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Background & Aims: Reports of tuberculosis (TB) in patients administered infliximab prompted the Food and Drug Administration to recommend that all patients being considered for this therapy be evaluated for the risk for latent TB infection by means of a tuberculin skin test (TST). The aim of this study is to evaluate the utility of a TST as an adequate screen for TB exposure in patients with inflammatory bowel disease (IBD). Methods: Eighty-two consecutive patients with IBD (Crohn's disease, 70 patients; ulcerative colitis, 4 patients; indeterminate colitis, 8 patients) seen at Cedars-Sinai Medical Center IBD Center (Los Angeles, CA) being treated with or considered for infliximab therapy underwent a standard intradermal purified protein derivative (PPD) TST before or between infusions of infliximab. One or more control antigens (Candida, tetanus, and/or mumps) were concurrently placed on 69 of these patients. Skin tests were read for induration at 48-72 hours after placement, and results were recorded. Results: None of 82 patients had a positive PPD TST result. Overall, 71% of patients (49 of 69 patients) with controls placed failed to react to any antigen. Eighty-three percent of patients (40 of 48 patients) who were administered corticosteroids and/or immunosuppressive medications, not including infliximab, for at least 1 month were anergic compared with 43% of patients (9 of 21 patients; P < 0.002) who were not administered those medications. Conclusions: Given the high prevalence of anergy, a negative TST result in patients with IBD administered infliximab is an unreliable indicator for TB exposure. Evaluation for TB risks should include not only a TST, but also a detailed history of travel, TB exposures, and such symptoms as chronic cough and weight loss, and a chest radiograph should be considered.

Background & Aims: Crohn's disease patients can be characterized by antibody responses against Crohn's disease-related bacterial sequence, Escherichia coli outer membrane porin C, Saccharomyces cerevisiae (oligomannan), and neutrophil nuclear antigens. Our aim was to determine whether expression of antibodies against Crohn's disease-related bacterial sequence and Escherichia coli outer membrane porin C is associated with distinct phenotypic manifestations. Methods: Sera from 303 patients were tested for antibodies to the Crohn's disease-related bacterial sequence (I2), anti-Escherichia coli outer membrane porin C, anti-Saccharomyces cerevisiae, and perinuclear antineutrophil cytoplasmic antibodies and for 3 Crohn's disease-associated variants of the NOD2 gene (R702W, G908R, and 1007fs) and compared with clinical data. Results: Patients expressing I2 were more likely to have fibrostenosing Crohn's disease (64.4% vs. 40.7%; P < 0.001) and to require small bowel surgery (62.2% vs. 37.4%; P < 0.001). Patients with anti-Escherichia coli outer membrane porin C were more likely to have internal perforating disease (50.0% vs. 30.7%; P = 0.001) and to require small bowel surgery (61.4% vs. 44.2%; P = 0.003). Anti-Crohn's disease-related bacterial sequence was independently associated with fibrostenosis (P = 0.027) and small bowel surgery (P = 0.01), whereas anti-Escherichia coli outer membrane porin C was independently associated with internal perforations (P < 0.006). Patients positive for I2, anti-Escherichia coli outer membrane porin C, and anti-Saccharomyces cerevisiae were the most likely to have undergone small bowel surgery (72.0%; odds ratio, 8.6; P < 0.001) compared with patients without reactivity (23.0%). When the presence and magnitude of antibody responses were considered, 90% of patients with small bowel disease who required surgery had high levels of I2, Escherichia coli outer membrane porin C, and oligomannan antibodies, compared with only 18.2% with low-titer responses (P < 0.001). Conclusions: I2 and anti-Escherichia coli outer membrane porin C are associated with Crohn's disease phenotypes, and patients with the highest level of serum reactivity toward an increasing number of microbiota have the greatest frequency of strictures, internal perforations, and small bowel surgery.

Background & Aims: Wireless capsule enteroscopy (WCE) offers the potential to directly visualize the entire small bowel and identify superficial lesions not detected by traditional endoscopy and radiography. The aim of this study is to assess the clinical utility of WCE in the evaluation of patients with known or suspected inflammatory bowel disease (IBD). Methods: Fifty patients with ongoing symptoms underwent Given M2A endoscopic capsule examinations. Indications included: (1) evaluation for small-bowel involvement in patients with IBD with isolated colitis (n = 22), (2) determination of the extent of small-bowel disease in patients with Crohn's disease (CD; n = 20), and (3) workup of suspected IBD (n = 8). Outcome measures were classified as diagnostic when multiple ulcerations were present, suspicious when @?3 ulcerations were seen, and nonspecific or normal. Results: WCE findings were diagnostic for CD in 20 patients and suspicious for small-bowel CD in 10 patients. Seventeen of 20 patients with diagnostic WCE findings improved with increased IBD-directed medical therapy, as did 7 of 10 patients with suspicious study results. WCE was normal or showed nonspecific findings in the remaining 20 patients. Notably, identification of small-bowel lesions in 5 patients with a previous history of isolated colitis resulted in a change in diagnosis to CD after confirmatory ileoscopy with biopsy. Conclusions: Results of this preliminary study suggest that WCE is a novel and potentially clinically useful method of directly visualizing and diagnosing small-bowel lesions in patients with IBD that can be missed by traditional endoscopic and radiological procedures.

Background & Aims:: Approximately 40% of inflammatory bowel disease (1B13) patients fail to benefit from 6-mercaptopurine (6-MP)/azathioprine (AZA). Recent reports suggest 6-thioguanine nucleotide (6-TGN) levels (>235) independently correlate with remission. An inverse correlation between 6-TGN and thiopurine methyl-transferase (TPMT) has been described. The objectives of this study were to determine whether dose escalation optimizes both 6-TGN levels and efficacy in patients failing therapy because of subtherapeutic 6-TGN levels and its effect on TPMT. Methods:: Therapeutic efficacy and adverse events were recorded at baseline and upon reevaluation after dose escalation in 51 IBD patients. 6-MP metabolite levels and TPMT activity were recorded blinded to clinical information. Results:: Fourteen of 51 failing 6-MP/AZA at baseline achieved remission upon dose escalation, which coincided with significant rises in 6-TGN levels. Despite increased 6-MP/AZA doses, 37 continued to fail therapy at follow-up. Dose escalation resulted in minor changes in 6-TGN, yet a significant increase in 6-methylmercaptopurine ribonucleotides (6-MMPR) (P @? 0.01) and 6-MMPR:6-TGN ratio (P < 0.001). 6-MMPR rises were associated with dose-dependent hepatotoxicity in 12 patients (24%). TPMT was not influenced by dose escalation. Conclusions:: Serial metabolite monitoring identifies a novel phenotype of IBD patients resistant to 6-MP/AZA therapy biochemically characterized by suboptimal 6-TGN and preferential 6-MMPR production upon dose escalation.

BackgroundPerinuclear antineutrophil cytoplasmic antibodies (pANCA) have been detected in a clinically distinct Crohn's disease subpopulation. Antibodies to Saccharomyces cerevisiae (ASCA) have been demonstrated in the majority of patients with Crohn's disease.AimsTo examine the relationship between selective marker antibody expression in Crohn's disease and disease onset, location, and clinical behaviour patterns.MethodsSera from 156 consecutive patients with established Crohn's disease were evaluated in a blinded fashion for the presence of ASCA and ANCA. Clinical profiles were generated by investigators blinded to immune marker status.ResultsUsing multiple regression analyses, higher ASCA levels were shown to be independently associated with early age of disease onset as well as both fibrostenosing and internal penetrating disease behaviours. Higher ANCA levels were associated with later age of onset and ulcerative colitis-like behaviour. Substratification of the Crohn's disease population using selective ANCA and ASCA expression (high levels of a single marker antibody): (1) distinguished homogeneous subgroups that manifested similar disease location and behaviours; and (2) identified patients with more aggressive small bowel disease.ConclusionsThe findings suggest that by taking into account the magnitude of the host immune response, Crohn's disease can now be stratified on an immunological basis into more homogeneous clinically distinct subgroups, characterised by greater uniformity among anatomical distribution of disease and disease behaviour.

Background & Aims: Thalidomide decreases production of tumor necrosis factor @a, a proinflammatory cytokine associated with Crohn's disease (CD). In this study the safety, tolerance, and efficacy of low-dose thalidomide were evaluated for treatment of moderate-to-severe, steroid-dependent CD. Methods: Twelve adult male patients with Crohn's Disease Activity Index (CDAI) scores of >=250 and @?500 despite >=20 mg prednisone/day were enrolled. The first 6 patients received 50 mg thalidomide every night, the next 6 received 100 mg every night. Steroid doses were stable during the first 4 weeks of treatment, then tapered during weeks 5-12. CDAI was used to assess response. Results: (1) Disease activity improved consistently in all patients during weeks 1-4: 58% response, 17% remission. (2) Clinical improvement was generally maintained despite steroid taper during weeks 5-12. All patients were able to reduce steroids by >=50%. Forty-four percent discontinued steroids entirely. In weeks 5-12, 70% of patients responded and 20% achieved remission. (3) Side effects were mild and mostly transient, with the most common being drowsiness, peripheral neuropathy, edema, and dermatitis. Conclusions: Low-dose thalidomide appears to be well tolerated and effective over a 12-week period. Results of this pilot study support the need for controlled multicenter trials of thalidomide for treatment of CD. GASTROENTEROLOGY 1999;117:1278-1287