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Autoantibody-Mediated Depletion of IL-1RA in Still’s Disease and Potential Impact of IL-1 Targeting Therapies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2024年1月17日

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  • Marie-Christin Hoffmann,
  • Giulio Cavalli,
  • Natalie Fadle,
  • Eleonora Cantoni,
  • Evi Regitz,
  • Octavian Fleser,
  • Philipp Klemm,
  • Marina Zaks,
  • Elisabeth Stöger,
  • Corrado Campochiaro,
  • Alessandro Tomelleri,
  • Elena Baldissera,
  • Jörg Thomas Bittenbring,
  • Vincent Zimmer,
  • Jochen Pfeifer,
  • Yvan Fischer,
  • Klaus-Dieter Preuss,
  • Moritz Bewarder,
  • Bernhard Thurner,
  • Sabrina Fuehner,
  • Dirk Foell,
  • Lorenzo Dagna,
  • Christoph Kessel,
  • Lorenz Thurner

摘要

Background

Adult-onset Still’s disease (AOSD) and systemic juvenile idiopathic arthritis (sJIA) resemble a continuum of a rare, polygenic IL-1β-driven disease of unknown etiology.

Objective

In the present study we sought to investigate a potential role of recently described autoantibodies neutralizing the interleukin-1(IL-1)-receptor antagonist (IL-1-Ra) in the pathogenesis of Still’s disease.

Methods

Serum or plasma samples from Still’s disease patients (AOSD, n = 23; sJIA, n = 40) and autoimmune and/or inflammatory disease controls (n = 478) were analyzed for autoantibodies against progranulin (PGRN), IL-1Ra, IL-18 binding protein (IL-18BP), and IL-36Ra, as well as circulating IL-1Ra and IL-36Ra levels by ELISA. Biochemical analyses of plasma IL-1Ra were performed by native Western blots and isoelectric focusing. Functional activity of the autoantibodies was examined by an in vitro IL-1β-signaling reporter assay.

Results

Anti-IL-1-Ra IgG were identified in 7 (27%) out of 29 Still’s disease patients, including 4/23 with AOSD and 3/6 with sJIA and coincided with a hyperphosphorylated isoform of endogenous IL-1Ra. Anti-IL-36Ra antibodies were found in 2 AOSD patients. No anti-PGRN or anti-IL-18BP antibodies were detected. Selective testing for anti-IL-1Ra antibodies in an independent cohort (sJIA, n = 34) identified 5 of 34 (14.7%) as seropositive. Collectively, 8/12 antibody-positive Still’s disease patients were either new-onset active disease or unresponsive to IL-1 blocking drugs. Autoantibody-seropositivity associated with decreased IL-1Ra plasma/serum levels. Seropositive plasma impaired in vitro IL-1Ra bioactivity, which could be reversed by anakinra or canakinumab treatment.

Conclusion

Autoantibodies neutralizing IL-1Ra may represent a novel patho-mechanism in a subgroup of Still’s disease patients, which is sensitive to high-dose IL-1 blocking therapy.