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Objective: Our objective was to describe the incidence and risk factors of legionellosis associated with tumor necrosis factor (TNF)-α antagonist use., Methods: From February 1, 2004, to January 31, 2007, we prospectively collected all cases of legionellosis among French patients receiving TNF-α antagonists in the Research Axed on Tolerance of Biotherapies (RATIO) national registry. We conducted an incidence study with the French population as a reference and a case-control analysis with four control subjects receiving TNF-α antagonists per case of legionellosis., Results: Twenty-seven cases of legionellosis were reported. The overall annual incidence rate of legionellosis for patients receiving TNF-α antagonists, adjusted for age and sex, was 46.7 (95% CI, 0.0-125.7) per 100,000 patient-years. The overall standardized incidence ratio (SIR) was 13.1 (95% CI, 9.0-19.1; P < .0001) and was higher for patients receiving infliximab (SIR, 15.3 [95% CI, 8.5-27.6; P < .0001]) or adalimumab (SIR, 37.7 [95% CI, 21.9-64.9; P < .0001]) than etanercept (SIR, 3.0 [95% CI, 1.00-9.2; P = .06]). In the case-control analysis, exposure to adalimumab (OR, 8.7 [95% CI, 2.1-35.1]) or infliximab (OR, 9.2 [95% CI, 1.9-45.4]) vs etanercept was an independent risk factor for legionellosis., Conclusions: The incidence rate of legionellosis for patients receiving TNF-α antagonists is high, and the risk is higher for patients receiving anti-TNF-α monoclonal antibodies than soluble TNF-receptor therapy. In case of pneumonia occurring during TNF-α antagonist therapy, specific urine antigen detection should be performed and antibiotic therapy should cover legionellosis., Trial Registry: ClinicalTrials.gov; No.: NCT00224562; URL: www.clinicaltrials.gov.

Background: Little is known in inflammatory bowel disease (IBD) regarding risk factors for psychological distress. The aim of this work was to study the disease characteristics and socioeconomic factors associated with anxiety and depression in IBD., Methods: From December 2008 to June 2009, 1663 patients with IBD (1450 were members of the Association Francois Aupetit, French association of IBD patients) answered a questionnaire about psychological and socioeconomic factors and adherence to treatment. In this study we focused the analysis on the characteristics of IBD (type, location, severity, treatment) and socioeconomic factors (professional, educational, and marital status and Evaluation of Precarity and Inequalities in Health Examination Centers [EPICES] score of socioeconomic deprivation; score established in medical centers in France; http://www.cetaf.asso.fr) associated with depression and anxiety. Anxiety and depression were assessed by the Hospital Anxiety and Depression Scale. Comparison between groups according to the existence of depression or anxiety was carried out using univariate and multivariate analysis., Results: In all, 181 patients (11%) were depressed; 689 patients (41%) were anxious. By multivariate analysis, factors associated with anxiety were: severe disease (P = 0.04), flares (P = 0.05), nonadherence to treatment (P = 0.03), disabled or unemployed status (P = 0.002), and socioeconomic deprivation (P < 0.0001). Factors associated with depression were: age (P = 0.004), flares (P = 0.03), disabled or unemployed status (P = 0.03), and socioeconomic deprivation (P < 0.0001)., Conclusions: In this large cohort of IBD patients, risk factors for anxiety and depression were severe and active disease and socioeconomic deprivation. Psychological interventions would be useful when these factors are identified., (Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.)

Background & Aims: Recent studies reported a role for more than 70 genes or loci in the susceptibility to Crohn's disease (CD). However, the impact of these associations in clinical practice remains to be defined. The aim of the study was to analyse the relationship between genotypes and phenotypes for the main 53 CD-associated polymorphisms., Method: A cohort of 798 CD patients with a median follow up of 7 years was recruited by tertiary adult and paediatric gastroenterological centres. A detailed phenotypic description of the disease was recorded, including clinical presentation, response to treatments and complications. The participants were genotyped for 53 CD-associated variants previously reported in the literature and correlations with clinical sub-phenotypes were searched for. A replication cohort consisting of 722 CD patients was used to further explore the putative associations., Results: The NOD2 rare variants were associated with an earlier age at diagnosis (p = 0.0001) and an ileal involvement (OR = 2.25[1.49-3.41] and 2.77 [1.71-4.50] for rs2066844 and rs2066847, respectively). Colonic lesions were positively associated with the risk alleles of IL23R rs11209026 (OR = 2.25 [1.13-4.51]) and 6q21 rs7746082 (OR = 1.60 [1.10-2.34] and negatively associated with the risk alleles of IRGM rs13361189 (OR = 0.29 [0.11-0.74]) and DEFB1 rs11362 (OR = 0.50 [0.30-0.80]). The ATG16L1 and IRGM variants were associated with a non-inflammatory behaviour (OR = 1.75 [1.22-2.53] and OR = 1.50 [1.04-2.16] respectively). However, these associations lost significance after multiple testing corrections. The protective effect of the IRGM risk allele on colonic lesions was the only association replicated in the second cohort (p = 0.03)., Conclusions: It is not recommended to genotype the studied polymorphisms in routine practice.

Background: Adherence to treatment is a key condition in preventing relapses in inflammatory bowel disease (IBD). The aims of this study were specifically to study socioeconomic and psychological factors and adherence to treatment in a large cohort of patients., Methods: A questionnaire concerning demographic, clinical, and psychosocial characteristics was mailed to 6000 IBD patients belonging to the French association of IBD patients (AFA). The questionnaire was also available on the Website of the AFA for nonmember patients to answer. Good adherence to treatment was defined as taking ≥ 80% of prescribed medication. Socioeconomic deprivation was assessed using the specific EPICES score (http://www.cetaf.asso.fr) developed in France. Anxiety and depression were assessed using the Hospital Anxiety and Depression scale., Results: A total of 1069 women and 594 men (43.6 ± 15.4 years) completed the questionnaire; 1450 (87.2%) of them belonged to the AFA. In all, 1044 had Crohn's disease, 36 indeterminate colitis, and 583 ulcerative colitis. Adherence ≥ 80% was reported by 89.6% of patients. Factors associated with good adherence were: older age (P < 0.01), treatment with anti-tumor necrosis factor (TNF) (P < 0.0001), membership in the AFA (P = 0.006). Nonadherence increases with smoking (P = 0.02), constraints related to treatment (P < 10(-9) ), anxiety (P < 10(-6) ), and moodiness (P < 10(-5) ). There were no differences in adherence for the following: gender, type of IBD, activity and severity of the disease, socioeconomic deprivation, marital status, education level, and depression., Conclusions: In this large cohort of IBD patients, psychological distress and constraints related to treatment decrease adherence to treatment, while membership in a patients' association improves it., (Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.)

Aims: Inflammatory bowel diseases (IBD) have a negative impact on patients' quality of life. The aims of this survey were to learn more about patients' concerns, and to compare their feelings with the beliefs of their close relations and physicians., Patients and Methods: A specific questionnaire, including the RFIPC and the MFI-20, was used. Patients' answers were compared with those given by their close relations and attending physicians., Results: This national survey included 2424 French patients. At the time of diagnosis, 73% of patients expressed having fears, but were also relieved to understand their symptoms. IBD was responsible for fatigue and weariness, and had a negative impact on daily, occupational, leisure, family and personal life. The main fears concerned unpredictable flare-ups followed by need for an ostomy bag and risk of surgery. The answers provided by close relations and physicians matched those of the patients, but physicians overestimated the patient's knowledge and underestimated disease impact., Conclusion: IBD has a deleterious effect on quality of life. Close relations of the patient realize the impact the disease has on the patients' life, but attending physicians still tend to minimize patients' symptoms., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Background and Aims: Few studies have been conducted addressing the safety of thiopurine treatment in pregnant women with inflammatory bowel disease (IBD). The aim of this study was to evaluate the pregnancy outcome of women with IBD who have been exposed to thiopurines., Methods: 215 pregnancies in 204 women were registered and documented in the CESAME cohort between May 2004 and October 2007. Physicians documented the following information from the women: last menstrual date, delivery term, details of pregnancy outcome, prematurity, birth weight and height, congenital abnormalities, medication history during each trimester, smoking history and alcohol ingestion. Data were compared between three groups: women exposed to thiopurines (group A), women receiving a drug other than thiopurines (group B) and women not receiving any medication (group C)., Results: Mean age at pregnancy was 28.3 years. 75.7% of the women had Crohn's disease and 21.8% had ulcerative colitis, with a mean disease duration of 6.8 years at inclusion. Of the 215 pregnancies, there were 138 births (142 newborns), and the mean birth weight was 3135 g. There were 86 pregnancies in group A, 84 in group B and 45 in group C. Interrupted pregnancies occurred in 36% of patients enrolled in group A, 33% of patients enrolled in group B, and 40% of patients enrolled in group C; congenital abnormalities arose in 3.6% of group A cases and 7.1% of group B cases. No significant differences were found between the three groups in overall pregnancy outcome., Conclusions: The results obtained from this cohort indicate that thiopurine use during pregnancy is not associated with increased risks, including congenital abnormalities.

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.

Background: There are few data on the incidence of benign infections (upper respiratory tract infections, herpes lesions and viral warts) during exposure to azathioprine., Aims: To determine the incidence of benign infections in IBD out-patients receiving azathioprine (AZA+) and to look at the influence of leucocyte counts in the onset of these events., Methods: A total of 230 patients were included in a prospective cohort and observed during 207 patient-years. Episodes of benign infections were collected and incidences of benign infections were compared between the AZA+ group and patients without AZA (AZA-)., Results: The incidence of upper respiratory tract infections in the cohort was 2.1 +/- 2.2 per observation-year. There was no difference between the AZA+ (n = 169) and AZA- (n = 61) groups (2.2 +/- 2.3 vs. 2.1 +/- 2.1, P = 0.77). The incidence of herpes flares was significantly increased in the AZA+ group compared to the AZA- group (1.0 +/- 2.6 vs. 0.2 +/- 0.8 per year, P = 0.04). Similarly, there were significantly more patients with appearance or worsening viral warts in the AZA+ group (17.2% (AZA+) vs. 3.3% (AZA-), P = 0.004)., Conclusion: This study suggests that the incidence of herpes flares and the appearance or worsening of viral warts are increased in IBD patients receiving AZA.

Introduction: This study was designed to evaluate the safety of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe Crohn's disease (CD)., Patients and Methods: Forty five patients with a CD activity index (CDAI) of 250-450 were randomised in a double blind, placebo controlled, dose escalating fashion to receive single doses of fontolizumab (0.1, 1.0, and 4.0 mg/kg) or placebo. By day 29, patients with clinical response were re-randomised to receive three additional doses of one half their initial fontolizumab dose or placebo at four weekly intervals. Primary objectives were safety and tolerability. Secondary outcomes included assessments of immunogenicity, clinical activity, and potential pharmacodynamic surrogates., Results: Treatment was generally well tolerated. There were slightly more reports of chills, flu-like syndrome, asthenia, nausea, and vomiting in the 1.0 mg and 4.0 mg/kg fontolizumab cohorts. Two serious adverse events rated as worsening of CD occurred under fontolizumab. Antibodies to fontolizumab were confirmed in one patient. No differences in clinical activity parameters were noted between any of the active treatment groups and placebo, with the placebo group having a particularly favourable outcome (60% response and 40% remission). By day 29, a more enhanced decrease in median Crohn's disease endoscopic index of severity (p = 0.02) and serum C reactive protein (p<0.001) was observed in the 4.0 mg/kg (n = 14) fontolizumab cohort compared with placebo (n = 10). Pharmacodynamic effects were observed by immunohistochemistry., Conclusions: Fontolizumab was well tolerated with minimal immunogenicity at doses of up to 4.0 mg/kg in patients with CD. A biological activity of fontolizumab is suggested.

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.

Objectives: To evaluate prescription practices and response to infliximab treatment for Crohn's disease (CD)., Patients and Methods: The files of CD patients treated with at least one infusion of infliximab treated in gastroenterology units belonging to university teaching hospitals of the Parisian hospitals group (Assistance Publique-Hôpitaux de Paris (AP-HP) during the year 2000 were analyzed retrospectively., Results: One hundred and thirty-seven patients (36.0 +/- 12.7 years, 92 females) from 12 centers were studied. Indication for treatment was fistulae or perianal disease in 39% of patients, active Crohn's disease in 45% and mixed conditions in 16%. Mean follow-up was 15.2 +/- 7.2 months. The overall response rate was 85%. No predictive factor of sustained remission could be identified. The mean time to relapse was to 3.9 +/- 3.1 months. Thirty-eight patients were on maintenance therapy at the end of the follow up; 37% exhibiting progressive lost of response to treatment. Immunosuppressive therapy was added to infliximab in 78% of cases but response to infliximab was not modified by addition of immunosuppressive drugs. Adverse events, most frequently minor, were noted in 23% of the patients., Conclusion: This retrospective study confirms the efficacy and safety of infliximab in CD.

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.

Purpose: To study the impact of fused (18)F-fluoro-deoxy-D-glucose (FDG)-hybrid positron emission tomography (PET) and computed tomography (CT) images on conformal radiotherapy planning for esophageal carcinoma patients., Methods and Materials: Thirty-four esophageal carcinoma patients were referred for concomitant radiotherapy and chemotherapy with radical intent. Each patient underwent CT and FDG-hybrid PET for simulation treatment in the same treatment position. PET images were coregistered using five fiducial markers. Target delineation was initially performed on CT images, and the corresponding PET data were subsequently used as an overlay to CT data to define the target volume., Results: (18)F-fluorodeoxy-D-glucose-PET identified previously undetected distant metastatic disease in 2 patients, making them ineligible for curative conformal radiotherapy. The gross tumor volume (GTV) was decreased by CT and FDG image fusion in 12 patients (35%) and increased in 7 patients (21%). The GTV reduction was > or =25% in 4 patients owing to a reduction in the length of the esophageal tumor. The GTV increase was > or =25% with FDG-PET in 2 patients owing to the detection of occult mediastinal lymph node involvement in 1 patient and an increased length of the esophageal tumor in 1 patient. Modifications of the GTV affected the planning treatment volume in 18 patients. Modifications of the delineation of the GTV and displacement of the isocenter of the planning treatment volume by FDG-PET also affected the percentage of total lung volume receiving >20 Gy in 25 patients (74%), with a dose reduction in 12 patients and dose increase in 13., Conclusion: In our study, CT and FDG-PET image fusion appeared to have an impact on treatment planning and management of esophageal carcinoma. The affect on treatment outcome remains to be demonstrated.

Purpose: To study the impact of fused (18)F-fluoro-deoxy-D-glucose (FDG)-hybrid positron emission tomography (PET) and computed tomography (CT) images on conformal radiation therapy (CRT) planning for patients with esophageal carcinoma., Patients and Methods: Thirty-four patients with esophageal carcinoma were referred for concomitant radiotherapy and chemotherapy with radical intent. Each patient underwent CT and FDG-hybrid PET for simulation treatment in the same radiation treatment position. PET-images were coregistered using five fiducial markers. Target delineation was initially performed on CT images and the corresponding PET data were subsequently used as an overlay to CT data to define the target volume., Results: FDG-PET identified previously undetected distant metastatic disease in 2 patients, making them ineligible for curative CRT. The Gross Tumor Volume (GTV) was decreased by CT and FDG image fusion in 12 patients (35%) and was increased in 7 patients (20.5%). The GTV reduction was >or=25% in 4 patients due to reduction of the length of the esophageal tumor. The GTV increase was >or=25% with FDG-PET in 2 patients due to the detection of occult mediastinal lymph node involvement in one patient and an increased length of the esophageal tumor in the other patient. Modifications of the GTV affected the planning treatment volume (PTV) in 18 patients. Modifications of delineation of GTV and displacement of the isocenter of PTV by FDG-PET also affected the percentage of total lung volume receiving more than 20 Gy (VL20) in 25 patients (74%), with a dose reduction in 12 patients and a dose increase in 13 patients., Conclusion: In our study, CT and FDG-PET image fusion appeared to have an impact on treatment planning and management of patients with esophageal carcinoma related to modifications of GTV. The impact on treatment outcome remains to be demonstrated.

Background: The impact of pregnancy on Crohn's disease activity has been poorly investigated., Aim: To determine the effect of pregnancy on Crohn's disease activity from the retrospective analysis of a cohort of women who had a regular clinical follow-up., Methods: Seventy pregnancies occurring in 61 women were studied. The Harvey-Bradshaw index was determined during the four quarters preceding each pregnancy, the three quarters of pregnancy and the four quarters following delivery., Results: The mean Harvey-Bradshaw index during pregnancy [0.68 (0.18), mean (S.E.M.)] was significantly lower than that of the year preceding pregnancy [0.98 (0.16), P = 0.03] and that of the year following delivery [1.10 (0.17), P = 0.04]. In non-smoking women (48 pregnancies), there was no significant change of Harvey-Bradshaw index between these intervals. Whereas in those who smoked (22 pregnancies), most of whom reduced tobacco consumption during pregnancy, the mean Harvey-Bradshaw index during pregnancy was significantly reduced compared with that of the year following delivery [0.58 (0.20) vs. 1.60 (0.33), P = 0.01]. The use of drugs was significantly lower during pregnancy., Conclusions: Crohn's disease activity is mildly but significantly lower during pregnancy. The reduction of tobacco consumption during pregnancy in smoking women may play an important role in this improvement.

Background/aim: Immunosuppressants are now used much earlier in the course of Crohn's disease; however their effect on the natural history of the disease, especially on the need for surgery, is not known. The aim of this study was to assess the evolution of the need for surgery in Crohn's disease during the last 25 years., Patients and Methods: The medical charts of 2573 patients were reviewed retrospectively. The use of immunosuppressants (azathioprine or methotrexate), the need for intestinal resection, and the occurrence of intestinal complications were assessed using Kaplan-Meier analysis in five consecutive cohorts of patients defined by the date of diagnosis of Crohn's disease (1978-82; 1983-87; 1988-92; 1993-97; 1998-2002)., Results: In 565 patients seen in the authors' unit within the first three months after diagnosis, characteristics of Crohn's disease at diagnosis did not differ from one cohort to another. The five year cumulative probability to receive immunosuppressants increased from 0 in the 1978-82 cohort to 0.13, 0.25, 0.25, and 0.56 in the 1983-87, 1988-92, 1993-97, and 1998-2002 cohorts, respectively (p<0.001). Concomitantly, the cumulative risk of intestinal resection remained unchanged (from 0.35 to 0.34 at five years; p=0.81). The cumulative risk of developing a stricturing or a penetrating intestinal complication remained also unchanged. Similar results were obtained in the 2008 patients seen during the same period who were referred to us more than three months after diagnosis., Conclusion: Although immunosuppressants have been used more frequently over the last 25 years, there was no significant decrease of the need for surgery, or of intestinal complications of Crohn's disease.

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.

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.

Background and Aims: The aim of this study was to examine in parallel the effect of smoking on ulcerative colitis and Crohn's colitis and assess the effect of gender on the response of colitis to smoking., Methods: Medical charts of 1784 adult consecutive patients (978 patients, ulcerative colitis; 118 patients, indeterminate colitis; and 688 patients, Crohn's colitis), whose smoking habits were specified by direct interview, were reviewed., Results: The proportion of ever smokers was 42% in ulcerative colitis, 43% in indeterminate colitis, and 61% in Crohn's colitis. Smoking cessation preceded the onset of colitis in 279 patients with ulcerative colitis or indeterminate colitis (61%) and only 52 patients (12%) with Crohn's colitis. In ulcerative colitis and indeterminate colitis, current smoking delayed mean age at disease onset in men (from 32 to 41 yr; P < 0.001), but not women (from 33 to 33 yr), and decreased the need for immunosuppressants in men (10-yr cumulative risk, 26% +/- 4% in nonsmokers vs. 8% +/- 4% in smokers; P < 0.01), but not significantly in women. Conversely, in Crohn's colitis, current smoking hastened disease onset in women (from 35 to 29 yr; P < 0.001), but not men (from 32 to 31 yr), and increased the need for immunosuppressants in women (10-yr cumulative risk, 48% +/- 5% in nonsmokers vs. 58% +/- 4% in smokers; P < 0.01), but not men., Conclusions: The dual effects of smoking in colitis, beneficial in ulcerative colitis and harmful in Crohn's colitis, are modulated importantly by gender, with women having more disadvantage than men.

Background: Crohn's disease (CD) is characterised by inflammation, muscle layer overgrowth, and collagenous fibrosis of the intestinal tract, with no effective therapy against collagen accumulation., Aims: We quantified production of collagen in resection specimens from normal and CD patients and investigated the effect of regenerating agents (RGTAs) on collagen production. RGTAs are chemically substituted dextrans engineered to mimic the growth factor protecting effects of heparan sulphates. RGTAs have been shown to enhance tissue repair in various in vivo models and to modulate in vitro collagen phenotype differentially according to their structure., Patients: We studied intestinal biopsies from two groups of CD patients: treated with glucocorticoids (CD-GC group: 10 patients) or not treated (CD group: seven patients), and from seven control patients., Methods: After 24 hours of ex vivo incubation with (3H) proline, collagen I, III, and V were extracted by pepsin and quantitatively separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. Biosynthesis of each collagen type was quantified on radiolabelled isolated collagen., Results: Total intestinal collagen production in CD patients compared with controls was increased up to 3.5-fold overall (p<0.001). In particular, collagen III biosynthesis was enhanced by 6.2-fold (p<0.001) in CD patients. In the CD-GC group, collagen production abnormalities were less marked. RGTAs added to the incubation medium in the CD group decreased total collagen production by 50% and decreased collagen III synthesis by 76%., Conclusion: This finding offers a rationale for using RGTAs in the treatment of intestinal fibrosis in CD, thus opening up a potential new therapeutic field for this family of drugs.

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.

Although the association of Crohn disease and Meckel diverticulum has been widely reported, the direct involvement of a Meckel diverticulum by Crohn disease is less common and is usually the result of contiguous spread. The presence of heterotopic tissues in an affected diverticulum is rare and most often consists of gastric mucosa. We report herein the presence of Crohn disease within a Meckel diverticulum, with a normal small bowel immediately adjacent to the diverticulum, associated with pancreatic heterotopia.

Background: Appendicectomy reduces the risk of having ulcerative colitis. However, its effect on the natural history of ulcerative colitis remains uncertain., Aim: To determine whether appendicectomy reduces the overall severity of ulcerative colitis., Patients and Methods: Appendicectomy status and smoking habits were specified by direct interview in 638 patients seen consecutively between 1997 and 2000. Severity of ulcerative colitis was assessed by reviewing therapeutic needs from the onset of colitis. Additionally, the annual incidence of flare up was assessed prospectively between 1997 and 2000 in patients who had not been colectomised., Results: The 10 year risk of colectomy was 16 (7)% in previously appendicectomised patients (n=49) compared with 33 (2)% in non-appendicectomised patients (n=589, p=0.05). Cox regression showed that previous appendicectomy and current smoking were independent factors protecting against colectomy (adjusted hazard ratio and 95% confidence intervals: 0.40 (0.20-0.78) and 0.60 (0.40-0.95), respectively). The respective proportions of appendicectomised and non-appendicectomised patients who required oral steroids and immunosuppressive therapy were not significantly different (67% v 70% and 27% v 19%, respectively). Between 1997 and 2000, ulcerative colitis was active for 48% of the time in appendicectomised patients (47 of 98 patient years) and for 62% of the time in non-appendicectomised patients (631 of 1024 patient years; p<0.01)., Conclusion: Previous appendicectomy is associated with a less severe course of ulcerative colitis. The beneficial effect of appendicectomy on the risk of colectomy is additive to that of current smoking.

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.

Objective: To emphasize the possibility of obtaining good quality and lasting remission of a severe idiopathic protein-loosing enteropathy with corticosteroid therapy., Observation: A 30 year-old woman was hospitalized for edema of the lower limbs related to hypoalbuminemia due to a protein-loosing enteropathy, demonstrated by measurement of alpha-1 antitrypsin clearance. Diagnosis of lupus was evoked but not confirmed. Nutritional treatment failed. Corticosteroids administered in a bolus, and subsequently per os, rapidly led to complete, lasting (22 months later) remission., Discussion: Corticosteroid therapy is the classical treatment of a protein-loosing enteropathy concomitant to disseminated lupus erythematosus, a rare combination. In the absence of lupus, a few cases of remission from a protein-loosing enteropathy have been reported. However, the delay before remission was longer than in our case report, and the remission-free period generally shorter., Conclusion: Corticosteroid therapy is an effective treatment of an idiopathic protein-loosing enteropathy.

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: Previous data have indicated low bone formation as a mechanism of osteoporosis in inflammatory bowel disease. Fluoride can stimulate bone formation., Aim: To assess the effect of fluoride supplementation on lumbar spine bone mineral density in osteoporotic patients with inflammatory bowel disease treated in parallel with calcium and vitamin D., Methods: In this prospective, randomized, double-blind, parallel and placebo-controlled study, 94 patients with inflammatory bowel disease (lumbar spine T score below - 2 standard deviations, normal serum 25OH vitamin D), with a median age of 35 years, were included. Bone mineral density was measured by dual-energy X-ray absorptiometry. Patients were randomized to receive daily either sodium monofluorophosphate (150 mg, n=45) or placebo (n=49) for 1 year, and all received calcium (1 g) and vitamin D (800 IU). The relative change in bone mineral density from 0 to 12 months was tested in each group (fluoride or placebo) and compared between the groups., Results: Lumbar spine bone mineral density increased significantly in both groups after 1 year: 4.8 +/- 5.6% (n=29) and 3.2 +/- 3.8% (n=31) in the calcium-vitamin D-fluoride and calcium-vitamin D-placebo groups, respectively (P < 0.001 for each group). There was no difference between the groups (P=0.403). Similar results were observed according to corticosteroid intake or disease activity., Conclusions: Calcium and vitamin D seem to increase lumbar spine density in osteoporotic patients with inflammatory bowel disease; fluoride does not provide further benefit.

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.)

Aim of the Study: To retrospectively evaluate the efficacy, the duration of response, and the tolerance of Remicade in anoperineal Crohn's disease., Methods: Fifty patients with severe symptomatic and refractory anoperineal Crohn's lesions (38 fistulae and 29 cavitating ulcers and superficial fissures) were treated with 3 intravenous infusions of Remicade (5 mg/kg) at weeks 0, 2 and 6. Efficacy was assessed using Allan's functional score and proctologic examination at 8 weeks (W8) and 24 weeks (W24) after the first infusion., Results: At W8, a response was noted for 71% (27/38) of fistulae and 79% (23/29) of ulcers and fissures. Healing rates were 39% and 49%, respectively. Efficacy of Remicade at W8 did not vary according to sex, number and type of fistulae and other treatments. At W24, 58% (15/26) of patients with fistulae and 63% (10/16) of patients with ulcers or fissures had a response. The response rate at W24 was higher in patients having anoperineal Crohn's lesions for less than one year: 77% vs 32% (P=0.004). Median Allan's score significantly decreased from 3.9 before treatment to 1.7 at W2 (P<0.001), 1.3 at W6 and 0.8 at W8. Median duration of response was 9.5 months (range: 0.5-12.5) after last infusion and was not influenced by associated treatments including immunomodulators. The relapse rate at 1 year was 64% for the responders followed at least one year (n=21). Minor adverse events occurred during 12% of all infusions. Eight patients had an infection, including one pneumonia. Eight patients developed a perineal abscess 16 weeks (range: 4-32) after the first infusion., Conclusion: Remicade is rapidly effective and well tolerated in anoperineal Crohn's lesions, but the high relapse rate stresses the need for long term therapeutic strategies in these patients.