Abstract

Objective . To assess the safety of anti-tumour necrosis factor (TNF)-α therapy in patients with rheumatoid arthritis (RA) or spondylarthropathies (SA) and concurrent chronic hepatitis B or C.

Methods . Records concerning 480 outpatients attending the Rheumatology Department of the University Hospital of Nice (France) for RA or SA were retrospectively reviewed for the duration of disease, treatment, serological status and biological data.

Results . Six relevant cases were identified: two of RA with chronic hepatitis B; one of SA with chronic hepatitis B and three of RA with chronic hepatitis C. Five patients had received etanercept and one infliximab; two had been given adalimumab after an unsuccessful trial of etanercept. Patients with concurrent chronic hepatitis B were also given lamivudine. In none of the cases had changes in serum aminotransferases or viral load been reported.

Conclusion . The use of anti-TNF-α therapy (plus lamivudine in the presence of concurrent underlying hepatitis B viral infection) appeared to be safe in that it had no effect on serum aminotransferases and/or viral load. However, repeated monitoring is necessary throughout the treatment period.

Introduction

There is good evidence that the cytokine tumour necrosis factor-α (TNF-α) mediates inflammation and cellular immune response [ 1 , 2 ] and plays a key role in the integrated host defence system against infection. Liver toxicity of anti-TNF-α agents is rare, other than in anecdotal reports of events, such as cholestasis after infliximab infusion [ 3 ] and hepatic inflammation after infliximab therapy [ 4 ]. TNF-α inhibition is followed by increased susceptibility to various infections [ 5 ]. Hepatitis B and C are common conditions that may be problematical because of the potential complications associated with immunosuppression in chronically infected individuals [ 6 ]. The literature regarding the safety of TNF-α inhibitors in the setting of chronic viral infections is limited. The present article reports experience with etanercept, adalimumab and infliximab in the management of patients with rheumatoid arthritis (RA) or spondylarthropathies (SA) and concurrent chronic hepatitis B or C.

Patients and methods

Inclusion criteria for the study were: The charts of all subjects were reviewed retrospectively for the duration of disease and its nature (RA or SA, chronic hepatitis B or C), clinical characteristics and use of disease-modifying anti-rheumatic drugs (DMARDs). Time-points of interest were baseline and once a month during anti-TNF-α therapy. Data were gathered on: serum aminotransferases (aspartate aminotransferase: ASAT, alanine aminotransferase: ALAT) and HCV or HBV load.

  • RA (American College of Rheumatology 1987 criteria) or SA (European Spondylarthropathy Group criteria);

  • documented seropositivity for hepatitis B virus (HBV) or hepatitis C virus (HCV);

  • no evidence of decompensated liver disease before anti-TNF-α therapy;

  • treatment with an anti-TNF-α medication.

All patients with hepatitis B were assessed for serological status (HBsAg, HBeAg, anti-HBs, anti-HBc and anti-HBe). In hepatitis B: HBsAg becomes detectable 6–10 weeks after exposure, anti-HBs increases after 4–6 months, when HBsAg falls. IgM anti-HBc appears shortly after HBsAg and during flares of chronic hepatitis. It persists for 6–24 months, and then gives way to IgG anti-HBc during the resolution of HBV infection. HBeAg can be detected 6–12 weeks after exposure. It is associated with transmissibility, infectivity and active viral replication, and persistence signifies advance to chronic HBV infection. Clearance of HBeAg is associated with seroconversion to anti-HBe [ 7 ].

HBV load was determined using a branched chain DNA assay technique (Bayer Versant HBV DNA Assay version 3.0). HCV RNA was quantified using a Versant HCV-RNA 3.0 (b-DNA Bayer) AFSSAPS S74302 assay.

Results

Viral hepatitis was identified in six of 480 outpatients receiving anti-TNF-α treatment. Two had RA with chronic hepatitis B; one had SA with chronic hepatitis B and three had RA with chronic hepatitis C ( Table 1 ). Five of the six received etanercept (three RA and HBV, two RA and HCV) and one infliximab (SA and HBV). Two were given adalimumab after an unsuccessful trial of etanercept. All HBV patients were given lamivudine 100 mg/day, which has been shown to be of benefit in HBeAg-negative chronic hepatitis B [ 8 ]. Methotrexate was administered with anti-TNF-α therapy in three cases.

T able 1.

Patient characteristics

 Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 
Age (yrs) 54 53 49 49 50 63 
Sex 
Anti-TNF-α treatment Etanercept, then adalimumab Etanercept Infliximab Etanercept, then adalimumab Etanercept Etanercept 
Anti-TNF-α treatment duration (months) 11 and 10 26 3 and 3 19 39 
Associated DMARDs MTX   MTX MTX  
Rheumatic disease RA RA SA RA RA RA 
Viral disease HBV HBV HBV HCV HCV HCV 
Rheumatic disease duration (months) 48 216 300 84 60 240 
Viral disease duration (months) 48 96 27 156 204 84 
 Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 
Age (yrs) 54 53 49 49 50 63 
Sex 
Anti-TNF-α treatment Etanercept, then adalimumab Etanercept Infliximab Etanercept, then adalimumab Etanercept Etanercept 
Anti-TNF-α treatment duration (months) 11 and 10 26 3 and 3 19 39 
Associated DMARDs MTX   MTX MTX  
Rheumatic disease RA RA SA RA RA RA 
Viral disease HBV HBV HBV HCV HCV HCV 
Rheumatic disease duration (months) 48 216 300 84 60 240 
Viral disease duration (months) 48 96 27 156 204 84 

MTX, methotrexate.

Follow-up data on viral load and aminotransferases are presented in Tables 2 and 3 .

T able 2.

Chronic viral hepatitis B: serological profile and viral load

 Case 1 Case 2 Case 3 
Serological profile    
    HBsAg 
    HBeAg − − − 
    Anti-HBs − − − 
    Anti-HBc 
    Anti-HBe 
Viral load    
    Baseline 38 IU/ml 1673 IU/ml <380 IU/ml 
    End of follow-up 69 IU/ml 6 IU/ml <380 IU/ml 
ASAT    
    Baseline 12 IU/ml 17 IU/ml 27 IU/ml 
    End of follow-up 14 IU/ml 20IU/ml 17 IU/ml 
ALAT    
    Baseline 14 IU/ml 22 IU/ml 17 IU/ml 
    End of follow-up 8 IU/ml 27 IU/ml 31 IU/ml 
 Case 1 Case 2 Case 3 
Serological profile    
    HBsAg 
    HBeAg − − − 
    Anti-HBs − − − 
    Anti-HBc 
    Anti-HBe 
Viral load    
    Baseline 38 IU/ml 1673 IU/ml <380 IU/ml 
    End of follow-up 69 IU/ml 6 IU/ml <380 IU/ml 
ASAT    
    Baseline 12 IU/ml 17 IU/ml 27 IU/ml 
    End of follow-up 14 IU/ml 20IU/ml 17 IU/ml 
ALAT    
    Baseline 14 IU/ml 22 IU/ml 17 IU/ml 
    End of follow-up 8 IU/ml 27 IU/ml 31 IU/ml 
T able 3.

Chronic viral hepatitis C: aminotransferase and viral load

 Case 4 Case 5 Case 6 
Viral load    
    Baseline <50 IU/ml <50 IU/ml 5767293 IU/ml 
    End of follow-up <50 IU/ml <615 IU/ml 2855514 IU/ml 
ASAT    
    Baseline 33 IU/ml 22 IU/ml 11 IU/ml 
    End of follow-up 23 IU/ml 23IU/ml 30 IU/ml 
ALAT    
    Baseline 36 IU/ml 23 IU/ml 19 IU/ml 
    End of follow-up 29 IU/ml 26 IU/ml 28 IU/ml 
 Case 4 Case 5 Case 6 
Viral load    
    Baseline <50 IU/ml <50 IU/ml 5767293 IU/ml 
    End of follow-up <50 IU/ml <615 IU/ml 2855514 IU/ml 
ASAT    
    Baseline 33 IU/ml 22 IU/ml 11 IU/ml 
    End of follow-up 23 IU/ml 23IU/ml 30 IU/ml 
ALAT    
    Baseline 36 IU/ml 23 IU/ml 19 IU/ml 
    End of follow-up 29 IU/ml 26 IU/ml 28 IU/ml 

Case 1

A 54-year-old man with a 48-month history of severe, destructive, rheumatoid factor (RF)-positive RA and chronic hepatitis B. Serological profile: HBsAg+, HBeAg-, anti-HBs-, anti-HBc+ and anti-HBe+. Serum transaminases were normal (ASAT 12 IU/ml, ALAT 14 IU/ml). Viral load was 38 IU/ml. Methotrexate 15 mg/week was ineffective, so etanercept was added at a dose of 25 mg twice a week for 11 months plus lamivudine 100 mg/day. As response was poor, adalimumab 40 mg was administered every 2 weeks for 10 months. Changes in aminotransferases were small, and the most recent findings were ASAT 14 IU/ml and ALAT 8 IU/ml. Viral load also changed little (most recently 69 IU/ml).

Case 2

A 53-year-old man with a 216-month history of severe destructive, RF-positive RA and a 96-month history of chronic hepatitis B. Serological profile: HBsAg+, HBeAg-, anti-HBs-, anti-HBc+ and anti-HBe+. Serum transaminases were normal (ASAT 17 IU/ml, ALAT 22 IU/ml). Viral load was 1673 IU/ml. As leflunomide 20 mg/day and methotrexate 15 mg/week were insufficiently effective, they were discontinued and etanercept was administered at 25 mg twice a week for 26 months, with lamivudine 100 mg/day during the last 6 months. ASAT and ALAT remained normal. Most recent values were ASAT 20 IU/ml, ALAT 27 IU/ml. Viral load decreased during the treatment, reaching 6 IU/ml at the latest assay.

Case 3

A 49-year-old man with a 300-month history of severe SA (in which trials of several DMARDs had been unsuccessful) and a 27-month history of chronic hepatitis B. Serological profile: HBsAg+, HBeAg-, anti-HBs-, anti-HBc+ and anti-HBe+. Serum transaminases were normal (ASAT 27 IU/ml, ALAT 17 IU/ml). Viral load was <380 IU/ml. Seven months of therapy with infliximab and lamivudine 100 mg/day resulted in transaminases remaining normal (most recently, ASAT 17 IU/ml, ALAT 31 IU/ml) with no change in viral load (persistently <380 IU/ml).

Case 4

A 49-year-old woman with an 84-month history of severe, destructive, RF-positive RA that leflunomide 20 mg/day and methotrexate 15 mg/week failed to adequately control. She had had chronic viral hepatitis C for 156 months. Serum transaminases were normal (ASAT 33 IU/ml, ALAT 36 IU/ml). Viral load was ≤50 IU/ml. Treatment for 3 months with etanercept 25 mg twice a week plus methotrexate 15 mg/week was not efficacious, resulting in ASAT 21 IU/ml, ALAT 25 IU/ml and a viral load of <50 IU/ml. Adalimumab 40 mg every 2 weeks was administered for a further 3 months, and the most recent findings were ASAT 23 IU/ml, ALAT 29 IU/ml and viral load <50 IU/ml.

Case 5

A 50-year-old woman with a 60-month history of severe, destructive, RF-positive RA (for which methotrexate 15 mg/week was ineffective) and a 204-month history of chronic hepatitis C. Serum transaminases were normal (ASAT 22 IU/ml, ALAT 23 IU/ml). Viral load was <50 IU/ml. Etanercept was administered at a dose of 25 mg twice a week, with lamivudine initially at 100 mg/day. The dose of etanercept was subsequently reduced to 25 mg every 2 weeks because of neutropaenia. Results were good over 19 months of therapy, with no change in serum aminotransferases (ASAT 23 IU/ml, ALAT 26 IU/ml). Minor variations in viral load were observed throughout (most recently <615 IU/ml).

Case 6

A 63-year-old woman with a 240-month history of severe, destructive, RF-positive RA and an 84-month history of chronic hepatitis C. Neither leflunomide 20 mg/day nor methotrexate 15 mg/week had been efficacious. Serum transaminases were normal (ASAT 11 IU/ml, ALAT 19 IU/ml). Viral load was 5767293 IU/ml. A liver biopsy performed 4 yrs previously yielded a Knodell score [ 9 ] of 7. As there was no evidence of advance, biopsy was not repeated, and etanercept was initiated at 25 mg twice a week and continued for 39 months. A 5-month period off treatment allowed gastroenterologists to assess the patient's clinical stability. Serum aminotransferases were unchanged (ASAT 30 IU/ml, ALAT 28 IU/ml) and viral loads fluctuated between 5767293 IU/ml and 1709002 IU/ml (most recently 2855514 IU/ml).

Discussion

Administration of TNF-α monoclonal antibody therapy to RA patients results in accumulation of T helper (Th1) CD4+ cells in peripheral blood [ 10 ]. Similarly, administering soluble TNF-α receptor treatment (etanercept) increases peripheral T-cell reactivity to several microbial antigens, and results in a significant increase in the production of INFγ [ 11 ]. Serum and hepatic TNF-α and TNF-α receptor (p75) expression are increased in acute and chronic hepatitis B [ 12 ]. The TNF-α/TNF receptor system has an important role in liver damage and viral clearance [ 13 ]. Moreover, TNF-related apoptosis ligand cytotoxicity in human hepatocytes is enhanced by HBV infection [ 14 ]. TNF-α produced by HBV-specific cytotoxic T lymphocytes down-regulates HBV replication in hepatocytes by non-cytopathic mechanisms in transgenic animal models of HBV infections [ 15 ]. The consequences of modifying this system with anti-TNF medication are potentially important as TNF-α production induced by HBV antigens is generally thought to enhance viral clearance.

Limited information is available concerning the use of anti-TNF-α in patients with chronic hepatitis B. One report documents fulminant hepatitis two weeks after a second infliximab infusion in a patient with positive HBsAg, anti-HBc IgG and anti-HBe described as refractory adult onset Still's disease with no evidence of HBV re-activation [ 16 ]. Other treatments may be implicated, but it is possible that infliximab promoted a sudden and massive intra-hepatic release of TNF-α, leading to liver damage.

HBV re-activation was observed after the use of infliximab and methotrexate in one RA patient positive for HBsAg, anti-HBc and anti-HBe [ 17 ]. Discontinuation of the treatment followed by secondary administration of lamivudine was effective.

One report describes three patients with Crohn's disease, all of whom remained positive for anti-HBs and anti-HBc when given infliximab alone [ 18 ]. After withdrawal of infliximab, re-activation occurred in two cases. Re-activation was also documented in a patient with severe SA and positive HBsAg and anti-HBe who was treated with infliximab alone and secondarily controlled with lamivudine [ 19 ]. Esteve et al . [ 18 ] reported that when lamivudine was co-administered with infliximab, the latter was well-tolerated with no increase in viral replication or exacerbation of chronic hepatitis. Findings in an HBsAg-positive patient with severe SA were similar [ 20 ]. The therapy was effective in that the HBV DNA level remained stable, and aminotransferase activity was normalized. Lamivudine was co-administered for 1 yr.

One report concerns a patient with severe RA and concurrent chronic hepatitis B who was treated with lamivudine [ 12 ]. Infliximab, and then etanercept (after methotrexate had been discontinued) were well-tolerated and efficacious, with no re-activation or exacerbation of the hepatitis.

In a patient with RA and renal amyloidosis, HBV DNA was undetectable after a 1 yr treatment with infliximab, although ALAT serum levels increased [ 21 ]. One group observed a transient re-activation of serum aminotransferases and increased HBV DNA after a single injection of infliximab was given to a patient with Crohn's disease who was also positive for HBsAg, HBeAg and anti-HBe [ 22 ]. Viral activation invariably occurs in patients not treated with lamivudine [ 17–19 , 22 ]. Immunosuppression should be withdrawn with caution because, as reported by Esteve et al . [ 18 ] and Ueno et al . [ 22 ], discontinuation often results in flares [ 23 ].

In our three asymptomatic contagious carriers who were given lamivudine concomitant therapy, serum aminotransferases remained normal, and there was no significant increase in viral load. This was despite the fact that, in theory at least, TNF-α inhibition may cause potent immunosuppression and lead to the escape of virus from host anti-viral mechanisms, thereby worsening chronic hepatitis B.

In patients with chronic HCV infection, TNF-α system activation [ 24 ] correlates with histological activity [ 25 ]; however, levels of soluble TNF receptors, particularly sTNF-R75, do not correlate with virological parameters such as quantitative viraemia and genotype [ 26 ].

An imbalance in the circulating T helper (Th1 and Th2) cell cytokine response is implicated in the risk associated with HCV. Patients able to clear acute HCV infections have a strong Th1 response, whereas those who remain chronically infected have a dominant Th2 response [ 27 ].

Reports on the use of anti-TNF-α in patients with chronic hepatitis C are limited: Campbell and Ghosh [ 28 ], Biancone et al . [ 29 ] and Khanna et al . [ 30 ] each describe one case. Peterson et al . [ 31 ] describe 24 cases, Holtmann et al . [ 32 ] two, Parke and Reveille [ 33 ] five, Magliocco and Gottlieb [ 34 ] two, Oniankitan et al . [ 20 ] one, Esteve et al . [ 18 ] one and Zein et al . [ 35 ] 19. In Calabrese et al . [ 12 ], 58% of the patients in the etanercept group had normal serum aminotransferases and negative HCV RNA. Anti-TNF-α therapy appears to be safe, even among patients receiving azathioprine.

In our three cases, no changes were seen in serum aminotransferases or clinical status. Viral load was low, and remained so, in Patients 4 and 5. In Patient 6 (etanercept) serum aminotransferases remained normal, but the viral load was consistently high throughout, with some fluctuations. According to Arase et al . [ 36 ], such fluctuations occur in 71% of the untreated HCV-infected patients. Here, the maximum fluctuation was 3.37-fold the initial level. As no changes were observed in serum aminotransferase or clinical status, the fluctuations were attributed to chance.

In summary, in six cases of RA or SA, anti-TNF-α therapy (plus lamivudine in patients with concurrent underlying HBV infection) appeared to be safe and to have no effect on serum aminotransferases or viral load. However, monitoring remains necessary throughout the treatment period.

graphic

The authors have declared no conflicts of interest.

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