Introduction

Chronic hepatitis C virus (HCV) infection is associated with a heterogeneous group of extrahepatic manifestations including joint involvement, pulmonary fibrosis, cutaneous vasculitis, glomerulonephritis, Mooren ulcers, porphyria cutanea tarda, and lichen planus, some more frequently encountered than others [1]. HCV-related arthritis can be rheumatoid-like, i.e., symmetric polyarthritis involving small joints, or may, less frequently, present as an intermittent monooligoarthritis, with medium and large joint involvement, often associated with the detection of cryoglobulins in the serum [2].

Chronic hepatitis C infection is frequently encountered in rheumatic patients. According to various reports, 10% of patients with polymyositis/dermatomyositis [3], 14% with Sjogren syndrome [4], 1–11% with systemic lupus erythematosus [5], 12% with psoriatic arthritis (PsA) [6], and 0.65–5.4% of patients with rheumatoid arthritis (RA) [7] have been identified as carriers of the HCV, a prevalence significantly higher than in the general population (∼2% in the United States) [8]. Whether or not this association is coincidental, the estimated frequency of both disorders occurring simultaneously is ∼0.018%, affecting about 40,000 Americans with RA alone [8]. Therefore, to ensure optimal management of the articular symptoms of patients with chronic hepatitis C infection, one has to clarify the issue of safety regarding the use of new efficient drugs, such as monoclonal antibodies targeted against TNFα. Data related to this subject are, unfortunately, still limited [8–10] and without detailed information regarding the clinical progression of the rheumatic disorder.

We report two patients, one with ankylosing spondylitis and one with PsA, who were efficiently treated with either intravenous or subcutaneous anti-TNF agents without any evidence of reactivation or flaring of their hepatitis C infection.

Case reports

Case 1

A 41-year-old man was diagnosed as having HCV infection (genotype 3a) in March 2004. Liver biopsy at diagnosis revealed stage 1 inflammatory activity of the disease and mild fibrosis. The patient received combination treatment with Peg-interferon (INF)-a-2a and ribavirin, which he discontinued after a period of 3 months due to the development of back pain and associated stiffness. Upon completion of treatment, HCV RNA was undetectable (initial value 5×105 IU/ml). In January 2005, the patient presented in the rheumatology clinic. He mentioned having chest pain since 2003 (sternal pain since May 2004). Laboratory evaluation revealed a moderately elevated erythrocyte sedimentation rate (ESR) value (59), radiologic evidence of sacroilitis, and the presence of HLA B27. At diagnosis, thoracic extension was 1 cm, tragus-to-wall distance was 12 cm, and the result of his Schober test was a 2.8-cm increase in lumbar flexion. Mantoux test was negative and the patient was initiated on intravenous administration of the anti-TNFα antibody, infliximab. The patient’s clinical condition improved significantly as early as during the third course of treatment. His symptoms resolved; disease activity markers, i.e., ESR and C-reactive protein, dropped to normal; and the patient was able to discontinue nonsteroidal anti-inflammatory medication. Thirteen months after the initiation of treatment, his HCV status remains unaffected, with HCV RNA (PCR) permanently undetectable (Table 1), while the markers of disease progression have remained stable or have even improved (thoracic extension 2 cm, tragus-to-wall distance 12.5 cm).

Table 1 Patient demographics, HCV genotype and disease duration, anti-TNF agent used/duration of treatment, and pre- and posttreatment laboratory and biopsy data for two patients with HCV infection treated with anti-TNF agents for ankylosing spondylitis and PsA.
Full size table

Case 2

A 47-year-old woman was diagnosed as having PsA (psoriasis since 1989, symmetric polyarthritis, involvement of distal phalango–phalangeal joints) in 2002. Her medical history included chronic hepatitis C infection (genotype 1b) initially diagnosed in 1993. The patient initially received ribavirin and Peg-INF-a-2b, which she discontinued after several months due to the exacerbation of a psoriatic rash. Ribavirin was continued in the form of monotherapy at a dosage of 800 mg/kg/day. At the time of the diagnosis of the rheumatic disorder, HCV was well controlled, with a quantitative RNA PCR value of 3.65×105 IU/ml. The patient was started on intravenous anti-TNFα (infliximab) administration in September 2002. Infliximab was discontinued 6 months later due to the development of an allergic reaction associated with the administration of the drug. The HCV RNA PCR value upon discontinuation of treatment was 2.2×105 IU/ml. The body surface area covered by psoriatic lesions had dropped to one third of the pretreatment value while the number of affected joints had gone down to 10 from 34 prior to anti-TNFα administration. The patient was started on subcutaneous anti-TNFα treatment (adalimumab), which was, however, also discontinued after a period of 6 months due to lack of efficacy.

Discussion

TNFα, a pleiotropic proinflammatory cytokine produced largely by activated macrophages and in smaller amounts by several other types of cells, acts as a potent inducer of the inflammatory response and a key regulator of innate immunity. Biological agents that specifically inhibit the effects of TNFα represent a major advancement in the treatment of rheumatic diseases, such as RA, ankylosing spondylitis, and PsA. By targeting a molecule that is directly involved in the pathogenesis of these disorders, they are proving to be efficacious, highly specific, and better tolerated than standard therapies [11].

Chronic infections (e.g., chronic hepatitis C) in the setting of rheumatic disorders pose a potential hindrance to optimal management because of possible complications linked to the institution of immune suppression, as well as the high incidence of hepatotoxicity associated with many of the disease-modifying antirheumatic drugs included in the conventional therapeutic regimens [12].

TNFα is known to play a pivotal role in host defense, representing a major accessory cytokine in the eradication of infectious agents. In the case of hepatitis C, however, TNFα blockade may prove to be beneficial because TNFα seems to be involved in the pathogenesis of inflammatory activity and, indeed, in attenuating liver fibrosis through the stimulation of apoptotic pathways [13]. Unfortunately, attempts to use it for systemic anticancer treatment have failed due to the appearance of severe side effects, one of which was hepatotoxicity due to the massive induction of apoptosis in hepatocytes [14]. In a Klebsiella pneumoniae murine model of bacterial infection-induced acute liver disease, anti-TNF treatment prevented liver injury. Treatment, however, resulted in decreased bacterial clearance and decreased overall survival, indicating a dampened antibacterial host response [15, 16].

The long-term safety or efficacy of anti-TNFα agents in patients with chronic hepatitis C is not known. Elevations in liver function tests in normal subjects have been observed with all three available anti-TNFα monoclonal antibodies (infliximab, adalimumab, and etanercept), although other concurrently used medications render the evaluation of this effect difficult [17, 18]. Frequently, liver function tests normalize despite the continuation of anti-TNF treatment. In hepatitis C patients, currently available data are restricted to small-scale studies mainly involving the use of etanercept on subjects with HCV infection either with or without concurrent antiviral treatment [10, 19], as well as a few reports of a limited number of patients followed up for liver function amelioration while being treated for their rheumatic disorder [8, 9]. In general, these reports did not reveal any significant increase in viral load or any increased incidence of adverse events. Unfortunately, they provide limited information regarding the control of their musculoskeletal symptoms and findings.

We report two cases of patients with chronic hepatitis C infection and specific rheumatic disorders who were successfully treated with TNFα antagonists without any laboratory or clinical evidence of flaring of their liver disease. Systematic, large-scale studies are needed to properly assess the risks and benefits of TNFα blockade in these patients.