Richard J. Farrell

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 Crohns disease, these data suggested that MIF is a new target for intervention in Crohns disease.

High multidrug resistance (P-glycoprotein 170) expression in inflammatory bowel disease patients who fail medical therapy

BACKGROUND & AIMS The multidrug resistance (MDR) gene codes for a drug efflux pump P-glycoprotein 170 (Pgp-170) expressed on the surface of lymphocytes and intestinal epithelial cells. Inflammatory bowel disease (IBD) poorly responsive to medical therapy may relate to MDR expression because glucocorticoids are known Pgp-170 substrates. METHODS Using flow cytometry, we measured peripheral blood lymphocyte (PBL) MDR in 153 IBD patients and 50 healthy volunteers, and assessed the relationship between PBL, mucosal intraepithelial lymphocyte (IEL), and mucosal epithelial cell (EC) MDR expression in a further 20 IBD patients and 19 controls. RESULTS Compared with controls, PBL MDR was significantly elevated in patients with Crohns disease who required bowel resection for failed medical therapy (mean +/- SEM, 26.7 +/- 2.8 vs. 11.9 +/- 1.0; P <0.0001) and patients with ulcerative colitis who required proctocolectomy for failed medical therapy (20.3 +/- 2.5 vs. 11.9 +/- 1.0; P = 0.001). PBL MDR remained stable over time and was not influenced by disease activity or glucocorticoid therapy. Both PBL and mucosal MDR expression appeared independent of disease activity, and there was a significant correlation between PBL MDR expression and both IEL expression (r = 0.92; P < 0.0001) and EC expression (r = 0.54; P < 0.001). CONCLUSIONS PBL and mucosal MDR expression may play an important role in determining the response of IBD patients to glucocorticoid therapy.

Clinical experience with infliximab therapy in 100 patients with Crohn's Disease

OBJECTIVE:The aim of this study was to assess our clinical experience with infliximab, a monoclonal antitumor necrosis factor antibody, following its approval for treatment of refractory Crohns disease (CD).METHODS:We followed 100 consecutive patients with CD (53 women and 47 men; mean age, 41 yr) who received a total of 233 infliximab (5 mg/kg) infusions. Adverse events were noted and clinical response assessed every 2 wk for 6 months after each infusion using the Harvey Bradshaw Index (HBI) for active disease, the Perianal Disease Activity Index (PDAI) for fistulous disease, and steroid withdrawal rates for steroid-sparing efficacy.RESULTS:Indications for therapy were active disease (n = 57), perianal fistulous disease (n = 33), and steroid dependency (n = 10). Significant infusion reactions occurred in 16 patients (6.9% of infusions) including anaphylactic shock in one patient. Fourteen patients experienced infectious adverse events, 13 of whom were on concurrent steroids. Sixty percent of patients with active disease experienced ≥50% HBI reduction at 2 wk; mean duration of response, 8.2 wk. Three of 26 first-time nonresponders with active disease (12%) responded to a second infusion. Sixty-nine percent of patients with fistulous disease experienced >50% reduction in their PDAI at 2 wk; mean duration of response, 10.9 wk. Four of 10 steroid-dependent patients (40%) discontinued steroid therapy, one of whom recommenced steroid therapy at 24 wk.CONCLUSIONS:Our clinical response rates mirror the efficacy reported in the controlled trials for active and fistulous disease. Steroid-sparing efficacy was seen in 40% of steroid-dependent patients. Concurrent steroids did not reduce the risk of significant infusion reactions (6.9%), but did increase the risk of infections.

Increased incidence of non-Hodgkin's lymphoma in inflammatory bowel disease patients on immunosuppressive therapy but overall risk is low

BACKGROUND There is concern that the incidence of non-Hodgkins lymphoma (NHL) will rise with increasing use of immunosuppressive therapy. AIMS Our aim was to determine the risk of NHL in a large cohort of patients with inflammatory bowel disease (IBD), and to study the association between IBD, NHL, and immunosuppressive therapy. METHODS We studied 782 IBD patients (238 of whom received immunosuppressive therapy) who attended our medical centre between 1990 and 1999 (median follow up 8.0 years). Standardised incidence ratios (SIRs) and 95% confidence intervals (CI) were calculated. Expected cases were derived from 1995 age and sex specific incidence rates recorded by the National Cancer Registry of Ireland. RESULTS There were four cases of NHL in our IBD cohort (SIR 31.2; 95% CI 2.0–85; p=0.0001), all of whom had received immunosuppressive therapy: azathioprine (n=2), methotrexate (n=1), and methotrexate and cyclosporin (n=1). Our immunosuppressive group had a significantly (59 times) higher risk of NHL compared with that expected in the general population (p=0.0001). Three cases were intestinal NHL and one was mesenteric. Mean age at NHL diagnosis was 49 years, mean duration of IBD at the time of NHL diagnosis was 3.1 years, and mean duration between initiation of immunosuppressive therapy and diagnosis of NHL was 20 months. CONCLUSIONS Although underlying IBD may be a causal factor in the development of intestinal NHL, our experience suggests that immunosuppressive drugs can significantly increase the risk of NHL in IBD. This must be weighed against the improved quality of life and clinical benefit immunosuppressive therapy provides for IBD patients.

Microbial factors in inflammatory bowel disease

An unsolved puzzle in IBD research is whether germs, genes, or a combination of the two with excessive immune responses to gut-associated bacteria explains the pathogenesis of UC and CD. Whatever the answer, there is little doubt that microbial factors are involved intimately in IBD pathogenesis. Although a long search has failed to confirm a direct pathogenic role for a specific infectious agent, compelling evidence suggests that commensal enteric bacteria and their products provide a local environmental trigger that initiates and perpetuates IBD, reactivates quiescent disease, results in the frequent septic complications of CD, and contributes to the development of several extraintesinal manifestations. The most compelling evidence for involvement of the enteric flora in the pathogenesis of IBD has been generated from studies of animal models, which collectively support the view that IBD is due to genetically determined dysregulation of the mucosal immune response to luminal antigens derived from the normal bacterial flora. Although removing or dampening the dominant antigenic stimuli with antibiotics or probiotics is conceptually superior to the current array of immunosuppressive and anti-inflammatory agents that nonspecifically block the inflammatory cascade, more definitive, rigorously designed, controlled trials of treatments directed at the microflora are needed. Future research investigating mechanisms of tolerance to luminal bacteria and an understanding of how probiotics can manipulate the intestinal flora beneficially will bring clinicians closer to identifying potential therapeutic targets and unraveling the bacterial connection to IBD pathogenesis.

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.

Role of virtual computed tomographic colonography in patients with colorectal cancers and obstructing colorectal lesions

PURPOSE: The aim of this study was to assess the ability of computed tomographic colonography to diagnose colorectal masses, stage colorectal cancers, image the proximal colon in obstructing colorectal lesions, and evaluate the anastomoses in patients with previous colorectal surgery. METHODS: We prospectively performed computed tomographic colonography examinations in 34 patients (20 males; mean age, 64.2; range, 19–91 years): 20 patients had colorectal masses (defined at endoscopy as intraluminal masses 2 cm or larger), 7 patients had benign obstructing colorectal strictures, and 7 patients had a prior colorectal resection. Final tumor staging was available in all 16 patients who had colorectal cancers and 15 patients were referred after incomplete colonoscopy. The ability of computed tomographic colonography to stage colorectal cancers, identify synchronous lesions in patients with colorectal masses, and image the proximal colon in patients with obstructing colorectal lesions was assessed. RESULTS: Computed tomographic colonography identified all colorectal masses, but overcalled two masses in patients who were either poorly distended or poorly prepared. Computed tomographic colonography correctly staged 13 of 16 colorectal cancers (81 percent) and detected 16 of 17 (93 percent) synchronous polyps. Computed tomographic colonography overstaged two Dukes Stage A cancers and understaged one Dukes Stage C cancer. A total of 97 percent (87/90) of all colonic segments were adequately visualized at computed tomographic colonography in patients with obstructing colorectal lesions compared with 60 percent (26/42) of segments at barium enema (P<0.01). Colonic anastomoses were visualized in all nine patients, but in one patient, computed tomographic colonography could not distinguish between local tumor recurrence and surgical changes. CONCLUSION: Computed tomographic colonography can accurately identify all colorectal masses but may overcall stool as masses in poorly distended or poorly prepared colons. Computed tomographic colonography has an overall staging accuracy of 81 percent for colorectal cancer and is superior to barium enema in visualizing colonic segments proximal to obstructing colorectal lesions.

Risk of early surgery for Crohn's disease: implications for early treatment strategies.

OBJECTIVES:In this study we aimed to define the rate of early surgery for Crohns disease and to identify risk factors associated with early surgery as a basis for subsequent studies of early intervention in Crohns disease.METHODS:We assembled a retrospective cohort of patients with Crohns disease diagnosed between 1991 and 1997 and followed for at least 3 yr, who were identified in 16 community and referral-based practices in New England. Chart review was performed for each patient. Details of baseline demographic and disease features were recorded. Surgical history including date of surgery, indication, and procedure were also noted. Risk factors for early surgery (defined as major surgery for Crohns disease within 3 yr of diagnosis, exclusive of major surgery at time of diagnosis) were identified by univariate analysis. Multiple logistic regression was used to identify independent risk factors.RESULTS:Of 345 eligible patients, 69 (20.1%) required surgery within 3 yr of diagnosis, excluding the 14 patients (4.1%) who had major surgery at the time of diagnosis. Overall, the interval between diagnosis and surgery was short; one half of all patients who required surgery underwent operation within 6 months of diagnosis. Risk factors identified by univariate analysis as significantly associated with early surgery included the following: smoking; disease of small bowel without colonic involvement; nausea and vomiting or abdominal pain on presentation; neutrophil count; and steroid use in the first 6 months. Disease localized to the colon only, blood in the stool, use of 5-aminosalicylate, and lymphocyte count were inversely associated with risk of early surgery. Logistic regression confirmed independent associations with smoking as a positive risk factor and involvement of colon without small bowel as a negative risk factor for early surgery.CONCLUSIONS:The rate of surgery is high in the first 3 yr after diagnosis of Crohns disease, particularly in the first 6 months. These results suggest that improved risk stratification and potent therapies with rapid onset of action are needed to modify the natural history of Crohns disease.

Endoscopy in inflammatory bowel disease: indications, surveillance, and use in clinical practice.

Endoscopy plays an integral role in the diagnosis, management, and surveillance of inflammatory bowel disease (IBD). Because there is no single pathognomonic test that establishes the diagnosis of IBD, endoscopy is useful in establishing the diagnosis, excluding other etiologies, distinguishing Crohns disease from ulcerative colitis, defining the patterns, extent, and activity of mucosal inflammation, and obtaining mucosal tissue for histologic evaluation. In established IBD, endoscopy helps define the extent and severity of involvement, which in turn influences medical and surgical decisions, aids in targeting medical therapies, and allows for the management of IBD-related complications. Furthermore, endoscopy plays a key role in the surveillance of patients with long-standing colitis who are at increased risk for dysplasia and the development of colorectal cancer.

Guided versus blind liver biopsy for chronic hepatitis C: clinical benefits and costs

BACKGROUND/AIMS Our objectives were: (1) to assess the clinical benefits and costs of performing ultrasound-guided liver biopsy with an automated needle compared to blind biopsy with a conventional Trucut needle in patients with chronic hepatitis C; (2) to compare the histological yield of automated needles with Trucut needles. METHODS We prospectively studied 166 patients with hepatitis C virus who underwent either ultrasound-guided biopsy using automated ASAP needles or blind biopsy using conventional Trucut needles. Both groups were matched for age, sex, cirrhosis, needle gauge and operator experience. Patient tolerance, complications and histological adequacy were assessed. In a separate in vitro study, we assessed the histological adequacy of liver biopsy specimens obtained using automated and Trucut needles from 10 fresh autopsy cases. RESULTS Ultrasound-guided biopsy caused significantly less biopsy pain (36.4% vs. 47.3%; p < 0.0001) and significantly less pain-related morbidity (1.8% vs. 7.7%, p < 0.05). Although, there was no significant difference in diagnostic yield between guided and blind biopsy (98% vs. 94%, p = 0.15), 3 blind biopsies (3.3%), including 2 which yielded extra-hepatic tissue, had to be repeated. The additional expense of performing guided liver biopsy with automated needles was 42 Irish Pounds per patient. In vitro, automated ASAP 15G needles provided liver specimens comparable to Trucut 15G needles and had the highest histopathologic score among the automated needles assessed. CONCLUSIONS Even in the absence of major complications, ultrasound-guided liver biopsy with an automated needle in HCV patients is safer, more comfortable and only marginally more expensive than blind Trucut biopsy.