•Hepatitis C virus

The true nature of the relationship between HCV and primary SS remains the subject of intense debate. Some believe that the manifestations of HCV infections comprise simply a virus-induced disease that mimics primary SS. Others contend that HCV is the etiopathogenical agent for a subset of patients with primary SS [18]. In 1992, Haddad et al. [19] found histological evidence of SS (Chisholm–Mason classification grade 3 or 4) in 16 of 28 patients with chronic HCV infections. Since then, more than 400 cases of SS-HCV have been reported, making SS one of the systemic autoimmune diseases most closely associated with HCV [20].

According to the HISPAMEC Registry [6], SS accounts for the 47% of the autoimmune conditions associated with HCV reported in the literature. Analysis of these cases has identified considerable overlap between SS classification criteria and extrahepatic features of HCV infection, especially with respect to sicca syndrome (both subjective and objective), histopathological criteria, and immunological markers such as antinuclear antibodies (ANA) and rheumatoid factor (RF). This shows that a clinical diagnosis of SS can be made easily in HCV patients who present with sicca syndrome, a positive ANA, or a positive RF. In contrast, anti-SSA/Ro and anti-SSB/La antibodies are described in only 25% of the SS-HCV patients, a prevalence half that of patients with primary SS. These data suggest that the main differential aspect between primary and HCV-related SS is the immunological pattern; that is, that HCV-related SS tends to have serological markers related to cryoglobulinemia – mixed cryoglobulinemia, RF, and hypocomplementemia – rather than markers traditionally viewed as being more “specific” for primary SS, the anti-SSA/Ro and – SSB/La [6].

Other studies have found a close association between SS and HCV. Sicca syndrome was the second most frequent extraglandular manifestation in the largest series of unselected HCV patients reported [21], with a prevalence of 11%. In another study, SS was diagnosed in 5% of 147 unselected HCV patients, a prevalence fivefold higher than that of the general population [22]. Finally, Caporali et al. [23] recently found that 15% of 501 patients in whom salivary gland biopsy was carried out due to a clinical suspicion of SS were HCV positive.

The lymphotropism of HCV links the virus to the synthesis of cryoglobulins and the development of lymphoma, while its sialotropism may explain the close association with sicca syndrome and SS. Recent experimental studies have found evidence supporting the sialotropism of HCV. Koike et al. [24] described the development of an exocrinopathy resembling SS in the salivary and lacrimal glands of transgenic mice that carry the HCV envelope genes. The findings of that study suggest that the envelope proteins of HCV can recruit lymphocytes into the salivary glands, thereby leading to the formation of lymphocytic infiltrates. De Vita et al. [25] detected HCV in human salivary glands, and two additional studies [7, 8] have demonstrated the capability of HCV to infect and replicate within the salivary gland tissue of HCV patients with sicca syndrome/SS. Arrieta et al. [7] found that HCV infects and replicates in epithelial cells from salivary glands of patients with SS or chronic sialadenitis, a fact also confirmed by Toussirot et al. [8] in 3 SS-HCV patients. The reasons for this predilection of HCV for exocrine gland tissue are unknown.

Chronic HCV infection and primary SS thus appear to have differing etiologies – infectious on the one hand and autoimmune on the other – but share certain etiopathogenic mechanisms. Both entities are characterized by B-cell hyperactivity and are closely associated with B-cell driven processes such as mixed cryoglobulinemia and B-cell lymphoma. The CD5+ B-cell subpopulation, a small group of B-cells involved in the production of natural autoantibodies and RF, may have a possible role in both diseases [26].

These findings have led to HCV infection being considered as an exclusion criterion for the diagnosis of primary SS in the 2002 American-European Criteria [27]. HCV may be considered as an important etiopathogenic agent for SS, with SS-HCV being indistinguishable in most cases from the primary form using the most recent sets of classification criteria. For these patients, we propose the term “SS secondary to HCV” when they fulfill the 2002 Classification Criteria for SS [20]. Chronic HCV infection should be considered an exclusion criterion for the classification of primary SS, not because it mimics primary SS, but because it may be implicated in the etiopathogenesis of SS in a specific subset of patients. However, this etiopathogenic role varies according to the geographical prevalence of HCV infection found in the general population.

4.2Hepatitis B Virus

Chronic HBV infection is associated with various extrahepatic manifestations including skin rash, arthritis, and glomerular disease [28]. In addition, the association between HBV and some cases of polyarteritis nodosa is well known [29]. Other studies have suggested a possible association between HBV and other systemic autoimmune diseases such as rheumatoid arthritis, polymyalgia rheumatica, antiphospholipid syndrome, and systemic lupus erythematosus [30]. However, there are no data suggestive of a causal role for HBV in these diseases [31], and one study has even suggested a lower frequency of HBV infection in patients with autoimmune diseases [32].

The association between SS and other types of chronic viral hepatitis such as HBV is very infrequent. Only three cases of HBV-related SS have been reported (one associated with HBV vaccination) [33–35], compared with more than 400 cases of HCV-related SS. Similarly, chronic HCV infection also plays an insignificant role in liver disease in SS patients [36]. This predominant etiopathogenic role of HCV is probably due to its specific lymphotropism and sialotropism, which mean it can infect and replicate in both circulating lymphocytes and epithelial cells from the salivary glands.

We have recently reported a prevalence of chronic HBV infection of 0.83% in primary SS [37], very similar to the prevalence in the general population in Spain (0.7%) [38]. In spite of the small number of reported SS-HBV cases, a comparison with primary and HCV-related SS reveals some differences. The clinical expression of SS-HBV is similar with respect to the prevalence of sicca features but shows a higher percentage

of patients with joint involvement. With respect to the immunological expression, SS-HBV patients showed a higher frequency of RF but a lower frequency of some immunological features typically described in SS-HCV patients such as hypocomplementemia and cryoglobulinemia [37].

In contrast to the close association between SS and HCV, chronic HBV infection is not associated with SS, with a ratio SS-HBV/SS-HCV cases of 1:10. Although the reasons for the specific predilection of HCV for exocrine tissue are unknown, differences either in the viral structure (HBV is a DNA virus, while HCV is a RNA virus) or in the autoimmune responses they trigger might explain the variation in sialotropism. Thus, Ram et al. have recently suggested a protective role of hepatitis B virus infection against autoimmune disorders given the lower prevalence of hepatitis B core antibody (HBcAb) found in patients with autoimmune diseases (including SS) when compared with healthy controls [39].

4.3Human Immunodeficiency Virus

In patients with HIV infection, the salivary glands may become infiltrated by lymphocytes in a manner similar to that of HCV infections, leading to a sicca syndrome and a broad spectrum of manifestations. However, salivary gland infiltration is predominantly composed of lymphocytes of the CD8 phenotype (in contrast to primary SS, where CD4+ lymphocytes predominate), and anti-SSA/Ro and anti-SSB/La autoantibodies are usually absent. The HIV-related sicca syndrome is often referred to as “diffuse infiltrative lymphocytosis syndrome” (DILS) [40]. The predominance of CD8 lymphocytes within the salivary glands of HIV patients is not surprising, due to the specific destruction of CD4 cells by the virus.

In 1998, Kordossis et al. described a prevalence of HIV-related sicca syndrome of 8% in Greek patients who were HIV-positive [41]. Kordossis et al. emphasized the clinical similarities between DILS and primary SS. In a similar study conducted in a larger HIV cohort in the USA, a prevalence of 3% was reported [42]. In contrast, data from a labial gland biopsy-based study of 30 unselected, treatment-naive HIVpositive patients in West Africa estimated the prevalence of SS to be 48% [43].

The impact of highly active antiretroviral treatments (HAART) on the incidence and prevalence of DILS is not clear. Panayiotakopoulos et al. [44] described an overall prevalence of HIV-related SS of 1.5% in an unselected HIV-positive population (2 out of 131 patients), substantially lower than the percentage found by the same group in the pre-HAART era (8%), suggesting that SS is rarely found in HIV patients treated with HAART. In contrast, Mastroiani et al. [45] have reported four HIV-positive patients with SS diagnosed 6–48 months after the introduction of HAART. These patients fulfilled objective diagnostic criteria for definite or possible SS, with the most common clinical features being xerostomia, xerophthalmia, fatigue, parotid swelling, and polyarthralgia. Salivary gland biopsy specimens showed diffuse lymphocytic infiltration and patients had abnormal Schirmer’s tests, parotid scanning, and ultrasonography. One patient reported a transient, moderate