Download Analysis of factors predictive of survival based on 49 patients with

Rheumatology 2001;40:492±498
Analysis of factors predictive of survival based
on 49 patients with systemic Wegener's
granulomatosis and prospective follow-up
A. Mahr, T. Girard, R. Agher1 and L. Guillevin
Service de MeÂdecine Interne, HoÃpital Avicenne, Universite Paris-Nord,
125, route de Stalingrad, 93009 Bobigny Cedex and 1Service des Maladies
Infectieuses et Tropicales, HoÃpital PitieÂ-SalpeÂtrieÁre, 47±83, boulevard de
l'HoÃpital, 75651 Paris Cedex 13, France
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 018.1 mgudl, age 057 yr, and erythrocyte sedimentation rate (ESR)
090 mmu1st 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 signi®cant effect. Multivariate analysis retained serum
creatinine 018.1 mgudl and age 057 yr as signi®cant 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.
KEY WORDS: Wegener's granulomatosis, Prognostic factors.
Wegener's granulomatosis (WG) is a necrotizing vasculitis of small- and medium-sized vessels de®ned by
granulomatous changes of the upper and lower airways,
and is frequently associated with glomerulonephritis w1x.
WG is further characterized by its strong association
with antineutrophil cytoplasmic antibodies (ANCA),
which generally have a cytoplasmic labelling pattern
(c-ANCA) in immuno¯uorescence assays and proteinase
3 as their target w2, 3x. Although initially described as a
triad combining ear, nose and throat (ENT), pulmonary
and renal involvement w4±6x, WG is currently recognized as a more polymorphous disorder that comprises
monovisceral forms as well as extensive multiorgan
disease w7x.
The spontaneous 2-yr mortality rate of 93% for
WG w8x has declined dramatically since the introduction
of immunosuppressive therapy. The gold standard
Submitted 5 May 2000; revised version accepted 14 November 2000.
Correspondence to: L. Guillevin, Service de MeÂdecine Interne,
HoÃpital Avicenne, 125, route de Stalingrad, 93009 Bobigny Cedex,
France.
492
for WG treatment combines corticosteroids (CS)
and cyclophosphamide (CYC) w9, 10x, although other,
less toxic, cytotoxic drugs, such as methotrexate w11x,
have been investigated. More aggressive therapy with
pooled immunoglobulins or plasma exchanges might
be required for WG that is refractory to standard
treatment w2x.
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 w12x, and the mortality rate was
more than three times higher than that of the corresponding general population w13x. Even though overall
survival was 87% in a series of 158 patients with a
median follow-up of 8 yr w14x, 1-yr mortality rates of up
to 56% have been reported by other authors w15x.
Little is known about prognostic factors and disease
activity assessment in WG. Several authors have proposed renal disease w16, 17x or impaired renal function
w12, 18±21x as predictors of poor outcome. The poor
prognostic value of pulmonary involvement has been
ß 2001 British Society for Rheumatology
Predictors of survival in Wegener's granulomatosis
proposed w14, 22x but could not be demonstrated statistically w20x. Older age w18, 21x, initial white blood cell
count 010 000uml w20x and anaemia w21x 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) w22x.
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 w24x. 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 w25x. Histopathological evidence of either necrotizing vasculitis with granulomatous in¯ammation 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 ®rst-line therapy was administered according to
the study protocol w24x. This regimen combined CYC
and CS. Every patient received a pulse of CYC (0.7 gum2)
and was then randomly assigned to receive either i.v.
(0.7 gum2) or oral (2 mgukg) 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 mgukguday) were given
before oral prednisone was started at a dose of
1 mgukguday. 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 ®rst
patients recruited, all patients were given co-trimoxazole
(400 mguday) as PCP prophylaxis. When only partial
remission (PR) was obtained, plasma exchanges were
added to the assigned treatment. Minor relapses were
managed by transient intensi®cation of the CS dose
until the attenuation of the symptoms, whereas the CYC
493
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 bene®ted 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 (de®ned as abnormal urinary sediment anduor serum creatinine 015.8 mgudl
anduor proteinuria of >0.5 guday); pulmonary involvement (de®ned as abnormal thoracic imaging in the
absence of concomitant infectious pneumopathy).
Furthermore, we assessed the following biological
parameters at diagnosis: serum creatinine level, ESR
(mmu1st h) and ANCA immuno¯uorescence assay
results. Each patient's outcome was evaluated with
regard to the response to treatment, relapses, severe
infectious complications and death. CR was de®ned 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 de®ned 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 w26x. 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 w27x. 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,
494
A. Mahr et al.
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 w28x.
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
signi®cantly 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 signi®cant.
All con®dence 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
TABLE 1. Principal demographic, clinical, biological and immunological data at diagnosis for 49 patients with systemic WG
Characteristic
Median age (yr)
Sex
Male
Female
ENT involvement
Pulmonary involvement
Glomerulonephritis
ELK involvement w7x
E
L
K
EL
EK
LK
ELK
Ophthalmological involvement
Peripheral neuropathy
Cutaneous involvement
Median serum creatinine level (mgudl)
Patients (n = 47)
Patients with glomerulonephritis (n=36)
Median ESR (mmu1st h) (n = 44)
Median BVAS
ANCA positivity
c-ANCA
p-ANCA
Undetermined
Median number of organs affected
Value
57 (range 23±78)
30
19
36
39
36
(61%)
(39%)
(73%)
(80%)
(73%)
2
4
3
7
5
6
22
16 (33%)
11 (22%)
18 (37%)
16.9 (range 7.82169.5)
18.1 (range 7.92169.5)
90 (range 52140)
18 (range 4±33)
43 (88%)
37 (76%)
4 (8%)
2 (4%)
4 (range 1±6)
ELK, ear, lung and kidney; p-ANCA, ANCA giving a perinuclear
labelling pattern in the immuno¯uorescence assay.
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 ®ndings
in the 39 patients with pulmonary involvement were
nodules (n = 29), pneumonia-like condensations (n = 2),
alveolar haemorrhage (n = 3), bilateral in®ltrates without evidence of alveolar haemorrhage (n = 3), and
pleural effusion (n = 2). Glomerulonephritis was present
in 36 patients and consisted of proteinuria >0.5 guday
(n = 27), abnormal urinary sediment (n = 32) or serum
creatinine 015.8 mgudl (n = 25); histological evidence
of necrotizing glomerulonephritis was obtained for 26
subjects.
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, 10u28 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,
®ve of invasive aspergillosis, four of cytomegalovirus
Predictors of survival in Wegener's granulomatosis
495
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.
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% (18u49 patients). The
mean survival rates were 77.5 " 11.7% (95% con®dence 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 ®ve cases.
Univariate analysis
According to univariate analysis (Table 3), the presence of the following parameters at diagnosis was signi®cantly associated with shorter survival: serum
creatinine level 018.1 mgudl (P = 0.03) (Fig. 1B), age
057 yr (P = 0.04) (Fig. 1C), and ESR 090 mmu1st h
(P = 0.02) (Fig. 1D).
Multivariate analysis
The following parameters were selected for the multivariate analysis: age < or 057 yr, serum creatinine
< or 018.1 mgudl, ENT involvement, cutaneous
496
A. Mahr et al.
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 w14, 22x.
Among the parameters selected for multivariate
analysis, only serum creatinine 018.1 mgudl (P = 0.02)
and age 057 yr (P = 0.02) were retained as independent
factors signi®cantly 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 signi®cance.
TABLE 2. Causes of death for 18 patients with systemic WG
Patient
Time after
diagnosis
1
2
3
4
3 months
14 months
1 months
4 months
5
6
7
8
9
10
11
12
13
14
15
16
3 months
1 months
3 months
27 months
17 months
3 months
2 days
30 months
3 months
33 months
2 days
14 months
17
5 months
18
5 months
Cause of death
PCP
Papovavirus multifocal leucoencephalitis
Haemoptysis of unknown origin
PCP and bacterial pneumonia,
acute renal failure
Cerebral haemorrhage
Unknown
Septic shock
Unknown
Alveolar haemorrhage
PCP and CYC-induced pneumopathy
Alveolar haemorrhage
Pulmonary haemorrhage
Suicide (chronic psychosis)
Acute renal failure, bacterial pneumonia
Unknown
Cerebral haemorrhage, multifactorial
thrombopenia
PCP and bacterial pneumonia,
invasive aspergillosis
PCP and cytomegalovirus pneumonia,
invasive aspergillosis
TABLE 3. Univariate analysis of factors associated with survival of 49
patients with systemic WG
Parameter
Sex
Age
Age < or 057 yr
ENT involvement
Pulmonary involvement
Glomerulonephritis
Peripheral neuropathy
Cutaneous involvement
Ophthalmological involvement
Serum creatinine
Serum creatinine < or 018.1 mgudl
Number of organs affected < or 04
One or more infectious complications
ESR
ESR < or 090 mmu1st h
BVAS ( or >18
Values in bold are statistically signi®cant.
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 mgudl; and older age, with a threshold value of
57 yr. Furthermore, the signi®cant 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 signi®cant 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 w16x
described a non-renal `limited' form of WG characterized by a better prognosis. The pejorative impact of
kidney involvement on prognosis was con®rmed by
Luqmani et al. w17x, who noted particularly poor outcomes for patients with serum creatinine >56.5 mgudl.
In our analysis, only those patients whose renal
involvement was associated with functional impairment
were at greater risk of death. These ®ndings suggest that
the prognosis might not depend on glomerulonephritis
itself but on the deterioration of renal function. Similar
®ndings were reported by other investigators w18, 21x.
The serum creatinine concentration associated with
shortened survival in our cohort was 18.1 mgudl, and
therefore lower than thresholds reported previously
w17, 21x.
An age of 057 yr at diagnosis was also a marker
of poorer prognosis. This ®nding is in agreement with
the results of previous univariate analyses which identi®ed ages of 060 w18, 29x and 50 yr w21x as predictors of
poorer outcome. It is not yet clear whether the increased
mortality of the older patients re¯ects 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. w29x demonstrated
P
0.94
0.26
0.04
0.09
0.29
0.39
0.56
0.07
0.92
0.55
0.02
0.84
0.38
0.07
0.02
0.40
TABLE 4. Multivariate analysis, using Cox proportional hazards
regression model, of factors associated with survival based on 49
patients with systemic WG
Parameter
Serum creatinine
018.1 mgudl
Age 057 yr
P
Relative
risk
95% con®dence
interval
0.02
3.5
2.5±4.5
0.02
3.6
2.5±4.6
The model included the following variables determined at diagnosis:
serum creatinine 018.1 mgudl; presence of pulmonary involvement;
absence of ENT involvement; absence of cutaneous involvement; and
age 057 yr. Variables that did not affect survival signi®cantly 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).
Predictors of survival in Wegener's granulomatosis
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 ®nding 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 re¯ected 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 ®ndings, as BVAS relies primarily on the cumulative evaluation of the anatomical extent of the disease
w23x. 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 w15x. In
particular, we noted a substantial early mortality rate, as
22.5% of the patients died within the ®rst 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 w24x, 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 con®rmed by
the multivariate analysis, this ®nding 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 signi®cance of the coexistence of these pathological ®ndings is unclear, the mechanisms leading to
granuloma formation or vasculitis might be different.
Indeed, it has been emphasized that the clinical
heterogeneity of WG re¯ects a broad spectrum of
disorders ranging from predominantly granulomatous
disease at one end to predominantly vasculitic disease
at the other w30x. 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 w31x. Furthermore, immunological
studies suggest that these two pathological hallmarks of
WG might correspond to different immune responses
involving T cells w32, 33x. Consequently, our ®nding
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
497
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 suf®ce for more benign
disease. This therapeutic approach might enhance treatment ef®cacy 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.
Acknowledgements
The following individuals contributed to the study:
P. Bielefeld, P. Bindi, O. BleÂtry, 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. DeÂtreÂe, 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. MeÂchali, P. Miossec,
E. MonchaÃtre, J. C. Piette, P. ReÂmy, J. Ribstein,
J. Rossert, I. Royer, A. Sacchi, B. Saugier,
C. Seigneuric and M. Stern.
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