Objectives: Abatacept is the only agent currently approved to treat rheumatoid arthritis (RA) that targets the co-stimulatory signal required for full T-cell activation. No studies have been conducted on its effect on the synovium, the primary site of pathology. The aim of this study was to determine the synovial effect of abatacept in patients with RA and an inadequate response to tumour necrosis factor alpha (TNFa) blocking therapy. Methods: This first mechanistic study incorporated both dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and arthroscopy-acquired synovial biopsies before and 16 weeks after therapy, providing tissue for immunohistochemistry and quantitative real-time PCR analyses. Results: Sixteen patients (13 women) were studied; all had previously failed TNFa-blocking therapy. Fifteen patients completed the study. Synovial biopsies showed a small reduction in cellular content, which was significant only for B cells. The quantitative PCR showed a reduction in expression for most inflammatory genes (Wald statistic of p,0.01 indicating a significant treatment effect), with particular reduction in IFNc of 252% (95% CI 273 to 215, p,0.05); this correlated well with MRI improvements. In addition, favourable changes in the osteoprotegerin and receptor activator of nuclear factor kappa B levels were noted. DCE-MRI showed a reduction of 15-40% in MRI parameters. Conclusion: These results indicate that abatacept reduces the inflammatory status of the synovium without disrupting cellular homeostasis. The reductions in gene expression influence bone positively and suggest a basis for the recently demonstrated radiological improvements that have been seen with abatacept treatment in patients with RA.Understanding of disease pathogenesis in rheumatoid arthritis (RA) has led to novel approaches in targeted drug development. Despite the demonstrated success of tumour necrosis factor (TNF) antagonists, up to 50% of patients have an inadequate response to TNF blockade therapy. [1][2][3][4] This observation has fuelled the search for alternative targeted approaches.Abatacept is a recombinant fusion protein comprising the extracellular domain of human cytotoxic T-lymphocyte antigen 4 and a fragment of the Fc domain of human IgG1. It acts by competing with CD28 for binding to CD80/CD86, modulating the second co-stimulatory signal required for full T-cell activation. 6Abatacept has demonstrated benefits in patients with RA and an inadequate response to methotrexate 7 that are comparable to those observed in studies of TNF blockade, with efficacy also confirmed in the particularly resistant group of patients who have failed TNF blockade therapy. 8There is limited information on the impact of costimulation modulation on the synovium. The objective of this first mechanistic study was to determine the synovial effect of abatacept in a TNF antagonist-resistant group of patients. A novel and validated method of gene expression analysis was employed in combination with immunohistochemistry to eval...
Background Pulse oximeter performance is degraded by motion artifacts and low perfusion. Manufacturers developed algorithms to improve instrument performance during these challenges. There have been no independent comparisons of these devices. Methods We evaluated the performance of four pulse oximeters (Masimo Radical-7, USA; Nihon Kohden OxyPal Neo, Japan; Nellcor N-600, USA; and Philips Intellivue MP5, USA) in 10 healthy adult volunteers. Three motions were evaluated: tapping, pseudorandom, and volunteer-generated rubbing, adjusted to produce photoplethsmogram disturbance similar to arterial pulsation amplitude. During motion, inspired gases were adjusted to achieve stable target plateaus of arterial oxygen saturation (SaO2) at 75%, 88%, and 100%. Pulse oximeter readings were compared with simultaneous arterial blood samples to calculate bias (oxygen saturation measured by pulse oximetry [SpO2] − SaO2), mean, SD, 95% limits of agreement, and root mean square error. Receiver operating characteristic curves were determined to detect mild (SaO2 < 90%) and severe (SaO2 < 80%) hypoxemia. Results Pulse oximeter readings corresponding to 190 blood samples were analyzed. All oximeters detected hypoxia but motion and low perfusion degraded performance. Three of four oximeters (Masimo, Nellcor, and Philips) had root mean square error greater than 3% for SaO2 70 to 100% during any motion, compared to a root mean square error of 1.8% for the stationary control. A low perfusion index increased error. Conclusions All oximeters detected hypoxemia during motion and low-perfusion conditions, but motion impaired performance at all ranges, with less accuracy at lower SaO2. Lower perfusion degraded performance in all but the Nihon Kohden instrument. We conclude that different types of pulse oximeters can be similarly effective in preserving sensitivity to clinically relevant hypoxia.
These results suggest that semiquantitative synovitis scores are valid and will enable feasible evaluation of the synovium in OA cohorts.
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