Association of baseline soluble immune checkpoints with the risk of relapse in PR3-ANCA vasculitis following induction of remission

Gabriele Gamerith, Finn Mildner, Peter A. Merkel, Kristina Harris, Laura Cooney, Noha Lim, Robert Spiera, Philip Seo, Carol A. Langford, Gary S. Hoffman, E. William St Clair, Fernando C. Fervenza, Paul Monach, Steven R. Ytterberg, Duvuru Geetha, Arno Amann, Dominik Wolf, Ulrich Specks, John H. Stone, Andreas Kronbichler

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)253-261
Number of pages9
JournalAnnals of the rheumatic diseases
Issue number2
StatePublished - Aug 16 2022


  • autoimmune diseases
  • rituximab
  • systemic vasculitis

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology
  • General Biochemistry, Genetics and Molecular Biology


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