Vasoprotective Effects of Genetically Engineered Biologic Drugs in Patients with Rheumatoid Arthritis

The aim of the investigation was to evaluate the impact of genetically engineered biologic drugs (GEBD) — infliximab and rituximab — on endothelium functional state in patients with rheumatoid arthritis (RA) without any concomitant cardiovascular diseases.

Materials and Мethods. The study involved 77 patients with RA aged from 18 to 50. The patients matched ACR (1987) or ACR/EULAR (2010) classification criteria, had no concomitant cardiovascular diseases, and had at least a two-year RA history. Based on the immunological subtype and the type of therapeutic intervention, the patients were divided into 4 groups. We assessed vasomotor endothelial function at micro- and macrocirculatory levels using AngioScan-01 device (AngioScan-Electronics, Russia) before treatment and after 12 months of treatment.

Results. RA patients were found to have the signs of endothelial dysfunction in micro- and macrocirculatory vasculature, being more prominent in RF/CCPA-positive (rheumatoid factor/cyclic citrullinated peptide antibodies) disease subtype. Endothelial dysfunction manifestations included the decrease of occlusion index in amplitude and the value of phase shift between the channels after a reactive hyperemia test; the values of these parameters correlating to RA duration, DAS 28 (disease activity score), rheumatoid factor level and CCPA concentration. The use of genetically engineered biologic drugs in RA patients was accompanied by a significant decrease of DAS 28 index, as well as by the reduction of endothelial vasomotor dysfunction signs. Both groups of RF/CCPA-negative patients, regardless of a therapeutic intervention type, were found to have the increase of occlusion index in amplitude up to the control values; as compared with the baseline values, the phase shift between the channels increased on average by 1.5 times (p=0.008) during infliximab use, and during rituximab treatment it grew by 1.6 times (p=0.024). In RF/CCPA-positive RA occlusion index in amplitude increased by 23.5% (p=0.005) after infliximab therapy and by 48.8% (p=0.001) during rituximab treatment; the value of phase shift between the channels increased on average by 1.3 times (p=0.028) in RA patients receiving infliximab, while in a group of patients taking rituximab this value was no different from that in the control group.

Conclusion. Genetically engineered biologic drug therapy, along with its high anti-inflammatory activity, produces a vasoprotective effect characterized by improved endothelial functional state in the system of small resistive vessels as well as in large muscular arteries. The higher activity of rituximab endothelial protective effect is achieved in RF/CCPA-positive disease subtype, and the use of infliximab has the greater effect on endothelial function in RF/CCPA-negative RA.

1. Revmatologiya: klinicheskie rekomendatsii [Rheumatology: clinical recommendations]. Pod red. Nasonova E.L. [Nasonov E.L. (editor)]. Moscow: GEOTAR-Media; 2010; 752 p.
2. Kremers H.M., Crowson C.S., Therneau T.M., Roger V.L., Gabriel S.E. High ten-year risk of cardiovascular disease in newly diagnosed rheumatoid arthritis patients: a population-based cohort study. Arthr Rheum 2008; 58(8): 2268–2274, http://dx.doi.org/10.1002/art.23650.
3. Naranjo A., Sokka T., Descalzo M.A., Calvo-Alén J., Hørslev-Petersen K., Luukkainen R.K., Combe B., Burmester G.R., Devlin J., Ferraccioli G., Morelli A., Hoekstra M., Majdan M., Sadkiewicz S., Belmonte M., Holmqvist A.C., Choy E., Tunc R., Dimic A., Bergman M., Toloza S., Pincus T.; QUEST-RA Group. Cardiovascular disease in patients with rheumatoid arthritis: results from the QUEST-RA study. Arthritis Res Ther 2008; 10(2): R30, http://dx.doi.org/10.1186/ar2383.
4. Wolfe F., Michaud K. The risk of myocardial infarction and pharmacologic and nonpharmacologic myocardial infarction predictors in rheumatoid arthritis: a cohort and nested case-control analysis. Arthr Rheum 2008; 58(9): 2612–2621, http://dx.doi.org/10.1002/art.23811.
5. Khan F., Galarraga B., Belch J.J. The role of endothelial function and its assessment in rheumatoid arthritis. Nat Rev Rheumatol 2010; 6(5): 253–261, http://dx.doi.org/10.1038/nrrheum.2010.44.
6. Sandoo A., Hodson J., Douglas K.M., Smith J.P., Kitas G.D. The association between functional and morphological assessments of endothelial function in patients with rheumatoid arthritis: a cross-sectional study. Arthritis Res Ther 2013; 15(5): R107, http://dx.doi.org/10.1186/ar4287.
7. Knyazeva L.A., Meshcherina N.S., Goryainov I.I., Knyazeva L.I., Stepchenko M.A., Bezgin A.V., Grishina O.V., Ponkratov V.I. Evaluation of arterial wall endothelial function and stiffness in patients with rheumatoid arthritis. Kurskiy nauchno-prakticheskiy vestnik “Chelovek i ego zdorov’e” 2013; 4: 78–84.
8. Fietta P., Delsante G. Atherogenesis in rheumatoid arthritis: the “rheumatoid vasculopathy”? Acta Biomed 2009; 80(3): 177–186.
9. Genno-inzhenernye biologicheskie preparaty v lechenii revmatoidnogo artrita [Genetically engineered biologic drugs in rheumatoid arthritis therapy]. Pod red. Nasonova E.L. [Nasonov E.L. (editor)]. Moscow: IMA-PRESS; 2013; 552 p.
10. Parfenov A.S. Instant diagnosis of cardiovascular diseases. Mir izmereniy 2008; 6: 74–82.
11. Kanishcheva E.M., Fedorovich A.A. State estimation possibilities of microvasculature and walls of great vessels. Serdtse 2010; 9(1): 65–70.
12. Sandoo A., Veldhuijzen van Zanten J.J., Metsios G.S., Carroll D., Kitas G.D. Vascular function and morphology in rheumatoid arthritis: a systematic review. Rheumatology (Oxford) 2011; 50(11): 2125–2139, http://dx.doi.org/10.1093/rheumatology/ker275.
13. Gonzalez-Gay M.A., Gonzalez-Juanatey C. Inflammation, endothelial function and atherosclerosis in rheumatoid arthritis. Arthritis Res Ther 2012; 14: 122, http://dx.doi.org/10.1186/ar3891.
14. Bergholm R., Leirisalo-Repo M., Vehkavaara S., Mäkimattila   S., Taskinen M.R., Yki-Järvinen H. Impaired responsiveness to NO in newly diagnosed patients with rheumatoid arthritis. Arterioscler Thromb Vasc Biol 2002; 22: 1637–1641, http://dx.doi.org/10.1161/01.ATV.0000033516.73864.4E.
15. Vaudo G., Marchesi S., Gerli R., Allegrucci R., Giordano A., Siepi D., Pirro M., Shoenfeld Y., Schillaci G., Mannarino E. Endothelial dysfunction in young patients with rheumatoid arthritis and low disease activity. Ann Rheum Dis 2004; 63(1): 31–35, http://dx.doi.org/10.1136/ard.2003.007740.
16. Lukina G.V., Sigidin Ya.A., Pozdnyakova E.S., Aleksandrova E.N., Novikov A.A., Smirnov A.V., Glukhova S.I., Nasonov E.L. Infliximab in Russian clinical practice. Sovremennaya revmatologiya 2012; 3: 37–43.
17. Amirdzhanova V.N., Goryachev D.V., Lukina G.V., Kuzikyants K.Kh., Nasonov E.L. The Russian registry of rituximab. Analysis of the efficiency of therapy and the functional state of patients with rheumatoid arthritis. Nauchno-prakticheskaya revmatologiya 48(4): 31–40, http://dx.doi.org/10.14412/1995-4484-2010-1163.
18. Komai N., Morita Y., Sakuta T., Kuwabara A., Kashihara N. Anti-tumor necrosis factor therapy increases serum adiponectin levels with the improvement of endothelial dysfunction in patients with rheumatoid arthritis. Mod Rheumatol 2007; 17(5): 385–390, http://dx.doi.org/10.1007/s10165-007-0605-8.
19. Gonzalez-Gay M.A., Gonzalez-Juanatey C., Vazquez-Rodriguez T.R., Miranda-Filloy J.A., Llorca J. Insulin resistance in rheumatoid arthritis: the impact of the anti-TNF-alpha therapy. Ann NY Acad Sci 2010; 1193(1): 153–159, http://dx.doi.org/10.1111/j.1749-6632.2009.05287.x.
20. Bosello S., Santoliquido A., Zoli A., Di Campli C., Flore R., Tondi P., Ferraccioli G. TNF-alpha blockade induces a reversible but transient effect on endothelial dysfunction in patients with long-standing severe rheumatoid arthritis. Clin Rheumatol 2008; 27(7): 833–839, http://dx.doi.org/10.1007/s10067-007-0803-y.
21. Volkov A.V., Lineva O.G., Kuzikyants K.Kh., Lukina G.V., Nasonov E.L. Impact of rituximab therapy on endothelial function and other markers of atherosclerosisin patients with active rheumatoid arthritis. Nauchno-prakticheskaya revmatologiya 2010; 6: 31–36, http://dx.doi.org/10.14412/1995-4484-2010-820.
22. Gonzalez-Juanatey C., Llorca J., Vazquez-Rodriguez T.R., Diaz-Varela N., Garcia-Quiroga H., Gonzalez-Gay M.A. Short-term improvement of endothelial function in rituximab-treated rheumatoid arthritis patients refractory to tumor necrosis factor alpha blocker therapy. Arthr Rheum 2008; 59(12): 1821–1824, http://dx.doi.org/10.1002/art.24308.
23. Kerekes G., Soltész P., Dér H., Veres K., Szabу 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(6): 705–710, http://dx.doi.org/10.1007/s10067-009-1095-1.

Meshcherina N.S., Knyazeva L.А., Goryainov I.I., Knyazeva L.I. Vasoprotective Effects of Genetically Engineered Biologic Drugs in Patients with Rheumatoid Arthritis. Sovremennye tehnologii v medicine 2015; 7(3): 130, https://doi.org/10.17691/stm2015.7.3.18