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Serum levels of soluble interleukin-2 receptor.

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Number 6, June 1994, pp 898-901
0 1994, American College of Rheumatology
A Marker of Disease Activity in Localized Scleroderma
Objective. To determine whether circulating serum levels of soluble interleukin-2 receptor (sIL-2R) are
elevated in patients with localized scleroderma, and if
levels of sIL-2R can differentiate between active and
inactive disease.
Methods. Seventeen patients with localized
scleroderma were categorized by overall physician assessment into active, inactive, and indeterminate
groups, according to disease activity. Serum sJL2R levels
were analyzed and correlated with disease activity.
Results. The mean sIL-2R level was significantly
higher (P = 0.005) in those with active disease (1,675 f
823 unitshl) than in those with inactive disease (722 A
218 unitshl).
Conclusion. Serum sIL-2R levels are elevated in
patients with localized scleroderma. When present, elevated sIL-2R levels appear to be able to differentiate
active from inactive disease. This fact also suggests
cell-mediated immune activation in this condition. Further serial studies are required to assess the value and
sensitivity of sIL-2R levels in measuring changes in
disease activity.
Localized scleroderma is a rare autoimmune
disease that occurs primarily in children, and differs
from systemic sclerosis (SSc) by being usually limited
to the skin and subcutaneous tissues (1). Nevertheless,
localized scleroderma can cause lifelong functional
disability. There is neither a sensitive nor a specific
laboratory test for measuring disease activity; monitoring is therefore done almost exclusively by clinical
assessment. However, the slowly evolving nature of
the lesion makes assessment of disease progression or
regression difficult. These difficulties result in problems in determining the need for, and the efficacy of,
drug therapy in patients with localized scleroderma.
Levels of soluble interleukin-2 receptors (sIL2R) have been assayed in a variety of malignant,
inflammatory, and infectious states (2), and appear to
accurately reflect cell-mediated immune activity.
Higher levels of sIL-2R have been found in patients
with early generalized SSc and were correlated with
disease outcome (3,4). We undertook this study to
determine whether the measurement of sIL-2R levels
can be used to reflect disease activity in patients with
localized scleroderma.
Yosef Uziel, MD, MSc: The Hospital for Sick Children,
Toronto, Ontario, Canada; Bernice R. Krafchik, MB, ChB, FRCP(C):
The Hospital for Sick Children; Brian Feldman, MD, FRCP(C): The
Hospital for Sick Children; Earl D. Silverman, MD, FRCP(C):
The Hospital for Sick Children; Laurence A. Rubin, MD, FRCP(C),
FACP: Women’s College Hospital, University of Toronto, Toronto,
Ontario, Canada; Ronald M. Laxer, MD, FRCP(C): The Hospital
for Sick Children. Dr. Uziel is the recipient of an Abraham
Shore Memorial Medical Fellowship and an American Physicians
Fellowship. Drs. Silverman, Laxer are Associates of the Arthritis
Address reprint requests to Ronald M. Laxer, MD,
FRCP(C), Division of Rheumatology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, MSG 1x8,Canada.
Submitted for publication August 10, 1993; accepted in
revised form December 28, 1993.
Patients. Serum samples were collected from 17
patients who were evaluated at the Localized Scleroderma
Clinic at The Hospital for Sick Children. Localized scleroderma was diagnosed clinically by an experienced dermatologist (BRK) and rheumatologist (RML); no patient had
internal organ involvement or systemic manifestations. A
retrospective chart review was performed by an independent
assessor (YU) who was unaware of the patients’ sIL-2R
Patients were divided into 3 groups according to their
disease activity status. These groups were defined as follows: group 1, active phase, were those with new lesions, an
increased size of previous lesions, or erythema or violaceous
Figure 1. Levels of soluble interleukin-2receptor (S-IL-2 R) in the 3 subgroups of patients with linear
scleroderma. Shaded area shows the mean + 2 SD in 23 samples from healthy age-matched children.
Bars show the mean 1 SD in individual patient groups.
color of the lesion; group 2, inactive phase, were those who
had no new lesion and no change in size of previous lesions,
but had softening and brownish discoloration of the skin;
group 3, indeterminate, were those in whom it was unclear
and difficult to determine clinically whether there was active
skin inflammation or changes from the previous evaluation.
Assays for sIL-2R. Serum samples were taken at the
time of clinical assessments and stored at -70°C. Levels of
sIL-2R were measured by enzyme-linked immunosorbent
assay (ELISA) as previously described (5). The monoclonal
antibodies used in the ELISA, anti-Tac (6) and 7G7/B6 (7),
have been characterized and shown to bind distinct epitopes
on the IL-2R molecule. Control samples were obtained from
age-matched healthy children.
Statistical analysis. An overall comparison of group
means was made using one-way analysis of variance
(ANOVA). Analysis of covariance was used to determine if
age, erythrocyte sedimentation rate (ESR), or disease duration confounded the relationship between sIL-2R level and
disease activity. Subsequently, the mean levels of sIL-2R in
the active, indeterminate, and inactive disease groups were
compared using pairwise t-tests, corrected by Fisher’s least
squares difference for multiple significance testing. To determine the sIL-2R test characteristics, we calculated the
sensitivity and specificity for various levels of sIL-2R.
Statistical calculations were carried out on a Macintosh
computer using Systat 5.2 (Systat, Inc., Evanston, IL).
Seventeen patients, 10 females and 7 males,
were studied. The mean age at disease onset was 8.1
years, with a range of 1-14 years. The mean disease
duration was 4.5 years.
The mean f SD sIL-2R level for the 5 patients
with active localized scleroderma was 1,675 5 823
units/ml (range 5742,399), that for the 8 patients with
inactive disease was 722 2 218 units/rnl (range 384l,lOl), and that for the indeterminate group was 1,310
f 365 unitdm1 (range 1,06&1,838) (Figure 1). There
were significant differences between the groups by
ANOVA (P = 0.013), with a significantly increased
mean level in the active group compared with the
inactive group (P = 0.005).
While there was a weakly negative correlation
between patient age and sIL-2R levels (r = -0.325, P
not significant), this did not alter the relationship
between sIL-2R and disease activity. Furthermore,
neither patient age, disease duration, ESR, nor eosinophilia changed the relationship between sIL-2R levels
and disease activity.
Table 1. Determination of best sIL-2R value for discriminating
active from inactive localized scleroderma
sIL-2R value
1 ,OOo*
1 .O
0. I
1 .o
* The best soluble interleukin-2 receptor (sIL-2R) value for discriminating active from inactive localized scleroderma is 1 ,OOO unitslml,
with a sensitivity of 80% and a specificity of 90%.
To determine the best cut-off level of sIL-2R
that could be used to discriminate active from inactive
disease, we calculated sensitivity and specificity at
different sIL-2R values (Table 1). A cut-off level of
1,000 units/ml provided a sensitivity of 0.8 and specificity of 0.9 for the assessment of active disease.
To date, there are no sensitive or specific
parameters for assessing disease activity in patients
with localized scleroderma. ESR, peripheral eosinophilia, antinuclear antibodies (ANA), and serum immunoglobulin levels may be abnormal in the active
phase of localized scleroderma but generally do not
predict disease activity (1). The clinical changes of
localized scleroderma evolve very slowly, and it is
therefore difficult to accurately assess disease activity
by either clinical evaluation or laboratory testing. This
lack of precision makes the interpretation of any
therapeutic intervention difficult. In the present study,
we did not find any correlation between ESR, eosinophilia, ANA, or serum immunoglobulin levels and
disease activity. We have previously shown that thermography demonstrated increased temperature in the
active phase of localized scleroderma when new skin
lesions appeared, but was difficult to interpret for
slowly changing or inactive lesions (8). Highresolution B-mode ultrasound may eventually be helpful in defining disease activity but currently serves
only as a research tool (9).
At the present time, clinical evaluation seems to
be the only practical way to monitor disease activity.
The development of sensitive and specific laboratory
or diagnostic imaging tests would be helpful in disease
evaluation. In this study, we have shown that sIL-2R
levels were significantly elevated in patients with
active localized scleroderma as compared with patients with inactive disease. We have demonstrated
that a cut-off level of 1,000 unitshl has both high
sensitivity and high specificity for assessing the active
phase of the disease.
Previous studies have shown that serum levels
of sIL-2R reflect disease activity in a variety of autoimmune disorders (2,lO). In rheumatoid arthritis, systemic lupus erythematosus, and polymyositis, high
levels of sIL-2R have been more commonly found in
the “active” disease states (10-13). In SSc, sIL-2R
levels have been found to be markedly elevated in
patients with early generalized disease, strongly associated with mortality, and inversely correlated with
disease duration (3). In another study, Clements et a1
(4) reported higher sIL-2R levels in patients with early,
untreated SSc. In our study, we did not find any
correlation between disease duration and sIL-2R levels. Since our data include only single time-point
measurements, we cannot yet draw conclusions about
the relationship of changes in sIL-2R levels and
changes in disease activity or long-term prognosis.
Unlike SSc, there is no mortality associated
with localized scleroderma, and the poor prognosis
results from the local effect of a sclerodermatous band
of tissue. This may be reflected by growth failure of an
extremity, loss of range of motion where a lesion
crosses a joint line, facial atrophy, seizure, uveitis,
and severe cosmetic deformities. We are now collecting sera in a prospective manner to examine whether
sIL-2R can not only serve to monitor disease activity,
but also indicate subsequent clinical change and help
predict outcome.
A number of nonspecific laboratory abnormalities
suggest an autoimmune basis for localized scleroderma.
They include the presence of ANA and rheumatoid
factor (1416), of anti-single-stranded DNA antibodies, which have been correlated with more extensive,
active, and prolonged skin disease (16,17), of antibodies to histone, particularly in patients with more extensive skin involvement (17), and of increased levels of
serum immunoglobulins. Rarely, anticentromere antibodies, which are generally associated with the CREST
variant of SSc (calcinosis, Raynaud’s phenomenon,
esophageal dysmotility, sclerodactyly , telangiectasias),
have been reported in localized scleroderma (18).
While a number of humoral immune abnormalities have been reported in patients with localized
scleroderma, no previous investigations of cellmediated immune disturbances have been reported.
Our study is the first to document cell-mediated
immune activation in localized scleroderma, as reflected by elevated levels of serum sIL-2R. In SSc, an
increase in the number of helper memory T
cells (CD4+,CD26+ and CD4+,CD25+) and a decrease in the number of suppressor killer T cells
(CD8-t ,CD29+) was found in early disease and correlated with disease activity, suggesting a role for T
cell-mediated immunity in SSc (19,20). The findings of
elevated sIL-2R levels as well as increased levels of
interleukin-2 (IL-2), IL-4, and B cell growth factor
activity in culture supernatants further support the
importance of T cell hyperactivity in SSc (21).
Even though localized scleroderma usually is
limited to the skin and subcutaneous tissues, the
clinical presentation may be indistinguishable from
SSc, and the skin histology is identical. These findings
strongly suggest that the local pathogenic mechanism
may be similar in both conditions. While the etiology
of localized scleroderma is unknown, we hypothesized
that, similar to SSc, activation of the immune system
by an as-yet-unidentified antigen(s) results in cytokine
release and a cascade of events that eventually leads to
fibroblast proliferation, excessive collagen production,
loss of subcutaneous tissue, fibrosis, and secondary
deformity (22). We suggest that the cell-mediated
immune activation in localized scleroderma leads to
overproduction of collagen in the active phase of the
disease, with the appearance of new lesions or an
increase in the size of old lesions. When the skin was
sclerosed or softened in the inactive phase, low levels
of sIL-2R were demonstrated, indicating a reduction in
immune T cell activation.
In summary, our findings support a role for
cell-mediated immune activation in localized scleroderma. Measurement of serum sIL-2R levels is a
rapid, easy, and reliable method for assessing immune
activation in vivo and, as such, may help delineate
disease status and monitor disease activity, particularly with respect to evaluating a response to medical
therapy, in localized scleroderma. Prospective serial
studies are required to extend these initial observations.
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