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.

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[1]. 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[4]. 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[9], RTX[10] and TCZ[11]. Nevertheless, bDMARD monotherapy might be considered in case of contraindications for csDMARDs[12]. 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[13]; similarly, ADA + methotrexate resulted in a remission rate of 34%, against 17% for methotrexate alone[14]. 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[20]. After TNFI failure, no particular bDMARD seems to be better than the others as second line choice[18-21].

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.

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[22]. 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[23]. In western countries the incidence of HBV infection has been furtherly diminished by widespread vaccination programs since the 1980s[24]. 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[25].

Natural history of HBV infection is a dynamic process and runs throughout 4 distinct phases[26].

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[28] (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[32]. Definitions of HBV status in virological, biochemical and serological terms are summarized in Table 2.

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[33]. 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[35].

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[36]. 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[36].

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[38]. The risk may be higher in the event of concomitant methotrexate therapy[38]. 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[39]. 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[38]. 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 1^st-generations NAs as compared with those with a favorable outcome (P = 0.07 and P = 0.03)[38].

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[40]. 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[41]. IL-6, a typical cytokine featuring redundancy and pleiotropic activity, also plays a key role in the development of RA[42], 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[43].

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[44]; moreover, an efficient control of HBV infection requires the synergic actions of both innate and adaptive immunity[45].

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[46]. 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[47]. 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’’)[48]. Genetic polymorphisms leading to lower TNF-α expression associate with an increased risk of HBV chronicization[49]. 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[49]. However, in patients with CHB this cytokine may contribute to liver injury[50]. 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[53]. 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[54]. Th17 cells can produce multiple cytokines that trigger the recruitment and activation of neutrophils leading to massive tissue inflammation[55]. 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[58]. In addition, several studies demonstrated that IL-6 facilitates in vivo and in vitro HBV infection[59] and might be able to predict the development of HCC in HBV infected patients[60]. 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[64]. In patients with HBeAg^- CHB, CD20⁺ B-cells infiltrate the liver and correlate with histologic necroinflammation and fibrosis[65]. 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.

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⁺).

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[39] 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[68]; 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%[68]. 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[88]. 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[89]. 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[90]. 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[91]. 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[92]. Droz et al[38] 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.

Hepatitis B vaccine (HBVv) is a recombinant DNA vaccine that provides protection against HBV infection and its complications, including cirrhosis and HCC[99]. As more than 1 billion doses of vaccine have been used since 1982, it is considered to be safe[100]. 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)[100].

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[103] have been reported[104]. 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)[105]; whilst two studies comparing the risk of RA flare following HBVv with RA controls[106] or with RA prevalence in the same community[104] 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[106]. 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[78]: 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.)[107]. 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[107]: 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[108]. 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[109]. In patients with resolved HBV infection and insufficient antibody protection (anti-HBc⁺/anti-HBs^-), a booster injection might be given to strengthen immunization[109] and to induce the production of protective anti-HBs, whose titer should be then measured.

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].

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.