Paucity of Sjögren-like syndrome in a cohort of HIV-1-positive patients in the HAART era. Part II

G. D. Panayiotakopoulos, K. Aroni1, D. Kyriaki2, S. Paikos3, N. Vouyioukas4, A. Vlachos4, A. N. Kontos and T. Kordossis

Academic Departments of Pathophysiology (AIDS Unit) and 1Pathology, School of Medicine, National and Kapodistrian University of Athens, 2Laboratory of Nuclear Medicine, 3Dental Clinic and 4Eye Clinic, Laikon General Hospital, Athens, Greece

Correspondence to: T. Kordossis, Department of Pathophysiology, School of Medicine, 75 Mikras Asias Street, Athens 11527, Greece. E-mail: tkordoss{at}med.uoa.gr


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. 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.

Methods. 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.

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 HAART.

KEY WORDS: Sjögren-like syndrome, HIV infection, HAART, Pathology.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Human immunodeficiency virus (HIV) infection is often accompanied by autoimmune phenomena such as Sjögren-like syndrome (SLS), polymyositis, mixed cryoglobulinaemia [1] and autoimmune thrombocytopenia due to HIV-induced immune dysregulation. Several autoantibodies are detected in patients’ serum—though they are not always related to a specific autoimmune condition—in the setting of polyclonal hyperglobulinaemia due to persistent immunological triggering by the virus. SLS presents clinically with salivary gland enlargement, xerostomia and keratoconjunctivitis sicca.

We have described a milder form of SLS, which we have named ‘possible Sjögren-like syndrome’, characterized 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 Sjögren’s syndrome. It affects 7.8% of Greek HIV-1 positive patients [2]. 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 [3]. 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% [4]. The prevalence in African Americans is reported to be twice as high as in Caucasians [5, 6].

Although SLS generally resembles classic Sjögren’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 prominent differences between SLS and classical Sjögren’s syndrome. Diffuse infiltrative lymphocytosis syndrome [7] 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 introduction of highly active anti-retroviral treatment (HAART), which has had a beneficial effect on the natural history of HIV infection, there are no data on the effects of HAART on SLS. HAART is defined as a combination anti-retroviral regimen consisting of two reverse transcriptase inhibitors and a protease inhibitor, or three reverse transcriptase inhibitors. The use of zidovudine alone in a small number of patients with primary Sjögren’s syndrome (non-HIV) was reported to relieve sicca symptoms [8]. 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 developing countries [9]. 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 on SLS.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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 the EU-validated questionnaire about xerostomia and xerophthalmia [10]. The diagnosis of HIV infection was established by antibody testing using the enzyme-linked immunosorbent assay (ELISA) and confirmed by western blotting.

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 37.3 yr (range 24–71 yr). Numbers of patients in risk groups for the acquisition of HIV infection were as follows: 106 homosexual/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 [11] 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 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. [12]. The methods used for processing the histology slides have been described previously [2]. 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 sulphonylurea; 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 questionnaire 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 sicca.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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.


View this table:
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TABLE 1. Data on the 17 HIV-positive patients studied who gave positive answers in the validated EU questionnaire on Sjögren’s syndrome [10]

 
Only two out of 17 minor labial salivary gland biopsies were classified as having a focus score of >= 1+ (at least one lymphocytic focus per 4 mm2) according to the criteria of Greenspan et al. [12]. The lymphocytic infiltrates were mainly perivascular; some were in periacinar and periductal areas. No mucoid degeneration 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 without SLS.

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 staining test.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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, 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 on direct questioning for symptoms of xerostomia and xerophthalmia dropped from 33.7% in our pre-HAART era study to 23.7% in the present HAART-era study.

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 do not confirm this observation, a phenomenon that might be attributed to HAART.

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 study.

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 (3.6/4 mm2) (Table 1, patient 4), and the male had a marginally positive biopsy score (1/4 mm2) (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 be negative.

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 (P = 0.003, 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 Sjögren’s syndrome among women in a closed rural Greek community has been estimated as 2.99% [13], 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 (P = 0.009, 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-related autoimmunity. This seems an attractive 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.


    Acknowledgments
 
The study was partly supported by grants from the Special Funding Research Account (ELKE) of the National and Kapodistrian University of Athens (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.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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  3. Williams FM, Cohen PR, Jumshyd J, Reveille JD. Prevalence of the diffuse infiltrative lymphocytosis syndrome among human immunodeficiency virus type 1-positive outpatients. Arthritis Rheum 1998;41:863–8[CrossRef][ISI][Medline]
  4. McArthur CP, Subtil-DeOliveira A, Palmer D et al. Characteristics of salivary diffuse infiltrative lymphocytosis syndrome in West Africa. Arch Pathol Lab Med 2000;124:1773–9[ISI][Medline]
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  9. Paton NI, Aboulhab J, Karim F. Hydroxychloroquine, hydroxycarbamide and didanosine as economic treatment for HIV-1. Lancet 2002;11:1667–8
  10. Vitali C, Bombardieri S, Moutsopoulos HM et al. Preliminary criteria for the classification of Sjogren’s syndrome. Arthritis Rheum 1993;36:340–7[ISI][Medline]
  11. Centers for Disease Control. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR 1992;41(RR-17):1–19
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Submitted 14 September 2002; Accepted 12 February 2003





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