Low levels of PCSK9 are associated with remission in patients with rheumatoid arthritis treated with anti-TNF-\u03b1: potential underlying mechanisms

Johan Frostegård,Sabbir Ahmed,Mizanur Rahman,Ingiäld Hafström,Sofia Ajeganova

doi:10.1186/s13075-020-02386-7

Abstract

BackgroundProprotein convertase subtilisin kexin 9 (PCSK9) targets the LDL-receptor (LDLR) which raises LDL-levels. In addition, PCSK9 has proinflammatory immunological effects. Here, we investigate the role of PCSK9 in relation to the inflammatory activity in patients with rheumatoid arthritis (RA).MethodsPCSK9-levels were determined at baseline by ELISA in 160 patients with RA not previously treated with biologics. The patients started anti-TNF-α (adalimumab, infliximab, or etanercept) treatment and were followed-up for 1 year. Disease activity was determined by DAS28.Effects of PCSK9 on cytokine production from macrophages of healthy individuals and synoviocytes from RA patients and inhibition by anti-PCSK9 antibodies were studied in supernatants by ELISA.ResultsA significantly lower level of PCSK9 at baseline, p = 0.035, was observed in patients who reached remission within 1 year, defined as DAS28 < 2.6, compared to those not in remission. At 12 months of TNF-α antagonist treatment, the mean DAS28 was reduced but was significantly greater in patients with highest quartile PCSK9 (Q4) compared to those at lowest PCSK9 (Q1) in both crude (p = 0.01) and adjusted analysis (p = 0.004).In vitro, PCSK9 induced TNF-alpha and IL-1beta in macrophages and monocyte chemoattractant protein-1 (MCP1) in synoviocytes. These effects were inhibited by anti-PCSK9 antibodies.ConclusionsLow levels of PCSK9 at baseline are associated with being DAS28-responder to anti-TNF-α treatment in RA. An underlying cause could be that PCSK9 stimulates the production of proinflammatory cytokines from macrophages and synoviocytes, effects inhibited by anti-PCSK9 antibodies. PCSK9 could thus play an immunological role in RA.

Highlights

Rheumatoid arthritis (RA) affects 0.5 to 1% of total population, placing a substantial burden on the affected individuals and on society [1]
We have reported that Proprotein convertase subtilisin kexin 9 (PCSK9)-levels are raised among patients with high disease activity in systemic lupus erythematosus (SLE) and that oxidized LDL (OxLDL) induced PCSK9 in dendritic cells (DC), effects which were significantly stronger in DCs from SLE patients than from controls [17]
About three times higher number of patients (35.9%) in the first quartile achieved remission after 1 year compared to those with the highest level of PCSK9 (12.8%) [risk ratio 0.36]

Summary

Introduction

Rheumatoid arthritis (RA) affects 0.5 to 1% of total population, placing a substantial burden on the affected individuals and on society [1]. Tumor necrosis factor α (TNF-α) antagonists are used as monotherapy as well as in combination with conventional antirheumatic drugs such as metotrexate [2]. These antagonists block the interaction of TNF-α with its receptors on cell surface, thereby lowering the systemic and local levels of pro-inflammatory cytokines, preventing infiltration of leukocytes and lymphocytes to the sites of inflammation, promoting inhibition of nuclear factor-KB, inducing apoptosis of TNF-α-producing cells, lowering the level of endothelial adhesion molecules, and improving endothelial function. We investigate the role of PCSK9 in relation to the inflammatory activity in patients with rheumatoid arthritis (RA)

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