Reactivation of hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs

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1 International Journal of Rheumatic Diseases 2016; 19: ORIGINAL ARTICLE Reactivation of hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs Jun NAKAMURA, Takao NAGASHIMA, Katsuya NAGATANI, Taku YOSHIO, Masahiro IWAMOTO and Seiji MINOTA Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, Tochigi, Japan Abstract Objective: To examine the incidence of hepatitis B virus (HBV) reactivation in patients with rheumatoid arthritis (RA) receiving biological disease-modifying antirheumatic drugs (DMARDs). Methods: We retrospectively reviewed RA patients treated with biological DMARDs at our institution from July 2010 to December Patients with antibodies for hepatitis B core antigen and/or hepatitis B surface antigen were regarded as having prior HBV infection. Clinical data on these patients, including HBV-DNA levels, were retrieved from the medical records. Results: During the study period, 251 patients were administered various biological DMARDs. Six patients with a history of HBV vaccination and one patient with positive HBV surface antigen were excluded from the study. Fifty-seven of the remaining 244 patients (23.4%) had prior HBV infection. These patients were followed for a median of 18 months (range: 2 27 months) and HBV-DNA was examined a median of seven times (range: 2 27). HBV-DNA was detected in three patients (5.3%), comprising two receiving tocilizumab and one receiving etanercept. However, HBV-DNA levels were below the quantitation limit (<2.1 log copies ml 1 ) in all three patients. HBV-DNA became negative again within several months in all three patients, while biological DMARDs were continued and liver function tests remained normal throughout. Conclusion: HBV-DNA reactivation occurred in 5.3% of RA patients with prior HBV infection during treatment with biological DMARDs, but there were no associated clinical manifestations. Accordingly, it seems that biological DMARDs can be used safely in patients with RA. Key words: de novo hepatitis, hepatitis B virus, rheumatoid arthritis, tumor necrosis factor. INTRODUCTION Rheumatoid arthritis (RA) is a systemic inflammatory arthritis in which proliferative synovitis is the essential pathology. Various biological disease-modifying Correspondence: Takao Nagashima, Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, Yakushiji , Shimotsuke, Tochigi, , Japan. naga4ma@jichi.ac.jp antirheumatic drugs (DMARDs) targeting specific molecules have been recently developed that strongly suppress inflammation and improve the quality of life of RA patients. However, biological DMARDs also have a strong influence on the immune system, leading to a risk of serious infection. 1 3 Reactivation of hepatitis B virus (HBV) is one of the recent emerging problems in RA patients on treatment with biological DMARDs. 4 There have been reports about HBV reactivation in patients with a history of HBV infection (i.e., negative for HBV surface antigen 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd

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

3 J. Nakamura et al. with TCZ and abatacept (ABT). None of the patients received prophylactic antiviral therapy. HBV-DNA was negative in all of the patients at the first examination. During the observation period, HBV-DNA was detected at least once in three out of 57 patients (5.3%). Two patients were using TCZ and one was taking etanercept (ETN) (Table 2). HBV-DNA levels were below the quantitation limit (<2.1 log copies ml 1 ) at all times in these three patients and HBV-DNA spontaneously became undetectable within several months while they continued to use biological DMARDs. Antiviral therapy was not required and liver function tests did not change significantly while HBV-DNA was positive. The patients in whom HBV- DNA was detected are described next. Patient 1 A 75-year-old man with a 1.5-year history of RA had been treated with methotrexate (6 mg week 1 ). He started TCZ therapy along with prednisolone (5 mg day 1 ) in May The disease activity score 28 C-reactive protein (DAS28-CRP) was 4.45 and the clinical disease activity index (CDAI) was HBV- DNA was undetectable at that time, and the assay was repeated at monthly intervals. Methotrexate was discontinued in June. HBV-DNA became detectable in July 2012, after two infusions of TCZ, although the actual level was <2.1 log copies ml 1. HBV-DNA fluctuated between being undetectable or detectable in August and September 2012, but finally became undetectable in Table 2 Comparison of clinical parameters between patients with and without HBV reactivation HBV reactivation (+) (n = 3) HBV reactivation ( ) (n = 54) P value Women, n (%) 2 (67) 45 (83) 0.92 Age, years 60 (55 75) 64 (36 81) Disease duration, years 8 (1.5 25) 7.5 ( ) Observation period, months 7 (5 21) 18.5 (2 27) Anti HBc positive, n (%) 3 (100) 46 (85) 0.63 Anti HBs positive, n (%) 2 (67) 44 (82) 0.91 Titer (miu ml 1 ) 31.0 ( ) ( ) No. of HBV DNA measurements 6 (6 9) 7 (2 27) AST (U L 1 ) 21 (15 39) 20 (9 58) ALT (U L 1 ) 14 (11 34) 14 (7 129) LD (U L 1 ) 197 ( ) 201 ( ) CRP (mg dl 1 ) 2.89 ( ) 1.6 ( ) DAS28 CRP 4.89 ( ) 4.52 ( ) DMARDs Methotrexate, n (%) 2 (67) 40 (74) 0.83 Methotrexate dose (mg week 1 ) 6 (2 8) 8 (2 16) Sulfasalazine, n 0 4 Bucillamine, n 0 4 Tacrolimus, n 0 1 Cyclosporine, n 0 1 Prednisolone (%) 3 (100) 39 (72) 0.39 Prednisolone dose (mg day 1 ) 5 (3 5) 5 ( ) Biological agent Infliximab, n 0 20 Etanercept, n 3 19 Adalimumab, n 1 11 Tocilizumab, n 2 16 Abatacept, n 0 2 Values are shown as the median (range), unless otherwise specified. HBV, hepatitis B virus; AST, aspartate aminotransferase (normal range, 30); ALT, alanine aminotransferase (normal range, 30); LD, lactate dehydrogenase (normal range, 216); CRP, C-reactive protein (normal range, 0.14); DAS, Disease Activity Score; DMARDs, disease-modifying antirheumatic drugs. Liver function tests are from the first day of HBV-DNA measurement, while CRP and DAS28-CRP are from the start of treatment with biological agents. Some patients were treated with several biological agents. Biological agents used before July 2010 were excluded from this table. 472 International Journal of Rheumatic Diseases 2016; 19:

4 HBV reactivation with biological DMARDs October. Due to lack of efficacy (DAS28-CRP and CDAI were 2.54 and 20.8, respectively), TCZ was switched to ETN in November HBV-DNA remained undetectable thereafter. Patient 2 A 55-year-old woman with an 8-year history of RA had been treated with infliximab (IFX) for 25 months, followed by ETN for a further 53 months. ETN was discontinued in February 2012, while TCZ was started as a third biological DMARD in June. Evidence of prior HBV infection was found at this time, but HBV- DNA was undetectable. She was taking prednisolone (5 mg day 1 ) plus methotrexate (8 mg week 1 ). The DAS28-CRP and CDAI were 4.89 and 30.6, respectively. Monthly assays were done thereafter and HBV-DNA was first detected in August 2012 after two infusions of TCZ. The HBV-DNA level was <2.1 log copies ml 1.In September 2012, TCZ was switched to adalimumab (ADA) because of a poor response (DAS28-CRP and CDAI were 5.0 and 33.7, respectively). After being detected for 3 months, HBV-DNA became undetectable in November 2012 while she was on ADA. The patient was hospitalized due to pericarditis in the same month and ADA was discontinued. Patient 3 A 60-year-old woman with a 25-year history of RA had been treated with ETN as well as prednisolone (3 mg day 1 ) plus methotrexate (2 mg week 1 ) since August Evidence of prior HBV infection was found in July 2010, but HBV-DNA was not detected. Although HBV-DNA became detectable at <2.1 log copies ml 1 in January 2011, it was not detected in August 2011 (HBV-DNA was not measured from February to July 2011). Thereafter, measurement was repeated three times at intervals of 2 5 months up to April 2012, but HBV-DNA remained undetectable. The patient remained on ETN therapy throughout this period. DISCUSSION In the present study, the incidence of HBV reactivation was 5.3% in RA patients on treatment with biological DMARDs, being found in one out of 48 patients (2.1%) receiving TNF inhibitors and two out of 18 patients (11.1%) using TCZ. However, HBV-DNA levels were always below the quantitation limit, fluctuating between the detectable and undetectable range. In addition, liver function tests did not change significantly, de novo hepatitis did not occur and no patient required antiviral therapy. In previous Japanese reports, the incidence of HBV reactivation among RA patients treated with biological DMARDs has varied. One study found no HBV reactivation among 42 patients with a history of HBV infection who were using TNF inhibitors. 11 In another study, the HBV reactivation rate was 3.2% (1/31 patients), and HBV-DNA disappeared spontaneously after 2 months. 12 The highest reported incidence of HBV reactivation is 11.5% (6/52 patients) by Urata et al. 4 In contrast, TNF inhibitors have not been associated with HBV reactivation in European studies According to a study from Taiwan, HBV-DNA was positive in 1/70 RA patients (1.4%) with prior HBV infection and that patient had occult HBV infection before starting treatment (HBsAg was negative, anti-hbc and HBV-DNA were positive). 16 One of the main reasons for the difference in the reported incidence seems to be the interval between HBV-DNA assays. In the studies from Europe and Taiwan, the interval between HBV- DNA assays was 6 12 months, or DNA was only measured once at the end of the study In contrast, testing was performed every 2 3 months in the Japanese studies. 4,11 In our patients 1 and 2 from the present study, HBV-DNA was tested at monthly intervals. If HBV-DNA is only measured once every 6 months, reactivation of HBV might well be missed. Another reason could be a difference of HBV genotypes, since the prevalence of HBV genotypes varies between countries. 18 Up to now, post-marketing surveillance of biological agents in Japan has not detected any cases of de novo hepatitis due to HBV reactivation These studies were of sufficient size to detect uncommon adverse events, although the observation period was only 6 months. A nationwide survey of fulminant hepatitis and late-onset hepatic failure was conducted in Japan from 2004 to Among 488 patients with fulminant hepatitis or late-onset hepatic failure, 17 patients had de novo hepatitis that developed after they started immunosuppressive therapy or chemotherapy. However, none of the 17 patients had rheumatic diseases. So far, only three cases of de novo hepatitis have been reported worldwide during treatment with TNF inhibitors Two of the patients were successfully treated with lamivudine, but one patient (reported from Japan) died of hepatic failure and sepsis. 22 Considering the large number of patients treated with TNF inhibitors worldwide for rheumatic, gastrointestinal and dermatologic diseases, we can conclude that de novo hepatitis is quite rare. International Journal of Rheumatic Diseases 2016; 19:

5 J. Nakamura et al. Compared with TNF inhibitors, there have been few reports about ABT and TCZ in patients with prior HBV infection. 4,25,26 Because ABT inhibits co-stimulation of T cells, it may suppress immune surveillance for HBV. 27 In fact, two cases of HBV reactivation have been reported in RA patients with prior HBV infection using ABT. 25,26 In our study, only 18 patients were treated with TCZ and two patients used ABT, with HBV reactivation being observed in two of the 18 patients receiving TCZ. However, it is unclear whether TCZ induces HBV reactivation more frequently than TNF inhibitors because the number of patients in our TCZ group was too small to draw a firm conclusion. Hepatitis B virus reactivation may be relatively frequent in RA patients receiving various immunosuppressive therapies. HBV reactivation does not necessarily lead to abnormal liver function and it could be missed in many cases. 28 As well as biological DMARDs, conventional DMARDs and glucocorticoids have been associated with HBV reactivation. 4,11,12,29,30 Two cases of de novo hepatitis have been reported in patients taking methotrexate plus prednisolone, with the outcome being fatal in one. 29,31 In the other patient, prior HBV infection was not confirmed because anti-hbc was not measured before starting treatment. 31 Generally, HBV reactivation is not clinically significant in most RA patients and HBV-DNA becomes negative again without antiviral therapy, as occurred in our patients. 4,12,30,32 Our study had several limitations. First, because it was retrospective, HBV-DNA was not measured according to a single protocol and testing was decided by the attending physicians. Second, HBV-DNA was not examined at our institution in patients treated with conventional DMARDs alone, so the incidence of HBV reactivation could not be compared between our patients before and after starting biological DMARDs. Third, serological parameters (including HBsAg and anti-hbs) were not examined simultaneously with measurement of HBV-DNA. Thus, it is unclear whether HBV reactivation occurred in association with disappearance of anti-hbs, or whether reappearance of HBsAg occurred simultaneously with detection of HBV-DNA. In conclusion, our findings suggest that biological DMARDs can be used safely in RA patients with prior HBV infection. Further studies are needed to determine whether the incidence of HBV reactivation is higher in patients treated with TCZ or ABT than in those receiving TNF inhibitors. REFERENCES 1 Komano Y, Tanaka M, Nanki T et al. 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