PMID- 33461620
OWN - NLM
STAT- MEDLINE
DCOM- 20210621
LR  - 20220531
IS  - 1478-6362 (Electronic)
IS  - 1478-6354 (Print)
IS  - 1478-6354 (Linking)
VI  - 23
IP  - 1
DP  - 2021 Jan 19
TI  - Low levels of PCSK9 are associated with remission in patients with rheumatoid 
      arthritis treated with anti-TNF-alpha: potential underlying mechanisms.
PG  - 32
LID - 10.1186/s13075-020-02386-7 [doi]
LID - 32
AB  - 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-alpha 
      (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-alpha 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-alpha 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.
FAU - Frostegard, Johan
AU  - Frostegard J
AUID- ORCID: 0000-0002-3569-3367
AD  - Section of Immunology and Chronic Disease, Institute of Environmental Medicine, 
      Karolinska Institutet, Nobels vag 13, IMM, 17177, Stockholm, Sweden. 
      johan.frostegard@ki.se.
FAU - Ahmed, Sabbir
AU  - Ahmed S
AD  - Section of Immunology and Chronic Disease, Institute of Environmental Medicine, 
      Karolinska Institutet, Nobels vag 13, IMM, 17177, Stockholm, Sweden.
FAU - Hafstrom, Ingiald
AU  - Hafstrom I
AD  - Division of Gastroenterology and Rheumatology, Department of Medicine Huddinge, 
      Karolinska Institutet, Stockholm, Sweden.
AD  - Rheumatology Unit, Karolinska University Hospital, Stockholm, Sweden.
FAU - Ajeganova, Sofia
AU  - Ajeganova S
AD  - Division of Gastroenterology and Rheumatology, Department of Medicine Huddinge, 
      Karolinska Institutet, Stockholm, Sweden.
AD  - Rheumatology Division, Universitair Ziekenhuis Brussel, Vrije Universiteit 
      Brussel, Brussels, Belgium.
FAU - Rahman, Mizanur
AU  - Rahman M
AD  - Section of Immunology and Chronic Disease, Institute of Environmental Medicine, 
      Karolinska Institutet, Nobels vag 13, IMM, 17177, Stockholm, Sweden.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210119
PL  - England
TA  - Arthritis Res Ther
JT  - Arthritis research & therapy
JID - 101154438
RN  - 0 (Tumor Necrosis Factor Inhibitors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.4.21.- (PCSK9 protein, human)
RN  - EC 3.4.21.- (Proprotein Convertase 9)
SB  - IM
MH  - *Arthritis, Rheumatoid/drug therapy
MH  - Humans
MH  - *Proprotein Convertase 9
MH  - Tumor Necrosis Factor Inhibitors
MH  - *Tumor Necrosis Factor-alpha
PMC - PMC7814540
OTO - NOTNLM
OT  - Disease activity
OT  - Macrophages
OT  - Proprotein convertase subtilisin kexin 9 (PCSK9)
OT  - Rheumatoid arthritis
OT  - Synoviocytes
OT  - Tumor necrosis factor (TNF)
COIS- There is no conflict of interest for any of the authors. JF has research grant 
      from Amgen, as indicated in the manuscript, but this is investigator-initiated 
      and Amgen has no influence on the research or presentation.
EDAT- 2021/01/20 06:00
MHDA- 2021/06/22 06:00
PMCR- 2021/01/19
CRDT- 2021/01/19 05:38
PHST- 2020/09/18 00:00 [received]
PHST- 2020/12/07 00:00 [accepted]
PHST- 2021/01/19 05:38 [entrez]
PHST- 2021/01/20 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2021/01/19 00:00 [pmc-release]
AID - 10.1186/s13075-020-02386-7 [pii]
AID - 2386 [pii]
AID - 10.1186/s13075-020-02386-7 [doi]
PST - epublish
SO  - Arthritis Res Ther. 2021 Jan 19;23(1):32. doi: 10.1186/s13075-020-02386-7.