals with DS visited mental health professional or psychiatrist within the past year. Conclusions IBD is independently associated with DS in the U.S. population. Further research is warranted on risk stratification, screening and management of those with IBD who are at risk of depression.

Increased Rate of Venous Thromboembolism in Hospitalized Inflammatory Bowel Disease Patients with Clostridium Difficile Infection

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.

Why Can’t I Just Stay on Prednisone? The Long-Term Adverse Effects of Steroids

Background: Risk of venous thromboembolism (VTE) in patients with inflammatory bowel disease (IBD) is well established; however, there is paucity of data on the potential added risk of VTE in patients with IBD with Clostridium difficile infection (CDI). We sought to study the difference in VTE rates in hospitalized patients with IBD with CDI compared to those without CDI. Methods: We queried Nationwide Inpatient Sample from year 2011 to identify patients ≥18 years of age with a discharge diagnosis of IBD (i.e., Crohns disease and ulcerative colitis) based on ICD-9-CM codes 555.xx and 556.xx, respectively. Patients were further divided into 2 groups: those with and without CDI. To adjust and control for potential baseline differences between groups, 1:1 propensity matching was performed. Multivariate regression analysis was used to evaluate the difference in VTE rates in 2 groups. Results: Of 312,147 patients with the discharge diagnosis of IBD, 12,560 (4%) had CDI. VTE was present 6% in group with CDI versus 3% in group without CDI (P < 0.001). On performing multivariate analysis after propensity-score matching, CDI was significantly associated with VTE (adjusted odds ratio 1.7, 95% confidence interval 1.4–2.2, P < 0.001). On subgroup analysis, Crohns disease with CDI had a higher association with VTE compared with Crohns disease only. Similarly, ulcerative colitis with CDI had a higher association with VTE compared with ulcerative colitis only. Conclusions: Rate of VTE was higher in hospitalized patients with IBD with CDI compared with those without CDI, necessitating extra vigilance in this patient population.

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

Glucocorticoids have been a mainstay of therapy for inflammatory bowel disease for many years and have proven to be very effective for inducing remission in IBD patients. However, they are fraught with many undesirable side effects that make their long-term use problematic. This chapter reviews the data behind how glucocorticoids can be effective in IBD and also reviews the many different side effects that come with both long-term and short-term usage.

Massage Acupuncture, Moxibustion, and Other Forms of Complementary and Alternative Medicine in Inflammatory Bowel Disease

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