PDF herunterladen
Horm Metab Res 2019; 51(03): 200-209
DOI: 10.1055/a-0833-4627
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Effect of IL-6 Receptor Blockade on Proprotein Convertase Subtilisin/Kexin Type-9 and Cholesterol Efflux Capacity in Rheumatoid Arthritis Patients

Iván Ferraz-Amaro
1   Division of Rheumatology, Hospital Universitario de Canarias, Tenerife, Spain
,
María Vanesa Hernández-Hernández
1   Division of Rheumatology, Hospital Universitario de Canarias, Tenerife, Spain
,
Beatriz Tejera-Segura
1   Division of Rheumatology, Hospital Universitario de Canarias, Tenerife, Spain
,
Esmeralda Delgado-Frías
1   Division of Rheumatology, Hospital Universitario de Canarias, Tenerife, Spain
,
María Macía-Díaz
1   Division of Rheumatology, Hospital Universitario de Canarias, Tenerife, Spain
,
Jose David Machado
2   Department of Pharmacology, Facultad de Medicina, Universidad de La Laguna, Tenerife, Spain
,
Federico Diaz-González
1   Division of Rheumatology, Hospital Universitario de Canarias, Tenerife, Spain
3   Department of Internal Medicine, Facultad de Medicina, Universidad de La Laguna, La Laguna, Spain
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 21. April 2018

accepted 09. Januar 2019

Publikationsdatum:
29. Januar 2019 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Abstract

The aim of the work was to examine whether abnormalities in the lipid profile that tocilizumab (TCZ), an anti-IL-6 receptor Ab, exerts in rheumatoid arthritis (RA) patients is related to changes in either proprotein convertase subtilisin/kexin-9 (PCSK9) serum concentrations or in serum cholesterol efflux capacity (CEC). TOCRIVAR is a one-year prospective clinical trial that analyzes the influence of TCZ on cardiovascular risk factors. Twenty-seven RA patients receiving TCZ (8 mg/kg IV/q4w) were assessed at baseline and weeks 12, 24, and 52. Disease activity indexes, adiposity composition, physical activity, serum CEC, PCSK9, and lipoproteins serum concentrations were assessed at every visit. Basal high-sensitivity C-reactive protein (hs-CRP) and disease activity were markedly reduced throughout one-year TCZ treatment. While initially total cholesterol and LDL cholesterol increased their plasma concentration, decreasing to basal afterwards, lipoprotein(a) was significantly lower than basal in all visits of the study. CEC increased after 24 week of treatment proportionally to hs-CRP reduction, and remained significantly higher after week 52 [median % change 32 (3–141), p=0.021]. Interestingly, variations in LDL cholesterol basal concentration along the one year of TCZ treatment correlated directly with changes of PCSK9 serum concentration (r=0.37, p=0.003). Basal abdominal adiposity, BMI, and physical activity remained stable during the study. Long-term TCZ-treated RA patients show an increment in CEC inversely proportional to hs-CRP reduction and changes in LDL cholesterol that might be explained, at least in part, by variations in PCSK9 plasma concentration. Overall, TCZ treatment produces a favorable qualitative net effect in terms of atherogenic implication in RA patients.

Key words

cholesterol/efflux - LDL/metabolism - PCSK9 - tocilizumab - rheumatoid arthritis
 

  • References

  • 1 Fleischmann RM, Halland AM, Brzosko M. et al. Tocilizumab inhibits structural joint damage and improves physical function in patients with rheumatoid arthritis and inadequate responses to methotrexate: LITHE study 2-year results. J Rheumatol 2013; 40: 113-126
    PubMedGoogle Scholar
  • 2 Singh JA, Beg S, Lopez-Olivo MA. Tocilizumab for rheumatoid arthritis: A Cochrane systematic review. J Rheumatol 2011; 38: 10-20
    PubMedGoogle Scholar
  • 3 Genovese MC, Rubbert-Roth A, Smolen JS. et al. Longterm safety and efficacy of tocilizumab in patients with rheumatoid arthritis: A cumulative analysis of up to 4.6 years of exposure. J Rheumatol 2013; 40: 768-780
    PubMedGoogle Scholar
  • 4 Zhang J, Xie F, Yun H. et al. Comparative effects of biologics on cardiovascular risk among older patients with rheumatoid arthritis. Ann Rheum Dis 2016; 75: 1813-1818
    CrossrefPubMedGoogle Scholar
  • 5 Avina-Zubieta JA, Choi HK, Sadatsafavi M. et al. Risk of cardiovascular mortality in patients with rheumatoid arthritis: A meta-analysis of observational studies. Arthritis Rheum 2008; 59: 1690-1697
    CrossrefPubMedGoogle Scholar
  • 6 Choy E, Ganeshalingam K, Semb AG. et al. Cardiovascular risk in rheumatoid arthritis: Recent advances in the understanding of the pivotal role of inflammation, risk predictors and the impact of treatment. Rheumatology (Oxford) 2014; 53: 2143-2154
    CrossrefPubMedGoogle Scholar
  • 7 Barnabe C, Martin BJ, Ghali WA. Systematic review and meta-analysis: Anti-tumor necrosis factor alpha therapy and cardiovascular events in rheumatoid arthritis. Arthritis Care Res (Hoboken) 2011; 63: 522-529
    CrossrefPubMedGoogle Scholar
  • 8 Choy E. Understanding the dynamics: Pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford) 2012; 51 (Suppl. 05) v3-11
    CrossrefPubMedGoogle Scholar
  • 9 Hartman J, Frishman WH. Inflammation and atherosclerosis: A review of the role of interleukin-6 in the development of atherosclerosis and the potential for targeted drug therapy. Cardiol Rev 2014; 22: 147-151
    CrossrefPubMedGoogle Scholar
  • 10 Ridker PM, Rifai N, Stampfer MJ. et al. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101: 1767-1772
    CrossrefPubMedGoogle Scholar
  • 11 Sarwar N, Butterworth AS, Freitag DF. et al. Interleukin-6 receptor pathways in coronary heart disease: A collaborative meta-analysis of 82 studies. Lancet 2012; 379: 1205-1213
    CrossrefPubMedGoogle Scholar
  • 12 Swerdlow DI, Holmes MV, Kuchenbaecker KB. et al. The interleukin-6 receptor as a target for prevention of coronary heart disease: A mendelian randomisation analysis. Lancet 2012; 379: 1214-1224
    CrossrefPubMedGoogle Scholar
  • 13 Cuchel M, Rader DJ. Macrophage reverse cholesterol transport: Key to the regression of atherosclerosis?. Circulation 2006; 113: 2548-2555
    CrossrefPubMedGoogle Scholar
  • 14 Prosser HC, Ng MK, Bursill CA. The role of cholesterol efflux in mechanisms of endothelial protection by HDL. Curr Opin Lipidol 2012; 23: 182-189
    CrossrefPubMedGoogle Scholar
  • 15 Rohatgi A, Khera A, Berry JD. et al. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med 2014; 371: 2383-2393
    CrossrefPubMedGoogle Scholar
  • 16 Ronda N, Favari E, Borghi MO. et al. Impaired serum cholesterol efflux capacity in rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis 2013; 73: 609-615
    PubMedGoogle Scholar
  • 17 Charles-Schoeman C, Lee YY, Grijalva V. et al. Cholesterol efflux by high density lipoproteins is impaired in patients with active rheumatoid arthritis. Ann Rheum Dis 2012; 71: 1157-1162
    CrossrefPubMedGoogle Scholar
  • 18 Robinson JG, Farnier M, Krempf M. et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372: 1489-1499
    CrossrefPubMedGoogle Scholar
  • 19 Lakoski SG, Lagace TA, Cohen JC. et al. Genetic and metabolic determinants of plasma PCSK9 levels. J Clin Endocrinol Metab 2009; 94: 2537-2543
    CrossrefPubMedGoogle Scholar
  • 20 Robertson J, Peters MJ, McInnes IB. et al. Changes in lipid levels with inflammation and therapy in RA: A maturing paradigm. Nat Rev Rheumatol 2013; 9: 513-523
    CrossrefPubMedGoogle Scholar
  • 21 Aletaha D, Neogi T, Silman AJ. et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62: 2569-2581
    CrossrefPubMedGoogle Scholar
  • 22 Prevoo ML, van’t Hof MA, Kuper HH. et al. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995; 38: 44-48
    CrossrefPubMedGoogle Scholar
  • 23 Aletaha D, Smolen J. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): A review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol 2005; 23: S100-S108
    PubMedGoogle Scholar
  • 24 Smolen JS, Breedveld FC, Schiff MH. et al. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford) 2003; 42: 244-257
    CrossrefPubMedGoogle Scholar
  • 25 Pincus T, Swearingen C, Wolfe F. Toward a multidimensional Health Assessment Questionnaire (MDHAQ): Assessment of advanced activities of daily living and psychological status in the patient-friendly health assessment questionnaire format. Arthritis Rheum 1999; 42: 2220-2230
    CrossrefPubMedGoogle Scholar
  • 26 van Poppel MN, Chinapaw MJ, Mokkink LB. et al. Physical activity questionnaires for adults: A systematic review of measurement properties. Sports Med 2010; 40: 565-600
    CrossrefPubMedGoogle Scholar
  • 27 Bassett Jr. DR. International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exerc 2003; 35: 1396
    CrossrefPubMedGoogle Scholar
  • 28 Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499-502
    CrossrefPubMedGoogle Scholar
  • 29 Thomas EL, Saeed N, Hajnal JV. et al. Magnetic resonance imaging of total body fat. J Appl Physiol (1985) 1998; 85: 1778-1785
    CrossrefPubMedGoogle Scholar
  • 30 Wang J, Heymsfield SB, Aulet M. et al. Body fat from body density: Underwater weighing vs. dual-photon absorptiometry. Am J Physiol 1989; 256: E829-E834
    PubMedGoogle Scholar
  • 31 Delgado-Frias E, Gonzalez-Gay MA, Muniz-Montes JR. et al. Relationship of abdominal adiposity and body composition with endothelial dysfunction in patients with rheumatoid arthritis. Clin Exp Rheumatol 2015; 33: 516-523
    PubMedGoogle Scholar
  • 32 Visser M, Pahor M, Tylavsky F. et al. One- and two-year change in body composition as measured by DXA in a population-based cohort of older men and women. J Appl Physiol (1985) 2003; 94: 2368-2374
    PubMedGoogle Scholar
  • 33 Khera AV, Cuchel M, de la Llera-Moya M. et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011; 364: 127-135
    CrossrefPubMedGoogle Scholar
  • 34 Ormseth MJ, Yancey PG, Solus JF. et al. Effect of drug therapy on net cholesterol efflux capacity of high-density lipoprotein-enriched serum in rheumatoid arthritis. Arthritis Rheumatol 2016; 68: 2099-2105
    PubMedGoogle Scholar
  • 35 Hirao M, Yamasaki N, Oze H. et al. Serum level of oxidative stress marker is dramatically low in patients with rheumatoid arthritis treated with tocilizumab. Rheumatol Int 2012; 32: 4041-4045
    CrossrefPubMedGoogle Scholar
  • 36 Marcil V, Delvin E, Sane AT. et al. Oxidative stress influences cholesterol efflux in THP-1 macrophages: Role of ATP-binding cassette A1 and nuclear factors. Cardiovasc Res 2006; 72: 473-482
    CrossrefPubMedGoogle Scholar
  • 37 Liao KP, Playford MP, Frits M. et al. The association between reduction in inflammation and changes in lipoprotein levels and HDL cholesterol efflux capacity in rheumatoid arthritis. J Am Heart Assoc 2015; 4 pii e001588 doi:10.1161/JAHA.114.001588
    PubMedGoogle Scholar
  • 38 Chaudhary R, Garg J, Shah N. et al. PCSK9 inhibitors: A new era of lipid lowering therapy. World J Cardiol 2017; 9: 76-91
    CrossrefPubMedGoogle Scholar
  • 39 Ferraz-Amaro I, Lopez-Mejias R, Ubilla B. Proprotein convertase subtilisin/kexin type 9 in rheumatoid arthritis. Clin Exp Rheumatol 2016; 34: 1013-1019
    PubMedGoogle Scholar
  • 40 Walley KR, Thain KR, Russell JA. et al. PCSK9 is a critical regulator of the innate immune response and septic shock outcome. Sci Transl Med 2014; 6: 258ra143
    CrossrefPubMedGoogle Scholar
  • 41 Ai D, Chen C, Han S. et al. Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice. J Clin Invest 2012; 122: 1262-1270
    CrossrefPubMedGoogle Scholar
  • 42 Lee YH, Choi SJ, Ji JD. et al. Lipoprotein(a) and lipids in relation to inflammation in rheumatoid arthritis. Clin Rheumatol 2000; 19: 324-325
    CrossrefPubMedGoogle Scholar
  • 43 Kamstrup PR, Tybjaerg-Hansen A, Steffensen R. et al. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 2009; 301: 2331-2339
    CrossrefPubMedGoogle Scholar
  • 44 Gabay C, McInnes IB, Kavanaugh A. et al. Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis. Ann Rheum Dis 2016; 75: 1806-1812
    CrossrefPubMedGoogle Scholar
  • 45 Monda KL, Ballantyne CM, North KE. Longitudinal impact of physical activity on lipid profiles in middle-aged adults: The Atherosclerosis Risk in Communities Study. J Lipid Res 2009; 50: 1685-1691
    CrossrefPubMedGoogle Scholar
  • 46 Hernandez-Hernandez V, Ferraz-Amaro I, Diaz-Gonzalez F. Influence of disease activity on the physical activity of rheumatoid arthritis patients. Rheumatology (Oxford) 2014; 53: 722-731
    CrossrefPubMedGoogle Scholar
  • 47 Prioreschi A, Hodkinson B, Tikly M. et al. Changes in physical activity measured by accelerometry following initiation of DMARD therapy in rheumatoid arthritis. Rheumatology (Oxford) 2014; 53: 923-926
    CrossrefPubMedGoogle Scholar
  • 48 Hubert HB, Feinleib M, McNamara PM. et al. Obesity as an independent risk factor for cardiovascular disease: A 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983; 67: 968-977
    CrossrefPubMedGoogle Scholar
  • 49 Curtis JR, Perez-Gutthann S, Suissa S. et al. Tocilizumab in rheumatoid arthritis: A case study of safety evaluations of a large postmarketing data set from multiple data sources. Semin Arthritis Rheum 2015; 44: 381-388
    CrossrefPubMedGoogle Scholar