Skip to main content

Advertisement

SpringerLink
Log in

Risks of hepatocellular carcinoma and cirrhosis-associated complications in patients with rheumatoid arthritis: a 10-year population-based cohort study in Taiwan

  • Original Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Background/purpose

Although rheumatoid arthritis (RA) has been linked to several important malignancies, data for the risks of hepatocellular carcinoma (HCC) in patients with RA are scarce. We aimed to examine the risk of HCC and cirrhosis-associated complications and the use of biologics in a national representative RA sample in Taiwan.

Methods

All study subjects aged ≥ 18 years in the Taiwan National Health Insurance program between January 1, 2000, and December 31, 2009 were enrolled. We matched RA and non-RA subjects by propensity scores in a 1:1 ratio. Our primary outcome was a diagnosis of HCC and cirrhosis-associated complications during a 10-year follow-up period. The risk of outcomes was represented as a hazard ratio (HR) calculated in Cox proportional hazard regression models.

Results

24,245 RA and 24,245 non-RA subjects were included in the primary outcome analysis. Mean overall person-years (PY) of follow-up were 116,608 PY for the RA cohort, and 234,280 PY for the non-RA cohort. The overall incidence of HCC and cirrhosis-associated complications was lower in the RA cohort than in the non-RA cohort (0.66% vs. 1.41% HCC events and 1.45% vs. 1.95% cirrhosis-associated complications events during 10-year follow-up). The HRs adjusted for age, sex, the frequency of medical visits, and CCI were 0.57 (0.46–0.71) for HCC and 0.67 (0.59–0.76) for HCC and cirrhosis-associated complications. Although immunomodulatory agents may alter the risk of malignancy, use of biologics did not increase HCC risk in RA patients.

Conclusions

RA is associated with a reduced risk of developing HCC and cirrhosis-associated complications.

Clinical trial registration

ClinicalTrials.gov identifier NCT02880306.

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
Fig. 3

Similar content being viewed by others

Abbreviations

HCC:

Hepatocellular carcinoma

RA:

Rheumatoid arthritis

HBV:

Hepatitis B virus

HCV:

Hepatitis C virus

HR:

Hazard ratio

NHIRD:

National Health Insurance Research Database

ICD-9-CM:

International Classification of Diseases, Ninth Revision, Clinical Modification

PY:

Person-years

CHB:

Chronic hepatitis B

RCIPD:

Registry for Catastrophic Illness Patient Database

DM:

Diabetes mellitus

HIV:

Human immunodeficiency virus

IHD:

Ischemic heart disease

COPD:

Chronic obstructive pulmonary disease

References

  1. Sangiovanni A, Prati GM, Fasani P, Ronchi G, Romeo R, Manini M, Del Ninno E, et al. The natural history of compensated cirrhosis due to hepatitis C virus: a 17-year cohort study of 214 patients. Hepatology 2006;43:1303–1310.

  2. Kao JH, Chen DS. Global control of hepatitis B virus infection. Lancet Infect Dis 2002;2:395–403.

  3. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, et al. GLOBOCAN 2012 v1.1, Cancer Incidence and Mortality Worldwide: IARC Cancer. Lyon, France: International Agency for Research on Cancer; 2014.

  4. El-Serag HB. Hepatocellular carcinoma. N Engl J Med 2011;365:1118–1127.

  5. Berrino F, De Angelis R, Sant M, Rosso S, Bielska-Lasota M, Coebergh JW, Santaquilani M, et al. Survival for eight major cancers and all cancers combined for European adults diagnosed in 1995–99: results of the EUROCARE-4 study. Lancet Oncol 2007;8:773–783.

  6. Verdecchia A, Francisci S, Brenner H, Gatta G, Micheli A, Mangone L, Kunkler I, et al. Recent cancer survival in Europe: a 2000–02 period analysis of EUROCARE-4 data. Lancet Oncol 2007;8:784–796.

  7. Lin CL, Kao JH. The clinical implications of hepatitis B virus genotype: recent advances. J Gastroenterol Hepatol 2011;26 (Suppl 1):123–130.

  8. Liaw YF. Natural history of chronic hepatitis B virus infection and long-term outcome under treatment. Liver Int 2009;29 (Suppl 1):100–107.

  9. Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, Chen DS, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2016;10:1–98.

  10. Omata M, Lesmana LA, Tateishi R, Chen PJ, Lin SM, Yoshida H, Kudo M, et al. Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma. Hepatol Int 2010;4:439–474.

  11. European Association For The Study Of The L, European Organisation For R, Treatment Of C. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:908–943.

  12. Bruix J, Sherman M, American Association for the Study of Liver D. Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020–1022.

  13. Cobb S, Anderson F, Bauer W. Length of life and cause of death in rheumatoid arthritis. N Engl J Med 1953;249:553–556.

  14. Listing J, Gerhold K, Zink A. The risk of infections associated with rheumatoid arthritis, with its comorbidity and treatment. Rheumatology (Oxford) 2013;52:53–61.

  15. Smitten AL, Simon TA, Hochberg MC, Suissa S. A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis. Arthritis Res Ther 2008;10:R45.

  16. Love T, Solomon DH. The relationship between cancer and rheumatoid arthritis: still a large research agenda. Arthritis Res Ther 2008;10:109.

  17. Simon TA, Thompson A, Gandhi KK, Hochberg MC, Suissa S. Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis. Arthritis Res Ther 2015;17:212.

  18. Cush JJ, Dao KH. Malignancy risks with biologic therapies. Rheum Dis Clin North Am 2012;38:761–770.

  19. Vassilopoulos D, Calabrese LH. Virally associated arthritis 2008: clinical, epidemiologic, and pathophysiologic considerations. Arthritis Res Ther 2008;10:215.

  20. Zou CJ, Zhu LJ, Li YH, Mo YQ, Zheng DH, Ma JD, Ou-Yang X, et al. The association between hepatitis B virus infection and disease activity, synovitis, or joint destruction in rheumatoid arthritis. Clin Rheumatol 2013;32:787–795.

  21. Permin H, Aldershvile J, Nielsen JO. Hepatitis B virus infection in patients with rheumatic diseases. Ann Rheum Dis 1982;41:479–482.

  22. Tanasescu C, Parvu M, Antohi I, Lazar S. The significance of chronic hepatitis B and C virus infections in some connective tissue diseases: the association with chronic liver disease. Rom J Intern Med 1999;37:53–64.

  23. Kojima H, Uemura M, Sakurai S, Ann T, Ishii Y, Imazu H, Yoshikawa M, et al. Clinical features of liver disturbance in rheumatoid diseases: clinicopathological study with special reference to the cause of liver disturbance. J Gastroenterol 2002;37:617–625.

  24. Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, Moreland LW, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2012;64:625–639.

  25. Hootman JM, Helmick CG. Projections of US prevalence of arthritis and associated activity limitations. Arthritis Rheum 2006;54:226–229.

  26. George MD, Baker JF. The obesity epidemic and consequences for rheumatoid arthritis care. Curr Rheumatol Rep 2016;18:6.

  27. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 2003;37:1202–1219.

  28. Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994;107:1103–1109.

  29. Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I, Khalil L, et al. Liver fibrosis in overweight patients. Gastroenterology 2000;118:1117–1123.

  30. Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 2002;36:1349–1354.

  31. Hatanaka K, Kudo M, Fukunaga T, Ueshima K, Chung H, Minami Y, Sakaguchi Y, et al. Clinical characteristics of NonBNonC-HCC: comparison with HBV and HCV related HCC. Intervirology 2007;50:24–31.

  32. Hsu CS, Lang HC, Huang KY, Lin HH, Chen CL. Association of rheumatoid arthritis and hepatitis B infection: a nationwide nested case-control study from 1999 to 2009 in Taiwan. Medicine (Baltimore) 2016;95:e3551.

  33. Hsu CS, Kao JH, Chao YC, Lin HH, Fan YC, Huang CJ, Tsai PS. Interferon-based therapy reduces risk of stroke in chronic hepatitis C patients: a population-based cohort study in Taiwan. Aliment Pharmacol Ther 2013;38:415–423.

  34. Hsu CS, Huang CJ, Kao JH, Lin HH, Chao YC, Fan YC, Tsai PS. Interferon-based therapy decreases risks of hepatocellular carcinoma and complications of cirrhosis in chronic hepatitis C patients. PLoS One 2013;8:e70458.

  35. Cheng CL, Kao YH, Lin SJ, Lee CH, Lai ML. Validation of the National Health Insurance Research Database with ischemic stroke cases in Taiwan. Pharmacoepidemiol Drug Saf 2011;20:236–242.

  36. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–324.

  37. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 1987;40:373–383.

  38. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999;94:496–509.

  39. Rosenbaum PR, Rubin DB. Difficulties with regression analyses of age-adjusted rates. Biometrics 1984;40:437–443.

  40. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell;140:883–899.

  41. Szekanecz Z, Szekanecz E, Bako G, Shoenfeld Y. Malignancies in autoimmune rheumatic diseases—a mini-review. Gerontology 2011;57:3–10.

  42. Weyand CM, Goronzy JJ, Kurtin PJ. Lymphoma in rheumatoid arthritis: an immune system set up for failure. Arthritis Rheum 2006;54:685–689.

  43. Boulton JG, Bax DE. An unusual cause of abnormal liver function in a patient with rheumatoid arthritis. Rheumatology (Oxford) 2008;47:226–227.

  44. Nickoloff BJ, Ben-Neriah Y, Pikarsky E. Inflammation and cancer: is the link as simple as we think? J Invest Dermatol 2005;124:x–xiv.

  45. Selmi C, De Santis M, Gershwin ME. Liver involvement in subjects with rheumatic disease. Arthritis Res Ther 2011;13:226.

  46. Ruderman EM, Crawford JM, Maier A, Liu JJ, Gravallese EM, Weinblatt ME. Histologic liver abnormalities in an autopsy series of patients with rheumatoid arthritis. Br J Rheumatol 1997;36:210–213.

  47. Manger B, Schett G. Paraneoplastic syndromes in rheumatology. Nat Rev Rheumatol 2014;10:662–670.

  48. Andras C, Csiki Z, Ponyi A, Illes A, Danko K. Paraneoplastic rheumatic syndromes. Rheumatol Int 2006;26:376–382.

  49. Stummvoll GH, Aringer M, Machold KP, Smolen JS, Raderer M. Cancer polyarthritis resembling rheumatoid arthritis as a first sign of hidden neoplasms. Report of two cases and review of the literature. Scand J Rheumatol 2001;30:40–44.

  50. Antonelli A, Ferri C, Galeazzi M, Giannitti C, Manno D, Mieli-Vergani G, Menegatti E, et al. HCV infection: pathogenesis, clinical manifestations and therapy. Clin Exp Rheumatol 2008;26:S39–47.

  51. Thong BY, Koh ET, Chng HH, Chow WC. Outcomes of chronic hepatitis B infection in Oriental patients with rheumatic diseases. Ann Acad Med Singapore 2007;36:100–105.

Download references

Acknowledgements

This study is based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health, and managed by National Health Research Institutes (NHRI). The interpretation and conclusions contained herein do not represent those of the Bureau of National Health Insurance, Department of Health, or NHRI. We thank our colleagues at the Department of Pharmacy, the Research Center of Taipei Tzu Chi Hospital, and the Buddhist Tzu Chi Medical Foundation, who assisted in the collection of data, references search, and manuscript preparation.

Funding

This work was supported in part by grants from the Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Ministry of Health and Welfare, and Ministry of Science and Technology, Executive Yuan, Taiwan [TCRD-TPE-106-RT-8, TCRD-TPE-104-31, TCMMP104-02-02, TCMMP104-02-01]. The funders had no role in study design, data collection, data analysis, data interpretation, the decision to publish, or preparation of the manuscript. The authors had full access to all data in the study and had authority over the decision to publish.

Author information

Authors and Affiliations

  1. Liver Diseases Research Center, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 289 Jianguo Rd, Xindian Dist, New Taipei City, 23142, Taiwan, ROC

    Ching-Sheng Hsu & You-Chen Chao

  2. School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan, ROC

    Ching-Sheng Hsu

  3. Division of Gastroenterology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei, Taiwan, ROC

    Ching-Sheng Hsu & You-Chen Chao

  4. School of Medicine, Tzu Chi University, Hualien, Taiwan, ROC

    Kuang-Yung Huang, You-Chen Chao & Chien-Lin Chen

  5. Institute of Hospital and Health Care Administration, National Yang-Ming University, Taipei, Taiwan, ROC

    Hui-Chu Lang

  6. Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan, ROC

    Kuang-Yung Huang

  7. Department of Life Science and Institute of Molecular Biology, National Chung Cheung University, Chiayi, Taiwan, ROC

    Kuang-Yung Huang

  8. Division of Gastroenterology, Department of Internal Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 707 Sec. 3, Chung Yang Rd, Hualien, 970, Taiwan, ROC

    Chien-Lin Chen

Authors
  1. Ching-Sheng Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hui-Chu Lang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kuang-Yung Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. You-Chen Chao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chien-Lin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design: CSH. Drafting of the article: CSH CLC. Literature search and figures: CLC HCL. Critical revision of the article for important intellectual content: KYH YCC. Data collection, data analysis and statistical expertise: HCL. Obtaining of funding: CSH CLC. Supervision of the article: CSH CLC.

Corresponding authors

Correspondence to Ching-Sheng Hsu or Chien-Lin Chen.

Ethics declarations

Conflict of interest

Ching-Sheng Hsu, Hui-Chu Lang, Kuang-Yung Huang, You-Chen Chao and Chien-Lin Chen declare that they have no conflict of interest.

Statement of ethics

This study was conducted in accordance with the Helsinki Declaration and was approved and granted a waiver of informed consent by the Institutional Review Board of the Taipei Tzu Chi Hospital (05-W01-030).

Data sharing

No additional data available.

Transparency

The lead authors affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 3200 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hsu, CS., Lang, HC., Huang, KY. et al. Risks of hepatocellular carcinoma and cirrhosis-associated complications in patients with rheumatoid arthritis: a 10-year population-based cohort study in Taiwan. Hepatol Int 12, 531–543 (2018). https://doi.org/10.1007/s12072-018-9905-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-018-9905-7

Keywords

Search

Navigation