Clinical Rheumatology

, Volume 31, Issue 8, pp 1169–1175 | Cite as

Prospective study of HBV reactivation risk in rheumatoid arthritis patients who received conventional disease-modifying antirheumatic drugs

  • Jing TanEmail author
  • Jingguo Zhou
  • Pan Zhao
  • Jing Wei
Original Article


Studies that reported hepatitis B virus (HBV) reactivation in rheumatoid arthritis (RA) patients have caused attention of disease-modifying antirheumatic drug (DMARD)-related HBV reactivation. Most of the studies were focused on HBV reactivation risk of biologic DMARDs; insufficient data are available to identify the exact risk of conventional DMARD (c-DMARD)-related HBV reactivation. This prospective study aimed to investigate the risk of HBV reactivation in HBV-infected RA patients who received c-DMARDs. A total of 476 RA patients were screened in this prospective non-randomized, non-controlled study. HBV-infected patients characterized by hepatitis B surface antigen (HBsAg) positive or HBsAg negative/anti-hepatitis B core antigen (anti-HBc) positive were analyzed for HBV DNA, followed with HBV DNA monitoring scheduled every 3 months, serum alanine aminotransferase test at 2-month intervals, or more frequently. Prevalence of HBsAg positive and HBsAg negative/anti-HBc positive was 6.51 and 51.1 %, respectively, among the 476 RA patients. Among 211 patients (23 patients were HBsAg positive and 188 patients were HBsAg negative/anti-HBc positive) who received c-DMARDs without antiviral prophylactic treatment, 4 patients developed HBV reactivation. Both HBsAg positive and HBsAg negative/anti-HBc positive patients have the possibility of developing HBV reactivation. There was no correlation between HBV reactivation and any specific c-DMARD. Glucocorticoid coadministration and negative anti-hepatitis B surface antigen (anti-HBs) at baseline showed correlation with reactivation. In conclusion, it would be rational to initiate antiviral prophylaxis according to risk stratification rather than universal prophylaxis for HBV-infected RA patients. Conventional DMARDs are relatively safe to HBV-infected patients with low reactivation risk (low HBV DNA level, no GCs administration, and anti-HB positive).


Conventional disease-modifying antirheumatic drugs Hepatitis B virus reactivation Rheumatoid arthritis 



This study was supported by the grant no. 08010110089 from the Chinese Medical Association.




  1. 1.
    Flowers MA, Heathcote J, Wanless IR, Sherman M, Reynolds WJ, Cameron RG, Levy GA, Inman RD (1990) Fulminant hepatitis as a consequence of reactivation of hepatitis B virus infection after discontinuation of low-dose methotrexate therapy. Ann Intern Med 112(5):381–382PubMedGoogle Scholar
  2. 2.
    Narvaez J, Rodriguez-Moreno J, Martinez-Aguila MD, Clavaguera MT (1998) Severe hepatitis linked to B virus infection after withdrawal of low dose methotrexate therapy. J Rheumatol 25(10):2037–2038PubMedGoogle Scholar
  3. 3.
    Hagiyama H, Kubota T, Komano Y, Kurosaki M, Watanabe M, Miyasaka N (2004) Fulminant hepatitis in an asymptomatic chronic carrier of hepatitis B virus mutant after withdrawal of low-dose methotrexate therapy for rheumatoid arthritis. Clin Exp Rheumatol 22(3):375–376PubMedGoogle Scholar
  4. 4.
    Weinbaum CM, Williams I, Mast EE, Wang SA, Finelli L, Wasley A, Neitzel SM, Ward JW (2008) Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR Recomm Rep 57(RR-8):1–20PubMedGoogle Scholar
  5. 5.
    Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, Paulus HE, Mudano A, Pisu M, Elkins-Melton M, Outman R, Allison JJ, Suarez Almazor M, Bridges SL Jr, Chatham WW, Hochberg M, MacLean C, Mikuls T, Moreland LW, O'Dell J, Turkiewicz AM, Furst DE (2008) American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 59(6):762–784PubMedCrossRefGoogle Scholar
  6. 6.
    Stine JG, Khokhar OS, Charalambopoulos J, Shanmugam VK, Lewis JH (2010) Rheumatologists' awareness of and screening practices for hepatitis B virus infection prior to initiating immunomodulatory therapy. Arthritis Care Res (Hoboken) 62(5):704–711CrossRefGoogle Scholar
  7. 7.
    Lau GK (2008) Hepatitis B reactivation after chemotherapy: two decades of clinical research. Hepatol Int 2(2):152–162PubMedCrossRefGoogle Scholar
  8. 8.
    Lan JL, Chen YM, Hsieh TY, Chen YH, Hsieh CW, Chen DY, Yang SS (2011) Kinetics of viral loads and risk of hepatitis B virus reactivation in hepatitis B core antibody-positive rheumatoid arthritis patients undergoing anti-tumour necrosis factor alpha therapy. Ann Rheum Dis 70(10):1719–1725PubMedCrossRefGoogle Scholar
  9. 9.
    Charpin C, Guis S, Colson P, Borentain P, Mattei JP, Alcaraz P, Balandraud N, Thomachot B, Roudier J, Gerolami R (2009) Safety of TNF-blocking agents in rheumatic patients with serology suggesting past hepatitis B state: results from a cohort of 21 patients. Arthritis Res Ther 11(6):R179PubMedCrossRefGoogle Scholar
  10. 10.
    Vassilopoulos D, Apostolopoulou A, Hadziyannis E, Papatheodoridis GV, Manolakopoulos S, Koskinas J, Manesis EK, Archimandritis AI (2010) Long-term safety of anti-TNF treatment in patients with rheumatic diseases and chronic or resolved hepatitis B virus infection. Ann Rheum Dis 69(7):1352–1355PubMedCrossRefGoogle Scholar
  11. 11.
    Kim YJ, Bae SC, Sung YK, Kim TH, Jun JB, Yoo DH, Kim TY, Sohn JH, Lee HS (2010) Possible reactivation of potential hepatitis B virus occult infection by tumor necrosis factor-alpha blocker in the treatment of rheumatic diseases. J Rheumatol 37(2):346–350PubMedCrossRefGoogle Scholar
  12. 12.
    Liang X, Bi S, Yang W, Wang L, Cui G, Cui F, Zhang Y, Liu J, Gong X, Chen Y, Wang F, Zheng H, Guo J, Jia Z, Ma J, Wang H, Luo H, Li L, Jin S, Hadler SC, Wang Y (2009) Epidemiological serosurvey of hepatitis B in China—declining HBV prevalence due to hepatitis B vaccination. Vaccine 27(47):6550–6557PubMedCrossRefGoogle Scholar
  13. 13.
    Kim DA, Kim TY (2010) Is screening for hepatitis necessary in diagnostic evaluation of rheumatoid arthritis in South Korea? J Rheumatol 37(3):674–675, author reply 675PubMedCrossRefGoogle Scholar
  14. 14.
    Juhl D, Luhm J, Gorg S, Ziemann M, Hennig H (2011) Evaluation of algorithms for the diagnostic assessment and the reentry of blood donors who tested reactive for antibodies against hepatitis B core antigen. Transfusion 51(7):1477–1485PubMedCrossRefGoogle Scholar
  15. 15.
    Kryger P, Aldershvile J, Mathiesen LR, Nielsen JO (1982) Acute type B hepatitis among HBsAg negative patients detected by anti-HBc IgM. Hepatology 2(1):50–53PubMedCrossRefGoogle Scholar
  16. 16.
    Urata Y, Uesato R, Tanaka D, Kowatari K, Nitobe T, Nakamura Y, Motomura S (2011) Prevalence of reactivation of hepatitis B virus replication in rheumatoid arthritis patients. Mod Rheumatol 21(1):16–23PubMedCrossRefGoogle Scholar
  17. 17.
    Hoofnagle JH (2009) Reactivation of hepatitis B. Hepatology 49(5 Suppl):S156–S165PubMedCrossRefGoogle Scholar
  18. 18.
    Lok AS, McMahon BJ (2007) Chronic hepatitis B. Hepatology 45(2):507–539PubMedCrossRefGoogle Scholar
  19. 19.
    Hsu C, Hsiung CA, Su IJ, Hwang WS, Wang MC, Lin SF, Lin TH, Hsiao HH, Young JH, Chang MC, Liao YM, Li CC, Wu HB, Tien HF, Chao TY, Liu TW, Cheng AL, Chen PJ (2008) A revisit of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in non-Hodgkin's lymphoma: a randomized trial. Hepatology 47(3):844–853PubMedCrossRefGoogle Scholar
  20. 20.
    Lau GK, Yiu HH, Fong DY, Cheng HC, Au WY, Lai LS, Cheung M, Zhang HY, Lie A, Ngan R, Liang R (2003) Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology 125(6):1742–1749PubMedCrossRefGoogle Scholar
  21. 21.
    Calabrese LH, Zein NN, Vassilopoulos D (2006) Hepatitis B virus (HBV) reactivation with immunosuppressive therapy in rheumatic diseases: assessment and preventive strategies. Ann Rheum Dis 65(8):983–989PubMedCrossRefGoogle Scholar
  22. 22.
    Yeo W, Johnson PJ (2006) Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. Hepatology 43(2):209–220PubMedCrossRefGoogle Scholar
  23. 23.
    Kalyoncu U, Yonem O, Calguneri M, Ersoy O, Karadag O, Akdogan A, Bilgen SA, Kiraz S, Ertenli I, Bayraktar Y (2009) Prophylactic use of lamivudine with chronic immunosuppressive therapy for rheumatologic disorders. Rheumatol Int 29(7):777–780PubMedCrossRefGoogle Scholar
  24. 24.
    Kato M, Atsumi T, Kurita T, Odani T, Fujieda Y, Otomo K, Horita T, Yasuda S, Koike T (2011) Hepatitis B virus reactivation by immunosuppressive therapy in patients with autoimmune diseases: risk analysis in hepatitis B surface antigen-negative cases. J Rheumatol 38(10):2209–2214PubMedCrossRefGoogle Scholar
  25. 25.
    Onozawa M, Hashino S, Izumiyama K, Kahata K, Chuma M, Mori A, Kondo T, Toyoshima N, Ota S, Kobayashi S, Hige S, Toubai T, Tanaka J, Imamura M, Asaka M (2005) Progressive disappearance of anti-hepatitis B surface antigen antibody and reverse seroconversion after allogeneic hematopoietic stem cell transplantation in patients with previous hepatitis B virus infection. Transplantation 79(5):616–619PubMedCrossRefGoogle Scholar
  26. 26.
    Perrillo RP (2001) Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease. Gastroenterology 120(4):1009–1022PubMedCrossRefGoogle Scholar
  27. 27.
    Markovic S, Drozina G, Vovk M, Fidler-Jenko M (1999) Reactivation of hepatitis B but not hepatitis C in patients with malignant lymphoma and immunosuppressive therapy. A prospective study in 305 patients. Hepatogastroenterology 46(29):2925–2930PubMedGoogle Scholar
  28. 28.
    Gorter SL, Bijlsma JW, Cutolo M, Gomez-Reino J, Kouloumas M, Smolen JS, Landewe R (2010) Current evidence for the management of rheumatoid arthritis with glucocorticoids: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis 69(6):1010–1014PubMedCrossRefGoogle Scholar
  29. 29.
    Kim TW, Kim MN, Kwon JW, Kim KM, Kim SH, Kim W, Park HW, Chang YS, Cho SH, Min KU, Kim YY (2010) Risk of hepatitis B virus reactivation in patients with asthma or chronic obstructive pulmonary disease treated with corticosteroids. Respirology 15(7):1092–1097PubMedCrossRefGoogle Scholar
  30. 30.
    Thong BY, Koh ET, Chng HH, Chow WC (2007) Outcomes of chronic hepatitis B infection in Oriental patients with rheumatic diseases. Ann Acad Med Singapore 36(2):100–105PubMedGoogle Scholar
  31. 31.
    Ito S, Nakazono K, Murasawa A, Mita Y, Hata K, Saito N, Kikuchi M, Yoshida K, Nakano M, Gejyo F (2001) Development of fulminant hepatitis B (precore variant mutant type) after the discontinuation of low-dose methotrexate therapy in a rheumatoid arthritis patient. Arthritis Rheum 44(2):339–342PubMedCrossRefGoogle Scholar
  32. 32.
    Watanabe K, Takase K, Ohno S, Ideguchi H, Nozaki A, Ishigatsubo Y (2011) Reactivation of hepatitis B virus in a hepatitis B surface antigen-negative patient with rheumatoid arthritis treated with methotrexate. Mod Rheumatol doi: 10.1007/s10165-011-0521-9
  33. 33.
    Tamori A, Koike T, Goto H, Wakitani S, Tada M, Morikawa H, Enomoto M, Inaba M, Nakatani T, Hino M, Kawada N (2011) Prospective study of reactivation of hepatitis B virus in patients with rheumatoid arthritis who received immunosuppressive therapy: evaluation of both HBsAg-positive and HBsAg-negative cohorts. J Gastroenterol 46(4):556–564PubMedCrossRefGoogle Scholar
  34. 34.
    Mori S (2011) Past hepatitis B virus infection in rheumatoid arthritis patients receiving biological and/or nonbiological disease-modifying antirheumatic drugs. Mod Rheumatol 21(6):621–627PubMedCrossRefGoogle Scholar
  35. 35.
    Gwak GY, Koh KC, Kim HY (2007) Fatal hepatic failure associated with hepatitis B virus reactivation in a hepatitis B surface antigen-negative patient with rheumatoid arthritis receiving low dose methotrexate. Clin Exp Rheumatol 25(6):888–889PubMedGoogle Scholar
  36. 36.
    Calabrese LH, Zein N, Vassilopoulos D (2004) Safety of antitumour necrosis factor (anti-TNF) therapy in patients with chronic viral infections: hepatitis C, hepatitis B, and HIV infection. Ann Rheum Dis 63(Suppl 2):ii18–ii24PubMedCrossRefGoogle Scholar
  37. 37.
    Lacaille D, Guh DP, Abrahamowicz M, Anis AH, Esdaile JM (2008) Use of nonbiologic disease-modifying antirheumatic drugs and risk of infection in patients with rheumatoid arthritis. Arthritis Rheum 59(8):1074–1081PubMedCrossRefGoogle Scholar

Copyright information

© Clinical Rheumatology 2012

Authors and Affiliations

  1. 1.Department of Rheumatology and HematologyAffiliated Hospital of North Sichuan Medical CollegeNanchongPeople’s Republic of China

Personalised recommendations