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.
The advent of direct acting antivirals (DAA) has completely changed the scenario in hepatits C virus associated diseases as viral eradication is achieved in almost 100% of patients. Lymphoproliferative diseases (LPDs) as mixed cryolgobulinemia and non-Hodgkin lymphomas (NHLs) are the most studied HCV-related diseases and DAA were seen as the possibility to definitively defeat these diseases. Immunologists and hematologists together with hepatologists have been using DAA in clinical practice for almost 5 years for the treatment of HCV associated LPDs and recent studies with long term follow up describe relapses or persistence of mixed cryolgobulinemia despite HCV eradication. In the case of NHL one single study, analyzing retrospectively 45 patients, reported hematological response in about 70% of them with one third of patients still needing an alternative therapeutic approach. Therefore mixed cryoglobulinemia and HCV-NHL exist beyond HCV. Who are the patients at risk for vasculits relapse after viral eradication or without clinical response is not known and biomarkers predictive for clinical outcome are greedily searched. It is possible that concomitant events as infections or cancers might contribute in disease reactivation but only single cases have been reported. This project will create a large cohort of patients, offering long term clinical and laboratory outcomes in patients with HCV-associated LPDs after clearance of the virus. As single centre observations, we have the advantage to study the patients homogenously and this will help the identification of reliable clinical and/or laboratory biomarkers able to predict relapses and clinical outcome.
For long time our group has been studying clonal B cells in HCV-associated LPDs and it has been suggested that these cells may have a role in the pathogenic mechanisms involved in disease reactivation after viral eradication. We will provide in vitro experiments that might demonstrate speculations risen from clinical observations as the possible role of immune complexes rich diseases in the reactivation of rheumatoid factor positive B cell clones.
In terms of translational and precision medicine the results of this project, might provide biomarkers associated with persistence or predicting relapse of MC vasculitis in HCV-cured patients, identifying subsets of patients at risk for these adverse clinical outcomes. In the era of patient tailored treatments, our project will contribute to improve the treatment approach of HCV-associated disorders identifying those patients to be treated with the only antivirals and those that might benefit from a combination treatment with rituximab (anti-CD20).