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THU0269 Interleukin-6 in ANCA-Associated Vasculitis: Rationale for the Successful Treatment with Tocilizumab
  1. A. Berti1,
  2. G. Cavalli1,
  3. C. Campochiaro1,
  4. E. Baldissera1,
  5. M.G. Sabbadini1,
  6. C. Doglioni2,
  7. L. Dagna1
  1. 1Internal Medicine And Clinical Immunology
  2. 2Pathology, San Raffaele Scientific Institute, Milan, Italy

Abstract

Background Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are systemic necrotizing vasculitides which predominantly affect small-sized blood vessels. MPA and GPA are often associated with the presence of circulating anti-neutrophil cytoplasmic autoantibodies (ANCA), and are thus classified among the ANCA-associated vasculitides (AAV). Rapidly progressive glomerulonephritis and hemorrhagic alveolitis are among the main causes of morbidity and mortality. Cyclophosphamide and Rituximab have been used as the first line treatment to induce disease remission.

Scarce data are available on the role of interleukin (IL)-6 in the pathogenesis of AAV; only few small case series and anecdotal reports describe inconstantly increased IL-6 serum levels in patients with AAV.

Objectives We aim to evaluate a potential role of interleukin (IL)-6 and its pathway in the pathogenesis of ANCA-associated vasculitides (AAV).

Methods Blood samples and renal biopsies from 8 untreated ANCA-positive patients with active MPA or GPA (5 and 3 patients respectively) were studied. A blood sample and a renal biopsy specimen were obtained from each patient at the diagnosis, during an active phase of the disease, and prior to any immunosuppressive treatment.

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 (using mouse antihuman IL-6 monoclonal antibody clone) and in situ hybridization techniques (using a single RNA target probe specific for IL-6 mRNA, RNAscope technology).

We thus treated a patient affected by MPA with renal and pulmonary involvement 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.

Results IL-6 serum levels were significantly increased in all the patients with AAV as compared to healthy controls (median 59.89pg/ml; range 46.08 - 84.30; versus 0.68pg/ml; range, 0.01 – 1.81; P<0.05). Also, IL-6 was expressed and produced at sites of active vasculitis in all these patients. Treatment with tocilizumab was able to induce a complete and sustained disease remission in a patient with severe multisystemic MPA as evaluated by clinical, radiological and laboratory assessment. This result was paralleled by the normalization of circulating levels of IL-6-associated pro-inflammatory cytokines and chemokines.

Conclusions In this study, we assessed the implication of IL-6 and its pathway in the pathogenesis of AAV, by evaluating the serum levels of IL-6 in untreated patients with MPA and GPA, and by providing evidence that IL-6 is actively produced at sites of vasculitis. Also, we provided proof-of-concept to this hypothesis by describing the clinical efficacy of specific IL-6 blockade with tocilizumab in one patient with MPA. 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.

References

  1. Chen M et al. Nat Rev Rheumatol 2010;6:653-6; Nishimoto N et al. Blood 2008;112:3959-6;

  2. Naka T et al. Arthritis Res 2002;4 Suppl 3:S233-42.

Disclosure of Interest None declared

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