Management of hepatitis C virus infection
Guidelines for the treatment of HCV infection have been published and include weekly subcutaneous peginterferon-a (either 2a at 180 mg or 2b at 1.5 mg/kg body weight per dose) plus twice daily oral ribavirin (either at 1000 or 1200 mg daily for those that weigh either < 75 kg or > 75 kg, respectively) for 48 months . Exceptional cases may respond to lower doses of ribavirin (800 mg daily) for shorter periods (24 weeks). Initiation of treatment must be individualized for each patient but is dictated mainly by persistence of viremia and evidence of progressive liver disease documented on biopsy. The same guidelines indicate that for patients who have significant extrahepatic manifestations, including cryoglobulinemia, antiviral therapy may result in improvement of the symptoms, and hence should be considered. For the most common rheumatoid arthritis type, however, antiviral treatment would be less imperative because the arthritis tends to be nondestructive to the joint and the treatment of HCV does not consistently lead to symptomatic improvement. In addition there are significant side effects associated with the use of antivirals. Of concern, because use of IFN-a has been associated with worsening of autoimmune disorders [43-45], depending on the mechanisms involved there is a possibility that arthritis may develop or deteriorate during therapy, a notion supported by some anecdotal reports [46,47]. Recent treatment trials have investigated this issue specifically. Nissen and colleagues  reviewed the cases of 40 patients who had chronic HCV infection and arthritis who had received IFN-a, either as monotherapy or combined with ribavirin, and noted that 12 of them had no change in the rheumatologic manifestation, whereas 17 had deterioration and only 8 had improvement. It is not clear whether the deterioration of the arthritic symptoms was attributable to the therapy or to natural progression of the disease. Zuckerman and coworkers  had a different experience: they reported 25 patients who had HCV arthritis who had received IFN-a therapy and 17 of them showed complete or partial response of the symptoms (no deterioration was reported). From the information provided in the articles it is not possible to speculate why the two studies may have had such differing findings. Other authors have assessed antiviral treatment of patients who have HCV infection and mixed cryoglobulinemia (some of whom had arthritis). Cacoub and colleagues  reported 19 such patients (5 of whom had arthralgia) treated with peginterferon-a 2b (1.5 mg/kg/wk) plus ribavirin (800-1200 mg daily) for at least 6 months and found good tolerability of the treatment (specifically, no hepatotoxicity was reported). Mazzaro and colleagues  treated 18 patients with a lower dose of peginterferon-a 2b (1 mg/kg/wk) plus ribavirin (1000 mg daily) for 48 weeks, and again found good tolerability of the treatment.
Regardless of the cause of the arthritis (coincidental or related to HCV) and regardless of the indications for antiviral treatment, the arthritic symptoms may need to be addressed, with the goal of therapy being to control joint inflammation without causing an exacerbation or worsening of liver disease. Arthritis is treated most commonly with NSAIDs, corticosteroids, or hydroxychloroquine. NSAIDs must be used with caution because they can cause hepatotoxicity . In particular, NSAIDs are contraindicated in patients who have cirrhosis because they have been associated with var-iceal bleeding . Rostom and coworkers  recently reviewed the literature on this topic and found that in patients who have arthritis (and no liver disease) elevation of transaminases three times greater than the upper limit of normal was seen more frequently in those receiving diclofenac (3.6%) or rofecoxib (1.80%) than placebo (0.29%); for other NSAIDs (naproxen, ibu-profen, celecoxib, valdecoxib, meloxicam) the frequency (<0.43%) was not significantly elevated. Riley and Smith  and Andrade and colleagues  have described three patients and one patient, respectively, who had HCV infection who developed marked increase in transaminases while receiving ibuprofen. Causality is difficult to infer from these few cases, but is highly suggested by recurrence of the complication on re-challenge in one of the cases. Corticosteroids are not hepatotoxic but have a relative contraindication in patients who have HCV infection because of the theoretical adverse effect they may have on the immune response to the infection. A review by the Cochrane Collaboration group  found insufficient evidence in favor or against the use of corticosteroids for chronic HCV or associated autoimmune processes. For hydroxychloroquine, there are limited data available. Although Lovy and coworkers  reported good tolerability and clinical response to hydroxychloroquine (and low-dose prednisone) in 19 patients who had HCV and arthritis, Mok and colleagues  noted transaminase elevation in 9 of 17 (53%) courses of treatment with hydroxychloroquine (and other antirheumatics) given to patients who had chronic viral hepatitis (hepatitis C or hepatitis B).
For arthritis unresponsive to the above medications, agents that block tumor necrosis factor (TNF)-a have been evaluated, mainly in anecdotal reports or small series, as reviewed by Khanna and colleagues . Peterson and coworkers  recently described 24 patients who received either etaner-cept or infliximab for 1 to 34 months without liver toxicity or increase in vi-remia. Similarly, Parke and Reveille  found anti-TNF therapy safe for treatment of rheumatoid arthritis in 5 patients for a mean of 41 months. In 2006, Marotte and colleagues  described 9 patients who received eta-nercept (at 25 mg twice a week for 3 months) for the treatment of HCV-related arthritis. The authors concluded that etanercept was safe to use in the treatment of rheumatologic manifestations of HCV infection because they saw no increase in viremia or liver inflammation during the period of treatment (but they did not see any clear improvement in the symptoms of arthritis, either). Additional observational studies have confirmed the finding that etanercept seems safe in patients who have chronic HCV infection and various rheumatologic diseases. Magliocco and Gottlieb  and Rokh-sar and coworkers  described three patients and one patient, respectively, who had psoriatic arthritis who received etanercept (25-50 mg twice weekly for 3-12 months) without deterioration of the concomitant HCV infection (stable viral load and transaminases) and improvement of psoriatic symptoms (including arthritis). In a large retrospective safety trial  assessing the safety of anti-TNF-a therapy, 480 patients who had rheumatoid arthritis and spondylarthropathies were identified, 6 of whom had concurrent chronic viral hepatitis: 3 with hepatitis B and 3 with hepatitis C. The authors noted that the therapy appeared to be safe in these 6 patients, with no worsening of the viral load or hepatitis. Still, caution should be used because not all patients may tolerate the therapy well. In one case reported by Pritchard and colleagues  worsening or exacerbation of HCV infection was noted by clinical symptoms, increase in transaminases, and viral load following the use of etanercept for rheumatoid arthritis.
Methotrexate, a disease-modifying antirheumatic drug, is used commonly in autoimmune disorders and rheumatoid arthritis. Because it can cause liver toxicity, the ACR has advised caution in its use; in particular the guidelines recommend testing the patients for hepatitis B or C infection and monitoring transaminases during therapy . In addition, methotrex-ate may have an immunosuppressive effect. Still, few reports have suggested that methotrexate may be used safely under controlled conditions. Mok and coworkers  described two patients who had chronic viral hepatitis who received methotrexate without elevation in their transaminases, and Kujaw-ska and colleagues  described five patients who had HCV infection and rheumatoid arthritis who tolerated methotrexate. More recently, Nissen and coworkers  evaluated the effects of methotrexate in a retrospective study; seven of their patients had received methotrexate (at 7.5-15 mg/wk for 5-28 weeks); six had no progression of HCV disease in viremia or liver enzyme elevations, and one demonstrated viral reactivation, which was subsequently controlled with ribavirin. Despite these encouraging small studies, experts recommend extreme caution and Palazzi and colleagues  have advised against the routine use of methotrexate in HCV-related arthritis until further studies can better assess its safety.
The literature available at this time is insufficient to guide the most appropriate course of treatment of HCV arthritis. Arthritis in HCV per se is not an indication for antiviral treatment but it may be considered, especially when associated with cryoglobulinemia, because mixed cryoglobulinemia may be a risk factor for the development of cirrhosis in chronic HCV
infection [27,69]. Treatment of HCV viremia does not seem to improve— and some treatments (eg, IFN-a) may exacerbate—the arthritic symptoms, so it should not be undertaken routinely. Standard antirheumatic treatment can be considered (eg, NSAIDs, corticosteroids, and others), but with caution, because some of these medications occasionally may be hepatotoxic and response to therapy seems variable. Treatment decisions should be determined on a case-by-case basis.
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