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Marvin J. Fritzler – One of the best experts on this subject based on the ideXlab platform.

  • Anti-Centromere Antibodies in a large cohort of systemic sclerosis patients: comparison between immunofluorescence, CENP-A and CENP-B ELISA.
    Clinica Chimica Acta, 2011
    Co-Authors: Michael Mahler, Daniel You, Murray Baron, Suzanne Taillefer, Marie Hudson, Marvin J. Fritzler

    Abstract:

    Abstract Introduction Anti-Centromere Antibodies (ACA) are useful biomarkers in the diagnosis of systemic sclerosis (SSc) where they are found in 20–40% of patients and, albeit with lower prevalence, in patients with other systemic autoimmune rheumatic diseases. Historically, ACA were detected by indirect immunofluorescence (IIF) on HEp-2 cells and confirmed by immunoassays using recombinant CENP-B. During the last few years, to accommodate high throughput diagnostics, a number of laboratories changed from IIF to ELISA assays. The objective of this study was to compare the detection of ACA by IIF to CENP-A and a CENP-B ELISA in a large cohort of SSc patients. Methods Sera collected from SSc patients (n = 834) were tested for ACA by IIF on HEp-2 cells (ImmunoConcepts, Sacramento, CA) and CENP-A and CENP-B ELISA (both Dr. Fooke Laboratorien GmbH, Neuss, Germany). Furthermore, other autoAntibodies were determined by QUANTA-PlexTM SLE 8 profile (INOVA, San Diego, CA), QUANTA Lite® RNA Pol III (INOVA) and PM1-Alpha ELISA (Dr. Fooke). Results The prevalence of ACA was 35.0% by IIF, 41.6% by CENP-A and 57.8% by CENP-B ELISA. When the CENP-A and the CENP-B ELISA results were compared to the IIF, the area under the curve value derived from receiver operating characteristic analysis was 0.98 for both assays. ACA and anti-topoisomerase I Antibodies co-occurred in 1.2% (ACA by IIF), in 3.5% (by CENP-A ELISA) and in 7.4% (by CENP-B ELISA). Anti-CENP-A Antibodies were negatively associated with anti-Scl-70, anti-RNA Pol III, (both p  Conclusion Although we found good agreement between IIF and ELISA for the detection of ACA in SSc, a significant portion of CENP ELISA positive sera did not show the typical ACA staining pattern. Based on these findings, we conclude that an IIF ACA negative result might not rule out the presence of ACA. In addition, new CENP ELISA kits are reliable for the detection of anti-CENP in SSc sera.

  • Anti-Centromere Antibodies in a large cohort of systemic sclerosis patients: comparison between immunofluorescence, CENP-A and CENP-B ELISA.
    Clinica chimica acta; international journal of clinical chemistry, 2011
    Co-Authors: Michael Mahler, Daniel You, Murray Baron, Suzanne Taillefer, Marie Hudson, Marvin J. Fritzler

    Abstract:

    Anti-Centromere Antibodies (ACA) are useful biomarkers in the diagnosis of systemic sclerosis (SSc) where they are found in 20-40% of patients and, albeit with lower prevalence, in patients with other systemic autoimmune rheumatic diseases. Historically, ACA were detected by indirect immunofluorescence (IIF) on HEp-2 cells and confirmed by immunoassays using recombinant CENP-B. During the last few years, to accommodate high throughput diagnostics, a number of laboratories changed from IIF to ELISA assays. The objective of this study was to compare the detection of ACA by IIF to CENP-A and a CENP-B ELISA in a large cohort of SSc patients.
    Sera collected from SSc patients (n=834) were tested for ACA by IIF on HEp-2 cells (ImmunoConcepts, Sacramento, CA) and CENP-A and CENP-B ELISA (both Dr. Fooke Laboratorien GmbH, Neuss, Germany). Furthermore, other autoAntibodies were determined by QUANTA-Plex(TM) SLE 8 profile (INOVA, San Diego, CA), QUANTA Lite RNA Pol III (INOVA) and PM1-Alpha ELISA (Dr. Fooke).
    The prevalence of ACA was 35.0% by IIF, 41.6% by CENP-A and 57.8% by CENP-B ELISA. When the CENP-A and the CENP-B ELISA results were compared to the IIF, the area under the curve value derived from receiver operating characteristic analysis was 0.98 for both assays. ACA and anti-topoisomerase I Antibodies co-occurred in 1.2% (ACA by IIF), in 3.5% (by CENP-A ELISA) and in 7.4% (by CENP-B ELISA). Anti-CENP-A Antibodies were negatively associated with anti-Scl-70, anti-RNA Pol III, (both p<0.0001), anti-U1-RNP (p=0.008) and anti-PM1-Alpha Antibodies (p=0.0337). The degree of association was dependent on the cut-off value used.
    Although we found good agreement between IIF and ELISA for the detection of ACA in SSc, a significant portion of CENP ELISA positive sera did not show the typical ACA staining pattern. Based on these findings, we conclude that an IIF ACA negative result might not rule out the presence of ACA. In addition, new CENP ELISA kits are reliable for the detection of anti-CENP in SSc sera.
    Copyright © 2011 Elsevier B.V. All rights reserved.

  • Primary biliary cirrhosis and autoAntibodies.
    Japanese Journal of Clinical Immunology, 2008
    Co-Authors: K. Miyachi, Hiroshi Miyakawa, Oda M, Tsuneyoshi Horigome, Marvin J. Fritzler

    Abstract:

    Abstract Fifty years have passed since anti-mitochondrial Antibodies were found in patients with primary biliary cirrhosis (PBC). PBC is an autoimmune hepatic disease in which 85-90% of patient Antibodies bind to mitochondrial antigens that include pyruvate dehydrogenase complex (PDC)-E2 and other members of the oxaloacid dehydrogenase family. In addition, indirect immunofluorescence (IIF) assays utilizing HEp-2 cell substrates have been used to identify Anti-Centromere Antibodies in 20-30% of PBC sera. These Antibodies are generally easily recognized, however, anti-nuclear envelope and anti-multiple nuclear dot Antibodies are occasionally more difficult to recognize with certainty by IIF. The use of enzyme linked immunosorbent assays that utilize recombinant gp210 (an autoantigen of the nuclear envelope) and/or sp100 (a protein target represented by multiple nuclear dots) should be particularly considered in anti-mitochondrial antibody negative PBC sera. Although the clinical significance of these Antibodies still remains to be determined, there is evidence that the existence of anti-gp210 Antibodies are related to poorer prognosis and more aggressive disease progression.

Kiyoshi Migita – One of the best experts on this subject based on the ideXlab platform.

  • Genetic polymorphisms in CTLA4 and SLC4A2 are differentially associated with the pathogenesis of primary biliary cirrhosis in Japanese patients
    Journal of gastroenterology, 2011
    Co-Authors: Yoshihiro Aiba, Kiyoshi Migita, Minoru Nakamura, Atsumasa Komori, Hitomi Horie, Satoru Joshita, Tatsuo Inamine, Kaname Yoshizawa, Takeji Umemura, Hiroshi Yatsuhashi

    Abstract:

    Background
    Anti-gp210 and Anti-Centromere Antibodies are different risk factors for the progression of primary biliary cirrhosis (PBC). In order to dissect the genetic basis for the production of these autoAntibodies, as well as the development and progression of PBC in Japanese patients, we examined single nucleotide polymorphisms (SNPs) in cytotoxic T-lymphocyte antigen 4 (CTLA4) and solute carrier family 4 anion exchanger, member 2 (SLC4A2), which have been associated with the pathogenesis of PBC in Caucasian patients.

  • Analysis of HLA-DRB1 polymorphisms in Japanese patients with primary biliary cirrhosis (PBC): The HLA-DRB1polymorphism determines the relative risk of antinuclear Antibodies for disease progression in PBC
    Hepatology research : the official journal of the Japan Society of Hepatology, 2010
    Co-Authors: Minoru Nakamura, Kiyoshi Migita, Hisayoshi Kondo, Atsumasa Komori, Masahiro Ito, Michio Yasunami, Hitomi Horie, Yoshihiro Aiba, Hiroshi Yatsuhashi, Shinji Shimoda

    Abstract:

    Aims:  Anti-gp210 and Anti-Centromere Antibodies are different risk factors for the progression of primary biliary cirrhosis (PBC). However, the association of human leukocyte antigen (HLA) polymorphisms with these risk factors is unknown.

    Methods:  We determined the HLA-DRB1 genotype in 334 Japanese PBC patients and studied their serum Antibodies to gp210 and centromere during the 1–452-month observation period.

    Results:  Anti-gp210 (odds ratio [OR] 46.56, 95% confidence interval [CI], 9.20–850.1) and Anti-Centromere Antibodies (OR, 2.36, 95% CI, 1.28–4.35) were significant risk factors for jaundice- and nonjaundice-type progression, respectively. HLA-DRB1*0405 and *0803 predisposed patients to anti-gp210 (OR, 1.61, 95% CI, 1.08–2.39) and Anti-Centromere (OR, 2.30, 95% CI, 1.41–3.73) antibody production, respectively. HLA-DRB1*1502 and *0901 patients were predisposed to nonjaundice-type progression (OR, 1.98, 95% CI, 1.13–3.40 and OR, 1.78, 95% CI, 1.02–3.03), while HLA-DRB1*0803 and *0405 patients were predisposed to disease development (OR, 2.24, 95% CI, 1.48–3.41 and OR, 1.53, 95% CI, 1.11–2.11, respectively). Stratifying patients by HLA-DRB1 alleles revealed that anti-gp210 Antibodies was a strong risk factor, regardless of the HLA-DRB1 alleles for jaundice-type progression, while Anti-Centromere Antibodies was a significant risk factor for nonjaundice-type progression in patients with HLA-DRB1*0405 (OR, 6.89, 95% CI, 2.18–26.56) and -DRB1*0803 (OR, 5.42, 95% CI, 1.47–24.62) but not other HLA-DRB1 alleles.

    Conclusions: HLA-DRB1 polymorphisms are significantly associated with not only disease development and progression but also antinuclear antibody production and the determination of the relative risk of antinuclear Antibodies that contribute to PBC disease progression.

  • anti gp210 and anti centromere Antibodies are different risk factors for the progression of primary biliary cirrhosis
    Hepatology, 2007
    Co-Authors: Minoru Nakamura, Hisayoshi Kondo, Tsuyoshi Mori, Atsumasa Komori, Mutsumi Matsuyama, Masahiro Ito, Yasushi Takii, Makiko Koyabu, Terufumi Yokoyama, Kiyoshi Migita

    Abstract:

    The predictive role of antinuclear Antibodies (ANAs) remains elusive in the long-term outcome of primary biliary cirrhosis (PBC). The progression of PBC was evaluated in association with ANAs using stepwise Cox proportional hazard regression and an unconditional stepwise logistic regression model based on the data of 276 biopsy-proven, definite PBC patients who have been registered to the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ). When death of hepatic failure/liver transplantation (LT) was defined as an end-point, positive anti-gp210 Antibodies (Hazard ratio (HR) = 6.742, 95% confidence interval (CI): 2.408, 18.877), the late stage (Scheuer’s stage 3, 4) (HR = 4.285, 95% CI:1.682,10.913) and male sex (HR = 3.266, 95% CI: 1.321,8.075) were significant risk factors at the time of initial liver biopsy. When clinical progression to death of hepatic failure/LT (i.e., hepatic failure type progression) or to the development of esophageal varices or hepatocellular carcinoma without developing jaundice (Total bilirubin < 1.5 mg/dL) (i.e., portal hypertension type progression) was defined as an end-point in the early stage (Scheuer's stage 1, 2) PBC patients, positive anti-gp210 Antibodies was a significant risk factor for hepatic failure type progression [odds ratio (OR) = 33.777, 95% CI: 5.930, 636.745], whereas positive Anti-Centromere Antibodies was a significant risk factor for portal hypertension type progression (OR = 4.202, 95% CI: 1.307, 14.763). Histologically, positive anti-gp210 Antibodies was most significantly associated with more severe interface hepatitis and lobular inflammation, whereas positive anticentromere Antibodies was most significantly associated with more severe ductular reaction. Conclusion: These results indicate 2 different progression types in PBC, hepatic failure type and portal hypertension type progression, which may be represented by positive-anti-gp210 and positive-anticentromere Antibodies, respectively. (HEPATOLOGY 2007;45:118–127.)

X Bossuyt – One of the best experts on this subject based on the ideXlab platform.

  • Anti-PM/Scl-100 and anti-RNA-polymerase III Antibodies in scleroderma
    Clinica Chimica Acta, 2010
    Co-Authors: L Maes, D Blockmans, P Verschueren, R Westhovens, K Op De Beéck, P Vermeersch, K Van Den Bergh, R W Burlingame, M Mahler, X Bossuyt

    Abstract:

    Abstract Background Systemic sclerosis (SSc) is a rare autoimmune disease characterized by the presence of various autoAntibodies, including Anti-Centromere, anti-topoisomerase (Scl-70), anti-PM/Scl-100, and anti-RNA-polymerase III (RNA Pol-III) Antibodies. Recently, new ELISA based immunoassays have become available for the detection of anti-PM/Scl and anti-RNA Pol-lII Antibodies. Objective We studied the prevalence and clinical association of anti-PM/Scl-100 (PM1-Alpha) and anti-RNA Pol-III Antibodies. Methods Antibodies to PM1-Alpha and RNA Pol-III were measured by ELISA (DR. Fooke Laboratories and Inova Diagnostics, respectively) in 242 patients with various connective tissue diseases (CTD) (including 70 SSc patients) and in 36 non-CTD controls. Results Low levels of PM1-Alpha Antibodies were found in various CTDs, whereas high levels were exclusively found in SSc, dermatomyositis and polymyositis, albeit at low frequency (4.7%). Anti-RNA Pol-III Antibodies were found in 7% of SSc and in 1% of non-CTD and CTD controls. Anti-Centromere and anti-Scl-70 Antibodies were found in 37% and 21% of SSc patients, respectively. Anti-Centromere Antibodies were associated with limited cutaneous SSc and anti-Scl-70 Antibodies with diffuse cutaneous SSc and interstitial lung disease. Because of the low number of samples positive for anti-PM/Scl-100 or RNA Pol-III Antibodies, no clinical feature was statistically correlated with the presence of either reactivity, but taken together the presence of either antibody was correlated with interstitial lung disease. Anti-PM1-Alpha and anti-RNA Pol-III Antibodies were mutually exclusive with anti-Scl-70 Antibodies. Conclusions At high levels, anti-PM/Scl-100 Antibodies were associated with SSc, PM, and DM, albeit at low frequency. Anti-RNA Pol-III Antibodies were associated with SSc (in 7%) with high specificity.

  • Anti-PM/Scl-100 and anti-RNA-polymerase III Antibodies in scleroderma.
    Clinica chimica acta; international journal of clinical chemistry, 2010
    Co-Authors: L Maes, D Blockmans, P Verschueren, R Westhovens, K Op De Beéck, P Vermeersch, K Van Den Bergh, R W Burlingame, M Mahler, X Bossuyt

    Abstract:

    Systemic sclerosis (SSc) is a rare autoimmune disease characterized by the presence of various autoAntibodies, including Anti-Centromere, anti-topoisomerase (Scl-70), anti-PM/Scl-100, and anti-RNA-polymerase III (RNA Pol-III) Antibodies. Recently, new ELISA based immunoassays have become available for the detection of anti-PM/Scl and anti-RNA Pol-lII Antibodies.
    We studied the prevalence and clinical association of anti-PM/Scl-100 (PM1-Alpha) and anti-RNA Pol-III Antibodies.
    Antibodies to PM1-Alpha and RNA Pol-III were measured by ELISA (DR. Fooke Laboratories and Inova Diagnostics, respectively) in 242 patients with various connective tissue diseases (CTD) (including 70 SSc patients) and in 36 non-CTD controls.
    Low levels of PM1-Alpha Antibodies were found in various CTDs, whereas high levels were exclusively found in SSc, dermatomyositis and polymyositis, albeit at low frequency (4.7%). Anti-RNA Pol-III Antibodies were found in 7% of SSc and in 1% of non-CTD and CTD controls. Anti-Centromere and anti-Scl-70 Antibodies were found in 37% and 21% of SSc patients, respectively. Anti-Centromere Antibodies were associated with limited cutaneous SSc and anti-Scl-70 Antibodies with diffuse cutaneous SSc and interstitial lung disease. Because of the low number of samples positive for anti-PM/Scl-100 or RNA Pol-III Antibodies, no clinical feature was statistically correlated with the presence of either reactivity, but taken together the presence of either antibody was correlated with interstitial lung disease. Anti-PM1-Alpha and anti-RNA Pol-III Antibodies were mutually exclusive with anti-Scl-70 Antibodies.
    At high levels, anti-PM/Scl-100 Antibodies were associated with SSc, PM, and DM, albeit at low frequency. Anti-RNA Pol-III Antibodies were associated with SSc (in 7%) with high specificity.
    Copyright 2010 Elsevier B.V. All rights reserved.