TNF-alpha blockade induces a reversible but transient effect on endothelial dysfunction in patients with long-standing severe rheumatoid arthritis (original) (raw)
Related papers
Arthritis and Rheumatism, 2004
ObjectiveCardiovascular disease is the major cause of excessive mortality in rheumatoid arthritis (RA). Atherosclerosis and RA share similar inflammatory mechanisms that include involvement of tumor necrosis factor α (TNFα). Anti-TNFα antibody improved endothelial function in RA patients after a 12-week treatment. The aim of the present study was to assess whether improvement of endothelial function is still effective in long-term infliximab-treated RA patients.Cardiovascular disease is the major cause of excessive mortality in rheumatoid arthritis (RA). Atherosclerosis and RA share similar inflammatory mechanisms that include involvement of tumor necrosis factor α (TNFα). Anti-TNFα antibody improved endothelial function in RA patients after a 12-week treatment. The aim of the present study was to assess whether improvement of endothelial function is still effective in long-term infliximab-treated RA patients.MethodsSeven RA patients (5 women; age range 25–73 years) were studied. They had been treated with infliximab for at least 1 year and were currently being treated with this drug every 8 weeks. Endothelial-dependent and independent vasodilatation were measured by brachial ultrasonography.Seven RA patients (5 women; age range 25–73 years) were studied. They had been treated with infliximab for at least 1 year and were currently being treated with this drug every 8 weeks. Endothelial-dependent and independent vasodilatation were measured by brachial ultrasonography.ResultsFollowing infliximab infusion, a rapid increase in the percentage of endothelial-dependent vasodilatation was found in all patients (mean ± SD 9.4 ± 5.5% 2 days postinfusion compared with 2.8 ± 2.5% 2 days before infusion). However, values returned to baseline by 4 weeks after infusion. There were no differences in the percentage of endothelial-independent vasodilatation prior to and after infusion. A decrease in the individual disease activity score for each patient was observed at day 7 postinfusion (P = 0.02).Following infliximab infusion, a rapid increase in the percentage of endothelial-dependent vasodilatation was found in all patients (mean ± SD 9.4 ± 5.5% 2 days postinfusion compared with 2.8 ± 2.5% 2 days before infusion). However, values returned to baseline by 4 weeks after infusion. There were no differences in the percentage of endothelial-independent vasodilatation prior to and after infusion. A decrease in the individual disease activity score for each patient was observed at day 7 postinfusion (P = 0.02).ConclusionOur study confirms an active but transient effect of infliximab on endothelial function in RA patients treated periodically with this drug. It may support long-term use of drugs that block TNFα function to reduce the high incidence of cardiovascular complications in RA.Our study confirms an active but transient effect of infliximab on endothelial function in RA patients treated periodically with this drug. It may support long-term use of drugs that block TNFα function to reduce the high incidence of cardiovascular complications in RA.
Arthritis Care & Research, 2004
Objective. Cardiovascular disease is the major cause of excessive mortality in rheumatoid arthritis (RA). Atherosclerosis and RA share similar inflammatory mechanisms that include involvement of tumor necrosis factor ␣ (TNF␣). Anti-TNF␣ antibody improved endothelial function in RA patients after a 12-week treatment. The aim of the present study was to assess whether improvement of endothelial function is still effective in long-term infliximab-treated RA patients. Methods. Seven RA patients (5 women; age range 25-73 years) were studied. They had been treated with infliximab for at least 1 year and were currently being treated with this drug every 8 weeks. Endothelial-dependent and independent vasodilatation were measured by brachial ultrasonography.
2002
Background-Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis and increased cardiovascular morbidity and mortality. Striking similarities exist in the inflammatory and immunologic response in RA and atherosclerosis. Indeed, adhesion molecules and cytokines, tumor necrosis factor (TNF)-␣ in particular, are key mediators of joint inflammation and of vascular dysfunction and progression of atherosclerotic vascular disease. Hence, the aim of the present study was to assess the effect of chronic antiinflammatory treatment with the anti-TNF-␣ antibody infliximab on disease activity and endothelial function in patients with active RA. Methods and Results-Eleven RA patients (mean age 46Ϯ5 years; disease duration 9Ϯ2 years) with high disease activity despite treatment with stable doses of methotrexate (Յ25 mg/wk) and prednisone (Յ10 mg/d) were investigated. Clinical status and endothelium-dependent and-independent vasodilation of the brachial artery as assessed by high-resolution ultrasound were measured before and after 12 weeks of infliximab therapy. Flow-mediated vasodilation improved from 3.2Ϯ0.4% to 4.1Ϯ0.5% (Pϭ0.018), whereas endothelium-independent vasodilation with nitroglycerin and baseline diameter remained unchanged (13.6Ϯ1.2% versus 12.8Ϯ1.4%, Pϭ0.98, and 3.74Ϯ0.15 versus 3.66Ϯ0.11 mm, Pϭ0.54, respectively). Disease activity score (DAS28) was significantly reduced, from 5.6Ϯ0.3 to 3.5Ϯ0.6 (Pϭ0.002). Erythrocyte sedimentation rate and C-reactive protein were lowered from 34Ϯ7 to 19Ϯ5 mm/h (Pϭ0.04) and from 38Ϯ11 to 15Ϯ10 mg/L (Pϭ0.08), respectively. Conclusions-This is the first study to show that anti-TNF-␣ treatment improves endothelial function in RA. The data suggest that in RA, endothelial dysfunction is part of the disease process and is mediated by TNF-␣. (Circulation. 2002; 106:2184-2187.
Scandinavian Journal of Rheumatology, 2009
Objectives: Vascular endothelial function and common carotid artery intima-medial thickness (CCA-IMT) are well-established surrogate markers for early atherosclerotic disease, which accounts for 30-40% of excess mortality in rheumatoid arthritis (RA) patients. Our aim was to investigate whether long-term treatment with anti-tumour necrosis factor (TNF)a agents can modulate endothelial function and CCA-IMT. Methods: Twelve patients with RA (mean age 54.8¡15 years) on anti-TNFa treatment (seven adalimumab, five infliximab) due to uncontrolled disease activity, with mean Disease Activity Score (DAS28) 5.7 (range 4.6-6.9) despite disease-modifying anti-rheumatic drugs (DMARDs), were studied prospectively. Patients were assessed at baseline and after 3 and 18 months for endothelial-dependent vasodilatation, assessed by flow-mediated vasodilatation (FMD), endothelial-independent vasodilatation and CCA-IMT. RA disease activity and response to therapy were assessed by the DAS28 index. Results: After 18 months of treatment, 67% of the patients were responders according to European League Against Rheumatism (EULAR) response criteria. Anti-TNFa treatment improved FMD (from 7¡4.3% to 11.1¡3.8%, p50.026) whereas CCA-IMT did not change significantly [from 0.67 (0.4-1) to 0.68 (0.39-1.2) mm; mean change 0.01 (20.06 to 0.08) mm]. Endothelial-independent vasodilatation remained stable (20.4¡7.3% to 22.9¡6.5%, p50.4). Conclusions: In this small cohort of patients with RA and no clinically overt cardiovascular disease (CVD), after 18 months of treatment with anti-TNFa agents, endothelial function improved significantly while CCA-IMT remained stable. Longitudinal studies using more patients are needed to determine the clinical significance of these findings in relation to the risk of atherosclerosis.
Biologics: Targets and Therapy, 2013
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.
Life Sciences, 2006
Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality, which may be attenuated by anti-inflammatory treatment. Endothelial progenitor cells (EPCs) have the ability to differentiate into mature endothelium and have a potentially reparative role protecting against ischemia and atherosclerosis. Objective: To investigate the effect of treatment with infliximab on the number and functional capacity of endothelial progenitor cells (EPCs) in patients with RA, as a possible mechanism for reducing cardiovascular morbidity in this disorder. Methods: Patients: Active seropositive RA patients (N = 14) considered candidates for starting infliximab treatment, were recruited. Assessment, based on DAS-28, was performed before treatment and 14 days later. Peripheral blood mononuclear cells were isolated and EPC numbers evaluated by the colony-forming unit (CFU) method. Endothelial phenotyping of CFU was performed by immunofluorescence employing antibodies to Tie-2 VEGF-receptor 2, and CD31. EPC Functional properties were evaluated by fibronectin adherance. Results: A significant 33.4% increase (p b 0.001) in EPC levels was observed after infliximab. A 60% increase was noted in the EPC differentiation scale, (p b 0.002) while a 37.6% increase was observed in mean EPC adhesion (p b 0.001). These changes were associated with a 17.5% decrease in the DAS-28 (p b 0.0001). A significant correlation was observed between the clinical response, reflected by changes in DAS-28 and the degree of increase in EPC CFUs. Conclusion: A single dose of infliximab improved the number and functional properties of EPCs, in parallel with an early clinical effect, suggesting a possible mechanism by which anti-inflammatory treatment may reduce cardiovascular risk in RA patients.
Arthritis & Rheumatism, 2008
Objective. Cardiovascular disease is the major cause of excessive mortality in rheumatoid arthritis (RA) and endothelial dysfunction plays a key role in atherosclerosis. The aim of the present study was to assess whether rituximab therapy was able to improve endothelial function in RA patients refractory to tumor necrosis factor ␣ (TNF␣) blockers. Methods. Six consecutive RA patients (5 women; age range 55-79 years) with active disease refractory to TNF␣ inhibitor therapy were studied. Patients received intravenous rituximab (1 course, consisting of 2 infusions of 1,000 mg each separated by 2 weeks). Flow-mediated endothelium-dependent vasodilatation (FMD%) and endothelium-independent vasodilatation (postnitroglycerin) were measured at day 0 prior to the first rituximab infusion, at week 2 (before the second infusion), and at month 6. Results. At week 2, a dramatic increase in FMD% values was observed in all patients (mean ؎ SD 7.02 ؎ 2.31%, median 7.29%, range 3.2-9.75%) compared with those observed before the first infusion (mean ؎ SD 3.35 ؎ 1.58%, median 3.04%, range 1.69 -5.89%). In addition, at month 6, FMD% values in all patients (mean ؎ SD 7.66 ؎ 1.73%, median 7.64%, range 5.61-9.98%) were greater than those found before the first infusion (P ؍ 0.03). The dramatic improvement of FMD% was associated with a significant decrease in C-reactive protein level and Disease Activity Score in 28 joints. Conclusion. Our study demonstrates an active effect of rituximab on endothelial function in RA patients refractory to TNF␣ blockers.
Rheumatology, 2005
Vascular pathology, in the form of angiogenesis, is important in the perpetuation of rheumatoid arthritis (RA) and, in the form of endothelial dysfunction, contributes to associated cardiovascular co-morbidity. Emerging evidence suggests that TNFα blockade may modify vascular pathology in RA. Serum concentrations of vascular endothelial growth factor (VEGF), a potent endothelial cell-specific growth factor that is up-regulated by pro-inflammatory cytokines and by hypoxia, are elevated in RA and correlate with disease ...