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Virologic, Clinical, and Immune Response Outcomes of Patients With Hepatitis C Virus–Associated Cryoglobulinemia Treated With Direct-Acting Antivirals

  • Author Footnotes
    a Authors share co-first authorship.
    Martín Bonacci
    Footnotes
    a Authors share co-first authorship.
    Affiliations
    Liver Unit, Hospital Clinic, Institut d'Investigacions Biomédiques August Pi i Sunyer, Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain
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  • Author Footnotes
    a Authors share co-first authorship.
    Sabela Lens
    Footnotes
    a Authors share co-first authorship.
    Affiliations
    Liver Unit, Hospital Clinic, Institut d'Investigacions Biomédiques August Pi i Sunyer, Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain
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  • María-Carlota Londoño
    Affiliations
    Liver Unit, Hospital Clinic, Institut d'Investigacions Biomédiques August Pi i Sunyer, Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain
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  • Zoe Mariño
    Affiliations
    Liver Unit, Hospital Clinic, Institut d'Investigacions Biomédiques August Pi i Sunyer, Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain
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  • Maria C. Cid
    Affiliations
    Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, Institut d'Investigacions Biomédiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain
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  • Manuel Ramos-Casals
    Affiliations
    Department of Autoimmune Diseases, Hospital Clínic, Laboratory of Autoimmune Diseases Josep Font, Institut d'Investigacions Biomédiques August Pi i Sunyer-CELLEX, University of Barcelona, Barcelona, Spain
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  • Jose María Sánchez-Tapias
    Affiliations
    Liver Unit, Hospital Clinic, Institut d'Investigacions Biomédiques August Pi i Sunyer, Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain
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  • Xavier Forns
    Correspondence
    Reprint requests Address requests for reprints to: Xavier Forns, MD, Liver Unit, Hospital Clínic, C/Villarroel 170, 08036, Barcelona, Spain. fax: 0034932271779.
    Affiliations
    Liver Unit, Hospital Clinic, Institut d'Investigacions Biomédiques August Pi i Sunyer, Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain
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  • José Hernández-Rodríguez
    Affiliations
    Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, Institut d'Investigacions Biomédiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain
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  • Author Footnotes
    a Authors share co-first authorship.
Published:October 07, 2016DOI:https://doi.org/10.1016/j.cgh.2016.09.158

      Background & Aims

      Cryoglobulins (circulating immune complexes of polyclonal IgG, monoclonal IgM, and rheumatoid factor) are detected in the circulation of 40% to 60% of patients with chronic hepatitis C virus infection, and cryoglobulinemic vasculitis (CV) is observed in approximately 10% of patients. We aimed to assess the clinical and immune effects of direct-acting antiviral treatment.

      Methods

      We performed a prospective study of 64 patients with HCV infection with circulating cryoglobulins receiving direct-acting antiviral therapy at a single center in Barcelona, Spain, from January 2014 through April 2016. Patients were classified as having CV (n = 35) or asymptomatic circulating cryoglobulins (ACC, n = 29). Clinical response was considered complete if a patient’s Birmingham Vasculitis Activity Score (version 3) was 0, or if all affected organs improved 12 weeks after the end of therapy. A complete immunologic response (CIR) was defined as no detection of circulating cryoglobulins and normalized levels of complement and/or rheumatoid factor.

      Results

      Clinical manifestations of CV included purpura (65%), weakness (70%), arthralgia (31%), myalgia (20%), peripheral neuropathy (50%), and renal involvement (20%). At baseline, patients with CV had significantly higher levels of rheumatoid factor and lower levels of C4 complement than patients with ACC, whereas cryocrits were similar between groups (3.2% vs 2.6%). Overall, 60 patients (94%) had a sustained viral response 12 weeks after therapy. Among patients with CV, the median Birmingham Vasculitis Activity Score (version 3) decreased from 9 (range, 2–31) to 3 (range, 0–12) (P < .001). Twenty-five patients with CV (71%) achieved a complete clinical response. Immune-suppressive therapy was reduced for 4 of 13 patients and withdrawn for 6 of 13. Overall, 48% of patients achieved a CIR. A low baseline cryocrit level (<2.7%) was the only factor associated with CIR (odds ratio, 9.8; 95% confidence interval, 2.2–44; P = .03).

      Conclusions

      Viral eradication was associated with clinical improvement in most patients with CV. Markers of immune activation, including circulating cryoglobulins, persisted in 52% of patients with CV or ACC, despite a sustained viral response 12 weeks after therapy. A longer follow-up period after viral eradication might be necessary to ensure a normal immune response.

      Keywords

      Abbreviations used in this paper:

      ACC (asymptomatic circulating cryoglobulins), BVAS.v3 (Birmingham Vasculitis Activity Score version 3), C4 (complement 4 fraction), CH50 (50% hemolytic complement activity), CV (cryoglobulinemic vasculitis), DAA (direct-acting antiviral), eGFR (glomerular filtration rate), HCV (hepatitis C virus), IFN (interferon), RF (rheumatoid factor), SVR (sustained virologic response), SVR12 (sustained virologic response 12 weeks after end of therapy), TE (transient elastography)
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