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Microheterogeneity of alpha1-acid glycoprotein in the detection of intercurrent infection in systemic lupus erythematosus.

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513
MICROHETEROGENEITY OF
ALPHAI-ACID GLYCOPROTEIN IN THE
DETECTION OF INTERCURRENT INFECTION IN
SYSTEMIC LUPUS ERYTHEMATOSUS
ANDRZEJ MACKIEWICZ, RENATA MARCINKOWSKA-PIETA, STANLEY BALLOU,
STEFAN MACKIEWICZ, and IRVING KUSHNER
We evaluated the clinical usefulness of determinations of al-acid glycoprotein microheterogeneity patterns in distinguishing patients who have active systemic
lupus erythematosus (SLE) from those who have SLE
with intercurrent infection. We used agarose affinity
electrophoresis with concanavalin A (Con A) as a ligand.
Results were expressed as reactivity coefficients (RC),
which are the ratios of variants reactive with Con A to
the variants not reactive with C m A. No significant
differences were found between the mean RC (fSD) in
healthy individuals (1.35 f 0.26) and that in patients
with various degrees of SLE activity. In contrast, a
significantly higher mean RC was found in sera from
patients with intercurrent infection (2.70 f 0.76) compared with each of the other groups studied (P < 0.001).
An RC >2.25 was found in none of 42 sera from patients
From the Department of Immunology and Rheumatology ,
Academy of Medicine. Poznan, Poland, and Case Western Reserve
University at Cleveland Metropolitan General Hospital, Cleveland,
Ohio.
Supported in part by Polish Academy of Sciences grant
10.5, the Irma Bender Arthritis Research Fund, and NIH grant
AG-02467.
Andrzej Mackiewicz, MD, PhD: Adjunct, Department of
Immunology and Rheumatology, Academy of Medicine, and Senior
Instructor in Medicine, Case Western Reserve University; Renata
Marcinkowska-Pieta, MD: Fellow, Department of Immunology and
Rheumatology, Academy of Medicine; Stanley Ballou, MD: Assistant Professor of Medicine and Acting Head, Division of Rheumatology, Case Western Reserve University at Cleveland Metropolitan General Hospital; Stefan Mackiewicz, MD, PhD: Professor
of Medicine and Head, Department of Immunology and Rheumatology, Academy of Medicine; Irving Kushner, MD: Professor of
Medicine and Pathology, Case Western Reserve University, and
Medical Director, Highland View Hospital, Cleveland, OH.
Address reprint requests to Andrzej Mackiewicz, MD,
Department of Immunology and Rheumatology, Szkolna 8/12,
60967, Poznan, Poland.
Submitted for publication September 22, 1986; accepted in
revised form December 9, 1986.
Arthritis and Rheumatism, Vol. 30, No. 5 (May 1987)
without infection and in 15 of 18 sera from patients with
infection (sensitivity 83%, specificity 100%). C-reactive
protein (CRP) levels were also significantly higher in
SLE patients with intercurrent infection than in patients
with very active disease (P < 0.05). Levels of CRP >60
mghter were found in 3 of 42 SLE patients without
infection and in 8 of 18 patients with infection (sensitivity 39%, specificity 93%). The results show that in SLE
patients, the finding of a relative increase in Con
A-bound serum cY1-acid glycoprotein is a more sensitive
indicator of intercurrent infection than is the finding of
increased levels of CRP.
Intercurrent infection, with or without fever,
presents a diagnostic problem in patients with systemic lupus erythematosus (SLE). Since fever may be
a symptom of active SLE, differentiation of an infection from an exacerbation of disease is often difficult.
The erythrocyte sedimentation rate (ESR), a nonspecific marker of inflammation, may be elevated both in
patients with very active SLE and in patients with
SLE and an accompanying infection (1). In most
cases, this measure is of little help clinically. Several
authors have suggested that elevated levels of Creactive protein (CRP) might serve as a marker for
infection in SLE (2-5). However, the usefulness of this
measure has been the subject of controversy (6-8). It
appears that the sensitivity of CRP levels is poor, and
the specificity is uncertain.
Recently, there has been interest in reports of
variations in the proportions of microheterogeneous
forms of certain plasma glycoproteins in various disease states (9-12). The human acute-phase protein,
a,-acid glycoprotein (AGP), has been of particular
interest (13-17). This molecule consists of a single
514
MACKIEWICZ ET AL
polypeptide chain containing 5 carbohydrate side
chains that account for approximately 45% of its mass.
AGP possesses 5 differerit antennary heteroglycan
structures (18) which contain the a-D-mannopyranose
residue; this is known to be reactive with concanavalin
A (Con A). Agarose affinity electrophoresis with Con
A as a ligand has revealed multiple microheterogeneous forms of AGP that differ in their reactivity
with Con A (10,12-17).
Abnormalities in the patterns of AGP reactivity
with Con A have been reported in patients with
various inflammatory states (10,14,17). Accordingly,
we evaluated the clinical usefulness of determinations
of the microheterogeneity of AGP in diagnosing infection in SLE patients. In addition, we compared the
sensitivity and specificity of this determination with
parallel studies of serum CRP levels. Finally, we
assessed AGP microheterogeneity in SLE patients
who had different degrees of disease activity.
PATIENTS AND METHODS
We studied 60 sera from 45 SLE patients and 12 sera
from 12 healthy individuals. Thirty-two of the patients had
been hospitalized in the Department of Immunology and
Rheumatology, Academy of Medicine (Poznan, Poland), and
13 had been in Cleveland Metropolitan General Hospital. All
patients fulfilled the American Rheumatism Association revised criteria for the classification of SLE (19).
Of the 60 SLE sera studied, 42 included samples
from patients with different levels of SLE activity, and 18
were from SLE patients who had intercurrent infection. SLE
activity was graded at the time of blood sampling, based on
criteria proposed by Rothfield and Pace (20). Briefly, involvement of 1 system in the absence of fever (e.g.,
arthralgia, arthritis, or rash) represented grade I activity; 16
patients met this criterion. Grade I1 included those patients
who had fever and involvement of 1 system, or had involvement of more than 1 system and had no fever; 12 patients fit
this category. Fever and involvement of at least 2 systems
represented grade 111 activity; 14 patients were in this group.
Thirteen of the 45 patients experienced 18 episodes
of intercurrent infection. Infection was diagnosed by positive culture in 14 instances, and by a clinical profile and
therapeutic response that was strongly suggestive of infection in 4 cases (Table 1).
Serum AGP levels were measured by electroimmunoassay using anti-AGP antibodies and AGP standards
obtained from Atlantic Antibodies (Boston, MA). CRP levels were determined by electroimmunoassay or by radial
immunodiffusion (21). Anti-CRP antibodies and CRP standards were obtained from Behnngwerke (Marburg, FRG).
The sensitivities of these methods were 0.5 mg/liter and 1.5
mgfliter, respectively.
The microheterogeneity of AGP was assessed by
agarose affinity electrophoresis using a modification of the
method of Bgg-Hansen (22), as described elsewhere in detail
Table 1. Alpha,-acid glycoprotein (AGP) reactivity coefficient
(RC) and levels of serum C-reactive protein (CRP) and AGP during episodes of intercurrent infections in 13 patients with systemic
lupus erythematosus
Type of infection
Urinary tract infection (Escherichia
coli)
Septicemia (Staphylococcus aureus)
Septicemia (Staphylococcus aureus)
Acute appendicitis
Urinary tract infection (Escherichia
coli)
Peritonitis (Escherichiu coli)
Pyogenic fasciitis (Salmonella
paratyphi)
Pneumonia*
Urinary tract infection (Escherichia
coli)
Pneumonia (Pneurnococcus)
Pharyngitis (Candida albicuns)
Pneumonia (Pneumocystis carinii)
Acute cholecystitis
Pneumonia (Klebsiellu pneumoniae)
Pneumonia*
Pleuropneumonia (Mycobacteriurn
tuberculosis)
Septic arthritis (Staphylococcus
aureus)
Subcutaneous abscess
(Staphylococcus aureus)
AGP
CRP
RC (mdliter)
AGP
(mdliter)
4.88
35
3,240
3.54
3.35
3.16
3.16
118
420
31
28
2,250
2,620
1,380
1.510
3.OO
2.85
132
36
3,680
1.290
2.70
2.57
42
13
1,080
2,110
2.45
2.45
2.45
2.33
2.33
2.33
2.03
330
35
35
435
72
46
213
1,380
2,610
1,500
2,410
3,330
1,080
3,800
1.63
60
2.460
1.50
19
1,980
* Infection responded to antibiotic therapy.
(23). Briefly, 50 pM Con A (batch 3212; Pharmacia, Uppsala,
Sweden) was included in t h e first dimension gel.
Electrophoresis was capied out for 60 minutes at 10 V/cm,
and the gel was transferred onto the second dimension plate.
Two gels adjacent to the first dimension gel, one containing
anti-AGP antibodies, and the other (intermediate gel) containing 7.5% of a-methyl-D-mannoside, were cast. Electrophoresis in the second dimension was carried out for 16-18
hours at 1.5 V/cm. The gel was then washed, dried, and
stained with Coomassie brilliant blue R250 (Sigma, St.
Louis, MO). This method reveals 4 microheterogeneous
variants of AGP. Variant 0 is nonreactive with Con A,
variant 1 is slightly reactive with Con A, variant 2 is strongly
reactive with Con A, and variant 3 is precipitated in the first
dimension (Figure 1). Alpha-methyl-D-mannoside, which
was included in the intermediate gel, dissolved the affinity
precipitate formed in the first dimension and permitted
detection of variant 3 in the second dimension gel.
The area under the precipitate curves was determined by planimetry, and the relative amounts of the different microheterogeneous forms were expressed as percentages of the total. A reactivity coefficient (RC) for each
sample was calculated according to the formula: (sum of Con
A-reactive vanants)/(Con A-nonreactive variant), where
variants 1, 2, and 3 = reactive, and variant 0 = nonreactive.
Serum AGP and CRP levels and the RC were compared in each group studied, using the Mann-Whitney test.
AGP IN SLE
515
Correlation between AGP and CRP serum levels, as well as
correlation between AGP and RC and between CRP and RC,
was sought using Pearson’s correlation coefficient.
RESULTS
Serum levels of AGP and CRP found in healthy
individuals and in patients with SLE are shown in
Table 2. AGP levels in all patient sera were significantly higher than those in healthy individuals (P <
0.001). In addition, increased disease activity was
associated with increased levels of AGP. Significant
differences between patients with grades I1 and I11
disease ( P < 0.01), as well as between patients with
grades I and I11 disease (P < O.Ol), were observed.
However, there was no difference in AGP levels in
patients with active SLE (grade 111) compared with
those who had SLE and an intercurrent infection.
There were higher serum levels of CRP in the
patients, compared with those in healthy individuals.
CRP concentrations were also correlated with disease
activity, and comparisons of all groups showed statistically significant differences. In SLE patients with
intercurrent infection, CRP levels were significantly
higher than in patients with very active disease (grade
111), but there was considerable overlap of individual
results between these 2 groups (Figure 2).
Mean AGP reactivity coefficients for each patient group are shown in Table 2; RC values for the
Figure 1. Affinity electrophoresis of a,-acid glycoprotein (AGP).
The first dimension gel was 50 f l concanavalin A (Con A), the
intermdiate gel was 7.5% a-methyl-D-mannoside, and the second
dimension gel was 25 pl of anti-AGP antibodies. a, A representative
systemic lupus erythematosus (SLE) patient with intercurrent infection; b, A representative SLE patient without infection (disease
activity grade 111; see Patients and Methods for details). Variant 3
precipitated in the first dimension gel, variant 2 was strongly
reactive with Con A, variant 1 was weakly reactive with Con A, and
variant 0 was nonreactive with Con A.
individual patients are presented in Figure 2. We found
no differences between the mean RC value in healthy
individuals and that in patients with various grades of
disease activity. However, the mean RC value in SLE
patients with intercurrent infection was significantly
higher than that of the other groups studied (P <
0.00 1).
Table 2. Alphal-acid glycoprotein (AGP) reactivity coefficients (RC) and serum levels of AGP and C-reactive protein (CRP) in healthy
subjects, patients with systemic lupus erythematosus (SLE), and patients with SLE and an intercurrent infection*
Group
Healthy subjects
(n = 12)
SLE grade I
(n = 16)
SLE grade I1
(n = 12)
S L E grade 111
(n = 14)
SLE + infection
(n = 18)
AGP RC
(mean ? SD)
1.35 f 0.26
AGP (mgiliter)
465 t 135
Median
400
1.40 ? 0.50
1,262 t 572t
1,230
1.42 2 0.37
1,363 2 647t
1,200
10.08 t 11.2tB
1.38 t 0.49
2,501 2 1,03ltlI#
2,430
42.70 2 34.9t#**
2.70
2,209 +- 880tll#
2,110
f 0.76t**tt$$
Mean 2 SD
CRP (mgiliter)
Mean 2 S D
1.80 t 2.3
3.46
2
7.2$
116.60 t 138t**tt§$
Median
0
0
6
37
42
* See Patients and Methods for details of grading system, assay techniques, and RC calculations. Significance levels were determined by
Mann-Whitney test (Pvalues 50.05 considered significant).
t P < 0.001 versus healthy subjects.
$ P < 0.05 versus healthy subjects.
5 P < 0.05 versus S L E grade I.
D P < 0.01 versus S L E grade I.
# P < 0.01 versus S L E grade 11.
** P < 0.001 versus S L E grade I.
tt P < 0.001 versus S L E grade 11.
$$ P < 0.001 versus S L E grade 111.
§§ P < 0.05 versus SLE grade 111.
516
MACKIEWICZ ET AL
DISCUSSION
-
..
E
m
2
5 30
7
.-e%
.-c>
&
100
-
.
50
-
J!&*
*
*
x +
!
6
a
t
:
**
0.
m
2-
t
I
*
0.0
-
'
I *
l}
*
I
*
0
..*
:*
t
Figure 2. Alpha,-acid glycoprotein-concanavalin A reactivity coef-
ficients and levels of C-reactive protein (CRP) in the sera of patients
with different grades of systemic lupus erythematosus (SLE) activity (I, 11, or 111; see Patients and Methods for details), and in patients
with SLE and an intercurrent infection (INF.). Horizontal lines
indicate mean values.
An RC >2.2S was found in none of the 42 sera
from SLE patients without infection and in 15 of the 18
sera from patients with infection (sensitivity 83%,
specificity 100%). An RC >2.0 was found in 4 of the 42
SLE patients without infection and in 16 of the 18
patients with infection (sensitivity 89%, specificity
90%). In comparison, CRP levels above 100 mg/liter
were found in 1 of the 42 SLE patients without
infection and in 6 of the 18 patients with infection
(sensitivity 33%, specificity 98%). Levels exceeding 60
mghter were found in 3 of 42 SLE patients without
infection and in 8 of the 18 patients with infection
(sensitivity 39%, specificity 93%).
Comparison of CRP and AGP levels in patients'
sera showed a linear correlation, with r = 0.33 (P <
0.005) when all sera were compared, and with r = 0.61
( P < 0.00s) when those who had SLE and an accompanying infection were excluded from comparison.
Comparison of RC values with either AGP or CRP
levels showed no linear correlation (r = 0.16 and r =
0.11, respectively).
We undertook this study because of recent
findings suggesting that determination of AGP
microheterogeneity might be useful in differentiating
inflammatory states of various causes. In serum, AGP
exists in several different microheterogeneous forms
which vary in their carbohydrate moieties, particularly
in antennary structures of their heteroglycan side
chains (24). These microheterogeneous forms can
readily be detected by affinity electrophoresis, which
demonstrates their different reactivities to concanavalin A (23). Using this technique, several authors
have demonstrated abnormal AGP microheterogeneity
patterns in several disease states, suggesting that acute
inflammation is accompanied by an increase in Con
A-reactive forms of AGP (10,14). However, in recent
studies of AGP microheterogeneity in patients with
rheumatoid arthritis (RA), we found that relative Con
A-AGP reactivity was unexpectedly low in patients
with severe disease (mean RC 0.7; normal 1.4) (17).
The observation that inflammatory changes in RA
were associated with AGP microheterogeneity that
was different from that observed in a variety of other
acute inflammatory states led us to explore the possibility that SLE activity might be associated with
similar changes in AGP glycosylation. If true, this
might permit clinical differentiation of active SLE
from certain other acute inflammatory states, specifically, bacterial infections.
In fact, we found a significant relative increase
in the reactivity of AGP with Con A in the sera of SLE
patients who had intercurrent infection. SLE activity
alone did not alter the reactivity of AGP with Con A,
compared with results using normal sera, although it
did cause an increase in serum levels of total AGP. All
except 2 SLE patients with intercurrent infections
demonstrated substantial increases in the percentage
of the Con A-reactive variants that fell outside the
range of values found in patients with uncomplicated
SLE. In these 2 patients, however, local inflammatory
foci (e.g., septic arthritis and subcutaneous abscess),
rather than systemic infection, were observed. Moreover, a more severe general infection, such as septicemia or peritonitis, usually resulted in a higher RC
than did pneumonia or pharyngitis. We did not determine AGP-Con A reactivity longitudinally in the sera
of individual patients, although such studies would be
interesting. Lupus activity alone did not affect the RC,
although it did cause an increase in total AGP levels in
serum. In contrast to the findings in studies comparing
5 17
AGP IN SLE
normal subjects and patients with RA, we observed no
differences in AGP reactivity in normal individuals
versus patients with SLE of various activity grades.
The results of tests for CRP levels in SLE
patients with different grades of disease activity, as
well as those with accompanying infection, are similar
to those reported previously by others (3,4). In patients with active SLE alone, CRP levels were relatively low or were moderately elevated. However,
there were statistically significant differences in these
levels when sera from patients with different disease
activity grades were compared. Nonetheless, it would
clearly be difficult to assess SLE activity in individual
patients based only on CRP levels. The group of
patients with SLE complicated by infection showed a
wide range of serum CRP levels. The results were
significantly higher (P < 0.05) in those with infections
than in patients with grade I11 SLE activity. However,
there was a large overlap between the groups. As a
result, the sensitivity of high CRP levels, >60 mg/liter,
for predicting infection was relatively poor compared
with the sensitivity of the RC values.
AGP concentrations in SLE patients’ sera were
higher than were those in healthy individuals, and the
concentrations were very high in those with the most
active disease. However, assessment of individual
patients’ disease activity based on AGP levels was not
possible because of the overlap of results between the
groups. In patients with intercurrent infection, AGP
levels were similar to those observed in patients with
active SLE (grade 111), indicating that quantitative
measurement of the glycoprotein seems to be of no
value in the diagnosis of superimposed infection.
The observation that changes in AGP reactivity
to Con A during the acute-phase response are usually
parallel to increases in the synthesis and glycosylation
of acute-phase glycoproteins has suggested to some
that both synthesis and glycosylation of acute-phase
glycoproteins may be under the same regulatory control. However, we did not observe a correlation between serum AGP levels and AGP-Con A reactivity
coefficients; thus, there was no support for the hypothesis that these processes are linked.
In conclusion, we found that Con A-reactive
forms of AGP in serum increased significantly in SLE
patients who had infections but did not increase in
parallel with an increased degree of disease activity in
SLE patients who did not have infections. Serum CRP
levels were similarly elevated in SLE patients who had
infections. The sensitivity of determinations of AGP
microheterogeneity for the prediction of infection in
these patients was substantially greater than was that
for CRP determinations. For evaluation of the activity
of S L E , AGP microheterogeneity testing was of no
value. CRP levels and total AGP levels were similarly
elevated in patients with active S L E , but the clinical
usefulness of these 2 measures was limited by the high
degree of overlap.
ACKNOWLEDGMENT
We thank Kathy Kaltenbach for excellent secretarial
assistance.
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