gms | German Medical Science

Introduction: In vivo signatures of antibodies targeting G protein-coupled receptors (GPCR) have been described as a novel immunological feature in healthy individuals and in different diseases (Cabral-Marques O, et al. Nat Commun. 2018). For instance, decreased antibody concentrations against complement-receptors C5a and C3a and endothelin receptor type A are detected in ANCA-associated vasculitis (AAV) and giant cell arteritis (GCA) and associated with relapse (Klapa S, et al. Ann Rheuma Dis. 2019; Klapa S, et al. Abstract: 20^th International Vasculitis and ANCA Workshop. Dublin, April 3^rd–6^th 2022). So far, clustering models of a wide range of antibodies targeting GPCRs have not been determined in AAV.

Methods: To determine circulating antibodies against G-protein coupled receptors (AT1, AT2, ACE-II, ETAR, ETBR, PAR1, a1-A, a2-AD, b1-A, b2-A, M1, M2, M3, M4, M5, N1, N2, CXCR3, CXR1, C3aR, C5aR, CB1, CB2) and analyze their diagnostic and/or prognostic value using a Kmeans clustering-model, sera of patients with AAV [granulomatosis with polyangiitis (GPA), n=59; microscopic polyangiitis (MPA), n=9] were analyzed by ELISA. Clinical data including vasculitis activity and damage scores BVAS V3.0 and VDI, respectively, inflammatory markers (ESR, C-reactive protein), creatinine, diagnostic autoantibodies (PR3-ANCA, MPO-ANCA) and treatment were assessed at the time of serum sampling and during follow-up for 60 months.

Results: Using Kmeans clustering model, we identified two subtypes of patients with AAV mainly defined by the correlation of antibody levels of anti-ETAR/anti-C3aR (cluster 1: r=-0.6844, p=0.0006 vs. cluster 2: r=-0.0991, p=0.5430), anti-AT2R/anti-ETBR (cluster 1: r=0.8047, p<0.0001 vs. cluster 2: r=0.5728, p=0.0001) and anti-M2R/anti-a1-AR (cluster 1: r=0.8554, p<0.0001 vs. cluster 2: r=0.5529, p=0.0002). There were no differences between both clusters according to inflammatory markers or clinical findings at baseline. However, patients of cluster 2 were characterized by an increased risk of major relapse (HR: 6.53, p=0.0372) and need for intensified immunosuppressive therapy (rituximab, cyclophosphamide) during follow-up at 36 and 60 months.

Conclusion: The findings of our study suggest a subsistence of different subtypes of AAV related to the clustering of anti-GPCR antibodies and may help to identify patients with an increased risk of relapse.

Disclosures: The authors declare that Harald Heidecke is CellTrend’s managing director and that Gabriele Riemekasten is an advisor of the company CellTrend and earned an honorarium for her advice.