Prevalence of reactivation of hepatitis B virus replication
in rheumatoid arthritis patients
Yukitomo Urata•Ryoko Uesato•
Dai Tanaka•Kenji Kowatari•Taisuke Nitobe•
Yoshihide Nakamura•Shigeru Motomura
Received: 14 May 2010/Accepted: 28 June 2010/Published online: 29 July 2010
? Japan College of Rheumatology 2010
pearance of active necroinflammatory liver disease after an
inactive hepatitis B surface antigen (HBsAg) carrier state
or resolved hepatitis B, occurring during or after immu-
nosuppression therapy or chemotherapy. We prospectively
investigated the reactivation rate for hepatitis B virus
(HBV) DNA replication in cases of rheumatoid arthritis
(RA) with resolved hepatitis B. HBV markers were eval-
uated in 428 RA patients. Patients with positive findings of
HBsAg or HBV DNA at enrolment were excluded. The
study population comprised 422 RA patients, with resolved
hepatitis B diagnosed in 135 patients based on HBsAg-
negative and antihepatitis B core antibody/antihepatitis B
surface antibody-positive results. HBV DNA was measured
every 3 months in this group, and if HBV DNA became
positive after enrolment, measurement was repeated every
month. HBV DNA became positive (C3.64 log copies/mL)
in 7 of 135 patients for 12 months. Use of biologic agents
was significantly more frequent in patients who developed
reactivation of HBV DNA replication (85.7%) than in
Reactivation of hepatitis B involves the reap-
patients who did not (36.0%, p = 0.008). Hazard ratios
for use of biologic agents and etanercept were 10.9
(p = 0.008) and 6.9 (p = 0.001), respectively. RA patients
with resolved hepatitis B need careful monitoring when
receiving biologic agents, regardless of HBV DNA levels.
Reactivation of hepatitis B ? Rheumatoid arthritis
Biologic ? Hepatitis B virus ?
More than one third of the population worldwide has been
infected with hepatitis B virus (HBV), and 350 million
individuals have chronic HBV infection , with 75%
living in the Southeast Asia and western Pacific regions.
HBV infection is a leading cause of cirrhosis and hepato-
cellular carcinoma (HCC)  and is estimated to be
responsible for 500,000–700,000 deaths annually. Reacti-
vation of hepatitis B in patients undergoing immunosup-
pressive therapy is considered to be a complication of
considerable clinical importance [3–5]. Reactivation of
hepatitis B can be transient and clinically silent, but is often
severe, resulting in acute hepatic failure. Two clinical
scenarios contribute to the reactivation of hepatitis B. The
first occurs in patients who have chronic hepatitis B. Ful-
minant HBV has been reported in hepatitis B surface
antigen (HBsAg)-positive patients with rheumatoid arthri-
tis (RA) taking tumor necrosis factor agents (TNFA) [6, 7].
In the second scenario, reactivation of hepatitis B occurs
in patients with resolved hepatitis B. In these patients,
low levels of HBV replication have been shown to persist
in the liver and in peripheral blood mononuclear cells
for decades [8–10], and reactivation of hepatitis B has
been described after transplantation, immunosuppressive
Y. Urata (&)
Department of Rheumatology, Seihoku Chuo Hospital,
41 Nunoyacho, Gosyogawara 037-0053, Japan
R. Uesato ? D. Tanaka ? K. Kowatari ? T. Nitobe
Department of Orthopaedic Surgery, Seihoku Chuo Hospital,
Department of Orthopaedic Surgery, Hirosaki University
Graduate School of Medicine, Hirosaki, Japan
Department of Pharmacology, Hirosaki University Graduate
School of Medicine, Hirosaki, Japan
Mod Rheumatol (2011) 21:16–23
therapy, and allogeneic and autologous hematopoietic
stem-cell transplantation, with the reappearance of HBsAg
[11–15]. Reactivation of hepatitis B sometimes occurs in
RA patients with resolved hepatitis B on immunosuppres-
sive therapy, including corticosteroids (CS), methotrexate
(MTX) , and TNFA [17, 18], and can result in
fulminant or lethal hepatitis . Optimal management of
this group of patients is unclear . This study aimed to
determine the rate of reactivation of HBV DNA replication
in RA patients with resolved hepatitis B.
Materials and methods
Patients and methods
In our departments, 428 patients were treated for RA
between January 2008 and March 2009 who fulfilled the
American College of Rheumatology (ACR) 1987 revised
criteria for RA. All patients were evaluated for HBV
markers, including HBsAg, antihepatitis B surface antibody
(anti-HBs), and antihepatitis B core antibody (anti-HBc).
After all, 422 patients entered the study, and 6 patients were
excluded by HBsAg-positive at baseline. HBV markers
were detected using commercial enzyme immunoassays
(HBsAg: ARCHITECT HBsAg QT; anti-HBs: ARCHI-
TECT Anti-HBs; anti-HBc: ARCHITECT Anti-HBc,
Abbott Laboratories, Wiesbaden, Germany). If patients
were HBsAg-positive, or HBsAg-negative and anti-HBs-
and/or anti-HBc-positive, HBV DNA levels were assessed.
Sensitivity was 2 log copies/mL. When negative results
were obtained for HBV DNA, measurements were repeated
every 3 months, and if HBV DNA became positive, mea-
surements were repeated
including biologic agents were generally not discontinued,
irrespective of HBV DNA levels. All study protocols were
approved by the ethics committees of the participating
centers, and all patients provided written informed consent
prior to enrolment.
every month. Medications
Quantification of HBV DNA in blood by real-time PCR
HBV DNA levels were quantified using the automated
COBAS TaqMan HBV Test version 2.0. Samples were
pretreated with the COBAS AmpliPrep System for ampli-
fication and quantification by real-time polymerase chain
reaction (PCR) and were analyzed using the COBAS
TaqMan gene analyzer .
Fisher’s exact test, Student’s t test, and Mann–Whitney
U test were used to compare baseline patient characteristics
between subgroups. Two-tailed values of p B 0.05 were
regarded as significant. Cox regression hazard analyses
were used to separately investigate the influence of bio-
logic agents, MTX, CS, and disease-modifying antirheu-
matic drugs (DMARDs) on reactivation of HBV DNA
replication. All analyses were performed using JMP
version 6.0 software (JMP Japan, Tokyo, Japan).
Background characteristics of the 422 patients are listed in
Table 1. Six patients were HBsAg-positive, whereas 135
were HBsAg-negative and anti-HBs- and/or anti-HBc-
positive (32.0%). Ninety-seven patients (71.9%) were anti-
HBs-positive, 38 (28.1%) were hepatitis B surface antibody
(HBsAb)-negative/hepatitis B core antibody (HBcAb)-
positive, and 12 (8.9%) were HBsAb-positive/HBcAb-
negative (Table 2). When comparing resolved hepatitis B
patients to anti-HBs- and anti-HBc-negative patients,
significant differences in age (65.6 ± 11.8 vs. 61.8 ±
14.0 years, respectively, p = 0.0169) and erythrocyte
sedimentation rate (ESR) (25.0 ± 25.6 vs. 21.0 ± 20.6,
respectively, p = 0.0471) at baseline were identified. No
significant differences in other background characteristics
were seen. No resolved hepatitis B patients were positive
for HBV DNA at baseline.
Patients were followed for 12 months, and HBV DNA
became positive (3.64 log copies/mL) in 7 of 135 patients
(5.2%), whereas hepatic function remained normal in all
cases (Table 3). Details of the patients who developed
reactivation of HBV DNA replication are listed in Table 4;
Table 1 Baseline demographic and clinical and laboratory charac-
teristics for the patient cohort
Number of patients422
Age (years) (mean)62.3 ± 13.5 (63.6)
Female (n) 349 (82.7%)
RA duration (years) 8.0 ± 9.4 (4.4)
CRP (mg/dL)0.83 ± 1.79 (0.16)
ESR (mm/h) 22.3 ± 22.4 (14.0)
IgM RF (IU/mL)85.4 ± 194.8 (25.0)
AST (U/L)27.8 ± 15.2 (23.0)
ALT (U/L)26.8 ± 20.7 (20.0)
IgG (mg/dL) 1,356.5 ± 415.0 (1,306.5)
Neutrophil count4,083 ± 1,907 (3,610)
Lymphocyte count 1,628 ± 648 (1,559)
Values are given as the mean ± standard deviation (median)
RA rheumatoid arthritis, CRP C-reactive protein, ESR erythrocyte
sedimentation rate, Ig immunoglobulin, RF rheumatoid factor,
AST aspartate aminotransferase, ALT alanine aminotransferase
Mod Rheumatol (2011) 21:16–23 17
six patients showed HBV DNA replication during biologic-
agent therapy [etanercept (ETN), n = 5; tocilizumab
(TCZ), n = 1], whereas one patient showed replication
without biologic-agent therapy. The types of DMARDs and
immunosuppressants used for RA treatment during the
study and numbers of patients on each pharmacotherapy
are shown in Tables 5 and 6. In two of the seven patients,
HBV DNA became negative without any therapy. In the
remaining five, HBV DNA became negative with entecavir
therapy (mean 1.7 months).
Exploratory analysis was conducted on factors poten-
tially associated with development of HBV replication
(Table 6). Among resolved hepatitis B patients who did
and did not develop reactivation of HBV DNA replication,
a significant difference was noted between the use of
biologic agent (85.7 vs. 36.0%, respectively; p = 0.008)
and use of ETN (85.7 vs. 25.0%, respectively; p = 0.001).
Cox regression hazard analysis also revealed use of a
biologic agent and ETN as predictors for reactivation of
HBV DNA replication. The hazard ratios (HR) for use of a
biologic agent and ETN were 10.9 (p = 0.008) and 6.9
(p = 0.001), respectively. Age at presentation, RA dura-
tion, male gender, use of MTX and CS, dose of MTX
and CS, and levels of alanine aminotransferase (ALT),
aspartate aminotransferase (AST), immunoglobulin (Ig)G,
neutrophil counts and lymphoid cell counts were not
associated with reactivation of HBV DNA replication.
HBV may persist in HBsAg-negative individuals after
infection. HBsAg negativity may occasionally be due to the
presence of mutant viruses missed by the commonly used
HBsAg assays. In most other cases, negative results are due
to suppressed viral replication and gene expression .
Such individuals are typically labeled as having occult
HBV infection if HBV DNA is detectable in peripheral
blood mononuclear cells and the liver .
The activity of chronic hepatitis B infection depends on
host immune response to the virus; immunosuppressive
therapy is known to alter this response [20, 21]. Acute
reactivation of hepatitis B following immunosuppression
has been observed in patients with resolved hepatitis B
. The timing of reactivation of HBV DNA replication
may vary but occurs most frequently following cessation of
Table 2 Distribution of hepatitis B surface antibody (HBsAb) and hepatitis B core antibody (HBcAb) results among hepatitis B surface antigen
(HBsAg)-negative and HBsAg-positive patients
Table 3 Comparison of hepatitis B virus (HBV) replication-positive and HBV replication-negative patients for baseline demographic, clinical,
and laboratory characteristics
Baseline demographic, clinical,
and laboratory characteristics
HBV replication (?) HBV replication (-)
Number of patients7 128
Age (years) (mean)63.3 ± 12.9 (64.7)65.8 ± 11.8 (66.8)0.695
Female (n)5 (71.4%) 105 (82.0%) 0.505
RA duration (years) 3.8 ± 2.6 (3.0) 7.8 ± 9.0 (4.6)0.439
CRP (mg/dL)0.57 ± 0.63 (0.40) 1.03 ± 2.00 (0.19)0.924
ESR (mm/h)17.6 ± 8.4 (16.0) 25.5 ± 26.3 (15.0)0.979
IgM RF (IU/mL)56.2 ± 64.8 (28.2) 73.9 ± 117.9 (28.1) 0.835
AST (U/L)23.0 ± 3.8 (23.0) 27.5 ± 17.8 (22.0) 0.103
ALT (U/L) 23.1 ± 5.4 (25.0) 25.8 ± 20.1 (20.0)0.419
IgG (mg/dL) 1,228 ± 401.5 (1,106)1,435 ± 470.7 (1,369)0.361
Neutrophil count2,680 ± 1,449 (2,094)4,389 ± 2,227 (3,843)0.186
Lymphocyte count1,367 ± 483 (1,450)1,698 ± 809 (1,534)0.349
Values are given as mean ± standard deviation (median)
RA rheumatoid arthritis, CRP C-reactive protein, ESR erythrocyte sedimentation rate, Ig immunoglobulin, RF rheumatoid factor, AST aspartate
aminotransferase, ALT alanine aminotransferase
18Mod Rheumatol (2011) 21:16–23
immunosuppression or during chemotherapy. The median
interval between initiation of chemotherapy and onset
of reactivation is about 4 months (range 4–36 months)
[22, 23]. Although HBV DNA and liver transaminase
levels may rise at the same time, increasing HBV DNA
levels tend to precede elevations of liver transaminases
 by days or even weeks [11, 24]. HBV DNA levels may
also already be declining when liver enzyme levels start
rising . Development of reactivation of hepatitis B
appears to be a result of immune-mediated liver injury
following restoration of host immune response .
A recent study investigated 244 HBsAg-negative lym-
phoma patients receiving cytotoxic chemotherapy .
Reactivation of hepatitis B developed following therapy in
eight of these 244 patients (3.3%). They appeared to have a
higher tendency to develop fulminant hepatic failure (3 of 8
patients, 37.5%). Direct DNA sequencing results confirmed
that all eight patients showed reactivation of hepatitis B
from resolved hepatitis B. These patients were initially
HBsAg-negative, and HBsAb- and/or HBcAb-positive, and
serum liver enzyme levels were not elevated. At the time
of hepatitis B reactivation, these patients became HBsAg-
positive. This was associated with a more than 100-fold
increase in serum HBV DNA levels, which occurred before
elevation of serum transaminases .
Management of patients with RA and HBV infection is a
complex issue that deserves particular care and cooperation
between different specialists. An unrecognized HBV
infection may expose patients with rheumatic diseases to
an increased risk of complications when receiving low
doses of CS or long-term use of MTX. CS has been shown
to have direct stimulatory effects on HBV replication
in addition to indirect effects mediated via generalized
suppression of the immune system .
TNF is a proinflammatory cytokine that plays a key role
in host responses to several types of infection and other
stimuli . Various observations have strongly implicated
TNF in the pathogenesis of RA and ankylosing spondylitis
(AS), and increased TNF production propagates rheuma-
toid synovitis, promotes osteoclast formation, and results in
characteristic bone and joint destruction . TNFA has
greatly affected the current treatment of RA and AS 
but is associated with adverse reactions such as reactivation
of tuberculosis . The literature regarding the safety of
TNFA with chronic viral infection remains limited. Several
theories have been put forward regarding how TNF
inhibitors might reactivate hepatitis B. Elevated levels of
TNF are seen in both the serum and hepatocytes of patients
with chronic hepatitis B  and are secreted by HBV-
specific cytotoxic T lymphocytes (CTL) . TNF has
biological activity and an amino acid sequence similar to
lymphotoxin, which inhibits HBV replication . Infected
cells are also reported to be selectively killed by TNF .
Table 4 Demographic, clinical, and laboratory characteristics of patients with hepatitis B virus (HBV) replication
Final status of
Time between emergence of
HBV DNA and its
Tacrolimus (1 mg/day)
Bucillamin (200 mg/day)
Leflunomide (10 mg/day)
RA rheumatoid arthritis, MTX methotrexate, DMARDs disease-modifying antirheumatic drugs, ALT alanine aminotransferase
aThis patient had received three biologic agents: infliximab, etanercept, and tocilizumab, sequentially
Mod Rheumatol (2011) 21:16–2319
TNF acts to suppress HBV DNA replication by reducing
intracellular HBV transcription . Animal studies have
shown that TNF-knockout mice have defects in the pro-
liferative capacity of HBV-specific CTL , suggesting
that TNF plays a role in clearing or controlling HBV
[34–36]. Moreover, HBV-specific CTL inhibit HBV gene
expression by secreting antiviral cytokines such as inter-
feron c and TNF and inducing apoptosis in HBV-infected
hepatocytes [37, 38].
To date, several case reports have shown that inhibition
of TNF facilitates reactivation of HBV DNA replication
and can cause fulminant hepatic failure or fatal outcomes
[6, 39–44]. According to the 2009 recommendations of the
Japan College of Rheumatology, biologic agents are con-
traindicated in chronic hepatitis B only in active HBsAg
carriers. However, as shown in our study, reactivation of
HBV DNA replication can occur in resolved hepatitis B,
and this finding supports the conclusion that careful mon-
itoring should be used if patients with resolved hepatitis B
are receiving TNFA, regardless of HBV DNA levels.
In our study, reactivation of HBV DNA replication was
identified in RA patients under TCZ medication. TCZ
might have influenced patient immune response to HBV, as
interleukin (IL)-6 is a cytokine that has an important role in
regulating immune responses, inflammation, and hemato-
poiesis . IL-6 also induces T-cell proliferation and
CTL differentiation and promotes antibody production
by B cells. Host immune responses to viral antigens on
infected hepatocytes represent the main cause of hepato-
cellular injury . Furthermore, a significant correlation
exists between serum IL-6 and aminotransferase levels in
patients with chronic hepatitis B . This suggests that
IL-6 plays a role in chronic hepatitis B and may contribute
to the elimination of HBV.
To the best of our knowledge, this study represents the
first systematic analysis investigating the rate of reactiva-
tion of HBV DNA replication in a homogenous population
of patients with resolved hepatitis B diagnosed with and
treated for RA over the course of more than 1 year. This
study demonstrated a high proportion of resolved hepatitis
B patients in RA and an association between biologic
agents and HBV DNA replication in RA patients with
resolved HBV. With increasing use of biologic agents such
as TNFA, anti-IL-6 receptor, anti-CD20 , and anti-
CD28, reactivation of HBV DNA replication in patients
who have resolved HBV will probably increase, particu-
larly in endemic areas. Among patients who are scheduled
to receive MTX, CS, and biologic agents, patients who are
Table 5 Number of patients
using concomitant drugs related
to rheumatoid arthritis during
the study [comparing patients
with resolved hepatitis B and
patients with HBsAg(-)/
HBsAg hepatitis B surface
antigen, HBcAb hepatitis B core
antibody, HBsAb hepatitis B
aValues are given as the
number of patients taking a
drug; patients can take more
than one drug and can switch to
another biologic agent
Variables Number of patientsa
Biologic agent52 (38.5%) 118 (41.1%)0.615
Adalimumab7 (5.2%)21 (7.3%) 0.402
Etanercept 38 (28.2%)94 (32.8%)0.339
Infliximab15 (16.5%)29 (10.1%) 0.332
Tocilizumab4 (3.0%)14 (4.9%) 0.349
Rituximab 1 (1.1%)0 (0%) 0.131
Methotrexate65 (48.2%) 158 (55.1%)0.185
Mean dose 6.7 ± 1.9 mg/week6.7 ± 1.8 mg/week0.987
Corticosteroids 52 (38.5%) 201 (70.0%) 0.080
Mean dose5.1 ± 4.3 mg/day4.2 ± 2.8 mg/day0.197
Sulfasalazine 28 (20.7%) 58 (20.2%)0.900
Bucillamine27 (20.0%) 49 (17.1%) 0.469
Tacrolimus hydrate9 (6.7%)12 (4.2%) 0.285
Sodium aurothiomalate 2 (1.5%)8 (2.8%) 0.391
Leflunomide3 (2.2%) 4 (1.4%)0.544
D-Penicillamine2 (1.5%) 1 (0.4%) 0.217
Actarit 1 (0.7%)00.131
Auranofin 3 (2.2)0 0.009
Cyclosporine 1 (0.1%)0 0.131
Minocycline hydrochloride2 (1.5%)0 0.032
Mizoribine0 1 (0.4%)0.380
20Mod Rheumatol (2011) 21:16–23
HBsAg-negative should be further screened for anti-HBc
The significantly higher prevalence of ETN among cases
with HBV reactivation represents a source of bias, as ETN
is the first biologic agent used for RA in our institutions.
Further information from controlled trials is required with
regard to the relative safety of various biologic agents, risk
after cessation of immunosuppression when immune
reconstitution may occur, and whether the risk of emer-
gence of entecavir resistance in patients receiving pro-
phylactic treatment is at a level that renders this approach
unsafe. What effects biologic agent therapy will have on
the risk of hepatic fibrosis, cirrhosis, and HCC in this high-
risk group remains to be seen, as there is strong evidence of
HBV itself being a direct cause of HCC . Furthermore,
reactivation of hepatitis B can be misdiagnosed as super-
imposition of another form of liver disease (e.g., drug-
induced liver disease, alcoholic liver disease) occurring
against a background of previously stable, resolved hepa-
titis B. Greater awareness is therefore needed regarding the
reactivation of hepatitis B, when and where reactivation
occurs, and how this phenomenon should be prevented or
Conflict of interest
1. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009.
2. Di Bisceglie AM. Hepatitis B and hepatocellular carcinoma.
3. HoofnagleJH. Reactivation
4. Calabrese LH, Zein NN, Vassilopoulos D. Hepatitis B virus
(HBV) reactivation with immunosuppressive therapy in rheu-
matic diseases: assessment and preventive strategies. Ann Rheum
5. Zingarelli S, Airo ` P, Frassi M, Bazzani C, Scarsi M, Puoti M.
Prophylaxis and therapy of HBV infection in 20 patients treated
with disease modifying antirheumatic drugs or with biological
agents for rheumatic diseases. Reumatismo. 2008;60:22–7.
6. Ostuni P, Botsios C, Punzi L, Sfriso P, Todesco S. Hepatitis B
reactivation in a chronic hepatitis B surface antigen carrier with
Table 6 Number of patients using concomitant drugs related to rheumatoid arthritis during the study [comparing hepatitis B virus (HBV)-
replication-positive patients with HBV-replication-negative patients]
Variables Number of patientsa
P value HR (95% CI)
HBV replication (?) HBV replication (-)
Biologic agent 6 (85.7%)46 (36.0%) 0.008 10.9 (1.4–87.7)
Adalimumab0 7 (5.5%) 0.382
Etanercept 6 (85.7%)32 (25.0%)0.001 6.9 (1.4–33.9)
Infliximab1 (14.3%) 17 (13.3%) 0.9401.08 (0.2–8.5)
Tocilizumab1 (14.3%) 3 (2.3%)0.175 5.5 (0.8–35.4)
Methotrexate5 (71.4%)60 (46.9%) 0.2002.7 (0.5–13.4)
Mean dose 6.3 ± 2.5 mg/week 6.7 ± 1.9 mg/week 0.980
Corticosteroids5 (71.4%) 47 (36.7%)0.070 4.0 (0.8–19.8)
Mean dose 3.4 ± 2.1 mg/day 5.2 ± 4.4 mg/day 0.380
Sulfasalazine0 28 (21.9%)0.067
Bucillamine 2 (28.6%)25 (19.5%)0.577 1.6 (0.3–7.8)
Tacrolimus hydrate1 (14.3%)8 (6.3%) 0.4632.3 (0.3–17.3)
Sodium aurothiomalate0 2 (1.6%) 0.643
Leflunomide1 (2.2%) 2 (1.6%) 0.1197.3 (1.2–43.5)
D-Penicillamine0 2 (1.6%)0.643
Actarit0 1 (0.8%)0.743
Auranofin03 (2.3%) 0.570
Cyclosporine0 1 (0.8%)0.744
Minocycline hydrochloride0 2 (1.6%)0.643
Cyclophosphamide0 1 (0.8%)0.743
HR hazard ratio, 95% CI 95% confidence interval
aValues are given as the number of patients taking a drug; patients can take more than one drug and can switch to another biologic agent
Mod Rheumatol (2011) 21:16–23 21
rheumatoid arthritis treated with infliximab and low dose meth-
otrexate. Ann Rheum Dis. 2003;62:686–7.
7. Cansu DU, Kalifoglu T, Korkmaz C. Short-term course of
chronic hepatitis B and C under treatment with etanercept asso-
ciated with different disease modifying antirheumatic drugs
without antiviral prophylaxis. J Rheumatol. 2008;35:421–4.
8. Zoulim F. New insight on hepatitis B virus persistence from the
study of intrahepatic viral cccDNA. J Hepatol. 2005;42:302–8.
9. Rehermann B, Ferrari C, Pasquinelli C, Chisari FV. The hepatitis
B virus persists for decades after patients’ recovery from acute
viral hepatitis despite active maintenance of a cytotoxic T-lym-
phocyte response. Nat Med. 1996;2:1104–8.
10. Yuki N, Nagaoka T, Yamashiro M, Mochizuki K, Kaneko A,
Yamamoto K, et al. Long-term histologic and virologic outcomes
of acute self-limited hepatitis B. Hepatology. 2003;37:1172–9.
11. Yeo W, Johnson PJ. Diagnosis, prevention and management of
hepatitis B virus reactivation during anticancer therapy. Hepa-
12. Kitano K, Kobayashi H, Hanamura M, Furuta K, Ueno M,
Rokuhara A, et al. Fulminant hepatitis after allogenic bone
marrow transplantation caused by reactivation of hepatitis B virus
with gene mutations in the core promoter region. Eur J Haematol.
13. Hui CK, Cheung WW, Zhang HY, Au WY, Yueng YH, Leung
AY, et al. Kinetics and risk of de novo hepatitis B infection in
HBsAg-negative patients undergoing cytotoxic chemotherapy.
14. Sera T, Hiasa Y, Michitaka K, Konishi I, Matsuura K, Tokumoto
Y, et al. Anti-HBs-positive liver failure due to hepatitis B virus
reactivation induced by rituximab. Intern Med. 2006;45:721–4.
15. Esteve M, Saro C, Gonza ´lez-Huix F, Suarez F, Forne ´ M, Viver
JM. Chronic hepatitis B reactivation following infliximab therapy
in Crohn’s disease patients: need for primary prophylaxis. Gut.
16. Ito S, Nakazono K, Murasawa A, Mita Y, Hata K, Saito N, et al.
Development of fulminant hepatitis B (precore variant mutant
type) after the discontinuation of low-dose methotrexate therapy
ina rheumatoid arthritis
17. Montiel PM, Solis JA, Chirinos JA, Casis B, Sa ´nchez F,
Rodrı ´guez S. Hepatitis B virus reactivation during therapy with
etanercept in an HBsAg-negative and anti-HBs-positive patient.
Liver Int. 2008;28:718–20.
18. Madonia S, Orlando A, Scimeca D, Olivo M, Rossi F, Cottone M.
Occult hepatitis B and infliximab-induced HBV reactivation.
Inflamm Bowel Dis. 2007;13:508–9.
19. Sasaki S, Sato S, Kano Y, et al. Validity of COBAS TaqMan HBV
Test v2.0. Igaku to Yakugaku. 2009;61:787–95 (in Japanese).
20. Raimondo G, Pollicino T, Cacciola I, Squadrito G. Occult hep-
atitis B virus infection. J Hepatol. 2007;46:160–70.
21. Togashi H, Hashimoto C, Yokozawa J, Suzuki A, Sugahara K,
Saito T, et al. What can be revealed by extending the sensitivity
of HBsAg detection to below the present limit? J Hepatol.
22. Liang R, Lau GK, Kwong YL. Chemotherapy and bone marrow
transplantation for cancer patients who are also chronic hepatitis
B carriers: a review of the problem. J Clin Oncol. 1999;17:394–8.
23. Lalazar G, Rund D, Shouval D. Screening, prevention and
treatment of viral hepatitis B reactivation in patients with hae-
matological malignancies. Br J Haematol. 2007;136:699–712.
24. Lau GK. Hepatitis B reactivation after chemotherapy: two dec-
ades of clinical research. Hepatol Int. 2008;2:152–62.
25. Lubel JS, Testro AG, Angus PW. Hepatitis B virus reactivation
following immunosuppressive therapy: guidelines for prevention
and management. Intern Med J. 2007;37:705–12.
patient. Arthritis Rheum.
26. Bradley JR. TNF-mediated inflammatory disease. J Pathol.
27. Harris ED Jr. Rheumatoid arthritis. Pathophysiology and impli-
cations for therapy. N Engl J Med. 1990;322:1277–89.
28. Gibbons LJ, Hyrich KL. Biologic therapy for rheumatoid arthri-
tis: clinical efficacy and predictors of response. BioDrug.
29. Winthrop KL. Risk and prevention of tuberculosis and other
serious opportunistic infections associated with the inhibition
of tumor necrosis factor. Nat Clin Pract Rheumatol. 2006;
30. Daniels HM, Meager A, Eddleston AL, Alexander GJ, Williams
R. Spontaneous production of tumour necrosis factor alpha and
interleukin-1 beta during interferon-alpha treatment of chronic
HBV infection. Lancet. 1990;335:875–7.
31. Fang JW, Shen WW, Meager A, Lau JY. Activation of the tumor
necrosis factor-alpha system in the liver in chronic hepatitis B
virus infection. Am J Gastroenterol. 1996;91:748–53.
32. Stoop JN, Woltman AM, Biesta PJ, Kusters JG, Kuipers EJ,
Janssen HL, et al. Tumor necrosis factor alpha inhibits the sup-
pressive effect of regulatory T cells on the hepatitis B virus-
specific immune response. Hepatology. 2007;46:699–705.
33. Wong GH, Goeddel DV. Tumour necrosis factors alpha and beta
inhibit virus replication and synergize with interferons. Nature.
34. Kasahara S, Ando K, Saito K, Sekikawa K, Ito H, Ishikawa T,
et al. Lack of tumor necrosis factor alpha induces impaired pro-
liferation of hepatitis B virus-specific cytotoxic T lymphocytes.
J Virol. 2003;77:2469–76.
35. Ganem D, Prince AM. Hepatitis B virus infection—natural
history and clinical consequences. N Engl J Med. 2004;
36. Herbein G, O’Brien WA. Tumor necrosis factor (TNF)-alpha and
TNF receptors in viral pathogenesis. Proc Soc Exp Biol Med.
37. Guidotti LG, Ishikawa T, Hobbs MV, Matzke B, Schreiber R,
Chisari FV. Intracellular inactivation of the hepatitis B virus by
cytotoxic T lymphocytes. Immunity. 1996;4:25–36.
38. Marinos G, Naoumov NV, Rossol S, Torre F, Wong PY, Gallati
H, et al. Tumor necrosis factor receptors in patients with chronic
hepatitis B virus infection. Gastroenterology. 1995;108:1453–63.
39. Chung SJ, Kim JK, Park MC, Park YB, Lee SK. Reactivation of
hepatitis B viral infection in inactive HBsAg carriers following
anti-tumor necrosis factor-alpha therapy. J Rheumatol. 2009;
40. Millonig G, Kern M, Ludwiczek O, Nachbaur K, Vogel W.
Subfulminant hepatitis B after infliximab in Crohn’s disease:
need for HBV-screening? World J Gastroenterol. 2006;14:974–6.
41. Michel M, Duvoux C, Hezode C, Cherqui D. Fulminant hepatitis
after infliximab in a patient with hepatitis B virus treated for an
adult onset still’s disease. J Rheumatol. 2003;30:1624–5.
42. Wendling D, Auge B, Bettinger D, Lohse A, Le Huede G,
Bresson-Hadni S, et al. Reactivation of a latent precore mutant
hepatitis B virus related chronic hepatitis during infliximab
treatment for severe spondyloarthropathy. Ann Rheum Dis.
43. Kaur PP, Chan VC, Berney SN. Histological evaluation of liver
in two rheumatoid arthritis patients with chronic hepatitis B and
C treated with TNF-alpha blockade: case reports. Clin Rheuma-
44. Sakellariou GT, Chatzigiannis I. Long-term anti-TNFalpha ther-
apy for ankylosing spondylitis in two patients with chronic HBV
infection. Clin Rheumatol. 2007;26:950–2.
45. Nishimoto N, Kishimoto T. Interleukin 6: from bench to bedside.
Nat Clin Pract Rheumatol. 2006;2:619–26.
22 Mod Rheumatol (2011) 21:16–23
46. Kakumu S, Shinagawa T, Ishikawa T, Yoshioka K, Wakita T, Ito Download full-text
Y, et al. Serum interleukin 6 levels in patients with chronic
hepatitis B. Am J Gastroenterol. 1991;86:1804–8.
47. Yeo W, Chan TC, Leung NW, Lam WY, Mo FK, Chu MT, et al.
Hepatitis B virus reactivation in lymphoma patients with prior
resolved hepatitis B undergoing anticancer therapy with or
without rituximab. J Clin Oncol. 2009;27:605–11.
48. Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al.
REVEAL-HBV Study Group. Risk of hepatocellular carcinoma
across a biological gradient of serum hepatitis B virus DNA level.
Mod Rheumatol (2011) 21:16–2323