HCV-related cryoglobulinemic vasculitis (mixed cryoglobulinemia syndrome) in the era of direct-acting antivirals: A 10-year experience from Italian tertiary referral centers

OBJECTIVE: To evaluate long-term clinico-serological response to direct-acting antivirals (DAAs) in patients with HCV-related cryoglobulinemic vasculitis (HCV-CV), and to compare the incidence of severe disease complications before/after antiviral therapy (AVT). The study also aimed to explore patterns of disease evolution following AVT. METHODS: This retrospective multicenter study included 161 HCV-CV patients (mean age 63.9 ± 11.1 years; 64.6% females) treated with DAAs and achieving sustained virological response. The mean observation period was 8.2 ± 5.2 years, including pre-AVT (2.2 ± 5.5) and post-AVT (5.6 ± 2.7) phases. Complete response (CR) was defined as full resolution of baseline CV symptoms, partial response (PR) as ≥50% improvement, all others were non-responders (NR). RESULTS: Post-AVT, significant reductions were observed in purpura (64% to 14%), fatigue (72% to 35%), arthralgias (55% to 26%), sicca syndrome (32% to 16%), skin ulcers (13% to 4%), and liver involvement (74% to 25%) (all p < 0.01), along with decreased cryocrit % (3.5 ± 4.6 to 0.5 ± 1.5, p < 0.0001) and increased C4 levels (9.6 ± 8.5 to 20.2 ± 11 mg/dl; p < 0.0001). CR was achieved in 74%, PR in 14%, NR in 12% of patients. Severe CV complications occurred more frequently pre-AVT than post-AVT (71% vs. 29%; p < 0.0001), particularly in NR patients (47% vs PR 26% and CR 12%; p = 0.0006), and those with persistent cryoglobulins (53% vs 12% without; p < 0.0001). Of note, NR patients showed mean higher cryocrit (p = 0.0046) and lower C4 (p = 0.025) levels evaluated within the last 12 months before DAAs. CONCLUSION: DAAs significantly improved the clinical course of HCV-CV. Three post-treatment subsets can be identified: CR patients with minor residual symptoms, PR requiring careful monitoring, and NR group at high-risk for severe CV complications. Persistent serum cryoglobulins are predictors of long-term worse clinical course.