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Background: Reports of an increased risk of lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease are controversial. We assessed this risk in a prospective observational cohort study., Methods: 19,486 patients with inflammatory bowel disease, of whom 11,759 (60.3%) had Crohn's disease and 7727 (39.7%) had ulcerative colitis or unclassified inflammatory bowel disease, were enrolled in a nationwide French cohort by 680 gastroenterologists, who reported details of immunosuppressive therapy during the observation period, cases of cancer, and deaths. The risk of lymphoproliferative disorder was assessed according to thiopurine exposure. Median follow-up was 35 months (IQR 29-40)., Findings: At baseline, 5867 (30.1%) of patients were receiving, 2809 (14.4%) had discontinued, and 10,810 (55.5%) had never received thiopurines. 23 new cases of lymphoproliferative disorder were diagnosed, consisting of one case of Hodgkin's lymphoma and 22 cases of non-Hodgkin lymphoproliferative disorder. The incidence rates of lymphoproliferative disorder were 0.90 per 1000 (95% CI 0.50-1.49) patient-years in those receiving, 0.20/1000 (0.02-0.72) patient-years in those who had discontinued, and 0.26/1000 (0.10-0.57) patient-years in those who had never received thiopurines (p=0.0054). The multivariate-adjusted hazard ratio of lymphoproliferative disorder between patients receiving thiopurines and those who had never received the drugs was 5.28 (2.01-13.9, p=0.0007). Most cases associated with thiopurine exposure matched the pathological range of post-transplant disease., Interpretation: Patients receiving thiopurines for inflammatory bowel disease have an increased risk of developing lymphoproliferative disorders., Funding: Programme Hospitalier de Recherche Clinique National (AOM05157), Association François Aupetit, Délégation Inter-régionale de la Recherche clinique Ile de France-Assistance Publique Hôpitaux de Paris (AP-HP), Ligue contre le Cancer, and Fonds de Recherche de la Société Nationale Française de Gastro-entérologie.

It has been suspected that there is an epidemiological link between irritable bowel syndrome (IBS) and ischaemic colitis (IC). We performed a retrospective case-control study to compare the frequency of IBS in patients hospitalized for IC compared with that of patients with peptic ulcer bleeding. Cases were patients with a first episode of IC and controls were patients with a first episode of peptic ulcer bleeding, matched to cases for sex and 10-year age-class. Diagnosis of IBS was based on medical information extracted from hospital medical files and a standard self-questionnaire. The association between IBS and IC was tested using Mc Nemar's paired odds ratio (OR); confidence interval at 95% (CI 95%) was calculated; Mantel-Haenzel's Chi(2) was applied. A total of 113 cases and 113 matched controls were studied. There were 37 males and 76 females and the mean age was 69 +/- 15 years in each group. The prevalence of IBS in cases was 16.9%vs 1.8% in controls. The risk of IBS was 11.05 times higher among cases than in controls (P < 0.001); CI 95%: (2.45-49.74). A total of 87 pairs with complete data were used for OR calculation. The risk of IBS was 7.5 times higher in cases than in controls (P = 0.002); CI 95%: (1.72-32.80). This case-control study shows that IBS is more frequent in IC patients than in controls.

The risk of lymphoproliferative disorders (LDs) has become a major concern for clinicians managing patients with inflammatory bowel disease (IBD). Yet it is difficult to distinguish the possible responsibility of immunosuppressive therapy from the background risk due to the inflammatory disorder itself. LDs are clonal B or T cell proliferation showing considerable heterogeneity and the incidence has increased since the 1970s. The strongest and best-established risk factors for LDs are primary and acquired immunodeficiency (HIV, immunosuppressant), notably via defective immune surveillance of Epstein-Barr virus. In many auto-immune diseases (eg, Sjögren's syndrome), inflammatory diseases (eg, rheumatoid arthritis) or chronic suppuration (chronic pyothorax), the risk of LD is increased. In IBD patients, in general, the risk of LD seems to be similar to or very slightly higher than in the general population. The role of immunosuppressants in lymphomagenesis is difficult to individualise because other factors potentially involved are inter-linked. Concordant data suggest that thiopurine therapy is associated with a moderately increased risk of LD. Data regarding methotrexate are scarce and come from diseases other than IBD but the risk seems low. Data regarding risk of LD in IBD patients receiving anti-tumour necrosis factor alpha (TNFalpha) agents are insufficient at this time, mainly because most of the patients are co-treated with thiopurines. The recently individualised risks of hepatosplenic T cell lymphoma and fatal post-mononucleosis LD, in young male patients with IBD who are co-treated with anti-TNFalpha and thiopurines, and EBV-seronegative IBD males, respectively, are probably low but remain to be better quantified.

Background: Cigarette smoking is associated with a more severe Crohn's disease (CD) course. However, the effect of light consumption is not known. Our aim was to characterize the effect of a light tobacco consumption on the course of CD., Methods: We analyzed the course of CD during the period 1995-2007 from data collected in 2795 consecutive patients in whom smoking habits were recorded. Patients were classified as nonsmokers (n = 1420), light smokers (1-10 cigarettes/day; n = 385), heavy smokers (>10 cigarettes/day; n = 638), and intermittent smokers (change in smoking habits; n = 352). Patient-years while smoking were compared to patient-years without smoking. The analyses considered patient-years regarding annual disease activity and therapeutic requirements., Results: The percentage of years with active disease was 37% in nonsmokers versus 46% in light smokers (P < 0.001; adjusted hazard ratio 1.30 [1.19-1.43]) and 48% in heavy smokers (P < 0.001; adjusted hazard ratio 1.68 [1.57-1.81]), despite an increased use of immunosuppressants in smokers. Hospitalization rates were also increased in both groups of smokers, with 12% in nonsmokers versus 15% in both groups of smokers (P < 0.001 for both comparisons). The annual rate of intestinal resection was 4.5% in nonsmokers, 5.1% in light smokers, and 5.5% in heavy smokers, with a significant difference observed between nonsmokers and heavy smokers only (P < 0.01)., Conclusions: Light smokers are doing worse than nonsmokers regarding disease activity and the need for immunosuppressants. Complete smoking cessation should be advised in all smokers with CD.

In patients with Crohn's disease, the risk of small bowel adenocarcinoma is 20-40 times higher than the low background risk of the general population. In the subset of patients with longstanding small bowel lesions, the absolute risk of small bowel adenocarcinoma exceeds 1 per 100 patient-years after 25 years of follow-up and becomes equivalent to the risk of colorectal cancer. Growing evidence suggests that the pathogenesis of small bowel adenocarcinoma arising in inflammatory lesions of Crohn's disease is similar to that of colorectal cancer complicating chronic colonic inflammation (inflammation-dysplasia-cancer sequence). However, contrasting with the established endoscopic detection of colonic advanced neoplasias in patients with longstanding extensive colitis, there is no consensus at this time how to face the excess-risk of small bowel adenocarcinoma in patients at high risk. There are no specific clinical or imaging alert signs and endoscopic surveillance of the totality of the inflamed small bowel mucosa would suppose to perform repeated enteroscopies, with the potential limiting factor of stenosis. Very preliminary data suggest that chemoprevention with salicylates could be an alternative way for reducing the risk. Data from referral centers and from the CESAME cohort suggest that intestinal lymphomas may arise in the chronically inflamed segments in patients with inflammatory bowel disease (IBD). Regarding nonintestinal lymphomas, it is now established that IBD patients treated with thiopurines have an excess risk of lymphomas, exhibiting in most cases pathological features of lymphomas associated with immunosuppression, including the frequent presence of EBV in neoplastic tissues. There is growing evidence that treatment with thiopurines is responsible by itself for this excess risk. IBD patients receiving immunomodulators, especially young men, are also at risk (0.4 for 10,000 patient-years in the CESAME study) for developing fatal early post-mononucleosis lymphomas, like in Purtilo's syndrome, maybe in association with a background genetic susceptibility. Finally, patients receiving thiopurines and/or TNF-inhibitors are at risk for developing fatal hepatosplenic T cell lymphomas, but this risk is low (no case in the CESAME study). Whether patients receiving a monotherapy with methotrexate and/or TNF inhibitors are at increased risk of lymphomas is not known. Concordant data suggest that women receiving immunosuppressive therapy are at increased risk for developing uterine cervix dysplasia and require closer surveillance. But it is not established whether the risk of uterine cervix cancer and basal and squamous cell skin cancers (that may be associated with chronic human papillomavirus infection) is increased in patients receiving immunomodulators., (Copyright 2009 S. Karger AG, Basel.)

Background and Aims: It is well established that Crohn's disease (CD) is associated with an increased risk of small bowel adenocarcinoma (SBA). The data concerning SBA risk factors in CD are scanty. The aim of this study was to identify them., Methods: In 11 French centers affiliated with the GETAID (Groupe d'Etude Thérapeutique des Affections Inflammatoires du Tube Digestif), we identified 29 patients with CD and SBA. Eighty-seven CD controls without SBA recruited in a single center were matched to the cases for sex, age, duration, and CD site. A conditional logistic regression, taking into account the matching between cases and controls, was performed., Results: In univariate analysis, the cases had had significantly less small bowel resection and received prolonged treatment with salicylates (more than 2 yr), less often than the controls (odds ratio, OR [95% confidence interval, CI] 0.07 [0.01-0.32] and 0.29 [0.10-0.82], respectively). In multivariate analysis, both associations remained significant (OR 0.04 [0.01-0.28], P= 0.001; OR 0.16 [0.03-0.79], P= 0.02, respectively)., Conclusion: This study suggests that small bowel resection and prolonged salicylates use may protect against SBA in CD patients.

Most of the cases of antibiotic-associated diarrhea are benign, self-limited and presumably related to functional consequences of the alteration of gut microflora. In few cases, changes in the gut flora ecosystem allow pathogens to proliferate. Clostridium difficile is responsible for approximately 10% of the cases of antibiotic-associated diarrhea in the community, most of the cases of antibiotic-associated colitis, and almost all the cases of pseudomembranous colitis. According to anatomoclinical increasing severity of the disease, C. difficile infections should be treated with metronidazole, vancomycin, intravenous immunoglobulins or colectomy. Klebsiella oxytoca is naturally resistant to bela-lactamins and causes occasionally heamorrhagic colitis, mimicking in some cases ischemic colitis.

Aim: To investigate the phenotype of inflammatory bowel disease associated with primary sclerosing cholangitis (PSC-IBD)., Methods: Data from 75 PSC-IBD patients evaluated in our tertiary center between 1963 and 2006 were collected and compared to 150 IBD patients without PSC, matched for sex, birth date, IBD diagnosis date and initial disease location regarding ileal, different colonic segments, and rectum, respectively., Results: While PSC-IBD patients received more 5-aminosalicylates (8.7 years/patient vs 2.9 years/patient, P < 0.001), they required less immuno-suppressors (24% vs 46% at 10 years; P < 0.001) and less intestinal resection (10% vs 44% at 10 years, P < 0.001). The 25-year cumulative rate of colectomy was 25.1% in PSC-IBD and 37.3% in controls (P = 0.004). The 25-year cumulative rate of colorectal cancer was 23.4% in PSC-IBD vs 0% in controls (P = 0.002). PSC was the only independent risk factor for the development of colorectal cancer (OR = 10.8; 95% CI, 3.7-31.3). Overall survival rate without liver transplantation was reduced in PSC-IBD patients (67% vs 91% in controls at 25 years, P = 0.001)., Conclusion: This study confirms that patients with PSC-IBD have a particular disease phenotype independent of the initial disease location. Although their disease is less active and they use more 5-aminosalicylates, they present a higher risk of colorectal cancer.

Objectives: Cyclosporine is an effective rescue therapy in steroid-refractory ulcerative colitis (UC) and may avoid immediate colectomy. However, the individual's response to cyclosporine is poorly predictable. The aim of this study was to identify predictive factors of the response to cyclosporine in steroid-refractory UC., Methods: One hundred thirty-five patients with steroid-refractory UC, admitted consecutively between 1992 and 2004, were included. Data were collected on the first day of the cyclosporine therapy. Colonoscopy was performed within 2 days preceding or following the cyclosporine treatment in 118 patients for assessing the presence of severe endoscopic lesions., Results: The actuarial rate of colectomy was 0.45 at 6 months. Cox analysis in the whole population selected three predictive criteria of colectomy: body temperature >37.5 degrees C (adjusted hazard ratio = 1.94, 95% confidence interval 1.51-2.49), heart rate >90 bpm (1.86, 1.45-2.38), and C-reactive protein (CRP) >45 mg/L (1.70, 1.34-2.16). In the 118 patients who underwent colonoscopy, the presence of severe endoscopic lesions was an independent predictive factor of colectomy (2.38, 1.80-3.14). Colonoscopy was decisive and changed the therapeutic decision in patients with one or two criteria: 71% of the patients with severe endoscopic lesions were colectomized versus 17% of the patients without severe endoscopic lesions (P < 0.001). Finally, the clinical, biological, and endoscopic criteria allowed the classification of the patients into two different groups (80%vs 20% colectomy at 6 months)., Conclusion: In patients with steroid-refractory UC, the combination of simple criteria is useful to predict the response to cyclosporine. Colonoscopy is crucial in patients with intermediate clinical and biological severity.

Background: Clinical manifestations of hypersensitivity to azathioprine may mimic symptoms of the initial disease. We report 5 cases of peculiar skin hypersensitivity reactions to azathioprine in patients with inflammatory bowel disease., Observations: In 5 patients with a recent azathioprine regimen, manifestations appeared between 8 and 18 days after drug introduction. All patients had a high fever. Three patients initially had erythema nodosum; 2 patients had sterile pustules. All had elevated neutrophil counts and serum C-reactive protein levels, whereas eosinophil counts were normal, ruling out drug-induced rash with eosinophilia and systemic symptoms. In 3 patients who were rechallenged with azathioprine or with 6-mercaptopurine, dermatological lesions recurred within hours., Conclusions: Erythema nodosum and pustules are rarely reported manifestations of azathioprine hypersensitivity. Both skin lesions may be related to the clinical activity of inflammatory bowel disease. Relapse of such lesions shortly after thiopurine rechallenge should raise the hypothesis of hypersensitivity rather than pharmacological manifestations.

Background & Aims: Early intensive therapy in Crohn's disease should be considered only in patients with disabling disease. The aim of our study was to identify at diagnosis factors predictive of a subsequent 5-year disabling course., Methods: Among the 1526 patients seen at our unit with Crohn's disease diagnosed between 1985 and 1998, we excluded patients operated on within the first month of the disease, patients with inadequate data, and patients with severe chronic nondigestive disease. In the 1188 remaining patients, Crohn's disease course within the first 5 years of the disease was categorized as disabling when at least 1 of the criteria of clinical severity, conventionally predefined, was present., Results: Among the 1123 patients with follow-up data allowing full 5-year course classification, the rate of disabling disease was 85.2%. Independent factors present at diagnosis and significantly associated with subsequent 5-year disabling were the initial requirement for steroid use (OR 3.1 [95% CI: 2.2-4.4]), an age below 40 years (OR 2.1 [95% CI: 1.3-3.6]), and the presence of perianal disease (OR 1.8 [95% CI: 1.2-2.8]). The positive predictive value of disabling disease in patients with 2 and 3 predictive factors of disabling disease was 0.91 and 0.93, respectively. These values were 0.84 and 0.91, respectively, when tested prospectively in an independent group of 302 consecutive patients seen at our institution from 1998., Conclusions: At diagnosis of Crohn's disease in a referral center, factors predictive of subsequent 5-year disabling course are an age below 40 years, the presence of perianal disease, and the initial requirement for steroids.

Aim: To determine whether prior appendectomy modifies the phenotype and severity of Crohn's disease., Methods: Appendectomy status and smoking habits were specified by direct interview in 2838 patients consecutively seen between 1995 and 2004. Occurrence of complications and therapeutic needs were reviewed retrospectively. Additionally, annual disease activity was assessed prospectively between 1995 and 2004 in patients who had not had ileocecal resection and of a matched control group., Results: Compared to 1770 non-appendectomized patients, appendectomized patients more than 5 years before Crohn's disease diagnosis (n=716) were more often females, smokers, with ileal disease. Cox regression showed that prior appendectomy was positively related to the risk of intestinal stricture (adjusted hazard ratio, 1.24; 95% confidence interval, 1.13 to 1.36; P=0.02) and inversely related to the risk of perianal fistulization (adjusted hazard ratio, 0.75; 95% confidence interval, 0.68 to 0.83; P=0.002). No difference was observed between the two groups regarding the therapeutic needs, except for an increased risk of surgery in appendectomized patients, attributable to the increased prevalence of ileal disease. Between 1995 and 2004, Crohn's disease was active during 50% of years in appendectomized patients (1318 out of 2637 patient-years) and 51% in non-appendectomized patients (1454 out of 2841 patient-years; NS)., Conclusion: Prior appendectomy is associated with a more proximal disease and has an increased risk of stricture and a lesser risk of anal fistulization. However, the severity of the disease is unaffected.

Unlabelled: New medical therapeutic options challenge the usual surgical management of Crohn's disease patients with intestinal perforation., Objectives: To determine factors predictive of surgery for perforation in Crohn's disease and define a group of patients that may benefit from non-surgical treatment., Methods: One hundred and sixty-two patients (69 males, 93 females, mean age 39) with perforated Crohn's disease (fistula, abscess, inflammatory mass) between January 1995 and September 2003 were studied retrospectively., Results: One hundred and fifty-one patients (93%) underwent surgery: 70 had planned surgery and 81 had surgery for symptomatic deterioration. At two years, the cumulative probability of intestinal resection was 0.89 +/- 0.03, and the cumulative probability of unplanned intestinal resection was 0.72 +/- 0.05. Predictive factors of unplanned surgery were elevated platelet count (adjusted hazard ratio 3.15; 95% CI 2.21-4.50) and absence of fistula (adjusted hazard ratio 3.14; 95% CI 2.48-3.99). The rate of postoperative complications, the need for a stoma, and the length of bowel resection were not significantly different whether the surgery was planned or not., Conclusion: A significant proportion of patients with intestinal perforation complicating Crohn's disease, particularly those with a fistula, might benefit from non-surgical treatment.

Background: Data concerning small bowel adenocarcinoma (SBA) in Crohn's disease (CD) come from case reports and small retrospective series. The aim of this study was to further describe SBA in patients with CD and compare it with SBA de novo., Methods: Twenty patients with CD with SBA recruited in French university hospitals were studied and compared with 40 patients with SBA de novo recruited from a population-based registry. SBA occurred after a median time of 15 years of CD and was located within the inflamed areas of the ileum (n=19) or jejunum (n=1), whereas in patients with SBA de novo, it was distributed all along the small intestine. Median age at diagnosis of SBA was 47 years (range, 33-72 yr) in patients with CD and 68 years (range, 41-95 yr) in those with SBA de novo., Results: The cumulative risk of SBA, assessed in a subgroup of patients, was 0.2% and 2.2% after 10 and 25 years of ileal CD, respectively. SBA accounted for 25% and 45% of the risk of gastrointestinal carcinoma after 10 and 25 years of CD, respectively. Diagnosis was made preoperatively in 1/20 patients with CD and 22/40 patients with SBA de novo. Signet ring cells were found in 35% of patients with CD but not in patients with SBA de novo. Relative survival was not significantly different in these 2 categories of patients (54 versus 37% and 35 versus 30% in patients with and without CD at 2 and 5 yr, respectively)., Conclusions: SBA in CD is different from SBA de novo. It arises from longstanding ileal inflammation and is difficult to diagnose. SBA cumulative risk increases after 10 years of CD and is likely to cause premature mortality in patients with early-onset CD.

The gastrointestinal toxicity of conventional nonsteroidal antiinflammatory drugs (NSAIDs) is not confined to the stomach and proximal duodenum but extends also to the rest of the small bowel, colon, and rectum. Long-term NSAID therapy usually induces clinically silent enteropathy characterized by increased intestinal permeability and inflammation. Chronic occult bleeding and protein loss may result in iron-deficiency anemia and hypoalbuminemia. NSAIDs can also induce small bowel ulcers that infrequently lead to acute bleeding, perforation, or chronic scarring responsible for diaphragm-like strictures. At the colon and rectum, NSAID use can result in de novo lesions such as nonspecific colitis and rectitis, ulcers, and diaphragm-like strictures. NSAIDs have been implicated in the development of segmental ischemic colitis. In patients with diverticular disease, NSAID use increases the risk of severe diverticular infection and perforation. NSAIDs can trigger exacerbations of ulcerative colitis or Crohn's disease. With selective COX-2 inhibitors, the risk of gastrointestinal toxicity is reduced as compared to conventional NSAIDs but is not completely eliminated. Experimental studies suggest that long-term COX-2 inhibitor therapy may cause damage to the previously healthy small bowel. Similar to conventional NSAIDs, COX-2 inhibitors may be capable of triggering exacerbations of inflammatory bowel disease.

Inflammatory bowel diseases are chronic conditions of unknown origin that result from continuous or intermittent inflammation of a part of the intestinal wall. The main classic types of IBD are ulcerative colitis, Crohn's disease and indeterminate colitis that cannot be classified accurately as ulcerative colitis or Crohn's disease with pure colonic involvement. The two main subtypes of microscopic colitis, namely lymphocytic and collagenous colitis, fulfill the criteria that define IBD and should be considered as true IBD.

Objectives: Patients frequently ask questions about the lifetime prognosis of Crohn's disease. The aim of this study was to describe the outcomes of Crohn's disease more than 20 years after diagnosis., Methods: Data from all patients with Crohn's disease whose diagnosis had been performed before 1st January 1978 were analyzed. All referred patients filled in a medical and health-related quality-of-life questionnaire., Results: Among 273 patients with Crohn's disease diagnosed more than 20 years ago, 141 (52%) patients answered our questionnaire, 45 (16%) patients were alive but did not wish to answer our questionnaire, 51 (19%) could not be traced and 36 (13%) died before July 1998. At the end of follow-up, 25.7 (20.0-59.3) years after diagnosis, 24% had a relapse in the previous 12 months, and 48% and 28% had quiescent disease with and without treatment, respectively. These ratios were not different from those observed three years after Crohn's disease diagnosis. Sixteen patients died within 20 years after CD diagnosis, including 11 from CD-related causes. The risk of death estimated by Kaplan-Meier life-tables analysis was non-significantly higher if death was related to CD. An ileal or colic adenocarcinoma was noted in 6 (3.4%) patients., Conclusions: Crohn's disease activity does not burn out with time, and roughly one-quarter of the patients had active disease 20 years after diagnosis.

Aim: Little is known about the long-term course of patients explored by push enteroscopy for gastrointestinal bleeding of obscure origin. This study aimed to determine the diagnostic yield and the therapeutic impact of enteroscopy, the rate of rebleeding and predictive factors of rebleeding in these patients., Patients and Methods: One hundred nineteen patients underwent push enteroscopy for overt bleeding (N=66) or anemia (N=53)., Results: Enteroscopy was positive in 42% of patients (colon 17%, stomach 13%, small bowel 12%) and diagnosed arteriovenous malformations in two-thirds of patients. Twenty-five additional diagnoses were established during the 2-month follow-up. Treatment was definitive in 13% of patients, without recurrent bleeding. Rebleeding occurred in 45% of patients, and was more frequent when a lesion was visualized (73% vs 28% after 5 years, P=0.02). In multivariate analysis, a lesion visualized by enteroscopy was the only independent predictive factor., Conclusion: Enteroscopy is not a high-performance diagnostic tool for obscure gastrointestinal bleeding and enables definitive treatment in less than 15% of patients.

Background & Aims: Adherent-invasive Escherichia coli (AIEC) pathovar has been identified in the intestinal mucosa of patients with Crohn's disease (CD). AIEC reference strain LF82 is able to adhere to intestinal epithelial cells, to invade epithelial cells via a mechanism involving actin polymerization and microtubules, and to survive and replicate within macrophages. This study was performed to assess the prevalence of AIEC associated with intestinal mucosa of patients with CD, ulcerative colitis (UC), and of controls., Methods: A search for E. coli strains was performed with ileal specimens of 63 patients with CD and 16 controls without inflammatory bowel disease (IBD), and with colonic specimens of 27 patients with CD, 8 patients with UC, and 102 controls. The abilities of E. coli strains to invade epithelial cells and to survive and replicate within macrophages were assessed using the gentamicin protection assay. Bacterial uptake by epithelial cells was analyzed using cytoskeletal inhibitors. Bacterial adhesion was quantified with Caco-2 and Intestine-407 cells. The presence of known E. coli virulence genes was assessed by polymerase chain reaction and DNA hybridization., Results: In ileal specimens, AIEC strains were found in 21.7% of CD chronic lesions vs. in 6.2% of controls. In neoterminal ileal specimens, AIEC strains were found in 36.4% of CD early lesions (P = 0.034 vs. controls) and 22.2% of healthy mucosa of CD patients. In colonic specimens, AIEC strains were found in 3.7% of CD patients, 0% of UC patients, and 1.9% of controls., Conclusions: AIEC strains are associated specifically with ileal mucosa in CD.

Most cases of antibiotic-associated diarrhoea (AAD) are directly or indirectly due to the alteration of gut microflora by antibiotics. 'Functional' diarrhoea, usually limited to a mild and brief change in stool frequency, is considered as the most frequent pattern of AAD. Reduced carbohydrate fermentation and impaired metabolism of bile acids have been claimed as the potential causes of this transient digestive discomfort but a critical analysis of the data supporting these theories is necessary. Alternatively, changes in the gut flora ecosystem allow pathogens to proliferate. Clostridium difficile is responsible for approximately 10% of cases of AAD and almost all cases of antibiotic-associated pseudomembranous colitis. The level of evidence which supports the potential responsibility of other candidate pathogens (Klebsiella oxytoca, enterotoxin-producing Clostridium perfringens and Staphylococcus aureus, Candida) needs to be appreciated according to the updated postulates of causality relationships between a bacterium and a disease.

Chronic use of non-salicylate NSAIDs causes in most individuals an asymptomatic enteropathy involving the small bowel, particularly its distal part. This enteropathy is characterised by an increase in intestinal permeability and a mild mucosal inflammation. Hypoalbuminemia and iron deficiency may occur. In addition, non-salicylate NSAIDs may cause focal lesions of the small intestine. Ulcerations and ulcers, that can be accidentally discovered during an ileoscopy, may cause acute or chronic bleeding. Deep ulcers may provoke sudden peritonitis. Small bowel diaphragms are rare fibrotic lesions, specifically associated with the use of non-salicylate NSAIDs or salicylates (duodenal diaphragms only). NSAID use is not associated with a constant toxicity on colonic mucosa. NSAID-induced colonic ulcers and diaphragms are rare. In patients with colonic diverticulosis, NSAID intake is a risk factor for severe attacks of diverticulitis. Acute or chronic use of non-salicylate NSAIDs increases the risk for ischemic colitis and flare-ups of inflammatory bowel disease. De novo colitis caused by non-salicylate NSAIDs are rare. The definite diagnosis of this entity relies on the absence of recurrence of colitis in the 2-3 following years. Such a recurrence would lead to the post-hoc diagnosis of first attack of inflammatory bowel disease triggered by NSAID use. Experimental data suggest that selective COX-2 inhibitors do not alter constantly mucosa of the small intestine. Pilot epidemiological works suggest that severe intestinal lesions are less frequent in association with COX-2 inhibitor use than in association with conventional NSAIDs. However, COX-2 appears as playing a beneficial role in mucosal healing, and it seems that COX-2 inhibitors, like conventional NSAIDs, may trigger flare-ups of inflammatory bowel disease.

Background: More than 80% of non-Hodgkin lymphomas (NHLs) occurring in transplant recipients on immunosuppressive therapy are associated with Epstein-Barr virus (EBV) infection. EBV viral load (EBV-VL) is predictive of NHL occurrence in this setting. The aim of this work was to determine EBV-VL in patients with Crohn's disease (CD), both according to disease activity and use of immunosuppressive therapy, including infliximab., Methods: Between December 1999 and July 2001, EBV-VL was determined 212 times by quantitative polymerase chain reaction (PCR) assay in 138 patients with CD and in 24 EBV-seropositive controls free of CD., Results: EBV-VL did not differ significantly between the controls and the patients with CD and was not influenced by CD activity or by immunosuppressive therapy, including recent infliximab infusion. High EBV-VL values were observed in two patients with severe uncontrolled CD, but returned to normal once the flare-up had been controlled (by immunosuppressive drugs in one case and by surgery in the other case)., Conclusions: EBV viral load is on the whole similar in patients with Crohn's disease and in EBV-seropositive controls. Infliximab infusion does not seem to increase significantly EBV-VL in the short-term. However, some patients with Crohn's disease have transient, very high EBV-VL values that are compatible with an increased risk of NHL in the transplant setting. The long-term clinical outcome of these patients must be determined.

Purpose: This study was designed to evaluate the predictive factors of response of perianal Crohn's disease to azathioprine or 6-mercaptopurine., Methods: Ninety-four patients (65 females; mean age, 31 years) with active perianal Crohn's disease were treated with azathioprine or 6-mercaptopurine for more than 6 (median, 27) months (median azathioprine dose, 2 mg/kg/day). The evolution of perianal lesions during azathioprine or 6-mercaptopurine therapy was analyzed retrospectively. Patients who had a clear anatomic improvement (fistula closure, fissure healing, stricture dilatation) and who did not develop any perianal complications requiring an antibiotic course or surgical intervention were considered responders regarding their perianal disease., Results: Three years after inclusion, the cumulative probabilities of remaining free of perianal complication and achieving a clear anatomic improvement were 0.47 (95 percent confidence interval, 0.36-0.58) and 0.4 (95 percent confidence interval, 0.29-0.53), respectively. On the whole, 27 patients (29 percent) were responders to azathioprine or 6-mercaptopurine therapy. The absence of fistula, duration of perianal disease shorter than 22 months, and aged 40 years or older at inclusion were three independent factors associated with response to azathioprine or 6-mercaptopurine therapy. There was no correlation between the response of perianal lesions and the achievement of intestinal remission with azathioprine or 6-mercaptopurine., Conclusion: One-third of patients with perianal lesions of Crohn's disease demonstrated a clear improvement during azathioprine or 6-mercaptopurine therapy. Patients aged 40 years or older with a recent perianal disease and without fistula were the best responders.

Background: Clostridium difficile is the main cause of nosocomial infectious diarrhoea and the causative agent of antibiotic-associated colitis. The involvement of C. difficile infection in antibiotic-associated diarrhoea in the community is poorly documented., Methods: We studied prospectively 266 adult out-patients in the Paris (France) area who were prescribed a 5-10-day course of antimicrobial chemotherapy. Stools were screened for C. difficile before and 14 days after the start of treatment by standard culture, toxigenic culture and testing for the cytopathic effect of toxin B. Patients were requested to note daily stool frequency and consistency. Diarrhoea was defined as the passage of at least three loose stools per day., Results: Forty-six (17.5%) of the 262 assessable patients had diarrhoea during the study period. Diarrhoea was mild and self-limited in all patients, and lasted for only 1 day in 65.6% of cases. C. difficile was isolated before and after treatment from one patient, who did not develop diarrhoea. C. difficile was detected only on day 14 in 10 patients (3.8%). The isolate was toxin producing in seven patients. Four of these seven patients had mild self-limited diarrhoea. Toxin-producing C. difficile was isolated significantly more frequently from patients who had diarrhoea than from those who were diarrhoea free (8.7% vs. 1.4%, P = 0.02)., Conclusion: The acquisition of toxin-producing C. difficile appears to be frequent during antimicrobial chemotherapy in the community [estimated rate of 2700 (1150-5400) cases per 100 000 exposures to antibiotics]. However, C. difficile is not the main agent of mild antibiotic-associated diarrhoea in out-patients.

Background and Aims: Several cases of acute colitis induced by non-steroidal anti-inflammatory drugs (NSAIDs) have been reported but the general role of recent NSAID intake as a risk factor for acute diarrhoea has not been studied to date. The aim of our study was to determine whether the risk of acute diarrhoea is increased by NSAIDs in a prospective series of acute diarrhoea cases which were seen by general practitioners in France and were serious enough to require a stool culture. Patients, physicians, and methods: A total of 285 consecutive patients with acute diarrhoea, seen by Sentinel general practitioners (GPs) between December 1998 and July 1999, were enrolled in a case crossover study in which each case served as his/her own control. GPs collected information on exposure to NSAIDs during the four month period preceding the onset of diarrhoea. The relative risk of NSAID related acute diarrhoea was estimated by comparing exposure to NSAIDs during a risk period preceding the onset of diarrhoea with exposure during the first part of the four month observation period. Three risk periods lasting for one, three, and six days before the onset of diarrhoea were considered., Results: The relative risks of acute diarrhoea due to recent NSAID intake were increased for all three risk periods. These risks and their confidence intervals were 2.9 (1.4-6.1) for the one day risk period, 2.7 (1.4-5.1) for the three day period, and 3.3 (2.0-5.4) for the six day period., Conclusion: Recent NSAID intake emerges as a risk factor for acute diarrhoea. We suggest that acute diarrhoea seen in general practice, and not only acute colitis seen by gastroenterologists, should be considered as a potential complication of recent NSAID intake.

Background: The Vienna classification of Crohn's disease (CD) distinguishes three patient subgroups according to disease behavior: stricturing, penetrating, and inflammatory. Our aim was to assess the long-term evolution of the disease behavior of CD and to determine the predictive factors and prognostic implications of this evolution., Methods: Occurrence and predictive factors of a stricturing and/or a penetrating complication were searched for in 2,002 patients with CD studied retrospectively. In addition, the 1995-2000 disease course was assessed prospectively in a cohort of 646 patients with disease duration >5 years, classified according to their previous disease behavior., Results: 1,199 patients (60%) developed a stricturing (n = 254) or a penetrating (n = 945) complication. Twenty-year actuarial rates of inflammatory, stricturing, and penetrating disease were 12, 18, and 70%, respectively. The initial location of lesions was the main determinant of the time and type of the complication. In the cohort study, year-by-year activity and therapeutic requirements did not show significant sustained differences between behavioral subgroups., Conclusion: Most patients with CD will eventually one day develop a stricturing or a perforating complication. Initial location determines the type of the complication. Classification of patients into a behavioral group from previous history has no impact upon activity during the following years.

Aims: This study was designed to assess the proportion of adult patients with celiac disease who had had undiagnosed symptoms during childhood and to determine the consequences of such diagnostic delay., Patients and Methods: One hundred eighty-four patients with celiac disease (56 males, 128 females, age range 17-88 years) were classified according to diagnosis and symptoms of celiac disease during childhood. Prevalence of short stature, low fertility, clinical osteoporosis, cancer, and autoimmune disease were assessed in each celiac group and compared with a control group matched for gender and age., Results: Compared with the control group, patients with celiac disease were shorter (men 171.4 +/- 9.0 cm vs 176.4 +/- 6.9 cm, P<0.01; women 159.7 + 7.3 cm vs 162.7 +/- 6.2 cm, P<0.01) and had a higher prevalence of symptomatic osteoporosis (5%) cancer (10%), and autoimmune disease (25%). Compared with matched controls and with patients whose celiac disease had been diagnosed during childhood (n=36), or who had remained symptom-free (n=95), patients who had undiagnosed symptomatic celiac disease during childhood exhibited higher prevalence of short stature (26%), low female fertility or low birth weight (36%). Multivariate analysis showed that short stature and low fertility correlated with duration of symptoms before diagnosis; osteoporosis and cancer correlated with age. The prevalence of autoimmune disease was unrelated to early onset of symptoms or delay to diagnosis., Conclusions: Missing the diagnosis of celiac disease in a symptomatic child may lead to short stature and low female fertility.

Background and Aims: Obesity is unusual in Crohn's disease and the particularities of the disease in obese patients have not been studied., Methods: 2065 patients were studied retrospectively. Obesity was defined by a BMI value >25.0 at disease onset and >30.0 at any time during the course of the disease. Disease characteristics, therapeutic needs, and year-by-year disease activity were determined in patients with and without obesity., Results: 62 patients (3%) were obese. When compared with non-obese patients, obese patients did not show differences regarding sex, intestinal disease location, and disease behavior, but at diagnosis they were older (32 vs 28 years, P = 0.01) and a larger proportion had anoperineal disease (35 vs 24%, P = 0.03). When the 62 obese patients were paired for sex, location of disease at onset, date of birth, and date of diagnosis with 124 non-obese patients, the disease severity assessed by the importance of medical therapy and excisional surgery did not differ in the two groups but time to development of anoperineal abscess or fistula was shorter in obese patients, and obese patients were more prone to develop an active disease (OR 1.50, 95% CI 1.07-2.11) and to require hospitalization (OR 2.35, 95% CI 1.56-3.52), Conclusion: Obesity in Crohn's disease is associated with more frequent anoperineal complications and a more marked year-by-year disease activity, but does not alter significantly the long-term course of the disease., (Copyright 2002 Elsevier Science Ltd. All rights reserved.)

Background: Several types of colitis can be NSAID-induced, but whether chronic use of NSAIDs alters colonic mucosa in patients without diarrhoea is not known., Patients and Methods: Biopsy specimens of rectal mucosa were taken in six patients with rheumatoid arthritis without diarrhoea receiving NSAIDs (group 1, n=6). Patients with rheumatoid arthritis without diarrhoea not receiving NSAIDs (group 2, n=9), and patients undergoing surveillance colonoscopy (group 3, n=23) served as controls. In all patients from the three study groups, intraepithelial lymphocyte count and apoptotic cell count were assessed, and sub-epithelial collagen band thickness was measured. Leucocyte population of lamina propria was evaluated semi-quantitatively. HLA-DR and CD25 expression of mucosal cells was appreciated by immunohistochemistry., Results: Intraepithelial lymphocyte count was in the normal range in all three group patients, and not statistically different between groups. Apoptotic epithelial cell count was not different between groups. Sub-epithelial collagen band thickness was normal in all the patients. No patient had a marked infiltration of lamina propria by leucocytes, and HLA-DR and CD25 were normally expressed in all patients., Conclusion: These results from a small sample of patients suggest that patients without diarrhoea receiving NSAIDs on a long-term basis do not develop microscopic or inflammatory colitis.

Aims: The incidence of thromboembolic disease is increased in patients with inflammatory bowel disease. Hyperhomocysteinemia is one of the risk factors for thrombosis. The aims were: 1) to assess the prevalence of hyperhomocysteinemia in a large series of patients with Crohn's disease; 2) to search for clinical and biological factors associated with hyperhomocysteinemia., Patients and Methods: One hundred seventy-one patients with Crohn's disease (64 males, 107 females), median age 31 years (range: 16-82), were studied. The median duration of the disease was 7 years. The concentrations of homocysteine, folate, cobalamin and C-reactive protein were measured in serum from blood sample of each patient., Results: The mean concentration of seric homocysteine was 14.8 micromol/L (N: 4.4 - 12.4 micromol/L). Hyperhomocysteinemia was observed in 89 patients (52%). It was significantly associated with age, sex, smoking habit, serum cobalamin level and history of ileal surgical resection (P<0.05). In the group of operated patients, there was a statistically significant association between hyperhomocysteinemia and the length of small bowel resected. In multivariate analysis, sex and smoking were associated with hyperhomocysteinemia., Conclusion: More than half of the patients with Crohn's disease have hyperhomocysteinemia. This result stresses the need for preventing reversible factors associated with hyperhomocysteinemia, such as smoking and cobalamin deficiency, in order to lower the thrombotic risk of patients with Crohn's disease.

Objectives: The incidence and severity of ulcerative colitis (UC) are higher in nonsmokers than in smokers. The natural course of UC in smokers who stop smoking is not known. The aim of this study was to determine the impact of cessation of smoking on the course of UC among the cohort of patients regularly seen at our institution., Methods: The severity of UC, as judged by the occurrence of flare-ups and the need for systemic steroids, immunosuppressive drugs and colectomy, was determined in 32 patients with UC who stopped smoking after the diagnosis of UC. We compared the period after cessation of smoking (7-yr mean follow-up) with the period between the onset of the disease and the cessation of smoking (9-yr mean duration). The course of UC in this group was compared with that of 32 nonsmokers and 32 continuing smokers matched for sex, age, and age at onset., Results: In patients who quit, cessation of smoking was followed by an increase in the rate of years with active disease (p < 0.01), years with hospitalization (p < 0.05) and years with major medical therapy (oral steroids, intravenous steroids, and azathioprine, p < 0.01). After cessation of smoking, the rate of years with immunosuppressive therapy was significantly greater in ex-smokers and nonsmokers than in continuing smokers (p < 0.01). The risk of colectomy in ex-smokers after smoking cessation was similar to that of nonsmokers and continuing smokers., Conclusions: In smokers with UC who stop smoking, the severity of the disease increases after smoking cessation, with an increase in the disease activity and the need for hospital admission and major medical therapy. In addition, the need for azathioprine therapy becomes similar to that of nonsmokers.

Background and Aims: To evaluate the benefit of smoking cessation in individuals with Crohn's disease, we performed an intervention study in a large cohort of smokers with the disease., Methods: Repeated counseling to stop smoking, with easy access to a smoking cessation program, was given to 474 consecutive smokers with Crohn's disease. Patients who stopped smoking for more than 1 year (quitters) were included in a prospective follow-up study, which compared disease course and therapeutic needs with 2 control groups, continuing smokers and nonsmokers, paired for age, gender, disease location, and activity., Results: There were 59 quitters (12%). Predictors of quitting were the physician, previous intestinal surgery, high socioeconomic status, and in women, oral contraceptive use. During a median follow-up of 29 months (1-54 months), the risk of flare-up in quitters did not differ from that in nonsmokers and was less than in continuing smokers (P < 0.001). Need for steroids and for introduction or reinforcement of immunosuppressive therapy, respectively, were similar in quitters and nonsmokers and increased in continuing smokers. The risk of surgery was not significantly different in the 3 groups., Conclusions: Patients with Crohn's disease who stop smoking for more than 1 year have a more benign disease course than if they had never smoked.

The aim of this study was to identify risk factors for acute diarrhoea (AD) during the summer in France. A matched case-control study was conducted at a national level among patients of 500 general practitioners (GPs). From July to September 1996, 468 case-control pairs were included. Cases were more likely than controls (i) to live away from their main residence (OR 3.0; 95% CI 1.6-5.7), (ii) to have returned from a country at high risk of AD (OR 4.6; CI 0.9-23.1), and (iii) to have been in contact with a case of AD (OR 2.0; CI 1.3-3.1). A significantly decreased risk of AD was found for consumption of well-cooked chicken (OR 0.5; CI 0.3-0.8) and raw or undercooked home-made egg-containing products (OR 0.6; CI 0.4-0.8). These findings suggest that travel to high-risk areas, or travel within France, and being in contact with a case of AD, are risk factors for the occurrence of AD in summer in France.