title: Virologic, Clinical, and Immune Response Outcomes of Patients With Hepatitis C Virus-Associated Cryoglobulinemia Treated With Direct-Acting Antivirals.
abstract: OBJECTIVE
  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 Immune-suppressive therapy was reduced for 4 of 13 patients and withdrawn for 6 of 13.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.
authors.affiliation: 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.
authors.forename: Martín
authors.initials: M
authors.lastname: Bonacci
authors.affiliation: 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.
authors.forename: Sabela
authors.initials: S
authors.lastname: Lens
authors.affiliation: 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.
authors.forename: María-Carlota
authors.initials: MC
authors.lastname: Londoño
authors.affiliation: 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.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Mariño
authors.affiliation: Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, Institut d'Investigacions Biomédiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Cid
authors.affiliation: 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.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ramos-Casals
authors.affiliation: 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.
authors.forename: Jose María
authors.initials: JM
authors.lastname: Sánchez-Tapias
authors.affiliation: 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. Electronic address: xforns@clinic.ub.es.
authors.forename: Xavier
authors.initials: X
authors.lastname: Forns
authors.affiliation: Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, Institut d'Investigacions Biomédiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Hernández-Rodríguez
mesh_terms: D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D003449:Cryoglobulinemia / Q000150:complications*; D005260:Female; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013030:Spain; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents
keywords: Antiviral Therapy; Cryoglobulinemic Vasculitis; DAA; Hepatitis C