|
1
|
Mihai IR, Rezus C, Burlui MA, Cardoneanu A, Macovei LA, Richter P, Bratoiu I, Rezus E. Autoimmune Liver Diseases and Rheumatoid Arthritis-Is There an Etiopathogenic Link? Int J Mol Sci 2024; 25:3848. [PMID: 38612658 PMCID: PMC11011907 DOI: 10.3390/ijms25073848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 02/28/2024] [Accepted: 03/23/2024] [Indexed: 04/14/2024] Open
Abstract
Rheumatoid arthritis (RA) is a systemic immune-mediated disease that, in addition to the articular involvement, can have extra-articular manifestations. Even though liver damage in RA is not very common, associated autoimmune liver diseases (AILDs) may occur. The most common AILD associated with RA is primary biliary cirrhosis (PBC), followed by autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). There are common underlying mechanisms that play a role in the emergence of autoimmunity and inflammation in both rheumatic and autoimmune liver diseases. Genetic studies have revealed the existence of several common disease-associated genes shared between RA and AILDs, and infectious triggers, particularly those associated with recurrent or complicated urinary tract infections, are also speculated to be potential triggers for these conditions. Moreover, these diseases share common serologic patterns characterized by the presence of specific autoantibodies and hyper-gammaglobulinemia. In this study, we focus on reviewing the association between RA and AILDs regarding the prevalence and possible etiopathogenic link.
Collapse
Affiliation(s)
- Ioana Ruxandra Mihai
- Department of Rheumatology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania (L.A.M.); (E.R.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Ciprian Rezus
- Department of Internal Medicine, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- “Sfantul Spiridon” Emergency Hospital, 700111 Iasi, Romania
| | - Maria Alexandra Burlui
- Department of Rheumatology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania (L.A.M.); (E.R.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Anca Cardoneanu
- Department of Rheumatology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania (L.A.M.); (E.R.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Luana Andreea Macovei
- Department of Rheumatology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania (L.A.M.); (E.R.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Patricia Richter
- Department of Rheumatology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania (L.A.M.); (E.R.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Ioana Bratoiu
- Department of Rheumatology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania (L.A.M.); (E.R.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Elena Rezus
- Department of Rheumatology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania (L.A.M.); (E.R.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| |
Collapse
|
|
2
|
van den Beukel MD, Stoelinga AEC, van der Meer AJ, van der Meulen S, Zhang L, Tushuizen ME, van Hoek B, Trouw LA. Antibodies against multiple post-translationally modified proteins aid in diagnosis of autoimmune hepatitis and associate with complete biochemical response to treatment. Front Med (Lausanne) 2023; 10:1195747. [PMID: 37564051 PMCID: PMC10411548 DOI: 10.3389/fmed.2023.1195747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 06/14/2023] [Indexed: 08/12/2023] Open
Abstract
Background (Auto)immune mediated and cholestatic liver disease (AILD) includes autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Especially AIH is characterized by the presence of autoantibodies and elevated serum immunoglobulins. In rheumatoid arthritis, autoantibodies against post-translational modifications (PTMs) such as citrullination (Cit) and carbamylation (CarP) are used as diagnostic and prognostic markers, respectively. We studied the presence of six anti-PTM antibodies in patients with the three AILDs and non-AILD. Methods Antibodies against six PTMs (malondialdehyde-acetaldehyde adducts (MAA), advanced glycation end-products (AGE), CarP, acetylation (AL), Cit, and nitration (NT)) were tested in sera of patients with AILD (n = 106), non-AILD (n = 101) and compared with healthy controls (HC) (n = 100). Levels and positivity were correlated with clinical and biochemical features in a well-defined cohort of untreated AIH patients. Results Anti-PTM antibodies were more often detectable in sera from AILD patients compared with HCs (anti-MAA: 67.9% vs. 2.0%, anti-AGE: 36.8% vs. 4.0%, anti-CarP: 47.2% vs. 5.0% and anti-AL: 18.9% vs. 5.0%). In untreated AIH, time to complete biochemical response (CBR) was associated with anti-MAA, anti-AGE, anti-CarP and anti-AL antibodies. Significantly more patients with at least three anti-PTM antibodies attained CBR at 12 months of treatment (13 vs. 3 p = 0.01). Conclusion Anti-PTM antibodies are frequently present in AILD. The presence of anti-MAA, anti-AGE and anti-CarP antibodies correlates with the presence of AIH within this cohort. In AIH, harboring at least three anti-PTM antibody responses is positively associated with CBR. Determination of anti-PTM antibodies in liver disease may have diagnostic and prognostic value.
Collapse
Affiliation(s)
| | - Anna E. C. Stoelinga
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands
| | - Adriaan J. van der Meer
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, Netherlands
| | - Stef van der Meulen
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
| | - Lu Zhang
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
| | - Maarten E. Tushuizen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands
| | - Leendert A. Trouw
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
| |
Collapse
|
|
3
|
Ghozzi M, Mankai A, Zneidi I, Manoubi W, Melayah S, Mechi F, Trabelsi A, Ghedira I. Serological markers of rheumatoid arthritis in patients with primary biliary cholangitis and the vice versa: A Tunisian study. Immunobiology 2023; 228:152398. [PMID: 37269587 DOI: 10.1016/j.imbio.2023.152398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 04/14/2023] [Accepted: 05/24/2023] [Indexed: 06/05/2023]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is an autoimmune disease of the liver characterized by destructive lymphocytic cholangitis and anti-mitochondrial antibodies (AMA). Anti-gp210 and anti-Sp100, are used for the diagnosis of PBC in AMA-negative PBC patients. Patients with PBC have a propensity to have an extrahepatic manifestation which is especially autoimmune. OBJECTIVE We aimed to determine the frequency of serological markers of rheumatoid arthritis (RA) (CCP-Ab or RF) in PBC patients and to do the vice versa. METHODS Our PBC study included 70 patients with PBC and 80 healthy blood donors (HBD) and our RA study included 75 patients with RA and 75 HBD. Anti-cyclic citrullinated peptide antibodies (CCP-Ab) and rheumatoid factor (RF) were performed by indirect ELISA. AMA, anti-Sp100 and anti-gp210 were determined by indirect immunofluorescence. RESULTS RA autoantibodies (CCP-Ab or RF) were more frequent in PBC patients than in HBD (65.7% vs. 8.7% p 〈10-6). CCP-Ab were significantly more frequent in patients than in controls (15.7% vs. 2.5%; p = 0.004). Nine patients had both CCP-Ab and RF vs. none of controls (12.8% vs. 0%; p = 0.001). RF were detected in 45 patients with PBC and in 5 HBD (64.3% vs. 6.2%; p 〈10-6). In PBC patients, RF were more frequent than CCP-Ab (64.3% vs. 15.7%; p 〈10-6). RF-IgG were present in 18.5% of patients; RF-immunoglobulin (Ig) A in 34.3% and RF-IgM in 54.3%. These frequencies were significantly higher than those found in control group (1.2% for RF-IgG (p 〈10-3); 0% for RF-IgA (p 〈10-6); and 6.2% for RF-IgM (p 〈10-6)). In our PBC patients, RF-IgA were more frequent than RF-IgG (34.3% vs. 18.5%; p = 0.03) and than CCP-Ab (34.3% vs. 15.7%; p = 0.01). Six patients had only RF-IgA versus none of the control group (8.6% vs. 0%; p = 0.01). AMA, anti-Sp100 and anti-gp 210 were absent in all RA patients. CONCLUSIONS Serological markers of RA were more frequent in PBC patients than in HBD and the vice versa was not true.
Collapse
Affiliation(s)
- Mariam Ghozzi
- Laboratory of Immunology, Farhat Hached University Hospital, Sousse, Tunisia; Faculty of Pharmacy, Department of Immunology, University of Monastir, Monastir, Tunisia; Research Laboratory for "Epidemiology and Immunogenetics of Viral Infections" (LR14SP02), Sahloul University Hospital, University of Sousse, Sousse, Tunisia.
| | - Amani Mankai
- High School of Sciences and Techniques of Health, Tunis El Manar University, Tunis, Tunisia; Research Unit "Obesity: Etiopathology and Treatment, UR18ES01", National Institute of Nutrition and Food Technology, Tunis, Tunisia
| | - Inssaf Zneidi
- Faculty of Pharmacy, Department of Immunology, University of Monastir, Monastir, Tunisia
| | - Wiem Manoubi
- Erasmus University Medical Centre, Department of Neuroscience, Rotterdam, Netherlands
| | - Sarra Melayah
- Laboratory of Immunology, Farhat Hached University Hospital, Sousse, Tunisia; Faculty of Pharmacy, Department of Immunology, University of Monastir, Monastir, Tunisia; LR12SP11, Biochemistry Department, Sahloul University Hospital, Sousse, Tunisia
| | - Fatma Mechi
- Laboratory of Immunology, Farhat Hached University Hospital, Sousse, Tunisia; Faculty of Pharmacy, Department of Immunology, University of Monastir, Monastir, Tunisia
| | - Abdelhalim Trabelsi
- Research Laboratory for "Epidemiology and Immunogenetics of Viral Infections" (LR14SP02), Sahloul University Hospital, University of Sousse, Sousse, Tunisia; Laboratory of Microbiology and Virology, Sahloul University Hospital, Sousse, Tunisia
| | - Ibtissem Ghedira
- Laboratory of Immunology, Farhat Hached University Hospital, Sousse, Tunisia; Faculty of Pharmacy, Department of Immunology, University of Monastir, Monastir, Tunisia
| |
Collapse
|
|
4
|
Tsagkaris C, Papadakos SP, Moysidis DV, Papazoglou AS, Koutsogianni A, Papadakis M. Hepatomusculoskeletal disorders: Coining a new term might improve the management of the musculoskeletal manifestations of chronic liver disease. World J Gastrointest Pathophysiol 2022; 13:124-127. [PMID: 36161230 PMCID: PMC9350596 DOI: 10.4291/wjgp.v13.i4.124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 04/07/2022] [Accepted: 06/27/2022] [Indexed: 02/06/2023] Open
Abstract
Chronic liver disease can affect many body systems including the musculoskeletal system. The pathogenetic crosstalk between the liver and organs such as the brain and the kidneys has already been described with compound terms merging the organs affected by the pathology, such as the hepatorenal syndrome. Nevertheless, the musculoskeletal manifestations of chronic liver disease have not been coined with such a term to date. Because of this shortage, documenting the musculoskeletal implications of chronic liver disease in both research and clinical practice is challenging. To fill this gap, the authors propose the term hepatomusculoskeletal disorders, a compound term of Greek origin that encompasses all the body structures involved in the aforementioned pathologic crosstalk.
Collapse
Affiliation(s)
- Christos Tsagkaris
- Public Health and Policy Working Group, Stg European Student Think Tank, Amsterdam, Netherlands
| | - Stavros P Papadakos
- Laiko General Hospital of Athens, National and Kapodistrian University of Athens, Athens 18233, Greece
| | - Dimitrios V Moysidis
- Hippokration University Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | | | - Alexandra Koutsogianni
- Laiko General Hospital of Athens, National and Kapodistrian University of Athens, Athens 18233, Greece
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Wuppertal 42283, Germany
| |
Collapse
|
|
5
|
Iwasaki T, Nakabo S, Terao C, Murakami K, Nakashima R, Hashimoto M, Imura Y, Yukawa N, Yoshifuji H, Miura Y, Yurugi K, Maekawa T, van Delft MAM, Trouw LA, Fujii T, Mimori T, Ohmura K. Long-term follow-up of patients with anti-cyclic citrullinated peptide antibody-positive connective tissue disease: a retrospective observational study including information on the HLA-DRB1 allele and citrullination dependency. Arthritis Res Ther 2020; 22:248. [PMID: 33076960 PMCID: PMC7574466 DOI: 10.1186/s13075-020-02351-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 10/08/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The anti-cyclic citrullinated peptide (CCP) antibody is a diagnostic biomarker of rheumatoid arthritis (RA). However, some non-RA connective tissue disease (CTD) patients also test positive for the anti-CCP antibody and, thus, may ultimately develop RA. We retrospectively investigated whether anti-CCP-positive non-RA CTD patients developed RA and attempted to identify factors that may differentiate RA-overlapping CTD from pure CTD. METHODS In total, 842 CTD patients with a primary diagnosis that was not RA were selected from our CTD database as of December 2012. Anti-CCP antibody titers were obtained from a retrospective chart review or measured using stored sera. RA was diagnosed according to the 1987 revised American College of Rheumatology classification criteria. Thirty-three anti-CCP-positive non-RA CTD patients were retrospectively followed up for the development of RA. Bone erosions on the hands and feet were assessed by X-ray. Citrullination dependency was evaluated by an in-house ELISA, the HLA-DRB1 allele was typed, and the results obtained were then compared between RA-overlapping and non-RA anti-CCP-positive CTD patients. RESULTS Two out of 33 anti-CCP-positive CTD patients (6.1%) developed RA during a mean follow-up period of 8.9 years. X-rays were examined in 27 out of the 33 patients, and only one (3.7%) showed bone erosions. The frequency of the HLA-DRB1 shared epitope (SE) and anti-CCP antibody titers were both significantly higher in anti-CCP-positive RA-overlapping CTD patients than in anti-CCP-positive non-RA CTD patients, while no significant differences were observed in citrullination dependency. CONCLUSIONS Anti-CCP-positive non-RA CTD patients rarely developed RA. HLA-DRB1 SE and anti-CCP antibody titers may facilitate the differentiation of RA-overlapping CTD from anti-CCP-positive non-RA CTD.
Collapse
Affiliation(s)
- Takeshi Iwasaki
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, Japan
| | - Shuichiro Nakabo
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, Japan
| | - Chikashi Terao
- Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.,Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan.,The Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Kosaku Murakami
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, Japan
| | - Ran Nakashima
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, Japan
| | - Motomu Hashimoto
- Department of Advanced Medicine for Rheumatic Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshitaka Imura
- Department of Clinical Immunology and Rheumatology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan
| | | | - Hajime Yoshifuji
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, Japan
| | - Yasuo Miura
- Department of Transfusion Medicine & Cell Therapy, Kyoto University Hospital, Kyoto, Japan
| | - Kimiko Yurugi
- Department of Transfusion Medicine & Cell Therapy, Kyoto University Hospital, Kyoto, Japan
| | - Taira Maekawa
- Department of Transfusion Medicine & Cell Therapy, Kyoto University Hospital, Kyoto, Japan
| | - Myrthe A M van Delft
- Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Leendert A Trouw
- Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.,Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Takao Fujii
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, Japan.,Department of Clinical Immunology and Rheumatology, Wakayama Medical University, Wakayama, Japan
| | - Tsuneyo Mimori
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, Japan.,Ijinkai Takeda General Hospital, Kyoto, Japan
| | - Koichiro Ohmura
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, Japan.
| |
Collapse
|
|
6
|
Fernandes B, Dias E, Mascarenhas-Saraiva M, Bernardes M, Costa L, Cardoso H, Macedo G. Rheumatologic manifestations of hepatic diseases. Ann Gastroenterol 2019; 32:352-360. [PMID: 31263357 PMCID: PMC6595923 DOI: 10.20524/aog.2019.0386] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Accepted: 04/01/2019] [Indexed: 02/06/2023] Open
Abstract
The course of hepatic diseases may be complicated by a multitude of rheumatologic manifestations, which can complicate the diagnostic approach and alter the natural history of primary liver disease, sometimes worsening prognosis due to associated multiple organ dysfunction. These manifestations can occur in association with a multitude of liver diseases, including viral hepatitis, autoimmune hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease, hemochromatosis, or Wilson’s disease. It is necessary not only for rheumatologists, but also for other clinicians, to be aware that these atypical manifestations may reflect an undiagnosed hepatic disease. On the other hand, it is crucial that, in a patient with known hepatic disease presenting with rheumatologic symptoms, an accurate distinction be made between the rheumatologic manifestations of hepatic disease and primary rheumatologic disease, since the treatment is often different. This review aims to summarize the current evidence regarding rheumatologic manifestations of hepatic diseases, how to distinguish them from primary rheumatologic disorders, and how to provide adequate management.
Collapse
Affiliation(s)
- Bruno Fernandes
- Rheumatology Department (Bruno Fernandes, Miguel Bernardes, Lúcia Costa)
| | - Emanuel Dias
- Gastrenterology Department (Emanuel Dias, Miguel Mascarenhas-Saraiva, Hélder Cardoso, Guilherme Macedo), Centro Hospitalar de São João, Porto, Portugal
| | - Miguel Mascarenhas-Saraiva
- Gastrenterology Department (Emanuel Dias, Miguel Mascarenhas-Saraiva, Hélder Cardoso, Guilherme Macedo), Centro Hospitalar de São João, Porto, Portugal
| | - Miguel Bernardes
- Rheumatology Department (Bruno Fernandes, Miguel Bernardes, Lúcia Costa)
| | - Lúcia Costa
- Rheumatology Department (Bruno Fernandes, Miguel Bernardes, Lúcia Costa)
| | - Hélder Cardoso
- Gastrenterology Department (Emanuel Dias, Miguel Mascarenhas-Saraiva, Hélder Cardoso, Guilherme Macedo), Centro Hospitalar de São João, Porto, Portugal
| | - Guilherme Macedo
- Gastrenterology Department (Emanuel Dias, Miguel Mascarenhas-Saraiva, Hélder Cardoso, Guilherme Macedo), Centro Hospitalar de São João, Porto, Portugal
| |
Collapse
|
|
7
|
Utiyama SRR, Zenatti KB, Nóbrega HAJ, Soares JZC, Skare TL, Matsubara C, Muzzilo DA, Nisihara RM. Rheumatic Disease Autoantibodies in Autoimmune Liver Diseases. Immunol Invest 2016; 45:566-73. [PMID: 27409579 DOI: 10.1080/08820139.2016.1186173] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND Autoimmune liver diseases (ALDs) are known to be associated with systemic autoimmune rheumatic diseases (SARDs) and their autoantibodies. We aimed to study the prevalence of SARDs and related autoantibodies, as well as their prognostic implications in a group of patients with ALDs. METHODS This was a cross-sectional study. Sixty patients with ALDs (38.3% with autoimmune hepatitis; 11.7% with primary biliary cirrhosis; 25% with primary sclerosing cholangitis and 25% with overlap syndrome) were studied for the presence of SARDs and their autoantibodies. RESULTS There was autoimmune rheumatic disease in 20% of the studied sample. Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) were the commonest (11.6% and 5%, respectively). Antinuclear antibodies (ANAs) were present in 35% of the patients, followed by anti-Ro (20.0%); anti-nucleosome (18.3%); rheumatoid factor (10%) anti-CCP (8.3%); anti-RNP (8.3%); anti-ds-DNA (6.6%); anti-La (3.3%); anti-Sm (3.3%), anti-ribosomal P (3.3%). Anti-Ro (p = 0.0004), anti-La (p = 0.03), anti-RNP (p = 0.04) and anti-Sm (p = 0.03) were commonly found in patients with SARD, but not anti-DNA, anti-nucleosome and anti-ribosomal P. No differences were found in liver function tests regarding to the presence of autoantibodies. CONCLUSIONS There was a high prevalence of SARD and their autoantibodies in ALD patients. Anti-Ro, anti-La, anti-RNP and anti-Sm positivity points to an association with systemic autoimmune rheumatic diseases. The presence of autoantibodies was not related to liver function tests.
Collapse
Affiliation(s)
- Shirley R R Utiyama
- a Immunopathology Laboratory , Clinics Hospital of Federal University of Paraná , Curitiba , Paraná , Brazil.,b Department of Clinical Analysis , Federal University of Paraná , Curitiba , Paraná , Brazil
| | - Katiane B Zenatti
- c Rheumatology Unit of Evangelic University Hospital , Curitiba , Paraná , Brazil
| | - Heloisa A J Nóbrega
- c Rheumatology Unit of Evangelic University Hospital , Curitiba , Paraná , Brazil
| | - Juliana Z C Soares
- a Immunopathology Laboratory , Clinics Hospital of Federal University of Paraná , Curitiba , Paraná , Brazil
| | - Thelma L Skare
- c Rheumatology Unit of Evangelic University Hospital , Curitiba , Paraná , Brazil
| | - Caroline Matsubara
- a Immunopathology Laboratory , Clinics Hospital of Federal University of Paraná , Curitiba , Paraná , Brazil
| | - Dominique A Muzzilo
- d Hepatology Unit , Clinics Hospital of Federal University of Paraná , Curitiba , Paraná , Brazil
| | - Renato M Nisihara
- a Immunopathology Laboratory , Clinics Hospital of Federal University of Paraná , Curitiba , Paraná , Brazil.,e Department of Medicine , Positivo University , Curitiba , Paraná , Brazil
| |
Collapse
|
|
8
|
Gatselis NK, Zachou K, Koukoulis GK, Dalekos GN. Autoimmune hepatitis, one disease with many faces: Etiopathogenetic, clinico-laboratory and histological characteristics. World J Gastroenterol 2015; 21:60-83. [PMID: 25574080 PMCID: PMC4284362 DOI: 10.3748/wjg.v21.i1.60] [Citation(s) in RCA: 124] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 10/30/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is an unresolving progressive liver disease of unknown etiology characterized by hypergammaglobulinemia, autoantibodies detection and interface hepatitis. Due to the absence of specific diagnostic markers and the large heterogeneity of its clinical, laboratory and histological features, AIH diagnosis may be potentially difficult. Therefore, in this in-depth review we summarize the substantial progress on etiopathogenesis, clinical, serological and histological phenotypes of AIH. AIH has a global distribution affecting any age, both sexes and all ethnic groups. Clinical manifestations vary from asymptomatic to severe or rarely fulminant hepatitis. Hypergammaglobulinemia with selective elevation of IgG is found in most cases. Autoimmune attack is perpetuated, possibly via molecular mimicry, and favored by the impaired control of T-regulatory cells. Histology (interface hepatitis, emperipolesis and hepatic rosette formation) and autoantibodies detection although not pathognomonic, are still the hallmark for a timely diagnosis. AIH remains a major diagnostic challenge. AIH should be considered in every case in the absence of viral, metabolic, genetic and toxic etiology of chronic or acute hepatitis. Laboratory personnel, hepato-pathologists and clinicians need to become more familiar with disease expressions and the interpretation of liver histology and autoimmune serology to derive maximum benefit for the patient.
Collapse
|
|
9
|
Ikeda T, Kaminaka C, Yamamoto Y, Furukawa F. Disseminated cryptococcosis-induced skin ulcers in a patient with autoimmune hepatitis. Case Rep Dermatol 2014; 6:98-102. [PMID: 24761142 PMCID: PMC3995400 DOI: 10.1159/000360978] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
We report the case of a 68-year-old woman with autoimmune hepatitis (AIH) who had leg ulcers induced by disseminated cryptococcosis. She had received prednisolone for her AIH at 20 mg/day for maintenance. On the initial visit, she complained of a painful ulcer that had round, shallow pockets with erythema and erythematous subcutaneous indurations on the right thigh. Several metacarpophalangeal joints and wrist joints were swollen, with tenderness and stiffness in the morning for over 3 h. Her serum rheumatoid factor was high. Since other autoimmune disorders such as rheumatoid arthritis can present with AIH, it was necessary to distinguish it from ulcers due to rheumatoid arthritis, although the characteristic features of these ulcers seemed to be different. A biopsy specimen from the erythematous skin showed globe-shaped organisms in the dermis and subcutaneous tissues; vasculitis and phlebostasis were not observed. The results from computed tomography scans and sputum culture led to the diagnosis of disseminated cryptococcosis. The administration of fluconazole, fosfluconazole, and voriconazole for about 2 months improved the cryptococcal pneumonia, but the size of the skin ulcer enlarged. The administration was changed to itraconazole, which reduced the size. Cryptococcal infections occur more commonly in immunocompromised hosts, including patients under immunosuppressive therapies such as corticosteroids. The possibility that the skin ulcers in immunocompromised hosts may be caused by cryptococcosis should be considered.
Collapse
Affiliation(s)
- Takaharu Ikeda
- Department of Dermatology, Wakayama Medical University, Wakayama, Japan
| | - Chikako Kaminaka
- Department of Dermatology, Wakayama Medical University, Wakayama, Japan
| | - Yuki Yamamoto
- Department of Dermatology, Wakayama Medical University, Wakayama, Japan
| | - Fukumi Furukawa
- Department of Dermatology, Wakayama Medical University, Wakayama, Japan
| |
Collapse
|
|
10
|
Yamagiwa S, Kamimura H, Takamura M, Aoyagi Y. Autoantibodies in primary biliary cirrhosis: Recent progress in research on the pathogenetic and clinical significance. World J Gastroenterol 2014; 20:2606-2612. [PMID: 24627596 PMCID: PMC3949269 DOI: 10.3748/wjg.v20.i10.2606] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Revised: 11/22/2013] [Accepted: 01/08/2014] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic liver disease characterized by immune-mediated destruction of the small- and medium-sized intrahepatic bile ducts and the presence of antimitochondrial antibodies (AMA) in the serum. AMA are detected in over 90% of patients with PBC, whereas their prevalence in the general population is extremely low, varying from 0.16% to 1%. Previous studies have shown that the unique characteristics of biliary epithelial cells undergoing apoptosis may result in a highly direct and very specific immune response to mitochondrial autoantigens. Moreover, recent studies have demonstrated that serum from AMA-positive PBC patients is reactive with a number of xenobiotic modified E2 subunits of the pyruvate dehydrogenase complex, which is not observed in the serum of normal individuals. These findings indicate that chemicals originating from the environment may be associated with a breakdown in the tolerance to mitochondrial autoantigens. While it is currently generally accepted that AMA are the most specific serological markers of PBC, more than 60 autoantibodies have been investigated in patients with PBC, and some have previously been considered specific to other autoimmune diseases. This review covers the recent progress in research on the pathogenetic and clinical significance of important autoantibodies in PBC. Determining the pathogenic role of those autoantibodies in PBC remains a priority of basic and clinical research.
Collapse
|
|
11
|
Zachou K, Muratori P, Koukoulis GK, Granito A, Gatselis N, Fabbri A, Dalekos GN, Muratori L. Review article: autoimmune hepatitis -- current management and challenges. Aliment Pharmacol Ther 2013; 38:887-913. [PMID: 24010812 DOI: 10.1111/apt.12470] [Citation(s) in RCA: 113] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Revised: 03/22/2013] [Accepted: 08/12/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a disease of unknown aetiology characterised by interface hepatitis, hypergammaglobulinaemia, circulating autoantibodies and a favourable response to immunosuppression. AIM To review recent advancements in understanding aetiopathogenesis, clinical, serological and histological features, diagnostic criteria and treatment strategies of AIH. METHODS Published studies on AIH extracted mainly from PubMed during the last 15 years. RESULTS Autoimmune hepatitis has a global distribution affecting any age, both sexes and all ethnic groups. Clinical manifestations are variable ranging from no symptoms to severe acute hepatitis and only seldom to fulminant hepatic failure. Autoimmune attack is perpetuated, possibly via molecular mimicry mechanisms, and favoured by the impaired control of regulatory T-cells. A typical laboratory finding is hypergammaglobulinaemia with selective elevation of IgG, although in 15-25% of patients - particularly children, elderly and acute cases - IgG levels are normal. Liver histology and autoantibodies, although not pathognomonic, still remain the hallmark for diagnosis. Immunosuppressive treatment is mandatory and life-saving; however, to meet strict response criteria, the conventional therapy with prednisolone with or without azathioprine is far from ideal. CONCLUSIONS Autoimmune hepatitis remains a major diagnostic and therapeutic challenge. The clinician, the hepato-pathologist and the laboratory personnel need to become more familiar with different expressions of the disease, interpretation of liver histology and autoimmune serology. According to the strict definition of treatment response issued by the 2010 AASLD guidelines, many patients are nonresponders to conventional treatment. Newer immunosuppressive agents targeting pathogenetic mechanisms can improve patient management, which needs to be tailored on a case-by-case basis.
Collapse
Affiliation(s)
- K Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, Thessaly University, Larissa, Greece
| | | | | | | | | | | | | | | |
Collapse
|
|
12
|
Komorbidität rheumatischer und hepatologischer Erkrankungen. Z Rheumatol 2013; 72:547-54. [DOI: 10.1007/s00393-012-1116-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
|
|
13
|
Abstract
Autoimmune hepatitis has a variable clinical phenotype, and the absence of conventional autoantibodies does not preclude its diagnosis or need for treatment. The goals of this review are to describe the frequency and nature of autoantibody-negative autoimmune hepatitis, indicate its outcome after corticosteroid treatment, and increase awareness of the diagnosis in patients with unexplained acute and chronic hepatitis. The frequency of presumed autoantibody-negative autoimmune hepatitis in patients with acute and acute severe presentations is ≤7%, and its frequency in patients with chronic presentations is 1-34%. Patients with acute presentations can have normal serum γ-globulin levels, centrilobular zone 3 necrosis, and low pre-treatment international diagnostic scores. Liver tissue examination is essential for the diagnosis, and hepatic steatosis can be a co-morbid feature. The comprehensive international scoring system can support but never override the clinical diagnosis pre-treatment, and non-standard serological markers should be sought if the clinical diagnosis is uncertain or the diagnostic score is low. A 3-month treatment trial with corticosteroids should be considered in all patients, regardless of the serological findings, and improvements have occurred in 67-87% of cases. Autoantibody-negative autoimmune hepatitis may be associated with an autoantibody outside the conventional battery; it may have a signature autoantibody that is still undiscovered, or its characteristic autoantibodies may have been suppressed or have a delayed expression. The pathogenic mechanisms are presumed to be identical to those of classical disease. Autoantibody-negative autoimmune hepatitis is an infrequent but treatable disease that must be considered in unexplained acute and chronic hepatitis.
Collapse
Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN 55905, USA.
| |
Collapse
|
|
14
|
Abstract
Primary biliary cirrhosis (PBC) is a chronic, progressive, cholestatic, organ-specific autoimmune disease of unknown etiology. It predominantly affects middle-aged women, and is characterized by autoimmune-mediated destruction of small- and medium-size intrahepatic bile ducts, portal inflammation and progressive scarring, which without proper treatment can ultimately lead to fibrosis and hepatic failure. Serum autoantibodies are crucial tools for differential diagnosis of PBC. While it is currently accepted that antimitochondrial antibodies are the most important serological markers of PBC, during the last five decades more than sixty autoantibodies have been explored in these patients, some of which had previously been thought to be specific for other autoimmune diseases.
Collapse
|
|
15
|
Czaja AJ. Autoantibodies as prognostic markers in autoimmune liver disease. Dig Dis Sci 2010; 55:2144-61. [PMID: 20464491 DOI: 10.1007/s10620-010-1268-4] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2010] [Accepted: 04/23/2010] [Indexed: 01/25/2023]
Abstract
Certain autoantibodies in autoimmune liver disease have prognostic implications that are under-utilized and under-developed. The goals of this review are to indicate progress in characterizing the autoantibodies with prognostic connotations and to indicate the feasibility and importance of discovering other markers. Prime source and review articles in English were selected by a Medline search through 2010. Antibodies to soluble liver antigen, actin, liver cytosol type 1, asialoglycoprotein receptor, chromatin, cyclic citrullinated peptide, and uridine glucuronosyltransferases have been associated with the occurrence, severity, and progression of autoimmune hepatitis, and antibodies to Sp100, gp210, and centromere have had similar implications in primary biliary cirrhosis. Antibodies to soluble liver antigen have shown the most promise in autoimmune hepatitis as they have been associated with severe histological changes, long durations of treatment, relapse after drug withdrawal, and high frequency of liver failure. Antibodies to the nuclear rim pore protein, gp210, have shown the most promise in primary biliary cirrhosis as they have been associated with severe interface hepatitis, lobular inflammation, and progression to liver failure. The major limitations of the autoantibodies have been their lack of standardized assays, low negative predictabilities, and fluctuating levels. Performance parameters will improve as critical pathogenic pathways, comprehensive testing batteries, and standardized assays through international exchange workshops are developed. Progress has been made in identifying the serological markers of prognosis in autoimmune liver disease, and they promise to reflect critical disease mechanisms and enhance patient management.
Collapse
Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
| |
Collapse
|
|
16
|
Oo YH, Hubscher SG, Adams DH. Autoimmune hepatitis: new paradigms in the pathogenesis, diagnosis, and management. Hepatol Int 2010; 4:475-93. [PMID: 20827405 DOI: 10.1007/s12072-010-9183-5] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2010] [Accepted: 03/13/2010] [Indexed: 02/06/2023]
Abstract
Autoimmune hepatitis (AIH), primary biliary cirrhosis, and primary sclerosing cholangitis are the three major autoimmune diseases affecting the liver, and of these three, AIH is the most typical autoimmune disease being characterized by a T-cell-rich infiltrate, raised circulating γ-globulins, autoantibodies, HLA associations, and links with other autoimmune diseases. It is the only one, of the three diseases, that responds well to immunosuppressive therapy. AIH is caused by dysregulation of immunoregulatory networks and the consequent emergence of autoreactive T cells that orchestrate a progressive destruction of hepatocytes leading untreated to liver failure. T cells play a major role in the immunopathogenesis, and both CD4(+) and CD8(+) T cells are involved together with effector responses mediated by NK cells, γδ T cells, and macrophages. A number of triggering factors have been proposed including viruses, xenobiotics, and drugs, but none have been conclusively shown to be involved in pathogenesis.
Collapse
|
|
17
|
Elkayam O, Segal R, Bendayan D, van Uitert R, Onnekink C, Pruijn GJ. The anti-cyclic citrullinated peptide response in tuberculosis patients is not citrulline-dependent and sensitive to treatment. Arthritis Res Ther 2010; 12:R12. [PMID: 20100318 PMCID: PMC2875640 DOI: 10.1186/ar2913] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2009] [Revised: 11/24/2009] [Accepted: 01/25/2010] [Indexed: 02/03/2023] Open
Abstract
Introduction Patients with tuberculosis (TB) frequently produce anti-citrullinated protein antibodies (ACPA). The objective of this study is to characterize the citrulline-dependence of the ACPA reactivity in sera of patients with mycobacterium infections. Methods Serum samples of 134 patients with untreated mycobacterium infections (122 TB, 12 nontuberculous mycobacterium) were tested for antibodies against both the citrullinated (Cit) and the non-citrullinated (Arg) form of 2 cyclic synthetic peptides. In 33 patients, a follow-up sample was tested six months after starting anti-mycobacterial drugs. Results A substantial proportion of patients with mycobacterial infections demonstrated antibodies against 0401Cit, 0401Arg, 0722Cit and 0722Arg. Fourteen patients demonstrated anti-0401Cit, 83 anti-0401Arg, 22 anti-0722Cit and 61 anti-0722Arg, while none of these antibodies were detected in the 20 healthy controls. All the patients but one, who were anti-0401Cit and anti-0722Cit positive, demonstrated reactivity against the respective Arg peptide. In the subset of 33 patients with a follow-up test six months after starting treatment, the mean levels of antibodies to 0401Cit, 0401Arg, 0722Cit and 0722Arg significantly decreased after treatment. All the patients who were anti-0401Cit and anti-0722Cit positive turned negative after treatment. The presence of anti-0401Cit/Arg and anti-0722Cit/Arg was found to be significantly correlated with the presence of HIV. Conclusions ACPA may be found in patients with TB. In most of the cases, the reactivity is citrulline independent. A positive cyclic citrullinated peptide (CCP) test in these patients should therefore be interpreted with care, and preferably followed by a control ELISA with a non-citrullinated antigen.
Collapse
Affiliation(s)
- Ori Elkayam
- Department of Internal Medicine F and the Department of Rheumatology, Tel Aviv Medical Center and The Sackler Faculty of Medicine, Tel Aviv University, 6 Weizman Street, Tel Aviv 64239, Israel.
| | | | | | | | | | | |
Collapse
|
|
18
|
Labrador-Horrillo M, Martinez MA, Selva-O'Callaghan A, Delgado JF, Martínez-Gómez X, Trallero-Araguás E, Rodriguez-Sanchez JL, Vilardell-Tarrés M. Anti-cyclic citrullinated peptide and anti-keratin antibodies in patients with idiopathic inflammatory myopathy. Rheumatology (Oxford) 2009; 48:676-9. [PMID: 19386818 DOI: 10.1093/rheumatology/kep065] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVE To investigate the prevalence of anti-cyclic citrullinated peptide (anti-CCP) and anti-keratin antibodies (AKAs) in a cohort of patients with idiopathic inflammatory myopathy. METHODS In a cross-sectional study, we determined the presence of anti-CCP and AKAs by ELISA and IIF, respectively, in a cohort of 90 consecutive patients with idiopathic inflammatory myopathy. Associations between anti-CCP and clinical manifestations or other autoantibodies were determined with the chi-square and Mann-Whitney U-tests. Radiographs of hands were retrospectively evaluated. Serum autoantibody profile was determined in all patients. RESULTS Twelve patients were positive to anti-CCP (13.3%); in eight cases values were moderate-high. AKAs were not detected in any patient. Comparison between patients positive and negative to anti-CCP did not show clinical or biological differences. Arthritis joint erosions or positive status to anti-synthetase antibodies were not more frequent in patients with anti-CCP antibodies. Prevalence of RF was the only variable significantly associated with the presence of these antibodies (P = 0.043). CONCLUSIONS High titres of anti-CCP can occasionally be found in patients with inflammatory myopathy. Therefore, a possible diagnosis of RA should be considered with caution in these patients.
Collapse
|
|
19
|
Bassyouni IH, Ezzat Y, Hamdy S, Talaat RM. Clinical significance of anti-cyclic citrullinated peptide antibodies in Egyptian patients with chronic hepatitis C virus genotype IV infection. Clin Chem Lab Med 2009; 47:842-7. [DOI: 10.1515/cclm.2009.189] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
|
|
20
|
Ribeiro S, Pereira H, Silva N, Neves R, Sato E. Anti-cyclic citrullinated peptide antibodies and rheumatoid factor in leprosy patients with articular involvement. Braz J Med Biol Res 2008; 41:1005-10. [DOI: 10.1590/s0100-879x2008001100010] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2008] [Accepted: 11/07/2008] [Indexed: 02/07/2023] Open
Affiliation(s)
- S.L.E. Ribeiro
- Universidade Federal de São Paulo, Brasil; Universidade Federal do Amazonas, Brasil
| | - H.L.A. Pereira
- Universidade Federal de São Paulo, Brasil; Universidade Federal do Amazonas, Brasil
| | - N.P. Silva
- Universidade Federal de São Paulo, Brasil
| | | | - E.I. Sato
- Universidade Federal de São Paulo, Brasil
| |
Collapse
|
|
21
|
Fabien N, Goetz J, Sordet C, Humbel RL, Sibilia J. [New autoanti-bodies in rheumatoid arthritis: anti-citrullinated protein or peptide autoanti-bodies and the others]. Presse Med 2008; 37:1756-66. [PMID: 18951757 DOI: 10.1016/j.lpm.2008.06.020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2007] [Revised: 03/07/2008] [Accepted: 06/19/2008] [Indexed: 10/21/2022] Open
Abstract
New treatment strategies require that rheumatoid arthritis (RA) be diagnosed as early as possible. New diagnostic markers were required, because rheumatoid factors (RF), until now criteria for classification of RA, are not sufficiently specific and sometimes appear late, thereby limiting their diagnostic usefulness. The objective of this review is to describe the current state of knowledge and more particularly to analyze the interest of new RA autoanti-bodies, called anti-peptide or anti-citrullinated protein anti-bodies (ACPA). Other autoanti-bodies have been described, including anti-Sa, anti-alpha enolase, and anti-calpastatin autoanti-bodies. Nonetheless, their diagnostic value remains limited compared to ACPA. Accordingly, in daily practice today, the only autoanti-bodies that must be tested for to diagnose RA are the ACPAs and RFs. The discovery of ACPA (initially called anti-keratin and anti-perinuclear anti-bodies) was a major step forward for the laboratory diagnosis of RA. The tests most often used routinely areenzyme-linked immunosorbent assays(ELISA) with cyclic citrullinated peptides, whence the name anti-CCP autoanti-bodies. Accordingly, the two terms ACPA and anti-CCP can both be used. The diagnostic value, in particular their specificity, is on the order of 95%, regardless of the method of identification. These markers are very useful and are often present earlier than RF. These ACPA also have prognostic value because they are associated with more aggressive forms of RA. On the other hand, their value over time, in particular, their fluctuation as a function of treatment, is more controversial. In practice, it is recommended to test for both RF and ACPA in a diagnostic work-up for early RA. During follow-up, the value of testing for these autoanti-bodies has not been demonstrated, but additional studies are still necessary with the anti-CCP autoanti-bodies and the new anti-citrullinated protein autoanti-bodies.
Collapse
Affiliation(s)
- Nicole Fabien
- Laboratoire d'auto-immunité, Hospices Civils de Lyon, Centre hospitalier Lyon-Sud, F-69495 Pierre Bénite Cedex, France
| | | | | | | | | | | |
Collapse
|
|
22
|
Santiago M, Baron M, Miyachi K, Fritzler MJ, Abu-Hakima M, Leclercq S, Bell M, Hudson M, Mathieu JP, Taillefer S, Jones N, Docherty P, Khraishi M, Markland J, Pope J, Robinson D, Smith D, Sutton E. A comparison of the frequency of antibodies to cyclic citrullinated peptides using a third generation anti-CCP assay (CCP3) in systemic sclerosis, primary biliary cirrhosis and rheumatoid arthritis. Clin Rheumatol 2007; 27:77-83. [PMID: 17570008 DOI: 10.1007/s10067-007-0656-4] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2007] [Revised: 05/16/2007] [Accepted: 05/18/2007] [Indexed: 12/12/2022]
Abstract
The objective was to investigate the frequency of anti-cyclic citrullinated peptides (CCP) antibodies in systemic sclerosis (SSc) and primary biliary cirrhosis (PBC), utilizing a new "third generation" anti-CCP ELISA (anti-CCP3) kit and a conventional anti-CCP2 assay. Patients with PBC, SSc, RA, and normal controls were included in the study. Serum samples were screened for autoantibodies by indirect immunofluorescence (IIF), antibodies to CCP by a second- and third-generation ELISA, antibodies to "scleroderma" antigens (CENP B, Scl-70, PM/Scl and fibrillarin-Scl-34) by a line immunoassay (LIA), and IgM RF by ELISA. The frequency of anti-CCP2 antibodies in SSc and PBC samples was 14.8% (11/74) and 6.2% (5/80), respectively, and the frequency of anti-CCP3 antibodies in SSc was 13.5% (10/74) and in PBC was 3.7% (3/80). By comparison, in the RA group the frequency of anti-CCP3 and anti-CCP2 antibodies was 79.1% (38/48) and 77% (37/48), respectively. Anti-CCP3 ELISA had a sensitivity, specificity, and positive and negative likelihood ratios (LR) of 79% (95% confidence interval [CI] = 64-89%), 93% (95% CI = 88-96%), 11.8 (95% CI = 6.8-20.3), and 0.22 (95% CI = 0.12-0.38), respectively. By comparison, the anti-CCP2 assay had a sensitivity, specificity, and positive and negative LRs of 77% (95% CI = 62-87), 90% (95% CI = 85-94), 8.3 (95% CI = 5.2-13.2), and 0.25 (95% CI = 0.15-0.42), respectively. In patients with SSc, there was an association of anti-CCP2 antibodies with the presence of arthritis, but there was no association of anti-CCP2 or anti-CCP3 with anti-CENP B, anti-Scl 70, or RF. This study confirmed the high specificity and sensitivity of both anti-CCP assays for the diagnosis of RA. The presence of anti-CCP antibodies in SSc was only correlated with the presence of arthritis.
Collapse
Affiliation(s)
- Mittermayer Santiago
- Servico de Reumatologia do Hospital do Santa Izabel, Escola Bahiana de Medicina e Saude Publica, Salvador, Brazil
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Caramella C, Avouac J, Sogni P, Puéchal X, Kahan A, Allanore Y. Association between rheumatoid arthritis and primary biliary cirrhosis. Joint Bone Spine 2007; 74:279-81. [PMID: 17369071 DOI: 10.1016/j.jbspin.2006.06.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2006] [Accepted: 06/07/2006] [Indexed: 11/20/2022]
Abstract
Primary biliary cirrhosis (PBC) is an autoimmune disease, characterized by chronic biliary duct destruction, which mainly affects women aged between 35 and 45 years. Prolonged liver inflammation can cause scarring, leading to cirrhosis. The most common first clinical manifestations are pruritus, asthenia or jaundice, but most patients remain asymptomatic. PBC can be associated by itself with arthralgia, but polyarthritis and synovitis are exceptional. PBC is often associated with other non-hepatic autoimmune diseases, especially primary Sjogren's syndrome, which may favour articular involvement. PBC and rheumatoid arthritis (RA) have been suggested to coexist in 1.8 to 5.6% of patients with PBC, but data supporting this association are scarce. We report two cases of such an association. Both of these patients presented severe erosive RA. We discuss the therapeutic management of these patients, taking into account hepatic involvement and drug toxicity.
Collapse
Affiliation(s)
- Caroline Caramella
- Service de Rhumatologie A, Université René Descartes, Faculté de Médecine, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, 75014 Paris, France
| | | | | | | | | | | |
Collapse
|
|
24
|
Vannini A, Cheung K, Fusconi M, Stammen-Vogelzangs J, Drenth JPH, Dall'Aglio AC, Bianchi FB, Bakker-Jonges LE, van Venrooij WJ, Pruijn GJM, Zendman AJW. Anti-cyclic citrullinated peptide positivity in non-rheumatoid arthritis disease samples: citrulline-dependent or not? Ann Rheum Dis 2007; 66:511-6. [PMID: 16984940 PMCID: PMC1856034 DOI: 10.1136/ard.2006.058933] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/01/2006] [Indexed: 12/29/2022]
Abstract
BACKGROUND Antibodies directed against citrullinated proteins (eg anti-cyclic citrullinated peptide (CCP)) have excellent diagnostic and good prognostic potential for rheumatoid arthritis. Type 1 autoimmune hepatitis (AIH-1) is a chronic liver disease characterised by a variety of serum autoantibodies. Recently, in a large group of patients with AIH-1 without clear rheumatoid arthritis overlap, a relatively high percentage (9%) of anti-CCP2 positivity was scored. OBJECTIVES To characterise the citrulline-dependence of the observed anti-CCP2 positivity in AIH-1 sera as well as in other groups of patients without rheumatoid arthritis (mainly rheumatic diseases). METHODS Serum samples of 57 patients with AIH-1 and 66 patients without rheumatoid arthritis, most of them reported as anti-CCP positive, were tested for citrulline-specific reactivity with a second generation anti-CCP kit, with the citrullinated and the corresponding non-citrullinated (arginine-containing) antigen. A subset of AIH-1 sera was also tested with a CCP1 ELISA (and arginine control). RESULTS The anti-CCP2 reactivity of most non-rheumatoid arthritis rheumatic diseases samples (87-93%) was citrulline-specific, whereas a relatively high percentage of AIH-1 samples (42-50%) turned out to be reactive in a citrulline-independent manner. The use of citrullinated and non-citrullinated CCP1 peptides confirmed a high occurrence of citrulline-independent reactivity in AIH-1 samples. CONCLUSIONS In rheumatoid arthritis and most non-rheumatoid arthritis rheumatologic disease sera, anti-CCP positivity is citrulline-dependent. However in some patients, particularly patients with AIH-1, citrulline-independent reactivity in the anti-CCP2 test can occur. A positive CCP test in a non-rheumatic disease (eg liver disease) should therefore be interpreted with care, and preferably followed by a control ELISA with a non-citrullinated antigen.
Collapse
Affiliation(s)
- A Vannini
- Department of Internal Medicine, Cardioangiology, Hepatology, University of Bologna, and Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna, Italy.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Abstract
PURPOSE OF REVIEW To review studies that clarify the rheumatic manifestations of autoimmune hepatitis, elucidate shared pathogenic pathways, and encourage innovative site-specific therapies. RECENT FINDINGS Autoimmune hepatitis has clinical manifestations, serological markers, pathogenic mechanisms, genetic predispositions, and therapies similar to the rheumatic diseases. The rheumatic manifestations may mask the underlying liver disease and vice versa. Variations in clinical phenotype and outcome for the autoimmune liver diseases may reflect host-specific and region-specific factors, and defects in counter-regulatory suppressor functions by regulatory T cells may facilitate cell-mediated cytotoxicity and autoreactivity. Mixed syndromes with hallmark features of one disease in another probably reflect a genetic predisposition for immune expression that is shared among the diseases. Mycophenolate mofetil, budesonide, rapamycin, and 6-thioguanine are promising treatments, and de-novo autoimmune hepatitis after liver transplantation suggests that the calcineurin inhibitors may have paradoxical effects on self-tolerance. SUMMARY Clinical phenotypes of autoimmune hepatitis commonly include rheumatic manifestations that can mask the liver disease. Defects in counter-regulatory functions enhance cell-mediated cytotoxicity, and pharmacological interventions that promise site-specific actions affecting immunocyte differentiation and proliferation are feasible.
Collapse
Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
| |
Collapse
|
|
26
|
Bibliography. Current world literature. Vasculitis syndromes. Curr Opin Rheumatol 2006; 19:81-5. [PMID: 17143101 DOI: 10.1097/bor.0b013e32801437a8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
|
|
27
|
Montano-Loza A, Czaja AJ, Carpenter HA, Piette A, Murphy D, Shums Z, Burlingame R, Norman GL. Frequency and significance of antibodies to cyclic citrullinated peptide in type 1 autoimmune hepatitis. Autoimmunity 2006; 39:341-8. [PMID: 16891223 DOI: 10.1080/08916930600783348] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVES Determine the frequency, clinical phenotype, and prognostic implications of antibodies against cyclic citrullinated peptides in patients with type 1 autoimmune hepatitis. METHODS Three hundred and ninety-five serum samples from 179 patients were tested by enzyme-linked immunosorbent assay, and findings correlated with clinical and histological features, frequency of HLA DR3 and DR4, and treatment outcome. RESULTS Twenty patients (11%) had antibodies against cyclic citrullinated peptides. Seropositivity was associated with a higher frequency of rheumatoid arthritis (RA) (25 vs. 0%, P < 0.001). Patients with antibodies against cyclic citrullinated peptides also had a significantly greater occurrence of histological cirrhosis at presentation (47 vs. 20%, P = 0.01) and death from hepatic failure than seronegative patients (25 vs. 9%, P = 0.04). Cirrhosis at presentation occurred more commonly in the patients with antibodies against cyclic citrullinated peptides and RA than in the other patients (100 vs. 21%, P = 0.005). CONCLUSIONS Antibodies against cyclic citrullinated peptides occur in a subgroup of patients with type 1 autoimmune hepatitis who have a greater occurrence of cirrhosis at presentation and death from hepatic failure. Their presence with RA at accession characterizes a subgroup with cirrhosis.
Collapse
Affiliation(s)
- Aldo Montano-Loza
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Abstract
PURPOSE OF REVIEW To review studies that improve the diagnosis and treatment of autoimmune hepatitis and presage new drug and molecular site-specific interventions. RECENT FINDINGS Autoimmune hepatitis can present as acute or chronic hepatitis and as allograft dysfunction after liver transplantation. Elderly patients have an indolent but aggressive disease that responds well to corticosteroid therapy, and human leukocyte antigen DR4 characterizes this population. Geographic and ethnic factors influence clinical phenotype and behavior, and defects in T-regulatory cells may enhance cell-mediated cytotoxicity. Treatment response is the best index of prognosis, and normalization of serum aminotransferase abnormalities prevents disease progression. Mycophenolate mofetil, budesonide, rapamycin, and 6-thioguanine have been effective in small clinical experiences. De-novo autoimmune hepatitis can occur in adults and children after liver transplantation, and rapamycin may be an effective treatment. SUMMARY Autoimmune hepatitis has a global distribution and diverse clinical manifestations. Phenotypes are affected by regional and ethnic factors which may provide clues to the etiologic agents. Defects in counter-regulatory functions enhance cell-mediated cytotoxicity, and interventions that promise site-specific actions affecting immunocyte differentiation and proliferation are now feasible. Autoimmune hepatitis must be considered in all patients with acute and chronic hepatitis and in all cases of allograft dysfunction after liver transplantation.
Collapse
Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
| |
Collapse
|