Paucity of Sjogren-like syndrome in a cohort of HIV-1-positive patients in the HAART era. Part II.
ABSTRACT This study was performed in order to investigate the prevalence of Sjögren-like syndrome (SLS) in the highly active anti-retroviral therapy (HAART) era in a cohort of HIV-1-positive Greek patients.
One hundred and thirty-one unselected patients were screened by the validated European Union (EU) criteria for Sjögren's syndrome. Of the 31 who gave a positive EU-validated questionnaire, 17 consented to undergo minor salivary gland biopsy and other tests.
Only two patients had a positive salivary gland biopsy and both belonged to the non-compliant HAART group, whereas none of the compliant HAART patients had histological findings.
It is concluded that SLS, the prevalence of which in the pre-HAART era was 7.8%, has disappeared, possibly as a result of the protective action of HAART.
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ABSTRACT: Ferritin-based nanoprobe (FBNP) hydrogel provides solutions to some of the traditional problems of bioassays. The schematic shows 3D and highly specific multiplex assays of markers for AIDS and Sjögren's syndrome using quantum-dot based reporters with different fluorescence emissions for the two syndromes. The advantages of using a hydrogel include that the stability of FBNPs is significantly enhanced within the hydrogel, FBNPs are distributed evenly throughout the hydrogel matrix, and the amount of FBNPs within the hydrogel can be well controlled.Advanced Materials 07/2012; 24(35):4739-44, 4730. · 14.83 Impact Factor
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ABSTRACT: Autoimmune rheumatic diseases, such as RA and SLE, are caused by genetic, hormonal and environmental factors. Human Endogenous Retroviruses (HERVs) may be triggers of autoimmune rheumatic disease. HERVs are fossil viruses that began to be integrated into the human genome some 30-40 million years ago and now make up 8% of the genome. Evidence suggests HERVs may cause RA and SLE, among other rheumatic diseases. The key mechanisms by which HERVS are postulated to cause disease include molecular mimicry and immune dysregulation. Identification of HERVs in RA and SLE could lead to novel treatments for these chronic conditions. This review summarises the evidence for HERVs as contributors to autoimmune rheumatic disease and the clinical implications and mechanisms of pathogenesis are discussed.The Open Rheumatology Journal 01/2013; 7:13-21.
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ABSTRACT: The transmission of herpesviruses depends on viral shedding at mucosal surfaces. The salivary gland represents a major site of persistent viral replication for many viruses, including cytomegalovirus. We established a mouse model of salivary gland dysfunction after acute viral infection and investigated the cellular requirements for the loss of secretion. Murine cytomegalovirus (MCMV) infection severely impaired saliva secretion independently of salivary gland virus levels. Lymphocytes or circulating monocytes/macrophages were not required for secretory dysfunction. Dysfunction occurred before glandular inflammation, suggesting that a soluble mediator initiated the disruption of acinar cell function. Despite genetic differences in innate resistance to MCMV, NK cells protected the host against acinar atrophy and the loss of secretions under conditions of an exceedingly low virus inoculum. NK cells also modulated the type of glandular inflammation after infection, as they prevented an influx of Siglec-F(+) polymorphonuclear leukocytes (PMNs). Therefore, beyond their recognized role in controlling MCMV replication, NK cells preserve organ integrity and function and regulate the innate inflammatory response within the gland.Journal of Virology 12/2011; 86(4):2132-42. · 5.08 Impact Factor
doi:10.1093/rheumatology/keg316, available online at www.rheumatology.oupjournals.org
Advance Access publication 30 May 2003
Paucity of Sjo ¨ gren-like syndrome in a cohort
of HIV-1-positive patients in the HAART era.
G. D. Panayiotakopoulos, K. Aroni1, D. Kyriaki2, S. Paikos3,
N. Vouyioukas4, A. Vlachos4, A. N. Kontos and T. Kordossis
Objective. This study was performed in order to investigate the prevalence of
Sjo ¨ gren-like syndrome (SLS) in the highly active anti-retroviral therapy
(HAART) era in a cohort of HIV-1-positive Greek patients.
Methods. One hundred and thirty-one unselected patients were screened by the
validated European Union (EU) criteria for Sjo ¨ gren’s syndrome. Of the 31 who
gave a positive EU-validated questionnaire, 17 consented to undergo minor
salivary gland biopsy and other tests.
Results. Only two patients had a positive salivary gland biopsy and both belonged
to the non-compliant HAART group, whereas none of the compliant HAART
patients had histological findings.
Conclusions. It is concluded that SLS, the prevalence of which in the pre-HAART
era was 7.8%, has disappeared, possibly as a result of the protective action of
KEY WORDS: Sjo ¨ gren-like syndrome, HIV infection, HAART, Pathology.
Human immunodeficiency virus (HIV) infection is
often accompanied by autoimmune phenomena such as
Sjo ¨ gren-likesyndrome(SLS),
cryoglobulinaemia  and autoimmune thrombocyto-
penia due to HIV-induced immune dysregulation.
serum—though they are not always related to a
specific autoimmune condition—in the setting of poly-
clonal hyperglobulinaemia due to persistent immu-
nological triggering by the virus. SLS presents clinically
We have described a milder form of SLS, which we
have named ‘possible Sjo ¨ gren-like syndrome’, char-
acterized by subjective symptoms of xerostomia and
xerophthalmia that may be accompanied clinically by
unilateral or bilateral parotid gland enlargement.
Ocular tests are usually negative, whereas parotid
gland scanning is usually positive and minor salivary
gland biopsy is similar to that in Sjo ¨ gren’s syndrome.
It affects 7.8% of Greek HIV-1 positive patients .
In a similar study conducted in a larger HIV cohort in
the USA and published almost concomitantly with the
above-mentioned study, a prevalence of 3% was found
on the basis of a different selection questionnaire .
Moreover, data from a labial gland biopsy-based study
of 30 unselected naive HIV-1-positive patients in West
Africa estimated the prevalence of SLS to be 48% .
The prevalence in African Americans is reported to be
twice as high as in Caucasians [5, 6].
Although SLS generally resembles classic Sjo ¨ gren’s
syndrome, certain aspects have been reported to differ.
Salivary gland infiltration by lymphocytes of the CD8
phenotype and the absence of anti-Ro and anti-La
autoantibodies in the patient’s serum are the most
Sjo ¨ gren’s syndrome. Diffuse infiltrative lymphocytosis
syndrome  is a broader term, including both sicca
syndrome and extraglandular manifestations (lung,
gastrointestinal tract, kidney, liver, muscle, nerves).
As these studies were performed before the introduc-
(HAART), which has had a beneficial effect on the
natural history of HIV infection, there are no data on
Correspondence to: T. Kordossis, Department of Pathophysiology, School of Medicine, 75 Mikras Asias Street, Athens 11527, Greece.
Academic Departments of Pathophysiology (AIDS Unit) and1Pathology, School of Medicine, National and Kapodistrian University of Athens,
2Laboratory of Nuclear Medicine,3Dental Clinic and4Eye Clinic, Laikon General Hospital, Athens, Greece.
Submitted 14 September 2002; revised version accepted 12 February 2003.
Rheumatology Vol. 42 No. 10 ? British Society for Rheumatology 2003; all rights reserved
by guest on June 1, 2013
the effects of HAART on SLS. HAART is defined as a
combination anti-retroviral regimen consisting of two
reverse transcriptase inhibitors and a protease inhibi-
tor, or three reverse transcriptase inhibitors. The use of
zidovudine alone in a small number of patients with
primary Sjo ¨ gren’s syndrome (non-HIV) was reported
to relieve sicca symptoms . Moreover, the older anti-
rheumatic agent hydroxychloroquine has been shown
to decrease HIV replication and has been studied
recently as an alternative anti-retroviral medication,
together with zidovudine and hydroxyurea, in devel-
oping countries . These two observations indicate
that the immune mechanisms of HIV infection are
of profound therapeutic interest. The present study
was designed to assess the possible effect of HAART
Patients and methods
Between November 1999 and January 2002, 131 consecutive
unselected HIV-positive patients being followed-up in our
unit were asked by the same investigator (GDP) to answer
xerophthalmia . The diagnosis of HIV infection was
established by antibody testing using the enzyme-linked
immunosorbent assay (ELISA) and confirmed by western
The majority of patients were of Greek (Caucasian) origin.
There were 123 Greek patients, two from the USA, one from
Bulgaria, one from Cuba and four from Africa. There were
113 men and 18 women. The patients belonged to all
categories of HIV infection, and had a mean age of 37.3yr
(range 24–71yr). Numbers of patients in risk groups for the
acquisition of HIV infection were as follows: 106 homo-
sexual/bisexual men, 12 heterosexuals, five homosexual/
bisexual intravenous drug users (IDUs), five heterosexual
IDUs and two blood transfusion recipients. Patients were
divided according to the Centers for Disease Control (CDC)
classification system of 1993  in the non-AIDS group
(categories A1, A2, B1 and B2) and the AIDS group
(categories A3, B3, C1, C2 and C3). Thirty-one of the 131
patients questioned (23.7%) gave a positive answer to at least
one question about ocular and one question about oral
symptoms. During the period between November 1999 and
January 2002, 11 patients died (nine males and two females)
and two were lost to follow-up. Ten of these 13 patients gave
a positive questionnaire, as defined above. Only one of the 13
patients who ceased to be available during the study
completed the study protocol. Of the remaining 21 patients
with a positive questionnaire (i.e. a questionnaire with a
positive answer to at least one question about ocular and oral
symptoms) and who remained available during the study
period, 16 consented to participate in the study protocol.
Thus, a total of 17 patients with a positive questionnaire
completed the study protocol (15 men and two women) after
informed consent had been obtained, and 14 did not. The
study protocol, which was approved by the Bioethics
Committee of the Laikon General Hospital, consisted of: (i)
Schirmer test, the tear break-up time test (BUT) and the slit-
lamp examination after Rose Bengal staining; (ii) parotid and
submandibular gland scanning with technetium 99m; (iii)
detection of autoantibodies to Ro/SSA and La/SSB in serum;
and (iv) minor labial salivary gland biopsy under local
about xerostomia and
anaesthesia. The biopsy was evaluated histologically and was
deemed compatible with SLS when there was a focus score
?1 according to the criteria of Greenspan et al. . The
methods used for processing the histology slides have been
described previously . Patients were divided according to
treatment as: recipients of HAART (73 patients); double anti-
retroviral therapy (ART) including two nucleoside reverse
transcriptase inhibitors (a subclass of antiretroviral drugs
comprising a major component of HAART) (nine patients);
and no treatment (49 patients, comprising two subgroups:
seven non-compliant HAART patients and 42 patients with
no medical indication for treatment).
Only one of the patients who completed the study protocol
had diabetes mellitus, and he was treated with a sulphonyl-
urea; another patient used tranquilizers. The former patient
reported heavy alcohol consumption in the past. No patient
was on parasympatholytic or antihypertensive medication.
Four patients had antibodies against hepatitis C virus (HCV)
in their serum, detected by ELISA. Eight HIV-1-positive
patients who had given a negative answer to the ques-
tionnaire and were HCV-negative served as controls (one
woman and seven men). They consented to parotid scanning
and eye testing for the detection of keratoconjunctivitis
Sixteen of the 17 patients who agreed to participate
were Greeks and one was Cuban. The results of the
study are given in Table 1 and are summarized below.
Only two out of 17 minor labial salivary gland
biopsies were classified as having a focus score of ? 1þ
(at least one lymphocytic focus per 4mm2) according
to the criteria of Greenspan et al. . The lymphocytic
infiltrates were mainly perivascular; some were in
periacinar and periductal areas. No mucoid degenera-
tion was found.
Five patients had a positive result in Schirmer’s test
(three bilaterally and two unilaterally), and two of
them also had a positive BUT test result (both
unilaterally). Both patients with histologically proven
SLS had a positive Schirmer’s I test. No Rose Bengal
staining test was positive.
Parotid gland scanning was positive in both patients
with histologically proven SLS and in three patients
Autoantibodies to Ro/SSA and La/SSB were not
detected in sera.
All control patients had negative parotid scanning
results and only one had a positive Rose Bengal
Our comments on the results of the present study must
be viewed in comparison with those of our previous
study, which was performed in the pre-HAART era
(1994–1995); the present study is a continuation of the
earlier one. The research methods used were identical
in the two studies and both study populations,
although different in size and patient composition,
Paucity of Sjo ¨ gren-like syndrome in the HAART era1165
by guest on June 1, 2013
included mainly Greeks; the main risk group was the
same (homo/bisexuals) and the numbers of patients
tested were nearly equal (14 and 17).
The proportion of patients who gave positive
answers ondirect questioning
xerostomia and xerophthalmia dropped from 33.7%
in our pre-HAART era study to 23.7% in the present
None of the patients tested had a positive result in
the Rose Bengal staining test, which is the most reliable
test for the evaluation of keratoconjunctivitis sicca.
This finding is consistent with the results of the
previous study. It has been reported that reduced
tear production occurs in 20–25% of patients with
HIV infection.Our data
observation, a phenomenon that might be attributed
In HIV-1-positive patients with reported xerostomia,
positive parotid scanning does not necessarily indicate
SLS, as this test may provide false-positive results.
As both studies confirm, however, positive parotid
scanning is expected to be positive in patients with SLS.
Some differences were found in the histology of the
biopsies between the two studies. Only two of the
patients were found to have histologically proven SLS in
the present study. One of them was a 26-yr-old male who
refused HAART (Table 1, patient 5) and the other was a
66-yr-old male who was known to be non-compliant
(Table 1, patient 6).
Thirty-seven of the 77 patients in the initial study
were known to be alive when the present study started
and also participated in the present study. The
remaining 94 patients were those who were followed
up by our unit after the end of the first study. Eleven
of the 15 patients who had a positive questionnaire in
the initial study also had one in the present study. Five
of the 22 patients with a negative questionnaire in the
first study gave a positive questionnaire in the present
Four of the six patients who had been proven
histologically to have SLS in the first study were alive
when this study started and three completed the
present study protocol. Two of them, a 32-yr-old
woman and a 30-yr-old homosexual man, had a
negative minor labial gland biopsy and both were on
HAART. The female had a strongly positive minor
labial gland biopsy score in the first study (3.6/4mm2)
(Table 1, patient 4), and the male had a marginally
positive biopsy score (1/4mm2) (Table 1, patient 9).
Only one patient from the group that participated in
the first study had positive labial gland histology for
SLS (Table 1, patient 6).
Four of the eight patients who had a negative labial
gland biopsy for SLS in the first study were alive when
the present study started. Three of them again gave a
positive questionnaire. Of these three, one died of low-
grade lung lymphoma and another of small-cell lung
cancer before completing the study protocol. The third
consented to the study protocol, and he was shown to
do not confirmthis
TABLE 1. Data on the 17 HIV-positive patients studied who gave positive answers in the validated EU questionnaire on Sjo ¨ gren’s syndrome 
Clinical entities included
in CDC system
Pulmonary TB, fever >1 month
Diarrhoea >1 month
TB, tuberculosis; VZV, varicella zoster virus; CIN, cervical intra-epithelial neoplasia; PCP, pneumocystis carinii pneumonia; HIV-RTP, HIV-related thrombocytopenia; KS, Kaposi’s
sarcoma; NHL, non-Hodgkin’s lymphoma; ART, anti-retroviral therapy that included two NRTIs.
1166 G. D. Panayiotakopoulos et al.
by guest on June 1, 2013
The overall prevalence of SLS in the unselected HIV-1-
positive population of our cohort in the HAART era
was 1.53% (2 out of 131). This is significantly different
from the prevalence rate of 7.8% (6/77 HIV patients)
that we found in our earlier study (P¼0.003, relative
risk 5.10, 95% confidence interval 1.06–24.67). No
patient compliant to HAART was found to have
histologically proven SLS.
Because the prevalence of Sjo ¨ gren’s syndrome among
women in a closed rural Greek community has been
estimated as 2.99% , it is evident that HAART is
capable of practically eliminating HIV-related SLS.
The results of this study are significant because they
prove that SLS disappears histologically from the
mouth after successful HAART. It is possible that anti-
retroviral agents exert a direct or indirect action on the
epithelial cells of the exocrine glands. When we tested
retrospectively, in both studies, the effect of successful
HAART on the likelihood of developing SLS in the
group of patients with a positive EU questionnaire, we
found a strong negative association (P¼0.009, odds
ratio 0.10, 95% confidence interval 0.00–0.99). From
our data, it is likely that HAART protects against the
development of SLS in HIV patients. Further studies
are needed to clarify the roles of the anti-retroviral
agents individually and in combination. Our findings
might also indicate a wider effect of HAART on HIV-
hypothesis as the reduction in viral load induced by
HAART decreases the persistent antigenic stimulation
induced by HIV. However, further studies are needed
to elucidate this.
The study was partly supported by grants from the
Special Funding Research Account (ELKE) of the
National and Kapodistrian
(no. 70/3/3734) to T. K. We thank Dr J. Pediaditis
for statistical analysis.
Conflict of interest
The authors have declared no conflicts of interest.
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