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Untying the correlation between apolipoproteins and rheumatoid arthritis

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Abstract

Aim and objective

The concentration of lipoproteins and apolipoprotein are extremely low in the synovial fluid of any healthy person as compared to the concentrations in plasma. However, in the synovial fluid of any diseased patient the amount of cholesterol and lipids is sharply increased. The current review defines the role of various apolipoproteins and lipoproteins and their constituent subfractions in the synovial fluid embarking its principal role in rheumatoid arthritis. It also explains the need to define synovial fluid lipids, lipoprotein particle subfractions and their constituent apolipoproteins in synovial fluid.

Materials and methods

Various research and review articles highlighting the role of apolipoproteins and lipoproteins were procured from medical websites mainly Pubmed, Medline, Science Direct, etc., and studied for the writing of the review paper.

Conclusion

Mainly apolipoproteins A-1, B and E are prominently increased in chronic inflammatory joint disorders. Several theories have been proposed to understand the source of increase of lipids and apolipoproteins in synovial fluid of the diseased patients compared to healthy individuals, yet the precise mechanism is still not lucid. Lipoproteins are believed to play both functional role and pathological role in the synovial fluid. The activated T-lymphocytes in patients of RA lead to activation of inflammatory cytokines such as tumor necrosis factor and interleukins which embark to be the principal mechanism for induction of the disease. It can be thus concluded that the apolipoproteins prevent the activation of monocytes by blocking their contact of activation and thus play critical role in management of RA by inhibiting the production of proinflammatory cytokines.

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References:

  1. Alamanos Y, Voulgari PV, Drosos AA. Incidence and prevalence of rheumatoid arthritis based on the 1987 American College of Rheumatology criteria: a systematic review. Semin Arthritis Rheum. 2006;36:182–8.

    Google Scholar 

  2. Li R, Sun J, Ren LM, Wang HY, Liu WH, Zhang XW, Chen S, Mu R, He J, Zhao Y. Epidemiology of eight common rheumatic diseases in China: a large-scale cross-sectional survey in Beijing. Rheumatology (Oxford). 2012;51:721–9.

    Google Scholar 

  3. Ranganath VK, Maranian P, Elashoff DA, Woodworth T, Khanna D, Hahn T, Sarkisian C, Kremer JM, Furst DE, Paulus HE. Comorbidities are associated with poorer outcomes in community patients with rheumatoid arthritis. Rheumatology (Oxford). 2013;52:1809–17.

    Google Scholar 

  4. Humphreys JH, Warner A, Chipping J, Marshall T, Lunt M, Symmons DP, Verstappen SM. Mortality trends in patients with early rheumatoid arthritis over 20 years: results from the Norfolk Arthritis Register. Arthritis Care Res (Hoboken). 2014;66:1296.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Symmons DP, Gabriel SE. Epidemiology of CVD in rheumatic disease, with a focus on RA and SLE. Nat Rev Rheumatol. 2011;7:399–408.

    PubMed  Google Scholar 

  6. Kahlenberg JM, Kaplan MJ. Mechanisms of premature atherosclerosis in rheumatoid arthritis and lupus. Annu Rev Med. 2013;64:249–63.

    CAS  PubMed  Google Scholar 

  7. Avouac J, Meune C, Chenevier-Gobeaux C, Dieudé P, Borderie D, Lefevre G, Kahan A, Allanore Y. Inflammation and disease activity are associated with high circulating cardiac markers in rheumatoid arthritis independently of traditional cardiovascular risk factors. J Rheumatol. 2014;41:248–55.

    CAS  PubMed  Google Scholar 

  8. Koivuniemi R, Paimela L, Suomalainen R, Leirisalo-Repo M. Cardiovascular diseases in patients with rheumatoid arthritis. Scand J Rheumatol. 2013;42:131–5.

    CAS  PubMed  Google Scholar 

  9. Toms TE, Symmons DP, Kitas GD. Dyslipidaemia in rheumatoid arthritis: the role of inflammation, drugs, lifestyle and genetic factors. CurrVascPharmacol. 2010;8:301–26.

    CAS  Google Scholar 

  10. Montecucco F, Mach F. Common inflammatory mediators orchestrate pathophysiological processes in rheumatoid arthritis and atherosclerosis. Rheumatology (Oxford). 2009;48:11–22.

    CAS  Google Scholar 

  11. Choy E, Sattar N. Interpreting lipid levels in the context of high-grade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional cardiovascular risk actions. Ann Rheum Dis. 2009;68:460–9.

    CAS  PubMed  Google Scholar 

  12. Boekholdt SM, Arsenault BJ, Mora S, Pedersen TR, LaRosa JC, Nestel PJ, Simes RJ, Durrington P, Hitman GA, Welch KM. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA. 2012;307:1302–9.

    CAS  PubMed  Google Scholar 

  13. Hahn BH, Grossman J, Chen W, McMahon M. The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: roles of inflammation and dyslipidemia. J Autoimmun. 2007;28:69–75.

    CAS  PubMed  Google Scholar 

  14. Choi HK, Seeger JD. Lipid profiles among US elderly with untreated rheumatoid arthritis–the third national health and nutrition examination survey. J Rheumatol. 2005;32:2311–6.

    CAS  PubMed  Google Scholar 

  15. Steiner G, Urowitz MB. Lipid profiles in patients with rheumatoid arthritis: mechanisms and the impact of treatment. Semin Arthritis Rheum. 2009;38:372–81.

    CAS  PubMed  Google Scholar 

  16. García-Gómez C, Nolla JM, Valverde J, Narváez J, Corbella E, Pintó X. High HDL-cholesterol in women with rheumatoid arthritis on low-dose glucocorticoid therapy. Eur J Clin Invest. 2008;38:686–92.

    PubMed  Google Scholar 

  17. Williams PT, Feldman DE. Prospective study of coronary heart disease vs. HDL2, HDL3, and other lipoproteins in Gofman’s Livermore Cohort. Atherosclerosis. 2011;214:196–202.

    CAS  PubMed  Google Scholar 

  18. Yang CY, Raya JL, Chen HH, Chen CH, Abe Y, Pownall HJ, Taylor AA, Smith CV. Isolation, characterization, and functional assessment of oxidatively modified subfractions of circulating low-density lipoproteins. ArteriosclerThrombVasc Biol. 2003;23:1083–90.

    CAS  Google Scholar 

  19. Toms TE, Panoulas VF, Kitas GD. Dyslipidaemia in rheumatological autoimmune diseases. Open Cardiovasc Med J. 2011;5:64–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Rizzo M, Spinas GA, Cesur M, Ozbalkan Z, Rini GB, Berneis K. Atherogenic lipoprotein phenotype and LDL size and subclasses in drug-naïve patients with early rheumatoid arthritis. Atherosclerosis. 2009;207:502–6.

    CAS  PubMed  Google Scholar 

  21. García-Gómez C, Nolla JM, Valverde J, Gómez-Gerique JA, Castro MJ, Pintó X. Conventional lipid profile and lipoprotein(a) concentrations in treated patients with rheumatoid arthritis. J Rheumatol. 2009;36:1365–70.

    PubMed  Google Scholar 

  22. Zhang C, Li X, Niu D, Zi R, Wang C, Han A, Wang X, Li K, Wang J. Increased serum levels of β2-GPI-Lp(a) complexes and their association with premature atherosclerosis in patients with rheumatoid arthritis. ClinChim Acta. 2011;412:1332–6.

    CAS  Google Scholar 

  23. Movva R, Rader DJ. Laboratory assessment of HDL heterogeneity and function. Clin Chem. 2008;54:788–800.

    CAS  PubMed  Google Scholar 

  24. Superko HR, Pendyala L, Williams PT, Momary KM, King SB, Garrett BC. High-density lipoprotein subclasses and their relationship to cardiovascular disease. J ClinLipidol. 2012;6:496–523.

    Google Scholar 

  25. Rader DJ. Molecular regulation of HDL metabolism and function: implications for novel therapies. J Clin Invest. 2006;116:3090–100.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Rosenson RS, Brewer HB, Davidson WS, Fayad ZA, Fuster V, Goldstein J, Hellerstein M, Jiang XC, Phillips MC, Rader DJ. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation. 2012;125:1905–19.

    PubMed  PubMed Central  Google Scholar 

  27. Breton CV, Yin F, Wang X, Avol E, Gilliland FD, Araujo JA. HDL anti-oxidant function associates with LDL level in young adults. Atherosclerosis. 2014;232:165–70.

    CAS  PubMed  Google Scholar 

  28. Huang Y, Wu Z, Riwanto M, Gao S, Levison BS, Gu X, Fu X, Wagner MA, Besler C, Gerstenecker G. Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex. J Clin Invest. 2013;123:3815–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters DD. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109–22.

    CAS  PubMed  Google Scholar 

  30. Ansell BJ, Fonarow GC, Navab M, Fogelman AM. Modifying the anti-inflammatory effects of high-density lipoprotein. CurrAtheroscler Rep. 2007;9:57–63.

    CAS  Google Scholar 

  31. Hb G, Rao VS, Kakkar VV, Friend Turns Foe. Transformation of anti-inflammatory HDL to proinflammatory HDL during acute-phase response. Cholesterol. 2011;2011:274629.

    Google Scholar 

  32. Hahn BH, Grossman J, Ansell BJ, Skaggs BJ, McMahon M. Altered lipoprotein metabolism in chronic inflammatory states: proinflammatory high-density lipoprotein and accelerated atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Res Ther. 2008;10:213.

    PubMed  PubMed Central  Google Scholar 

  33. Ferraz-Amaro I, González-Gay MA, García-Dopico JA, Díaz-González F. Cholesteryl ester transfer protein in patients with rheumatoid arthritis. J Rheumatol. 2013;40:1040–7.

    CAS  PubMed  Google Scholar 

  34. McMahon M, Grossman J, FitzGerald J, Dahlin-Lee E, Wallace DJ, Thong BY, Badsha H, Kalunian K, Charles C, Navab M. Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. 2006;54:2541–9.

    CAS  PubMed  Google Scholar 

  35. Popa CD, Arts E, Fransen J, van Riel PL. Atherogenic index and high-density lipoprotein cholesterol as cardiovascular risk determinants in rheumatoid arthritis: the impact of therapy with biologicals. Mediators Inflamm. 2012;2012:785946.

    PubMed  PubMed Central  Google Scholar 

  36. Popa C, van Tits LJ, Barrera P, Lemmers HL, van den Hoogen FH, van Riel PL, Radstake TR, Netea MG, Roest M, Stalenhoef AF. Anti-inflammatory therapy with tumour necrosis factor alpha inhibitors improves high-density lipoprotein cholesterol antioxidative capacity in rheumatoid arthritis patients. Ann Rheum Dis. 2009;68:868–72.

    CAS  PubMed  Google Scholar 

  37. Jamnitski A, Levels JH, van den Oever IA, Nurmohamed MT. High-density lipoprotein profiling changes in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors: a cohort study. J Rheumatol. 2013;40:825–30.

    CAS  PubMed  Google Scholar 

  38. Raterman HG, Levels H, Voskuyl AE, Lems WF, Dijkmans BA, Nurmohamed MT. HDL protein composition alters from proatherogenic into less atherogenic and proinflammatory in rheumatoid arthritis patients responding to rituximab. Ann Rheum Dis. 2013;72:560–5.

    CAS  PubMed  Google Scholar 

  39. Yamashita S, Tsubakio-Yamamoto K, Ohama T, Nakagawa-Toyama Y, Nishida M. Molecular mechanisms of HDL-cholesterol elevation by statins and its effects on HDL functions. J AtherosclerThromb. 2010;17:436–51.

    CAS  Google Scholar 

  40. Charles-Schoeman C, Khanna D, Furst DE, McMahon M, Reddy ST, Fogelman AM, Paulus HE, Park GS, Gong T, Ansell BJ. Effects of high-dose atorvastatin on antiinflammatory properties of high density lipoprotein in patients with rheumatoid arthritis: a pilot study. J Rheumatol. 2007;34:1459–64.

    CAS  PubMed  Google Scholar 

  41. Nikolic D, Katsiki N, Montalto G, Isenovic ER, Mikhailidis DP, Rizzo M. Lipoprotein subfractions in metabolic syndrome and obesity: clinical significance and therapeutic approaches. Nutrients. 2013;5:928–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Björkbacka H, Fredrikson GN, Nilsson J. Emerging biomarkers and intervention targets for immune-modulation of atherosclerosis—a review of the experimental evidence. Atherosclerosis. 2013;227:9–17.

    PubMed  Google Scholar 

  43. Delporte C, Van Antwerpen P, Vanhamme L, Roumeguère T, Zouaoui BK. Low-density lipoprotein modified by myeloperoxidase in inflammatory pathways and clinical studies. Mediators Inflamm. 2013;2013:971579.

    PubMed  PubMed Central  Google Scholar 

  44. Mayr M, Kiechl S, Tsimikas S, Miller E, Sheldon J, Willeit J, Witztum JL, Xu Q. Oxidized low-density lipoprotein autoantibodies, chronic infections, and carotid atherosclerosis in a population-based study. J Am Coll Cardiol. 2006;47:2436–43.

    CAS  PubMed  Google Scholar 

  45. Peters MJ, van Halm VP, Nurmohamed MT, Damoiseaux J, Tervaert JW, Twisk JW, Dijkmans BA, Voskuyl AE. Relations between autoantibodies against oxidized low-density lipoprotein, inflammation, subclinical atherosclerosis, and cardiovascular disease in rheumatoid arthritis. J Rheumatol. 2008;35:1495–9.

    CAS  PubMed  Google Scholar 

  46. Fuhrman B. Regulation of hepatic paraoxonase-1 expression. J Lipids. 2012;2012:684010.

    PubMed  PubMed Central  Google Scholar 

  47. Makedou KG, Mikhailidis DP, Makedou A, Iliadis S, Kourtis A, Vavatsi-Christaki N, Papageorgiou GE. Lipid profile, low-density lipoprotein oxidation and ceruloplasmin in the progeny of families with a positive history of cardiovascular diseases and/or hyperlipidemia. Angiology. 2009;60:455–61.

    CAS  PubMed  Google Scholar 

  48. Balagopalakrishna C, Paka L, Pillarisetti S, Goldberg IJ. Lipolysis-induced iron release from diferric transferrin: possible role of lipoprotein lipase in LDL oxidation. J Lipid Res. 1999;40:1347–56.

    CAS  PubMed  Google Scholar 

  49. Winyard PG, Tatzber F, Esterbauer H, Kus ML, Blake DR, Morris CJ. Presence of foam cells containing oxidised low density lipoprotein in the synovial membrane from patients with rheumatoid arthritis. Ann Rheum Dis. 1993;52:677–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Dai L, Lamb DJ, Leake DS, Kus ML, Jones HW, Morris CJ, Winyard PG. Evidence for oxidised low density lipoprotein in synovial fluid from rheumatoid arthritis patients. Free Radic Res. 2000;32:479–86.

    CAS  PubMed  Google Scholar 

  51. Kim SH, Lee CK, Lee EY, Park SY, Cho YS, Yoo B, Moon HB. Serum oxidized low-density lipoproteins in rheumatoid arthritis. Rheumatol Int. 2004;24:230–3.

    CAS  PubMed  Google Scholar 

  52. Vuilleumier N, Bratt J, Alizadeh R, Jogestrand T, Hafström I, Frostegård J. Anti-apoA-1 IgG and oxidized LDL are raised in rheumatoid arthritis (RA): potential associations with cardiovascular disease and RA disease activity. Scand J Rheumatol. 2010;39:447–53.

    CAS  PubMed  Google Scholar 

  53. Ajeganova S, de Faire U, Jogestrand T, Frostegård J, Hafström I. Carotid atherosclerosis, disease measures, oxidized low-density lipoproteins, and atheroprotective natural antibodies for cardiovascular disease in early rheumatoid arthritis—an inception cohort study. J Rheumatol. 2012;39:1146–54.

    PubMed  Google Scholar 

  54. Profumo E, Di Franco M, Buttari B, Masella R, Filesi C, Tosti ME, Scrivo R, Scarno A, Spadaro A, Saso L. Biomarkers of subclinical atherosclerosis in patients with autoimmune disorders. Mediators Inflamm. 2012;2012:503942.

    PubMed  PubMed Central  Google Scholar 

  55. Ahmed HM, Youssef M, Mosaad YM. Antibodies against oxidized low-density lipoprotein are associated with subclinical atherosclerosis in recent-onset rheumatoid arthritis. ClinRheumatol. 2010;29:1237–43.

    Google Scholar 

  56. Ajeganova S, Fiskesund R, de Faire U, Hafström I, Frostegård J. Effect of biological therapy on levels of atheroprotective antibodies against phosphorylcholine and apolipoproteins in rheumatoid arthritis - a one year study. ClinExpRheumatol. 2011;29:942–50.

    Google Scholar 

  57. Berg K. A new serum type system in man–the lp system. Acta Pathol Microbiol Scand. 1963;59:369–82.

    CAS  PubMed  Google Scholar 

  58. Enkhmaa B, Anuurad E, Zhang W, Tran T, Berglund L. Lipoprotein(a): genotype-phenotype relationship and impact on atherogenic risk. MetabSyndrRelatDisord. 2011;9:411–8.

    CAS  Google Scholar 

  59. Lanktree MB, Rajakumar C, Brunt JH, Koschinsky ML, Connelly PW, Hegele RA. Determination of lipoprotein(a) kringle repeat number from genomic DNA: copy number variation genotyping using qPCR. J Lipid Res. 2009;50:768–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Dumitrescu L, Glenn K, Brown-Gentry K, Shephard C, Wong M, Rieder MJ, Smith JD, Nickerson DA, Crawford DC. Variation in LPA is associated with Lp(a) levels in three populations from the third national health and nutrition examination survey. PLoS ONE. 2011;6:e16604.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009;361:2518–28.

    CAS  PubMed  Google Scholar 

  62. Scanu AM, Bamba R. Niacin and lipoprotein(a): facts, uncertainties, and clinical considerations. Am J Cardiol. 2008;101:44B–7B.

    CAS  PubMed  Google Scholar 

  63. Kurian AK, Cardarelli KM. Racial and ethnic differences in cardiovascular disease risk factors: a systematic review. Ethn Dis. 2007;17:143–52.

    PubMed  Google Scholar 

  64. Kronenberg F, Utermann G. Lipoprotein(a): resurrected by genetics. J Intern Med. 2013;273:6–30.

    CAS  PubMed  Google Scholar 

  65. Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, Marcovina SM, Collins R, Thompson SG, Emerging Risk Factors Collaboration. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302:412–23.

    CAS  PubMed  Google Scholar 

  66. Liu L, Boffa MB, Koschinsky ML. Apolipoprotein(a) inhibits in vitro tube formation in endothelial cells: identification of roles for Kringle V and the plasminogen activation system. PLoS ONE. 2013;8:e52287.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Koschinsky ML. Lipoprotein(a) and atherosclerosis: new perspectives on the mechanism of action of an enigmatic lipoprotein. CurrAtheroscler Rep. 2005;7:389–95.

    CAS  Google Scholar 

  68. Missala I, Kassner U, Steinhagen-Thiessen E. A systematic literature review of the association of lipoprotein(a) and autoimmune diseases and atherosclerosis. Int J Rheumatol. 2012;2012:480784.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Dominiczak MH, Caslake MJ. Apolipoproteins: metabolic role and clinical biochemistry applications. Ann Clin Biochem. 2011;48(6):498–515.

    CAS  PubMed  Google Scholar 

  70. Hjeltnes G, Hollan I, Førre O, Wiik A, Lyberg T, Mikkelsen K, Agewall S. Serum levels of lipoprotein(a) and E-selectin are reduced in rheumatoid arthritis patients treated with methotrexate or methotrexate in combination with TNF-α-inhibitor. ClinExpRheumatol. 2013;31:415–21.

    Google Scholar 

  71. Schultz O, Oberhauser F, Saech J, Rubbert-Roth A, Hahn M, Krone W, Laudes M. Effects of inhibition of interleukin-6 signalling on insulin sensitivity and lipoprotein (a) levels in human subjects with rheumatoid diseases. PLoS ONE. 2010;5:e14328.

    CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Chitkara College of Pharmacy, Chitkara University, Punjab, India

    Rashita Makkar, Tapan Behl & Arun Kumar

  2. Department of Pharmacy, Southeast University, Dhaka, Bangladesh

    Md. Sahab Uddin

  3. Pharmakon Neuroscience Research Network, Dhaka, Bangladesh

    Md. Sahab Uddin

  4. Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania

    Simona Bungau

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  1. Rashita Makkar
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  2. Tapan Behl
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Correspondence to Tapan Behl.

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Makkar, R., Behl, T., Kumar, A. et al. Untying the correlation between apolipoproteins and rheumatoid arthritis. Inflamm. Res. 70, 19–28 (2021). https://doi.org/10.1007/s00011-020-01410-5

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