Ulcerative Colitis: Plevy S

Sheikh S, Uno J, Matsuoka K, Plevy S. · Department of Medicine, Division of Gastroenterology and Hepatology, Inflammatory Bowel Disease Center, University of North Carolina FOCiS Center of Excellence, Chapel Hill, NC 27599, USA. · Clin Immunol. · Pubmed #18499066 No free full text.

Abstract: A patient from the University of North Carolina Hospitals is presented who developed Crohn's disease of the ileal J-pouch following restorative proctocolectomy for ulcerative colitis. Inflammation of the ileal pouch in human inflammatory bowel disease (IBD) represents the best clinical example of the importance of host-enteric microbial interactions, and this case highlights rapid advances in our understanding of the role of the enteric microbiota in the immunopathogenesis of IBD, impacting on clinical care. Successful management of this patient necessitated accurate diagnosis as there are several inflammatory and non-inflammatory conditions of the pouch that present with similar symptoms. Diagnostic measures included serologic assays of response to microbial antigens, including ASCA, anti-OmpC, anti-Cbir1, and pANCA with DNAse sensitivity. Although the serologic detection of selective loss of tolerance to microbial antigens defines clinically important subgroups of inflammatory bowel disease patients, the clinical value of these serodiagnostic tests is a matter of debate. Genome wide screens have also identified NOD2/CARD15, IL23 receptor, and ATG16L1 variants as important in IBD susceptibility and pathogenesis. These genetic associations have also provided new insights into the importance of interaction between the host and microbes in the pathogenesis of IBD, but the precise mechanisms by which these gene variants contribute to disease development remain to be determined. Genetic associations and serological markers will ultimately be used to define important clinical subgroups of disease, predict natural history, and ultimately identify patient populations for early therapeutic intervention.

Abreu MT, Plevy S, Sands BE, Weinstein R. · Inflammatory Bowel Disease Center, New York, NY, USA. · J Clin Gastroenterol. · Pubmed #18090155 No free full text.

Abstract: The etiology of inflammatory bowel disease (IBD) is not completely understood, thus current therapies have been empirical and directed at treating symptoms rather than addressing the cause. In IBD, the overexpression of proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, leads to a persistent intestinal inflammatory response that damages the intestinal mucosa. Recent advances in pharmacologic therapies that target specific cytokines, chemokines, and adhesion molecules have proved successful in alleviating symptoms for some patients. There are 2 selective adsorption apheresis devices that remove leukocytes from whole blood, which are currently available in Japan and Europe-the Cellsorba leukocytapheresis column and the Adacolumn adsorptive extracorporeal granulocyte/monocyte apheresis device. The purported mechanisms of action of these devices have been extensively reviewed and are believed to exert an immunomodulatory and/or anti-inflammatory effect on patients with systemic inflammatory disease. The clinical trials presented here indicate that selective leukocyte apheresis effectively removes activated granulocytes and monocytes/macrophages from peripheral blood while maintaining an excellent safety profile. Despite these findings, large controlled trials of selective leukocyte apheresis in the treatment of IBD are needed to determine the true efficacy of this approach.

Papachristou GI, Plevy S. · Division of Gastroenterology, Hepatology and Nutrition, The University of Pittsburgh School of Medicine, Scaife Hall, Room 566, 3550 Terrace Street, Pittsburgh, PA 15261, USA. · Gastroenterol Clin North Am. · Pubmed #15177537 No free full text.

Abstract: Understanding of immunologic mechanisms involved in the initiation and perpetuation of chronic inflammation has led to new therapeutic opportunities in the inflammatory bowel diseases. The term "biologics" is used to distinguish new biotechnologic therapeutics from the conventional drugs used in the treatment of immune-mediated inflammatory disorders. This article reviews novel biologic therapies that are being investigated for the treatment of Crohn's disease and ulcerative colitis.

Plevy S, Salzberg B, Van Assche G, Regueiro M, Hommes D, Sandborn W, Hanauer S, Targan S, Mayer L, Mahadevan U, Frankel M, Lowder J. · Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA. · Gastroenterology. · Pubmed #17920064 No free full text.

Abstract: BACKGROUND & AIMS: To evaluate the safety and biological activity of visilizumab (a humanized anti-CD3 monoclonal antibody) and to determine a maximum tolerated dose in patients with severe ulcerative colitis that had not responded to 5 days of treatment with intravenous corticosteroids. METHODS: In this open-label phase 1 study, 32 subjects received visilizumab at a dose of 10 or 15 microg/kg, administered intravenously on 2 consecutive days. Clinical response was defined as a Modified Truelove and Witts Severity Index <10 with a minimum decrease of 3 points; remission was <4 points. Endoscopic remission was a Mayo endoscopic subscore of 0 or 1. RESULTS: Eight patients received 15 microg/kg visilizumab. Because of dose-limiting toxicities (T-cell recovery >30 days in 2 of 8 patients), the dose was reduced to 10 microg/kg in 24 patients. On day 30, 84% of patients demonstrated a clinical response, 41% achieved clinical remission, and 44% achieved endoscopic remission. Forty-five percent of patients did not require salvage therapies or colectomy during the first year postdose. Mild to moderate symptoms of cytokine release occurred in 100% and 83% of patients in the 15- and 10-microg/kg dose groups, respectively. All patients exhibited a rapid decrease in circulating CD4(+) T-cell counts, which returned to baseline values by day 30 in 26 of 30 evaluable patients (86%). There were no serious infections. CONCLUSIONS: Visilizumab had an acceptable safety profile at the 10-microg/kg dose level and may be clinically beneficial in patients with severe intravenous corticosteroid-refractory ulcerative colitis.

Regueiro M, Curtis J, Plevy S. · Inflammatory Bowel Disease Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. · J Clin Gastroenterol. · Pubmed #16825928 No free full text.

Abstract: To evaluate the efficacy of infliximab in hospitalized ulcerative colitis (UC) patients refractory to intravenous corticosteroids. Treatment options for steroid-refractory UC patients are limited and include cyclosporine and colectomy. Although two recent studies (ACT I/II) demonstrate a benefit from infliximab in outpatients with moderate to severely active UC, the utility of infliximab in severe i.v. steroid-refractory UC is less clear. We report our open-label experience with infliximab in hospitalized UC patients at the University of Pittsburgh Medical Center. All hospitalized UC patients who had received infliximab were identified. Age, sex, extent of UC, duration of disease, concomitant medication, hospital course, and response to infliximab were recorded. Response to infliximab was defined as avoidance of colectomy and cessation of corticosteroids. There were 12 UC inpatients refractory to intravenous corticosteroids and subsequently treated with infliximab. Nine of the 12 patients (75%) failed to respond to infliximab and required a colectomy; median time to colectomy was 3 months. Three patients (25%) did respond to infliximab and were able to withdraw from corticosteroids. In this open-label analysis, infliximab was not effective for the majority of UC patients refractory to intravenous corticosteroids. Whether earlier use of infliximab would prevent the need for hospitalization and colectomy is uncertain.

Regueiro M, Kip KE, Cheung O, Hegazi RA, Plevy S. · Inflammatory Bowel Disease Center and Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. · Inflamm Bowel Dis. · Pubmed #15674112 No free full text.

Abstract: OBJECTIVES: The incidence and age of onset of inflammatory bowel disease (IBD) appear to be changing. The aim of this study was to determine whether the prevalence of cigarette smoking differs among patients with Crohn's disease (CD) or ulcerative colitis (UC) at the time of diagnosis compared with the general population and whether smoking history is related to the type and age of IBD onset. METHODS: Prevalence rates of smoking at the time of IBD diagnosis were compared between patients with CD and UC from the IBD Center at the University of Pittsburgh Medical Center versus age-, gender-, and time period-adjusted rates in the Pennsylvania general population. Analyses also were stratified by gender and diagnoses before and after 40 years of age, i.e., early and late onset. RESULTS: There were 263 IBD patients (144 UC patients and 119 CD patients) seen in the IBD center between August 2000 and December 2002. The prevalence of active smoking was significantly higher at diagnosis in CD patients compared with the Pennsylvania general population (33% versus 24%, P = 0.04), particularly in those with CD onset at 40 years of age or later (47% versus 27%, P = 0.005). In contrast, smoking prevalence was significantly lower in UC patients than the general population (9% versus 28%, P < 0.0001), particularly among those with UC onset before the age of 40 years (6% versus 27%, P < 0.0001). Smoking cessation was associated with an approximate, but nonsignificant, 3-fold higher likelihood of late-onset UC compared with CD. CONCLUSIONS: Cigarette smoking is associated with the development of late-onset CD and is protective against developing UC at any age, particularly early onset. Former smoking is associated with a high likelihood of developing late-onset UC, but not CD.

Plevy S. · Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Scaife Hall Room 566, 3550 Terrace Street, Pittsburgh, PA 15261, USA. · J Clin Gastroenterol. · Pubmed #15115933 No free full text.

Abstract: There is a general sense that indeterminate colitis (IC) runs an aggressive clinical course, is medically refractory, and is associated with higher pouch failure rates following restorative proctocolectomy. The question has been raised whether IC can be assigned to a diagnosis of Crohn's disease or ulcerative colitis through the characterization of immunogenetic similarities, or whether IC may represent a distinct subgroup within these heterogeneous disorders. In this article, the use of serologic markers, genetics, and immune responses to understand the pathogenesis of inflammatory bowel disease (IBD) and define clinically important subgroups of patients will be discussed. Then, how these scientific advances have been applied to the entity of IC will be reviewed. Importantly, a recent prospective study suggests that the absence of IBD-associated serologic markers defines the majority of IC as a separate entity within the spectrum of IBD. The development of serologic, genetic, and immune response markers will allow for rational description of clinically important subgroups, redefine natural history, and predict responses to therapy in IBD.