SEARCH

SEARCH BY CITATION

Keywords:

  • HBV infection;
  • infliximab;
  • rheumatoid arthritis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Objective

To evaluate the safety of tumor necrosis factor-α (TNF-α) monoclonal antibody (infliximab) therapy in patients with rheumatoid arthritis (RA) and previous exposure to hepatitis B virus (HBV) who had normal liver function.

Methods

This is a retrospective study from a 26-week, prospective, multicenter trial in 234 patients with RA who received infusions of infliximab (3 mg/kg at week 0, 2, 6, 14 and 22). The medical records of these patients were reviewed, including the information on disease duration, laboratory tests and HBV markers. The data on liver function during the study was analyzed, as well as comparison between patients with previous exposure to HBV and patients without such exposure.

Results

Forty-one patients with previous exposure to HBV were HBsAg(-). Forty patients had normal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and only one patient with positive anti-HBc showed an elevated ALT level before administration of infliximab, and had a further increase of ALT level at week 14, but decreased thereafter. The average ALT and AST levels rose slightly during the treatment but remained in normal range and the differences were insignificant compared with baseline. There was no statistically significant difference in the incidence of liver function abnormalities during the treatment of infliximab between the patients with previous exposure to HBV and those without such exposure.

Conclusion

In patients with RA and previous exposure to HBV but with a negative HBsAg and normal liver function at baseline, liver function abnormalities were not observed during infliximab treatment.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Rheumatoid arthritis (RA) is an autoimmune disease with unknown etiology. The efficacy of traditional disease-modifying anti-rheumatic drugs (DMARDs) and immunosuppressive drugs in treating RA is not satisfactory. Biological agents such as infliximab are becoming increasingly important in the treatment of autoimmune diseases such as RA. There is evidence proving the significant efficacy of these drugs in inhibiting disease progression and structural damage.[1] However, the risk of inducing or exacerbating infections by biological agents has also been increasingly recognized.[2] Furthermore, there have been debates over whether to use biological agents in patients with histories of hepatitis B virus (HBV) infection.[3, 4] This review from a multicenter study in China retrospectively investigated the safety of infliximab in 41 RA patients with chronic HBV infection history (negative serologic status of HBsAg, positive HBsAb and/or positive anti-HBeAb and/or positive anti-HBc) whose liver functions were normal before treatment. The laboratory results we studied included liver function, renal function and changes in peripheral blood at multiple time points during infliximab treatment. We provided evidence for the clinical application of biological agents for these patients.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Patient selection

A randomized, multicenter trial had been done in China, in which 234 patients from the rheumatology departments of 21 hospitals in China (from 2007 to 2008) were included, and all patients met the American College of Rheumatology (ACR) 1987 revised criteria for RA.[5] Data from patients with previous HBV infection and negative HBsAg (but positive for one or more other serologic HBV markers) in the trial were selected to analyze the safety of infliximab. Forty-one patients (seven men and 34 women) were included, with average age of 46.2 ± 2.7 years and average disease duration of 11.4 ± 5.7 years. The baseline characteristics of serologic HBV markers of these 41 patients are summarized in Table 1. Forty out of 41 patients had normal (0–40 U/L) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at baseline. One patient showed elevated ALT (twice the upper limit of normal range) at baseline. All patients had been receiving methotrexate on a stable dose for at least 3 months before the administration of infliximab, without marked relief of joint symptoms. Patients were excluded if they had heart failure, latent tuberculosis infection, active severe infection, active hepatitis B or hepatitis C, or with positive HBsAg or HBeAg.

Table 1. Characteristics of serologic HBV markers of the 41 patients at baseline
ItemsNo. (%)
Anti-HBc(+).49.8
Anti-HBsAb and anti-HBc(+)1434.1
Anti-HBsAb and anti-HBeAb(+)614.6
Anti-HBeAb and anti-HBc(+)24.9
Anti-HBsAb, anti-HBeAb and anti-HBc (+)1536.6

Laboratory tests

The changes of ALT, AST, total-bilirubin (T-bil), serum creatinine (sCr), leukocytes (WBC: white blood cell) and platelet (PLT) in peripheral blood from baseline to week 26 were observed. Because HBV markers were not regular testing items in the trial design, only 30 of the 41 patients with pre-existing HBV infection at baseline were retested for HBV markers at week 26.

Treatment

All patients received 3 mg/kg infliximab infusions at weeks 0, 2, 6, 14 and 22. Laboratory data before each infusion for ALT, AST, T-bil, sCr, WBC count and PLT count were reviewed. All tests were repeated at week 26. Infliximab infusion was discontinued if patients showed WBC ≤ 3.0 × 109/L or PLT ≤ 8 × 109/L or liver enzyme exceeded twice the upper limit of normal range.

Statistical analysis

Paired t-test was utilized to compare data between pre- and post-treatment conditions within the two groups of patients with previous exposure to HBV and those without such exposure. Rank sum test was used to analyze data among different groups. Statistical significance was defined as < 0.05. Statistical analyses were performed using SPSS 12.0 software (SPSS Inc., Chicago, IL, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Demography

Seven of the 41 RA patients with pre-existing HBV infection were male and 34 of them were female, with an average age of 46.2 ± 2.72 years and average disease duration of 11.40 ± 5.72 years.

Changes in liver function of infliximab-treated RA patients through week 26

We focused on liver enzyme levels at different time points from week 0 to week 26. Our results indicated that the average ALT and AST levels of 41 RA patients with previous exposure to HBV rose slightly from week 0 to week 26 but were still within the normal range. Compared with baseline, no statistically significant changes in ALT and AST were observed at any time point during infliximab treatment (Table 2). There was no statistically significant difference for the proportion of patients with normal ALT and AST between patients with previous HBV infection and those without previous HBV infection after the combined therapy of infliximab and methotrexate (Fig.1). One patient who had previously elevated ALT levels (twice the upper limit of normal range) with no clear reasons before the infliximab infusion had a further increase of ALT level to 143 U/L at week 14, but decreased thereafter. Statistical analysis showed no significant difference in T-bil levels between pre- and post-treatment conditions (Table 2).

Table 2. Changes in ALT, AST and T-bil levels for the 41 patients
ItemsPre-treatmentPost-treatment (weeks)
26142226
  1. ALT, alanine aminotransferase; AST, aspartate aminotransferase; T-bil, total bilirubin.

ALT (U/L)20.2 ± 17.021.8 ± 20.022.9 ± 20.531.9 ± 23.030.9 ± 22.532.0 ± 24.5
AST (U/L)21.1 ± 18.523.2 ± 20.022.9 ± 21.028.7 ± 23.027.1 ± 24.029.2 ± 24.0
T-bil (μmol/L)10.16 ± 3.6311.12 ± 3.5110.90 ± 3.5410.16 ± 2.8511.56 ± 3.6311.62 ± 2.87
image

Figure 1. The proportion of patients with normal alanine aminotransferase (ALT) levels in the two groups during the administration of infliximab and methotrexate. All P-values are > 0.05, which suggested that no significant difference existed in the distribution of patients who had elevated ALT levels in two groups after the combined therapy of infliximab and methotrexate.

Download figure to PowerPoint

Changes in hematology and renal function during the treatment

We also observed that hematology (WBC, PLT) and biochemistry (sCr) values of RA patients at weeks 0, 2, 6, 14, 22 and 26 were normal at any given time point. Statistical analysis showed no significant differences between pre- and post-treatment conditions.

Serological HBsAg test before and after infliximab treatment

Of 41 patients with previous exposure to HBV, 30 were tested again for HBsAg at week 26 and all of them remained HBsAg(−).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Rheumatoid arthritis (RA) is a common autoimmune disease with typical manifestations of polyarticular swelling, pain and functional impairments. Some patients may suffer from multi-organ impairments. DMARDs and/or cytotoxic agents have been widely used in treating RA with clinical efficacy.[6-8] However, some patients do not respond to these agents. It has been reported that biological agents represent a major advancement in the treatment of RA with proven efficacy in inhibiting disease progression and bone erosion.[9-11] However, the risk of inducing or exacerbating infections by biological agents has also been increasingly recognized. The infection rate of HBV is relatively high in China, and about 10% of RA patients are HBV carriers or have chronic hepatitis B.[12] So it is important to investigate the impact of TNF-α monoclonal antibody (infliximab) on patients with previous exposure to HBV. At present, there are limited reports on this topic and the effect is non-definitive. In 2004, Esteve et al. reported the application of infliximab in inflammatory bowel disease patients with concurrent HBV or HCV infection. Their results showed that in three patients with positive HBsAg, two experienced abnormal liver function and one previously treated with lamivudine did not.[13] In 2006, Roux retrospectively analyzed the application of infliximab in six of 480 RA and ankylosing spondylitis (AS) patients with concurrent HBV (three patients) or HCV infection (three patients). They observed changes in liver function, which also showed that the concomitant lamivudine therapy could keep liver function within normal range.[14] ACR guidelines for the use of biological agents in RA patients recommended that biologic agents were contraindicated in both chronic hepatitis B and C and significant liver function impairment (with/without corresponding therapy).[15, 16] But Nathan et al. pointed out that all patients undergoing anti-TNF therapy should be screened for HBV but not all the HBV patients should be excluded from anti-TNF treatment. Patients with evidence of active HBV liver disease should have their disease treated and controlled prior to commencing anti-TNF agents.[17] European Crohn's and Colitis Organisation (ECCO) consensus about opportunistic infections in inflammatory bowel disease recommended prophylactic antiviral treatment with nucleotide/nucleoside analogues should be started prior to the introduction of steroids, azathioprine or anti-TNF-α therapy and continued for 6 months after their withdrawal.[18] Recommendations are not available in guidelines about biological agents used in patients with previous but not current HBV. However, the American Association for the Study of Liver Diseases (AASLD) Practice Guidelines mentioned HBV reactivation is infrequent in persons who are HBsAg(−) but anti-HBc(+) and anti-HBs(+). These patients should be monitored and antiviral therapy should be initiated when serum HBV DNA becomes detectable.[19]

There has been a consensus that liver-protective agents (such as lamivudine) should be used during biological agent treatment for RA. Case reports about adalimumab revealed that RA patients with HBV infection developed a reactivation or an acute liver failure without prophylaxis, while appropriate prophylaxis measures led to good outcomes.[20] However, no reports worldwide have discussed the safety profile of biological agents (such as infliximab) for RA patients who had previous HBV infection but were HBsAg(−). This study is a retrospective study in China to discuss the safety of infliximab in such patients. The results of this 26-week study showed that as long as liver function was normal and HBsAg was negative at baseline, infliximab plus methotraxate had no negative impact on liver function. Further analysis also revealed that there was no statistically significant differences in ALT and AST elevations when RA patients with previous HBV infection were compared with those without history of HBV infection. The ALT and AST levels rose to plateau at week 14 within the normal range and the differences were insignificant. These results indicated that there was no evidence to suggest that infliximab would aggravate liver damage in patients with normal liver function and previous HBV infection history.

It is inevitable that retrospective studies have their limitations. Some tests (such as HBsAg test of 11 patients at week 26 and serum HBV-DNA viral load) were not carried out prospectively, and a 26-week follow-up may not generate sufficient evidence to predict the outcome after long-term therapy.

In conclusion, this study provided some safety data on using infliximab in RA patients with previous exposure to HBV and current inactive HBV infection. These patients showed normal liver function and negative HBsAg prior to and after infliximab treatment. Infliximab therapy for these patients showed no correlation with liver impairments, which suggested the safety profile of infliximab for inactive HBV patients. Under certain circumstances, HBV-DNA replication should be quantified and preventive lamivudine therapy should be initiated when necessary. In line with recommendations from the American Association for the Study of Liver Disease (AASLD), patients with high baseline HBV DNA levels (> 2000 IU/mL) should continue antiviral treatment until endpoints applicable to immunocompetent patients are reached. Most data exists for lamivudine, but other nucleotide/nucleoside analogues may be used.[18]

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Thanks to our colleagues An Yuan, Liu Xia and Liu Xu.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  • 1
    Schett G, Coates LE, Ash ZR et al. (2011) Structural damage in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: traditional views, novel insights gained from TNF blockade, and concepts for the future. Arthritis Res Ther 13(Suppl. 1), S4.
  • 2
    Galloway JB, Hyrich KL, Mercer LK et al. (2011) Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology (Oxford) 50, 12431.
  • 3
    Nordgaard-Lassen I, Dahlerup JF, Belard E et al. (2012) Guidelines for screening, prophylaxis and critical information prior to initiating anti-TNF-alpha treatment. Dan Med J 59, C4480.
  • 4
    Mori S (2011) Past hepatitis B virus infection in rheumatoid arthritis patients receiving biological and/or nonbiological disease-modifying antirheumatic drugs. Mod Rheumatol 21, 6217.
  • 5
    Arnett FC, Edwarthy SM, Bloch DA et al. (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31, 31524.
  • 6
    Dass S, Vital EM, Emery P (2006) Rituximab: novel B-cell depletion therapy for the treatment of rheumatoid arthritis. Expert Opin Pharmacother 7, 255970.
  • 7
    Kato T, Ubara Y, Sawa N et al. (2004) A case of rheumatoid arthritis exhibiting accelerating rheumatoid pleurisy during low-dose weekly methotrexate therapy. Mod Rheumatol 14, 4148.
  • 8
    Sanmarti R, Gomez CA, Ercilla G et al. (2007) Prognostic factors of radiographic progression in early rheumatoid arthritis: a two year prospective study after a structured therapeutic strategy using DMARDs and very low doses of glucocorticoids. Clin Rheumatol 26, 11118.
  • 9
    Weinblatt ME, Schiff MH, Ruderman EM et al. (2008) Efficacy and safety of etanercept 50 mg twice a week in patients with rheumatoid arthritis who had a suboptimal response to etanercept 50 mg once a week: Results of a multicenter, randomized, double-blind, active drug-controlled study. Arthritis Rheum 58, 192130.
  • 10
    Park MC, Jung SJ, Park YB et al. (2008) Relationship of serum TWEAK level to cytokine level, disease activity, and response to anti-TNF treatment in patients with rheumatoid arthritis. Scand J Rheumatol 37, 1738.
  • 11
    Alonso-Ruiz A, Pijoan JI, Ansuategui E et al. (2008) Tumor necrosis factor alpha drugs in rheumatoid arthritis: systematic review and meta analysis of efficacy and safety. BMC Musculoskelet Disord 9, 52.
  • 12
    Lu ZH, Chen W, Ju ZC et al. (2011) Pathological features and prognosis in chronic hepatitis B virus carriers. J Int Med Res 39 (1), 717.
  • 13
    Esteve M, Saro C, González-Huix F et al. (2004) Chronic hepatitis B reactivation following infliximab therapy in Crohn's disease patients: need for primary prophylaxis. Gut 53, 13635.
  • 14
    Roux CH, Brocq O, Breuil V et al. (2006) Safety of anti-TNF-a therapy in rheumatoid arthritis and spondylarthropathies with concurrent B or C chronic hepatitis. Rheumatology 45, 12947.
  • 15
    Saag KG, Teng GG, Patkar NM et al. (2008) American College of Rheumatology 2008 Recommendations for the Use of Nonbiologic and Biologic Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis. Arthritis Rheum 59, 76284.
  • 16
    Kasahara S, Ando K, Saito K et al. (2003) Lack of tumor necrosis factor _ induces impaired proliferation of hepatitis B virus-specific cytotoxic T lymphocytes. J Virol 77, 246976.
  • 17
    Nathan DM, Angus PW, Gibson PR (2006) Hepatitis B and C virus infections and anti-tumor necrosis factor-therapy: guidelines for clinical approach. J Gastroenterol Hepatol 21, 136671.
  • 18
    Rahier JF, Ben-Horin S, Chowers Y et al. (2009) European evidence-based Consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis 3 (2), 4791.
  • 19
    Lok ASF, McMahon BJ (2009) AASLD Practice Guidelines update- Chronic Hepatitis B: Update. Hepatology 50 (3), 136.
  • 20
    Verhelst X, Orlent H, Colle I et al. (2010) Subfulminant hepatitis B during treatment with adalimumab in a patient with rheumatoid arthritis and chronic hepatitis B. Eur J Gastroenterol Hepatol 22, 4949.