Anti-tumor necrosis factor-α therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a systemic inflammatory condition associated with increased cardiovascular risk. This is not fully explained by traditional risk factors, but direct vascular inflammation and aortic stiffening may play a role. We hypothesized that patients with RA exhibit aortic inflammation, which can be reversed with anti-tumor necrosis factor-α therapy and correlates with aortic stiffness reduction. METHODS AND RESULTS: Aortic inflammation was quantified in 17 patients with RA, before and after 8 weeks of anti-tumor necrosis factor-α therapy by using (18)F-fluorodeoxyglucose positron emission tomography with computed tomography coregistration. Concomitantly, 34 patients with stable cardiovascular disease were imaged as positive controls at baseline. Aortic fluorodeoxyglucose target-to-background ratios (TBRs) and aortic pulse wave velocity were assessed. RA patients had higher baseline aortic TBRs in comparison with patients who have cardiovascular disease (2.02±0.22 versus 1.74±0.22, P=0.0001). Following therapy, aortic TBR fell to 1.90±0.29, P=0.03, and the proportion of inflamed aortic slices (defined as TBR >2.0) decreased from 50±33% to 33±27%, P=0.03. Also, TBR in the most diseased segment of the aorta fell from 2.51±0.33 to 2.05±0.29, P<0.0001. Treatment also reduced aortic pulse wave velocity significantly (from 9.09±1.77 to 8.63±1.42 m/s, P=0.04), which correlated with the reduction of aortic TBR (R=0.60, P=0.01). CONCLUSIONS: This study demonstrates that RA patients have increased aortic (18)F-fluorodeoxyglucose uptake in comparison with patients who have stable cardiovascular disease. Anti-tumor necrosis factor-α therapy reduces aortic inflammation in patients with RA, and this effect correlates with the decrease in aortic stiffness. These results suggest that RA patients exhibit a subclinical vasculitis, which provides a mechanism for the increased cardiovascular disease risk seen in RA.

Local activation and systemic dysregulation of T lymphocytes in Sjögren's syndrome.

T cells are implicated in both local and systemic pathophysiology of primary Sjögren's syndrome (PSS). Lymphocytic infiltrates in exocrine glands are dominated by CD4+ T cells, some contributing to ectopic lymphoid tissue, others, unusually, exhibiting cytotoxic potential. Cytokine secretion patterns are complex, with Th1 and Th17 components implicated in pathology. Circulating T cells exhibit phenotypes consistent with hyperactivation, cytokine imbalance, and homeostatic alterations; CD4 lymphopenia is recognized as a risk factor for developing lymphoma. Evidence of oligoclonal expansion is found locally and systemically. Functional alterations (e.g. cytokine secretion profile, migratory potential, target cell interactions) are less clearly defined. Attempts at T cell-targeted therapy of PSS have been limited, although therapy targeted at other arms of the immune response may also affect T cells. A better understanding of T-cell dysregulation in PSS is required in order to understand its contribution to disease, aid prognosis, and improve therapeutic interventions aimed at this aspect of the disease.

Rheumatoid arthritis is associated with increased aortic pulse-wave velocity, which is reduced by anti-tumor necrosis factor-alpha therapy.

BACKGROUND: Rheumatoid arthritis (RA) is associated with increased cardiovascular risk, which is not explained by traditional cardiovascular risk factors but may be due in part to increased aortic stiffness, an independent predictor of cardiovascular mortality. In the present study, our aim was to establish whether aortic stiffness is increased in RA and to investigate the relationship between inflammation and aortic stiffness. In addition, we tested the hypothesis that aortic stiffness could be reduced with anti-tumor necrosis factor-alpha (TNF-alpha) therapy. METHODS AND RESULTS: Aortic pulse-wave velocity (PWV), augmentation index, and blood pressure were measured in 77 patients with RA and in 142 healthy individuals. Both acute and chronic inflammatory measures and disease activity were determined. The effect of anti-TNF-alpha therapy on PWV and endothelial function was measured in 9 RA patients at 0, 4, and 12 weeks. Median (interquartile range) aortic PWV was significantly higher in subjects with RA than in control subjects (8.35 [7.14 to 10.24] versus 7.52 [6.56 to 9.18] m/s, respectively; P = 0.005). In multiple regression analyses, aortic PWV correlated independently with age, mean arterial pressure, and log-transformed C-reactive protein (R2 = 0.701; P < 0.0001). Aortic PWV was reduced significantly by anti-TNF-alpha therapy (8.82+/-2.04 versus 7.94+/-1.86 versus 7.68+/-1.56 m/s at weeks 0, 4, and 12, respectively; P < 0.001); concomitantly, endothelial function improved. CONCLUSIONS: RA is associated with increased aortic stiffness, which correlates with current but not historical measures of inflammation, suggesting that increased aortic stiffness may be reversible. Indeed, anti-TNF-alpha therapy reduced aortic stiffness to a level comparable to that of healthy individuals. Therefore, effective control of inflammation may be of benefit in reducing cardiovascular risk in patients with RA.

Autoreactive human peripheral blood CD8+ T cells with a regulatory phenotype and function.

Despite substantial advances in our understanding of CD4+ CD25+ regulatory T cells, a possible equivalent regulatory subset within the CD8+ T cell population has received less attention. We now describe novel human CD8+/TCR alphabeta+ T cells that have a regulatory phenotype and function. We expanded and cloned these cells using autologous LPS-activated dendritic cells. The clones were not cytolytic, but responded in an autoreactive HLA class I-restricted fashion, by proliferation and production of IL-4, IL-5, IL-13 and TGFbeta1, but not IFN-gamma. They constitutively expressed CD69 and CD25 as well as molecules associated with CD4+ CD25+ regulatory T cells, including cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and Foxp3. They suppressed IFN-gamma production and proliferation by CD4+ T cells in vitro in a cell contact-dependent manner, which could be blocked using a CTLA-4-specific mAb. They were more readily isolated from patients with ankylosing spondylitis and may therefore be up-regulated in response to inflammation. We suggest that they are the CD8+ counterparts of CD4+ CD25+ regulatory T cells. They resemble recently described CD8+ regulatory cells in the rat that were able to abrogate graft-versus-host disease. Likewise, human HLA-restricted CD8+ regulatory T cells that can be cloned and expanded in vitro may have therapeutic applications.