Abstract

Objectives. This prospective study attempted to determine factors predictive of survival in systemic Wegener's granulomatosis (WG) based on 49 patients.

Patients and methods. All patients had previously untreated systemic WG. Treatment was with oral or pulse cyclophosphamide plus corticosteroids. Univariate and multivariate analyses of survival were performed using 13 parameters evaluated at diagnosis.

Results. The mortality rate was 37% during a mean follow‐up period of 1.9 yr. Among the 13 parameters evaluated, univariate analysis selected the following factors as predictors of a poor outcome: serum creatinine ⩾18.1 mg/dl, age ⩾57 yr, and erythrocyte sedimentation rate (ESR) ⩾90 mm/1st h. The absence of ear, nose and throat (ENT) involvement also tended to predict a greater risk of mortality. Glomerulonephritis, when present and regardless of creatininaemia, and pulmonary involvement had no significant effect. Multivariate analysis retained serum creatinine ⩾18.1 mg/dl and age ⩾57 yr as significant predictors of poor prognosis.

Conclusions. Our results suggest that impaired renal function and older age are independent factors predicting poor outcome in WG. ESR proved to be a good marker of disease severity. Conversely, univariate analysis indicated that patients with ENT involvement tended to have a better outcome, suggesting a more benign evolution of granulomatous disease compared with more aggressive vasculitis.

Wegener's granulomatosis (WG) is a necrotizing vasculitis of small‐ and medium‐sized vessels defined by granulomatous changes of the upper and lower airways, and is frequently associated with glomerulonephritis [1]. WG is further characterized by its strong association with antineutrophil cytoplasmic antibodies (ANCA), which generally have a cytoplasmic labelling pattern (c‐ANCA) in immunofluorescence assays and proteinase 3 as their target [2, 3]. Although initially described as a triad combining ear, nose and throat (ENT), pulmonary and renal involvement [46], WG is currently recognized as a more polymorphous disorder that comprises monovisceral forms as well as extensive multiorgan disease [7].

The spontaneous 2‐yr mortality rate of 93% for WG [8] has declined dramatically since the introduction of immunosuppressive therapy. The gold standard for WG treatment combines corticosteroids (CS) and cyclophosphamide (CYC) [9, 10], although other, less toxic, cytotoxic drugs, such as methotrexate [11], have been investigated. More aggressive therapy with pooled immunoglobulins or plasma exchanges might be required for WG that is refractory to standard treatment [2].

Although remission is generally obtained with immunosuppressive therapy, the relapse rate of WG remains elevated and mortality high. Evaluation of the long‐term outcome of WG patients showed a median survival time of 8.5 yr [12], and the mortality rate was more than three times higher than that of the corresponding general population [13]. Even though overall survival was 87% in a series of 158 patients with a median follow‐up of 8 yr [14], 1‐yr mortality rates of up to 56% have been reported by other authors [15].

Little is known about prognostic factors and disease activity assessment in WG. Several authors have proposed renal disease [16, 17] or impaired renal function [12, 1821] as predictors of poor outcome. The poor prognostic value of pulmonary involvement has been proposed [14, 22] but could not be demonstrated statistically [20]. Older age [18, 21], initial white blood cell count ⩾10 000/μl [20] and anaemia [21] might also be predictive of increased risk of mortality.

The aim of the present study was to identify factors predictive of survival based on 49 patients newly diagnosed with systemic WG and prospective follow‐up. We also attempted to correlate patient survival with initial disease activity, as assessed by the erythrocyte sedimentation rate (ESR) and the Birmingham vasculitis activity score (BVAS) [22].

Patients and methods

Patient selection

The study included 49 patients with newly diagnosed and untreated systemic WG. These individuals were selected from among 50 subjects who had participated in a prospective therapeutic multicentre trial conducted in France between October 1990 and December 1995. The results of that trial, which compared the effectiveness and safety of two CYC regimens for systemic WG, have been published [24]. One patient who had been included in the original trial was not evaluated for the present study because certain data were missing.

All the subjects were over 15 yr old and had systemic WG that met the American College of Rheumatology criteria [25]. Histopathological evidence of either necrotizing vasculitis with granulomatous inflammation or segmental necrotizing glomerulonephritis was required. The patients were considered to have systemic disease based on the presence of multiorgan involvement. However, subjects with monovisceral disease and severe life‐threatening disease were also eligible.

Treatment

The first‐line therapy was administered according to the study protocol [24]. This regimen combined CYC and CS. Every patient received a pulse of CYC (0.7 g/m2) and was then randomly assigned to receive either i.v. (0.7 g/m2) or oral (2 mg/kg) CYC. Intravenous CYC was administered at 3‐week intervals for 1 yr and then at longer intervals. Oral CYC was taken daily; it was maintained at full dose for 1 yr and then tapered. CYC treatment could be discontinued after 2 yr when remission had been obtained. Initially, three consecutive daily pulses of methylprednisolone (15 mg/kg/day) were given before oral prednisone was started at a dose of 1 mg/kg/day. After 6 weeks, tapering of the CS dose could be started and, when complete remission (CR) was obtained, continued until total discontinuation 12–18 months later. Because of the high frequency of Pneumocystis carinii pneumonia (PCP) among the first patients recruited, all patients were given co‐trimoxazole (400 mg/day) as PCP prophylaxis. When only partial remission (PR) was obtained, plasma exchanges were added to the assigned treatment. Minor relapses were managed by transient intensification of the CS dose until the attenuation of the symptoms, whereas the CYC dose was increased for severe relapses. Alternatively, patients who relapsed while receiving i.v. CYC were switched to oral CYC. In the case of complete treatment failure or the need for treatment after the completion of the study regimen, the therapeutic strategy was left to the discretion of the treating physician.

Methods

The medical charts of the 49 patients enrolled in the original study were reviewed in January 1998. All the patients had undergone an in‐depth evaluation of their disease at the time of diagnosis and benefited from close monitoring during the therapeutic trial. After achievement of the trial end‐points, further medical information about each patient's disease course was obtained by questioning the treating physicians, telephone contact with the patients or family members, or by consulting the local death registries.

The following information was recorded for every patient at the time of diagnosis: clinical ENT and cutaneous involvement; ophthalmological involvement; peripheral neuropathy (based on electromyography results); glomerulonephritis (defined as abnormal urinary sediment and/or serum creatinine ⩾15.8 mg/dl and/or proteinuria of >0.5 g/day); pulmonary involvement (defined as abnormal thoracic imaging in the absence of concomitant infectious pneumopathy). Furthermore, we assessed the following biological parameters at diagnosis: serum creatinine level, ESR (mm/1st h) and ANCA immunofluorescence assay results. Each patient's outcome was evaluated with regard to the response to treatment, relapses, severe infectious complications and death. CR was defined as the complete absence of disease activity and PR as the stabilization of disease activity. To be considered severe, an infectious disease necessitated hospitalization.

Statistical analysis

Patient survival was assessed by life‐table analysis. Because all the patients had acute‐onset systemic disease which resulted in the rapid initiation of treatment after diagnosis, we confounded the dates of diagnosis and treatment onset, and survival time was calculated from the date of inclusion in the therapeutic trial. The end‐point of the present study was defined as the last time the patient's status could be determined or as the time of death. Survival curves were plotted using the Kaplan–Meier method [26]. The potential predictive value for survival of the following parameters assessed at diagnosis was investigated: age; sex; ENT involvement; pulmonary involvement; glomerulonephritis; peripheral neuropathy; ophthalmological involvement; cutaneous involvement; number of organs affected; serum creatinine level; ESR; the presence of ANCA; and BVAS.

Univariate analysis was performed using log‐rank tests [27]. To increase the power of univariate analysis, quantitative parameters (age, serum creatinine level, number of organs affected, ESR, BVAS) were also investigated as dichotomous qualitative parameters, using as the dividing threshold the median values observed for the whole population or, for the serum creatinine value, the median value observed for the patients with glomerulonephritis. The multivariate analysis used the Cox proportional hazards regression model [28].

The multivariate model included all the parameters that had a P value of <0.20 in univariate analysis. Then, a backward stepwise procedure was used to remove from the original model those parameters that did not significantly explain patient survival according to a likelihood ratio test. To minimize a potential confounding bias in the survival analysis attributable to the difference in the initial CYC treatment modality (oral or i.v. administration), the mode of CYC administration was introduced as an adjusting parameter into the multivariate model. Statistical analysis was computed using the SAS statistical package, version 6.12 (SAS Institute, Cary, NC, USA). For all statistical analyses, P values of <0.05 were considered to be significant. All confidence intervals were calculated at the 95% level.

Results

Patient data

All the patients had been diagnosed between October 1990 and March 1994. Principal data at diagnosis for the 49 patients are summarized in Table 1. Although monovisceral disease with ENT or pulmonary involvement were each diagnosed in one subject, both of these patients were considered to have systemic WG as they had severe general symptoms bearing a high risk of fatal outcome. The most prominent radiological findings in the 39 patients with pulmonary involvement were nodules (n=29), pneumonia‐like condensations (n=2), alveolar haemorrhage (n=3), bilateral infiltrates without evidence of alveolar haemorrhage (n=3), and pleural effusion (n=2). Glomerulonephritis was present in 36 patients and consisted of proteinuria >0.5 g/day (n=27), abnormal urinary sediment (n=32) or serum creatinine ⩾15.8 mg/dl (n=25); histological evidence of necrotizing glomerulonephritis was obtained for 26 subjects.

Table 1.

Principal demographic, clinical, biological and immunological data at diagnosis for 49 patients with systemic WG

Characteristic
 
Value
 
Median age (yr) 57 (range 23–78) 
Sex  
   Male 30 (61%) 
   Female 19 (39%) 
ENT involvement 36 (73%) 
Pulmonary involvement 39 (80%) 
Glomerulonephritis 36 (73%) 
ELK involvement [7 
   E 
   L 
   K 
   EL 
   EK 
   LK 
   ELK 22 
Ophthalmological involvement 16 (33%) 
Peripheral neuropathy 11 (22%) 
Cutaneous involvement 18 (37%) 
Median serum creatinine level (mg/dl)  
   Patients (n=47) 16.9 (range 7.8−169.5) 
   Patients with glomerulonephritis (n=36) 18.1 (range 7.9−169.5) 
Median ESR (mm/1st h) (n=44) 90 (range 5−140) 
Median BVAS 18 (range 4–33) 
ANCA positivity 43 (88%) 
   c‐ANCA 37 (76%) 
   p‐ANCA 4 (8%) 
   Undetermined 2 (4%) 
Median number of organs affected 4 (range 1–6) 
Characteristic
 
Value
 
Median age (yr) 57 (range 23–78) 
Sex  
   Male 30 (61%) 
   Female 19 (39%) 
ENT involvement 36 (73%) 
Pulmonary involvement 39 (80%) 
Glomerulonephritis 36 (73%) 
ELK involvement [7 
   E 
   L 
   K 
   EL 
   EK 
   LK 
   ELK 22 
Ophthalmological involvement 16 (33%) 
Peripheral neuropathy 11 (22%) 
Cutaneous involvement 18 (37%) 
Median serum creatinine level (mg/dl)  
   Patients (n=47) 16.9 (range 7.8−169.5) 
   Patients with glomerulonephritis (n=36) 18.1 (range 7.9−169.5) 
Median ESR (mm/1st h) (n=44) 90 (range 5−140) 
Median BVAS 18 (range 4–33) 
ANCA positivity 43 (88%) 
   c‐ANCA 37 (76%) 
   p‐ANCA 4 (8%) 
   Undetermined 2 (4%) 
Median number of organs affected 4 (range 1–6) 

ELK, ear, lung and kidney; p‐ANCA, ANCA giving a perinuclear labelling pattern in the immunofluorescence assay.

Treatment

Initially, all the patients received CYC and CS. CYC was administered i.v. to 28 patients and taken orally by 21 patients. After PR to the assigned treatment, four patients transiently underwent plasma exchanges and one patient received i.v. immunoglobulins. During the course of the study, 10/28 patients receiving i.v. CYC were switched to oral CYC because of unresponsiveness (n=8) or side‐effects (vomiting, n=1; haemorrhagic cystitis, n=1). Azathioprine was prescribed after a severe reaction to CYC (toxic epidermal necrolysis, n=1), and for a relapse occurring after discontinuation of CYC (n=1). Two patients received methotrexate, one in combination therapy with cyclosporin because of unresponsiveness to CYC and the other for a late relapse after discontinuation of CYC. For one patient, CYC was switched to i.v. immunoglobulins because of haematological toxicity. Eight patients required dialysis because of renal failure, and four patients died while on dialysis for acute renal failure. One patient was able to stop dialysis after recovery of renal function while three other patients required chronic dialysis for end‐stage renal disease.

Follow‐up

The mean follow‐up was 1.9 yr (median 1.8 yr, range 2 days to 5.8 yr). Initial CR was achieved by 23 (47%) patients and PR by 20 (41%) patients; six (12%) patients had disease refractory to therapy. Twenty‐one (43%) patients relapsed after a mean interval of 16 months (range 4–50 months). Nineteen of these patients experienced a single relapse; the remaining two each had two relapses. At the time of the last update, 21 (43%) patients were in CR and 10 (20%) patients in PR. Eighteen (37%) patients died during follow‐up. The status of the 31 survivors was last determined within the last 12 months for six patients (19%), 24 months for two (6%), 36 months for two (6%), 36 months for 13 (42%), 48 months for 5 (16%), 60 months for 2 (6%), and 72 months for one (3%).

Severe infectious complications occurred in 19 (39%) patients. The 31 severe infectious events recorded comprised 10 cases of PCP, three of bacterial pneumonia, five of invasive aspergillosis, four of cytomegalovirus pneumonia, one of cytomegalovirus retinitis, one of meningeal tuberculosis, one of pulmonary tuberculosis, two of herpes zoster, one of papovavirus leucoencephalitis, one of Serratia marcescens arthritis, one of Listeria monocytogenes septicaemia and one of septic shock of undetermined origin.

The overall mortality was 37% (18/49 patients). The mean survival rates were 77.5±11.7% (95% confidence interval) at 6 months and 67.5±13.7% at 2 yr of follow‐up (Fig. 1A). The causes of death are detailed in Table 2, and were attributed to active vasculitis in six, severe infectious complication in seven and miscellaneous conditions in five cases.

Fig. 1.

(A) Overall survival curve for the 49 patients with systemic WG. (B–D) Survival rate as a function of (B) serum creatinine level (P=0.03), (C) age (P=0.04) and (D) ESR (P=0.02) at diagnosis.

Fig. 1.

(A) Overall survival curve for the 49 patients with systemic WG. (B–D) Survival rate as a function of (B) serum creatinine level (P=0.03), (C) age (P=0.04) and (D) ESR (P=0.02) at diagnosis.

Table 2.

Causes of death for 18 patients with systemic WG

Patient
 
Time after diagnosis
 
Cause of death
 
3 months PCP 
14 months Papovavirus multifocal leucoencephalitis 
1 months Haemoptysis of unknown origin 
4 months PCP and bacterial pneumonia,  acute renal failure 
3 months Cerebral haemorrhage 
1 months Unknown 
3 months Septic shock 
27 months Unknown 
17 months Alveolar haemorrhage 
10 3 months PCP and CYC‐induced pneumopathy 
11 2 days Alveolar haemorrhage 
12 30 months Pulmonary haemorrhage 
13 3 months Suicide (chronic psychosis) 
14 33 months Acute renal failure, bacterial pneumonia 
15 2 days Unknown 
16 14 months Cerebral haemorrhage, multifactorial  thrombopenia 
17 5 months PCP and bacterial pneumonia,  invasive aspergillosis 
18 5 months PCP and cytomegalovirus pneumonia,  invasive aspergillosis 
Patient
 
Time after diagnosis
 
Cause of death
 
3 months PCP 
14 months Papovavirus multifocal leucoencephalitis 
1 months Haemoptysis of unknown origin 
4 months PCP and bacterial pneumonia,  acute renal failure 
3 months Cerebral haemorrhage 
1 months Unknown 
3 months Septic shock 
27 months Unknown 
17 months Alveolar haemorrhage 
10 3 months PCP and CYC‐induced pneumopathy 
11 2 days Alveolar haemorrhage 
12 30 months Pulmonary haemorrhage 
13 3 months Suicide (chronic psychosis) 
14 33 months Acute renal failure, bacterial pneumonia 
15 2 days Unknown 
16 14 months Cerebral haemorrhage, multifactorial  thrombopenia 
17 5 months PCP and bacterial pneumonia,  invasive aspergillosis 
18 5 months PCP and cytomegalovirus pneumonia,  invasive aspergillosis 

Univariate analysis

According to univariate analysis (Table 3), the presence of the following parameters at diagnosis was significantly associated with shorter survival: serum creatinine level ⩾18.1 mg/dl (P=0.03) (Fig. 1B), age ⩾57 yr (P=0.04) (Fig. 1C), and ESR ⩾90 mm/1st h (P=0.02) (Fig. 1D).

Table 3.

Univariate analysis of factors associated with survival of 49 patients with systemic WG

Parameter
 
P
 
Sex 0.94 
Age 0.26 
Age < or ⩾57 yr 0.04 
ENT involvement 0.09 
Pulmonary involvement 0.29 
Glomerulonephritis 0.39 
Peripheral neuropathy 0.56 
Cutaneous involvement 0.07 
Ophthalmological involvement 0.92 
Serum creatinine 0.55 
Serum creatinine < or ⩾18.1 mg/dl 0.02 
Number of organs affected < or ⩾4 0.84 
One or more infectious complications 0.38 
ESR 0.07 
ESR < or ⩾90 mm/1st h 0.02 
BVAS ⩽ or >18 0.40 
Parameter
 
P
 
Sex 0.94 
Age 0.26 
Age < or ⩾57 yr 0.04 
ENT involvement 0.09 
Pulmonary involvement 0.29 
Glomerulonephritis 0.39 
Peripheral neuropathy 0.56 
Cutaneous involvement 0.07 
Ophthalmological involvement 0.92 
Serum creatinine 0.55 
Serum creatinine < or ⩾18.1 mg/dl 0.02 
Number of organs affected < or ⩾4 0.84 
One or more infectious complications 0.38 
ESR 0.07 
ESR < or ⩾90 mm/1st h 0.02 
BVAS ⩽ or >18 0.40 

Values in bold are statistically significant.

Multivariate analysis

The following parameters were selected for the multivariate analysis: age < or ⩾57 yr, serum creatinine < or ⩾18.1 mg/dl, ENT involvement, cutaneous involvement and pulmonary involvement. All these variables except the latter had P values <0.20 in univariate analysis. Pulmonary involvement was, nevertheless, retained for the multivariate analysis because it had been reported previously to be a major prognostic factor in WG [14, 22].

Among the parameters selected for multivariate analysis, only serum creatinine ⩾18.1 mg/dl (P=0.02) and age ⩾57 yr (P=0.02) were retained as independent factors significantly predictive of poor prognosis (Table 4). Pulmonary involvement, ENT involvement and cutaneous involvement had been removed from the multivariate model using a backward stepwise procedure as their P values did not reach significance.

Table 4.

Multivariate analysis, using Cox proportional hazards regression model, of factors associated with survival based on 49 patients with systemic WG

Parameter
 
P
 
Relative risk
 
95% confidence interval
 
Serum creatinine 0.02 3.5 2.5–4.5 
   ⩾18.1 mg/dl    
Age ⩾57 yr 0.02 3.6 2.5–4.6 
Parameter
 
P
 
Relative risk
 
95% confidence interval
 
Serum creatinine 0.02 3.5 2.5–4.5 
   ⩾18.1 mg/dl    
Age ⩾57 yr 0.02 3.6 2.5–4.6 

The model included the following variables determined at diagnosis: serum creatinine ⩾18.1 mg/dl; presence of pulmonary involvement; absence of ENT involvement; absence of cutaneous involvement; and age ⩾57 yr. Variables that did not affect survival significantly were removed by a backward stepwise procedure according to a likelihood ratio test. Results were adjusted according to the initial CYC regimen (i.v. or oral).

Discussion

According to the results of these univariate and multivariate analyses of factors predicting survival based on 49 patients with systemic WG, we conclude that the following parameters, when present at diagnosis, are independent predictors of poor outcome: impaired renal function, with a serum creatinine threshold value of 18.1 mg/dl; and older age, with a threshold value of 57 yr. Furthermore, the significant association between ESR and survival suggested that ESR could be a serological marker of prognosis in WG. No relationship could be established between any of the other demographic, clinical or biological parameters and patient survival. In particular, no significant prognostic value could be attributed to pulmonary or renal disease when present and regardless of the serum creatinine level.

Renal disease has been advocated as a predictor of poor outcome in WG since Carrington and Liebow [16] described a non‐renal ‘limited’ form of WG characterized by a better prognosis. The pejorative impact of kidney involvement on prognosis was confirmed by Luqmani et al. [17], who noted particularly poor outcomes for patients with serum creatinine >56.5 mg/dl. In our analysis, only those patients whose renal involvement was associated with functional impairment were at greater risk of death. These findings suggest that the prognosis might not depend on glomerulonephritis itself but on the deterioration of renal function. Similar findings were reported by other investigators [18, 21]. The serum creatinine concentration associated with shortened survival in our cohort was 18.1 mg/dl, and therefore lower than thresholds reported previously [17, 21].

An age of ⩾57 yr at diagnosis was also a marker of poorer prognosis. This finding is in agreement with the results of previous univariate analyses which identified ages of ⩾60 [18, 29] and 50 yr [21] as predictors of poorer outcome. It is not yet clear whether the increased mortality of the older patients reflects more aggressive disease or whether it is the consequence of greater sensitivity to the toxicity of immunosuppressants in this category of patients. Krafcik et al. [29] demonstrated increased mortality attributable to infectious complications in the elderly, even though the overall incidence of infections was similar to that of younger patients.

We also found a strong association between the ESR at diagnosis and patient survival. This finding suggests that ESR could be a good marker of disease severity in WG. On the other hand, we could not establish a relationship between the anatomical extent of the disease and survival, and there was, in particular, no evidence of shortened survival of patients with multiorgan involvement compared with those having less extensive disease. We therefore think that the intrinsic activity of WG might be reflected more accurately by markers such as the serum creatinine level and ESR rather than by more or less extensive disease. Similarly, disease activity assessment with BVAS could not be statistically correlated to survival. This is consistent with previous findings, as BVAS relies primarily on the cumulative evaluation of the anatomical extent of the disease [23]. Therefore, on the basis of our results, disease activity scoring with the BVAS does not seem appropriate for the assessment of prognosis in WG.

The overall mortality rate of 37% in our series is higher than that reported by other authors [15]. In particular, we noted a substantial early mortality rate, as 22.5% of the patients died within the first 6 months of follow‐up. Two deaths occurred only a few days after diagnosis and treatment onset. This higher mortality might be explained by the fact that we studied exclusively subjects with systemic WG. As discussed elsewhere [24], the multicentre enrolment of the individuals, who were treated in primary, secondary and tertiary care centres, could have resulted in the inclusion of a higher number of critically ill patients in our cohort.

It is noteworthy that, according to our univariate analysis, patients with ENT symptoms tended to have a better outcome than patients without such involvement. Even though this observation was not confirmed by the multivariate analysis, this finding merits further examination. As mentioned above, two distinct pathological features are associated in WG: granulomatosis, predominantly involving the airways, and vasculitis, predominantly localized in the kidney. Although the precise significance of the coexistence of these pathological findings is unclear, the mechanisms leading to granuloma formation or vasculitis might be different. Indeed, it has been emphasized that the clinical heterogeneity of WG reflects a broad spectrum of disorders ranging from predominantly granulomatous disease at one end to predominantly vasculitic disease at the other [30]. It has also been suggested that granuloma formation occurs early during the course of WG, whereas the vasculitis might be a marker of later stages of the disease [31]. Furthermore, immunological studies suggest that these two pathological hallmarks of WG might correspond to different immune responses involving T cells [32, 33]. Consequently, our finding suggesting that ENT involvement might be a potential predictor of a better outcome could be explained by a possibly more benign course of granulomatous WG than vasculitic WG. Further studies are needed to assess adequately the potential prognostic value of ENT involvement, which, in turn, might provide further insight into the pathogenesis of WG.

The prognostic scoring of WG remains challenging. Certainly, the effectiveness of WG therapy could be improved by the choice of appropriate treatment guided by the severity of the disease. In this strategy, aggressive disease would be managed with intensive therapy while less toxic drugs could suffice for more benign disease. This therapeutic approach might enhance treatment efficacy in the severely ill patient and reduce therapy‐associated toxicity in the milder forms. Further studies are needed to explore in greater detail potential prognostic factors in WG, and then to validate them.

Correspondence to: L. Guillevin, Service de Médecine Interne, Hôpital Avicenne, 125, route de Stalingrad, 93009 Bobigny Cedex, France.

The following individuals contributed to the study: P. Bielefeld, P. Bindi, O. Blétry, D. Boutin, M. Brouillard, J. Cadranel, P. Camus, P. Cohen, Y. Cohen, B. Combe, P. Congy, J. F. Cordier, A. Dallot, P. David, J. F. Desson, F. Détrée, A. Dubois, D. Glotz, D. Grenet, E. Hachulla, D. Halloun, B. Hoen, D. Jacomy, B. Jarrousse, C. Jacquot, J. P. Jaulin, M. F. Kahn, A. Lassoued, D. Lauque, R. Leblay, P. Leclerc, P. Lesavre, E. Le Guen, H. Lena, F. Lhote, M. Longy‐Boursier, D. Méchali, P. Miossec, E. Monchâtre, J. C. Piette, P. Rémy, J. Ribstein, J. Rossert, I. Royer, A. Sacchi, B. Saugier, C. Seigneuric and M. Stern.

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