J Korean Med Sci.  2016 Feb;31(2):202-207. 10.3346/jkms.2016.31.2.202.

The Effects of Rituximab on Lipids, Arterial Stiffness and Carotid Intima-Media Thickness in Rheumatoid Arthritis

• Novikova D
• Popkova TV
• Lukina GV
• Luchikhina EL
• Karateev D
• Volkov AV
• Novikov AA
• Aleksandrova EN
• Nasonov EL

• KMID: 2360043
• DOI: http://doi.org/10.3346/jkms.2016.31.2.202

Abstract

The aim of the study was to examine lipid profiles, arterial stiffness (AS), carotid intima-media thickness (cIMT), in 55 women with RA without overt cardiovascular disease (capital ES, CyrillicVD) treated with rituximab (RTX).The following parameters were recorded before and 24 weeks after RTX therapy (2 infusions of 500 or 1,000 mg RTX intravenously, fortnightly): plasma total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, DAS 28-ESR, serum C-reactive protein (CRP), RF IgM, AS (SI - stiffness index, RI - reflection index) by digital volume pulse contour analysis (Micro Medical, UK), and common cIMT by high-resolution B-mode carotid ultrasound. Based on the European League Against Rheumatism (EULAR) criteria, patients were divided into two groups: 1) moderate/good response to RTX therapy after 24 weeks (41 patients, 75%), 2) no response to RTX therapy (14 patients, 25%). Effective RTX therapy resulted in 9% increase in TC, 23% increase in HDL-C and 14% decrease in atherogenic index, 57% decrease in SI and 24% decrease in RI. We observed a 9% decrease of cIMTmax at 24 weeks. The improvement of cardiovascular parameters was accompanied by statistically significant decreases of CRP, ESR, RF IgM and DAS 28 in group 1 (P < 0.05). There were not significant changes in lipid profile, AS parameters, and cIMT in group 2. Two infusions of RTX in case of moderate/good EULAR effect of therapy exerted favorable effects on lipid profile, AS and cIMT in women with RA without overt CVD.

Keyword

Rheumatoid Arthritis; Lipids; Carotid Atherosclerosis; Arterial Stiffness; Rituximab

MeSH Terms

Antirheumatic Agents/*therapeutic use
Arthritis, Rheumatoid/complications/*drug therapy/physiopathology
Biomarkers/blood
C-Reactive Protein/analysis
Cardiovascular Diseases/complications
Carotid Intima-Media Thickness
Cholesterol, HDL/blood
Cholesterol, LDL/blood
Female
Humans
Lipids/*blood
Middle Aged
Rituximab/*therapeutic use
Treatment Outcome
Triglycerides/blood
Vascular Stiffness
Antirheumatic Agents
Biomarkers
C-Reactive Protein
Cholesterol, HDL
Cholesterol, LDL
Lipids
Rituximab
Triglycerides

Reference

1. Mellana WM, Aronow WS, Palaniswamy C, Khera S. Rheumatoid arthritis: cardiovascular manifestations, pathogenesis, and therapy. Curr Pharm Des. 2012; 18:1450–1456.

2. Aviña-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum. 2008; 59:1690–1697.

3. Kerekes G, Szekanecz Z, Dér H, Sándor Z, Lakos G, Muszbek L, Csipö I, Sipka S, Seres I, Paragh G, et al. Endothelial dysfunction and atherosclerosis in rheumatoid arthritis: a multiparametric analysis using imaging techniques and laboratory markers of inflammation and autoimmunity. J Rheumatol. 2008; 35:398–406.

4. del Rincón I, Polak JF, O’Leary DH, Battafarano DF, Erikson JM, Restrepo JF, Molina E, Escalante A. Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis. Ann Rheum Dis. 2015; 74:1118–1123.

5. Ambrosino P, Tasso M, Lupoli R, Di Minno A, Baldassarre D, Tremoli E, Di Minno MN. Non-invasive assessment of arterial stiffness in patients with rheumatoid arthritis: a systematic review and meta-analysis of literature studies. Ann Med. 2015; 47:457–467.

6. Van Bortel LM, Laurent S, Boutouyrie P, Chowienczyk P, Cruickshank JK, De Backer T, Filipovsky J, Huybrechts S, Mattace-Raso FU, Protogerou AD, et al. Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity. J Hypertens. 2012; 30:445–448.

7. Peters SA, den Ruijter HM, Bots ML, Moons KG. Improvements in risk stratification for the occurrence of cardiovascular disease by imaging subclinical atherosclerosis: a systematic review. Heart. 2012; 98:177–184.

8. Gasparyan AY, Stavropoulos-Kalinoglou A, Mikhailidis DP, Toms TE, Douglas KM, Kitas GD. The rationale for comparative studies of accelerated atherosclerosis in rheumatic diseases. Curr Vasc Pharmacol. 2010; 8:437–449.

9. Im CH, Kim NR, Kang JW, Kim JH, Kang JY, Bae GB, Nam EJ, Kang YM. Inflammatory burden interacts with conventional cardiovascular risk factors for carotid plaque formation in rheumatoid arthritis. Rheumatology (Oxford). 2015; 54:808–815.

10. Emery P. Rheumatoid arthritis in 2014: exciting times for RA research. Nat Rev Rheumatol. 2015; 11:69–70.

11. Solomon DH, Reed GW, Kremer JM, Curtis JR, Farkouh ME, Harrold LR, Hochberg MC, Tsao P, Greenberg JD. Disease activity in rheumatoid arthritis and the risk of cardiovascular events. Arthritis Rheumatol. 2015; 67:1449–1455.

12. Gonzalez-Juanatey C, Llorca J, Vazquez-Rodriguez TR, Diaz-Varela N, Garcia-Quiroga H, Gonzalez-Gay MA. Short-term improvement of endothelial function in rituximab-treated rheumatoid arthritis patients refractory to tumor necrosis factor alpha blocker therapy. Arthritis Rheum. 2008; 59:1821–1824.

13. Benucci M, Saviola G, Manfredi M, Sarzi-Puttini P, Atzeni F. Factors correlated with improvement of endothelial dysfunction during rituximab therapy in patients with rheumatoid arthritis. Biologics. 2013; 7:69–75.

14. Hsue PY, Scherzer R, Grunfeld C, Imboden J, Wu Y, Del Puerto G, Nitta E, Shigenaga J, Schnell Heringer A, Ganz P, et al. Depletion of B-cells with rituximab improves endothelial function and reduces inflammation among individuals with rheumatoid arthritis. J Am Heart Assoc. 2014; 3:e001267.

15. 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; 72:560–565.

16. Novikova DS, Popkova TV, Gerasimova EV, Novikov AA, Aleksandrova EN, Nasonov EL. Changes in heart rate, heart rate variability and QT interval in women with rheumatoid arthritis during rituximab treatment. Rheumatol Sci Pract. 2014; 52:270–276.

17. Provan SA, Berg IJ, Hammer HB, Mathiessen A, Kvien TK, Semb AG. The impact of newer biological disease modifying antirheumatic drugs on cardiovascular risk factors: a 12-month longitudinal study in rheumatoid arthritis patients treated with rituximab, abatacept and tociliziumab. PLoS One. 2015; 10:e0130709.

18. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988; 31:315–324.

19. Smolen JS, Breedveld FC, Schiff MH, Kalden JR, Emery P, Eberl G, van Riel PL, Tugwell P. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford). 2003; 42:244–257.

20. The Arthritis, Rheumatism, and Aging Medical Information System. Aramis: HAQ;accessed on 29 October 2015. Available at http://aramis.stanford.edu/HAQ.html.

21. van Gestel AM, Prevoo ML, van ’t Hof MA, van Rijswijk MH, van de Putte LB, van Riel PL. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum. 1996; 39:34–40.

22. Conroy RM, Pyörälä K, Fitzgerald AP, Sans S, Menotti A, De Backer G, De Bacquer D, Ducimetière P, Jousilahti P, Keil U, et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J. 2003; 24:987–1003.

23. Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Desvarieux M, Ebrahim S, Fatar M, Hernandez Hernandez R, Kownator S, et al. Mannheim intima-media thickness consensus. Cerebrovasc Dis. 2004; 18:346–349.

24. Mason JC, Libby P. Cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions. Eur Heart J. 2015; 36:482–489c.

25. Schroeder LL, Tang X, Wasko MC, Bili A. Glucocorticoid use is associated with increase in HDL and no change in other lipids in rheumatoid arthritis patients. Rheumatol Int. 2015; 35:1059–1067.

26. Avouac J, Allanore Y. Cardiovascular risk in rheumatoid arthritis: effects of anti-TNF drugs. Expert Opin Pharmacother. 2008; 9:1121–1128.

27. Rasch LA, Bultink IE, van Tuyl LH, Lems WF. Glucocorticoid safety for treating rheumatoid arthritis. Expert Opin Drug Saf. 2015; 14:839–844.

28. Chatzidionysiou K, van Vollenhoven RF. Rituximab versus anti-TNF in patients who previously failed one TNF inhibitor in an observational cohort. Scand J Rheumatol. 2013; 42:190–195.

29. Novikova DS, Popkova TV, Nasonov EL. The effect of anti-B-cell therapy on the development of atherosclerosis in patients with rheumatoid arthritis. Curr Pharm Des. 2012; 18:1512–1518.

30. Tsiantoulas D, Sage AP, Mallat Z, Binder CJ. Targeting B cells in atherosclerosis: closing the gap from bench to bedside. Arterioscler Thromb Vasc Biol. 2015; 35:296–302.

31. Kerekes G, Soltész P, Dér H, Veres K, Szabó Z, Végvári A, Szegedi G, Shoenfeld Y, Szekanecz Z. Effects of rituximab treatment on endothelial dysfunction, carotid atherosclerosis, and lipid profile in rheumatoid arthritis. Clin Rheumatol. 2009; 28:705–710.

32. 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. Clin Exp Rheumatol. 2011; 29:942–950.

33. Mathieu S, Pereira B, Dubost JJ, Lusson JR, Soubrier M. No significant change in arterial stiffness in RA after 6 months and 1 year of rituximab treatment. Rheumatology (Oxford). 2012; 51:1107–1111.

34. Tomasson G, Aspelund T, Jonsson T, Valdimarsson H, Felson DT, Gudnason V. Effect of rheumatoid factor on mortality and coronary heart disease. Ann Rheum Dis. 2010; 69:1649–1654.

35. Gasparyan AY, Ayvazyan L, Cocco G, Kitas GD. Adverse cardiovascular effects of antirheumatic drugs: implications for clinical practice and research. Curr Pharm Des. 2012; 18:1543–1555.

36. van Vollenhoven RF, Emery P, Bingham CO 3rd, Keystone EC, Fleischmann RM, Furst DE, Tyson N, Collinson N, Lehane PB. Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients. Ann Rheum Dis. 2013; 72:1496–1502.

37. van Sijl AM, van der Weele W, Nurmohamed MT. Myocardial infarction after rituximab treatment for rheumatoid arthritis: Is there a link? Curr Pharm Des. 2014; 20:496–499.