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.

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.

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.

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.

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.

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.

Is dysplasia visible during surveillance colonoscopy in patients with ulcerative colitis?

OBJECTIVE: Patients with ulcerative colitis (UC) have an increased risk of developing colorectal cancer. It was widely believed that dysplastic lesions are invisible on colonoscopy and can only be detected by random biopsies, as 95% of dysplastic lesions occur in flat colonic mucosa indistinct from surrounding tissue. The aim of this study was to determine whether dysplasia is visible during routine surveillance colonoscopy by evaluating only patients who had dysplasia without overt carcinoma. MATERIAL AND METHODS: The medical records, endoscopy and pathology databases were systematically reviewed between 1997 and 2004 at the University of Pennsylvania Health System. Patients with inflammatory bowel disease and dysplasia were identified and their medical charts reviewed. RESULTS: Of the 113 patients with colonic dysplasia confirmed by pathology at our center, 102 (90%) had UC. Forty-nine of the 102 (48%) patients with UC underwent colonoscopic evaluation prior to dysplasia detection. This group was selected as our study cohort. Overall, 72 macroscopic abnormalities were detected at 49 colonoscopies, including 55 polypoid lesions, 12 areas of ulceration, 3 areas of nodularity, 1 irregular hemicircumferential lesion and 1 area of stricture. Overall, 58 dysplastic sites were detected; 51 were macroscopically visible (87.9%) and 7 were macroscopically invisible (12.1%). CONCLUSIONS: Most of the dysplasia in UC is endoscopically visible, but further prospective evaluation of a large number of patients is needed to validate the current observations. Our findings have the potential to modify current recommendations for surveillance biopsies in UC if validated by prospective studies.

High-grade dysplastic adenoma-like mass lesions are not an indication for colectomy in patients with ulcerative colitis.

OBJECTIVE: The management of high-grade dysplasia (HGD) in polypoid lesions in patients with ulcerative colitis (UC) is not well characterized. The purpose of this study was to characterize the clinical course of patients with HGD in adenoma-like dysplasia-associated lesion or masses (DALMs) in the absence of any synchronous flat dysplasia. We hypothesize that colectomy is not warranted in patients who undergo complete excision of adenoma-like DALMs with HGD in UC. MATERIAL AND METHODS: Pathology and clinical databases were systematically searched for the presence of dysplastic lesions in inflammatory bowel disease from 1997 to 2004. Patients with UC who had adenoma-like DALMs were identified, and a subset with HGD lesions was defined as our study cohort. RESULTS: A total of 102 patients with UC were identified. Thirty of them (29%) had adenoma-like DALMs without synchronous flat dysplasia; 9 of these patients (30%) had HGD in these lesions. Thirty-two surveillance colonoscopies were performed in this cohort (mean 3.6 colonoscopies/patient). The patients were followed for a mean of 76.5 months (52-99 months). Three out of 9 patients (33%) had colectomy. None of the patients in this cohort was detected to have carcinoma in surveillance biopsies and/or in the resection specimens. CONCLUSIONS: Our data suggest that the presence of HGD in DALMs does not warrant colectomy. Continued close observation is suggested in this patient cohort after complete excision of polyps. Further prospective evaluation of this patient population is merited.

Risk for active tuberculosis in inflammatory bowel disease patients.

BACKGROUND & AIMS: The primary aim of this study was to determine the incidence of active tuberculosis in an inflammatory bowel disease population compared with the general population before the availability of infliximab. METHODS: We performed a retrospective cohort study with the General Practice Research Database from January 1988-October 1997. Ulcerative colitis and Crohn's disease subjects with a minimum of 1 year of follow-up were matched to randomly selected subjects from the remaining population on year of birth (+/-5 years), sex, and primary care practice at ratio of 1:4. Active tuberculosis was determined by tuberculosis diagnostic codes. The incidence of active tuberculosis in the inflammatory bowel disease population and the relative risk for active tuberculosis in inflammatory bowel disease population compared with the general population were calculated. Multivariate logistic regression analysis was performed to adjust for confounders. RESULTS: There were 16,213 inflammatory bowel disease subjects and 66,512 control subjects. The annual incidence of active tuberculosis was 20/100,000 in inflammatory bowel disease subjects compared with 9/100,000 in control subjects, yielding an unadjusted relative risk for active tuberculosis of 2.36 (95% confidence interval, 1.17-4.74). Adjusting for confounders, corticosteroid use and smoking, the odds ratio of inflammatory bowel disease for active tuberculosis was 1.88 (95% confidence interval, 0.68-5.20). CONCLUSIONS: During the pre-infliximab era, inflammatory bowel disease subjects appeared to be at higher risk for active tuberculosis than the general population, with immunosuppressant medications likely the main reason for this increased risk.

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.

Methods to avoid infections in patients with inflammatory bowel disease.

Infections have been reported in patients with inflammatory bowel disease (IBD), especially in association with anti-inflammatory and immunomodulatory medications used to treat IBD. Unfortunately, there is a dearth of information on infectious complication risk in patients with IBD. This review describes infectious complications reported in patients with IBD and provides a framework for future studies to assess potential risk factors and incidence for infection. Recommendations are also provided for prevention of infection.

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.