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The advent of biological therapy has revolutionized inflammatory bowel disease (IBD) care. Nonetheless, not all patients require biological therapy. Selection of patients depends on clinical characteristics, previous response to other medical therapy, and comorbid conditions. Availability, reimbursement guidelines, and patient preferences guide the choice of first-line biological therapy for luminal Crohn's disease (CD). Infliximab (IFX) has the most extensive clinical trial data, but other biological agents (adalimumab (ADA), certolizumab pegol (CZP), and natalizumab (NAT)) appear to have similar benefits in CD. Steroid-refractory, steroid-dependent, or complex fistulizing CD are indications for starting biological therapy, after surgical drainage of any sepsis. For fistulizing CD, the efficacy of IFX for inducing fistula closure is best documented. Unique risks of NAT account for its labeling as a second-line biological agent in some countries. Patients who respond to induction therapy benefit from systematic re-treatment. The combination of IFX with azathioprine is better than monotherapy for induction of remission and mucosal healing up to 1 year in patients who are naïve to both agents. Whether this applies to other agents remains unknown. IFX is also effective for treatment-refractory, moderate, or severely active ulcerative colitis. Patients who have a diminished or loss of response to anti-tumor necrosis factor (TNF) therapy may respond to dose adjustment of the same agent or switching to another agent. Careful consideration should be given to the reasons for loss of response. There are insufficient data to make recommendations on when to stop anti-TNF therapy. Preliminary evidence suggests that a substantial proportion of patients in clinical remission for >1 year, without signs of active inflammation can remain in remission after stopping treatment.

Objectives: Abdominal colectomy has been used in patients with inflammatory bowel disease unclassified (IBDU), requiring surgery to allow histopathological evaluation of the colectomy specimen to rule out Crohn's disease (CD). We evaluated whether any histopathological feature was associated with an adverse postoperative outcome., Methods: Patients with ulcerative colitis (UC) or IBDU undergoing ileal pouch-anal anastomosis (IPAA) were prospectively examined. A checklist of 17 histopathological features atypical for UC was developed. Outcomes of acute pouchitis (AP), chronic pouchitis (CP), and de novo CD were assessed., Results: The 153 study patients included 119 (78%) UC and 34 (22%) IBDU patients. The following atypical features were identified (n; %): broad-based ulcer (99; 65%), appendiceal involvement (78; 51%), V-shaped ulcer (48; 31%), crypt-associated granuloma (42; 27%), isolated giant cells (39; 25%), discontinuous active inflammation (36; 24%), slit-like fissure (32; 21%), discontinuous chronic inflammation (16; 10%), ileal villous architectural distortion (12; 8%), neural hypertrophy (10; 7%), backwash ileitis (10; 7%), transmural inflammation (8; 5%), discontinuous ileitis (8; 5%), muscle hypertrophy (5; 3%), ileal ulcer (4; 3%), and ileal pyloric metaplasia (1; 1%). A total of 29 patients (19%) developed AP, 17 (11%) developed CP, and 13 patients (8%) developed de novo CD. On univariate analysis, de novo CD developed in 3 of the 10 patients (30%) with neural hypertrophy compared with only 10 of the 143 patients (7%) without neural hypertrophy (P=0.01). Multivariate regression did not show a single atypical histopathological feature, which predicted a worse outcome after IPAA., Conclusions: No single atypical histopathological feature of UC, or combination of features, was associated with any adverse pouch outcome after IPAA. There seems to be no value in performing a staged IPAA in IBDU patients.

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.

Objectives: Confronted with nonspecific symptoms, accurate screening tests would be useful to clinicians to distinguish between functional childhood disorders and inflammatory bowel disease (IBD), thus avoiding invasive diagnostic testing. Traditional ulcerative colitis-specific perinuclear antineutrophil cytoplasmic antibody (pANCA) and Crohn's disease-specific anti-Saccharomyces cerevisiae antibody (ASCA) serodiagnostic assays have recently been modified, with ELISA cut-off values recalculated to maximize sensitivity. The aim of this study was to determine whether the combination of these serodiagnostic tests could maximize diagnostic accuracy and minimize invasive investigations in pediatric patients presenting with nonspecific symptoms suggestive of IBD., Methods: With investigators blinded to clinical diagnoses, ASCA, ANCA, and pANCA profiles were obtained prospectively from 128 patients undergoing complete diagnostic evaluation for IBD. In phase I, diagnostic accuracy and predictive values of the modified and traditional assays were compared for the IBD (n = 54) and non-IBD groups (n = 74). In phase II, the overall accuracy of a novel sequential diagnostic testing strategy was determined. Additionally, the potential number of invasive investigations avoided with the hypothetical application of this strategy to the cohort was determined., Results: For phase I, the modified serodiagnostic assay was more sensitive (81 vs 69%), whereas the traditional assay had a higher specificity (96 vs 72%) for IBD (p < 0.05) For phase II, false-positive diagnoses would have been reduced by 81%, yielding an overall sequential testing strategy accuracy of 84%., Conclusions: The incorporation of sequential noninvasive testing into a diagnostic strategy may avoid unnecessary and costly evaluations and facilitate clinical decision making when the diagnosis of IBD in children is initially uncertain.

Objectives: Irritable bowel syndrome, a common gastrointestinal diagnosis, has not been clearly studied in inflammatory bowel disease. Some of the residual symptoms in subjects treated with Crohn's disease and ulcerative colitis are thought to be related to irritable bowel syndrome. The aims of this study were 1) to describe the duration and nature of complaints before the diagnosis of Crohn's disease and ulcerative colitis (prodromal period), and 2) to determine the role of IBS in this prodromal period., Methods: A total of 66 patients with confirmed inflammatory bowel disease were enrolled in the study. The subjects received a questionnaire to ascertain the nature and duration of symptoms preceding the diagnosis of Crohn's disease or ulcerative colitis, including features described under the Rome criteria for irritable bowel syndrome., Results: Of the 66 subjects analyzed, 45 had Crohn's disease and 21 had ulcerative colitis. The prodromal period was 7.7 +/- 10.7 yr for Crohn's disease and 1.2 +/- 1.8 yr for ulcerative colitis (p < 0.05). Once patients meeting the Rome criteria for irritable bowel syndrome during the prodrome were excluded, the duration of the prodromal period (non-IBS) for ulcerative colitis dropped to 0.8 +/- 1.3 yr compared to 6.9 +/- 9.8 yr in the Crohn's disease group (p < 0.05). The symptoms of the non-IBS prodrome in subjects with Crohn's disease were bloating, diarrhea, stomach pain, heartburn, fever, weight loss, and fatigue. Further analysis demonstrated that subjects whose Crohn's disease initially began as colonic disease had a longer prodrome than with small bowel. In the non-IBS Crohn's group, there was also a correlation between the age at the time of diagnosis and the duration of prodrome (r = 0.67, p < 0.0001)., Conclusions: There is a significant prodromal period before the time of diagnosis of Crohn's disease that is not found in ulcerative colitis even after exclusion of subjects with IBS.

Objective: Cyclosporin-A (CSA) has been demonstrated to be effective for treatment of severe, steroid-resistant ulcerative colitis (UC). Use of CSA has been limited, however, because of low 1-yr response rates and the potential for complications. The aim of this study is to define clinical and laboratory factors predictive of response in severe, steroid-resistant UC., Methods: A retrospective review of 36 cases of severe, steroid-resistant UC treated with CSA was performed. Intravenous (i.v.) CSA was administered at an initial dose of 2.5 mg/kg, and oral (p.o.) CSA was given as twice the i.v. dose. Clinical response was recorded and logistic regression analysis was performed on clinical and laboratory factors for prediction of response to CSA., Results: Of 36 patients, 25 responded to i.v. CSA and were switched to p.o. CSA. Of the 25, 13 required colectomy by 9 months. The other 12 patients had a sustained response to CSA and avoided colectomy at 9 months. Overall, 24 of 36 patients treated with CSA required colectomy by 9 months. A high percentage of band neutrophils (bands) on admission was found to be a significant predictor of response to CSA., Conclusions: Bands on admission are predictive of response to CSA and ultimately, the requirement for surgery in steroid-resistant UC.

Objectives: The aim of this study was to compare the efficacy of mesalamine rectal suspension enema (Rowasa) alone, oral mesalamine tablets (Asacol) alone, and the combination of mesalamine enema and mesalamine tablets in patients with active mild-to-moderate distal ulcerative colitis., Methods: Sixty outpatients with ulcerative colitis at least 5 cm above the anal verge and not more than 50 cm, inclusive, and a total disease activity index (DAI) score between 4 and 10, inclusive, were randomized to either mesalamine rectal enema (n = 18) once nightly, oral mesalamine 2.4 g/day (n = 22), or a combination of both treatments (n = 20). Placebo capsules and enemas were used to maintain a blind procedure. Total DAI scores and abbreviated DAI scores were evaluated at wk 3 and 6, and wk 1 and 2, respectively. Patients recorded the amount of blood in stools, urgency, straining at stools, and abdominal pain in daily diaries. Physicians and patients rated overall improvement at each visit., Results: At wk 6, combination therapy produced a greater improvement (-5.2) in total DAI scores than did either mesalamine enema (-4.4) or mesalamine tablet (-3.9) therapy alone; similar treatment differences were observed at wk 3. Compared with patients given mesalamine enemas or mesalamine tablets, combination-therapy patients reported an absence of blood in stools significantly sooner and, at all visits, the combination therapy group had the highest percentage of patients who reported no blood in their stools. Physicians' and patients' ratings of improvement indicated that combination therapy significantly improved disease status, compared with mesalamine tablet therapy alone. All treatments were well tolerated., Conclusions: The combination of oral and rectal mesalamine therapy was well tolerated and produced earlier and more complete relief of rectal bleeding than oral or rectal therapy alone.

Objective: Primary sclerosing cholangitis is associated with the development of pouchitis after ileal pouch-anal anastomosis for ulcerative colitis. This study determined the effect of liver transplantation for primary sclerosing cholangitis on the disease course of pouchitis., Methods: Seven patients with an ileal pouch-anal anastomosis for ulcerative colitis underwent liver transplantation for primary sclerosing cholangitis. The medical record was reviewed to determine the pouchitis activity and pattern (no pouchitis, single acute, recurrent acute, chronic) before and after transplantation., Results: Five of seven patients had pouchitis before transplant [recurrent acute (n = 3), chronic (n = 2)], and four of those five continued to have pouchitis after transplant (all chronic). Pretransplant sera were positive for antineutrophil cytoplasmic antibody in 6/6 patients, compared to 5/6 patients posttransplant. One patient with pouchitis pretransplant became negative for antineutrophil cytoplasmic antibody posttransplant but continued to have pouchitis., Conclusion: Pouchitis occurs frequently in patients with primary sclerosing cholangitis and an ileal pouch-anal anastomosis for ulcerative colitis. Liver transplantation does not alter the disease course of pouchitis for most of these patients.

Objectives: Studies have suggested that antineutrophil cytoplasmic antibodies (ANCA), known as a useful diagnostic marker in patients with ulcerative colitis (UC), may have a genetic basis, particularly in association with HLA class II genes. Because most studies examining the role of ANCA in UC have been performed in ethnically undefined populations, we have analyzed ANCA status in an ethnically distinct group of patients with UC., Methods: Serum samples from 24 Korean patients with a known diagnosis of UC and 58 healthy Koreans were examined for the presence of ANCA, using a fixed neutrophil enzyme-linked immunosorbent assay. ANCA-binding patterns were examined by indirect immunofluorescence., Results: The incidence of ANCA in 83.3% of Korean patients with UC was significantly higher than in controls (p < 0.0001). The mean binding level at a 1:100 dilution and the titer of ANCA were significantly higher in patients with UC than in controls. Among UC patients with ANCA, there was also a high incidence of perinuclear binding pattern. In contrast, there was no relationship between ANCA and age of patients, duration, activity, or extent of disease., Conclusions: High sensitivity and specificity of ANCA in an ethnically distinct group of patients with UC show that ANCA expression may not be ethnically determined, and they confirm the utility of ANCA as a useful diagnostic indicator of UC in an ethnically diverse groups of patients.

Background: Perinuclear antineutrophil cytoplasmic antibodies, present in 60% of patients with ulcerative colitis, may be a marker for a genetically distinct subset of patients who develop chronic pouchitis after undergoing ileal pouch-anal anastomosis. The frequency of these antibodies in chronic pouchitis was determined., Methods: Four groups were studied: patients who underwent ileal pouch-anal anastomosis for colitis with and without chronic pouchitis, familial polyposis without pouchitis and ileostomy for colitis. Antineutrophil cytoplasmic antibody levels and titers were detected by ELISA, and positive results were confirmed by perinuclear staining with indirect immunofluorescence., Results: The frequency of perinuclear antineutrophil cytoplasmic antibodies in chronic pouchitis (100%) was significantly greater than in colitis (50%) or familial polyposis (0%) without pouchitis and colitis with an ileostomy (70%); p = 0.00, 0.00, and 0.01, respectively., Conclusions: The finding that perinuclear antineutrophil cytoplasmic antibodies occur more frequently in patients with chronic pouchitis raises the possibility that this antibody may mark a genetically distinct subset of ulcerative colitis patients. Further studies are needed to determine whether the presence of this antibody before ileal pouch-anal anastomosis is predictive for later development of chronic pouchitis.