Reduced Imaging Radiation Exposure and Costs Associated with Anti-Tumor Necrosis Factor Therapy in Crohn's Disease.

BACKGROUND: Radiation exposure from diagnostic imaging may increase cancer risk of Crohn's disease (CD) patients, who are already at increased risk of certain cancers. AIM: To compare imaging radiation exposure and associated costs in CD patients during the year pre- and post-initiation of anti-tumor necrosis factor (anti-TNF) agents or corticosteroids. METHODS: Adults were identified from a large US claims database between 1/1/2005 and 12/31/2009 with ≥ 1 abdominal imaging scan and 12 months of enrollment before and after initiating therapy with anti-TNF or corticosteroids. Imaging utilization, radiation exposure, and healthcare costs pre- and post-initiation were examined. RESULTS: Anti-TNF-treated patients had significantly fewer imaging examinations the year prior to initiation than corticosteroid-treated patients. Cumulative radiation doses before initiation were significantly higher for corticosteroid patients compared to anti-TNF patients (22.3 vs. 17.7 millisieverts, P = 0.0083). After therapy initiation, anti-TNF-treated patients had significantly fewer imaging examinations (2.9 vs. 5.2, P < 0.0001) and less radiation exposure (7.4 vs. 15.4 millisieverts, P <0.0001) than corticosteroid-treated patients in the follow-up period. Reductions in imaging costs adjusted for 1000 patient-years after initiation of therapy were - $275,090 and - $121,960 (P = 0.0359) for anti-TNF versus corticosteroid patients, respectively. CONCLUSIONS: This analysis demonstrated that patients treated with anti-TNF agents have fewer imaging examinations, less radiation exposure, and lower healthcare costs associated with imaging than patients treated with corticosteroids. These benefits do not account for additional long-term benefits that may be gained from reduced radiation exposure.

Characteristics of Clostridium difficile infection in patients hospitalized with myelodysplastic syndrome or acute myelogenous leukemia.

AIM: To evaluate factors associated with Clostridium difficile infection (CDI) and outcomes of CDI in the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) population. METHODS: After IRB approval, all MDS/AML patients hospitalized at the University of Maryland Greenebaum Comprehensive Cancer Center between August 2011 and December 2013 were identified. Medical charts were reviewed for demographics, clinical information, development of CDI, complications of CDI, and mortality. Patients with CDI, defined as having a positive stool PCR done for clinical suspicion of CDI, were compared to those without CDI in order to identify predictors of disease. A t-test was used for comparison of continuous variables and chi-square or Fisher's exact tests were used for categorical variables, as appropriate. RESULTS: Two hundred and twenty-three patients (60.1% male, mean age 61.3 years, 13% MDS, 87% AML) had 594 unique hospitalizations during the study period. Thirty-four patients (15.2%) were diagnosed with CDI. Factors significantly associated with CDI included lower albumin at time of hospitalization (P < 0.0001), prior diagnosis of CDI (P < 0.0001), receipt of cytarabine-based chemotherapy (P = 0.015), total days of neutropenia (P = 0.014), and total days of hospitalization (P = 0.005). Gender (P = 0.10), age (P = 0.77), proton-pump inhibitor use (P = 0.73), receipt of antibiotics (P = 0.66), and receipt of DNA hypomethylating agent-based chemotherapy (P = 0.92) were not significantly associated with CDI. CONCLUSION: CDI is common in the MDS/AML population. Factors significantly associated with CDI in this population include low albumin, prior CDI, use of cytarabine-based chemotherapy, and prolonged neutropenia. In this study, we have identified a subset of patients in which prophylaxis studies could be targeted.

Reply to "On the Effect of Common Excipients on the Oral Absorption of Class 3 Drugs".

We previously concluded that 12 common excipients need not be qualitatively the same and quantitatively very similar to reference for Biopharmaceutics Classification System-based biowaivers. This conclusion for regulatory relief is based upon a series of bioequivalence studies in humans involving cimetidine and acyclovir. Limitations were also discussed. We understand the major concern of García-Arieta et al. is that "results obtained by Vaithianathan et al. should not be extrapolated to other drugs." We understand that individuals conducting their own risk/benefit analysis may reach that conclusion, and we reply to the concerns of García-Arieta et al. We continue to conclude that the 12 common excipients need not be qualitatively the same nor quantitatively very similar to reference, but rather, simply be not more than the quantities studied in our manuscript for cimetidine and acyclovir, and potentially other class 3 drugs with similar properties.

Biological and Immunomodulator Use in Crohn's Disease in a Medicaid Population.

BACKGROUND: Immunomodulator and biological use in African Americans (AA) with Crohn's disease (CD) has been reported to be lower than in whites (W); less data exist for Hispanics (H). METHODS: Medicaid databases from 3 states were examined for patients with CD from August 1998 to July 2009. CD-related treatments, comorbidities, location, surgery, and health care utilization were assessed from diagnosis until the first biological claim or end of claims. A Cox proportional hazard regression model was used to assess the effect of race on biological initiation. RESULTS: A total of 5575 patients with CD (3590 W; 924 AA; 494 H; and 567 "other") were analyzed; 18%, 17%, and 17% of W, AA, and H patients, respectively, started immunomodulators (P = not significant); and 7%, 9%, and 5% of W, AA, and H, respectively, initiated biologics after CD diagnosis (P = not significant). After adjusting for demographics and CD-related medications and comorbidities in Cox models, no association was found between AA and W for biological use (hazard ratio 1.19; 95% confidence interval [CI], 0.91-1.54) or H and W (hazard ratio 0.68, 95% CI, 0.45-1.02). Analyzing patients hospitalized after CD diagnosis (n = 3428) to adjust for disease severity demonstrated that H were significantly less likely to use biologics than W (hazard ratio 0.40, 95% CI, 0.22-0.74). No differences between W and AA were found. CONCLUSIONS: Our findings suggest that differences between AA and W in exposure to immunomodulators or biologics may not exist, although they may be present in H with more severe disease. Further research is needed to confirm these findings.

Effect of Common Excipients on the Oral Drug Absorption of Biopharmaceutics Classification System Class 3 Drugs Cimetidine and Acyclovir.

The objective was to assess the impact of larger than conventional amounts of 14 commonly used excipients on Biopharmaceutics Classification System (BCS) class 3 drug absorption in humans. Cimetidine and acyclovir were used as model class 3 drugs across three separate four-way crossover bioequivalence (BE) studies (n = 24 each) in healthy human volunteers, denoted as study 1A, 1B, and 2. In study 1A and 1B, three capsule formulations of each drug were manufactured, collectively involving 14 common excipients. Capsule formulations that incorporated hydroxypropyl methylcellulose (HPMC) or magnesium stearate exhibited lower absorption. The cimetidine commercial solution contained sorbitol and also resulted in lower absorption. Hence, in study 2, two capsule formulations with lower amounts of HPMC and magnesium stearate, the sorbitol-containing commercial solution, and a sorbitol-free solution were assessed for BE. Overall, 12 common excipients were found in large amounts to not impact BCS class 3 drug absorption in humans, such that these excipients need not be qualitatively the same nor quantitatively very similar to reference, but rather simply be not more than the quantities studied here. Meanwhile, for each HPMC and microcrystalline cellulose, BCS class 3 biowaivers require these two excipients to be qualitatively the same and quantitatively very similar to the reference.

Anti-Tumor Necrosis Factor-α Antibody Therapy Management Before and After Intestinal Surgery for Inflammatory Bowel Disease: A CCFA Position Paper.

Biologic therapy with anti-tumor necrosis factor (TNF)-α antibody medications has become part of the standard of care for medical therapy for patients with inflammatory bowel disease and may help to avoid surgery in some. However, many of these patients will still require surgical intervention in the form of bowel resection and anastomosis or ostomy formation for the treatment of their disease. Postsurgical studies suggest up to 30% of patients with inflammatory bowel disease may be on or have used anti-TNF-α antibody medications for disease management preoperatively. Significant controversy exists regarding the potential deleterious impact of these medications on the outcomes of surgery, specifically overall and/or infectious complications. In this position statement, we systematically reviewed the literature regarding the potential risk of anti-TNF-α antibody use in the perioperative period, offer recommendations based both on the best-available evidence and expert opinion on the use and timing of anti-TNF-α antibody therapy in the perioperative period, and discuss whether or not the presence of these medications should lead to an alteration in surgical technique such as temporary stoma formation.

What is the need for comparative effectiveness studies in IBD?

Unlike traditional clinical trial research, Comparative Effectiveness Research seeks to determine what is 'best' for a typical patient when deciding between effective options used in daily practice - a therapy, diagnostic test, or course of action. There is a clear need for Comparative Effectiveness Research in Inflammatory Bowel Disease, a point emphasized by the Institute of Medicine and supported by governmental agencies and escalating funding. This review highlights the rationale and support for Comparative Effectiveness Research, provides examples of Comparative Effectiveness Research in Inflammatory Bowel Disease, and outlines current and future focus for Comparative Effectiveness Research in Inflammatory Bowel Disease.

Racial differences in disease activity and quality of life in patients with Crohn's disease.

BACKGROUND: The existing literature on racial differences in Crohn's disease (CD) activity and quality of life (QOL) is limited and extrapolated from surrogate measures. AIM: The aim of our study was to compare objective markers of disease activity and QOL over time by race. STUDY: A clinical data repository of inflammatory bowel disease (IBD) patients at University of Maryland, Baltimore IBD Program, was used. CD patients from 2004 to 2009 were included if they had greater than or equal to two clinic visits with disease activity and QOL scores during the study period. Differences in disease activity and QOL were compared by race over time. RESULTS: A total of 296 patients with CD met inclusion criteria; of these, 19% (56/296) were African Americans (AA) and 81% (240/296) were Caucasian. Baseline disease activity and QOL scores did not differ by race (p > 0.05). Caucasians had a steady decline in disease activity and increase in QOL. AA experienced a similar pattern of change in disease activity and QOL scores over time; however, the declines were not statistically significant between groups. At each time point post-baseline, disease activity and QOL scores were similar between races. CONCLUSION: We found that Caucasian and AA patients with CD had similar disease activity and QOL scores at initial presentation and over time. Thus, AA do not represent a more severe subgroup of CD patients to treat. These findings have important implications for clinicians that care for patients with CD.

A Health Survey of Gastroenterologist Prescribing Practices of Adalimumab for Treatment of Crohn's Disease: Final Results.

Adalimumab (Humira, AbbVie) has efficacy in treatment-naive and infliximab (Remicade, Janssen)-exposed patients with Crohn's disease (CD). An e-survey was sent to US gastroenterologists who were members of the American Gastroenterological Association. A total of 398 gastroenterologists (3%) completed the survey. Seventy-two percent prescribed adalimumab more than a few times yearly, 58% followed more than 50 patients with CD, and 15% followed 200 or more patients with CD. Ninety percent of gastroenterologists felt that adalimumab had a moderately significant positive impact on patient care. Eighty-two percent correctly identified the US Food and Drug Administration-approved adalimumab induction and maintenance regimens. These gastroenterologists were more likely to follow 200 or more patients with CD (P=.045) and prescribe adalimumab more than a few times per year (P=.037). Years in practice, practice setting, gender, and region did not impact prescribing. Correct dosing was associated with higher prescribing frequency (P=.014) and volume of patients with CD (P=.025). The frequency of adalimumab prescribing and volume of patients with CD were predictive of the total number of correct survey answers (P=.014 and P=.017, respectively). Only 50% of gastroenterologists always administered loading doses when switching to adalimumab from another anti-tumor necrosis factor (TNF) agent; 43.5% reported unclear loading efficacy and 24.3% reported infection concerns from excess anti-TNF as reasons. Eighteen percent of gastroenterologists reported that pharmacies had reduced their prescribed adalimumab doses. To our knowledge, this is the only study evaluating prescribing patterns of adalimumab in patients with CD in the United States. Our findings demonstrate that many gastroenterologists are not using optimal adalimumab dosing strategies, which may lead to a decreased rate of response in patients with CD. Further research is needed to confirm our findings and identify barriers to optimal adalimumab use by gastroenterologists for treatment of CD.

Step up versus early biologic therapy for Crohn's disease in clinical practice.

BACKGROUND: Recent studies have demonstrated superior outcomes of early biologic therapy. Our purpose was to evaluate differences in disease course among patients in clinical practice treated with early biologic therapy compared with those receiving conventional Step Up therapy. METHODS: Patients with Crohn's disease evaluated from July 2004 to November 2010 at a tertiary referral center were included. Demographic data were obtained from a prospectively maintained database. Patients were categorized into 1 of 2 groups: Early Bio group (with or without concomitant immune suppressants) or Step Up group (initial immune suppressants with or without escalation to biologic). Disease activity, quality of life, use of steroids, and number of hospitalizations, and surgeries were assessed. RESULTS: Ninety-three patients with Crohn's disease met inclusion criteria: 39 (45%) in the Step Up group and 54 (58%) in the Early Bio group. There was no significant difference in demographic and clinical variables between groups. Mean Harvey-Bradshaw index and Short Inflammatory Bowel Disease Questionnaire scores at 3, 6, and 12 months were not different between groups. Response rates were higher in the Step Up group compared with the Early Bio group only at 3 months. Early Bio patients had a greater number of hospitalizations at 1 year (P = 0.04). CONCLUSIONS: In clinical practice, early biologic therapy did not improve disease activity or quality of life and did not decrease the need for steroids or surgeries 1 year after therapy. Our results suggest that clinical outcomes are not worsened using the conventional approach. Therefore, an accelerated Step Up approach for most patients seems reasonable.

Anti-tumor necrosis factor therapy is associated with infections after abdominal surgery in Crohn's disease patients.

OBJECTIVES: Anti-tumor necrosis factor (anti-TNF) therapy effects on postoperative complications in Crohn's disease (CD) patients are unclear. We examined a retrospective cohort to clarify this relationship. METHODS: CD patients followed at a referral center between July 2004 and May 2011 who underwent abdominal surgery were identified. Postoperative complications (major infection, intra-abdominal abscess, peritonitis, anastomotic leak, wound infection, dehiscence, fistula, thrombotic, and death) were compared in patients exposed and unexposed to anti-TNF ≤8 weeks preoperatively. Demographics, surgical history, comorbidities, corticosteroid (CS) and immunomodulator use, Montreal classification, operative details, and preoperative nutritional status were assessed. Multivariate analysis measured the independent effect of preoperative anti-TNF on postoperative complications. RESULTS: Overall, 325 abdominal surgeries were performed; 150 (46%) with anti-TNF ≤8 weeks before surgery. The anti-TNF group developed overall infectious (36% vs. 25%, P=0.05) and a trend toward surgical site complications (36% vs. 25%, P=0.10) more frequently. Major postoperative and intra-abdominal septic complications did not differ between groups. Multivariable analysis showed that preoperative anti-TNF was an independent predictor of overall infectious (odds ratio (OR) 2.43; 95% confidence interval (CI) 1.18-5.03) and surgical site (OR 1.96; 95% CI 1.02-3.77) complications. CONCLUSIONS: In a tertiary referral center, use of anti-TNF therapy in CD patients ≤8 weeks before intestinal resection or any intra-abdominal surgery was independently associated with increases in infectious and surgical complications.

Anti-TNF therapy is associated with decreased imaging and radiation exposure in patients with Crohn's disease.

BACKGROUND: Diagnostic imaging is frequently used in Crohn's disease (CD) for diagnosis, evaluation of complications, and determination of response to treatment. Patients with CD are at risk for high radiation exposure in their lifetime. The aim of our study was to compare the effective dose of radiation in CD patients the year prior to and the year after initiation of anti-tumor necrosis factor (anti-TNF) agents or corticosteroids. METHODS: We conducted a retrospective review of 99 CD patients initiated on anti-TNF therapy or corticosteroids between 2004 and 2009 in a tertiary care center. RESULTS: Sixty-five patients were initiated on anti-TNF agents and 34 were initiated on corticosteroids. The anti-TNF cohort was significantly younger at diagnosis and at the time of initiation of anti-TNF or steroid therapy. The anti-TNF group had significantly more stricturing, penetrating, and perianal disease than the corticosteroid group. The anti-TNF cohort had a significant reduction in number of radiologic exams (5.5 vs. 3.7, P < 0.01) as well as a significant reduction in the cumulative radiation dose (28.1 vs. 15.0 mSv, P < 0.01) the year after initiation of therapy. This reduction was largely attributable to decreased use of computed tomography (CT) scans. In contrast, there was no significant change in radiation exposure in the corticosteroid cohort. Logistic regression analysis showed a strong trend toward higher exposure in patients with complicated disease behavior (stricturing or penetrating phenotype) (odds ratio [OR] 2.87, 95% confidence interval [CI] 0.98-8.38). CONCLUSIONS: Initiation of anti-TNF therapy for treatment of CD is associated with a significant reduction in diagnostic radiation exposure. Conversely, steroid treatment does not reduce diagnostic radiation exposure.

Clostridium difficile-associated disease: adherence with current guidelines at a tertiary medical center.

AIM: To assess adherence with the the Society for Healthcare Epidemiology of America (SHEA)/ the Infectious Diseases Society of America (IDSA) guidelines for management of Clostridium difficile (C. difficile)-associated disease (CDAD) at a tertiary medical center. METHODS: All positive C. difficile stool toxin assays in adults between May 2010 and May 2011 at the University of Maryland Medical Center were identified. CDAD episodes were classified as guideline adherent or non-adherent and these two groups were compared to determine demographic and clinical factors predictive of adherence. Logistic regression analysis was performed to assess the effect of multiple predictors on guideline adherence. RESULTS: 320 positive C. difficile stool tests were identified in 290 patients. Stratified by disease severity criteria set forth by the SHEA/IDSA guidelines, 42.2% of cases were mild-moderate, 48.1% severe, and 9.7% severe-complicated. Full adherence with the guidelines was observed in only 43.4% of cases. Adherence was 65.9% for mild-moderate CDAD, which was significantly better than in severe cases (25.3%) or severe-complicated cases (35.5%) (P < 0.001). There was no difference in demographics, hospitalization, ICU exposure, recurrence or 30-d mortality between adherent and non-adherent groups. A multivariate model revealed significantly decreased adherence for severe or severe-complicated episodes (OR = 0.18, 95%CI: 0.11-0.30) and recurrent episodes (OR = 0.46, 95%CI: 0.23-0.95). CONCLUSION: Overall adherence with the SHEA/IDSA guidelines for management of CDAD at a tertiary medical center was poor; this was most pronounced in severe, severe-complicated and recurrent cases. Educational interventions aimed at improving guideline adherence are warranted.

Contrast does not affect cholangioscope image quality.

BACKGROUND/AIMS: Peroral cholangioscopy is a rapidly evolving technique that allows direct examination of the bile duct. We sought to determine if there was a difference in image quality with the cholangioscope immersed in normal saline compared with radiologic contrast or a mixture of contrast and normal saline. METHODS: Images were captured using the SpyGlass® cholangioscope system (Boston Scientific Corp.) immersed in solutions ranging from 0 to 100% contrast. The images were then reviewed in a blinded fashion by a panel of 9 endoscopists with experience using the SpyGlass® system. The reviewers scored the quality of each image based on a scale of 0 (extremely poor) to 10 (excellent). RESULTS: With the cholangioscope immersed in saline and 100% contrast, the mean image quality scores were 7.6 (95% confi dence interval [CI], 6.7-8.5) and 6.9 (95% CI, 5.8-8.0), respectively. The highest mean image quality score was 7.8 (95% CI, 6.7-8.9), obtained in 70% contrast. No signifi cant difference was noted in mean image quality scores using a one way analysis of variance technique (p=0.414). CONCLUSIONS: Although there are limitations to ex vivo studies, we encourage endoscopists to use intraductal contrast prior to peroral cholangioscopy, if needed for lesion localization.

Current and future role of serogenomics in ulcerative colitis.

Ulcerative colitis (UC), a chronic inflammatory bowel disease, occurs in genetically susceptible individuals who mount inappropriate immune responses to endoluminal antigens. Serologic and genetic markers have shown great potential for clinical application in Crohn's disease (CD), particularly for prognostication. However, their use is not as well established in UC. The aim of this paper is to highlight the clinical relevance of these markers for diagnostics and prognostication in UC. This review identified studies that cited the use of serum and genetic biomarkers in UC when these biomarkers were used in diagnostic, prognostic, and therapeutic response prediction applications. Several serologic and genetic markers associated with UC were identified, and this review presents and summarizes these data, focusing on the biomarkers' established and emerging diagnostic and prognostic utility. Although more established in CD, the data provided by serologic and genetic testing in UC has the potential to enhance clinical decision making.

Dialysis reduces portal pressure in patients with chronic hepatitis C.

The purpose of this study was to characterize changes in hepatic venous pressures in patients with chronic hepatitis C. The histology and laboratory data from patients with chronic hepatitis C who underwent a transjugular liver biopsy (TJLB) and hepatic venous pressure gradient measurement were analyzed. Portal hypertension was defined as hepatic venous pressure gradient > or =6 mm Hg. A single pathologist masked to hepatic venous pressure gradient scored liver sections for inflammation and fibrosis. The patients with high-grade inflammation (relative risk [RR] 2.82, P = 0.027, multivariate analysis) and late-stage fibrosis (RR 2.81, P = 0.022) were more likely to have a hepatic venous pressure gradient > or =6 mm Hg, while the patients on dialysis (RR 0.32, P = 0.01) were less likely to have a hepatic venous pressure gradient > or =6 mm Hg. The patients on dialysis (n = 58) had an elevated serum blood urea nitrogen and creatinine when compared with those who were not (n = 75) (47.6 +/- 3.3 and 7.98 +/- 0.4 vs. 25.9 +/- 2.0 and 1.66 +/- 0.22 mg/dL, respectively; P < 0.001). While the hepatic venous pressure gradient increased with the rising levels of liver fibrosis in the latter group (P < 0.01), it did not change in the patients on dialysis (P = 0.41). The median hepatic venous pressure gradient was especially low in late-stage fibrosis patients on dialysis when compared with the latter group (5 vs. 10 mm Hg, P = 0.017). In patients on dialysis, serum transaminases were low across all levels of fibrosis. Twenty-three of the 92 patients with early fibrosis had a hepatic venous pressure gradient > or =6 mm Hg. In patients with chronic hepatitis C, concomitant TJLB and hepatic venous pressure gradient measurement identify those who have early fibrosis and portal hypertension. Long-term hemodialysis may reduce portal pressure in these patients.

Outcome of medical treatment of stricturing and penetrating Crohn's disease: a retrospective study.

BACKGROUND: Outcomes of medical treatment in patients with stricturing and penetrating Crohn's disease (CD) are not well characterized. METHODS: Adults with stricturing and penetrating CD who underwent medical treatment from 2004 to 2008 were evaluated. We assessed response rates to medical treatment, time to relapse or surgery, and postoperative complications. RESULTS: In all, 53 patients underwent medical therapy. 60% had stricturing disease, 11% had penetrating, and 28% had both. Disease location was ileal in 38%, colonic in 2%, and ileocolonic in 60%. At 30, 60, and 90 days, 54%, 60%, and 64% experienced a response to medical therapy, respectively. At 30 days, 75% of patients with ileal CD responded to therapy compared to 38% of patients with ileocolonic CD (P = 0.026). Overall, 64% of patients required surgery. Patients with ileocolonic disease required surgery at 0.55 years versus 1.07 years in patients with ileal disease (P = 0.023). 24% of patients experienced an anastomotic leak, fistula, or abscess (IASC). 29% of patients with penetrating disease developed IASC compared to 6% of patients with stricturing disease (P = 0.047). 32% of patients on biologic therapy had IASC compared to 0% of those not on biologics (P = 0.059). CONCLUSIONS: The outcomes of medical treatment of stricturing or penetrating CD are poor, as 64% ultimately require surgery. Important factors that seem to be associated with either failed therapy include ileocolonic or colonic disease location. We report a high rate of IASC, especially in patients with penetrating disease and those treated with biologic therapy. This should be considered prior to attempted medical therapy.