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Wegener' granulomatosis.

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501
WEGENER’S GRANULOMATOSIS
LONG-TERM FOLLOWUP OF PATIENTS
TREATED W I T H CYCLOPHOSPHAMIDE
MICHAEL J. REZA, LESLIE DORNFELD, LEONARD S. GOLDBERG,
RODNEY BLUESTONE, and CARL M. PEARSON
Ten patients with Wegener’s granulomatosis
were treated with cyclophosphamide and followed for
periods up to 7 years. I n all cases cyclophosphamide
induced complete remissions. T h e mean duration of
remission (to date) was 38 months. Six patients have
been in remission for a mean of 46 months after
cyclophosphamide was discontinued; 2 have been
disease-free for 7 years. Of the 10 patients treated,
only 1 relapsed and she responded to a second course
of cyclophosphamide. These results indicate that cyclophosphamide is the drug of choice in Wegener’s
granulomatosis. T h e long-term effectiveness of this
drug suggests that it may induce permanent remissions in certain patients with Wegener’s granulomatosis.
From the Department of Medicine, University of California at Los Angeles School of Medicine, Los Angeles, California
90024, and the Wadsworth VA Hospital, Los Angeles,
California
90073.
Supported in part by grants from the USPHS (GM
15759) and the Kroc Foundation. VA Project No. 1008-03.
Michael J. Reza, M.D.: Resident in Internal Medicine;
Leslie Dornfield, M.D.: Clinical Assistant Professor of Medicine;
Leonard S. Goldberg, M.D.: Associate Professor of Medicine;
Rodney Bluestone, M.B., M.R.C.P.: Associate Professor of Medicine; Carl M. Pearson, M.D.: Professor of Medicine.
Address reprint requests to Dr. Michael J. Reza, U.C.L.A.
Medical Center, 10833 Le Conte Avenue, Los Angeles, California
90024.
Submitted for publication December 13, 1974; accepted
February 14, 1975.
Arthritis and Rheumatism, Vol. 18, No. 5 (September-October 1975)
Prior to the use of immunosuppressive agents,
Wegener’s granulomatosis (WG) appeared to be a uniformly fatal disorder. In 1958, the average survival
time in patients with this disease was 5 months (1).
During the 1960s, the prognosis appeared to improve
when selected patients were treated with a variety of
cytotoxic agents including nitrogen mustard, methotrexate, and azatliioprine (2). More recently, dramatic
responses to cyclophosphamide have been described
in sul>jectswith WG (3). However, with the exception
of a recent report from the National Institutes of
Health (4), no information is available regarding the
long-term prognosis of this disorder following treatment with cyclophospliamide. This paper describes
the long-term followup of 10 patients with WG who
were treated with cyclophosphamide.
MATERIALS A N D METHODS
T e n patients with WG were initially seen a n d followed a t either t h e U CLA Medical Center or the Wadsworth Veterans Hospital. T h i s g r o u p represents all patients
with WG seen a t these two hospitals between 1967 a n d
1974. All h a d been treated with cyclophosphamide, a n d
each hatl received prednisone previously without benefit.
No o t h er immunosuppressive agents were administered to
these patients. Fo u r of the cases hatl been previously reported (3).
Clinical Features. T h e patient g r o u p consisted of 7
males a n d 3 females; the median age a t the time of diagnosis was 41 years with a range f r o m 18 to 71 years. The
diagnostic criteria used i n the present study were similar
or identical to those described by Fauci and Wolff (5).
REZA E T AL
502
Table 1. Clinical Features in I0 Patients with
Wegener’s Granulomatosus
Age at
Patient Diagnosis
Sex
Initial Symptoms
52
49
47
F
M
M
M
M
8
36
18
71
21
45
9
23
M
10
47
F
Rhinorrhea, cough, fever
Sinusitis, headache, obtundation
Rhinorrhea, otalgia, deafness,
facial palsy
Fcver, rhinorrhea, weight loss
Sinusitis, otitis, weight loss
Rhinorrhea, hemoptysis
Rhinorrhea, polyarthritis, rash
Fever, night sweats, headache,
confusion
Fever, night sweats, hemoptysis,
polyarthralgias, weight loss
Rhinorrhea, otalgia, deafness, fever
1
2
3
4
5
6
I
M
F
M
Table 1 shows the prominent presenting symptoms. Symptoms attributable to involvement of the nasopharyngeal
and paranasal sinuses were the most common. T a b l e 2
outlines the major organ systems involved i n these patients.
All had nasopharyngeal a n d pulmonary involvement and
all but 1 had renal dysfunction. Hematuria a n d proteinuria
were present i n the 9 subjects with renal involvement; 6
of these had diminished creatinine clearances. Eight of the
10 showed symptoms o r signs consistent with impairment
of the nervous system (peripheral neuropathy, cranial nerve
palsy, pseudotumor cerebri, obtundation). Five subjects had
ocular involvement including proptosis, papilledema, granulomatous abscess, and episderitis. All patients had nodular
inflltrates o n chest x-rays, and anemia, leukocytosis, and
markedly elevated sedimentation rates. T h e diagnosis i n
all subjects was confirmed by renal, pulmonary, or nasopharyngeal biopsies.
Cyclophosphamide Therapy. All patients were receiving varying doses of prednisone when initially seen;
the dose was gradually tapered over several months. Cyclophosphamide was given intravenously in 6 patients initially,
followed i n 7 to 10 days by orally administered cyclophosphamide. Initially the remaining 4 subjects were treated
orally with cydophosphamide. Kesponse to cyclophospha-
mide was assessed by both clinical and laboratory parameters. Once the disease was shown to be i n remission
by these parameters, the dose of cyclophosphamide was
slowly tapered. T h e dose and duration of treatment are
listed i n T a b l e 3. T h e average oral dose was 117 mg daily
a n d the mean duration of therapy was 17 months. Leukopenia and secondary infections were not observed during
treatment. One patient developed cystitis and 1 had a n
onset of ammennorrhea while o n therapy.
RESULTS
Tables 4 and 5 show the effects of therapy with
cyclophosphamide i n 10 patients with WG. A complete remission occurred in all patients, usually within
4 to 6 months. Pulmonary and nasopharyngeal lesions
resolved in every patient and the hematuria and proteinuria present in 9 patients disappeared. T h e creatinine clearance that was diminished in 6 patients
either returned to normal or was markedly improved
following treatment. T h e mean duration of remission
(to date) was 38 months. I n 6 patients cyclophosphamide has been discontinued (mean duration: 46
months) with no evidence of relapse i n 5. Patients
2 and 4 have been in total remission for 7 years.
Patient 7 recently was hospitalized with hematuria
and abdominal pain; a renal biopsy was nondiagnostic, but cyclophosphamide was reinstituted with
subsequent resolution of hematuria. Three other patients, 8, 9, and 10, diagnosed in the past 16 months
are still receiving therapy but are currently i n remission.
Typical responses to cyclophosphamide are
shown i n Figures 1 and 2 . Patient 1 presented with
clense pulmonary infiltrates; 4 months following institution of therapy the pulmonary lesions resolved
(Figures 1 and 2). Patient 5 developed renal failure
Table 2. Organ System Involvement in 10 Patients with Wegener’s Granulomatosus
Patient
1
2
3
4
5
6
7
8
9
10
Pharynx
Paranasal
Sinuses
+
++
++
+
++
++
+++
+
+
+++
+
+++
++
+++
+
++
++
++
+++
+ = mild.
++ = moderate.
+++ = severe.
++++ = extremely severe.
Ears
Eyes
Lungs
+
-
+++
++++
+++
-
+++
+++
++
++
+++
+++
+++
+++
+++
++
++
++
-
+++
-
+
-
-
+
+++
Kidney
++f
+
+
+++
+++
++
+
+++
+
Skin
-
Joint
-
-
++
-
+++
-
++
++
-
-
-
-
Nervous
System
+
+++
+
+++
+
+++
+++
+
-
503
WEGENERS GRANULOMATOSIS
Fig 1. Patient I . Chest x-ray prior to cyclophosphamide shows dense pulmonary infiltrates.
Table 3. Cyclophosphamide Therapy in 10 Patients with Wegener's Granulomatosus
Patient
Initial IV Therapy
(mg/kg)
Duration
(mo)
Maximum Daily
Dose (mg)
Average Daily
Dosc (mg)
1
15 mg/kg X 4 days
6
11
10
16
11
150
200
150
150
150
150
75
130
175
80
100
150
65
67.5
15
150
105
15
10
100
100
200
200
2
-
39
32
10 mg/kg X 4 days
-
8
9
10
8 mg/kg X 2 days
then
4 mg/kg X 2 days
10 mg/kg X 3 days
then
q week X 2
5 mg/kg X 2 days
5 mg/kg X 2 days
REZA E T AL
504
Fig 2. Patient 1 . Chest x-day obtained after 3 months
resolution of infiltrates.
with an active urinary sediment and a rising creatinine despite therapy with prednisone; after 6 months
of cyclopliosphamide the serum creatinine (Figure 3)
and other parameters of renal function returned to
normal. I n summary, 9 of the 10 patients with WG
treated with cyclophosphamide remain in remission
without evidence of reactivation of disease. Patient 7
appeared to relapse 30 months after cyclophosphamide
was discontinued but she responded rapidly to reinstitution of therapy.
of
cyclophosphamide shows dramatic
3 0-
2 5-
2 0SERUM
CREAT~N~NE
mq%
15-
IO-
T h e results of this stutly confirm [lie effectivencss of c)clol,lio\l,li;iinitle
in p;itiettts w i t l i \V(; ;ind
.
clearly clemonstratc the long-term benefits of this
therapy. I n every instance cyclopliosp1i;iniitle induced
complete resolution of the disease with ii mean tlura-
WEGENERS DISEASE
Cose#S Y-I8
PREDklSONE
mpld
-
;;
CYCLOPHOSPHAMIDE
ka,b,
I
505
WEGENER’S GRAN ULOMATOSIS
Table 4. Z.ongternz Followup on Patients with Generalized M’ege?rer’\ Grrinulotttatosiis Trented with Cyclophosphnmide
Total patients
Died
Complete remission
Relapses
In remission (still on therapy)
In remission (off therapy)
10
0
10
1
In remission (lost to followup)
1
3
6
Mean time from diagnosis: 50 months (range: 10-116 months)
>.lean time on therapy: 13 months (range: 10-15 months)
Mean time on therapy before discontinuance: 14 months (range: 8-32 months)
Mean time off therapy: 46 month5 (range: 12-80 months)
On therapy: 39 months
In remission: 37 months
therapy was stopped, but she responded well to a
second course of therapy. Similar results were recently reported by WolR et al (4), who noted excellent
responses to cyclophosphamide in 15 of I 7 patients
with WG; 2 subjects died despite therapy. (Three
additional patients died before adequate therapy
could be instituted.) Of the remaining 15, 7 remained
i n remission following cessation of therapy, and 8 are
in remission on therapy. Three of these patients relapsed after cyclophosphamide was discontinued but
responded to reinstitution of therapy. T h e mean duration of remission in the surviving patients was 34
months; similarly, the mean duration of remission in
our patients was 38 months. Combining the patient
group from the National Institutes of Health and
from UCLA, it seems clear that cyclophosphamide is
the therapeutic agent of choice in WG; in certain
patients the length of remission following therapy is
of sufficient duration to suggest possible cure of the
underlying disorder.
T h e optimum dose and duration of therapy
with cyclophosphamide in W G cannot be stated with
absolute certainty. Nor is it possible to predict which
patients will remain in long-term remission following
cessation of therapy. I n the study reported here, 6 of
tlie I0 patients were initially given cyclophosphamide,
4-15 mg/kg intravenously, followed in 7-10 days by
orally administered cyclophospliamide, 1-2 mg/kg.
These patients were for the most part critically ill
at the time of admission. I n the N I H study many of
the patients were given the drug orally, 1-2 mg/kg,
although several ot tlie very ill were initially treated
wi tli cyclophosphamide intravenously. T h e duration
of therapy in patients who have remained in remission following cessation of cyclophospliamide has
varied considerably; in our patients the length of therapy ranged from ti to 39 months, whereas tlie duration in tlie NIH group was 3 to 61 months. In the
present series long-term remission did not appear to
be a function of dose or duration of therapy. However, the single patient who relapsed had received one
of the lowest average daily closes of cyclophosphamide.
From these observations the following treatment in
WG is recommended: a) Critically ill patients, such
as those with fulminant renal disease, should receive
cyclophospliamide, 5-1 0 mg/kg intravenously for 2-3
day>, followed in 7-10 days (depending on WBC
count) by orally administered cyclopliospliamitle, 1-2
mg/kg. b) Those not acutely ill may be treated initially with oral therapy, 1-2 mg/kg, because most of
Table 5. Followup Data on 10 Patients with Wegener’s
Granulonratosus Treated with Cycloplrospharriide
Patient
Duration of
Therapy
(mo)
Time Since
Diagnosis
(mo)
Time off
Therapy
(mo)
6
11
85
116
40
56
80
97
58
10
48
16
11
15
29
39
12
30
1
2
3
4
5
6
7
8
9
10
*Lost to followup.
39
32
41
15
15
16
10
10
*
0
0
0
Total Time
in Remission
(4
57
84
37
84
40
Total Time
in Remission
off Therapy
(mo)
56
80
*
58
39
23
12
30
10
10
6
30
0
0
0
REZA E T AL
these patients will respond to oral cyclophosphamide
Patients should be maintained on treatment for 12 to
18 months after all evidence of the disease has subsided (4). Periodic followups are essential because certain patients will relapse and these will usually respond to second courses of treatment with cyclophosphamide.
T h e mechanism by which cyclophosphamide
induces remissions in Wegener’s granulomatosis is not
known. Although this agent is a known immunosuppressive, there is no definite evidence showing that
WG is an immune-mediated disorder. Whether or not
the immunosuppressive properties of cyclophosphamide relate to its therapeutic effectiveness in WG remains unclear.
REFERENCES
1. Walton EW: Giant-cell granuloma of the respiratory
2.
3.
4.
5.
tract (Wegener’s granulomatosis). Br Med J 2:265-270,
1958
Aldo MA, Benson MD, Comerford FR, et al: Treatment
of Wegener’s granulomatosis with immunosuppressive
agents. Arch Intern Med 126:298-305, 1970
Novak SN, Pearson CM: Cyclophosphamide therapy in
Wegener’s granulomatosis. N Engl J Med 284:938-942,
1971
Wolff SM, Fauci AS, Horn RG, et al: Wegener’s granulomatosis. Ann Intern Med 81:513-525, 1974
Fauci AS, Wolff SM: Wegener’s granulomatosis: studies
in eighteen patients and a review of the literature. Medicine 52:535-561, 1973
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