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Hepatitis C Virus Infection Mimicking Primary Sjögren Syndrome

2001; Wolters Kluwer; Volume: 80; Issue: 1 Linguagem: Inglês

10.1097/00005792-200101000-00001

1536-5964

Manuel Ramos‐Casals, Mario Garcı́a-Carrasco, Ricard Cervera, J Rosas, Olga Trejo, Gloria de la Red, José M. Sánchez–Tapias, Josep Font, M Ingelmo,

Systemic Lupus Erythematosus Research

Introduction Sjögren syndrome (SS) is an autoimmune disease that mainly affects the exocrine glands and usually presents as persistent dryness of the mouth and eyes due to functional impairment of the salivary and lachrymal glands (17). In the absence of an associated systemic autoimmune disease, patients with this condition are classified as having primary SS. The histologic hallmark is a focal lymphocytic infiltration of the exocrine glands, and the spectrum of the disease extends from an organ-specific autoimmune disease (autoimmune exocrinopathy) (58) to a systemic process with diverse extraglandular manifestations (4, 10, 24, 50, 51, 54, 55). Due to this heterogeneity, attempts have been made to identify subsets of patients who would permit more reliable prediction of the course of primary SS in affected individuals (9, 26, 49). Viral infection has long been suspected as a potential cause of SS, and a number of viruses, such as herpesviruses and retroviruses, have been implicated (53). Additionally, recent experimental studies performed in murine models have shown a direct link between some viruses and SS (23, 34). Hepatitis C virus (HCV) is a linear, single-stranded RNA virus of the Flaviviridae family that was identified in 1989 (12). HCV infection is emerging as an extremely common and insidiously progressive liver disease that is often associated with several extrahepatic manifestations (7, 30). A relationship between SS and HCV infection was first postulated by Haddad et al (31) in 1992. Subsequently, several studies have demonstrated that a "true" SS, with the same clinical and histologic features seen in primary SS, may occur in some patients with chronic HCV infection (14, 27, 32, 56). We conducted this study to describe the clinical and immunologic characteristics of 35 patients with chronic HCV infection in whom a diagnosis of SS was well documented. Methods Patients Between 1994 and 1999, we recruited 35 consecutive patients with HCV infection (32 patients from the Hospital Clinic and 3 from the Hospital Vila-Joiosa) in whom a diagnosis of SS was well established. The diagnosis of primary SS was made in 25 patients before the diagnosis of HCV infection. We also investigated the clinical and immunologic characteristics of 60 consecutive patients with primary SS who tested negative for HCV antibodies. All patients fulfilled 4 or more of the preliminary diagnostic criteria for SS proposed by the European Community Study Group in 1993 (62) and underwent a complete history and physical examination. Diagnostic tests for SS were applied according to the recommendations of the European Community Study Group (62). Liver involvement was considered if at least 1 of the following findings was present: clinical signs of hepatopathy (hepatomegaly, splenomegaly, and/or jaundice), elevated liver enzymes (aspartate/alanine transaminases [AST/ALT] ≥ 40 IU/L, and/or γ-glutamyltranspeptidase [GGT] ≥ 40 IU/L), abdominal ultrasound showing diffuse change in liver structure, or evidence of chronic hepatitis or cirrhosis on transcutaneous liver biopsy specimen. Laboratory studies Serum from all patients was tested for HCV antibodies by a third generation ELISA (Axsym System 3.0, Abbot), and positive results were confirmed by a third generation recombinant immunoblot assay (Chiron RIBA HCV 3.0 SIA, Ortho-Clinical Diagnostics, Chiron Corporation). In 21 anti-HCV positive serum samples, presence of HCV-RNA was detected by polymerase chain reaction (PCR) (Amplicor HCV, Roche Diagnostic System). Reverse transcription and cDNA synthesis were carried out in a single-step reaction using 10 μL of RNA with specific oligonucleotides NCR1 and NCR2 derived from the well-conserved 5′NC region of HCV. Immunologic tests included antinuclear antibodies (ANA) (indirect immunofluorescence using mouse liver/kidney/stomach as substrates), antimitochondrial antibodies (AMA), anti-parietal cell gastric antibodies (PCGA), anti-smooth muscle antibodies (SMA) and anti-liver-kidney microsome antibodies type-1 (LKM-1) (indirect immunofluorescence), precipitating antibodies to the extractable nuclear antigens (ENA) Ro/SS-A and La/SS-B (ELISA) and rheumatoid factor (RF) (latex fixation and Waaler-Rose tests). Complement factors (C3 and C4) were estimated by nephelometry (Behring BNA nephelometer). Serum cryoglobulins were measured after centrifugation. Blood samples were obtained and kept at 37 °C for 30 minutes before separation. Serum was prepared by centrifuging at 37 °C for 10 minutes at 2,500 rpm. Fresh, centrifuged serum was incubated at 4 °C for 7 days after collection, and examined for cryoprecipitation. Statistical analysis The chi-square and Fisher exact tests were applied to analyze qualitative differences. For comparison of quantitative parameters, the Student t-test was used in large samples of similar variance, and the nonparametric Mann-Whitney U-test for small samples. Values of quantitative variables are expressed as mean ± standard error of the mean (SEM). A value of p < 0.05 indicated statistical significance. The odds ratio (OR) was calculated for assessing the risk of appearance of each variable, with a confidence interval (CI) of 95%. Statistical analysis was performed by means of the SPSS program, using the information stored in the database program. Results Description of SS features The demographic and clinical SS features of patients with HCV-related SS are summarized in Table 1. Of the 35 patients, 31 were women and 4 were men, and, at the time of study, the mean age of patients was 66 years (range, 46–79 yr). In 25 patients, SS was diagnosed before HCV detection, in 3 both diagnoses were made simultaneously, and in the remaining 7 patients, SS was diagnosed after HCV detection. Thirty-four (97%) patients showed xerostomia, 33 (94%) xerophthalmia, and 6 (17%) parotidomegaly. (See Table 2.) Moreover, 30 (86%) were positive (according to European criteria) for ocular diagnostic tests (Schirmer test and/or rose Bengal staining). Parotid scintigraphy was positive in 18 of 24 (75%) patients, and salivary gland biopsy showed lymphocytic infiltrates (grade 3 or 4) in 18 of 23 (78%) patients. The main extraglandular features were articular involvement in 16 (46%) patients, cutaneous vasculitis in 8 (23%), peripheral neuropathy in 7 (20%), thyroiditis in 7 (20%), Raynaud phenomenon in 6 (17%), and pulmonary fibrosis in 3 (9%) patients. The main immunologic features were ANA in 22 (63%) patients, hypocomplementemia in 21 (60%), cryoglobulinemia in 21 (60%), RF in 18 (51%), antiSMA in 15 (43%), antiPCGA in 11 (31%), anti-Ro/SS-A in 6 (17%), AMA in 5 (14%), and anti-La/SS-B in 5 (14%) patients. (See Table 3.)TABLE 1: Clinical features of 35 patients with Sjögren syndrome (SS) and hepatitis C virus infectionTABLE 2: Demographic and clinical features of patients with HCV-related and primary SSTABLE 3: Immunologic features of patients with HCV-related and primary SSCharacteristics of liver involvement Liver involvement was detected in 33 (94%) patients. The most common clinical manifestations of liver disease were hepatomegaly in 17 patients, splenomegaly in 9, and jaundice in 6 patients. Only 7 patients presented clinical manifestations of hepatic de-compensation (ascites, encephalopathy, or gastrointestinal bleeding). Biochemical tests showed raised transaminases (ALT > 40 IU/L and/or AST > 40 IU/L) in 23 patients, raised GGT in 14, and raised bilirubin (>1 mg/dL) or raised alkaline phosphatase (>300 IU/L) in 11. Abdominal ultrasound showed diffuse change in liver structure in 19 patients. Transcutaneous liver biopsy was performed in 13 patients after informed consent. Specimens obtained showed a chronic active hepatitis with varying degrees of portal inflammation in 8 patients and parenchymal nodules with loss of normal liver structure in 5. Finally, 6 patients developed neoplasia: hepatocellular carcinoma was diagnosed in 3 patients, non-Hodgkin lymphoma in 2 and gastric adenocarcinoma in 1 patient. Comparison of HCV-related SS and primary SS patients Clinical and immunologic features of SS were analyzed according to the presence or absence of HCV infection (Tables 2 and 3). HCV-related SS patients showed a higher mean age (65.9 ± 1.3 years versus 61.5 ± 1.4 years, p = 0.04), a lower prevalence of parotidomegaly (17% versus 47%, p = 0.004, OR = 0.24, CI = 0.07–0.70), and a higher prevalence of liver involvement (94% versus 3%, p < 0.001, OR = 464, CI = 51.35–5404.5). Moreover, those patients with HCV-related SS showed a higher prevalence of antiPCGA (31% versus 13%, p = 0.03, OR = 2.98, CI = 0.98–9.63), AMA (14% versus 2%, p = 0.01, OR = 9.83, CI = 1.01–472.73), cryoglobulinemia (60% versus 10%, p < 0.001, OR = 14.54, CI = 4.40–51.58), and hypocomplementemia (60% versus 8%, p < 0.001, OR = 17.77, CI = 4.00– 69.22), and a lower prevalence of anti-Ro/SS-A (17% versus 38%, p = 0.03, OR = 0.33, CI = 0.10–1.00) compared with primary SS patients. Discussion In this study, we describe the clinical and immunologic picture of 35 patients with HCV infection who fulfilled 4 (17 patients), 5 (11 patients), or all 6 (7 patients) European criteria (62) for the classification of primary SS. The first study of the existence of SS features in patients with chronic HCV infection was performed in 1992 by Haddad et al (31). Of the 28 patients studied, 16 (57%) had histologic evidence of SS (Chisholm-Mason classification grade 3 or 4) (11) compared with 1 (5%) of the 20 controls. Since then, the existence of sicca symptoms and positive diagnostic tests for SS in patients with chronic HCV infection has been well studied (29, 45–47, 65), and a recent study of 321 HCV patients found mouth and/or eyes sicca symptoms in 10%(7). Furthermore, several studies (14, 44, 55) have focused on the morphologic and immunohistochemical characteristics of sialadenitis in HCV patients, and concluded that HCV patients can develop patterns of salivary gland disease similar to those seen in primary SS patients. Finally, chronic HCV infection has been associated with the presence of some circulating autoantibodies (1, 13, 16, 41, 45) and, recently, Cacoub et al (7) found positive ANA in 41% of patients, RF in 38%, anticardiolipin antibodies in 27%, and antithyroglobulin antibodies in 13% of patients. These studies have shown the existence of sicca symptomatology, positive ocular tests, lymphocytic infiltration of salivary glands, and autoantibodies in patients with HCV infection, and these findings may give rise to a diagnosis of SS in some patients with HCV (Table 4).TABLE 4: Clinical, histologic, immunologic and experimental similarities between chronic hepatitis C virus infection and primary Sjögren syndromeThe spectrum of SS features in our 35 HCV-related SS patients was broad. We found some HCV-positive patients who fulfilled the 6 European criteria (including positive salivary biopsy and presence of antiENA antibodies) and others who fulfilled only 4 criteria. In fact, when we applied the modified criteria proposed in 1996 (64), only 22 HCV-related SS patients fulfilled these more restrictive criteria, suggesting that the modified European criteria show a higher specificity for the diagnosis of primary SS. Several studies (27, 32) have suggested that HCV infection may account for the pathogenesis of a subgroup of patients with "primary" SS, especially in patients with evidence of liver involvement or associated cryoglobulinemia. Chronic HCV infection could remain subclinical for many years, and might be clinically expressed as a feature of liver disease (hepatomegaly or elevated transaminases) or as the appearance of dryness of the mouth and eyes (52). HCV in these patients may be diagnosed as primary SS for a considerable period. In fact, both these diseases might be considered "systemic" diseases: SS patients frequently show so-called extraglandular manifestations while HCV patients have "extrahepatic" features. Additionally, most of these systemic features are common to both diseases. Another common point is the association with 2 specific conditions: mixed cryoglobulinemia and non-Hodgkin lymphoma. A strong association between mixed cryoglobulinemia and HCV infection is well known (8, 42, 43). In 1998, we noted that cryoglobulinemia in SS is associated with a high incidence of HCV prevalence (51), leading to the conclusion that the cryoglobulinemia observed in some cases of primary SS might be due to HCV infection (especially in those cases with liver involvement). In our 35 HCV-related SS patients, the main immunologic feature was cryoglobulinemia, present in 60% of patients, which further highlights the strong relationship between SS, HCV, and mixed cryoglobulinemia. Another condition associated with both diseases is B-cell lymphoma, the most serious complication in the evolution of primary SS (28), which has also been described in patients with chronic HCV infection (22, 48). Of note, we describe the development of non-Hodgkin lymphoma in 2 of our HCV-related SS patients, both of whom had cryoglobulinemia. In 1999, Selva-O'Callaghan et al (56) described a patient with primary SS who was subsequently diagnosed as HCV positive and who finally developed non-Hodgkin lymphoma. It is possible that the coincidence of these 3 diseases (HCV infection, SS, and cryoglobulinemia) in the same patient may favor the development of lymphoproliferative processes. Primary SS and HCV infection also have similar pathogenic characteristics. In both diseases, overproduction of autoantibodies is due to B-lymphocyte hyperactivity. Moreover, the CD5+ B-cell population, a small B-cell subset involved in the production of polyreactive autoantibodies and RF, expands in primary SS (18) and in patients with chronic HCV infection (15). Furthermore, a recent experimental study (34) has shown a direct link between HCV infection and SS. Koike et al (34) described the development of an exocrinopathy resembling SS in the salivary and lachrymal glands of transgenic mice carrying the HCV envelope genes. There are, however, some differences between HCV-related SS and primary SS. In this study, we found a different clinical and immunologic profile in SS-HCV patients compared with patients with primary SS. First, SS-HCV patients showed an older age at protocol, a lower prevalence of parotidomegaly, and a higher prevalence of liver involvement. In our geographic area, liver involvement appeared to be an uncommon extraglandular feature of SS in the absence of an associated HCV infection. Second, HCV-SS patients showed a clearly differentiated immunologic profile, with a lower frequency of anti-Ro/SS-A antibodies and a higher prevalence of AMA, antiPCGA, cryoglobulinemia, and hypocomplementemia. Most previous studies have suggested a lower prevalence of specific antiENA (Ro and La) antibodies in HCV infection (33, 44, 55). In addition, in 1998 we reported the high association of cryoglobulinemia to HCV infection in patients with SS (51). The high prevalence of cryoglobulinemia and hypocomplementemia in our SS-HCV patients is noteworthy and might represent the main differential features in the immunologic profile of this subset of SS-HCV patients. Finally, the different epidemiologic impact of HCV infection according to the geographic area in which studies were performed should be considered. Several authors (2, 5, 6, 19–21, 25, 27, 33, 35, 37–40, 46, 58, 61, 63, 65) have analyzed the prevalence of HCV antibodies in patients with primary SS from different European countries, which ranges from 3%–75% using second-generation ELISA, 14%–19% using third-generation ELISA, and 5%–19% using a RIBA-2 technique (Table 5). In contrast, in American patients with primary SS, serologic evidence of HCV infection has been demonstrated in a lower percentage (0–1%, using a RIBA-2 technique) (33, 38, 46). This lower American prevalence may be related to the lower prevalence of HCV infection in United States, in contrast with southern Europe, which suggests the need to test for HCV infection systematically in Mediterranean patients with autoimmune diseases showing liver involvement or cryoglobulinemia.TABLE 5: Prevalence of hepatitis C virus infection in patients with Sjögren syndrome, previous reportsIn conclusion, chronic HCV infection may mimic the main clinical, histologic, and immunologic features of primary SS. Patients with HCV-related SS showed some differential clinical and immunologic characteristics compared with primary SS patients. Our findings suggest that the "true" SS observed in some HCV patients can be considered 1 of the extrahepatic manifestations of HCV. For this reason, HCV infection can be considered as an exclusion criterion for the diagnosis of primary SS. Finally, the association of non-Hodgkin lymphoma, SS, and HCV may be an interesting example of the overlap between autoimmune, lymphoproliferative, and infectious diseases. Summary Hepatitis C virus (HCV) infection is emerging as an extremely common and insidiously progressive liver disease that is often associated with several extrahe-patic manifestations. In 1992, a possible relationship between Sjögren syndrome (SS) and patients with HCV infection was first postulated. Subsequently, several studies demonstrated that a "true" SS, with similar clinical and histologic features to those observed in primary SS, may occur in some patients with chronic HCV infection. We report the clinical and immunologic characteristics of 35 patients with chronic HCV infection and a well-documented diagnosis of SS. Compared with 60 patients with primary SS who tested negative for HCV antibodies, SS-HCV patients showed a higher mean age (65.9 yr versus 61.5 yr, p = 0.04), a lower prevalence of parotidomegaly (17% versus 47%, p = 0.004), and a higher prevalence of liver involvement (94% versus 3%, p < 0.001). Moreover, those patients with HCV-related SS showed a higher prevalence of anti-parietal cell gastric antibodies (31% versus 13%, p = 0.03), antimitochondrial antibodies (14% versus 2%, p = 0.02), cryoglobulinemia (60% versus 10%, p < 0.001), hypocomplementemia (60% versus 8%, p < 0.001), and a lower prevalence of anti-Ro/SS-A (17% versus 38%, p = 0.03). The "true" SS observed in some patients with HCV may be considered 1 of the extrahepatic manifestations of HCV, and we suggest that HCV infection can be considered as an exclusion criterion for the diagnosis of primary SS.