Ulcerative Colitis: Papadakis KA

Saruta M, Papadakis KA. · Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan. · Expert Rev Mol Diagn. · Pubmed #19099347 No free full text.

Abstract: Wireless capsule endoscopy (WCE) has emerged as an important diagnostic tool for the evaluation of patients with suspected small intestinal (SI) disease, including obscure gastrointestinal bleeding, Crohn's disease (CD), malabsorptive disorders and SI tumors. Since a great number of patients with CD have small-bowel (SB) involvement, it is important for newly diagnosed patients to undergo an evaluation of the SB, which has traditionally been performed using a radiographic study such as a SB follow-through. The greatest utility of WCE in the evaluation of SB CD has been observed in cases of suspected CD, where the initial evaluation with upper and lower endoscopy as well as traditional radiographic techniques have failed to establish the diagnosis. WCE can detect SB involvement in CD, particularly early lesions that can be overlooked by traditional radiological studies. The sensitivity of diagnosing SB CD by WCE is superior to other endoscopic or radiological methods such as push enteroscopy, computed tomography or magnetic resonance enteroclysis. The utility of WCE in patients with known CD, indeterminate colitis and a select group of patients with ulcerative colitis can help to better define the diagnosis and extent of the disease, and assist in the management of patients with persistent symptoms. A disadvantage of WCE is that the device may be retained in a strictured area of the SB, which may often be present in patients with CD, in addition to a lower specificity. WCE may replace classical studies and become the gold standard for diagnosing SB involvement in patients with suspected, or known CD, in the absence of strictures and fistulae.

Simpson P, Papadakis KA. · Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Inflamm Bowel Dis. · Pubmed #18300282 No free full text.

Abstract: Endoscopy plays a critical role in the diagnosis and management of inflammatory bowel disease (IBD). This article reviews the utility of endoscopy in the diagnosis of ulcerative colitis (UC) and Crohn's disease (CD), recommendations for cancer surveillance, and the use of newer techniques for the enhanced detection of dysplasia in chronic UC. Finally, the use of endoscopy for the management of certain complications of IBD is also discussed.

Papadakis KA. · Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, D-4063, Los Angeles, CA 90048, USA. · Curr Allergy Asthma Rep. · Pubmed #14680627 No free full text.

Abstract: Ulcerative colitis (UC) and Crohn's disease (CD), collectively termed inflammatory bowel diseases (IBD), represent chronic relapsing and remitting inflammatory disorders of the gastrointestinal tract that are characterized by leukocytic infiltration of the intestinal mucosa and submucosa. In CD, the inflammation is transmural and frequently associated with granuloma formation. Chemokines have emerged as the most important regulators of leukocyte trafficking during infection or inflammation and, therefore, have been implicated in the pathogenesis of IBD. In this review, recent advances on the role of chemokines and their receptors in mucosal immunity and inflammation are discussed, and the potential use of chemokine/chemokine-receptor antagonists as novel therapeutic targets for the treatment of human IBD is highlighted.

Papadakis KA, Tabibzadeh S. · Department of Medicine, Division of Gastroenterology and Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, UCLA School of Medicine, 8700 Beverly Boulevard, D-4063, Los Angeles, CA 90048, USA. · Gastrointest Endosc Clin N Am. · Pubmed #12486937 No free full text.

Abstract: Several diseases can mimic IBD clinically, but careful and repeated evaluations, if necessary, will dramatically decrease the likelihood of misdiagnosis. A careful consideration of patient's clinical, radiographic, endoscopic, and histopathologic features will establish the correct diagnosis in the majority of cases.

Papadakis KA, Targan SR. · *Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, D-4062, Los Angeles, CA 90048, USA. · Curr Gastroenterol Rep. · Pubmed #10980990 No free full text.

Abstract: Serologic testing in inflammatory bowel disease provides a unique tool to classify these diseases into more homogeneous groups. Serum markers can also be used to identify common antigenic triggers and specific defects in mucosal immune regulation and cytokine imbalance in different parts of the gastrointestinal tract. ANCA (antineutrophil cytoplasmic antibodies) and ASCA (anti-Saccharomyces cerevisiae antibodies), the most extensively studied serologic markers, have been used to classify ulcerative colitis and Crohn's disease into such groups with certain phenotypic characteristics and responses to treatment. Similar studies have been initiated in indeterminate colitis, and these results will help in the future to define the immunopathogenesis, prognosis, and response to certain treatments in patients with this type of disease.

Papadakis KA, Targan SR. · Division of Gastroenterology, Cedars-Sinai Medical Center, University of California, Los Angeles 90048, USA. · Annu Rev Med. · Pubmed #10774465 No free full text.

Abstract: Recent advances in the drug treatment of inflammatory bowel disease (IBD) have paralleled our understanding of the pathophysiology of ulcerative colitis and Crohn's disease. Several proinflammatory and immune-regulatory cytokines are upregulated in the mucosa of patients with IBD, and differences and similarities in the cytokine profiles of ulcerative colitis and Crohn's disease have been elucidated. Several clinical trials involving a chimeric anti-TNF-alpha (tumor necrosis factor-alpha) antibody have shown marked clinical benefit in the majority of patients with Crohn's disease, verifying the importance of TNF-alpha in the pathogenesis of Crohn's disease. In preliminary studies, treatment with recombinant human interleukin-10 has been beneficial in Crohn's disease but not in ulcerative colitis. Future treatment of IBD may include combination or sequential cytokine and anticytokine administration in defined groups of patients based on their mucosal cytokine profiles.

Yu QT, Saruta M, Papadakis KA. · Burns and Allen Research Institute, Division of Gastroenterology and Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, USA. · Clin Immunol. · Pubmed #18424236 No free full text.

Abstract: Visilizumab, a humanized low-Fc receptor binding anti-CD3 antibody, induces rapid clinical response in patients with steroid-refractory ulcerative colitis (UC). Several effective treatments in IBD have been linked to the induction of mucosal T cell apoptosis. The aim of the present study was to evaluate the effect of visilizumab on the apoptosis of lamina propria (LP) and peripheral blood (PB) lymphocytes isolated from patients with UC. Visilizumab induced dose- and time-dependent apoptosis of LP T cells isolated from non-IBD individuals, UC or CD patients. Maximal effect was seen at a concentration of 100 ng/ml and it was 33% for normal, 34% for UC and 23% for CD LP T cells following 24 h stimulation. Visilizumab induced apoptosis predominantly of CD4(+) LP T cells, whereas CD8(+) LP T cells were relatively resistant to apoptosis. Visilizumab did not induce apoptosis of PB T cells from UC patients. Visilizumab-induced apoptosis of LP T cells was dependent on caspase 3 and 8, but not caspase 9 activation and did not involve the Fas/FasL pathway. Low-Fc receptor binding Abs such as visilizumab may be highly effective for the treatment of UC through induction of apoptosis of LP T cells and rapid elimination of lesional pathogenic T cells in the gut mucosa.

Fleshner P, Ippoliti A, Dubinsky M, Vasiliauskas E, Mei L, Papadakis KA, Rotter JI, Landers C, Targan S. · Division of Colon and Rectal Surgery, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Clin Gastroenterol Hepatol. · Pubmed #18378498 No free full text.

Abstract: BACKGROUND & AIMS: Acute pouchitis (AP) and chronic pouchitis (CP) are common after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis. The aim of this study was to assess associations of preoperative perinuclear antineutrophil cytoplasmic antibody (pANCA) and anti-CBir1 flagellin on AP or CP development. METHODS: Patients were assessed prospectively for clinically and endoscopically proven AP (antibiotic responsive) or CP (antibiotic-dependent or refractory to antibiotic therapy). Sera from 238 patients were analyzed for ANCA and anti-CBir1 using an enzyme-linked immunosorbent assay. pANCA(+) patients were substratified into high-level (>100 EU/mL) and low-level (<100 EU/mL) groups. RESULTS: After a median follow-up period of 47 months, 72 patients (30%) developed pouchitis. Pouchitis developed in 36% of pANCA(+) patients versus 16% of pANCA(-) patients (P = .005), 46% of anti-CBir1(+) patients versus 26% of anti-CBir1(-) patients (P = .02), and 54% of 35 pANCA(+)/anti-CBir1(+) patients versus 31% of 136 pANCA(+)/anti-CBir1(-) patients (P = .02). AP developed in 37 pANCA(+) patients (22%) versus 6 pANCA(-) patients (9%) (P = .02), and 12 anti-CBir1(+) patients (26%) versus 31 anti-CBir1(-) patients (16%) (P = .1). Although AP was not influenced by pANCA level, AP was seen in 38% of low-level pANCA(+)/anti-CBir1(+) patients versus 18% low-level pANCA(+)/anti-CBir1(-) patients (P = .03). CP was seen in 29% of high-level pANCA(+) patients versus 11% of low-level pANCA(+) patients (P = .03). CONCLUSIONS: Both pANCA and anti-CBir1 expression are associated with pouchitis after IPAA. Anti-CBir1 increases the incidence of AP only in patients who have low-level pANCA expression, and increases the incidence of CP only in patients who have high-level pANCA expression. Diverse patterns of reactivity to microbial antigens may manifest as different forms of pouchitis after IPAA.

Melmed GY, Fleshner PR, Bardakcioglu O, Ippoliti A, Vasiliauskas EA, Papadakis KA, Dubinsky M, Landers C, Rotter JI, Targan SR. · Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. · Dis Colon Rectum. · Pubmed #18085333 links to  free full text

Abstract: PURPOSE: Approximately 5 to 10 percent of patients undergoing ileal pouch-anal anastomosis with a diagnosis of ulcerative colitis are subsequently diagnosed with Crohn's disease. Preoperative predictors for Crohn's disease post-ileal pouch-anal anastomosis have not been prospectively defined. METHODS: A total of 238 consecutive patients with ulcerative colitis or indeterminate colitis undergoing ileal pouch-anal anastomosis were prospectively enrolled into a longitudinal database. Clinical factors were assessed perioperatively. Serum drawn preoperatively was assayed for anti-Saccharomyces cerevisiae, antiouter membrane porin-C, anti-CBir1, and perinuclear antineutrophil cytoplasmic antibody using enzyme-linked immunosorbent assay. Crohn's disease was defined by small bowel inflammation proximal to the ileal pouch or a perianal fistula identified at least three months after ileostomy closure. Predictors were assessed in a multivariate Cox proportional hazards model to predict the rate of Crohn's disease after ileostomy closure. RESULTS: Sixteen patients (7 percent) were diagnosed with Crohn's disease; median time to Crohn's disease was 19 (range, 1-41) months. Significant factors for postoperative Crohn's disease after ileal pouch-anal anastomosis included family history of Crohn's disease (hazard ratio, 8.4; 95 percent confidence interval, 2.96-24.1; P < 0.0001) and anti-Saccharomyces cerevisiae immunoglobulin-A seropositivity (hazard ratio, 3.14; 95 percent confidence interval, 1.1-9.81; P = 0.04). Crohn's disease developed in only 8 of 198 patients (4 percent) without these predictors vs. 8 of 40 patients (20 percent) in those with at least one of these factors (P = 0.002). The cumulative risk of Crohn's disease among patients with two risk factors (67 percent) was higher than in patients with either risk factor (18 percent) or neither risk factor (4 percent, P < 0.001). CONCLUSIONS: Patients with ulcerative colitis and indeterminate colitis with a family history of Crohn's disease or preoperative anti-Saccharomyces cerevisiae immunoglobulin-A seropositivity are more likely to be diagnosed with Crohn's disease after ileal pouch-anal anastomosis.

Mehdizadeh S, Chen G, Enayati PJ, Cheng DW, Han NJ, Shaye OA, Ippoliti A, Vasiliauskas EA, Lo SK, Papadakis KA. · Division of Gastroenterology, Cedars-Sinai Medical Center and the UCLA School of Medicine, Los Angeles, California, USA. · Endoscopy. · Pubmed #18058654 No free full text.

Abstract: BACKGROUND AND STUDY AIMS: Capsule endoscopy is increasingly reported as an important diagnostic procedure in patients with known or suspected Crohn's disease, but its clinical utility in patients with ulcerative colitis or unclassified type inflammatory bowel disease (IBDU) is unclear. The aim of our study was to determine the diagnostic yield of capsule endoscopy for small-bowel disease in patients with ulcerative colitis and IBDU. PATIENTS AND METHODS: All data from patients with a history of ulcerative colitis or IBDU who underwent capsule endoscopy between October 2001 and August 2005 were analyzed for procedure indications and findings. Images were reviewed by an experienced capsule endoscopist. The finding of multiple ulcerations (three or more) on capsule endoscopy was classified as diagnostic of small-bowel Crohn's disease. RESULTS: 120 patients had undergone 122 capsule endoscopy procedures. Overall, 19 of 120 patients (15.8 %) had capsule endoscopy findings consistent with the diagnosis of Crohn's disease. The proportion of patients with small-bowel disease was significantly higher among patients with a history of colectomy (7 of 21 patients, 33 %) compared with those without colectomy (12/99, 12 %) ( P = 0.04). Among patients with positive findings on capsule endoscopy, 18 had also previously undergone a small-bowel follow-through study and only one showed findings consistent with Crohn's disease. CONCLUSIONS: Many patients with a diagnosis of ulcerative colitis and atypical features or IBDU may have small-bowel findings on capsule endoscopy that are consistent with Crohn's disease. Capsule endoscopy should be considered in ulcerative colitis patients with atypical clinical features particularly after colectomy.

Schluender SJ, Ippoliti A, Dubinsky M, Vasiliauskas EA, Papadakis KA, Mei L, Targan SR, Fleshner PR. · Division of Colon and Rectal Surgery, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8737 Beverly Boulevard, Suite 101, Los Angeles, California 90048, USA. · Dis Colon Rectum. · Pubmed #17704969 No free full text.

Abstract: PURPOSE: Since infliximab has been approved for treatment of patients with refractory ulcerative colitis, surgeons will be increasingly faced with operating on patients who have failed therapy with this potent immunosuppressant. This study was designed to compare short-term complications in patients with ulcerative colitis who were treated with and without infliximab before colectomy. METHODS: The charts of patients undergoing ileal pouch-anal anastomosis or subtotal colectomy for refractory ulcerative colitis during the five-year period ending October 2005 were reviewed. Postoperative medical and surgical complications were assessed. RESULTS: Seventeen patients had failed infliximab treatment and 134 patients were never treated with infliximab. Ileal pouch-anal anastomosis was performed in 112 patients (74 percent) and subtotal colectomy in 39 patients (36 percent). There were no deaths. Postoperative complications were observed in 43 patients (28 percent), with no significant difference observed between infliximab-treated (37 percent) and infliximab-untreated patients (27 percent). Of 61 patients (40 percent) treated with preoperative cyclosporine A, 5 patients also had been treated with infliximab. The infliximab and cyclosporine A-treated patient group had an 80 percent complication rate, significantly higher than the 29 percent complication rate noted in the cyclosporine A only-treated group (P = 0.04). CONCLUSIONS: Although preoperative treatment with infliximab alone does not significantly increase the incidence of postoperative complications, using both inflixiamb and cyclosporine A before colectomy in refractory ulcerative colitis is associated with high surgical morbidity.

Melmed GY, Elashoff R, Chen GC, Nastaskin I, Papadakis KA, Vasiliauskas EA, Liu W, Landers C, Ippoliti AF, Targan SR. · Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, David Geffen School of Medicine, University of California Los Angeles, California, USA. · Clin Gastroenterol Hepatol. · Pubmed #17478347 No free full text.

Abstract: BACKGROUND & AIMS: Some patients diagnosed with UC undergo a change in diagnosis to CD. Identification of predictors of a diagnostic change could potentially impact the management of patients with colonic inflammation. Our aim was to characterize clinical and serologic predictors of a change in diagnosis from UC to CD. METHODS: A nested, case-controlled study was performed to compare individuals with a change in diagnosis from UC to CD (cases) with age-matched UC and CD controls; primary analysis compared cases with UC controls. Subjects underwent chart review for clinical "red flags" identified by gastroenterologists with expertise in IBD. Serum collected at the time of database enrollment was tested for antibodies to oligomannan (anti-Saccharomyces cerevisiae), Pseudomonas fluorescens-related protein, Escherichia coli outer membrane porin C, CBir1 flagellin, and perinuclear antineutrophil cytoplasmic antibodies. RESULTS: Twenty-one cases, 52 UC controls, and 56 CD controls were assessed. Three red flags, but no serologic markers, differed between cases and UC controls. At initial colonoscopy, cases were more likely to have extensive colonic involvement than UC controls (P = .008). Multivariate regression identified non-bloody diarrhea at initial presentation (P = .01) and weight loss >10% at presentation (P = .007) as independent predictors of diagnostic change. Serologic markers did not add to the contribution of these 2 clinical factors in predicting a change in diagnosis from UC to CD. Diagnostic change was evident in 6 of 6 (100%) patients with both predictors, compared with 8 of 50 (16%) with neither of these factors (P < .0001). CONCLUSIONS: Patients with a diagnosis of UC with initial non-bloody diarrhea or weight loss have an increased likelihood of subsequent change in diagnosis to CD and might thus warrant further diagnostic work-up.

Papadakis KA, Yang H, Ippoliti A, Mei L, Elson CO, Hershberg RM, Vasiliauskas EA, Fleshner PR, Abreu MT, Taylor K, Landers CJ, Rotter JI, Targan SR. · Cedars-Sinai Inflammatory Bowel Disease Center, Los Angeles, California, USA. · Inflamm Bowel Dis. · Pubmed #17260364 links to  free full text

Abstract: BACKGROUND: Antibody reactivity to microbial antigens correlates with distinct Crohn's disease (CD) phenotypes such as fistulizing or fibrostenosing disease. We examined the association between anti-CBir1 and clinical phenotypes and NOD2 variants in a large cohort of adult CD patients. METHODS: Sera and genomic DNA were collected from 731 patients with CD and tested for immune responses to I2, CBir1, oligomannan, and outer membrane porin C (OmpC) and the 3 most common CD-associated NOD2 variants. RESULTS: Anti-CBir1 reactivity was significantly associated with fibrostenosis (FS), internal penetrating (IP) disease phenotypes, small bowel (SB) involvement, and SB surgery but negatively associated with ulcerative colitis (UC)-like CD. Multivariate logistic regression analysis showed that anti-CBir1 was independently associated with FS and UC-like CD irrespective of the antibody reactivity to I2, oligomannan, or OmpC, but not with SB involvement or SB surgery. The magnitude of anti-CBir1 reactivity, when added to the quantitative response toward the other 3 CD-associated antigens, enhances the discrimination of FS, IP, UC-like CD, and SB involvement, but not SB surgery. Finally, although the frequency of anti-CBir1 was similar in patients with none versus at least 1 NOD2 variant, the quantitative response to CBir1 flagellin was significantly higher in patients with CD carrying at least 1 NOD2 variant versus those carrying no variants (median anti-CBir1 titer 33.39 versus 28.36, respectively; P = 0.01). CONCLUSIONS: Anti-CBir1 serum reactivity in CD patients is independently associated with FS and complicated SB CD. Quantitative, but not qualitative, response to CBir1 is also significantly associated with the CD-associated NOD2 variants.

Yu QT, Saruta M, Avanesyan A, Fleshner PR, Banham AH, Papadakis KA. · Burns and Allen Research Institute, Division of Gastroenterology and Inflammatory Bowel Disease Center Cedars-Sinai Medical Center, 8700 Beverly Blvd., D-4063, Los Angeles CA 90048, USA. · Inflamm Bowel Dis. · Pubmed #17206665 links to  free full text

Abstract: BACKGROUND: CD4+CD25+ regulatory T cells (TR) can prevent or treat experimental murine colitis but little is known about their potential role in human inflammatory bowel disease (IBD). FOXP3 is a transcription factor that plays a critical role in the development and function of CD4+CD25+ TR. The aim of this study was to examine the presence and functional characteristics of TR cells in colonic lymphoid tissues in patients with ulcerative colitis (UC). METHODS: FOXP3 expression was assessed by flow cytometry, immunohistochemistry, and reverse-transcriptase polymerase chain reaction (RT-PCR). Functional characterization of CD4+CD25+ cells was analyzed by suppression of proliferation and secretion of cytokines by cocultured effector CD4+CD25- T cells. RESULTS: FOXP3 +CD4+ T cells are increased in the lamina propria (LP) of inflamed and noninflamed areas of UC colon compared to normal colon. CD4+CD25+ T cells in UC mesenteric lymph nodes (MLN) express FOXP3 mRNA and protein and suppress the proliferation of autologous MLN CD4+CD25 T cells. The suppressor activity of MLN CD4+CD25+ T cells is cell contact-dependent but cytokine-independent. In addition, CD4+CD25+ T cells potently suppress the production of both Thl (IFN-gamma, IL-2) and Th2 (IL-5, IL-13) cytokines by cocultured CD4+CD25 T cells. FOXP3' cells localized in the T-cell-rich areas of MLN and occasionally present in the follicles. CONCLUSIONS: There is an expansion of FOXP3+CD4+ T cells in mucosal lymphoid tissues in UC. CD4+CD25+ isolated from UC MLN express FOXP3 and display features of TR cells in spite of active mucosal inflammation. These data suggest that their suppressor activity may be abrogated in vivo or they are unable to counterbalance the chronic mucosal inflammation in UC.

Mei L, Targan SR, Landers CJ, Dutridge D, Ippoliti A, Vasiliauskas EA, Papadakis KA, Fleshner PR, Rotter JI, Yang H. · Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. · Gastroenterology. · Pubmed #16618402 No free full text.

Abstract: BACKGROUND & AIMS: Crohn's disease (CD) is a genetically complex disorder with strong familial aggregation. Pathogenesis appears to involve dysregulation of the immune response to endogenous bacteria. Anti-Escherichia coli outer membrane porin C (anti-OmpC) expression reflects an exaggerated response to commensal bacteria and occurs with higher frequency in CD. The aim of this study was to determine whether there is familial aggregation and genetic determination of anti-OmpC expression in CD families. METHODS: Study groups consisted of 787 CD patients, 389 ulcerative colitis (UC) patients, 619 unaffected relatives, and 216 healthy controls. Serum anti-OmpC was detected by enzyme-linked immunosorbent assay. RESULTS: CD patients had a greater percentage of anti-OmpC than UC patients and healthy controls. Anti-OmpC expression was more frequent in unaffected relatives from CD-only or mixed families, compared with healthy controls (P = .002 and .0001, respectively), and it was more frequent in UC patients from mixed families than those from UC-only families (P = .02). There was a significant familiality in anti-OmpC expression: P = .02 for qualitative concordance and P < .0001 for quantitative intraclass correlation. The heritability estimate for anti-OmpC level was .39 (P < .0001). CONCLUSIONS: Anti-OmpC is a heritable immunophenotype. Increased anti-OmpC expression in the unaffected family members of CD patients suggests that anti-OmpC may be an immunologic risk marker for CD. That UC patients in mixed families had a higher response to OmpC than those in UC-only families indicates pathophysiologic heterogeneity within UC.

Okon A, Dubinsky M, Vasiliauskas EA, Papadakis KA, Ippoliti A, Targan SR, Fleshner PR. · Division of Colon and Rectal Surgery, Department of Surgery, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Am Surg. · Pubmed #16468527 No free full text.

Abstract: Acute pouchitis (AP) after ileal pouch-anal anastomosis (IPAA) is common and easily treated. However, chronic pouchitis (CP) remains a difficult management problem and may represent a form of Crohn disease (CD) of the ileal pouch. Because CD patients have higher platelet counts than ulcerative colotis (UC) patients, we prospectively evaluated the association between preoperative platelet count and pouchitis development in 159 patients undergoing IPAA. Reactive thrombocytosis (RT) was defined as a platelet count > 450 x 10(9)/L. Median preoperative platelet count was 312 x 10(9)/L (range, 103 x 10(9)/L to 886 x 10(9)/L). One hundred twenty-five patients (79%) had a normal (150 x 10(9)/L to 450 x 10(9)/L) platelet count (-RT patient group). Twenty-eight patients (18%) had RT. Six patients (3%) had a platelet count below 150 x 10(9)/L. After a median follow-up of 13 months, 45 patients (28%) developed pouchitis. Pouchitis developed in 33 +RT patients (26%) versus 9 -RT patients (32%) (P = NS). UC patients who had +RT had a 25 per cent incidence of CP compared to only 7 per cent of those UC patients who had -RT (P = 0.03). The incidence of CP was significantly higher after IPAA in UC patients having thrombocytosis before surgery compared to UC patients having a normal platelet count before surgery.

Targan SR, Landers CJ, Yang H, Lodes MJ, Cong Y, Papadakis KA, Vasiliauskas E, Elson CO, Hershberg RM. · Cedars-Sinai Inflammatory Bowel Disease Center, Los Angeles, California 90048, USA. · Gastroenterology. · Pubmed #15940634 No free full text.

Abstract: BACKGROUND & AIMS: Antibody responses to certain microbial antigens define heterogeneous groups of Crohn's patients; multiple and high-level responses to these antigens are associated with aggressive clinical phenotypes. The flagellin, CBir1, identified by investigations in the C3H/HeJBir mouse model, has been identified as a dominant antigen capable of inducing colitis in mice and eliciting antibody responses in a subpopulation of patients with Crohn's disease (CD). The aim of this study was to evaluate serum response to CBir1 flagellin in CD patients and to compare this response to responses defined previously to oligomannan (anti-Saccharomyces cerevisiae antibody), I2, OmpC, and neutrophil nuclear autoantigens (pANCA), and to determine anti-CBir1-associated phenotypes. METHODS: A total of 484 sera from the Cedars Sinai Medical Center repository, previously typed for anti-Saccharomyces cerevisiae antibody, anti-I2, anti-OmpC, and pANCA were tested for anti-CBir1 by enzyme-linked immunosorbent assay, and results were assessed for clinical phenotype associations. RESULTS: The presence and level of immunoglobulin G anti-CBir1 were associated with CD independently. Anti-CBir1 was present in all antibody subgroups and expression increased in parallel with increases in the number of antibody responses. pANCA+ CD patients were more reactive to CBir1 than were pANCA+ ulcerative colitis patients. Anti-CBir1 expression is associated independently with small-bowel, internal-penetrating, and fibrostenosing disease features. CONCLUSIONS: Serum responses to CBir1 independently identify a unique subset of patients with complicated CD. This bacterial antigen was identified in a murine model and has a similar pattern of aberrant reactivity in a subset of CD patients.

Hui T, Landers C, Vasiliauskas E, Abreu M, Dubinsky M, Papadakis KA, Price J, Lin YC, Huiying Y, Targan S, Fleshner P. · Division of Colon and Rectal Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Dis Colon Rectum. · Pubmed #15868228 No free full text.

Abstract: PURPOSE: Although acute pouchitis after ileal pouch-anal anastomosis is common and easily treated, continuous pouch inflammation seen clinically as chronic, antibiotic-dependent pouchitis, and/or Crohn's disease remains a difficult management problem. Compared with ulcerative colitis, indeterminate colitis patients undergoing ileal pouch-anal anastomosis have a higher incidence of continuous pouch inflammation, which may represent persistent immune reactivity to microbial antigens. Antibody responses to three microbial antigens (oligomannan anti-Saccharomyces cerevisiae, outer membrane porin C of Escherichia coli, and an antigen (I2) from Pseudomonas flourescens) are more commonly seen in Crohn's disease, whereas antibodies to a cross-reactive antigen (perinuclear antineutrophil cytoplasmic antibodies) is more suggestive of ulcerative colitis. We examined whether preoperative serologic responses to these antigens were associated with Crohn's disease in indeterminate colitis patients after ileal pouch-anal anastomosis. METHODS: Twenty-eight indeterminate colitis patients undergoing ileal pouch-anal anastomosis were prospectively assessed for the development of pouchitis or Crohn's disease. Serologic responses were determined by enzyme-linked immunosorbent assay and immunofluorescence. Patients were classified based on four predominant profiles of antibody expression. Antibody profiles were determined before knowledge of clinical outcome. RESULTS: Median follow-up was 38 (range, 3-75) months. Of 16 patients (61 percent) who developed pouch inflammation, 4 (25 percent) had acute pouchitis and 12 (75 percent) had continuous pouch inflammation (9 had chronic pouchitis, 3 had Crohn's disease). No preoperative clinical factor predicted the development of these pouch complications. Overall, 16 patients (57 percent) had a positive antibody reactivity profile. Serologic expression of any marker alone did not predict the development of continuous pouch inflammation. However, continuous pouch inflammation developed in 10 of 16 patients (63 percent) who had a positive antibody reactivity profile compared with only 2 of 12 patients (17 percent) who had a negative antibody reactivity profile (P = 0.015). CONCLUSIONS: Indeterminate colitis patients who have a positive antibody reactivity profile before ileal pouch-anal anastomosis have a significantly higher incidence of continuous pouch inflammation after surgery than those with a negative profile.

Papadakis KA, Prehn J, Zhu D, Landers C, Gaiennie J, Fleshner PR, Targan SR. · Inflammatory Bowel Disease Center and Burns and Allen Research Institute, Los Angeles, CA 90048, USA. · Inflamm Bowel Dis. · Pubmed #15626897 No free full text.

Abstract: Chemokine receptors play an important role in the recruitment of activated T cells to inflammatory sites. The aim of this study was to analyze the expression of the chemokine receptor CXCR3 on T lymphocytes in intestinal lymphoid tissues and to document the altered disposition of these cells in patients with inflammatory bowel disease (IBD). The expression and regulation of CXCR3 on mucosal lymphoid tissue and peripheral blood lymphocytes (PBLs) were analyzed by flow cytometry and Northern blotting. The migration of lamina propria lymphocytes (LPLs) and PBLs to interferon (IFN)-gamma-inducible protein (IP)-10 (or CXCL10) was evaluated by chemotaxis assays. IFN-gamma and interleukin-4-producing T lymphocytes were quantitated by intracellular staining, and IFN-gamma was measured in culture supernatants by enzyme-linked immunosorbent assay. CXCR3 is expressed on the majority of CD4 lamina propria (LP) T cells and correlates with a T-helper (Th) type 1/Th-0 cytokine phenotype on LP and mesenteric lymph node (MLN) CD4 T lymphocytes. IP-10/CXCL10 is more chemotactic in vitro for both CD4 and CD8 T cells that have been isolated from the LP compared with peripheral blood. CXCR3 protein, but not messenger RNA, expression was lower in inflamed LPLs compared with uninvolved LPLs in patients with ulcerative colitis but not in those with Crohn's disease. However, CXCR3 was expressed on a higher percentage of MLN CD4 T cells isolated from inflamed intestinal tissue, and CXCR3 expression could be induced in vitro with T-cell activation in MLN CD4 T cells. In summary, most CXCR3 T lymphocytes in normal intestinal tissues are Th-1/Th-0 effector/memory cells. Activation-dependent receptor regulation and alteration in receptor-bearing cells, primarily in MLN draining inflamed intestinal tissue, suggest an important role for this T-cell subset in the pathogenesis of human IBD.

Matuk R, Crawford J, Abreu MT, Targan SR, Vasiliauskas EA, Papadakis KA. · Department of Medicine, Division of Gastroenterology, Cedars-Sinai Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. · Inflamm Bowel Dis. · Pubmed #15475742 No free full text.

Abstract: The safety and toxicity associated with the use of selective cyclooxygenase-2 (COX-2) inhibitors in patients with inflammatory bowel disease (IBD) has not been extensively studied. Thirty-three patients with IBD who were prescribed celecoxib or rofecoxib were identified from questionnaire during their clinic visit at the Cedars-Sinai IBD Center between 1999 and 2002. Twenty-six had Crohn's disease (CD), 6 had ulcerative colitis (UC), and 1 had indeterminate colitis (IC). Twenty-one received rofecoxib, 10 celecoxib, and 2 received both medications at different time points. Overall, 13 (39%) patients experienced disease exacerbation, 7 of which had received celecoxib and six rofecoxib. IBD exacerbation associated with COX-2 treatment did not correlate with age, disease activity, or use of immunosuppressive medications. All patients experienced flare-up of their underlying IBD within 6 weeks of initiating COX-2 therapy. Five of 13 (38%) patients had resolution of their symptoms after discontinuing the COX-2 inhibitor, but the remaining patients required additional medical therapy to control their disease. Six other patients (18%) experienced GI side effects not associated with their underlying IBD. Five developed abdominal pain, and one developed a duodenal ulcer and a circumferential ileo-colonic ulceration with GI bleeding. Treatment with COX-2 inhibitors is associated with a high incidence of exacerbation of the underlying IBD and GI-related complications.

Mow WS, Abreu-Martin MT, Papadakis KA, Pitchon HE, Targan SR, Vasiliauskas EA. · Department of Medicine, Division of Gastroenterology, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. · Clin Gastroenterol Hepatol. · Pubmed #15067625 No free full text.

Abstract: BACKGROUND & AIMS: Reports of tuberculosis (TB) in patients administered infliximab prompted the Food and Drug Administration to recommend that all patients being considered for this therapy be evaluated for the risk for latent TB infection by means of a tuberculin skin test (TST). The aim of this study is to evaluate the utility of a TST as an adequate screen for TB exposure in patients with inflammatory bowel disease (IBD). METHODS: Eighty-two consecutive patients with IBD (Crohn's disease, 70 patients; ulcerative colitis, 4 patients; indeterminate colitis, 8 patients) seen at Cedars-Sinai Medical Center IBD Center (Los Angeles, CA) being treated with or considered for infliximab therapy underwent a standard intradermal purified protein derivative (PPD) TST before or between infusions of infliximab. One or more control antigens (Candida, tetanus, and/or mumps) were concurrently placed on 69 of these patients. Skin tests were read for induration at 48-72 hours after placement, and results were recorded. RESULTS: None of 82 patients had a positive PPD TST result. Overall, 71% of patients (49 of 69 patients) with controls placed failed to react to any antigen. Eighty-three percent of patients (40 of 48 patients) who were administered corticosteroids and/or immunosuppressive medications, not including infliximab, for at least 1 month were anergic compared with 43% of patients (9 of 21 patients; P < 0.002) who were not administered those medications. CONCLUSIONS: Given the high prevalence of anergy, a negative TST result in patients with IBD administered infliximab is an unreliable indicator for TB exposure. Evaluation for TB risks should include not only a TST, but also a detailed history of travel, TB exposures, and such symptoms as chronic cough and weight loss, and a chest radiograph should be considered.

Mow WS, Lo SK, Targan SR, Dubinsky MC, Treyzon L, Abreu-Martin MT, Papadakis KA, Vasiliauskas EA. · Inflammatory Bowel Disease Center, Los Angeles, California, USA. · Clin Gastroenterol Hepatol. · Pubmed #15017630 No free full text.

Abstract: BACKGROUND AND AIMS: Wireless capsule enteroscopy (WCE) offers the potential to directly visualize the entire small bowel and identify superficial lesions not detected by traditional endoscopy and radiography. The aim of this study is to assess the clinical utility of WCE in the evaluation of patients with known or suspected inflammatory bowel disease (IBD). METHODS: Fifty patients with ongoing symptoms underwent Given M2A endoscopic capsule examinations. Indications included: (1) evaluation for small-bowel involvement in patients with IBD with isolated colitis (n = 22), (2) determination of the extent of small-bowel disease in patients with Crohn's disease (CD; n = 20), and (3) workup of suspected IBD (n = 8). Outcome measures were classified as diagnostic when multiple ulcerations were present, suspicious when </=3 ulcerations were seen, and nonspecific or normal. RESULTS: WCE findings were diagnostic for CD in 20 patients and suspicious for small-bowel CD in 10 patients. Seventeen of 20 patients with diagnostic WCE findings improved with increased IBD-directed medical therapy, as did 7 of 10 patients with suspicious study results. WCE was normal or showed nonspecific findings in the remaining 20 patients. Notably, identification of small-bowel lesions in 5 patients with a previous history of isolated colitis resulted in a change in diagnosis to CD after confirmatory ileoscopy with biopsy. CONCLUSIONS: Results of this preliminary study suggest that WCE is a novel and potentially clinically useful method of directly visualizing and diagnosing small-bowel lesions in patients with IBD that can be missed by traditional endoscopic and radiological procedures.

Papadakis KA, Treyzon L, Abreu MT, Fleshner PR, Targan SR, Vasiliauskas EA. · Division of Gastroenterology, Cedars-Sinai Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. · Aliment Pharmacol Ther. · Pubmed #14510748 links to  free full text

Abstract: AIM: To examine the outcome of infliximab intervention in refractory indeterminate colitis. METHODS: Twenty patients with severe, medically refractory indeterminate colitis were treated with infliximab. All patients initially received infliximab, 5 mg/kg, intravenously and, in some patients, the dose was subsequently increased to 10 mg/kg. The number of infusions ranged from one to 16 per patient. Indeterminate colitis was defined as colitis that could not be classified with certainty as Crohn's disease or ulcerative colitis based on traditional clinical, endoscopic and histopathological criteria. The clinical response to infliximab was classified as complete response, partial response or non-response. RESULTS: Fourteen of the 20 patients (70%) showed a complete response to infliximab treatment, two showed a partial response and four showed no response. The four non-responders underwent colectomy with ileal pouch-anal anastomosis. The resected colon specimen was consistent with ulcerative colitis in all four cases, although two were subsequently re-classified as Crohn's disease. Eight additional patients were subsequently re-classified as having Crohn's disease on longer follow-up evaluation, whilst eight continued to have features of indeterminate colitis. The response rate to infliximab treatment was similar in both groups. CONCLUSIONS: Infliximab is effective in approximately two-thirds of patients with indeterminate colitis, and thus may be considered for patients with refractory disease prior to colectomy. The follow-up time afforded by infliximab treatment may allow for more accurate classification of the disease in a significant proportion of patients whose colitis has indeterminate features at initial presentation.

Papadakis KA, Tung JK, Binder SW, Kam LY, Abreu MT, Targan SR, Vasiliauskas EA. · Division of Gastroenterology, Cedars-Sinai Inflammatory Bowel Disease Center, Los Angeles, California 90048, USA. · Am J Gastroenterol. · Pubmed #11467645 No free full text.

Abstract: OBJECTIVE: The aim of this study was to determine the outcome of cytomegalovirus (CMV) infections complicating the course of inflammatory bowel disease (IBD). METHODS: The records and clinical courses were reviewed for all IBD patients who were evaluated at the IBD Center of the Cedars-Sinai Medical Center and who developed CMV infection. RESULTS: Ten patients with severe, medically refractory IBD (five ulcerative colitis, three Crohn's colitis, and two indeterminate colitis) developed CMV infection. All but two were hospitalized with exacerbation of their underlying disease and were receiving immunosuppressive treatment with steroids, thiopurines, and/or cyclosporine at the time CMV infection was recognized. Eight patients had documented colonic CMV (one had concurrent upper GI tract involvement), one developed interstitial CMV and Pneumocystis carinii pneumonia, and one developed primary CMV mononucleosis. Prompt treatment with ganciclovir and withdrawal of immunosuppressive treatment resulted in gradual improvement and induction of remission of the underlying IBD in five patients. The patient with concomitant CMV and P. carinii pneumonitis died. In two patients, treatment with ganciclovir did not alter the clinical course of their IBD, and one of them underwent colectomy. In one patient CMV was found on the resected colonic specimen. One patient with primary CMV infection responded also to ganciclovir treatment. CONCLUSIONS: CMV infection may aggravate the course of seemingly refractory IBD in patients who either fail to respond or experience worsening of symptoms despite immunosuppressive therapy. Expedient evaluation, prompt treatment intervention with ganciclovir, and withdrawal of immunosuppressive treatment may avoid complications and mortality. This regimen leads to improvement of the underlying IBD in most patients.