Relationship Between Cryoglobulinemia-associated Nephritis and HCV Infection

Dario Roccatello; Osvaldo Giachino; Elisa Menegatti; Simone Baldovino


Expert Rev Clin Immunol. 2008;4(4):515-524. 

In This Article

Antiviral Therapy

The optimal therapeutic strategy for HCV-associated MC is still undefined. The discovery of an association between MC and HCV and the possible pathogenetic implications of this prompted researchers to develop new approaches to disease control by eradicating the infection. IFN-α treatment has been increasingly used in the past decade. Results have been conflicting because of the high relapse rate. Only a minority of patients (less than 10%) reached a sustained viral response in a very large cohort of nephritic patients.[3] Since this retrospective study referred to cases collected between 1990 and 1995, antiviral treatment was less potent (comprising of only nonpegylated interferons) and doses were lower than those recommended by current protocols. Some reports have shown that interferon produces significant clinical improvement in HCV-positive patients with MC ( Table 1 ).[13,14,15,16,17,18] However, the use of IFN-α is limited because of its transient efficacy, frequent patient relapse upon discontinuation combined with the reappearance of viral RNA, occasional worsening of skin ulcers (possibly due to the antiangiogenic effects of IFN-α), precipitation of renal failure and nephrotic syndrome, peripheral neuropathy and autoimmune hepatitis. Moreover, a number of adverse effects are associated with interferon therapy, including bone marrow suppression, influenza-like symptoms, hair loss, visual disorders (especially in hypertensive patients), weight loss, hearing loss, gastrointestinal complaints, interstitial pneumonitis and psychiatric and neurological manifestations. Contraindications include diabetes, psychosis, decompensated cyrrhosis and autoimmune thyroiditis (not exceptionally occurring in HCV infection).

Ribavirin, an oral guanosine nucleoside analogue that induces a significant decrease in serum aminotransferase but is unable to achieve a long-term virologic and biochemical response, has been used on occasion as monotherapy in patients with HCV-associated glomerulopathy, which led to some response in both immunocompetent and transplant recipient patients. At present, ribavirin is almost exclusively used in combination with IFN-α[19,20,21,22] and only a few studies have been reported in the literature ( Table 2 ).

Calleja et al. treated 13 patients with IFN-α and ribavirin for 12 months.[19] All patients had previously received IFN-α in monotherapy and eight were nonresponders and five relapsed. Five out of the eight nonresponders to interferon alone showed an initial response, but this was sustained in only three cases after 12 months; four out of five previous relapsers had sustained responses. Loss of response was accompanied by the reappearance of HCV RNA, worsening of clinical manifestations and increasing levels of cryoglobulins and hepatic enzymes. In the study by Zuckerman et al., all nine patients who were refractory to IFN-α, and who were then treated with IFN-α and ribavirin for 6 months, achieved a substantial improvement in MC-related symptoms, although polyneuropathy was resistant to treatment.[20] Sustained responses were also reported by Donada et al..[21] In Mazzaro's report, 18% of patients who were 'relapsers' to the first IFN-α treatment experienced complete recovery from viral infection and from all signs and symptoms of the disease after 1 year of combined treatment.[22] A marked clinical improvement occurred in the majority of cases within 2-3 weeks of treatment. Regrettably, 70% of patients relapsed within a few weeks after the end of treatment. Finally, a single study showed an improvement in renal histology in a few patients with biopsy-proven GN who underwent antiviral combination therapy with IFN-α and ribavirin.[23]

Mild, dose-related hemolytic anemia is commonly observed in patients treated with the combination therapy. However, it is noteworthy that even small doses of ribavirin can cause severe anemia before the delayed clearance of the drug in patients with renal failure. Moreover, this drug is not dialyzable.

Antiviral treatment with IFN-α also proved to be effective in determining regression of monoclonal B-cell expansion. Several series reported that antiviral treatment with IFN-α alone or with ribavirin is effective in HCV-associated indolent and marginal-zone lymphoma associated with cryoglobulinemia.[24,25,26,27] In these studies, in which the majority of patients had splenic lymphoma, most cases achieved a sustained response of the lymphoma and regression of cryoglobulinemic symptoms following HCV-RNA clearance.

Further progress with regard to response to therapy can be expected by the widespread use of pegylated interferon (peg-IFN), which is endowed with improved pharmacokinetic characteristics. Peg-IFN, alone or combined with ribavirin, has proven to be more effective than IFN-α alone or in combination with ribavirin, in patients with HCV infection, particularly those infected with genotype 1b. Patients with HCV-related MC also seemed to benefit from this new combination therapy, even though 44% of patients relapsed a few weeks after the end of therapy in Mazzaro's study.[28] Cacoub et al. obtained remarkable results in clinical, virological and serologic parameters of nine patients with cryoglobulinemic vasculitis.[29]

Nowadays, the therapeutic strategy for HCV eradication in chronic hepatitis patients undergoing treatment with the combination of peg-IFN and ribavirin takes into account genotype. Patients with genotype 2 could be treated for 24 week. Genotype 2 can be eradicated (obtaining sustained virologic response, that is, undetectable HCV RNA 24 weeks after the end of treatment) in 75-80% of cases by a 24-week course of peg-IFN plus ribavirin 800 mg/day in two divided doses.[30] Although this is a controversial issue, very recent studies suggest some efficacy of even shorter therapy duration (16 weeks).[31]

Patients infected with genotype 3 should be treated for 24 weeks.[30] High viral load, advanced fibrosis, obesity, black ethnicity and male gender are negative prognostic indexes. In these cases, a more prolonged treatment could be considered (up to 48 weeks). The presence of genotype 1 calls for a 48-week course of therapy with weekly injections of either peg-IFN-α2a or -α2b, and oral ribavirin 1000 mg/day for patients weighing 75 kg or less, or 1200 mg/day for patients weighing greater than 75 kg. Patients with detectable HCV RNA at week 24 will probably not have a sustained virologic response. However, the rate of sustained virologic response is only 40-50% and, in the absence of a decrease in HCV-RNA concentration of log2 at week 12, the chances of responding are remarkably reduced (up to 20%).

While we are waiting for adequate clinical trials on genotypes 4, 5 and 6, patients infected with these genotypes should be treated the same as those infected genotype 1.

The presumed efficacy of the antiviral therapy with peg-IFN in MC, which is drawn from limited observations of small cohorts of patients, should be the target of future trials. At present, some data suggest that patients with HCV and circulating cryoglobulins do respond at least as well as HCV-positive patients without cryoglobulinemia.[32]


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