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ELEVATED SERUM LEVELS OF INTERLEUKIN-1 RECEPTOR ANTAGONIST IN POLYMYOSITISDERMATOMYOSITIS. A Biologic Marker of Disease Activity with a Possible Role in the Lack of Acute-Phase Protein Response

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ARTHRITIS & RHEUMATISM Volume 37
Number 12, December 1994, pp. 1744-1751
0 1994, American College of Rheumatology
1744
ELEVATED SERUM LEVELS OF
INTERLEUKIN-1 RECEPTOR ANTAGONIST IN
POLYMYOSITIS/DERMATOMYOSITIS
A Biologic Marker of Disease Activity with a Possible Role in the
Lack of Acute-Phase Protein Response
CEM GABAY, FABIENNE GAY-CROISIER, PASCALE ROUX-LOMBARD, OLIVIER MEYER,
C. MAINETI, PIERRE-ANDRE GUERNE, THOMAS VISCHER, and JEAN-MICHEL DAYER
Objective. To determine whether the lack of
acute-phase protein (APP) response in numerous patients with polymyositis/dermatomyositis (PWDM) is
related to an imbalance between cytokines and cytokine
inhibitors.
Methods. Levels of C-reactive protein (CRP),
interleukin-lp (IL-lP), tumor necrosis factor LY
(TNFa), IL-6, IL-1 receptor antagonist (IL-lra), TNF
soluble receptor 55 kd (sTNFR 55 kd), and sTNFR 75 kd
were tested in the serum of 15 patients with PWDM, 14
patients with spondylarthropathies (SPA), and 12
healthy blood donors. Serum IL-lp, TNFa, IL-6, ILIra, sTNFR were measured by specific immunoassays.
Results. Serum levels of CRP were lower in
PM/DM patients than in SPA patients. Normal or
slightly elevated CRP values were found in 10 of the 15
PM/DM patients, 7 of whom had active myositis. Serum
IL-6 levels were significantly higher in SPA patients
Supported in part by grants 31-33786.92 (to Dr. Dayer) and
31-30076.90 (to Dr. Guerne) from the Swiss National Science
Foundation, and by the “Subvention fkdkrale pour la lutte contre Ie
Rhumatisme.”
Cem Gabay, MD: HBpital Cantonal Universitaire de Genkve, Geneva, Switzerland; Fabienne Gay-Croisier, MD: HBpital
Cantonal Universitaire de Genkve; Pascale Roux-Lombard, MD,
PhD: HBpital Cantonal Universitaire de Genbve; Olivier Meyer,
MD: Centre Hospitalier Universitaire Bichat, Paris, France;
C. Maineti, MD: HBpitaI Cantonal Universitaire de Genbve;
Pierre-Andrk Guerne, MD: Hdpital Cantonal Universitaire de Geneve; Thomas Vischer, MD: HBpital Cantonal Universitaire de
Geneve; Jean-Michel Dayer, MD: HBpital Cantonal Universitaire
de Geneve.
Address reprint requests to Cem Gabay, MD, Division de
Rhumatologie, HBpital Beau Skjour, 26 avenue Beau-Skjour, CH1211 GenBve, Switzerland.
Submitted for publication March 21, 1994; accepted in
revised form July 7, 1994.
than in PM/DM patients, whereas serum IL-lra and
sTNFR levels were significantly higher in PWDM than
in SPA patients. IL-lra levels were particularly elevated
in patients with active myositis and decreased in response to treatment.
Conclusion. These differences in cytokine levels,
particularly IL-lra, between PM/DM and SPA patients
are indicative of distinct pathogenic mechanisms. High
levels of IL-lra may account for the weak APP response
in some PM/DM patients. Our results suggest that
measurement of IL-lra, together with clinical examination, may provide useful information for the followup of
PM/DM patients.
Polymyositis (PM) and dermatomyositis (DM)
are uncommon inflammatory conditions characterized
by skeletal muscle involvement, typical cutaneous
lesions (in DM), and more rarely, other organ system
manifestations. Although little is known about the
pathogenesis, studies support the role of an immunemediated mechanism (1). Despite an evident inflammatory process, the response of the acute-phase proteins (APP), such as C-reactive protein (CRP), is
lacking or weak in a large proportion of cases of
PM/DM (2,3).
APP are mainly produced by hepatocytes.
Interleukind (IL-6) is considered to be the principal
inducer of APP synthesis ( 4 3 , although several other
mediators, such as IL-1 (6), tumor necrosis factor a
(TNFa) (4), leukemia inhibitory factor (7), and IL-11
(8), have been identified. The fact that the APP response in PMDM is different from that in other
inflammatory conditions suggests at least 2 different
1745
ELEVATED SERUM IL-lra IN PM/DM
Table 1. Clinical features and muscle enzyme levels in 15 patients with PWDM at the time of cytokine determination
Patient/
agelsex
Disease
duration
(months)
Diagnosis*
Treatment,
daily doset
TGl78lM
MN531M
SSl35lF
PM
PM
PM
0
7
72
KFl30lF
PDISSIF
DJl37lF
LGl44lF
DA/45/M
RMl53lF
FYISOIF
PCl60lF
MDJIl l/M
PM
DM
DM
DM
DM
DM
DMIpneo.
DMIpneo.
JDM
57
2
4
3
1
24
2
3
1
None
Pred. 45 mg
Pred. 15 mg,
AZA 100 mg
Pred. 20 mg
None
Pred. 80 mg
None
None
None
None
Pred. 45 mg
None
CJ-D/22/M
GC164lF
JDM
DMIScl
84
2
None
Pred. 60 mg
TM571F
DMISS
120
Pred. 5 mg
~-~~~
~
~
Muscle enzymes
(unitsfliter)$
CK
Ald.
LDH
Prox. MW, RPS
Normal muscle strength
Myalgia, no MW, RP, RPS
17,298
324
38
51.7
4.8
3.2
2,328
ND
339
Prox. MW
Diffuse MW, DM rash
Diffuse MW, DM rash, RPS
Prox. MW, DM rash
Prox. MW, DM rash
Prox. MW, DM rash
Prox. MW, DM rash
Prox. MW, DM rash
Prox. MW, DM rash, fever,
pericardial effusion
DM rash disappeared, no MW
Prox. MW, dysphagia,
DM rash, sclerodactyly
Myalgia, DM rash,
arthritis, salivary, RPS
1,950
153
4,587
1,830
526
36
13,200
38
6,306
31.6
12.6
78
21.5
11
3.6
63
6
98.7
642
570
1,510
1,002
900
362
2,070
820
2,404
536
4,725
ND
23
453
1,266
35
1.7
283
Clinical features$
~
* PM = polymyositis; DM = dermatomyositis; pneo. = paraneoplastic process; JDM = juvenile DM; Scl = scleroderma; SS = Sjogren’s
syndrome.
t Pred. = prednisone; AZA = azathioprine.
$ Prox. MW = proximal muscle weakness; RPS = restrictive pulmonary syndrome; RP = Raynaud’s phenomenon; salivary = salivary gland
swelling.
8 CK = creatine kinase (normal 150 unitsiliter for female, 270 unitslliter for male); Ald. = aldolase (normal 9.5 unitsiliter); LDH = lactate
dehydrogenase (normal 470 unitslliter); ND = not determined.
hypotheses: (a) the levels of the cytokines, mainly
monokines, implicated in the induction of APP synthesis could be relatively low in PM/DM as compared
with other rheumatic diseases; or (b) the hepatocyte
response to these monokines may be impaired by
inhibitors.
The aim of this study was to test serum samples
from patients with PM/DM for levels of CRP, cytokines, and cytokine inhibitors, all of which are possibly involved in the regulation of CRP synthesis. The
results were compared with those obtained from the
serum of patients with spondylarthropathies (SPA),
who are known to have elevated levels of CRP (9) and
IL-6 (9) that increase proportionately with the activity
of the disease. We studied patients with SPA rather
than patients with rheumatoid arthritis to rule out
possible interference of rheumatoid factor with the
cytokine determinations by enzyme-linked immunosorbent assay (ELISA).
PATIENTS AND METHODS
Patients. The study included 15 patients with PMI
DM, according to the criteria of Bohan and Peter (lo), and 14
patients with SPA, according to criteria recently proposed
by the European Spondylarthropathy Study Group (1 1).
Age, duration of disease, treatment, and clinical and laboratory data on the PMIDM patients at the time of cytokine
determination are shown in Table 1.
There were 5 subgroups of PM/DM patients, as
proposed by Bohan (10): primary idiopathic PM (4 patients),
primary idiopathic DM (5 patients), DM associated with
neoplasia (2 patients), juvenile DM (2 patients), and overlap
syndromes (2 patients, 1 with scleroderma and 1 with
Sjogren’s syndrome).
Electromyographic (EMG) examination and muscle
biopsy were performed at the time of the diagnosis in 13 and
11 of the PM/DM patients, respectively. EMG findings
showed typical signs of inflammatory myopathy in all cases.
Muscle histology was diagnostic for inflammatory myopathy
in 9 patients.
Physical examination was performed in all patients at
the time of cytokine determination, with particular attention
to muscle strength and systemic features. Clinical findings
and muscle enzyme levels are shown in Table 1.
Among the SPA patients, 12 had psoriatic arthritis
and 2 had ankylosing spondylitis. Active synovitis was
present in 12 patients at the time of cytokine determination.
Details concerning the duration of disease, number of swollen joints, and medications are listed in Table 2.
No intraarticular or bolus steroid was administered
during the month preceding cytokine determination.
1746
GABAY ET AL
Table 2. Clinical characteristics of the 14 SPA patients at the time
of cytokine determination
Patient/
ageisex
Disease No. of
duration swollen
(months) joints
Diagnosis*
CYvi64iF
PA
60
8
CYi38iM
APi48lM
BJi41iM
PA
PA
PA
24
144
36
1
5
4
MG/4I/M
PA
24
3
HJi35iF
VAi58iM
PA
PA
48
I20
1
1
CMI27M
MYl72lM
RMi24iM
PA
PA
AS
12
2
108
1
4
0
MFi35iM
PA
60
1
WPi37iM
SBi35iM
BYi35iM
PAiCrohn's
PA
AS
244
0
1
4
1
180
Controls. Sera from 12 healthy blood donors were
used a s controls. All sera were aliquoted, stored a t -2O"C,
and tested for their cytokine and CRP contents.
Cytokine determination. Cytokine levels were determined by commercially available ELISAs, according t o
the manufacturers' instructions: TNFa by T N F a EASIA
from Medgenix (Fleurus, Belgium), IL-6 by Coaliza IL-6 from
Chromogenix (Molndal, Sweden), I L - l p by IL-1 EIA
from Immunotech (Marseille, France), and IL-1 receptor
antagonist (IL-lra) by Quantikine from R & D (Minneapolis,
MN). All immunoassays were performed in monoplicate on
serum diluted 1:2.
All cytokine determinations were performed a t the
same time. Intra-assay variation, assessed in some serum
samples, was always lower than 5%. The sensitivity of these
assays was 30 pg/ml, 15 pg/ml, and 15 pg/ml, respectively.
For statistical analysis, we arbitrarily attributed these values
t o the cases in which cytokine levels were below the
detection threshold.
Sera were tested for tumor necrosis factor soluble
receptor types 1 and 2 (sTNFR 55 kd and 75 kd) by
enzyme-linked immunobiologic assay (Hoffmann-La Roche,
Basel, Switzerland) as described previously (12). The addition of up t o 10 ng/ml of recombinant human T N F a had no
effect on the sTNFR assay, the sensitivity of which was 150
pg/ml.
CRP determination. Serum CRP levels were measured by nephelometry using a nephelometer analyzer
(Behring, Marburg, Germany). The detection limit of CRP in
this assay was 0.26 mg/dl (normal 50.26 mg/dl). For statis-
Treatment, doset
MTX 20 mdweek,
NSAIDs
NSAIDs
NSAIDs
SSZ 2 gdday,
NSAIDs
SSZ 2 gdday,
NSAIDs
Pred. 7.5 mg/day
Gold 100 mg/
week, NSAIDs
NSAIDs
NSAIDs
MTX 25 mg/week,
NSAIDs
Pred. 5 mg/day,
AZA 100 mg/
day, NSAIDs
NSAIDs
None
NSAIDs
* PA = psoriatic arthritis; AS = ankylosing spondylitis; Crohn's =
Crohn's disease.
't MTX = methotrexate; NSAIDs = nonsteroidal antiinflammatory
drugs; SSZ = sulfasalazine; Red. = prednisone; AZA = azathioprine.
Serum levels of IL-10, IL-6, IL-lra, TNFa, sTNFR 55 and 75 kd, CRP, and ESRs in
patients with PM/DM*
Table 3.
Patient
TG
MA
TNFa
(pg/ml)
<15
39
<30
<30
<30
<30
<30
32
52
44
37
<30
<30
<30
26
16
<15
<15
<I5
<15
<I5
ND
<15
<I5
<15
ss
KF
PD
DJ
LG
DA
RM
FY
PC
MDJ
CJ-D
GC
TA
<15
<15
<I5
Median
(IQR)
~
IL-10
(pg/ml)
15
(0)
~~~~~
50
39
30
(9)
IL-6
(pg/ml)
49
< 15
21
<I5
34
<I5
<15
25
<15
47
<15
37
22
41
19
21
(21)
~
IL-Ira
(pg/ml)
7,092
347
816
404
1,816
575
755
6,164
616
6, I44
581
4,536
290
4,916
260
755
(4,374)
sTNFR (ngfml)
55 kd
75 kd
5.2
1.5
2.5
1.1
4.0
4.4
7.5
4.3
2.1
2.7
3.7
4.7
3.5
3.5
2.3
13.0
3.0
7.5
4.0
10.9
8.9
9.9
10.8
5.9
10.5
6.7
14.2
5.6
16.1
5.8
3.5
(2.02)
8.9
(5.05)
CRP
(mg/dl)
ESR
(mmlhour)
3.06
<0.26
3.89
0.46
<0.26
1.54
C0.26
0.46
<0.26
6.27
1.90
0.7
<0.26
0.48
<0.26
0.48
(2.51)
35
6
40
78
ND
10
23
16
26
54
16
19
ND
8
ND
21
(24.5)
~
* IL = interleukin; IL-lra = IL-1receptor antagonist; TNFa = tumor necrosis factor a;sTNFR
TNF soluble receptor; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; PMIDM
polymyositis/dermatomyositis;ND = not done; IQR = interquartile range.
=
=
1747
ELEVATED SERUM IL-lra IN PM/DM
RESULTS
0
0
6Q
d 3000
E
2000
y1
1000
I
PM-DM
SPA
C
D
300
50
-
0
PM-DM
SPA
PM-DM
C
SPA
C
t
PM-DM SPA
C
Figure 1. Levels of A, interleukin-1 receptor antagonist (IL-IRa),
B, tumor necrosis factor soluble receptor 55 kd (TNF-sR55), C,
TNF-sR 75 kd (TNF-sR75), D, IL-6, and E, C-reactive protein
(CRP) in 15 patients with polymyositis-dermatomyositis(PM-DM),
14 patients with spondylarthropathies (SPA), and 12 normal control
subjects (C). Except for CRP, which was determined by nephelometry, levels were determined by immunoassay (see Patients and
Methods for details). Horizontal bars within boxes show the median; boxes show the interquartile range ( 2 2 5 % of the median);
vertical bars show the 95% confidence interval (values above and
below these levels plotted separately).
tical analysis we arbitrarily attributed this value when the
CRP level was below the detection limit.
Statistical analysis. Kruskal-Wallis and MannWhitney tests were used to compare the levels of cytokines,
CRP, and erythrocyte sedimentation rates (ESR) in the 3
groups. Comparisons between 2 groups were made only
when the Kruskal-Wallis test yielded statistically significant
results. For multiple pairwise comparisons, Bonferroni's
correction was applied to P values obtained by MannWhitney test; corrected P values less than 0.05 were considered significant. Correlation was assessed using Spearman's
rank correlation coefficient. Cytokine and CRP levels as well
as ESRs are also given as the median and interquartile range.
The interquartile range was calculated by subtracting the
25th percentile from the 75th percentile.
Serum levels of IL-lP and IL-lra. Individual
serum concentrations of IL-1p and 1L-lra in the 15
patients with PMDM are listed in Table 3. Serum
IL-1p levels were below the detection limit in most
cases and were not significantly different among the 3
groups. IL-lra was detectable in all patients and
controls (Figure 1A), and levels were significantly
different in the 3 groups (P > 0.001, by Kruskal-Wallis
test). IL-lra concentrations were higher in PM/DM
patients (range 260-7,092 pg/ml, median 755) than in
SPA patients (range 103-851, median 391; P < 0.05)
and in controls (range 92-580, median 192.5; P <
0.001). IL-lra concentrations were particularly elevated in certain PMDM patients with highly active
disease, as defined by severe muscle weakness. Lower
levels were found in patients with less active or
inactive disease.
Five patients were tested longitudinally for
changes in IL-lra levels; the results confirmed these
observations (Table 4). Interestingly, high serum ILIra concentrations were found in patients PD and DA,
who had untreated DM with pronounced muscle weakness, but whose levels of CK and other muscle enzymes were only moderately increased (Tables 1 and 3).
Serum levels of TNFa and sTNFR. Serum concentrations of TNFa and sTNFR in patients with
PM/DM are listed in Table 3. TNFa levels were not
significantly different in the 3 groups of subjects.
Significant differences were detected when comparing
sTNFR 55 kd (Figure 1B) and sTNFR 75 kd (Figure
1C) levels in the 3 groups, by the Kruskal-Wallis test
(P < 0.01 for both). Serum concentrations of sTNFR
55 kd were significantly higher in PhUDM patients (range
1.1-7.5 nglml, median 3.5) than in SPA patients
(range 0.8-7.2, median 1.45) (P< 0.01). Serum levels
of sTNFR 75 kd were higher in PMDM patients (range
3-16.1 ng/ml, median 8.9) than in SPA patients
(range 2.5-15.9, median 3.75; P < 0.05) and in controls
(range 3.8-6.4, median 4.65; P < 0.01).
Serum levels of IL-6. Serum concentrations of
IL-6 in patients with PM/DM are listed in Table 3. IL-6
levels were significantly different in the 3 groups tested
(P < 0.001, by Kruskal-Wallis test). Serum levels of
IL-6 were higher in SPA patients (range 15-292, median 32) than in controls (range 15-22, median 15) (P <
0.001). Serum concentrations of IL-6 tended to be
higher in SPA patients than in PMDM patients (range
15-49 pg/ml, median 21). The ratio between IL-6 and
GABAY ET AL
1748
Table 4. Changes in IL-lra and CK levels in 5 patients with
PM/DM*
Patient,
serum
collection
MA
First
Second
DA
First
Second
FY
First
Second
MDJ
First
Second
GC
First
Second
Treatment,
dose
None
Pred. 45 mg/day
Time
between
CK
IL-lra
serum
(unitsfiiter) (pg/ml) collections
2,520
324
649
347
89days
526
45
6,164
524
85days
None
Pred. 70 mg/day
13,200
1,650
6,144
851
7days
None
Pred. 70 mg/day
6,306
1,338
4,536
1,053
34 days
Pred. 60 mg/day
Pred. 60 mg/day,
MTX 15 mg/week
4,725
320
4,916
2,168
73 days
None
Pred. 55 mg/day,
CSA 150 mg/day
* IL-lra = interleukin-1 receptor antagonist; CK = creatine kinase;
PM/DM = polymyositis/dennatomyositis;Pred. = prednisone; CSA
= cyclosporine A; MTX = methotrexate.
cytokine inhibitors, i.e., IL-6fIL-lra X (sTNFR 55 kd
+ 75 kd), was clearly higher in SPA patients (median
0.84) than in PMDM patients (median 0.25) (P <
0.01).
ESR and CRP levels. Individual serum levels of
CRP in patients with PMDM are listed in Table 3.
Comparison between groups revealed significant differences (P < 0.0001, by Kruskal-Wallis test), in that
CRP levels were significantly higher in SPA patients
(range 0.38-11.4 mg/dl, median 3.88) than in controls
(range 0.26-0.77, median 0.26) (P < 0.001) (Figure
1E). In addition, serum concentrations of CRP were
significantly higher in SPA patients than in PMDM
patients (range 0.26-6.27, median 0.48; P < 0.05). CRP
levels were normal or only slightly elevated (<1 mg/dl)
in 10 of the 15 patients with PM/DM, 7 of whom
presented with clinical or biologic signs of active
myositis (Table 1). No statistically significant difference was detected in ESR levels in SPA and PM/DM
patients. ESR was not assessed in controls.
Correlation between serum CK and cytokine
levels. As shown in Table 1, serum concentrations of
muscle enzymes were measured in PM/DM patients at
the time of cytokine determination. Spearman’s rank
coefficient was used for correlations between CK and
cytokines (or CRP). We found a positive correlation
between the serum CK level and IL-Ira and sTNFR 75
kd (r = 0.54, P = 0.05; r = 0.55, P = 0.05, respectively). No other correlation was found between serum
CK and cytokine or CRP levels.
Correlation between CRP and cytokines. A positive correlation between serum CRP levels and IL-6
was found in SPA patients (r = 0.74, P < O.Ol), but not
in PM/DM patients.
DISCUSSION
This study yielded the first data on serum levels
of TNFa, IL-lp, IL-6, sTNFR, and IL-Ira in patients
with PM/DM as compared with patients with another
inflammatory condition and with a normal population.
In general, serum levels of both IL-Ip and TNFa were
not detected or were only slightly elevated in all
subjects. In contrast, serum levels of IL-6, IL-lra,
and, to a lesser extent, sTNFR were clearly higher in
the patients than in the controls. Furthermore, there
were significant differences in the 2 groups of patients.
Serum levels of cytokine inhibitors were higher in
PM/DM patients than in SPA patients. This difference
was even more obvious in cases of active PM/DM. In
contrast, serum concentrations of IL-6 tended to be
higher in patients with SPA than in those with PMDM.
The presence of high serum concentrations of
IL-lra in PMDM in comparison to those found in
rheumatoid arthritis and SPA patients is indicative of a
distinct pathologic mechanism, with differences in the
expression and recruitment of cytokines. A body of
evidence supports the central role of lymphocytemediated immune activity in PMDM (13,14), whereas
monocyte-like or fibroblast-like cells seem to take a
more predominant role in other forms of chronic
inflammation. Histologic findings in muscle biopsy
samples from patients with myositis show the presence of inflammatory infiltrates, predominantly constituted by activated lymphocytes (15). Recent studies
have shown that markers of lymphocyte activation are
present in significant amounts in PM/DM patients and
correlate with disease activity (16-19). The origin of
IL-Ira in PM/DM has not yet been established. When
stimulated by various cytokines, numerous cells, including monocyte/macrophages, neutrophils, fibroblasts, and keratinocytes, have been shown to synthetize IL-Ira (20). Among lymphocyte products that
have been reported to stimulate IL-lra production are
granulocyte-macrophage colony-stimulating factor,
IL-3, IL-4 (20), and IL-13 (21). It is therefore possible
that an elevated level of IL-Ira in PM/DM sera might
in fact be a sensitive indirect marker of cell activation
ELEVATED SERUM IL-lra IN PM/DM
by lymphocyte products. Recent findings seem to lend
support to this hypothesis: 1) neopterin, a product of
interferon- ?stimulated monocytes, has been found in
elevated levels in the serum of PM/DM patients; it
proved to correlate with disease activity (22) and is
considered a marker of monocyte stimulation by activated T cells (23); 2) we recently observed similarly
high IL-lra levels in the serum of patients with scleroderma (unpublished data), another disease in which
the presence of T cell mediators in the serum has been
reported (24,25).
Histologic studies suggest that pathogenic
mechanisms involved in PM are different from those in
DM. In contrast to possible antigen-specific cytotoxicity with a preponderance of CD8+ T cells in PM,
humoral immunity with B cell and CD4+ T cell
preponderance may play a greater role in DM. In
addition, in juvenile DM, a vasculopathy may be the
perpetuating event (1). Because of the small number of
patients included in the present study, it was not
possible to compare serum cytokine and APP levels in
PM and in DM. Nekertheless, we found high IL-lra
and low CRP levels in the different subgroups of
inflammatory myopathies.
Serum levels of sTNFR, particularly the 75-kd
form, were elevated in patients with active PM/DM.
The two TNF inhibitors originate from the cellular
extramembranous portion of the TNF receptors. Activated lymphocytes express high levels of sTNFR 75
kd and may therefore be one of the sources of the
sTNFR 75 kd (20). Thus, the presence of high levels of
sTNFR 75 kd in active myositis supports the idea that
activated lymphocytes play a role in the pathogenesis
of PM/DM. Levels of sTNFR 55 kd in SPA patients
were slightly lower than those in controls. We do not
think that this finding is biologically significant with
regard to the pathogenicity of the disease. In contrast
to PM/DM patients, serum sTNFR levels were not
increased in SPA patients.
Serum levels of CRP were lower in PM/DM
patients than in SPA patients. Low CRP concentrations were also found in some patients with highly
active myositis, which is consistent with previous
observations (2,3). We observed that serum IL-6 levels increased modestly in PM/DM patients. This certainly contributes to the weak acute-phase reaction in
PM/DM. In addition, high levels of cytokine antagonists in the serum of these patients could also participate in the weak APP response.
IL-1 acts synergistically with IL-6 in inducing
the production of various APP (4,26). Furthermore,
1749
the presence of IL-1 is essential for CRP synthesis in
some in vitro models (27,28) and IL-Ira inhibits IL-linduced synthesis of APP by a hepatoma cell line (29).
Recently, it has been reported that 1L-lra completely
inhibits the effect of the supernatant of lipopolysaccharide-stimulated monocytes on the production of
CRP by hepatoma cell line cultures (30). Taken together, the results warrant the conjecture that the high
serum levels of IL-lra found in our patients with PM/DM
contribute to the relative lack of CRP elevation.
In contrast to IL-1, TNFa plays a minor part in
the induction of APP production (4,27). Nevertheless,
there is strong evidence that both TNF and IL-1
contribute indirectly to the production of CRP by
inducing the synthesis of IL-6 (31), which suggests that
the high levels of cytokine inhibitors in the serum of
patients with PMDM might also down-regulate CRP
synthesis. In studies of systemic lupus erythematosus,
in which the acute-phase reaction is frequently weak,
we (32) and others (33) have found serum sTNFR
levels to be particularly elevated. Soluble IL-lR, another IL-1 inhibitor, might also interfere in these
interactions.
It has recently been claimed that CRP in the
serum of patients with moderate inflammatory conditions stimulates the monocyte- or fibroblast-induced
production of IL-6 (34), IL-1, and TNFa (34,35). This
would suggest that CRP can indirectly up-regulate its
own production, which might be another explanation
for the rather moderate increase of CRP in PM/DM.
The assessment of disease activity in PM/DM
patients is based on different clinical and biologic
parameters, including muscle weakness, EMG findings, histologic findings, and CK levels. However, as
reported in a recent editorial (36), all these tests lack
either sensitivity or specificity. Muscle weakness,
which remains one of the most reliable clinical signs of
disease activity, may also occur after an injury or after
the administration of steroids. The levels of muscle
enzymes, usually high at onset and during flares, may
fail to rise in 4 3 6 % of newly diagnosed cases (37,38)
or to correlate with other indices of activity after
initiation of therapy (2,39). The presence of particularly high levels of IL-lra in the serum of patients with
very active myositis might therefore be useful in
assessing the response to treatment and could be as
sensitive as CK. In addition, determination of IL-lra
levels, as shown in 2 of our patients (patients PD and
DA), might be clinically useful in patients who have
only slight elevations of muscle enzyme concentra-
GABAY ET AL
1750
tions. A prospective, longitudinal study should be
performed to confirm this observation.
ACKNOWLEDGMENTS
W e would like to t h a n k Ms B. Mermillod (Centre
d’lnformatique Hospitalikre, Hbpital Cantonal Universitaire, G e n e v a , Switzerland) for useful statistical a d v i c e and
Ms F. M e z i n f o r technical assistance.
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