Objective. Gene-expression studies have demonstrated increased expression of interferon (IFN)-inducible genes (IFIGs) in peripheral blood mononuclear cells (PBMCs) of many patients with systemic lupus erythematosus (SLE), with a predominant effect of type I IFN. This study examined the hypothesis that increased disease severity and activity, as well as distinct autoantibody specificities, characterize SLE patients with activation of the type I IFN pathway.Methods. Freshly isolated PBMCs from 77 SLE patients, 22 disease controls, and 28 healthy donors were subjected to real-time polymerase chain reaction for 3 IFIGs that are preferentially induced by IFN␣, and the data were used to derive IFN␣ scores for all individuals. Expression of IFIGs was significantly higher in SLE patients compared with disease controls or healthy donors. SLE patients with high and low IFN␣ scores were compared for clinical manifestations of disease, disease severity, disease activity, serologic features, and potential confounders, by bivariate and multivariate analyses.Results. SLE patients with a high IFN␣ score had a significantly higher prevalence of renal disease, a greater number of American College of Rheumatology criteria for SLE, and a higher Systemic Lupus International Collaborating Clinics damage index (SDI) score than did SLE patients with low IFN␣ scores. Patients with high scores showed increased disease activity, as measured by lower C3 levels, hemoglobin levels, absolute lymphocyte counts, and albumin levels, and a higher anti-double-stranded DNA (dsDNA) titer, erythrocyte sedimentation rate, and SLE Disease Activity Index 2000 score. The presence of antibodies specific for Ro, U1 RNP, Sm, and dsDNA, but not phospholipids, was significantly associated with a high IFN␣ score. Logistic regression analysis confirmed that renal disease, higher SDI scores, low complement levels, and presence of anti-RNA binding protein (RBP) autoantibodies were associated with a high IFN␣ score.Conclusion. Activation of the IFN␣ pathway defines a subgroup of SLE patients whose condition is characterized by increased disease severity, including renal disease, increased disease activity, reflected in complement activation, and autoreactivity to RBP.Systemic lupus erythematosus (SLE) is characterized by extensive defects of the immune system that culminate in the production of autoantibodies reactive with intracellular particles, consisting of nucleic acids and nucleic acid binding proteins. These autoantibodies contribute to the pathologic process underlying the protean clinical manifestations, ranging from skin rash and arthralgias to involvement of major organ systems, and often leading to renal, neurologic, or cardiovascular morbidity. The diversity of serologic and clinical manifestations observed among SLE patients presents important challenges in the diagnosis and management of the disease. In addition, this heterogeneity has hampered the ability of clinical trials to test the efficacy of promising therapeutic agents. Characterization of c...

Objective. To study the contribution of interferon-␣ (IFN␣) and IFN␥ to the IFN gene expression signature that has been observed in microarray screens of peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE).Methods. Quantitative real-time polymerase chain reaction analysis of healthy control PBMCs was used to determine the relative induction of a panel of IFN-inducible genes (IFIGs) by IFN␣ and IFN␥. PBMCs from 77 SLE patients were compared with those from 22 disease controls and 28 healthy donors for expression of IFIGs.Results. Expression of IFN␣-inducible genes was significantly higher in SLE PBMCs than in those from disease controls or healthy donors. The level of expression of all IFIGs in PBMCs from SLE patients with IFN␣ pathway activation correlated highly with the inherent responsiveness of those genes to IFN␣, suggesting coordinate activation of that cytokine pathway. Expression of genes preferentially induced by IFN␥ was not significantly increased in SLE PBMCs compared with control PBMCs. IFN␣-regulated gene-inducing activity was detected in some SLE plasma samples.Conclusion. The coordinate activation of IFN␣-induced genes is a characteristic of PBMCs from many SLE patients, supporting the hypothesis that IFN␣ is the predominant stimulus for IFIG expression in lupus.

Objective To compare the clinical, angiographic, neurocognitive, and quality of life outcomes of off-pump coronary artery bypass surgery with conventional coronary artery bypass grafting surgery using cardiopulmonary bypass. Design Randomised controlled clinical trial. Setting Tertiary cardiothoracic centre in Middlesex, England. Participants 168 patients (27 women) requiring primary isolated coronary artery bypass grafting surgery. Interventions Patients were randomised to conventional coronary artery bypass grafting surgery using cardiopulmonary bypass (n = 84) or off-pump coronary artery bypass surgery (n = 84), carried out by one surgeon. Angiographic examination was carried out at three months postoperatively. Neurocognitive tests were carried out at baseline and at six weeks and six months postoperatively. Main outcome measures Clinical outcome, graft patency at three months, neurocognitive function at six weeks and six months, and health related quality of life. Results Graft patency was evaluated by angiography in 151 (89.9%) patients and was similar between the cardiopulmonary bypass and off-pump groups (risk difference − 1%, 95% confidence interval − 5% to 4%), with the off-pump group considered the treatment group. Patients in the off-pump group required fewer blood transfusions (1.7 units v 1.0 unit, P = 0.02), shorter duration of mechanical ventilation (7.7 hours v 3.9 hours, P = 0.03), and shorter hospital stay (10.8 days v 8.9 days). Scores for neurocognitive function showed a significant difference in three memory subtests at six weeks and two memory subtests at six months in favour of the off-pump group. Conclusions Patients who underwent off-pump coronary artery bypass surgery showed similar patency of grafts, better clinical outcome, shorter hospital stay, and better neurocognitive function than patients who underwent conventional coronary artery bypass grafting surgery using cardiopulmonary bypass.