Contents. Systemic Lupus Erythematosus. Ellen M. Ginzler
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1 Systemic Lupus Erythematosus Preface Ellen M. Ginzler xiii ChangingWorldwide Epidemiology of Systemic Lupus Erythematosus 1 Archana Vasudevan and Aneesa Niravel Krishnamurthy Developed countries have better systemic lupus erythematosus survival rates than developing countries, or countries with lower economic performance. This is in part because of a higher human development index, defined by standard of living (a marker for gross domestic product), literacy rates, and life expectancy, with contribution from ethnic variations within individual countries, and unique environmental factors. Health-Related Quality of Life and Employment Among Persons with Systemic Lupus Erythematosus 15 Jinoos Yazdany and Edward Yelin This article assesses the effect of systemic lupus erythematosus (SLE) on the shealth-related quality of life (HRQOL) and employment of persons with this condition. Far more than impaired health status can affect an individual s quality of life. The term health-related quality of life is used to connote the decrement in an individual s quality of life specifically attributable to a decrease in health status. The article presents evidence on employment because this plays a crucial role in determining the quality of life of most Americans of normal working age. However, evidence is also presented with respect to other domains of activity, because most people work to live but not many live to work. Cutaneous Lupus and the Cutaneous Lupus Erythematosus Disease Area and Severity Index Instrument 33 Rachel S. Klein, Pamela A. Morganroth, and Victoria P. Werth This article provides an overview of cutaneous lupus erythematosus, including classification schemes, disease subtypes, and therapy. It also describes the Cutaneous Lupus Erythematosus Disease Area and Severity Index, a novel clinical outcome instrument that quantifies cutaneous activity and damage in cutaneous lupus erythematosus. Pediatric LupusçAreThere Differences in Presentation, Genetics, Response to Therapy, and Damage Accrual Compared with Adult Lupus? 53 Rina Mina and Hermine I. Brunner Some complement deficiencies predispose to systemic lupus erythematosus (SLE) early in life. Currently, there are no known unique physiologic or
2 viii genetic pathways that can explain the variability in disease phenotypes. Children present with more acute illness and have more frequent renal, hematologic, and central nervous system involvement compared to adults with SLE. Almost all children require corticosteroids during the course of their disease; many are treated with immunosuppressive drugs. Mortality rates remain higher with pediatric SLE. Children and adolescents accrue more damage, especially in the renal, ocular and musculoskeletal organ systems. Conversely, cardiovascular mortality is more prevalent in adults with SLE. The Metabolic Syndrome in Systemic Lupus Erythematosus 81 Ben Parker and Ian N. Bruce The metabolic syndrome (MetS) is a recently defined clustering of cardiovascular risk factors associated with increased insulin resistance and a high risk of developing type II diabetes mellitus. Systemic lupus erythematosus (SLE) is associated with an increased prevalence of the MetS and patients also show evidence of increased insulin resistance. Controversy remains, however, regarding the precise definition of the MetS and its exact role in predicting long-term coronary heart disease risk both in SLE and in the general population. The major benefit of identifying the MetS in patients with SLE is likely to be from highlighting patients for focused lifestyle interventions and helping to guide individualized therapeutic regimes that take into account cardiovascular risk. Gonadal Failure with Cyclophosphamide Therapy for Lupus Nephritis: Advances in Fertility Preservation 99 Jennifer Mersereau and Mary Anne Dooley Intravenous cyclophosphamide remains an important therapy for patients with severe systemic lupus erythematosus including lupus nephritis, which primarily affects women in their reproductive years. As prognosis improves, the chronic toxicity of this therapy assumes greater importance. This article reviews cyclophosphamide use, its effect on gonadal function, and protection of gonadal reserve during therapy. Egg, embryo, or gonadal tissue cryopreservation and alternative therapeutic strategies are considered. B-cell Biology and Related Therapies in Systemic Lupus Erythematosus 109 Sadia Ahmed and Jennifer H. Anolik Systemic lupus erythematosus (SLE) is a complex disease characterized by numerous autoantibodies and clinical involvement in multiple organ systems. The immunologic events triggering the onset and progression of clinical manifestations have not yet been fully defined, but a central role for B cells in the pathogenesis has been brought to the fore in the last several years. The breakdown of B-cell tolerance is likely a defining and early event in the disease process and may occur by multiple pathways, including alterations in factors that affect B-cell activation thresholds, B-cell longevity, and apoptotic cell processing. Antibodydependent and -independent mechanisms of B cells are important in
3 ix SLE. Thus, autoantibodies contribute to autoimmunity by multiple mechanisms including immune complex mediated type III hypersensitivity reactions, type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines including interferon a, tumor necrosis factor, and interleukin 1. Recent data have highlighted the critical role of toll-like receptors as a link between the innate and adaptive immune system in SLE immunopathogenesis. Given the large body of evidence implicating abnormalities in the B-cell compartment in SLE, there has been a therapeutic focus on developing interventions that target the B-cell compartment. Several different approaches to targeting B cells have been used, including B-cell depletion with monoclonal antibodies against B-cell specific molecules, induction of negative signaling in B cells, and blocking B-cell survival and activation factors. Overall, therapies targeting B cells are beginning to show promise in the treatment of SLE and continue to elucidate the diverse roles of B cells in this complex disease. Biomarkers in Lupus Nephritis 131 Anup Manoharan and Michael P. Madaio Biomarkers have the potential to be useful tools for noninvasively evaluating and managing patients with lupus nephritis. Many candidate biomarkers have been identified, but they require validation in larger cohorts. It is likely that combinations or biomarker profiles, rather than individual markers, will emerge to help better predict the severity of inflammation, the extent of fibrosis, degree of drug responsiveness, and other variables. This approach has the potential to reduce the use of the renal biopsy, improve therapeutic efficacy, and limit toxicity. We predict algorithms based on genotype and biomarkers combined with clinical presentation will emerge to help guide physicians in management. Assays that show the most potential include serum erythrocyte bound complement C4d, interleukin 17, interleukin 23, interferon score/chemokine score ratio, and anti-c1q antibodies. Such urinary biomarkers as fractional excretion of endothelial-1, monocyte chemoattractant protein 1, vascular cell adhesion molecule 1, and TWEAK (tumor necrosis factor like weak inducer of apoptosis) may also be useful but require validations. Endothelial Function and its Implications for Cardiovascular and Renal Disease in Systemic Lupus Erythematosus 145 Robert Clancy and Ellen M. Ginzler Vascular manifestations associated with systemic lupus erythematosus (SLE) span a broad range, including vasculopathy. An understudied pathway of this morbidity is a repair component. Recent studies have elevated the anti-injury biomarkers, adiponectin and membrane endothelial protein C receptor (EPCR), for consideration with roles to antagonize premature atherosclerosis and SLE nephritis, respectively. For example, adiponectin was found to serve as an independent predictor of carotid plaque, and its elevations were persistent over more than one visit. Unexpectedly, this biomarker was present despite clinical quiescence. In vasculopathy as a comorbidity to SLE nephritis, the persistent expression of membrane
4 x EPCR at peritubular capillaries may represent a response to the local cues of a deficit of active protein C. Under conditions of unresolved morbidity, higher levels of adiponectin and membrane EPCR may represent a physiologic attempt to limit further endothelial damage, and the observed increase in plaque and progression of SLE nephritis represent an overwhelming of this reparative process by disease-provoking stimuli. Cell-Bound Complement Biomarkers for Systemic Lupus Erythematosus: From Benchtop to Bedside 161 Chau-Ching Liu, Susan Manzi, Amy H. Kao, Jeannine S. Navratil, and Joseph M. Ahearn Systemic lupus erythematosus is arguably the most clinically and serologically diverse autoimmune disease. This article highlights the biomarkers helpful in diagnosing this disease. The authors own research is presented. Interferon-alpha: A TherapeuticTarget in Systemic Lupus Erythematosus 173 Mary K. Crow The long history of elevated interferon (IFN)-a in association with disease activity in patients who have systemic lupus erythematosus (SLE) has assumed high significance in the past decade, with accumulating data strongly supporting broad activation of the type I IFN pathway in cells of patients who have lupus, and association of IFN pathway activation with significant clinical manifestations of SLE and increased disease activity based on validated measures. In addition, a convincing association of IFN pathway activation with the presence of autoantibodies specific for RNA-binding proteins has contributed to delineation of an important role for Toll-like receptor activation by RNA-containing immune complexes in amplifying innate immune system activation and IFN pathway activation. Although the primary triggers of SLE and the IFN pathway remain undefined, rapid progress in lupus genetics is helping define lupus-associated genetic variants with a functional relationship to IFN production or response in patients. Together, the explosion of data and understanding related to the IFN pathway in SLE have readied the lupus community for translation of those insights to improved patient care. Patience will be needed to allow collection of clinical data and biologic specimens across multiple clinical centers required to support testing of IFN activity, IFN-inducible gene expression and chemokine gene products as candidate biomarkers. Meanwhile, promising clinical trials are moving forward to test the safety and efficacy of monoclonal antibody inhibitors of IFN-a. Other therapeutic approaches to target the IFN pathway may follow close behind. Glutamate Receptor Biology and its Clinical Significance in Neuropsychiatric Systemic Lupus Erythematosus 187 Cynthia Aranow, Betty Diamond, and Meggan Mackay The recent appreciation that a subset of anti-dna antibodies crossreacts with the N-methyl-d-aspartate receptor encourages a renewed
5 xi examination of antibrain reactivity in systemic lupus erythematosus (SLE) autoantibodies. Moreover, investigations of their autospecificity present a paradigm for studies of antibrain reactivity and show that (1) serum antibodies access brain tissue only after a compromise of blood-brain barrier integrity, (2) the same antibodies have differential effects on brain function depending on the region of brain exposed to the antibodies, and (3) insults to the blood-brain barrier are regional rather than diffuse. These studies suggest that an anatomic classification scheme for neuropsychiatric SLE may facilitate research on etiopathogenesis and the design of clinical trials. Index 203
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