Ulcerative Colitis: Abreu MT

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.

Fukata M, Abreu MT. · Inflammatory Bowel Disease Center, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. · Biochem Soc Trans. · Pubmed #18031248 No free full text.

Abstract: The colonic epithelium is lined along its apical membrane with approximately 10(14) bacteria/g of tissue. Commensal bacteria outnumber mammalian cells in the gut severalfold. The reason for this degree of commensalism probably resides in the recent recognition of the microbiome as an important source of metabolic energy in the setting of poorly digestible nutrients. As in many themes in biology, the host may have sacrificed short-term benefit, i.e. nutritional advantages, for long-term consequences, such as chronic inflammation or colon cancer. In the present review, we examine the role of TLR (Toll-like receptor) signalling in the healthy host and the diseased host. We pay particular attention to the role of TLR signalling in idiopathic IBD (inflammatory bowel disease) and colitis-associated carcinogenesis. In general, TLR signalling in health contributes to homoeostatic functions. These include induction of antimicrobial peptides, proliferation and wound healing in the intestine. The pathogenesis of IBD, ulcerative colitis and Crohn's disease may be due to increased TLR or decreased TLR signalling respectively. Finally, we discuss the possible role of TLR signalling in colitis-associated neoplasia.

Abreu MT, Sparrow MP. · Inflammatory Bowel Disease Center, Mount Sinai School of Medicine, New York, NY 10029, USA. · Rev Gastroenterol Mex. · Pubmed #17966376 No free full text.

Abstract: The idiopathic inflammatory bowel diseases, broadly classified as either Crohn's disease or ulcerative colitis, are caused by a dysregulated mucosal immune response to a luminal antigen, possibly a bacterium, in a genetically predisposed host. A rapid expansion of knowledge in recent years has greatly increased our understanding of the pathophysiology of these disorders. For example, the relatively recent discovery of the NOD2 gene, a protein involved in bacterial sensing, has provided further evidence of the complex interplay between hosts and microbes in Crohn's disease. Significant recent advances have also occurred with the discovery of the role of Toll-like receptors and dendritic cells in the development of gut inflammation, and the role of proinflammatory cytokines in the development and potentiation of gut inflammation. This article presents an update on these key developments and emphasizes the translational aspects of research that are directly related to patient care.

Abreu MT, Harpaz N. · Division of Gastroenterology and the Inflammatory Bowel Disease Center, Mount Sinai, New York, New York 10029, USA. · Clin Gastroenterol Hepatol. · Pubmed #17368227 No free full text.

Abstract: The evaluation of patients with colitis of recent onset is a relatively common clinical challenge. The main considerations are infectious colitides, idiopathic IBD, ie, ulcerative and Crohn's colitis, and colonic ischemia. An initial risk assessment on the basis of such factors as concurrent symptoms in contacts, travel history, medications, and human immunodeficiency virus risk factors should be followed by a thorough clinical history, physical examination, stool studies, blood tests, and, in selected cases, endoscopic examination and serologic tests. Biopsies can be decisive in distinguishing among the different types of acute colitis and might help identify specific etiologies. The diagnostic yield of biopsies is maximized by appropriate sampling of the colonic mucosa and by sharing the clinical and endoscopic findings with the pathologist, eg, via a copy of the endoscopy report.

Abreu MT, Sparrow MP. · Inflammatory Bowel Disease Center, Mount Sinai School of Medicine, 1 East 100th Street, Box 1069, New York, NY 10029, USA. · Mt Sinai J Med. · Pubmed #17285196 links to  free full text

Abstract: The idiopathic inflammatory bowel diseases (IBDs), broadly classified as either Crohn's disease (CD) or ulcerative colitis (UC), are caused by a dysregulated mucosal immune response to a luminal antigen, possibly a bacterium, in a genetically predisposed host. A rapid expansion of knowledge in recent years has greatly increased our understanding of the pathophysiology of these disorders. For example, the relatively recent discovery of the NOD2 gene, a protein involved in bacterial sensing, has provided further evidence of the complex interplay between hosts and microbes in Crohn's disease. Significant recent advances have also occurred with the discovery of the role of Toll-like receptors and dendritic cells in the development of gut inflammation, and the role of proinflammatory cytokines in the development and potentiation of gut inflammation. This article presents an update on these key developments and emphasizes the translational aspects of research that are directly related to patient care.

Rochester J, Abreu MT. · Inflammatory Bowel Disease Center, Department of Gastroenterology, Mount Sinai School of Medicine, New York, NY, USA. · Rev Gastroenterol Disord. · Pubmed #16369217 No free full text.

Abstract: Since the initial observation that mesalamine or 5-aminosalicylate (5-ASA) has an anti-inflammatory effect on ulcerative colitis, investigators have been trying to improve on the delivery mechanisms of this compound. As it is believed that the anti-inflammatory effect of 5-ASAs is mediated topically, current formulations are designed to release 5-ASA in the small intestine and colon, or predominantly in the colon. A dose-response curve is seen with some preparations of mesalamine but not all. In general, 5-ASAs are effective in patients with ulcerative colitis and much less effective in Crohn's disease. Evidence demonstrates that 5-ASAs are effective for induction of remission and maintenance of remission. Preparations that deliver 5-ASA in a pH-dependent manner are most affected by variability in luminal pH, whereas those that depend on bacterial cleavage for release of the active 5-ASA are most affected by transit time. Most studies have not compared different preparations of mesalamine and examined differences in colonic delivery. Depending on the endpoint examined in the studies, efficacy of the various 5-ASA products appears similar at the most optimal doses. For a given patient, however, it may be necessary to experiment with more than one preparation if an initial trial results in a suboptimal response.

Brown SJ, Abreu MT. · The Mount Sinai School of Medicine, Division of Gastroenterology, 1 Gustave L Levy Place, New York, NY 10029, USA. · Curr Opin Drug Discov Devel. · Pubmed #15782540 No free full text.

Abstract: Crohn's disease is characterized by acute and chronic intestinal inflammation, and can involve any part of the gastrointestinal tract. The most frequently involved areas of the intestine (the terminal ileum and colon) have higher bacterial loads than the rest of the intestine, suggesting a role for a dysregulated immune response to luminal bacteria. Research into the pathogenesis of Crohn's disease using animal models supports a role for Th1-mediated immune responses, and inhibition of the generation of a Th1 response is known to prevent disease. Based on these observations, antitumor necrosis factor-alpha (anti-TNFalpha) therapies have been used to treat patients with Crohn's disease and more recently with ulcerative colitis. Certain anti-TNFalpha therapies, such as infliximab, have resulted in dramatic clinical responses in patients with Crohn's disease. Other therapies such as etanercept, however, have not been effective. In this review we will discuss the different strategies that have been employed to inhibit TNFalpha and their relative merits. We will also address factors that predict response to therapy such as concurrent immunomodulators, high C-reactive protein expression, and polymorphisms in the Fcgamma receptor.

Fukata M, Hernandez Y, Conduah D, Cohen J, Chen A, Breglio K, Goo T, Hsu D, Xu R, Abreu MT. · Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33101, USA. · Inflamm Bowel Dis. · Pubmed #19229991 No free full text.

Abstract: BACKGROUND: Patients with ulcerative colitis are at increased risk for developing colorectal cancer. We have shown that Toll-like receptor-4 (TLR4) is overexpressed in human colitis-associated cancer (CAC) and that mice deficient in TLR4 are markedly protected against colitis-associated neoplasia. We wished to elucidate the specific contributions of TLR4 signaling by myeloid cells and colonic epithelial cells (CEC) in colitis-associated tumorigenesis. METHODS: TLR4-deficient mice or wildtype littermates (WT) were transplanted with bone marrow (BM) cells: TLR4(-/-) BM-->WT mice (TLR4-expressing CEC) and WT BM-->TLR4(-/-) mice (TLR4-expressing myeloid cells). Colitis-associated neoplasia was induced by azoxymethane (AOM 7.3 mg/kg) injection and 2 cycles of dextran sodium sulfate (DSS) treatment. RESULTS: The number and size of dysplastic lesions were greater in TLR4(-/-) BM-->WT mice than in WT BM-->TLR4(-/-) mice (P < 0.005). Histologically, TLR4(-/-) BM-->WT mice had greater numbers of mucosal neutrophils and macrophages compared to WT BM-->TLR4(-/-) mice. The chemokines KC and CCL2, important in recruitment of neutrophils and macrophages, respectively, were induced in mice expressing TLR4 in CEC rather than the myeloid compartment. The lamina propria infiltrate of mice expressing TLR4 in CEC was characterized by macrophages expressing Cox-2. Moreover, mice expressing TLR4 in CEC rather than the myeloid compartment had increased production of amphiregulin and EGFR activation. CONCLUSIONS: These findings indicate that TLR4 signaling on CEC is necessary for recruitment and activation of Cox-2-expressing macrophages and increasing the number and size of dysplastic lesions. Our results implicate innate immune signaling on CEC as a key regulator of a tumor-promoting microenvironment.

Swaminath A, Ullman T, Rosen M, Mayer L, Lichtiger S, Abreu MT. · Division of Digestive and Liver Diseases, Columbia University Presbyterian Hospital, New York, NY 10032, USA. · Aliment Pharmacol Ther. · Pubmed #19006540 No free full text.

Abstract: BACKGROUND: Adalimumab, at an induction dose of 160/80 mg followed by 40 mg every other week is approved for treatment of refractory Crohn's disease (CD) and for patients with loss of response to infliximab. AIM: To evaluate the indications for adalimumab, the proportion of inflammatory bowel disease patients who require dose escalation and to identify whether this strategy is effective in inducing or maintaining remission. METHODS: Patients prescribed adalimumab for CD were identified and included for analysis, if they had follow-up of at least 6 weeks. Adalimumab dose was escalated if patients had return of symptoms prior to next dose. Clinical judgment was used to determine severity of disease. A second GI physician confirmed disease severity as determined by the first physician. RESULTS: A total of 48 out of 60 patients met inclusion criteria. Adalimumab was used to treat CD in 47/48 (98%) and ulcerative colitis in one (2%). Most patients had moderate 30/48 (63%) or severe 17/48 (35%) disease. Prior infliximab exposure was present in 42/48 (88%). Adalimumab dose escalation occurred in 14/48 (29%) within an average time of 2.2 months (s.d. 1.5 months). A majority of patients who required dose escalation, nine of 14 (64%) did not improve clinically. Steroids could be discontinued in three of 16 (18.8%). Clinical improvement was noted in 21/48 (43.8%) and one of 48 (2%) patients achieved clinical remission. Adverse drug reactions necessitated drug discontinuation in four of 48 (8%) of patients. CONCLUSIONS: This retrospective review from a single academic medical centre suggests that a minority of patients, who cannot be maintained on 40 mg every other week, of adalimumab benefit from an increased dose. This suggests the need for a treatment with an alternative mode of action in anti-TNF failures.

Marion JF, Waye JD, Present DH, Israel Y, Bodian C, Harpaz N, Chapman M, Itzkowitz S, Steinlauf AF, Abreu MT, Ullman TA, Aisenberg J, Mayer L, Anonymous00103. · Mount Sinai School of Medicine, New York, New York 10028-0517, USA. · Am J Gastroenterol. · Pubmed #18844620 No free full text.

Abstract: OBJECTIVES: Patients with extensive, longstanding chronic ulcerative or Crohn's colitis face greater risks of developing colorectal cancer. Current standard surveillance relies on detecting dysplasia using random sampling at colonoscopy but may fail to detect dysplasia in many patients. Dye spraying techniques have been reported to aid in detecting otherwise subtle mucosal abnormalities in the setting of colitis. We prospectively compared dye-spray technique using methylene blue to standard colonoscopic surveillance in detecting dysplasia. METHODS: One hundred fifteen patients were referred to the Chromoendoscopy Study Group and prospectively screened for the study. One hundred two (64 M, 38 F) (79 UC 23 CC) patients meeting the inclusion criteria were enrolled. Following a standard bowel preparation, each patient was examined using standard office endoscopic equipment by three methods: (a) standard surveillance colonoscopy with four random biopsies every 10 cm (for a total of at least 32 samples); (b) a targeted biopsy protocol; and finally (c) methylene blue (0.01%) dye spray was segmentally applied throughout the colon and any pit-pattern abnormality or lesion rendered visible by the dye spray was targeted and biopsied. Each patient had a single examination, which included two passes of the colonoscope. Specimens were reviewed in a blinded fashion by a single gastrointestinal pathologist. The three methods were then compared with each patient serving as his or her own control. RESULTS: Targeted biopsies with dye spray revealed significantly more dysplasia (16 patients with low grade and 1 patient with high grade) than random biopsies (3 patients with low-grade dysplasia) (P= 0.001) and more than targeted nondye spray (8 patients with low-grade and 1 patient with high-grade dysplasia) (P= 0.057). Targeted biopsies with and without dye spray detected dysplasia in 20 patients compared with 3 using Method (a) (P= 0.0002, two-tailed exact McNemar's Test). There were no adverse events. CONCLUSIONS: Colonoscopic surveillance of chronic colitis patients using methylene blue dye-spray targeted biopsies results in improved dysplasia yield compared to conventional random and targeted biopsy methods. Accordingly, this technique warrants incorporation into clinical practice in this setting and consideration as a standard of care for these patients. The value of multiple random biopsies as a surveillance technique should be revisited.

Yip JS, Woodward M, Abreu MT, Sparrow MP. · Mount Sinai School of Medicine, New York, NY, USA. · Inflamm Bowel Dis. · Pubmed #18088072 links to  free full text

Abstract: BACKGROUND: Azathioprine (AZA) and 6-mercaptopurine (6-MP) are accepted as effective therapy for Crohn's disease and ulcerative colitis. Although general guidelines have been suggested for weight-based dosing of thiopurines, no standard of care has been established. Clinical trials have demonstrated efficacy for weight-based dosing of AZA at 2.5 mg/kg/day and 6-MP at 1.5 mg/kg/day. Escalation of dosing is recommended within 2 weeks of initiating therapy. The aim was to determine the prescribing practices of community practice gastroenterologists with respect to 6-MP/AZA dosing. METHODS: Questionnaires were distributed via a mail database or during gastroenterology society meetings to gastroenterologists in NY, NJ, and CT. Questionnaires ascertained starting doses of AZA/6-MP, use of thiopurine methyltransferase (TPMT) enzyme testing, and strategy for dose optimization. RESULTS: A total of 145 questionnaires were collected. Twenty-four percent of gastroenterologists escalated the dose within 2 weeks after initiating therapy. The majority used weight-based dosing as their target of therapy. Thirty-five percent reported measuring TPMT levels and 46% used metabolite monitoring. CONCLUSIONS: Most gastroenterologists take longer than recommended to raise the dose of AZA/6-MP. Although the majority of gastroenterologists reported maximal dosages based on weight, there may be a delay in achieving this goal. Optimizing dosing of AZA/6-MP may improve efficacy and reduce the need to use additional therapy.

Fukata M, Chen A, Vamadevan AS, Cohen J, Breglio K, Krishnareddy S, Hsu D, Xu R, Harpaz N, Dannenberg AJ, Subbaramaiah K, Cooper HS, Itzkowitz SH, Abreu MT. · Inflammatory Bowel Disease Center, Mount Sinai School of Medicine, New York, New York, USA. · Gastroenterology. · Pubmed #18054559 links to  free full text

Abstract: BACKGROUND & AIMS: Chronic inflammation is a risk factor for colon cancer in patients with ulcerative colitis (UC). The molecular mechanisms linking inflammation and colon carcinogenesis are incompletely understood. We tested the hypothesis that Toll-like receptor 4 (TLR4) is involved in tumorigenesis in the setting of chronic inflammation. METHODS: Tissues from UC patients with cancer were examined for TLR4 expression. Colitis-associated neoplasia was induced using azoxymethane injection followed by dextran sodium sulfate treatment in TLR4-deficient or wild-type mice. Inflammation, polyps, and microscopic dysplasia were scored. Cyclooxygenase (Cox)-2 and prostaglandin E(2) production were analyzed by real-time polymerase chain reaction, immunohistochemistry, or enzyme immunoassay. Epidermal growth factor receptor (EGFR) phosphorylation and amphiregulin production were examined by Western blot analysis and enzyme-linked immunosorbent assay, respectively. RESULTS: We show that TLR4 is overexpressed in human and murine inflammation-associated colorectal neoplasia. TLR4-deficient mice were protected markedly from colon carcinogenesis. Mechanistically, we show that TLR4 is responsible for induction of Cox-2, increased prostaglandin E(2) production, and activation of EGFR signaling in chronic colitis. Amphiregulin, an EGFR ligand, was induced in a TLR4, Cox-2-dependent fashion and contributes to activation of EGFR phosphorylation in colonic epithelial cells. CONCLUSIONS: TLR4 signaling is critical for colon carcinogenesis in chronic colitis. TLR4 activation appears to promote the development of colitis-associated cancer by mechanisms including enhanced Cox-2 expression and increased EGFR signaling. Inhibiting TLR4 signaling may be useful in the prevention or treatment of colitis-associated cancer.

Cooney RM, Warren BF, Altman DG, Abreu MT, Travis SP. · Gastroenterology Unit, John Radcliffe Hospital, Oxford, OX3 9DU, UK. · Trials. · Pubmed #17592647 links to  free full text

Abstract: Clinical trials on novel drug therapies require clear criteria for patient selection and agreed definitions of disease remission. This principle has been successfully applied in the field of rheumatology where agreed disease scoring systems have allowed multi-centre collaborations and facilitated audit across treatment centres. Unfortunately in ulcerative colitis this consensus is lacking. Thirteen scoring systems have been developed but none have been properly validated. Most trials choose different endpoints and activity indices, making comparison of results from different trials extremely difficult. International consensus on endoscopic, clinical and histological scoring systems is essential as these are the key components used to determine entry criteria and outcome measurements in clinical trials on ulcerative colitis. With multiple new therapies under development, there is a pressing need for consensus to be reached.

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.

Beaven SW, Abreu MT. · Basic and Translational Research, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. · Curr Opin Gastroenterol. · Pubmed #15703659 No free full text.

Abstract: PURPOSE OF REVIEW: Inflammatory bowel disease is characterized by chronic intestinal inflammation in the absence of a recognized pathogen. In its classic description, there are two principal forms of inflammatory bowel disease: Crohn disease and ulcerative colitis. The clinical heterogeneity of these disorders alludes to the possibility of diverse pathogenetic mechanisms underlying inflammatory bowel diseases. The purpose of this review is to summarize the latest information on biomarkers of Crohn disease and ulcerative colitis. RECENT FINDINGS: The authors have focused on serologic markers for which emerging data support their use as predictors of disease evolution. Serologic markers such as perinuclear antineutrophil cytoplasmic antibody, anti-Saccharomyces cerevisiae antibody, anti-OmpC, and anti-I2 may be useful in distinguishing inflammatory bowel diseases from functional disorders and ulcerative colitis from Crohn disease and predicting complications of disease. Genetic markers such as CARD15/NOD2 may be useful in the future when combined with other markers to predict disease course. Biochemical markers of inflammation such as C-reactive protein are useful to stratify patients likely to respond to biologic therapies and to follow response to treatment. In the future, functional genomics and proteomics will be used to rapidly screen patients for subclinical characteristics that can predict disease course and response to therapy. SUMMARY: A variety of biomarkers can be used to stratify patients with inflammatory bowel disease into more homogeneous subgroups with respect to response to therapy and disease progression.

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.

Abreu MT, Kantorovich V, Vasiliauskas EA, Gruntmanis U, Matuk R, Daigle K, Chen S, Zehnder D, Lin YC, Yang H, Hewison M, Adams JS. · Division of Gastroenterology, Inflammatory Bowel Disease Center, Steven Spielberg Pediatric Research Center, Burns and Allen Research Institute, Los Angeles, CA 90048, USA. · Gut. · Pubmed #15247180 links to  free full text

Abstract: OBJECTIVES: Many patients with Crohn's disease (CD) have low bone mineral density (BMD) that may not be solely attributable to glucocorticoid use. We hypothesised that low BMD in patients with CD is associated with elevated circulating levels of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)(2)D). We further hypothesised that this was secondary to increased synthesis of 1,25(OH)(2)D by inflammatory cells in the intestine. The aim of this study was to examine the relationship between 1,25(OH)(2)D levels and BMD in patients with CD. METHODS: An IRB approved retrospective review of medical records from patients with CD (n = 138) or ulcerative colitis (UC, n = 29). Measurements of vitamin D metabolites and immunoreactive parathyroid hormone (iPTH) were carried out. BMD results were available for 88 CD and 20 UC patients. Immunohistochemistry or real time reverse transcription-polymerase chain reaction (RT-PCR) for the enzyme 1alpha-hydroxylase was performed on colonic biopsies from patients with CD (14) or UC (12) and normal colons (4). RESULTS: Inappropriately high levels of serum 1,25(OH)(2)D (>60 pg/ml) were observed in 42% of patients with CD compared with only 7% in UC, despite no differences in mean iPTH. Serum 1,25(OH)(2)D levels were higher in CD (57 pg/ml) versus UC (41 pg/ml) (p = 0.0001). In patients with CD, there was a negative correlation between 1,25(OH)(2)D levels and lumbar BMD (r = -0.301, p = 0.005) independent of therapeutic glucocorticoid use. 1,25(OH)(2)D levels also correlated with CD activity. Lastly, immunohistochemistry and RT-PCR demonstrated increased expression of intestinal 1alpha-hydroxylase in patients with CD. CONCLUSIONS: These data demonstrate that elevated 1,25(OH)(2)D is more common in CD than previously appreciated and is independently associated with low bone mineral density. The source of the active vitamin D may be the inflamed intestine. Treatment of the underlying inflammation may improve metabolic bone disease in this subgroup of patients.

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.