SEARCH

SEARCH BY CITATION

Keywords:

  • Rheumatoid arthritis;
  • Tumor Necrosis Factor blockers;
  • Treatment;
  • Hepatitis C

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Objective

To examine the safety of using anti–tumor necrosis factor (TNF) therapy in patients with rheumatoid arthritis (RA) in the setting of hepatitis C virus (HCV) infection.

Methods

The charts of 5 patients known to have RA requiring anti-TNF therapy as well as established HCV infection were reviewed retrospectively for laboratory data of hepatic parenchymal inflammation and viral proliferation while taking these agents.

Results

In a mean ± SD followup period of 41 months (± 28.2 months), no patient displayed evidence of sustained elevation of serum aminotransferases during therapy with anti-TNF. Additionally, 1 patient was observed to have a decreased HCV viral load after extended treatment with only anti-TNF (no therapy for HCV).

Conclusion

Anti-TNF therapy for RA in the setting of HCV appears to be safe and well tolerated without apparent influence on the underlying HCV infection. Therefore, this approach should be further evaluated prospectively for longterm safety.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Hepatitis C virus (HCV) infection is a global entity with >170 million persons infected worldwide. Recent investigations estimate that ∼3.9 million Americans are seropositive for HCV, representing a prevalence of ∼1.8% in the general population (1). The prevalence of rheumatoid arthritis (RA), on the other hand, in the general population is ∼1% worldwide (2). Based on these data, the estimated prevalence of both disorders occurring simultaneously is ∼0.018%, translating to about 40,000 Americans.

The ramifications of the HCV epidemic are myriad. The most obvious and well-known consequences of HCV are related to hepatocyte destruction leading to cirrhosis and hepatocellular carcinoma. Rheumatologic manifestations have been reported, including seropositivity for rheumatoid factor and antinuclear antibodies, arthralgia, myalgia, Sjögren-like syndrome, cryoglobulinemia, and vasculitis (3). Additionally, the articular symptoms associated with HCV have been reported to resemble RA (4).

Chronic HCV in the setting of RA looms as a potential obstacle to optimal management because of possible untoward complications associated with the institution of immune suppression in the setting of a chronic infection, as well as the high incidence of hepatotoxicity documented with many of the disease-modifying antirheumatic drugs (DMARDs) conventionally used to treat RA (5). One particular modality that has significantly impacted the treatment and quality of life of patients with RA in the past decade involves the inhibition of the inflammatory cytokine tumor necrosis factor α (TNFα). TNFα plays a dominant role in host defense as well as inflammation. It has been well documented that TNFα is a significant component of the inflammatory response associated with RA. Investigations are currently underway to further define the spectrum of diseases responsive to these therapies and to discover more indications, thus expanding the number of patients treated with these agents.

Anti-TNF therapy for RA in the setting of HCV may be of particular interest in light of the growing body of evidence that suggests that the pathogenesis of hepatocyte destruction in chronic HCV may be mediated by upregulation of inflammatory cytokines including TNFα (6, 7). Based on these premises, we sought to analyze the safety of treating RA with anti-TNF in patients who are also infected with chronic HCV.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Patients eligible for the study were those previously meeting the 1987 American College of Rheumatology (formerly American Rheumatism Association) revised criteria for the classification of RA (8) who also had documented seropositivity for HCV. These patients were selected from our university practice and the rheumatology clinic at the Harris County clinics staffed by members of our division. Their charts were reviewed for medication history, duration of disease for both RA and HCV, and clinical characteristics, including joint erosions and extraarticular manifestations. Laboratory data consisting of serum aminotransferases and HCV viral load were analyzed for evidence of hepatic parenchymal inflammation and viral proliferation, respectively. Additionally, charts were reviewed for HCV genotype and biopsy reports. The values were recorded for the entire period of patient followup. Polynomial regression was used to establish trend lines indicated on graphed data.

Laboratory studies for the university practice patients were typically performed through the commercial laboratories contracted by the respective patient's insurance company and the studies for the Harris County patients were done at the Harris County Hospital District's chemistry and immunology laboratories. In general, all studies were performed by the same methodology. Both aspartate aminotransferase and alanine aminotransferase assays were performed by kinetic spectrophotometry in all laboratories and the reference values were between 0 and 40 units/liter. Studies performed for evaluation of HCV included hepatitis C antibody, quantitative HCV viral load, and genotyping. HCV antibodies were detected universally by enzyme-linked immunosorbent assay. Quantitative HCV viral RNA was performed by real-time polymerase chain reaction. All private laboratories used Quantasure methodology from Roche Molecular Diagnostics (Indianapolis, IN) with a reference range of 10 IU/ml to 100,000,000 IU/ml. County clinic specimens were evaluated using the Roche Cobas Amplicor Analyzer with a reference interval between 600 IU/ml and 500,000 IU/ml. HCV genotyping was performed with line probe assay by all laboratories.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Five patients with both RA and HCV infection who were given anti-TNF therapy (etanercept or infliximab) were identified. All patients had high rheumatoid factor titers. The mean ± SD age of the patients was 47.2 ± 3.77 years. The mean duration of RA was 12 ± 9 years, and the mean ± SD duration of HCV infection since RA diagnosis was 42.6 ± 19.8 months. The average ± SD duration of treatment with etanercept was 18 ± 9.3 months and that of infliximab was 8 ± 4.4 months (Table 1).

Table 1. Patient demographics, disease duration, anti-TNF duration, and past therapies*
Patient no.12345
  • *

    TNF = tumor necrosis factor; H = Hispanic; A = African American; W = White; RA = rheumatoid arthritis; HCV = hepatitis C virus; DMARDs = disease-modifying antirheumatic drugs; HQ = hydrochloroquine; MTX = methotrexate; LEF = leflunomide; AZA = azathioprine; SSZ = sulfasalazine; N/A = not available.

Age, years5349484744
SexFFMMM
RACEHAWWW
RA duration since diagnosis, years7205234
HCV duration, years35453
Anti-TNF duration, months141129498
Previous DMARDsHQ, MTX, LEF, AZA, SSZMTX, LEFHQ, SSZ, LEFSSZ, MTX, HQHQ
Total duration of DMARDs, months9569649636
HCV genotypeN/AIBN/A1A3E
Biopsy resultsActivity grade 2–3N/AN/AActivity grade 1N/A
 Stage 2 Fibrosis Stage 1–2 Fibrosis 

To date, these patients have been followed for a mean ± SD period of 41 ± 28.2 months. All patients had been treated with and clinically failed a variety of DMARDs for their RA prior to initiation of anti-TNF therapy. These drugs included methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine. Additionally, each patient had been taking prednisone of varying dosages up to 20 mg/day. No patient as of the completion of this study had any documented manifestations judged specific for HCV, such as jaundice or clinical manifestations of hepatic insufficiency. Additionally, no patient had received any specific therapy directed toward HCV.

Two patients had taken both etanercept and infliximab. One patient discontinued infliximab and another discontinued etanercept secondary to inadequate articular responses. In both cases, the patient's RA responded clinically to the other anti-TNF agent. No patient treated with anti-TNF therapy was found to have evidence of hepatic inflammation based on serial serum aminotransferase levels observed during treatment (Figure 1). HCV viral load measurements displayed variable trends (Figure 2), although the only patient with multiple values over an extended period of time (patient 3) showed a linear decline in viral load concentrations.

thumbnail image

Figure 1. Time course of changes in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) measurements in patients with hepatitis C and rheumatoid arthritis before and after treatment with anti-tumor necrosis factor (TNF). Time 0 represents the point at which anti-TNF therapy was initiated with pretreatment values to the left of this point.

Download figure to PowerPoint

thumbnail image

Figure 2. Time course of changes in pre- and posttherapy measurements of hepatitis C viral load in patients before and after anti-tumor necrosis factor therapy for rheumatoid arthritis.

Download figure to PowerPoint

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Hepatitis C infection has emerged as a worldwide entity affecting millions of people. HCV's coexistence with other diseases, particularly those that require immunosuppressive or hepatotoxic therapy, stands as a significantly confounding problem. The management and natural history of RA has undergone a remarkable transformation with the addition of anti-TNF agents. These medications have endured the test of time in regard to efficacy and safety in uncomplicated RA. The manufacturers of both medications evaluated in this study have documented observations of aminotransferase elevation in their package inserts, although there has been no link established between these drugs and liver disease. The safety of anti-TNF therapy with HCV is at this time uncertain and there have been no guidelines or investigations to date adequately assessing the use of these agents in patients with chronic infections, such as HCV. This study attempts to offer some insight into this very question.

This was a retrospective analysis of 5 patients with documented RA and HCV who required treatment with anti-TNF for their RA after clinical failure with various DMARDs. The therapy was well tolerated and proved to be efficacious for their articular symptoms. More importantly, no patient displayed persistent laboratory evidence suggestive of hepatic inflammation based on serial transaminase measurements as surrogate markers. Figure 2 shows that most patients actually had few episodes of elevated transaminases prior to initiation of anti-TNF therapy as well. This observation may be the result of a selection bias in that any patient with elevated transaminases would not have been started on anti-TNF or other therapies that may predispose them to an acceleration of their liver disease. It is now known that the lack of elevated transaminases does not necessarily exclude active disease in the liver. Patients with chronic hepatitis C infection have been shown to have biopsy evidence of inflammation, necrosis, and fibrosis despite persistently normal alanine aminotransferase values. Most of these patients showed significantly lower biopsy scores but ∼15% of this population actually was found to have evidence of significant, progressive liver disease only evident by biopsy (9). This issue underscores the importance for a long-term controlled prospective trial using histologic data in addition to surrogate markers of inflammation. Despite this information, we found it encouraging that these patients were able to benefit from anti-TNF therapy for their RA without an apparent worsening of their HCV based on these surrogate markers.

The serial measurements of viral load were somewhat inconclusive. Only patient 3 had multiple measurements that could be considered relatively reliable and that demonstrated a linear decrease over ∼2 years; on the other hand, patient 2 displayed an exponential rise in viral load over the course of ∼15 months. The reliability of the comparison between these patients may be handicapped by the lack of adequate characterization of their infections. We have incomplete genotype and biopsy data, as well as an inadequate estimation of the duration of their HCV. These limitations are in most part secondary to the retrospective nature of this study and could be better addressed with a systematic prospective trial.

Altogether, this evidence supports the concept that the blockade of TNFα for RA may be safe in the setting of HCV infection. However, definitive proof of the safety of TNFα blockers in the setting of HCV infection will require longer followup as well as prospective investigations analyzing histologic data in addition to serological markers.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES
  • 1
    Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, et al. The prevalence of hepatitis C infection in the United States, 1988 through 1994. N Engl J Med 1999; 341: 55662.
  • 2
    Wolfe AM. The epidemiology of rheumatoid arthritis: a review. Bull Rheum Dis 1968; 19: 518.
  • 3
    Cacoub P, Paynard T, Ghilani P, Charlotte F, Olivi M, Piette JC, et al. Extrahepatic manifestations of chronic hepatitis C. Arthritis Rheum 1999; 42: 220412.
  • 4
    Lovy MR, Starkebaum G, Uberoi S. Hepatitis C infection presenting with rheumatic manifestations: a mimic of rheumatoid arthritis. J Rheumatol 1996; 23: 97983.
  • 5
    Mok MY, Ng WL, Yuen MF, Wong RW, Lau CS. Safety of disease modifying anti-rheumatic agents in rheumatoid arthritis patients with chronic viral hepatitis. Clin Exp Rheumatol 2000; 18: 3638.
  • 6
    Zylberberg H, Rimaniol AC, Pol S, Masson A, De Groote D, Berthelot P, et al. Soluble tumor necrosis factor receptors in chronic hepatitis C: a correlation with histological fibrosis and activity. J Hepatol 1999; 30: 18591.
  • 7
    Kakumu S, Okumura A, Ishikawa T, Yano M, Enomoto A, Nishimura H, et al. Serum levels of IL-10, IL-15 and soluble tumour necrosis factor-alpha (TNF-alpha) receptors in type C chronic liver disease. Clin Exp Immunol 1997; 109: 45863.
  • 8
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 31524.
  • 9
    Kyrlagkitsis I, Portmann B, Smith H, O'Grady J, Cramp ME. Liver histology and progression of fibrosis in individuals with chronic hepatitis C and persistently normal ALT. Am J Gastroenterol 2003; 98: 158893.
    Direct Link: