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SSA autoantibodies in autoimmune hepatitis and association with unexplained pregnancy loss
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Poster Sessions
Results: The combined endpoint ’death or liver transplantation’ occurred in 7/97 (7.2%) patients in the UDCA group vs. 11/101 (10.9%) patients in the placebo group (p=0.368). Occurrence of liver transplantation as a single endpoint showed a similar advatage of UDCA treatment (5/97 (5.2%) vs. 8/101 (7.9%)). Three UDCA and 4 placebo patients died from cholangiocarcinoma, one placebo patient died from liver failure. ALP and ALT tended to decrease during the first 6 months. There were no differences between the two groups in symptoms, or Quality of life as recorded by SF-36. Conclusion: No statistically significant benefit from 20 mg/kg bw UDCA in PSC was demonstrated. However, there was a tendency to improved survival in the UDCA treated patients. Furthermore, we had estimated before the study that based on a type I error of =5%,and a type II error of =20%, at least 346 patients was required for detection of a difference in events of at least =50%, a goal we did not reach within the predetermined recruitment time of 15 months. Therefore,the study may have been undernumbered to exclude a significant beneficial effect on survival.
552 PRIMARY BILIARY CIRRHOSIS (PBC) SPECIFIC ANTINUCLEAR ANTIBODIES (ANA) HAVE PROGNOSTIC VALUE AND A DISTINCT IMMUNOGLOBULIN ISOTYPE PROFILE
E.I. Rigopoulou 1 , E.T. Davies 2 , D.P. Bogdanos 3 , G. Koukoulis 4 , G.N. Dalekos 1 , D. Vergani 3 . 1 Academic Liver Unit, Dept. of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece; 2 Department of Immunology, King’s College, London, UK; 3 Institute of Liver Studies, King’s College Hospital, London, UK; 4 Department of Pathology, Medical School, University of Thessaly, Larissa, Greece Background/aim: PBC is characterized by anti-mitochondrial (AMA) and disease-specific ANA generating a rim-like/membranous (RL/M) or multiple nuclear dot (MND) pattern by indirect immunofluorescence (IIF). The aim of the present study was to investigate the prevalence and clinical significance of the isotypes of PBC-specific ANA and their relation to the AMA isotypes. Methods: PBC-specific ANA and AMA were investigated by conventional IIF on triple rodent tissue and on HEp-2010 cells in 44 Greek PBC patients. Revealing reagents comprised antisera targeting IgG or IgA or IgM or individual IgG (1-4) subclasses. Results: Thirty-seven of 44 (84%) PBCs tested positive for IgM and/or IgG (class or subclasses) PBC-specific ANA, 27 (61.4%) being positive for RL/M and 21 (47.7%) for the MND pattern. The prevailing isotype was IgG1 for anti-RL/M and IgG3 for anti-MND reactivity. PBC patients positive for either RL/M or MND had a histologically more advanced liver disease and were more frequently cirrhotic compared to those ANA negative. In addition, PBC-specific ANAs of the IgG3 subclass were significantly associated with more severe disease and higher frequency of cirrhosis. AMA belonging to any isotype were present in 41 (93.2%) PBC patients, the prevailing isotype pattern comprising IgG1, 2 and 3 subclass. Comparison of AMA and ANA revealed identical Ig isotype profile in only 8 PBC patients. Conclusions: PBC-specific ANAs, especially of the IgG3 isotype, are associated with a more advanced disease. The different isotypes profiles of MND, RL/M and AMA suggest that distinct antigen driven mechanisms are responsible for their production.
553 PREVALENCE OF RO/SSA AUTOANTIBODIES IN AUTOIMMUNE HEPATITIS AND ASSOCIATION WITH UNEXPLAINED PREGNANCY LOSS
C. Schramm, J. Herkel, J.-P. Modrow, I. Ernst, S. Kanzler, P.R. Galle, A.W. Lohse. I. Department of Medicine, University of Mainz, Mainz, Germany Introduction: Ro/SSA autoantibodies have been associated with unexplained pregnancy loss in rheumatic diseases. We therefore determined the
prevalence of Ro/SSA antibodies in autoimmune liver disease and assessed the risk of pregnancy loss in a cohort of patients with AIH. Patients and Methods: Test sera were obtained from 293 consecutive patients attending our liver outpatient clinic. 29 pregnancies in 14 patients with known Ro/SSA status and autoimmune hepatitis were reviewed retrospectively and patients were specifically asked about miscarriages in a questionnaire. Results: 14% of the patients with AIH (n=96) and 20% of the patients with an AIH/PBC overlap syndrome (n=20) manifested autoantibodies to the Ro/SSA antigen. In contrast, Ro/SSA autoantibodies were absent in all of the 120 patients with viral hepatitis, PSC, NASH, toxic hepatitis and also in the 57 PBC patients. There was no difference in the clinical characteristics of AIH patients with and without Ro/SSA autoantibodies. Five pregnancy losses occurred in four patients with autoantibodies to the Ro/SSA molecule, whereas only one unexplained pregnancy loss occurred in a patient without Ro/SSA autoantibodies. Thus, the odds ratio for an unexplained pregnancy loss in the presence of Ro/SSA autoantibody was 14 (95% confidence interval: 0.94 to 207.74). Conclusions: Ro/SSA autoantibodies might be an additional marker for AIH and the AIH/PBC overlap syndrome. Moreover, Ro/SSA autoantibodies seem to be associated with unexplained pregnancy loss in patients with AIH. A prospective study seems to be warranted and testing for Ro/SSA antibody should be included in the counselling of young female patients with AIH.
554 HLA DR7 POSITIVE PATIENTS WITH TYPE 2 AUTOIMMUNE HEPATITIS ARE CHARACTERISED BY A PROLONGED CLINICAL COURSE
J. Underhill 1 , D.P. Bogdanos 1 , M.S. Longhi 1 , S. Bansal 2 , G. Mieli-Vergani 1,2 , D. Vergani 1 , Y. Ma 1 . 1 Institute of Liver Studies, King’s College Hospital, London, UK; 2 Department of Child Health, King’s College Hospital, London, UK Background: HLA-DRB1∗07 (DR7) is over-represented in LKM1+ autoimmune hepatitis (AIH-2) (J Hepatol 2002;36:S1, 156), DR7+ patients having a broader and more vigorous cellular immune response to CYP2D6 – the target of LKM1 – than those DR7- (J Hepatol 2003;38:S2, 719). Aim: To compare the clinical features of DR7+ and DR7- AIH-2 patients. Patients and Methods: Thirty-five patients with AIH-2 were investigated (6 male, median age 6.8 yrs, range 1 to 15.4). Class II genotyping for HLADRB was performed by PCR/SSO using oligonucleotide probes (BSHI, Bristol, UK). Results: 20 patients (57%) were HLA-DR7 positive. Of 15 DR7-, 9 were DR3 (26%, p<0.01), 1 DR4 (3%, p<0.001) and 5 had other allotypes (DR1, 13, 14 and 15; 17%, p<0.001). Age at diagnosis (6 vs 9 yrs), mode of presentation (chronic/acute: 6/14 vs 2/13), biochemical (AST: 321 vs 449 IU/l; Bilirubin: 49 vs 33 micromol/l) and histological (HAI: 7 vs 8) disease severity were similar, while male sex was more frequent (6/20, 30% vs 0/15, 0% p=0.02) in DR7+ than in DR7- patients. DR7+ patients required longer time to achieve remission (12 vs 7 months, p=0.05) and tended to relapse more often than DR7- patients (10/15, 67% vs 4/12, 33%, p=0.08). The frequency of patients who died or required transplantation, however, was similar (5/20, 25% vs 3/15, 20%). Conclusion: DR7+ patients have a relatively more severe course of liver disease, possibly a consequence of their broader and stronger cellular immune response to CYP2D6.
Poster Sessions
Results: The combined endpoint ’death or liver transplantation’ occurred in 7/97 (7.2%) patients in the UDCA group vs. 11/101 (10.9%) patients in the placebo group (p=0.368). Occurrence of liver transplantation as a single endpoint showed a similar advatage of UDCA treatment (5/97 (5.2%) vs. 8/101 (7.9%)). Three UDCA and 4 placebo patients died from cholangiocarcinoma, one placebo patient died from liver failure. ALP and ALT tended to decrease during the first 6 months. There were no differences between the two groups in symptoms, or Quality of life as recorded by SF-36. Conclusion: No statistically significant benefit from 20 mg/kg bw UDCA in PSC was demonstrated. However, there was a tendency to improved survival in the UDCA treated patients. Furthermore, we had estimated before the study that based on a type I error of =5%,and a type II error of =20%, at least 346 patients was required for detection of a difference in events of at least =50%, a goal we did not reach within the predetermined recruitment time of 15 months. Therefore,the study may have been undernumbered to exclude a significant beneficial effect on survival.
552 PRIMARY BILIARY CIRRHOSIS (PBC) SPECIFIC ANTINUCLEAR ANTIBODIES (ANA) HAVE PROGNOSTIC VALUE AND A DISTINCT IMMUNOGLOBULIN ISOTYPE PROFILE
E.I. Rigopoulou 1 , E.T. Davies 2 , D.P. Bogdanos 3 , G. Koukoulis 4 , G.N. Dalekos 1 , D. Vergani 3 . 1 Academic Liver Unit, Dept. of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece; 2 Department of Immunology, King’s College, London, UK; 3 Institute of Liver Studies, King’s College Hospital, London, UK; 4 Department of Pathology, Medical School, University of Thessaly, Larissa, Greece Background/aim: PBC is characterized by anti-mitochondrial (AMA) and disease-specific ANA generating a rim-like/membranous (RL/M) or multiple nuclear dot (MND) pattern by indirect immunofluorescence (IIF). The aim of the present study was to investigate the prevalence and clinical significance of the isotypes of PBC-specific ANA and their relation to the AMA isotypes. Methods: PBC-specific ANA and AMA were investigated by conventional IIF on triple rodent tissue and on HEp-2010 cells in 44 Greek PBC patients. Revealing reagents comprised antisera targeting IgG or IgA or IgM or individual IgG (1-4) subclasses. Results: Thirty-seven of 44 (84%) PBCs tested positive for IgM and/or IgG (class or subclasses) PBC-specific ANA, 27 (61.4%) being positive for RL/M and 21 (47.7%) for the MND pattern. The prevailing isotype was IgG1 for anti-RL/M and IgG3 for anti-MND reactivity. PBC patients positive for either RL/M or MND had a histologically more advanced liver disease and were more frequently cirrhotic compared to those ANA negative. In addition, PBC-specific ANAs of the IgG3 subclass were significantly associated with more severe disease and higher frequency of cirrhosis. AMA belonging to any isotype were present in 41 (93.2%) PBC patients, the prevailing isotype pattern comprising IgG1, 2 and 3 subclass. Comparison of AMA and ANA revealed identical Ig isotype profile in only 8 PBC patients. Conclusions: PBC-specific ANAs, especially of the IgG3 isotype, are associated with a more advanced disease. The different isotypes profiles of MND, RL/M and AMA suggest that distinct antigen driven mechanisms are responsible for their production.
553 PREVALENCE OF RO/SSA AUTOANTIBODIES IN AUTOIMMUNE HEPATITIS AND ASSOCIATION WITH UNEXPLAINED PREGNANCY LOSS
C. Schramm, J. Herkel, J.-P. Modrow, I. Ernst, S. Kanzler, P.R. Galle, A.W. Lohse. I. Department of Medicine, University of Mainz, Mainz, Germany Introduction: Ro/SSA autoantibodies have been associated with unexplained pregnancy loss in rheumatic diseases. We therefore determined the
prevalence of Ro/SSA antibodies in autoimmune liver disease and assessed the risk of pregnancy loss in a cohort of patients with AIH. Patients and Methods: Test sera were obtained from 293 consecutive patients attending our liver outpatient clinic. 29 pregnancies in 14 patients with known Ro/SSA status and autoimmune hepatitis were reviewed retrospectively and patients were specifically asked about miscarriages in a questionnaire. Results: 14% of the patients with AIH (n=96) and 20% of the patients with an AIH/PBC overlap syndrome (n=20) manifested autoantibodies to the Ro/SSA antigen. In contrast, Ro/SSA autoantibodies were absent in all of the 120 patients with viral hepatitis, PSC, NASH, toxic hepatitis and also in the 57 PBC patients. There was no difference in the clinical characteristics of AIH patients with and without Ro/SSA autoantibodies. Five pregnancy losses occurred in four patients with autoantibodies to the Ro/SSA molecule, whereas only one unexplained pregnancy loss occurred in a patient without Ro/SSA autoantibodies. Thus, the odds ratio for an unexplained pregnancy loss in the presence of Ro/SSA autoantibody was 14 (95% confidence interval: 0.94 to 207.74). Conclusions: Ro/SSA autoantibodies might be an additional marker for AIH and the AIH/PBC overlap syndrome. Moreover, Ro/SSA autoantibodies seem to be associated with unexplained pregnancy loss in patients with AIH. A prospective study seems to be warranted and testing for Ro/SSA antibody should be included in the counselling of young female patients with AIH.
554 HLA DR7 POSITIVE PATIENTS WITH TYPE 2 AUTOIMMUNE HEPATITIS ARE CHARACTERISED BY A PROLONGED CLINICAL COURSE
J. Underhill 1 , D.P. Bogdanos 1 , M.S. Longhi 1 , S. Bansal 2 , G. Mieli-Vergani 1,2 , D. Vergani 1 , Y. Ma 1 . 1 Institute of Liver Studies, King’s College Hospital, London, UK; 2 Department of Child Health, King’s College Hospital, London, UK Background: HLA-DRB1∗07 (DR7) is over-represented in LKM1+ autoimmune hepatitis (AIH-2) (J Hepatol 2002;36:S1, 156), DR7+ patients having a broader and more vigorous cellular immune response to CYP2D6 – the target of LKM1 – than those DR7- (J Hepatol 2003;38:S2, 719). Aim: To compare the clinical features of DR7+ and DR7- AIH-2 patients. Patients and Methods: Thirty-five patients with AIH-2 were investigated (6 male, median age 6.8 yrs, range 1 to 15.4). Class II genotyping for HLADRB was performed by PCR/SSO using oligonucleotide probes (BSHI, Bristol, UK). Results: 20 patients (57%) were HLA-DR7 positive. Of 15 DR7-, 9 were DR3 (26%, p<0.01), 1 DR4 (3%, p<0.001) and 5 had other allotypes (DR1, 13, 14 and 15; 17%, p<0.001). Age at diagnosis (6 vs 9 yrs), mode of presentation (chronic/acute: 6/14 vs 2/13), biochemical (AST: 321 vs 449 IU/l; Bilirubin: 49 vs 33 micromol/l) and histological (HAI: 7 vs 8) disease severity were similar, while male sex was more frequent (6/20, 30% vs 0/15, 0% p=0.02) in DR7+ than in DR7- patients. DR7+ patients required longer time to achieve remission (12 vs 7 months, p=0.05) and tended to relapse more often than DR7- patients (10/15, 67% vs 4/12, 33%, p=0.08). The frequency of patients who died or required transplantation, however, was similar (5/20, 25% vs 3/15, 20%). Conclusion: DR7+ patients have a relatively more severe course of liver disease, possibly a consequence of their broader and stronger cellular immune response to CYP2D6.