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Direct-Acting Antiviral Therapy Restores Immune Tolerance to Patients With Hepatitis C Virus-Induced Cryoglobulinemia Vasculitis
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Gastroenterology June 2017 - Cloe Comarmond,1,2,3,4 Marlene Garrido,1,2,3 Stanislas Pol,5 Anne-Claire Desbois,1,2,3,4Myrto Costopoulos,6 Magali Le Garff-Tavernier,6 Si Nafa Si Ahmed,7 Laurent Alric,8Helene Fontaine,5 Bertrand Bellier,1,2,3 Anna Maciejewski,1,2,3 Michelle Rosenzwajg,1,2,3David Klatzmann,1,2,3 Lucile Musset,9 Thierry Poynard,10 Patrice Cacoub,1,2,3,4, andDavid Saadoun1,2,3,4,
"Twenty-four patients (88.9%) had a complete clinical response of CV to DAA therapy at week 24, defined by improvement of all the affected organs and the absence of relapse......Our results indicate that in addition to their virologic effect, DAA-based therapy effectively normalizes many of the disturbances in peripheral B- and T-lymphocytes homeostasis......Circulating mixed cryoglobulins are detected in 40%-60% of patients with chronic hepatitis C virus (HCV) infection, whereas overt cryoglobulinemia vasculitis (CV) is observed in only 5%-10% of cases.1, 2, 3, 4 It involves the activation of B cells, which generates pathogenic IgM and IgG with rheumatoid factor activity.5, 6 CV leads to clinical manifestations ranging from purpura, arthralgia, and fatigue, to more serious lesions with neurologic and renal involvement.2 Despite success with combination antiviral treatment with or without immunosuppressive drugs, HCV-CV remains a serious disease, with an estimated 5-year survival rate of 75%.4, 7"
In the present study we have shown further that after DAA use, complete remission in autoimmune manifestations as well as viral clearance are associated with normalization of the significant disturbances in peripheral T- and B-lymphocyte homeostasis.
Twenty-seven consecutive patients with HCV-CV were treated with DAAs according to current guidelines. Twenty-one patients received antiviral therapy with sofosbuvir 400 mg/day plus ribavirin (200-1400 mg/day orally) for 24weeks. Four patients received sofosbuvir plus daclatasvir for 12 weeks. Two patients received sofosbuvir plus simeprevir for 12 weeks. None of the patients received corticosteroids, immunosuppressants, or rituximab in the 6 months before inclusion. Twenty-four patients (88.9%) had a complete clinical response of their CV at week 24.
Patient characteristics are detailed in Table1. Twenty-seven patients with HCV-CV, with a median age of 59 years (range, 53-66 y) were included. The main clinical features of cryoglobulinemia vasculitis included purpura (89%), peripheral neuropathy (48%), glomerulonephritis (26%), and skin ulcers (15%). The median cryoglobulin level was 0.35 g/L (IQR, 0.17-0.81 g/L). Twenty-four patients (88.9%) had a complete clinical response of their CV. Twenty-two patients (81.5%) had a sustained virologic response (HCV-RNA negative) at week 12 PT. Ten (27%) patients presented negativation of cryoglobulinemia and 17 (63%) patients had persistent cryoglobulinemia after DAA-based therapy.
In conclusion, our study identified Tfh expansion associated with Th1 and Th17 polarization, and marked expansion of IgM+CD21-/low memory B cells and Treg deficiency in HCV-CV. We also showed that IFN-free DAA-based therapy dramatically improves abnormalities in B-cell homeostasis, with a decreased proportion of autoreactive memory B cells and decreased cryoglobulin levels after treatment. In addition, the results reported herein indicate that DAA may be an efficient therapy in HCV-CV patients not only because it reduces or abolishes the production of cryoglobulin, but also because it improves T-cell homeostasis by restoring regulation/activation and Th1/Th17 imbalances.
Editor's Notes
Circulating mixed cryoglobulins are detected in 40%-60% of patients with chronic hepatitis C virus (HCV) infection, whereas overt cryoglobulinemia vasculitis (CV) is observed in only 5%-10% of cases.1, 2, 3, 4 It involves the activation of B cells, which generates pathogenic IgM and IgG with rheumatoid factor activity.5, 6 CV leads to clinical manifestations ranging from purpura, arthralgia, and fatigue, to more serious lesions with neurologic and renal involvement.2 Despite success with combination antiviral treatment with or without immunosuppressive drugs, HCV-CV remains a serious disease, with an estimated 5-year survival rate of 75%.4, 7
Treatment of HCV-CV remains difficult and requires targeting the downstream B-cell arm of autoimmunity and the viral trigger to obtain clinical resolution of symptoms.8, 9 Two prospective randomized controlled trials have shown the superiority of rituximab monotherapy compared with conventional immunosuppressive therapy in patients with HCV-CV in whom prior antiviral therapy failed to induce disease remission.10, 11 Rituximab was effective in 71.4%-83% of patients with CV.10, 11 However, in the absence of HCV clearance, frequent relapses occurred when B cells re-emerged in the peripheral blood. Direct-acting antivirals (DAAs) have proven to be very effective in patients with HCV-CV. A complete clinical response was achieved in 87.5% of HCV-CV patients treated with sofosbuvir plus ribavirin, and was correlated closely with virologic response.12, 13, 14 We previously reported a quantitative defect in regulatory T cells (Tregs) and clonal expansion of CD27+IgM+CD21-/low memory B cells in patients with HCV-CV.15, 16, 17 It has been shown that antiviral treatment can lead to the disappearance of symptoms and can induce an immunologic response (ie, a significant decrease in plasma cryoglobulin levels and increase in Tregs).15, 18 In addition, a decrease in B-lymphocyte stimulator receptor 3 (BR3) staining on B cells was associated with an increase in serum B-cell-activating factor of the tumor necrosis factor family (BAFF) after rituximab in HCV-CV.19
However, little evidence is available about immunologic dynamics after IFN-free DAA-based therapy. As a first examination of the immunologic effects of DAAs in HCV-CV, we evaluated both B- and T-cell subsets in patients at baseline (W0) and after DAA therapy at end of treatment (EOT) and post-treatment (PT). Our results indicate that in addition to their virologic effect, DAA-based therapy effectively normalizes many of the disturbances in peripheral B- and T-lymphocytes homeostasis.
ABSTRACT
Background & Aims
Interferon-free direct-acting antiviral (DAA) therapies are effective in patients with hepatitis C virus-induced cryoglobulinemia vasculitis (HCV-CV). We analyzed blood samples from patients with HCV-CV before and after DAA therapy to determine mechanisms of these drugs and their effects on cellular immunity.
Methods
We performed a prospective study of 27 consecutive patients with HCV-CV (median age, 59 y) treated with DAA therapy (21 patients received sofosbuvir plus ribavirin for 24 weeks, 4 patients received sofosbuvir plus daclatasvir for 12 weeks, and 2 patients received sofosbuvir plus simeprevir for 12 weeks) in Paris, France. Blood samples were collected from these patients before and after DAA therapy, and also from 12 healthy donors and 12 individuals with HCV infection without CV. HCV load, cryoglobulins, and cytokines were quantified by flow cytometry, cytokine multiplex assays, and enzyme-linked immunosorbent assay.
Results
Twenty-four patients (88.9%) had a complete clinical response of CV to DAA therapy at week 24, defined by improvement of all the affected organs and the absence of relapse. Compared with healthy donors and patientswith HCV infection without CV, patients with HCV-CV, beforeDAA therapy, had a lower percentage of CD4+CD25hiFoxP3+ regulatory T cells (P < .01), but higher proportions ofIgM+CD21-/low memory B cells (P < .05), CD4+IFNγ+ cells (P< .01), CD4+IL17A+ cells (P < .01), and CD4+CXCR5+interleukin 21+ follicular T-helper (Tfh) cells (P< .01). In patients with HCV-CV, there was a negative correlation between numbers of IgM+CD21-/low memory B cells and T-regulatory cells (P= .03), and positive correlations with numbers of Tfh cells (P= .03) and serum levels of cryoglobulin (P= .01). DAA therapy increased patients' numbers of T-regulatorycells (1.5% ± 0.18% before therapy vs 2.1% ± 0.18% after therapy), decreased percentages of IgM+CD21-/low memory B cells (35.7% ± 6.1% before therapy vs 14.9% ± 3.8% after therapy), and decreased numbers of Tfh cells (12% ± 1.3% before therapy vs 8% ± 0.9% after therapy). Expression levels of B lymphocyte stimulator receptor 3 and programmed celldeath 1 on B cells increased in patients with HCV-CV after DAA-based therapy (mean fluorescence units, 37 ± 2.4 before therapy vs 47 ± 2.6 after therapy, P < .01; and 29 ± 7.3 before therapy vs 48 ± 9.3 after therapy, P < .05, respectively).
Conclusions
In a prospective clinical trial of patients with HCV-CV, DAA-based therapy restored disturbances in peripheral B- and T-cell homeostasis.
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