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Prospective study of primary Sjogren syndrome associated to HCV-infected patients: Clinical, immunological, genetical and viral genotype characteristics
352A
981
AASLD ABSTRACTS
INFECTION BY HCV AND OTHER LYMPHOTROPIC VIRUSES IN BCELL NON-HODGKIN'S LYMPHOMA. C Fen/*, M Mona, F Lo Jacono*. F Caracciolo*, L La Civita*. G Carccci3. G Loneomhardo*. C Giannini. F Greco*. A Mazzoni*, L Ceecherini-Nelli*. AL Ziene~o. Instimt of Internal Medicine, Florence, Patologia Medica I, Haematology Unit, and Dep. of Biomedicine, Pisa, Italy*.
982
R H E U M A T O L O G I C A N D I M M U N O L O G I C MANIFESTATtONS O F HEPATITIS C INFECTION. E. Zuckerman- I. Rosner. M. Ashkar. N. Elias. M. Rozenbaum. Y. N~ehitz. D. Golan. E. Toubi. and D. Y~hurun. Department of Medicine A, Rheumatology Unit and Immunology Institute, Bnai Zion Medical Center, Technion School of Medicine, Halfa, Israel. Hepatitis C virus has been increasingly recognized as a cause of rheumatologic disease and autoimmune phenomena. We studied prospectively 41 consecutive patients with hepatitis C infection presenting to a deparmaent of internal medicine and evaluated them for a broad rang~" of rheumatologic/immunologicdisease. All patients were diagnosed on basis of HCV 2nd generation ELISA and H C V - R N A by PCR. Liver biopsy was performed in 34 of 41 patients. The 41 patients had: Joints] arthralglas-22, arthritis-9 (non-erosive by x-ray); xerostomia-15, xeropthalmia-3 (minor labial salivary gland biopsy showed focal lymphocytic infiltrate in 2/24 and Schirmer's test was positivein 1/28): skin] vasculitis-3, Raynaud's-4. Positive lab t'mdings: rheumatoid factor-20; cryoglobulins-17; low C3-19; low C:27. Antibodies] anti parietal ce11-25 (low serum Bt2-7 of 24; bone marcow megaloblastosis-4 of 10, gastric atrophy on endoseopy-1 of 8); anti centromere-11; ANA-3; anti DNA-0; ANCA-2; anti cardiolipin lgM (ACLM)-9; anti SSA-2; anti SSB-4; anti RNP-5; anti SCL 70-0. While confirnfing previously reported rheumatologic/immunologic associations with HCV including arthropathy, vasculitis, ACL-M, low C 3and C 4, rheumatoid factor and cryoglobulins, we herein describe for the first time the added associations with anti parietal cell and anti centromere antibodies. The role of HCV in pernicious anemia and CREST subset ofscleroderma remains to be further evaluated.
HEPATITIS IS ASSOCIATED OF ANTI-NEUTROPNIL AND ANTI-CARDIOLIPIN
WITH A HIGH CYTOPLASMIC ANTIBODIES.
S.D.H. Malnick. Y. Lurie. N. Fo~el. P. Cohen. D. Geltner. D.D. Bass. and Z.M. Sthoeuer. Departments of Internal Medicine 'C', Pathology and Gastroenterology, Kaplan Hospital, Rehovot 76100, Israel.
Lymphotropic viruses such as Epstein-Barr virus (EBV) and human herpesvirns-6 (HHV-6) have been proposed as causative agents of B-cell nonHodgkin's lymphoma (NHL). More recently, HCV, a hepatotrepic and lymphotropic virus, has also been implicated. The AIM of this study was to investigate the prevalence of HCV, EBV and HHV-6 infection and their potential relationship in a series of B-cell NHL pts. PATIENTS. 18 anselected pts with B-cell NHL (I0 m./8w.; mean age 62 yrs.) were studied. 20 age-matched healthy subjects (I-IS: anti-HCV, HCVRNA, antiEBV and anti-HllV-6 IgM class negative) were used as controls. METHODS. HCVRNA sequences (in serum and fresh or cultured PBMC), EBDNA-1 gene sequences in PBMC and HHV-6 DNA sequences in PBMC were detected by PCR as described (1-4).DNA ampliticubility was tested by beta-glubin PCR. Anli-HCV, -EBV, -HHV-6, HBV and -HIV were detected by commercially available kits. RESULTS. I-HV infection was excluded in all cases. HCVRNA, EBVDNA and HI-IV-6DNAsequences were detected in PBMC in 6 (33%), 7 (39%) and 4 pts (22%), respectively. Anti-HCV were found in 6 ce.ses.; anti-EBV and anti-HI-IV-6 IgM class were not detected, In HS, PBMC were infected by HCV, EBV and HI-IV-6in 0%, 7% in 18% of eases respectively. At least one of the viruses studied was detected in PBMC from the majority of NHL pts (14=78%). In 11 cases it was a single infection and in the remaining 3 a coinfeetion by two viruses. No correlation was observed between presence/absence of different viruses in PBMCs and various grades of malignancy, disease duration, and concomitant therapies. CONCLUSIONS. These data are consistent with the hypothesis that a viral agent is involved in the pathogenesis of the majority of B-cell NHL. Since the coinfectian seems to be uncommon condition it should be important to investigate other factors (genetic and/or environmental), possibly involved in the oncogenesis of such malignancies. REFERENCES 1) Blood, 1993; 82: 3701-4; 2) Blood 1991; 77: 2251-8; 3) Lancet 1993; 342 (i): 398; 4) Cancer 1992;70: 1985-9.
983
CHRONIC HCV INCIDENCE ANTIBODIES
HEPATOLOGY October 1995
Chronic HCV infection has been linked to extra-hepatic autoimmune phenomena. We therefore studied 48 consecutive chronic HCV patients w i t h no evidence of previous HBV infection or other autoimmune disease for the presence of anti-cardiolipin antibodies (ACA) and anti-neutrophil cytoplasmic antibodies (ANCA) which have been linked to the above phenomena. High levels of ACA were detected in 21/48 (43.8%) and ANCA in 23/30 (70%) of these patients whereas no such antibodies were detected in controls. Cryoglobulin was present in 15/39 (38.5%) patients. ACA-positive patients revealed a higher incidence of viremia (13/13 VS. 7/12) of ANF (4/8 vs. 1/17) and a higher total IgG concentration (2392 mg/dl vs. 1678 mg/dl, p<0.04) in comparison with ACAnegative patients. There was no difference in Knodell score, incidence of cryoglobulinemia and ANCA between these 2 groups. Cryoprecipitate was isolated from 7 patients with ANCA seropositivity of whom 3 also had ACA in the serum. ANCA was found in the cryoprecipitate in 2/7 and ACA in 2/3 of these samples. The high incidence of both ACA and ANCA in chronic HCV patients, together with the localization in the cryoprecipitate, raises the possibility that this may be linked to the pathogenesis of the extra-hepatic manifestations of HCV infection.
984
P R O S P E C T I V E STUDY O F P R I M A R Y S J O G R E N SYNDROME A S S O C I A T E D T O H C V - I N F E C T E D PATIENTS : C L I N I C A L , I M M U N O L O G I C A L , G E N E T I C A L AND V I R A L G E N O T Y P E C H A R A C T E R I S T I C S . P Pemev. C Jor~ensen. MC Le~ouffe. L Bourat. V ¢~?~te. I Serre. C Bologna. F Blanc. J Sariv. CHU Montpellier, France. The etiologic role of hepatitis C virus (HCV) infection in primary Sjogren syndrome (PSS) has been suggested, but remains a controversial issue. The aim of our study was to assess the prevalence of this association and the clinical, immunological and genotypic status of patients (pts) with PSS and infected by HCV. M e t h o d s : Sixty-two consecutive pts with PSS according to European criteria were included. An exhaustive clinical evaluation was performed. HCV infection was diagnosed on the presence of antibodies (Ab) against HCV by ELISA 2, RIBA 2 and the detection of HCV RNA by PCR ; HCV g e n o t y p e s have been also determined. R h e u m a t o i d factor, cryoglobulinemia, antinuclear Ab, anti-SSA Ab, anti SSb Ab, HLA typing were determined in all the pts. HCV RNA was detected in the saliva by PCR, and detection of HCV in labial salivary glands was assessed by immano-histology using monoclonal Ab against non structural proteins NS3 and capsid protein. Results : The prevalence of HCV infection in PSS pts was 19 % (12/62). No difference was observed in age, disease duration or sex ratio between infected pts (group 1) and non infected pts (group 2)~ The prevalence of vaseularitis and Raynand's syndrome were not different between the 2 groups. In group 1, there was significant increase of polynevritis (19% vs 4%, p<0.05), rheumatoid factor and cryoglobulinemia (respectively 62% vs 30%, p<0.03; 55% vs 9.7%, p<0.001). In contrast, anti-SSA and/or antiSSB Ab were more frequently present in group 2 (38% vs 8%, p<0.01). No specific HLA phenotype was observed in HCV positive pts. RNA HCV was present in saliva in 83% of group 1 pts, but not in pts of group 2. A positive immannstaining in salivary glands has been shown in both groups (50% in group 1, 38% in group 2) suggesting a cross reactivity. PSS was not associated to a specific HCV genotype (Ib : 43%, others genotypes : 57%). Conclusion : In our study, high prevalence of HCV infection was observed in pts with PSS (19 %). Clinical and biological characteristics observed in group 1 suggest a particular form of PSS in HCV infected pts.
981
AASLD ABSTRACTS
INFECTION BY HCV AND OTHER LYMPHOTROPIC VIRUSES IN BCELL NON-HODGKIN'S LYMPHOMA. C Fen/*, M Mona, F Lo Jacono*. F Caracciolo*, L La Civita*. G Carccci3. G Loneomhardo*. C Giannini. F Greco*. A Mazzoni*, L Ceecherini-Nelli*. AL Ziene~o. Instimt of Internal Medicine, Florence, Patologia Medica I, Haematology Unit, and Dep. of Biomedicine, Pisa, Italy*.
982
R H E U M A T O L O G I C A N D I M M U N O L O G I C MANIFESTATtONS O F HEPATITIS C INFECTION. E. Zuckerman- I. Rosner. M. Ashkar. N. Elias. M. Rozenbaum. Y. N~ehitz. D. Golan. E. Toubi. and D. Y~hurun. Department of Medicine A, Rheumatology Unit and Immunology Institute, Bnai Zion Medical Center, Technion School of Medicine, Halfa, Israel. Hepatitis C virus has been increasingly recognized as a cause of rheumatologic disease and autoimmune phenomena. We studied prospectively 41 consecutive patients with hepatitis C infection presenting to a deparmaent of internal medicine and evaluated them for a broad rang~" of rheumatologic/immunologicdisease. All patients were diagnosed on basis of HCV 2nd generation ELISA and H C V - R N A by PCR. Liver biopsy was performed in 34 of 41 patients. The 41 patients had: Joints] arthralglas-22, arthritis-9 (non-erosive by x-ray); xerostomia-15, xeropthalmia-3 (minor labial salivary gland biopsy showed focal lymphocytic infiltrate in 2/24 and Schirmer's test was positivein 1/28): skin] vasculitis-3, Raynaud's-4. Positive lab t'mdings: rheumatoid factor-20; cryoglobulins-17; low C3-19; low C:27. Antibodies] anti parietal ce11-25 (low serum Bt2-7 of 24; bone marcow megaloblastosis-4 of 10, gastric atrophy on endoseopy-1 of 8); anti centromere-11; ANA-3; anti DNA-0; ANCA-2; anti cardiolipin lgM (ACLM)-9; anti SSA-2; anti SSB-4; anti RNP-5; anti SCL 70-0. While confirnfing previously reported rheumatologic/immunologic associations with HCV including arthropathy, vasculitis, ACL-M, low C 3and C 4, rheumatoid factor and cryoglobulins, we herein describe for the first time the added associations with anti parietal cell and anti centromere antibodies. The role of HCV in pernicious anemia and CREST subset ofscleroderma remains to be further evaluated.
HEPATITIS IS ASSOCIATED OF ANTI-NEUTROPNIL AND ANTI-CARDIOLIPIN
WITH A HIGH CYTOPLASMIC ANTIBODIES.
S.D.H. Malnick. Y. Lurie. N. Fo~el. P. Cohen. D. Geltner. D.D. Bass. and Z.M. Sthoeuer. Departments of Internal Medicine 'C', Pathology and Gastroenterology, Kaplan Hospital, Rehovot 76100, Israel.
Lymphotropic viruses such as Epstein-Barr virus (EBV) and human herpesvirns-6 (HHV-6) have been proposed as causative agents of B-cell nonHodgkin's lymphoma (NHL). More recently, HCV, a hepatotrepic and lymphotropic virus, has also been implicated. The AIM of this study was to investigate the prevalence of HCV, EBV and HHV-6 infection and their potential relationship in a series of B-cell NHL pts. PATIENTS. 18 anselected pts with B-cell NHL (I0 m./8w.; mean age 62 yrs.) were studied. 20 age-matched healthy subjects (I-IS: anti-HCV, HCVRNA, antiEBV and anti-HllV-6 IgM class negative) were used as controls. METHODS. HCVRNA sequences (in serum and fresh or cultured PBMC), EBDNA-1 gene sequences in PBMC and HHV-6 DNA sequences in PBMC were detected by PCR as described (1-4).DNA ampliticubility was tested by beta-glubin PCR. Anli-HCV, -EBV, -HHV-6, HBV and -HIV were detected by commercially available kits. RESULTS. I-HV infection was excluded in all cases. HCVRNA, EBVDNA and HI-IV-6DNAsequences were detected in PBMC in 6 (33%), 7 (39%) and 4 pts (22%), respectively. Anti-HCV were found in 6 ce.ses.; anti-EBV and anti-HI-IV-6 IgM class were not detected, In HS, PBMC were infected by HCV, EBV and HI-IV-6in 0%, 7% in 18% of eases respectively. At least one of the viruses studied was detected in PBMC from the majority of NHL pts (14=78%). In 11 cases it was a single infection and in the remaining 3 a coinfeetion by two viruses. No correlation was observed between presence/absence of different viruses in PBMCs and various grades of malignancy, disease duration, and concomitant therapies. CONCLUSIONS. These data are consistent with the hypothesis that a viral agent is involved in the pathogenesis of the majority of B-cell NHL. Since the coinfectian seems to be uncommon condition it should be important to investigate other factors (genetic and/or environmental), possibly involved in the oncogenesis of such malignancies. REFERENCES 1) Blood, 1993; 82: 3701-4; 2) Blood 1991; 77: 2251-8; 3) Lancet 1993; 342 (i): 398; 4) Cancer 1992;70: 1985-9.
983
CHRONIC HCV INCIDENCE ANTIBODIES
HEPATOLOGY October 1995
Chronic HCV infection has been linked to extra-hepatic autoimmune phenomena. We therefore studied 48 consecutive chronic HCV patients w i t h no evidence of previous HBV infection or other autoimmune disease for the presence of anti-cardiolipin antibodies (ACA) and anti-neutrophil cytoplasmic antibodies (ANCA) which have been linked to the above phenomena. High levels of ACA were detected in 21/48 (43.8%) and ANCA in 23/30 (70%) of these patients whereas no such antibodies were detected in controls. Cryoglobulin was present in 15/39 (38.5%) patients. ACA-positive patients revealed a higher incidence of viremia (13/13 VS. 7/12) of ANF (4/8 vs. 1/17) and a higher total IgG concentration (2392 mg/dl vs. 1678 mg/dl, p<0.04) in comparison with ACAnegative patients. There was no difference in Knodell score, incidence of cryoglobulinemia and ANCA between these 2 groups. Cryoprecipitate was isolated from 7 patients with ANCA seropositivity of whom 3 also had ACA in the serum. ANCA was found in the cryoprecipitate in 2/7 and ACA in 2/3 of these samples. The high incidence of both ACA and ANCA in chronic HCV patients, together with the localization in the cryoprecipitate, raises the possibility that this may be linked to the pathogenesis of the extra-hepatic manifestations of HCV infection.
984
P R O S P E C T I V E STUDY O F P R I M A R Y S J O G R E N SYNDROME A S S O C I A T E D T O H C V - I N F E C T E D PATIENTS : C L I N I C A L , I M M U N O L O G I C A L , G E N E T I C A L AND V I R A L G E N O T Y P E C H A R A C T E R I S T I C S . P Pemev. C Jor~ensen. MC Le~ouffe. L Bourat. V ¢~?~te. I Serre. C Bologna. F Blanc. J Sariv. CHU Montpellier, France. The etiologic role of hepatitis C virus (HCV) infection in primary Sjogren syndrome (PSS) has been suggested, but remains a controversial issue. The aim of our study was to assess the prevalence of this association and the clinical, immunological and genotypic status of patients (pts) with PSS and infected by HCV. M e t h o d s : Sixty-two consecutive pts with PSS according to European criteria were included. An exhaustive clinical evaluation was performed. HCV infection was diagnosed on the presence of antibodies (Ab) against HCV by ELISA 2, RIBA 2 and the detection of HCV RNA by PCR ; HCV g e n o t y p e s have been also determined. R h e u m a t o i d factor, cryoglobulinemia, antinuclear Ab, anti-SSA Ab, anti SSb Ab, HLA typing were determined in all the pts. HCV RNA was detected in the saliva by PCR, and detection of HCV in labial salivary glands was assessed by immano-histology using monoclonal Ab against non structural proteins NS3 and capsid protein. Results : The prevalence of HCV infection in PSS pts was 19 % (12/62). No difference was observed in age, disease duration or sex ratio between infected pts (group 1) and non infected pts (group 2)~ The prevalence of vaseularitis and Raynand's syndrome were not different between the 2 groups. In group 1, there was significant increase of polynevritis (19% vs 4%, p<0.05), rheumatoid factor and cryoglobulinemia (respectively 62% vs 30%, p<0.03; 55% vs 9.7%, p<0.001). In contrast, anti-SSA and/or antiSSB Ab were more frequently present in group 2 (38% vs 8%, p<0.01). No specific HLA phenotype was observed in HCV positive pts. RNA HCV was present in saliva in 83% of group 1 pts, but not in pts of group 2. A positive immannstaining in salivary glands has been shown in both groups (50% in group 1, 38% in group 2) suggesting a cross reactivity. PSS was not associated to a specific HCV genotype (Ib : 43%, others genotypes : 57%). Conclusion : In our study, high prevalence of HCV infection was observed in pts with PSS (19 %). Clinical and biological characteristics observed in group 1 suggest a particular form of PSS in HCV infected pts.