Hepatitis C virus, Sjögren's syndrome and B-cell lymphoma: linking infection, autoimmunity and cancer

doi:10.1016/j.autrev.2004.04.004

Autoimmunity Reviews

Volume 4, Issue 1, January 2005, Pages 8-15

https://doi.org/10.1016/j.autrev.2004.04.004 Get rights and content

Abstract

An increased prevalence of hematologic malignancies is often described in patients with Sjögren's syndrome (SS). Viruses have been proposed as possible etiologic or triggering agents of systemic autoimmune diseases (SADs), with hepatitis C virus (HCV) being one of the viruses most frequently associated with autoimmune features and with systemic autoimmune diseases such as mixed cryoglobulinemia or SS. Moreover, the association between HCV infection and hematologic malignancies, mainly non-Hodgkin's lymphoma (NHL), is supported by several studies. For these reasons, the recognized association of specific systemic autoimmune diseases (mainly SS and mixed cryoglobulinemia) with HCV infection, added to the possible evolution of any one of these entities into a B-cell NHL, suggests the possibility of a close relationship among SS, HCV and B-cell lymphoproliferative disorders, especially in patients with type II mixed cryoglobulinemia.

Section snippets

HCV-related exocrinopathy

Several viruses show a specific tropism for the epithelium of the exocrine glands mainly herpesviruses, retroviruses and hepatitis viruses. Thus, patients infected by retroviruses such as HIV-1 and HTLV-I quite often present sicca features. In patients with HIV infection, the histological analysis of salivary glands demonstrates a similar etiopathogenic mechanism to that observed in primary SS (lymphocytic infiltration), although the immunophenotypic analysis shows that the predominant cells

Association between SS and HCV

The association of SS with HCV has originated an intense debate in the last decade. In 1992, Haddad et al. [6] found histological evidence of SS (Chisholm–Mason classification grade 3 or 4) in 16 of 28 patients with chronic HCV infection. In recent years, experimental, virological and clinical evidence has revealed a close association between HCV and SS. Since 1989, more than 250 cases of SS–HCV have been reported, making SS one of the systemic autoimmune disease (SAD) most-closely associated

SS-HCV patients with anti-Ro/La antibodies

Although nearly 70% of SS–HCV patients had positive ANA, two-thirds of these ANA+ patients had negative Ro/La antibodies; an immunological pattern (ANA+/ENA−) typically observed in chronic HCV infection [12]. Negative Ro/La has been considered as a typical immunological feature of SS associated with HCV [13], [14], but it is interesting to note the existence of a small subset of SS–HCV patients with positive ENA. Of note, a higher rate of anti-Ro/La positivity has been recently reported when

Role of cryoglobulinemia in HCV-related SS

Half of SS–HCV patients presented cryoglobulinemia which may be considered the key immunological marker of SS associated with HCV. Although a similar prevalence of glandular features was found, specific extraglandular manifestations, such as articular, vasculitic and neuropathic involvement (the classic triad of the cryoglobulinemic syndrome), were more frequently observed in SS–HCV patients. This suggests that cryoglobulinemia may play a more important role in the extraglandular features

Differentiating primary and HCV-associated SS

There are several epidemiological, clinical and immunological differences of the SS associated with HCV in comparison with a large series of patients with primary SS [16]. Demographically, SS–HCV is characterized by a reduced female–male ratio (3:1) and by an older age at SS diagnosis. The clinical expression of SS–HCV is similar to primary SS with respect to the prevalence of extraglandular features and the percentage of fulfillment of the 2002 Criteria [9] but shows a higher percentage of

Classifying HCV patients with sicca syndrome

Although some SS–HCV patients fulfilled all six European Classification Criteria for SS, most only fulfilled the minimum four criteria required. However, when the criteria proposed in 2002 [9] were applied in SS–HCV patients in whom all diagnostic tests were performed, only 15% did not fulfill these more restrictive criteria; a very similar percentage to that observed in large series of primary SS patients [16]. The reason is the substantial number of SS-HCV patients who had one of the two

HCV and B-cell lymphoma

HCV is a linear, single-stranded RNA virus of the Flaviviridae family, identified in 1989, which is emerging as a chronic viral infection often associated with clinical and immunological autoimmune manifestations. There is a growing interest in the relationship between chronic HCV infection and systemic autoimmune diseases, on the one hand, and with hematologic neoplasias, on the other hand. In addition, the fact that patients with HCV and systemic autoimmune diseases show a higher frequency of

Triple association among HCV, SS and lymphoma

Several patients with SS, HCV infection and non-Hodgkin's lymphoma (NHL) have been recently described [17]. The main clinical characteristics of these patients were hypocomplementemia and cryoglobulinemia, negative anti-Ro/SS-A and anti-La/SS-B antibodies and extranodal involvement in specific sites such as the liver, ocular annexa, prostate or ovary. We identified 25 cases in the literature review, most incompletely described (Table 2) [17], [18], [19], [20], [21], [22], [23], [24], [25]. The

Conclusion

HCV may be considered as the most important etiopathogenic causal agent for SS identified to date, with SS–HCV being indistinguishable in most cases from the primary form using the most recent sets of classification criteria. Chronic HCV infection should be considered an exclusion criterion for the classification of primary SS, not because it mimics primary SS, but because it seems to be directly responsible for the development of SS in a specific subset of patients. We propose using the term

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Hepatitis C virus, Sjögren's syndrome and B-cell lymphoma: linking infection, autoimmunity and cancer

Abstract

Section snippets

HCV-related exocrinopathy

Association between SS and HCV

SS-HCV patients with anti-Ro/La antibodies

Role of cryoglobulinemia in HCV-related SS

Differentiating primary and HCV-associated SS

Classifying HCV patients with sicca syndrome

HCV and B-cell lymphoma

Triple association among HCV, SS and lymphoma

Conclusion

Rheum. Clin. Dis. North Am.

Am. J. Pathol.

Am. J. Pathol.

Lancet

Autoimmun. Rev.

Blood

Ann. Oncol.

Med. Clin. (Barc.)

Sialadenitis histologically resembling Sjögren syndrome in mice transgenic for hepatitis C virus envelope genes

Proc. Natl. Acad. Sci. U. S. A.

Presence of hepatitis C virus RNA in the salivary glands of patients with Sjögren's syndrome and hepatitis C virus infection

J. Rheumatol.

Clinical manifestations and immunology associated with chronic infection with hepatitis C virus

Rev. Clin. Esp.

Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American–European Consensus Group

Ann. Rheum. Dis.

True primary Sjögren's syndrome in a subset of patients with hepatitis C infection: a model linking chronic infection to chronic sialadenitis

Isr. Med. Assoc. J.

Sjögren's syndrome and hepatitis C virus

Clin. Rheumatol.

Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients

Medicine (Baltimore)

Sicca syndrome associated with hepatitis C virus infection

Arthritis Rheum.