Alvise Berti1, Giulio Cavalli2, Corrado Campochiaro2, Barbara Guglielmi3, Elena Baldissera3, Stefano Cappio4, Maria Grazia Sabbadini2, Claudio Doglioni5, Lorenzo Dagna2. 1. 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. 2. Vita-Salute San Raffaele University, Milan, Italy; Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy. 3. Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy. 4. Unit of Radiology, IRCCS San Raffaele Scientific Institute, Milan, Italy. 5. Vita-Salute San Raffaele University, Milan, Italy; Unit of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
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. CONCLUSION: 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.
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. CONCLUSION: 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: Alvise Berti; Roscoe Warner; Kent Johnson; Divi Cornec; Darrell R Schroeder; Brian F Kabat; Carol A Langford; Cees G M Kallenberg; Philip Seo; Robert F Spiera; E William St Clair; Fernando C Fervenza; John H Stone; Paul A Monach; Ulrich Specks; Peter A Merkel Journal: J Autoimmun Date: 2019-07-15 Impact factor: 7.094
Authors: Alvise Berti; Roscoe Warner; Kent Johnson; Divi Cornec; Darrell Schroeder; Brian Kabat; Carol A Langford; Gary S Hoffman; Fernanado C Fervenza; Cees G M Kallenberg; Philip Seo; Robert Spiera; E William St Clair; Paul Brunetta; John H Stone; Peter A Merkel; Ulrich Specks; Paul A Monach Journal: Arthritis Rheumatol Date: 2018-05-07 Impact factor: 10.995