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Treatment of refractory rheumatoid arthritis with a monoclonal antibody to intercellular adhesion molecule 1.

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ARTHRITIS & RHEUMATISM Volume 37
Number 7, July 1994, pp 992-999
0 1994, American College of Rheumatology
992
TREATMENT OF REFRACTORY RHEUMATOID ARTHRITIS
WITH A MONOCLONAL ANTIBODY TO
INTERCELLULAR ADHESION MOLECULE 1
ARTHUR F. KAVANAUGH, LAURIE S. DAVIS, LISA A. NICHOLS, STEPHEN H. NORRIS,
ROBERT ROTHLEIN, LINDA A. SCHARSCHMIDT, and PETER E. LIPSKY
Objective. To ~ssessthe safety and efficacy of a
monoclonal antibody (MAb) to intercellular adhesion molecule l (ICAM-l; CD54) in rheumatoid arthritis (RA).
Methods. A phase 1/11, open-label, doseescalation study of 32 patients.
Results. During treatment, a peripheral CD3 +I
CD4+ lymphocytosis was noted, and several patients
demonstrated transient cutaneous anergy, which suggests that therapy modified T cell recirculation. Thirteen of the 23 patients who received 5 days of treatment
demonstrated clinical improvement through day 29, and
9 of 23 through day 60. Adverse effects were minor and
transient.
Conclusion. Anti-ICAM-1 MAb therapy was
well tolerated, resulted in a transient alteration in T
lymphocyte recirculation, and effected clinical improvement in some RA patients.
Rheumatoid arthritis (RA) is a chronic, progressive, systemic inflammatory disease which causes
significant morbidity and increased mortality in affected patients (1,2). Data accrued from a variety of
studies suggest that CD4+ T lymphocytes subserve a
pivotal role in the initiation and perpetuation of the
immunologically driven inflammation characteristic of
Supported in part by USPHS grant RR-00633 (AFK).
Arthur F. Kavanaugh, MD: University of Texas Southwestern Medical Center, Dallas; Laurie s. Davis, PhD: University
of Texas Southwestern Medical Center; Lisa A. Nichols, MSN:
University of Texas Southwestern Medical Center; Stephen H.
Noms, PhD: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Robert Rothlein, PhD: Boehringer Ingelheim
Pharmaceuticals, Inc.; Linda A. Scharschmidt, MD: Boehringer
Ingelheim Pharmaceuticals, Inc.; Peter E. Lipsky, MD: University
of Texas Southwestern Medical Center.
Address reprint requests to Peter E. Lipsky, MD, University of Texas Southwestern Medical Center, 5323 Harry Hines
Boulevard, Dallas, TX 75235-8884.
Submitted for publication October 12, 1993; accepted in
revised form January 5, 1994.
RA (1,3,4). One approach to the treatment of RA,
therefore, is to utilize T cells as targets of therapy.
This might include medications such as cyclosporine,
which limit T cell cytokine function, and monoclonal
antibodies (MAb) that diminish T cell number or
function (5,6).
A novel therapeutic approach for systemic inflammatory diseases such as RA is directed toward the
cell surface adhesion receptors. These adhesion molecules mediate the heterotypic intercellular interactions governing the recruitment of inflammatory
cells into extravascular sites, as well as the function of
these cells (7). The most widely employed approach to
block adhesion molecule function has been to use
MAb. The potential usefulness of this approach has
been established in animal models of human inflammatory disease (8).
Of the repertoire of adhesion receptors, one
receptor-counterreceptor pair plays a central role in
adhesive interactions that mediate the transendothelial
migration of T lymphocytes: leukocyte-functionassociated antigen 1 (LFA-1; CDl ldCD18) and one of
its counterreceptors, intercellular adhesion molecule 1
(ICAM-1; CD54) (9). These adhesion receptors are
therefore attractive therapeutic targets for T cellmediated diseases such as RA. We report here the
findings of our study concerning the safety and efficacy
of an anti-ICAM-1 MAb in a group of RA patients
whose disease had been refractory to conventional
therapy.
PATIENTS AND METHODS
Patients. The study population consisted of 32 patients with an established diagnosis of RA, as defined by the
American College of Rheumatology 1987 criteria (10). To be
eligible for enrollment, patients must have had: 1) disease
duration of 2 4 years at the time of study entry, and 2) failure
993
TREATMENT OF RA WITH AN ANTI-ICAM-1 MAb
of previous therapeutic trials with at least 2 diseasemodifying antirheumatic drugs (DMARDs). The patients
also were required to have had active disease, as defined by
the presence of 6 or more swollen joints, plus 2 of the
following criteria: (a) 2 9 tender joints, (b) morning stiffness
2 4 5 minutes, or (c) erythrocyte sedimentation rate (ESR)
228 m d h o u r by the Westergren method. Exclusion criteria
included functional class IV according to Steinbrocker’s
criteria (Il), serious pulmonary, cardiac, or renal disease,
intercurrent infection, and allergy to murine products.
All DMARDs were discontinued at least 1 month
before treatment, but patients were allowed to remain on
stable doses of nonsteroidal antiinflammatory drugs and
low-dose corticosteroids (maximum dose 5 1 0 mg prednisone per day). Local Institutional Review Board approval
was obtained, and all patients gave informed consent before
entering the study.
Monoclonal antibody preparation and administration.
The anti-ICAM- 1 MAb employed (BIRRl) is a murine IgG2a
MAb (previously designated R6.5) directed against extracelM a r domain 2 of the ICAM-1 molecule (12). The protocol
was originally designed as a 5-day (study days 1 through 5 )
in-hospital administration, following a dose-escalation
schedule. The amounts of antibody administered were based
upon preliminary data from renal allograft recipients (13):
140 mg (a 60-mg loading dose followed by 4 daily 20-mg
doses), 280 mg (a 120-mg loading dose followed by 4 daily
40-mg doses), and 560 mg (a 240-mg loading dose followed
by 4 daily 80-mg doses). In some patients, a 2-day regimen
was employed, with a total of 240 mg of BIRRl administered
(120 mg on each of 2 days). Anti-ICAM-1 was administered
intravenously over a period of approximately 20 minutes.
Clinical assessment. For evaluation of the clinical
response, a modification of the criteria established by Paulus
et a1 for the assessment of efficacy of antirheumatic drugs
(14) was employed. These criteria were established in order
to distinguish responses related to a therapeutic intervention
from those related to placebo. In this evaluation, 6 parameters of disease activity are measured: 1) tender joint
score, rated on a scale of CL3 for each of 69 diarthrodial
joints (maximum score 207); 2) swollen joint score, rated on
a scale of 0-3 for each of 66 diarthrodial joints (maximum
score 198); 3) duration of morning stiffness in minutes; 4)
patient global assessment of disease activity, rated on a scale
of 0-4; 5) physician global assessment of disease activity,
rated on a scale of 0-4;and 6) ESR (mm/hour) by the
Westergren method. Using these criteria, a complete response to treatment is defined as a 75-100% improvement in
at least 4 of the 6 parameters tested, a marked response as a
50-74% improvement in at least 4 parameters, and a moderate response as a 2049% improvement in at least 4 parameters. All other changes are considered to be no response.
In addition to these parameters of disease activity, a
Modified Health Assessment Questionnaire (MHAQ) assessment of functional status (15), serum C-reactive protein
(CRP) concentration, and serum rheumatoid factor (RF)
concentrations were also measured. Evaluation was performed at study entry, at days 8, 15, and 29, and monthly
thereafter until the patient exited the protocol. Patients were
exited from the protocol if they withdrew their consent, or if
there was any alteration in their treatment regimen.
Table 1. Demographics and initial evaluation parameters in 32
patients with rheumatoid arthritis (RA)
Parameter
Value*
Age
Females/males
Duration of RA (years)
No. of DMARDs previously usedt
Tender joint score (maximum 207)
Swollen joint score (maximum 198)
AM stiffness (minutes)
Erythrocyte sedimentation rate (mmihour)
C-reactive protein ( d d l )
Rheumatoid factor (IU/ml)
Patient global assessment (0-4 scale)
Physician global assessment (0-4 scale)
Modified Health Assessment Questionnaire
score (ref. 15)
48.3
? 11.3
2616
15.2 9.2
4.3 ? 1.5
26 (1 1-83)
28 (9-116)
180 (20-960)
47 (10-120)
2.9 (<0.8-14.4)
290 (<30-1,840)
3( 1 4
2(14
2.2 (1.0-3.5)
*
* Data are reported as the mean * SD or as the median (range).
t DMARD = disease-modifying antirheumatic drugs. These included methotrexate (30 patients), intramuscular gold (28 patients),
hydroxychloroquine (22 patients), sulfasalazine (17 patients),
D-penicillamine (15 patients), auranofin (13 patients), azathioprine
(12 patients), and cyclosporine (1 patient).
Immunologic assessment. Delayed-type hypersensitivity (DTH) testing. In some patients, DTH testing was
performed at sequential time points either before, during, or
after treatment with BIRRl. Recall antigens tested included
mumps, Candida, and Trichophyton.
Lymphocyte subpopulations. Sequential analysis of
lymphocyte subpopulations was performed in some patients
as described elsewhere (16). Briefly, peripheral blood mononuclear cells were obtained by density centrifugation, and
incubated with saturating concentrations of directly labeled
MAb to various cell surface determinants (anti-CD2O
[Coulter, Hialeah, FL], anti-CD3, anti-DR, anti-interleukin2 receptor [IL-2R], anti-CD4, anti-CD8, anti-CD45RA
[Becton Dickinson, Mountain View, CAI). Cells were examined by fluorescence-activated cell sorter analysis. The total
number of cells expressing each marker was calculated as
the percent positive cells multiplied by the absolute cell
counts at each time point.
Statistical analysis. Differences in the various clinical
parameters were assessed by the paired, nonparametnc
Wilcoxon test. Changes in cell numbers and pharmacokinetic data were assessed by the parametric paired t-test.
Data are reported as the mean 2 SD for normally distributed
data, or as the median and range.
RESULTS
Changes in clinical parameters. Patient demographics, as well as initial evaluation data, are shown
in Table 1. The number of patients who experienced a
response to therapy is shown in Table 2. For purposes
of analysis, patients have been grouped into those who
received 5 days of therapy (n = 23) and those who
994
KAVANAUGH ET AL
Table 2. Response to therapy*
Day of followup
5-day regimen
No. of patients
Responders
Marked response
Moderate response
I-day or 2-day regimen
No. of patients
Responders
Marked response
Moderate response
8
I5
29
60
90
23
23
23
23
23
6
7
5
8
5
8
4
2
5
1
9
9
9
9
9
0
3
0
0
1
0
0
1
1
1
* See Patients and Methods for definitions.
received 1 or 2 days of therapy (n = 9). For the 23
patients who received the 5-day treatment, 13 (57%)
had a marked or moderate response to treatment at
day 8 of followup. A marked or moderate response
was sustained for 13 of 23 patients (57%) at day 15, 13
of 23 patients (57%) at day 29,9 of 23 patients (39%) at
day 60, and 3 of 23 patients (13%) at day 90.
Patients who did not achieve a clinical response
to therapy at day 29 were allowed to begin other
therapies at that time. For purposes of analysis, these
patients are counted as nonresponders to anti-ICAM-1
throughout the time points indicated in Table 2. In
addition, 3 patients who initially achieved a clinical
response were subsequently considered nonresponders because of exiting from the protocol for
personal reasons (n = l), undergoing an elective
surgical procedure (n = l), and being required to
observe strict bedrest for unrelated reasons on the
advice of another physician.
The patients who responded through day 60 of
followup included 1 of the 2 patients receiving the
lowest dose, 7 of the 20 receiving the middle dose, and
the only patient who completed the high-dose regimen.
Treatment with the shorter regimens was less efficacious. Although 3 of the 9 patients (33%) demonstrated
a moderate response at day 8, the response was
sustained beyond that time for only 1 patient (11%).
The extent of improvement in the clinical parameters in the 10 patients classified as responders to
therapy (9 who were treated on the 5-day protocol and
1 on the 1-2-day protocol) through day 60 of followup
is shown in Table 3. There was significant improvement in the tender and swollen joint scores, patient
and physician global assessment, duration of morning
stiffness, and MHAQ score at various time points, as
shown in Table 3. There was no consistent, significant
change in serum RF titer or the ESR for any of the
patients (data not shown). Two of the responding
patients demonstrated a substantial decrease in serum
CRP concentration following therapy (from 14.4 to 3.3
mg/dl and from 5.8 to <0.8 mg/dl, respectively, day 0
and day 60).
During therapy, 24 of the 32 patients experienced some adverse event, consisting predominantly
of headache (n = 18), fever (maximum temperature
539.6"C; n = 16), nausedvomiting (n = 13), pruritus
(n = 7), light-headedness (n = 5 ) , and urticaria (n = 3).
Adverse reactions were mild to moderate in severity,
usually occurred on the first or second day of therapy,
and abated despite continued therapy. The occurrence
Table 3. Clinical outcome in responders*
Day
0
8
15
29
60
33 (11-83)
38 (28-116)
150 (60-960)
24 (633)t
31 (19-55)t
60 (0-540)
20 (4-35)$
27 (16-63)$
45 (0-540)
15 (3-27)$
24 (16-73)$
45 (0-90)$
18 (3-30)$
21 (1746)$
60 (0-180)
4 (24)
2 (2-4)
2.5 (1-3.5)
2 (1-3)t
2 (1-311
1.9 (1-3.1)t
2 (14)t
2 (1-3)t
2.0 (1.1-3.1)
2 (1-3)"
1 (1-2)$
1.9 (1-2.5)"
2 (14)
1 (1-3)$
2.0 (1-2.5)
Parameter
Joint score
Tender
Swollen
AM stiffness
(minutes)
Global assessment
Patient
Physician
MHAQ score
~
~
~
~
~~~~~~~~~~
* Responders are those
~
~
who had a sustained response to therapy through day 60 of followup (10
patients). Values are the median (range). MHAQ = Modified Health Assessment Questionnaire (see
ref. 15).
t P = 0.0313 versus day 0, by Wilcoxon rank sum test.
$- P = 0.0156 versus day 0, by Wilcoxon rank sum test.
995
TREATMENT OF RA WITH AN ANTI-ICAM-1 MAb
Table 4. Results of delayed-type hypersensitivity tests*
Patient
no.
One month
pretreatment
During
treatment
One month
posttreatment
3
4
6
7
8
10
12
20
21
24
25
26
31
32
ND
ND
ND
ND
ND
ND
0
0
0
2
1
0
2
0
0
0
1
1
2
1
0
0
1
2
ND
1
1
1
1
1
2
1
0
0
0
0
0
0
0
0
0
1
* Values are the number of recall antigens (Candida, Trichophyton,
and mumps) to which there was a positive response. ND = not
done.
of adverse reactions appeared to correlate with the
initial loading dose; reactions were noted in neither of
the 2 patients who received the 60-mg loading dose, 2 1
of the 27 who received the 120-mg dose, and 3 of the 3
who received the 240-mg dose. There were no changes
in hemodynamic parameters during or after treatment,
and no infectious complications related to antiICAM-1 therapy were noted.
Changes in laboratory parameters. Pharmacokinetic analysis revealed that all patients had detectable serum anti-ICAM-1 during treatment (data not
shown). Those receiving the middle dose regimen had
a mean serum anti-ICAM-1 trough concentration of 17
? 6 pg/ml during therapy, which exceeded the initial
goal of 10 ,ug/ml. This goal was based upon previous
observations that anti-ICAM-1 MAb concentrations
210 pglml effected 100% inhibition of LFA-1/ICAMl-dependent adhesive interactions in vitro (17). No
patients had detectable serum anti-ICAM-1 through
day 15.
There was a significant correlation between
serum BIRR1 concentrations and an in vitro test of
ICAM-l-dependent adhesive interactions, namely,
the capacity of the patients' sera to inhibit homotypic
JY cell aggregation (r = -0.81, P < 0.01; data not
shown) (17). However, there was no correlation between clinical improvement and any of the pharmacokinetic parameters measured. All patients who were
tested had developed IgG human anti-mouse antibodies by day 15 of followup.
Results of DTH testing. Serial DTH testing was
performed on 14 patients (Table 4). DTH tests were done
during the course of therapy and at intervals 1 month after
and, in some cases, I month before therapy. Patients
demonstrating cutaneous anergy prior to treatment
were not tested at subsequent time points. Six patients
were anergic both during and after therapy. However,
3 patients who were anergic during therapy displayed
reactivity when tested 1 month after therapy. In addition, 3 patients were reactive prior to therapy, anergic
during therapy, and reactive after therapy. This suggests that transient cutaneous anergy may be a result
of anti-ICAM-1 MAb therapy. This finding was not
universal, however; 2 patients remained reactive during therapy. In addition, there were 3 patients who
were reactive before treatment, but remained anergic
both during and subsequent to therapy, suggesting that
the cutaneous anergy may persist beyond the duration
of treatment.
+
14000
Lymphocytes
Monocytes
12000
10000
8000
6000
4000
4000
r)
3000
-
I
4
2000
a,
0
1000
900 '
800
.
T
T
700
600
.
500
400 I
I
I
I
I
1
I
I
I
J
0
1
2
3
4
5
8
15
29
day of treatment
Figure 1. Alterations in leukocyte numbers as a result of therapy
with anti-intercellular adhesion molecule 1 (anti-ICAM- 1). Values
are the mean and SD for 32 patients with rheumatoid arthritis. * =
P < O.OOO5 versus day 0 and day 1 (pretreatment).
KAVANAUGH ET AL
LYMPHOCYTES
0
MOO
,---CD4+ CD45RA+
CD3+
,lloo
CD4+ CD45RA-
1
5
addition, in the T cell population, there was an increase in the number of activated circulating T cells, as
evidenced by the increased expression of HLA-DR (P
< 0.05) (Figure 2) and the LY chain of the IL-2R (CD25;
P < 0.05) (data not shown).
CD4+
OR+ C03+
300T
8
1
5
8
DAYS OF TREATMENT
Figure 2. Lymphocyte phenotype during anti-intercellular adhesion molecule 1 treatment. Results shown are for 7 rheumatoid
arthritis patients treated on the 5-day regimen. Values are the
absolute number of cells/mm3. Significant increases in total number
of lymphocytes, CD3+ cells, and CD4+ cells were seen
(P< 0.001). Both CMSRA+ and CMSRA- subsets of CD4+ cells
were increased, as were CD3+/DR+ T cells (all P < 0.05).
Changes in cell numbers and phenotypic subpopulations. The absolutecellcountsforcirculatinglymphocytes, neutrophils, and monocytes during the different
days of treatment are shown in Figure 1. There was a
significant increase in the number of lymphocytes on
days 2 through 5 of therapy, as compared with values
at enrollment (day 0) and immediately prior to treatment (day 1). There was no consistent, significant
change in the absolute counts of neutrophils or monocytes.
Results of phenotypic analysis. Analysis of the
phenotype of circulating cells indicated that during
therapy, there was a significant increase in the numbers of circulating T cells, as indicated by CD3+ cell
counts (Figure 2). There was no significant change in
circulating B cell numbers (data not shown). Further
analysis revealed that the increase in T cell numbers
primarily reflected an increase in CD4+ T cells. Although most of the increase in circulating T cells could
be accounted for by CD4+ cells, there was a small but
statistically significant increase in CD8+ T cells during
therapy (mean _t SD absolute number of CD8+ T
cells/mm3 724 & 122 on day 1,97f & 181 on day 5, and
623 & 160 on day 8; the change from day 1 to day 5 was
statistically significant [P < 0.051). In the CD4+
population, there was an increase in both memory
(CD45RA-) as well as naive (CD45RA+) T cells. In
DISCUSSION
RA is a systemic inflammatory disease in which
CD4+ T cells orchestrate chronic synovial inflammation. Several lines of investigation support this thesis,
including analysis of the phenotypic characteristics of
the cellular infiltrate in the rheumatoid synovium (18),
the association of RA with certain alleles of the class I1
major histocompatibility complex (19), and extrapolation of data from animal studies (8). Perhaps the most
compelling evidence supporting the role of T cells in
RA is the established clinical efficacy of various therapeutic interventions that have in common a profound
impact on T cell numbers or function. Such therapies
include lymphapheresis (20), thoracic duct drainage
(21), total lymphoid irradiation (22), medications such
as cyclosporine (23), and, most recently, anti-T cell
MAb (6,24). Although these interventions have all
shown some efficacy, various concerns have kept
them from widespread use.
One novel approach to the treatment of inflammatory diseases such as RA employs adhesion receptors as therapeutic targets. These cell surface molecules mediate the heterotypic intercellular interactions
that govern not only cellular adhesion and traffic, but
also cellular activation. Because they perform such a
crucial role in the initiation and propagation of inflammatory reactions, therapy directed at adhesion receptors might be anticipated to modulate inflammatory
responses. Indeed, in several animal models of human
inflammatory disease, including antigen-induced and
adjuvant arthritis (25,26), ischemia-reperfusion injury
(8), inflammatory asthma (27), and renal allograft
rejection (12), anti-adhesion therapy has been shown
to abrogate inflammation effectively.
Transient inhibition of inflammation would be
expected to be beneficial in acute human inflammatory
diseases as it has been in animal models. However,
RA is a chronic disease that is characterized by
persistent inflammation and, presumably, is driven by
the continuous activation of autoreactive T cells.
Importantly, it can reasonably be postulated that therapy directed against adhesion receptors could effect a
long-term modulation of the activity of inflammatory
disease. It has been established that adhesion receptors serve an important role as accessory molecules in
TREATMENT OF RA WITH AN ANTI-ICAM-1 MAb
the propagation of immune responses (7,16). During
the generation of immune responses, inhibition of
interactions with accessory molecules has been suggested to be a mechanism through which immunologic
tolerance can be induced (28). Interference with adhesion receptor function might therefore induce tolerance to the arthritogenic antigen(s), and thereby
achieve long-term mitigation of disease activity. In this
regard, treatment with anti-LFA-1 and anti-ICAM- 1
MAb was shown to result in long-term tolerance to a
cardiac allograft in an animal model (29). Such treatment might therefore be an important therapeutic
approach in RA.
Conceivably, any adhesion receptor could be a
target for antiinflammatory therapy. The leukocyte
integrins, which play a particularly important role in
leukocyte extravasation, have been a prominent target
of adhesion receptor-directed therapy. One integrin,
LFA-1, plays a crucial role in the transendothelial
migration of T cells (9), and is an important accessory
molecule for T cell activation (16). Because T cells
appear to be the relevant etiopathogenic cell type in
RA, LFA-1 and one of its counterreceptors, ICAM-I,
are attractive targets of anti-adhesion receptor therapy. Furthermore, it has been demonstrated that
ICAM-1 is expressed at high concentrations in the
rheumatoid synovium (30), and that serum concentrations of circulating ICAM-1, presumably shed from the
surface of cells, are increased in patients with RA
compared with controls (31). Therapy directed against
this adhesion receptor would therefore be anticipated
to be more specific for active inflammatory processes
and less nonspecifically immunosuppressive. Indeed,
animal studies have suggested that interference with
the function of the p chain of LFA-1 (CD18) may be
associated with an increased susceptibility to severe
infectious complications (32). Studies in rabbits, however, have not demonstrated a similar reduced resistance to infection with either gram-negative or grampositive organisms after administration of anti-ICAM- 1
MAb (Mileski WJ, Lipsky PE: unpublished observations). Moreover, anti-ICAM-1 MAb has been administered safely to human renal allograft recipients (13).
Therapeutic use of an anti-ICAM- 1 monoclonal
antibody was well tolerated in this study. Side effects
related to therapy were similar to those reported with
the use of other MAb in various diseases. In all
instances, untoward effects were transient. Importantly, no infectious sequelae related to anti-ICAM-1
therapy were noted.
Therapeutic use of anti-ICAM-1 resulted in
997
clinical improvement in this group of patients whose
DMARDs were discontinued at least 1 month before
study entry. Although this was an uncontrolled trial,
the criteria used to determine clinical effect were a
modification of the Paulus criteria (14). These criteria
were established to differentiate true therapeutic responses in patients with RA from those related to
placebo. Utilizing these criteria, patients showing improvement in only one or a few indices of disease
activity are not considered responders. It is therefore
anticipated that therapeutic efficacy might reasonably
be estimated, even in uncontrolled trials. The significant difference in the responses noted in patients
receiving 5 versus 2 days of therapy supports the
conclusion that the improvement in the patients receiving the longer course of treatment was not the
result of a placebo effect.
The mechanisms of action of anti-ICAM-1 therapy have not been unequivocally defined. However,
the data suggest that administration of the MAb may
cause an alteration in lymphocyte recirculation.
ICAM-1 is expressed by a variety of cell types, including endothelial cells, antigen-presenting cells, and activated T cells (7). The rationale for the use of antiICAM-1 was to inhibit the function of ICAM-1 on
endothelial cells of the inflamed synovium, such that T
cells would be inhibited from accessing this site. This
may have been one of the mechanisms of action, since
during therapy, there was a peripheral lymphocytosis.
Phenotypic analysis suggested that the increase in
circulating cells resulting from therapy consisted primarily of CD3+, CD4+ T cells, with both memory and
naive populations being increased. There was no consistent significant increase in the numbers of circulating B cells, monocytes, or neutrophils. Of note, some
of the T cells which may have been retained in the
circulation as a result of anti-ICAM-1 therapy bore an
activated phenotype, as demonstrated by the expression of HLA-DR and IL-2R. In addition, several of the
patients demonstrated transient cutaneous anergy during therapy. These results suggest that treatment with
anti-ICAM-1 inhibited the recirculation of T cells,
including those with an enhanced migratory capacity.
Although no attempt was made to characterize
the cellular infiltrate in the synovium during therapy,
the data suggest the possibility that anti-ICAM-I MAb
therapy may have caused a redistribution of T cells out
of the rheumatoid synovium. Interestingly, similar
changes have been noted during thoracic duct drainage, with peripheral lymphocytosis and egress of lymphocytes from the inflamed synovium (21). The results
KAVANAUGH ET AL
suggest the possibility that temporary interference
with lymphocyte recirculation might have effected a
long-lasting attenuation of synovial inflammation. Alternatively, anti-ICAM-l MAb may have exerted an
immunomodulatory effect by interfering with the interaction of T cells and antigen-presenting cells at the
site of inflammation. These possibilities are currently
being examined.
Clinical efficacy was sustained for several
months in some patients. However, patients eventually experienced a recrudescence of disease activity or
required a change in their therapeutic regimen that
made further clinical analysis suspect. This pattern of
response is similar to that reported for other one-time
therapies, such as thoracic duct drainage (21). It is
relevant that the patients treated in this study had
longstanding, refractory disease. In several animal
models of inflammation, immunomodulatory therapies, including anti-adhesion receptor therapy, are
most efficacious when implemented early in the disease process. By extrapolation, anti-ICAM- 1 or other
therapies that target adhesion receptors might have the
greatest chance to induce remission in autoimmune
diseases such as RA when given to patients with a
recent onset of disease (28). This possibility remains to
be tested.
In conclusion, therapy of RA with an antiICAM-1 MAb was effective in some patients, possibly
as a result of an alteration in the recirculation of T
lymphocytes.
ACKNOWLEDGMENTS
The authors wish to thank all those physicians who
allowed us to participate in the care of their patients. We also
thank Beverly A d a m s for providing statistical assistance.
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