Long‐lasting persistence of large B‐cell clones in hepatitis C virus‐cured patients with complete response of mixed cryoglobulinaemia vasculitis

Abstract

Background & Aims Hepatitis C virus (HCV)‐related mixed cryoglobulinaemia vasculitis (MCV) is characterized by the expansion of rheumatoid factor‐producing B‐cell clones. The aim of this study was to assess whether B‐cell clones may persist in these patients after the clearance of the virus with antiviral therapy, and whether their persistence influences clinical outcomes. Methods Forty‐five HCV‐cured MCV patients were followed up for a median of 18.5 (range 9‐38) months after the clearance of HCV. Circulating B‐cell clones were detected using flow cytometry either by the skewing of kappa/lambda ratio or by the expression of a VH1‐69‐encoded idiotype. Results The clinical response of vasculitis was 78% complete, 18% partial and 4% null. However, cryoglobulins remained detectable in 42% of patients for more than 12 months. Circulating B‐cell clones were detected in 18 of 45 patients, and in 17 of them persisted through the follow‐up; nine of the latter patients cleared cryoglobulins and had complete response of vasculitis. Several months later, two of these patients had relapse of MCV. Conclusions B‐cell clones persist in MCV patients long after HCV infection has been cleared but halt the production of pathogenic antibody. These ‘dormant’ cells may be reactivated by events that perturb B‐cell homeostasis and can give rise to the relapse of cryoglobulinaemic vasculitis.

The Successful Treatment of a Case of HCV-associated Cryoglobulinemic Glomerulonephritis with Rituximab, Direct-acting Antiviral Agents, Plasmapheresis and Long-term Steroid Despite Serologically Persistent Cryoglobulinemia

“…There have been several previous reports of persistent cryoglobulinemia after HCV eradication by DAAs (10-13). These can be explained by the presence of persistent B-cell clones producing cryoglobulins after HCV eradication (10). Therefore, B-cell depletion therapy is needed to treat these cases of cryoglobulinemia.…”

Clinico‐immunological outcomes of HCV‐cured cryoglobulinemia: Lower relapse rate with interferon‐based than interferon‐free therapy

“…The overall response rates of 92% and 86% in the IFN-treated and DAA-treated cohorts, respectively, were similar to the average response rates reported in previous studies using IFN (88%-97%) 3,4 or DAAs (average 93%). [5][6][7][8][9] NHLs were found in 8% and 16% of IFN-treated and DAA-treated patients, respectively, and there was a trend to more frequent complete hematological responses of splenic marginal zone lymphomas (2/2 vs 0/2) and of overall NHLs (2/3 vs 0/11, P = .033) in IFN-treated patients (Table S1).…”

Cryoglobulins: Identification, classification, and novel biomarkers of mysterious proteins

“…In fact, we provide evidence that after antiviral therapy, the predominantly CD21 low clonal B-cell population is gradually substituted by a clonal population mostly made up of CD21 high cells lacking the peculiar array of homing and inhibitory receptors typical of CD21 low B cells. These cases suggest that abundant immune complexes produced during infection might reactivate B-cell clones, leading to the relapse of MC [113] . IgG subclasses in the form of immune complexes circulating could be the autoantigenic trigger responsible for the survival and reactivation of B-cell clones beyond HCV.…”

“…The possibility that rheumatoid factor-bearing monoclonal B cells in MC might be reactivated by circulating immune complexes could explain why a proportion of MC patients experience vasculitis relapse after eradication of HCV in the course of infections or tumors [112] . B-cell clones persist in MC vasculitis patients long after HCV infection has been cleared but halt the production of pathogenic antibody [113] . These “dormant” cells may be reactivated by events that perturb B-cell homeostasis and can give rise to the relapse of cryoglobulinemic vasculitis.…”

“…These “dormant” cells may be reactivated by events that perturb B-cell homeostasis and can give rise to the relapse of cryoglobulinemic vasculitis. The hypothesis of a switch to a non-pathogenic state is supported by the phenotypic and functional changes that take place in clonal B cells once HCV is cleared [113] . In fact, we provide evidence that after antiviral therapy, the predominantly CD21 low clonal B-cell population is gradually substituted by a clonal population mostly made up of CD21 high cells lacking the peculiar array of homing and inhibitory receptors typical of CD21 low B cells.…”