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Lack of Superiority of Steroids Plus Plasma Exchange to Steroids Alone in the Treatment of Polyarteritis Nodosa and Churg-Strauss Syndrome.

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208
LACK OF SUPERIORITY OF STEROIDS PLUS PLASMA
EXCHANGE TO STEROIDS ALONE IN THE
TREATMENT OF POLYARTERITIS NODOSA AND
CHURG-STRAUSS SYNDROME
A Prospective, Randomized Trial in 78 Patients
LOIC GUILLEVIN, OLIVIER FAIN, FRANCOIS LHOTE, BERNARD JARROUSSE,
DU LE THI HUONG, ANNETTE BUSSEL, and ANNE LEON
Objective. To define the most effective treatment
for polyarteritis nodosa (PAN) and Churg-Strauss syndrome (CSS).
Methods. We conducted a prospective, randomized, multicenter trial in which 78 patients were randomly assigned to receive either prednisone and plasma
exchange (group A; n = 36) or prednisone alone (group
B; n = 42) as first-line treatment of PAN and CSS.
Patients with hepatitis B virus-related PAN were not
included in this study. The end point of the study was
control of the disease (recovery and remission) or death.
Results. Clinical symptoms and laboratory findings did not differ statistically in the 2 groups at study
entry. Initial control of the disease was similar in both
groups. The assigned treatment was stopped in 16
patients because of lack of efficacy. Oral cyclophosphamide or dapsone therapy reversed the disease evolution
in 7 of these 10 group A patients and in 4 of these 6
group B patients. At 7 years of followup, 56 patients had
completely recovered (27in group A, 29 in group B), 7
patients were in clinical remission, and 15 patients had
died (19.2%; 6 group A patients and 9 group B pa__.____
This research was conducted with the help of the Cooperative Study Group for Polyarteritis Nodosa and the SocietC Nationale Francaise de MCdecine Interne (SNFMI).
Supported by a grant from the Institut National pour la
Sante et la Recherche Mtdicale (INSERM), the Caisse Nationale
d’ Assurance Maladie des Travailleurs Salaries (CNAMTS), and the
Association pour la Recherche sur les Angtites Ndcrosantes
(ARAN).
Lolc Guillevin, MD; Olivier Fain, MD; FranGois Lhote,
MD; Bernard Jarrousse, MD; Du Le Thi Huong, MD; Annette
Bussel, MD; Anne Leon, MD.
Address reprint requests to Lo’ic Guillevin, MD, HGpital
Avicenne, Service de Mtdecine Interne, 125 route de Stalingrad,
Universitt Paris-Nord, 93009 Bobigny Cedex, France.
Submitted for publication March 29, 1991; accepted in
revised form October 10, 1991.
Arthritis and Rheumatism, Vol. 35, No. 2 (February 1992)
tients). The prednison+plasma exchange combination
was no more beneficial than corticosteroids alone in
preventing relapses over the long term. There was no
significant difference in the 7-yearcumulative survival
rates of the two groups (83% and 79%, respectively).
Conclusion. Based on our data, we conclude that
combined treatment with prednisone and plasma exchange is not superior to treatment with prednisone
alone and must not be systematically employed for
initial treatment of PAN and CSS. In most cases,
cyclophosphamide as second-line treatment is effective
and well tolerated.
Polyarteritis nodosa (PAN), first described by
Kussmaul and Maier (l), is a well-known form of
necrotizing angiitis, the main manifestations of which
are weight loss, fever, asthenia, peripheral neuropathy, renal involvement, musculoskeletal and cutaneous involvement, hypertension, gastrointestinal tract
involvement, and cardiac failure. Churg-Strauss syndrome (CSS) is a disorder characterized by hypereosinophilia and systemic necrotizing vasculitis, which is
similar to that of PAN, and occurs in individuals with
asthma and allergic rhinitis.
Thirty years ago, the treatment of PAN consisted primarily of corticosteroids (2), and the 5-year
survival rate with steroid treatment alone was 48%.
Since 1979, retrospective studies have shown that
adding immunosuppressive agents, especially cyclophosphamide (CYC) (3,4), to the treatment regimen
was effective and improved the prognosis for PAN.
However, other investigators, who systematically instituted azathioprine therapy at the onset of disease,
did not observe such improvements (5,6). Several
studies have also indicated that plasma exchange
TREATMENT OF PAN AND CSS
therapy is effective in the treatment of PAN (7-10). All
these studies (2-9) were retrospective, did not use a
control group, and included only “selected” patients;
these features explain the different conclusions concerning the therapeutic strategy for PAN and CSS.
In a previous randomized study (1 I), we demonstrated that the concomitant use of CYC with corticosteroids and plasma exchange therapy significantly
contributed to a lower incidence of relapse and an
improvement in the quality of the clinical response to
therapy. On the other hand, there was no significant
difference in the 10-year cumulative survival rates of
the group treated with prednisone and plasma exchange and the group treated with prednisone, plasma
exchange, and CYC (72% and 75%, respectively).
Therefore, our present study was designed to prospectively determine an effective treatment for PAN and
CSS and to decide upon the optimal initial therapeutic
regimen.
The study patients were randomly assigned to 1
of 2 treatment groups: prednisone plus plasma exchange (group A) or prednisone alone (group B). To
limit the side effects caused by cytotoxic agents, CYC
was introduced only if the assigned treatment was not
able to induce or to maintain remission. We studied
patients who had systemic vasculitis of the polyarteritis nodosa type, without markers for hepatitis B virus
(HBV). Consistent with Fauci’s classification system
(12), PAN and CSS were not treated as separate
diseases in this study, because we think that these two
forms of necrotizing angiitis belong to the same disease group. This idea is supported by data in several
recent publications (13,14), which show the lack of
diagnostic specificity of Churg-Strauss granuloma as
evidence of CSS and, conversely, the great diagnostic
value of the clinical symptoms.
PATIENTS AND METHODS
Patients. Criteria for study entry were as follows: 1)
age >15 years and (75 years, 2) systemic PAN and CSS
diagnosed clinically, by the presence of multiple system
involvement, 3) histologic evidence of vascular lesions indicative of a diagnosis of vasculitis (focal or segmental
vascular lesions, fibrinoid necrosis, andor pleomorphic inflammatory cell infiltration of the arterial wall) (15), 4) in the
absence of histologic criteria, arteriographic evidence of
vasculitis (microaneurysms, multiple stenoses, and occlusions of medium-sized arteries [161) that is not a result of
arteriosclerosisor noninflammatorycauses, and 5 ) vasculitis
sufficientlyactive to justify the use of corticosteroids.
Only patients who were not taking high doses of
steroids were included in the study. Patients who were
209
taking low doses of steroids (<lo mg/day) that had been
prescribed for asthma were included. Patients with cutaneous PAN or with limited forms of the disease were excluded
from the study, as were patients with other forms of the
systemic vasculitides and those in whom high-dose corticosteroids or plasma exchange therapy was contraindicated.
Patients with HBV-related PAN were not eligible for this
study. The patients were formally enrolled in the trial after
the study had been explained to them and their informed
consent had been obtained.
Study protocol. Patients fulfilling the inclusion criteria were consecutively enrolled in the trial by members of
the Polyarteritis Nodosa Study Group.* The patients were
randomly assigned by the coordinating center to treatment
group A or B (prednisone plus plasma exchange or prednisone alone, respectively). The calculated sample size
needed to obtain 75% complete recovery in the corticosteroid plus plasma exchange therapy group and 50% complete
recovery in the corticosteroid group was 160 patients (80 in
each treatment group), with an alpha error of 5% and a beta
error of 10%. Recruitment began in December 1983. Interim
analyses during the course of the study were planned for 1
year and 3 years after study entry. The end point of the study
was control of the disease (recovery and remission, as
defined below) or the patient’s death. The study protocol
was approved by the Biomedical Ethics Committee of the
University of Paris-Nord.
* The following institutions and principal investigators
comprise the Polyarteritis Nodosa Study Group and contributed to
this study: R. Makdassi, A. Fournier, A. Smail, J. Baillet (Centre
Hospitalier Universitaire [CHU] Amiens), Y.Pennec (CHU Brest),
G. Baralis (Centre Hospitalier [CHI Arles), V. Jeantils (CHU
Bondy), J. Brun (CHU Caen), L. Sary (CH Chartres), J. F.
Delfraissy (CHU Clamart), P. Veyssier (CH Compibgne), M. Mougeot-Martin, G. Pagniez (CH Creil), J. F. Besancenot, Y. Tanter, J.
M. Chalopin (CHU Dijon), F. Coulomb, J. Mallecourt (CH Dreux),
P. Dournovo (CH Eaubonne), A. Leonard (CH Elbeuf), A. Franco,
F. Dechelette (CHU Grenoble), C. Guillemot, M. Huart (CH La
Roche-sur-Yon), F. Cordier (CH Laval), F. Liozon, R. Treves, R.
Desproges-Gotteron, E. Vidal (CHU Limoges), D. Vital-Durand, J.
Pasquier (CHU Lyon), G. Janin (CH Macon), P. Lebon (CH Mans),
J. M. Beaufils (CH Mayenne), M. Echard (CH Montfermeil), G.
Dorsit (CH Moulins), B. You, J. Barrier, T. Ponge (CHU Nantes),
P. Dujardin, J. P. Cassuto, J. G. Fuzibet (CHU Nice), P. Dreyfus,
D. Daupleix, L. Guillevin, A. Lton, G. Andreu (CHU Avicenne,
Bobigny), F. Delrieu, B. Amor, B. Christoforov, D. Sereni (CHU
Cochin-Port-Royal, Paris), P. Pasquier (CH Croix Saint-Simon), A.
M. Piette (Centre Medico-Chirurgical [CMC] Foch, Suresnes), A.
Schaeffer, A. Sobel, B. Roualdes, M. Vanderstiegel, J. C. Roujeau,
E. Eliazewicz (CHU Henri-Mondor, Crtteil), G. Huchon (CHU
Laennec, Paris), B. Ptpin, J. Lecoz, A. Schannen (CHU Lariboisi&re, Saint-Louis Paris), 0. Blktry, P. Godeau, D. Laplane, J.
Cabane, J. C. Piette, B. Wechsler, J . M. Ziza, C. de Gennes, D. Le
Thi Huong (CHU Pitit-Salp6tri6re, Paris), J. Cabane, J. C. Imbert,
P. Amarenco, R. Marteau, J. Debray, Ph. Brissaud (CHU SaintAntoine, Paris), M. Bentata-Pessayre (CH Saint-Germain), A. Bussel (CHU Saint-Louis, Paris), P. Babinet (CH Saint-Denis), M.
Alcalay (CHU Poitiers), M. Bourel, S. Gie, B. Grosbois, B. Desrumeaux, B. Pinel, 0. Deshayes (CHU Rouen), K. S. Ang, J. M.
Simon (CH Saint-Brieuc), H. Rousset (CHU Saint-Etienne), M.
Rue1 (CH Senlis), H. Mallet (CH Thonon-les-Bains), B. de Toffol
(CH Tours), and F. Rossi (CH Vendome).
210
Treatment protocol. Prednisone. Every patient took
prednisone at a dosage of 1 mgkglday for 1 month. In those
patients who had clinical and laboratory evidence of improvement, the dosage was tapered according to the following system. The daily dose was decreased by 2.5 mg every 10
days for 1 month, and then by 2.5 mg every week until a level
equivalent to half the initial dosage was reached. This dosage
was maintained for 3 weeks, and was then further decreased
by 2.5 mg every week, to approximately 20 mg/day.
A more careful tapering schedule was followed for
dosages <20 mg/day. The daily dose was decreased by 1 mg
each week, to a dosage of 10 mg/day. This level was
maintained for 3 weeks, and was further decreased by 1 mg
each week until a dosage of 5 mglday was reached.
When there was clinical improvement, but no improvement in the erythrocyte sedimentation rate (ESR) or
other laboratory parameters of inflammation, the prednisone
dosage was maintained for at least 1 month before further
reduction was attempted. After 1 month, the dosage was
reduced (according to the above schedule) in parallel with
improvements in laboratory indicators of inflammation.
When there were new symptoms, regression of the
initial symptoms, or lack of normalization andor improvement in laboratory indicators of inflammation, the prednisone dosage was either increased or was kept at the same
level until the symptoms resolved andor the laboratory
indices of inflammation improved. At this time, the prednisone dosage was tapered according to the above schedule.
Plasma exchange. Patients assigned to group A
underwent 12 plasma exchange treatments during the first 2
months of treatment (3 during each of the first 2 weeks, 2
during the third week, then 1 session 10, 15,21, and 30 days
later). The amount of plasma scheduled for each session was
60 mVkg of body weight. The replacement fluid consisted of
500 ml gelatin and 4% albumin. Fresh-frozen plasma was
used in some situations, mainly for patients with decreased
levels of coagulation factors. When side effects of the plasma
exchange treatments occurred, or when venous access was
not possible, exchanges were stopped or withdrawn entirely.
Cyclophospharnide. Oral CYC (2 mgkglday) was
prescribed only in the case of failure of the assigned treatment (i.e., relapse or partial remission which necessitated a
higher steroid dosage than previously planned in the protocol, followed by a lack of improvement in symptoms).
Neutropenia was not a necessary criterion for using optimal
dosages of CYC.
Patients’ white blood cell counts were carefully
monitored so that the CYC dosage could be adjusted to
avoid severe neutropenia (defined as a neutrophil count
< 1,500 cells/mm3).CYC was stopped after 1 year in order to
avoid or to reduce the incidence of such long-term side
effects as leukemia or lymphoma, which can result from the
use of immunosuppressive agents (17). If cytotoxic agents
were contraindicated, the clinician could give dapsone, 100
mglday, which has been shown to be effective in some cases
of these vasculitides (18). The dapsone dosage was modified
according to the patient’s hematologic tolerance. In the case
of hemolysis, with a hemoglobin value decreased by more
than 2 gm/ml, the dapsone dosage was reduced to 50 mg/day.
Evaluation of disease activity. Disease activity was
defined by clinical and laboratory criteria. The disease was
GUILLEVIN ET AL
classified as controlled when there was improvement in the
patient’s general condition (i.e., no fever, myalgias, arthralgias, or regression of the initial clinical manifestations); no
new clinical manifestations related to PAN; and normalization of the ESR. Stabilization or improvement (partial or
total) in peripheral neuropathy and in renal and cardiac
function (if abnormalities existed previously) were also
necessary.
The patient was considered to be in “complete
recovery” when the required criteria for control of the
disease were met and maintained for at least 18 months after
discontinuation of treatment.
Clinical remission was considered when there was
stabilization or improvement in clinical symptoms and normalization of laboratory abnormalities during constant treatment. If there was no evidence of control of the disease
activity under the assigned treatment or if relapse occurred,
the trial medication was stopped, and the patient was withdrawn from the study. Study withdrawal because of assigned
treatment failure was recorded by the coordinating committee.
Relapses were defined as new systemic manifestations of PAN or worsening of the initial manifestations of the
disease. The continued positivity of laboratory indices of
inflammation without clinical deterioration was not considered a relapse.
The occurrence of serious side effects induced by
corticosteroids or plasma exchange led to discontinuationof
treatment and withdrawal of the patient from the study.
Followup evaluations. The clinical and laboratory
data were collected at the time of study inclusion, 15 days
later, and 30 days later (30 days after study entry), then
every month for 6 months, every 3 months for 1 year, and
every 6 months for the next 5 years. In the case of a relapse
or incomplete control of the disease, additional studies were
performed. At each visit, compliance with the treatment
regimen was assessed, side effects were recorded, and the
necessity of adjunctive therapy was evaluated (e.g., treatment of hypertension). All data were recorded on protocol forms which were then sent to the trial coordinator.
All events related to the study were reported to the trial
coordinator.
Statistical analysis. A chi-square test with Yates’
correction for small numbers, when appropriate, was used
for comparison of qualitative variables (e.g., data on remission, relapses, withdrawals from study), and Student’s t-test
was used for comparison of quantitative variables that had
been expressed as mean +- SD values (19). The actuarial
method was used to construct life-table plots. Log rank
analysis was used to compare the survival curves (20).
Survival time was evaluated relative to the time of diagnosis.
RESULTS
Clinical findings. Between December 1983 and
December 1988, 78 patients were eligible for study.
The clinical manifestations of PAN (60 patients) and
CSS (18 patients) in the 78 study patients (36 in group
A and 42 in group B) are summarized in Table 1. These
were manifestations that are classically encountered in
PAN and CSS.
TREATMENT OF PAN AND CSS
21 1
Table 1. Clinical manifestations of systemic vasculitis at the time
of diagnosis in patients*
Age, mean ? SD
Sex ratio, M/F
Peripheral neuropathy
Fever
Weight loss
Myalgias
Cutaneous symptoms
PUrpUE3
Nodules
Livedo reticularis
Urticaria
Arthralgias
Polyarthritis
Renal involvement
Renal insufficiency
Glomerulonephritis
Hypertension
Abdominal symptoms
Abdominal pain
Lung involvement
Asthma
Cardiac involvement
Central nervous system
involvement
Distal limb ischemia
Group A
(n = 36)
Group B
(n = 42)
52.6 f 13.7
14/22
25 (69.4)
24 (66.6)
22 (61.1)
20 (55.5)
18 (50.0)
10
5
6
5
12 (33.3)
8 (22.2)
12 (33.3)
10 (27.7)
12 (33.3)
11 (30.5)
11 (30.5)
10 (27.7)
9 (25.0)
7 (19.4)
5 (13.8)
3 (8.3)
55.0 f 14.7
2u20
34 (80.9)
26 (61.9)
27 (64.2)
25 (59.5)
22 (52.3)
9
8
6
1
20 (47.6)
4 (9.5)
I 1 (26.1)
9 (21.4)
9 (21.4)
13 (30.9)
7 (16.6)
7 (16.6)
12 (26.2)
10 (23.8)
5 (11.9)
3 (7.1)
2 (5.5)
2 (4.7)
* Patients were randomly assigned to treatment group A (corticosteroids plus plasma exchange treatments) or group B (corticosteroids alone), as described in Patients and Methods. Values are the
number (%).
While there were some between-group differences,
they were not statistically significant. Seventeen patients had a history of asthma. Abdominal signs were
present in 23% of the patients: 21.7% had transient
abdominal pain, which regressed spontaneously or in
response to corticosteroid therapy and required no
further investigation. One patient had acute cholecystitis, and 1 had pancreatitis.
Histopathologic or angiographic evidence of
vasculitis was identified in 74 patients. Sixty-five patients had biopsy-proven vasculitis in one or more
organ, as follows: sural nerve in 29, skin in 28, muscle
in 16, kidney in 4, liver in 4, appendix in 1, gallbladder
in 1, and temporal artery in 1. Fifteen patients had
angiographic evidence of vasculitis; the renal artery
was involved in 9 and the mesenteric artery in 6.
Needle aspiration biopsy of the kidney was performed
in 7 patients, and revealed glomerulonephritis of variable intensity in 5 patients (2 had rapidly progressive
glomerulonephritis, 3 had focal and segmental glomerulonephritis), vascular lesions in 4, and tubular involvement in 3.
Laboratory findings. A high ESR (>40 mm/
hour) was found in 24 patients in group A and 31
patients in group B. Eosinophilia r500/mm3 was observed in 31 patients, and was associated with asthma
in 16 of them. Nine patients (7 in group A and 2 in
group B) had severe renal disease, with serum creatinine levels 1 3 mg/dl; 7 of them needed hemodialysis
during the acute phase of polyarteritis. One of these 9
patients (group A) died of cerebral bleeding, 2 were
started on long-term hemodialysis, 5 recovered normal
or subnormal renal function, and 1 successfully underwent renal transplantation.
Results of plasma exchange treatments. Four
hundred twelve plasma exchange treatments were
performed in 36 patients. The mean volume exchanged
was 3,362 ml (2,000-5,OOo ml). Eight complications
were reported in 7 patients. The most common problems were technical difficulties (in 4 sessions) and
moderate hypotension (in 2). In 1 patient, these treatments were stopped after 8 sessions because of severe
hypotension. No patient died during a treatment session. The side effects and complications of plasma
exchange were usually mild and transient.
Results of followup. The high rate of relapse in
both groups (10 in group A and 8 in group B) and the
lack of superior efficacy of prednisone plus plasma
exchange therapy on survival were of primary consideration in the coordinating committee’s decision to
stop the trial before the calculated adequate samplesize of 160 subjects (80 per treatment group) was
reached. The study recruitment was stopped after 78
patients had entered the study, since the interim
analysis at 3 years demonstrated no greater efficacy of
corticosteroids plus plasma exchange on disease control than of corticosteroids alone. The censoring date
for the trial was December 31, 1988, which was 1
month after the last patient started treatment. Followup continued until the censoring date, even after
study withdrawal because of treatment failure or side
effects, or until the patient’s death. The mean ? SD
followup period was 42.2 f 23 months (range 1-82
months) for group A and 45.8 23.7 months (range
1-83 months) for group B.
Disease activity during the 6rst 6 months after
diagnosis. Regardless of the treatment administered,
disease activity during the first 6 months of treatment
was controlled in 63 patients: 28 (77.7%) in group A
and 35 (83.3%) in group B (P not significant). Nine
patients died during this period: 5 group A and 4 group
B patients. In 6 patients (3 in group A and 3 in group
B), the study treatment failed to control disease activity, and deterioration or relapse of PAN or CSS
*
212
occurred. Oral cyclophosphamide therapy (2 mg/kg/
day) was therefore added to the therapeutic regimen in
these 6 patients. Five of them recovered and 1 died
before the sixth month after diagnosis.
Outcome. One year after the start of treatment,
the average steroid dosage was 10 mg/day in group A
patients and 13.7 mg/day in group B patients (P not
significant). A high rate of relapse was observed in
both groups (10 in group A, 8 in group B). In 26
patients (14 in group A, 12 in group B), the study
therapy failed to control the disease activity, and the
patients experienced deterioration or relapse, despite
therapy. The steroid dosage was increased for 10 of
the 26 patients (4 in group A, 6 in group B). Sixteen
patients (10 in group A, 6 in group B) received an
additional treatment. In group A, oral CYC (2 mg/kg/
day) was added to the regimen for 9 patients who had
not improved, and dapsone (100 mg/day) was added
for 1 patient; in group B, CYC was added for 5
patients, and dapsone for 1. Nine of the 26 patients (5
in group A, 4 in group B), continued to experience
deterioration of their condition and subsequently died.
Two of them had received CYC plus steroids, and 1
had also been treated with prednisone plus plasma
exchange. Of the remaining 17 patients, 15 recovered,
and the disease went into remission in the other 2.
Among the 63 patients still alive at the end of
the study, 56 (71.7%) recovered completely, with no
clinical or laboratory evidence of systemic vasculitis
after at least 18 months without treatment. Seven
(8.9%) no longer had manifestations of PAN or CSS
and were considered to be in remission; that is, they
remained on a maintenance regimen of low-dose steroids, which was necessary to control the disease and
to avoid relapse. Long-term hemodialysis was begun
for 2 patients. Treatment failure and death attributable
to the vasculitis typically occurred during the first 6
months of the trial, except for 2 group B patients, who
died at 38 months and at 60 months, respectively, after
the beginning of the study. In both cases, the cause of
death was myocarditis with cardiac failure.
Causes of death. A total of 15 patients (19.2%)
died during the study period: 6 group A patients
(16.6%) and 9 group B patients (21.4%). The causes of
these deaths are shown in Table 2. Survival curves
showed that at 5 years, 83% of the patients in group A
were alive, versus 79% in group B (Pnot significant);
survival rates at 7 years were the same (Figure 1).
Side effects of treatment. Side effects of the
steroid treatment were severe diffuse osteoporosis in
2 patients, aseptic necrosis of the femoral head in 2
patients, aseptic necrosis of the humeral head in 1
patient, duodenal ulcers in 2 patients, and pneumonia
GUILLEVIN ET AL
Table 2. Cause of death of 15 patients during the study period*
Systemic vasculitis
Bowel infarction
Hernoperitoneum
Stroke
Respiratory failure
Cardiac failure
Infections as side effects
of treatment
Septicemia (treatment
with
cyclophosphamide)
Other cause
Pulmonary embolism
Unknown
Cancer
Group A
(n = 6)
Group B
(n = 9)
Total
(n = 15)
4
5
9
1
0
1
2
2
0
1
0
1
It
2t
1
3
0
1
1
0
It
1
2
0
3
5
1
1
I
1
I
2
2
2
I
1
* Patients were randomly assigned
to treatment group A (corticosteroids plus plasma exchange treatments) or group B (corticosteroids alone), as described in Patients and Methods.
t These patients (n = 3) died during treatment with prednisone plus
cyclophosphamide.
in 1 patient. No serious side effects were observed in
patients treated with dapsone. One patient died of
septicemia during CYC and steroid treatment, but did
not have leukopenia. No other side effects of CYC
were reported.
DISCUSSION
For several decades, an overall improvement in
the prognosis for PAN and CSS has been observed as
a consequence of the systematic use of steroids (1,6)
8070
-
6050
____...___._.._____.___
..__--__._.._....._._
-
n = 42
79%
.....-....
4030
20
10
0
-
Months
I
Figure 1. Rates of survival at 7 years in the 78 study patients with
systemic vasculitis. Patients were randomly assigned to treatment
group A (corticosteroids [CS] plus plasma exchange [PE]treatments) or group B (CS alone). See Patients and Methods for details.
TREATMENT OF PAN AND CSS
and the extensive use of CYC (3,4). Results obtained
with steroids and CYC are a subject of controversy.
Fauci et a1 (3) demonstrated that treatment with CYC
improved survival in PAN when steroids and other
immunosuppressive agents had failed. They observed
that 14 of 17 patients with PAN that was still uncontrolled after 22 months of prednisone therapy improved when oral CYC was introduced to the prednisone regimen. Their findings favored the systematic
prescription of CYC in association with steroids at the
time of diagnosis of PAN or CSS. No prospective
studies have yet substantiated this approach. Analysis
of a large series of patients undergoing immunosuppressive therapy showed that survival rates were
similar to those obtained with steroid therapy alone:
55% in the study by Cohen et a1 (5) and 58% in our
previous study (6). In contrast, Leib et al (4) demonstrated the superiority of the concomitant use of
cytotoxic agents with steroids to control PAN; they
noted a 5-year survival rate of 53% with steroids alone
and 80% with steroids plus cytotoxic agents.
We tested the systematic use of CYC with
steroids and plasma exchange therapy at the onset of
PAN and CSS in a previous randomized study (11) of
71 patients, and demonstrated that CYC provided
better control of disease and prevented relapse but did
not improve survival rates. The 10-year survival rate
was 75% when patients were treated with prednisone
plus CYC plus plasma exchange and 72% when patients had received prednisone plus plasma exchange.
The lack of positive influence on survival rates was a
consequence of infections that occurred as side effects
of the CYC treatment. When we decided to conduct
the present randomized trial, our aim was to determine
the optimal therapeutic strategy for non-HBV-related
PAN and for CSS. For HBV-related PAN, we have
proposed the use of a regimen of vidarabine plus
plasma exchange, which is effective in lowering viral
replication rates and removing immune complexes
(21). This treatment has been demonstrated to be
successful in 72% of patients (unpublished observations). When HBV is absent, however, the therapeutic
strategy includes steroids and, sometimes, cytotoxic
agents and/or plasma exchange.
The diagnoses of PAN and CSS were based on
nonspecific clinical features that include systemic
complaints, such as fever or weight loss, and focal
symptoms resulting from vascular impairment in specific organ systems. In the present study, we required
histologic or arteriographic confirmation of the presence of vasculitis. Four patients did not fulfill these
213
criteria, but clinically, they had severe multisystemic
CSS and were not excluded from the study. We
retrospectively evaluated our 78 patients for conformity with the PAN and CSS classification criteria published in 1990 by the American College of Rheumatology (ACR) (22,23). Only 6 of the 60 patients with PAN
did not meet these criteria. Five of them had biopsyproven vasculitis and 1 had multiple microaneurysms
of branches of the mesenteric artery, as demonstrated
on angiography. Among the 18 patients with CSS, 4
did not fulfill the ACR criteria, but otherwise met the
criteria for diagnosis of CSS that were proposed by
Lanham et a1 in 1984 (14).
In the present study, we tested the indications
for plasma exchange therapy and evaluated its ability
to improve the control of the disease and the survival
rate. Plasma exchange treatments remove immune
complexes (7) and facilitate their clearance from the
reticuloendothelial system. The pathogenetic role of
these immune complexesjustified the concomitant use
of plasma exchange and steroid therapy in our study.
We demonstrated that plasma exchange therapy did
not improve the survival rate or the control of the
disease; the results in the group that underwent this
treatment were not significantly different from those in
the group who took steroids alone. The randomization
of patients into the 2 treatment groups resulted in a
higher number of patients with severe renal disease
(serum creatinine 2 3 mg/dl) being included in group A
(n = 7; only 2 in group B). Since it has been suggested
that immune complexes play a role in vasculitis and in
severe renal disease (lo), the plasma exchange therapy
may have produced additional benefit in this small
subgroup. Severe renal disease was not associated
with higher mortality in this study population.
The number of patients in whom an increased
dosage of prednisone or the introduction of cyclophosphamide or dapsone therapy was needed because of
failure of the assigned treatment was much higher in
the present study than in our previous study, in which
CYC was given initially in combination with prednisone and plasma exchange (11). In contrast, fatal
infections as side effects of CYC treatment were rare
in this study (1 case), and the survival rate was higher
than has been observed in other studies, including our
own (ll), 83% versus 75% at 7 years. Fourteen patients required CYC therapy for l year, and dapsone
was given to 2 additional patients. These drugs were
able to control the disease in most cases without
jeopardizing the patients’ lives. Sequelae were rare,
most of them due to the prednisone therapy (os-
GUILLEVIN ET AL
214
teoporosis). Only 2 patients had end-stage renal failure, necessitating hemodialysis (1 in each group).
Thus, the therapeutic strategy for PAN and for
CSS without HBV markers can be limited to the
institution of prednisone alone as the first-line treatment. In patients in whom prednisone fails to reverse
the evolution of the disease, cytotoxic agents that have
been proven effective in the treatment of PAN can
then be added to the regimen. This approach reduces
the side effects of cytotoxic agents and improves
survival. In this study, the side effects of the plasma
exchange therapy were minor and well tolerated, and
there is therefore no reason to avoid this treatment.
Nevertheless, we have shown that, in most cases,
plasma exchange treatments were not useful. If it were
possible to reduce the side effects of cytotoxic agents,
the systematic use of CYC would likely be the best
therapeutic approach. We foresee that other modalities of treatment with CYC, for example, pulse therapy, as has been demonstrated in the treatment of
systemic lupus erythematosus (24), could favor better
clinical results and lower the rate of infectious side
effects. This approach is currently being investigated
by our study group.
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