AB0129 PCSK9 IS ASSOCIATED WITH DISEASE ACTIVITY AND IMPLICATED IN IMMUNE ACTIVATION IN SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: A. Liu, M. Rahman, I. Hafström, S. Ajeganova, J. Frostegård
Journal: Annals of the Rheumatic Diseases (2020)

Background: LDL-levels are increased by Proprotein convertase subtilisin kexin 9 (PCSK9) which targets the LDL-receptor (LDLR). We reported that PCSK9 has immune modulatory properties in addition to LDL-lowering and ameliorates dendritic cell (DC) activation by oxidized LDL (OxLDL) 1 , which is abundant in atherosclerotic plaques. OxLDL is also raised and associated with cardiovascular disease (CVD) in SLE. 1-3 Objectives: We here investigate the role of PCSK9 in SLE both in a clinical context and in experimental ex vivo studies. The objective is to investigate if PCSK9 and its inhibition could be of relevance in SLE in addition to LDL-level related properties Methods: PCSK9-levels were determined by ELISA among SLE patients (n=109) and age- and sex-matched population-based controls (n=91). Common carotid intima-media thickness (IMT) and plaque occurrence were determined by B-mode ultrasound. Plaques were graded by echogenicity. Human peripheral blood monocytes from SLE patients or controls were differentiated into DCs. Effects of PCSK9 and its inhibition by silencing were studied. Results: PCSK9-levels were non-significantly higher among SLE-patients as compared to controls but associated significantly with SLE disease activity, as determined by SLAM (0.020) or SLEDAI (0.0178). There was no association between PCSK9-levels and atherosclerosis as determined by IMT, prevalence of plaques or echolucent (potentially vulnerable) plaques. PCSK9 levels were significantly associated with CVD among SLE-patients but not after adjustment for age. OxLDL induced PCSK9 in DCs and DC-maturation with increased expression of CD86 and HLA-DR. The effects were significantly stronger in DC from SLE patients than from controls. Silencing of PCSK9 abolished OxLDL-induced DC-maturation. Conclusion: PCSK9 is associated with disease activity in SLE. One underlying cause could be OxLDL, promoting DC-activation which depends on PCSK9. OxLDL induces PCSK9, an effect which is higher among SLE-patients.PCSK9 could play an unexpected immunological role in SLE and inhibition of PCSK9 could potentially play a role in disease amelioration, pending on clinical studies. References: [1]Liu A and Frostegard J. PCSK9 plays a novel immunological role in oxidized LDL-induced dendritic cell maturation and activation of T cells from human blood and atherosclerotic plaque. J Intern Med . 2018. [2]Frostegard J, Svenungsson E, Wu R, Gunnarsson I, Lundberg IE, Klareskog L, Horkko S and Witztum JL. Lipid peroxidation is enhanced in patients with systemic lupus erythematosus and is associated with arterial and renal disease manifestations. Arthritis Rheum . 2005;52:192-200. [3]Frostegard J. Immunity, atherosclerosis and cardiovascular disease. BMC Med . 2013;11:117. Disclosure of Interests: Anquan Liu: None declared, Mizanur Rahman: None declared, Ingiäld Hafström: None declared, Sofia Ajeganova: None declared, Johan Frostegård Grant/research support from: Unconditional competitive grant from Amgen, related only to PCSK9, not the topic of this abstract