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

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Abstract

Background

Proprotein 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).

Methods

PCSK9-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.

Results

A 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.

Conclusions

Low 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.

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Most cited references 22

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Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.

Jonathan C. Cohen, Eric Boerwinkle, Thomas H. Mosley … (2006)

A low plasma level of low-density lipoprotein (LDL) cholesterol is associated with reduced risk of coronary heart disease (CHD), but the effect of lifelong reductions in plasma LDL cholesterol is not known. We examined the effect of DNA-sequence variations that reduce plasma levels of LDL cholesterol on the incidence of coronary events in a large population. We compared the incidence of CHD (myocardial infarction, fatal CHD, or coronary revascularization) over a 15-year interval in the Atherosclerosis Risk in Communities study according to the presence or absence of sequence variants in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) that are associated with reduced plasma levels of LDL cholesterol. Of the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P=0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P=0.03). Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P=0.003). These data indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non-lipid-related cardiovascular risk factors. Copyright 2006 Massachusetts Medical Society.

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Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.

Marianne Abifadel, Mathilde Varret, Jean-Pierre Rabès … (2003)

Autosomal dominant hypercholesterolemia (ADH; OMIM144400), a risk factor for coronary heart disease, is characterized by an increase in low-density lipoprotein cholesterol levels that is associated with mutations in the genes LDLR (encoding low-density lipoprotein receptor) or APOB (encoding apolipoprotein B). We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH. PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis.

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The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study.

Marita Cross, Emma Smith, Damian Hoy … (2014)

To estimate the global burden of rheumatoid arthritis (RA), as part of the Global Burden of Disease 2010 study of 291 conditions and how the burden of RA compares with other conditions. The optimum case definition of RA for the study was the American College of Rheumatology 1987 criteria. A series of systematic reviews were conducted to gather age-sex-specific epidemiological data for RA prevalence, incidence and mortality. Cause-specific mortality data were also included. Data were entered into DisMod-MR, a tool to pool available data, making use of study-level covariates to adjust for country, region and super-region random effects to estimate prevalence for every country and over time. The epidemiological data, in addition to disability weights, were used to calculate years of life lived with disability (YLDs). YLDs were added to the years of life lost due to premature mortality to estimate the overall burden (disability-adjusted life years (DALYs)) for RA for the years 1990, 2005 and 2010. The global prevalence of RA was 0.24% (95% CI 0.23% to 0.25%), with no discernible change from 1990 to 2010. DALYs increased from 3.3 million (M) (95% CI 2.6 M to 4.1 M) in 1990 to 4.8 M (95% CI 3.7 M to 6.1 M) in 2010. This increase was due to a growth in population and increase in aging. Globally, of the 291 conditions studied, RA was ranked as the 42nd highest contributor to global disability, just below malaria and just above iodine deficiency (measured in YLDs). RA continues to cause modest global disability, with severe consequences in the individuals affected. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

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Author and article information

Contributors

Johan Frostegård:

ORCID: http://orcid.org/0000-0002-3569-3367

johan.frostegard@ki.se

Journal

Journal ID (nlm-ta): Arthritis Res Ther

Journal ID (iso-abbrev): Arthritis Res Ther

Title: Arthritis Research & Therapy

Publisher: BioMed Central (London )

ISSN (Print): 1478-6354

ISSN (Electronic): 1478-6362

Publication date (Electronic): 19 January 2021

Publication date PMC-release: 19 January 2021

Publication date (Print): 2021

Volume: 23

Electronic Location Identifier: 32

Affiliations

[1 ]GRID grid.4714.6, ISNI 0000 0004 1937 0626, Section of Immunology and Chronic Disease, Institute of Environmental Medicine, , Karolinska Institutet, ; Nobels väg 13, IMM, 17177 Stockholm, Sweden

[2 ]GRID grid.4714.6, ISNI 0000 0004 1937 0626, Division of Gastroenterology and Rheumatology, Department of Medicine Huddinge, , Karolinska Institutet, ; Stockholm, Sweden

[3 ]GRID grid.24381.3c, ISNI 0000 0000 9241 5705, Rheumatology Unit, , Karolinska University Hospital, ; Stockholm, Sweden

[4 ]Rheumatology Division, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium

Author information

Johan Frostegård http://orcid.org/0000-0002-3569-3367

Article

Publisher ID: 2386

DOI: 10.1186/s13075-020-02386-7

PMC ID: 7814540

SO-VID: d20008b8-821c-4cfc-9499-264c3b199466

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 18 September 2020

Date accepted : 7 December 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000042, Amgen Foundation;

Funded by: FundRef http://dx.doi.org/10.13039/501100007949, Reumatikerförbundet;

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ScienceOpen disciplines: Orthopedics

Keywords: proprotein convertase subtilisin kexin 9 (pcsk9),rheumatoid arthritis,disease activity,tumor necrosis factor (tnf),macrophages,synoviocytes

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ScienceOpen disciplines: Orthopedics

Keywords: proprotein convertase subtilisin kexin 9 (pcsk9), rheumatoid arthritis, disease activity, tumor necrosis factor (tnf), macrophages, synoviocytes

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

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Most cited references 22

Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.

Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.

The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study.

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