The treatment of extrahepatic disease manifestations of HCV has largely paralleled that of hepatic disease. Interferon was reported to have efficacy for MC even before linkage of the syndrome to HCV in 1989, and successful combination therapy with ribavirin was found to eliminate virus and lead to the resolution of immunologic abnormalities associated with extrahepatic disease. In addition, \~75% of HCV-associated indolent asymptomatic lymphoproliferative diseases remit with successful antiviral therapy. However, in many instances, MC (notably cutaneous vasculitis) will relapse with recurrence of virus, and may occasionally persist even after clearance. In particular, side effects of Interferon alpha, including the uncovering of frank autoimmune disease, theoretically may mitigate response of extrahepatic disease to treatment. Peg-interferon increased the response rate of MC, and decreased the duration of treatment, but side effects remained problematic.

An alternative approach to the treatment of MC has been the use of immunomodulatory agents. In particular, B-cell expansion in peripheral blood and in lymphoid follicles in the liver prevalent amongst HCV-infected persons provided a rationale for the use of depletion as a therapeutic strategy. Rituximab (anti-CD20) monotherapy has been used mostly for treatment failures/intolerance or in the setting NHL, and has yielded response rates in the setting of involvement of skin (73%); MPGN (70%); joint (53%); and nerve (36%). However, this monoclonal antibody (MAb) has the potential to form immune-complexes with mixed cryoglobulin RF and cause clinical vasculitis in patients with high cryocrits, and may raise the HCV RNA level in rare patients, causing cytotoxicity. Following Rituximab with Peg-IFN plus ribavirin achieved greater than a 60% complete response (CR) in patients resistant to combination treatment alone. Other approaches include the use of Aldesleukin, an inducer of regulatory T-cell activity, MAbs targeted to specific B-cell subsets or costimulatory signal molecules (e.g. BAFF) or agents inhibiting the interaction of HCV core antigen with C1q in cryoprecipitates via the receptor for the globular domain of C1q (gC1qR).

The development of low molecular weight inhibitors of the non-structural proteins (NSPs) elaborated by HCV, in particular 5A, 5B nucleoside and non-nucleoside polymerase inhibitors, and inhibitors of 3/4A serine proteases; to selectively inhibit HCV replication has raised the prospect of "all-oral" treatment for both hepatic and extrahepatic manifestations of disease. However, the use of first generation direct-acting antiviral agents (Telaprevir® and Boceprevir® linear NS3/4A protease inhibitors) was limited by frequent escape mutants, efficacy restricted to genotype-1, need to retain protocols including PegIFN and ribavirin, potential for significant drug interactions, and serious side effects. In a trial of combination therapy including Telaprevir® for 13 patients with MC, all had significant AEs, including asthenia (92%), anemia (84%), neutropenia and bacterial infection (54%). Approval of an uridine nucleoside analogue that selectively inhibits HCV NS5B RNA-dependent RNA polymerase (Sofosbuvir) by the FDA late 2013 has led to proof-of-concept trials in which combination all-oral therapy has proven effective for both genotype 1 and other genotypes, with a number of other regimens under development. In particular, the combination of Sobosbuvir (SOF) and Ledipasvir (LDV) has been reported to have almost universal efficacy in a 12 week regimen for genotype 1, and the combination of SOF and Ribavirin (RBV) for genotypes 2-6 in a 24 week regimen. However, persistence of cryoglobulinemia even after viral clearance with the newer regimens has also raised the question of whether longer treatment regimens may be appropriate in the setting of significant extrahepatic disease. Thus, the timing is right to initiate a trial of all-oral treatment to rigorously evaluate the effect on extrahepatic disease, and to re-establish the efficacy of antiviral therapy in halting the direct and indirect role of HCV in driving autoimmune disease and lymphoproliferation. Using an interferon-sparing regimen to treat patients with HCV-related cryoglobulinemia will help answer the question as to whether immunomodulating therapy plays a role at all in eradicating cryoglobulins long-term, and whether antiviral therapy alone is adequate. If the latter, appreciable morbidity and mortality may be saved in avoiding treating these potentially sick, often cirrhotic patients, with immunomodulatory therapies.