Factors correlated with improvement of endothelial dysfunction during rituximab therapy in patients with rheumatoid arthritis

Abstract

Maurizio Benucci,1 Gianantonio Saviola,2 Mariangela Manfredi,3 Piercarlo Sarzi-Puttini,4 Fabiola Atzeni41Rheumatology Unit, Department of Internal Medicine, Hospital di S Giovanni di Dio, Azienda Sanitaria di Firenze, Florence, Italy; 2Rheumatology and Rehabilitation Unit, Salvatore Maugeri Foundation IRCCS, Mantua, Italy; 3Immunology and Allergology Laboratory Unit, Hospital di S Giovanni di Dio, Azienda Sanitaria di Firenze, Florence, Italy; 4Rheumatology Unit, Sacco University Hospital, Milan, ItalyAbstract: Increased cardiovascular mortality has been associated with rheumatoid arthritis (RA). There are reports indicating that tumor necrosis factor (TNF) blockers may exert favorable but transient effects on the lipid profile, flow-mediated vasodilatation (FMD) of the brachial artery, and the common carotid intima–media thickness (ccIMT) in RA. We evaluated 38 RA patients (33 females and five males with a mean age of 66.7 ± 10.2 years) who were unresponsive to TNF blockers. The patients received one or more courses of two rituximab (RTX) 1000 mg infusions. Disease activity was evaluated at each visit. Investigations included erythrocyte sedimentation rate, C-reactive protein (CRP) levels, the 28-joint disease activity score (DAS28), DAS28CRP, the Health Assessment Questionnaire, the FMD percent change from baseline (FMD%), and the postnitroglycerine endothelium-independent vasodilatation. In comparison with the baseline, there was a significant improvement in clinical variables and acute-phase reactants 24 months after the start of RTX therapy. There was also a major improvement in FMD% (from baseline 5.24 ± 1.12 to 5.43 ± 1.16; P = -0.03) and a smaller change in the ccIMT (from baseline 0.69 ± 0.16 to 0.67 ± 0.12 mm P = 0.25). Univariate analysis showed that global health (P < 0.034) was associated with the improvement in FMD%. Multivariate models showed that GH (odds ratio [OR] 0.91; 95% CI: 0.99–0.83; P = 0.032), CD19+ cells (OR 1.024; 95% CI: 1.045–1.003; P = 0.025), IgM (OR 1.025; 95% CI: 1.045–1.004; P = 0.016), and interleukin (IL)-8 (OR 0.487; 95% CI: 0.899–0.264; P = 0.021) were statistically associated with the improvement of FMD%, and that IL-8 (OR 0.717; 95% CI: 0.926–0.555; P = 0.018) was also statistically associated with improvement of ccIMT. The findings of the study confirm that RTX reduces the progression of accelerated atherosclerosis in patients with RA. They also show that improvement in CD19+ cells, IgM and GH after treatment are statistically associated with the improvement of FMD%, and that improvement in IL-8 levels after treatment is statistically associated with improved FMD% and with decrease in the ccIMT.Keywords: rituximab, rheumatoid arthritis, endothelial dysfunction