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Association of baseline soluble immune checkpoints with the risk of relapse in PR3-ANCA vasculitis following induction of remission
  1. Gabriele Gamerith1,
  2. Finn Mildner1,
  3. Peter A Merkel2,
  4. Kristina Harris3,
  5. Laura Cooney3,
  6. Noha Lim3,
  7. Robert Spiera4,
  8. Philip Seo5,
  9. Carol A Langford6,
  10. Gary S Hoffman6,
  11. E William St Clair7,
  12. Fernando C Fervenza8,
  13. Paul Monach9,
  14. Steven R Ytterberg10,
  15. Duvuru Geetha11,
  16. Arno Amann1,
  17. Dominik Wolf1,
  18. Ulrich Specks12,
  19. John H Stone13,
  20. Andreas Kronbichler14
  1. 1 Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University of Innsbruck, Innsbruck, Austria
  2. 2 Division of Rheumatology and Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  3. 3 Immune Tolerance Network (ITN), Bethesda, Maryland, USA
  4. 4 Hospital for Special Surgery, New York City, New York, USA
  5. 5 Department of Internal Medicine, Division of Rheumatology, Johns Hopkins University, Baltimore, Maryland, USA
  6. 6 Rheumatic and Immunologic Diseases, Cleveland Clinic Foundation, Cleveland, Ohio, USA
  7. 7 Rheumatology, Duke University School of Medicine, Durham, North Carolina, USA
  8. 8 Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
  9. 9 VA Boston Healthcare System, West Roxbury, Massachusetts, USA
  10. 10 Division of Rheumatology, Mayo Clinic, Rochester, Minnesota, USA
  11. 11 Division of Nephrology, Johns Hopkins University, Baltimore, Maryland, USA
  12. 12 Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, New York, USA
  13. 13 Rheumatology Unit, Division of Rheumatology Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
  14. 14 Department of Medicine, University of Cambridge, Cambridge, UK
  1. Correspondence to Dr Andreas Kronbichler, Department of Medicine, University of Cambridge, Cambridge, UK; ak2283{at}


Objectives We investigated whether soluble immune checkpoints (sICPs) predict treatment resistance, relapse and infections in patients with antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV).

Methods Plasma sICP concentrations from available samples obtained during conduct of the RAVE trial were measured by immunoabsorbent assays from patients with either proteinase 3 (PR3) or myeloperoxidase (MPO)-ANCA vasculitis and were correlated with clinical outcomes, a set of biomarkers and available flow cytometry analyses focusing on T cell subsets. Log-rank test was used to evaluate survival benefits, and optimal cut-off values of the marker molecules were calculated using Yeldons J.

Results Analysis of 189 plasma samples at baseline revealed higher concentrations of sTim-3, sCD27, sLag-3, sPD-1 and sPD-L2 in patients with MPO-ANCA vasculitis (n=62) as compared with PR3-ANCA vasculitis (n=127). Among patients receiving rituximab induction therapy (n=95), the combination of lower soluble (s)Lag-3 (<90 pg/mL) and higher sCD27 (>3000 pg/mL) predicted therapy failure. Twenty-four out of 73 patients (32.9%) in the rituximab arm reaching remission at 6 months relapsed during follow-up. In this subgroup, high baseline values of sTim-3 (>1200 pg/mL), sCD27 (>1250 pg/mL) and sBTLA (>1000 pg/mL) were associated with both sustained remission and infectious complications. These findings could not be replicated in 94 patients randomised to receive cyclophosphamide/azathioprine.

Conclusions Patients with AAV treated with rituximab achieved remission less frequently when concentrations of sLag-3 were low and concentrations of sCD27 were high. Higher concentrations of sTim-3, sCD27 and sBTLA at baseline predicted relapse in patients treated with rituximab. These results require confirmation but may contribute to a personalised treatment approach of AAV.

  • rituximab
  • systemic vasculitis
  • autoimmune diseases

Data availability statement

Data are available on reasonable request.

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Data availability statement

Data are available on reasonable request.

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  • Handling editor Josef S Smolen

  • Contributors All authors contributed to sample collection. GG, FM, US, JHS and AK designed the study. KH, LC, NL and FM performed statistical analyses. All authors contributed to drafting the manuscript, revised it and approved the final version. AK takes full responsibility for the work and/or the conduct of the study.

  • Funding This research was performed as a project of the Immune Tolerance Network (Protocol number ITN401).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.