Ulcerative Colitis: Binion DG

Issa M, Ananthakrishnan AN, Binion DG. · Inflammatory Bowel Disease Center, Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. · Inflamm Bowel Dis. · Pubmed #18484669 No free full text.

Abstract: Clostridium difficile colitis has doubled in North America over the past 5 years and recent reports have demonstrated an increase in incidence and severity of these infections in patients with inflammatory bowel disease (IBD; Crohn's disease, ulcerative colitis). Studies from single institutions as well as trends identified in nationwide inpatient databases have shown that IBD patients with concomitant C. difficile infection experience increased morbidity and mortality. Results from our center have shown that over half of C. difficile-infected IBD patients will require hospitalization and the colectomy rate may approach 20%. Because C. difficile colitis will both mimic and precipitate an IBD flare, it is essential that clinicians be vigilant to identify and address this infectious complication, as empiric treatment with corticosteroids without appropriate antibiotics may precipitate deterioration. The majority of IBD patients appear to contract C. difficile as outpatients, and a prior history of colitis appears to be the most significant risk factor for acquiring this infection. In addition to C. difficile colitis, IBD patients are now known to be at risk for C. difficile enteritis as well as infections in reconstructed ileoanal pouches. An additional challenge facing C. difficile infections in IBD patients is the decreased efficacy of metronidazole, and the need for oral vancomycin in patients requiring hospitalization. In this review we summarize the present knowledge regarding C. difficile infection in the setting of IBD, including unique clinical scenarios facing IBD patients, diagnostic algorithms, and treatment approaches.

Ananthakrishnan AN, Attila T, Otterson MF, Lipchik RJ, Massey BT, Komorowski RA, Binion DG. · Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA. · J Clin Gastroenterol. · Pubmed #17667053 No free full text.

Abstract: Azathioprine and 6-mercaptopurine (6-MP) are effective in inflammatory bowel disease (IBD). However, between 10% and 29% of patients treated with these drugs are forced to stop therapy due to side effects. Pulmonary toxicity due to azathioprine/6-MP has been reported infrequently. We describe 3 patients who developed severe, noninfectious pulmonary toxicity within 1 month after the initiation of azathioprine or 6-MP for the treatment of IBD colitis (2 Crohn's disease and 1 ulcerative colitis). All patients presented with dyspnea, cough, and fever after initiation of azathioprine/6-MP. Evaluation for infectious etiologies, including bronchoscopy (3/3 patients) and open-lung biopsy (2/3 patients) was negative. Histopathologic examination of the lung biopsies revealed bronchiolitis obliterans organizing pneumonia in one, and usual interstitial pneumonitis in another patient. Cessation of purine analog therapy resulted in clinical improvement in all 3 cases. Azathioprine/6-MP-related pulmonary toxicity is a rare but serious side effect, and it is important for clinicians to have a high index of suspicion for this adverse reaction which occurs within 1 month after initiation of treatment for IBD.

Hatoum OA, Heidemann J, Binion DG. · Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, USA. · Ann N Y Acad Sci. · Pubmed #17057192 No free full text.

Abstract: Chronic inflammation is a complex biologic process which involves immune as well as non-immune cells including the microvasculature and its endothelial lining. Growing evidence suggests that the microvasculature plays an integral role in the pathophysiology of inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis). The microvasculature contributes to chronic inflammation through altered leukocyte recruitment, impaired perfusion, and angiogenesis leading to tissue remodeling. These diverse areas of IBD microvascular biology represent therapeutic targets that are currently undergoing investigation.

Hatoum OA, Binion DG. · Division of Cardiovascular Medicine, Department of Medicine, Cardiovascular Research Center, Froedtert Memorial Lutheran Hospital, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. · Inflamm Bowel Dis. · Pubmed #15735437 No free full text.

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Bielefeldt K, Davis B, Binion DG. · Center for Pain Research, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. · Inflamm Bowel Dis. · Pubmed #19130619 No free full text.

Abstract: Abdominal pain is a common symptom of inflammatory bowel disease (IBD: Crohn's disease, ulcerative colitis). Pain may arise from different mechanisms, which can include partial blockage and gut distention as well as severe intestinal inflammation. A majority of patients suffering from acute flares of IBD will experience pain, which will typically improve as disease activity decreases. However, a significant percentage of IBD patients continue experiencing symptoms of pain despite resolving inflammation and achieving what appears to be clinical remission. Current evidence suggests that sensory pathways sensitize during inflammation, leading to persistent changes in afferent neurons and central nervous system pain processing. Such persistent pain is not only a simple result of sensory input. Pain processing and even the activation of sensory pathways is modulated by arousal, emotion, and cognitive factors. Considering the high prevalence of iatrogenic as well as essential neuropsychiatric comorbidities including anxiety and depression in IBD patients, these central modulating factors may significantly contribute to the clinical manifestation of chronic pain. The improved understanding of peripheral and central pain mechanisms is leading to new treatment strategies that view pain as a biopsychosocial problem. Thus, improving the underlying inflammation, decreasing the excitability of sensitized afferent pathways, and altering emotional and/or cognitive functions may be required to more effectively address the difficult and disabling disease manifestations.

Rubin DT, Siegel CA, Kane SV, Binion DG, Panaccione R, Dubinsky MC, Loftus EV, Hopper J. · Section of Gastroenterology, Department of Medicine, University of Chicago Medical Center, Chicago, Illinois, USA. · Inflamm Bowel Dis. · Pubmed #19067414 No free full text.

Abstract: BACKGROUND: Two national internet surveys were conducted to understand how patients perceive the impact of ulcerative colitis (UC) relative to gastroenterologists. METHODS: In total, 451 patients with UC (20% mild, 63% moderate, 13% severe, 4% unsure [patient self-assessment]) were recruited for one survey and 300 gastroenterologists (not associated with the patients) were recruited for the other survey. RESULTS: Patients reported, on average, 8 (self-defined) flares per year; this was more than the number anticipated by gastroenterologists. Sixty-two percent of patients with UC reported that their disease made it difficult to lead a normal life, compared with gastroenterologists' estimations of 36%. Only 42% of patients believed that being in remission could mean living without symptoms. Both patients and gastroenterologists reported that it is difficult for patients to take medication as prescribed every day (42% and 90%) and that managing UC medication is a struggle for patients (49% and 41%). Forty-six percent of patients admitted nonadherence to their therapy over the previous week, while gastroenterologists believed that 41% of their patients were not adherent. CONCLUSIONS: These surveys identified disparities between patients' and gastroenterologists' perceptions of the impact of UC on patients' lives. The results suggest that more patients than gastroenterologists estimated chose to adapt their lives to accommodate UC rather than act to optimize therapy and adherence. Improved communication between patients and gastroenterologists, as well as better management strategies and education are necessary.

Ananthakrishnan AN, McGinley EL, Binion DG. · Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. · Am J Gastroenterol. · Pubmed #18684184 No free full text.

Abstract: OBJECTIVE: To examine if a high hospital volume was associated with superior outcomes in inflammatory bowel disease (IBD) patients requiring hospitalization. METHODS: This was a cross-sectional study using data from the Nationwide Inpatient Sample (NIS 2004). IBD-related hospitalizations were identified using appropriate International Classification of Diseases, Ninth revision, Clinical modification (ICD-9-CM) codes. Hospital volume was divided into low, medium, and high by assigning the threshold cutoff values of 1-50, 51-150, and >150 annual IBD hospitalizations, respectively. Our primary outcomes were in-hospital mortality, length of stay, and postoperative complications and stay. RESULTS: Patients at high-volume centers were more likely to be hospitalized with fistulizing or stricturing disease. The adjusted mortality was lower for IBD-related discharges from high-volume centers for those undergoing abdominal surgery (odds ratio [OR] 0.38, 95% confidence interval [CI] 0.18-0.78), but not among those who did not undergo surgery (OR 0.90, 95% CI 0.53-1.52). Patients at high-volume centers were also more likely to undergo surgery (OR 2.24, 95% CI 1.40-3.58). These differences were more prominent in Crohn's disease than in ulcerative colitis. CONCLUSION: Hospitals with a high annual IBD volume have lower in-hospital mortality among surgical IBD patients. This suggests a need for future research into identifying the quality-of-care measures in IBD and instituting appropriate interventions to improve overall IBD outcomes.

Ananthakrishnan AN, Issa M, Beaulieu DB, Skaros S, Knox JF, Lemke K, Emmons J, Lundeen SH, Otterson MF, Binion DG. · Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. · Inflamm Bowel Dis. · Pubmed #18680197 No free full text.

Abstract: BACKGROUND: Patients who require hospitalization for the management of ulcerative colitis (UC) may represent a subset with severe disease. These patients may be more likely to require future colectomy. There are limited data examining whether medical hospitalization is predictive of subsequent colectomy. METHODS: This was a retrospective case-control study utilizing the inflammatory bowel disease center database at our academic referral center. Cases comprised UC patients who underwent colectomy for disease refractory to medical management. The control population was comprised of all patients with UC who had not undergone colectomy. Multivariate logistic regression was used to identify independent predictors of requiring colectomy. RESULTS: There were a total of 246 UC patients included in our study, with 103 being hospitalized sometime in their disease course (41.9%). A total of 27 patients underwent colectomy (11%). Colectomy patients were significantly more likely to have been on infliximab therapy (51.8% versus 22.4%, P = 0.001) but no more likely to have been on immunomodulator therapy (74.1% versus 59.4%, P = 0.14). Patients who required medical hospitalization for UC were more likely to require future colectomy (20.4% versus 4.2%, P < 0.001) than those who had not required hospitalization. On multivariate analysis, requiring medical hospitalization for management of UC (odds ratio [OR] 5.37, 95% confidence interval [CI] 2.00-14.46) and ever requiring infliximab therapy (OR 3.12, 95% CI 1.21-8.07) were independent predictors of colectomy. CONCLUSIONS: Requiring medical hospitalization for the management of disease activity in UC is an independent predictor of the need for colectomy. Future studies will determine whether aggressive medical management may modify the need for colectomy in this cohort.

Ananthakrishnan AN, McGinley EL, Binion DG. · Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. · Inflamm Bowel Dis. · Pubmed #18668678 No free full text.

Abstract: BACKGROUND: Inflammatory bowel disease (IBD) has a bimodal peak of incidence with approximately 15% of the cases manifesting after 65 years. Previous reports on the outcomes of IBD in the elderly have been single-center studies or have predated the use of biologics. The aim of our study was to compare outcomes of IBD-related hospitalizations in a nationwide representative cohort of patients 65 years and older with younger patients. METHODS: This was a cross-sectional study utilizing data from the Nationwide Inpatient Sample (NIS) for the year 2004. We identified all IBD-related hospitalizations through the presence of the appropriate ICD-9-CM codes for Crohn's disease, ulcerative colitis, or associated complications. We compared the differences in disease presentation as well the frequency of utilization of different interventions. We calculated the adjusted odds of mortality in older compared to the younger IBD patients using multivariate logistic regression. RESULTS: Patients older than 65 years accounted for approximately 25% of all IBD-related hospitalizations in 2004. They were less likely to be hospitalized with fistulizing (4.0 versus 8.8%, P < 0.001) or stricturing disease (4.0 versus 5.8%, P = 0.001). Even after adjusting for comorbidity, they had higher in-hospital mortality (odds ratio [OR] 3.91, 95% confidence interval [CI] 2.50-6.11). Older patients with fistulizing disease are more likely to undergo surgery (OR 1.55, 95% CI 1.00-2.40). Among IBD patients who underwent surgery, older patients also had a longer postoperative stay (1.73 days, 95% CI 1.04-2.21). CONCLUSIONS: Older patients with IBD-related hospitalizations have substantial morbidity and higher mortality than younger patients. Further research is needed to better characterize the natural history and treatment outcomes in this cohort.

Ananthakrishnan AN, McGinley EL, Binion DG. · Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA. · Gut. · Pubmed #17905821 No free full text.

Abstract: BACKGROUND: Clostridium difficile is an important cause of diarrhoea in hospitalised patients. An increasing number of cases of C difficile colitis occur in patients with inflammatory bowel disease (IBD)-Crohn's disease (CD), ulcerative colitis (UC). OBJECTIVE: To estimate the potential excess morbidity and mortality associated with C difficile in hospitalised patients with IBD. METHODS: Data from the Nationwide Inpatient Sample (2003) were analysed and outcomes were examined of patients hospitalised with both C difficile colitis and IBD compared with those hospitalised for either condition alone. The primary outcome was in-hospital mortality. A subgroup analysis was also performed comparing outcomes of C difficile infection in patients with CD and UC. RESULTS: 2804 discharges were diagnosed as having both C difficile and IBD, 44,400 as having C difficile alone, and 77,366 as having IBD alone. On multivariate analysis, patients in the C difficile-IBD group had a four times greater mortality than patients admitted to hospital for IBD alone (aOR = 4.7, 95% CI 2.9 to 7.9) or C difficile alone (aOR = 2.2, 95% CI 1.4 to 3.4), and stayed in the hospital for three days longer (95% CI 2.3 to 3.7 days). Significantly higher mortality, endoscopy and surgery rates were found in patients with UC compared with CD (p<0.05), but no significant difference in length of stay or median hospital charge between the two groups was seen. CONCLUSIONS: C difficile colitis is associated with a significant healthcare burden in hospitalised patients with IBD and carries a higher mortality than in patients with C difficile without underlying IBD.

Lundeen SJ, Otterson MF, Binion DG, Carman ET, Peppard WJ. · Department of Surgery, Medical College of Wisconsin, 9200 W. Wisconsin Ave., Milwaukee, WI 53226, USA. · J Gastrointest Surg. · Pubmed #17390162 No free full text.

Abstract: Clostridium difficile, the leading cause of hospital-acquired diarrhea, is known to cause severe colitis. C. difficile small bowel enteritis is rare (14 case reports) with mortality rates ranging from 60 to 83%. C. difficile has increased in incidence particularly among patients with inflammatory bowel disease. This case series of six patients from 2004 to 2006 is the largest in the literature. All patients received antibiotics before colectomies for ulcerative colitis and developed severe enteritis that was C. difficile toxin positive. Three patients underwent ileal pouch anal anastomosis and loop ileostomy. Four of the six patients had C. difficile colitis before colectomy. Presenting symptoms were high volume watery ileostomy output followed by ileus in five of six patients. Four of the six patients presented with fever and elevated WBC. Five of the six developed complications requiring further surgery or prolonged hospitalization. Patients were treated with intravenous hydration and metronidazole then converted to oral metronidazole and/or vancomycin. None of the patients died. A high suspicion of C. difficile enteritis in patients with inflammatory bowel disease and history of C. difficile colitis may lead to more rapid diagnosis, aggressive treatment, and improved outcomes for patients with C. difficile enteritis.

Issa M, Vijayapal A, Graham MB, Beaulieu DB, Otterson MF, Lundeen S, Skaros S, Weber LR, Komorowski RA, Knox JF, Emmons J, Bajaj JS, Binion DG. · Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. · Clin Gastroenterol Hepatol. · Pubmed #17368234 No free full text.

Abstract: BACKGROUND & AIMS: Clostridium difficile-associated disease has increased significantly in North American medical centers. The impact of C difficile on patients with IBD (Crohn's disease, ulcerative colitis) at the present time is unknown. METHODS: A retrospective, observational study evaluating IBD patients followed in a referral center to evaluate the impact of C difficile was performed. Diagnosis was confirmed with stool toxin analysis. Demographic information, diagnosis, anatomic location, IBD therapy, antibiotic exposure, hospitalizations, and surgeries were recorded. Available endoscopic and histologic data were evaluated. RESULTS: Rate of C difficile infection increased from 1.8% of IBD patients in 2004 to 4.6% in 2005 (P < .01). Proportion of IBD patients within the total number of C difficile infections at our institution increased from 7% in 2004 to 16% in 2005 (P < .01). IBD colonic involvement was found in the majority of C difficile-infected patients in 2005 (91%), and the majority contracted infection as an outpatient (76%). Antibiotic exposure was identified in 61% of IBD patients with C difficile infection in 2005. Pseudomembranes and fibrinopurulent eruptions were not seen endoscopically or histologically. During 2004-2005 more than half of the infected IBD patients required hospitalization, and 20% required colectomy. Univariate and multivariate analysis identified maintenance immunomodulator use and colonic involvement as independent risk factors for C difficile infection in IBD. CONCLUSIONS: C difficile infection has increased significantly in IBD patients and negatively impacts clinical outcome. Increased vigilance regarding this infection in IBD patients with colitis activity is warranted.

Horowitz S, Binion DG, Nelson VM, Kanaa Y, Javadi P, Lazarova Z, Andrekopoulos C, Kalyanaraman B, Otterson MF, Rafiee P. · Dept. of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA. · Am J Physiol Gastrointest Liver Physiol. · Pubmed #17218473 links to  free full text

Abstract: Nitric oxide (.NO) generation from conversion of l-arginine to citrulline by nitric oxide synthase isoforms plays a critical role in vascular homeostasis. Loss of .NO is linked to vascular pathophysiology and is decreased in chronically inflamed gut blood vessels in inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis). Mechanisms underlying decreased .NO production in IBD gut microvessels are not fully characterized. Loss of .NO generation may result from increased arginase (AR) activity, which enzymatically competes with nitric oxide synthase for the common substrate l-arginine. We characterized AR expression in IBD microvessels and endothelial cells and its contribution to decreased .NO production. AR expression was assessed in resected gut tissues and human intestinal microvascular endothelial cells (HIMEC). AR expression significantly increased in both ulcerative colitis and Crohn's disease microvessels and submucosal tissues compared with normal. TNF-alpha/lipopolysaccharide increased AR activity, mRNA and protein expression in HIMEC in a time-dependent fashion. RhoA/ROCK pathway, a negative regulator of .NO generation in endothelial cells, was examined. The RhoA inhibitor C3 exoenzyme and the ROCK inhibitor Y-27632 both attenuated TNF-alpha/lipopolysaccharide-induced MAPK activation and blocked AR expression in HIMEC. A significantly higher AR activity and increased RhoA activity were observed in IBD submucosal tissues surrounding microvessels compared with normal control gut tissue. Functionally, inhibition of AR activity decreased leukocyte binding to HIMEC in an adhesion assay. Loss of .NO production in IBD microvessels is linked to enhanced levels of AR in intestinal endothelial cells exposed to chronic inflammation in vivo.

Kugathasan S, Judd RH, Hoffmann RG, Heikenen J, Telega G, Khan F, Weisdorf-Schindele S, San Pablo W, Perrault J, Park R, Yaffe M, Brown C, Rivera-Bennett MT, Halabi I, Martinez A, Blank E, Werlin SL, Rudolph CD, Binion DG, Anonymous00155. · Division of Pediatric Gastroenterology and Nutrition, the Department of Epidemiology and Biostatistics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. · J Pediatr. · Pubmed #14571234 No free full text.

Abstract: OBJECTIVE: To define epidemiologic and clinical characteristics of newly diagnosed pediatric inflammatory bowel disease (IBD) in a large population-based model. STUDY DESIGN: All pediatric gastroenterologists providing care for Wisconsin children voluntarily identified all new cases of IBD during a 2-year period. Demographic and clinical data were sent to a central registry prospectively for analysis. RESULTS: The incidence of IBD in Wisconsin children was 7.05 per 100,000, whereas the incidence for Crohn's disease was 4.56, more than twice the rate of ulcerative colitis (2.14). An equal IBD incidence occurred among all ethnic groups, and children from sparsely and densely populated counties were equally affected. The majority (89%) of new IBD diagnoses were nonfamilial. CONCLUSIONS: This study provides novel, prospective, and comprehensive information on pediatric IBD incidence within the United States. The surprisingly high incidence of pediatric IBD, the predominance of Crohn's disease over ulcerative colitis, the low frequency of patients with a family history, the equal distribution of IBD among all racial and ethnic groups, and the lack of a modulatory effect of urbanization on IBD incidence collectively suggest that the clinical spectrum of IBD is still evolving and point to environmental factors contributing to the pathogenesis.

Hatoum OA, Binion DG, Otterson MF, Gutterman DD. · Department of Medicine and VA Medical Center, Medical College of Wisconsin, Milwaukee, USA. · Gastroenterology. · Pubmed #12851871 No free full text.

Abstract: BACKGROUND & AIMS: Inflammatory bowel disease (IBD; i.e., Crohn's disease, ulcerative colitis) is characterized by refractory inflammatory ulceration and damage to the intestine. Mechanisms underlying impaired healing are not defined. Because microvascular dysfunction resulting in diminished vasodilatory capacity and tissue hypoperfusion is associated with impaired wound healing, we hypothesized that microvascular dysfunction may also occur in chronic IBD. METHODS: Intact submucosal arterioles from control, involved, and uninvolved IBD specimens were assessed using in vitro videomicroscopy to assess endothelium-dependent vasodilation in response to acetylcholine (Ach) and fluorescence microscopy to detect oxyradicals. RESULTS: Normal microvessels dilated in a dose-dependent and endothelium-dependent manner to Ach (maximum, 82% +/- 2%; n = 34). Inhibition of nitric oxide synthase with N(G)-nitro-L-arginine methyl ester (L-NAME) reduced maximal dilation to 54% +/- 6% (P < 0.05, n = 7), and further reduction was observed after inhibiting cyclooxygenase (indomethacin; 23% +/- 10%, n = 6). Chronically inflamed IBD microvessels showed significantly reduced Ach-induced vasodilation (maximum, 15% +/- 2%; n = 33), with no effect of L-NAME. Indomethacin eliminated the remaining Ach-induced vasodilation, resulting in frank vasoconstriction (-54% +/- 9%, n = 6). Uninvolved IBD gut vessels and non-IBD inflammatory controls responded in a fashion similar to normal vessels. IBD-involved microvessels generated significantly higher levels of reactive oxygen species compared with control and uninvolved IBD vessels (P < 0.01). CONCLUSIONS: Human intestinal microvessels from chronically inflamed IBD show microvascular endothelial dysfunction, characterized by loss of NO-dependent dilation that may contribute to reduced perfusion, poor wound healing, and maintenance of chronic inflammation.

Book DT, Smith TL, McNamar JP, Saeian K, Binion DG, Toohill RJ. · Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. · Am J Rhinol. · Pubmed #12751702 No free full text.

Abstract: BACKGROUND: The objective of this study was to explore the possible relationship between inflammatory bowel disease (IBD) and chronic sinonasal disease. METHODS: A cross-sectional study was undertaken of 241 patients with Crohn's disease (CD) or ulcerative colitis from a tertiary medical center IBD clinic. Patient demographic data and information regarding IBD diagnosis and management, sinonasal disease diagnosis and management, and complications related to these diagnoses were gathered by retrospective chart review and a standardized patient survey. RESULTS: One hundred sixty surveys (67%) were returned and analyzed. Overall 48% of patients with IBD reported chronic sinonasal disease symptoms. Patients with CD had a higher prevalence of sinonasal disease than patients with ulcerative colitis (53% versus 32%; p < 0.02). The subgroup of CD patients with obstructive bowel complications had the highest prevalence of sinonasal disease (68% versus 27%; p = < 0.001), with 23% reporting chronic rhinosinusitis, 13% reporting chronic rhinitis, and an additional 32% reporting chronic nasal or sinus symptoms. CONCLUSION: The prevalence of chronic sinonasal disease is elevated in patients with IBD, occurring in approximately one-half of patients followed at a tertiary IBD center. Patients with CD experiencing obstructive complications had significantly increased rates of sinonasal disease. The relationship between chronic sinonasal disease and obstructive CD is not defined, but several hypotheses are generated.

Ina K, Kusugami K, Shimada M, Tsuzuki T, Nishio Y, Binion DG, Imada A, Ando T. · First Department of Internal Medicine, Nagoya University School of Medicine, Japan. · Inflamm Bowel Dis. · Pubmed #11837932 No free full text.

Abstract: An intravenous infusion of cyclosporine A (CsA) shows clinical benefits in patients with steroid-resistant ulcerative colitis (UC). To clarify its mechanisms, we investigated the ability of CsA to inhibit the functions of neutrophils and T cells. The cytotoxic activity by mucosal T cells was analyzed by anti-CD3-triggered cytotoxicity after lamina propria mononuclear cells were cultured with recombinant interleukin (IL)-2. The chemotactic response, the generation of superoxide, and the production of chemokines, IL-8, and macrophage inflammatory protein-1alpha by neutrophils were examined using a multiple-well chamber assay, a chemiluminescence method, and an enzyme-linked immunosorbent assay (ELISA), respectively. Mucosal chemokine activity was determined by an ELISA using the organ culture supernatant of mucosal biopsy tissues. Pretreatment with CsA caused consistent inhibitions of cytotoxic activity by mucosal T cells and chemotactic migration, superoxide generation, and chemokine production by neutrophils mostly in a dose-dependent manner. In patients who received an intravenous infusion of CsA, mucosal chemokine activity decreased after therapy in parallel with decreases in the numbers of neutrophils and mononuclear cells in the biopsy tissues. These results suggest that suppressive effects of CsA on neutrophils and T cells may be related to therapeutic benefits in patients with steroid-resistant UC.

Ina K, Itoh J, Fukushima K, Kusugami K, Yamaguchi T, Kyokane K, Imada A, Binion DG, Musso A, West GA, Dobrea GM, McCormick TS, Lapetina EG, Levine AD, Ottaway CA, Fiocchi C. · Division of Gastroenterology, Molecular Cardiovascular Research Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. · J Immunol. · Pubmed #10395708 links to  free full text

Abstract: Crohn's disease (CD) is a condition characterized by excessive numbers of activated T cells in the mucosa. We investigated whether a defect in apoptosis could prolong T cell survival and contribute to their accumulation in the mucosa. Apoptotic, Bcl-2+, and Bax+ cells in tissue sections were detected by the TUNEL method and immunohistochemistry. T cell apoptosis was induced by IL-2 deprivation, Fas Ag ligation, and exposure to TNF-alpha and nitric oxide. TUNEL+ leukocytes were few in control, CD, and ulcerative colitis (UC) mucosa, with occasional CD68+ and myeloperoxidase+, but no CD45RO+, apoptotic cells. Compared with control and UC, CD T cells grew remarkably more in response to IL-2 and were significantly more resistant to IL-2 deprivation-induced apoptosis. CD T cells were also more resistant to Fas- and nitric oxide-mediated apoptosis, whereas TNF-alpha failed to induce cell death in all groups. Compared with control, CD mucosa contained similar numbers of Bcl-2+, but fewer Bax+, cells, while UC mucosa contained fewer Bcl-2+, but more Bax+, cells. Hence, the Bcl-2/Bax ratio was significantly higher in CD and lower in UC. These results indicate that CD may represent a disorder where the rate of T cell proliferation exceeds that of cell death. Insufficient T cell apoptosis may interfere with clonal deletion and maintenance of tolerance, and result in inappropriate T cell accumulation contributing to chronic inflammation.