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Recombinant human interleukin-1 receptor type I in the treatment of patients with active rheumatoid arthritis.

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ARTHRITIS & RHEUMATISM
Vol. 39, No. 2, February 1996, pp 257-265
0 I%,
American College of Rheumatology
257
RECOMBINANT HUMAN INTERLEUKIN-1 RECEPTOR TYPE I IN THE
TREATMENT OF PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS
BARBARA E. DREVLOW, ROSA LOVIS, MARY ANN HAAG, JAMES M. SINACORE, CINDY JACOBS,
CONSUELO BLOSCHE, ALAN LANDAY, LARRY W. MORELAND, and RICHARD M. POPE
Objective. To determine the safety and efficacy of
recombinant soluble human interleukin-1 receptor type
I (rHuIL-1RI) administered subcutaneously in patients
with active rheumatoid arthritis (RA).
Methods. Twenty-three patients with active RA
(>5 swollen joints) were enrolled into a randomized,
double-blind, 2-center study. Patients received subcutaneous doses of rHuIL-1RI or placebo for 28 consecutive
days. Patients were treated with 125,250,500, or 1,OOO
pg/mz/day of rHuIL-1RI. Physical examinations and
laboratory assessments were performed at baseline (day
l), and 8, 15, 22, 29, 43, and 57 days after the start of
the study. Analysis of peripheral blood by flow cytometry was performed on days 1 and 29 to determine the
effects of rHuIL-1RI on the distribution and phenotypic
characteristics of circulating inflammatory cells.
Results. Four of 8 patients who received rHuIL1RI at 1,000 Crglm’lday demonstrated improvement in
at least 1 of 8 individual measures of disease activity;
however, only 1of these 4 patients experienced clinically
relevant improvement as defined by predetermined criteria. None of the patients treated with smaller doses of
rHuIL-1R1, and none of the placebo-treated control
patients, experienced any improvement as defined by
.
.-
Supported in part by Immunex Corporation, by an NIH
Multipurpose Arthritis and Musculoskeletal Diseases Center grant
(AR-30692), and by the Veterans Administration Medical Research
Service.
Barbara E. Drevlow, MD, Rosa Lovis, BS, Mary Ann
Haag, BS, James M. Sinacore, PhD, Richard M. Pope, MD:
Northwestern University and the Veterans Affairs Lakeside Medical Center, Chicago, Illinois; Cindy Jacobs, MD, PhD, Consuelo
Blosche, MD: Immunex Corporation, Seattle, Washington; Alan
Landay, PhD: Rush Medical Center, Chicago, Illinois; Larry W.
Moreland, MD: The University of Alabama at Birmingham, Birmingham, Alabama.
Address reprint requests to Richard M. Pope, MD, Northwestern University School of Medicine, Division of Arthritis and
Connective Tissue Diseases, 303 E. Chicago Avenue, Chicago, IL
60611.
Submitted for publication May 12, 1995; accepted in revised
form September 1, 1995.
the predetermined criteria. Monocyte cell surface IL-1a
was significantly reduced following treatment with
rHuIL-1RI at each dosage. Administration of rHuIL1RI was stopped prematurely because of dose-limiting
rashes in 2 patients treated with 1,000 pg/mz/day. No
other adverse events prevented completion of the study.
Conclusion. Only 1patient, who was treated with
the highest concentration of rHuIL-1RI employed (1,000
pg/mZ/day), demonstrated clinically relevant improvement in this phase 1study on this small group of patients
with active RA. Dose-limiting toxicity was also observed
in 2 patients treated with this highest concentration of
rHuIL-1RI. Treatment with rHuIL-1RI did result in a
reduction of monocyte cell surface IL-la, which indicates that the dosages of rHuIL-1RI employed were
functional.
Evidence suggests that interleukin-1 (IL-1) may
be important in mediating the joint damage observed in
patients with rheumatoid arthritis (RA). IL-1 is present
in the synovial tissue of patients with RA, and the
concentration of circulating IL-1 has been shown to
correlate with disease activity (1-4). Cytokines such as
IL-1 bind to specific membrane proteins or receptors
that are composed of an extracellular cytokinebinding, membrane-spanning domain and an intracellular signal-transducing domain (5-7). Both IL-1 a and
IL-1 p bind to and mediate their biologic activity
through 2 specific membrane receptors, designated
type I and type I1 (8). Soluble forms of both receptors
have been detected in human body fluids and the
supernatants of experimental cell cultures (9-1 I). Recombinant comlementary DNA encoding for the human type I IL-1 receptor sequence was isolated and
truncated to produce a soluble form of the extracellular portion of the receptor (rHuIL-lRI) (12). Quantitative binding studies showed that the affinity of rHuIL1RI was equivalent to the full-length membrane-bound
IL-IRI (12).
DREVLOW ET AL
258
Use of this soluble receptor has been proposed
as a means of competitive binding to IL-1, to suppress
IL- 1-mediated inflammation (13). Soluble rHuIL- 1RI
suppressed inflammation in several animal models,
including adjuvant-induced arthritis and experimental
autoimmune encephalomyelitis, and it prolonged allogenic mouse heart graft survival (14-17).
In the present study, escalating doses of rHuILIRI (125, 250, 500, or 1,000 &m2/day) or placebo
were administered subcutaneously for 28 consecutive
days to patients with active RA to determine its safety
and efficacy in modifying joint inflammation. At the
highest dosage employed, marginal clinical benefit and
treatment-limiting toxicity were observed.
PATIENTS AND METHODS
Patients, Twenty-three patients fulfilling the American College of Rheumatology (formerly, the American Rheumatism Association) 1987 criteria for the classification of RA
(18) were entered into a phase I, double-blind, randomized,
2-center study. Eligibility criteria included failure of at least
1 disease-modifying antirheumatic drug (DMARD), active
RA (defined by swelling of at least 5 joints), Steinbrocker’s
functional class 1-111 (19), use of 510 mg of prednisone or its
equivalent, use of <125% of recommended dosage of nonsteroidal antiinflammatory drugs (NSAIDs), and age between 18 and 75 years.
Pregnant or lactating women were not included.
Patients were also excluded if they had signs or symptoms of
active infection or significant concurrent medical or psychiatric disease, other concurrent forms of arthritis, intraarticular steroid injection within the previous 4 weeks, blood
chemistry values >20% above the upper limit of normal, a
white blood cell count <4,000 cells/mm3, a granulocyte
count <2,OOO cells/mm3, and a platelet count <150,000
cells/mm3.
Women of child-bearing age were required to use an
adequate method of contraception. All but 1 patient (placebo
group) had received 1 or more DMARDs prior to entering
the study. The mean number of DMARDs prior to the study
was 2.6. Five patients had not received methotrexate (1
placebo and 4 rHuIL-lRI [l at 125, 1 at 250, and 2 at 1,OOO
pg/m*/day]). If patients were receiving DMARDs, the treatment was discontinued prior to enrollment: 3 weeks for
methotrexate and 6 weeks for the other DMARDs.
At study entry, 4 patients (3 rHuIL-1RI and 1 placebo) were assigned to each dosage level. Each patient
self-administered rHuIL-1RI or diluent (placebo) subcutaneously for 28 consecutive days, followed by a 28-day observation period. Additional patients were recruited for those
patients who did not complete day 29 of the trial and for the
highest dosage level. Prior to escalation to the next dosage
level, 4 patients (3 rHuIL-1RI and 1 placebo) successfully
completed a dosage level without evidence of dose-limiting
toxicity, and the sera of treated patients were examined to
exclude the development of circulating antibodies to rHuIL-
IRI. Four dosage levels of rHuIL-1RI were studied: 125,
250, 500, and 1,OOO pg/m2/day.
Assessment. Clinical assessments were made at baseline (day l), and on days 8,15,22,29,43, and 57. The safety
assessment included a physical examination, symptom/
toxicity assessment, hematology and chemistry profile, urinalysis, and rHuIL- 1RI antibody levels. Improvement
(240%) in the total swollen joint score (sum of each swollen
joint multiplied by the severity of its swelling, on a scale of
1-3) was the primary measure of clinical efficacy for this
study. Secondary criteria included the number of tender
joints or joints painful on motion, patient and physician
global assessments (on a 1-10 scale, 1 being the best),
modified Health Assessment Questionnaire (HAQ), 50-foot
walk time (in seconds), morning stiffness (in hours), and
Westergren erythrocyte sedimentation rate (ESR).
Criteria for a clinically relevant response were defined prior to initiating the study. The criteria were a 40%
decrease in the swollen joint score by day 29 or 2 3 of the
following: a 40% decrease in the number of tender joints,
30% decrease in the ESR, 40% reduction in the duration of
morning stiffness, 30% decrease in 50-foot walk time, a
2-integer (out of 10) improvement in patient or physician
global assessment, or a 20% improvement in modified HAQ.
Flow cytometry. Two-color flow cytometry of peripheral blood was performed, as previously described (20),
prior to initiation of rHuIL-lRI and on day 29. Peripheral
blood mononuclear cells (PBMC) were isolated by Hypaque
gradient centrifugation. Mononuclear cells were incubated
with fluorescein isothiocyanate (FITCtlabeled anti-CD3 or
anti-CD14 plus phycoerythrin-labeled anti-CD25 (IL-2R),
anti-CD54 (intercellular adhesion molecule type l), antiCD69, and anti-HLA-DR (all from Becton Dickinson, Palo
Alto, CA). Appropriate 2-color staining, employing irrelevant monoclonal antibodies, was used as the control for each
patient.
Single-color immunofluorescence staining with Fluorokine phycoerythrin-labeled recombinant human tumor necrosis factor a (TNFa) and IL-1p was performed by gating
on the monocyte population by forward angle and side
scatter to assess functional TNF and IL-1R (reagents kindly
donated by R&D Corp., Minneapolis, MN). Phycoerythrinlabeled streptavidin served as the control. Monocyte cell
Table 1. Demographics of patients with rheumatoid arthritis
treated with recombinant human interleukin-1 receptor type I
(rHuIL-1R1)
Feature
Sex
Female
Male
Race
Caucasian
Black
Hispanic
Asian
Mean age, years
Rheumatoid factor positive
rHuIL- 1RI,
no. (%)
Placebo,
no. (%)
17 (89)
2 (11)
2 (50)
2 (50)
14 (74)
2 (10.5)
4 (100)
2 (10.5)
1 (5)
54.4
17 (89)
49.8
4 (100)
259
rHuIL-1RI TREATMENT FOR ACTIVE RA
40
-
M
-
30
-
20
-
>
0
401
e
.r(
c
(
a,
3
v)
2oi
1 wopg
I
I
0
29
0
29
Day
Day
-c
50
-
40
-
30
-
20
-
1
bn
.m
3
a,
3
v)
1"
0
29
I
I
0
29
Day
Day
M
c
._
c
4
(
Y
v)
placebo
I I,
I
I
Figure 1. Total joint swelling scores (swelling) in patients with rheumatoid arthritis treated with recombinant human
interleukin-1 receptor type I (rHuIL-IRI) or placebo, before (day I)and after (day 29) 28 days of treatment. Each
set of data points connected by the lines represents the results of an individual patient. The dosage of rHuIL-1RI
(in &m*/day) injected subcutaneously is indicated on each panel. Data on the patients at the 1,OOO &mz/day
dosage who prematurely terminated the study secondary to drug-related toxicity are represented by the symbols
connected by a dashed line and by the open boxes connected by a solid line.
260
DREVLOW ET AL
surface IL-la was monitored by gating on the monocyte
population, employing a mouse monoclonal FITC-labeled
anti-IL-1 a. An irrelevant FITC-labeled mouse IgG served as
the control (Donated by R&D Corp.).
Cell-mediated immunity. Cell-mediated immunity
was examined in vitro on day 1 and day 29, as previously
described (21,221. Cells from only 2 patients treated with
1,OOO Clg/m2/day were examined in vitro. In vitro testing
included examination of proliferative responses to mitogens
and antigens, employing PBMC obtained on day 1 and day
29. The mitogens employed were phytohemagglutinin (PHA;
at 0.1, 0.5, and 1 d 2 0 0 pl) and mitogenic anti-CD3 monoclonal antibody (at 10 and 25 d 2 0 0 pl), and the antigens
were tetanus toxoid (1.25 and 2.5 LFU/ml) and acetoneprecipitated water-soluble mycobacterial antigens (10and 20
pglml), as previously described (22). Proliferative responses
were measured by 3H incorporation, after 3 days for mitogens and 7 days for antigens (22).
Statistical analysis. Data analysis was performed using an SPSS program. Frequency data (e.g., number of
patients who improved on therapy) were analyzed with a
chi-square test. Other data (e.g., painful joint score, ESR,
etc.) were examined by analysis of variance.
RESULTS
Demographics. The demographics of the patients included in the study are shown in Table l .
There were no statistical differences between the
placebo- and rHuIL-1RI-treated groups with regard to
sex, race, age, or rheumatoid factor status. As expected, a predominance of women was included in the
study.
Efficacy. Nineteen of the 23 patients enrolled in
this study received rHuIL-1R1, while 4 received placebo. The data on 17 of the 19 patients treated with
rHuIL-1RI were analyzed for efficacy (3 at 125, 250,
and 500 pg/m2/day and 8 at 1,000 pg/m2/day). The 2
patients who were not evaluated had terminated the
study prior to day 29 for reasons unrelated to rHuIL1RI. Data on 2 additional patients treated with 1 , W
pg/m2/day of rHuIL- 1RI who had terminated the study
prematurely (days 14 and 21) because of side effects
that were thought to be related t o the study medication
were included in the analysis.
Individual patients demonstrated quite vaned
clinical responses following treatment with rHuIL1RI. Some reduction of joint swelling, the primary
criterion for clinical response employed in this study,
was observed in each patient treated with 250 &m2/
day of rHuIL-IRI and in 6 of 8 patients treated with
1 ,O00 pg/m2/day (Figure I). However, 3 of 4 placebotreated patients showed a comparable reduction in
joint swelling. None of these changes were significant,
however, and there were no significant differences
between the groups. The laboratory parameter used to
monitor clinical activity, the ESR, increased, although
not significantly, in each rHuIL-1RI treatment group
as well as in those treated with placebo (Figure 2).
Only 1 patient who took 125 pg/m2/day of rHuIL-IRI
and another who took 1,OOO &m2/day of rHuIL-lRI
showed any reduction in the ESR (Figure 2).
As described in the Patients and Methods, 8
clinical measures were employed to monitor response.
Clinically relevant improvement was defined as 40%
improvement in the total swollen joint score or fulfillment of 3 of the secondary criteria. Of the patients
treated with rHuIL-1R1, only 4 of the 17 included in
the final analysis showed improvement in at least I of
the 8 clinical parameters (Table 2). None of the patients treated either with 125, 250, or 500 Ccg/m*/day of
rHuIL-1RI or with the placebo showed any improvement as defined by these criteria for clinical response.
Although 4 of the 8 patients treated with 1,000 &m2/
day of rHuIL-1RI improved according to the predetermined criteria, only 1 of these patients demonstrated
clinically relevant improvement. This individual experienced a >40% improvement in the total swollen joint
score, the number of tendedpainful joints, morning
stiffness, and patient and physician global assessments.
Despite the small numbers in each group, deterioration was observed in some parameters when the
groups were compared. Morning stiffness, walk time,
ESR, and patient and physician global assessments
(data not shown) all worsened in those taking 250
&m2/day, although these changes were not significantly different from those noted in the other treatment groups. Even though a slight reduction in joint
swelling was observed in patients treated with 250
Ccg/m2/day of rHuIL-IRI, there was a significant increase from baseline in the number of tendedpainful
joints (P < 0.05) compared with that noted in the 125
and 1,O00 &m2/day groups (data not shown). The
patients taking 250 Ccg/m2/day also demonstrated significantly more deterioration from baseline (P< 0.05),
as evaluated by the subsections of the HAQ that
measured physical function on the day of the evaluation, difficulty in performing daily activities, and overall satisfaction, compared with the changes noted in
the groups taking 500 and 1,000 &m2/day (data not
shown).
Flow cytometry. No consistent or significant
changes were observed in the cell surface expression
of HLA-DR, CD25, CD54, and CD69 on either CD3positive T cells or CD14-positive monocytes (data not
261
rHuIL-1RI TREATMENT FOR ACTIVE RA
a,
Y
2
100-
100-
50-
50
0
._
Y
cd
Y
2
-
vl
90
1
80
-
70
-
1
J
60 -
A
50
-
40
-
J"
1000 pg
I
I
0
29
Day
29
Day
s
2
v-
-
,
0
I
Day
29
Figure 2. Erythrocyte sedimentation rate in patients with rheumatoid arthritis treated with recombinant human
interleukin-1 receptor type I (rHuIL-IRI) or placebo before (day 1) and after (day 29) 28 days of therapy. Each set of data
points connected by the lines represents the results of an individual patient. The dosage of rHuIL-IRI (in pg/m2/day)
injected subcutaneously is indicated on each panel. Data on the patients at the 1,OOO pg/m2/day dosage who prematurely
terminated the study secondary to drug-related toxicity are represented by the open triangles connected by a dashed line
and by the open boxes connected by a solid line. The values for I patient treated at 1 ,OOO pg/m*/day were incomplete.
DREVLOW ET AL
262
Frequency of patients fulfilling predetermined criteria for
clinical improvement on treatment with recombinant human interleukin-1 receptor type 1 (rHuIL-IRI) and placebo
Table 2.
Dosage
(pg/mGay)
rHuIL-1RI
I25
250
No. of
patients
500
1 ,OOo
3
3
3
8
Placebo
4
Secondary
criteriat
Primary
criterion.
swelling*
1
2
3
0
0
0
1
0
0
0
0
3
0
0
0
0
0
0
0
0
0
I$
0
* Primary measure of clinical efficacy was >40% improvement in
the total swollen joint score. See Patients and Methods for details.
t Secondary criteria were the number of tender joints or joints
painful on motion, patient and physician global assessments (1-10
scale; 1 is best), modified Health Assessment Questionnaire, 5GfOOt
walk time (in seconds), morning stiffness (in hours), and erythrocyte
sedimentation rate.
$ Patient fulfilled the primary criterion and 4 secondary criteria for
clinical response.
rHuIL-1RI withdrew from the study because of abdominal pain and diarrhea, and another patient, taking
250 &m2/day, withdrew because of hospitalization
for intestinal obstruction. Data from these patients
were not included in the analysis.
Two patients treated with 1,OOO pg/m2/day of
rHuIL-lRI also terminated treatment prematurely, at
days 14 and 21, because of a diffuse erythematous rash
in one patient and hives in the other. Inflammation of
the injection site was observed in 2 additional patients
(125 and 1,OOO pg/m2/day), which did not result in
early termination of therapy. The skin reactions in all
4 patients was thought by the investigators to be
definitely associated with the medication. One placebotreated patient developed an urticaria1 rash that was
thought to be probably drug-related. No other adverse
events prevented completion of the trial.
DISCUSSION
presented). There were no consistent or statistically
significant changes seen in the expression of monocyte
TNF receptor or IL-1 receptor, as determined by
binding to the respective labeled cytokines (data not
presented). In contrast, cell surface IL-la, expressed
on monocytes, was significantly reduced ( P < 0.007)
following treatment with rHuIL-1RI at every dosage
level studied (Figure 3). No reduction of cell surface
IL-la was observed in the placebo-treated patients.
Cell-mediated immunity. Cell-mediated immunity was assessed by measuring the T cell proliferative
responses of PBMC in response to 2 recall antigens,
the mitogen PHA and a mitogenic anti-CD3 monoclonal antibody. The majority of the patients did not
exhibit proliferative responses to either tetanus toxoid
or to the mycobacterial antigen at the beginning of the
study. After 29 days of treatment with rHuIL-IRI, no
increase in responsiveness to these antigens was noted
(Table 3). In response to the anti-CD3 and the PHA,
no change in proliferative responses was observed in
placebo-treated patients or in those treated with 125 to
500 pg/m*/day of rHuIL-1RI (Table 3). Although the
peripheral blood mononuclear cells of only 2 patients
treated with 1,000 pg/m*/day were available for study,
both showed dramatic reduction following treatment
with rHuIL-lRI (Table 3).
Toxicity. Nineteen patients received rHuILIRI, 3 at 125 and 500 pg/m2/day, 4 at 250, and 9 at
1,000 pg/m2/day. Two patients did not complete the
clinical trial for reasons unrelated to rHuIL-1RI administration. One patient taking 1,OOO pg/mZ/dayof
This was the first study to examine the safety
and efficacy of receptor-mediated therapy in patients
with RA. Although some clinical improvement occurred in 4 of 8 patients treated with 1,000 pg/m2/day
of rHuIL-IRI, only 1 patient fulfilled predetermined
1
2x
15-
0
0
C
2
Q)
.->
50-
.
I
Y
\
0
A
Day
placebo
29
Figure 3. Expression of monocyte cell surface interleukin-1 a (ILla) in patients with rheumatoid arthritis treated with recombinant
human IL-1 receptor type I (rHuIL-IRI) or placebo before (day I )
and after (day 29) 28 days of therapy. Each set of data points
connected by a line represents the mean percentage of monocytes
positive for the cell surface expression of IL-1 a for patients at the
dosages indicated (3 each at 125 and 250 pg/m2/day, 4 placebotreated patients, and 4 patients at 500+ &m*/day of rHuIL-IRI,
which includes 3 at 500 and 1 at 1,000 pg/m2/day).
263
rHuIL-1RI TREATMENT FOR ACTIVE RA
Effects of treatment with rHuIL-IRI on in vitro parameters of cell-mediated immunity
between days 1 and 29*
Table 3.
AntLCD3
Dosage,
pg/m2/day
No. of
patients
rHuIL-IRI
I25
3
12,738
21,207
(7,492)t (23,970)
250
3
28,386
(8,846)
500
3
7,878
11,674
(12,288)t (10,708)
I ,OOo
2
44,639
(45,684)
Placebo
4
Day 1
Day 29
PHA
Day 1
Day 29
7
(10)
89
(124)
421
(730)
44,051
57,869 70,858 1,311
1,118
(10,091) (14,855) (13,635) (1,411) (2,224)
1,457
(900)
1,053
(1,249)
16,408
15,677
(11,169)t (17,044)
Day 29
Day 1
AP-MT
Day 29
7,535
(1,515)
Day 1
Tetanus
toxoid
42,442 48,500
683
(4,368) (18,513) (1,160)
46,890 49,568
(2,790) (14,567)
156
(270)
255
(218)
530
(212)
154
(168)
103,401 33,502
(17,266) (17,020)
317
(173)
55
(34)
185
(261)
55
(77)
68,338 779,082
741
(40,751) (18,380) (1,001)
1,860
(2,341)
22
(25)
I64
(164)
* Values are the mean (SD), obtained at the concentrations providing the strongest responses for each
patient. rHulL-IRI = recombinant human interleukin-I receptor type I; PHA = phytohemagglutinin;
AP-MT = acetone-precipitated water-soluble mycobacterial antigen.
+ One nonresponder was not included in this analysis.
criteria for a clinically relevant response. Of the 8
patients treated at the highest dosage, 2 experienced
dose-limiting toxicity due to rashes, while another
experienced an injection-site reaction. Although further study will be required to determine the clinical
effectiveness and safety of rHuIL-IRI, this phase I
placebo-controlled trial suggests that the prolonged
administration of rHuIL-1RI at 1,000 pg/m21day, or
higher, may not be feasible.
There are a number of potential explanations
for the lack of benefit noted in these studies. It is
possible that cessation of DMARDs prior to the study
may have allowed the disease activity to flare in some
patients during the administration of rHuIL-IRI, perhaps obscuring a more substantial effect of this compound. It is also possible that larger numbers of
patients or a longer period of treatment will document
clinical benefit. Systemic administration of rHuIL- 1RI
may not have resulted in sufficient concentrations of
soluble receptor in joint tissue to affect the balance
between IL-1 activity and inhibition. Given the toxicity noted, however, use of higher doses does not seem
feasible. Additionally, in an earlier study, we failed to
observe any beneficial effect of local administration of
rHuIL-1RI intraarticularly (23).
Another possibility is that rHuIL-1RI may not
be effective because the activity of IL-1 is already
neutralized locally. Consistent with this possibility,
high concentrations of IL-lR, both types I and 11, as
well as IL-1 receptor antagonist (IL-lRa), have been
detected in the synovial fluids of patients with RA
(1 1,24). In these fluids, biologically active IL-1 was not
detectable, which suggests that local factors may
already be optimal for inhibition of 1L-1 activity.
However, it is possible that a balance toward activation by IL-1 exists within the joint tissue. IL-1, IL-lR,
and IL- 1Ra have all been detected immunohistologically within synovial tissue macrophages (3,25,26).
Further, the ratio of IL-1 to IL-1Ra in synovial tissue
extractshpernatants was relatively high, suggesting
an imbalance favoring IL-1-mediated inflammation (27).
IL-1RI binds to IL-la and IL-lP less avidly
than to IL-lRa, and the interaction of IL-1RI with
IL-1Ra is essentially irreversible (1 1,28). Therefore, it
is possible that rHuIL-IRI, particularly at lower concentrations, might exacerbate disease activity. In fact,
a number of secondary criteria worsened in the group
taking 250 pg/m*/day compared with patients taking
higher dosages, even though there was marginal improvement in the joint swelling scores in these patients. The patients' responses to pain and inflammation may have been altered at this dosage level due to
inhibition of the effects of IL-1 on the central nervous
system, which are mediated in part through corticotropin-releasing hormone (2P-3 1). It is also possible
that soluble rHuIL- 1RI might diminish the normal
IL-1-mediated enhancement of corticosteroid release
from the adrenal gland (32), which might secondarily
DREVLOW ET AL
264
affect joint inflammation and the central nervous system. An exacerbation ofjoint swelling was observed in
1 of 12 patients treated intraarticularly with rHuIL1R1, but none of the 4 placebo-injected control patients (23). Consistent with the possibility that inhibition of IL-1Ra by IL-1RI might worsen disease
activity, neutralization of IL- 1Ra exacerbated rabbit
immune colitis (33).
The effects of systemic administration of
rHuIL-1RI on the immune system were not dramatic.
Earlier studies have documented inhibition of the
human cutaneous allergic late-phase response by
rHuIL-lRI (34). In our study, monocyte cell surface
IL-la was reduced at all dosage levels examined. This
effect could have been due to down-modulation of cell
surface IL-la or to blocking the detection of cell
surface IL-la. A reduction of monocyte cell surface
IL-la was also noted after a single intraarticular
injection of rHuIL-lRI at the highest dosage examined
(500 &joint) (23). The functional consequences of the
binding of rHuIL-1RI to cell surface IL- 1a are unclear.
Anti-IL1 a resulted in increased accessory cellinduced T cell activation, although this may have been
due in part to potential cross-linking by the antibody
itself, and not directly to engagement of 1L-la (35).
However, a trend toward reduction of T cell proliferative responses was noted in the highest dosage group,
although the number of patients examined was very
small. We observed no consistent changes in monocyte cell surface IL-1R. However, our detection system for cell surface IL-1R would be unlikely to detect
rHuIL-IRI adherent to IL-la because of the monovalent binding of our soluble IL-1RI (12).
Recent studies have suggested that type I1
IL-1R does not function in signal transduction, and
that its major function is to serve as a decoy molecule
to adsorb IL-I (36). Since IL-1R type I1 binds more
avidly to IL-1 than to IL-lRa, it may be more effective
clinically than rHuIL-1RI (1 1). It is also possible that
an imbalance of IL-1 is not critical in the chronic
inflammation observed in patients with RA. Further
study will be required to differentiate these possibilities and to definitively determine the clinical effectiveness of rHuIL-lRI in patients with RA.
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