International Journal of Rheumatic Diseases 2016; 19: 470–475

ORIGINAL ARTICLE

Reactivation of hepatitis B virus in rheumatoid arthritis

patients treated with biological disease-modifying
antirheumatic drugs
Jun NAKAMURA, Takao NAGASHIMA, Katsuya NAGATANI, Taku YOSHIO,
Masahiro IWAMOTO and Seiji MINOTA
Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, Tochigi, Japan

Abstract
Objective: To examine the incidence of hepatitis B virus (HBV) reactivation in patients with rheumatoid arthritis
(RA) receiving biological disease-modifying antirheumatic drugs (DMARDs).
Methods: We retrospectively reviewed RA patients treated with biological DMARDs at our institution from July
2010 to December 2012. Patients with antibodies for hepatitis B core antigen and/or hepatitis B surface antigen
were regarded as having prior HBV infection. Clinical data on these patients, including HBV-DNA levels, were
retrieved from the medical records.
Results: During the study period, 251 patients were administered various biological DMARDs. Six patients with
a history of HBV vaccination and one patient with positive HBV surface antigen were excluded from the study.
Fifty-seven of the remaining 244 patients (23.4%) had prior HBV infection. These patients were followed for a
median of 18 months (range: 2–27 months) and HBV-DNA was examined a median of seven times (range: 2–
27). HBV-DNA was detected in three patients (5.3%), comprising two receiving tocilizumab and one receiving
etanercept. However, HBV-DNA levels were below the quantitation limit (<2.1 log copies mL 1) in all three
patients. HBV-DNA became negative again within several months in all three patients, while biological DMARDs
were continued and liver function tests remained normal throughout.
Conclusion: HBV-DNA reactivation occurred in 5.3% of RA patients with prior HBV infection during treatment
with biological DMARDs, but there were no associated clinical manifestations. Accordingly, it seems that biolog-
ical DMARDs can be used safely in patients with RA.
Key words: de novo hepatitis, hepatitis B virus, rheumatoid arthritis, tumor necrosis factor.

INTRODUCTION antirheumatic drugs (DMARDs) targeting specific mole-

Rheumatoid arthritis (RA) is a systemic inflammatory
arthritis in which proliferative synovitis is the essential
pathology. Various biological disease-modifying
Correspondence: Takao Nagashima, Division of Rheumatology
and Clinical Immunology, Department of Medicine, Jichi
Medical University, Yakushiji 3311–1, Shimotsuke, Tochigi,
329–0498, Japan.
Email: naga4ma@jichi.ac.jp
cules have been recently developed that strongly sup-
press inflammation and improve the quality of life of
RA patients. However, biological DMARDs also have a
strong influence on the immune system, leading to a
risk of serious infection.1–3
Reactivation of hepatitis B virus (HBV) is one of the
recent emerging problems in RA patients on treatment
with biological DMARDs.4 There have been reports
about HBV reactivation in patients with a history of
HBV infection (i.e., negative for HBV surface antigen

© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd

[HBsAg] but positive for antibody to HBV core antigen
[anti-HBc] and/or antibody to HBsAg [anti-HBs])
receiving immunosuppressive therapy and/or chemo-
therapy for autoimmune diseases, organ transplanta-
tion and malignancy.5–7 Hepatitis due to HBV
reactivation in patients with a history of HBV infection
is called de novo hepatitis, and it can lead to fulminant
hepatic failure with a poor prognosis.8,9 Patients with
malignant lymphoma receiving rituximab-containing
regimens are at particularly high risk of developing de
novo hepatitis.10
The optimum management of RA patients with a his-
tory of HBV infection is still unclear. While HBV reacti-
vation has been reported in Japanese RA patients
treated with immunosuppressive agents and/or biologi-
cal DMARDs,4,11,12 tumor necrosis factor (TNF) inhibi-
tors were found to be safe in European studies.13–15 A
Taiwanese study showed that TNF inhibitors could be
used safely in patients with prior HBV infection who
were positive for both anti-HBc and anti-HBs.16 In the
present study, we retrospectively examined the inci-
dence of HBV reactivation among RA patients with a
history of HBV infection who received therapy with bio-
logical DMARDs at our hospital.
PATIENTS AND METHODS
All RA patients who were treated with biological
DMARDs at our hospital from July 2010 to December
2012 were reviewed for this study. Patients who were
positive for HBsAg and those with a history of HBV vac-
cination were excluded. RA was diagnosed according to
the 1987 American Rheumatism Association classifica-
tion criteria.17 Since July 2010, all patients treated with
biological DMARDs at our hospital have been tested for
anti-HBc and anti-HBs antibodies using a chemilumi-
nescent immunoassay, and those who were positive for
anti-HBc and/or anti-HBs were regarded as having prior
HBV infection. In these patients, HBV-DNA was exam-
ined repeatedly over time, with the interval between
tests being decided by each attending physician. The
following information was retrieved from the clinical
records: demographic data on the patients, anti-HBc,
anti-HBs and HBV-DNA status, liver function tests and
medications. The hospital ethics committee approved
the protocol for this study.
Detection of HBV-DNA
Hepatitis B virus-DNA was measured by an external lab-
oratory (SRL, Tokyo, Japan) using a real-time polymer-
ase chain reaction (COBASâ TaqMan HBV test v2.0,
International Journal of Rheumatic Diseases 2016; 19: 470–475
HBV reactivation with biological DMARDs
Roche Diagnostics, Basel, Switzerland). The assay range
was 2.1–9.0 log copies mL 1, and the minimum detec-
tion limit was 2.0 log copies mL 1. If the HBV-DNA
level was 2.0–2.1 log copies mL 1, it was reported as
‘<2.1 log copies mL 1’. HBV reactivation was defined
as an HBV-DNA level higher than 2.0 log copies mL 1.
Statistical analysis
Fisher’s exact test was used to compare categorical data
between patients with and without HBV reactivation.
We could not employ the Mann-Whitney test to com-
pare continuous variables due to the small number of
patients with HBV reactivation (n = 3). Probability (P)
values of < 0.05 were considered significant. All analy-
ses were performed using STATVIEW version 5 for Macin-
tosh (SAS Institute Inc., Cary, NC, USA).
RESULTS
From July 2010 to December 2012, 251 patients
received biological DMARDs at our hospital. Six
patients with HBV vaccination and one with positive
HBsAg were excluded from the study. Fifty-seven of the
remaining 244 patients (23.4%) were positive for anti-
HBs and/or anti-HBc (Table 1). These patients were
classed as having prior HBV infection and were fol-
lowed for a median of 18 months (range: 2–
27 months). HBV-DNA was measured a median of
seven times (range: 2–27 times) during the follow-up
period and the interval between tests ranged from 1 to
12 months. Anti-HBs, anti-HBc and HBV-DNA were
measured just before the start of treatment with biologi-
cal DMARDs in 33 out of 57 patients. In the other 24
patients, measurement was performed while they were
using biological DMARDs because treatment had
already been started before July 2010. Hepatitis B e anti-
gen and hepatitis B e antibody were not measured. TNF
inhibitors were used by 48 out of 57 patients, including
39 patients who were only treated with TNF inhibitors
and nine patients who received both TNF inhibitors
and tocilizumab (TCZ). Another seven patients were
treated with TCZ alone, while two patients were treated
Table 1 Serologic data of patients with prior hepatitis B virus
infection
HBV serology Number of patients (%)
Anti-HBs (+)/anti-HBc (+) 38 (67)
Anti-HBs ( )/anti-HBc (+) 11 (19)
Anti-HBs (+)/anti-HBc ( ) 8 (14)
HBV, hepatitis B virus; anti-HBc, antibody for HBV core antigen; anti-
HBs, antibody for HBV surface antigen.
471
J. Nakamura et al.

with TCZ and abatacept (ABT). None of the patients

received prophylactic antiviral therapy. HBV-DNA
was negative in all of the patients at the first examina-
tion. During the observation period, HBV-DNA was
detected at least once in three out of 57 patients
(5.3%). Two patients were using TCZ and one was
taking etanercept (ETN) (Table 2). HBV-DNA levels
were below the quantitation limit (<2.1 log cop-
ies mL 1) at all times in these three patients and
HBV-DNA spontaneously became undetectable within
several months while they continued to use biological
DMARDs. Antiviral therapy was not required and liver
function tests did not change significantly while
HBV-DNA was positive. The patients in whom HBV-
DNA was detected are described next.
Patient 1
A 75-year-old man with a 1.5-year history of RA had
been treated with methotrexate (6 mg week 1). He
started TCZ therapy along with prednisolone
(5 mg day 1) in May 2012. The disease activity score
28 – C-reactive protein (DAS28-CRP) was 4.45 and the
clinical disease activity index (CDAI) was 32.3. HBV-
DNA was undetectable at that time, and the assay was
repeated at monthly intervals. Methotrexate was discon-
tinued in June. HBV-DNA became detectable in July
2012, after two infusions of TCZ, although the actual
level was <2.1 log copies mL 1. HBV-DNA fluctuated
between being undetectable or detectable in August and
September 2012, but finally became undetectable in

Table 2 Comparison of clinical parameters between patients with and without HBV reactivation
HBV reactivation (+) HBV reactivation ( ) P–value
(n = 3) (n = 54)
Women, n (%) 2 (67) 45 (83) 0.92
Age, years 60 (55–75) 64 (36–81)
Disease duration, years 8 (1.5–25) 7.5 (0.25–48)
Observation period, months 7 (5–21) 18.5 (2–27)
Anti–HBc positive, n (%) 3 (100) 46 (85) 0.63
Anti–HBs positive, n (%) 2 (67) 44 (82) 0.91
Titer (mIU mL 1) 31.0 (10.2–51.8) 113.1 (11.4–1000)
No. of HBV–DNA measurements 6 (6–9) 7 (2–27)
AST (U L 1) 21 (15–39) 20 (9–58)
ALT (U L 1) 14 (11–34) 14 (7–129)
LD (U L 1) 197 (185–341) 201 (101–293)
CRP (mg dL 1) 2.89 (0.45–4.28) 1.6 (0.03–8.39)
DAS28–CRP 4.89 (4.45–5.95) 4.52 (1.60–6.46)
DMARDs
Methotrexate, n (%) 2 (67) 40 (74) 0.83
Methotrexate dose (mg week 1) 6 (2–8) 8 (2–16)
Sulfasalazine, n 0 4
Bucillamine, n 0 4
Tacrolimus, n 0 1
Cyclosporine, n 0 1
Prednisolone (%) 3 (100) 39 (72) 0.39
Prednisolone dose (mg day 1) 5 (3–5) 5 (1.5–17.5)
Biological agent†
Infliximab, n 0 20
Etanercept, n 3 19
Adalimumab, n 1 11
Tocilizumab, n 2 16
Abatacept, n 0 2
Values are shown as the median (range), unless otherwise specified. HBV, hepatitis B virus; AST, aspartate aminotransferase (normal range, ≤30);
ALT, alanine aminotransferase (normal range, ≤30); LD, lactate dehydrogenase (normal range, ≤216); CRP, C-reactive protein (normal range,
≤0.14); DAS, Disease Activity Score; DMARDs, disease-modifying antirheumatic drugs. Liver function tests are from the first day of HBV-DNA mea-
surement, while CRP and DAS28-CRP are from the start of treatment with biological agents.
†Some patients were treated with several biological agents. Biological agents used before July 2010 were excluded from this table.

472 International Journal of Rheumatic Diseases 2016; 19: 470–475


October. Due to lack of efficacy (DAS28-CRP and CDAI
were 2.54 and 20.8, respectively), TCZ was switched to
ETN in November 2012. HBV-DNA remained undetect-
able thereafter.
Patient 2
A 55-year-old woman with an 8-year history of RA had
been treated with infliximab (IFX) for 25 months,
followed by ETN for a further 53 months. ETN was
discontinued in February 2012, while TCZ was started
as a third biological DMARD in June. Evidence of
prior HBV infection was found at this time, but HBV-
DNA was undetectable. She was taking prednisolone
(5 mg day 1) plus methotrexate (8 mg week 1). The
DAS28-CRP and CDAI were 4.89 and 30.6, respectively.
Monthly assays were done thereafter and HBV-DNA
was first detected in August 2012 after two infusions of
TCZ. The HBV-DNA level was <2.1 log copies mL 1. In
September 2012, TCZ was switched to adalimumab
(ADA) because of a poor response (DAS28-CRP and
CDAI were 5.0 and 33.7, respectively). After being
detected for 3 months, HBV-DNA became undetectable
in November 2012 while she was on ADA. The patient
was hospitalized due to pericarditis in the same month
and ADA was discontinued.
Patient 3
A 60-year-old woman with a 25-year history of RA had
been treated with ETN as well as prednisolone
(3 mg day 1) plus methotrexate (2 mg week 1) since
August 2005. Evidence of prior HBV infection was
found in July 2010, but HBV-DNA was not detected.
Although HBV-DNA became detectable at <2.1 log
copies mL 1 in January 2011, it was not detected in
August 2011 (HBV-DNA was not measured from
February to July 2011). Thereafter, measurement was
repeated three times at intervals of 2–5 months up to
April 2012, but HBV-DNA remained undetectable. The
patient remained on ETN therapy throughout this
period.
DISCUSSION
In the present study, the incidence of HBV reactivation
was 5.3% in RA patients on treatment with biological
DMARDs, being found in one out of 48 patients (2.1%)
receiving TNF inhibitors and two out of 18 patients
(11.1%) using TCZ. However, HBV-DNA levels were
always below the quantitation limit, fluctuating
between the detectable and undetectable range. In addi-
tion, liver function tests did not change significantly,
International Journal of Rheumatic Diseases 2016; 19: 470–475
HBV reactivation with biological DMARDs
de novo hepatitis did not occur and no patient required
antiviral therapy.
In previous Japanese reports, the incidence of HBV
reactivation among RA patients treated with biological
DMARDs has varied. One study found no HBV reacti-
vation among 42 patients with a history of HBV infec-
tion who were using TNF inhibitors.11 In another
study, the HBV reactivation rate was 3.2% (1/31
patients), and HBV-DNA disappeared spontaneously
after 2 months.12 The highest reported incidence of
HBV reactivation is 11.5% (6/52 patients) by Urata
et al.4 In contrast, TNF inhibitors have not been associ-
ated with HBV reactivation in European studies.13–15
According to a study from Taiwan, HBV-DNA was posi-
tive in 1/70 RA patients (1.4%) with prior HBV infec-
tion and that patient had occult HBV infection before
starting treatment (HBsAg was negative, anti-HBc and
HBV-DNA were positive).16 One of the main reasons
for the difference in the reported incidence seems to be
the interval between HBV-DNA assays. In the studies
from Europe and Taiwan, the interval between HBV-
DNA assays was 6–12 months, or DNA was only mea-
sured once at the end of the study.13–16 In contrast,
testing was performed every 2–3 months in the Japa-
nese studies.4,11 In our patients 1 and 2 from the pres-
ent study, HBV-DNA was tested at monthly intervals. If
HBV-DNA is only measured once every 6 months, reac-
tivation of HBV might well be missed. Another reason
could be a difference of HBV genotypes, since the prev-
alence of HBV genotypes varies between countries.18
Up to now, post-marketing surveillance of biological
agents in Japan has not detected any cases of de novo
hepatitis due to HBV reactivation.19–21 These studies
were of sufficient size to detect uncommon adverse
events, although the observation period was only
6 months. A nationwide survey of fulminant hepatitis
and late-onset hepatic failure was conducted in Japan
from 2004 to 2009.9 Among 488 patients with fulmin-
ant hepatitis or late-onset hepatic failure, 17 patients
had de novo hepatitis that developed after they started
immunosuppressive therapy or chemotherapy. How-
ever, none of the 17 patients had rheumatic diseases. So
far, only three cases of de novo hepatitis have been
reported worldwide during treatment with TNF inhibi-
tors.22–24 Two of the patients were successfully treated
with lamivudine, but one patient (reported from Japan)
died of hepatic failure and sepsis.22 Considering the
large number of patients treated with TNF inhibitors
worldwide for rheumatic, gastrointestinal and dermato-
logic diseases, we can conclude that de novo hepatitis is
quite rare.
473
J. Nakamura et al.
Compared with TNF inhibitors, there have been
few reports about ABT and TCZ in patients with
prior HBV infection.4,25,26 Because ABT inhibits
co-stimulation of T cells, it may suppress immune
surveillance for HBV.27 In fact, two cases of HBV
reactivation have been reported in RA patients with
prior HBV infection using ABT.25,26 In our study,
only 18 patients were treated with TCZ and two
patients used ABT, with HBV reactivation being
observed in two of the 18 patients receiving TCZ.
However, it is unclear whether TCZ induces HBV
reactivation more frequently than TNF inhibitors
because the number of patients in our TCZ group
was too small to draw a firm conclusion.
Hepatitis B virus reactivation may be relatively
frequent in RA patients receiving various immunosup-
pressive therapies. HBV reactivation does not necessar-
ily lead to abnormal liver function and it could be
missed in many cases.28 As well as biological DMARDs,
conventional DMARDs and glucocorticoids have been
associated with HBV reactivation.4,11,12,29,30 Two cases
of de novo hepatitis have been reported in patients
taking methotrexate plus prednisolone, with the out-
come being fatal in one.29,31 In the other patient, prior
HBV infection was not confirmed because anti-HBc
was not measured before starting treatment.31 Gener-
ally, HBV reactivation is not clinically significant in
most RA patients and HBV-DNA becomes negative
again without antiviral therapy, as occurred in our
patients.4,12,30,32
Our study had several limitations. First, because it
was retrospective, HBV-DNA was not measured accord-
ing to a single protocol and testing was decided by the
attending physicians. Second, HBV-DNA was not
examined at our institution in patients treated with
conventional DMARDs alone, so the incidence of HBV
reactivation could not be compared between our
patients before and after starting biological DMARDs.
Third, serological parameters (including HBsAg and
anti-HBs) were not examined simultaneously with
measurement of HBV-DNA. Thus, it is unclear whether
HBV reactivation occurred in association with disap-
pearance of anti-HBs, or whether reappearance of
HBsAg occurred simultaneously with detection of
HBV-DNA.
In conclusion, our findings suggest that biological
DMARDs can be used safely in RA patients with prior
HBV infection. Further studies are needed to determine
whether the incidence of HBV reactivation is higher in
patients treated with TCZ or ABT than in those receiving
TNF inhibitors.
474
REFERENCES
1 Komano Y, Tanaka M, Nanki T et al. (2011) Incidence
and risk factors for serious infection in patients with rheu-
matoid arthritis treated with tumor necrosis factor inhibi-
tors: a report from the Registry of Japanese rheumatoid
arthritis patients for longterm safety. J Rheumatol 38,
1258–64.
2 Komano Y, Harigai M, Koike R et al. (2009) Pneumocystis
jiroveci pneumonia in patients with rheumatoid arthritis
treated with infliximab: a retrospective review and case-
control study of 21 patients. Arthritis Rheum 61, 305–12.
3 Tanaka M, Sakai R, Koike R et al. (2012) Pneumocystis ji-
rovecii pneumonia associated with etanercept treatment
in patients with rheumatoid arthritis: a retrospective
review of 15 cases and analysis of risk factors. Mod Rheu-
matol 22, 849–58.
4 Urata Y, Uesato R, Tanaka D et al. (2011) Prevalence of
reactivation of hepatitis B virus replication in rheumatoid
arthritis patients. Mod Rheumatol 21, 16–23.
5 Lubel JS, Angus PW (2010) Hepatitis B reactivation in
patients receiving cytotoxic chemotherapy: diagnosis and
management. J Gastroenterol Hepatol 25, 864–71.
6 Raimondo G, Pollicino T, Cacciola I, Squadrito G (2007)
Occult hepatitis B virus infection. J Hepatol 46, 160–70.
7 Kusumoto S, Tanaka Y, Mizokami M, Ueda R (2009) Reac-
tivation of hepatitis B virus following systemic chemother-
apy for malignant lymphoma. Int J Hematol 90, 13–23.
8 Umemura T, Tanaka E, Kiyosawa K, Kumada H (2008)
Mortality secondary to fulminant hepatic failure in
patients with prior resolution of hepatitis B virus infection
in Japan. Clin Infect Dis 47, e52–6.
9 Oketani M, Ido A, Uto H, Tsubouchi H (2012) Prevention
of hepatitis B virus reactivation in patients receiving
immunosuppressive therapy or chemotherapy. Hepatol Res
42, 627–36.
10 Kusumoto S, Tanaka Y, Ueda R, Mizokami M (2011)
Reactivation of hepatitis B virus following rituximab-
plus-steroid combination chemotherapy. J Gastroenterol
46, 9–16.
11 Tamori A, Koike T, Goto H et al. (2011) Prospective study
of reactivation of hepatitis B virus in patients with rheu-
matoid arthritis who received immunosuppressive ther-
apy: evaluation of both HBsAg-positive and HBsAg-
negative cohorts. J Gastroenterol 46, 556–64.
12 Mori S (2011) Past hepatitis B virus infection in rheuma-
toid arthritis patients receiving biological and/or nonbio-
logical disease-modifying antirheumatic drugs. Mod
Rheumatol 21, 621–7.
13 Vassilopoulos D, Apostolopoulou A, Hadziyannis E et al.
(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, 1352–5.
14 Charpin C, Guis S, Colson P et al. (2009) Safety of TNF-
blocking agents in rheumatic patients with serology sug-
International Journal of Rheumatic Diseases 2016; 19: 470–475

gesting past hepatitis B state: results from a cohort of 21
patients. Arthritis Res Ther 11, R179.
15 Caporali R, Bobbio-Pallavicini F, Atzeni F et al. (2010)
Safety of tumor necrosis factor alpha blockers in hepatitis
B virus occult carriers (hepatitis B surface antigen nega-
tive/anti-hepatitis B core antigen positive) with rheumatic
diseases. Arthritis Care Res 62, 749–54.
16 Lan JL, Chen YM, Hsieh TY et al. (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, 1719–25.
17 Arnett FC, Edworthy SM, Bloch DA et al. (1988) The
American Rheumatism association 1987 revised criteria
for the classification of rheumatoid arthritis. Arthritis
Rheum 31, 315–24.
18 Lin CL, Kao JH (2011) The clinical implications of hepati-
tis B virus genotype: recent advances. J Gastroenterol Hepa-
tol 26 (Suppl 1), 123–30.
19 Takeuchi T, Tatsuki Y, Nogami Y et al. (2008) Postmarket-
ing surveillance of the safety profile of infliximab in 5000
Japanese patients with rheumatoid arthritis. Ann Rheum
Dis 67, 189–94.
20 Koike T, Harigai M, Inokuma S et al. (2009) Postmarket-
ing surveillance of the safety and effectiveness of etaner-
cept in Japan. J Rheumatol 36, 898–906.
21 Koike T, Harigai M, Ishiguro N et al. (2013) Safety and
effectiveness of adalimumab in Japanese rheumatoid
arthritis patients: postmarketing surveillance report of
7740 patients. Mod Rheumatol. doi: 10.3109/14397595.
2013.843760. [Epub ahead of print].
22 Matsumoto T, Marusawa H, Dogaki M, Suginoshita Y, Ino-
kuma T (2010) Adalimumab-induced lethal hepatitis B
virus reactivation in an HBsAg-negative patient with clini-
cally resolved hepatitis B virus infection. Liver Int 30,
1241–2.
23 Montiel PM, Solis JA, Chirinos JA, a Casis B, Sanchez F,
Rodriguez S (2008) Hepatitis B virus reactivation during
International Journal of Rheumatic Diseases 2016; 19: 470–475
HBV reactivation with biological DMARDs
therapy with etanercept in an HBsAg-negative and anti-
HBs-positive patient. Liver Int 28, 718–20.
24 Madonia S, Orlando A, Scimeca D, Olivo M, Rossi F, Cot-
tone M (2007) Occult hepatitis B and infliximab-induced
HBV reactivation. Inflamm Bowel Dis 13, 508–9.
25 Germanidis G, Hytiroglou P, Zakalka M, Settas L (2012)
Reactivation of occult hepatitis B virus infection, following
treatment of refractory rheumatoid arthritis with abata-
cept. J Hepatol 56, 1420–1.
26 Fanouriakis A, Vassilopoulos D, Repa A, Boumpas DT,
Sidiropoulos P (2014) Hepatitis B reactivation following
treatment with abatacept in a patient with past hepatitis B
virus infection. Rheumatology (Oxford) 53, 195–6.
27 Rehermann B, Ferrari C, Pasquinelli C, Chisari FV (1996)
The hepatitis B virus persists for decades after patients’
recovery from acute viral hepatitis despite active mainte-
nance of a cytotoxic T-lymphocyte response. Nat Med 2,
1104–8.
28 Raimondo G, Caccamo G, Filomia R, Pollicino T (2013)
Occult HBV infection. Semin Immunopathol 35, 39–52.
29 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 arthri-
tis receiving low dose methotrexate. Clin Exp Rheumatol
25, 888–9.
30 Tan J, Zhou J, Zhao P, Wei J (2012) Prospective study of
HBV reactivation risk in rheumatoid arthritis patients who
received conventional disease-modifying antirheumatic
drugs. Clin Rheumatol 31, 1169–75.
31 Watanabe K, Takase K, Ohno S, Ideguchi H, Nozaki A, Ish-
igatsubo Y (2012) Reactivation of hepatitis B virus in a
hepatitis B surface antigen-negative patient with rheuma-
toid arthritis treated with methotrexate. Mod Rheumatol
22, 470–3.
32 Loras C, Gisbert JP, Minguez M et al. (2010) Liver dys-
function related to hepatitis B and C in patients with
inflammatory bowel disease treated with immunosuppres-
sive therapy. Gut 59, 1340–6.
475