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Sjgren's syndrome associated with systemic lupus erythematosusClinical and laboratory profiles and comparison with primary Sjgren's syndrome.

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ARTHRITIS & RHEUMATISM
Vol. 50, No. 3, March 2004, pp 882–891
DOI 10.1002/art.20093
© 2004, American College of Rheumatology
Sjögren’s Syndrome Associated With
Systemic Lupus Erythematosus
Clinical and Laboratory Profiles and Comparison With
Primary Sjögren’s Syndrome
Menelaos N. Manoussakis,1 Chryssoula Georgopoulou,1 Elias Zintzaras,2 Marilyn Spyropoulou,3
Aikaterini Stavropoulou,3 Fotini N. Skopouli,4 and Haralampos M. Moutsopoulos1
a clinically similar sicca syndrome, but were significantly younger and had an increased frequency of
perivascular infiltrates in the salivary glands associated
with anticardiolipin antibodies in the serum. SLE–SS
patients had a high frequency of the DRB1*0301 allele.
This HLA profile distinguished the SLE–SS group from
the SLE–no SS group, who had an increased frequency
of DRB1*1501 and DQB1*0602 alleles, but was similar
to the HLA profile of the primary SS group, who had an
increased frequency of DRB1*0301.
Conclusion. SLE–SS appears to constitute a subgroup of patients with distinct clinical, serologic, pathologic, and immunogenetic features, in whom SS is
expressed as an overlapping entity and is largely similar
to primary SS.
Objective. To address the clinical, serologic,
pathologic, and immunogenetic features of sicca syndrome that occurs in systemic lupus erythematosus
(SLE), as well as its similarities to, and differences
from, sicca syndrome that occurs in primary Sjögren’s
syndrome (SS).
Methods. A cohort of 283 consecutive unselected
SLE patients was evaluated for the presence of associated SS using the American–European classification
criteria. Clinical and laboratory parameters in SLE
patients with SS (SLE–SS) were compared with those in
SLE patients without SS (SLE–no SS) and with a group
of 86 unselected patients with primary SS.
Results. SS was identified in 26 SLE patients
(9.2%); the SS preceded the development of lupus in 18
of them (69.2%). Compared with the SLE–no SS group,
patients with SLE–SS were significantly older, had a
higher frequency of Raynaud’s phenomenon, anti-Ro/
SSA, anti-La/SSB, and rheumatoid factor, but had a
significantly lower frequency of renal involvement,
lymphadenopathy, and thrombocytopenia. Compared
with the primary SS group, SLE–SS patients displayed
Sjögren’s syndrome (SS) is a chronic autoimmune
disorder of the exocrine glands with associated lymphocytic infiltration of the affected glands. Dryness of the
mouth and/or the eyes, resulting from involvement of
the salivary and lacrimal glands, is most often present
(1). The exocrinopathy may be encountered alone or in
the presence of another autoimmune disorder.
Features of SS may be found in almost every
autoimmune rheumatic disease, including rheumatoid
arthritis (RA), systemic lupus erythematosus (SLE),
scleroderma, and others (1). With regard to the pathogenesis, it is unclear whether this form of SS associated
with another autoimmune rheumatic disease represents
a distinct overlapping entity or a manifestation in the
clinical spectrum of the accompanying rheumatic disorder (2). In fact, comparisons of the clinical, serologic,
and immunogenetic features of patients with SS who
have no evidence of another autoimmune disease and
1
Menelaos N. Manoussakis, MD, Chryssoula Georgopoulou,
MD, Haralampos M. Moutsopoulos, MD, FACP, FRCP (Edin):
School of Medicine, National University of Athens, Athens, Greece;
2
Elias Zintzaras, MSc, PhD: School of Medicine, Biomathematics
Unit, University of Thessaly, Larissa, Greece; 3Marilyn Spyropoulou,
MD, Aikaterini Stavropoulou, MD: National Tissue Typing Center,
George Gennimatas General Hospital, Athens, Greece; 4Fotini N.
Skopouli, MD: Harokopio University, Athens, Greece.
Address correspondence and reprint requests to Menelaos N.
Manoussakis, MD, Department of Pathophysiology, Medical School,
University of Athens, 75 Mikras Asias Street, Athens 115 27, Greece.
E-mail: menman@med.uoa.gr.
Submitted for publication October 8, 2002; accepted in revised form December 3, 2003.
882
CLINICAL AND LABORATORY PROFILES IN SS–SLE COMPARED WITH PRIMARY SS
those of patients with SS associated with RA have
revealed distinct profiles (3,4). Consequently, the terms
“primary SS” and “secondary SS” were proposed for the
former and the latter groups of patients, respectively (3).
Such a clear distinction has not been established between primary SS and the sicca syndrome that coexists in
autoimmune diseases other than RA, mainly because of
a lack of comprehensive studies. Nevertheless, during
the recent decade, the term “secondary SS” has generally been applied to connote sicca disorder that occurs
together with any autoimmune disorder, without regard
for the presence of true overlap cases.
The clinical coexistence of SLE and SS (SLE–SS)
was recognized almost half a century ago (5). The
prevalence of SS among patients with SLE varies considerably among the published studies (from 8% to
30%), most likely due to the application of different
classification and patient selection criteria (6–9). Although controversy exists (10,11), studies have indicated
that in patients with SLE–SS, the associated lupus
appears to be relatively more benign, and that these
patients exhibit a relatively increased frequency of autoantibodies to Ro/SSA and La/SSB RNPs and rheumatoid factor (7,8,12). However, these studies are limited,
and for most of them, the application of SS criteria that
are not well established and the low number of patients
studied precludes meaningful evaluation and conclusions. Therefore, the expression of SS that coexists with
SLE needs to be further addressed. In addition, several
issues pertaining to SLE–SS need to be clarified, including the severity of sicca manifestations in these patients,
the temporal relationship between the development of
sicca disorders and lupus itself, as well as the possible
association with the immunogenetic background.
In the present study, we sought to determine the
clinical, serologic, pathologic, and immunogenetic features of SLE–SS using well-defined SS classification
criteria (13,14). For this purpose, we studied a cohort of
unselected SLE patients and compared the expression of
sicca manifestations, as well as systemic disease features
in patient subgroups with and without SS, and in patients
with primary SS.
PATIENTS AND METHODS
Patients. Patients studied included 283 consecutive
unselected SLE patients (15) who were followed up in our
department (Department of Pathophysiology, Medical School,
National University of Athens) from 1994 to 1999. All patients
were Caucasians of Greek origin and were evaluated for
evidence of secondary SS according to the established European classification criteria (13). These classification criteria for
883
secondary SS do not include serologic items, and they remained unchanged in the recently published revised form of
criteria proposed by the American–European Consensus
group (14).
All patients were initially evaluated by questionnaire
for the presence of subjective symptoms of oral or ocular sicca
(13). None of the patients with subjective sicca problems had a
history or clinical evidence of primary lymphoma, infection
with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus, head and neck radiation therapy, sarcoidosis,
graft-versus-host disease, or were receiving treatment known
to cause mucosal dryness. Patients with affirmative responses
to the questionnaire(s) underwent objective assessment of
lacrimal and salivary gland involvement, which included slit
lamp examination of the eye with rose bengal staining of
conjunctivae (abnormal if ⱖ4 of 9, according to the scoring
system of Van Bijsterveld), Schirmer I test (abnormal if ⱕ5
mm in 5 minutes), and measurement of unstimulated salivary
flow (whole saliva; abnormal if ⱕ1.5 ml in 15 minutes).
Patients with subjective sicca problems but without objective
findings were excluded from further study.
Patients with subjective complaints and objective findings of sicca consented to undergo a minor labial salivary gland
biopsy under local anesthesia. Lip biopsy was not performed in
6 patients (4 declined biopsy; 2 others declined for medical
reasons [anticoagulation treatment]). Tissue specimens were
scored according to the method described by Chisholm and
Mason (16).
SLE patients who met the classification criteria for
secondary SS (14) were designated as the SLE–SS group. Data
from these patients were compared with data obtained from a
group of 76 consecutive, randomly selected SLE patients (1:3
randomized selection, according to the hospital registry) who
had no subjective or objective findings of sicca (SLE–no SS
group), as well as with data obtained from a group of 86
consecutive, unselected patients with primary SS (14).
The patients’ medical records were retrospectively
analyzed for demographic, clinical, and laboratory data. For all
patients, the onset and duration of either SLE (for the SLE–no
SS and the SLE–SS groups) or SS (for the SLE–SS and the
primary SS groups) were defined from the time when the
diagnosis of SLE or SS could be ascertained by the established
classification criteria (14,15). For patients with SS, the duration of sicca manifestations was determined from the date
when the first sicca symptom (either xerostomia or xerophthalmia) had appeared.
Clinical features. Various clinical manifestations were
recorded and analyzed separately. Renal involvement was
based on the presence of at least 1 of the following 4 criteria:
1) persistently elevated urinary pH value (ⱖ6.0), 2) persistently elevated serum creatinine level (⬎1.5 mg/dl) and/or
impaired creatinine clearance (⬍50 ml/minute), 3) persistent
proteinuria (ⱖ500 mg/day) for more than 3 months, or 4) a
pathologic urine sediment (consisting of ⬎10 red blood cells
per high-power field or red blood cell casts), which was
confirmed by kidney biopsy, according to standard criteria
(17). Pulmonary involvement was identified by the presence of
at least 1 of the following 4 criteria: 1) chronic interstitial
infiltrates on chest roentgenography, 2) restrictive or obstructive disease on pulmonary function testing, 3) decreased
884
MANOUSSAKIS ET AL
Table 1. Comparison of the general features of the study patients, by diagnostic group*
P
Feature
SLE–no SS
(n ⫽ 76)
SLE–SS
(n ⫽ 26)
Primary SS
(n ⫽ 86)
SLE–SS vs.
SLE–no SS
SLE–SS vs.
primary SS
Age, years
% female
Age at SLE onset, years
Age at SS onset, years
Duration of SLE, years
Duration of SS, years
36.1 ⫾ 1.6
81.6
29.7 ⫾ 1.5
NA
5.9 ⫾ 0.5
NA
48.3 ⫾ 2.5
100
44.8 ⫾ 2.4
44.7 ⫾ 2.7
3.5 ⫾ 0.5
3.7 ⫾ 0.7
56.5 ⫾ 1.5
93.0
NA
51.5 ⫾ 1.6
NA
4.9 ⫾ 0.4
⬍0.001
0.018
⬍0.001
NA
0.011
NA
0.007
0.333
NA
0.010
NA
0.068
* The onset (and therefore, duration) of systemic lupus erythematosus (SLE) or Sjögren’s syndrome (SS) was defined from the time when the
diagnosis of SLE or SS could be ascertained by the established classification criteria (14,15). Except where indicated otherwise, values are the
mean ⫾ SEM. P values less than 0.05 are considered significant. NA ⫽ not applicable.
diffusion capacity for carbon monoxide (DLCO ⬍80%), or 4)
pulmonary hypertension.
The occurrence of peripheral neuropathy was established based on symptoms associated with the clinical presence
of motor or sensory deficits and compatible electrophysiologic
findings. Central nervous system (CNS) involvement was defined according to the American College of Rheumatology
nomenclature and case definitions for neuropsychiatric lupus
syndromes (18). Myositis was documented by the presence of
proximal muscle weakness associated with increased aldolase
or creatine phosphokinase levels and compatible findings on
electromyography and muscle biopsy. The diagnosis of antiphospholipid syndrome was based on established criteria
(19). Serositis was defined as pleurisy documented by clinical
examination and pleural effusion on chest radiography or
pericarditis documented by pericardial effusion on echocardiography. The development of lymphoma was documented by
biopsy.
Laboratory features. The occurrence of laboratory
abnormalities (verified on at least 2 successive measurements)
was also recorded, including hemolytic anemia (features of
hemolysis with a hemoglobin level ⬍12 gm/dl), leukopenia
(white blood cell count ⬍4,000/mm3), lymphopenia (lymphocyte count ⬍1,500/mm3), and thrombocytopenia (platelet
count ⬍100,000/mm3), or the presence of serum cryoglobulins,
rheumatoid factor (by latex test; positive at a titer ⱖ1:80 or a
value ⱖ20 IU/ml), antinuclear antibodies (ANAs) (by indirect
immunofluorescence; positive at a titer ⱖ1:160), antibodies to
Sm, U1 RNP, Ro/SSA, and La/SSB cellular antigens (by
counterimmunoelectrophoresis), IgG antibodies to doublestranded DNA (dsDNA) (by enzyme-linked immunosorbent
assay [ELISA]), or IgG and IgM antibodies to cardiolipin (by
ELISA) (20).
Patients also underwent typing for HLA–DRB, DQA,
and DQB, which was performed by polymerase chain reaction
and hybridization with sequence-specific oligonucleotide
probes. These results were compared with the data obtained
from 246 unrelated healthy controls.
Statistical analysis. Statistical analyses were performed using SAS software (version 6; SAS Institute, Cary,
NC). The data from the 3 patient groups (SLE–no SS, SLE–SS,
and primary SS) were analyzed for statistically significant
associations using a multinomial logit model (21) or Fisher’s
exact test for binary values and the Kruskal-Wallis and the
Mann-Whitney nonparametric tests for continuous responses.
The multinomial logit model is a vigorous method for the
simultaneous detection of significant variables that can distinguish the 3 groups. The multinomial logit model was not
utilized for variables that were not applicable to all 3 groups or
had unbalanced data. For such isolated comparisons, Fisher’s
exact test was applied, whereas a logit model was used for the
evaluation of differences in sicca manifestations between the 2
SS groups (SLE–SS and primary SS). The association of
phenotypic or allelic HLA frequencies in the various groups of
patients was tested using the chi-square test with Yates’
correction. P values less than 0.05 were considered significant.
RESULTS
Taken as a whole, the SLE and primary SS
patient groups studied were similar to other larger
patient cohorts previously described (22,23), as supported by the comparison of clinical and laboratory
profiles. Fifty-one of the 283 SLE patients (18.0%) had
subjective complaints of oral and/or ocular sicca,
whereas 35 of the 283 patients (12.4%) also had objective evidence of ocular and/or oral glandular involvement. Twenty-six of these 35 patients with SLE and sicca
manifestations (9.2% of the total SLE population) fulfilled the American–European classification criteria for
secondary SS (14 met 4 criteria; 12 met 3 criteria) (14)
and were designated as the SLE–SS group. Full-blown
SS (subjective complaints of both xerostomia and xerophthalmia corroborated by findings of objective assessments) was observed in 16 of the 26 patients with
SLE–SS (61.5%; 5.7% of the total SLE population).
Demographic data. The demographic and general characteristics of the 3 patient groups (SLE–SS,
SLE–no SS, and primary SS) are summarized in Table 1.
Patients with SLE–SS were significantly older than those
with SLE–no SS (P ⬍ 0.001) but were younger than
those with primary SS (P ⫽ 0.007). As determined by the
time when patients met the clinical diagnosis of SLE, the
development of lupus was relatively delayed in patients
CLINICAL AND LABORATORY PROFILES IN SS–SLE COMPARED WITH PRIMARY SS
Figure 1. Onset of sicca manifestations in relation to the onset of
systemic lupus erythematosus (SLE) in the 26 patients with SLE–Sjögren’s syndrome.
with SLE–SS compared with those with SLE–no SS (P ⬍
0.001). Compared with the primary SS group, SS was
clinically recognized relatively earlier in the SLE–SS
group (P ⫽ 0.010).
Sicca manifestations. Sicca manifestations preceded the onset of SLE by 1–15 years in 18 of the 26
patients with SLE–SS (69.2%). In fact, these 18 patients
885
were being followed up and treated primarily for the
sicca symptoms and mild extraglandular manifestations.
Among all 26 SLE–SS patients, the median onset of
sicca manifestations was ⫺4 years relative to the onset of
SLE (range ⫺15 years to ⫹3 years) (Figure 1). Another
4 of the 26 patients experienced the concurrent development of symptoms and findings that signified the
diagnoses of both SLE and SS. In the remaining 4
patients of this group, the diagnosis of SLE preceded the
diagnosis of SS by 2–3 years.
Twenty-three of the 26 SLE–SS patients (88.5%)
had subjective complaints of both xerophthalmia and
xerostomia, whereas the 3 remaining patients reported
only xerophthalmia (2 patients) or only xerostomia (1
patient). Xerophthalmia was self-reported by 15 patients
(57.7%) and xerostomia was self-reported by 14 patients
(53.8%) of the SLE–SS group. Objective assessments
revealed the occurrence of both ocular and oral sicca
involvement in 19 of the 26 patients (73.1%), whereas 6
patients had only ocular involvement and 1 had only oral
involvement. Comparison of sicca manifestations between the SLE–SS and primary SS groups revealed
distinct similarities and differences (Table 2).
As in patients with primary SS, in the majority of
Table 2. Comparison of sicca manifestations between patients with SLE–SS and patients with
primary SS*
Sicca manifestation
Subjective sicca symptoms
Age at onset, mean ⫾ SEM years
Duration prior to SS diagnosis, mean ⫾ SEM years
Xerophthalmia
% positive
Duration, mean ⫾ SEM years
Xerostomia
% positive
Duration, mean ⫾ SEM years
Dyspareunia
% positive
Salivary gland enlargement
% positive
Duration, mean ⫾ SEM years
Objective assessment of ocular involvement
% positive on Schirmer I testing
% positive on rose bengal staining
Objective assessment of salivary gland involvement
% with positive findings
Salivary flow, mean ⫾ SEM ml/15 minutes
Histologic features of minor salivary gland biopsy
% with positive findings
No. of foci/4 mm2, mean ⫾ SEM
% with perivascular infiltrates
SLE–SS
(n ⫽ 26)
Primary SS
(n ⫽ 86)
40.7 ⫾ 2.7
3.9 ⫾ 0.9
48.5 ⫾ 1.5
4.1 ⫾ 0.5
0.015
0.798
96.2
6.3 ⫾ 0.9
94.2
8.4 ⫾ 0.6
0.547
0.139
92.3
7.4 ⫾ 0.9
97.7
8.2 ⫾ 0.6
0.118
0.748
46.2
20.9
0.004
46.2
7.6 ⫾ 1.3
51.2
ND
0.857
NA
76.9
65.4
84.9
83.7
0.115
0.022
75.0
1.4 ⫾ 0.4
74.3
1.0 ⫾ 0.3
0.781
0.260
91.3
1.6 ⫾ 0.3
38.9
97.6
1.7 ⫾ 0.1
2.4
0.205
0.130
⬍0.001
P
* P values less than 0.05 are considered significant. SLE ⫽ systemic lupus erythematosus; SS ⫽ Sjögren’s
syndrome; ND ⫽ not done; NA ⫽ not applicable.
886
MANOUSSAKIS ET AL
1.4 versus 4.8 ⫾ 1.0 years; P ⫽ 0.037), and salivary gland
enlargement (9.2 ⫾ 1.9 versus 2.8 ⫾ 0.6 years; P ⫽
0.019).
Clinical and laboratory features. The prevalence
of distinct disease manifestations in the groups of patients with SLE–no SS, SLE–SS, and primary SS are
presented in Table 3. As derived from the multinomial
logit model, a particular set of clinical variables, namely,
Raynaud’s phenomenon, renal involvement, lymphadenopathy, and thrombocytopenia, was found to be important overall for discriminating SLE–SS patients from
SLE–no SS patients. In contrast, the set of Raynaud’s
phenomenon, arthritis, serositis, lymphadenopathy, and
CNS involvement was found to be important for discriminating SLE–SS patients from primary SS patients (Table 3).
Histologic evidence of kidney disease was obtained in 3 patients with SLE–SS and in 35 patients with
SLE–no SS. Among the patients with SLE–SS, 2 had
histologic lesions of focal segmental proliferative glomerulonephritis (GN) (World Health Organization
[WHO] class III), and 1 had diffuse membranous
GN (WHO class V). Among those with SLE–no SS,
kidney disease was classified as mesangial hyperplasia
(WHO class II) in 3 patients, focal segmental proliferative GN (WHO class III) in 12, diffuse proliferative GN (WHO class IV) in 7, membranoproliferative
GN (WHO class V) in 11, and advanced sclerosing GN
Figure 2. Characteristic presentation of perivascular mononuclear
cell infiltrates in the minor salivary gland tissue of a patient with
systemic lupus erythematosus–Sjögren’s syndrome.
SLE–SS patients, minor salivary gland lesions were
characterized by periductal lymphocytic infiltrates,
which occasionally were extensive. Nevertheless, lymphocytic infiltrative lesions that were primarily located
perivascularly were recorded in a considerable proportion of SLE–SS patients (38.9%), but not in those with
primary SS (P ⬍ 0.001) (Table 2 and Figure 2). Compared with patients without perivascular infiltrates,
SLE–SS patients with perivascular infiltrates had longer
durations of disease (mean ⫾ SEM 16.6 ⫾ 3.9 versus
7.4 ⫾ 1.3 years; P ⫽ 0.030), sicca manifestations (9.0 ⫾
Table 3. Comparison of various disease manifestations between the study groups*
P
% positive
Disease manifestation
SLE–no SS
(n ⫽ 76)
SLE–SS
(n ⫽ 26)
Primary SS
(n ⫽ 86)
SLE–SS vs.
SLE–no SS
SLE–SS vs.
primary SS
Raynaud’s phenomenon
Arthritis
Mucocutaneous involvement
Livedo reticularis
Purpura
Myositis
Lung involvement
Kidney involvement
Peripheral nerve involvement
CNS involvement
Antiphospholipid syndrome
Serositis
Lymphadenopathy
Hemolytic anemia
Thrombocytopenia
Leukopenia
Lymphopenia
Lymphoma
43.4
51.3
80.3
39.5
36.8
2.6
11.8
55.3
5.3
19.7
22.4
36.8
46.1
18.4
26.3
51.3
52.6
0.0
80.8
76.9
88.5
15.4
30.8
3.8
11.5
11.5
11.5
11.5
7.7
50.0
19.2
7.7
7.7
38.5
50.0
0.0
43.0
31.4
NA
11.6
25.6
3.5
9.3
4.7
11.6
0.0
0.0
4.7
44.2
0.0
1.2
44.2
34.9
7.0
⬍0.001
0.277
0.552
0.082
0.673
0.622
0.891
0.005
0.129
0.552
0.144
0.779
0.004
0.348
0.030
0.331
0.741
NA
0.033
0.002
NA
0.402
0.634
0.558
0.610
0.148
0.783
0.012
0.052
⬍0.001
0.002
0.055
0.104
0.790
0.222
0.113
* P values less than 0.05 are considered significant. SLE ⫽ systemic lupus erythematosus; SS ⫽ Sjögren’s syndrome; NA ⫽ not
applicable; CNS ⫽ central nervous system.
CLINICAL AND LABORATORY PROFILES IN SS–SLE COMPARED WITH PRIMARY SS
887
Table 4. Comparison of serologic features between the study groups*
P
% positive
Serologic feature
SLE–no SS
(n ⫽ 71)
SLE–SS
(n ⫽ 26)
Primary SS
(n ⫽ 86)
SLE–SS vs.
SLE–no SS
SLE–SS vs.
primary SS
Anti-Ro/SSA antibodies alone
Anti-La/SSB antibodies
Anti-Sm antibodies
Anti–U1 nRNP antibodies
Anti-dsDNA antibodies
Anticardiolipin antibodies
Rheumatoid factor
Cryoglobulins
23.9
7.0
11.3
12.7
77.3 (58/75)
52.9 (37/70)
28.6 (14/49)
14.7 (5/34)
38.5
38.5
7.7
11.5
69.2
45.8 (11/24)
64.0 (16/25)
15.8 (3/19)
33.7
29.1
0.0
1.2
0.0
10.3 (4/39)
61.7 (50/81)
15.1 (8/53)
0.008
⬍0.001
0.999
0.999
0.436
0.639
⬍0.001
0.999
0.291
0.192
0.056
0.013
⬍0.001
⬍0.001
0.999
0.999
* Anti-Ro/SSA antibodies were detected either alone or in the presence of anti-La/SSB antibodies. Anti-La/SSB antibodies
were always detected in the presence of anti-Ro/SSA antibodies. Values in parentheses are the number of patients
positive/number tested. P values less than 0.05 are considered significant. SLE ⫽ systemic lupus erythematosus; SS ⫽ Sjögren’s
syndrome; anti–U1 nRNP ⫽ anti–U1 nuclear RNP; anti-dsDNA ⫽ anti–double-stranded DNA.
(WHO class VI) in 2. Along with GN, 2 of the SLE–no
SS patients also had evidence of interstitial nephritis.
Among the patients with primary SS, 4 had evidence of
renal involvement (4.7%); 3 of these 4 patients had
distal tubular acidosis type I and nephrocalcinosis (kidney biopsy in 2 of them revealed changes of interstitial
nephritis), and 1 had lesions of membranoproliferative
GN.
CNS involvement in the 15 patients with SLE–no
SS included cerebrovascular disease (6 patients), seizures (5 patients), and psychosis (2 patients), as well as
myelopathy and chorea (1 patient each). The neuropsychiatric manifestations in the SLE–SS group were cerebrovascular disease (2 patients), cognitive dysfunction (1
patient), and chorea (1 patient). Six of the patients with
SLE–no SS and 2 with SLE–SS had features of antiphospholipid syndrome along with CNS involvement.
Serologic analyses. The serologic profiles of the 3
groups of patients are presented in Table 4. All patients
who were evaluated had positive findings on tests for
ANAs. Anti-Ro/SSA autoantibodies were found in the
presence or absence of anti-La/SSB, whereas anti-La/
SSB autoantibodies were always detected in association
with anti-Ro/SSA. Therefore, the occurrence of anti-Ro/
SSA without anti-La/SSB antibodies (i.e., anti-Ro/SSA
alone) was analyzed separately.
Compared with the SLE–no SS group (but not
the group with primary SS), significantly more patients
in the SLE–SS group exhibited serum anti-Ro/SSA
antibodies alone (P ⫽ 0.008), anti-La/SSB antibodies
(P ⬍ 0.001), as well as rheumatoid factor (P ⬍ 0.001).
The statistical difference in the presence of anti-Ro/SSA
alone between the SLE–SS group and the SLE–no SS
group was revealed by the logit model (which also
included the data on anti-La/SSB as a separate variable),
but not by Fisher’s exact test (which involved only
separate analyses; P ⫽ 0.202), a fact that likely indicates
an interdependence between anti-Ro/SSA and anti-La/
SSB autoantibodies. The logit model also revealed significant differences in the prevalence of anti-Ro/SSA
alone (P ⫽ 0.012) and anti-La/SSB (P ⬍ 0.001) between
the SLE–no SS and primary SS groups. In contrast,
SLE–SS patients had a significantly higher frequency of
anti-dsDNA (P ⬍ 0.001), anticardiolipin (P ⬍ 0.001),
and anti–U1 nuclear RNP (P ⫽ 0.013) antibodies than
did the patients with primary SS, but not the patients
with SLE–no SS. A high frequency of anticardiolipin
antibodies was observed in the subgroup of SLE–SS
patients with perivascular infiltrates on lip biopsy
(100%) compared with the remaining SLE–SS patients
without this feature (9.1%) (P ⫽ 0.003).
Immunogenetic analyses. The immunogenetic
analysis of HLA–DRB, DQA, and DQB alleles in the 3
groups of study patients revealed several statistically
significant associations as compared with the healthy
control group (Table 5). Compared with healthy controls, patients with SLE–SS had an increased frequency
of the DRB1*0301 allele (P ⫽ 0.042). In addition, an
increased frequency of the DQB1*0201 allele was found
(43.5% versus 24.4% in controls), but this did not reach
statistical significance (P ⫽ 0.081), most likely because
of the relatively low number of observations. These
HLA associations distinguished the SLE–SS group from
the SLE–no SS group, in whom there were increased
phenotype and allele frequencies for DRB1*1501 (P ⫽
0.020 and P ⫽ 0.015, respectively) and DQB1*0602
(both P ⬍ 0.001). Also in the SLE–no SS group, the
frequency of the DQA1*0102 allele was marginally
888
MANOUSSAKIS ET AL
Table 5. Statistically significant immunogenetic associations for HLA–DRB, DQA, and DQB alleles in the patient groups compared with the
healthy control group*
% frequency
SLE–no SS (n ⫽ 41)
SLE–SS (n ⫽ 23)
Primary SS (n ⫽ 55)
Healthy controls (n ⫽ 246)
Allele
Phenotype
(n ⫽ 41)
Allele
(n ⫽ 82)
Phenotype
(n ⫽ 23)
Allele
(n ⫽ 46)
Phenotype
(n ⫽ 55)
Allele
(n ⫽ 110)
Phenotype
(n ⫽ 246)
Allele
(n ⫽ 492)
DRB1*0301
DRB1*1501
DQB1*0602
19.5
26.8¶
29.3**
9.8
14.6#
15.9††
30.4†
8.7
8.7
15.2
4.3
4.3
27.3‡
12.7
12.7
14.5§
7.3
7.3
12.6
11.8
6.9
6.5
6.3
3.5
* Only statistically significant differences (P ⬍ 0.05) between the patient groups and the healthy controls are shown. SLE ⫽ systemic lupus
erythematosus; SS ⫽ Sjögren’s syndrome.
† P ⫽ 0.042 versus healthy controls.
‡ P ⫽ 0.012 versus healthy controls.
§ P ⫽ 0.009 versus healthy controls.
¶ P ⫽ 0.020 versus healthy controls.
# P ⫽ 0.015 versus healthy controls.
** P ⬍ 0.001 versus healthy controls.
†† P ⬍ 0.001 versus healthy controls.
higher than that in the control group (35.4% versus
25.2% in controls, P ⫽ 0.073). However, there was a
similarity between the SLE–SS group and the primary
SS group, in whom there were increased phenotype and
allele frequencies for DRB1*0301 (P ⫽ 0.012 and P ⫽
0.009, respectively, versus controls). A relatively increased phenotype frequency for the DRB1*1104 allele
was also noted in the primary SS patients studied (47.3%
versus 34.1% in controls), but the difference was not
statistically significant (P ⫽ 0.094).
DISCUSSION
With the exception of SS associated with RA
(3,4), comparative studies of well-defined groups of
patients manifesting SS in association with another
autoimmune rheumatic disease and patients with primary SS are lacking. Despite this fact, the term “secondary SS” (denoting SS identifiable in the context of
another disorder) has been arbitrarily granted to SS that
occurs in patients with any autoimmune disorder. More
specifically, in regard to sicca syndrome that occurs in
the context of SLE, studies have not satisfactorily addressed whether such a form of SS represents one more
feature in the spectrum of lupus (i.e., SLE with “secondary SS”) or whether it represents a separate coexisting
entity (i.e., a lupus–SS overlap disease). In the present
study, in an attempt to better define the nature and
expression of SS that accompanies SLE, we conducted a
more in-depth study of the clinical, serologic, pathologic,
and immunogenetic features of these patients. For this
purpose, a fairly large number of unselected patients
with well-defined SLE were evaluated for evidence of
SS, and their data were compared with the data obtained
from patients with well-defined primary SS. The analysis
of our population of 283 unselected SLE patients revealed the occurrence of sicca manifestations in 12.4%,
whereas SS was found in 9.2% according to the established criteria for secondary SS (13,14).
Overall, our data indicate that SS that occurs
together with SLE resembles, in several aspects, primary
SS and that such SLE–SS patients constitute a subgroup
of patients with SLE characterized by milder lupus and
distinctive clinical, serologic, pathologic, and immunogenetic features. These findings corroborate and extend
certain lines of evidence presented previously (7,8,24–
26). Patients with SLE–SS were found to be older with a
later onset of disease compared with patients with
SLE–no SS, but younger with an earlier onset of disease
compared with patients with primary SS. In terms of
clinical manifestations, there was a significantly higher
frequency of Raynaud’s phenomenon, but a lower frequency of renal involvement, thrombocytopenia, and
lymphadenopathy, in patients with SLE–SS than in
patients with SLE–no SS.
Our data indicate that in most respects, the
clinical presentation of sicca syndrome that occurs in
SLE–SS patients is very similar to that in primary SS
patients, including the presence of salivary gland enlargement, which has been shown to be infrequent in RA
patients with secondary SS (3). Dyspareunia was reported significantly more frequently by patients with
SLE–SS than by patients with primary SS, possibly
CLINICAL AND LABORATORY PROFILES IN SS–SLE COMPARED WITH PRIMARY SS
related to vasculitic processes that are common in lupus.
In addition, our results have established that SLE–SS
patients possess a classic primary SS–associated autoantibody profile, namely, antibodies to the Ro/SSA and
La/SSB RNP complex and rheumatoid factor, which
further distinguishes them from patients with SLE–no
SS. However, the SLE–SS patients displayed 2 features
that differentiated them from patients with primary SS
and that apparently result from the influence of background factors of lupus. The first is the serologic autoantibody indices of lupus (i.e., anti-dsDNA and anticardiolipin antibodies), which are retained by patients with
SLE–SS and do not distinguish them from patients with
SLE–no SS. The second is the presence of perivascular
infiltrates in the minor salivary gland lesions of SLE–SS
patients, which are clearly different from the classic
periductal lymphoepithelial infiltrates of primary SS, as
first described by investigators from our group (27).
The present study was able to reconfirm these
observations in a completely different patient population. Perivascular infiltrates were observed among vessels that were located in close proximity to ducts in a
considerable proportion of SLE–SS patients. The occurrence of such perivascular infiltrates in SLE–SS patients
was found to correlate significantly with a longer duration of lupus-related and of SS-related symptoms, possibly indicating a time-dependent complication. In addition, in a manner reminiscent to an antiphospholipidassociated vasculopathy (28), the presence of
perivascular infiltrates on lip biopsy was found to correlate highly significantly with the presence of serum
anticardiolipin antibodies.
The statistically significant association of antiRo/SSA and anti-La/SSB antibodies with SLE–SS deserves special attention. These particular autoantibodies
appear to represent a meaningful link between sicca
syndrome that occurs in primary SS as well as in SS that
coexists with lupus. Previous assessments of anti-Ro/
SSA– and/or anti-La/SSB–positive SLE patients and
mothers of offspring with neonatal lupus indicated the
immunogenetic similarity between these patients and
patients with primary SS (29,30), a fact that strengthens
the association between these autoantibodies and SS. In
fact, patients with primary SS and patients with SLE–SS
have previously been reported to manifest a similar
peptide and protein specificity of autoantibody responses to Ro/SSA and La/SSB (31–33). These findings
are especially important not only for classification purposes (2), but also because they strongly suggest a
relationship between the biologic processes that gener-
889
ate these specific immunologic responses and the autoimmune sicca disorder itself.
The distinctive clinical and serologic presentation
of SLE–SS patients among the total SLE population
may be the result of immunogenetic variability, which in
turn would be associated with the expression of particular disease phenotypes. In fact, the existence of certain
HLA–DR and DQ alleles has been shown to correlate
highly significantly with the development of SLE as well
as primary SS (30,34,35). Previous studies of primary SS
patients revealed associations with various HLA–DR
alleles (DRB1 genes), including DR3 (DRB1*0301) and
DR5 (DRB1*1104). In addition, significant associations
with alleles at the HLA–DQ locus, such as the
DQA1*0501, DQB1*0201, and DQB1*0301 alleles,
have been also demonstrated in patients with primary SS
with autoantibody responses to Ro/SSA and La/SSB
RNPs (34,35).
To our knowledge, however, no previous studies
have addressed the immunogenetic profile in welldefined SLE–SS patients in comparison with that in SLE
patients without SS and in patients with primary SS.
Despite the relatively low number of SLE–SS patients
tested, this is the first study to demonstrate that this
particular subgroup of SLE patients bears an immunogenetic background that strongly resembles that of primary SS and differs from that of SLE–no SS. Similar to
patients with primary SS, those with SLE–SS were found
to display an increased prevalence of DRB1*0301
(DR3). In contrast, our findings clearly distinguished
SLE–SS patients from SLE–no SS patients, as illustrated
by the high frequency of the DRB1*0301 allele, coupled
with the significantly lower frequency of the lupusrelated alleles DRB1*1501 and DQB1*0602.
Taken together, our findings strongly imply that
SS occurring in association with SLE represents a coexisting entity that is distinct from lupus (i.e., a lupus–SS
overlap disease). In direct contrast, the occurrence of SS
in patients with RA has not been shown to be associated
with the primary SS–related immunogenetic background, but with that of RA, which suggests that this
form of SS corresponds to a feature in the spectrum of
RA (i.e., “secondary SS” in the context of RA) (3,4).
Consistent with this primary SS–associated immunogenetic profile, we found that in the majority of SLE–SS
patients, sicca manifestations had begun well before the
outbreak of signs indicative of lupus. A few cases of
patients with longstanding primary SS who eventually
developed a systemic disorder that fulfilled the criteria
for SLE have also been described previously (36,37).
According to our data these SLE manifestations are
890
MANOUSSAKIS ET AL
mild and usually include arthritis, serositis, and mucocutaneous manifestations, whereas in the majority of
such patients, the development of lupus is denoted by
high titers of anti-dsDNA antibodies.
In conclusion, SS that occurs in association with
SLE appears to be a form of the primary sicca disorder
that progresses to, or is followed by, lupus that results in
a form of “lupus–SS overlap” disease. From this point of
view, disease expression in patients with SLE–SS may
represent a continuous spectrum, ranging from the
classic presentation of primary SS with minimal lupoid
manifestations to a more recognizable lupus process
with sicca features. Thus, SLE–SS may be considered a
specific subgroup of primary SS. SLE–SS patients have a
immunogenetic profile compatible with that of primary
SS, but they develop sicca manifestations at a younger
age, often have serum anti-dsDNA antibodies and
perivascular infiltrates in the salivary glands, and usually
proceed to develop mild features of SLE.
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