Supported by grants from 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, Fonds de Recherche de la Société Nationale Française de Gastro-entérologie, and Institut de Recherche sur les Maladies de l'Appareil Digestif (IRMAD).
Excess primary intestinal lymphoproliferative disorders in patients with inflammatory bowel disease†
Article first published online: 23 JAN 2012
Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Volume 18, Issue 11, pages 2063–2071, November 2012
How to Cite
Sokol, H., Beaugerie, L., Maynadié, M., Laharie, D., Dupas, J.-L., Flourié, B., Lerebours, E., Peyrin-Biroulet, L., Allez, M., Simon, T., Carrat, F., Brousse, N. and for the CESAME Study Group (2012), Excess primary intestinal lymphoproliferative disorders in patients with inflammatory bowel disease. Inflamm Bowel Dis, 18: 2063–2071. doi: 10.1002/ibd.22889
- Issue published online: 15 OCT 2012
- Article first published online: 23 JAN 2012
- Manuscript Accepted: 22 DEC 2011
- Manuscript Received: 16 DEC 2011
- CESAME study;
- primary intestinal lymphomas;
- inflammatory bowel disease;
It remains to be shown whether inflammatory bowel disease (IBD) is associated with an increased risk of primary intestinal lymphoproliferative disorders (PILD). We assessed this risk in the CESAME French nationwide prospective observational cohort.
In all, 680 gastroenterologists enrolled 19,486 patients with IBD (Crohn's disease in 60.3%) from May 2004 to June 2005. Follow-up ended on 31 December 2007. Available biopsy samples and surgical specimens from patients with PILD (n = 14) were centralized for review. The reference incidence of PILD in the general population was obtained from the Côte d'Or registry and was used as a comparator to assess the standardized incidence ratio (SIR). The influence of thiopurine exposure was explored in a nested case-control study.
In the CESAME population the crude incidence of PILD was 0.12/1000 patient-years, with a corresponding SIR of 17.51 (95% confidence interval [CI], 6.43–38.11; P < 0.0001). The risk was highest in patients exposed to thiopurines (SIR 49.52, 95% CI 13.49–126.8; P < 0.0001), while it did not reach statistical significance in patients naïve to thiopurines (SIR 4.83, 95% CI, 0.12–26.91; P = 0.37). The odds ratio associated with ongoing thiopurine exposure (vs. naïve) was 2.97 (95% CI, 0.30–infinity; P = 0.38). All 14 cases of PILD were non-Hodgkin's B-cell LD, 78.6% occurred in males, 85.7% arose in IBD lesions, and 45.5% were Epstein–Barr virus-positive. Eleven cases occurred in patients with Crohn's disease. Mean (SD) age at PILD diagnosis was 55.1 (5.6) years and the median time since IBD onset was 8.0 years (interquartile range, 3.0–15.8).
Patients with IBD have an increased risk of developing PILD. (Inflamm Bowel Dis 2012;)
Primary intestinal lymphoproliferative disorders (PILDs) are defined as lymphoproliferative disorders (LDs) with predominantly digestive symptoms and gastrointestinal extranodal lesions,1, 2 therefore excluding secondary gastrointestinal involvement from diffuse nodal LD. PILDs are the most frequent form of extranodal LD in industrialized countries3 but represent less than 5% of gastrointestinal tumors.4, 5 PILDs comprise primary gastric LD (slightly predominant),3 and primary intestinal LD involving the small intestine (including the duodenum), colon, or rectum.3, 6
In some chronic inflammatory disorders such as rheumatoid arthritis, chronic systemic inflammation is intrinsically associated with an increase in the incidence of LD.7 No such increase has been observed in large populations of inflammatory bowel disease (IBD) patients not exposed to immunosuppressants.8–10 However, IBD patients exposed to thiopurines and/or anti-tumor necrosis factor (TNF) agents exhibit an excess of LD (mainly posttransplant-like and Epstein–Barr virus [EBV]-associated).9, 11, 12
Patients with chronic local suppuration, and particularly pyothorax, are at risk of EBV-associated LD in situ.13, 14 There are increasing reports, notably from the Mayo Clinic15, 16 and other centers,17 of PILD in IBD patients, mostly arising in inflamed tissues and affecting patients exposed to immunosuppressants.15, 17 These LD are often EBV-associated.18 In a previous report of LDs from the CESAME observational cohort, the intestine was noted to be involved in one-quarter of the cases, providing also a signal of a possible overrepresentation of PILD in IBD.9
We thus decided to explore in depth the entity of IBD-related PILD from the CESAME cohort data. For this purpose, we examined the possible excess risk of incident PILD, and the influence of immunosuppressant exposure on this risk. We also examined the characteristics of IBD-related PILD, both in patients who developed primary intestinal LD during the prospective cohort follow-up and in patients who had a history of PILD on entering the cohort.
PATIENTS AND METHODS
CESAME Cohort Design and Patients
This study was restricted to patients enrolled in the French nationwide CESAME observational cohort (Cancers Et Surrisque Associé aux Maladies inflammatoires intestinales En France) who had a history of PILD when enrolled in the cohort or who developed PILD during prospective follow-up of the cohort. The CESAME cohort was designed to assess the risk of any malignancy or high-grade dysplasia in patients with IBD. Details on the design and running of the cohort are available elsewhere.9 In brief, from May 2004 to June 2005, 680 French gastroenterologists (38.4% with full-time hospital practice, 24.3% with mixed public/private practice, and 37.3% with full-time private practice) enrolled, on an unpaid basis, 19,486 consecutive IBD patients from their individual practices. There were no exclusion criteria.
Data were collected on an electronic case-report form. The patients' demographic characteristics, IBD type, date of diagnosis, cumulative disease location (small bowel, colon [more or less than 50% of total affected mucosal area, estimated from macroscopic or microscopic findings], anus), previous history of cancer, and exposure to immunosuppressive therapy were recorded at inclusion in the cohort. The gastroenterologists were asked to report all cases of high-grade dysplasia, cancer, or death among their patients during the follow-up period, and to provide information on each surviving patient, obtained during a final visit between 1 January and 31 December 2007. They were also asked to notify all changes in immunosuppressive treatment status at interim visits. Follow-up ended on 31 December 2007. Follow-up was complete (i.e., included the final visit) in 16,459 cases (84.5%), partial (interim visits but no final visit) in 588 cases (3.0%), and nonexistent in 2439 cases (12.5%). Median follow-up of the overall population was 35 months (interquartile range [IQR], 29–40].
The protocol was approved by the Institutional Review Boards of the French National Society of Gastroenterology, Association François Aupetit (the French IBD patient association), and Groupe d'Etude Thérapeutique des Affections Inflammatoires du Tube Digestif (GETAID). The study was authorized by the French Data Protection Agency (CNIL, registration number 04-1239, dated 6 July 2004). The patients' specific written informed consent was not required for this observational study.
Of the 19,486 CESAME patients, 45.1% were male, 60.3% had Crohn's disease (CD), and 39.7% had ulcerative colitis (UC) or unclassified IBD. At entry, mean age (standard deviation [SD]) was 40.3 (15.6) years, mean disease duration was 8.2 (8.0) years, 30.1% of the patients were receiving thiopurines, 14.4% had discontinued thiopurines, and 55.5% had never received thiopurines. Details of exposure to various immunosuppressants at cohort entry are shown in Table 1 according to the IBD subtype. The ileum, less than half the colon, more than half the colon, and the anus were affected at cohort entry in respectively 42%, 20%, 24%, and 15% of patients with CD. Among patients with UC or unclassified IBD, less than half the colon and more than half the colon was affected in respectively 61% and 39% of cases.
|Exposure to Immunosuppressants|
|Crohn's Disease (n = 11,759)||Ulcerative Colitis or IBDU (n = 7727)||All (n = 19,486)|
|Ongoing, n (%)||4452 (37.9)||1415 (18.3)||5867 (30.1)|
|Discontinued, n (%)||2154 (18.3)||655 (8.5)||2809 (14.4)|
|Never received, n (%)||5153 (44.8)||5657 (73.2)||10,810 (55.5)|
|Ongoing, n (%)||600 (5.1)||94 (1.2)||694 (3.6)|
|Discontinued, n (%)||617 (5.3)||82 (1.1)||699 (3.6)|
|Never received, n (%)||10,542 (89.6)||7551 (97.7)||18,093 (92.8)|
|Ongoing, n (%)||877 (7.5)||48 (0.6)||925 (4.7)|
|Discontinued, n (%)||929 (7.9)||85 (1.1)||1014 (5.2)|
|Never received, n (%)||9953 (84.6)||7594 (98.3)||17,547 (90.1)|
|Ongoing, n (%)||77 (0.7)||119 (1.5)||197 (1.0)|
|Discontinued, n (%)||179 (1.5)||301 (3.9)||480 (2.5)|
|Never received, n (%)||11,503 (97.8)||7307 (94.6)||18,809 (96.5)|
Incidence of PILD and Impact of Thiopurine Exposure
Only cases of PILD involving jejunum, ileum, colon and rectum in which the first compatible symptoms occurred after the beginning of the CESAME prospective follow-up period were taken into account in this part of the study. Gastric and Duodenal PILD were excluded of the analysis.
Data on the incidence of PILD in the general population were obtained from the population-based Côte d'Or registry of hematopoietic malignancies.19 In this registry, covering the entire population of the Côte d'Or Department of France (around 500,000 inhabitants), all hematopoietic malignancies, characterized by their site and type according to the third version of the International Classification of Diseases in Oncology, were prospectively recorded from 1980 until the end of 2005. For the purposes of this study, the reference incidence of primary intestinal LD was that observed during the period 2000–2005. In 2005, considering the population of the FRANCIM French nationwide cancer registries database as the reference population, the SIR of non-Hodgkin's LD in the Côte d'Or population was 1.00 (95% confidence interval [CI], 0.79–1.24; P = 0.96), validating extrapolation of the expected incidence of LD in a single French department to the national level.
To assess the influence of thiopurine exposure, we distinguished patients who never received thiopurines from those who had discontinued thiopurines and those who were receiving thiopurines. For the periods between the entry visit and interim visits, and between two interim visits, changes in thiopurine exposure were assumed to have occurred during the visit with a change reported, and thiopurine exposure status during the relevant period (naive, discontinued, or ongoing) was assumed to be the same as at the start of the period. For periods ending with the final visit, or in case of death or LD diagnosis, changes in treatment were imputed to the midpoint of the period.20
The expected number of cases of PILD in the general population was obtained by multiplying patient-years at risk in each 5-year age group by the corresponding sex- and age-specific incidence rate for the period 2000–2005, as provided by the Côte d'Or registry of hematopoietic malignancies. The observed number of incident cases of PILD was divided by the expected number in order to obtain a standardized incidence ratio (SIR) estimate. CIs for rates and SIRs were calculated with an exact method based on the Poisson distribution.21
To assess the role of thiopurine exposure status at clinical onset of PILD on the risk of PILD, we used a nested case-control study matched for propensity, age, sex, IBD duration, and IBD type. The propensity score, i.e., the probability of being treated with thiopurines in view of the observed covariates, was calculated with a logistic regression model for each subject.22 Ongoing thiopurine therapy was associated with a longer IBD duration (odds ratio [OR] = 1.017 per 1-year increase, 95% CI 1.01–1.02; P < 0.0001), lower age (OR = 0.98 per 1-year increase, 95% CI, 0.98–0.99; P < 0.0001), male sex (vs. female sex; OR = 1.09, 95% CI, 1.02–1.16; P = 0.0083), CD (vs. UC or unclassified IBD; OR = 2.52, 95% CI, 2.35–2.70; P < 0.0001), and extensive colon involvement (vs. less than 50% or no colonic involvement, OR = 1.84, 95% CI, 1.72–1.96; P < 0.0001). The propensity score for thiopurine prescription was the predicted probability obtained from the logistic equation in view of the covariate values. A conditional logistic regression model using an exact inferential method was estimated, in which the only covariate was thiopurine exposure at the date of LD onset in the cases and their matched controls. The analysis was repeated to assess the role of any immunosuppressant status at PILD diagnosis on the risk of PILD.
Characteristics of PILD
For this part of the study, we considered all cases of PILD occurring in patients enrolled in the cohort, whether diagnosed during prospective cohort follow-up or prior to cohort entry. PILDs were defined as LD with predominant digestive symptoms and gastrointestinal extranodal lesions.1, 2 A specific case report form was used for all cases of PILD. Clinical data were reviewed by two senior gastroenterologists (L.B., H.S.), and available biopsy samples and surgical specimens were centralized and examined by an experienced pathologist (N.B.). The 2008 WHO classification of LD was used.23 EBV status was recorded as positive if EBV proteins or RNA were detected in neoplastic tissues.
Incidence of PILD
During 49,713 patient-years of follow-up, 23 patients were diagnosed with incident LD, of whom six fulfilled the diagnostic criteria for PILD. There were no cases of secondary gastrointestinal involvement from diffuse nodal LD. Crude incidence rates of PILD are shown in Figure 1, both for the overall population and according to thiopurine exposure. One case of PILD occurred in a patient cotreated with thiopurines and infliximab, and one case occurred in a patient treated with thiopurines and previously cotreated with thiopurines and infliximab. No cases of PILD were diagnosed in patients currently or previously treated with an immunosuppressant other than a thiopurine or infliximab. PILD represented respectively 2.1% and 13.6% of all incident cancers and incident intestinal cancers observed in the CESAME cohort.
Table 2 shows the SIRs for PILD according to thiopurine status at clinical onset of PILD. A significant excess of PILD was noted in the overall population and also in patients taking thiopurines at PILD diagnosis. In a nested case-control study adjusted for propensity to receive thiopurines, the OR associated with ongoing thiopurine exposure vs. thiopurine-naïve status was 2.97 (95% CI, 0.30–infinity; P = 0.38). The OR associated with ongoing exposure to any immunosuppressant vs. immunosuppressant-naïve status was 2.81 (95% CI, 0.28–infinity; P = 0.40).
|Patient-Years||Reported Cases||Expected Casesa||SIR||95% CI||P-value|
|All IBD patients||49,713||6||0.34||17.51||6.43-38.11||<0.0001|
|Discontinued or never received||33,054||2||0.26||7.46||0.92-27.58||0.054|
Characteristics of PILD
Table 3 shows clinical and pathological data for the 14 cases of PILD (six incident cases and eight cases diagnosed before cohort entry) according to thiopurine exposure and EBV status. All 14 cases of PILD were non-Hodgkin's B-cell LD, 78.6% occurred in males (vs. 60% in the Côte d'Or reference population, P = 0.28), 85.7% arose in inflamed IBD lesions, and 45.5% (among the 11 cases that could be tested) were EBV-positive. Eleven cases involved patients with CD. Mean age at PILD diagnosis was 55.1 (5.6) years (vs. 79.7 [7.8] years in the Côte d'Or population, P = 0.12) and the median time since IBD onset was 8.0 years (IQR, 3.0–15.8).
|Agea (Years)||Sex||Type of IBD||Intestinal Segment||Chronic Inflammationb||Type of LD||Type of ISc||Exposure to IS (Year)||EBV Status|
|Incident cases of PILD|
|20||M||CD||Ileum cecum||Yes||Early post-mononucleosis B LD||AZAd||2||+|
|55||M||CD||Ileum||Yes||Monomorphic B LD||AZAe||13||−|
|56||M||CD||Jejunum ileum||No||Diffuse large B-cell lymphoma||0||9||−|
|60||M||CD||Rectum||Yes||Diffuse large B-cell LD||AZA+IFX||2||+|
|79||F||CD||Ileum cecum||Yes||Polymorphic B-cell LD||AZA||6||−|
|80||M||CD||Ileum cecum||Yes||Monomorphic large B-cell LD||0||0||+|
|Previous history of PILD at entry into the cohort|
|36||M||UC||Colon||Yes||Polymorphic B LD||AZA||8||+|
|51||M||CD||Ileum||Yes||Diffuse large B-cell lymphoma||0||0||−|
|54||M||UC||Rectum||Yes||CD5+ small B-cell lymphomaf||AZA||2||ND|
|61||F||UC||Rectum||Yes||Diffuse large B-cell LD||0||NA||ND|
|69||M||CD||Ileum||Yes||Diffuse large B-cell lymphoma||AZA||4||−|
|69||M||CD||Ileum sigmoid||Yes||Monomorphic large B-cell LD||AZA||3||+|
|74||F||CD||Rectum||Yes||Mantle cell lymphoma||0||NA||−|
Table 4 shows PILD characteristics according to thiopurine exposure and EBV status. Among the six cases that occurred in patients who were not receiving thiopurines at clinical onset of PILD, five belonged to the spectrum of posttransplant LD in the WHO classification, and one (among the four that could be tested) was EBV-positive. Among the eight cases that occurred in patients who were receiving immunosuppressive therapy at clinical onset of PILD (thiopurines in all eight cases, plus infliximab in one case), four belonged to the spectrum of posttransplant LD, and four (among the seven who could be tested) were EBV-positive. All the EBV-positive PILD arose in intestinal segments affected by IBD.
|Thiopurine Exposure at PILD Diagnosis||EBV Status of PILDa|
|Yes (n = 8)||No (n = 6)||P-value||Positive (n = 5)||Negative (n = 6)||P-value|
|Male sex (n (%))||7 (87.5)||4 (66.7)||0.54||5 (100.0)||4 (66.7)||0.45|
|Ageb (mean (SD))||55 (19)||55 (25)||1.00||53 (25)||64 (11)||0.70|
|PILD arising in intestinal segment involved by IBDc (n (%))||8 (100.0)||4 (66.7)||0.16||5 (100.0)||5 (83.3)||1.00|
|Thiopurine exposure (n (%))||NA||NA||NA||4 (80.0)||3 (50.0)||0.50|
|Positive EBV status (n (%))||4d (57.1)||1e (25.0)||0.50||NA||NA||NA|
This study demonstrates an excess risk of PILD in patients with IBD, particularly those exposed to thiopurines. Most of the patients with PILD were male and middle-aged, and most PILD arose in intestinal segments affected by chronic inflammation. Finally, evidence of EBV infection was detected in about half the cases tested.
IBD patients with long-standing extensive colitis are known to have an increased risk of high-grade dysplasia and colorectal adenocarcinoma.24, 25 Macroscopic mucosal lesions and persistent active microscopic inflammation of colonic mucosa, irrespective of the endoscopic aspect, are independent risk factors for adenocarcinoma.25–27 There is also emerging evidence that long-standing inflammation of ileal mucosa is associated with an increased risk of adenocarcinoma.28–30 The mechanisms by which chronic intestinal inflammation may lead to adenocarcinoma are numerous and currently speculative,31 but there is a clear inflammation–dysplasia–cancer sequence, distinguishing these forms from sporadic intestinal adenocarcinomas.32
The pathogenesis of inflammation-related organ LD appears to be different, these forms often being associated with local chronic EBV infection.13, 14, 18 A long-term risk of local LD has been reported in various contexts of chronic local suppuration (osteomyelitis, chronic venous ulcers, pyothorax), and EBV is consistently found in tumoral lymphocytes.13, 14 Chronic intestinal inflammation in IBD does not strictly correspond to chronic suppuration, but EBV is frequently found in tumoral lymphocytes from PILD arising in intestinal segments affected by IBD,15, 16, 18 as confirmed here. Interestingly, in a study of primary IBD colonic LD and inflammation-associated IBD adenocarcinomas, EBV was found in the majority of PILD but in none of the adenocarcinomas.18 It has been suggested that chronic local inflammation is associated with cytokine-driven lymphoproliferation, and that local cytokine-induced immunosuppression may favor clonal proliferation of EBV-infected cells.14, 18 Relevant animal models are needed to test these hypotheses.33
Among IBD patients, we observed a nonsignificant trend toward an increased risk of PILD in those exposed to thiopurines. The lack of statistical significance is probably due to the small number of cases. This could be regarded as paradoxical, as thiopurines reduce chronic intestinal inflammation in a significant proportion of patients. A reduction in the incidence in inflammation-driven intestinal cancers might be expected, as recently reported for excess colorectal cancers in high-risk patients belonging to the same CESAME cohort.34 One possible explanation for this apparent paradox is that thiopurine exposure is associated with a marked increase in posttransplant-like EBV-associated LD,9 which could include EBV-associated PILD. This promoting effect could outweigh the beneficial effects of thiopurines on inflammation. Another possible explanation is that patients exposed to thiopurines who developed PILD in inflamed intestinal segments had suboptimal control of inflammation. If this latter hypothesis is true, we can speculate that higher doses of thiopurines or addition of anti-TNF could lead to a lower risk of PILD. In addition, most cases of extranodal immunosuppression-associated LD affect the digestive tract,35 and particularly the ileum, meaning that some cases of immunosuppression-related LD observed in thiopurine-treated IBD patients may develop by chance in a segment previously or currently affected by IBD. We were unable to determine whether methotrexate and anti-TNF agents are also associated with an increased risk of PILD, as the number of patients receiving single-agent therapy with these immunosuppressants was, until recently, too small to address this question.
In our study the IBD patients at highest risk of PILD were middle-age men with CD, especially those treated with immunosuppressants. These characteristics are identical to those observed in the Mayo Clinic experience.15, 16 Unfortunately, PILD cannot be distinguished from IBD lesions on the basis of clinical and imaging features,16 as is also the case of small-bowel adenocarcinomas complicating ileal CD.30 In addition, PILD accounts for only a small minority of intestinal cancers that occur in IBD patients (14% in the CESAME cohort), meaning that specific cost-effective screening procedures for patients at high risk of PILD are unlikely to be developed in the near future. Endoscopic examination of patients with long-standing disease who develop new symptoms or lesions may be advisable.
In conclusion, we report an excess incidence of PILD in IBD patients. These LDs should be added to the list of potential complications of IBD. They may result from intestinal chronic inflammation in conjunction with EBV infection and/or drug-induced immunosuppression.
The authors thank Dr. Ruskone-Fourmestraux for help in abstracting the literature on PILD. Guarantor of the article: Laurent Beaugerie. Author contributions: L.B., N.B., F.C., M.M., and H.S. were jointly responsible for the study design and implementation, and they jointly produced the first draft of the report. L.B. and F.C. were jointly responsible for the global cohort concept, design, coordination, and implementation; they are members of the steering committee of the cohort. F.C. was responsible for all statistical analyses. N.B. was responsible for the centralization and review of histological data and is a member of the steering committee of the cohort. M.M. was responsible for providing the data extracted from the cancer registries and for the calculation of expected cases; he is also a member of the steering committee of the cohort. D.L., J.L.D., B.F., E.L., L.P.B., and M.A. were six of the investigators who included the greatest numbers of patients in the cohort; J.L.D. is also a member of the steering committee of the cohort. T.S. was involved in the design and implementation of the collection.
- 6Changing epidemiology and risk factors for gastrointestinal non-Hodgkin's lymphoma in a North American population: population-based study. Am J Gastroenterol. 2008; 103: 1762–1769., , , et al.Direct Link:
- 21Statistical Methods in Medical Research, 3rd ed. Oxford, UK: Blackwell Science; 1994., .
- 23WHO Classification of Tumours of Haematopoietic an Lymphoid Tissues, 4th ed. Lyon, France: International Agency for Research on Cancer; 2008., , , et al.
- 24Increased risk of intestinal cancer in Crohn's disease: a meta-analysis of population-based cohort studies. Am J Gastroenterol. 2005; 100: 2724–2729., , , et al.Direct Link:
- 34Thiopurine therapy is associated with a three-fold decrease in the incidence of advanced colorectal neoplasia in IBD patients with longstanding extensive colitis: results from the CESAME cohort. Gastroenterology. 2009; 136: A–54., , , et al.
The CESAME Study Group
In addition to the authors, the following persons, not listed as authors, were members of the Steering Committee that controlled the conduct of the Study: Jean-Pierre Gendre; Philippe Godeberge; Jean-Pierre Hugot; Marc Lémann; Stéphane Nahon;Jean-Marc Sabaté; Gilbert Tucat.
The following investigators participated in the study, listed from highest to lowest number of patients enrolled in the cohort: Jean-Frédéric Colombel; Jacques Cosnes; Jean-Pierre Gendre; Marc Lémann; Xavier Hébuterne; Antoine Cortot; Yoram Bouhnik; David Laharie; Jean Louis Dupas; Bernard Flourié; Eric Lerebours; Laurent Beaugerie; Laurent Peyrin-Biroulet; Matthieu Allez; Bernard Messing; Guillaume Cadiot; Philippe Marteau; Jean- Claude Soulé; Jean-Marc Gornet; Michel Veyrac; Bernard Duclos; Philippe Beau; Arnaud Bourreille; Philippe Baumer; Franck Carbonnel; Denis Heresbach; Etienne-Henry Metman; Christian Florent; Antoine Blain; Jean-Luc Faucheron; Pascal Potier; Christian Boehm; Thierry Kurtz; Hervé Lamouliatte; Isabelle Nion-Larmurier; Jean-Charles Delchier; Stanislas Chaussade; Anne Marie Weiss; Jean Pierre Cézard; Laurent Siproudhis; Stéphane Nahon; Daniel Sondag; Raymond Jian; Jean-Christophe Souquet; Pierre Bord; Benoit Coffin; Hélène D'almagne; Patrick Delasalle; Régis Fournier; Maryan Cavicchi; Marc-Henry Souffran; Luc Vandromme; Claire Guedon; Philippe Seksik; Christophe Michiels; Pascal Renard; Patrice Rogier; Sylvie Gouilloud; André Rotenberg; Guillaume Savoye; Alain Thevenin; Laurent Mallet; Franck Brazier; Francois Jean; Anne-Marie Justum; Jean-Paul Latrive; Jean-Luc Gerbal; Robert Pierrugues; Gérard Chardonnal; Laurence Picon; Nicole Reix; Nicolas Drouët D'aubigny; Hervé Uettwiller; Anne Courillon Mallet; Alain Palacci; Raoul-Jacques Bensaude; Pierre Bonniaud; Olivier Empinet; Andrée Nisard; Alain Rudelli; Bernard Tubiana; Philippe Capelle; Alain Dabadie; Daniel Evard; Pierre-Emile Julien; Magali Picon-Coste; Stéphane Schneider; Denis Goldfain; Jérôme Bellanger; Jean-Pierre Blondelot; Philippe Lamy; Sébastien Lemière; Jean Francois Mockly; Benoit Pellat; Gilles Gatineau-Sailliant; Bernard Nalet; Stéphane Nancey; Daniel Kusielewicz; Patrick Loison; Jean-Michel Popot; François Merite; Jean-Pol Roux; Pauline Afchain; Alain Blanquart; Laurent Heyries; Marc Reville; Dominique Viron; Frank Zerbib; Christophe Claviere; Didier Léostic; Philippe Pouderoux; Alain Moitry; Hervé Hagège; Jean-Pierre Hugot; Benoit Humeau; Jean-Marc Sabate; Emmanuel Lederman; Dominique Lescut; Fabrice Luneau; Bruno Mesnard; Lionel Smadja; Michel Steinberg; Marc Brun; Gilles Macaigne; Jean Luc Marchal; Stéphane Ollivier; Dominique Ouvry; Jean Paul Perche; Serge Rambaud; Robert Benamouzig; Jean Louis Cazenave; Jean-Charles Coffin; Martine Blazquez; Marion Lagneau; Bruno Person; Christian Wittersheim; Bertrand Napoleon; Israël Cemachovic; Franck Iglicki; Mehran Howaizi; Eric Leprince; Bruno Leurent; Thierry Morin; Riad Darsouni; Alain Attar; Philippe Baron; Anne Breton; Jean Marie Gillion; Jean-Marc Guemene; Claude Jouffre; Xavier Moreau; Pierre Claude; André Quinton; Vered Abitbol; Jean Michel Brichard; Benoit Desaint; Martin Bouygues; Philippe Chatrenet; Marcelo Salmeron; Jean Silvie; Bruno Waldner; Yves Emery; Armand Moraillon; Daniel Kunkel; Philippe Dubois; Patrick Faure; Christian L'Hirondel; Jean-Eric Labérenne; Pierre Moreau; Adelino Pereira; Genevieve Plihon; Thierry Wolff; Yann Ngo; Arnaud Boruchowicz; Béatrice Jost; Jean Pierre Gotlib; Odile Danne; Philippe Raoux; Marie-José Ramond-Bouhali; Andre Baetz; Bruno Veyres; Christian Chapoutot; Gérard Le Dréau; Jérôme Filippi; Jean Mudry; Philippe Kalt; Sophie Minault; Pierre-André Bounin; Tony Andréani; Jacky Charneau; Didier Reijasse; Jean-Louis Bolze; Jean Luc Thaunat; Christian Le Couteulx; Chantal Maurage; Robert Bader; Philippe Codjovi; Jean-Luc Migairou; Alain Morali; Philippe Rey; Bruno Richard Molard; Richard Petit; Stéphane Koch; Philippe Cassan; Jean-Paul Deschamps; Christine Meicler Caby; Jean-Jacques Meurisse; Philippe Prades; James Boulant; Michel Diacono; Jean-Marie Monsch; J-François Dupuy; Guy Bellaiche; Martine Guegan; Jean-Marc Comte; Jean-Michel Cayla; Francois Le Tallec; Franck Meurisse; Philippe Desurmont; Laurent Roget; Philippe Bouyssou; Bruno Le Gall; Francis Bloch; Loic Larvol; Monique Jullien; Jacques Moreau; Laurent Rebouissoux; Bruno Decroix; Nina Dib; Paul Dieterling; Frédéric Lenormand; Emmanuel Lagier; Philippe Fallourd; Serge Charpin; Hugues Bertrand; Gilles Bommelaer; Daniel Battistelli; Bernard Delon; Lionel Dentant; Etienne Dorval; Jérôme Dumortier; Eric Gaye-Bareyt; Yves Gerosa; Chantal Guez; Martine Mornet; Paul Benfredj; René Piperaud; Noel Stremsdoerfer; Eric Verdier; Alain Grinholtz; Georges Barjonet; Antoine See; Ramuntxo Arotçarena; Anne Baudet; Joel Broyer; Antoine Charachon; Hugues Blondon; Pascal Mouton; Hubert Claudez; Jacques Labat-Labourdette; Jacques Haëm; Patrick Estable; Patrick Levy; Alain Rosenbaum; Yvon Balavoine; Alain Blanchi; Pierre Coutarel; Nadege Delaperriere; Michel Dervichian; Francis Marois; Jacques Seroka; Laurent Michaud; Olivier Leroy; Emmanuel Meyran; Bernard Poilroux; Abdallah Tensaouti; Thierry Paupard; Dominique Agard; Sandrine Beaulieu; Kader Benfiguig; Patrice Capony; Jean Cottereau; Pierre Desreumaux; Jean-Michel Dramard; Mathieu Duché; Patrick Mamou; Isabelle Etienney; Gilles D'Abrigeon; Béatrice Godeberge; Gilbert Tucat; Jean Puech; Jean Roger; Marie-George Lapalus; Paul Bauret; Philippe Houcke; Béatrice Pornin; Bruno Champigneulle; Laurent Cuissard; Xavier-Richard David; Frédéric Lombard; Antoine Granveau; Jean-François Hamon; Olivier Ink; Fabienne Blondel; Alain Namias; Didier Pillon; Antoine Reignier; Gilles Tordjman; Christos Christidis; Simon Zirabe; Michel Audebert; Eric Bion; Claude Bourgeaux; Cécile Poupardin; Philippe Deplaix; Gérard Fratini; Thierry Garnier; Gerard Desseaux; Hervé Magois; Sylvain Lochum; Jean-Francois Vergier; Patrick Texereau; Christel Rat; Francoise Uzzan; Alain Vidal; Nadia Vinante; Bernard Watrin; Cécile Wurtz-Huckert; Bruno Barre; Dominique Chaslin Ferbus; Jean-François Contou; Dominique Coupier; Benoit David; Dany Gargot; Denis Huc; Remy Barraya; Roger Faroux; Jean-Luc Fourgeaud; Hubert Grimprel; Jean Auroux; Jean-François Rey; Jean Pierre Arnoux; Franck Lentini; Ludovic Tardy; Olivier Mouterde; Claire Spyckerelle; Bruno Vacherot; Alain Weissman; Michel Alpérine; Anne Le Sidaner; Pierre-Olivier Bonnet-Eymard; Jean Louis Colson; Daniel Pellet; Bernard Deltombe; André Edouard; Henri Maechel; Jean-Claude Jaillet; Julien Genes; Anne-Marie Leveque; Damien Lucidarme; Philippe Maignan; Nathalie Mallier Gehrke; Jérôme Sanchez; Frank Tusseau; Alban Casteur; Jacques Bottlaender; Denis Constantini; Thierry Coton; Philippe Even; Francois Druart; François Riot; Jean-Michel Gauchet; Geneviève Hecquet; Gerard Henry; Patrick Hochain; Jean Pierre Arpurt; Abdelkrim Medini; Michele Dartois-Hoguin; Henri Moindrot; Philippe Emery; Pierre Periac; Annie Prunier; Pascal Renkes; Christine Tawil-Longreen; Edmond Vincent; René-Louis Vitte; Christian Loeb; Alain Carwana; Didier Barbereau; Philippe Bohon; Céline Corrieri-Baizeau; Daniel Sahy; Philippe Derreveaux; Dominique David; François Desbazeille; Patrick Fontenelle; Jean Luc Slama; Yvon Le Mercier; Michel Certin; Jean Jacques Reig; Isabelle Rosa; Thierry Helbert; Patrick Tounian; Luc Turner; Valéry Perot; Luc Aillet; Arnaud Pauwels; Philippe Barré; Bernard Nury; Claude Cazalbou; Franck Devulder; Alain Durget; Jeanne Dubroca; Daniele Gaudy; Michel Greff; Christian Jacques; Jocelyne Lafarge; Gilles Kezachian; Ronan Le Gall; Alex Pariente; Tiphaine Pinault; Michaël Bismuth; Nathalie Boyer-Darrigrand; Philippe Bretagnolle; Stephane Carpentier; Franck Cholet; Christian Theodore; Rémi Combes; Francois Combet; Christophe Delanoe; Stéphanie De Montigny; Denis Soudan; Olivier Fourdan; Gilles Minier; Jeanne Languepin; Jean Roche; Jean-Louis Ginies; Olivier Nouel; Philippe Petitgars; Edith Robin; Romain Hamm; Jean François Roques; Sylvie Roussin-Bretagne; Agnès Sénéjoux; Sophie Muron; Nicolas Bardoux; Philippe Berthelemy; Patrick Madonia; Bertrand Carles; Catherine Reynier; Emmanuel Cuillerier; Innocenti Dadamessi; Jacques Danis; Bernard Debenes; Nathalie Dubuc-Rey; Gilles Lesur; Pauline Jouet; Catherine Lenaerts; Marc Garret; Alexandra Mineur; Bernard Chabry; Francois Pigot; Valérie Rossi; Ruth Tennenbaum; Julien Salloum; Maurice Hakim Slaoui; Stéphane Mathieu; Valérie Papapietro; Sheila Viola; Alexis Bezet; Claude Altman; Alain Audan; Jean Calabet; Claude Masliah; Laurent Fayemendy; Marc Duruy; Benoit Gauffeny; Ludovic Helie; Kamran Imani; Raoul Janin-Manificat; Jean-Paul Galmiche; Anne Kerlirzin; Laurent Bedenne; Christophe Locher; Gilles Michaudel; Gilles Missonnier; Michel Rinaldi-Dovio; Jean-Michel Rouillon; Stéphane Ecuer; Arnaud Patenotte; Jean Ariel Bronstein; Vincent Baty; Michel Bougnol; Pierre Bourbon; Philippe Cerbelaud; Annick Chavaillon; Franck Boiffin; Béatrice Dubern; Isabelle Duval De Laguierce; Fernand Greco; Florence Bouhot; Philippe Godeberge; Brigitte Grandmaison; Pascal Gros; Guy Targues; Jacques Corallo; Jean Boutin; Jacques Guillan; Jean Pierre Barbieux; Isabelle Loury Lariviere; Henri Le Genissel; Henri Leroi; Marc Bellaiche; Marie-Claire Elie-Legrand; Michel Dapoigny; Philippe Denoyel; Patrice Pienkowski; Philippe Pouche; Marc Michel Saurfelt; Jean Marie Thorel; Thierry Piche; Bruno Travers; Patrick Tuvignon; Marc Zalcberg; Guy Boulay; Christophe Zamora; Joelle Samama; Etienne Ricotie; Patrice De Fleury; Francois Maille; Jean Louis Mougenel; Olivier Gonot; Jean Philippe Menat; Mehdi Kaassis; Francoise Lang; Laurent Abramowitz; Nathalie Ganne; Olivier Pecriaux; Jacques-Arnaud Seyrig; Iradj Sobhani; Thierry Parmentier; Antoine Van Nieuwenhuyse; Francois-Xavier Weber; André Glibert; Catherine Bineau; Bernard Canet; Catherine Collin; Frederic Cordet; David David Parlier; Dominique Carre; Annie Peytier; Francine Fein; Jerome Barouk; Jacques Dewannieux; Johannes Hartwig; Jean-Louis Jouve; Bertrand Laplane; Gilles Lascar; Christophe Legrand; Pierre Le Marchand; Marie Pierre Liebaert; Michele Terdiman-Pire; Naceur Abdelli; Dominique Neveu; Philippe De La Lande; Patrick De Saint Louvent; Cécile Pelatan; Agnès Petit; Martial Richecoeur; Frederic Texier; Jean Brice Cazals; Bertrand Tissot; Christian Mourrut; Marie Doubremelle; Marc Foltz; Florence Gautier-Jubé; Jacques Martin; Elie Khouri; Thierry Lons; Martine Carlier-Bandu; Jean-Luc Monnin; Hervé Roche; Bernard Willemin; Xavier Houard; Abdelaziz Fatisse; Michèle Algard; Kamel Arab; Isabelle Borel; Cécile Lagarrigue; Ariane Chryssostalis; Dominique Boutroux; Jean-Pierre Dupuychaffray; Saïd Khaddari; François Mion; Thierry Puy-Montbrun; Jean-Philippe Girardet; Bruno Gury; Alain Landau; Monique Le Bihan; Sandrine Nieuviarts; Jean Ollivry; Philippe Le Bourgeois; Marie-Astrid Piquet; Michel -Pierre Escartin; Remi Systchenko; Franck Venezia; Michel Wantiez; Xavier Lesage; Elie Zrihen; Philippe Aygalenq; Barbara Dieumegard; Bernard Savarieau; Philippe Bulois; Stéphane Cattan; Jean-Lucien Diez; Olivier Fauchot; Eric Durous; Valérie Gazut; Christian Guilleminet; Jean-Marc Bories; Isabelle Joly Le Floch; Jean-Paul Vove; Stéphane Lelouch; Philippe Lévy; François Lhopital; Norma Marcato; Marianne Mozer-Bernardeau; Jean-Baptiste Nousbaum; Philippe Cattan; Alain Plane; Jean-Michel Raymond; Gilles Roseau; Gerald Rozental; Christian Boustière; Corinne Bonny; Mariepierre Cordier-Collet; Laurent Courat; Bernard Croguennec; Karine Delaunay- Tardy; Damien Labarriere; Edmond Geagea; Frédéric Gottrand; Eve Gelsi; Gerard Thiefin; Eric Wohlschies; Mathieu Miguet; Philippe Ponsot; Jean Suzanne; Yves Teste; Anne-Claire Dupont Gossart; Jean-Luc Baroni; Benabdallah Benchaa; Georges Blanc; Bernard Maroy; Philippe Bonjean; Catherine Brézault; Laure Bridoux-Henno; Claude Chayette; Dominique Auby; Robert Fiorucci; Georges Galindo; Gilles Hubert; Gilles Bonneau; Evelyne Marinier; Michele Pouteau; Afchine Alamdari; Bruno Delbende; Patrick Chamouard; Pascale D'Abravanel; Hélène Dall'Osto; Sophie Hervé; Jean Lefebvre; Damien Levoir; Philippe Lillo; Michel Rouch; Muriel Mathonnet; Mercédes De Lustrac; François-Jean Ramond; Bernard Roupret; Alain Soupison;
The following persons participated in the central Coordination of the Study: Djamila Ait-Ouadda, Yves Barbaza, Brice Bayart, Thomas Bottini, Franck Cochet, Isabelle Goderel, Orélien Maury, Léa Mbonyingo, Vanessa Pourtau, Laure Romain-Huttin, Anne-Violaine Sallé, Jonathan Trang (Unité UMR-S 707); Hakeem Admane, Elodie Drouet (Unité de Recherche Clinique de l'Est Parisien).