Safety of infliximab in Crohn's disease: a large single-center experience.

BACKGROUND: The aim of this study was to evaluate the short- and long-term safety experience of infliximab treatment in patients with Crohn's disease (CD) in clinical practice. METHODS: The medical records of 297 consecutive patients with CD treated with infliximab at the Beth Israel Deaconess Medical Center were reviewed for demographic features and adverse events. RESULTS: The 297 patients received a total of 1794 infusions. Patients received a median of four infusions and had a median follow-up of 14.3 months. Forty-four patients (15%) experienced a serious adverse event, requiring the infusion to be stopped in 33 patients (11%). Acute infusion reactions occurred in 18 patients (6%) including respiratory problems in 10 patients (3%) and an anaphylactoid reaction in 1 patient (0.3%). Serum sickness-like disease occurred in one patient (0.3%) and three patients (1%) developed drug-induced lupus. One patient developed a probable new demyelination disorder. Eight patients (2.7%), all of whom were on concurrent immunosuppressants, developed a serious infection, one resulting in fatal sepsis. Six patients (2%) developed malignancies including two lymphomas and two skin cancers. A total of four (1.3%) deaths were observed (median age 72.5 years); two due to gastrointestinal bleeding, one due to sepsis, and one due to malignancy. CONCLUSIONS: While short- and long-term infliximab therapy was generally well tolerated, serious adverse events occurred in 15% of patients including drug-induced lupus, fatal sepsis, and malignancy. Concomitant immunosuppressants were significantly associated with infections and deaths, particularly among elderly patients.

Glucocorticoid resistance in inflammatory bowel disease.

Glucocorticoids are potent inhibitors of T cell activation and proinflammatory cytokines and are highly effective treatment for active inflammatory bowel disease (IBD). However, failure to respond, acutely or chronically, to glucocorticoid therapy is a common indication for surgery in IBD, with as many as 50% of patients with Crohn's disease (CD) and approximately 20% of patients with ulcerative colitis (UC) requiring surgery in their lifetime as a result of poor response to glucocorticoids. Studies report that approximately one-third of patients with CD are steroid dependent and one-fifth are steroid resistant while approximately one-quarter of patients with UC are steroid dependent and one-sixth are steroid resistant. While the molecular basis of glucocorticoid resistance has been widely assessed in other inflammatory conditions, the pathophysiology of the glucocorticoid resistance in IBD is poorly understood. Research in IBD suggests that the phenomenon of glucocorticoid resistance is compartmentalised to T-lymphocytes and possibly other target inflammatory cells. This review focuses on three key molecular mechanisms of glucocorticoid resistance in IBD: (i) decreased cytoplasmic glucocorticoid concentration secondary to increased P-glycoprotein-mediated efflux of glucocorticoid from target cells due to overexpression of the multidrug resistance gene (MDR1); (ii) impaired glucocorticoid signaling because of dysfunction at the level of the glucocorticoid receptor; and (iii) constitutive epithelial activation of proinflammatory mediators, including nuclear factor kappa B, resulting in inhibition of glucocorticoid receptor transcriptional activity. In addition, the impact of disease heterogeneity on glucocorticoid responsiveness and recent advances in IBD pharmacogenetics are discussed.

P-glycoprotein-170 inhibition significantly reduces cortisol and ciclosporin efflux from human intestinal epithelial cells and T lymphocytes.

AIM: To assess the role of P-glycoprotein-170 (P-gp) in transporting cortisol and ciclosporin from human intestinal epithelium and T lymphocytes. METHODS: The effect of P-gp inhibitors (verapamil, 0-100 microM; PSC 833, 0-20 microM) on the intracellular accumulation of 3H-cortisol and 3H-ciclosporin was studied in confluent layers of human Caco-2 cells (n=6), a P-gp-dependent absorptive intestinal epithelial cell phenotype, and moderately resistant MDRhigh CEM/VBL 100 T cells (n=6). The transport of 3H-vinblastine, a strong multidrug resistance (MDR) substrate, and 3H-progesterone, a poor MDR substrate, was also studied. RESULTS: Caco-2 cells had a 2.4-, 6.6-, 6.7- and 1.03-fold higher net basal to apical transport (efflux) of 3H-cortisol, 3H-ciclosporin, 3H-vinblastine and 3H-progesterone, respectively. PSC 833 (20 microM) reduced cortisol efflux by 69% (0.23 +/- 0.04 to 0.07 +/- 0.01 pmol/cm2/h, P < 0.05) and ciclosporin efflux by 76% (11.1 +/- 1.4 to 2.7 +/- 0.6 pmol/cm2/h, P < 0.001). MDRlow CEM T cells had a 1.4-, 1.9-, 3.2- and 1.02-fold higher intracellular accumulation of cortisol, ciclosporin, vinblastine and progesterone than MDRhigh CEM/VBL 100 T cells. Increasing concentrations of PSC 833 (> 0.1 microM) and verapamil (> 1 microM) restored the intracellular level of 3H-cortisol and 3H-ciclosporin in MDRhigh CEM/VBL 100 T cells to that of MDRlow CEM cells with little change in accumulation in the MDRlow parental cell line. CONCLUSIONS: P-gp inhibitors significantly increase intracellular cortisol and ciclosporin levels in human intestinal epithelium and T lymphocytes in a dose-dependent manner, demonstrating a potential mechanism for overcoming poor response to immunosuppressant therapy in refractory inflammatory bowel disease.

Development of chronic colitis is dependent on the cytokine MIF.

The cytokine macrophage-migration inhibitory factor (MIF) is secreted by a number of cell types upon induction by lipopolysaccharide (LPS). Because colitis is dependent on interplay between the mucosal immune system and intestinal bacteria, we investigated the role of MIF in experimental colitis. MIF-deficient mice failed to develop disease, but reconstitution of MIF-deficient mice with wild-type innate immune cells restored colitis. In addition, established colitis could be treated with anti-MIF immunoglobulins. Thus, murine colitis is dependent on continuous MIF production by the innate immune system. Because we found increased plasma MIF concentrations in patients with Crohn's disease, these data suggested that MIF is a new target for intervention in Crohn's disease.

Clostridium difficile.

Clostridium difficile is a major cause of antibiotic-associated diarrhea and colitis. The incidence of infection with this organism is increasing in hospitals worldwide, consequent to the widespread use of broad-spectrum antibiotics. Pathogenic strains of C. difficile produce two protein exotoxins, toxin A and toxin B, that cause colonic mucosal injury and inflammation. Many patients who are colonized are asymptomatic, and recent evidence indicates that diarrhea and colitis occur in those individuals who lack a protective antitoxin immune response. In patients who do develop symptoms, the spectrum of C. difficile disease ranges from mild diarrhea to fulminant pseudomembranous colitis. Prevention of nosocomial C. difficile infection involves judicious use of antibiotics and multidisciplinary infection control measures to reduce environmental contamination and patient cross-infection. Ultimately, active or passive immunization against C. difficile may be an effective means of controlling the growing problem of nosocomial C. difficile diarrhea and colitis.

The combination of stricture dilation, endoscopic needle aspiration, and biliary brushings significantly improves diagnostic yield from malignant bile duct strictures.

BACKGROUND: Brush cytology, routinely performed at ERCP to assess malignant-appearing biliary strictures, is limited by relatively low sensitivity and negative predictive value. This study assessed whether the combination of stricture dilation, endoscopic needle aspiration, and biliary brushing improves diagnostic yield. METHODS: In a prospective nonrandomized study, 46 consecutive patients were evaluated with malignant-appearing biliary strictures at ERCP. Twenty-four patients (Group A) underwent standard brush cytology alone and 22 patients (Group B) underwent stricture dilatation to 10F, endoscopic needle aspiration, and subsequent biliary brushing by using the Howell biliary system. The diagnostic yields for both techniques were compared. RESULTS: Of the 46 patients, 34 had proven malignant strictures (14 Group A, 20 Group B). Compared with brushing alone, the combination of stricture dilatation, endoscopic needle aspiration, and subsequent biliary brushing significantly increased both the sensitivity (57% vs. 85%, p < 0.02) and specificity (80% vs. 100%, p < 0.02) of cytology with positive brushings in all patients with pancreatic or gallbladder carcinoma. CONCLUSIONS: The combination of stricture dilation, endoscopic needle aspiration, and biliary brushing significantly improves diagnostic yield for malignant bile duct strictures and may particularly be of benefit for extrinsic strictures caused by pancreatic or gallbladder carcinoma.

Vaccines: an ongoing promise?

Over the past decade, intensive research has focused on developing a vaccine therapy for Helicobacter pylori. Substantial unresolved questions cloud the current approach, and the development of a vaccine against this unique organism has proved very challenging. Many candidate vaccines have been tested in animal models. The immunogenicity and the safety of some vaccine formulations have been recently evaluated through clinical trials, and the efficacy of these vaccine therapies in humans will be determined in the near future. This article will provide an overview of the current knowledge of natural and vaccine-induced immune responses to H. pylori infection. It will also review past vaccine successes and failures in animal models and the limited experience to date in using vaccine therapy in humans. Several obstacles to H. pylori vaccine development efforts along with the future direction of these efforts will be discussed.

Potential impact of magnetic resonance cholangiopancreatography on endoscopic retrograde cholangiopancreatography workload and complication rate in patients referred because of abdominal pain.

BACKGROUND AND STUDY AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) has a significant mortality, morbidity, and failed cannulation rate. Magnetic resonance cholangiopancreatography (MRCP) is a safer, noninvasive method of imaging the pancreaticobiliary tree. A substantial number of patients are referred for ERCP because of abdominal pain, a high proportion of whom have normal ducts or pathology not requiring interventional ERCP. The aim was to assess the potential impact of MRCP on overall ERCP workload and patient outcome if MRCP were the primary investigation in patients referred for ERCP because of abdominal pain. PATIENTS AND METHODS: 1758 consecutive ERCPs performed in 1148 patients over a 3-year period in a single tertiary referral center in the pre-MRCP era were reviewed. Cannulation failure, ERCP findings, need for follow-up ERCP and all 30-day major complication rates were analyzed with regard to clinical indications. RESULTS: The overall workload comprised 1108 (63 %) successful initial ERCPs, 188 (11 %) failed cannulation attempts and 462 (26 %) follow-up ERCPs. Of the patients, 299 (27 %) had normal ERCP findings, 331 (30 %) had choledocholithiasis and 246 (22 %) had strictures. lf MRCP had been used as the primary imaging investigation in the 451 patients (39 %) referred for ERCP because of abdominal pain, we estimate that 197 patients (44 %) would have avoided ERCP, and the overall ERCP workload would have been reduced by 13 %. Initial MRCP in suspected gallstone pancreatitis and certain miscellaneous groups, it was estimated, would have further decreased ERCP workload by 9 %. Four of 40 major ERCP-related complications (3.5 %) and one of four ERCP-related deaths (0.35 %) would potentially have been avoided. CONCLUSIONS: Initial MRCP in patients referred with abdominal pain would potentially have avoided ERCP in 44 % of cases, reduced ERCP workload by 13 % and significantly reduced patient morbidity and mortality. The relatively small reduction in ERCP workload among these patients reflects the fact that over half of them had probable sphincter dysfunction, a significant proportion of whom might have benefited from biliary manometry and/or endoscopic intervention despite a normal MRCP. Furthermore, a small number of patients with calculi and subtle biliary and pancreatic strictures would be missed by this approach.

Gastroenterological causes of pelvic pain.

Chronic pelvic pain is a common condition, which accounts for up to 10% of gynecological consultations and for over a third of diagnostic laparoscopies. In addition to gynecological etiologies for the pelvic pain, the physician must also consider gastroenterological, urological, and neurological disease as a possible basis for the pain. This article discusses the major gastroenterological causes of pelvic pain.

Diverticular disease in the elderly.

Diverticular disease is common among the elderly. Because of the advanced age and muted symptoms and signs of many of those affected, diagnosis can be difficult. Consequently, great demands are placed on the physician to diagnose and treat clinically evident diverticular disease. Endoscopic, radiologic, and surgical advances have increased the availability of more definitive therapies for patients with complicated diverticular disease and diverticular hemorrhage.

State-of-the-art ultrasonography is as accurate as helical computed tomography and computed tomographic angiography for detecting unresectable periampullary cancer.

OBJECTIVE: To compare the ability of state-of-the-art ultrasonography with that of helical computed tomography and computed tomographic angiography in detecting unresectable periampullary cancer. In most patients periampullary cancer is unresectable because of either distant metastasis or local vascular involvement. The advent of gray scale and color Doppler ultrasonography has improved the ability of ultrasonography to detect vascular involvement. METHODS: Twenty-three consecutive patients with periampullary cancer were enrolled for prospective staging of their disease by comparing helical computed tomography and computed tomographic angiography with gray scale and color Doppler ultrasonography of the abdomen. Portal vein, superior mesenteric vein, splenic vein, and superior mesenteric artery involvement was graded 0 to 4, grade 0 being no vascular involvement and grade 4 being total occlusion of the vessel. Agreement between ultrasonography and computed tomographic angiography for determining vascular involvement was measured by chi2 analysis. RESULTS: Two patients (9%) were excluded because excessive overlying bowel gas hampered the ability of ultrasonography to visualize the pancreas. For the remaining 21 patients, there was significant agreement between ultrasonography and computed tomographic angiography for detecting vascular involvement in all vessels (P < .001; portal vein, kappa = 0.67; superior mesenteric vein, kappa = 0.67; splenic vein, kappa = 0.85; and superior mesenteric artery, kappa = 0.59). Ultrasonography was in agreement with computed tomographic angiography in all cases of unresectability. Both modalities were equally poor in preoperatively showing lymphadenopathy and metastases. CONCLUSIONS: Provided that there is adequate visualization on ultrasonography of the head of the pancreas in the periampullary region, then state-of-the-art gray scale and color Doppler ultrasonography are as accurate as helical computed tomography and computed tomographic angiography for detecting the unresectability of periampullary cancer. If performed as the initial investigation and the region of the pancreatic head is clearly shown, and if vascular encasement or occlusion or distant metastasis is identified, further investigations are unnecessary.

Recent advances in inflammatory bowel disease.

The last decade has seen tremendous advances in our knowledge, which has led to genuine improvements in our understanding of the pathogenesis and management of inflammatory bowel disease (IBD). The combined power of cellular and molecular biology has begun to unveil the enigmas of IBD, and, consequently, substantial gains have been made in the treatment of IBD. Refinements in drug formulation have provided the ability to target distinct sites of delivery, while enhancing the safety and efficacy of older agents. Simultaneous progress in biotechnology has fostered the development of new agents that strategically target pivotal processes in disease pathogenesis. This article addresses our current understanding of the pathogenesis of IBD, including the latest developments in animal models and covers agents currently used in the treatment of IBD as well as emerging therapies.

Diagnostic and therapeutic ERCP: a large single centre's experience.

BACKGROUND: Most large published series on endoscopic retrograde cholangiopancreatography (ERCP) are multicentre-based and consequently reflect varying experience. AIMS: To assess morbidity and mortality rates of ERCP in a single tertiary referral centre. METHODS: A series of 1,758 consecutive ERCPs performed in 1,148 patients between 1991 and 1994 were reviewed to evaluate indications, findings, procedures, success, complication and mortality rates. RESULTS: There were 1,108 (63%) successful initial ERCPs, 11% failed cannulation attempts and 26% follow-up ERCPs. The desired duct was successfully cannulated in 96.5% of cases. Initial cannulation failure rate was 8.8%. Twenty-seven per cent had normal ERCPs, 30% had choledocholithiasis and 22% had strictures. Fifty-five per cent had therapeutic ERCPs. Major complications occurred in 3.5% with four ERCP-related deaths (0.35%). Therapeutic ERCP had a higher incidence of major complications compared to diagnostic ERCP: 4.6% vs 2.1%, (p=0.02); and mortality rate was 0.5% vs 0.2%, (p=0.4). Significant haemorrhage secondary to biliary sphincterotomy, pre-cut papillotomy and snare papillectomy accounted for most of the difference (1.6%). CONCLUSIONS: The majority of ERCPs were performed in elderly patients, over half of whom required therapeutic ERCP. Therapeutic ERCP carried significantly higher complication rate compared with diagnostic ERCP. Unsuccessful cannulation and follow-up ERCP accounted for 11% and 26% of ERCP workload, respectively.

Diagnosis of celiac sprue.

Celiac sprue is a common lifelong disorder affecting 0.3-1% of the Western world and causing considerable ill health and increased mortality, particularly from lymphoma and other malignancies. Although high prevalence rates have been reported in Western Europe, celiac sprue remains a rare diagnosis in North America. Whether celiac sprue is truly rare among North Americans or is simply underdiagnosed is unclear, although serological screening of healthy American blood donors suggests that a large number of American celiacs go undiagnosed. Celiac sprue is an elusive diagnosis, and often its only clue is the presence of iron or folate deficiency anemia or extraintestinal manifestations, such as osteoporosis, infertility, and neurological disturbances. The challenge for gastroenterologists and other physicians is to identify the large population of undiagnosed patients that probably exists in the community and offer them treatment with a gluten-free diet that will restore the great majority to full health and prevent the development of complications. The advent of highly sensitive and specific antiendomysium and tissue transglutaminase serological tests has modified our current approach to diagnosis and made fecal fat and D-xylose absorption testing obsolete. A single small bowel biopsy that demonstrates histological findings compatible with celiac sprue followed by a favorable clinical and serological response to gluten-free diet is now considered sufficient to definitely confirm the diagnosis. We review the wide spectrum of celiac sprue, its variable clinical manifestations, and the current approach to diagnosis.

Utility of intravenously administered contrast material at CT colonography.

PURPOSE: To determine if intravenously administered contrast material improves overall reader confidence in the assessment of the colon, large-bowel wall conspicuity, and diagnostic accuracy in the detection of colorectal polyps and cancers at computed tomographic (CT) colonography. MATERIALS AND METHODS: Two hundred patients underwent CT colonography in both supine and prone positions. A five-point scale was used to assess the effect of contrast enhancement on overall reader confidence and bowel wall conspicuity. Eighty-one patients underwent CT colonography with complete colonoscopic or surgical correlation; diagnostic accuracy was compared in 48 patients who received contrast material and 33 who did not. RESULTS: Bowel preparation was ideal in 38 (19%) of 200 patients. Enhanced prone CT images had significantly better scores for reader confidence (4.9 +/- 0.1 vs 4.6 +/- 0.1, P: <.005) and bowel wall conspicuity (4.6 +/- 0.2 vs 4.2 +/- 0.2, P: <.005) compared with those of nonenhanced prone images despite no significant difference in bowel distention (3.8 +/- 0.2 vs 3.9 +/- 0. 1, P: =.8). Enhancement significantly improved the ability to depict medium (6-9-mm) polyps (75% vs 58%, P: <.05). Three large (10-19-mm) polyps were detected only with contrast enhancement; two remained submerged despite dual positioning. CONCLUSION: The use of intravenously administered contrast material significantly improved reader confidence in the assessment of bowel wall conspicuity and the ability of CT colonography to depict medium polyps in suboptimally prepared colons.