Rheumatologic Patients With a Previously Resolved
Hepatitis B Viral Infection
Michele Barone,1 Antonella Notarnicola,2 Giuseppe Lopalco,2 Maria Teresa Viggiani,3 Francesco Sebastiani,3 Michele Covelli,2 Florenzo Iannone,2 Alfonso W. Avolio,4 Alfredo Di Leo,3 Luca Cantarini,5 and
Giovanni Lapadula2
European and Asian studies report conflicting data on the risk of hepatitis B virus (HBV) reactivation in rheumatologic patients with a previously resolved HBV (prHBV) infection undergoing long-term biologic therapies. In this patient category, the safety of different immunosuppressive biologic therapies, including rituximab, was assessed. A total of 1218 Caucasian rheumatologic patients, admitted consecutively as outpatients between 2001 and 2012 and taking biologic therapies, underwent evaluation of anti–HCV and HBV markers as well as liver amino transferases every 3 months. Starting from January 2009, HBV DNA monitoring was performed in patients with a prHBV infection who had started immunosup-pressive biologic therapy both before and after 2009. Patients were considered to have ele-vated aminotransferase levels if values were >13 upper normal limit at least once during follow-up. We found 179 patients with a prHBV infection (14 treated with rituximab, 146 with anti–tumor necrosis factor-alpha, and 19 with other biologic therapies) and 959 patients without a prHBV infection or other liver disease (controls). The mean age in the for-mer group was significantly higher than the controls. Patients with a prHBV infection never showed detectable HBV DNA serum levels or antibody to hepatitis B surface antigen/hepati-tis B surface antigen seroreversion. However, when the prevalence of elevated amino transfer-ases in patients with prHBV infection was compared to controls, it was significantly higher in the former group only for aminotransferase levels >13 upper normal limit but not when aminotransferase levels >23 upper normal limit were considered. Conclusion: Among patients with a prHBV infection and rheumatologic indications for long-term biologic thera-pies, HBV reactivation was not seen; this suggests that universal prophylaxis is not justified and is not cost-effective in this clinical setting. (HEPATOLOGY2015;62:40-46)
See Editorial on Page 16
N
owadays, biologic therapies offer various options for effective treatment of several dis-eases, as demonstrated in numerous clinical studies conducted with different types of tumor necro-sis factor-alpha (TNF-alpha) blockers,anti-interleukin-1 (IL-anti-interleukin-1) and anti-IL-6 receptors, CTLA4-Ig, as well as rituximab (a chimeric monoclonal antibody anti-CD20).1-7 In this scenario, an increasing use of bio-logic therapies is expected in the future.
The serologic markers indicating recovery from atitis B viral (HBV) infection include antibody to hep-atitis B surface antigen (anti-HBs) and antibody to hepatitis B core antigen (anti-HBc). In this case, HBV DNA is typically undetectable and alanine Abbreviations: anti-HBc, antibody to hepatitis B core antigen; anti-HBs, antibody to hepatitis B surface antigen; DMARD, disease-modifying antirheumatic drug; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; IL, interleukin; NSAID, nonsteroidal anti inflammatory drug; OBI, occult hepatitis B viral infection; prHBV, previously resolved HBV; TNF, tumor necrosis factor; UNL, upper normal limit.
From the1Gastroenterology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy;2Rheumatology Unit, Medical School, University of Bari, Bari, Italy;3Gastroenterology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy;4Department of Surgery–Transplantation Service, Catholic University of Rome, Rome, Italy; 5Rheumatology Unit, Department Research Center of Systemic Autoimmune and Autoinflammatory Diseases, University of Siena, Siena, Italy.
Received July 14, 2014; accepted January 18, 2015. 40
aminotransferase levels are normal. In the context of solid or bone marrow transplant or treatment with potent immunosuppressive therapy for oncological conditions, reactivation of HBV can occur in these patients,8-10 inducing a potentially life-threatening, severe acute hepatitis.8,11-13
Occult HBV infection (OBI) is defined as the per-sistence of HBV DNA in the liver (with detectable or undetectable HBV DNA in the serum) of individuals with negative hepatitis B surface antigen (HBsAg) by currently available assays. When detectable, the amount of HBV DNA in the serum is usually very low (<200 IU/mL). On the basis of the HBV antibody profile, OBI may be distinguished as seropositive OBI HBc1 and/or anti-HBs1) or seronegative OBI (anti-HBc2 and anti-HBs2).14An OBI should be suspected in patients with serum HBc, with or without anti-HBs and with or without HBV DNA in the serum.
15-17 In fact, as reported by Raimondo et al.17 the
anti-HBc test has a sensitivity of 62.5% in predicting the presence of intrahepatic HBV DNA.
On these premises, it is important to emphasize that patients with a previously resolved HBV (prHBV) infection could have an occult HBV infection. Since biologic therapies administered to rheumatologic patients have significant immunosuppressive effects, there are concerns about the risk of HBV reactivation in those with a prHBV infection, who could have an OBI. For this reason, it has been suggested that all rheumatologic patients who are receiving or are sched-uled to receive biologic therapies should be screened for HBV in order to identify both carriers and individ-uals with a prHBV infection.18
While there is substantial agreement on the thera-peutic strategy to adopt in HBsAg carriers,19,20 European and Asian studies report conflicting data on the risk of HBV reactivation in rheumatologic patients with a prHBV infection undergoing long-term biologic therapies.21-29The present study is the largest prospec-tive trial aimed at evaluating the safety of biologic therapies, including 14 cases treated with rituximab, in rheumatologic patients with a prHBV infection. Our patients underwent follow-up every 3 months, assessing HBV serological markers and liver aminotransferases, while HBV DNA was evaluated
every 12 months or whenever elevated aminotransfer-ases were found.
Patients and Methods
This study was performed in 1218 Caucasian rheu-matologic patients admitted consecutively as outpa-tients to our Rheumatic Diseases Unit, Policlinic Hospital, Bari, Italy, between January 2001 and May 2012, treated with immunosuppressive biologic ther-apy, and included in a prospective register (ClinicalTrials.gov identifier NCT01543594). All patients received biologic drugs (rituximab, anti–TNF-alpha, anti–IL-1 and –IL-6 receptors, and CTLA4-Ig) with or without other antirheumatic drugs (disease-modifying antirheumatic drugs [DMARDs], predni-sone, nonsteroidal anti-inflammatory drugs [NSAIDs]) as required. Our research was carried out in compli-ance with the Helsinki Declaration, and all procedures received local ethics committee approval. All patients gave informed consent to take part in the study.
In all 1218 patients, liver aminotransferases were evaluated from the beginning of biologic therapy in view of the potential hepatic toxicity related to anti-rheumatic drugs. In addition, all patients were screened for HBV markers (HBsAg, anti-HBs, anti-HBc) and anti–hepatitis C virus (HCV). Determination of HBV DNA was introduced as a screening test before 2009, but monitoring (HBV DNA determination prior to and yearly after the beginning of therapy) in all patients was introduced after January 2009. All viral markers were tested at our hospital. Seroreversion was defined as the reversion of negative to positive HBsAg.30
Since liver diseases could be a confounding factor in the assessment of HBV reactivation (exclusion crite-rion), 41 patients were excluded because they were HBV carriers (HBsAg-positive and HBV DNA–posi-tive patients), anti-HCV–posiDNA–posi-tive, or suffering from cholangiopathies or metabolic syndrome. As a result, 183 patients affected by a prHBV infection (cases 183/183 HBc–positive, of which 145 were anti-HBs–positive) and 994 with no previous HBV infec-tion (controls anti-HBc–negative and anti-HBs– negative) were considered in our analyses; 4/183 cases and 35/994 controls were lost to follow-up (Fig. 1).
Address reprint requests to: Michele Barone, M.D., Ph.D., Gastroenterology Unit, Department of Medical and Surgical Sciences, University of Foggia, Ospedali Riuniti di Foggia, Viale Pinto 1, 71122 Foggia, Italy. E-mail: michele.barone@unifg.it; tel: 139-0881-733848; fax: 139-0881-733848.
CopyrightVC2015 by the American Association for the Study of Liver Diseases.
View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27716
In all patients, liver aminotransferases were moni-tored every 3 months, while in the cases with a prHBV infection, HBV markers were also monitored every 3 months. In the latter group, starting from 2009, HBV DNA serum levels were monitored every 12 months. The demographic characteristics and type of treatment of the 179 patients with a prHBV infec-tion are summarized in Table 1.
Levels of HBV DNA were determined by real-time polymerase chain reaction assay (COBAS AmpliPrep/ COBAS Taq-Man HBV Test version 2; Roche Diagnostics). The detection threshold was 19 IU/mL (2.0 log copies/mL).
The HBV serology (HBsAg, HBs, total anti-HBc) was tested by commercial enzyme immunoassay (DiaSorin, Saluggia, Italy). Anti-HCV was detected by commercial enzyme immunoassay (HCV 3.0; Ortho Clinical Diagnostics, Amersham, UK).
Since our patients were from a vast area of southern Italy, routine analyses, including aminotransferase lev-els, were done in different laboratories. For this reason, to avoid bias due to the use of different normal value ranges, we expressed aminotransferase levels as the value found in the patient (international units) and the upper normal limit (UNL, international units), which were considered normal when the ratio was <1. Using this method, each aminotransferase value was compara-ble with its reference value, which was always the same for each patient, and allowed comparison with all the other patients’ values.
Patients were considered to have elevated amino-transferase levels when they were >13 UNL at least once during follow-up.
Statistical Analysis. Statistical analysis for unpaired continuous variables was performed by a t test or the Kruskal-Wallis test. For dichotomous varia-bles the chi-squared test was used. Considering that the percentage of reactivation in the population never exposed to HBV is zero (controls) and in a previously resolved HBV infection is equal to or higher than 3.3% (cases)27 and given a power of 0.90, we needed 143 cases and 715 controls in order to test the study hypothesis, i.e., the percentage of HBV reactivation in patients with a prHBV infection. P < 0.05 was consid-ered statistically significant. Statistical analysis was car-ried out using the SPSS package for Windows (version 20.0).
Results
Patients With a prHBV Infection Treated With Rituximab. A total of 14 patients with rheumatoid arthritis received rituximab (1000 mg, followed by an additional 1000 mg after 2 weeks) for a period of 33.5 6 16.4 months, starting in 10 patients before 2009 and four patients after. In addition to rituximab, 11 patients received low-dose prednisone (<7.5 mg/ day) and 10 patients DMARDS or both, whereas
Table 1. Demographic Characteristics and Type of Rheumatologic Treatment in Patients With and Without
prHBV Infection With prHBV Without prHBV No. patients 179 959 Age (mean6 SD) 57.36 9.6 52.3613.3 Sex (f/m) 104/75 679/280 Diseases Psoriatic arthritis 54 (30.1%) 213 (22.2%) Rheumatoid arthritis 58 (32.4%) 400 (41.7%) Spondyloarthritis 43 (24.0%) 204 (21.3%) Ankylosing spondylitis 17 (9.4%) 59 (6.1%) Others 7 (4.0%) 83 (8.7%)
Patients with rituximab6 other biologic therapy
14 (7.8%) 178 (18.5%)
Treatment duration* 32.2 (15-46) 27.5 (13-38) Patients with anti–TNF-alpha alone 146 (81.5%) 537 (56%)
Treatment duration* 54.8 (22-84) 43.8 (17-70) Patients with other biologic
therapies6 anti–TNF-alpha
19 (10.6%) 244 (25.5%)
Treatment duration* 17.2 (5- 30) 15.7 (4-31) Patients receiving also
DMARDs
135 806
Treatment duration* 50.4 (16-86) 40.6 (8-82) Patients receiving also
prednisone at low dose
82 683
Treatment duration* 42.1 (17-63) 35.9 (13-60) Patients receiving also
prednisone at high dose
7 108
Treatment duration* 21.6 (5-34) 17.5 (10-31)
*Months (median [interquartile range]).
Fig. 1. Study design. *A previously resolved HBV infection. Abbreviation: Pts, patients.
NSAIDs were taken on demand. In all 14 patients, starting from 2009, HBV DNA serum levels were assessed during follow-up and always resulted negative.
In one patient who showed elevated aminotransfer-ases >23 UNL at 3 months from the beginning of the therapy (T1), we immediately performed HBV
DNA determination and HBsAg, which resulted nega-tive. These findings were confirmed at the following controls excluding a possible seroreversion. A 10% decrease of anti-HBs was observed by the end of follow-up (98 IU/L at screening).
Patients With a prHBV Infection Receiving Anti– TNF-Alpha. Anti–TNF-alpha blockers (etanercept 74 patients, infliximab 43 patients, adalimumab 29 patients) were administered to 146 patients for a period of 56.3 6 30.9 months, starting in 88 patients before 2009 and in 58 after. In addition to biologic therapies, 115 patients took DMARDS and 74 predni-sone (67 at low dose and 7 at high dose). The NSAIDs were taken on demand. These 146 patients resulted HBV DNA–negative at the first control in 2009. During follow-up, all 146 patients resulted HBV DNA–negative, while 12 patients showed ele-vated aminotransferases at least once, which resulted >23 UNL only in two cases. In the majority of these patients the increase was observed within 1 year from the beginning of biologic therapy, and only in one case was the condition observed at two consecutive determinations in the course of follow-up. In cases of increased aminotransferase levels, we immediately per-formed HBV DNA and HBsAg determination, which resulted negative. Also in these cases the HBV DNA determination was negative at the following controls and no sign of seroreversion was observed. A decrease of 8 6 7% in anti-HBs was observed by the end of follow-up, which was more evident in patients taking methotrexate (in patients expressing HBsAg anti-bodies, the mean value was 152.4 6 82.7 IU/L at screening). We did not perform separate analyses for patients with different rheumatologic diseases since we never observed any HBV reactivation.
Patients With a prHBV Infection Receiving Other Biologic Therapies With or Without Anti–TNF-Alpha. Nineteen patients received anti–IL-1 recep-tors (anakinra, three patients), anti–IL-6 receprecep-tors (tocilizumab, seven patients), or CTLA4-Ig (abatacept nine patients) for a period of 17.7 6 13.0 months, starting in 10 patients before 2009 and in nine after. In 13 of them, TNF-alpha blockers were associated with the above therapies.
In addition to biologic therapies, 10 patients took DMARDS, four took low-dose prednisone, and all of
them took NSAIDs on demand. All these 19 patients resulted HBV DNA–negative at the first control in 2009 and during follow-up. Five patients showed ele-vated aminotransferases <23 UNL at least once. In these cases aminotransferase elevations were observed in different time periods from the beginning of bio-logic therapy and were transient. Anti-HBs were reduced by 9 6 4% at the end of follow-up, this find-ing befind-ing more evident in patients takfind-ing methotrexate (in patients expressing anti-HBsAg antibodies, the mean value was 62.4 6 52.5 IU/L at screening).
High Aminotransferase Levels in All Patients Undergoing Biologic Therapy. Since we evaluated HBV DNA levels only once per year and, thus, could not exclude the possibility of temporary HBV flares and considering that elevated aminotransferases can represent a surrogate marker of HBV reactivation, we assessed the prevalence of hypertransaminasemia in the group of 179 patients with a prHBV infection and in the group of 959 patients with no history of a prHBV infection. In all patients, aminotransferase levels never increased by more than 3.53 UNL.
During the entire duration of biologic therapies, 17 of the 179 patients with a prHBV infection (three
Table 2. Demographic Characteristics, Type of Rheumatologic Disease, and Treatment in Rheumatologic
Patients With Elevated Aminotransferases
Anti-HBc–Positive Anti-HBc–Negative P No. patients 17 42 Age (mean6 SD) 59.36 9.2 51.96 12.9 0.01* Sex (f/m) 9/8 27/15 0.41† Diseases Psoriatic arthritis 6 (35.3%) 18 (42.85%) 0.59† Rheumatoid arthritis 7 (41.1%) 17 (42.47%) 1† Spondyloarthritis 2 (11.7%) 5 (11.9%) 1† Ankylosing spondylitis 1 (5.9%) 0 (0%) 0.07† Others 1 (5.9%) 2 (4.76%) 0.85† Treatment Rituximab 1 4 0.64† Anti–TNF-alpha alone 12 31 0.80† Other immunosuppressive biologic treatments 4 7 0.53† Associated DMARDs 12/17 37/42 0.10† Follow-up¶ Rituximab 29 32.2 (16-50) n.d.‡ Anti–TNF-alpha 45.5 (20-72) 57.5 (31-98) 0.15§
Other biologic therapies with or without anti–TNF-alpha 19.5 (6-46) 22.7 (9-33) 0.43§ DMARDs 49.0 (28-76) 49 (18-82) 0.72§ *By t test. † By chi-squared test. ‡ Not determinable. § By Kruskal-Wallis test.
¶¶Follow-up corresponds to the overall period of observation and was expressed as months (median [interquartile range]).
patients with values >2x UNL and 14 with <23 UNL) and 42 of the 959 patients with no history of HBV infection (nine patients with values >23 UNL and 33 with <23 UNL) showed increased amino-transferase levels. As shown in Table 2, the two groups of patients were significantly different for age (P < 0.01, by t test) but not for the use of DMARDs or other immunosuppressive treatments. In addition, since in the majority of cases the biologic therapy was added to first-line therapy with methotrexate, it was difficult to establish a cause–effect relationship between aminotransferase elevations and the latter drug. The follow-up period is reported in Table 2.
In our analyses, when we considered all patients with elevated aminotransferases, the prevalence of hypertransaminasemia was significantly higher in patients with a prHBV infection (17/179) compared to anti–HBc-negative patients (42/959) (P < 0.01, by v2 test). On the contrary, when we compared only patients with increased aminotransferases >23 UNL (3/179 versus 9/959), no statistically significant differ-ence was found between the two groups.
Discussion
In the last 10 years, numerous case reports have been published on the risk of HBV reactivation in HBsAg-positive rheumatologic patients treated with immuno-suppressive biologic therapies. These findings have led to the conclusion that in rheumatologic patients who are candidates for immunosuppressive therapy it is essential to carefully evaluate HBV status prior to therapy in order to treat HBV reactivation (in active and inactive HBV carriers at high risk of reactivation exposed to immunosuppressive therapies) or prevent it by universal prophylaxis (in inactive HBV carriers at low risk of reac-tivation exposed to immunosuppressive therapies).8,18
Current American Association for the Study of Liver Diseases and European Association for the Study of the Liver guidelines suggest that patients with a prHBV infection (HBsAg-negative/anti-HBc–positive, undetectable serum HBV DNA) should be carefully monitored, regardless of anti-HBs status, for alanine aminotransferase levels and HBV DNA if receiving chemotherapy and/or immunosuppression and treated with antiviral therapy upon confirmation of HBV reac-tivation.19,20 In addition, Marzano et al.8 have pro-posed universal prophylaxis in patients with a prHBV infection who need to be treated with monoclonal antibodies (rituximab).
Recently, several studies have been focused on rheu-matologic patients with a prHBV infection treated
with TNF-alpha blockers. In European patients, anti– TNF-alpha therapy appears to be safe since no HBV reactivation was observed despite the fact that no anti-viral prophylaxis had been administered.21-23 In these studies, the HBV DNA detection threshold ranged from 1.7 to 2.5 log copies/mL, the number of patients with past HBV infection ranged 19-67, and the mean follow-up period ranged 12-43 months. Two case reports, however, led to opposite conclusions, demon-strating HBV reactivation in patients with a prHBV infection treated with TNF-alpha blockers.24,25On the other hand, in three studies conducted in Asian rheu-matologic patients with a prHBV infection, HBV DNA reactivation was reported in 2.2%-5.2% of cases26-28 after biologic therapy or conventional DMARDs. In addition, Kim et al.,29 in a study con-ducted in 88 rheumatologic patients with a prHBV infection treated with TNF-alpha blockers, using eval-uation of aminotransferases as a surrogate marker of HBV reactivation, suggested that the therapy can induce HBV reactivation. However, the same authors recommended that further studies be conducted to confirm whether abnormal aminotransferase levels are really related to the reactivation of an occult HBV infection.29
As far as the risk of HBV reactivation in patients taking rituximab is concerned, several studies in the literature show that 3%-45% of patients with lympho-proliferative disease can suffer HBV reactivation.31 For this reason, some experts suggest administering lamivu-dine prophylaxis in all HBsAg-negative/anti-HBc–posi-tive patients receiving rituximab and/or combined regimens for hematological malignancies (grade of evi-dence and recommendation C2).8,19,20 However, there are no specific recommendations for rheumatologic patients with a prHBV infection receiving rituximab. To our knowledge, only one study has been reported in the literature, which included 12 rheumatologic patients with a prHBV infection treated with rituxi-mab for a median period of 13 months. The authors concluded that no patient underwent HBV reactiva-tion, as demonstrated by close monitoring of HBV DNA, but did not report any information about ami-notransferase levels,32 which could have been useful to evaluate possible drug-related hepatotoxicity.
Our data demonstrate that none of the 179 patients with a prHBV infection underwent seroreversion dur-ing biologic treatment. In fact, HBV DNA always resulted negative and no statistically significant increase of aminotransferase levels was observed when compar-ing patients with a prHBV infection with anti-HBc– negative patients, using an aminotransferases cutoff of
>23 UNL. The higher prevalence of aminotransferase elevations >13 UNL in anti-HBc–positive patients compared to patients without a prHBV infection was not related to the use of DMARDs since the propor-tion of patients taking these drugs was similar in the two groups but was probably due to the significantly older age of anti-HBc–positive patients (Table 2), pos-sibly associated with an increased number of comor-bidities and the use of other drugs. In addition, it was difficult to establish a cause–effect relationship between aminotransferase elevations and methotrexate since in the majority of cases the biologic therapy was added to first-line therapy with methotrexate.
Regarding HBV reactivation, the apparent discrep-ancy between Asian and European studies (including ours) could be explained by the different virological characteristics in the two geographic areas.33 In fact, as recently suggested, this virological aspect has a poten-tial role in influencing the outcome of reactivation in oncohematological patients undergoing immunosup-pressive therapy.34
The prevalence of anti-HBc positivity is related to the prevalence of HBV infection in the general popu-lation and is low in most Western countries (about 7%), although it appears to increase with age.35In our 1218 rheumatologic patients we found anti-HBc posi-tivity in 216 (17.7%), a similar value to the one observed in Italian patients with oncohematological disease with a prHBV infection (18.8%).36
Finally, since we demonstrated that the incidence of seroreversion in our patient population was zero and considering that the kinetics of HBV marker serorever-sion are similar to those of aminotransferases, i.e., 8-10 weeks after HBV DNA elevation,30 simply deter-mining liver enzymes may be considered adequate for monitoring our patient population.
Our study suffers from some limitations. (1) We did not evaluate the HBV genotype; however, all our patients were Italian and so presumed to have been previously affected by a genotype D virus. (2) Our findings are applicable to our geographic area and can-not be extended to Asian countries. (3) We evaluated HBV DNA levels only once a year considering the large number of patients enrolled, and therefore, we cannot exclude the possibility that temporary HBV flares could have occurred during follow-up (as described in Asian studies on rheumatologic patients with a prHBV infection)26,27; however, since we eval-uated HBV markers and aminotransferases every 3 months, we can reliably state that HBV reactivation never occurred in our patients. (4) We are aware that HBV reactivation during immunosuppressive treatment
is higher in the first year of the treatment,26 and there-fore the incidence of HBV reactivation might be underestimated in patients starting immunosuppressive therapy before 2009; however, HBV DNA was eval-uated prospectively in the 72 (40.2%) patients enrolled after 2009. (5) We did not perform liver biopsy to identify the OBI status since we already know that about 60% of anti-HBc–positive Italian patients have an OBI17; in addition, since there is the possibility that an OBI could be anti-HBc– and anti-HBs– negative, the evaluation of OBI status by liver biopsy should also have been extended to patients without signs of a prHBV infection.
The strengths of our study are (1) the large number of patients enrolled (n 5 1218); (2) the long period of observation; (3) the evaluation of 14 patients treated with rituximab (the highest number reported in the lit-erature); (4) the evaluation of immunosuppressive bio-logic therapies other than anti–TNF-alpha in 19 patients treated with IL-1 receptors (anakinra, three patients), anti–IL-6 receptors (tocilizumab, seven patients), or CTLA4-Ig (abatacept nine patients).
Considering that the prevalence of rheumatologic patients with a prHBV infection is high, while the incidence of seroreversion among our patient popula-tion was zero, universal prophylaxis is not justified and is not cost-effective in this clinical setting. Even if the number of patients receiving rituximab was limited, this concept may be extended to these patients.
References
1. Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343: 1586-1593.
2. St Clair EW, Van Der Heijde DM, Smolen JS, Maini RN, Bathon JM, Emery P, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 2004;50:3432-3443.
3. Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimu-mab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 2006; 54:26-37.
4. Rubbert-Roth A. Assessing the safety of biologic agents in patients with rheumatoid arthritis. Rheumatology (Oxford) 2012;51:38-47. 5. Ash Z, Emery P. The role of tocilizumab in the management of
rheu-matoid arthritis. Expert Opin Biol Ther 2012;12:1277-1289. 6. Moots RJ, Naisbett-Groet B. The efficacy of biologic agents in patients
with rheumatoid arthritis and an inadequate response to tumour necro-sis factor inhibitors: a systematic review. Rheumatology (Oxford) 2012; 51:2252-2261.
7. Bokarewa M, Lindholm C, Zendjanchi K, Nadali M, Tarkowski A. Efficacy of anti-CD20 treatment in patients with rheumatoid arthritis
resistant to a combination of methotrexate/anti-TNF therapy. Scand J Immunol 2007;66:476-483.
8. Marzano A, Angelucci E, Andreone P, Costantino L, Colloredo G, Cucinotta E, et al.; Italian Association for the Study of the Liver. Prophylaxis and treatment of hepatitis B in immunocompromised patients. Dig Liver Dis 2007;39:397-408.
9. Perrillo RP. Acute flares in chronic hepatitis B: the natural and unnatu-ral history of an immunologically mediated liver disease. Gastroenterology 2001;120:1009-1022.
10. Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok AS. Management of hepatitis B: summary of a clinical research workshop. HEPATOLOGY
2007;45:1056-1075.
11. Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. HEPATOLOGY 2006;43:
209-220.
12. Lubel JS, Angus PW. Hepatitis B reactivation in patients receiving cytotoxic chemotherapy: diagnosis and management. J Gastroenterol Hepatol 2010;25:864-871.
13. Targhetta C, Cabras MG, Mamusa AM, Mascia G, Angelucci E. Hepatitis B virus–related liver disease in isolated anti-hepatitis B-core positive lymphoma patients receiving chemo- or chemo-immune ther-apy. Haematologica 2008;93:951-952.
14. Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS, Colombo M et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol 2008;49:652-657. 15. Torbenson M, Thomas DL. Occult hepatitis B. Lancet Infect Dis
2002;2:479-486.
16. Raimondo G, Pollicino T, Cacciola I, Squadrito G. Occult hepatitis B virus infection. J Hepatol 2007;46:160-170.
17. Raimondo G, Navarra G, Mondello S, Costantino L, Colloredo G, Cucinotta E, et al. Occult hepatitis B virus in liver tissue of individuals without hepatic disease. J Hepatol 2008;48:743-746.
18. Calabrese LH, Zein NN, Vassilopoulos D. Hepatitis B virus (HBV) reactivation with immunosuppressive therapy in rheumatic diseases: assessment and preventive strategies. Ann Rheum Dis 2006;65:983-989.
19. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. HEPATOLOGY
2009;50:661-662.
20. 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.
21. Vassilopoulos D, Apostolopoulou A, Hadziyannis E, Papatheodoridis GV, Manolakopoulos S, Koskinas J, et al. 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.
22. Caporali R, Bobbio-Pallavicini F, Atzeni F, Sakellariou G, Caprioli M, Montecucco C, et al. 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.
23. Charpin C, Guis S, Colson P, Borentain P, Mattei JP, Alcaraz P, et al. Safety of TNF-blocking agents in rheumatic patients with serology sug-gesting past hepatitis B state: results from a cohort of 21 patients. Arthritis Res Ther 2009;11:R179.
24. Montiel PM, Solis JA, Chirinos JA, Casis B, Sanchez F, Rodriguez S. Hepatitis B virus reactivation during therapy with etanercept in an HBsAg-negative and anti-HBs-positive patient. Liver Int 2008;28:718-720. 25. Zingarelli S, Frassi M, Bazzani C, Scarsi M, Puoti M, Airo P. Use of
tumor necrosis factor–alpha-blocking agents in hepatitis B virus–posi-tive patients: reports of 3 cases and review of the literature. J Rheumatol 2009;36:1188-1194.
26. Urata Y, Uesato R, Tanaka D, Kowatari K, Nitobe T, Nakamura Y, et al. Prevalence of reactivation of hepatitis B virus replication in rheu-matoid arthritis patients. Mod Rheumatol 2011;21:16-23.
27. Mori S. Past hepatitis B virus infection in rheumatoid arthritis patients receiving biological and/or nonbiological disease-modifying antirheu-matic drugs. Mod Rheumatol 2011;21:621-627.
28. Tamori A, Koike T, Goto H, Wakitani S, Tada M, Morikawa H, et al. Prospective study of reactivation of hepatitis B virus in patients with rheumatoid arthritis who received immunosuppressive therapy: evalua-tion of both HBsAg-positive and HBsAg-negative cohorts. J Gastroenterol 2011;46:556-564.
29. Kim YJ, Bae SC, Sung YK, Kim TH, Jun JB, Yoo DH, et al. Possible reactivation of potential hepatitis B virus occult infection by tumor necrosis factor-alpha blocker in the treatment of rheumatic diseases. J Rheumatol 2010;37:346-350.
30. Hui CK, Cheung WW, Zhang HY, Au WY, Yueng YH, Leung AY, et al. Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy. Gastroenterology 2006;131:59-68.
31. Evens AM, Jovanovic BD, Su YC, Raisch DW, Ganger D, Belknap SM, et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. Ann Oncol 2011;22:1170-1180.
32. 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.
33. Lin CL, Kao JH. The clinical implications of hepatitis B virus geno-type: recent advances. J Gastroenterol Hepatol 2011;26:123-130. 34. Sugauchi F, Tanaka Y, Kusumoto S, Matsuura K, Sugiyama M,
Kurbanov F, et al. Virological and clinical characteristics on reactivation of occult hepatitis B in patients with hematological malignancy. J Med Virol 2011;83:412-418.
35. Samuel D, Forns X, Berenguer M, Trautwein C, Burroughs A, Rizzetto M, et al. Report of the monothematic EASL conference on liver trans-plantation for viral hepatitis (Paris, France, January 12-14, 2006). J Hepatol 2006;45:127-143.
36. Marignani M, Gigante E, Begini P, Marzano A, di Fonzo M, Deli I, et al. Patients with hematological malignancies and serological signs of prior resolved hepatitis B. World J Gastrointest Oncol 2012;4:37-45.
