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Utility of anti-Sm anti-RNP antiRoSS-A and antiLaSS-B extractable nuclear antigens detected by enzyme-linked immunosorbent assay for the diagnosis of systemic lupus erythematosus.

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ARTHRITIS & RHEUMATISM
Vol. 39, No. 6 , June 1996, pp 1055-1061
0 1996. American College of Rlieumatology
1055
UTILITY OF ANTI-Sm, ANTI-RNP, ANTI-Ro/SS-A, AND
ANTI-La/SS-B (EXTRACTABLE NUCLEAR ANTIGENS) DETECTED BY
ENZYME-LINKED IMMUNOSORBENT ASSAY FOR THE
DIAGNOSIS OF SYSTEMIC LUPUS ERYTHEMATOSUS
JORGE S b C H E Z - G U E R R E R O . ROBERT A. LEW, ANNE H. FOSSEL, and PETER H. SCHUR
Objective. To determine the utility of antiextractable nuclear antigen (anti-ENA) antibodies detected by enzyme-linked immunosorbent assay as a
predictor for the diagnosis of systemic lupus erythematosus (SLE).
Methods. Among 2,185 serum samples sent for
testing for antinuclear antibodies (ANA) by indirect
immunofluorescence, 259 consecutive patients with positive ANA were identified. Medical charts of these
patients were reviewed to assess the clinical diagnosis,
with the reviewer having no knowledge of the anti-ENA
result. Clinical data were abstracted for all patients,
and diagnoses established using American College of
Rheumatology criteria. The utility of ENA antibodies in
the diagnosis of SLE was determined by univariate and
multivariate analysis among all patients who were positive for ANA, patients who were positive for ANA and
for anti-double-stranded DNA (anti-dsDNA), and patients who were positive for ANA and negative for
anti-dsDNA. Clinical differences between SLE patients
with and those without anti-ENA antibodies were assessed.
Supported in part by Diamedix. Dr. Sanchez-Guerrero‘s work
was supported by a Research Fellowship Award from the Fogarty
International Center (NIH 5F05-TW04573-02).
Jorge Sanchez-Guerrero, MD, MSc (current address: Instituto Nacional de la Nutrici6n Salvador Zubiran. Vasco de Quiroga.
Mexico). Robert A. Lew. PhD, Anne H. Fossel: Robert B. Brigham
Multipurpose Arthritis and Musculoskeletal Diseases Center,
Brigham and Women’s Hospital, Boston, MA; Peter H. Schur, MD:
Brigham and Women’s Hospital. Harvard Medical School, Boston,
MA.
Dr. Schur has served as a umsultant to biotechnolow companies and as an expert witness on antinuclear antibodies and related
matters.
Address reprint requests to Peter H. Schur, MD. Brigham and
Women’s Hospital, Division of Rheumatology and Immunology, 75
Francis Street, Boston, MA 02115.
Submitted for publication September 8, 1995; accepted in
revised form January 24, 1996.
Results. Anti-ENA antibodies, especially anti-Ro/
SS-A, showed strong predictive diagnostic value among
ANA+/anti-dsDNA- patients, but were of no utility
among ANA+/anti-dsDNA+ patients. The only clinical
manifestations th a t were more common among
anti-ENA+ SLE patients were pleuritis and the use of
hydroxychloroquine.
Conclusion. The presence of anti-ENA antibodies,
especially anti-Ro/SS-A, is a useful predictor for the
diagnosis of SLE, primarily among patients attending a
referral rheumatology center who are positive for ANA
and negative for anti-dsDNA. No major clinical differences were noted among ANA+ SLE patients with
versus those without ENA.
Systemic lupus erythematosus (SLE) is a disease
of unknown etiology in which patients develop distinct
immunologic abnormalities, especially autoantibodies.
Among the antibodies found in patients with SLE,
particular attention has been focused on nuclear,
double-stranded DNA (dsDNA), phospholipid, and histone antibodies, and to extractable nuclear antigens
(ENA).
Anti-ENA antibodies are believed to be markers
of particular clinical manifestations of SLE, and may
hold clues to its pathogenesis (1,2). Most of the current clinical knowledge about these antibodies is based
on data from studies in which immunodiffusion techniques were used for their detection (3). Recently,
enzyme-linked immunosorbent assays (ELISAs) for
anti-ENA antibodies have been developed. ELISA has
been proven to be a sensitive and specific detection
method, having advantages over immunodiffusion (3-6),
and is becoming widely used. In the present crosssectional study, we investigated the utility of anti-ENA
antibodies detected by ELISA as a predictor for the
diagnosis of SLE.
SANCHEZ-GUERRERO ET AL
1056
PATIENTS AND METHODS
Patients. Between August 1990 and June 1991, 6,313
sera were sent to the Brigham and Women’s Hospital (BWH)
Clinical Immunology Laboratory for 29.292 tests; 2,185 of
these samples were sent for testing for antinuclear antibodies
(ANA). Sixty-five percent of the ANA tests were ordered by
BWH rheumatologists on patients in whom a rheumatic or
autoimmune disorder was suspected.
The present study was conducted among all patients
who had a positive ANA test result (titer >1:20 on mouse liver
substrate and/or ?1:40 on HEp-2 cells). Patients with a
negative ANA result were not studied, since the probability of
SLE in this group is only 0.14% (7), and several studies have
failed to detect anti-ENA antibodies among these patients
(8,9). All ANA-positive sera are automatically tested for
antibodies to dsDNA, single-stranded DNA, Srn, RNP, Ro/
SS-A, and La/SS-B (ENA).
The medical charts of 259 patients who had a positive
ANA result during the study period were reviewed by one of
the authors (JS-G) to assess the clinical diagnosis according to
the attending physician; at the time of the chart review, this
author was blinded to the anti-ENA antibody results. For 127
patients with a diagnosis of SLE, further data on events
occurring ever in the patient’s history were abstracted. These
events included hemolytic anemia, unintentional weight loss of
>10 Ib, fever, esophageal symptoms (dysphagia, hypomotility),
pulmonary symptoms (restrictive disease, decreased carbon
monoxide diffusing capacity), myositis (elevated creatinine
phosphokinase isoenzyme level, muscle biopsy result consistent with inflammatory myositis), central nervous system
(CNS) manifestations (defined as disturbances in mental function, motor disorders, or neuropathy), leukopenia (white blood
cell count <4,000/mm3 on 2 or more occasions), lyrnphopenia
(lymphocyte count <1.500/mm3 on 2 or more occasions),
thrombocytopenia (platelet count < 100,000/mm3 in the absence of causative drugs)? hematuria (urinary sediment with
2 5 red blood cells/high-power field), and proteinuria ( 21+ on
dipstick examination). Missing or nonexisting data in the
medical chart were considered negative. Duration of the
disease was defined as the time between the date of diagnosis
and the date of the index ENA laboratory test. Clinical and
laboratory features were not compared in ANA+/ENA+
versus A N A t / E N A - patients with a diagnosis other than
SLE. Diagnoses were made using accepted published criteria
(10 -14).
Patients were classified as ENA+ if they had at least 1
positive ENA result ( 2 2 0 units/ml), and ENA- if they did not
have any positive ENA result. One hundred ninety-seven
patients (76%) had more than 1 determination of anti-ENA
antibodies. Because of the retrospective nature of the analysis,
it is difficult to assess with certainty whether the attending
physician used the results of the anti-ENA tests to help
establish the diagnosis of SLE. For this reason, we computed
the number of American College of Rheumatology (ACR)
SLE criteria (10) met by any patient, and report the number of
patients in whom the fourth SLE criterion was anti-Sm antibodies.
ANA, ENA, and dsDNA testing. ANA were detected by
indirect immunofluorescence, utilizing both cryostat sections
of mouse liver and HEp-2 cells as substrate, and fluorescein-
Table 1. Distribution of the 259 antinuclear antibody (ANA) posi-
tive study subjects, according to extractable nuclear antigen (ENA)
status, systemic lupus erythematosus (SLE) diagnosis, and sex
ANA+/ENA+
ANA+/ENA= 112 [43%])
(n = 147 [57%])
(n
Other
(n = 97
[66%])
diagnoses
(n = 50
[34%])*
2(I%)
95 (65%)
44 (30%)
SLE
Male (n = 22)
Female (n = 237)
6(4%)
Other
= 30
[27%])
diagnoses
(n = 82
[73%])t
0
30 (27%)
14 (12%)
68 (61%)
SLE
(n
* Connective tissue diseases (CTD) n = 26 (rheumatoid arthritis 8,
juvenile rheumatoid arthritis 6, mixed connective tissue disease 6,
Raynaud’s phenomenon 3, subacute cutaneous lupus erythernatosus 1,
dermatomyositis 1, Sjogren’s syndrome 1); probable CTD n = 3,
non-autoimmune rheumatic disease n = 3, non-rheumatic diseases
n = 18.
t CTD n = 32 (Raynaud’s phenomenon 10, rheumatoid arthritis 10,
systemic sclerosis or CREST syndrome 5, Sjogren’s syndrome 2,
overlap syndrome 2, antiphospholipid syndrome 1, juvenile rheumatoid arthritis 1, polymyositis 1); non-rheumatic diseases n = 35; other
rheumatic diseases n = 15 (fibromyalgia 8, osteoarthritis 5, spinal
stenosis 1, rotator cuff syndrome 1).
conjugated goat anti-Ig (15,16). The presence and levels of
anti-Sm, anti-RNP, anti-Ro/SS-A, and anti-La/SS-B antibodies were determined by a commercially available IgG isotypespecific ELISA method (Diamedk, Miami, FL) using microtiter wells coated with purified Sm, RNP, Ro/SS-A, and
La/SS-B, according to the manufacturer’s instructions. Test
samples with values 220.0 units/ml were considered positive.
Antibodies to dsDNA were tested by ELISA as described
previously (17).
Statistical analysis. Data analysis was performed using
the SAS statistical computing software package. The factor
ENA antibodies had 2 levels, positive (220) and negative
(<20). The sensitivity and specificity of combinations of ENA
antibodies were tabulated and analyzed using contingency
tables. For continuous variables, analysis was performed by
t-test. Categorical variables were analyzed by chi-square test,
or Fisher’s exact test whenever an expected cell size was <5.
Multivariate analysis was performed using a logistic regression
model. All tests were 2-tailed. P values less than or equal to
0.05 were considered significant.
RESULTS
Study population. Three h u n d r e d sixty-five sera
(of 2,185 tested) had a positive ANA result; for 74% of
these 365 sera, t h e testing h a d been ordered by a
rheumatologist. The 365 sera were from 298 patients.
The computerized medical records of t h e s e 298 patients
were reviewed, and only 259 had information on-line:
78% f r o m t h e Arthritis C e n t e r and 22% from o t h e r
BWH services. These 259 patients were f u r t h e r a n a lyzed. T h e sex, ENA status, a n d diagnoses o f t h e patients
1057
ANTI-ENA IN SLE DIAGNOSIS
are shown in Table 1. Two hundred thirty-seven patients
(91.5%) were female; 147 patients (57%) were classified as
ANA+/ENA+, and 112 patients (43%) as ANA+/ENA-.
Among the ANA+/ENA+ patients, there were 97 (66%)
with a diagnosis of SLE according to their physician (91
[94%] met 8 4 of the ACR criteria for SLE [lo]). In 7 of
these 97 patients, anti-ENA (Sm) constituted the fourth
classification criterion. Most of these SLE patients
(98%) were female. Fifty ANA+/ENA+ patients had
a diagnosis other than SLE, including 26 with another
connective tissue disease (CTD); 18 patients had a
diagnosis of a non-rheumatic disease (Table 1).
Among the ANA+/ENA- patients, there were
30 with a diagnosis of SLE (according to their physician); 26 (87%) met 2 4 criteria for SLE (10). All SLE
patients in this group were female. Eighty-two patients
had a diagnosis other than SLE, including 32 with
another CTD and 35 with a diagnosis of a non-rheumatic
disease (Table 1). The difference in the proportion with
SLE among ANA+/ENA+ and ANA+/ENA- patients
was statistically significant ( P < 0.0001).
Distribution of ENA antibodies. Among all 259
ANA+ patients, anti-Sm was found in 23%, anti-RNP in
27%, anti-RoISS-A in 40%, and anti-La/SS-B in 23%
(Table 2). When we analyzed only the patients with SLE
(n = 127), anti-Sm was found in 34%, anti-RNP in 39%,
anti-Ro/SS-A in 61%. and anti-La/SS-B in 35%. When
the analysis was restricted to the 67 SLE patients who
were negative for anti-dsDNA antibodies, the prevalence of each of the ENA antibodies was similar to that
in the group of all SLE patients. Anti-Ro/SS-A antibodies showed the highest prevalence among the entire
group of patients as well as the patients with SLE.
Significance of antibodies to ENA for the diagnosis of SLE among ANA+ patients. Table 3 shows the
sensitivities and specificities of 4 ENA antibodies and 11
combinations of ENA antibodies with respect to the
diagnosis of SLE in patients with a positive ANA result
(primarily those attending a referral arthritis center).
Anti-Ro/SS-A antibodies showed the highest sensitivity
Table 2. Distribution of anti-ENA antibodies among all ANA+
patients. all SLE patients, and SLE patients without anti-doublestranded DNA (anti-dsDNA) antibodies'
All patients (n = 259)
All SLE patients (n = 127)
Anti-dsDNA- SLE patients
(n = 67)
Srn
RNP
SS-A
SS-B
59 (23)
43 (34)
23 (34)
71 (27)
50 (39)
26 (39)
104 (40)
78 (61)
39 (58)
60 (23)
44 (35)
23 (34)
* Values are the number (96).See Figure 1 for other definitions.
Table 3. Sensitivity and specificity of ENA antibodies for the diagnosis of SLE in all patients with a positive ANA result and in patients
with a positive ANA result and a negative anti-double-stranded DNA
(anti-dsDNA) result'
All ANA+ patients
(n = 259)
ANA+/dsDNA patients
(n = 184)
Sensitivity
Specificity
Sensitivity
RNP
Ro
La
34
39
61
35
88
84
80
88
34
39
58
34
90
86
82
89
Sm. RNP
Srn, Ro
Sm, La
RNP, R o
RNP. La
Ro, La
24
25
20
27
19
32
94
95
94
95
96
93
25
22
17
24
19
30
96
96
95
97
98
94
Sm. RNP, R o
Sm, RNP. La
Sni, Ro, La
RNP. Ro, La
18
14
17
17
98
97
95
98
15
13
12
15
99
98
97
99
Srn, RNP, Ro, La
12
98
9
100
Srn
+
Specificity
See Figure I for other definitions.
(61%), but also the lowest specificity (80%). Anti-Sm
antibodies had high specificity (88%), but low sensitivity
(34%). As expected, the specificity of ENA antibodies
increased as more of them were added, but the sensitivity decreased.
By univariate analysis, the presence of each of the
ENA antibodies as well as the 11 combinations were
statistically significant for the diagnosis of SLE (P 4
0.001). By multivariate analysis, after controlling for 2
significant factors (anti-Ro/SS-A [P = 0.00011 and
anti-RNP [P = 0.0015]), no other factors were associated with the diagnosis of SLE. The combination of
these 2 antibodies had an odds ratio (OR) of 7.68 (95%
confidence interval [95% CI] 3.1-10.04) and a receiver
operating characteristic (ROC) curve value of 0.75 for
the diagnosis of SLE. Anti-Ro/SS-A had an O R of 6.5
(95% CI 3.8-11.1) and an ROC curve value of 0.71;
anti-RNP had an odds ratio of 3.4 (95% CI 1.9-6.1) and
an ROC curve value of 0.61 for the diagnosis of SLE.
Significance of anti-dsDNA antibodies for the
diagnosis of SLE. Of the 259 ANA+ patients, 251 were
tested for anti-dsDNA antibodies. Of these 251 patients,
67 (27%) tested positive. Sixty of the 67 (90%) had a
diagnosis of SLE; the diagnoses in the other 7 patients
were mixed connective tissue disease in 3, rheumatoid
arthritis in 2, Sjogren's syndrome in 1, and congestive
heart failure in 1. The anti-dsDNA+ SLE patients
SANCHEZ-GUERRERO ET AL
1058
constituted 47% of the SLE group as a whole (60 of
127). The presence of anti-dsDNA antibodies in those
with a positive ANA result had a sensitivity of 49% and
a specificity of 95% for the diagnosis of SLE. The O R for
the diagnosis of SLE in the presence of dsDNA antibodies was 16.9 (95% CI 7.3-39.0), and the ROC curve
value was 0.72. Among the 67 patients with anti-dsDNA
antibodies, none of the ENA antibodies alone or in any
of the 11 possible combinations were of additional aid
for the diagnosis of SLE, either in the univariate or the
multivariate analysis.
Significance of ENA antibodies for the diagnosis
of SLE among patients without dsDNA antibodies.
Among the 184 ANA+/dsDNA- patients, the specificity of each ENA antibody and of the 11 combinations for
the diagnosis of SLE was slightly greater compared with
that shown when all 259 ANA+ patients were studied
(Table 3). Among the ENA antibodies, anti-Ro/SS-A
showed the highest sensitivity (58%) and specificity
(82%) for the diagnosis of SLE. All other ENA antibodies and their possible combinations showed lower sensitivity (139%), but higher specificity (286%).
By univariate analysis, all ENA antibodies and
the 11 different combinations were statistically significant for the diagnosis of SLE. By multivariate analysis,
only 2 factors reached statistical significance: anti-Ro/
SS-A was the strongest ( P = O.OOOl), and the combination Sm and RNP was the next strongest predictor (P =
0.0013). This combination had an ROC curve value of
0.75. Anti-Ro/SS-A alone had an O R of 6.5 (95% CI
3.8-11.1) and an ROC curve value of 0.70 for the
diagnosis of SLE.
Clinical manifestations. The ANA+/ENA+ and
ANA+/ENA- SLE patient groups did not show any
major difference in terms of clinical manifestations
(Table 4). Pleuritis (P = 0.039) and hydroxychloroquine
use ( P = 0.018) were more frequent among ANA+/
ENA+ patients. Other clinical manifestations, such as
renal, hematologic, and CNS involvement and skin
manifestations (malar rash, photosensitivity), were not
significantly different between groups. The prevalence of
dsDNA antibodies, dosage of prednisone, and use of
immunosuppressive agents were also similar in the 2
groups. Nine patients in the ANA+/ENA+ group received treatment with intravenous cyclophosphamide
versus none in the ANA+/ENA- group; this difference
was not significant ( P = 0.11). The mean age of the
patients at the time of the index test and the duration of
disease were similar in the 2 groups, although M A + /
ENA- patients had disease of shorter duration (9.27
years versus 11.23 years). We did not compare clinical
Table 4. Clinical manifestations among ANA+/ENA+ and ANA+/
ENA- SLE patients*
Clinical manifestation
Leukopenia
Lymphopenia
Thrombocytopenia
Hematuria
Proteinuria
Autoimmune hemolytic
anemia
Arthritis
Art hralgias
Weight loss
Fatigue
Fever
Raynaud’s phenomenon
Myalgias
Myositis
Rash
Discoid lupus
Alopecia
Photosensitivity
Mouth sores
Pleuritis
Pericarditis
Seizures
Psychosis
CNS other
dsDNA
Treatment
Hydroxychloroquine
Prednisone
Immunosuppressive
drugs
IV cyclophosphamide
Prednisone dosage,
mean f SD mglday
Disease duration, mean
2 SD years
Age, mean 5 SD years
ENAt
patients
(n = 97)
ENApatients
(n = 30)
P
29 (30)
41 (42)
13 (13)
41 (42)
37 (38)
5 (5)
7 (23)
7 (23)
3 (10)
10 (33)
10 (33)
0
NS
NS
NS
NS
NS
NS
72 (74)
79 (81)
11 (11)
51 (53)
24 (25)
56 (58)
5 (5)
1(1)
67 (69)
10 (10)
40 (41)
40 (41)
15 (15)
50 (52)
24 (25)
12 (12)
3 (3)
7 (7)
46 (47)
25 (83)
28 (93)
2 (7)
12 (40)
5 (17)
15 (50)
0
0
18 (60)
2 (7)
13 (43)
10 (33)
4 (13)
9 (30)
4 (13)
2 (7)
0
4 (13)
14 (47)
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
0.039
NS
NS
NS
NS
NS
53 (55)
55 (57)
14 (15)
9 (30)
12 (40)
3 (10)
0.018
NS
NS
9 (9)
16.98 f 14.46
0
15.66 t 12.56
NS
NS
11.23 ? 7.97
9.27 t 8.56
NS
40.26 f 11.89
40.44 -+ 12.22
NS
~
* Except where otherwise indicated, values are the number (‘31).NS =
not significant; CNS = central nervous system; dsDNA = doublestranded DNA; IV = intravenous.
and laboratory features in ANA+/ENA+ and ANA+/
ENA- patients with diagnoses other than SLE.
DISCUSSION
In many cases, a diagnosis of systemic lupus
erythematosus has a level of uncertainty. The ANA test,
the best screening study for SLE, is positive in 99% of
SLE patients (7,lO) and should be performed whenever
SLE is suspected. However, a positive ANA test result
has a positive predictive value for SLE of 19-35%
(7,18); for this reason, after ANA testing, patients may
need further tests in order to help confirm a diagnosis of
ANTI-ENA IN SLE DIAGNOSIS
SLE. We studied the utility of anti-ENA antibodies
detected by ELISA as a predictor for the diagnosis of
SLE in patients with a positive ANA result seen in a
referral hospital.
In our study, the prevalence of anti-ENA antibodies among all of the patients with positive ANA, and
the percentage of SLE patients who tested positive for
anti-ENA antibodies, were consistent with reported data
(2,3,5,6,19). The distribution of anti-ENA antibodies
among SLE patients fell within the range described
(2-4,6,19,20) except for anti-La, which showed a higher
frequency.
We noted a diagnosis of SLE more commonly
among ANA+/ENA+ patients than among M A + /
ENA- patients ( P < 0.0001). In our study, which
primarily included patients attending a referral rheumatology center, the positive predictive value increased
from 49% when a patient had a positive ANA result to
66% when a patient had both a positive ANA and a
positive ENA result.
Anti-dsDNA antibodies have high specificity for
the diagnosis of SLE (10). In our study, this specificity
was 95%. It has been suggested that if anti-dsDNA
antibodies are positive in a patient with SLE symptoms
and positive ANA, it is diagnostically irrelevant whether
that same serum is positive for other antibodies (8,21).
This statement was confirmed in our study. When we
studied the utility of anti-ENA antibodies for the diagnosis of SLE among patients with anti-dsDNA antibodies, none of them was additionally useful.
The prevalence of anti-dsDNA antibodies in our
SLE patients (47%) falls within the reported range of
20-91% (7,8). The distribution of anti-dsDNA antibodies was identical among ANA+/ENA+ and M A + /
ENA- SLE patients. This result is consistent with the
findings of previous studies in which the prevalence of
anti-dsDNA antibodies was similar between patients
with and without anti-Sm (22) or anti-Ro (23) antibodies. However, a higher prevalence of anti-DNA
antibodies has been reported among patients with antiRo antibodies compared with patients with both anti-Ro
and anti-la antibodies (24). We did not evaluate the
frequency of anti-dsDNA antibodies in relation to specific anti-ENA antibodies.
Among ANA+/dsDNA- patients, all anti-ENA
antibodies and 11 different combinations were statistically significant predictors for the diagnosis of SLE.
Anti-Sm or any combination of anti-ENA antibodies
showed a specificity of 290% for the diagnosis of SLE.
In previous studies, a substantial percentage of patients
with other CTDs have been shown to have anti-Sm
1059
antibodies (2,3,25). Whether the specificity for SLE of
anti-Sm antibodies detected by ELISA is similar to or
lower than the specificity of these antibodies detected by
immunodiffusion is controversial (2,19).
Anti-Ro/SS-A antibodies are a common finding
in the serum of SLE patients, suggesting a high degree of
sensitivity for SLE (26). Testing for these antibodies has
been recommended as a diagnostic study for SLE among
patients with persistently negative ANA results (26). In
our study population, anti-Ro/SS-A was the strongest
predictor for the diagnosis of SLE.
No major clinical differences were found between
ANA+/ENA+ and ANA+/ENA- SLE patients. Only
pleuritis and use of hydroxychloroquine were significantly higher among SLE ANA+/ENA+ patients. We
do not know with certainty why ANA+/ENA+ SLE
patients in our study were receiving hydroxychloroquine
more frequently than were ANA+/ENA- patients. Several studies have shown an association between specific
anti-ENA antibodies and clinical manifestations (21),
including photosensitivity (26,27), malar rash (2),
Raynaud’s phenomenon (2,28), lung fibrosis, and pericarditis (29); nevertheless, these associations have not
been consistent (9,19,22,30). Although we did not specifically analyze the association of any clinical manifestations and antibodies, our results are consistent with
those of another study in which the clinical association of
anti-ENA antibodies was studied among 94 SLE patients
with a mean followup 11.8 years (30).
Some limitations of our study must be considered. The study was conducted in a referral rheumatology center; this is reflected in the high percentage of
patients with CTD (71%), especially SLE (49%). The
high prevalence of SLE among our clinic population
leads to overestimation of the predictive value of ENA
antibodies (31), and may not reflect the predictive value
in the general population. It may also reflect the selectiveness of rheumatologists in deciding when to order an
ANA test. The strong female predominance in the study
population (91.5%) suggests that the study may be
biased toward SLE or that rheumatologists order ANA
tests mostly on SLE patients and not on all CTD
patients.
A potential bias arises if attending physicians
used the results of the anti-ENA antibody tests to
establish the diagnosis of SLE in their patients. Because
of the retrospective nature of the analysis, it is impossible to know with certainty if this situation occurred.
However, we consider it unlikely, since in only 7 of the
97 SLE ANA+/ENA+ patients did anti-Sm constitute
the fourth ACR classification criterion.
SANCHEZ-GUERRERO
1060
Our cross-sectional study represents prevalent,
not incident, findings. The duration of the disease in the
ANA+/ENA+ and ANA+/ENA- SLE groups was 11
years and 9 years, respectively. If long-term survival
accounts for the frequencies of anti-ENA antibodies and
the clinical manifestations in our population, then
anti-ENA antibody status may be only an epiphenomenon.
We did not study the relationship between
anti-ENA antibodies and SLE activity. In the patients
studied, we did not ascertain race, which has been
associated with differences in the frequency of anti-Sm
and anti-RNP antibodies (32).
In our experience, ELISA testing for anti-ENA is
morq sensitive than immunodiffusion testing. Furthermore, we have observed variability in ELISA anti-ENA
kits from different manufacturers. Therefore, the results
of the present investigation cannot necessarily be extrapolated to derive predictive values of anti-ENA determined by methods not used in this study.
Based on the results of this study, we may conclude that testing for anti-ENA antibodies, especially
anti-Ro/SS-A, improves the ability to diagnose SLE,
primarily among patients attending a referral rheumatology center who are positive for ANA. This improvement is significant among patients without anti-dsDNA
antibodies. The prevalence of anti-dsDNA antibodies
seems to be independent of the presence of anti-ENA
antibodies. We did not find major clinical differences
among SLE patient groups divided according to ENA
status.
ACKNOWLEDGMENTS
The authors thank the staff of the Clinical Immunology
Laboratory, Brigham and Women’s Hospital for their help and
support, and Matthew H. Liang, MD, MPH for reviewing the
manuscript.
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detected, systemic, antigen, erythematosus, anti, utility, assays, lupus, antilass, nuclear, immunosorbent, extractable, antiross, enzymes, rnp, diagnosis, linked
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