Ulcerative Colitis: Bickston SJ

Bickston SJ, Cominelli F. · No affiliation provided · Clin Gastroenterol Hepatol. · Pubmed #15017510 No free full text.

This publication has no abstract.

Behm BW, Bickston SJ. · UVA Digestive Health Center of Excellence, University of Virginia Health Systems, 800708 UVAHS, Charlottesville, VA 22908, USA. · Cochrane Database Syst Rev. · Pubmed #19160337 No free full text.

Abstract: BACKGROUND: Cellular adhesion molecules play an important role in the pathogenesis of ulcerative colitis, making selective blockade of these molecules a promising therapeutic strategy. MLN-02, a recombinant humanized IgG1 monoclonal antibody, inhibits adhesion and migration of leukocytes into the gastrointestinal tract by binding the alpha4beta7 integrin. Animal studies have suggested that MLN-02 may be a useful therapy for ulcerative colitis. This systematic review summarizes the current evidence on the use of MLN-02 for induction of remission in ulcerative colitis. OBJECTIVES: To determine the efficacy and safety of MLN-02 for induction of remission in ulcerative colitis. SEARCH STRATEGY: A computer-assisted search of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Inflammatory Bowel Disease Specialized Trial Register was performed to identify relevant publications. References from recent reviews and published articles were searched to identify additional citations. Manual searches to identify key conference abstracts were performed. Unpublished data from on-going trials were identified by correspondence with authors and experts in the field and from the manufacturer of MLN-02. SELECTION CRITERIA: Randomized controlled trials comparing MLN-02 to placebo or a control therapy for the induction of remission in ulcerative colitis were included. DATA COLLECTION AND ANALYSIS: Two independent reviewers performed data extraction and assessment of the methodological quality of each trial. Data were analyzed using Review Manager (RevMan 4.2). MAIN RESULTS: One study satisfied the inclusion criteria for this review. In this study, MLN-02 was found to be effective for induction of clinical response (RR = 1.78, 95% CI 1.22 to 2.60) and remission (RR = 2.25, 95% CI 1.17 to 4.36) in patients with moderately severe ulcerative colitis. Patients receiving MLN-02 had higher IBDQ scores than patients receiving placebo. There was a trend toward increased endoscopic remission with MLN-02 relative to placebo, although this difference was not statistically significant (total MLN-02 20% versus placebo 8%; P = 0.05; RR = 2.46, 95% CI 0.98 to 6.15). Adverse events occurred in a similar proportion of patients treated with MLN-02 compared to placebo (RR = 1.60, 95% CI 0.67 to 3.83). Neutralizing antibodies were found in a significant proportion of patients receiving MLN-02, and in the group of patients with high antibody titers clinical remission rates were no different than placebo. No opportunistic infections were reported. AUTHORS' CONCLUSIONS: Data from one trial suggests that MLN-02 may be effective for induction of clinical response and remission in patients with moderately severe ulcerative colitis. Adverse events appear to be similar to placebo, although immunogenicity may be an issue. Further trials are needed to confirm the results of this study and to define the optimal dose and frequency of administration of MLN-02.

Bickston SJ, Waters HC, Dabbous O, Tang BI, Rahman M. · University of Virginia Health System, Charlottesville, VA 22908, USA. · J Manag Care Pharm. · Pubmed #18500913 links to  free full text

Abstract: BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory disease with peak incidence in the third decade of life and a second peak in the sixth or seventh decade. While drug therapy can be used to control the inflammation and reduce symptoms, patients with UC may be treated surgically. There is little information in the published literature evaluating the all-cause health care costs of patients with UC according to age. OBJECTIVE: To assess from administrative claims the direct all-cause (not disease-related) costs of care and resource utilization for patients with UC compared with members without UC by 3 age categories. METHODS: A retrospective analysis was conducted using the PharMetrics database of patients with a diagnosis of UC (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 556.x) from January 1, 2000, through June 30, 2005. This database contains enrollment data and pharmacy and medical claims from more than 85 different managed care organizations and more than 55 million patients in the United States. Patients had to be continuously enrolled for 6 months before and 12 months after the initial UC diagnosis and have at least 2 distinct claims with a diagnosis code for UC. The mean per-patient health care resource utilization and costs were calculated for patients in the year following their initial UC diagnosis and compared with the same measures for a group of age- and gender-matched members (without UC claims) at a ratio of 4:1. Three age groups were analyzed: pediatric-adolescent (aged < 18 years), adults (aged 18 to 64 years), and older adults (aged e 65 years). Differences in the measures of all-cause health care resource utilization (claims and costs) between the UC and non-UC groups were tested for statistical significance using the Wilcoxon signed-rank test, a non-parametric alternative to the paired t test. Differences between the 3 age cohorts were tested using the Mann-Whitney U test. RESULTS: Data were collected for 15,105 patients with UC and for 59,159 members in the comparator cohort without UC matched by age and gender. The average age for both cohorts was 44 years, and 54% were female. Mean ([SD], median) annual all-cause total health care costs in 2005 dollars for patients with UC were $13,233 ([$40,715], $5,190) versus $3,214 ([$12,741], $753) for the comparator group (P < 0.001). For all UC patients, all-cause inpatient hospitalization costs constituted the largest component ($5,771, 43.6%) of the mean annual total costs, followed by prescription medications ($2,423, 18.3%); miscellaneous services, such as hospice, psychiatric facility, and nursing home care ($2,092, 15.8%); outpatient hospital visits ($1,310, 9.9%); physician office visits ($899, 6.8%); laboratory procedures ($470, 3.6%); and emergency department visits ($268, 2.0%). Resource utilization (e.g., physician visits, laboratory claims, pharmacy claims) was highest for older adults aged e 65 years, followed by pediatricadolescent patients and adults aged 18 to 64 years (all comparisons P < 0.01). The mean ([SD], median) all-cause total health care costs were highest for pediatric-adolescent patients with UC (n = 589, 3.9%) at $23,113 ([$70,999], $6,214), followed by older adults (n = 650, 4.3%) at $15,811 ([$23,882], $6,886, P < 0.001), while adults aged 18 to 64 years (n = 13,866, 91.8%) incurred the lowest cost at $12,693 ([$39,505], $5,108, P < 0.001). CONCLUSION: Patients with UC identified from medical claims incurred significantly higher all-cause health care costs for all 3 age categories than did the comparator group of health plan members without diagnosis for UC.

Behm BW, Bickston SJ. · Stephen J. Bickston, MD University of Virginia Digestive Health Center of Excellence, 800708 UVAHS, Charlottesville, VA 22908, USA. · Curr Treat Options Gastroenterol. · Pubmed #17547855 No free full text.

Abstract: Infliximab is arguably the first major advance in therapy for inflammatory bowel disease in more than a quarter of a century. Although it is important to distinguish efficacy from effectiveness, the data from clinical practice mirror those from randomized controlled trials. Infliximab has proven efficacious for luminal manifestations of Crohn's disease (CD) regardless of location. It also has proven efficacy in the subset of penetrating disease to the skin and perianal area, and it increases rates of steroid-free remission. These benefits are reflected in improved quality of life, with limited data showing that infliximab can decrease rates of hospitalization and CD-related surgery. Infliximab also has proven to be efficacious in patients with ulcerative colitis (UC) and has increased rates of steroid-free remission. Whether infliximab will have an impact on the risk of colorectal cancer in UC and Crohn's colitis has yet to be determined. The combination of strong evidence from large randomized controlled trials with substantial examination of use in the practice setting has moved biologic therapy with infliximab from novel to mainstream. In this review, the data for the efficacy of infliximab in controlled trials will be discussed in the context of real world effectiveness.

Arseneau KO, Sultan S, Provenzale DT, Onken J, Bickston SJ, Foley E, Connors AF, Cominelli F. · Division of Gastroenterology & Hepatology, University of Virginia Health System, Charlottesville, Virginia, USA. · Clin Gastroenterol Hepatol. · Pubmed #16829206 No free full text.

Abstract: BACKGROUND & AIMS: Patients with steroid-refractory ulcerative colitis face a difficult treatment decision between colectomy and therapy with infliximab or cyclosporine. The aim of this study was to understand how individual patient preferences for the various treatment outcomes influence the optimal treatment decision for a given patient. METHODS: A Markov model was used to simulate treatment with total colectomy with an ileo pouch-anal anastomosis (TC/IPAA), cyclosporine (CSA), infliximab (INFLX), and infliximab followed by cyclosporine for treatment failures (INFLX-->CSA). Utility weights for treatment outcomes were elicited from 48 patients using both time trade-off and visual rating scale methods. Preference sets were applied to the model to identify the therapy that maximized quality-adjusted life years (QALYs) for each patient. Sensitivity analyses were performed to assess model robustness. RESULTS: Optimal treatment was highly variable among patients (INFLX-->CSA = 42%, 20/48; TC/IPAA = 37%, 18/48; CSA = 21%, 10/48; INFLX = 0%, 0/48). However, when average preference weights from our sample were applied to the model, medical treatments were superior to TC (CSA = .26 QALYs gained vs TC/IPAA; INFLX-->CSA = .25 QALYs gained vs TC/IPAA). CONCLUSIONS: Patient preferences have a clear impact on the optimal treatment for steroid-refractory ulcerative colitis. Although averaged preferences support the use of medical interventions, a third of individual patients may benefit most from proceeding directly to colectomy. Failure to fully assess individual preferences may result in suboptimal treatment for these patients.

Bamias G, Martin C, Marini M, Hoang S, Mishina M, Ross WG, Sachedina MA, Friel CM, Mize J, Bickston SJ, Pizarro TT, Wei P, Cominelli F. · Digestive Health Center of Excellence, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA. · J Immunol. · Pubmed #14568967 links to  free full text

Abstract: TL1A is a novel TNF-like factor that acts as a costimulator of IFN-gamma secretion through binding to the death domain-containing receptor, DR3. The aim of this study was to test the hypothesis that TL1A may play an important role in inflammatory bowel disease (IBD) by functioning as a Th1-polarizing cytokine. The expression, cellular localization, and functional activity of TL1A and DR3 were studied in intestinal tissue specimens as well as isolated lamina propria mononuclear cells from IBD patients and controls. TL1A mRNA and protein expression was up-regulated in IBD, particularly in involved areas of Crohn's disease (CD; p < 0.03 vs control). TL1A production was localized to the intestinal lamina propria in macrophages and CD4(+) and CD8(+) lymphocytes from CD patients as well as in plasma cells from ulcerative colitis patients. The amount of TL1A protein and the number of TL1A-positive cells correlated with the severity of inflammation, most significantly in CD. Increased numbers of immunoreactive DR3-positive T lymphocytes were detected in the intestinal lamina propria from IBD patients. Addition of recombinant human TL1A to cultures of PHA-stimulated lamina propria mononuclear from CD patients significantly augmented IFN-gamma production by 4-fold, whereas a minimal effect was observed in control patients. Our study provides evidence for the first time that the novel cytokine TL1A may play an important role in a Th1-mediated disease such as CD.

Pizarro TT, Michie MH, Bentz M, Woraratanadharm J, Smith MF, Foley E, Moskaluk CA, Bickston SJ, Cominelli F. · Department of Medicine, Digestive Health Center, University of Virginia Health Sciences Center, Charlottesville 22908, USA. · J Immunol. · Pubmed #10352304 links to  free full text

Abstract: IL-18, a novel immunoregulatory cytokine with potent IFN-gamma-inducing activities, may play an important role in Th1-mediated chronic inflammatory disorders. The aim of the present study was to characterize the expression and localization of IL-18 in colonic specimens and isolated mucosal cell populations from patients with Crohn's disease (CD), a prototypic Th1-mediated disorder. Using a semiquantitative RT-PCR protocol, IL-18 mRNA transcripts were found to be increased in freshly isolated intestinal epithelial cells (IEC) and lamina propria mononuclear cells (LPMC) from CD compared with ulcerative colitis (UC) and noninflamed control (cont) patients, and were more abundant in IEC compared with LPMC. Immunohistochemical analysis of surgically resected colonic tissues localized IL-18 to both LPMC (specifically, macrophages and dendritic cells) as well as IEC. Staining was more intense in CD compared with UC and cont, and in involved (inv) vs noninvolved (n inv) areas. Western blot analysis revealed that an 18. 3-kDa band, consistent with both recombinant and mature human IL-18 protein, was found predominantly in CD vs UC intestinal mucosal biopsies; a second band of 24 kDa, consistent with the inactive IL-18 precursor, was detected in n inv areas from both CD and UC biopsies and was the sole form found in noninflamed cont. To our knowledge, this report is the first describing increased expression of IL-18 in a human Th1-mediated chronic inflammatory disease. In addition, our studies further support the concept that IEC and dendritic cells may possess important immunoregulatory functions in both normal, as well as pathological, mucosal immunity.