Safety of Recombinant Zoster Vaccine in Patients with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Patients with inflammatory bowel disease [IBD] have an increased risk of contracting herpes zoster [HZ] infection. However, vaccination rates for HZ are low among IBD patients. A contributing factor may be fear of an IBD flare associated with vaccination. Our aim here was to evaluate if recombinant zoster vaccine [RZV] is associated with an IBD flare. METHODS: This was a retrospective cohort study using data from the Veterans Affairs Healthcare System [VAHS]. The exposure of interest was receiving RZV. We randomly matched such exposed patients with unexposed individuals. The primary outcome was the first episode of IBD flare within 90 days of the index date. Baseline characteristics were compared between groups using a t-test for continuous variables and Chi-square test for categorical variables. Conditional logistic regression was used to estimate the odds ratio [OR] and 95% confidence interval [CI]. RESULTS: Among the eligible study cohort, 1677 patients received RZV. Thirty-six patients, 20 in the exposed group and 16 in the unexposed group, had a confirmed flare by chart review. The 90-day cumulative incidence of IBD flare was not different between the vaccinated and unvaccinated groups [1.2% among those exposed vs 1.0% among those unexposed, p = 0.503]. The OR for IBD flare associated with RZV vaccination was 1.25 [95% CI: 0.65-2.41]. CONCLUSION: In a nationwide cohort of stable IBD patients, administration of RZV was not associated with the risk of IBD flare within 90 days. These findings should motivate further use of this highly effective vaccine.

Influence of Corticosteroid Use on Short- and Long-Term Outcomes of Biologic Therapy for Inflammatory Bowel Diseases.

BACKGROUND: Corticosteroids (CS) are widely used to treat Crohn's disease (CD) and ulcerative colitis (UC), but are not recommended as maintenance therapy. Biologic drugs are widely used as an alternative to or in conjunction with CS to induce and maintain remission. This meta-analysis tested the hypothesis that CS use is associated with differential response to biologics. METHODS: We identified published placebo-controlled clinical trials of biologic drugs approved for the treatment of CD or UC. Pooled estimates of the risk difference (RD) and 95% confidence intervals were derived from random effects models for induction of response and remission and maintenance of remission comparing biologic with CS versus biologic alone. Heterogeneity of response was estimated using I2. RESULTS: Fifteen studies met the inclusion criteria. Pooled estimates of the RD and I2 comparing biologic plus CS versus biologic alone were as follows: induction of UC response 0.15 (0.05, 0.25), I2 = 57.29% and CD response 0.02 (- 0.03, 0.06), I2 = 0.01%; induction of UC remission 0.03 (- 0.01, 0.08), I2 = 0.00% and CD remission 0.08(0.02, 0.14), I2 = 7.81%; and maintenance of UC remission - 0.06 (- 0.13, 0.01), I2 = 0.00% and CD remission - 0.06 (- 0.14, 0.03), I2 = 11.24%. Patients in the placebo arm of CD trials who were receiving CS were less likely to achieve remission during the induction phase (pooled RD - 0.05 (- 0.09, - 0.00), I2 = 0.00%). CONCLUSIONS: In this meta-analysis of placebo-controlled trials, CS use was associated with higher biologic response rates for UC and remission rates for CD during the induction phase, but were not associated with improved maintenance of remission.

Indeterminate QuantiFERON-TB Gold Increases Likelihood of Inflammatory Bowel Disease Treatment Delay and Hospitalization.

Background: QuantiFERON-TB Gold (QFTG) is a blood test used to diagnose latent tuberculosis infection (LTBI) prior to TNF-α inhibitor (anti-TNF) initiation. We sought to determine factors associated with indeterminate QFTG results in inflammatory bowel disease (IBD) patients and whether indeterminate results are associated with IBD-related morbidity. Methods: This nested case-control study included IBD patients who underwent QFTG testing. Cases were patients with indeterminate QFTG and controls were those with negative QFTG. The association of demographic and clinical data with indeterminate QFTG result was assessed using logistic regression. We examined the clinical impact of indeterminate QFTG results on risk of hospitalization and delay in anti-TNF initiation using inverse probability-of-treatment weighting (IPTW) regression. Results: We identified 411 patients with QFTG testing (320 negative, 80 indeterminate, and 11 positive results). No patient with an indeterminate result subsequently had LTBI. Systemic corticosteroid use (OR, 4.4; 95% CI, 2.0-9.6) and hospitalization at the time of QFTG (OR, 3.8; 95% CI, 1.9-7.7) were associated with indeterminate QFTG, while immunomodulator use was nearly statistically significant (OR, 3.1; 95% CI, 0.9-9.8) and anti-TNF use was not (OR, 0.9; 95% CI, 0.2-4.6). After IPTW adjustment, indeterminate QFTG was associated with a 23.1% (95% CI, 8.2%-37.9%) greater probability of delay in anti-TNF initiation beyond 30 days and an 11.9% (95% CI, 0.6%-23.1%) greater probability of hospitalization within 60 days. Conclusions: Systemic corticosteroid use and hospitalization were associated with an indeterminate QFTG result. Indeterminate QFTG results were associated with delayed anti-TNF initiation and subsequent hospitalization.

Measurement of Inflammatory Bowel Disease Symptoms: Reliability of an Abbreviated Approach to Data Collection.

BACKGROUND: The Crohn's Disease Activity Index (CDAI) and Mayo score for ulcerative colitis (UC) require symptom recall and/or use of a symptom diary. We examined patients' abilities to recall their symptoms and the day-to-day variability of symptoms. METHODS: Patients with UC or CD completed a questionnaire including items from the short CDAI (sCDAI) and the 6-point Mayo score. Patients were randomized to receive a follow-up questionnaire testing recall of the bowel symptom items between 1 and 7 days later. In a second study, patients completed a 7-day electronic diary recording their symptoms. sCDAI and 6-point Mayo scores were computed. Analyses estimated daily variability in the indices and misclassification rates when using fewer than 7 days of data. RESULTS: 100%, 82%, and 90% of CD participants recalled the same disease activity status (i.e., active versus remission) as reported on the initial survey when the follow-up questionnaire was administered 1 to 2, 3 to 5, and 6 to 8 days later, respectively. Compared with using 7 days of data, when using only day 7 data, 3.7% of patients with CD were misclassified as active or inactive. Disease activity was misclassified in 2.8%, 4.9%, and 3.3% of patients by using the last 2, 3, or 4 days, respectively. Results were similar for patients with UC. CONCLUSIONS: Patients with CD and UC demonstrated good recall of bowel symptoms for up to 8 days. Additionally, bowel symptoms have relatively little variability within a 7-day period allowing for accurate computation of the sCDAI and 6-point Mayo score using 1 to 3 days of data.

Mesalamine dose escalation reduces fecal calprotectin in patients with quiescent ulcerative colitis.

BACKGROUND & AIMS: Among patients with quiescent ulcerative colitis (UC), lower fecal concentrations of calprotectin are associated with lower rates of relapse. We performed an open-label, randomized controlled trial to investigate whether increasing doses of mesalamine reduce concentrations of fecal calprotectin (FC) in patients with quiescent UC. METHODS: We screened 119 patients with UC in remission on the basis of Simple Clinical Colitis Activity Index scores, FC >50 µg/g, and intake of no more than 3 g/day mesalamine. Participants taking mesalamine formulations other than multimatrix mesalamine were switched to multimatrix mesalamine (2.4 g/day) for 6 weeks; 52 participants were then randomly assigned (1:1) to a group that continued its current dose of mesalamine (controls, n = 26) or a group that increased its dose by 2.4 g/day for 6 weeks (n = 26). The primary outcome was continued remission with FC <50 µg/g. Secondary outcomes were continued remission with FC <100 µg/g or <200 µg/g (among patients with pre-randomization values above these levels). RESULTS: The primary outcome was achieved by 3.8% of controls and 26.9% of the dose escalation group (P = .0496). More patients in the dose escalation group reduced FC to below 100 µg/g (P = .04) and 200 µg/g (P = .005). Among the patients who were still in remission after the randomization phase, clinical relapse occurred sooner in patients with FC >200 µg/g compared with those with FC <200 µg/g (P = .01). CONCLUSIONS: Among patients with quiescent UC and increased levels of FC, increasing the dose of mesalamine by 2.4 g/day reduced fecal concentrations of calprotectin to those associated with lower rates of relapse. Clinicaltrials.gov number: NCT00652145.

Impact of JC virus antibody testing in patients with Crohn's disease with loss of response to infliximab: a Markov model.

BACKGROUND: The optimal treatment strategy for patients with Crohn's disease who have loss of response to the anti-tumor necrosis factor α medication infliximab is uncertain. Natalizumab has an alternative mechanism of action, but its use has been limited by the risk of progressive multifocal leukoencephalopathy. In this study, we performed a decision analysis assessing the impact of JC virus (JCV) antibody testing and natalizumab utilization for loss of response to infliximab. METHODS: We constructed a Markov model to assess the difference between unscreened natalizumab use (option 1), JCV antibody testing with natalizumab when appropriate (option 2), and second anti-tumor necrosis factor α use (option 3). The base case was a 35-year-old man with severe Crohn's disease with loss of response to infliximab. The time horizon was 3 years. Results are reported in quality-adjusted life years (QALYs). Deterministic and probabilistic analyses were conducted. Markov analysis using a cohort of 5000 individuals was performed. The impact of JCV antibody status on outcomes in this model was assessed. RESULTS: Option 2 was the preferred strategy (2.0880 QALYs), followed by option 1 (2.0875 QALYs) and option 3 (2.0808 QALYs). Patients in option 2 required fewer surgeries compared with option 3. Previous JCV infection was associated with reduced QALYs with all options that allowed for natalizumab use. CONCLUSIONS: JCV antibody testing and subsequent treatment selection yield improved outcomes over natalizumab without testing or using only a second anti-tumor necrosis factor α in all patients.

Teduglutide in Crohn's disease.

INTRODUCTION: The currently available medications for treatment of Crohn's disease (CD) include aminosalicylates, corticosteroids, antibiotics, immunomodulators and biologic agents (infliximab, certolizumab pegol, adalimumab and natalizumab). These agents target the immune and inflammatory pathways of CD, while there is a shortage of agents that target the barrier functions of the gut that are impaired in CD. Glucagon-like peptide 2 is an enterogastrone with strong trophic effects on the intestinal mucosa. Teduglutide , the analog of glucagon-like peptide has been already approved by the US Food and Drug Administration as a treatment of short bowel syndrome. This review discusses the potential use of teduglutide in patients with CD. AREAS COVERED: As there has been only one randomized placebo controlled trial of teduglutide in CD, there is a shortage of data regarding the efficacy of this agent in CD. The literature search was performed using Medline database with the use of the following key words: teduglutide, glucagon-like peptide-2, CD and inflammatory bowel disease. EXPERT OPINION: Based on available data, it can be concluded that this agent seems to be a promising medication in CD and further trials are required to define the place of teduglutide in treatment of CD.

Papillary thyroid cancer and inflammatory bowel disease: is there a relationship?

AIM: To formally study age of diagnosis of papillary thyroid cancer (PTC) in inflammatory bowel disease (IBD) patients and evaluate the prevalence of PTC in IBD patients compared to a control population. METHODS: We were interested in testing the hypothesis that patients with IBD are more likely to be diagnosed with PTC than a control population. A retrospective cohort analysis was performed using the University of Pennsylvania Health System's electronic database. Outpatients from 1998-2009 were included in the search, and patients in the cohort were selected based on ICD-9 codes. Inclusion criteria included the diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) and the concurrent diagnosis of thyroid cancer in comparison to a control population. Using these methods 912 patients with CD and 1774 with UC were compared to 1638 diverticulitis and 19 447 asthma controls. Statistics were performed using corrected chi-square analysis. The primary outcome for this study was the diagnosis of PTC. Approval to conduct this study was obtained by the Institutional Review Board at the University of Pennsylvania. RESULTS: The mean age was 47.5 years (range: 18-102 years) and 66% patients were female. An analysis of variance model was used to compare the age of PTC diagnosis between the CD, UC, asthma and diverticulitis groups, and a statistically significant difference in age at PTC diagnosis was noted across all groups (F = 6.35, df = 3, P = 0.0006). The age of PTC diagnosis in CD patients was statistically significantly lower than UC, asthma, and diverticulitis patients (average PTC diagnosis age for CD 25, UC 49, asthma 45, diverticulitis 63). After covarying for sex and age in 2009, the difference in age at PTC diagnosis remained statistically significant (F = 4.13, df = 3, P = 0.0089). A total of 86 patients were diagnosed with PTC. Nine patients (0.5%) with UC were diagnosed with PTC. Patients with UC were not shown to be more likely to develop PTC [odds ratio (OR): 1.544, 95%CI 0.767-3.108] compared to asthma controls. Four patients (0.4%) with CD were diagnosed with PTC. Patients with CD were not shown to be more likely to develop PTC (OR: 1.334, 95%CI 0.485-3.672) compared to a control population with asthma. Nine patients (0.5%) with a history of diverticulitis were diagnosed with PTC. Patients with diverticulitis were not shown to be more likely to develop PTC (OR: 1.673, 95%CI 0.831-3.368) compared to asthma controls. Patients with CD or UC were not less likely to develop PTC compared to those with diverticulitis (CD OR: 0.80, 95%CI 0.25-2.60; UC OR: 0.92, 95%CI 0.37-2.33). None of the patients used immunosuppressant medications prior to the diagnosis of PTC (azathioprine, 6-mercaptopurine, and methotrexate). CONCLUSION: There is a significant difference in age of diagnosis of PTC in patients with CD compared to patients with UC and the control populations studied.

Vitamin d deficiency is associated with ulcerative colitis disease activity.

PURPOSE: Previous studies on experimental mouse models have suggested a role of vitamin D in immune system regulation and IBD disease severity. In this study, we examine the relationship between vitamin D levels and clinical disease activity in human subjects with ulcerative colitis (UC). We hypothesized that patients with vitamin D deficiency will display increased UC disease activity as compared to patients with normal vitamin D levels. METHODS: A cross-sectional study was performed by querying the outpatient electronic medical record of our health system for patients seen in the gastroenterology clinic from January 2007 to October 2009 who carried both a diagnosis of UC and a documented 25-OH vitamin D level within 30 days of their clinic visit. Demographic and clinical variables were collected. Clinical disease activity was calculated using the six-point partial Mayo index. Active disease was defined as a six-point index score of ≥ 1. Vitamin D deficiency was defined as a 25-OH D level below 30 ng/ml. Data were analyzed using the chi-square distribution test. RESULTS: Thirty-four patients met inclusion criteria (53 % female, mean age 45.7 ± 24.7 years). Fifteen patients had normal vitamin D levels and 19 patients were vitamin D deficient. Twelve patients had vitamin D levels <20 ng/ml. Vitamin D deficient patients were statistically more likely to have increased disease activity than patients with normal vitamin D levels (p = 0.04), with 68 % of deficient patients displaying active disease compared with 33 % in the sufficient group. There was also a statistically significant association between vitamin D status and need for treatment with steroids, with a higher percentage of vitamin D deficient patients (47 %) requiring such treatment compared with 7 % in the sufficient group (p = 0.02). There was no association between season of visit and disease activity. CONCLUSION: Vitamin D deficiency is common among patients with active UC, particularly those requiring corticosteroids. Further investigation is needed to determine the clinical utility of vitamin D monitoring in patients with UC and whether there is a role for vitamin D as a treatment for UC.

Antiviral effects of autologous CD4 T cells genetically modified with a conditionally replicating lentiviral vector expressing long antisense to HIV.

We report the safety and tolerability of 87 infusions of lentiviral vector­modified autologous CD4 T cells (VRX496-T; trade name, Lexgenleucel-T) in 17 HIV patients with well-controlled viremia. Antiviral effects were studied during analytic treatment interruption in a subset of 13 patients. VRX496-T was associated with a decrease in viral load set points in 6 of 8 subjects (P = .08). In addition, A → G transitions were enriched in HIV sequences after infusion, which is consistent with a model in which transduced CD4 T cells exert antisense-mediated genetic pressure on HIV during infection. Engraftment of vector-modified CD4 T cells was measured in gut-associated lymphoid tissue and was correlated with engraftment in blood. The engraftment half-life in the blood was approximately 5 weeks, with stable persistence in some patients for up to 5 years. Conditional replication of VRX496 was detected periodically through 1 year after infusion. No evidence of clonal selection of lentiviral vector­transduced T cells or integration enrichment near oncogenes was detected. This is the first demonstration that gene-modified cells can exert genetic pressure on HIV. We conclude that gene-modified T cells have the potential to decrease the fitness of HIV-1 and conditionally replicative lentiviral vectors have a promising safety profile in T cells.

Disruption of intestinal CD4+ T cell homeostasis is a key marker of systemic CD4+ T cell activation in HIV-infected individuals.

HIV infection is associated with depletion of intestinal CD4(+) T cells, resulting in mucosal immune dysfunction, microbial translocation, chronic immune activation, and progressive immunodeficiency. In this study, we examined HIV-infected individuals with active virus replication (n = 15), treated with antiretroviral therapy (n = 13), and healthy controls (n = 11) and conducted a comparative analysis of T cells derived from blood and four gastrointestinal (GI) sites (terminal ileum, right colon, left colon, and sigmoid colon). As expected, we found that HIV infection is associated with depletion of total CD4(+) T cells as well as CD4(+)CCR5(+) T cells in all GI sites, with higher levels of these cells found in ART-treated individuals than in those with active virus replication. While the levels of both CD4(+) and CD8(+) T cell proliferation were higher in the blood of untreated HIV-infected individuals, only CD4(+) T cell proliferation was significantly increased in the gut of the same patients. We also noted that the levels of CD4(+) T cells and the percentages of CD4(+)Ki67(+) proliferating T cells are inversely correlated in both blood and intestinal tissues, thus suggesting that CD4(+) T cell homeostasis is similarly affected by HIV infection in these distinct anatomic compartments. Importantly, the level of intestinal CD4(+) T cells (both total and Th17 cells) was inversely correlated with the percentage of circulating CD4(+)Ki67(+) T cells. Collectively, these data confirm that the GI tract is a key player in the immunopathogenesis of HIV infection, and they reveal a strong association between the destruction of intestinal CD4(+) T cell homeostasis in the gut and the level of systemic CD4(+) T cell activation.

Unintended effects of a computerized physician order entry nearly hard-stop alert to prevent a drug interaction: a randomized controlled trial.

BACKGROUND: The effectiveness of computerized physician order entry (CPOE) systems has been modest, largely because clinicians frequently override electronic alerts. METHODS: To evaluate the effectiveness of a nearly "hard stop" CPOE prescribing alert intended to reduce concomitant orders for warfarin and trimethoprim-sulfamethoxazole, a randomized clinical trial was conducted at 2 academic medical centers in Philadelphia, Pennsylvania. A total of 1981 clinicians were assigned to either an intervention group receiving a nearly hard stop alert or a control group receiving the standard practice. The study duration was August 9, 2006, through February 13, 2007. RESULTS: The proportion of desired responses (ie, not reordering the alert-triggering drug within 10 minutes of firing) was 57.2% (111 of 194 hard stop alerts) in the intervention group and 13.5% (20 of 148) in the control group (adjusted odds ratio, 0.12; 95% confidence interval, 0.045-0.33). However, the study was terminated early because of 4 unintended consequences identified among patients in the intervention group: a delay of treatment with trimethoprim-sulfamethoxazole in 2 patients and a delay of treatment with warfarin in another 2 patients. CONCLUSIONS: An electronic hard stop alert as part of an inpatient CPOE system seemed to be extremely effective in changing prescribing. However, this intervention precipitated clinically important treatment delays in 4 patients who needed immediate drug therapy. These results illustrate the importance of formal evaluation and monitoring for unintended consequences of programmatic interventions intended to improve prescribing habits. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00870298.