Mark H. Flasar

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 Crohns 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.

Disparities in the use of immunomodulators and biologics for the treatment of inflammatory bowel disease: a retrospective cohort study.

Background: Treatment disparities between African Americans (AA) and Caucasians exist in multiple diseases. There are limited studies in inflammatory bowel disease (IBD). Our objectives were to assess differences in IBD therapies between AA and Caucasians, controlling for disease severity. Methods: We identified outpatients with ulcerative colitis (UC) or Crohns disease (CD) evaluated at the University of Maryland and the Baltimore Veterans Affairs Medical Center from 1997–2005. We assessed medications used and the presence of covariates by race. Results: We identified 406 patients; 102 were AA (25%). AA were less likely to receive steroids (56% versus 68%; P = 0.02), mercaptopurine/azathioprine (6‐MP/AZA) (28% versus 40%; P = 0.03), infliximab (IFX) (10% versus 20%; P = 0.03), or either 6‐MP/AZA or IFX (28% versus 44%; P = 0.005). Age at diagnosis <40 (odds ratio [OR] 2.22, 95% confidence interval [CI] 1.06–4.54), steroid use (OR 4.75, 95% CI 1.93–11.7), and CD (OR 6.25, 95% CI 3.22–12.5) were positively associated with IFX use, while AA (OR 0.50, 95% CI 0.23–1.08) was negatively associated with IFX use. Age at diagnosis <40 (OR 1.84, 95% CI 1.12–3.23), steroid use (OR 10.2, 95% CI 5.37–19.2), and CD (OR 2.32, 95% CI 1.43–3.20) were positively associated with either 6‐MP/AZA or IFX use, while AA (OR 0.57, 95% CI 0.32–1.01) was negatively associated with 6‐MP/AZA or IFX use. Conclusions: There were trends toward lower odds of treatment with IFX or either 6‐MP/AZA or IFX in AA when compared with Caucasians. Further studies are needed to determine if these differences are due to less severe disease in AA patients or due to disparities in care.

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 Crohns 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. (Inflamm Bowel Dis 2009)

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

Abstract:Biologic therapy with anti–tumor necrosis factor (TNF)-&agr; 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-&agr; 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-&agr; 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-&agr; 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.

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 Crohns 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 Crohns 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.

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.

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

Background:Diagnostic imaging is frequently used in Crohns 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.

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.

Radiating Disparity in IBD

In remote corners of the rapidly expanding IBD literature universe, two separate areas of investigation and controversy continue to grow independently. The first is in regard to the risks of diagnostic radiation exposure, whereas the second concerns the disparities in access to care and health care resource utilization in IBD patients. Abdominal imaging is frequently utilized to diagnose disease, detect complications, and ascertain response to treatment in IBD patients. Given a 20-fold rise in the amount of CT imaging between 1980 and 2000, it is not surprising that an estimated three-quarters of the radiation to which IBD patients are exposed is due to CT scanning [1, 2], mostly from abdomino-pelvic examinations, which have largely supplanted conventional contrast enterography in IBD patients. As an example, an 840 % increase in CT enterography use was reported between 2002 and 2007 [3]. Further, as many as 1 in 6 IBD patients are exposed to moderate-high cumulative effective doses (CED) of diagnostic ionizing radiation as measured in millisieverts (mSv) [4]. These figures are important, as frequent exposure to low levels of ionizing radiation have been hypothesized to increase the incidence of malignancy, with as many as 2 % of all cancers worldwide attributable to diagnostic radiation exposure [1, 5]. Although equipoise exists as to the legitimacy of this possible association, there is nonetheless a growing interest in and discussion surrounding the limitation of diagnostic radiation exposures in IBD patients to what is truly necessary for optimal patient management [6]. Parallel to concerns about radiation exposure, several studies have revealed that the IBD universe is not immune to some of the issues that plague the field of medicine as a whole. Racial and socioeconomic disparities in the availability, delivery, and utilization of IBD healthcare resources have been repeatedly demonstrated [7–9]. As these disparities have included differences in use of highly effective medical therapies, emergency department (ED) visits, and gastroenterologist subspecialist care, resultant differences in the degree and frequency of diagnostic radiation exposures are likely. Possible reasons may include barriers to highly effective medical therapy, delays in definitive surgical therapy, and reduced access to gastroenterology specialist and IBD subspecialist care. In this issue of Digestive Diseases and Sciences, Hou et al. [10] report the findings of a retrospective cohort study with the aim of identifying factors associated with highdose radiation exposure in a cohort of IBD patients treated in a county-based ‘‘safety net’’ healthcare system in Houston, TX, USA, from 2000 to 2010. Such healthcare delivery systems are designed to offer universal care access regardless of ability to pay. Since these systems have high proportions of uninsured and under-insured individuals, it is likely that this study population is enriched in IBD patients at risk for increased diagnostic radiation exposure stemming from care disparity issues. The authors identified all possible IBD patients from the 3 inpatient and 14 outpatient facilities in the studied healthcare system using ICD-9 codes. The authors subsequently reviewed electronic medical records and applied accepted IBD diagnostic criteria to reasonably verify a racially and ethnically diverse 278-patient IBD cohort. M. Flasar (&) S. Patil Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, 100 North Greene Street, Lower Level, Baltimore, MD 21201, USA e-mail: mflasar@medicine.umaryland.edu