Raymond Jian

Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped.

BACKGROUND & AIMS It is important to determine whether infliximab therapy can be safely interrupted in patients with Crohns disease who have undergone a period of prolonged remission. We assessed the risk of relapse after infliximab therapy was discontinued in patients on combined maintenance therapy with antimetabolites and identified factors associated with relapse. METHODS We performed a prospective study of 115 patients with Crohns disease who were treated for at least 1 year with scheduled infliximab and an antimetabolite and had been in corticosteroid-free remission for at least 6 months. Infliximab was stopped, and patients were followed up for at least 1 year. We associated demographic, clinical, and biologic factors with time to relapse using a Cox model. RESULTS After a median follow-up period of 28 months, 52 of the 115 patients experienced a relapse; the 1-year relapse rate was 43.9% ± 5.0%. Based on multivariable analysis, risk factors for relapse included male sex, the absence of surgical resection, leukocyte counts >6.0 × 10(9)/L, and levels of hemoglobin ≤145 g/L, C-reactive protein ≥5.0 mg/L, and fecal calprotectin ≥300 μg/g. Patients with no more than 2 of these risk factors (approximately 29% of the study population) had a 15% risk of relapse within 1 year. Re-treatment with infliximab was effective and well tolerated in 88% of patients who experienced a relapse. CONCLUSIONS Approximately 50% of patients with Crohns disease who were treated for at least 1 year with infliximab and an antimetabolite agent experienced a relapse within 1 year after discontinuation of infliximab. However, patients with a low risk of relapse can be identified using a combination of clinical and biologic markers.

Biodiversity of the mucosa-associated microbiota is stable along the distal digestive tract in healthy individuals and patients with IBD

Background: The mucosa‐associated microbiota, being very close to the inflammatory process associated with inflammatory bowel disease (IBD), may have a pathogenic role. We used a culture‐independent method to analyze the mucosa‐associated microbiota in IBD patients at various points of the distal digestive tract. Methods: Thirty‐five patients (20 with Crohns disease, 11 with ulcerative colitis, and 4 controls) underwent colonoscopy. Biopsies (n = 126) were taken from 4 sites: the ileum, right colon, left colon, and rectum. Fecal samples were also obtained from 7 individuals. Temporal temperature gradient gel electrophoresis (TTGE) of 16S rDNA was used to evaluate dominant species diversity. TTGE profiles were compared using software that measures the degree of similarity. Results: In a given individual, the overall similarity percentage between the 4 segments of the distal digestive tract was 94.7 ± 4.0%, regardless of clinical status. The average similarity of all profiles for a given segment was 59.3 ± 18.3% in the overall population. Dendrogram analysis showed that TTGE profiles did not cluster with clinical status. Differences were observed between the dominant fecal microbiota and the mucosa‐associated microbiota of all 4 sites, with similarity percentages less than 92%. Conclusions: These results confirm that the dominant species differ between the mucosa‐associated and fecal microbiota. They also show that, in a given individual, the microbiota is relatively stable along the distal digestive tract, showing a slight evolution in dominant species diversity from the ileum to the rectum, in both healthy subjects and patients with IBD.

Long term outcome of patients with active Crohn's disease exhibiting extensive and deep ulcerations at colonoscopy.

OBJECTIVE:Prediction of the clinical course of Crohns disease (CD) is difficult in the long term. Our aim was to determine whether the presence of severe endoscopic lesions (SELs) may predict a higher risk of colectomy and penetrating complications.METHODS:All patients at our institution with active ileocolonic CD who had colonoscopies between 1990 and 1996 were included in the study. SELs were defined as extensive and deep ulcerations covering more than 10% of the mucosal area of at least one segment of the colon.RESULTS:Among the 102 patients included, 53 had SELs at index colonoscopy. During the follow-up (median = 52 months), 37 patients underwent colonic resection. Probabilities of colectomy at 1, 3, and 8 yr were 20%, 26%, and 42%. Risk of colectomy was independently affected by the presence of SELs at index colonoscopy (relative risk [RR] = 5.43, 95% CI = 2.64–11.18), a Crohns Disease Activity Index level greater than 288 (RR = 2.21, 95% CI = 1.09–4.47), and the absence of immunosuppressive therapy during the follow-up (RR = 2.44, 95% CI = 1.20–5.00). Probabilities of colectomy were, respectively, 31% and 6% at 1 yr, 42% and 8% at 3 yr, and 62% and 18% at 8 yr in patients with and without SELs. We performed a second analysis excluding the 14 patients operated on within the 3 months after the index colonoscopy: presence of SELs remained the only significant factor predictive of colectomy (RR = 6.72, 95% CI = 2.26–20.03). All six patients with penetrating complications during the follow-up had SELs at index colonoscopy.CONCLUSIONS:Patients with CD exhibiting deep and extensive ulcerations at colonoscopy have a more aggressive clinical course with an increased rate of penetrating complications and surgery.

Selective expansion of intraepithelial lymphocytes expressing the HLA-E–specific natural killer receptor CD94 in celiac disease

Abstract Background & Aims: Celiac disease is a gluten-induced enteropathy characterized by the presence of gliadin-specific CD4+ T cells in the lamina propria and by a prominent intraepithelial T-cell infiltration of unknown mechanism. The aim of this study was to characterize the subset(s) of intraepithelial lymphocytes (IELs) expanding during active celiac disease to provide insights into the mechanisms involved in their expansion. Methods: Flow-cytometric analysis of isolated IELs and/or immunohistochemical staining of frozen sections were performed in 51 celiac patients and 50 controls with a panel of monoclonal antibodies against T-cell and natural killer (NK) receptors. In addition, in vitro studies were performed to identify candidate stimuli for NK receptor expression. Results: In normal intestine, different proportions of IELs, which were mainly T cells, expressed the NK receptors CD94/NKG2, NKR-P1A, KIR2D/3D, NKp46, Pen5, or CD56. During the active phase of celiac disease, the frequency of CD94+ IELs, which were mostly αβ T cells, was conspicuously increased over controls. In contrast, the expression of other NK markers was not modified. Furthermore, expression of CD94 could be selectively induced in vitro by T-cell receptor activation and/or interleukin 15, a cytokine produced by intestinal epithelial cells. Conclusions: The gut epithelium favors the development of T cells that express NK receptors. In active celiac disease, there is a specific and selective increase of IELs expressing CD94, the HLA-E–specific NK receptor that may be related to T-cell receptor activation and/or interleukin 15 secretion. GASTROENTEROLOGY 2000;118:867-879

Thymidylate Synthase Gene Polymorphism Predicts Toxicity in Colorectal Cancer Patients Receiving 5-Fluorouracil-based Chemotherapy

Purpose: The target enzyme for 5-fluorouracil (5-FU) is thymidylate synthase (TS). The TYMS gene encoding this enzyme is polymorphic, having either double (2R) or tri-tandem (3R) repeats of a 28-bp sequence in the promoter region and a 6-bp variation in the 3′-untranslated region (3′-UTR). TS expression predicts response to 5-FU-based chemotherapy, and the expression seems to be determined by the TYMS gene promoter. The aim of this study was to investigate the utility of determining these two TYMS gene polymorphisms to predict the toxicity and efficacy of 5-FU treatment in patients with colorectal cancer. Experimental Design: The determination of TYMS genotypes was performed in tumor and normal tissues by PCR amplification from 90 patients with colorectal cancer who were treated with adjuvant or palliative 5-FU-based chemotherapy. Associations between polymorphisms in the TYMS promoter and in the 3′-UTR gene and clinical outcome of these 90 patients treated with 5-FU based chemotherapy were evaluated individually. The linkage between TYMS promoter and TYMS 3′-UTR region polymorphisms was evaluated and a haplotype analysis was performed. Results: Individuals who were homozygous for the double repeat in the TYMS promoter region had more severe side effects to 5-FU. Patients with a 2R/2R, a 2R/3R, or a 3R/3R genotype had a grade 3 or 4 toxicity rate of 43, 18, and 3% respectively (P < 0.01). The TYMS promoter and TYMS 3′-UTR polymorphisms were in linkage disequilibrium, and the haplotype 2R/ins 6-bp was significantly associated with a high risk of severe side effects to 5-FU. The TYMS promoter and TYMS 3′-UTR polymorphisms were not associated with a response to 5-FU and survival of patients who received palliative 5-FU-based chemotherapy. Conclusions: This study demonstrated that TYMS genotyping could be of help in predicting toxicity to 5-FU-based chemotherapy. TYMS genotyping might make it possible to individualize treatment for patients with colorectal cancer.

The antitumoral effect of the long-acting somatostatin analog lanreotide in neuroendocrine tumors

OBJECTIVE:Somatostatin analogs are the first-line drugs for controlling hormone-mediated symptoms of carcinoid tumors. Prospective and retrospective studies have suggested that somatostatin analogs also have antiproliferative activity. The octapeptide lanreotide is available in sustained-release form, obviating the need for daily injections.METHODS:A total of 46 patients were enrolled in this open, prospective, phase II trial. They received lanreotide 30 mg i.m. every 14 days for 6 months when they had symptomatic carcinoid tumors, and lanreotide 30 mg i.m. every 10 days if they had nonsymptomatic tumors. Nonsymptomatic tumors were progressive before the start of the study. Tumor size was assessed every 3 months by means of computed tomography. The assessment was centralized and was made by an external panel.RESULTS:In all, 30 patients had symptomatic neuroendocrine tumors and 16 had asymptomatic neuroendocrine tumors. Five patients in the group with symptomatic tumors and two in the group with nonsymptomatic tumors were considered not to be evaluable. The mean duration of treatment was 12 months in the group with symptomatic tumors and 13 months in the other group. Among the 39 evaluable patients, two objective responses were obtained, giving an objective response rate of 5% (one in the group with symptomatic tumors and one in the other group). Nineteen patients had no significant increase in their tumor size for a mean of 9.5 months.CONCLUSIONS:Lanreotide is safe and well tolerated in patients with carcinoid tumors. It seems to have both symptomatic and antitumoral effects in this setting.

Chromoendoscopic Colonoscopy for Detecting Preneoplastic Lesions in Hereditary Nonpolyposis Colorectal Cancer Syndrome

BACKGROUND & AIMS In hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, flat and small adenomas are particularly prone to malignant transformation but might be missed by standard colonoscopy. We prospectively studied the diagnostic yield of high-resolution colonoscopy coupled with chromoendoscopy for preneoplastic and neoplastic colorectal lesions in patients with HNPCC syndrome. METHODS Thirty-six consecutive asymptomatic patients (mean age, 42 years) belonging to HNPCC families and receiving genetic counseling were enrolled in this prospective study. Colonoscopy was performed in 2 steps. Conventional colonoscopy was performed first, followed by a second colonoscopy with chromoendoscopy with indigo carmine (.4%) dye sprayed onto the entire proximal colon. RESULTS Conventional colonoscopy identified 25 lesions (mean size, 4 +/- 3 mm) in 13 patients. Seven lesions, detected in 5 patients, were adenomas, 3 of which were located in the proximal colon. Chromoendoscopy identified additional 45 lesions (mean size, 3 +/- 1 mm) in 20 patients; most of these lesions were flat and hyperplastic. Eleven additional adenomas were detected in the proximal colon of 8 patients, and 8 of these 11 lesions were flat. The use of chromoendoscopy significantly increased the detection rate of adenomas in the proximal colon, from 3 of 33 patients to 10 of 33 patients (P = .045). CONCLUSION Relative to conventional colonoscopy, high-resolution colonoscopy with chromoendoscopy markedly improves the detection of adenomas in patients with HNPCC syndrome and might help to prevent colorectal carcinoma in these patients with a very high risk of colorectal cancer.

Long-Term Outcome of Patients Treated With Double Balloon Enteroscopy for Small Bowel Vascular Lesions

OBJECTIVES:Early rebleeding rate after endoscopic therapy with double balloon enteroscopy (DBE) of hemorrhagic small bowel vascular lesions (SBVL) varies between 10 and 50%. In recent reports, long-term follow-up of patients have been described but rebleeding risk factors are still not well established. The aim of the current study was to identify long-term treatment success rate and rebleeding risk factors after DBE therapy in a large cohort.METHODS:We conducted a single-center, retrospective cohort study in a large French tertiary-referral center between January 2004 and December 2007.RESULTS:Among 261 patients presenting with obscure gastrointestinal bleeding (OGIB), SBVL was present in 133 patients and was treated successfully in 129 (97%) using mainly argon plasma coagulation. Ninety-eight patients were followed up for a mean period of 22.6±13.9 months (range 1–52). Rebleeding rate was 46% (45/98 patients) at 36 months. On multivariate analysis, the total number of observed lesions (hazard ratio (HR): 1.15, 95% confidence interval (CI): 1.06–1.25, P=0.001) and the presence of a valvular and/or arrhythmic cardiac disease (HR: 2.50, 95% CI: 1.29–4.87, P=0.007) were significantly associated with the risk of rebleeding. Complication rate of therapeutic DBE was 2.3% with no mortality.CONCLUSIONS:Endoscopic therapy using DBE for SBVL in patients with recurrent OGIB allows a long-term remission in more than half of the patients. Independent rebleeding risk factors after a first endoscopic therapy are an increased number of SBVL and an associated valvular/arrhythmic heart disease.

Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn's disease.

Background:Crohns disease (CD)–associated dysbiosis could predispose patients to relapse. Gut microbiota composition of patients from the prospective cohort study designed to identify predictive factors of clinical relapse after infliximab discontinuation (STORI Study) was investigated to determine the impact of dysbiosis in CD relapse. Methods:Fecal samples from 33 patients with CD in this cohort were collected at baseline, 2 months, 6 months, and at the end of the follow-up period (19 relapsers and 14 nonrelapsers). Healthy volunteers subjects (n = 29) were used as a control group. The fecal microbiota composition was assessed using quantitative PCR, and comparisons between the patient groups were made at different time points using the Wilcoxon test. The analysis of the time-to-relapse was performed according to the baseline median level of each bacterial signal. Results:Dysbiosis was observed in patients with CD compared with healthy subjects, and it was characterized by low mean counts of Firmicutes (Clostridium coccoides [P = 0.0003], C. leptum [P < 0.0001], and Faecalibacterium prausnitzii [P = 0.003]). Lower rates of Firmicutes were seen in relapsers compared with nonrelapsers. Moreover, a low rate of F. prausnitzii (P = 0.014) and a low rate of Bacteroides (P = 0.030) predicted relapse independently from high C reactive protein level (P = 0.0001). Conclusions:In this work, we report that CD-associated dysbiosis, characterized by a decrease in Firmicutes, correlates with the time-to-relapse after infliximab withdrawal. A deficit in some bacterial groups or species, such as F. prausnitzii, may represent a predictive factor for relapse. Restoring normobiosis in CD could be a new goal for optimal CD management.

Azathioprine induced nodular regenerative hyperplasia in IBD patients

Purine analogues are major drugs in the treatment of inflammatory bowel diseases (IBD). We present four cases of nodular regenerative hyperplasia of the liver (NRH) developed in patients with IBD treated with azathioprine. All patients had either abnormal liver tests and/or low platelet count. Although biochemical and hematological abnormalities regressed after azathioprine withdrawal, the long term evolution of the hepatic lesions (and the risk to develop further complications including portal hypertension) remains to be determined. Male gender seems to be a major risk factor by providing a predisposing pharmacogenetic profile of purine analogue metabolism. Clinicians should be aware of this serious complication which may occur with any of the purine analogues (azathioprine, 6-mercaptopurine, and 6-thioguanine).