Though concern of hepatitis B virus (HBV) reactivation by antirheumatic agents has limited therapeutic opportunities in HBV-infected rheumatoid arthritis (RA) patients, the relative risks (RR) among such agents have not been clarified.

We compared the reporting of antirheumatic-agent-associated hepatitis B.

We assessed 92 hepatitis B cases and 98,069 controls from a population of 98,161 RA patients registered into the US Food and Drug Administration's (FDA's) adverse event database between 2004 and 2010.

A reporting odds ratio (ROR), a signal suggesting a risk for hepatitis B among antirheumatic agents, was measured.

Treatment with corticosteroids [ROR 2.3 (95% confidence interval 1.3-4.0)], methotrexate [4.9 (3.9-6.0)], rituximab [7.2 (5.3-9.9)], tacrolimus [4.2 (1.5-11.9)], or reporting from Japan [2.2 (1.1-4.2)] were associated with higher signal, whereas adalimumab had a lower ROR [0.2 (0.1-0.4)].

There are known limitations of spontaneous reporting, such as underreporting, the Weber effect, reporting bias, indication bias, and limited clinical information such as HBV status.

Adalimumab's low reporting rate is most likely be due to notoriety. However, the possibility that adalimumab might suppress reactivation of HBV cannot be denied. Until the possibility is clarified in well-designed clinical studies, physicians should use adalimumab cautiously in patients with HBV.

The emergence of tumor necrosis factor-α (TNF-α)-targeted therapies as a key therapeutic option for patients with rheumatic, digestive, and dermatologic autoimmune diseases has been associated with increasing reports of liver damage in patients with hepatitis B virus (HBV) infection. We studied the current evidence on the use of anti-TNF agents in patients with HBV through a systematic analysis of cases reported in the MEDLINE and EMBASE databases using the MeSH term "hepatitis B virus" combined with the terms "infliximab," "etanercept," "adalimumab," "certolizumab," "golimumab," and "anti-TNF agents," and summarize the results here. We analyzed 257 patients with positive HBV markers who received anti-TNF therapy (255 identified in the search strategy and 2 new cases), 89 HBsAg+ carriers, and 168 anti-HBc+ persons. HBV reactivation was reported in 35 (39%) HBsAg+ carriers. The percentage of reactivation was higher in patients previously treated with immunosuppressive agents (96% vs. 70%, p=0.033) and lower in those who received antiviral prophylaxis (23% vs. 62%, p=0.003). Acute liver failure was reported in 5 patients, 4 of whom died. Infliximab was associated with a higher rate of induced liver disease (raised transaminase levels, clinical signs, viral reactivation, and acute liver failure) compared with etanercept. In anti-HBc+ persons, reactivation was reported in 9 (5%) cases, including 1 patient who died due to fulminant liver failure.In summary, our search of the current evidence identified 257 reported HBV+ patients treated with anti-TNF agents, with a significant percentage of liver damage in HBsAg+ carriers, including raised transaminase levels (42%), signs and symptoms of liver disease (16%), reappearance of serum HBV-DNA (39%), and death related to liver failure (5%). The rate of reactivation in anti-HBc+ persons was 7-fold lower than in HBsAg+ carriers. The increasing number of reported cases of HBV reactivation following TNF-targeted therapies and the associated morbidity and mortality demand specific preventive strategies.

Biological disease-modifying anti-rheumatic drugs (bDMARDs) are effective in the management of inflammatory arthritides. Reactivation of hepatitis B virus (HBV) is a potential adverse outcome in patients treated with bDMARDs. There is currently no consensus on the approach to identifying and treating these patients with underlying HBV infection.

The aims of this study were to assess the risk of HBV reactivation in patients treated with bDMARDs, and to determine whether HBV screening should be carried out in all patients prior to commencing bDMARDs.

A literature search was undertaken to identify all reports of patients with inflammatory arthritides and concurrent HBV infection being treated with bDMARDs.

Forty-three patients with HBV infection were identified, of whom eight patients developed HBV reactivation after exposure to bDMARDs. Of the patients who experienced reactivation, two had unknown infection that surfaced during bDMARD therapy. Patients who experienced reactivation were promptly treated with antiviral therapy and saw clinical improvement. There are no long-term data on these patients.

HBV reactivation may result in serious consequences, including death. Tuberculosis screening prior to bDMARD treatment is already standard practice, as is HBV screening for patients undergoing cancer chemotherapy. Implementing HBV screening for all patients prior to bDMARD treatment can identify patients with chronic HBV who may require antiviral therapy.

A 59-year-old woman with rheumatoid arthritis was treated quite successfully with infliximab, but her serum aminotransferase levels were markedly elevated; this was diagnosed as acute exacerbation of hepatitis B and she was treated with lamivudine, and infliximab was discontinued. The rheumatoid arthritis disease activity was uncontrollable after the discontinuation of infliximab, and we therefore initiated tocilizumab treatment (after obtaining the patient's informed consent) together with lamivudine prophylaxis. After tocilizumab administration her rheumatoid arthritis disease activity was significantly attenuated, and the activity has remained low, without re-exacerbation of the hepatitis, for more than 2 years since the initiation of the tocilizumab.

The conventional treatment of inflammatory bowel disease (IBD) has focused on nonspecifically targeting mucosal inflammation. In the last decade, with the advent of novel biological agents that directly inhibit proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), rapid progress has been made in clinical management of complex and challenging patients with IBD. However, there remain many unanswered questions about the short and long-term side effects; this article focuses on hepatic complications. This review aims to provide a concise update to gastroenterologists on the well-known, as well as the potential rare consequences of anti-TNFα therapy on the liver and recommendations for clinical management. We performed a focused literature review for reports of the effect of anti-TNF therapy on preexisting liver disease as well as de novo hepatitis and drug-induced hepatotoxicity. Search terms used included anti-TNF therapy, biologics, liver disease, inflammatory bowel disease, hepatitis, hepatotoxicity, opportunistic infections,, and hepatitis virus reactivation. There are multiple potential effects of anti-TNF therapy on the liver during treatment of patients with IBD. Often treatment may be complicated by preexisting chronic liver disease. Clinicians should be aware of potential hepatic side effects and appropriate management options.

To evaluate the recent published data on the safety of biological agents, mainly anti-TNFalpha and rituximab, and diagnostic difficulties in the setting of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and inflammatory arthritides.

There are important differences between HBV and HCV carriers; however, clinical observations suggest that hepatotropic virus infection should not preclude the treatment with biologic agents in rheumatic diseases. Retrospective reports on limited series of HBV-infected patients with concomitant chronic arthritis convey that careful patients' clinico-virological assessment, in collaboration with the hepatologist, is necessary before starting immunosuppressive treatments, especially biological agents. Preemptive or combined antiviral treatment is mandatory, mainly in active and inactive HBV carriers. Occult HBV infection should be also carefully evaluated due to potential virus reactivation. In HCV-infected patients without chronic active hepatitis the treatment with biological agents, anti-TNFalpha or rituximab, is generally useful and well tolerated. Preliminary data suggest the possible synergic effects of combined antivirals (alpha-interferon and ribavirin) and anti-TNFalpha (or rituximab) in patients with chronic arthritis and active hepatitis C.

In all patients with chronic arthritis requiring immunomodulating treatments both HBV and HCV infection along with liver conditions should be evaluated before any therapeutic decisions, including differential diagnosis among virus-related autoimmune disease and simple comorbidity. Patients with HBV infection should be referred to the hepatologist and correctly classified into active, inactive, and occult carriers. Similarly, rheumatic patients with active chronic hepatitis C must be treated with sequential or combined treatment with antiviral and biological agents.

To assess the safety of anti-tumor necrosis factor alpha (anti-TNFalpha) therapy on the course of hepatitis B virus (HBV) infection in carriers of antibodies to hepatitis B core antigen (anti-HBc) affected by chronic inflammatory arthropathies.

From January 2001 to December 2008, HBV markers were determined before the first administration of anti-TNFalpha agents in all 732 patients affected by inflammatory arthropathies treated with anti-TNFalpha at 2 outpatient rheumatologic clinics in Northern Italy. Anti-HBc-positive patients were prospectively evaluated and HBV markers and HBV DNA were assessed every 6 months, in case of aminotransferase elevation, and at the end of the study.

At the time of recruitment, 72 patients were anti-HBc carriers, 5 of whom were positive for hepatitis B surface antigen (HBsAg) and not included in the study. The ratio of men:women was 26:41 and the mean +/- SD followup was 42.52 +/- 21.33 months. Of the patients, 25 were treated with infliximab, 23 with etanercept, and 19 with adalimumab. Fifty-one patients were treated also with methotrexate, 52 with nonsteroidal antiinflammatory drugs, and 43 with prednisone (3 with a dosage >7.5 mg/day). All anti-HBc patients were HBV DNA negative at the first observation. During followup, no patient presented HBV reactivation with viral load increase and no patient became HBsAg positive.

Anti-HBc positivity in HBsAg-negative patients is a sign of previous HBV infection and does not indicate chronic hepatitis. In these patients, anti-TNFalpha therapy appears to be quite safe, as no HBV reactivation was found in our study. Nevertheless, careful monitoring is necessary.

Anti-tumour necrosis factor (TNF) therapy is now well established in the treatment of inflammatory bowel disease and the risk of opportunistic infection is recognized. However, specific considerations regarding screening, detection, prevention and treatment of chronic viral infections in the context of anti-TNF therapy in inflammatory bowel disease are not widely adopted in practice.

To provide a detailed and comprehensive review of the relevance of chronic viral infections in the context of anti-TNF therapy in inflammatory bowel disease.

Literature search was conducted using Medline, Pubmed and Embase using the terms viral infection, hepatitis, herpes, CMV, EBV, HPV, anti-TNF, infliximab, adalimumab, certolizumab pegol and etanercept. Hepatitis B and C and HIV had the largest literature associated and these have been summarized in Tables.

Particular risks are associated with the use of anti-TNF drugs in patients with hepatitis B infection, in whom reactivation is common unless anti-viral prophylaxis is used. Reactivation of herpes zoster is the most common viral problem associated with anti-TNF treatment, and may be particularly severe. Primary varicella infection may present with atypical features in patients on anti-TNF.

Appreciation of risks of chronic viral disease associated with anti-TNF therapy may permit early recognition, prophylaxis and treatment.

To evaluate the development of hepatitis B virus (HBV) infection in patients receiving tumor necrosis factor-alpha-blocking agents (TNFBA), and to evaluate whether lamivudine (LAM) prophylaxis can reduce the risk of viral reactivation in inactive HBsAg carriers.

Local experience and published reports were reviewed. Patients with HBV infection were classified as having chronic HBV hepatitis, or being inactive HBsAg carriers or occult carriers.

Three patients in our series and 24 patients in the literature were identified: 2 had active HBV-associated disease, 23 were inactive HBsAg carriers, and 2 occult carriers. When exposed to TNFBA, HBsAg-inactive carriers pretreated with LAM had lower risk of having detectable HBV-DNA (p=0.02) or viral reactivation (p=0.046) than those without LAM prophylaxis. In 3 patients who discontinued TNFBA, LAM prophylaxis was also discontinued 10-12 months thereafter without hepatitis flares. Two cases of reactivation in occult carriers (HBsAg-negative, anti-HBs+, anti-HBc+) were described in the literature.

TNFBA should be avoided in patients with active HBV replication and should be used with caution in inactive HBsAg carriers. In these patients, the risk of viral reactivation seems to be high, but it might be reduced by prophylactic LAM, which should probably be given for a long time when TNFBA are discontinued (e.g., 12 mo). Potential occult carriers might carry a low, but not negligible, risk of viral reactivation. They should therefore be monitored with particular care.

Anti-tumour necrosis factor (TNF) therapy is increasingly used in the management of inflammatory bowel disease; however, concerns have been raised regarding risk of infection with such drugs. Little is known about their effect upon viral infection.

A search of PubMed using the terms 'infliximab', 'etanercept', 'adalimumab' or 'anti-TNF therapy' combined with the names of specific viruses was performed. A search of cited papers was used to identify further relevant reports.

Numerous reports of the use of anti-TNF in patients with chronic or latent viral infection appear in the literature. Specific problems related to hepatitis B virus and varicella zoster virus may exist. The safety profile of anti-TNF in chronic viral infection is generally reassuring.

Numerous consensus statements relating to pre-treatment serology or vaccination have recently appeared; however, significant variation exists in their recommendations.

Increasing awareness of the implications of anti-TNF therapy on viral infection may allow safer use of such drugs.

The clinical and cost-effectiveness of screening for viral infections prior to anti-TNF requires further study.