Non-Invasive B-Cell Clonality Markers May Help in the Rational Approach to HCV Svr Cryoglobulinemic Patients with Persisting Manifestations

Background: The mixed cryoglobulinemia syndrome (MCS), a benign lymphoproliferative disorder (LPD), is the most frequent HCV extrahepatic manifestation. DAAs can improve or heal MCS, but persistence or recurrence may be observed even in SVR patients. Rituximab (RTX) is the first-choice therapy in such cases. However, MCS persistence may also be due to causes different from persisting clonal B-cell expansion (eg, the occurrence of irreversible organ/tissue damage). Consequently, the evaluation of B-cell clonal expansion is the key for a correct clinical, prognostic and therapeutic approach. Methods: We prospectively evaluated HCV patients consecutively referred to the MASVE Center, with the following features: Group A: DAA-treated SVR MCS patients with complete clinical response; Group B: DAA-treated SVR MCS patients maintaining symptoms. B-cell clonal expansion was evaluated, after DAA-therapy, by flow cytometry, Free Light Chains ratio (κ/λ) and t(14;18). Results: We evaluated 36 patients: 11 group A and 25 group B (mean FU 25.7 months, range: 36-3). B-cell clonality markers were not observed in group A patients, despite small levels of cryocrit in some cases (30%). At least one clonality marker was detected in 19/25 (76%) patients with persisting symptoms, including five patients with lymphoma, in hematological regression after DAAs. Three patients had systemic symptoms (e.g. itchiness, nocturnal sweating) suggestive of the evolution the LPD. The remaining patients, negative for B-cell clonality, were generally characterized by persisting arthralgia, sicca syndrome, and neuropathy. κ/λ ratio was altered in 74 % of cases, flow cytometry in 24% and t(14;18) in 30%. In 20% of cases more than a marker was detected. Conclusion: Previous studies showed the association between MCS and B-cell clonal expansion. In this study, whereas subjects with a complete clinical response did not have clonality markers, the majority of patients who maintained vasculitis symptoms did. Interestingly, clonality markers were associated with more severe pre-therapy vasculitis, including patients with lymphoma in remission. This suggests the hypothesis of having gone beyond the LPD point of no return and the rationale for RTX treatment. Furthermore, this study suggests that the κ/λ ratio, may be a very useful and easy marker in MCS patients with persisting symptoms, in the light of a more rational clinical and therapeutic approach to these patients