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Plasmapheresis and immunosuppressive drug therapy in scleroderma.

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1128
PLASMAPHERESIS AND IMMUNOSUPPRESSIVE
DRUG THERAPY IN SCLERODERMA
PETER C. DAU, M. B. KAHALEH, and RICHARD W. SAGEBIEL
In an uncontrolled clinical trial, plasmapheresis
combined with prednisone and cyclophosphamide therapy produced clinical improvement in 14 of 15 scleroderma patients with varying degrees of skin and internal
organ involvement. All improved patients showed a
gradual loosening of hidebound skin, relaxation of contractures, and healing of cutaneous ulcers, when present. Severe gastrointestinal symptoms were ameliorated
in 4 patients, severe polymyositis was largely reversed in
2 patients, and pulmonary and cardiac function was improved in others. After initial improvement, however, 2
patients died during the period of study and another
withdrew unimproved. Antinuclear antibody (ANA) titers declined relatively more than total IgG levels with
plasmapheresis in 6 of the 9 patients who had elevated
titers. Increased levels of endothelial cell cytotoxic activity found in 11 of the 15 patients were significantly reduced by plasmapheresis. Elevated levels of circulating
immune complexes were found in only 4 of the 15 patients. Skin biopsies from adjacent sites taken before
and after plasmapheresis in 10 patients all showed less
From the Paul M.Aggeler Memorial Laboratory, Children’s
Hospital of San Francisco, the Departments of Medicine and Pathology, School of Medicine, University of California, San Francisco, and
the Division of Rheumatology and Immunology, Department of
Medicine, Medical University of South Carolina.
Supported by the Zimmerman Fund, the Muscular Dystrophy Association, National Institutes of Health Grant AM 20571.
the RGK Foundation, and the Charlotte and Sidney Lifschultz Foundation.
Peter C. Dau, MD:Children’s Hospital of San Francisco; M.
B. Kahaleh, MD: Medical University of South Carolina; Richard W.
Sagebiel, MD: University of California.
Address reprint requests to Dr. Peter Dau at Children’s Hospital of San Francisco, Paul M.Aggeler Memorial Laboratory, P. 0.
Box 3805, San Francisco, CA 941 19.
Submitted for publication May 27, 1980; accepted in revised
form March 26, 1981.
Arthritis and Rheumatism, Vol. 24, No. 9 (September 1981)
swollen dermal collagen with increased ground substance between collagen bundles in the second biopsy.
Although the effects of plasmapheresis cannot be dissociated from those of the immunosuppressive drug
therapy, our results suggest that plasmapheresis combined with immunosuppressive drug therapy may find a
place in the management of patients with moderate to
severe scleroderma. This study implicates circulating
factors in the pathogenesis of the disease.
Scleroderma is a generalized, multisystem disease in which characteristic vascular alterations are seen
together with severe fibrosis of skin, synovium, and certain internal organs, chiefly the intestinal tract, lung,
heart, and kidney (1). An autoimmune etiology has
been suggested by: 1) the clinical association with other
diseases of presumed autoimmune etiology (l), 2) the
presence of antinuclear antibodies, which may be of a
specificity unique to scleroderma (2), in 60% of patients
(3), 3) the occasional occurrence of inflammatory infiltration of affected organs (4), and 4) the Occurrence of a
scleroderma-like clinical syndrome in chronic graft versus host disease (5,6).
The presence of Raynaud’s phenomenon in 95%
of scleroderma patients called attention to a possible
vascular pathogenesis of the disease (7). Raynaud’s phenomenon in scleroderma is probably due in part to intimal thickening of the digital arteries (8,9) and is partially reversible with plasmapheresis (10- 12).
Vascular lesions in scleroderma could possibly
be caused by the deposition of immune complexes (1 317), the action of autoantibodies (18), or cytotoxic factors (19).
Therapy in scleroderma has been generally discouraging, though corticosteroids may relieve myositis
PLASMAPHERESIS IN SCLERODERMA
in some patients (I), and others may respond to cytotoxic immunosuppressive drug therapy (20-22). The
present study describes the treatment of 15 scleroderma
patients modeled on the treatment of myasthenia gravis,
where a synergism between plasmapheresis and immunosuppressive drug therapy has been found to produce
stable clinical improvement associated with the sustained lowering of pathogenic autoantibody titers (23).
PATIENTS AND METHODS
Fifteen scleroderma patients (Table 1) were treated.
All referred patients were accepted for treatment, except for
those whose sole manifestation of the disease was uncomplicated, indolent sclerodactyly or acrosclerosis. Patients were
classified according to Barnett (24) as follows: Type I is sclerodactyly with minimal internal involvement and normal life
expectancy. Type I1 is acrosclerotic and slowly progressive; it
may involve the hands, arms, face, neck, upper chest, feet, and
ankles. Internal involvement is only gradual, and life expectancy is usually greater than 10 years. Patients with Type 111
scleroderma have diffuse skin involvement from the onset.
The disease is rapidly progressive and the 5-year mortality,
usually from internal involvement, approaches 909'.
Plasmapheresis was carried out on an outpatient basis
with an Aminco Celltrifuge as previously described (25). A
volume of plasma equivalent to 5-6% of the body weight was
exchanged weekly for up to 10 exchanges, and thereafter at I to 4-week intervals as required to control the patient's symptoms. One-half or more of the replacement fluids consisted of
purified protein fraction; the amount was adjusted to try to
maintain a total protein of at least 6 gm/dl at the onset of
each plasmapheresis. The remainder of the replacement fluids
were either gentran-75 in normal saline or lactated Ringer's
solution. All replacement fluids contained physiologic concentrations of K', Ca2+,and Mg2+. Immune serum globulin, 9.9
gm, was injected intramuscularly in divided doses after each
1129
plasmapheresis, or modified immune serum globulin (MISG,
Cutter Laboratories, Berkeley, CA), 5 gm per liter of plasma
exchanged, was administered intravenously after each exchange.
Patients initially received prednisone, 50 mg daily
beginning with the first plasmapheresis; those who were already receiving prednisone were maintained at their prior
dosage (Table 1). Patients were later tapered to alternate-day
prednisone as their condition permitted. Patient 9 refused
prednisone because of previous side effects with prednisone
therapy. Except for patient 7, who was already taking azathioprine 3.4 mg/kg of body weight/day, and patient 4 who was
initially treated with azathioprine 3.0 mg/kg of body weight/
day, patients also received cyclophosphamide from the time
of the first plasmapheresis, 2.5 mg per kg of body weight per
day. Patients 4 and 7 were switched to cyclophosphamide after 2--3months of plasmapheresis. After 2 to 3 months of combined therapy, patients 5, 6, and 10 were switched from cyclophospharnide to chlorambucil, 0.12 mg/kg body weight/day,
because they had developed leukopenia or cystitis. The patients continued pharmacologic immunosuppression after
plasmapheresis was hished.
The extent and degree of tight, hide-bound skin was
assessed by manually trying to move it or pinch it up from the
subcutaneous tissue. Contractures were measured with a goniometer.
Serum samples were drawn just before each plasmapheresis, divided into aliquots, and stored at -76OC. The
presence of immune complexes prior to plasmapheresis was
sought using the solid (26) and liquid (27) phase C l q assays.
ANA was measured by indirect immunofluorescence using
mouse connective tissue fibroblasts as substrate and antibodies to extractable nuclear antigen (ENA) by hemagglutination. Microcytotoxicity for cultured human endothelial cells
was measured before the first, fourth, and last plasmapheresis,
as previously described (19). Control sera were obtained from
10 patients with polymyositis or dermatomyositis who underwent a similar course of plasmaphereses and immunosuppressive drug therapy, Adjacent punch skin biopsies from
Table 1. Clinical features of patients with scleroderma
Patient
no.
Sex/age,
Y rs
1
2
3
4
5
6
7
8
9
10
I1
12
13
14
15
F/37
F/30
F/45
F/67
F/30
F/49
F/3 1
F/4 1
F/33
F/6 1
F/3 1
M/33
F/35
M/65
F/21
Duration
of
disease,
Y rs
1.2
3
5
2
2
1.3
I .3
I
2.8
7
16
4
4
10
I .5
Type of
scIerodema*
Prednisone
dosage,
mg/day
I11
I11
111
I11
111
I11
I11
111
111
I1
50
30
50
50
50
50
60
11
50
50
15
30
50
I1
I1
I1
Linear
Roman numerals refer to the Barnett classification.
40
0
10
No.of
plasmapherphereses
36
41
33
52
26
26
34
17
6
19
9
33
10
4
4
Duration of
plasrnapherpheresis
therapy, mos
22
22
16
24
10
11
12
7
1
6
2.5
13
2.5
1
1
DAU ET AL
1130
the thigh or forearm were obtained before and after the series
of plasmaphereses in 10 patients (patients 1-6, 8, 10, 12, and
13), and paraffin sections were stained with hematoxylin and
eosh and with the Verhoff-Van Giesson elastic tissue stain.
The Alcian blue stain for ground substance and trichrome
stains for collagen were used where indicated. The paired
biopsies were read by one of us (RWS) without knowledge of
whether they were taken before or after plasmapheresis. Our
goal was to determine if recognizable differences between
paired samples were present.
RESULTS
During a plasmapheresis procedure, the only untoward reaction encountered was occasional mild hypotension, which was readily reversible by expanding the
plasma volume. Patient 14 died unexpectedly at home
with cardiac symptoms 2 weeks after his fourth plasmapheresis. Deterioration of cardiac function may have
been precipitated by the sodium load which he received
with the priming solution or in rinsing the blood bank
after each plasmapheresis. Autopsy showed diffuse cardiac fibrosis consistent with scleroderma. One patient
developed ascending pseudomonas lymphangitis from
an infected ulcer and later localized Herpes zosrer. Otherwise, no unusual or severe infections were seen. Antibiotics were used where indicated for infection and also
in patient 2 to control diarrhea. Cimetidine was used to
treat aymptomatic gastroesophageal reflux in 6 patients.
Nonsteroidal antiinflammatory drugs were not administered.
With the exception of patient 9, who left the
study early for personal reasons, all patients improved
during combined therapy. The manifest clinical changes
are listed in Table 2. Patients 1 through 4 with advanced
Type 111 scleroderma had severe skin involvement, disfiguring contractures (Figure 1A), and multiple ulcers
(Figure 2A). All of them had severe esophageal and
proximal small intestinal involvement leading to progressive inanition. Loosening of the hide-bound skin
and flexion contractures (Figure IB), healing of ulcers
(Figure 2B), and improved nutritional status occurred
during treatment. Patient 4 died of a drug overdose. The
3 surviving patients are currently being maintained in a
substantial clinical remission with plasmapheresis once
every 3 weeks. Cyclophosphamide has been continued,
and prednisone tapered to a mean dose of 40 mg on alternate days.
Patients 5 and 6 had less advanced Type 111
scleroderma. In patients 7 through 9 with Type 111
scleroderma, the major manifestation of the disease was
severe muscle weakness. Patient 7 is described in detail
in reference 28. Patients 10 through 14 had acrosclerotic
Type I1 sclerodema. Patient 11, who had the terminal
phalanges of 3 fingers amputated previously because of
intractable ulceration and gangrene, completely healed
a deep thumb ulcer of 3 months duration. A severe sensory neuropathy in patient 12 did not improve. Patient
15, with linear scleroderma, showed pronounced improvement with only 4 plasmaphereses. In general, patients treated earlier in the course of their illness showed
the most improvement.
Since this study was concluded, 10 more scleroderma patients have been treated with similar clinical
results, and further followup has been obtained on the
first 15 patients. Patients I , 2, 3, and 5 required 3, 5, 6,
and 6 more plasmaphereses, respectively, but their disease then became apparently inactive, and they have
now been without further plasmapheresis for 5 , 4, 2,
and 3 months. Patient 2 developed increased post-prandial distention and diarrhea, thought to be due to antibiotic-resistant bacterial colonization of the small intestine, and had to resume hyperalimentation after
having been off it for 25 months. Patient 8 had had 7
more plasmaphereses because of the recurrence of dysphagia and neck weakness when plasmapheresis was interrupted for more than 1 month. Patient 10 noted increasing dyspnea, sclerodactyly, and Raynaud’s
phenomenon 16 months after completing plasmapheresis and developed ulceration of 3 digits. Patients 6, 7,
1 1, 12, 13, and 15 have been stable for 14, 24, 20, 16, 23,
and 16 months, respectively, without further plasmapheresis. Patient 9 was lost to followup.
Pathology. Study of unlabeled, paired biopsies
taken before and after combined therapy from 10 patients showed abnormalities of dermal collagen in each
instance. Prior to plasmapheresis, the collagen was
swollen with fibrillar stranding, and the ground substance between collagen bundles was diminished (Figure 3A). Following treatment, the collagen bundles
were more distinctly set off from one another by the
ground substance and were less swollen and reticulated
(Figure 3B). Although our patients had diffuse skin involvement, there is no assurance that the site chosen or
plane of tissue section resulted in a followup biopsy
comparable to the pretreatment biopsy. Immunofluorescence staining of biopsy sections for immunoglobulin and complement was not carried out.
Immune complexes. With the solid phase Clq assay, the mean amount of circulating immune complexes
expressed as pg equivalents of heat aggregated IgG per
ml of serum for 16 normal controls was 2.1 f 2.95 (SD).
The highest amount of immune complexes in any
scleroderma patient was 5.7 pg equivalents (patient 9),
1131
PLASMAPHERESIS IN SCLERODERMA
Table 2. Changes in clinical parameters of scleroderma during plasmapheresis
-_
- --.
~
Patient
no.
I
Cutaneous
__
Loosening of skin, decrease in Raynaud's phenomenon
Healing of 17/ 17 ulcers
Loosening of contractures (90" to 28' at elbow)
Jaw opening increased from I .2 to 2.0 cm
New hair growth on forearms
2
Loosening of skin. decrease in Raynaud's phenomenon
[lealing of 5/5 ulcers
Loosening of contractures (88" to 37" at elbow)
Lessening of hyperpigmentation and depigmentation
New hair growth on hands and forearms
3
Loosening of skin and contractures
Healing of 3/3 ulcers
Jaw opening increased from 1.7 to 2.2 cm
New hair growth on forearms
4
Loosening of skin and contractures
Decrease in Raynaud's phenomenon
Healing of 5/5 ulcers
New hair growth on fc irms
Loosening of skin and ntractures
New hair growth on k 3s and forearms
Jaw opening increaser om 1.5 to 2.2 cm
Decrease in Raynaud's phenomenon
5
7
Loosening of skin and contractures
Jaw opening increased from 2.7 to 3.5 cm
Loosening of skin and contractures
8
Loosening of skin
9
10
No change
Loosening of skin
11
Loosening of skin
Healing of a single ulcer
Loosening of skin and contractures
Healing of 2/2 ulcers
Decrease in Raynaud's phenomenon
Loosening of skin and contractions
Decrease in Raynaud's phenomenon
New hair growth on forearms
Jaw opening increased from 1.8 to 3.0 cm
Decrease in Raynaud's phenomenon
Decrease in ulcer pain
Softening of indurated skin
Lessening of hyperpigmentation
6
12
13
14
15
Internal
- .~
-~
Decreased dysphagia and post-prandial distension
Body weight increased from 35 to 4 3 Kg
Barium swallow showed a return of normal
peristalsis in previously aperistaltic esophagus
Resolution of mild weakness (CPK
decreased from 466 to 25 IU/l, normal < SO)
Vital capacity increased from 38 to 63%of predicted
Improvement in severe post-prandial
distension and dysphagia
Cessation of' intravenous hyperalimentation
and resumption of oral feeding
Body weight increased from 43 to 56 Kg
Pulmonary vital and diffusion capacities
increased from 5 I and 7 1% to 7 I and 78%of predicted
Resolution of severe dysphagia and post-prandial
distension
Body weight increased from 5 I to 63 Kg
Vital capacity increased from 52 to 7 1% of predicted
Normalization of ECG (multiple PVCs. left
anterior fascicle block. ST-T abnormalities)
and palpitations
Less post-prandial emesis
Body weight increased from 42 to 46 Kg
Lessening ofjoint pain and stiffness
Decrease in dysphagia and post-prandial distension
Body weight increased from 42 to 46 Kg
Resolution of mild weakness (CPK decreased
from 168 to 22 IU/L)
Decrease in joint pain and stiffness
Cessation of low grade fever
Normalization of ECG (PACs, poor R-wave
progression, prominent U-waves)
Resolution of pleural effusion
No change
Resolution of severe weakness (bulbar and respiratory failure)
Body weight increased from 37 to 66 Kg
Resolution of severe weakness (bulbar and respiratory failure)
Body weight increased from 46 to 64 Kg
No change
Decrease in fatigueability and dyspnea
Inspiratory capacity increased from 56 to 66%of predicted
Lessening of pain in hands
Sensory neuropathy unchanged
Resolution of dysphagia and post-prandial distension
Died of scleroderma heart disease
No involvement
DAU ET AL
1132
and in 9 patients no immune complexes were detectable. With the liquid phase Clq assay, 5 normal controls had undetectable levels of circulating immune
complexes (less than 40 pg equivalents of heat aggregated IgG per ml of serum) and one had 40 pg equivalents. Eleven scleroderma patients had undectectable
levels of circulating immune complexes, but 4 had detectable low levels (patient 4 = 140, patient 8 = 100, patient 10 = 60, and patient 13 = 58 pg equivalents),
which were no longer present at the time of their last
plasmapheresis.
Antinuclear antibody. Nine patients had detectable ANA at the onset of combined therapy (Table 3);
the remainder were negative. Measured at the time of
their last plasmapheresis, the titers had fallen in 7 of the
9. In 6 cases, the fall was 2 dilutions or greater, which
was more than could be explained by the reduction in
total IgG levels (Table 3). The 2 patients whose titer did
not fall had only 3 plasmaphereses before the second
measurement. No patient in this series had antibody to
ENA in a titer greater than 1 :200 and, therefore, did
not have mixed connective tissue disease by the criteria
of Sharp et a1 (29).
Microcytotoxicity. The cytotoxicity of scleroderma sera from cultured human endothelial cells was
greatly increased over that of the inflammatory myopathy control group (Figure 4). Cytotoxicity of greater
than 18% is considered to be significant in our laboratory (19). Thus, 11 of 15 scleroderma patients, but none
of the 10 controls, manifested significantly elevated
A
cytotoxicity prior to plasmapheresis. It should be noted
that all of the initially negative scleroderma patients
(patients 5, 7, 13, and 15) manifested increased cytotoxicity in at least one of the other 2 determinations. In
all 11 of the initially positive scleroderma patients, the
cytotoxicity remained below the initial value during
plasmapheresis. The patient (patient 4) with the extraordinarily high cytotoxicity of 100?6 was one of the most
fulminating cases in this series.
Prior to combined therapy, the mean cytotoxicity
in the scleroderma group was 34 21% (SD), and the
4%.
mean cytotoxicity in the control group was 8
Measured at the time of the fourth and the last plasmaphereses, the mean cytotoxicity of the scleroderma
sera had fallen significantly to 19 & 10%and 20 f 8% (P
= 0.01, paired t-test), respectively, whereas cytotoxicity
in the control group remained unchanged. The mean
number of plasmaphereses in the scleroderma group
was 21 and in the control group was 18.
*
*
DISCUSSION
There was a palpable loosening of the skin and
measurable reduction in contractures when present in
14 of our 15 patients. A remarkable new hair growth occurred in the upper extremities of 6 patients. Skin
biopsies from 10 patients before plasmapheresis revealed swollen dermal collagen in each instance. Upon
biopsy after plasmapheresis, each patient appeared to
have less collagen swelling and increased ground sub-
B
Figure 1. A, Pre-plasmapheresis. Flexion contractwe at left elbow in patient I is 90'. B,Post-plasmapheresis. The contractwe is reduced 10 28".
PLASMAPHERESIS IN SCLERODERMA
1133
Table 3. Changes in ANA titers and IgG levels before first and last in a series of plasmaphereses
Before Erst
Patient
no.
ANA titer
1 : 1280
1:80
3
4
5
9
10
12
13
14
15
1 :640
1:640
I :2560
1 : 160
1 :2560
1:640
1 :40
Before last
-
IgG Level
(gm/liter)
12.6
9.6
14.8
16.1
8.2
14.2
19.3
14.2
14.2
ANA titer
I : 160
1 :20
1:20
1:20
1 :320
I :40
1 : 1280
1:640
1 :40
IgG level
(gm/liter)
No. of
plasmaphereses
1.4
8.6
10.5
10.1
7.8
9. I
12.6
11.6
8.6
29
52
22
6
19
33
10
4
4
stance between collagen bundles. Cutaneous ulcers
healed in all 6 patients who had an adequate course of
plasmapheresis, and there was a prompt decrease in
Raynaud’s phenomenon in all 7 patients in whom it had
been pronounced.
These preliminary c h i c a l observations suggest
that combined therapy with plasmapheresis, prednisone, and an alkylating agent produced decreased collagenosis and an improved blood supply to skin and
subcutaneous tissue in our scleroderma patients. However, the beneficial effects of combined therapy could
conceivably have been produced by prednisone and the
alkylating agent acting by themselves.
Four of our patients with Type I11 scleroderma
had a limited prognosis because of severe intestinal tract
involvement leading to progressive inanition. Plasmapheresis led to considerable symptomatic relief in
each case, and an ensuing average of a 9-Kg increase in
body weight. Although the introduction of corticosteroid therapy at the onset of plasmapheresis in 3 of these
4 patients could have stimulated increased appetite and
weight gain, other effects of the treatment also probably
contributed, since all 4 patients had less dysphagia and
postprandial distension. Two of our Type I11 patients
with severe corticosteroid-refractory muscle weakness,
including bulbar and respiratory failure, recovered almost normal strength. Both the clinical syndromes of
polymyositis with bulbar and respiratory failure (30)
and polymyositis with scleroderma (3 1,32) carry a poor
prognosis.
Eight of 9 of our Type I11 patients improved, and
the only fatality occurred from a drug overdose in an
improved but depressed patient with considerable residual disease after 2 years of treatment. Deterioration of
cardiac function may have been precipitated by plasmapheresis in one Type I1 patient with scleroderma
heart disease. Electrocardiographic evidence of cardiac
involvement together with cardiac symptoms resolved
in 2 other previously symptomatic patients.
The basis for the observed c h i c a l improvemen:
in our patients is unknown, but it could rest upon removal and decreased production of autoantibody, im-
A
B
Figure 2. A, Pre-plasmapheresis.Ulcers over the second and fifth proximal interphalangealjoints of both hands in patient 1. B, Post-plasmapheresis; the ulcers have healed.
DAU ET AL
1134
A
B
Figure 3. Skin biopsy from the anterior thigh of patient 1 A, pre-plasmapheresis and B, post-plasmapheresis. In A the collagen has a swollen,
fibrillar appearance, whereas in B the bundles are more compact and set off from one another by an increase in ground substance (magnification
x 350).
mune complexes, or a toxic factor damaging capillaries
and small arteries. Histologically, the most distinctive
vascular abnormality in scleroderma occurs in small arteries and arterioles; it consists of an intimal proliferation of cells arranged concentrically in a matrix of
ground substance (1) and may be triggered by endothelial injury (33-35). Evidence for endothelial injury in
scleroderma has been provided by electron microscopic
observations of endothelial swelling and capillary basement membrane thickening and reduplica?'/n (36,37),
as well as increased plasma levels of coagulation Factor
VIII-Von Willebrand factor antigen and von Willebrand factor-which may reflect in vivo endothelial
cell injury (38). We found elevated pre-treatment serum
levels of endothelial cell toxic factor in 11 of our 15 patients, which were significantly reduced by combined
therapy. However, the activity of endothelial cell cytotoxic factor became mildly abnormal during plasmapheresis in the 4 patients with initially normal levels,
although they were clinically improving with plasmapheresis. The action of cytotoxic factor is independent of complement, and on molecular sieve chromatography it is eluted after IgG (19). Preliminary studies
indicate that cytotoxic factor has protease activity
(Kahaleh MB:unpublished observation).
I00
*
k
0
80
70
X
0
I-
0
50
SCLERODERMA
CONTROL
V
I-
z
W
u
a
W
a
"
FIRST FOURTH LAST
FIRST
FOURTH LAST
SERA DRAWN BEFORE INDICATED PLASMAPHERESIS
Figure 4. Microcytotoxicity of scleroderma and control sera. The
mean percent cells containing dye in quadruplicate determinations is
given for each scleroderma and control patient from before the first,
fourth, and last plasmaphereses. The horizontal bars indicate the
mean value for each group of determinations. The dashed horizontal
line represents the upper limit of normal.
PLASMAPHERESIS IN SCLERODERMA
T h e presence of anti-capillary antibodies (18)
and t h e deposition of immunoglobulins and complement components in capillaries (13) and small arteries (14-17) in scleroderma tissues suggest an autoantib o d y or i m m u n e c o m p l e x - m e d i a t e d p a t h o g e n i c
mechanism. Pisko et a1 (39) detected circulating immune complexes with a fluorescent Raji cell assay in
44% of scleroderrna patients, which were also found
within polymorphonuclear leukocytes from scleroderma
patients by van d e Menden et a1 (40). However, immune
complexes were not detected by Chia et a1 (41) using
polyethylene glycol precipitation. In the present study,
elevated levels of immune complexes were not detected
with the solid phase Clq binding assay, but a small increase in circulating levels of immune complexes, which
disappeared during plasmapheresis, was detected in 4 of
the 15 patients, as determined by the liquid phase C l q
binding assay.
Plasmapheresis and immunosuppressive drug
therapy are effective in reducing autoantibody levels
and producing clinical improvement in diseases such as
Goodpasture’s syndrome (42) and myasthenia gravis
(23). A strong decline in ANA titers, relatively greater
than the decline in total IgG levels, was seen in the patients in this series who received extensive plasmapheresis, suggesting that the treatment applied might also
have been effective in reducing the titers of other as yet
undetected autoantibodies of pathogenic significance.
ACKNOWLEDGMENTS
The authors thank Paul Morand, Irene Osborn, and
Charlotte Yano for technical assistance, Marsha Ashwell, Ann
Cussen-Long, Noreen Moms, and Majorie Poole for plasmapheresis, and Mary Romaides for photography. Modified
immune serum globulin was a gift of Cutter Laboratories,
Berkeley, CA.
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