Ricerc@Sapienza

Hepatitis C virus (HCV) associated mixed cryoglobulinemia (MC) is a B-cell lymphoproliferative disorder, associated in some cases with non-Hodgkin¿s lymphoma (MC-NHL), clinically characterized by systemic vasculitis. The monoclonal B¿cells of MC and MC-NHL patients produce rheumatoid factors (RF), putatively cross¿reactive with HCV, forming cold¿precipitable immune complexes responsible for vasculitis. Direct acting antivirals (DAAs), which eradicate HCV in almost 100% of cases, yield clinical response rates of 90-100% in MC and of ¿70% in MC-NHL. However, studies with longer follow-up revealed the persistence of cryoglobulins in almost half of patients, and the persistence or relapse of MC vasculitis in a significant proportion of them. Recently, our group showed that pathogenic B-cell clones persist in many HCV-cured MC or MC-NHL patients, most likely explaining the persistence or relapse of vasculitis; more recently, we got evidence that stimulation of these RF-producing B-cells by endogenous immune complexes may underlie their prolonged survival.
The aim of this study is to correlate, in a large cohort of HCV-associated MC or MC-NHL patients, the long-term clinical outcomes of DAA therapy with putative biomarkers predicting disease persistence or relapse, namely the persistence of pathogenic B-cell clones and their responsiveness to stimulation with immune complexes.
In terms of translational and precision medicine the objective of this project, providing biomarkers associated with persistence or predicting relapse of MC vasculitis in HCV-cured patients, will serve to identify subsets of patients at risk for these adverse clinical outcomes. Demonstrating that persistence of pathogenic monoclonal B-cells is indeed associated with these adverse outcomes, and clarifying its underlying mechanism(s), would open the way to develop tailored treatments for at risk patients, e.g. by using preemptive anti-B-cell therapy with rituximab or with other therapeutic agents.