LYON, France—Despite initial concerns that TNF inhibitor treatment in patients with hepatitis virus C (HCV) would stimulate progression of viraemia or worsening of hepatitis, a 3-month course of etanercept seems to be safe and effective for the treatment of HCV-associated rheumatological manifestations, according to phase II data reported in the January issue of Rheumatology.1
High TNF levels linked to worse HCV outcome
Methotrexate has been used safely in some cases, but elevated levels of TNF-α have been seen in patients with HCV and are linked to a more significant disease course, suggesting that blocking the cytokine may be beneficial, the study authors point out. While TNF-blockers, including etanercept, are known to increase risk of infection in other settings, the potential effects of etanercept treatment in patients with HCV infection are not clear. Studies in other autoimmune diseases have not resulted in the progression of HCV viraemia or worsening of hepatitis.
In the new study, nine patients with rheumatological manifestations associated with HCV were treated with 25 mg of etanercept twice a week for 3 months. Five patients had a positive viral load at study entry and four were negative. Researchers recorded disease duration, painful and swollen joint count, patient and physician global assessment, the number of 18 specified fibromyalgia tender points, and the Health Assessment Questionnaire score. They also tested for the presence of cryoglobulinaemia and transaminase levels.
The study showed that none of the patients had any evidence of increased hepatic inflammation based on serial serum transaminase levels at 3 months, and there was no significant viral load increase observed among the five patients with positive viral load at the study's inception. Moreover, the four patients with undetectable HCV RNA showed no reactivation. The researchers point out that a lack of elevated transaminase levels does not necessarily discount active liver disease. "Patients with chronic HCV infection have been shown to have biopsy evidence of inflammation, necrosis, and fibrosis despite persistent normal transaminase values," they write.
While the small size of the study prevented the authors from interpreting efficacy, no flares were observed. "If a positive trend was observed, the treatment efficacy of etanercept appears to be lower than that observed in RA, where a 60% to 70% response rate is commonly observed," the researchers conclude. They point out that additional studies are needed to further assess efficacy and stress that long-term safety issues need to be further assessed. "In particular the context of B-cell activation in these HCV patients implies a concern regarding the occurrence of B-cell non-Hodgkin's lymphoma as already discussed in RA," they note.
"Musculoskeletal symptoms are fairly prominent among patients with hepatitis virus C (HCV) infection and rheumatologists see patients with this condition quite frequently in areas such as the Bronx where I practice," said John Hardin, MD, chief scientific officer of the Arthritis Foundation, in Atlanta, and professor of medicine at the Albert Einstein College of Medicine, in the Bronx, New York. Patients come in many different varieties, he added.
"Patients with HCV may have joint aches and pains and present with an RA-like picture, while some have what is probably classical RA who happen to have acquired HCV somewhere along the line and are probably asymptomatic from a standpoint of HCV," Dr. Hardin said. He also pointed out that another category of patients are those with classical HCV who are started on antiviral therapy that leads to expression of an autoimmune disease. "The treatment for HCV, interferon-α, can induce an autoimmune-like picture in its own right, including lupus," he explained. "We know that interferon-α is the principle driving cytokine in lupus."
Treatment dilemma
Clinicians are faced with a dilemma in treating rheumatological manifestations of HCV, Dr. Hardin said. "The drug we like to use most is MTX, but its most common side effect is inflammation in the liver, so there is great debate on whether it is safe, and there is no definitive answer, but the best data show that when all things are considered, it's reasonable to treat these patients with MTX."
And, what about etanercept and the biologics? "It is not clear whether TNF-inhibitors augment the problem of HCV viral infections, but there is minimal liver toxicity with anti-TNF therapies, and we know that anti-TNF therapies can sometimes benefit arthritis among people with HCV," he said. "This phase I study shows no evidence of toxicity in the form of augmented viral load or augmented inflammation in the liver, and that's very encouraging and will likely add further encouragement for the off-label use of TNF-inhibitors as a treatment modality in people with arthritis and HCV."
Dr. Hardin said he believed these findings would be generalized to apply to other existing TNF- inhibitors. "[The new findings] would provide me with reassurance should I need to treat a patient with HCV infection and arthritis," he said. "It does add some degree of reassurance that this is a reasonable approach to a patient who falls into a difficult-to-manage category."
Cancer concerns
Echoing concerns raised by study authors, Dr. Hardin said that there is a theoretic possibility that TNF-inhibitors lead to an increase of certain tumors, and RA is linked with an increased risk for B-cell lymphomas. "HCV is associated with an increase of hepatocellular carcinoma, and what is unaddressed at the present time is whether TNF inhibitors may add to this risk," he said. "We need a longer study in a larger cohort to make that determination."
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Reference
1. Marotte H, Fontanges E, Bailly F, et al. Etanercept treatment for three months is safe in patients with rheumatological manifestations associated with Hepatitis C virus. Rheumatology. 2007;46:97–99.
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