Proprotein convertase subtilisin kexin 9 is associated with disease activity and is implicated in immune activation in systemic lupus erythematosus

Liu, Anquan; Rahman, Mizanur; Hafström, Ingiäld; Ajeganova, Sofia; Frostegård, Johan

doi:10.1177/0961203320926253

Cited by 26 publications

(40 citation statements)

References 35 publications

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“…Similarly to our findings, CRP was positively correlated with PCSK9 and patients on hydroxychloroquine had lower levels of PCSK9. 15 In another study, 16 PCSK9 levels were non-significantly different among SLE patients compared with controls but significantly associated with SLE disease activity, as determined by the SLEDAI. This study also lacked full lipid profiles assessment and multivariable adjustment.…”

Section: Discussionmentioning

confidence: 91%

“…Remarkably, PCSK9 levels were still downregulated in SLE patients after the multivariable analysis [beta coefficient -77 (95% CI -96 to −58) ng/ml, p ⩽ 0.001]. ACA IgM, n (%) 20 (10) ACA IgG, n (%) 31 (16) Anti beta2 glycoprotein IgM, n (%) 13 7Anti beta2 glycoprotein IgG, n (%) 22 (11) C3, mg/dl 96 ± 27 C4, mg/dl 17 ± 7…”

Section: Multivariable Analysis Of the Differences In Lipid Profiles mentioning

confidence: 99%

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Proprotein convertase subtilisin/kexin type 9 is related to disease activity and damage in patients with systemic erythematosus lupus

Sánchez-Pérez

Quevedo-Abeledo

Tejera-Segura

et al. 2020

Therapeutic Advances in Musculoskeletal

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Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that regulates cholesterol metabolism through low-density lipoprotein receptor degradation and that has been linked to cardiovascular (CV) disease. The purpose of the present study was to examine whether PCSK9 levels are disrupted compared with controls in patients with systemic lupus erythematosus (SLE). We additionally sought to establish whether PCSK9 is related to both the abnormalities in the lipid profile and to the disease activity or damage of patients with SLE. Methods: We performed a cross-sectional study that encompassed 366 individuals: 195 SLE patients and 171 age-, sex-, and statin intake-matched controls. PCSK9, lipoproteins serum concentrations, and lipid profiles were assessed in patients and controls. A multivariable analysis, adjusted for standard CV risk factors, was performed to evaluate the role of PCSK9 in SLE-related dyslipidemia. Results: Most lipid related-molecules were decreased in patients with SLE compared with controls. This downregulation included PCSK9, with PCSK9 levels being lower in patients than controls in the full multivariable analysis, including the modifications in lipid profiles that the disease itself produces {beta coefficient –73 [95% confidence interval (CI) –91 to –54] ng/ml, p ⩽ 0.001}. Both SLICC and SLEDAI scores were independently and positively related to PCSK9. Patients currently on hydroxychloroquine exhibited decreased levels of PCSK9 compared with those that were not taking hydroxychloroquine [beta coefficient –30 (95% CI −54 to −6) ng/ml, p = 0.015]. Conclusion: PCSK9 is downregulated in SLE compared with controls, but SLE patients with higher disease activity and damage exhibited higher PSCK9 serum levels.

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Section: Discussionmentioning

confidence: 91%

Section: Multivariable Analysis Of the Differences In Lipid Profiles mentioning

confidence: 99%

Proprotein convertase subtilisin/kexin type 9 is related to disease activity and damage in patients with systemic erythematosus lupus

Sánchez-Pérez

Quevedo-Abeledo

Tejera-Segura

et al. 2020

Therapeutic Advances in Musculoskeletal

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“…16 Earlier we have reported that PCSK9-levels are raised among patients with high disease activity in systemic lupus erythematosus (SLE), and that OxLDL induced PCSK9 in dendritic cells (DC), effects which were significantly stronger in DCs from SLE patients than from controls. 17 OxLDL, which is increased in SLE, induced PCSK9, an effect which was higher among SLE patients. We suggested that PCSK9 could play an imunological role in SLE.…”

Section: Introductionmentioning

confidence: 87%

“…We suggested that PCSK9 could play an imunological role in SLE. 17 Also other studies demonstrate pro-inflammatory effects of PCSK9. 15,18 We here report that low PCSK9-levels at start of anti-TNF treatment in patients with RA are associated with being a responder to that therapy and elucidate potential underlying mechanisms.…”

Section: Introductionmentioning

confidence: 93%

Low levels of PCSK9 are Associated with Remission in Patients with Rheumatoid Arthritis Treated with Anti- TNF-α: Potential Underlying Mechanisms

Frostegård

Ahmed

Hafström

et al. 2020

Preprint

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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 as 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 one 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 one 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 is associated with being DAS28-responder to anti-TNF-α treatment in RA. An underlying cause could be that PCSK9 stimulates 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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“…Earlier, we have reported that PCSK9-levels are raised among patients with high disease activity in systemic lupus erythematosus (SLE) and that OxLDL induced PCSK9 in dendritic cells (DC), effects which were significantly stronger in DCs from SLE patients than from controls [17]. OxLDL, which is increased in SLE, induced PCSK9, an effect which was higher among SLE patients.…”

Section: Introductionmentioning

confidence: 92%

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

et al. 2021

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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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Proprotein convertase subtilisin kexin 9 is associated with disease activity and is implicated in immune activation in systemic lupus erythematosus

Cited by 26 publications

References 35 publications

Proprotein convertase subtilisin/kexin type 9 is related to disease activity and damage in patients with systemic erythematosus lupus

Proprotein convertase subtilisin/kexin type 9 is related to disease activity and damage in patients with systemic erythematosus lupus

Low levels of PCSK9 are Associated with Remission in Patients with Rheumatoid Arthritis Treated with Anti- TNF-α: Potential Underlying Mechanisms

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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