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Systemic Lupus Erythematosus
01 Jun 1976-
TL;DR: Contributions are gathered from physicians and researchers from North America, South America, Europe, and Asia that highlight several important and/or novel aspects of the molecular pathogenesis, clinical organ involvement, and experimental therapies in this prototypical systemic autoimmune disease.
Abstract: In sharp distinction to organ-specific autoimmune diseases such as thyroiditis, diabetes, or myasthenia gravis, systemic lupus erythematosus (SLE) is a constellation of signs and symptoms classified as one nosologic entity. Indeed, it is the diversity of presentation, accumulation of manifestations over time, and undulating disease course that challenge the most astute of clinicians. With rare exception, the unifying laboratory abnormality is the presence of circulating antinuclear antibodies (ANA). Acknowledging the complexity of this disease, its broad differential diagnosis, and the need to develop better and more specific therapies, the American College of Rheumatology (ACR) has designated 11 diagnostic criteria (presented in Table 15A-1) (1,2). These criteria reflect the major clinical features of the disease (mucocutaneous, articular, serosal, renal, neurologic) and incorporate the associated laboratory findings (hematologic and immunologic). The presence of four or more criteria is required for diagnosis. They need not necessarily present simultaneously: a single criterion such as arthritis or thrombocytopenia may recur over months or years before the diagnosis can be confirmed by the appearance of additional features. While there is incomplete agreement among rheumatologists as to whether these criteria need to be strictly applied in a practice setting, or reserved only for formal academic studies, they do facilitate a methodologic approach to evaluate a patient.
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TL;DR: The role of triglyceride-rich lipoproteins (TRLs) in the evaluation and management of CVD risk was discussed in this article, where the authors highlighted approaches aimed at minimizing the adverse public health-related consequences associated with hypertriglyceridemic states.
Abstract: A long-standing association exists between elevated triglyceride levels and cardiovascular disease* (CVD).1,2 However, the extent to which triglycerides directly promote CVD or represent a biomarker of risk has been debated for 3 decades.3 To this end, 2 National Institutes of Health consensus conferences evaluated the evidentiary role of triglycerides in cardiovascular risk assessment and provided therapeutic recommendations for hypertriglyceridemic states.4,5 Since 1993, additional insights have been made vis-a-vis the atherogenicity of triglyceride-rich lipoproteins (TRLs; ie, chylomicrons and very low-density lipoproteins), genetic and metabolic regulators of triglyceride metabolism, and classification and treatment of hypertriglyceridemia. It is especially disconcerting that in the United States, mean triglyceride levels have risen since 1976, in concert with the growing epidemic of obesity, insulin resistance (IR), and type 2 diabetes mellitus (T2DM).6,7 In contrast, mean low-density lipoprotein cholesterol (LDL-C) levels have receded.7 Therefore, the purpose of this scientific statement is to update clinicians on the increasingly crucial role of triglycerides in the evaluation and management of CVD risk and highlight approaches aimed at minimizing the adverse public health–related consequences associated with hypertriglyceridemic states. This statement will complement recent American Heart Association scientific statements on childhood and adolescent obesity8 and dietary sugar intake9 by emphasizing effective lifestyle strategies designed to lower triglyceride levels and improve overall cardiometabolic health. It is not intended to serve as a specific guideline but will be of value to the Adult Treatment Panel IV (ATP IV) of the National Cholesterol Education Program, from which evidence-based guidelines will ensue. Topics to be addressed include epidemiology and CVD risk, ethnic and racial differences, metabolic determinants, genetic and family determinants, risk factor correlates, and effects related to nutrition, physical activity, and lipid medications.
In the United States, the National Health and …
1,499 citations
TL;DR: Regardless of its physiological or pathophysiological functions, the assay of serum CRP is a valuable aid to clinical management in a number of different situations and in different diseases provided results are interpreted in the light of full clinical information.
Abstract: The acute phase response among plasma proteins is a normal response to tissue injury and is therefore a fundamental aspect of many diverse disease processes. It probably usually has a beneficial net function in limiting damage and promoting repair but in some circumstances it may have pathological consequences. Sustained high levels of acute phase proteins and especially SAA are associated with the development of amyloidosis in some individuals. Increased concentrations of CRP may, by activating the complement system, contribute to inflammation and enhance tissue damage. Failure of the normal or appropriate CRP response may also possibly have deleterious effects. SAA is a polymorphic protein which is normally present only in trace amounts but which, during the acute phase response, becomes one of the major apolipoproteins associated with high-density lipoprotein particles. The function of apoSAA is not known but it must have considerable physiological significance apart from its role as the putative precursor of amyloid A protein fibrils. CRP and SAP have been very stably conserved throughout vertebrate evolution and homologous proteins are apparently present even in vertebrates. This strongly suggests that they have important functions although these have not yet been precisely delineated. The main role of CRP may be to provide for enhanced clearance of inappropriate materials from the plasma whether these are of extrinsic origin, such as microorganisms and their products, or the autologous products of cell damage and death. The interaction between aggregated CRP and plasma low-density lipoprotein may play a significant part in the normal function of CRP and may also have a role in lipoprotein metabolism, clearance, and deposition. SAP is a normal tissue protein as well as being a plasma protein. Aggregated SAP selectively binds fibronectin and this may represent an aspect of the normal function of SAP. The deposition of SAP in amyloid is evidently not a normal function but it is not known whether this deposition is involved in the pathogenesis of amyloid or whether it is merely an epiphenomenon. In any case immunohistochemical staining for SAP is useful in the diagnosis of amyloid, in investigation of glomerulonephritis, and in studying disorders of elastic tissue. Regardless of its physiological or pathophysiological functions, the assay of serum CRP is a valuable aid to clinical management in a number of different situations and in different diseases provided results are interpreted in the light of full clinical information.(ABSTRACT TRUNCATED AT 400 WORDS)
1,258 citations
01 Jan 2011
1,252 citations
TL;DR: An important role is shown for neutrophils in lupus pathogenesis, whereby neutrophil activated by anti-self antibodies release NETs, which contain antimicrobial peptides complexed with self-DNA and activate plasmacytoid dendritic cells, leading to interferon release and furtherment and aggravation of inflammation and disease.
Abstract: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a breakdown of tolerance to nuclear antigens and the development of immune complexes. Genomic approaches have shown that human SLE leukocytes homogeneously express type I interferon (IFN)–induced and neutrophil-related transcripts. Increased production and/or bioavailability of IFN-α and associated alterations in dendritic cell (DC) homeostasis have been linked to lupus pathogenesis. Although neutrophils have long been shown to be associated with lupus, their potential role in disease pathogenesis remains elusive. Here, we show that mature SLE neutrophils are primed in vivo by type I IFN and die upon exposure to SLE-derived anti-ribonucleoprotein antibodies, releasing neutrophil extracellular traps (NETs). SLE NETs contain DNA as well as large amounts of LL37 and HMGB1, neutrophil proteins that facilitate the uptake and recognition of mammalian DNA by plasmacytoid DCs (pDCs). Indeed, SLE NETs activate pDCs to produce high levels of IFN-α in a DNA- and TLR9 (Toll-like receptor 9)–dependent manner. Our results reveal an unsuspected role for neutrophils in SLE pathogenesis and identify a novel link between nucleic acid–recognizing antibodies and type I IFN production in this disease.
1,157 citations
TL;DR: This review discusses the sources of mercury and the potential for human exposure; its biogeochemical cycling in the environment; its systemic, immunotoxic, genotoxic/carcinogenic, and teratogenic health effects; and the dietary influences on its toxicity; as well as the important considerations in risk assessment and management of mercury poisoning.
Abstract: Mercury is a toxic and hazardous metal that occurs naturally in the earth's crust. Natural phenomena such as erosion and volcanic eruptions, and anthropogenic activities like metal smelting and industrial production and use may lead to substantial contamination of the environment with mercury. Through consumption of mercury in food, the populations of many areas, particularly in the developing world, have been confronted with catastrophic outbreaks of mercury-induced diseases and mortality. Countries such as Japan, Iraq, Ghana, the Seychelles, and the Faroe Islands have faced such epidemics, which have unraveled the insidious and debilitating nature of mercury poisoning. Its creeping neurotoxicity is highly devastating, particularly in the central and peripheral nervous systems of children. Central nervous system defects and erethism as well as arrythmias, cardiomyopathies, and kidney damage have been associated with mercury exposure. Necrotizing bronchitis and pneumonitis arising from inhalation of mercury vapor can result in respiratory failure. Mercury is also considered a potent immunostimulant and -suppressant, depending on exposure dose and individual susceptibility, producing a number of pathologic sequelae including lymphoproliferation, hypergammaglobulinemia, and total systemic hyper- and hyporeactivities. In this review we discuss the sources of mercury and the potential for human exposure; its biogeochemical cycling in the environment; its systemic, immunotoxic, genotoxic/carcinogenic, and teratogenic health effects; and the dietary influences on its toxicity; as well as the important considerations in risk assessment and management of mercury poisoning.
1,139 citations
References
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TL;DR: Systemic lupus erythematosus is a relapsing and remitting disease, and treatment aims are threefold: managing acute periods of potentially life-threatening ill health, minimizing the risk of flares during periods of relative stability, and controlling the less life- threatening, but often incapacitating day to day symptoms.
Abstract: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease, which is autoimmune in origin and is characterized by the presence of autoantibodies directed against nuclear antigens. It is a multi-system disease, and patients can present in vastly different ways. Prevalence varies with ethnicity, but is estimated to be about 1 per 1000 overall with a female to male ratio of 10:1. The clinical heterogeneity of this disease mirrors its complex aetiopathogenesis, which highlights the importance of genetic factors and individual susceptibility to environmental factors. SLE can affect every organ in the body. The most common manifestations include rash, arthritis and fatigue. At the more severe end of the spectrum, SLE can cause nephritis, neurological problems, anaemia and thrombocytopaenia. Over 90% of patients with SLE have positive anti-nuclear antibodies (ANA). Significant titres are accepted to be of 1:80 or greater. SLE is a relapsing and remitting disease, and treatment aims are threefold: managing acute periods of potentially life-threatening ill health, minimizing the risk of flares during periods of relative stability, and controlling the less life-threatening, but often incapacitating day to day symptoms. Hydroxychloroquine and non-steroidal anti-inflammatory drugs are used for milder disease; corticosteroids and immunosuppressive therapies are generally reserved for major organ involvement; anti-CD20 monoclonal antibody is now used in patients with severe disease who has not responded to conventional treatments. Despite enormous improvements in prognosis since the introduction of corticosteroids and immunosuppressive drugs, SLE continues to have a significant impact on the mortality and morbidity of those affected.
4,376 citations
TL;DR: An examination of the deaths in a long-term systematic analysis of 81 patients followed for five years at the University of Toronto Rheumatic Disease Unit found death is associated with inactive lupus, long duration of steroid therapy and a striking incidence of myocardial infarction due to atherosclerotic heart disease.
957 citations
TL;DR: The immunochemical evidence for the high specific activity of antinuclear antibodies and the association of DNA antigen with DNA antibody in glomeruli add further support for the antigen-antibody complex hypothesis for renal injury in systemic lupus erythematosus.
Abstract: Antibodies were eluted from the isolated glomeruli prepared from the kidneys of 10 patients with the nephritis of systemic lupus erythematosus. Antibodies reacting primarily with buffer extracts of nuclei were eluted by acid treatment, and antibodies reacting mainly with DNA and nucleoprotein were eluted with deoxyribonuclease. Quantitative immunochemical studies revealed a high concentration of antinuclear antibody per milligram of γ-globulin in glomerular eluates compared with that in the corresponding serums. The γ-globulin of two eluates was found to consist predominantly of antinucleoprotein antibody. The selective elution of antinuclear antibodies was also indicated by the absence of other serum antibodies in the eluates. DNA antigen was demonstrated in the glomeruli of two kidneys with nephritis by means of isolated anti-DNA antibody labeled with fluorescein. In one of these cases, anti-DNA antibodies were also found concentrated in the glomeruli and, in the second, circulating anti-DNA antibodies were demonstrated in the patient's serum. The immunochemical evidence for the high specific activity of antinuclear antibodies and the association of DNA antigen with DNA antibody in glomeruli add further support for the antigen-antibody complex hypothesis for renal injury in systemic lupus erythematosus.
797 citations
776 citations
TL;DR: Serial immunochemical observations may be useful in the management of patients with systemic lupus erythematosus, as they reflect the in vivo formation of immune complexes that cause nephritis.
Abstract: To clarify the association between certain immunologic factors and clinical activity in patients with systemic lupus erythematosus, 96 patients were studied. Those with antibodies to deoxyribonucleic acid (DNA) or heat-denatured DNA, or with serum complement levels of less than 50 C′H50 units per ml, were more likely to have renal involvement. Very low complement levels and high titers of complement-fixing antibodies to DNA were always associated with active disease, especially active renal disease, whereas the absence of these abnormalities usually indicated inactive renal disease. A 50 per cent fall in serum complement levels in 22 patients was accompanied by, or preceded the onset of, active nephritis in 19 patients. These serologic factors may thus reflect the in vivo formation of immune complexes that cause nephritis. Serial immunochemical observations may be useful in the management of patients with systemic lupus erythematosus.
540 citations