Skip to main content

Advertisement

SpringerLink
Log in

High prevalence of primary biliary cirrhosis and disease-associated autoantibodies in Japanese patients with systemic sclerosis

  • Original Article
  • Published:
Modern Rheumatology

Abstract

Objective

To investigate the prevalence of primary biliary cirrhosis (PBC) and PBC-associated autoantibodies in Japanese systemic sclerosis (SSc) patients.

Methods

Clinical data from 225 Japanese SSc patients were retrospectively obtained. Serum samples from these patients were examined for PBC-associated autoantibodies, anti-mitochondrial M2 antibodies (AMA), anti-sp100 antibodies (anti-sp100), and anti-gp210 antibodies (anti-gp210) by enzyme-linked immunosorbent assay.

Results

Of 225 patients, 37 (16.4%) had AMA, 13 (5.8%) had anti-sp100, and 3 (1.3%) had anti-gp210. Three patients were positive for both AMA and anti-sp100, and 2 were positive for both AMA and anti-gp210. PBC was found in 22 (9.8%) patients positive for AMA with or without anti-sp100 or anti-gp210, but not in those with anti-sp100 or anti-gp210 without AMA. Furthermore, 13 patients lacking these three antibodies were diagnosed with or suspected of PBC by liver biopsy and/or their clinical manifestation. Multivariable analysis revealed that AMA and anti-centromere antibodies were independently associated with PBC in SSc patients, while anti-sp100 and anti-gp210 were not.

Conclusions

This study has demonstrated even higher prevalence of both PBC-associated autoantibodies and PBC in the Japanese SSc population than in the Caucasian SSc population. AMA and anti-centromere antibodies are likely to indicate increasing risk of PBC in SSc patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117:557–67.

    Article  PubMed  CAS  Google Scholar 

  2. Katsumoto TR, Whitfield ML, Connolly MK. The pathogenesis of systemic sclerosis. Annu Rev Pathol. 2011;6:509–37.

    Article  PubMed  CAS  Google Scholar 

  3. Fujimoto M, Sato S. B cell signaling and autoimmune diseases: CD19/CD22 loop as a B cell signaling device to regulate the balance of autoimmunity. J Dermatol Sci. 2007;46:1–9.

    Article  PubMed  CAS  Google Scholar 

  4. Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005;353:1261–73.

    Article  PubMed  CAS  Google Scholar 

  5. Coppel RL, Gershwin ME. Primary biliary cirrhosis: the molecule and the mimic. Immunol Rev. 1995;144:17–49.

    Article  PubMed  CAS  Google Scholar 

  6. Moritoki Y, Lian ZX, Ohsugi Y, Ueno Y, Gershwin ME. B cells and autoimmune liver diseases. Autoimmun Rev. 2006;5:449–57.

    Article  PubMed  CAS  Google Scholar 

  7. Worman HJ, Courvalin JC. Antinuclear antibodies specific for primary biliary cirrhosis. Autoimmun Rev. 2003;2:211–7.

    Article  PubMed  Google Scholar 

  8. Zuchner D, Sternsdorf T, Szostecki C, Heathcote EJ, Cauch-Dudek K, Will H. Prevalence, kinetics, and therapeutic modulation of autoantibodies against Sp100 and promyelocytic leukemia protein in a large cohort of patients with primary biliary cirrhosis. Hepatology. 1997;26:1123–30.

    PubMed  CAS  Google Scholar 

  9. Evans J, Reuben A, Craft J. PBC 95k, a 95-kilodalton nuclear autoantigen in primary biliary cirrhosis. Arthr Rheum. 1991;34:731–6.

    Article  CAS  Google Scholar 

  10. Nickowitz RE, Wozniak RW, Schaffner F, Worman HJ. Autoantibodies against integral membrane proteins of the nuclear envelope in patients with primary biliary cirrhosis. Gastroenterology. 1994;106:193–9.

    PubMed  CAS  Google Scholar 

  11. Lassoued K, Brenard R, Degos F, Courvalin JC, Andre C, Danon F, Brouet JC, Zine-el-Abidine Y, Degott C, Zafrani S, et al. Antinuclear antibodies directed to a 200-kilodalton polypeptide of the nuclear envelope in primary biliary cirrhosis. A clinical and immunological study of a series of 150 patients with primary biliary cirrhosis. Gastroenterology. 1990;99:181–6.

    PubMed  CAS  Google Scholar 

  12. Murray-Lyon IM, Thompson RP, Ansell ID, Williams R. Scleroderma and primary biliary cirrhosis. Br Med J. 1970;1:258–9.

    Article  Google Scholar 

  13. Reynolds TB, Denison EK, Frankl HD, Lieberman FL, Peters RL. Primary biliary cirrhosis with scleroderma, Raynaud’s phenomenon and telangiectasia. New syndrome. Am J Med. 1971;50:302–12.

    Article  PubMed  CAS  Google Scholar 

  14. Powell FC, Schroeter AL, Dickson ER. Primary biliary cirrhosis and the CREST syndrome: a report of 22 cases. Q J Med. 1987;62:75–82.

    PubMed  CAS  Google Scholar 

  15. Fujimoto M, Sato S, Ihn H, Kikuchi K, Tamaki K, Takehara K. Autoantibodies to pyruvate dehydrogenase complex in patients with systemic sclerosis. Possible role of anti-E1 alpha antibody as a serologic indicator for development of primary biliary cirrhosis. Arthr Rheum. 1995;38:985–9.

    Article  CAS  Google Scholar 

  16. Rigamonti C, Shand LM, Feudjo M, Bunn CC, Black CM, Denton CP, Burroughs AK. Clinical features and prognosis of primary biliary cirrhosis associated with systemic sclerosis. Gut. 2006;55:388–94.

    Article  PubMed  CAS  Google Scholar 

  17. Assassi S, Fritzler MJ, Arnett FC, Norman GL, Shah KR, Gourh P, Manek N, Perry M, Ganesh D, Rahbar MH, Mayes MD. Primary biliary cirrhosis (PBC), PBC autoantibodies, and hepatic parameter abnormalities in a large population of systemic sclerosis patients. J Rheumatol. 2009;36:2250–6.

    Article  PubMed  Google Scholar 

  18. Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthr Rheum. 1980;23:581–90.

    Google Scholar 

  19. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TAJ, Rowell N, Wollheim F. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15:202–5.

    PubMed  CAS  Google Scholar 

  20. Sasaki H, Inoue K, Higuchi K, Yasuyama T, Koyata H, Kuroki T, Yamamoto S, Ichida F. Primary biliary cirrhosis in Japan: national survey by the Subcommittee on Autoimmune hepatitis. Gastroenterol Jpn. 1985;20:476–85.

    PubMed  CAS  Google Scholar 

  21. Inoue K, Hirohara J, Nakano T, Seki T, Sasaki H, Higuchi K, Ohta Y, Onji M, Muto Y, Moriwaki H. Prediction of prognosis of primary biliary cirrhosis in Japan. Liver. 1995;15:70–7.

    Article  PubMed  CAS  Google Scholar 

  22. Watt FE, James OF, Jones DE. Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study. QJM. 2004;97:397–406.

    Article  PubMed  CAS  Google Scholar 

  23. Jacobsen S, Halberg P, Ullman S, Van Venrooij WJ, Hoier-Madsen M, Wiik A, Petersen J. Clinical features and serum antinuclear antibodies in 230 Danish patients with systemic sclerosis. Br J Rheumatol. 1998;37:39–45.

    Article  PubMed  CAS  Google Scholar 

  24. Gabeta S, Norman GL, Liaskos C, Papamichalis PA, Zografos T, Garagounis A, Rigopoulou EI, Dalekos GN. Diagnostic relevance and clinical significance of the new enhanced performance M2 (MIT3) ELISA for the detection of IgA and IgG antimitochondrial antibodies in primary biliary cirrhosis. J Clin Immunol. 2007;27:378–87.

    Article  PubMed  CAS  Google Scholar 

  25. Norman GL, Bialek A, Encabo S, Butkiewicz B, Wiechowska-Kozlowska A, Brzosko M, Shums Z, Milkiewicz P. Is prevalence of PBC underestimated in patients with systemic sclerosis? Dig Liver Dis. 2009;41:762–4.

    Article  PubMed  CAS  Google Scholar 

  26. Mytilinaiou MG, Bogdanos DP. Primary biliary cirrhosis-specific autoantibodies in patients with systemic sclerosis. Dig Liver Dis. 2009;41:916. (author reply-7).

    Article  PubMed  CAS  Google Scholar 

  27. Akiyama Y, Tanaka M, Takeishi M, Adachi D, Mimori A, Suzuki T. Clinical, serological and genetic study in patients with CREST syndrome. Intern Med. 2000;39:451–6.

    Article  PubMed  CAS  Google Scholar 

  28. Bandin O, Courvalin JC, Poupon R, Dubel L, Homberg JC, Johanet C. Specificity and sensitivity of gp210 autoantibodies detected using an enzyme-linked immunosorbent assay and a synthetic polypeptide in the diagnosis of primary biliary cirrhosis. Hepatology. 1996;23:1020–4.

    Article  PubMed  CAS  Google Scholar 

  29. Nakamura M, Kondo H, Mori T, Komori A, Matsuyama M, Ito M, Takii Y, Koyabu M, Yokoyama T, Migita K, Daikoku M, Abiru S, Yatsuhashi H, Takezaki E, Masaki N, Sugi K, Honda K, Adachi H, Nishi H, Watanabe Y, Nakamura Y, Shimada M, Komatsu T, Saito A, Saoshiro T, Harada H, Sodeyama T, Hayashi S, Masumoto A, Sando T, Yamamoto T, Sakai H, Kobayashi M, Muro T, Koga M, Shums Z, Norman GL, Ishibashi H. Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis. Hepatology. 2007;45:118–27.

    Article  PubMed  CAS  Google Scholar 

  30. Varga J, Pasche B. Transforming growth factor beta as a therapeutic target in systemic sclerosis. Nat Rev Rheumatol. 2009;5:200–6.

    Article  PubMed  CAS  Google Scholar 

  31. Ihn H. Autocrine TGF-beta signaling in the pathogenesis of systemic sclerosis. J Dermatol Sci. 2008;49:103–13.

    Article  PubMed  CAS  Google Scholar 

  32. Oertelt S, Lian ZX, Cheng CM, Chuang YH, Padgett KA, He XS, Ridgway WM, Ansari AA, Coppel RL, Li MO, Flavell RA, Kronenberg M, Mackay IR, Gershwin ME. Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice. J Immunol. 2006;177:1655–60.

    PubMed  CAS  Google Scholar 

  33. Neuman M, Angulo P, Malkiewicz I, Jorgensen R, Shear N, Dickson ER, Haber J, Katz G, Lindor K. Tumor necrosis factor-alpha and transforming growth factor-beta reflect severity of liver damage in primary biliary cirrhosis. J Gastroenterol Hepatol. 2002;17:196–202.

    Article  PubMed  CAS  Google Scholar 

  34. Gaudy-Marqueste C, Roll P, Esteves-Vieira V, Weiller PJ, Grob JJ, Cau P, Levy N, De Sandre-Giovannoli A. LBR mutation and nuclear envelope defects in a patient affected with Reynolds syndrome. J Med Genet. 2010;47:361–70.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Ms. M. Matsubara for technical assistance. This work was supported by a research grant on intractable diseases from the Ministry of Health, Labor, and Welfare of Japan.

Conflict of interest

Susan Encabo, Zakera Shums, and Gary L. Norman are employees of INOVA Diagnostics Inc.

Author information

Authors and Affiliations

  1. Department of Dermatology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan

    Sayako Imura-Kumada, Minoru Hasegawa, Takashi Matsushita, Yasuhito Hamaguchi, Kazuhiko Takehara & Manabu Fujimoto

  2. INOVA Diagnostics, Inc., 9900 Old Grove Road, San Diego, CA, 92131-1638, USA

    Susan Encabo, Zakera Shums & Gary L. Norman

Authors
  1. Sayako Imura-Kumada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Minoru Hasegawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takashi Matsushita
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasuhito Hamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Susan Encabo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zakera Shums
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gary L. Norman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kazuhiko Takehara
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Manabu Fujimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Manabu Fujimoto.

About this article

Cite this article

Imura-Kumada, S., Hasegawa, M., Matsushita, T. et al. High prevalence of primary biliary cirrhosis and disease-associated autoantibodies in Japanese patients with systemic sclerosis. Mod Rheumatol 22, 892–898 (2012). https://doi.org/10.1007/s10165-012-0607-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10165-012-0607-z

Keywords

Search

Navigation