Frances C. Hall

Rheumatoid Arthritis Is Associated With Increased Aortic Pulse-Wave Velocity, Which Is Reduced by Anti–Tumor Necrosis Factor-α 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-&agr; (TNF-&agr;) 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-&agr; 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-&agr; 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-&agr; 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.

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-&agr; 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-&agr; therapy by using 18F-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 18F-fluorodeoxyglucose uptake in comparison with patients who have stable cardiovascular disease. Anti-tumor necrosis factor-&agr; 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.

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+/TCRαβ+ 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 TGFβ1, but not IFN‐γ. 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‐γ 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.

HLA class II transgenic mice: models of the human CD4+ T‐cell immune response

Summary: This review examines the field of current HLA class II transgenic mouse models and the individual approaches applied in production of these mice. The majority of these mice have been created with the objective of obtaining a disease model with clinical features mimicking human autoimmune disease. The development process of a different type of HLA class II transgenic mice, which are designed to function as a substitute for a normal human immune system in studies of human autoantigens, is described. Several HLA‐DR4 transgenic lines with normally expressed HLA‐DR4 molecules have been produced. To obtain adequate positive selection of the HLA‐DR4‐restricted CD4+ T‐cell repertoire in these mice it is essential both to introduce a human CD4 transgene. and to delete the murine major histocompatibility complex (MHC) class II molecules. These HLA‐DR4 transgenic mice have been used to determine the immunogenic CD4+ T‐cell epitopes of several human autoantigenic proteins.

Relationship between kinetic stability and immunogenicity of HLA-DR4/peptide complexes

Immunodominant T cell epitopes from the autoantigen human cartilage glycoprotein 39 have previously been mapped in the context of HLA‐DR*0401 and *0402, using mice expressing HLA‐DR4 transgenes. We measured the dissociation rates of these epitopes from soluble recombinant DR*0401 and DR*0402 to assess the relationship between peptide/HLA‐DR4 kinetic stability and immunogenicity. Experiments were performed at endosomal pH (5.5) and at cell surface pH (7), in the absence and presence of soluble recombinant HLA‐DM (sDM). All (4/4) immunodominant peptide/HLA‐DR complexes exhibit dissociation half‐times of 1 h to several days. In contrast, most (3/4) non‐immunodominant complexes dissociate with half‐times <30 min under at least one of these conditions. Interestingly, a complex which is stable except in the presence of HLA‐DM at pH 5.5 is immunogenic only following peptide immunization, while a complex which is stable at acidic but not at neutral pH, is non‐immunogenic following either whole protein or peptide immunization. These data indicate that kinetic stability of peptide/MHC complexes in vivo is a key determinant of immunogenicity.

Inducible nitric oxide synthase activity is increased in patients with rheumatoid arthritis and contributes to endothelial dysfunction

BACKGROUND Recent in vitro studies suggest that inducible nitric oxide synthase (iNOS) activity mediates endothelial dysfunction. Rheumatoid arthritis (RA) is a chronic inflammatory condition and is associated with endothelial dysfunction and increased risk of cardiovascular disease. The aim of the study was to establish the contribution of iNOS to endothelial function. METHODS Forearm blood flow (FBF) was measured during intra-arterial infusions of acetylcholine (ACh), sodium nitroprusside (SNP), N(G)-monomethyl-l-arginine (l-NMMA) and aminoguanidine (AG) in 12 RA patients and 13 healthy control subjects. Levels of C-reactive protein (CRP) and myeloperoxidase (MPO) were assessed. FBF data are presented as mean percentage changes in the ratio (infused/control arm) of FBF + or - SEM. RESULTS FBF response to ACh was reduced in patients with RA compared to controls (179 + or - 29 v. 384 + or - 72%, respectively; P=0.01), but SNP response was not (P=0.5). FBF response to AG differed between patients and controls (-15 + or - 2% v. 13 + or - 4%, respectively; P<0.001), whereas the response to l-NMMA did not (P=0.4). In a multiple regression model log CRP, AG response and LDL were found to be independent predictors of endothelial function (R(2)=0.617, P<0.001). CONCLUSION RA patients have endothelial dysfunction and increased iNOS activity in comparison to controls. Furthermore, CRP and iNOS activity were independently associated with endothelial function. Our data demonstrates that inflammation is a key mediator in a process of endothelial dysfunction possibly via activation of iNOS and increased production of MPO.

The TRACTISS Protocol: a randomised double blind placebo controlled clinical TRial of Anti-B-Cell Therapy In patients with primary Sjögren's Syndrome

BackgroundPrimary Sjögren’s Syndrome (PSS) mainly affects women (9:1 female:male ratio) and is one of the commonest autoimmune diseases with a prevalence of 0.1 – 0.6% of adult women. For patients with PSS there is currently no effective therapy that can alter the progression of the disease. The aim of the TRACTISS study is to establish whether in patients with PSS, treatment with rituximab improves clinical outcomes.Methods/designTRACTISS is a UK multi-centre, double-blind, randomised, controlled, parallel group trial of 110 patients with PSS. Patients will be randomised on a 1:1 basis to receive two courses of either rituximab or placebo infusion in addition to standard therapy, and will be followed up for up to 48 weeks. The primary objective is to assess the extent to which rituximab improves symptoms of fatigue and oral dryness. Secondary outcomes include ocular dryness, salivary flow rates, lacrimal flow, patient quality of life, measures of disease damage and disease activity, serological and peripheral blood biomarkers, and glandular histology and composition.DiscussionThe TRACTISS trial will provide direct evidence as to whether rituximab in patients with PSS leads to an improvement in patient symptoms and a reduction in disease damage and activity.Trial registrationUKCRN Portfolio ID:9809 ISRCTN65360827.

Randomized controlled trial of rituximab and cost-effectiveness analysis in treating fatigue and oral dryness in primary Sjogren's Syndrome

To investigate whether rituximab, an anti–B cell therapy, improves symptoms of fatigue and oral dryness in patients with primary Sjögrens syndrome (SS).

Autoreactivity versus autoaggression: a different perspective on human autoantigens

Antigen-specific B and T cell responses against myelin basic protein, as well as responses against beta-islet-cells or joint tissue, are commonly found both in patients with autoimmune disease and in normal control subjects with disease-associated HLA-DR/DQ alleles. Thus, autoreactive immune responses are not disease-specific; however, the presence of certain autoantibodies may have prognostic value and may aid in disease management.

[Accepted Manuscript] Randomized Controlled Trial of Rituximab and cost-effectiveness analysis in treating fatigue and oral dryness in primary Sjogren's Syndrome.

To investigate whether rituximab, an anti–B cell therapy, improves symptoms of fatigue and oral dryness in patients with primary Sjögrens syndrome (SS).