Aine d’une famille modeste de quatre enfants, dont le pere etait artisan bourrelier et la mere tenait le magasin de maroquinerie d’Evreux, Jean-Jacques Bernier (figure 1) est ne au cœur de la Normandie, au Gros-Theil, a 40 km de Rouen. Remarque pour ses capacites par sa premiere institutrice et pousse par l’inspecteur d’Academie, il voulait, au depart, etre ingenieur. Il avait 19 ans lorsque la guerre eclata. Il partit a la Faculte des sciences de Caen pour une triple [...]

Background: Leukocyte scintigraphy is a noninvasive investigation to assess inflammation. We evaluated the utility of labeled leukocytes to detect small bowel inflammation and disease complications in Crohn's disease and compared it to whole small bowel enteroscopy and laparotomy findings.Methods: Scintigraphy with technetium-99m exametazime-labeled leukocytes was prospectively performed in 48 patients with Crohn's disease a few days before laparotomy; 41 also had an intraoperative small bowel enteroscopy. The same procedures were performed in 8 control patients. Independent grading of scans was compared with the results of enteroscopy and with surgical, histopathologic, and clinical data.Results: In the 8 control patients leukocyte scan, endoscopy, and histopathology were all negative for the small bowel. In patients with Crohn's disease and small bowel inflammation seen at enteroscopy and/or laparotomy (n = 39) the scan was positive in 33. In 8 patients without macroscopic small bowel inflammation, the scan was positive for the small bowel in 3 patients; at histology, 2 of 3 had inflammation. When combining results for patients and controls, the sensitivity of leukocyte scan for macroscopically evident small bowel inflammation was 0.85, specificity 0.81, accuracy 0.84, positive predictive value 0.92, and negative predictive value 0.68. Scintigraphy detected inflammatory lesions not known before laparotomy in 16 of 47 (34%) Crohn's disease patients and showed uptake in 25 of 35 (71%) bowel strictures. It was diagnostic regarding 4 of 8 abscesses and 9 of 15 fistulas. In 6 patients (13%) lesions first demonstrated by leukocyte scintigraphy were treated during the surgery performed.Conclusions: Leukocyte scintigraphy reliably detects small bowel inflammation in Crohn's disease. It gives additional information on the presence of inflammatory lesions in a fraction of patients planned for surgery.

Diffuse and primitive fat replacement of the exocrine pancreas is a rare cause of exocrine pancreatic insufficiency in adults. We report two adult patients with chronic diarrhoea and steatorrhea whose morphologic abnormalities revealed diffuse fat replacement of the pancreas. Tomodensitometry detected diffuse characteristic abnormalities with fat intermixed with normal pancreatic lobules or a "vanishing pancreas". In one patient, magnetic resonance imaging and echo-endoscopy suggested abnormalities. Administration of pancreatic extracts improved symptoms.

Background: In Crohn's disease, studies have evaluated the ability of biological markers to predict relapse in the next 12 to 18 months, without differentiating early from late relapses. The aim of this study was to look for biological markers of short-term relapse.Materials and Methods: In a previous therapeutic trial, patients with a medically induced clinical remission had biological markers evaluated and updated every 6 weeks. A Cox model with time-dependent covariates was used for analysis.Results: Among the 71 patients, 38 had a relapse. Multivariate analysis selected 2 markers predictive of relapse: C-reactive protein >20 mg/L and erythrocyte sedimentation rate >15 mm. A binary biological predictive score was derived: "negative" when both were lower than their limits, "positive" when otherwise. The relative risk of short-term relapse for patients with a positive score compared to those with a negative score was 8.0 (95% confidence interval 2.8-22.9). Sensitivity of the score was 89% and specificity was 43%. Assuming a 10% relapse rate every 6 weeks, negative and positive predictive values were 97% and 15%, respectively.Conclusions: This simple biological score can predict short-term maintenance of remission in Crohn's disease and may help physicians in the follow-up of patients in clinical remission.

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.

Nous rapportons un cas d'atteinte gastrique inaugurale d'une varicelle disseminee chez une malade ayant un antecedent de greffe de moelle osseuse pour lymphome. Une atteinte viscerale symptomatique, notamment gastrique, est exceptionnelle au cours de l'evolution de la varicelle disseminee. La gastrite precedant habituellement l'eruption cutanee, ce diagnostic doit etre envisage pour debuter un traitement precoce dans cette infection dont la mortalite reste elevee chez l'immunodeprime.

AIM:To evaluate the safety and long-term efficacy of per-endoscopic hydrostatic balloon dilatation in a retrospective series of patients with Crohn's disease.METHODS:Thirty-eight patients had balloon dilatation for intestinal symptomatic strictures which were located as follows: ileo-colonic (26) or colocolic (2) anastomosis, colon (4), ileum (3), proximal jejunum (1) and ileo-caecal valve (5); three patients had two strictures accessible to dilatation. The mean length of the strictures was 2.1 cm (s.d., 0.3 cm).RESULTS:Thirty-two of the 38 patients were successfully dilated and followed for a median of 22.8 months (0.2-103 months) until surgery or last news. The probabilities of obstructive symptom recurrence were 36% at 1 year and 60% at 5 years. Twelve patients had a second dilatation, and three a third. The probabilities of surgery for stricture were 26% at 1 year and 43% at 5 years. Results were not influenced by age, sex, activity of the disease, passage of the stricture by the colonoscope or concomitant medical therapies. Complications occurred in 9.4% of the 53 dilatation sessions, with only one perforation.CONCLUSIONS:Hydrostatic balloon dilatation is effective for Crohn's symptomatic strictures, and can avoid or postpone surgery, with an acceptable rate of complications.

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

UNLABELLED Failure or intolerance of treatments by azathioprine (AZA) or methotrexate (MTX) is an important problem in the maintenance treatment of refractory CD. Results of the alternative use of mycophenolate mofetil (MMF) are conflicting. AIM To assess the efficacy and tolerance of MMF in patients with refractory CD included in a multicentre and retrospective study. PATIENTS AND METHODS Twenty patients (5 men, 15 women, median age 33 years) have been enrolled. The disease was located in the small intestine (n=7), colon (n=5) or in both ileon and colon (n=8). Five patients had perineal disease. Neighteen patients had an active CD and 13 of them received steroids (30 mg daily). All of them had been treated by AZA (failure, n=5; intolerance, n=15) and/or MTX (failure, n=12; intolerance, n=6). The dose of MMF was 750 mg to 2 g daily for a median of 4 months (range: 4 days-21 months). Response to MMF was determined according to an Harvey-Bradshaw index<4 and the possibility to taper steroids. RESULTS Four patients (AZA: failure, n=2; intolerance, n=2; MTX: failure, n=2; intolerance, n=1) achieved remission under MMF. Three of them had an active CD before start of MMF, 1 patient was already in remission. Those 4 patients remained in remission during follow up (10-18 months). One of the 5 patients with perineal involvement achieved a complete closure of perineal fistula. Ten patients had to stop the medication for a median of 4 months (range: 2-12 months) because of inefficiency. Eleven patients had early adverse reactions and 5 of them had to stop the medication within 4 days to 3 months: pancreatitis (n=2), toxidermia (n=2), diarrhea and abdominal pain (n=1). CONCLUSION In this short cohort of 20 patients with refractory CD, either intolerant or non responder to AZA or MTX, treatment with MMF resulted in only 20% of success. Intolerance to MMF was observed in 25% of patients.

GASTROENTEROLOGY 2002;122:512-530

CARD15/NOD2 encodes a protein involved in bacterial recognition by monocytes. Mutations in CARD15 have recently been found in patients with Crohn disease (CD), a chronic inflammatory condition of the digestive tract. Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects. Of 67 sequence variations identified, 9 had an allele frequency >5% in patients with CD. Six of them were considered to be polymorphisms, and three (R702W, G908R, and 1007fs) were confirmed to be independently associated with susceptibility to CD. Also considered as potential disease-causing mutations (DCMs) were 27 rare additional mutations. The three main variants (R702W, G908R, and 1007fs) represented 32%, 18%, and 31%, respectively, of the total CD mutations, whereas the total of the 27 rare mutations represented 19% of DCMs. Altogether, 93% of the mutations were located in the distal third of the gene. No mutations were found to be associated with UC. In contrast, 50% of patients with CD carried at least one DCM, including 17% who had a double mutation. This observation confirmed the gene-dosage effect in CD. The patients with double-dose mutations were characterized by a younger age at onset (16.9 years vs. 19.8 years; P=.01), a more frequent stricturing phenotype (53% vs. 28%; P=.00003; odds ratio 2.92), and a less frequent colonic involvement (43% vs. 62%; P=.003; odds ratio 0.44) than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of patients with CD with or without mutation. These findings provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel disease.

Crohn's disease 1 , 2 and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped 3 to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2 , encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.

Crohn's disease (CD) is a complex genetic disorder for which a susceptibility gene, IBD1, has been mapped within the pericentromeric region of chromosome 16. In order to refine the location of IBD1, 77 multiplex CD families were genotyped for 26 microsatellite markers evenly spaced by approximately 1 cM. Nonparametric linkage analyses exhibited a maximum NPL score of 3.49 (P=2.37x10(-4)) in a region centred by markers D16S3136, D16S3117 and D16S770. Simulation studies showed that the probability for IBD1 to be located in a 5 cM region around these markers was 70%. A 2.5 Mb YAC and BAC contig map spanning this genetic region on chromosome band 16q12 was built. TDT analyses demonstrated suggestive association between the 207 bp allele of D16S3136 (P<0.05) and a new biallellic marker hb27g11f-end (P=0.01). These markers were located in the hb27g11 and hb87b10 BAC clones from the contig. Taken together, the present results provide a crucial preliminary step before an exhaustive linkage disequilibrium mapping of putatively transcribed regions to identify IBD1.

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.

OBJECTIVE: A 16-wk, placebo-controlled trial has recently shown weekly low-dose methotrexate to be an effective treatment for patients with chronically active Crohn's disease. The long-term efficacy and safety of this antimetabolite drug, however, are not yet well established and are assessed in this study. METHODS: A total of 49 patients with Crohn's disease who were treated with methotrexate for ≥6 months were studied. All patients had been chronically treated with steroids; but at the time of initiation, only 27 were still on steroids. Of the 49 patients, 42 had previously taken azathioprine but were no longer on this drug because of intolerance or failure. Clinical remission was defined as a Harvey-Bradshaw index of <4. RESULTS: In all, 41 patients achieved complete clinical remission and were maintained on methotrexate for a median of 18 months (range, 7–59 months). In these patients the probabilities of relapse were 29%, 41%, and 48% at 1, 2, and 3 yr, respectively. A higher rate of relapse was observed in women and in patients with ileocolitis. Adverse reactions were recorded in 24 patients, requiring discontinuation of methotrexate in five. A liver biopsy was performed in 11 patients; a mild steatosis was found in five, a slight dilation of the sinusoids in one, a granulomatous hepatitis with a mild portal fibrosis in one, and a slight periportal fibrosis in one patient. CONCLUSIONS: This study suggests a long-term benefit of maintenance treatment with methotrexate in patients with chronically active Crohn's disease, with side effects that are usually only moderate.

The purpose of this review is to highlight new developments during the past year regarding diagnosis and clinical features of inflammatory bowel disease. Endoscopy remains the cornerstone for diagnosis and evaluation of ileocolonic inflammatory bowel disease. In ulcerative colitis, recent studies have challenged the concept of a continuous and homogeneous inflammatory process with constant rectal involvement: patchy inflammation and rectal sparing were reported in treated ulcerative colitis, and frequent cecum and appendiceal orifice skip lesions were confirmed. Cross-sectional imaging techniques usefully complement endoscopy by assessing whole-bowel thickness and detecting abscesses and fistulae. Furthermore, echo Doppler ultrasound is able to measure mesenteric blood flow, which is increased in active inflammatory bowel disease and seems to parallel inflammatory disease activity. Osteopenia, which affects approximately half of patients with inflammatory bowel disease, can be detected by dual-energy x-ray absorptiometry and prevented. Hyperhomocysteinemia, a predisposing factor for thrombosis, seems to be more frequent in inflammatory bowel disease, and can be corrected by folate supplementation. The concept of an aggressive, penetrating form of Crohn disease with early postoperative recurrence as opposed to a more indolent, nonpenetrating form of the disease, with later recurrence, was recently challenged. The most significant predictor of the risk of malignancy in inflammatory bowel disease remains the presence of dysplasia in colonic biopsy specimens. A dysplastic polypoid lesion or mass is a strong predictor of cancer but should be distinguished from the dysplasia inherent in a coincident sporadic adenoma.

Generalized pustular psoriasis can result in systemic complications. We report the case of a woman with relapsing generalized pustular psoriasis and recurring episodes of cholestatic jaundice. Liver biopsy performed during an attack showed a neutrophilic infiltrate surrounding and invading portal triad bile ducts. Ultrasonographic exams and retrograde cholangiography ruled out biliary tract disease. This observation suggests that recurring cholestatic jaundice in pustular psoriasis is related to a neutrophilic cholangitis.