Low levels of PCSK9 are associated with remission in patients with rheumatoid arthritis treated with anti-TNF-α: potential underlying mechanisms
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 arth...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-01-01
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| Series: | Arthritis Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13075-020-02386-7 |
| _version_ | 1818665012056555520 |
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| author | Johan Frostegård Sabbir Ahmed Ingiäld Hafström Sofia Ajeganova Mizanur Rahman |
| author_facet | Johan Frostegård Sabbir Ahmed Ingiäld Hafström Sofia Ajeganova Mizanur Rahman |
| author_sort | Johan Frostegård |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T05:41:52Z |
| format | Article |
| id | doaj.art-6a105a596b644bcd828fcc0d989a7075 |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-12-17T05:41:52Z |
| publishDate | 2021-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-6a105a596b644bcd828fcc0d989a70752022-12-21T22:01:25ZengBMCArthritis Research & Therapy1478-63622021-01-012311910.1186/s13075-020-02386-7Low levels of PCSK9 are associated with remission in patients with rheumatoid arthritis treated with anti-TNF-α: potential underlying mechanismsJohan Frostegård0Sabbir Ahmed1Ingiäld Hafström2Sofia Ajeganova3Mizanur Rahman4Section of Immunology and Chronic Disease, Institute of Environmental Medicine, Karolinska InstitutetSection of Immunology and Chronic Disease, Institute of Environmental Medicine, Karolinska InstitutetDivision of Gastroenterology and Rheumatology, Department of Medicine Huddinge, Karolinska InstitutetDivision of Gastroenterology and Rheumatology, Department of Medicine Huddinge, Karolinska InstitutetSection of Immunology and Chronic Disease, Institute of Environmental Medicine, Karolinska InstitutetAbstract 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.https://doi.org/10.1186/s13075-020-02386-7Proprotein convertase subtilisin kexin 9 (PCSK9)Rheumatoid arthritisDisease activityTumor necrosis factor (TNF)MacrophagesSynoviocytes |
| spellingShingle | Johan Frostegård Sabbir Ahmed Ingiäld Hafström Sofia Ajeganova Mizanur Rahman Low levels of PCSK9 are associated with remission in patients with rheumatoid arthritis treated with anti-TNF-α: potential underlying mechanisms Arthritis Research & Therapy Proprotein convertase subtilisin kexin 9 (PCSK9) Rheumatoid arthritis Disease activity Tumor necrosis factor (TNF) Macrophages Synoviocytes |
| title | Low levels of PCSK9 are associated with remission in patients with rheumatoid arthritis treated with anti-TNF-α: potential underlying mechanisms |
| title_full | Low levels of PCSK9 are associated with remission in patients with rheumatoid arthritis treated with anti-TNF-α: potential underlying mechanisms |
| title_fullStr | Low levels of PCSK9 are associated with remission in patients with rheumatoid arthritis treated with anti-TNF-α: potential underlying mechanisms |
| title_full_unstemmed | Low levels of PCSK9 are associated with remission in patients with rheumatoid arthritis treated with anti-TNF-α: potential underlying mechanisms |
| title_short | Low levels of PCSK9 are associated with remission in patients with rheumatoid arthritis treated with anti-TNF-α: potential underlying mechanisms |
| title_sort | low levels of pcsk9 are associated with remission in patients with rheumatoid arthritis treated with anti tnf α potential underlying mechanisms |
| topic | Proprotein convertase subtilisin kexin 9 (PCSK9) Rheumatoid arthritis Disease activity Tumor necrosis factor (TNF) Macrophages Synoviocytes |
| url | https://doi.org/10.1186/s13075-020-02386-7 |
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