A variety of rheumatic syndromes have been found in HIV-infected patients, such as Reiter's syndrome, psoriatic arthritis, polymyositis, Sjögren's syndrome (SS), vasculitis syndromes, AIDS-associated arthritis, and septic arthritis . Rheumatic diseases occur in more than half of patients infected with HIV, and may present earlier than clinical signs of the infection itself .
In recent years, there has been increasing awareness that highly active antiretroviral therapy (HAART) may contribute to the development of autoimmune manifestations.
The aim of this study was to evaluate prospectively the association of SS with the progression of HIV-related disease in a cohort of HIV patients treated with HAART. In a prospective study of 150 HIV patients treated with HAART, we analysed the incidence of SS after starting HAART. We looked at HIV-positive patients treated with HAART compared with 250 age-matched patients not treated with HAART to determine the incidence and clinical outcome of cases of SS during the period Janaury 1997 to October 2003. Although SS was diagnosed in accordance with the clinical and laboratory criteria proposed by Fox et al. , the criteria had been slightly modified from those of Fox et al.  to allow symptomatic xerostomia as a criterion without necessarily performing salivary flow studies.
A full clinical assessment was made, looking for evidence of extraglandular manifestations (skin rashes, Raynaud's syndrome, lymphadenopathy, arthritis, lung involvement, serositis and neuropathy) and glandular manifestations, including a Schirmer's test. The Schirmer's test was considered abnormal if there was less than 9 mm wetting from each eye over 5 min or a total of under 15 mm. X-rays of the hands and chest were performed together with pulmonary function tests (spirometry, Kco and TLco). Blood was taken for a full blood count, erythrocyte sedimentation rate, liver function tests, urea and electrolytes, C-reactive protein, thyroid function tests, immunoglobulins and serum electrophoresis. An extended autoantibody profile was carried out including rheumatoid factor, antinuclear antibody, antibodies to DNA, Ro, La, RNP and Sm, and antibodies to hepatitis C virus (HCV). Human leukocyte antigen typing was performed for A, B and DR antigens.
We have identified four HIV-positive patients with SS that was diagnosed after the introduction of HAART. These patients fulfilled objective diagnostic criteria for definite or possible SS and they had a previous diagnosis of AIDS. The most important demographic and laboratory features of HIV-positive patients with SS are summarized in Table 1.
No patients not treated with HAART developed SS during the study period. The most common clinical features in these four patients with SS included xerostomia, xerophtalmia, fatigue, parotid swelling and polyarthralgia. These clinical manifestations occurred after 6–48 months after the introduction of HAART. Salivary gland biopsy specimens showed diffuse lymphocytic infiltration of the glandular parenchyma; these lymphocytes were prevalently with the CD8 phenotype.
A Schirmer's test was abnormal in all patients. Parotid scanning and ultrasonography were positive in all patients, and clinically there was evidence of mild parotid swelling. One patient reported a transient and moderate improvement of both xerostomia and xerophtalmia after stopping HAART. In all cases there was evidence of hypertriglyceridemia, a high level of CD8 lymphocytes, erythrocyte sedimentation rate and immunoglobulins, a CD4 cell count greater than 500 cells/mm3 (except in patient 1 who had a CD4 cell count of 62 cells/μl), hypocomplementemia C3/C4 and a low HIV viral load (< 5000 copies/ml), in the absence of anti-Ro/SSA or anti-La/SSB antibodies. Serological tests for HCV were positive in all patients, whereas serological tests for Epstein–Barr virus and cytomegalovirus were positive only for IgG. There were no cases of lymphoma or of organ-specific autoimmune disease in these patients.
SS is a chronic immune-mediated inflammatory disorder characterized by lymphocytic infiltration of the exocrine glands, especially the lacrimal and salivary glands, and by extraglandular manifestations in approximately 30% of cases. It is a systemic disease, with manifestations from several organ systems such as lungs, kidneys, skin, blood vessels and muscles, and a malignant lymphoproliferative disease may appear in approximately 5–10% of patients. It can occur in a secondary form in association with various autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, myositis and others, whereas in the absence of these conditions, the disease is classified as primary SS. Patients with anti-Ro autoantibodies may have a statistically significant increased incidence of parotid swelling, lymphadeno pathy, respiratory symptoms and lymphoma. Seronegative patients are unlikely to develop significant systemic features, whereas antinuclear antibody or rheumatoid factor-positive patients who are negative for Ro and La antibodies may evolve into connective tissue diseases distinct from SS.
The prevalence of primary SS in the general population is largely unknown, but there is a male to female ratio of 1 : 9 . As in the case with autoimmune diseases, the aetiology of SS is unknown. The aetiology of SS consists of genetic, infectious, endocrine, and psychoneuroimmunological factors. Immunological research has shown an increased prevalence of HLA-B8, DR2, DR3 and DRw52 genes in SS. Lymphocytes in the salivary glands of SS are predominantly CD4 cells. Several viruses, such as Epstein–Barr virus, cytomegalovirus, HCV, and retroviruses, are considered important co-factors in the development of SS .
Retroviruses have been implicated in the aetiology of various autoimmune diseases and in the initiation and maintenance of autoimmunity in SS. It has also been suggested that zidovudine could be potentially beneficial for patients with primary SS . Hormones, including oestrogen and prolactin, may also play important roles in immune reactivity in autoimmune diseases.
Diagnosis and classification has been difficult and at least five different classification criteria have been proposed over the past few years. In a British geriatric population, clinical SS had a prevalence of 3.3% , and in a Swedish population the prevalence was reported as 2.7% in the age group 52–72 years . HIV infection and the sicca syndrome have been associated in several reports [1,9]. The overall prevalence of possible SS in a mixed population of HIV-positive patients was 7.79%, which is more than 2.5 times higher than that observed in normal adults .
HIV patients usually manifested certain features that were unusual for SS. HIV-positive patients with the sicca syndrome were more frequently men with a significant parotid swelling and large neck masses, a decreased CD4 lymphocyte count and an increased number of CD8 lymphocytes in the blood and tissue, no significant levels of autoantibodies (including tests for cytoplasmic RNA antibodies and Ro and La antibodies), and they were usually negative for HLA-B8, HLA-DR2 or HLA-DR3 cell-surface antigens. Salivary gland biopsy samples from all these patients usually showed intense lymphoplasmocytic infiltrates of the glandular parenchyma without epithelial lesions .
Drug treatment of individuals with SS and HIV infection poses the problem of the immunosuppressive effects of systemic corticosteroids and cytostatic agents, which should be used only in the presence of severe extraglandular manifestations and life-threatening conditions, including respiratory, neurological or renal disease. In fact, steroid and cytostatic treatment of rheumatic diseases may worsen the HIV disease. The treatment of SS in these individuals mu must thus us be essentially symptomatic.
In contrast with a recent study suggesting a paucity of SS in the HAART era in a cohort of HIV-positive Greek patients , we have recognized four cases of SS in a cohort of 150 HIV-positive patients treated with HAART. In our analysis, none of the HIV-positive patients not treated with HAART fulfilled the diagnostic criteria for SS. The four patients with SS were also positive for HCV. The pathogenetic mechanism responsible for SS in these patients remained unknown. We hypothesized that HAART may play an important role in the aetiology of SS, and that SS may be a new and important complication of long-term HAART regimens. We also speculated that HCV and HIV itself may be important co-factors in the development of SS in patients with HIV infection during HAART.
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