Should rituximab be the rescue therapy for refractory mixed cryoglobulinemia associated with hepatitis C?

Mixed cryoglobulinemia (CG) is a systemic immune complex-mediated disease that involves small-to-medium vessel vasculitis, provoked by the CG containing immune complexes that precipitate in cold. It is associated with hepatitis C virus (HCV) infection in 80% of patients. Mixed CG-mediated vasculitis can affect vital organs such as kidney, liver and heart. Laboratory parameters show presence of cryoglobulin, and in most cases of mixed CG, rheumatoid factor IgM kappa. The current treatment strategy of HCV-associated CG includes targeting the viral trigger HCV with a combination of antiviral medication, interferon-alpha (IFN-alpha) and ribavirin, or the downstream pathogenic events by means of plasmapheresis, steroids or immunosuppression. With multiorgan involvement, the antiviral therapy may be limited due to severity of renal disease, treatment failure, side effects or contraindications. On the other hand, immunosuppressive therapy may be poorly tolerated or ineffective. Therefore, new treatment options such as rituximab (RIT), a chimeric monoclonal anti-CD20 antibody, have been proposed as a rescue therapy.

We reviewed the literature to evaluate the current evidence in treating HCV-related refractory mixed CG.

The use of RIT in treatment of HCV-related CG was first described by Zaja et al. Since then there have been numerous published case series and case reports. So far there has been no randomized controlled trial. In the literature, there have been 60 patients with CG treated with RIT. The male to female ratio was 14:46. Fifty-three patients were HCV-positive. Forty-six patients had mixed type II CG, 7 had type III CG and for 7 the type was not specified. Twenty-five patients had renal involvement ranging from proteinuria, to nephrotic syndrome, to nephritic syndrome to chronic kidney disease. Eight patients had had a renal transplant and were on immunosuppression. Most patients responded to RIT, with only 17 of 60 patients relapsing, and 8 of 17 of those were rechallenged with RIT with a good response. Total follow-up period varied between 3 and 31 months.

RIT is a suitable rescue therapy in recalcitrant CG associated with HCV. There is evidence supporting the use of RIT as first-line therapy, as opposed to the proposals of others who would strongly recommend antiviral therapy. However, a prospective randomized controlled trial is required to evaluate the efficacy and safety of RIT compared with current standard therapy, which includes antiviral therapy, immunosuppression and plasmapheresis.