- Email: [email protected]
542 Steroid and azathioprine for autoimmune hepatitis: A cochrane systematic review
Category 7: Autoimmune and Chronic Cholestatic Liver Diseases (UREB)(22-36) antigen of H. pylori (HELPY) shares extensive (87%) similarity with PDC-E2(212-226), we hypothesized that this would also lead to crossreactivity. We thus constructed the UREB HELPY/PDC-E2 mimics and tested them by ELISA in 99 PBC patients. Reactivity to PDC-E2(212226) was found in 96 patients but to UREB(22-36) in only 2. In these two patients, the double reactivity was not crossreactive. The lack of surface antibody accessibility to HELPY UREB(22-36) as demonstrated through three-dimensional model prediction analysis may explain this unexpected finding. Since B and T-cell epitopes frequently do not co-localise, we wondered whether the HELPY UREB(22-36) may act as a cross-reactive CD4 T cell epitope. Seven PBC patients, tested in a standard proliferation assay against PDC-E2(212-226), gave all a positive response. All seven were unresponsive to HELPY UREB(22-36). These data demonstrate that, contrary to common belief, extensive sequence homology (molecular mimicry) between self and microbe does not necessarily results in cross-reactivity. It is therefore likely that, when present, crossreactivity between self and microbes is of pathogenic importance.
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Results: Of 640 identified references, 5 randomised trials were included. We were able to extract data on mortality rates from three trials with 216 patients on initial therapy. Steroid reduced mortality by 75% compared to placebo or no intervention (0.25; 0.11-0.53). Steroid reduced mortality significantly compared to azathioprine (0.18; 0.07-0.45), but was not significantly different from combination therapy with steroid plus azathioprine (1.23; 0.25-5.97). Compared to placebo or no intervention, combination therapy reduced mortality by 88% (0.12; 0.02-0.69). Azathioprine alone had no significant effect (1.23; 0.52-2.92). We were able to extract data on relapse rates from five trials with 311 patients on initial or maintenance therapy. Combination therapy reduced relapse rates by 58% compared to azathioprine (0.42; 0.20-0.85), but not compared to steroid (0.49; 0.063.71) or placebo (0.61; 0.17-2.21). Neither azathioprine nor steroid had a significant effect on relapse compared to placebo or no intervention (1.64; 0.76-3.53 and 0.63; 0.39-1.03, respectively). Conclusion: Steroid with or without azathioprine reduces mortality in autoimmune hepatitis. Azathioprine has no effect on mortality in the initial therapy, and its role in maintenance therapy is unclear.
541 HYPERCHOLESTEROLAEMIA IS NOT ASSOCIATED WITH INCREASED CAROTID-ARTERY INTIMA AND MEDIA THICKNESS IN PRIMARY BILIARY CIRRHOSIS
M. Allocca, A. Crosignani, P.M. Battezzati, A. Gritti, M. Podda. Division of Internal Medicine, School of Medicine San Paolo, University of Milan, Milan, Italy Primary biliary cirrhosis (PBC) is frequently associated with hypercholesterolaemia but it is still debated if such condition is a risk factor for the development of cardiovascular events. The carotid-artery intima and media thickness was shown to be associated with the risk of cardiovascular events. Aim of the present study is to evaluate if the carotid-artery intima and media thickness is increased in patients with PBC or, at least, in the subgroup of hypercholesterolaemic patients. One hundred and three patients with PBC underwent measurement of the carotid-artery intima and media thickness by high resolution ultrasonography. A control group of 101 healthy subjects, in whom the presence of additional risk factors for cardiovascular disease was carefully excluded, was enrolled and matched for sex and age with PBC patients. An additional control group of 37 hypercholesterolaemic patients with normal liver function was also enrolled and matched with PBC patients with serum cholesterol concentrations >240 mg/dl. Among the PBC group (95 females, mean age 60 ± 12 yrs, 45 with cirrhosis), 74 patients had serum cholesterol >200 mg/dl while in 37 it was >240 mg/dl. The carotid-artery intima and media thickness of PBC patients was comparable with that of healthy subjects (0.60 ± 0.13 mm vs. 0.66 ± 0.16 mm, N.S.), while the carotid-artery intima and media thickness of hypercholesterolaemic PBC patients was significantly lower, compared with hypercholesterolaemic patients without liver disease (0.61 ± 0.13 vs 0.91 ± 0.26, p=0.0001). In conclusion, hypercholesterolaemia does not represent a risk factor for cardiovascular events in PBC.
542 STEROID AND AZATHIOPRINE FOR AUTOIMMUNE
543 IDENTIFICATION OF F1-ATPASE AS A NEW TARGET ANTIGEN OF ANTIMITOCHONDRIAL ANTIBODIES (AMA) IN PRIMARY BILIARY CIRRHOSIS (PBC)
M. Feuchtinger 1 , J. Dengjel 2 , S. Stevanovic 2 , R. Klein 1 . 1 Medizinische Klinik, Abt. II, Universitaet Tuebingen, Tuebingen, Germany; 2 Interfakultaeres Institut Fuer Zellbiologie, Abt. Immunologie, Universitaet Tuebingen, Tuebingen, Germany 95% of PBC patients have AMA reacting with the M2-antigen of the inner mitochondrial membrane (IMM) identified as 2-oxo-acid-dehydrogenase complex (OADC). We observed, however, that some PBC-sera are anti-M2 negative but show in the immunofluorescence test (IFT) a typical AMAstaining. Aim of the present study was, therefore, to verify the existence of further AMA-subspecificities and to characterize their target antigen(s). Sera from 72 patients with well defined PBC being AMA positive by IFT but negative for anti-M2 by ELISA and Western blotting (WB) using different OADC-related antigens/epitopes were tested against various mitochondrial subfractions. Positive reactions were characterized by WB, and the corresponding determinant was analysed by mass spectrometry (MALDI-TOF). 36,4% of the 72 sera reacted with an antigen present in a 100.000g supernatant from beef heart submitochondrial particles cumulating at a sucrose densitiy of 1.14-1.16. Gel electrophoresis and WB revealed a determinant at 60kD. MALDI-TOF analysis identified the corresponding protein as F1-ATPase. Sera from patients with other disorders were negative with this antigen. Interestingly, however, anti-F1-ATPase antibodies were observed not only in anti-M2 negative but also in about 60% of anti-M2 positive PBC patients. These data indicate that in PBC besides the antibodies to OADC further AMA exist reacting with F1-ATPase, an enzyme, which is - like OADC - associated with IMM but involved in oxidative phosphorylation. Furthermore, it becomes evident, that IFT is still a helpful screening method to identify PBC patients, who are anti-M2 negative but may express antibodies to other mitochondrial antigens.
HEPATITIS: A COCHRANE SYSTEMATIC REVIEW
E. Efsen 1,2 , L.L. Gluud 2 , P. Schlichting 1 . 1 Dep. of Gastroenterology, Herlev Hospital, Herlev, Denmark; 2 Cochrane Hepato-Biliary Group, Rigshospitalet, Copenhagen, Denmark Objective: To evaluate the effects of steroid, azathioprine, and steroid plus azathioprine combination therapy as initial and maintenance therapy for autoimmune hepatitis. Design: Systematic review of randomised trials. Methods: We searched electronic databases, specialist journals, conference proceedings, and wrote to investigators and pharmaceutical companies. Data were presented as risk ratios (RR) with 95% confidence intervals (CI). Outcome measures: All-cause mortality and relapse of autoimmune hepatitis.
544 PROGNOSTIC VALUE OF AUTOANTIBODIES AGAINST PROTEINS OF NUCLEAR PORE COMPLEXES (ANTI-NPCS) IN EARLY PRIMARY BILIARY CIRRHOSIS (PBC)
P. Invernizzi 1 , J. Wesierska-Gadek 2 , P.M. Battezzati 1 , S. Oertelt 1 , P.L. Busatto 1 , A. Benetti 1 , E. Penner 3 , E. Hitchman 3 , M. Podda 1 . 1 Dept. of Internal Medicine, San Paolo Hospital, Univ. of Milan, Milan, Italy; 2 Inst of Cancer Research, Univ. of Vienna, Vienna, Austria; 3 Fourth Dept. of Internal Medicine, Univ. of Vienna, Vienna, Austria In a cross-sectional survey we have shown that anti-NPCs are strongly associated with more advanced disease in PBC (J Hepatol 2001;34:366). The present study addressed the prognostic value of anti-NPCs in PBC.
159
Results: Of 640 identified references, 5 randomised trials were included. We were able to extract data on mortality rates from three trials with 216 patients on initial therapy. Steroid reduced mortality by 75% compared to placebo or no intervention (0.25; 0.11-0.53). Steroid reduced mortality significantly compared to azathioprine (0.18; 0.07-0.45), but was not significantly different from combination therapy with steroid plus azathioprine (1.23; 0.25-5.97). Compared to placebo or no intervention, combination therapy reduced mortality by 88% (0.12; 0.02-0.69). Azathioprine alone had no significant effect (1.23; 0.52-2.92). We were able to extract data on relapse rates from five trials with 311 patients on initial or maintenance therapy. Combination therapy reduced relapse rates by 58% compared to azathioprine (0.42; 0.20-0.85), but not compared to steroid (0.49; 0.063.71) or placebo (0.61; 0.17-2.21). Neither azathioprine nor steroid had a significant effect on relapse compared to placebo or no intervention (1.64; 0.76-3.53 and 0.63; 0.39-1.03, respectively). Conclusion: Steroid with or without azathioprine reduces mortality in autoimmune hepatitis. Azathioprine has no effect on mortality in the initial therapy, and its role in maintenance therapy is unclear.
541 HYPERCHOLESTEROLAEMIA IS NOT ASSOCIATED WITH INCREASED CAROTID-ARTERY INTIMA AND MEDIA THICKNESS IN PRIMARY BILIARY CIRRHOSIS
M. Allocca, A. Crosignani, P.M. Battezzati, A. Gritti, M. Podda. Division of Internal Medicine, School of Medicine San Paolo, University of Milan, Milan, Italy Primary biliary cirrhosis (PBC) is frequently associated with hypercholesterolaemia but it is still debated if such condition is a risk factor for the development of cardiovascular events. The carotid-artery intima and media thickness was shown to be associated with the risk of cardiovascular events. Aim of the present study is to evaluate if the carotid-artery intima and media thickness is increased in patients with PBC or, at least, in the subgroup of hypercholesterolaemic patients. One hundred and three patients with PBC underwent measurement of the carotid-artery intima and media thickness by high resolution ultrasonography. A control group of 101 healthy subjects, in whom the presence of additional risk factors for cardiovascular disease was carefully excluded, was enrolled and matched for sex and age with PBC patients. An additional control group of 37 hypercholesterolaemic patients with normal liver function was also enrolled and matched with PBC patients with serum cholesterol concentrations >240 mg/dl. Among the PBC group (95 females, mean age 60 ± 12 yrs, 45 with cirrhosis), 74 patients had serum cholesterol >200 mg/dl while in 37 it was >240 mg/dl. The carotid-artery intima and media thickness of PBC patients was comparable with that of healthy subjects (0.60 ± 0.13 mm vs. 0.66 ± 0.16 mm, N.S.), while the carotid-artery intima and media thickness of hypercholesterolaemic PBC patients was significantly lower, compared with hypercholesterolaemic patients without liver disease (0.61 ± 0.13 vs 0.91 ± 0.26, p=0.0001). In conclusion, hypercholesterolaemia does not represent a risk factor for cardiovascular events in PBC.
542 STEROID AND AZATHIOPRINE FOR AUTOIMMUNE
543 IDENTIFICATION OF F1-ATPASE AS A NEW TARGET ANTIGEN OF ANTIMITOCHONDRIAL ANTIBODIES (AMA) IN PRIMARY BILIARY CIRRHOSIS (PBC)
M. Feuchtinger 1 , J. Dengjel 2 , S. Stevanovic 2 , R. Klein 1 . 1 Medizinische Klinik, Abt. II, Universitaet Tuebingen, Tuebingen, Germany; 2 Interfakultaeres Institut Fuer Zellbiologie, Abt. Immunologie, Universitaet Tuebingen, Tuebingen, Germany 95% of PBC patients have AMA reacting with the M2-antigen of the inner mitochondrial membrane (IMM) identified as 2-oxo-acid-dehydrogenase complex (OADC). We observed, however, that some PBC-sera are anti-M2 negative but show in the immunofluorescence test (IFT) a typical AMAstaining. Aim of the present study was, therefore, to verify the existence of further AMA-subspecificities and to characterize their target antigen(s). Sera from 72 patients with well defined PBC being AMA positive by IFT but negative for anti-M2 by ELISA and Western blotting (WB) using different OADC-related antigens/epitopes were tested against various mitochondrial subfractions. Positive reactions were characterized by WB, and the corresponding determinant was analysed by mass spectrometry (MALDI-TOF). 36,4% of the 72 sera reacted with an antigen present in a 100.000g supernatant from beef heart submitochondrial particles cumulating at a sucrose densitiy of 1.14-1.16. Gel electrophoresis and WB revealed a determinant at 60kD. MALDI-TOF analysis identified the corresponding protein as F1-ATPase. Sera from patients with other disorders were negative with this antigen. Interestingly, however, anti-F1-ATPase antibodies were observed not only in anti-M2 negative but also in about 60% of anti-M2 positive PBC patients. These data indicate that in PBC besides the antibodies to OADC further AMA exist reacting with F1-ATPase, an enzyme, which is - like OADC - associated with IMM but involved in oxidative phosphorylation. Furthermore, it becomes evident, that IFT is still a helpful screening method to identify PBC patients, who are anti-M2 negative but may express antibodies to other mitochondrial antigens.
HEPATITIS: A COCHRANE SYSTEMATIC REVIEW
E. Efsen 1,2 , L.L. Gluud 2 , P. Schlichting 1 . 1 Dep. of Gastroenterology, Herlev Hospital, Herlev, Denmark; 2 Cochrane Hepato-Biliary Group, Rigshospitalet, Copenhagen, Denmark Objective: To evaluate the effects of steroid, azathioprine, and steroid plus azathioprine combination therapy as initial and maintenance therapy for autoimmune hepatitis. Design: Systematic review of randomised trials. Methods: We searched electronic databases, specialist journals, conference proceedings, and wrote to investigators and pharmaceutical companies. Data were presented as risk ratios (RR) with 95% confidence intervals (CI). Outcome measures: All-cause mortality and relapse of autoimmune hepatitis.
544 PROGNOSTIC VALUE OF AUTOANTIBODIES AGAINST PROTEINS OF NUCLEAR PORE COMPLEXES (ANTI-NPCS) IN EARLY PRIMARY BILIARY CIRRHOSIS (PBC)
P. Invernizzi 1 , J. Wesierska-Gadek 2 , P.M. Battezzati 1 , S. Oertelt 1 , P.L. Busatto 1 , A. Benetti 1 , E. Penner 3 , E. Hitchman 3 , M. Podda 1 . 1 Dept. of Internal Medicine, San Paolo Hospital, Univ. of Milan, Milan, Italy; 2 Inst of Cancer Research, Univ. of Vienna, Vienna, Austria; 3 Fourth Dept. of Internal Medicine, Univ. of Vienna, Vienna, Austria In a cross-sectional survey we have shown that anti-NPCs are strongly associated with more advanced disease in PBC (J Hepatol 2001;34:366). The present study addressed the prognostic value of anti-NPCs in PBC.