OP0244 28 NEW AUTOANTIBODIES AGAINST GPCR, GROWTH FACTORS AND GROWTH FACTOR RECEPTORS ARE ASSOCIATED WITH DISEASE MANIFESTATIONS IN SYSTEMIC SCLEROSIS
Authors: Sterner K. , Fouodo C. J. K. , König I. , Künstner A. , Busch H. , Heidecke H. , Schumann A. , Müller A. , Riemekasten G. , Schinke S. 
Published: May 2021

Background:

The morbidity and mortality of systemic sclerosis (SSc) are largely determined by vascular and fibrotic pathologies. Levels of autoantibodies (ab) against G protein-coupled receptors (GPCR), growth factors (GF) and growth factor receptors (GFR) are altered in SSc compared to healthy controls (HC) 1. Thus, higher angiotensin II receptor type 1 - (AT1R) and endothelin receptor type A - (ETAR) ab levels are associated with severe disease and SSc-related mortality 2. CXC motiv chemokine receptor 3 - (CXCR3) and 4 - (CXCR4) ab have predictive value for deterioration of pulmonary fibrosis (PF) 3.

Objectives:

We used statistical methods to identify associations between disease manifestations and 28 new ab directed against GPCR, GF and GFR in SSc.

Methods:

Ab against the following targets were measured in sera from SSc patients (n = 177) and HC (n = 88): Adrenoceptors alpha-1 (ADRA1), alpha-2 (ADRA2), beta-1 (ADRB1), beta-2 (ADRB2); muscarinoceptors 1-5 (M1R - M5R); AT1R, ETAR, endothelin B receptor (ETBR); CXCR3, CXCR4; complement receptors 3a (C3aR) and 5a (C5aR); protease-activated receptors 1 (PAR1) and 2 (PAR2); vascular endothelial growth factor A (VEGFA) and its receptors 1 (VEGFR1) and 2 (VEGFR2), epithelial growth factor (EGF)/ - receptor (EGFR); hepatocyte growth factor (HGF)/ - receptor (HGFR), platelet-derived growth factor-AA (PDGFAA), placental growth factor (PlGF).

The organ involvement (PF, cardiac involvement, PAH, gastrointestinal tract) and quantitative markers (modified Rodnan skin score, SSc activity score, pulmonary function, cardiac enzymes and echocardiography, routine laboratory, autoimmune diagnostics) as well as demographic data were recorded retrospectively at the time of sample collection. Statistical analysis was performed using the Mann-Whitney U test (MWU), Pearson correlations, ROC analysis, and age-adjusted logistic regression models.

Results:

In SSc 20 of 28 measured ab levels are significantly altered compared to HC. According to the Pearson correlation matrix, the ab-levels are highly correlated and build a network that differs between HC and SSc. Furthermore, altered network signatures are formed in the differentiated analysis of several disease manifestations of SSc such as SSc-subtype or PF. Based on ROC analysis, FGF-ab, ADRB1-ab and PlGF-ab are well suited to predict SSc (Figure 1).

In addition, limited cutaneous SSc (lSSc) patients displayed lower levels of most ab than diffuse cutaneous SSc patients, whereas cardiac and pulmonary involvement are associated with higher ab levels. In the logistic regression lSSc is associated with lower levels of ab against M1R, M2R, C5aR, ETAR, AT1R, PAR1, EGFR. Higher levels for ab against M1R, M2R, ETBR, C5aR are associated with PF, higher levels of ab against complement receptors, adrenoreceptors and EGF with NT-proBNP elevation.

Conclusion:

The newly described antibodies against GPCR, GF and GFR are highly correlated. Associations with morbidity- and mortality-determining organ involvement indicate their possible functional relevance and novel pathophysiological mechanisms. As new biomarkers, some of the ab have prognostic value for SSc; for other manifestations, their value should be evaluated in further studies.

References:

[1]Cabral-Marques, O., Marques, A., Giil, L.M. et al. GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis. Nat Commun9, 5224 (2018). https://doi.org/10.1038/s41467-018-07598-9

[2]Riemekasten G, Philippe A, Näther M, et al. Involvement of functional autoantibodies against vascular receptors in systemic sclerosis Annals of the Rheumatic Diseases 2011;70:530-536.

[3]Weigold, F., Günther, J., Pfeiffenberger, M. et al. Antibodies against chemokine receptors CXCR3 and CXCR4 predict progressive deterioration of lung function in patients with systemic sclerosis. Arthritis Res Ther 20, 52 (2018). https://doi.org/10.1186/s13075-018-1545-8

Disclosure of Interests:

Kristina Sterner: None declared, Césaire J. K. Fouodo: None declared, Inke König: None declared, Axel Künstner: None declared, Hauke Busch: None declared, Harald Heidecke Shareholder of: Owner of CellTrend, Anja Schumann: None declared, Antje Müller: None declared, Gabriela Riemekasten: None declared, Susanne Schinke Grant/research support from: UCB sponsors EULAR registration fees