Autor:innen:
S. Klapa (Lübeck, DE)
C. Meyer (Luckenwalde, DE)
A. Müller (Lübeck, DE)
H. Heidecke (Luckenwalde, DE)
L. Schumacher (Lübeck, DE)
A. Koch (Kronshagen, DE)
W. Kähler (Kronshagen, DE)
G. Riemekasten (Lübeck, DE)
P. Lamprecht (Lübeck, DE)
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 [1]. For instance, decreased antibody concentrations against complement-receptors C5a and C3a are detected in ANCA-associated vasculitis (AAV) and associated with early relapse [2]. 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, alpha1-A, alpha2-AD, beta1-A, beta2-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-alpha1-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; Figure 1) and need for intensified immunosuppressive therapy (rituximab, cyclophosphamide) during follow-up at 36 and 60 months.
Conclusions
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.