Rituximab has been considered as a possible therapy for HCV-associated cryoglobulinemic vasculitis based on retrospective, uncontrolled studies of cohorts that included some patients with non-HCV-associated cryoglobulinemic vasculitis. In contrast to prior reports, our study was a prospective, randomized, controlled trial that enrolled only patients with HCV-associated cryoglobulinemic vasculitis in whom antiviral therapy had failed. Furthermore, standard forms of immunosuppressive therapy had also failed to induce remission in 75% of the patients in our study. Thus, patients in this trial were highly representative of those patients with HCV-associated cryoglobulinemic vasculitis for whom effective therapy is lacking.
The trial was originally designed to enroll 30 patients but was halted at 24 when an interim analysis revealed that a sufficient difference existed between groups to warrant stopping the trial. Eighty-three percent of patients randomized to rituximab met the primary endpoint of remission at study month 6 as compared to 8% of those in the control group. The median duration of remission for the 10 rituximab-treated patients reaching the primary endpoint was 7 months. The three patients who relapsed after month 6 were all retreated with a second course of rituximab leading to sustained remission lasting more than 6 months in all three. These data indicate that therapy with rituximab is able to induce remission in a high percentage of patients, and that remission can be sustained beyond 6 months despite the presence of continuing HCV infection.
The current investigation was based upon the hypothesis that rituximab-induced depletion of the expanded population of autoreactive B cells would decrease pathogenic cryoglobulin formation and result in clinical improvement in the vasculitis. Depletion of peripheral blood B cells was observed in all patients who received four infusions of rituximab. B cell depletion was associated with a decrease in cryoglobulin levels and improvement in vasculitis activity. A return of B cells to pre-treatment levels occurred within 6–8 months, but this did not correlate with a relapse of disease activity. Although most patients remained in remission for months after the return of peripheral B cells, the persistence of low-level cryoglobulinemia and ongoing HCV infection suggests that rituximab treatment did not eradicate the pathogenic B cell population and these patients remain at risk for future relapse.
Immunosuppression is known to increase HCV viremia and accelerate the progression of chronic HCV liver disease (21
) and a prior uncontrolled study suggested that rituximab treatment was associated with a similar risk (12
). In our controlled trial, we found no evidence for worsening HCV infection. No significant change in plasma viral levels over time was detected in the rituximab group compared with the control group and there was no biochemical evidence of worsening hepatitis. Rituximab treatment was well tolerated with the frequency of adverse events not significantly different from the control group and no serious infections were seen.
A significant strength of this study is that the primary outcome measure of remission was determined prior to study initiation and was based upon the BVAS, a validated instrument previously used to assess vasculitis disease activity (18
). In addition, patients in this trial received standardized monthly clinical and laboratory evaluations that allowed for accurate determination of time to remission, time to relapse, and potential adverse effects of rituximab on the underlying HCV infection.
This trial does have limitations that must be weighed. Accrual into the study was slow for several reasons including the low incidence of HCV-associated vasculitis in the United States (24
), restricting enrollment to patients in whom antiviral therapy had failed, and the availability of rituximab for off label use in the United States. However, the slow accrual rate should not have a major effect on study outcomes, as no new treatments for either HCV infection or HCV-associated vasculitis became available during the period in which the study was conducted. Although the study was randomized, it was not blinded. This design was chosen as the study endpoints were all based on objective measures of improvement in manifestations of vasculitis. Although BVAS has potential limitations with assignment of disease activity to subjective symptoms particularly in open-label studies, it remains the most recognized validated instrument for standardized assessment of disease activity in vasculitis clinical trials. The sample size of the study was small, due to the efficacy of rituximab and lack of efficacy of standard forms of immunosuppressive therapy in this patient population. No patients with immediately life-threatening manifestations of vasculitis involving the central nervous system, heart, or gastrointestinal tract was enrolled in our trial. Hence, the results of this trial may not be applicable to patients with these rare manifestations of HCV-associated cryoglobulinemic vasculitis. However, patients in our study did have significant disease activity as evidenced by distribution of organ involvement and their BVAS scores. Finally, our study was limited to patients with HCV-associated cryoglobulinemic vasculitis and the results cannot be extrapolated to patients with cryoglobulin disease not associated with chronic HCV infection.
It is important to emphasize that the first line treatment for HCV-associated vasculitis should be antiviral therapy. Our study only enrolled patients in whom antiviral therapy failed to induce remission either because a lack of sustained virologic response or regimen related toxicity. Limiting our study to such patients made it possible to assess the efficacy, toxicity, and effect on the underlying HCV infection of rituximab without the confounders of concomitant antiviral therapy. Recent studies suggest that combining rituximab with interferon-based antiviral therapy results in improved response rates compared to antiviral therapy alone (17
) a hypothesis which cannot be directly addressed by our trial.
In conclusion, our data suggests that rituximab can induce sustained remissions in patients with HCV-associated cryoglobulinemic vasculitis following failure of antiviral therapy. Rituximab treatment was well tolerated and did not appear to increase HCV replication or worsen the underlying hepatitis.