Systemic Lupus Erythematosus (SLE) Therapy: The Old and the New.

Despite recent improvements in the treatment of systemic lupus erythematosus (SLE), disease activity, comorbidities and drug toxicity significantly contribute to the risk of progressive irreversible damage accrual and increased mortality in patients with this chronic disease. Moreover, even lupus patients in remission often report residual symptoms, such as fatigue, which have a considerable impact on their health-related quality of life. In recent decades, SLE treatment has moved from the use of hydroxychloroquine, systemic glucocorticosteroids and conventional immunosuppressive drugs to biologic agents, of which belimumab is the first and only biologic agent approved for the treatment for SLE to date. Novel therapies targeting interferons, cytokines and their receptors, intracellular signals, plasma cells, T lymphocytes and co-stimulatory molecules are being evaluated. In the context of a holistic approach, growing evidence is emerging of the importance of correct lifestyle habits in the management of lupus manifestations and comorbidities. The aim of this paper is to provide an overview of current pharmacological and non-pharmacological treatment options and emerging therapies in SLE.

Both flow-mediated dilation and constriction are associated with changes in blood flow and shear stress: Two complementary perspectives on endothelial function.

INTRODUCTION: Flow-mediated dilation (FMD) quantifies endothelium-dependent vasomotor responses to short-term increases in blood flow. Low-flow mediated vasoconstriction (L-FMC) has been more recently introduced as additional measure of endothelial function, and its relationship with changes in blood flow, cardiovascular risk factors and FMD ha∧s been less well characterized. MATERIALS AND METHODS: We evaluated radial artery FMD and L-FMC along with the changes in blood flow and shear rate/stress in 584 patients with known or suspected coronary artery disease (72.9% men, mean age 67+/-11 years). Baseline blood flow and shear rate showed a modest association with radial artery FMD and L-FMC (R2 = 0.04 and R2 = 0.02, P < 0.0001). Resting diameter showed a stronger association with FMD but not with L-FMC (R2 = 0.11, P < 0.0001 and R2 = 0.005, P = 0.09). Analysis with generalized additive models showed that age, sex and presence and extent of coronary artery disease were strongly related to both endothelial function measures (P < 0.001 for both), but they explained only 12.4% and 10.1% of the variance in L-FMC and FMD. When the corresponding changes in blood flow were added to these statistical models, the % of variance explained raised to 20.4% and 17.7% for L-FMC and FMD. L-FMC was a strong predictor of FMD even after correction for the changes in blood flow. DISCUSSION: Changes in blood flow are the most important determinants of both L-FMC and FMD. These observations support the concept that both FMD and L-FMC measure endothelium-dependent, shear-induced, vasomotion.

Genetics and pathophysiology of granulomatosis with polyangiitis (GPA) and its main autoantigen proteinase 3.

Granulomatosis with polyangiitis (GPA) is a severe autoimmune disease and one of the small vessel anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Although its etiology and pathophysiology are still widely unknown, it is accepted that infections, environmental factors, epigenetic modifications, and a genetic predisposition provide the basis for this systemic disorder. GPA typically evolves into two phases: an initial phase characterized by ear, nose and throat (ENT) manifestations, such as chronic sinusitis and otitis, ulceration of the oral cavity and pharynx, as well as pulmonary nodules and a severe generalized phase, defined by the occurrence of rapidly progressive glomerulonephritis, pulmonary hemorrhage, and arthritis. ANCAs, directed against the neutrophilic enzymes proteinase 3 and myeloperoxidase, are present in up to 90% of the affected patients in the systemic phase. As the humoral immunity is predominantly directed against neutrophilic antigens, it is apparent that neutrophils play a critical role in GPA both as target and effector cells. Although GPA pathogenesis is not well known, some susceptibility genes and loci have been identified by candidate gene approaches, genome-wide association studies, and meta-analyses, as well as familial association studies. Such genes are CTLA4, PTPN22, COL11A2, SERPINA1, and the MHC class II gene cluster. This review highlights the clinical, pathophysiological, and genetic background of GPA and aims to give an overview of recent efforts to identify GPA susceptibility genes. We point out the genetic basis of the main autoantigen PR3 and why it is so difficult to establish a murine GPA model.

Evidence of a weak correlation between peripheral endothelial function measures and carotid intima-media thickness.

Previous studies from our and other laboratories have demonstrated the existence of a clear relationship between different measures of endothelial function and the extent of coronary atherosclerosis. The relationship between endothelial function and carotid intima-media thickness has not been extensively investigated. Endothelial function using radial artery flow-mediated constriction (L-FMC) and dilation (FMD) was assessed in 513 consecutive patients undergoing diagnostic coronary angiography. Intima-media thickness of both carotid arteries was also measured. IMT was greater in patients with diabetes, males, those with body mass index >30, and in those older than 65 years (all p < 0.05). There was a strong correlation between age and IMT (p < 0.0001). Hypercholesterolemia and a family history for cardiovascular disease had no impact on IMT. In contrast, the relationship between either L-FMC or FMD and IMT was weak at best (p = 0.008 for the relationship between L-FMC and IMT, p = 0.13 for the relationship between FMD and IMT). There was a positive correlation between IMT and resting radial artery diameter (p = 0.008). IMT increased with the extent of coronary artery disease, but this trend did not reach statistical significance (p = 0.07). Resting (L-FMC), but not recruitable (FMD) endothelial function correlates with the extent of subclinical carotid atherosclerosis. This correlation is however weaker in comparison to that with age.

Endothelial function and hemorheological parameters modulate coronary blood flow in patients without significant coronary artery disease.

BACKGROUND: Coronary (micro)vascular resistance is regulated by the complex interplay of several factors. Two potentially important determinants include endothelial function and the rheological properties of blood. However, their impact on the control of the coronary resistance vasculature is poorly understood. METHODS: The corrected Thrombolysis In Myocardial Infarction frame count (TIMIfc, an index of coronary flow velocity), conduit artery endothelial function, intima-media thickness of the common carotid artery and complete blood counts were measured in 145 patients undergoing elective coronary angiography. Patients with obstructive coronary artery disease or systemic conditions thought to be associated with microvascular disease were excluded from the analysis. RESULTS: There was a strong correlation between the TIMIfc measured in the three main coronary artery distributions (R values between 0.71 and 0.85, P < 0.00001). The TIMIfc was higher in males (P < 0.05), but there was no association with traditional risk factors for coronary artery disease (all P > 0.1). There was a correlation between TIMIfc and L-FMC, a parameter of resting endothelial function (R = 0.33, P < 0.0005). TIMIfc also correlated with mean platelet volume (a marker of platelet activation, R = 0.33, P < 0.001), and hematocrit (R = 0.33, P = 0.0002). There was no correlation between TIMIfc and carotid intima-media thickness and the degree of coronary atherosclerosis. Logistic regression analysis showed that L-FMC and hemorheological variables may explain as much as 19% of the variability in TIMIfc. CONCLUSIONS: Resting peripheral endothelial function, as well as parameters of platelet function, correlate with coronary TIMIfc. These data emphasize the existence of an association between endothelial function, hemorheological variables and coronary blood flow velocity.

Endothelial function assessment: flow-mediated dilation and constriction provide different and complementary information on the presence of coronary artery disease.

AIMS: A number of risk factors for atherosclerosis have been identified, but it remains difficult, on an individual patient basis, to predict how these factors interact in determining the development of coronary artery disease (CAD). It also remains unclear whether the study of endothelial function provides information that is additive to that of traditional risk factors. METHODS AND RESULTS: Flow-mediated dilation (FMD) and low-flow-mediated constriction (L-FMC) were measured in 451 consecutive patients before coronary angiography. Low-flow-mediated constriction (P< 0.0001) and FMD (P=0.0005) progressively decreased with the number of diseased vessels, and L-FMC showed a significant linear correlation with the SYNTAX score (R=0.38; P< 0.0001). Logistic regression analysis confirmed the association between endothelial function parameters and CAD (P=0.001 for L-FMC, P=0.02 for FMD). Receiver operating characteristic analysis demonstrated that the addition of L-FMC alone and of the combination of FMD and L-FMC improved the predictive power of a model based on traditional risk factors for CAD (area under the curve of the risk factor model=0.716; risk factor model + FMD=0.734, P=0.1 compared with risk factor model; risk factor model + L-FMC=0.771, P=0.004; risk factor model + L-FMC + FMD=0.779, P=0.002). Reclassification statistics showed that the introduction of FMD to the model based on the traditional risk factors correctly reclassified an additional 5% of patients, and that the introduction of L-FMC net correctly reclassified 19% of the patients. There was no correlation between different parameters of endothelial function. CONCLUSION: Endothelial function assessment provides modest but statistically significant additional information in predicting the presence of CAD.

Peripheral hemorheological and vascular correlates of coronary blood flow.

The slow coronary flow phenomenon (SCF), a condition described by the presence of inappropriate delay in the progression of intracoronary contrast during angiography in the absence of stenoses, has been shown in some patients presenting with chest pain. While several conditions leading to "secondary" slow flow are known, there are no definitive conclusions regarding the exact pathogenesis of "primary" SCF. The present paper outlines the mechanisms that may lead to SCF, emphasizing the role of hemorheological and vascular factors in the pathogenesis of this phenomenon. Small vessel dysfunction has been proposed in the pathogenesis of SCF since the first description of this syndrome in 1972. Abnormalities in coronary microvascular function result from increased microvascular resistances and impaired endothelial release of vasoactive substances, especially in production and bioavailability of endothelium derived NO. Inflammatory conditions (increased levels of C-reactive protein, interleukin-6 and adhesion molecules) and metabolic abnormalities such as impaired glycemic control, hyperuricemia and elevated serum gamma-glutamyltransferase were also found to contribute to microvascular dysfunction in patients with SCF. New studies have also indicated that increased blood viscosity and one of its major determinants, erythrocyte aggregation, is associated with the SCF. Rheological variables play a role in the control of shear stress and contribute to blood flow velocity changes. Although platelets do not have a significant influence on blood viscosity, it has been demonstrated that they are involved in the development of SCF. Increased mean platelet volume (MPV), an indicator of platelet activation and platelet aggregability is also significantly higher in patients with SCF compared with patients with normal coronary flow.

Endothelial functions: Translating theory into clinical application.

The vascular endothelium plays a pivotal role in modulating endothelial homeostasis. A number of methods have been developed to assess the function of this important tissue in humans in vivo, in the hope that such data may contribute to the early diagnosis and risk stratification of patients at risk for, or with, cardiovascular disease. Despite these efforts, a number of issues, both practical and theoretical, arise from the attempt of quantifying the elusive "endothelial function", and from the attempt of defining what is "endothelial dysfunction". The present paper, based on a lecture held at the conference of the European Society of Hemorheology and Microcirculation, will try to deal with these issues.

Ischemic and non-ischemic preconditioning: Endothelium-focused translation into clinical practice.

Pathophysiological studies have clearly demonstrated that the relationship between endothelial [dys]function and tissue ischemia is bidirectional: while it is well accepted that endothelial dysfunction has a key role in the progression and destabilization of coronary atherosclerosis, it is also well known that the endothelium is particularly sensitive to ischemia and reperfusion injury, and that this damage critically determines the extent of tissue damage, e.g. myocardial infarct size. Therefore, protecting the endothelium from ischemia could potentially have important clinical implications. In this scenario, reactive oxygen species [ROS] play a particularly important role: these elusive mediators are involved in determining the endothelial toxic effect of risk factors and are involved in reperfusion injury; however, most importantly, ROS are also key mediators of endothelial preconditioning, a protective process that is characterized by a reduced sensitivity to ischemia and reperfusion injury. We report considerations regarding these phenomena and their potential pharmacologic manipulation as discussed in a lecture at the recent Conference of the European Society of Clinical Hemorheology and Microcirculation held in Pontresina, Switzerland.