title: Interleukin-6 in ANCA-associated vasculitis: Rationale for successful treatment with tocilizumab.
abstract: OBJECTIVE
  Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are systemic, necrotizing, small-vessel vasculitis associated with circulating anti-neutrophil cytoplasmic autoantibodies (ANCA), and thus called ANCA-associated vasculitides (AAV). The aim of the present study is to evaluate a potential role of interleukin (IL)-6 and its pathway in the pathogenesis of AAV and to review previous evidence of IL-6 in MPA and GPA.
  
  
  METHODS
  Blood and histological samples from 10 untreated myeloperoxidase (MPO)-ANCA/proteinase 3 (PR3)-ANCA-positive patients with active AAV were studied. Serum levels of cytokines/chemokines were evaluated by means of a Bio-Plex Multiple Cytokine Assay. IL-6 production at sites of active vasculitis was assessed by means of both immunohistochemistry and in situ hybridization techniques. We also treated a patient with MPA who was resistant or allergic to conventional treatments with a 12-month course of the IL-6 inhibitor tocilizumab and followed him up for 24 additional months. We also reviewed all the published cases in the English literature of histologically confirmed MPA or GPA, in which elevated IL-6 serum levels or intralesional IL-6 expression were reported.
  
  
  RESULTS
  IL-6 serum levels were significantly increased in patients with AAV as compared to controls (median = 51.96pg/mL; range: 34.11-84.30; versus 0.68pg/mL; range: 0.01-1.81; P < 0.005). Also, IL-6 was expressed and produced at sites of active vasculitis. Treatment with tocilizumab was able to induce a complete and sustained disease remission in a patient with severe multisystemic MPA, as well as normalization of circulating levels of IL-6-associated pro-inflammatory cytokines and chemokines. Previous evidence of IL-6 pathway activation in AAV is scarce. Increased serum levels of IL-6 were reported in seven clinical studies for a total of approximately 120 patients, mainly affected by GPA.
  
  
  CONCLUSIONS
  The finding of an activated IL-6 pathway in patients with AAV, together with the observed effects of tocilizumab monotherapy, provides evidence for a possible central role of IL-6 in the pathogenesis of AAV and suggests its targeting as a potential treatment.
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy; Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: berti.alvise@hsr.it.
authors.forename: Alvise
authors.initials: A
authors.lastname: Berti
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy; Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Cavalli
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy; Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Campochiaro
authors.affiliation: Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Guglielmi
authors.affiliation: Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Baldissera
authors.affiliation: Unit of Radiology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cappio
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy; Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Sabbadini
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy; Unit of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy; Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Dagna
mesh_terms: D000328:Adult; D000368:Aged; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000097:blood* / Q000188:drug therapy*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015850:Interleukin-6; C502936:tocilizumab
keywords: ANCA-associated vasculitis; Interleukin-6; Microscopic polyangiitis; Tocilizumab