MCS is a small to medium vessel vasculitis characterized by the expansion of B cells resulting in production of cryoglobulins: immune complexes of polyclonal immunoglobulin (Ig) G and monoclonal or polyclonal IgM with rheumatoid factor that precipitate at lower temperatures [
12]. These fix complement and lead to endothelial tissue damage and vasculitis [
10,
11]. The resulting syndrome can manifest in skin, major joints, peripheral nerves, and renal disease. As high as 90 % of cases of MCS are associated with chronic HCV [
13]. Dermatological manifestations are the most common with palpable purpura [
10,
11]. Other manifestations include arthritis, non-healing ulcers, peripheral neuropathy, central nervous involvement, and glomerulonephritis [
10,
11]. The diagnosis is confirmed by the presence of cryoglobulins, elevated rheumatoid factor and immunofluorescence of complement fixing IgM in tissues.
Treatment of HCV-associate MCS may target HCV, or the downstream B cell arm of autoimmunity. Until recently, HCV therapy was dependent upon interferon and mixed cryoglobulinemia is identified as a negative prognostic factor of virologic response [
14]. In a large prospective study of HCV treatment with pegylated interferon alpha among 253 patients with MCS or mixed cryoglobulinemia (circulating cryoglobulins but without MCS), 48.6 % achieved SVR. All but 2 of the 121 patients with MCS saw clinical-immunological resolution at 6 month follow up. Among the patients with MCS who did not achieve SVR, a transient improvement the syndrome was seen in some patients by the end of treatment; however, improvements did not persist at follow up [
14]. This study supports that of an earlier, smaller study where HCV viral relapse occurred within 2 months of follow up in 8 patients, 6 of whom also saw a relapse in MCS [
15]. The first generation NS3/4A protease inhibitors boceprevir and telaprevir were among the earliest DAA agents to be approved for HCV therapy. Triple therapy with pegylated interferon, ribavirin, and telaprevir or boceprevir was studied among participants with MCS in a pilot study. In this study, SVR rates were still low despite addition of boceprevir with none of the 5 patients with MCS and only 5 out of 16 of patients with mixed cryoglobulinemia without symptoms achieving SVR [
16]. In contrast, a more recent study of 30 patients with MCS reported improved SVR (66.7 %) rates, with 70 % or patients achieving complete resolution of MCS clinical parameter [
17]. This regimen, however, was associated with significant side effects. Newer DAA agents have excellent tolerability, are highly effective when used in combination, and do not require concurrent interferon therapy for the vast majority of patients. Subsequently, triple therapy with the first generation protease inhibitors is no longer recommended for HCV therapy. There are few publications reporting the efficacy of novel DAA therapy among patients with MCS. A case report documents successful clinical response associated with SVR in one patient with severe MCS after 12 weeks of combination therapy with ombitasvir, paritaprevir, ritonavir, and dasabuvir [
18]. The VASCUVALDIC study was a prospective study that treated 24 patients with MCS with sofosbuvir and ribavirin. By end of treatment 87.5 % of patients had complete clinical response (improvement of all affected organs and absence of clinical relapse). Cryoglobulin disappearance occurred in 46.1 % of cases, and overall SVR was 74 %. Gragnani et al. treated 17 (7 with mixed cryoglobulinemia, and 10 with MCS) patients with interferon-free, DAA-based therapy and report improvement in clinical parameters in all the patients with MCS [
19]. Sise et al. treated 12 patients with HCV-associated MCS (including 7 with renal involvement) with sofosbuvir (an NS5A inhibitor and the backbone of most DAA-based therapies currently approved for use in USA and Europe) in combination with either simeprevir (an NS3A/4A protease inhibitor) or ribavirin. The majority of patients were treated with 12 weeks of therapy and overall SVR rate was 87 %. Six of the patients with renal involvement achieved SVR, and this was associated with improvement in renal function and reduction in proteinuria. Cryoglobulin levels at follow up decreased for all patients compared to baseline, except for one patient who experienced virological relapse, with complete cryoglobulin loss in 4 of the 9 patients with levels available at follow up [
20]. Importantly, 5 patients were on immunosuppression (4 with rituximab, and1 with ustekinemab for psoriasis) while on HCV treatment and several were able to reduce immunosuppression with only 1 (who experienced virologic failure) requiring increase in immunosuppression [
20].
Several studies have supported the efficacy and safety of rituximab—a monoclonal antibody against CD20 that results in B cell depletion—for the treatment of HCV-associated MCS [
21]. Only 2 prospective, randomized controlled trials have been published so far, reporting success in attaining remission and symptomatic relief [
22] and greater survival (64.3 % versus 3.5 %,
P < 0.0001) at month 12 [
23] among patients who did not achieve SVR with antiviral therapy or intolerant to interferon alpha and ribavirin. A systemic review by Visentini et al. found that 32 % of patients experienced relapse after clinical response after rituximab monotherapy [
21]. The same authors conducted a phase II study of low-dose rituximab for the treatment of MCS and reported a 41 % relapse [
21]. Therefore, the proportion of patients who relapse after clinical response with rituximab monotherapy remains sizeable, solidifying the need for virological treatment.
MCS is a multisystem disease with significant morbidity. Current evidence supports the resolution of MCS for most patients who are treated for HCV and achieve SVR. Therefore, patients with mixed cryoglobulinemic vasculitis should be prioritized for treatment with current DAA-based therapy. It is expected that over time, this syndrome will be occurring with lower frequency.