Ricerc@Sapienza

Hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC) is a benign lymphoproliferative disorder characterized by the expansion of a B cell clone producing IgM endowed with rheumatoid factor (RF) activity that forms cold-precipitable immune complexes (cryoglobulins) causing small vassel vasculits. The treatment for HCV-associated MC is the eradication of the virus that is now achieved in almost 100% of patients with the new direct acting antivirals (DAAs). Recent data have shown that DAA induce a complete clinical response of MC in 71-90% of patients after HCV eradication and, thus, 10-29% of HCV patients fail to recover from cryoglobulinemic vasculitis or relapse after initial response. Persistence of cryoglobulinemia after the clearance of HCV appears to be due to the persistence of pathogenic B-cell clones. Therefore additional treatment with the B cell depleting monoclonal antibody rituximab (RTX) might increase vasculitis¿response.
The purpose of this project is to study the efficacy of combined treatment of RTX with DAA for the treatment of HCV-associated MC and to analyze whether, after removal of viral stimulation together with B cell depletion, recovery of B cell homeostasis is achieved. To this aim circulating B cell clones will be investigated by flow cytometry and at a molecular level before therapy and throughout the follow-up.
In addition B cell clones will be investigated at the functional level (at baseline or in patients treated with only DAA) in order to individualize alternative stimuli that, after HCV clearance, might be responsible for their persistence. To this aim in vitro studies will investigate whether immune complexes induce a proliferative response in RF-positive B cell clones.
These studies might provide new insights in the pathogenic mechanisms involved in the persistence or relapse of MC after HCV eradication that might also be responsible for lymphoma evolution, a frequent complication of MC patients.