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High-dose immunoglobulin therapy as an immunomodulatory treatment of rheumatoid arthritis.

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1126
HIGH-DOSE IMMUNOGLOBULIN THERAPY AS AN
IMMUNOMODULATORY TREATMENT OF
RHEUMATOID ARTHRITIS
BRUNO TUMIATI, PATRIZIA CASOLI, MAURA VENEZIANI, and GABRIELE RINALDI
Objective. To investigate the efficacy of high-dose
intravenous immunoglobulin (IVIg) in the treatment of
refractory rheumatoid arthritis (RA).
Methods. Ten patients with active, severe RA
that was unresponsive to first- and second-line agents
were administered IVIg monthly, for 6 months.
Results. Following IVIg treatment, there was
significant improvement in both subjective and objective
parameters of disease activity in all 9 patients who
completed the protocol. This improvement was noted to
occur as early as after the second infusion of IVIg. After
discontinuation of the treatment, all patients had a
relapse of the disease within a few weeks.
Conclusion. Since the reduction in clinical activity paralleled a decrease in the CD4+CDw29 +:
CD4+CD45RA+ cell ratio, some of the therapeutic
benefits associated with IVIg may be due to a direct
influence on the CD4+CD45RA+ subset. Although the
possibility of carrying out further controlled studies
on a larger scale is limited by the high cost of the
From the Second Department of Medicine, Rheumatologic
Section, and the United Laboratories, Ospedale S. Maria Nuova,
Reggio Emilia, Italy.
Bruno Tumiati, MD: Assistant Professor, Second Department of Medicine, Rheumatologic Section; Patrizia Casoli, MD:
Assistant, Second Department of Medicine, Rheumatologic Section;
Maura Veneziani, MD: Assistant, Second Department of Medicine,
Rheumatologic Section; Gabriele Rinaldi, MD: Assistant, United
Laboratories.
Address reprint requests to Bruno Tumiati, MD, Second
Department of Medicine, Ospedale S. Maria Nuova, Wale Umberto
I, 50, 42100 Reggio Emilia, Italy.
Submitted for publication February 12, 1992; accepted in
revised form June 2, 1992.
Arthritis and Rheumatism, Vol. 35, No. 10 (October 1992)
treatment, IVIg appears to be an effective therapy for
refractory RA.
High-dose intravenous immunoglobulin (IVIg)
has become one of the most important therapies for
some acute autoimmune diseases, such as idiopathic
thrombocytopenic purpura (1) and Kawasaki disease
(2). Its effects in chronic autoimmune disorders are
less clear, although several reports have shown that
IVIg can be beneficial in various chronic autoimmune
diseases, including autoimmune neutropenia (3), recent-onset diabetes mellitus (4), systemic lupus
erythematosus (SLE) (5,6), bullous pemphigoid (7),
anticardiolipin antibody syndrome (S), myasthenia
gravis (9), polymyositis (10,l l ) , and juvenile chronic
arthritis (12,13). Studies of the use of IVIg in the
treatment of rheumatoid arthritis (RA) have shown
impressive results with respect to clinical findings, as
well as evidence of an immunomodulatory effect
(14-16).
The use of monoclonal antibodies (MAb) 2H4
(17) and 4B4 (18) has resulted in the separation of the
CD4+ T cell population into 2 maturation stages, the
“naive” (2H4+ ,CD45RA, suppressodinducer) subpopulation and the “memory” (4B4+ ,CDw29, helper/
inducer) subpopulation. The naive subpopulation has
been shown to be reduced in RA peripheral blood (19)
and synovial fluid (19,20).
In this report we describe the clinical results of
treatment with high doses of IVIg in 10 patients with
severe RA. The treatment led to a significant enhancement of the percentage of peripheral blood
CD4+CD45RA+ cells. We propose a heretofore un-
1127
IVIg TREATMENT IN RA
Table 1. Clinical features of the rheumatoid arthritis patients treated with intravenous immunoglobulin (IVIg) therapy
Patient
Agehex
1
2
3
4
5
6
7
8
9
10
68lF
67/M
621F
67iF
281F
66lF
52lF
511F
561F
29lF
Disease
duration
(years)
Rheumatoid
factor
Functional
class*
+
+
I1
-
I1
I11
I1
I1
6
3
1
8
5
6
I1
-
+
+
+
+
4
4
6
5
I1
111
111
I1
Previous therapy?
Steroid dosage
(mdday)
before IVIg
therapy
AUR
AUR, MTX
GST
MTX
AUR, GST, MTX
MTX
AUR
GST
AUR, GST, MTX
AUR, MTX
8
0
4
8
0
0
8
8
6
4
* See ref. 23.
f AUR = auranofin; MTX
=
methotrexate; GST
described immunoregulatory role of IVIg in the treatment of RA.
PATIENTS AND METHODS
Patients. Ten patients with active classic RA according to the criteria of the American College of Rheumatology
(formerly, the American Rheumatism Association) (21) were
selected for the trial. All patients had severe disease, fulfilling at least 4 of the following 5 criteria: 2 6 painful joints, 2 3
swollen joints, morning stiffness lasting longer than 45 minutes, Ritchie articular index (RAT) >15 (22), and Westergren
erythrocyte sedimentation rate (ESR) >30 mmlhour. Patients in functional class I or IV (23) were excluded. Patients
had to have undergone prior treatment with nonsteroidal
antiinflammatory drugs and either gold salts or methotrexate
(or both), which was unsuccessful because of toxicity or lack
of efficacy. Every eligible patient gave informed consent to
participate in the study. Characteristics of the patients are
shown in Table 1 .
IVIg treatment. Patients were hospitalized for the
IVIg treatment. A slow infusion of immunoglobulin (Sandoglobulin; Sandoz, Basel, Switzerland) at 400 mg/kg/day
was given for 5 days. Maintenance therapy consisted of 400
mg/kg of immunoglobulin once a month for 6 months.
Clinical and laboratory assessment. Clinical evaluation of patients was performed before each treatment. Patients were always examined in the morning, at the same
hour and by the same investigator. Clinical assessment
included assessment of pain by visual analog scale (VAS),
duration of morning stiffness, RAI (22), Lee functional index
(24), number of swollen joints, grip strength, reduction in the
dosage of steroids, and the global ratings of disease severity
by both the physician and the patient.
Blood and urine samples were obtained at each visit.
Laboratory studies consisted of testing for the ESR, C-reactive protein (CRP) level, hemoglobin level, platelet count,
white blood cell count, blood urea nitrogen level, levels of
creatinine, uric acid, bilirubin, transaminases, electrolytes,
=
gold sodium thiomalate.
C3 and C4, serum IgG, IgA, and IgM, and routine urinalysis.
Before and 3 months and 6 months after initiation of IVIg
treatment, testing for rheumatoid factor (RF) by latex fixation (NA Latex; Behringwerke, Marburg, Germany) and for
antinuclear antibodies (ANA) by irnmunofluorescence (Fluoroset; Ortho Diagnostic, Raritan, NJ) was performed.
Analysis of lymphocyte subpopulations. Lymphocyte
subpopulations in peripheral blood were determined
monthly. The analysis was carried out on mononuclear cells
isolated, by MLS centrifugation (1.077 gm/ml; Eurobio, Les
Ulis Cedex, France), from heparinized blood samples. The
loss of subsets of mononuclear cells could not be determined
from this procedure. Lymphocyte subpopulations were evaluated using MAb conjugated with fluorescein isothiocyanate
(FITC) or with a phycoerythrin derivative (RD-1; Coulter,
Hialeah, FL) and an EPICS C flow cytometer (Coulter). The
MAb used in this study are shown in Table 2.
The lymphoid population was gated at 90” forward
light scatter. For each MAb, 10,000 cells were analyzed. The
day-to-day stability of the instrument (laser output optics,
fluidics, and photomultiplier tube function) was monitored
Table 2.
Monoclonal antibodies (MAb) used in the study
Clone MAb*
Cluster
designation
T11
CD2
T3
T4
T8
CD3
CD4
CD8
CD20
CD29
CD45RA
CD25
B1
4B4
2H4
IL-2RI
Antigen
expressiont
E-rosette T cells
Thymocytes
Some N K cells
T cells
T helperlinducer cells
T cytotoxichppressor cells
Pan-B cells
CD4 cells, “memory”
CD4 cells, “naive”
Activated T and B cells and
monocytes (IL-2R)
* From Coulter (Hialeah, FL).
t NK
= natural killer; 1L-2R = interleukin-2 receptors.
1128
20
15
X
w
TUMIATI ET AL
-
4
-
Ritchie index
-
15
-
e,
’
D
-
D
20
.-C
.-C
10-3
Lee index
-
L
U
._
c
2
.
5 -
0’
0’
1
’
1
1
.
7
’
7
0
2
4
6
8
-
0
2
4
months
I
I
IVlG lherapy
I
follow-up
I
6
8
months
I
IVlG therapy
J
follow-up
Figure I. Changes in the Ritchie articular index and the Lee functional index during intravenous immunoglobulin (IVIG) therapy and
during the followup period. Values are the mean and SEM. * = P <
0.01 versus month 0.
using fluorescent beads (Immunobrite; Coulter). In 1-color
analysis, cells were scored as positive or negative according
to their fluorescence with reference to that of negative (not
stained) samples. Positive cells were expressed as a percentage of the total cells counted. In 2-color analysis, a bivariate
scatter plot (Quad Stat program; Coulter) showed the distribution of the cells recognized by each antibody in each of the
4 quadrants.
Negative cells were defined using appropriate RD-1and FITC-conjugated mouse immunoglobulin isotypes, and
horizontal and vertical cursors placed at least 95% of cells in
the left lower quadrant. The stained cells, expressed as a
percentage of the total cells counted, were recorded using
fixed settings established by the isotype controls, except in
the case of antibody pairs, in which cursors are set based on
operator judgment. We also calculated the T cell ratio
(CD4:CDS) and the CD4+CDw29+:CD4+CD45RA+ cell
ratio.
Statistical analysis. Clinical and immunologic data are
expressed as the mean and SEM. Normally distributed
variables were evaluated by t-test; others were evaluated by
the Wilcoxon matched pairs signed rank test.
RESULTS
Clinical findings. Nine patients completed the
6-month course of therapy with IVIg. The treatment
resulted in an improvement in both the subjective and
the objective parameters of disease activity. From
week 4, a statistically significant improvement was
seen in the RAI, the functional index (Figure I), the
number of swollen joints, and the pain VAS, but not in
grip strength. Morning stiffness decreased by 250% in
all patients (Table 3). This improvement was noted to
occur as early as after the second infusion of IVIg. Of
the 7 patients initially treated with steroids, this drug
was discontinued in 3. The dosage was reduced in
another 3 and was unchanged in the remaining patient.
Clinical followup. Followup examinations were
performed every 4 weeks for a minimum of 3 months
after the last IVIg treatment, or until RA symptoms
reappeared. In 6 patients, clinical improvement was
sustained for 8 weeks. After 12 weeks, clear remission
persisted in only I patient, and this improvement was
sustained for more than 6 months.
Treatment tolerability. No patient had adverse
effects at the site of IVIg infusion. Two patients had
mild nausea, dizziness, and hypotension during infusion. One patient was withdrawn from the study after
4 months of treatment, due to noncompliance.
Laboratory data. A statistically significant decrease in the mean CRP level was observed beginning
at week 4, while the ESR showed a mild, but not
significant, reduction (Figure 2). No changes were
observed in the R F or ANA titers or in C3 or C4 levels.
Immunoglobulin levels were unchanged before each
treatment period. Other laboratory parameters studied
were not affected; in particular, no change in creatinine levels was noted.
Immunologic data. Peripheral blood mononuclear cells were characterized in the patients with
active RA and in 30 normal subjects. Although the
number of B cells and interleukin-2 receptor (IL-2R)positive cells was similar in the 2 groups, a significant
reduction was found in the percentage and in the
number of T cells in the RA group (mean C SEM
1,461.7 t 45.8 [70.1 2 2.2%], versus 1,703.8 k 28.0
179.1 & 1.3%] in the controls; P < 0.05). This was
predominantly due to a mild, selective reduction in the
CD8+ subset (400.3 c 43.7 [19.2 2 2.1%], versus
544.9 f 53.8 [25.3 k 2.5%] in controls; P < 0.05),
resulting in a nonsignificant increase in the CD4+ :
CD8+ cell ratio.
The CD4+ subpopulation was analyzed to determine the percentage cells of the naive (CD45RA+)
and memory (CDw29+) subsets. The results indicated
that the number of cells expressing CD4+CD45RA+
markers was significantly decreased in the peripheral
blood of RA patients compared with controls (316.9 k
41.7 [15.2 t 2.0%] versus 570.8 k 43.0 [26.5 k 2.0%];
P < 0.01). The ratio of CD4+CDw29+:CD4+
CD45RA+ cells was thus increased in RA patients
compared with healthy subjects (1.69 ? 0.57 versus
1.02 0.1; P < 0.01). The number of CD4+CDw29+
cells was similar in the 2 groups. Following IVIg
*
15
60
45
90
120
90
10
10
30
30
0
30
10
5
10
3
2
2
4
8
5
4
1
5
1
Month
0
4
2
2
2
0
4
4
0
1
1
Month
3
0
0
0
0
2
0
1
0
0
-
Month
6
No. of
swollen joints
2
2
6
5
3
1
4
1
0
Month
9
45
50
58
64
65
50
63
40
80
70
Month
0
20
20
40
50
30
70
53
71
50
60
Month
3
20
30
25
35
28
25
30
30
30
Month
6
Pain
(0-100-mm VAS)
40
50
40
58
70
58
30
50
30
Month
9
1
2
2
2
2
2
2
1
2
2
Month
1
2
2
2
2
3
3
3
2
2
2
Month
3
3
3
3
3
3
3
2
2
2
-
Month
6
Physician global
evaluation?
0
2
2
2
2
2
2
2
1
2
Month
1
2
1
1
2
2
3
2
3
2
2
Month
3
3
3
3
3
3
2
3
2
3
Month
6
Patient global
evaluation?
assessment of patient's condition compared with baseline, where 0 = no improvement, 1 = minimal improvement, 2 = moderate improvement,
and 3 = good improvement.
$ Patient was withdrawn from the study prior to month 6, due to noncompliance.
t Physician's or patient's
90
90
60
Month
9
Month
6
= visual analog scale.
30
15
30
60
30
30
60
30
30
5
240
90
60
60
120
180
90
60
120
120
I$
2
3
4
5
6
7
8
9
10
* VAS
Month
3
Month
0
Morning stiffness
(minutes)
Effects of intravenous immunoglobulin treatment on clinical parameters in patients with rheumatoid arthritis*
Patient
Table 3.
1130
TUMIATI ET AL
IVlG therapy
h
80
-
70
-
i/
i,
follow-up
r 7
-6
E
E
- 5 0
v
%;
Study of the CDw29+ and CD45RA+ CD4
subpopulations showed a statistically significant increase in the number of CD45RA-t cells, with no
change in the number of CDw29+ cells, after IVIg
treatment (Figure 3). Consequently, as early as after
the second infusion, a notable decrease to the normal range was observed in the CD4+CDw29+:
CD4+CD45RA+ ratio. These immunologic data
showed a strict correlation with the clinical improvement. Discontinuation of treatment was followed by a
relapse of RA activity and by a progressive increase of
the CD4+CDw29+:CD4+CD45RA+ ratio to the
value observed before initiation of IVIg therapy (Figure 4).
i,
-% T
-
60-
3.
- 4%
2
!
c
G5
w
vr
50
40
-
-3
-
-2
I
I
I
I
I
I
0
1
2
3
4
5
I
I
I
I
6
7
8
9
time ( m o n t h s )
Figure 2. Changes in the erythrocyte sedimentation rate (ESR) and
the C-reactive protein (CRP) level during intravenous immunoglobulin (IVIG) therapy and during the followup period. Values are the
mean and SEM. * = P < 0.01 versus month 0.
DISCUSSION
IVIg induced a clear-cut clinical improvement
in 9 of 10 rheumatoid arthritis patients. The treatment
was well tolerated, and no patient withdrew because of
side effects. The toxicity of high-dose IVIg was minimal. It included mild nausea, dizziness, skin rash, and
hypotension during the infusion. The results of our
study confirm the positive effects of IVIg treatment in
RA patients demonstrated in previous trials (14-16)
and show that the treatment exerts a very rapid and
therapy, a nonsignificant increase in the total number
of lymphocytes, in the total number of T cells (CD3+),
in the number of helper (CD4+) and suppressor
(CDS+) cells, and in the CD4+:CD8+ ratio was
evident. No change in the number of B lymphocytes or
of IL-2R-positive lymphocytes was observed.
IVlG therapy
follow-up
I
V
V
1
501
T
T
6o
T
I
I
I
I
I
I
0
1
2
3
4
5
0: CD45RA+ m: CD29+
-
I
6
I
7
8
9
time (months)
: CD4
Figure 3. Total CD4+ cell population and CD4+CD45RA+ and CD4+CD29+ cell subsets (percentages) in
normal subjects, and in rheumatoid arthritis patients during intravenous immunoglobulin (IVIG) therapy and
during the followup period. Values are the mean and SEM. * = P < 0.01 versus month 0.
1131
IVIg TREATMENT IN RA
n.s.
I
P
<
I
0.01
1
P < 0.01
m
0
0
normal
range
i
3
I
IVlG therapy
1
6
9
AI
AI
months
follow-up
Figure 4. Changes in the CD4+CD29+:CD4+CD45RA+ cell ratio
in individual rheumatoid arthritis patients during intravenous immunoglobulin (IVIG) therapy and during the followup period. Horizontal lines are means. n.s. = not significant.
pronounced effect on the inflammatory signs and
symptoms of RA. Within 4 weeks of the start of
therapy, the RAI, Lee index, duration of morning
stiffness, required dosage of steroid, and CRP, as well
as the subjective ratings by the patient and physician,
were significantly improved, and this improvement
was maintained throughout the duration of treatment.
The fact that within 12 weeks after discontinuation of
IVIg therapy a relapse of symptoms was observed in
most patients seems to indicate that the mode of action
is more antiinflammatory than disease modifying.
The mechanism of the action of IVIg in autoimmune disorders remains unclear. Its effects have
been proposed to be related to an Fc-mediated blockage on cells of the reticuloendothelial system (25),
interference with the binding of immune complexes
(26), a decrease of the activation of monocytes and
macrophages (27), and possible modulation of the
synthesis and/or the release of proinflammatory and
immunoregulatory cytokines (28). Gamma globulins
might also exert their effects by providing a source of
antiidiotypic antibodies, which can regulate the immune response at both the B cell and the T cell levels
(29,30). In addition, they can induce an inhibitory
effect on immunoglobulin production by modifying the
T cell subset or enhancing T suppressor activity
(31,32). In the present study, 2-color flow cytometric
analysis of the CD4+ subset showed a possible, heretofore undescribed, immunoregulatory role for IVIg
treatment.
The use of monoclonal MAb 2H4 and 4B4 has
resulted in the separation of the CD4+ T cell population into 2 subsets: the CD4SRA+ and the CDw29+
subpopulations. The CD45RA+ subset has been
shown to be reduced in RA peripheral blood and, to a
greater extent, in RA synovial fluid (19,20). The CD4+
CDw29+:CD4+CD45RA+ lymphocyte ratio is higher
in the blood of patients with RA and other autoimmune
diseases, compared with that of healthy controls,
because of a deficiency in the CD4-tCD45RA-t subset. This reduction has been associated with kidney
disease and with disease severity in SLE (19,33).
In the present study, there was a relative increase in the total number of lymphocytes and in the
helper and suppressor cell populations after IVIg
therapy, but analysis of the helper population showed
a statistically significant increase in only the CD4+
CD45RA+ subset (Figure 3). The CD4+CDw29+:
CD4+CD45RA+ cell ratio showed a significant reduction with IVIg treatment, with values reaching the
normal range for healthy controls (Figure 4).
Since a reduction in the RA disease activity was
seen in parallel with the decrease in the CD4+
CDw29+:CD4+CD45RA+ ratio, some of the therapeutic effects associated with IVIg may be due to a
direct influence on the CD4+CD45RA+ subset. Indeed, an increase in synovial CD4+CD45RA+ cells
has been demonstrated in a small group of patients
treated with slow-acting antirheumatic drugs (34).
Thus far, however, in these cases as in our own, it has
not been possible to establish whether this increase is
responsible for, or is only a marker for, the clinical
improvement (34).
In conclusion, our data indicate that IVIg therapy is effective in the treatment of refractory RA. The
only drawback of this therapy is its cost, and this limits
the possibility of our carrying out further controlled
studies on a larger scale. We believe high-dose IVIg
will find its place as a treatment in well-selected
patients with RA.
1132
TUMIATI ET AL
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