Letters to the Editor
Reactivation of occult hepatitis B virus infection, following treatment of refractory rheumatoid arthritis with abatacept To the Editor: Abatacept is a biologic response modifier that is used in the treatment of refractory rheumatoid arthritis. This agent is not known to be associated with reactivation of hepatitis B virus (HBV) infection [1]. We report a patient with occult HBV infection, who developed severe hepatitis B following treatment with abatacept. This 72-year-old woman, with a 30-year history of rheumatoid arthritis, was treated up to 2007 with methotrexate (15 mg/week, orally) and, periodically, with various non-steroidal anti-inflammatory drugs (NSAIDs). Prednisolone was used almost continuously during the last decade (10 mg daily). The patient also received the TNFa antagonist adalimumab (40 mg every other week) for a period of two years, up to September 2009, due to refractory, severe and progressive debilitating disease. Before starting adalimumab, she had serologic evidence of occult chronic HBV infection: negative HBsAg, positive HBcAb, positive HBsAb, negative HBeAg, and positive HBeAb. Serologic markers for HCV and HIV infections were negative. During this whole period, her AST and ALT serum levels remained below the upper limits of normal (ULN). Her rheumatoid arthritis remained resistant and severe, and abatacept (750 mg/dose, at 0, 2, 4 weeks and every 4 weeks thereafter) was started in October 2009, with concomitant use of prednisolone (10 mg daily) and leflunomide (20 mg daily). At the time, serum HBV DNA was undetectable. At the start of abatacept treatment, her serologic HBV markers were exactly the same as before administration of adalimumab, and her AST/ALT levels were below the ULN. The aminotransferase levels were routinely checked every three months, and remained within normal limits (WNL) up to April 2010. In July 2010, ALT was 1.76 ULN and cGT was 1.62 ULN. After two months, ALT was 2 ULN, and became 2.76 ULN in November 2010. At the time, cGT was 2.92 ULN, and HBV serology remained unchanged. Abatacept and leflunomide were discontinued. Serum HBV DNA was found to be 12,000 IU/ml (COBAS TaqMan, analytical sensitivity 6 IU/ml). In January 2011, ALT was increased to 5 ULN and cGT was 2.44 ULN. The patient was hospitalized in February 2011, with ALT 11.58 ULN, cGT 4.5 ULN, bilirubin WNL, anti-HBs serum titer 328.4 mIU/ml, and serum HBsAg barely detectable (2.49 S/N) for the first time. A liver biopsy was performed. Six days after admission, ALT became 20.7 ULN, cGT 5.7 ULN, and bilirubin 2.2 ULN (direct bilirubin: 86%). Serum HBV DNA was 437,000 IU/ml (by the same method), and treatment with tenofovir 300 mg/day was immediately started. In May 2011, AST, ALT, and cGT were WNL, under tenofovir treatment. Serum HBV DNA became undetectable in June 2011, four months after initiation of tenofovir treatment. Histologic examination of the liver biopsy specimen revealed hepatitis with severe lobular necroinflammatory activity and mild to moderate fibrosis. There was marked spotty necrosis,
with many apoptotic and ballooned hepatocytes (Fig. 1A). Moderate steatosis was also present. Portal inflammatory cell infiltration was mild. Immunohistochemical stain for HBcAg showed extensive nuclear and cytoplasmic expression in hepatocytes, indicative of active viral replication (Fig. 1B). Immunohistochemical stain for HBsAg was negative. The basic medical treatments and laboratory data pertaining to HBV infection over time are depicted in Fig. 2. Abatacept is a soluble fusion protein which links the cytotoxic T-lymphocyte antigen-4 (CTLA-4) extracellular domain to the Fc region of the IgG molecule. CTLA-4 is an inhibitory T cell receptor, similar to CD28 in structure, expressed by activated and regulatory T cells (Tregs). CTLA-4 is constitutively expressed on CD4+ CD25+ Tregs, and such expression is important for Treg-mediated
A
B
Fig. 1. Liver histology. (A) Liver biopsy specimen with marked lobular necroinflammatory activity. (B) Immunohistochemical stain for HBcAg showing extensive nuclear and cytoplasmic positivity of hepatocytes. (A, hematoxylin– eosin, 200; B, streptavidin–biotin, 100.)
Journal of Hepatology 2012 vol. 56
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JOURNAL OF HEPATOLOGY Abatacept
Tenofovir (300 mg)
900
5.0
800
4.5
700
4.0 3.5
600
3.0
500
2.5 400
2.0
300
1.5
200
HBV DNA (IU/ml) x 100,000
ALT (U/L)
Adalimumab
1.0
100
0.5
0
0.0 August 2011 July 2011 June 2011 May 2011 February 2011 January 2011 November 2010 September 2010 July 2010 March 2010 November 2009 October 2009 September 2009 June 2009 February 2009 October 2008 May 2008 January 2008 September 2007
Fig. 2. Diagram of treatments and HBV reactivation. Diagram showing the biological and antiviral treatments as well as the basic laboratory findings related to HBV infection status over time.
suppression of T cell proliferation. Through the inhibition of the co-stimulatory signaling of T cells in rheumatoid arthritis, abatacept has demonstrated clinical efficacy in multiple trials [1]. Occult HBV infection is characterized by absence of HBsAg and HBV DNA in the serum; however, low level HBV replication may persist, and HBV DNA may be found in the liver. HBcAbs, with or without HBsAb, are detectable in the serum. Immunosuppression may lead to reactivation of HBV infection in these individuals. The outcome of a HBV infection varies according to the rigor of the immune response, a process that is regulated by a number of molecules, including the cell surface receptor CTLA-4. Some CTLA-4 haplotypes (1722C, +49G) that lead to the activation of antiviral T cell responses were found to be associated with spontaneous clearance of HBV infection, whereas others leading to a decreased T cell response (i.e. +6230A) were associated with viral persistence [2]. The CTLA-4 influences on the natural recovery from HBV infection are consistent with the emerging role of Tregs, possibly restraining the rigor of the immune response, in the pathogenesis of HBV liver disease. In our case, there was a time lag of two months between discontinuation of abatacept treatment and ALT flare, suggesting that reactivation of HBV infection and hepatitis evolved in parallel to gradual T cell immune reconstitution. It is also important to
note that HBV reactivation occurred with HBsAb serum titers above 300 mIU/ml, a fact consistent with the key role of T cell functions in HBV immune control. Interestingly, cases of HBV reactivation due to the anti-CD20 B cell depleting agent rituximab have been described even with HBsAb serum titers of 300–1000 mIU/ml [3], a level considered to confer efficient neutralization of HBsAg and HBV circulating virion particles in the liver transplant setting. This is due to the fact that B cells not only produce antibodies, but also provide key co-stimulatory and cytokine signals for CD4+ cells, thus activating certain T cell functions.
Conflict of interest The authors declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. References [1] Carroll MB. The impact of biologic response modifiers on hepatitis B virus infection. Expert Opin Biol Ther 2011;11:533–544. [2] Thio CL, Mosbruger TL, Kaslow RA, Karp CL, Strathdee SA, Vlahov D, et al. Cytotoxic T-lymphocyte antigen 4 gene and recovery from hepatitis B virus infection. J Virol 2004;78:11258–11262. [3] Tsutsumi Y, Ogasawara R, Kamihara Y, Ito S, Yamamoto Y, Tanaka J, et al. Rituximab administration and reactivation of HBV. Hepat Res Treat 2010;2010:182067, [Epub 2010 Dec 1].
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Georgios Germanidis First Department of Internal Medicine, Gastroenterology and Hepatology Section, AHEPA Hospital of the Aristotle University Medical School, 1, St. Kyriakidi Str., 546 36 Thessaloniki, Greece ⇑ Corresponding author. Tel.: +30 2310 993156; fax: +30 2310 994603 E-mail address:
[email protected] Prodromos Hytiroglou Department of Pathology, AHEPA Hospital of the Aristotle University Medical School, 1, St. Kyriakidi Str., 546 36 Thessaloniki, Greece Marina Zakalka Loukas Settas First Department of Internal Medicine, Rheumatology Section, AHEPA Hospital of the Aristotle University Medical School, 1, St. Kyriakidi Str., 546 36 Thessaloniki, Greece
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