BackgroundPsoriatic arthritis (PsA) is a chronic inflammatory disease that affects the skin, nails, tendons and joints. In addition, several comorbidities have been identified with PsA. In particular, a frequent occurrence of fatigue and mental disorders such as depression have been described in patients with PsA. Key cellular players in pathophysiology of PsA are T cells. However, in recent years, various autoantibodies such as anti-LL37 and anti-Pso-p27 have been identified in PsA as well [1]. Autoantibodies targeting G protein-coupled receptors (GPCRs) have been identified in several diseases and are involved in disease pathophysiology [2]. Many of these autoantibodies are agonists that enhance the effect of the natural ligand at the receptor [3].ObjectivesThe aim of this study was to investigate the association between autoantibodies directed to distinct GPCRs and disease activity as well as comorbidities in PsA.MethodsIn a prospective observational study forty-five patients with an active PsA according to CASPAR criteria and 24 healthy controls (HCs) matched according to age and sex were included in this study. The serum-concentrations of 20 autoantibodies directed to GPCRs involved in the renin-angiotensin-aldosterone system, the sympathetic and parasympathetic nervous system as well as chemokine, complement and scavenger receptors, were measured by the company CellTrend GmbH (Luckenwalde, Germany). Autoantibodies measured in patient’s sera at baseline were transformed and adjusted for age as confounder for further analyses. To compare autoantibody concentrations between PsA and HCs we applied Two-Way-ANOVA. Correlation analyses were performed using Pearson correlation. Autoantibody concentrations between patients with and without depression were analyzed by Student’s T test and binary logistic regression.ResultsPatients were equally distributed according to sex (male 51.1%, female 48.9%) and of a mean age of 47.5 ± 13.2 years. Mean arthritic disease manifestation assessed by DAPSA was 44.4 ± 21.2. Patients displayed a disease activity with a mean PASI of 6.19 ± 6.33, and high impact on patient reported outcomes with a mean DLQI of 10.3 ± 7.4 and a mean HAQ of 1.0 ± 0.8. Autoantibody concentrations did not differ significantly between patients with PsA and HCs. Further analysis revealed significant correlations between autoantibody levels, disease activity scores and treatment response of cutaneous disease manifestation after 16 weeks of treatment (Δ PASI),Figure 1. Moreover, the levels autoantibodies directed to the MAS receptor, CXCR3, PAR1 and stabilin were significantly higher in patients with PsA suffering from depression compared to patients without depression (MASR: p=0.035; CXCR3: p=0.011; PAR1: p=0.047; stabilin: p=0.035), although binary logistic regression did not prove any predictive value for these four antibodies.ConclusionAutoantibodies directed to GPCRs correlated with disease activity scores in patients with PsA. Further larger analyses regarding the functional role of these autoantibodies in PsA are required.References[1]Koussiouris J, Chandran V. Autoantibodies in Psoriatic Disease. The Journal of Applied Laboratory Medicine (2022) 7:281–293. doi: 10.1093/jalm/jfab120[2]Skiba MA, Kruse AC. Autoantibodies as Endogenous Modulators of GPCR Signaling. Trends in Pharmacological Sciences (2021) 42:135–150. doi: 10.1016/j.tips.2020.11.013[3]Yue X, Yin J, Wang X, Heidecke H, Hackel AM, Dong X, Kasper B, Wen L, Zhang L, Schulze-Forster K, et al. Induced antibodies directed to the angiotensin receptor type 1 provoke skin and lung inflammation, dermal fibrosis and act species overarching. Ann Rheum Dis (2022)annrheumdis-2021-222088. doi: 10.1136/annrheumdis-2021-222088Figure 1.Heatmap displaying Pearson’s correlation coefficient of correlation analyses between diseases activity scores and autoantibody concentrations adjusted for age at baseline. Pearson correlation analyses with a p-value <0.05 are marked with a box.Acknowledgements:NIL.Disclosure of InterestsHanna Grasshoff Speakers bureau: Abbvie, Sara Comduehr: None declared, Justus Ohmes: None declared, Diamant Thaçi Speakers bureau: Diamant Thaçi has received honoraria as an advisor, speaker and/or investigator from AbbVie, Almirall, Amgen, Biogen-Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galapagos, Galderma, Janssen-Cilag, LEO Pharma, Novartis, Pfizer, Regeneron, Roche-Possay, Samsung, Sanofi and UCB., Consultant of: Diamant Thaçi has received honoraria as an advisor, speaker and/or investigator from AbbVie, Almirall, Amgen, Biogen-Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galapagos, Galderma, Janssen-Cilag, LEO Pharma, Novartis, Pfizer, Regeneron, Roche-Possay, Samsung, Sanofi and UCB, Kai Schulze-Forster Shareholder of: board of management: CellTrend, Harald Heidecke Shareholder of: board of management: CellTrend, Peter Lamprecht: None declared, Gabriela Riemekasten: None declare.d.
Background:Systemic sclerosis (SSc) is an autoimmune disorder with chronic and persistent inflammation. Interleukin-16 was originally described as a factor that could attract activated T cells in humans [1]. Elevated amounts of IL-16 have been demonstrated in SSc [2].Objectives:This study was undertaken to find out if IL-16 is associated with clinical characteristics of SSc.Methods:IL-16 was measured by Elisa in serum of patients with SSc (n=119) and healthy controls (n=50). Further, the presence of active IL-16 in mononuclear cells from peripheral blood of SSc patients (n=10) was examined by Western blot. Statistical analyses were done employing Graph Pad prism software (v 8). Patients with SSc were characterized based upon epidemiological and clinical parameters.Results:The serum concentration of IL-16 was higher in patients with SSc than in healthy controls (272.7±165.4 vs 172.8±64.84 pg/ml, p<0.0001). Further, the difference in the IL-16 serum concentration was more prominent in females (265.6±174.2 vs 160.1±53.37 pg/ml, p=0.0002) than in males (287.1±144.1 vs 187.6±74.64 pg/ml, p=0.0034). In addition, the concentration of IL-16 was elevated in patients with diffuse SSc compared to limited SSc (p=0.0206). The concentration of IL-16 in serum of SSc patients positively correlated with CRP (n=115, r=0.49, p<0.0001). There was a weak positive correlation between IL-16 in serum of SSc patients and the mRSS (n=112, r=0.22, p=0.0175). Noteworthy, the concentration of IL-16 was heightened in SSc patients with lung fibrosis compared to SSc patients without lung fibrosis (p=0.009). The ROC value of SSc patients with lung fibrosis was 0.64 (95%CI: 0.58-0.83). Moreover, active IL-16 derived from peripheral blood mononuclear cells (PBMC) of SSc patients with lung fibrosis was present in higher amounts compared to PBMC of SSc patients without lung fibrosis (5 vs 5, p=0.0557).Conclusion:Our results confirm and extend previous data by showing not only an increased concentration of IL-16 in the circulation of SSc patients, but new findings pointing towards a role of IL-16 for contributing to lung fibrosis in SSc.References:[1]Cruikshank, W. and D.M. Center, Modulation of lymphocyte migration by human lymphokines. II. Purification of a lymphotactic factor (LCF). J Immunol, 1982. 128(6): p. 2569-74.[2]Kawabata, K., et al., IL-16 expression is increased in the skin and sera of patients with systemic sclerosis. Rheumatology (Oxford), 2019.Disclosure of Interests:Jiao Luo: None declared, Anja Kerstein-Staehle: None declared, Sara Comduehr: None declared, TatjanaKathleen Dreyer: None declared, Antje Müller: None declared, Susanne Schinke Speakers bureau: Pfizer, Gabriela Riemekasten Consultant of: Cell Trend GmbH, Janssen, Actelion, Boehringer Ingelheim, Speakers bureau: Actelion, Novartis, Janssen, Roche, GlaxoSmithKline, Boehringer Ingelheim, Pfizer
Background:Systemic sclerosis (SSc) is a heterogeneous disease characterized by fibrosis, vasculopathy and autoimmunity. Dysfunctions causing disease pathology are characterized by the activation and recruitment of immune cells, as well as the formation of autoantibodies and cytokines. Profibrotic cytokines, such as interleukin-(IL)13, IL4 or IL6 play a crucial role in collagen production and fibrosis development [1]. Preliminary data reveal IL13 as a main driver for obliterative vasculopathy characterized by severe Raynaud phenomenon, acral ulcers and pulmonary arterial hypertension (PAH). Particularly acral ulcerations lead to a severe impairment in functional capacity in everyday life. In addition, pulmonary arterial hypertension is one of the main causes of the high mortality rate in SSc [2].Objectives:To prove the impact of IL13 in the pathogenesis of systemic sclerosis and thus provide the rationale for the identification of a potential new therapeutic target, we investigated IL13 expression in CD4 and CD8 T cells in patients suffering from systemic sclerosis compared to healthy controls.Methods:Peripheral blood mononuclear cells (PBMC) obtained from systemic sclerosis (SSc, n=31) patients and healthy controls (HC, n=13) were cultured without or in the presence of phorbol myristate acetate and ionomycin to activate T cells for cytokine production. Brefeldin A was used as an inhibitor of cytokine secretion. The intracellular IL13 and IL4 expression of CD4 and CD8 positive T cells were measured by flow cytometry and were compared between the investigated subgroups.To identify a disease phenotype mediated by IL13, the expression levels in the SSc group were correlated to clinical, laboratory and apparative parameters assessing organ dysfunction.Results:While there were no significant differences in IL4 expression between healthy and diseased individuals, analyses of IL13 positive CD4 and CD8 T cells showed significant differences compared to HC (CD8+IL13 p=0.048; CD4+IL13 p=0.0046) revealing the functional differences though high structural homology of the two interleukins. The increased expression of IL13 in T cells from patients with systemic sclerosis further supports the assumption of an interleukin mediated pathomechanism. Considering the IL13-mediated clinical phenotype, high levels were detected in patients showing signs for vasculopathy, correlation with sPAP (CD8+IL13 p=0.0392), NTproBNP (CD4+IL13 p=0.0461), creatinine (CD4+IL13 p=0.0227), angiotensin II receptor type I and endothelin receptor type A antibodies (CD4+IL13 p=0.0105, p=0.0042) was demonstrated. In addition, patients in the fourth quartile of CD4+IL13 expression showed a higher incidence of acral ulcers and pits than patients with low interleukin levels. Moreover, this group of patients had an increased cardiovascular comorbidity including atherosclerosis, coronary heart disease and arterial hypertension.Conclusion:Increased IL13 levels could be detected in patients with SSc, especially in patients with the phenotype of an obliterative vasculopathy. This indicates preliminary evidence for the use of IL13 blockers as a new therapeutic approach in systemic sclerosis.References:[1]Furue M, Mitoma C, Mitoma H, Tsuji G, Chiba T, Nakahara T, Uchi H, Kadono T. Pathogenesis of systemic sclerosis-current concept and emerging treatments. Immunol Res. 2017 Aug;65(4):790-797. doi: 10.1007/s12026-017-8926-y.[2]Tyndall AJ, Bannert B, Vonk M, et alCauses and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database Annals of the Rheumatic Diseases 2010;69:1809-1815. doi: 10.1136/ard.2009.114264Disclosure of Interests:None declared
BackgroundAutoantibodies (ab) against G protein-coupled receptors (GPCR), such as ab against angiotensin II receptor type 1 (AT1R), endothelin receptor type A (ETAR) or CXC chemokine receptor 3 and 4 (CXCR3/4) may contribute to the pathogenesis of systemic sclerosis (SSc) [1]. AT1R- and ETAR-ab are associated with SSc-related mortality and CXCR3/4- ab predict a deteriorating pulmonary fibrosis [2,3].ObjectivesWe aim to identify new ab targets and ab discriminating healthy controls (HC) from SSc patients or SSc clinical phenotypes, organ involvements and therapy.MethodsSerum ab levels against a panel of GPCR, GF and GFR were measured by ELISA in SSc (n=177) and compared to HC (n=88). Gender matched and age adjusted data were screened for univariate differences of ab levels in clinical phenotypes, explored for multivariate predictive performance of ab levels by a random-forest classifier and tested for differences of ab correlations.ResultsIn SSc ab levels against 19 targets were higher compared to HC. Abs against fibroblast growth factor-2 (FGF-2), beta-adrenergic receptor 1 (ADRB1), and placental growth factor (PIGF) discriminated best SSc patients from HC. Multivariate predictions supported the ranking value of FGF-2 and ADRB1-abs for SSc and abs against ADRB1/2, muscarinic receptor 1 (M1R) and alpha-adrenergic receptor 2 ADRA2 for diffuse cutaneous SSc (dSSc) versus limited cutaneous SSc (lSSc). Ab levels were denser and stronger correlated in SSc than in HC (figure 1), suggesting a disturbed regulation of ab with a prominent role of FGF-2-abs in SSc. Comparing dSSc to lSSc, dSSc showed higher ab levels and correlated with several disease characteristics, but the multivariate classification showed poor accuracy.Figure 1.Different univariate correlations between abs in HC and SSc. The correlations of the ab concentrations are generally increased in SSc compared to HC. Largest accumulated differences are found for ETAR, VEGFA, AT1R and EGFR as indicated by the covered degrees in the circle. Dark bands depict significant differences after FDR-correction (p<.05)ConclusionSSc is characterized by both quantitative and qualitative alterations in ab levels and ab correlations. This study reveals ab against FGF-2, ADRB1 and PIGF to be new biomarkers of SSc. Alterations within these ab correlation networks could help to identify pathways promoting SSc and its clinical manifestations.References[1]Cabral-Marques O et al. 2018. GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasisNature Communications95224[2]Riemekasten G et al. 2011. Involvement of functional autoantibodies against vascular receptors in systemic sclerosisAnnals of the Rheumatic Diseases70530–6[3]Weigold F et al. Antibodies against chemokine receptors CXCR3 and CXCR4 predict progressive deterioration of lung function in patients with systemic sclerosis.Arthritis Res Ther20, 52AcknowledgementsWe thank G. Marschner for excellent technical assistance and Prof Goerg and his team from UKSH Campus Lübeck, bloodbank, for helping to acquire healthy blood donors.Disclosure of InterestsSusanne Schinke Grant/research support from: Abbvie, Kristina Sterner: None declared, Harald Heidecke Shareholder of: Celltrend Company, Hauke Busch: None declared, Axel Kuenstner: None declared, Imke König: None declared, Césaire J. K. Fouodo: None declared, Antje Müller: None declared, Sara Comduehr: None declared, Tanja Lange: None declared, Finn Lübber: None declared, Frieder Paulus: None declared, Hanna Grasshoff: None declared, Gabriela Riemekasten: None declared.
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