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Risk of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing biologic treatment: Extending perspective from old to newer drugs
Francesca De Nard, Monica Todoerti, Vittorio Grosso, Sara Monti, Silvia Breda, Silvia Rossi, Carlomaurizio Montecucco, Roberto Caporali
Francesca De Nard, Monica Todoerti, Vittorio Grosso, Sara Monti, Silvia Breda, Silvia Rossi, Carlomaurizio Montecucco, Roberto Caporali, IRCCS Policlinico San Matteo Foundation, Chair and Division of Rheumatology, University of Pavia, 27100 Pavia, Italy
ORCID number: $[AuthorORCIDs]
Author contributions: Montecucco C revised the paper; De Nard F, Grosso V, Monti S, Breda S and Rossi S performed research; De Nard F and Grosso V analyzed the data; De Nard F, Todoerti M and Caporali R wrote the paper.
Conflict-of-interest: No potential conflicts of interest relevant to this article were reported.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Francesca De Nard, MD, IRCCS Policlinico San Matteo Foundation, Chair and Division of Rheumatology, University of Pavia, piazzale Golgi 2, 27100 Pavia, Italy. email@example.com
Telephone: +39-38-2503171 Fax: +39-38-2503171
Received: September 9, 2014 Peer-review started: September 9, 2014 First decision: October 14, 2014 Revised: November 25, 2014 Accepted: December 16, 2014 Article in press: December 16, 2014 Published online: March 27, 2015
Hepatitis B virus (HBV) reactivation in rheumatoid arthritis (RA) patients undergoing biological therapy is not infrequent. This condition can occur in patients with chronic hepatitis B as well as in patients with resolved HBV infection. Current recommendations are mainly focused on prevention and management strategies of viral reactivation under tumor necrosis factor-α inhibitors or chimeric monoclonal antibody rituximab. In recent years, growing data concerning HBV reactivation in RA patients treated with newer biological drugs like tocilizumab and abatacept have cumulated. In this review, epidemiology, pathogenesis and natural history of HBV infection have been revised first, mainly focusing on the role that specific therapeutic targets of current biotechnological drugs play in HBV pathobiology; finally we have summarized current evidences from scientific literature, including either observational studies and case reports as well, concerning HBV reactivation under different classes of biological drugs in RA patients. Taking all these evidences into account, some practical guidelines for screening, vaccination, prophylaxis and treatment of HBV reactivation have been proposed.
Core tip: Hepatitis B virus (HBV) infection represents a major issue in patients with rheumatoid arthritis (RA) undergoing biological disease-modifying anti-rheumatic drugs (bDMARDs). While several observational studies and trials deal with the risk of HBV reactivation under anti-TNF agents, there is limited experience with newer drugs as tocilizumab (TCZ) and abatacept (ABA). In this paper, literature concerning the risk of HBV reactivation in RA patients undergoing different classes of bDMARDs, including ABA and TCZ, has been revised. Finally, some evidence-based practical suggestions for the management of this condition are proposed.
Citation: Nard FD, Todoerti M, Grosso V, Monti S, Breda S, Rossi S, Montecucco C, Caporali R. Risk of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing biologic treatment: Extending perspective from old to newer drugs. World J Hepatol 2015; 7(3): 344-361
Over the last decade, the introduction of biologic drugs for the treatment of rheumatoid arthritis (RA) led to significant improvements in clinical and radiographic disease outcomes. From available scientific evidences, low disease activity or even clinical remission resulted more frequently achievable with biologic and conventional synthetic disease-modifying antirheumatic drugs in combination (bDMARDs and csDMARDs, respectively) rather than with therapeutic regimens including csDMARDs only. According to the current recommendations for RA management[2-6], bDMARDs may be initiated in patients who have failed to respond to at least one csDMARD, including methotrexate (if not contraindicated). Table 1 summarizes the principal bDMARDs currently licensed for RA treatment. The first generation of biological drugs targeting specific effector molecules in RA pathogenesis is represented by tumor necrosis factor alpha (TNF-α) inhibitors (TNFI). Five agents of such class of bDMARDs are currently approved for RA: three monoclonal antibodies [infliximab (IFX), adalimumab (ADA), and golimumab (GOL)], one modified antibody Fab fragment [certolizumab pegol (CZP)] and one soluble receptor [etanercept (ETN)]. Moreover, B-cell targeted therapy with rituximab (RTX), a chimeric monoclonal antibody against CD20, a B-lymphocyte antigen that specifically depletes mature B-cells, is another well-established therapeutic option for RA treatment. Recently other therapeutic agents targeting molecules involved in RA pathogenesis have been approved: tocilizumab (TCZ), a humanized monoclonal antibody against interleukin 6 (IL-6) receptor which selectively blocks IL-6 biological effects, and abatacept (ABA), a soluble CTLA4-Fc fusion protein, that, by mimicking the cytotoxic T-lymphocyte antigen 4 (CTLA4), a negative regulator of T-cell costimulation, mainly prevents the activation of the T-cell compartment. Either anti-TNF, anti-IL-6 or costimulation blockade agents can be prescribed as first-line biologic therapies, while RTX is usually indicated as a second-line treatment option, that means for patients who failed and/or are intolerant to a first bDMARD, even if under certain circumstances, it can be considered as a first-line drug. The combination therapy of a biologic agent with methotrexate (or another equivalent csDMARD such as leflunomide[7,8]) is generally more effective than monotherapy, as shown for TNFI, RTX and TCZ. Nevertheless, bDMARD monotherapy might be considered in case of contraindications for csDMARDs. Biologic therapy is more effective than csDMARDs in achieving clinical response (measured by validated composite indexes) and in preventing radiographic damage as well. For instance, randomised controlled trials on TNFI show a remission rate of 50% vs 28% with ETN + methotrexate over methotrexate alone respectively; similarly, ADA + methotrexate resulted in a remission rate of 34%, against 17% for methotrexate alone. Furthermore, most evidences support the superiority of bDMARDs over csDMARDs in preventing structural and functional deterioration, even for long-term periods[14-17]. Compared to TNFI, newer bDMARDs, like TCZ and ABA, showed similar efficacy profiles, even if slight differences have been reported in specific contexts[18,19]. Despite their recognised therapeutic effects in most treated patients, biologic therapy with TNFI might result inadequate in approximately 30% of cases, thus carrying on the risk of further joint damage. After TNFI failure, no particular bDMARD seems to be better than the others as second line choice[18-21].
Table 1 Four classes of immunotherapies licensed to treat rheumatoid arthritis.
All these drugs carry a potential for serious infective complications, especially involving the reactivation of latent infections with intracellular pathogens. This is particularly the case for latent tuberculosis, or latent infection with viruses such as Herpes Simplex Virus, hepatitis C and hepatitis B virus (HBV). The prevalence of HBV infection in patients affected by rheumatic diseases is similar to the one of the general population. In the last decade, increasing attention has been paid to the possibility of HBV reactivation in RA patients undergoing treatment with bDMARDs. Growing evidences, coming first from oncology, then from gastroenterology and rheumatology fields, suggest that HBV reactivation can occur not only in hepatitis B surface antigen (HBsAg) carriers, but also in HBsAg negative individuals presenting liver HBV-DNA with detectable or undetectable serum HBV-DNA [occult HBV infection (OBI)], during or eventually after immunosuppression. Among the available bDMARDs approved for RA, the risk of HBV reactivation under TNFI has been well-described in several observational studies. Moreover, the evidences about the well-established risk of HBV reactivation in hematological patients treated with RTX, have been replicated in several reports on RA patients. In contrast, for this topic, observational data for newer bDMARDs with different targets like ABA and TCZ are still lacking, with only a few reports published. Consequently the existing practical guidelines for the prevention and management of viral reactivation are mostly targeted to the “older” rather than to the newer bDMARDs.
In this paper, literature concerning the risk of HBV reactivation in RA patients undergoing different classes of the most commonly prescribed bDMARDs has been revised. Finally, some evidence-based practical suggestions for the prevention and the treatment of this condition are proposed.
HBV: EPIDEMIOLOGY AND NATURAL HISTORY
Chronic infection with HBV is still a significant global health problem: about 2 billion people worldwide have been infected with HBV and approximately 5% of the world population is affected with chronic HBV infection, which is the leading cause of HBV-related complications such as chronic hepatitis, HBV-related cirrhosis, and hepatocellular carcinoma (HCC), accounting for 500000 to 700000 deaths per year. The geographic distribution of HBV infection can be described as follows: 88% of global population lives in areas of intermediate (HBsAg+ prevalence 2%-7%) or high endemicity (> 7%) corresponding to African and East-Asian territories where most infections occur from vertical transmission; whereas the remaining 12% lives in low endemicity areas (HBsAg+ prevalence < 2%), roughly corresponding to North Europe and United States, where HBV infection usually primarily occurs in adulthood. In western countries the incidence of HBV infection has been furtherly diminished by widespread vaccination programs since the 1980s. HBV is a partially double-stranded DNA virus transmitted by percutaneous or permucosal exposure to infected body fluids and perinatally from mother to infant. The virus genome is able to convert into a covalently closed circular form (cccDNA) that can persist lifelong into the nuclei of infected cells, leading to the likelihood of viral reactivation during or after immunosuppression.
Natural history of HBV infection is a dynamic process and runs throughout 4 distinct phases.
The immune tolerant phase is characterized by positive serum hepatitis B e antigen (HBeAg), serum HBV-DNA >105 copies/mL, and normal aminotransferase levels. In this phase cellular response is absent, with consequent minimal liver inflammation. After vertical infection this phase may last > 40 years (possibly leading to HBV genome integration, with decreased likelihood of viral eradication), while it is usually short-term in adults.
The HBeAg-positive immunoactive phase is characterized by a weak cellular response against infected hepatocytes, expressed by elevated aminotransferase levels (hepatitis), HBV DNA levels > 105 or between 104-105 copies/mL, and histological evidence of liver inflammation. As serum viral load falls, HBe seroconversion (from HBeAg to anti-HBe) can occur at a rate of 4%-10% per year.
Most people after HBeAg seroconversion enter the so-called HBV inactive phase, associated with a more effective cytotoxic T-cell response leading to normalization of aminotransferases and undetectable or < 2000 UI/mL serum viral load (inactive carrier state). During this phase, which may last lifelong, liver inflammation improves along with a lower risk of serious complications. Nevertheless, an estimated 20% of patients will reactivate, possibly leading to HBV-related complications: this condition, known as HBeAg-positive or HBeAg-negative chronic hepatitis B (CHB), is defined as HBsAg serum positivity for > 6 mo, along with serum HBV-DNA between 2000 and 20000 IU/mL or > 20000 IU/mL as well as elevated aminotransferases[26,27].
A proportion of patients develops HBsAg clearance at a rate of 0.5%-0.8% per year (resolution phase). Generally in these patients only anti-hepatitis B core antigen (anti-HBc) antibodies are detectable, because protective anti-HBs antibodies can be lost in time. The concept of occult HBV infection (OBI, defined with detectable liver HBV-DNA with serum undetectable or < 200 IU/mL HBV-DNA in HBsAg- individuals) has been recently introduced to describe the underlying risk of HBV reactivation under immunosuppressive therapy[29-31]. In this phase the risk of development of cirrhosis is minimal, whereas the risk of HCC is reduced but still significant. Definitions of HBV status in virological, biochemical and serological terms are summarized in Table 2.
Table 2 Nomenclatures and definitions used in hepatitis B virus infection.
Chronic inactive carrier
HBeAg positive CHB
HBeAg negative CHB
“Resolved hepatitis B”
Undetectable/< 2000 IU/mL
Persistent/intermittent ↑ (> 20000 IU/mL)
Persistent/intermittent ↑ (> 2000 UI/mL)
Detectable or undetectable
Minimal to severe CHB
No (> 90%)
Yes (> 90%)
No (> 90%)
CHB: Chronic hepatitis B; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B e antigen; anti-HBe: Antibodies to hepatitis B e antigen; anti-HBs: Antibodies to hepatitis B surface antigen; anti-HBc: Antibodies to hepatitis B core antigen; ALT: Alanine aminotransferase.
CURRENT MANAGEMENT OF CHRONIC HEPATITIS B
Antiviral therapy is generally recommended for CHB patients who have HBV DNA levels > 2000 IU/mL, serum aminotransferases above the upper limit of normal (ULN) and moderate to severe active liver necroinflammation and/or at least moderate fibrosis. Patients with alanine aminotransferase (ALT) > 2 times ULN and serum HBV-DNA > 20000 IU/mL may start treatment even without liver biopsy. The ideal end-points of antiviral therapies are long-term suppression of viral replication, sustained HBeAg seroconversion for HBeAg+ individuals, and HBsAg clearance. Long-term viral suppression can now be achieved in > 95% cases with oral nucleic acid analogues (NAs), although HBsAg loss remains a hard to achieve target (< 10%). Drugs available for the treatment of CHB include interferon-α (IFN), pegylated-INF-α2a (PEG-IFN) and six NAs, that can be classified into nucleosides (lamivudine, telbivudine, emtricitabine, entecavir) and nucleotides (adefovir and tenofovir) analogues. While IFN-based regimens, despite a good efficacy profile, lead to frequent side effects and contraindications[33,34]; oral NAs show a better safety profile. Though inexpensive, the first generation agents (such as lamivudine) are associated with a high rate of viral resistance (about 70% after 5 years), which limit their use in clinical practice. Entecavir and tenofovir are potent HBV inhibitors with a high barrier to resistance, and they are currently recommended as first-line monotherapies. These agents have to be given either indefinitely (HBeAg- CHB) or for 12 mo following HBeAg seroconversion in HBeAg+ CHB.
HBV REACTIVATION: DEFINITION AND RISK FACTORS
HBV reactivation in patients with chronic inactive/resolved HBV infection undergoing immunosuppressive treatment is defined as the combination of two findings: a > 1 log10 IU/mL increase in serum HBV-DNA level or the detection of previously undetectable HBV-DNA; and serum ALT elevation > 2-3 times the ULN[36,37]. The increase in liver function tests (hepatitis) usually follows viral reactivation. Reactivation clinically ranges from a subclinical and transient event to severe hepatitis; in a limited proportion of patients acute liver failure and death have been reported, with a higher risk for patients affected by CHB and advanced histological injury.
The host serological status and HBV-DNA levels are major risk factors for HBV reactivation: HBsAg carriers are at greater risk, and the risk increases with HBV-DNA load[36,37]. For HBsAg negative patients, the risk of reactivation is considerably lower in individuals with both anti-HBc and anti-HBs antibodies. The risk may be higher in the event of concomitant methotrexate therapy. A variety of immunosuppressive drugs may lead to HBV reactivation: corticosteroids, cytotoxic agents, cs- and bDMARDs. In most cases reactivation occurs after treatment withdrawal, as a result of the restored immunity. The liver damage due to HBV reactivation is a two-stage process: initially during intense immunosuppression an enhanced viral replication occurs as reflected by increased serum and liver HBV-DNA; then, during the subsequent immune restoration after treatment withdrawal a rapid immune-mediated destruction of HBV-infected hepatocytes overcomes, clinically manifested with hepatitis, hepatic failure and even death. In a recent retrospective study of 35 cases of HBV reactivation in patients undergoing immunosuppressive treatment for immune-mediated inflammatory disease, reactivation appeared a median of 35 wk (2-397) after treatment start, with earlier occurrence in RTX-treated and in HBsAg+/HBV-DNA+ patients. However, earlier appearance was not associated with an increased clinical severity. Factors significantly associated with HBV-related serious complications (death and/or fulminant hepatitis) were identified in Asian ethnicity, delay from immunosuppressive therapy initiation to HBV reactivation diagnosis, HBV-DNA load and aminotransferases at HBV diagnosis. The use of specific TNFI/antiviral molecules did not differ between patient who experienced or not serious events, but patients with a poor outcome tended to receive IFX, ADA or 1st-generations NAs as compared with those with a favorable outcome (P = 0.07 and P = 0.03).
ROLE OF PRO-INFLAMMATORY CYTOKINES IN HBV INFECTION
RA is a chronic inflammatory disease affecting 1% of adult population that predominantly involves the synovial membrane of diarthrodial joints. The disease is characterized by the activation of resident synovial macrophages in association with a massive synovial infiltration of lymphocytes and neutrophils, and by the local development of an inflammatory milieu, which in turn promotes the proliferation of synoviocytes and fibroblasts, and neoangiogenesis: all this leads to the production of an aberrant, hyperplastic tissue, the so-called rheumatoid pannus, and to the differentiation and activation of chondrocytes and osteoclasts and subsequent cartilage and bone destruction. Apart from macrophages and other innate immunity “effector” cell types (dendritic cells, neutrophils, synoviocytes, osteoblasts, osteoclasts, and chondrocytes), three major pathways of RA immunity response have become recognized as pivotal: B-cells, T-cells, and a wide range of inflammatory cytokines that, acting as an intricate and redundant network both systemically and locally, shift the balance towards a proinflammatory state. Synovitis is ultimately driven by a number of pro-inflammatory cytokines, such as TNF-α, IL-6 and IL-1. TNF-α is overexpressed in the synovial fluid of patients with RA. Moreover, TNF-α transgenic mice spontaneously develop arthritis. IL-6, a typical cytokine featuring redundancy and pleiotropic activity, also plays a key role in the development of RA, promoting an imbalance between Th17 and regulatory T (Treg) cells and the production of autoantibodies, such as rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPA). IL-6 also promotes synovial inflammation and cartilage and bone destruction and exerts systemic effects leading to cardiovascular, psychological, and skeletal disorders.
RA was historically considered a T-cell driven disease, although adaptive humoral immunity also plays a pivotal role in its pathogenesis, as shown by the production of RF and ACPA, that are considered to be the serological hallmarks of RA. It has long been recognised that activated CD4 and CD8+ T-cell subsets, B-cells, plasmablasts and plasma cells are abundant in rheumatoid synovial tissue. A substantial proportion of patients show ectopic germinal centres that may support B cell maturation and class switching and thereby promote autoantibody production.
HBV infection causes acute and chronic necroinflammatory hepatitis. The pathogenesis of HBV infection, similarly to that of RA, is still largely unknown. Massive hepatic injury occurring during CHB seems to be immune-mediated and depends on HBV-specific cytotoxic T-cells; moreover, an efficient control of HBV infection requires the synergic actions of both innate and adaptive immunity.
Innate immunity induces in HBV infected cells the production of typeIinterferons and several proinflammatory cytokines, including TNF-α, IL-1, IL-6, and IL-10, some of which are reported to suppress viral replication and/or to exert non-cytolytic viral clearance. In HBV infected patients TNF-α is produced by intrahepatic leukocytes in a HBc-dependent fashion. Several reports show intrahepatic and serum TNF-α elevation in patients with acute or chronic hepatitis B, suggesting a potential role in inhibiting viral replication. The persistence of HBV infection may be associated with CD8+ T-cell loss of the ability to secrete enough TNF-α to kill infected hepatocytes (the so-called “exhausted phenotype’’). Genetic polymorphisms leading to lower TNF-α expression associate with an increased risk of HBV chronicization. It has been recently demonstrated that in TNF-α knockout mice and in ETN-treated mice HBV infection persists, with subsequent increase in HBV-specific CD8+ T-cells, serum and liver HBV-DNA, and antigen expression. Thus in this animal model TNFI may be able to suppress HBc-dependent viral clearance effects. However, in patients with CHB this cytokine may contribute to liver injury. Other cytokines, like IL-1, might be involved in the natural history of HBV infection but data concerning their real role and meaning are still most elusive[51,52].
Cellular immunity is critical for the outcome of HBV infection, too: HBV-specific T-cells are involved in the control of viral infection, whilst non-specific NK cells infiltrate the liver leading to hepatocellular injury. In humans, IL-6 in combination with TGF-β and IL-1β drive naive CD4+ T-cell to differentiate into Th17 cells in a HBc-dependent fashion. Th17 cells can produce multiple cytokines that trigger the recruitment and activation of neutrophils leading to massive tissue inflammation. Recent reports showed that in CHB patients antigen non-specific Th17 response is increased and that the peripheral Th17 frequency is associated with the degree of liver damage[56,57]. A recent study revealed that the increased Th17 response in CHB patients correlates with the enhanced IL-6 receptor (IL-6R) expression on CD4+ T-cells, suggesting IL-6R as a potential novel target for CHB immunotherapy. In addition, several studies demonstrated that IL-6 facilitates in vivo and in vitro HBV infection and might be able to predict the development of HCC in HBV infected patients. However, conclusive data are still lacking and the immunosuppressive action of the anti-IL-6R antibody TCZ might actually play a detrimental role.
CTLA-4, an inhibitory receptor expressed by activated T-cells that acts as a negative regulator of T-cell responses seems to be involved in HBV infection: studies in humans suggest an influence of CTLA4 polymorphisms in HBV clearance, HBV-related carcinogenesis and HBV reactivation after immunosuppression, but the underlying mechanisms are still unclear[61-63].
Recent reports suggest that humoral immunity plays an important role in the immune response to HBV. HBcAg is able to directly activate B-cells to produce specific antibodies in the absence of regulatory T-cells. In patients with HBeAg- CHB, CD20+ B-cells infiltrate the liver and correlate with histologic necroinflammation and fibrosis. However, immunosuppression and B-cell suppression are associated with viral reactivation. B-cells are thus involved in liver inflammation in HBV infected patients, but whether their influence on disease progression is harmful or beneficial is still unknown.
SAFETY OF BMARDS IN PATIENTS WITH COMORBID HBV INFECTION
While in the last decade an amount of data has been cumulated regarding the effect of TNFI and RTX on RA patients with CHB or even OBI; the likelihood of HBV reactivation in patients undergoing newer bDMARDs TCZ and ABA has been more recently described. Available evidences stratified by bDMARDs about this topic will be exposed in the following sections.
It has been 11 years since the first reports of HBV reactivation after TNF-α blockade have been reported[66,67]; since then, a cumulative evidence from case reports and small retrospective or prospective studies has been collected[68-81]. TNFI-induced immunosuppression is able to decrease HBV antigen presentation: the abrupt increase in viral presentation at treatment discontinuation induces an acute cytotoxic response, which can cause extremely severe hepatitis. Table 3 summarizes the observational studies of HBV reactivation in RA patients undergoing TNFI. A distinction has to be made between CHB patients (HBsAg+) and patients with resolved infection (HBsAg-/anti-HBc+).
Table 3 Hepatitis virus B reactivation in rheumatoid arthritis patients receiving tumor necrosis factor-α inhibitors: studies in patients with markers of chronic or remote hepatitis virus B infection.
RA (66), SpA (64), other (1) patients with actual/remote HBV infection or vaccinated for HBV
43 treated with IFX, 64 with ETN, 62 with ADA
14 pts (100% of CHB group): 11 with lamivudine, 2 with entecavir, 1 with telbivudine
0 pts among CHB group
19 pts (vaccinated)
No cases of HBV reactivation in pts with resolved HBV infection. In vaccinated pts, slight decrease in anti-HBs titres (median 163 > 105 IU/mL,P= 0.01). Among CHB pts, 1 (7%) treated withLamivudine + ETN developed HBV reactivation due to a resistant mutant strain
HBV reactivation in 35 (39%) pts among HBsAg+ group, fatal in 4 cases. Lower risk if pre-emptive NAs (23%vs62%,P= 0.003). Higher risk with IFXvsETN. Nine cases (5%) of HBV reactivation in HBcAb+/HBsAg- pts, fatal in 1 pt
Among HBsAg+ pts, no cases of HBV reactivation if pre-emptive NAs; mean decrease in HBV-DNA = 153 IU/mL (P < 0.001); 5/8 cases of reactivation without antivirals. 1 case of HBV reactivation in the HBsAg-/anti-HBs- group
Pts with immune-mediated inflammatory diseases (RA 14, CTD 7, vasculitis 5, other 9) developing HBV reactivation
7 pts treated with TNF-α inhibitors (not specified), 4 with RTX, 1 with ABA, 1 with TCZ, the others with steroids and/or other immunosuppressants
5 pts (drug not specified)
Reactivation occurred a median of 35 wk after therapy start. 88.6% were asymptomatic; 25.7% had severe hepatitis. Management were NAs in 91.4% cases and decrease/withdrawal of immunosuppressants in 45.7%. Pooling these data with literature, earlier reactivation for RTX and HBsAg/HBV-DNA+ pts
TNFα inhibitors: 56 treated with IFX, 31 with ETN)
4 pts among CHB group , 9 pts among inactive carriers (not specified)
37 (6 HBV-DNA+, 31 HBV-DNA-) pts
2 cases of HBV reactivation among CHB pts not receiving pre-emptive NAs, none in those receiving it. Among inactive HBsAg carriers, 6 cases of reactivation in pts who didn’t receive NAs, none in those who did. No cases in HBsAg- pts
In a 2011 review of 87 published cases of TNFI-treated CHB patients, Perez-Alvarez et al reported an HBV reactivation rate of 38%, similar to that observed under chemotherapy (50%). Half of the patients had received IFX, 33% ETN and 17% ADA. In most cases (about 75%), viral reactivation was accompanied by an increase in aminotransferase levels. Among patients with severe reactivation, 5 developed liver failure and 4 died from HBV-related complications. Interestingly, only 25% of the patients who developed HBV reactivation had received antiviral prophylaxis, compared to 62% of those who didn’t experience viral reactivation. Apart from potential publication bias, these data indicate an increased risk of HBV reactivation in TNFI-treated CHB patients, particularly without proper antiviral prophylaxis. In a 2010 prospective study 14 HBsAg+/anti-HBc+/anti-HBs- patients, 8 classified as inactive HBsAg carriers and 6 suffering from active CHB, were treated with combination therapy with oral NAs and TNFI: antiviral prophylaxis could prevent viral reactivation in > 90% of cases. Only one active CHB patient developed HBV reactivation (7%) after 3-year prophylactic lamivudine: viral sequencing indicated a resistant mutant strain, as frequently happens during long-term lamivudine administration. Lee et al have recently reported 15 HBV reactivation cases (12.3%) in a systematic review of 122 HBsAg+ rheumatic patients undergoing TNFI or csDMARDs. 10/15 patients provided clinical data: 4 cases occurred in RA patients (none treated with TNFI) and no HBV-related complication occurred. Percent of 39.3 patients had received pre-emptive NAs. Similarly, a recent prospective study reported in a cohort of 37 HBsAg+ patients with inflammatory arthritis a reactivation rate of 33.3% without pre-emptive antiviral prophylaxis with no cases in patients treated with NAs. Of the 6 CHB patients (HBV-DNA > 105 copies/mL, elevated ALT), both of the 2 patients not receiving oral NAs developed viral reactivation; and the other 4 treated with pre-emptive NAs showed no viral replication. In the 31 inactive HBsAg carriers (HBV-DNA < 104 copies/ml, normal ALT), out of the 22 patients not receiving NAs, a transient HBV-DNA increase was detected in 4 cases, with a gradual viremic normalization after therapy withdrawal. No cases were detected in the 9 inactive carriers receiving antiviral prophylaxis. It is currently unknown whether different TNFI affect HBV reactivation to different extents. The risk may be lower with ETN, whose affinity for TNF-α is lower; whilst IFX seems to be more frequently associated with HBV reactivation. A possible explanation could be that IFX administration scheme at intervals of 8 wk may result in a cytokine wash-out leading to a possible “immune-reconstitution” effect.
Patients with resolved HBV infection (HBsAg-/anti-HBc+)
Data from oncology and hematology indicate that HBV reactivation occurs in < 5% of patients with resolved HBV infection treated with chemotherapy[83,84]. Similar data among rheumatic patients have cumulatively been published in recent years. In two prospective studies from Southern Europe no cases of HBV reactivation among 88 TNFI-treated patients with remote HBV infection were described[70,72] although none of these patients had detectable HBV-DNA at baseline. Similarly, in a retrospective taiwanese study no reactivation was observed among 58 HBsAg-/anti-HBc+/anti-HBs+ patients under TNFI, although one case of HBV reactivation was recorded between 12 HBsAg-/anti-HBc+/anti-HBs- patients, involving a patient with detectable baseline HBV-DNA. These data suggest that the risk of HBV reactivation is rather low in anti-HBc+/anti-HBs+ patients, although the likelihood of this event could be higher for HBV-DNA+ and/or for anti-HBs- patients. A chinese prospective study did not report any reactivation case in 50 TNFI-treated patients with resolved HBV infection and inflammatory arthritis. Lee et al have recently reported in a systematic review of 468 anti-HBc+/HBsAg- rheumatic patients undergoing TNFI a reactivation rate of 1.7%. Out of 8 cases, 7 were RA patients, and in all cases clinical outcome was satisfactory. In a japanese prospective study of 50 RA HBcAb+ patients treated with csDMARDs and/or TNFI, reactivation occurred in only 1 out of 45 HBsAg- patients (2.2%), treated with csDMARDs only. Interestingly, in TNFI-treated patients, anti-HBs titres decreased significantly in the middle- and low-titer groups (P = 0.032 and P = 0.007), remaining high in high-titer group (P = 0.875), but did not became negative in any patient. It remains to be clarified whether a long period of TNFI therapy in RA patients induces the disappearance of anti-HBs leading to viral reactivation as well as in hematological field. A recent japanese retrospective study of 244 HBsAg-/anti-HBc+ RA patients, HBV-DNA was detected in three patients (5.3%), only one receiving a TNFI, particularly ETN (out of a total of 48 TNFI-treated patients indicating a 2.1% reactivation rate). Reactivation consisted in a subclinical, transient HBV-DNA elevation, subsequently turning undetectable within months. Even if limited by a possible publication bias, these data indicate that HBV reactivation in patients with serological markers of past HBV infection is a quite rare event and that for these patients no specific prophylaxis is required.
As suggested by a prospective study, a possible decrease in anti-HBs titer in TNFI-treated patients with remote HBV infection can occur, but this might not be systematically followed by viral reactivation such as in hematological field. Similarly, in a prospective study of 19 HBV vaccinated patients a slight decrease in anti-HBs levels during TNFI treatment was reported, although a comparable decrease was observed in patients treated with methotrexate alone, indicating no specific effect of TNFI on HBV protective immunity.
A growing scientific literature indicates high rates of HBV reactivation in patients undergoing RTX for hematological diseases not receiving proper antiviral prophylaxis, ranging from 27% to 80% in HBsAg+ patients and from 3% to 25% in HBsAg-/anti-HBc+ patients, with higher risk for anti-HBs- individuals[86,87]. Reports of HBV reactivation in rheumatic patients treated with RTX are summarized in Table 4. There are limited data regarding the safety of RTX in rheumatic CHB patients; although, the efficacy of pre-emptive NAs (mainly lamivudine) in preventing reactivation in HBsAg+ patients treated with RTX appears to be similar to that observed in patients under chemotherapy, with a reactivation rate of 0%-13%. Three recent reports from Southern Europe have described HBV reactivation in RA patients undergoing RTX, occurring not only in HBsAg carriers but also in two patients with resolved HBV infection. The first patient experienced HBV reactivation 1 mo after RTX administration, even though she had been receiving pre-emptive lamivudine for CHB. Lamivudine was thus switched to tenofovir with aminotransferases and HBV-DNA normalization. In the second report, a RA patients with resolved HBV infection experienced HBV reactivation following 2 years of therapy, 3 mo after the last RTX infusion. RTX was then withdrawn and entecavir initiated, with a gradual amelioration of aminotransferase levels and HBV-DNA normalization. The third report involved a HBsAg-/anti-HBc+/HBV-DNA- RA patient that developed HBV reactivation with subsequent acute hepatitis after 2 years of RTX + methotrexate combination therapy. Discontinuation of immunosuppressive treatment and antiviral therapy with entecavir resulted in the control of HBV infection within a few months. A 2013 prospective study did not report any case of HBV reactivation under RTX neither in a series of 2 HBsAg+/HBV-DNA- rheumatic patients treated with antiviral prophylaxis nor in a series of 12 HBsAg-/anti-HBc+ rheumatic patients, indicating a quite safe profile. Interestingly, in the 4 patients with history of HBV vaccination, a slight decrease in antibody titers that did not reach statistical significance was noted. However, antibody titers did not fall below protective levels. Droz et al reported other 4 cases of HBV reactivation under RTX in patients affected with inflammatory diseases; indicating an earlier timing of viral reactivation for patient receiving anti-CD20 treatment.
Table 4 Case reports and studies of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing rituximab.
There is limited experience with TCZ, a humanized anti-IL-6 receptor antibody, among HBV-infected RA patients (Table 5). Nagashima et al reported that TCZ was administered safely and effectively in a RA patient affected with CHB, not recognised at baseline since serological screening for HBV had not been performed. In another case report, a patient with active RA stopped IFX due to HBV reactivation (pre-treatment viral status unknown). She was then treated with lamivudine until HBV-DNA turned undetectable, and later started TCZ; this resulted in a prompt disease control together with persistently normal serum aminotransferases and undetectable HBV-DNA. A similar report regarding a CHB patient with adult-onset Still’s disease indicates an excellent disease control with no viral reactivation by introducing TCZ after complete viral control with entecavir. A recent retrospective study from Nakamura et al described 2 cases of HBV reactivation in RA patients undergoing TCZ without pre-emptive antivirals (out of a total of 18 TCZ-treated HBsAg-/anti-HBc+ patients, with a reactivation rate of 11.1%): in both patients HBV-DNA rised but remained below quantitation limits (< 2.1 log copies/mL), and then it spontaneously turned undetectable, along with normal aminotransferases throughout the entire period of follow-up: such data might suggest the possibility of a transient HBV-DNA fluctuation during the first 3-6 mo of TCZ, which doesn’t necessarily lead to de novo hepatitis and possibly resolves within a few months. This evidence suggests that TCZ, if co-administred with pre-emptive NAs, could be a treatment option for RA HBV carrier patients when disease activity is uncontrolled with csDMARDs. However, periodic monitoring of liver function tests and HBV-DNA is mandatory.
Table 5 Case reports of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing tocilizumab.
Studies regarding HBV reactivation in rheumatic patients undergoing ABA are summarized in Table 6. A recent monocentric retrospective study has been performed including 8 ABA-treated RA patients showing active CHB (n = 2) or inactive HBsAg carriers (n = 6). All patients not receiving antiviral prophylaxis (n = 4), which were all inactive HBsAg carriers at baseline, experienced viral reactivation, with a > 10 fold increase of HBV-DNA. None of the NAs-treated patients (3 with entecavir and one with tenofovir) had viral reactivation. Moreover, patients who had been receiving both ABA and NAs showed a statistically significant improvement in DAS28 compared to those without prophylaxis (P = 0.025). This is the first study suggesting that the use of ABA in RA/CHB patients appears to be safe and efficacious as long as pre-emptive antiviral prophylaxis is properly given. A case of severe hepatitis due to HBV reactivation has been reported in a RA patient with resolved HBV infection (HBV-DNA-) previously treated with a TNFI without antiviral prophylaxis and then with ABA, leflunomide and steroids. Nine month after the first ABA infusion, she experienced viral reactivation with liver function tests increase; this led to suspension of biological therapy. As expected, liver function tests continued to increase along with the gradual T-cell immune reconstitution, with a time lag of 2 mo between ABA withdrawal and viral flare. She was then treated with tenofovir with gradual amelioration of aminotransferases and undetectable HBV-DNA. Another case of HBV reactivation in a RA patient with resolved HBV infection (basal HBV-DNA unknown) undergoing ABA was lately reported: 10 mo after treatment start, HBsAg turned positive along with a rise in HBV-DNA; treatment was then stopped and tenofovir was started, with a gradual amelioration of liver function tests and HBV-DNA within a few months. In a recent italian case series of 9 RA patients treated with ABA (8 with resolved HBV infection and 1 chronic inactive carriers), one patient with comorbid HCV chronic infection started lamivudine for liver function tests elevation (< 2-fold ULN) occurring 2 mo after ABA initiation, with a gradual amelioration of lab levels along with persistently undetectable viral load. Other 2 patients (1 chronic inactive carrier and 1 with resolved infection) underwent lamivudine before ABA with no HBV-related adverse event, whilst among the other 6 HBsAg- patients not receiving antiviral prophylaxis only 1 developed HBV-DNA positivity (85 UI/mL) without aminotransferase elevation at 12 mo, with subsequent fluctuations of viral load, turning initially negative at 18 mo and then rising again at 24 mo (290 UI/mL) without liver function tests alterations and without specific antiviral treatment. After infectivologist consult the patient thus started entecavir, concomitantly with switch to adalimumab for arthritis flare, with undetectable HBV-DNA 3 mo after TNFI start (unpublished data).
Table 6 Case reports of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing abatacept.
1 pt affected with immune-mediated inflammatory disease treated with ABA
median of 35 wk after therapy start (global data)
No cases of fulminant hepatitis (global data)
Early reactivation in HBsAg+/HBV-DNA+ pts (global data)
Pts: Patients; CHB: Chronic hepatitis B; NAs: Nucleot(s)ide analogues; ADA: Adalimumab; HBsAg: Hepatitis B surface antigen; HCV: Hepatitis B virus.
CONCERNS ABOUT HBV VACCINATION
Hepatitis B vaccine (HBVv) is a recombinant DNA vaccine that provides protection against HBV infection and its complications, including cirrhosis and HCC. As more than 1 billion doses of vaccine have been used since 1982, it is considered to be safe. Vaccination scheme usually involves 3 booster injections and is currently indicated for high risk patients: newborns, health care workers and adults presenting conditions of immunosuppression or behavioral risk factors (multiple sexual partners, drug abusers, travelers to endemic areas).
Some concerns have been raised on the possible development of autoimmune adverse events after HBVv: cases of multiple sclerosis, Guillain-Barre syndrome, idiopathic thrombocytopenic purpura, optic neuritis, glomerulonephritis, transverse myelitis, vasculitis, systemic lupus erythematosus diagnosis or flare-up[101,102] and even the so-called autoimmune/inflammatory syndrome induced by adjuvants have been reported. Conflicting data about a possible association with HBVv and arthritis (RA or other) diagnosis or flare-up have been reported in 32 cases and 3 controlled studies. In one study HBVv, compared to rubella vaccination, showed an increased risk of chronic arthritis incidence (attributable risk 5.1-9.0); whilst two studies comparing the risk of RA flare following HBVv with RA controls or with RA prevalence in the same community did not find a significant association between HBVv and the risk of arthritis. Interestingly, in one of these studies a decreased efficacy of HBVv in RA patients was noticed. These results do not provide solid scientific data to support the existence of a causal link between arthritis and HBVv: the most likely explanation still remains the coincidental temporal association. However, in a panorama of decreasing worldwide incidence of hepatitis B, mainly due to immunization programs, a recent “anti-vax” misconception is concentrating public attention and the media on vaccine adverse events rather than on prevention and control, which may lead to lower vaccine coverage and subsequent community wide outbreaks.
Routine vaccination before biotherapy initiation in patients with negative screening tests seems to be obviously appropriate; nevertheless, in patients affected with autoimmune diseases some precautions should be taken: the risk of infection must be weighed against the theoretical risk of vaccine side effects, according to each patient’s profile (age, family history, risk factors, etc.). On the other hand, HBVv administration may delay biotherapy initiation, and the immune response may be blunted in patients affected with chronic arthritis taking immunosuppressants: if we consider that a single injection is insufficient to induce protective immunization, if the following injections are administered under TNFI (most of all IFX and to a lesser degree ETN), they often fail to generate an immune response. Since the risk of contracting HBV during adulthood is low, except for high-risk situation, HBVv might be postponed. In contrast, in high risk patients, particularly the younger ones, HBVv should be administered before treatment initiation. In patients with resolved HBV infection and insufficient antibody protection (anti-HBc+/anti-HBs-), a booster injection might be given to strengthen immunization and to induce the production of protective anti-HBs, whose titer should be then measured.
RECOMMENDATIONS FOR CLINICAL MANAGEMENT OF RA PATIENTS WITH CHRONIC/RESOLVED HBV INFECTION UNDERGOING BDMARDS
Since proper prospective studies comparing different screening and treatment options for HBV-infected RA patients starting bDMARDs therapy are lacking, only expert-opinion-based suggestions can be made[2-4,6,33,38,68,82].
As stated by all the recent recommendations, all patients starting bDMARDs should be screened for HBV infection with HBsAg, anti-HBc and anti-HBs antibodies, as well as HBV-DNA load and liver function tests in patients found to be positive[2-4,6,68,82]. Considering the cost of chronic bDMARD therapy and the potential for serious HBV-related complications, such screening results to be cost-effective. Recent studies have shown that only 69% of US rheumatologists routinely performs universal HBV screening before biologic therapy. When the results indicate active/remote HBV infection, a full battery of liver tests must be obtained, and it is appropriate to consult an hepatologist to evaluate whether antiviral treatment or prophylaxis is indicated before starting bDMARDs therapy.
As stated before, a careful risk-benefit assessment should be made concerning HBVv administration before bDMARD treatment. According to current recommendations, HBVv is only recommended in patients “at risk” (e.g., travel to or residence in endemic countries, medical profession, infected family member; only if protective antibodies against HBV are absent. Grade of evidence II-III; strength of recommendation B-D) and should ideally be administered during stable disease. Nevertheless, vaccination could also be considered in selected patients with active disease for whom the benefits of HBVv outweight the risks. HBVv can be administered during the use of csDMARDs and TNFI but should ideally be administered before starting RTX (or, when treatment with RTX is already ongoing, at least 6 mo after the start but 4 wk before the next course). Further studies are needed to establish indication and proper time of immunization in RA patients undergoing TCZ or ABA.
Antiviral pre-emptive therapy and follow-up
Given the risk associated with IFN-based schemes in patients with autoimmune diseases, only NAs are recommended for these patients. To date, no consensus or recommendations are available regarding the specific bDMARD that should be preferentially chosen according to HBV infection profile. Pre-emptive treatment must be started (at least 1 mo) before the biotherapy, and must be prolonged (as well as virological monitoring) until at least 6 mo after its discontinuation. The efficacy of pre-emptive lamivudine has been retrospectively assessed in 88 RA patients treated with TNFI showing markers of recent/remote HBV infection: for HBsAg+ patients, 5 of 8 untreated patients underwent HBV reactivation versus none of 10 treated patients. Regarding the 70 HBsAg-/anti-HBc+ patients, without antiviral prophylaxis, a single case of HBV reactivation was reported in a patient with OBI (HBV-DNA+, anti-HBs-). Nevertheless, newer NAs such as entecavir and tenofovir are considered the first choice for patients at high risk of HBV reactivation, due to lower risk of drug resistance. However, comparative data between lamivudine and newer NAs for pre-emptive therapy of HBV reactivation are lacking. In addition, the potential side effects of entecavir and tenofovir must be weighed against the excellent safety profile of lamivudine. The current recommendations are summarized below.
For HBsAg+ patients, antiviral therapy should be initiated before any bDMARDs therapy. The choice of the appropriate NA mainly depends on the duration of the scheduled therapy and on HBV serology status (CHB vs inactive carrier). In general, patients receiving long-term immunosuppression (> 12 mo) and/or suffering from CHB are placed on the newer NAs. For patients with HBV-DNA < 2.000 IU/mL who are scheduled for short-term immunosuppression (< 12 mo) treatment with lamivudine should be considered. Biotherapy should not be started until the HBV-DNA levels become undetectable, and thus frequent (after 1 mo, then every 3-6 mo) monitoring of HBV-DNA and liver function tests is mandatory[35,81]. This recommendation might safely be applied to patients undergoing TCZ and ABA.
For HBsAg-/anti-HBc+ patients undergoing bDMARDs, additional risk factors should be taken into account: HBV-DNA positivity, presence of anti-HBs (which should protect against reactivation, although this effect is controvertial, mostly with RTX), and the degree of immunosuppression induced by different bDMARDs, particularly for RTX. Baseline screening for HBV-DNA is always recommended, and if found to be positive, it is appropriate to start newer NAs. In patients with resolved HBV infection (undetectable HBV-DNA) undergoing TNFI, simple monitoring without pre-emptive treatment is recommended (particularly if also anti-HBs+): liver function tests, HBsAg and HBV-DNA should be assessed 1 mo after treatment start, and then every 3-6 mo. Pre-emptive treatment should also be strongly considered, regardless of HBV-DNA status, for patients undergoing RTX. Moreover, although there are few data concerning newer bDMARDs, we suggest that also for ABA-treated patients, regardless of HBV-DNA status, antiviral prophylaxis should be taken into account; whilst TCZ is relatively safe. In these cases, regular monitoring of aminotransferases, HBsAg and/or HBV-DNA every 3-6 mo of follow-up is mandatory.
When HBV reactivation is diagnosed, as soon as HBV-DNA becomes detectable and before hepatocellular damage starts, antiviral therapy must be promptly initiated and immunosuppressive therapy must be discontinued. If HBV-DNA becomes positive during lamivudine therapy, the patient should be switched to tenofovir, since cross-resistance has been reported between lamivudine and entecavir.
HBV infection is a relevant worldwide condition, affecting also rheumatologic patients. Immunosuppressive treatment with bDMARDs might interfere with HBV natural history, leading to an increasing risk of viral reactivation, with consequent liver damage, up to possible fulminant hepatitis and death. Rheumatologists should be well-aware about such risk in RA patients undergoing different classes of bDMARDs, in order to define drug by drug proper preventive and therapeutic strategies. More robust evidences about newer bDMARDs (TCZ and ABA) are still needed in order to better define their specific drug-related risk in HBV infected RA patients and to draw univocal recommendations. An integrated management of this subset of patients should be encouraged between rheumatologists and virologists.
P- Reviewer: Thibault V S- Editor: Qi Y L- Editor: A E- Editor: Wu HL
Navarro-Millán I, Curtis JR. Newest clinical trial results with antitumor necrosis factor and nonantitumor necrosis factor biologics for rheumatoid arthritis.Curr Opin Rheumatol. 2013;25:384-390.
Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, Paulus HE, Mudano A, Pisu M, Elkins-Melton M. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis.Arthritis Rheum. 2008;59:762-784.
Furst DE, Keystone EC, So AK, Braun J, Breedveld FC, Burmester GR. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2012.Ann Rheum Dis. 2013;72 Suppl 2:ii2-34.
Smolen JS, Landewé R, Breedveld FC, Buch M, Burmester G, Dougados M, Emery P, Gaujoux-Viala C, Gossec L, Nam J. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update.Ann Rheum Dis. 2014;73:492-509.
Caporali R, Conti F, Alivernini S, Atzeni F, Seriolo B, Cutolo M, Valesini G, Ferraccioli G, Sarzi-Puttini P, Salvarani C. Recommendations for the use of biologic therapy in rheumatoid arthritis: update from the Italian Society for Rheumatology I. Efficacy.Clin Exp Rheumatol. 2011;29:S7-S14.
Favalli EG, Caporali R, Sinigaglia L, Pipitone N, Miniati I, Montecucco C, Matucci-Cerinic M. Recommendations for the use of biologic therapy in rheumatoid arthritis: update from the Italian Society for Rheumatology II. Safety.Clin Exp Rheumatol. 2011;29:S15-S27.
Benucci M, Saviola G, Baiardi P, Manfredi M, Sarzi-Puttini P, Atzeni F. Efficacy and safety of leflunomide or methotrexate plus subcutaneous tumour necrosis factor-alpha blocking agents in rheumatoid arthritis.Int J Immunopathol Pharmacol. 2011;24:269-274.
De Stefano R, Frati E, Nargi F, Baldi C, Menza L, Hammoud M, Galeazzi M. Comparison of combination therapies in the treatment of rheumatoid arthritis: leflunomide-anti-TNF-alpha versus methotrexate-anti-TNF-alpha.Clin Rheumatol. 2010;29:517-524.
Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, Sharp J, Perez JL, Spencer-Green GT. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment.Arthritis Rheum. 2006;54:26-37.
Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis.N Engl J Med. 2004;350:2572-2581.
Nettelbladt O, Tengblad A, Hällgren R. High-dose corticosteroids during bleomycin-induced alveolitis in the rat do not suppress the accumulation of hyaluronan (hyaluronic acid) in lung tissue.Eur Respir J. 1990;3:421-428.
Emery P, Sebba A, Huizinga TW. Biologic and oral disease-modifying antirheumatic drug monotherapy in rheumatoid arthritis.Ann Rheum Dis. 2013;72:1897-1904.
Emery P, Breedveld FC, Hall S, Durez P, Chang DJ, Robertson D, Singh A, Pedersen RD, Koenig AS, Freundlich B. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial.Lancet. 2008;372:375-382.
Kavanaugh A, Fleischmann RM, Emery P, Kupper H, Redden L, Guerette B, Santra S, Smolen JS. Clinical, functional and radiographic consequences of achieving stable low disease activity and remission with adalimumab plus methotrexate or methotrexate alone in early rheumatoid arthritis: 26-week results from the randomised, controlled OPTIMA study.Ann Rheum Dis. 2013;72:64-71.
Jones G, Halbert J, Crotty M, Shanahan EM, Batterham M, Ahern M. The effect of treatment on radiological progression in rheumatoid arthritis: a systematic review of randomized placebo-controlled trials.Rheumatology (Oxford). 2003;42:6-13.
Bukhari MA, Wiles NJ, Lunt M, Harrison BJ, Scott DG, Symmons DP, Silman AJ. Influence of disease-modifying therapy on radiographic outcome in inflammatory polyarthritis at five years: results from a large observational inception study.Arthritis Rheum. 2003;48:46-53.
Egsmose C, Lund B, Borg G, Pettersson H, Berg E, Brodin U, Trang L. Patients with rheumatoid arthritis benefit from early 2nd line therapy: 5 year followup of a prospective double blind placebo controlled study.J Rheumatol. 1995;22:2208-2213.
Bergman GJ, Hochberg MC, Boers M, Wintfeld N, Kielhorn A, Jansen JP. Indirect comparison of tocilizumab and other biologic agents in patients with rheumatoid arthritis and inadequate response to disease-modifying antirheumatic drugs.Semin Arthritis Rheum. 2010;39:425-441.
Salliot C, Finckh A, Katchamart W, Lu Y, Sun Y, Bombardier C, Keystone E. Indirect comparisons of the efficacy of biological antirheumatic agents in rheumatoid arthritis in patients with an inadequate response to conventional disease-modifying antirheumatic drugs or to an anti-tumour necrosis factor agent: a meta-analysis.Ann Rheum Dis. 2011;70 Suppl 2:266-271.
Mewar D, Wilson AG. Treatment of rheumatoid arthritis with tumour necrosis factor inhibitors.Br J Pharmacol. 2011;162:785-791.
Schoels M, Aletaha D, Smolen JS, Wong JB. Comparative effectiveness and safety of biological treatment options after tumour necrosis factor α inhibitor failure in rheumatoid arthritis: systematic review and indirect pairwise meta-analysis.Ann Rheum Dis. 2012;71:1303-1308.
Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures.J Viral Hepat. 2004;11:97-107.
Yu MC, Yuan JM, Govindarajan S, Ross RK. Epidemiology of hepatocellular carcinoma.Can J Gastroenterol. 2000;14:703-709.
Lavanchy D. Viral hepatitis: global goals for vaccination.J Clin Virol. 2012;55:296-302.
Levrero M, Pollicino T, Petersen J, Belloni L, Raimondo G, Dandri M. Control of cccDNA function in hepatitis B virus infection.J Hepatol. 2009;51 Suppl 3:581-592 [PIMD: 22999800].
McMahon BJ. Natural history of chronic hepatitis B.Clin Liver Dis. 2010;14:381-396.
McMahon BJ, Holck P, Bulkow L, Snowball M. Serologic and clinical outcomes of 1536 Alaska Natives chronically infected with hepatitis B virus.Ann Intern Med. 2001;135:759-768.
Simonetti J, Bulkow L, McMahon BJ, Homan C, Snowball M, Negus S, Williams J, Livingston SE. Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus.Hepatology. 2010;51:1531-1537.
Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS, Colombo M, Craxì A, Donato F, Ferrari C, Gaeta GB. Statements from the Taormina expert meeting on occult hepatitis B virus infection.J Hepatol. 2008;49:652-657.
Chemin I, Guillaud O, Queyron PC, Trépo C. Close monitoring of serum HBV DNA levels and liver enzymes levels is most useful in the management of patients with occult HBV infection.J Hepatol. 2009;51:824-825.
Samal J, Kandpal M, Vivekanandan P. Molecular mechanisms underlying occult hepatitis B virus infection.Clin Microbiol Rev. 2012;25:142-163.
Yuen MF, Wong DK, Fung J, Ip P, But D, Hung I, Lau K, Yuen JC, Lai CL. HBsAg Seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma.Gastroenterology. 2008;135:1192-1199.
American Association for the Study of Liver Diseases, European Association for the Study of the Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection.J Hepatol. 2012;57:167-185.
Lee HW, Lee HJ, Hwang JS, Sohn JH, Jang JY, Han KJ, Park JY, Kim do Y, Ahn SH, Paik YH. Lamivudine maintenance beyond one year after HBeAg seroconversion is a major factor for sustained virologic response in HBeAg-positive chronic hepatitis B.Hepatology. 2010;51:415-421.
Hoofnagle JH. Reactivation of hepatitis B.Hepatology. 2009;49:S156-S165.
Yeo W, Chan HL. Hepatitis B virus reactivation associated with anti-neoplastic therapy.J Gastroenterol Hepatol. 2013;28:31-37.
Droz N, Gilardin L, Cacoub P, Berenbaum F, Wendling D, Godeau B, Piette AM, Dernis E, Ebbo M, Fautrel B. Kinetic profiles and management of hepatitis B virus reactivation in patients with immune-mediated inflammatory diseases.Arthritis Care Res (Hoboken). 2013;65:1504-1514.
Vassilopoulos D. Should we routinely treat patients with autoimmune/rheumatic diseases and chronic hepatitis B virus infection starting biologic therapies with antiviral agents? Yes.Eur J Intern Med. 2011;22:572-575.
McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis.N Engl J Med. 2011;365:2205-2219.
Thalayasingam N, Isaacs JD. Anti-TNF therapy.Best Pract Res Clin Rheumatol. 2011;25:549-567.
Tanaka T, Ogata A, Kishimoto T. Targeting of interleukin-6 for the treatment of rheumatoid arthritis: a review and update.Rheumatol Curr Res. 2013;S4:002.
Humby F, Bombardieri M, Manzo A, Kelly S, Blades MC, Kirkham B, Spencer J, Pitzalis C. Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium.PLoS Med. 2009;6:e1.
Penna A, Artini M, Cavalli A, Levrero M, Bertoletti A, Pilli M, Chisari FV, Rehermann B, Del Prete G, Fiaccadori F. Long-lasting memory T cell responses following self-limited acute hepatitis B.J Clin Invest. 1996;98:1185-1194.
Bertoletti A, Ferrari C. Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection.Postgrad Med J. 2013;89:294-304.
Tzeng HT, Tsai HF, Chyuan IT, Liao HJ, Chen CJ, Chen PJ, Hsu PN. Tumor necrosis factor-alpha induced by hepatitis B virus core mediating the immune response for hepatitis B viral clearance in mice model.PLoS One. 2014;9:e103008.
Höhler T, Kruger A, Gerken G, Schneider PM, Meyer zum Büschenefelde KH, Rittner C. A tumor necrosis factor-alpha (TNF-alpha) promoter polymorphism is associated with chronic hepatitis B infection.Clin Exp Immunol. 1998;111:579-582.
Peng G, Li S, Wu W, Tan X, Chen Y, Chen Z. PD-1 upregulation is associated with HBV-specific T cell dysfunction in chronic hepatitis B patients.Mol Immunol. 2008;45:963-970.
Ben-Ari Z, Mor E, Papo O, Kfir B, Sulkes J, Tambur AR, Tur-Kaspa R, Klein T. Cytokine gene polymorphisms in patients infected with hepatitis B virus.Am J Gastroenterol. 2003;98:144-150.
Schlaak JF, Tully G, Löhr HF, Gerken G, Meyer zum Büschenfelde KH. HBV-specific immune defect in chronic hepatitis B (CHB) is correlated with a dysregulation of pro- and anti-inflammatory cytokines.Clin Exp Immunol. 1999;115:508-514.
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;335:875-877.
Watashi K, Liang G, Iwamoto M, Marusawa H, Uchida N, Daito T, Kitamura K, Muramatsu M, Ohashi H, Kiyohara T. Interleukin-1 and tumor necrosis factor-α trigger restriction of hepatitis B virus infection via a cytidine deaminase activation-induced cytidine deaminase (AID).J Biol Chem. 2013;288:31715-31727.
Rehermann B. Chronic infections with hepatotropic viruses: mechanisms of impairment of cellular immune responses.Semin Liver Dis. 2007;27:152-160.
Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells.Nat Immunol. 2007;8:942-949.
O’Quinn DB, Palmer MT, Lee YK, Weaver CT. Emergence of the Th17 pathway and its role in host defense.Adv Immunol. 2008;99:115-163.
Zhang JY, Zhang Z, Lin F, Zou ZS, Xu RN, Jin L, Fu JL, Shi F, Shi M, Wang HF. Interleukin-17-producing CD4(+) T cells increase with severity of liver damage in patients with chronic hepatitis B.Hepatology. 2010;51:81-91.
Ge J, Wang K, Meng QH, Qi ZX, Meng FL, Fan YC. Implication of Th17 and Th1 cells in patients with chronic active hepatitis B.J Clin Immunol. 2010;30:60-67.
Zhang F, Yao S, Yuan J, Zhang M, He Q, Yang G, Gao Z, Liu H, Chen X, Zhou B. Elevated IL-6 receptor expression on CD4+ T cells contributes to the increased Th17 responses in patients with chronic hepatitis B.Virol J. 2011;8:270.
Galun E, Nahor O, Eid A, Jurim O, Rose-John S, Blum HE, Nussbaum O, Ilan E, Daudi N, Shouval D. Human interleukin-6 facilitates hepatitis B virus infection in vitro and in vivo.Virology. 2000;270:299-309.
Wong VW, Yu J, Cheng AS, Wong GL, Chan HY, Chu ES, Ng EK, Chan FK, Sung JJ, Chan HL. High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B.Int J Cancer. 2009;124:2766-2770.
Thio CL, Mosbruger TL, Kaslow RA, Karp CL, Strathdee SA, Vlahov D, O’Brien SJ, Astemborski J, Thomas DL. Cytotoxic T-lymphocyte antigen 4 gene and recovery from hepatitis B virus infection.J Virol. 2004;78:11258-11262.
Jiang Z, Feng X, Zhang W, Gao F, Ling Q, Zhou L, Xie H, Chen Q, Zheng S. Recipient cytotoxic T lymphocyte antigen-4 +49 G/G genotype is associated with reduced incidence of hepatitis B virus recurrence after liver transplantation among Chinese patients.Liver Int. 2007;27:1202-1208.
Gu X, Qi P, Zhou F, Ji Q, Wang H, Dou T, Zhao Y, Gao C. +49G & gt; A polymorphism in the cytotoxic T-lymphocyte antigen-4 gene increases susceptibility to hepatitis B-related hepatocellular carcinoma in a male Chinese population.Hum Immunol. 2010;71:83-87.
Marra F, Aleffi S, Galastri S, Provenzano A. Mononuclear cells in liver fibrosis.Semin Immunopathol. 2009;31:345-358.
Mohamadkhani A, Naderi E, Sotoudeh M, Katoonizadeh A, Montazeri G, Poustchi H. Clinical feature of intrahepatic B-lymphocytes in chronic hepatitis B.Int J Inflam. 2014;2014:896864.
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;30:1624-1625.
Ostuni P, Botsios C, Punzi L, Sfriso P, Todesco S. Hepatitis B reactivation in a chronic hepatitis B surface antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate.Ann Rheum Dis. 2003;62:686-687.
Vassilopoulos D, Calabrese LH. Viral hepatitis: review of arthritic complications and therapy for arthritis in the presence of active HBV/HCV.Curr Rheumatol Rep. 2013;15:319.
Carroll MB, Bond MI. Use of tumor necrosis factor-alpha inhibitors in patients with chronic hepatitis B infection.Semin Arthritis Rheum. 2008;38:208-217.
Charpin C, Guis S, Colson P, Borentain P, Mattéi JP, Alcaraz P, Balandraud N, Thomachot B, Roudier J, Gérolami R. 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. 2009;11:R179.
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;36:2416-2420.
Caporali R, Bobbio-Pallavicini F, Atzeni F, Sakellariou G, Caprioli M, Montecucco C, Sarzi-Puttini P. Safety of tumor necrosis factor alpha blockers in hepatitis B virus occult carriers (hepatitis B surface antigen negative/anti-hepatitis B core antigen positive) with rheumatic diseases.Arthritis Care Res (Hoboken). 2010;62:749-754.
Vassilopoulos D, Apostolopoulou A, Hadziyannis E, Papatheodoridis GV, Manolakopoulos S, Koskinas J, Manesis EK, Archimandritis AI. Long-term safety of anti-TNF treatment in patients with rheumatic diseases and chronic or resolved hepatitis B virus infection.Ann Rheum Dis. 2010;69:1352-1355.
Mori S. Past hepatitis B virus infection in rheumatoid arthritis patients receiving biological and/or nonbiological disease-modifying antirheumatic drugs.Mod Rheumatol. 2011;21:621-627.
Tamori A, Koike T, Goto H, Wakitani S, Tada M, Morikawa H, Enomoto M, Inaba M, Nakatani T, Hino M. 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. 2011;46:556-564.
Pérez-Alvarez R, Díaz-Lagares C, García-Hernández F, Lopez-Roses L, Brito-Zerón P, Pérez-de-Lis M, Retamozo S, Bové A, Bosch X, Sanchez-Tapias JM. Hepatitis B virus (HBV) reactivation in patients receiving tumor necrosis factor (TNF)-targeted therapy: analysis of 257 cases.Medicine (Baltimore). 2011;90:359-371.
Lan JL, Chen YM, Hsieh TY, Chen YH, Hsieh CW, Chen DY, Yang SS. Kinetics of viral load and risk of hepatitis B virus reactivation in hepatitis B core antibody-positive rheumatoid arthritis patients undergoing anti-tumor necrosis factor therapy.Ann Rheum Dis. 2011;70:1719-1725.
Lee YH, Bae SC, Song GG. Hepatitis B virus reactivation in HBsAg-positive patients with rheumatic diseases undergoing anti-tumor necrosis factor therapy or DMARDs.Int J Rheum Dis. 2013;16:527-531.
Lee YH, Bae SC, Song GG. Hepatitis B virus (HBV) reactivation in rheumatic patients with hepatitis core antigen (HBV occult carriers) undergoing anti-tumor necrosis factor therapy.Clin Exp Rheumatol. 2013;31:118-121.
Ye H, Zhang XW, Mu R, Fang LK, Gu JR, Lin J, Du JF, Chen JW, Chen YJ, Wu LJ. Anti-TNF therapy in patients with HBV infection--analysis of 87 patients with inflammatory arthritis.Clin Rheumatol. 2014;33:119-123.
Nakamura J, Nagashima T, Nagatani K, Yoshio T, Iwamoto M, Minota S. Reactivation of hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs.Int J Rheum Dis. 2014;Apr 4; Epub ahead of print.
Lunel-Fabiani F, Masson C, Ducancelle A. Systemic diseases and biotherapies: understanding, evaluating, and preventing the risk of hepatitis B reactivation.Joint Bone Spine. 2014;81:478-484.
Lok AS, Liang RH, Chiu EK, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study.Gastroenterology. 1991;100:182-188.
Yeo W, Chan TC, Leung NW, Lam WY, Mo FK, Chu MT, Chan HL, Hui EP, Lei KI, Mok TS. Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab.J Clin Oncol. 2009;27:605-611.
Wands JR, Chura CM, Roll FJ, Maddrey WC. Serial studies of hepatitis-associated antigen and antibody in patients receiving antitumor chemotherapy for myeloproliferative and lymphoproliferative disorders.Gastroenterology. 1975;68:105-112.
Koo YX, Tay M, Teh YE, Teng D, Tan DS, Tan IB, Tai DW, Quek R, Tao M, Lim ST. Risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen negative/hepatitis B core antibody positive patients receiving rituximab-containing combination chemotherapy without routine antiviral prophylaxis.Ann Hematol. 2011;90:1219-1223.
Lu S, Xu Y, Mu Q, Cao L, Chen J, Zhu Z, Lou Y, Meng H, Qian W, Tong H. The risk of hepatitis B virus reactivation and the role of antiviral prophylaxis in hepatitis B surface antigen negative/hepatitis B core antibody positive patients with diffuse large B-cell lymphoma receiving rituximab-based chemotherapy.Leuk Lymphoma. 2014;Aug 19; Epub ahead of print.
Pyrpasopoulou A, Douma S, Vassiliadis T, Chatzimichailidou S, Triantafyllou A, Aslanidis S. Reactivation of chronic hepatitis B virus infection following rituximab administration for rheumatoid arthritis.Rheumatol Int. 2011;31:403-404.
Ghrénassia E, Mékinian A, Rouaghe S, Ganne N, Fain O. Reactivation of resolved hepatitis B during rituximab therapy for rheumatoid arthritis.Joint Bone Spine. 2012;79:100-101.
Gigi E, Georgiou T, Mougiou D, Boura P, Raptopoulou-Gigi M. Hepatitis B reactivation in a patient with rheumatoid arthritis with antibodies to hepatitis B surface antigen treated with rituximab.Hippokratia. 2013;17:91-93.
Mitroulis I, Hatzara C, Kandili A, Hadziyannis E, Vassilopoulos D. Long-term safety of rituximab in patients with rheumatic diseases and chronic or resolved hepatitis B virus infection.Ann Rheum Dis. 2013;72:308-310.
Nagashima T, Minota S. Long-term tocilizumab therapy in a patient with rheumatoid arthritis and chronic hepatitis B.Rheumatology (Oxford). 2008;47:1838-1840.
Tsuboi H, Tsujii A, Nampei A, Yoshihara H, Kawano K, Takeuchi E, Shi K. A patient with rheumatoid arthritis treated with tocilizumab together with lamivudine prophylaxis after remission of infliximab-reactivated hepatitis B.Mod Rheumatol. 2011;21:701-705.
Kishida D, Okuda Y, Onishi M, Takebayashi M, Matoba K, Jouyama K, Yamada A, Sawada N, Mokuda S, Takasugi K. Successful tocilizumab treatment in a patient with adult-onset Still’s disease complicated by chronic active hepatitis B and amyloid A amyloidosis.Mod Rheumatol. 2011;21:215-218.
Kim PS, Ho GY, Prete PE, Furst DE. Safety and efficacy of abatacept in eight rheumatoid arthritis patients with chronic hepatitis B.Arthritis Care Res (Hoboken). 2012;64:1265-1268.
Germanidis G, Hytiroglou P, Zakalka M, Settas L. Reactivation of occult hepatitis B virus infection, following treatment of refractory rheumatoid arthritis with abatacept.J Hepatol. 2012;56:1420-1421.
Bell A. The management and utilisation of operating departments. A review of the Bevan Report.NATNEWS. 1990;27:5-7.
De Nard F, Todoerti M, Grosso V, Rossi S, Caporali R, Montecucco C. Safety of the newer biological DMARDs, tocilizumab and abatacept, in rheumatoid arthritis patients with a history of HBV infection: a real life experience. Proceedings of the European League Against Rheumatism Congress; 2014 June 11-14; Paris, France.Ann Rheum Dis. 2014;73:499.
McMahon BJ, Bruden DL, Petersen KM, Bulkow LR, Parkinson AJ, Nainan O, Khristova M, Zanis C, Peters H, Margolis HS. Antibody levels and protection after hepatitis B vaccination: results of a 15-year follow-up.Ann Intern Med. 2005;142:333-341.
Bijl M, Agmon-Levin N, Dayer JM, Israeli E, Gatto M, Shoenfeld Y. Vaccination of patients with auto-immune inflammatory rheumatic diseases requires careful benefit-risk assessment.Autoimmun Rev. 2012;11:572-576.
Geier DA, Geier MR. A case-control study of serious autoimmune adverse events following hepatitis B immunization.Autoimmunity. 2005;38:295-301.
Sturkenboom MC, Fautrel B, Rozenberg S, Bégaud B, Roullet E, Hainzlef O. Vaccinations against hepatitis B and lupus erythematosus.Pharmacoepidemiol Drug Safety. 2000;9:s71.
Shoenfeld Y, Agmon-Levin N. ‘ASIA’ - autoimmune/inflammatory syndrome induced by adjuvants.J Autoimmun. 2011;36:4-8.
Maillefert JF, Sibilia J, Toussirot E, Vignon E, Eschard JP, Lorcerie B, Juvin R, Parchin-Geneste N, Piroth C, Wendling D. Rheumatic disorders developed after hepatitis B vaccination.Rheumatology (Oxford). 1999;38:978-983.
Geier DA, Geier MR. A one year followup of chronic arthritis following rubella and hepatitis B vaccination based upon analysis of the Vaccine Adverse Events Reporting System (VAERS) database.Clin Exp Rheumatol. 2002;20:767-771.
Elkayam O, Yaron M, Caspi D. Safety and efficacy of vaccination against hepatitis B in patients with rheumatoid arthritis.Ann Rheum Dis. 2002;61:623-625.
Ansemant T, Ornetti P, Garrot JF, Pascaud F, Tavernier C, Maillefert JF. Usefulness of routine hepatitis C and hepatitis B serology in the diagnosis of recent-onset arthritis. Systematic prospective screening in all patients seen by the rheumatologists of a defined area--brief report.Joint Bone Spine. 2012;79:268-270.
Salinas GF, De Rycke L, Barendregt B, Paramarta JE, Hreggvidstdottir H, Cantaert T, van der Burg M, Tak PP, Baeten D. Anti-TNF treatment blocks the induction of T cell-dependent humoral responses.Ann Rheum Dis. 2013;72:1037-1043.
Lok AS, Lai CL, Wu PC. Prevalence of isolated antibody to hepatitis B core antigen in an area endemic for hepatitis B virus infection: implications in hepatitis B vaccination programs.Hepatology. 1988;8:766-770.
Stine JG, Khokhar OS, Charalambopoulos J, Shanmugam VK, Lewis JH. Rheumatologists’ awareness of and screening practices for hepatitis B virus infection prior to initiating immunomodulatory therapy.Arthritis Care Res (Hoboken). 2010;62:704-711.
van Assen S, Agmon-Levin N, Elkayam O, Cervera R, Doran MF, Dougados M, Emery P, Geborek P, Ioannidis JP, Jayne DR. EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases.Ann Rheum Dis. 2011;70:414-422.