Hepatitis C Virus Infection Mimicking Primary Sjögren Syndrome: A Clinical and Immunologic Description of 35 Cases
RAMOS-CASALS, MANUEL M.D., PH.D.; GARCÍA-CARRASCO, MARIO M.D., PH.D.; CERVERA, RICARD M.D., PH.D.; ROSAS, JOSÉ M.D., PH.D.; TREJO, OLGA M.D.; DE LA RED, GLORIA M.D.; SÁNCHEZ-TAPIAS, JOSÉ M. M.D., PH.D.; FONT, JOSEP M.D., PH.D.; INGELMO, MIGUEL M.D., PH.D.
From Systemic Autoimmune Diseases Unit (MR-C, MG-C, RC, OT, GDLR, JF, MI), and Hepatology Unit (JMS-T), Department of Medicine, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, School of Medicine, University of Barcelona, Barcelona, and Rheumatology Unit (JR), Hospital de la Vila-Joiosa, Vila-Joiosa, Alacant, Spain.
Supported by Grant FIS 99/0280 from the Fondo de Investigaciones Sanitarias. M. Ramos-Casals is a Research Fellow sponsored by a grant from the Generalitat of Catalonia (CIRIT, 2000FI 00332).
Address reprint requests to: Dr. Josep Font, Unitat de Malalties Autoimmunes Sistèmiques, Hospital Clínic, C/Villarroel, 170, 08036-Barcelona, Catalonia, Spain.
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.
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.
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.
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.
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.)
Characteristics 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.
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).
The 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.
In 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.
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.
1. Abuaf N, Lunel F, Giral P, Borotto E, Laperche S, Poupon R, Opolon P, Huraux JM, Homberg JC. Non-organ specific autoantibodies associated with chronic C virus hepatitis. J Hepatol 18: 359–64, 1993.
2. Aceti A, Taliani G, Sorice M, Amendolea MA. Hepatitis C virus and Sjogren’s syndrome. Lancet 339: 1425–26, 1992.
3. Almasio A, Provenzano G, Scimeni M, Cascio G, Craxi A, Pagliaro L. Hepatitis C virus and Sjogren’s syndrome. Lancet 339: 989–90, 1992.
4. Anaya JM, Gutierrez M, Espinosa LR. Sindrome de Sjogren primario. Manifestaciones clinicas extraglandulares. Rev Esp Reumatol 21: 337–42, 1994.
5. Barrier JH, Magadur-Joly G, Gassin M. Le VHC: Un agent etiologique improbable du SGS [letter]. Presse Med 22: 1108, 1993.
6. Boscagli A, Hatron PY, Canva-Delcambre V, Hachulla E, Janin A, Paris C, Devulder B. Syndrome sec et infection par le virus C de l’hepatite: Un pseudosyndrome de Gougerot-Sjogren? Rev Med Interne 17: 375–80, 1996.
7. Cacoub P, Renou C, Rosenthal E, Cohen P, Loury I, Loustaud-Ratti V, Yamamoto AM, Camproux AC, Hausfater P, Musset L, Veyssier P, Raguin G, Piette JC. Extrahepatic manifestations associated with hep-atitis C virus infection. A prospective multicenter study of 321 patients. Medicine (Baltimore) 79: 47–56, 2000.
8. Casato M, Taliani G, Pucillo LP, Goffredo F, Lagana B, Bonomo L. Cryoglobulinemia and hepatitis C virus. Lancet 337: 1047–48, 1991.
9. Cervera R, Font J, Ramos-Casals M, Garcia-Carrasco M, Rosas J, Morla RM, Munoz FJ, Artigues A, Pallares L, Ingelmo M. Primary Sjogren’s syndrome in men: Clinical and immunological characteristics. Lupus 9: 61–64, 2000.
10. Cervera R, Garcia-Carrasco M, Font J, Ramos M, Reverter JC, Munoz FJ, Miret C, Espinosa G, Ingelmo M. Antiphospholipid antibodies in primary Sjogren’s syndrome: Prevalence and clinical significance in a series of 80 patients. Clin Exp Rheumatol 15: 361–65, 1997.
11. Chisholm DM, Mason DK. Labial salivary gland biopsy in Sjogren’s syndrome. J Clin Pathol 21: 656–60, 1968.
12. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244: 359–62, 1989.
13. Clifford BD, Donahue D, Smith L, Cable E, Luttig B, Manns M, Bonkovsky HL. High prevalence of serological markers of autoimmunity in patients with chronic hepatitis C. Hepatology 21: 613–19, 1995.
14. Coll J, Gambus G, Corominas J, Tomas S, Esteban JI, Guardia J. Immunochemistry of minor salivary gland biopsy specimens from patients with Sjogren’s syndrome with and without hepatitis C virus. Ann Rheum Dis 56: 390–92, 1997.
15. Curry MP, Golden-Mason L, Nolan N, Parfrey NA, Hegarty JE, O’Farrelly C. Expansion of peripheral CD5+ B cells is associated with mild disease in chronic hepatitis C virus infection. J Hepatol 32: 121–25, 2000.
16. Czaja AJ, Carpenter HA, Santrach PJ, Moore SB. Immunological features and HLA associations in chronic viral hepatitis. Gastroenterology 108: 157–64, 1995.
17. Daniels T, Fox PC. Salivary and oral components of Sjogren’s syndrome. Rheum Clin Dis North Am 18: 571–89, 1992.
18. Dauphinee M, Tovar Z, Talal N. B cells expressing CD5 are increased in Sjogren’s syndrome. Arthritis Rheum 31: 642–47, 1988.
19. De Bandt M. Role du virus de l’hepatite C dans les cryoglobulinemies mixtes “essentielles” et le syndrome de Gougerot-Sjogren. Presse Med 21: 1750–52, 1992.
20. Fernandez-Campillo J, Martin-Mola E, Martinez-Zapico J, Gijon-Banos J. Sindrome de Sjogren asociado a infeccion por virus de hepatitis C: Prevalencia y caracteristicas clinicas. Rev Esp Reumatol 24: 150, 1997.
21. Ferri C, Greco F, Longombardo G, Palla P, Moretti A, Marzo E, Fosella PV, Pasero G, Bombardieri S. Antibodies to hepatitis C virus in patients with mixed cryoglobulinemia. Arthritis Rheum 34: 1606–10, 1991.
22. Ferri C, Monti M, La Civita L, Careccia G, Mazzaro C, Longombardo G, Lombardini F, Greco F, Pasero G, Bombardieri S, Zignego L. Hepatitis C virus infection in non-Hodgkin’s B cell lymphoma complicating mixed cryoglobulinemia. Eur J Clin Invest 24: 781–84, 1994.
23. Fleck M, Kern ER, Zhou T, Lang B, Mountz JD. Murine cytomegalovirus induces a Sjogren’s syndrome-like disease in C57Bl/6-lpr/lpr mice. Arthritis Rheum 41: 2175–84, 1998.
24. Font J, Ramos-Casals M, Cervera R, Bosch X, Mirapeix E, Garcia-Carrasco M, Morla RM, Ingelmo M. Antineutrophil cytoplasmic antibodies in primary Sjogren’s syndrome: Prevalence and clinical significance. Br J Rheumatol 37: 1287–91, 1998.
25. Frisoni M, Baffoni L, Miniero R, Boni P, Falasconi C, Ferri S. Virus de l’hepatite C et syndrome de Sjogren: Quel lien [letter]? Presse Med 23: 1272, 1994.
26. Garcia-Carrasco M, Cervera R, Rosas J, Ramos M, Morla RM, Siso A, Font J, Ingelmo M. Primary Sjogren’s syndrome in the elderly: Clinical and immunological characteristics. Lupus 8: 20–23, 1999.
27. Garcia-Carrasco M, Ramos M, Cervera R, Font J, Vidal J, Munoz FJ, Miret C, Espinosa G, Ingelmo M. Hepatitis C virus infection in “primary” Sjogren’s syndrome: Prevalence and clinical significance in a series of 90 patients. Ann Rheum Dis 56: 1–3, 1997.
28. Garcia-Carrasco M, Ramos-Casals M, Cervera R, Font J. Sindrome de Sjogren y linfoproliferacion. Med Clin (Barc) 114: 740–46, 2000.
29. Guisset M, Klotz F, Debonne JM, Vitte S. Syndrome sec et hepatite virale chronique C de bas grade. A propos d’une serie de 50 cas. Ann Med Interne 14: 1006, 1993.
30. Gumber SC, Chopra S. Hepatitis C: A multifaceted disease. Review of extrahepatic manifestations. Ann Intern Med 123: 615–20, 1995.
31. Haddad J, Deny P, Munz-Gotheil C, Ambrosini JC, Trinchet JC, Pateron D, Mal F, Callard P, Beaugrand M. Lymphocytic sialadenitis of Sjogren’s syndrome associated with chronic hepatitis C virus liver disease. Lancet 339: 321–23, 1992.
32. Jorgensen C, Legouffe MC, Perney P, Coste J, Tissot B, Segarra C, Bologna C, Bourrat L, Combe B, Blanc F, Sany J. Sicca syndrome associated with hepatitis C virus infection. Arthitis Rheum 39: 1166–71, 1996.
33. King PD, McMurray RW, Becherer PR. Sjogren’s syndrome without mixed cryoglobulinemia is not associated with hepatitis C virus infection. Am J Gastroenterol 89: 1047–59, 1994.
34. Koike K, Moriya K, Ishibashi K, Yotsuyanagi H, Shintani Y, Fujie H, Kurokawa K, Matsuura Y, Miyamura T. Sialadenitis histologically resembling Sjogren syndrome in mice transgenic for hepatitis C virus envelope genes. Proc Natl Acad Sci U S A 94: 233–26, 1997.
35. Loustaud-Ratti V, Vidal E, Delaire L. Gougerot-Sjogren, syndrome sec et hepatite C. Rev Med Interne 13: S346, 1992.
36. Manns MP, Rambusch EG. Autoimmunity and extrahepatic manifestations in hepatitis C virus infection. J Hepatol 31(Suppl 1): 39–42, 1999.
37. Mariette X, Agbalika F, Daniel MT, Bisson M, Lagrange P, Brouet JC, Morinet F. Detection of HTLV-I tax gene in salivary gland epithelium from two patients with Sjogren’s syndrome. Arthritis Rheum 36: 1423–28, 1993.
38. Marrone A, Di Bisceglie AM, Fox P. Absence of hepatitis C viral infection among patients with primary Sjogren’s syndrome [letter]. J Hepatol 22: 599, 1995.
39. Marson P, Ostuni PA, Vicarioto M, Ongaro G, Gambari PF. Antihepatitis C virus serology in primary Sjogren’s syndrome: No evidence of cross-reactivity between rheumatoid factor and specific viral proteins [letter]. Clin Exp Rheumatol 9: 661–62, 1991.
40. Masaki N, Hayashi S. Autoimmune liver disease complicating Sjogren’s syndrome. Nippon Rinsho 10: 2530–35, 1995.
41. McMurray RW, Elbourne K. Hepatitis C virus and autoimmunity. Semin Arthritis Rheum 26: 689–701, 1997.
42. Misiani R, Bellavita P, Fenili D, Borelli G, Marchesi D, Massazza M, Vendramin G, Comotti B, Tanzi E, Scudeller G, Zanetti A. Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 117: 573–77, 1992.
43. Pascual M, Perrin L, Giostra E, Schifferli JA. Hepatitis C virus in patients with cryoglobulinemia type II. J Infect Dis 162: 569–70, 1990.
44. Pawlotsky JM, Ben Yahia M, Andre C, Voisin MC, Intrator L, Roudot-Thoraval F, Deforges L, Duvoux C, Zafrani ES, Duval J, Dhumeaux D. Immunological disorders in C virus chronic active hepatitis: A prospective case-control study. Hepatology 19: 841–48, 1994.
45. Pawlotsky JM, Roudot-Thoraval F, Simmonds P, Mellor J, Ben Yahia MB, Andre C, Voisin MC, Intrator L, Zafrani ES, Duval J, Dhumeaux D. Extrahepatic immunologic manifestations in chronic hepatitis C virus serotypes. Ann Intern Med 122: 169–73, 1995.
46. Pirisi M, Scott C, Fabris C, Ferraccioli G, Soardo G, Ricci R. Mild sialoadenitis: A common finding in patients with hepatitis C virus infection. Scand J Gastroenterol 29: 940–42, 1994.
47. Poet JL, Tonelli-Serabian Y, Garnier PP. Chronic hepatitis C and Sjogren’s syndrome. J Rheumatol 21: 1376–77, 1994.
48. Pozzato G, Mazzaro C, Crovatto M, Modolo ML, Ceselli S, Mazzi G, Sulfaro S, Franzin F, Tulissi P, Moretti M, et al. Low-grade malignant lymphoma, hepatitis C virus infection and MC. Blood 84: 3047–53, 1994.
49. Ramos-Casals M, Cervera R, Font J, Garcia-Carrasco M, Espinosa G, Reino S, Pallares L, Ingelmo M. Young onset of primary Sjogren’s syndrome: Clinical and immunological characteristics. Lupus 7: 202–6, 1998.
50. Ramos-Casals M, Cervera R, Garcia-Carrasco M, Miret C, Munoz FJ, Espinosa G, Font J, Ingelmo M. Sindrome de Sjogren primario: Caracteristicas clinicas e inmunologicas en una serie de 80 pacientes. Med Clin (Barc) 108: 652–57, 1997.
51. Ramos-Casals M, Cervera R, Yague J, Garcia-Carrasco M, Trejo O, Jimenez S, Morla RM, Font J, Ingelmo M. Cryoglobulinemia in primary Sjogren’s syndrome: Prevalence and clinical characteristics in a series of 115 patients. Semin Arthritis Rheum 28: 200–205, 1998.
52. Ramos-Casals M, Garcia-Carrasco M, Cervera R, Font J. Sjogren’s syndrome and hepatitis C virus. Clin Rheumatol 18: 93–100, 1999.
53. Ramos-Casals M, Garcia-Carrasco M, Cervera R, Gaya J, Halperin I, Ubieto I, Aymami A, Morla RM, Font J, Ingelmo M. Thyroid disease in primary Sjogren syndrome. Study in a series of 160 patients. Medicine (Baltimore) 79: 103–9, 2000.
54. Ramos-Casals M, Garcia-Carrasco M, Font J, Cervera R. Sjogren’s syndrome and lymphoproliferative disease. In: Shoenfeld Y, Gershwin ME, eds. Cancer and autoimmunity. Amsterdam: Elsevier, pp 55–80, 2000.
55. Scott CA, Avellini C, Desinan L, Pirisi M, Ferraccioli GF, Bardus P, Fabris C, Casatta L, Bartoli E, Beltrami CA. Chronic lymphocytic sialoadenitis in HCV-related chronic liver disease: Comparison of Sjogren’s syndrome. Histopathology 30: 41–48, 1997.
56. Selva-O’Callaghan A, Rodriguez-Pardo D, Sanchez-Sitjes L, Matas-Pericas L, Solans-Laque R, Bosch-Gil JA, Vilardell-Tarres M. Hepatitis C virus infection, Sjogren’s syndrome, and non-Hodgkin’s lymphoma. Arthritis Rheum 42: 2489–90, 1999.
57. Talal N. Clinical and pathogenetic aspects of Sjogren’s syndrome. Semin Clin Immunol 6: 11–20, 1993.
58. Theilmann L, Blazek M, Goeser T, Gmelin K, Kommerell B, Fiehn W. False positive anti-HCV tests in rheumatoid arthritis [letter]. Lancet 335: 1346, 1990.
59. Unoki H, Moriyama A, Tabaru A, Masumoto A, Otsuki M. Development of Sjogren’s syndrome during treatment with recombinant human interferon-alpha-2b for chronic hepatitis C. J Gastroenterol 31: 723–27, 1996.
60. Verbaan H, Carlson J, Eriksson S, Larsson A, Liedholm R, Manthorpe R, Tabery H, Widell A, Lindgren S. Extrahepatic manifestations of chronic hepatitis C infection and the interrelationship between primary Sjogren’s syndrome and hepatitis C in Swedish patients. J Intern Med 245: 127–32, 1999.
61. Vidal E, Ranger S, Loustaud V, Verdier M, Liozon F, Denis F. Suspected multiviral involvement in primary Sjogren’s syndrome. Clin Exp Rheumatol 12: 227–33, 1994.
62. Vitali C, Bombardieri S, Moutsopoulos HM, Balestrieri G, Bencivelli W, Bernstein RM, Bjerrum KB, Braga S, Coll J, de Vita S, Drosos AA, Ehrenfeld M, Hatron PY, Hay EM, Isenberg DA, Janin A, Kalden JR, Kater L, Kontinnen YT, Maddison PJ, Maini RN, Manthorpe R, Meyer O, Ostuni P, Pennec Y, Prause JU, Richards A, Sauvezie B, Shiodt M, Sciuto M, Scully C, Shoenfeld Y, Skopouli FN, Smolen JS, Snaith ML, Tishler M, Todesco S, Valesini G, Venables PJW, Wattiaux MJ, Youinou P. Preliminary criteria for the classification of Sjogren’s syndrome. Arthritis Rheum 36: 340–47, 1993.
63. Vitali C, Sciuto M, Neri R, Greco F, Mavridis AK, Tsioufas AG, Tsianos EV. Anti-hepatitis C virus antibodies in primary Sjogren’s syndrome: False positive results are related to hypergammaglobulinaemia. Clin Exp Rheumatol 10: 103–4, 1992.
64. Vitali C, Bombardieri S, Moutsopoulos HM, Coll J, Gerli R, Hatron PY, Kater L, Konttinen YT, Manthorpe R, Meyer O, Mosca M, Ostuni P, Pellerito RA, Pennec Y, Porter SR, Richards A, Sauvezie B, Schiodt M, Sciuto M, Shoenfeld Y, Skopouli FN, Smolen JS, Soromenho F, Tishler M, Tomsic M, van de Merwe JP, Yeoman CM, Wattiaux MJ. Assessment of the European classification criteria for Sjogren’s syndrome in a series of clinically defined cases: Results of a prospective multicentre study. The European Study Group on Diagnostic Criteria for Sjogren’s Syndrome. Ann Rheum Dis 55: 116–21, 1996.
65. Wattiaux MJ, Jouan-Flahault C, Youinou P, Cabane J, Andreani T, Serfaty L, Imbert JC. Association of Gougerot-Sjogren syndrome and viral hepatitis C. Apropos of 6 cases. Ann Med Interne (Paris) 146: 247–50, 1995.
This article has been cited 66 time(s).
Prevalence of hepatitis C virus infection in patients with systemic lupus erythematosus: A case-control study
Hepatitis Monthly, 8(1):
Journal of Rheumatology
Triple association between hepatitis C virus infection, systemic autoimmune diseases, and B cell lymphoma
Journal of Rheumatology, 31(3):
Annals of the Rheumatic DiseasesSalivary gland ultrasonography: can it be an alternative to sialography as an imaging modality for Sjogren's syndrome?Annals of the Rheumatic Diseases
Annals of the Rheumatic Diseases
Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group
Annals of the Rheumatic Diseases, 61(6):
Clinical ImmunologyRheumatoid factors: Host resistance or autoimmunity?Clinical Immunology
Rheumatic Disease Clinics of North AmericaHepatitis C virus and arthritisRheumatic Disease Clinics of North America
Nephrology Dialysis TransplantationA 70-year-old man with weight loss, dry mouth and renal insufficiencyNephrology Dialysis Transplantation
LupusClinical and serological features of 35 patients with anti-Ki autoantibodiesLupus
Journal of Rheumatology
Characterization and differentiation of autoimmune versus viral liver involvement in patients with Sjogren's syndrome
Journal of Rheumatology, 33(8):
RheumatologyHepatitis C-associated mixed cryoglobulinaemia: a crossroad between autoimmunity and lymphoproliferationRheumatology
Revista Clinica Espanola
Sjogren syndrome and hepatitis C virus: causal or etiopathogenic relationship?
Revista Clinica Espanola, 201(9):
Alimentary Pharmacology & TherapeuticsHepatitis C virus-related extra-hepatic disease - aetiopathogenesis and managementAlimentary Pharmacology & Therapeutics
Clinical and Experimental Rheumatology
Difficulties in the differential diagnosis between primitive rheumatic diseases and hepatitis C virus-related disorders
Clinical and Experimental Rheumatology, 23(1):
Leukemia & LymphomaAutoimmunity and hematologic malignancies: associations and mechanismsLeukemia & Lymphoma
Annals of Hepatology
Prevalence of hepatitis C virus infection in patients with cardiomyopathy
Annals of Hepatology, 8(2):
Journal of Rheumatology
Hepatitis C virus infection in systemic lupus erythematosus: A case-control study
Journal of Rheumatology, 30(7):
Primary Sjogren's syndrome: clinical and immunological characteristics of 114 patients
Medicina Clinica, 116():
Joint Bone Spine
Fibromyalgia in Italian patients with primary Sjogren's syndrome
Joint Bone Spine, 69(1):
Critical Reviews in Oral Biology & Medicine
Oral diseases possibly associated with hepatitis C virus
Critical Reviews in Oral Biology & Medicine, 14(2):
Hepatitis C virus and Sjogren's syndrome
Internal Medicine, 44(6):
Experimental Eye ResearchEffect of inflammation on lacrimal gland functionExperimental Eye Research
Autoimmunity ReviewsB-cells and mixed cryoglobulinemiaAutoimmunity Reviews
American Journal of Pathology
Is hepatitis C virus a sialotropic virus?
American Journal of Pathology, 159(4):
Journal of Gastroenterology and Hepatology
Incidence of Sjogren's syndrome in Japanese patients with hepatitis C virus infection
Journal of Gastroenterology and Hepatology, 18(3):
Seminars in Arthritis and RheumatismHematologic malignancies in patients with cryoglobulinemia: Association with autoimmune and chronic viral diseasesSeminars in Arthritis and Rheumatism
LupusTreatment of B-cell lymphoma with rituximab in two patients with Sjogren's syndrome associated with hepatitis C virus infectionLupus
Autoimmunity ReviewsHepatitis C virus, Sjogren's syndrome and B-cell lymphoma: linking infection, autoimmunity and cancerAutoimmunity Reviews
Digestive and Liver DiseaseHepatitis C virus and non-Hodgkin's lymphoma 10 years laterDigestive and Liver Disease
Autoimmunity ReviewsHepatitis C virus infection and primary Sjogren's Syndrome: A clinical and serologic description of 9 patientsAutoimmunity Reviews
Autoimmunity ReviewsTreatment with etanercept in six patients with chronic hepatitis C infection and systemic autoimmune diseasesAutoimmunity Reviews
Journal of Viral HepatitisAntimitochondrial antibodies in patients with chronic hepatitis C virus infection: description of 18 cases and review of the literatureJournal of Viral Hepatitis
Rheumatic Disease Clinics of North AmericaHepatitis C Virus and Sjogren's Syndrome: Trigger or Mimic?Rheumatic Disease Clinics of North America
Journal of Rheumatology
Rheumatoid factors: What do they tell us?
Journal of Rheumatology, 29():
Extrahepatic immunological complications of hepatitis C virus infection
Spectrum, incidence and prognostic value of systemic manifestations in chronic hepatitis C of low activity
Terapevticheskii Arkhiv, 77(2):
Medical Science Monitor
Hepatitis C associated cardiomyopathy: Potential pathogenic mechanisms and clinical implications
Medical Science Monitor, 14(5):
Scandinavian Journal of Clinical & Laboratory Investigation
The epidemiology and significance of autoimmune diseases in health care
Scandinavian Journal of Clinical & Laboratory Investigation, 61():
Clinical Infectious Diseases
Clinical features related to antiphospholipid syndrome in patients with chronic viral infections (hepatitis C virus/HIV infection): Description of 82 cases
Clinical Infectious Diseases, 38(7):
Aktuelle RheumatologieEtiology and pathogenesis of Sjogren's syndrome: an overviewAktuelle Rheumatologie
Journal of Internal Medicine
Systemic autoimmune diseases co-existing with chronic hepatitis C virus infection (the HISPAMEC Registry): patterns of clinical and immunological expression in 180 cases
Journal of Internal Medicine, 257(6):
Oral DiseasesOral diseases associated with hepatitis C virus infection. Part 1. sialadenitis and salivary glands lymphomaOral Diseases
Primary Sjogren's syndrome: diagnostic criteria, diagnostic aspects and controversies
Pain Clinic, 13(4):
Seminars in Arthritis and RheumatismTh1/Th2 cytokine imbalance in patients with Sjogren syndrome secondary to hepatitis C virus infectionSeminars in Arthritis and Rheumatism
RheumatologyPrimary Sjogren's syndrome: current and emergent aetiopathogenic conceptsRheumatology
Archives of Internal Medicine
Renal tubular acidosis, Sjogren syndrome, and bone disease
Archives of Internal Medicine, 164(8):
Seminars in Arthritis and RheumatismMixed cryoglobulinemia: Demographic, clinical, and serologic features and survival in 231 patientsSeminars in Arthritis and Rheumatism
European Journal of Immunology
Salivary gland B cell lymphoproliferative disorders in Sjogren's syndrome present a restricted use of antigen receptor gene segments similar to those used by hepatitis C virus-associated non-Hodgkins's lymphomas
European Journal of Immunology, 32(3):
Seminars in Arthritis and RheumatismAutoimmune disease complicating antiviral therapy for hepatitis C virus infectionSeminars in Arthritis and Rheumatism
Journal of Gastrointestinal and Liver Diseases
Extrahepatic manifestations of chronic HCV infection
Journal of Gastrointestinal and Liver Diseases, 16(1):
Autoimmunity ReviewsChronic hepatitis B virus infection in Sjogren's syndrome. Prevalence and clinical significance in 603 patientsAutoimmunity Reviews
Metabolic Brain Disease
Hepatitis C virus-associated extrahepatic manifestations: A review
Metabolic Brain Disease, 19():
Autoimmunity, Pt DAdvances in lupus and Sjogren's syndrome - A tribute to Josep FontAutoimmunity, Pt D
Prevalence and clinical significance of hepatitis C virus infection in systemic autoimmune diseases
Medicina Clinica, 116():
Israel Medical Association Journal
True primary Sjogren's syndrome in a subset of patients with hepatitis C infection: A model linking chronic infection to chronic sialadenitis
Israel Medical Association Journal, 4():
Sjogren's syndrome associated with chronic hepatitis C, severe thrombocytopenia, hypertrophic cardiomyopathy, and diabetes mellitus
Internal Medicine, 44(6):
Orphanet Journal of Rare DiseasesMixed cryoglobulinemiaOrphanet Journal of Rare Diseases
Journal of Rheumatology
Presence of hepatitis C virus RNA in the salivary glands of patients with Sjogren's syndrome and hepatitis C virus infection
Journal of Rheumatology, 29():
Immunologic ResearchGenetics and autoantibodiesImmunologic Research
The American Journal of the Medical SciencesExtrahepatic Manifestations of Hepatitis C InfectionThe American Journal of the Medical Sciences
The American Journal of the Medical SciencesPrevalence of Active Hepatitis C Virus Infection in Patients with Systemic Lupus ErythematosusThe American Journal of the Medical Sciences
Current Opinion in RheumatologyCryoglobulinemic vasculitisCurrent Opinion in Rheumatology
Current Opinion in RheumatologyExtrahepatic manifestations in patients with chronic hepatitis C virus infectionCurrent Opinion in Rheumatology
© 2001 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Data is temporarily unavailable. Please try again soon.