Exploring the Link between Plasma Levels of PCSK9, Immune Dysregulation and Atherosclerosis in Patients with Primary Sjögren’s Syndrome
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients and Healthy Controls
2.2. Laboratory Parameters
2.3. Cardiovascular Variables
2.4. Subclinical Atherosclerosis Parameters
2.5. Statistical Analysis
3. Results
3.1. Characteristics of pSS Patients and HCs
3.2. PCSK9, Immune-Inflammatory Parameters, and Clinical Features of pSS Patients
3.3. PCSK9, CV Risk Factors and Atherosclerosis Burden in pSS Patients and HCs
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Mariette, X.; Criswell, L.A. Primary Sjögren’s Syndrome. N. Engl. J. Med. 2018, 378, 931–939. [Google Scholar] [CrossRef] [PubMed]
- Wu, X.F.; Huang, J.Y.; Chiou, J.Y.; Chen, H.H.; Wei, J.C.; Dong, L.L. Increased risk of coronary heart disease among patients with primary Sjögren’s syndrome: A nationwide population-based cohort study. Sci. Rep. 2018, 8, 2209. [Google Scholar] [CrossRef]
- Yong, W.C.; Sanguankeo, A.; Upala, S. Association between primary Sjogren’s syndrome, arterial stiffness, and subclinical atherosclerosis: A systematic review and meta-analysis. Clin. Rheumatol. 2019, 38, 447–455. [Google Scholar] [CrossRef] [PubMed]
- Beltai, A.; Barnetche, T.; Daien, C.; Lukas, C.; Gaujoux-Viala, C.; Combe, B.; Morel, J. Cardiovascular morbidity and mortality in primary Sjögren’s Syndrome: A systematic review and meta-Analysis. Arthritis Care Res. 2020, 72, 131–139. [Google Scholar] [CrossRef]
- Melissaropoulos, K.; Bogdanos, D.; Dimitroulas, T.; Sakkas, L.I.; Kitas, G.D.; Daoussis, D. Primary Sjögren’s Syndrome and cardiovascular disease. Curr. Vasc. Pharmacol. 2020, 18, 447–454. [Google Scholar] [CrossRef] [PubMed]
- Santos, C.S.; Salgueiro, R.R.; Morales, C.M.; Castro, C.Á.; Álvarez, E.D. Risk factors for cardiovascular disease in primary Sjögren’s syndrome (pSS): A 20-year follow-up study. Clin. Rheumatol. 2023; epub ahead of print. [Google Scholar] [CrossRef]
- Vaudo, G.; Bocci, E.B.; Shoenfeld, Y.; Schillaci, G.; Wu, R.; Del Papa, N.; Vitali, C.; Delle Monache, F.; Marchesi, S.; Mannarino, E.; et al. Precocious intima-media thickening in patients with primary Sjögren’s syndrome. Arthritis Rheum. 2005, 52, 3890–3897. [Google Scholar] [CrossRef]
- Gerli, R.; Vaudo, G.; Bocci, E.B.; Schillaci, G.; Alunno, A.; Luccioli, F.; Hijazi, R.; Mannarino, E.; Shoenfeld, Y. Functional impairment of the arterial wall in primary Sjögren’s syndrome: Combined action of immunologic and inflammatory factors. Arthritis Care Res. 2010, 62, 712–718. [Google Scholar] [CrossRef]
- Lu, Y.; Luo, Q.; Liu, Y.; Wang, H. Relationships between inflammation markers and the risk of hypertension in primary Sjögren’s syndrome: A retrospective cohort study. Mod. Rheumatol. 2023; epub ahead of print. [Google Scholar] [CrossRef]
- Bartoloni, E.; Baldini, C.; Schillaci, G.; Quartuccio, L.; Priori, R.; Carubbi, F.; Bini, V.; Alunno, A.; Bombardieri, S.; De Vita, S.; et al. Cardiovascular disease risk burden in primary Sjögren’s syndrome: Results of a population-based multicentre cohort study. J. Intern. Med. 2015, 278, 185–192. [Google Scholar] [CrossRef]
- Mofors, J.; Holmqvist, M.; Westermark, L.; Björk, A.; Kvarnström, M.; Forsblad-d’Elia, H.; Magnusson Bucher, S.; Eriksson, P.; Theander, E.; Mandl, T.; et al. Concomitant Ro/SSA and La/SSB antibodies are biomarkers for the risk of venous thromboembolism and cerebral infarction in primary Sjögren’s syndrome. J. Intern. Med. 2019, 286, 458–468. [Google Scholar] [CrossRef]
- Berardicurti, O.; Ruscitti, P.; Cipriani, P.; Ciccia, F.; Liakouli, V.; Guggino, G.; Carubbi, F.; Di Benedetto, P.; Triolo, G.; Giacomelli, R. Cardiovascular disease in primary Sjögren’s Syndrome. Rev. Recent. Clin. Trials. 2018, 13, 164–169. [Google Scholar] [CrossRef]
- Bartoloni, E.; Alunno, A.; Bistoni, O.; Caterbi, S.; Luccioli, F.; Santoboni, G.; Mirabelli, G.; Cannarile, F.; Gerli, R. Characterization of circulating endothelial microparticles and endothelial progenitor cells in primary Sjögren’s syndrome: New markers of chronic endothelial damage? Rheumatology 2015, 54, 536–544. [Google Scholar] [CrossRef]
- Karakasis, P.; Patoulias, D.; Stachteas, P.; Lefkou, E.; Dimitroulas, T.; Fragakis, N. Accelerated atherosclerosis and management of cardiovascular risk in autoimmune rheumatic diseases: An updated review. Curr. Probl. Cardiol. 2023, 48, 101999. [Google Scholar] [CrossRef] [PubMed]
- Łuczak, A.; Małecki, R.; Kulus, M.; Madej, M.; Szahidewicz-Krupska, E.; Doroszko, A. Cardiovascular risk and endothelial dysfunction in primary Sjögren’s Syndrome is related to the disease activity. Nutrients 2021, 13, 2072. [Google Scholar] [CrossRef]
- Casian, M.; Jurcut, C.; Dima, A.; Mihai, A.; Stanciu, S.; Jurcut, R. Cardiovascular disease in primary Sjögren’s Syndrome: Raising clinicians’ awareness. Front. Immunol. 2022, 13, 865373. [Google Scholar] [CrossRef] [PubMed]
- Cesaro, A.; Bianconi, V.; Gragnano, F.; Moscarella, E.; Fimiani, F.; Monda, E.; Scudiero, O.; Limongelli, G.; Pirro, M.; Calabrò, P. Beyond cholesterol metabolism: The pleiotropic effects of proprotein convertase subtilisin/kexin type 9 (PCSK9). Genetics, mutations, expression, and perspective for long-term inhibition. Biofactors 2020, 46, 367–380. [Google Scholar] [CrossRef] [PubMed]
- Seidah, N.G.; Garçon, D. Expanding Biology of PCSK9: Roles in Atherosclerosis and Beyond. Curr. Atheroscler. Rep. 2022, 24, 821–830. [Google Scholar] [CrossRef]
- Panahi, Y.; Ghahrodi, M.S.; Jamshir, M.; Safarpour, M.A.; Bianconi, V.; Pirro, M.; Farahani, M.M.; Sahebkar, A. PCSK9 and atherosclerosis burden in the coronary arteries of patients undergoing coronary angiography. Clin. Biochem. 2019, 74, 12–18. [Google Scholar] [CrossRef]
- Ragusa, R.; Basta, G.; Neglia, D.; De Caterina, R.; Del Turco, S.; Caselli, C. PCSK9 and atherosclerosis: Looking beyond LDL regulation. Eur. J. Clin. Investig. 2021, 51, e13459. [Google Scholar] [CrossRef]
- Luquero, A.; Badimon, L.; Borrell-Pages, M. PCSK9 Functions in atherosclerosis are not limited to plasmatic LDL-Cholesterol regulation. Front. Cardiovasc. Med. 2021, 8, 639727. [Google Scholar] [CrossRef]
- Patriki, D.; Saravi, S.S.S.; Camici, G.G.; Liberale, L.; Beer, J.H. PCSK 9: A link between inflammation and atherosclerosis. Curr. Med. Chem. 2022, 29, 251–267. [Google Scholar] [CrossRef] [PubMed]
- Punch, E.; Klein, J.; Diaba-Nuhoho, P.; Morawietz, H.; Garelnabi, M. Effects of PCSK9 Targeting: Alleviating Oxidation, Inflammation, and Atherosclerosis. J. Am. Heart. Assoc. 2022, 11, e023328. [Google Scholar] [CrossRef] [PubMed]
- Wu, N.Q.; Shi, H.W.; Li, J.J. Proprotein Convertase Subtilisin/Kexin Type 9 and inflammation: An updated review. Front. Cardiovasc. Med. 2022, 9, 763516. [Google Scholar] [CrossRef]
- Fang, C.; Luo, T.; Lin, L. Elevation of serum proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations and its possible atherogenic role in patients with systemic lupus erythematosus. Ann. Transl. Med. 2018, 6, 452. [Google Scholar] [CrossRef] [PubMed]
- Sánchez-Pérez, H.; Quevedo-Abeledo, J.C.; Tejera-Segura, B.; de Armas-Rillo, L.; Rúa-Figueroa, I.; González-Gay, M.A.; Ferraz-Amaro, I. Proprotein convertase subtilisin/kexin type 9 is related to disease activity and damage in patients with systemic erythematosus lupus. Ther. Adv. Musculoskelet. Dis. 2020, 12, 1759720X20975904. [Google Scholar] [CrossRef]
- Liu, A.; Rahman, M.; Hafström, I.; Ajeganova, S.; Frostegård, J. Proprotein convertase subtilisin kexin 9 is associated with disease activity and is implicated in immune activation in systemic lupus erythematosus. Lupus 2020, 29, 825–835. [Google Scholar] [CrossRef]
- Ferraz-Amaro, I.; López-Mejías, R.; Ubilla, B.; Genre, F.; Tejera-Segura, B.; de Vera-González, A.M.; González-Rivero, A.F.; Olmos, J.M.; Hernández, J.L.; Llorca, J.; et al. Proprotein convertase subtilisin/kexin type 9 in rheumatoid arthritis. Clin. Exp. Rheumatol. 2016, 34, 1013–1019. [Google Scholar]
- Ferraz-Amaro, I.; Delgado-Frías, E.; Hernández-Hernández, V.; Sánchez-Pérez, H.; de Armas-Rillo, L.; García-Dopico, J.A.; Díaz-González, F. Proprotein convertase subtilisin/kexin type 9 in patients with systemic sclerosis. Clin. Exp. Rheumatol. 2020, 38 (Suppl. S125), 18–24. [Google Scholar]
- Frostegård, J.; Ahmed, S.; Hafström, I.; Ajeganova, S.; Rahman, M. Low levels of PCSK9 are associated with remission in patients with rheumatoid arthritis treated with anti-TNF-α: Potential underlying mechanisms. Arthritis Res. Ther. 2021, 23, 32. [Google Scholar] [CrossRef]
- Arida, A.; Legaki, A.I.; Kravvariti, E.; Protogerou, A.; Sfikakis, P.P.; Chatzigeorgiou, A. PCSK9/LDLR system and rheumatoid arthritis-related atherosclerosis. Front. Cardiovasc. Med. 2021, 8, 738764. [Google Scholar] [CrossRef] [PubMed]
- Shiboski, C.H.; Shiboski, S.C.; Seror, R.; Criswell, L.A.; Labetoulle, M.; Lietman, T.M.; Rasmussen, A.; Scofield, H.; Vitali, C.; Bowman, S.J.; et al. 2016 American College of Rheumatology/European League against rheumatism classification criteria for primary Sjögren’s syndrome: A consensus and data-driven methodology involving three international patient cohorts. Ann. Rheum. Dis. 2017, 76, 9–16. [Google Scholar] [CrossRef] [PubMed]
- Seror, R.; Ravaud, P.; Bowman, S.J.; Baron, G.; Tzioufas, A.; Theander, E.; Gottenberg, J.E.; Bootsma, H.; Mariette, X.; Vitali, C.; et al. EULAR Sjogren’s syndrome disease activity index: Development of a consensus systemic disease activity index for primary Sjögren’s syndrome. Ann. Rheum. Dis. 2010, 69, 1103–1109. [Google Scholar] [CrossRef]
- Vitali, C.; Palombi, G.; Baldini, C.; Benucci, M.; Bombardieri, S.; Covelli, M.; Del Papa, N.; De Vita, S.; Epis, O.; Franceschini, F.; et al. Sjögren’s Syndrome Disease Damage Index and disease activity index: Scoring systems for the assessment of disease damage and disease activity in Sjögren’s syndrome, derived from an analysis of a cohort of Italian patients. Arthritis Rheum. 2007, 56, 2223–2231. [Google Scholar] [CrossRef] [PubMed]
- Seror, R.; Ravaud, P.; Mariette, X.; Bootsma, H.; Theander, E.; Hansen, A.; Ramos-Casals, M.; Dörner, T.; Bombardieri, S.; Hachulla, E.; et al. EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI): Development of a consensus patient index for primary Sjögren’s syndrome. Ann. Rheum. Dis. 2011, 70, 968–972. [Google Scholar] [CrossRef]
- Pirro, M.; Mannarino, M.R.; Ministrini, S.; Fallarino, F.; Lupattelli, G.; Bianconi, V.; Bagaglia, F.; Mannarino, E. Effects of a nutraceutical combination on lipids, inflammation and endothelial integrity in patients with subclinical inflammation: A randomized clinical trial. Sci. Rep. 2016, 6, 23587. [Google Scholar] [CrossRef]
- Mach, F.; Baigent, C.; Catapano, A.L.; Koskinas, K.C.; Casula, M.; Badimon, L.; Chapman, M.J.; De Backer, G.G.; Delgado, V.; Ference, B.A.; et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Eur. Heart J. 2020, 41, 111–188, Erratum in: Eur. Heart J. 2020, 41, 4255. [Google Scholar] [CrossRef] [PubMed]
- Bianconi, V.; Mannarino, M.R.; Figorilli, F.; Schiaroli, E.; Cosentini, E.; Batori, G.; Marini, E.; Sahebkar, A.; Grignani, F.; Gidari, A.; et al. Low brachial artery flow-mediated dilation predicts worse prognosis in hospitalized patients with COVID-19. J. Clin. Med. 2021, 10, 5456. [Google Scholar] [CrossRef]
- Pirro, M.; Schillaci, G.; Savarese, G.; Gemelli, F.; Vaudo, G.; Siepi, D.; Bagaglia, F.; Mannarino, E. Low-grade systemic inflammation impairs arterial stiffness in newly diagnosed hypercholesterolaemia. Eur. J. Clin. Investig. 2004, 34, 335–341. [Google Scholar] [CrossRef]
- Francisci, D.; Pirro, M.; Schiaroli, E.; Mannarino, M.R.; Cipriani, S.; Bianconi, V.; Alunno, A.; Bagaglia, F.; Bistoni, O.; Falcinelli, E.; et al. Maraviroc intensification modulates atherosclerotic progression in HIV-suppressed patients at high cardiovascular risk. A randomized, crossover pilot Study. Open Forum Infect. Dis. 2019, 6, ofz112. [Google Scholar] [CrossRef]
- Lodde, B.M.; Sankar, V.; Kok, M.R.; Leakan, R.A.; Tak, P.P.; Pillemer, S.R. Serum lipid levels in Sjögren’s syndrome. Rheumatology 2006, 45, 481–484. [Google Scholar] [CrossRef] [PubMed]
- Tavori, H.; Rashid, S.; Fazio, S. On the function and homeostasis of PCSK9: Reciprocal interaction with LDLR and additional lipid effects. Atherosclerosis 2015, 238, 264–270. [Google Scholar] [CrossRef] [PubMed]
- Bianconi, V.; Schiaroli, E.; Pirro, M.; Cardaci, S.; Busti, C.; Mannarino, M.R.; Baldelli, F.; Francisci, D. Effects of antiretroviral therapy on proprotein convertase subtilisin/kexin 9: Focus on lipids, inflammation and immunovirological parameters. HIV Med. 2020, 21, 512–522. [Google Scholar] [CrossRef] [PubMed]
- Frostegård, J. The role of PCSK9 in inflammation, immunity, and autoimmune diseases. Expert Rev. Clin. Immunol. 2022, 18, 67–74. [Google Scholar] [CrossRef] [PubMed]
- Atzeni, F.; Sarzi-Puttini, P.; Signorello, M.C.; Gianturco, L.; Stella, D.; Boccassini, L.; Ricci, C.; Bodini, B.D.; Batticciotto, A.; De Gennaro-Colonna, V.; et al. New parameters for identifying subclinical atherosclerosis in patients with primary Sjögren’s syndrome: A pilot study. Clin. Exp. Rheumatol. 2014, 32, 361–368. [Google Scholar] [CrossRef]
- Sabio, J.M.; Sánchez-Berná, I.; Martinez-Bordonado, J.; Vargas-Hitos, J.A.; Navarrete-Navarrete, N.; Expósito Ruíz, M.; Jiménez-Alonso, J. Prevalence of and factors associated with increased arterial stiffness in patients with primary Sjögren’s syndrome. Arthritis Care Res. 2015, 67, 554–562. [Google Scholar] [CrossRef]
- Sezis Demirci, M.; Karabulut, G.; Gungor, O.; Celtik, A.; Ok, E.; Kabasakal, Y. Is There an Increased arterial stiffness in patients with primary Sjögren’s Syndrome? Intern. Med. 2016, 55, 455–459. [Google Scholar] [CrossRef]
pSS Patients (n = 52) | HCs (n = 26) | p | |
---|---|---|---|
Age, years | 56 ± 11 | 53 ± 14 | NS |
Females/Males, n (%) | 48 (92)/4 (8) | 24 (92)/2 (8) | NS |
Family history of CV disease, % | 21 | 0 | 0.013 |
BMI, kg/m2 | 25 ± 5 | 23 ± 4 | NS |
Waist circumference, cm | 91 (85–99) | 92 (82–102) | NS |
Current smoking, % | 21 | 4 | 0.046 |
Previous smoking, % | 27 | 11 | NS |
Hypertension, % | 25 | 16 | NS |
Diabetes, % | 2 | 0 | NS |
Dyslipidemia, % | 61 | 85 | 0.042 |
Chronic kidney disease, % | 2 | 0 | NS |
Carotid plaque, % | 10 | 0 | 0.038 |
Low-to-moderate/high-to-very-high CV risk, % | 75/25 | 89/11 | NS |
IMTmax, mm | 1.09 (0.88–1.23) | 1.01 (0.8–1.12) | NS |
IMTmean, mm | 0.87 (0.79–0.99) | 0.80 (0.67–0.94) | NS |
bFMD, % | 6.9 (3.9–12.6) | 10.3 (5.1–15.1) | 0.054 |
aPWV, m/s | 6.9 (6.1–7.5) | 5.5 (5.1–7.1) | 0.005 |
SBP, mmHg | 127 ± 14 | 120 ± 14 | 0.043 |
DBP, mmHg | 78 ± 7 | 72 ± 13 | 0.011 |
Anti-thrombotic drugs, % | 1 | 0 | NS |
Lipid-lowering drugs, % | 11 | 8 | NS |
Statins, % | 6 | 8 | NS |
Corticosteroids, % | 4 | 0 | NS |
Immunomodulators, % | 27 | 0 | 0.004 |
Anti-SSA/Ro antibodies, % | 84 | 0 | <0.001 |
Anti-SSB/La antibodies, % | 41 | 0 | <0.001 |
Rheumatoid factor, % | 66 | 0 | <0.001 |
ANA, % | 100 | 0 | <0.001 |
TC, mg/dL | 195 ± 34 | 226 ± 32 | <0.001 |
LDL-C, mg/dL | 118 ± 30 | 138 ± 27 | 0.008 |
HDL-C, mg/dL | 60 ± 12 | 68 ± 13 | 0.008 |
Triglycerides, mg/dL | 81 (68–118) | 90 (60–116) | NS |
TC-to-HDL-C ratio | 3.37 ± 0.78 | 3.41 ± 0.65 | NS |
Glucose, mg/dL | 91 (85–96) | 85 (80–95) | NS |
eGFR, mL/min | 88 ± 22 | 94 ± 17 | NS |
hsCRP, mg/L | 0.24 (0.00–2.7) | 0.12 (0.00–0.72) | NS |
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Bianconi, V.; Cafaro, G.; Mannarino, M.R.; Perricone, C.; Cosentini, E.; Bistoni, O.; Paltriccia, R.; Lombardini, R.; Gerli, R.; Pirro, M.; et al. Exploring the Link between Plasma Levels of PCSK9, Immune Dysregulation and Atherosclerosis in Patients with Primary Sjögren’s Syndrome. Biomolecules 2023, 13, 1384. https://doi.org/10.3390/biom13091384
Bianconi V, Cafaro G, Mannarino MR, Perricone C, Cosentini E, Bistoni O, Paltriccia R, Lombardini R, Gerli R, Pirro M, et al. Exploring the Link between Plasma Levels of PCSK9, Immune Dysregulation and Atherosclerosis in Patients with Primary Sjögren’s Syndrome. Biomolecules. 2023; 13(9):1384. https://doi.org/10.3390/biom13091384
Chicago/Turabian StyleBianconi, Vanessa, Giacomo Cafaro, Massimo Raffaele Mannarino, Carlo Perricone, Elena Cosentini, Onelia Bistoni, Rita Paltriccia, Rita Lombardini, Roberto Gerli, Matteo Pirro, and et al. 2023. "Exploring the Link between Plasma Levels of PCSK9, Immune Dysregulation and Atherosclerosis in Patients with Primary Sjögren’s Syndrome" Biomolecules 13, no. 9: 1384. https://doi.org/10.3390/biom13091384