Ulcerative Colitis: Harris ML

Nguyen GC, Harris ML, Dassopoulos T. · Division of Gastroenterology, The Johns Hopkins Hospital, 600 North Wolfe Street/Blalock 461, Baltimore, MD 21287, USA. · Curr Gastroenterol Rep. · Pubmed #17105689 No free full text.

Abstract: Immunomodulators are a class of drugs that attenuate the underlying inflammatory processes of Crohn's disease (CD) and ulcerative colitis (UC), the two major inflammatory bowel diseases (IBD). These agents play a prominent role in the management of refractory and steroid-dependent IBD. The immunomodulatory drugs in the IBD arsenal include azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, and tacrolimus. Azathioprine and 6-mercaptopurine are considered first-line immunosuppressants due to their proven efficacy in both CD and UC and their safety profile, whereas cyclosporine occupies a niche as a surgery-sparing agent in the acute management of severe, steroid-refractory UC. Immunomodulators also appear to have a role as adjunctive therapy when used with infliximab or other biologic agents to reduce immunogenicity. Although data have been limited to observational studies, azathioprine and 6-mercaptopurine may be used during pregnancy.

Nguyen GC, Boudreau H, Harris ML, Maxwell CV. · Mount Sinai IBD Centre, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. · Clin Gastroenterol Hepatol. · Pubmed #19027089 No free full text.

Abstract: BACKGROUND & AIMS: Pregnant women with Crohn's disease (CD) or ulcerative colitis (UC) are at increased risk of adverse outcomes compared with pregnant women without these disorders. We estimated the occurrence of pregnancies in women with CD and UC in the United States and compared outcomes between these patients and the non-inflammatory bowel disease (IBD) obstetric population. METHODS: By using the 2005 Nationwide Inpatient Sample, we estimated the number of obstetric hospitalizations, deliveries, and Cesarean deliveries in women with CD, UC, and those without IBD. Outcomes included prevalences of Cesarean delivery, venous thromboembolism (VTE), blood transfusion, and malnutrition. RESULTS: Of an estimated 4.21 million deliveries, 2372 and 1368 occurred in women with CD and UC, respectively. Compared with the non-IBD population, adjusted odds of Cesarean delivery were higher in women with CD (adjusted odds ratio [aOR], 1.72; 95% confidence interval [CI], 1.44-2.04) and UC (aOR, 1.29; 95% CI, 1.01-1.66). The risk of VTE was substantially higher in women with CD (aOR, 6.12; 95% CI, 2.91-12.9) and UC (aOR, 8.44; 95% CI, 3.71-19.2) vs the non-IBD population. Blood transfusions occurred more frequently in women with CD (aOR, 2.82; 95% CI, 1.51-5.26), whereas protein-calorie malnutrition occurred more frequently in women with CD (aOR, 20.0; 95% CI, 8.8-45.4) or UC (aOR, 60.8; 95% CI, 28.2-131.0). CONCLUSIONS: Adverse pregnancy and maternal outcomes occur more frequently in women with IBD. Measures should be undertaken to reduce maternal complications such as VTE and malnutrition in women with these disorders.

Wu F, Zikusoka M, Trindade A, Dassopoulos T, Harris ML, Bayless TM, Brant SR, Chakravarti S, Kwon JH. · The Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Division of Gastroenterology, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21205-2195, USA. · Gastroenterology. · Pubmed #18835392 No free full text.

Abstract: BACKGROUND & AIMS: Chronic inflammatory bowel diseases such as ulcerative colitis (UC) are associated with differential expression of genes involved in inflammation and tissue remodeling. MicroRNAs (miRNAs), which direct mRNA degradation and translational inhibition, influence a number of disease processes. We examined whether miRNAs are differentially expressed in UC tissues and are associated with expression of genes that regulate inflammation. METHODS: miRNA expression was assessed in patients with active UC, inactive UC, Crohn's disease, irritable bowel syndrome, infectious colitis, and microscopic colitis, as well as in healthy subjects by microarray, quantitative reverse transcription-polymerase chain reaction and in situ hybridization analyses. Colonic epithelial cell (HT29) expression of miRNAs was assessed. Regulation of gene expression by miRNAs was assessed by luciferase reporter construct assays and transfection of specific miRNA mimics. RESULTS: Active UC was associated with the differential expression of 11 miRNAs; 3 were significantly decreased and 8 were significantly increased in UC tissues. In situ hybridization analysis indicated that miR-192, an miRNA with decreased expression in active UC, was predominantly localized to colonic epithelial cells. Macrophage inflammatory peptide (MIP)-2 alpha, a chemokine expressed by epithelial cells, was identified as a target of miR-192. In colon epithelial cells, induction of MIP-2 alpha expression by tumor necrosis factor-alpha was accompanied by a concomitant reduction in miR-192 expression and miR-192 was observed to regulate the expression of MIP-2 alpha. CONCLUSIONS: These findings expand the known roles of miRNAs, indicating that tissues from patients with UC, and possibly other chronic inflammatory diseases, have altered miRNA expression patterns. These findings also demonstrate that miRNAs regulate colonic epithelial cell-derived chemokine expression.

Nguyen GC, Kaplan GG, Harris ML, Brant SR. · Mount Sinai Hospital IBD Centre, University of Toronto School of Medicine, Toronto, Ontario, Canada. · Am J Gastroenterol. · Pubmed #18513271 No free full text.

Abstract: BACKGROUND: We sought to determine nationwide, population-based trends in rates of Clostridium difficile (C. difficile) infection among hospitalized inflammatory bowel disease (IBD) patients in the United States, and to determine its mortality and economic impact. METHODS: We analyzed discharge records from the Nationwide Inpatient Sample, and used the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes to identify Crohn's disease (CD) and ulcerative colitis (UC) cases, and cases of C. difficile infection between 1998 and 2004. Temporal patterns of C. difficile incidence in IBD patients were compared to non-IBD gastroenterology patients and all-hospitalized patients. The impact of C. difficile on in-hospital mortality and resource utilization was quantified using multiple regression analysis. RESULTS: The prevalence of C. difficile among UC patients (37.3 per 1,000, 95% confidence interval [CI] 34.0-40.7 per 1,000) was higher than that among CD patients (10.9 per 1,000, 95% CI 9.9-12.0 per 1,000), non-IBD gastrointestinal (GI) patients (4.8 per 1,000, 95% CI 4.6-5.0 per 1,000), and general medical patients (4.5 per 1,000, 95% CI 4.2-4.7 per 1,000). C. difficile incidence nearly doubled among UC patients (26.6 per 1,000 to 51.2 per 1,000) over 7 yr. After adjustment for confounders, C. difficile infection was associated with greater mortality among patients with UC (odds ratio [OR] 3.79, 95% CI 2.84-5.06), but not CD (OR 1.66, 95% CI 0.75-3.66). C. difficile was also associated with 65% and 46% longer lengths of stay, which correlated with 63% and 46% higher average hospital charges, for CD and UC patients, respectively. CONCLUSIONS: C. difficile infection is a growing public health issue among hospitalized IBD patients, especially those with UC, and is associated with higher mortality and resource utilization, prompting the need for better preventative measures and early detection.

Nguyen GC, Munsell M, Harris ML. · Mount Sinai Hospital IBD Centre, University of Toronto School of Medicine, Toronto, Ontario, Canada. · Inflamm Bowel Dis. · Pubmed #18302272 links to  free full text

Abstract: BACKGROUND: Inflammatory bowel disease (IBD) patients are at increased risk of protein-calorie malnutrition. We sought to determine the prevalence of clinically diagnosable malnutrition among those hospitalized for IBD throughout the United States and whether this malnutrition influenced health outcomes. METHODS: We queried the Nationwide Inpatient Sample between 1998 and 2004 to identify admissions for Crohn's disease (CD) or ulcerative colitis (UC) and a representative sample of non-IBD discharges. We assessed the prevalence and predictors of malnutrition and its association with in-hospital mortality and resource utilization. RESULTS: The prevalence of malnutrition was greater in CD and UC patients than in non-IBD patients (6.1% and 7.2% versus 1.8%, P < 0.0001). The adjusted odds ratio for malnutrition among IBD admissions compared with non-IBD admissions was 5.57 [95% confidence interval (CI): 5.29-5.86]. More IBD discharges than non-IBD discharges with malnutrition received parenteral nutrition (26% versus 6%, P < 0.0001). There was increased likelihood of malnutrition among those with fistulizing CD (OR 1.65; 95% CI: 1.50-1.82) and among those who had undergone bowel resection (OR 1.37; 95% CI: 1.27-1.48). Malnutrition was associated with increased in-hospital mortality 3.49 (95% CI: 2.89-4.23), length of stay (11.9 days versus 5.8 days, P < 0.00001), and total charges ($45,188 versus $20,295, P < 0.0001). CONCLUSIONS: Clinically apparent malnutrition is more frequent among IBD admissions than among non-IBD admissions. Its association with greater mortality and resource utilization may reflect more severe underlying disease that can lead to both malnutrition and worse outcomes. Nonetheless, diagnosable malnutrition may serve as a clinical marker of poor IBD prognosis in hospitalized patients.

Nguyen GC, Tuskey A, Dassopoulos T, Harris ML, Brant SR. · Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Inflamm Bowel Dis. · Pubmed #17828784 links to  free full text

Abstract: BACKGROUND: Recent epidemiological studies suggest that the prevalences of Crohn's disease (CD) and ulcerative colitis (UC) are increasing in the United States. We sought to determine whether nationwide rates of inflammatory bowel disease (IBD) hospitalizations have increased in response to temporal trends in prevalence. METHODS: We identified all admissions with a primary diagnosis of CD or UC, or 1 of their complications in the Nationwide Inpatient Sample between 1998 and 2004. National estimates of hospitalization rates and rates of surgery were determined using the U.S. Census population as the denominator. RESULTS: There were an estimated 359,124 and 214,498 admissions for CD and UC, respectively. The overall hospitalization rate for CD was 18.0 per 100,000 and that for UC was 10.8 per 100,000. There was a 4.3% annual relative increase in hospitalization rate for CD (P < 0.0001) and a 3.0% annual increase for UC (P < 0.0001). Surgery rates were 3.4 bowel resections per 100,000 for CD and 1.2 colectomies per 100,000 for UC and remained stable. There were no temporal patterns for average length of stay for CD (5.8 days) or for UC (6.8 days). The national estimate of total inpatient charges attributable to CD increased from $762 million to $1,330 million between 1998 and 2004, and that for UC increased from $592 million to $945 million.CONCLUSIONS: Hospitalization rates for IBD, particularly CD, have increased within a 7-year period, incurring a substantial rise in inflation-adjusted economic burden. The findings reinforce the need for effective treatment strategies to reduce IBD complications.

Wu F, Dassopoulos T, Cope L, Maitra A, Brant SR, Harris ML, Bayless TM, Parmigiani G, Chakravarti S. · Department of Medicine (Gastroenterology Division), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. · Inflamm Bowel Dis. · Pubmed #17262812 links to  free full text

Abstract: BACKGROUND: Ulcerative colitis (UC) and Crohn's disease (CD) are inflammatory bowel diseases (IBD) with variable, overlapping clinical features and complex pathophysiologies. METHODS: To identify pathogenic processes underlying these disease subtypes, we used single endoscopic pinch biopsies to elucidate patterns of gene expression in active and inactive areas of UC and CD and compared these to infectious colitis and healthy control samples. RESULTS: Unsupervised classification of a total of 36 samples yielded promising separation between the affected IBD, unaffected IBD, non-IBD colitis, and normal control samples, suggesting each sample type had a distinctive gene expression pattern. Genes differentially expressed in the CD samples compared to in the controls were related to IFNgamma-inducible TH1 processes (IFITM1, IFITM3, STAT1, and STAT3) and antigen presentation (TAP1, PSME2, PSMB8). The most noticeable change in the UC samples was reduced expression of genes regulating biosynthesis, metabolism, and electrolyte transport (HNF4G, KLF5, AQP8, ATP2B1, and SLC16A). Twenty-five percent of genes down-regulated in the UC samples were also down-regulated in the infectious colitis samples. Unaffected biopsy samples of IBD patients also registered differences expression of genes compared to in the normal controls. Of these differentially expressed genes, only 2 were up-regulated, PSKH1, a regulator of mRNA processing, and PPID, a suppressor of apoptosis. CONCLUSIONS: The study shows that the gene expression patterns of IBD, CD in particular, are quite different from those of infectious colitis, highlighting distinctive expression of genes and pathways in UC and CD.

Nguyen GC, Torres EA, Regueiro M, Bromfield G, Bitton A, Stempak J, Dassopoulos T, Schumm P, Gregory FJ, Griffiths AM, Hanauer SB, Hanson J, Harris ML, Kane SV, Orkwis HK, Lahaie R, Oliva-Hemker M, Pare P, Wild GE, Rioux JD, Yang H, Duerr RH, Cho JH, Steinhart AH, Brant SR, Silverberg MS. · Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Am J Gastroenterol. · Pubmed #16696785 No free full text.

Abstract: OBJECTIVES: Inflammatory bowel disease (IBD), comprising primarily of Crohn's disease (CD) and ulcerative colitis (UC), is increasingly prevalent in racial and ethnic minorities. This study was undertaken to characterize racial differences in disease phenotype in a predominantly adult population. METHODS: Phenotype data on 830 non-Hispanic white, 127 non-Hispanic African American, and 169 Hispanic IBD patients, recruited from six academic centers, were abstracted from medical records and compiled in the NIDDK-IBD Genetics Consortium repository. We characterized racial differences in family history, disease location and behavior, surgical history, and extraintestinal manifestations (EIMs) using standardized definitions. RESULTS: African American CD patients were more likely than whites to develop esophagogastroduodenal CD (OR = 2.8; 95% CI: 1.4-5.5), colorectal disease (OR = 1.9; 95% CI: 1.1-3.4), perianal disease (OR = 1.7; 95% CI: 1.03-2.8), but less likely to have ileal involvement (OR = 0.55; 95% CI: 0.32-0.96). They were also at higher risk for uveitis (OR = 5.5; 95% CI: 2.3-13.0) and sacroiliitis (OR = 4.0; 95% CI: 1.55-10.1). Hispanics had higher prevalence of perianal CD (OR = 2.9; 95% CI: 1.8-4.6) and erythema nodosum (3.3; 95% CI: 1.7-6.4). Among UC patients, Hispanics had more proximal disease extent. Both African American and Hispanic CD patients, but not UC patients, had lower prevalences of family history of IBD than their white counterparts. CONCLUSIONS: There are racial differences in IBD family history, disease location, and EIMs that may reflect underlying genetic variations and have important implications for diagnosis and management of disease. These findings underscore the need for further studies in minority populations.