Dubois' Lupus Erythematosus and Related Syndromes, 10e (Mar 11, 2024)_(0323932320)_(Elsevier)

For more than 50 years, Dubois’ Lupus Erythematosus and Related Syndromes has been recognized internationally as the go-to clinical reference on lupus and other connective tissue diseases . From basic scientific principles to practical points of clinical management, the 10th edition provides extensive, authoritative coverage of systemic lupus erythematosus (SLE) and its related diseases in a logical, clearly written, user-friendly manner. It’s an ideal resource for rheumatologists and internal medicine practitioners who need a comprehensive clinical reference on all aspects of SLE, connective tissue diseases, and the antiphospholipid syndromes. Provides complete clinical coverage of every aspect of cutaneous and systemic lupus erythematosus , including definitions, pathogenesis, autoantibodies, clinical and laboratory features, management, prognosis, and patient education. Includes significant new content throughout : a new chapter on the endocrine system and hormones; newly distinct chapters on the heart and lung; new content on social disparities in lupus, clinical presentation of nephritis, and pulmonary hypertension; a new concluding chapter on future directions in the field; new basic science coverage of the microbiome, autoinflammatory, and monogenic lupus; and new coverage of diversity, inclusion, gender, compliance, and adherence. Offers a fresh perspective from two new associate editors and many new authors with representation from 30 countries. Contains an up-to-date overview of significant advances in cellular, molecular, and genetic technologies , including genetic advancements in identifying at-risk patients. Discusses the clinical management of related disorders such as Sjogren’s syndrome, scleroderma, polymyositis, and antiphospholipid syndrome (APS). Presents the knowledge and expertise of international contributors to provide new global perspectives on manifestations, diagnosis, and treatment. Features a vibrant, full-color format, with graphs, algorithms, differential diagnosis comparisons, new and improved figures, and schematic diagrams throughout. An eBook version is included with purchase. The eBook allows you to access all of the text, figures, and references, with the ability to search, customize your content, make notes and highlights, and have content read aloud. Additional digital ancillary content may publish up to 6 weeks following the publication date. Cover Inside front cover Front matter Dubois’ Lupus Erythematosus and Related Syndromes Copyright Dedication Preface Acknowledgments Contributors Contents Section 1 What is lupus? Section 2 Pathogenesis Section 3 Mechanisms of tissue injury Section 4 Autoantibodies Section 5 Clinical aspects of lupus erythematosus Section 6 Assessment of lupus Section 7 Management of lupus Section 8 Outcomes 1 History of lupus Prescientific period Differentiation from tuberculosis Recognition of systemic lupus erythematosus Systemic lupus erythematosus and “collagen disease” Serologic aspects Pathogenesis: Some breakthroughs Epidemiology Classification criteria and disease indices Management: Some breakthroughs Related diseases Antiphospholipid syndrome Neonatal lupus Lupoid hepatitis Prognosis: Just a few comments References 2 Definition and classification of lupus and lupus-related disorders Systemic lupus erythematosus Definition of systemic lupus erythematosus Development of the american college of rheumatology systemic lupus erythematosus classification criteria Constraints of the american college of rheumatology systemic lupus erythematosus classification criteria Systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus 2019 European league against rheumatism/american college of rheumatology classification criteria for systemic lupus erythematosus Chronic cutaneous lupus Drug-induced lupus erythematosus Mixed connective tissue disease Undifferentiated connective tissue disease and overlap syndromes Antiphospholipid antibody syndrome Neonatal lupus Summary References 3 The epidemiology of lupus Introduction The fundamentals of epidemiology Case definition Case ascertainment Population at risk Pediatric systemic lupus erythematosus Cutaneous lupus erythematosus Other considerations Conclusion References 4 Overview of lupus pathogenesis Phases of SLE: Evolution of disease in susceptible persons Overview: The major pathways favoring development of SLE Stimulation of innate and adaptive immune responses by foreign and autoantigens Autoantibodies and immune complexes of SLE Regulatory mechanisms fail to control autoimmune responses Abnormalities in T and B lymphocytes in SLE Cytokines/chemokines and SLE Genetics and epigenetics Gender influences Environmental factors Complement activation and tissue damage in SLE Current approved and investigational therapies for SLE4 Suggested reading 5 Genetics of SLE Genetic studies on SLE Early days of SLE genetic studies Genome-wide association studies SLE susceptibility genes in cell death and clearance of self-antigens Complements and nucleases NCF1 and NCF2 ITGAM and SLC29A3 Other genes involved in cell death and clearance Fc gamma receptors SLE genes in toll-like receptor and IFN-I signaling TLR7 IRF5 and IRF3 IRF7 IFN-α miR-146a and USP18 TASL and SLC15A4 IFIH1 STIM1 IFN-II (IFN-γ) and IFN-III signaling NF-κB signaling TNFAIP3 and TNIP1 UBE2L3 RELA IKBKB and IKBKE B-cell signaling in SLE genetics LYN TNFSF13B TACI PTPN22 CSK TRAF3 CD40 and FCRL5 TAOK3 RASGRP1 and RASGRP3. IL7R SLE genes in T cell signaling HLA class II genes TNFSF4 PTPRC (CD45) CTLA4 and CD80 DEF6 DUSP22 CXCR5 and RGS1 GRB2 and PDCD5 WDFY4 CD37 IL12 and JAK/STAT signaling IL12A and IL12RB2 STAT4, JAK2, and TYK2 Transcription factors and epigenetic modifiers in SLE IKZF1 BACH2 and PRDM1 ETS1 TET3 Applications of the genetic findings Future directions References 6 Single gene defects and autoinflammation Introduction Type I interfons and their role in autoimmune disease Interferonopathies and associated molecular defects Aicardi-Goutières syndrome STING-associated vasculopathy with onset in infancy COPA syndrome Spondyloenchondrodysplasia Informing monogenic lupus Ultraviolet sensitivity and cGAS-STING Complement protein defects driving monogenic lupus Therapeutic implications of RNA/DNA sensing in monogenic autoimmune disease and future directions References 7 Epigenetics of lupus DNA methylation in SLE Introduction to DNA methylation Dysregulated DNA methylation and gene expression in SLE Mediators and factors contributing to dysregulated DNA methylation in SLE Histone modification in SLE Introduction to histone modification Dysregulated histone modification in SLE Mediators and factors contributing to dysregulated histone modification in SLE 3D genome and SLE Introduction of 3D genome Genetic variants and 3D genome Identification of 3D genome associated with functional variants Dysfunctional enhancers in SLE 3D genome as targets for SLE therapy RNA modification m6A modification A-to-I editing C-to-U editing miRNA in SLE Introduction to miRNA miRNA biogenesis miRNA regulation Roles of miRNAs in SLE Functions of miRNAs in the immune system Regulating the development of immune cells Regulating innate and adaptive immune responses Dysfunctional miRNAs in lupus Dysfunctional miRNAs in innate immunity Dysfunctional miRNAs in adaptive immunity Dysfunctional miRNAs in resident cells of target tissues Roles of lncRNAs in SLE Functions of lncRNA in the immune system Dysfunctional lncRNAs in lupus Roles of circrnas in SLE Translational application of epigenetics in lupus Prospective epigenetic biomarkers Epigenetic therapeutic targets References 8 The role of the environment and microbiome in lupus Interplay between environmental, genetic, and epigenetic factors Dietary influences on SLE Gut microbiome and SLE Environmental exposures and SLE Silica exposure Smoking Smoking and the role of gene-environment interactions Epstein-Barr virus exposure Vitamin D status and ultraviolet radiation exposure Metals Pesticides and persistent organic pollutants Air pollution Other environmental agents and SLE Methodologic considerations The SLE exposome Future considerations References 9 The innate immune system in SLE Cellular components of the innate immune system Monocytes, macrophages, and dendritic cells Neutrophils Plasmacytoid dendritic cells Natural killer cells Platelets Innate lymphoid cells Extracellular components of the innate immune system Pattern recognition receptors: Pamps, damps, and pathways of innate immune stimulation in SLE Toll-like receptors TLR7 and TLR9 in SLE Cytosolic sensors Ligands responsible for stimulating IFN-I and other inflammatory cytokines Innate immune detection of self versus nonself nucleic acid Therapeutic approaches References 10 B cells and generation of antibodies Structure of the antibody molecule Generation of antibody diversity Class switch recombination Somatic hypermutation Posttranscriptional modifications of antibodies Pathogenic autoantibodies Genetic and molecular analysis of anti-DNA antibodies B-cell subsets: Implications for SLE Innate B cells Follicular B cells Memory B cells Plasma cells Age/autoimmune-associated B cells Regulatory B cells B-cell activation B-cell receptor signaling Toll-like receptors in B-cell function Cytokine activation Plasma cell differentiation Germinal center and extrafollicular activation of B cells B-cell tolerance Apoptosis and autoimmunity Autoantibody induction Triggers Regulation of autoantibody production in the germinal center Therapeutic interventions Depleting autoreactive B cells Interfering with T-cell help Antiinflammatory therapies Antigen-based therapies Summary References 11 T cells Role of T cells in autoimmunity and inflammation B cell help Inflammation CD8 and double negative T cells Regulatory function Intrinsic T cell defects Assembly and selection of the T cell repertoire T cell activation and signaling Regulation of gene expression Metabolic dysfunction Apoptosis induction Acquired defects Concluding remarks References 12 Immunoregulatory cells and networks in lupus T-regulatory cells CD4+ T-regulatory cells CD4+ Tregs and SLE CD8+ Tregs CD8+ Tregs and SLE B-regulatory cells B-regulatory cells and SLE Myeloid-derived suppressor cells Myeloid-derived suppressor cells and SLE Dendritic cells Dendritic cells and SLE Natural killer cells NK cells and SLE NKT cells iNKT cells and SLE Conclusions References 13 Cytokines in lupus Properties of cytokines and their receptors Assessment of cytokine production Use of gene expression to study cytokine effects Activation of the immune response in systemic lupus erythematosus Cytokines of the innate immune response Type I interferons in immune responses Type I interferons in the pathogenesis of systemic lupus erythematosus Tumor necrosis factor Osteopontin Interleukin-1 Interleukin-10 B-lymphocyte stimulator Interleukin-6 Other cytokines Cytokines of the adaptive immune response Cytokines generated in the adaptive immune response: T-cell–derived cytokines T helper cell cytokines Interleukin-2 Interferon-γ T helper 2 cytokines Transforming growth factor-β Other T-cell–derived cytokines Cytokines generated in the adaptive immune response: B-cell–derived cytokines Cytokines in preclinical lupus Summary References 14 Metabolic control of immunopathogenesis in systemic lupus erythematosus Metabolic pathways regulate proinflammatory immune cell lineage specification via MTOR activation in SLE Mitochondrial oxidative stress underlie MTOR activation in SLE Mechanistic checkpoints of metabolic pathways represent targets for treatment in SLE Conclusions Acknowledgement References 15 Animal models of systemic lupus erythematosus (SLE) Multigenic spontaneous SLE NZB/BL (NZB) mice Clinical characteristics and autoantibodies B cells, T cells, and other factors Genetics Summary New Zealand White mice Clinical characteristics and autoantibodies Genetics (NZB x NZW) F1 mice (BWF1) Autoantibodies Nephritis in BWF1 females: Autoantibodies, infiltrating cells, and predisposing glomerular structures Neurologic tissue Lymphoproliferation Sex influences Hematopoietic cell abnormalities Interferons and TGF-β Abnormalities of dendritic cells in BWF1 mice Abnormalities of monocytes/macrophages Other abnormalities Genetic predisposition Summary New Zealand mixed mice Clinical and immunologic characteristics of NZM2410 NZM2328: Clinical and immune characteristics NZM triple congenics (C57BL/6.NZM.Sle1.Sle2.Sle3), clinical manifestations, and immunologic features (SWR x NZB) F1 (SNF1) mice Characteristics Genetics Summary MRL-lpr mice and MRL/Mp (MRL+/+) Clinical characteristics Immune cell characteristics Genetics Summary Nonfunctional Fas ligand in GLD mice BXSB mice Clinical manifestations and autoantibodies Genetics Summary (NZW×BXSB) F1 model of antiphospholipid syndrome and coronary artery disease Disease characteristics and autoantibodies Other disease features Genetics Summary BXD2 RI model of spontaneous lupus nephritis and erosive polyarthritis (“rhupus”) Genetics Summary Monogenic spontaneous SLE Fcgr2b−/− mice Lyn−/− mice TLR7.1 mice Induced lupus-like disease in nonautoimmune strains Chronic GVHD (cGVHD) model Lupus induced by injection of hydrocarbon oil Xenobiotic-induced autoimmunity TLR7 agonist-induced autoimmunity Other induced models Lupus in genetically manipulated mice Modified genes in nonautoimmune strains Modified genes in lupus mice Therapeutic interventions in mouse models of lupus Immunosuppressive therapies Therapies targeting B cells Therapies targeting T cells Activation of suppressor networks Treatments targeting complement, cytokines, chemokines and their activation pathways Treatments targeting innate immunity Stem cell replacement Diet, gut inflammation, and the microbiome Manipulating sex hormones Target organ protection Lupus in domestic animals Spontaneous canine SLE SLE in cats, monkeys, and horses References 16 Abnormalities in clearance of immune complexes and dying cells in lupus Introduction Defective apoptotic cell clearance mechanisms in autoimmunity Phosphatidylserine receptors Role of “don’t eat me” receptors in systemic lupus erythematosus Role of scavenger receptors in apoptotic cell clearance Role of efferosome maturation in apoptotic cell clearance Abnormalities in immune complex clearance Tissue clearance mechanisms Complement receptors Role of C1q Fcγ receptors Genetic abnormalities of Fcγ receptors Other cell types involved in immune complex interactions Other tissue clearance mechanisms Acknowledgments Disclosures of interest Summary References 17 Complement and systemic lupus erythematosus Historical overview Biology of the complement system Complement activation pathways Regulators of complement activation Receptors for complement proteins Effector functions of complement Complements as a bridge between innate immunity and adaptive immunity Novel roles for complement Complement dysregulation and SLE Immune complex abnormalities, complement activation, and tissue injury Other potential mechanisms of complement dysregulation in SLE Complement defiency and SLE Hereditary complement deficiency and SLE Acquired complement deficiency and anticomplement autoantibodies Deficiency and dysfunction of complement regulatory proteins Possible mechanisms underlying the complement deficiency–SLE association Analyses of complement Measurement of complement functional activity Measurement of complement proteins Measurement of complement activation products Genetic testing Diagnostic considerations for complement dysregulation and deficiency Soluble complement components as biomarkers for SLE Soluble complement components and SLE diagnosis and activity monitoring Problems associated with measurement of soluble complement components Cell-bound complements as biomarkers for SLE Cell-bound complement activation products as diagnostic biomarkers Cell-bound complement activation products as biomarkers of disease activity Cell-bound complement activation products as biomarkers for predicting the development of SLE Complement-targeted therapeutics for SLE Conclusion References 18 Apoptosis and inflammatory forms of cell death Introduction and definitions Biochemistry of apoptosis Caspases Intrinsic apoptosis: Bcl-2 proteins and the mitochondria Abnormalities in the expression of Bcl-2 family members cause lupus-like autoimmunity in mice Intrinsic death pathways from cellular damage or stress Metabolic stress Genotoxic stress Endoplasmic reticulum stress Extrinsic signaling through death receptors Regulation of death receptors Function in immune regulation Deficiencies in death receptor signaling lead to systemic autoimmunity Removal of dead and dying cells: Tolerance versus autoimmunity Receptors and ligands implicated in the removal of intact dead cells by phagocytes How a cell dies affects the immune response Apoptotic cell death leads to a lack of immune response or immune suppression and tolerance. Defective clearance of apoptotic cells predispose to lupus-like disease in mice Cells that die by necrosis, pyroptosis, necroptosis, netosis or ferroptosis, stimulate inflammation and, in some cases, au ... The critical role of nucleases and the degradation of extracellular and intracellular nucleic acids. Cell death abnormalities in human SLE Apoptosis, clearance of apoptotic cells, and necrosis The pivotal role of nucleic acids in stimulation of IFN-I in SLE Cell death and treatment of SLE Conclusions Acknowledgments References 19 Tissue damage in lupus Introduction Overview of reactive oxygen and nitrogen intermediates Regulation of oxidant stress Mechanisms through which ROI can modify DNA and change transcription Association of ROI and RNI with SLE disease activity Autoantibodies T-cell regulation and function Apoptosis Autophagy regulation and induction Neutrophil net formation Podocyte dysfunction induced by RNI Fibrosis The role of NO• in vascular homeostasis Conclusion References 20 Lupus nephritis Renal anatomy and physiology Glomerular structure and function Glomerular filtration barrier Podocytes Mesangium Glomerular endothelial cells The renal tubules and the kidney interstitium Renal tubular epithelial cells Renal interstitial fibroblasts Resident renal immune cells Histologic classification of lupus nephritis Genetic risk for lupus nephritis Mouse models of lupus nephritis NZB/W F1 and inbred strains Mice overexpressing TLR7 Fas overexpression Inducible models of lupus nephritis Mechanisms for immune complex deposition in the kidneys Site of immune complex deposition in SLE The characteristics of pathogenic autoantibodies Mechanisms of tissue deposition of immune complexes Pauci-immune glomerulonephritis Dissociation of immune complex deposition and/or glomerular injury from end-stage renal disease Effector mechanisms in the kidney Complement Fc receptors Innate immune receptors Immune cell influx T cells B cells Myeloid cells Soluble mediators of tissue injury Chemokines Cytokines Lipid mediators Hypoxia and other metabolic disturbances The renin-angiotensin system MMPs and tissue repair Blood vessels and endothelium Integrin ligands Heparan sulfate proteoglycan Progression to fibrosis and sclerosis Natural history of progressive lupus nephritis Pathways that contribute to or protect from fibrosis TGFβ Hepatocyte growth factor PPARγ and obesity LCN2 and KIM-1 Systems biology of lupus nephritis Serum and urine biomarkers Modular signatures Insights from molecular profiling and single-cell RNA sequencing Future directions in lupus nephritis References 21 Pathogenesis of accelerated atherosclerosis and vascular injury in systemic lupus erythematosus Epidemology of cardiovascular disease in systemic lupus erythematosus Major adverse cardiovascular events Subclinical and clinical vascular damage in SLE Pathogenesis of atherosclerosis in the general population Pathogenesis of premature atherosclerosis in SLE The role of altered immune cell subtypes in SLE atherosclerosis Dysregulation of innate immune responses and SLE-related cardiovascular disease Monocytes/macrophages Plasmacytoid dendritic cells and type I interferons Neutrophils and low-density granulocytes Dysregulation of adaptive immune responses and SLE-related cardiovascular disease CD4+ T cells Th1 cells and interferon-γ Th17s and IL-17A Tregs Follicular helper T cells B cells Autoantibodies and immune complexes Cytokines and other soluble mediators Alarmins S100A8, S100A9, and S100A8/A9 Tumor necrosis factor-aymor nex Monocyte chemotactic protein-1 B cell activating factor/B lymphocyte stimulator The role of inflammatory lipids Oxidized low-density lipoproteins High-density lipoprotein structure and function Other factors associated with cardiovascular disease in SLE Homocysteine The PREDICTS model Vitamin D deficiency Genetic risk factors Potential treatments to mitigate cardiovascular disease in SLE Statins Antihypertensives Treatment of disease activity Antimalarials Mycophenolate mofetil Peptidylarginine deiminase inhibitors Methotrexate Anti–B cell therapies Antiinterferon therapies Conclusions Acknowledgments Key points References 22 Pathogenesis of cutaneous lupus Introduction Clinical considerations Epidemiology Triggers of cutaneous lupus erythematosus Ultraviolet light Medications Smoking Etiopathogenesis Genetics Contribution of sex bias Microbiome The importance of interferons Etiology of the interferon signature Other type II and type III interferons Cell death Immune cell populations in cutaneous lupus erythematosus How understanding pathogenesis is changing treatment References 23 Pathogenesis of neuropsychiatric lupus Introduction Neuroimmune interfaces Blood-brain barrier Blood–cerebrospinal fluid barrier Cell-mediated inflammation Autoantibodies Autoantibody-mediated vasculopathy Brain-reactive autoantibodies Cytokines and chemokines Complement-mediated immunity Glial cells Summary References 24 Pathogenesis of Sjögren syndrome Introduction Disease triggers Viruses Neuroendocrine axis Sex hormones Smoking Diet and microbiome Genetics Epigenetics Autoimmune epithelitis Salivary glands and immune system Innate immunity and salivary glands epithelium Adaptive immunity and salivary gland epithelium Stromal cells of salivary glands Mechanisms of dryness From a gland disease to a systemic disease B-cell hyperactivity Tertiary lymphoid structures Autoantibodies Lymphoma Research tools Animal models OMICs From pathogenesis to targeted treatment Major knowledge gaps Fatigue Environmental factors Chronic inflammation Conclusions References 25 Antinuclear antibodies, antibodies to DNA, histones, and nucleosomes Antinuclear antibody overview History Choice of substrate Patterns of immunofluorescence and links to target antigen Clinical interpretation New methods for antinuclear antibody detection Identification of lupus-related antibodies Antinuclear antibody–negative lupus Summary Antibodies to DNA, histones, and nucleosomes Measurement of anti-dsDNA antibodies Work from experimental models that emphasized the potential importance of anti-dsDNA antibodies How pathogenic anti-dsDNA antibodies bind to tissues: The importance of binding to nucleosomes Cross-reaction of anti-DNA antibodies with intracellular antigens Cell-penetrating anti-DNA antibodies in SLE Antihistone antibodies Structure and origin of pathogenic anti-dsDNA and antinucleosome antibodies Can measuring anti-dsDNA levels help manage patients with SLE? Acknowledgments Summary References 26 Antibodies against extractable nuclear antigens (RNP, Sm, SS-A/RO, and SS-B/La) Structure of the antigens Sm and RNP complexes SS-A/RO and SS-B/La ribonucleoprotein complexes Assays for measuring anti-ENA antibodies Prevalence and clinical associations in SLE Origins of anti-ENA autoimmunity Viral infections as trigger for autoimmunity Sequential presentation of anti-ENA antibodies and relationship of anti-ENA to other SLE-specific autoantibodies Role of apoptosis for the generation of anti-ENA antibodies Toll-like receptors as key molecules for the generation of anti-ENA antibodies Genetic risks and anti-ENA antibodies Pathogenic importance of anti-RNP and anti-Sm antibodies Pathogenic role of anti–SS-A/Ro and anti–SS-B/La antibodies Autoantibodies against other ENA Anti–proliferating cell nuclear antigen antibodies/anti-cyclin antibodies References 27 Other autoantibodies Introduction Anti-C1q antibodies Antilipoprotein antibodies Antiendothelial cell antibodies References 28 Pathogenesis of antiphospholipid antibody syndrome The clinical importance of antiphospholipid antibodies Epidemiology of aPL and APS Which aPL tests should be done and how should they be interpreted? Standard laboratory “criteria” assays Noncriteria assays Antiphospholipid antibody–induced mechanisms of disease Mechanisms of thrombosis Animal models Interactions with cell surface receptors Cell activation and signaling pathways leading to thrombosis Endothelial cells. Monocytes. Platelets. Neutrophils. Dysregulation of coagulation and complement pathways. Mechanisms of pregnancy morbidity Animal models Mechanisms of cellular activation leading to obstetric APS Dysregulation of coagulation and complement pathways Coronavirus disease 2019 and antiphospholipid antibodies Conclusions References 29 Drug-induced lupus Introduction Etiology Implicated drugs Genetic contributions to idiopathic and drug-induced lupus Roles of age and gender in idiopathic and drug-induced lupus Summary Pathogenesis Genetic predisposition Drug biotransformation Epigenetics and gene expression Epigenetics, chromatin structure, and gene expression Histone modification DNA methylation T cells, DNA methylation, and drug-induced lupus T cells, DNA methylation, and idiopathic lupus T cells, DNA methylation, and the environment Innate immune system Role of cytokines—evidence from biologic agents Interferon α (IFN-α) Tumor necrosis factor α (TNF-α) inhibitors Summary Clinical aspects Comparison of drug-induced versus idiopathic lupus Patient characteristics Hydralazine. Procainamide. Tnf-α inhibitors. Drug-induced subacute cutaneous lupus erythematosus Laboratory findings Clinical course Summary References 30 Overview and clinical presentation Clinical manifestations and racial disparities Chief complaint, autoantibody development, and immunologic changes Variations in clinical presentation Incomplete lupus Late-onset lupus Male lupus Categorization of lupus symptoms Fatigue Brain fog Fever Lymphadenopathy Weight loss References 31 Skin disease in cutaneous lupus erythematosus Epidemiology Triggers of cutaneous lupus erythematosus Clinical features Classification of cutaneous lupus erythematosus Lupus-specific skin lesions Acute cutaneous lupus erythematosus Subacute cutaneous lupus erythematosus Chronic cutaneous lupus erythematosus Discoid lupus erythematosus. Hypertrophic/verrucous DLE. Lupus panniculitis/lupus profundus. Lupus erythematosus tumidus. Chilblain LE. Lichen planus–lupus erythematosus overlap. Bullous SLE. Relationship with systemic disease features Pathology Immunopathology Laboratory findings Differential diagnosis Lupus-nonspecific skin lesions Photosensitivity Mucosal ulceration Nonscarring alopecia Cutaneous vascular reactions Vasculitis Vasculopathy Raynaud phenomenon Antiphospholipid antibodies Cryoglobulins Other cutaneous vascular reactions Urticaria Periungual telangiectasias Erythromelalgia and palmar erythema Other LE-nonspecific skin lesions Papulonodular mucinosis Calcinosis cutis Nail changes Anetoderma Interstitial granulomatous dermatitis Conclusion References 32 The musculoskeletal system and bone metabolism Introduction Arthritis Arthritis definition by classification criteria Diagnosis Imaging Synovial fluid analysis and synovial tissue pathology Immunologic profiles in erosive arthritis in SLE arthritis Jaccoud arthropathy Rhupus: Revisiting concepts of erosive arthritis Treatment Muscle involvement Lupus myositis Orbital myositis Drug-induced myopathies in SLE Infection-related myopathies Soft tissue disorders and other pain syndromes Musculoskeletal infections Avascular necrosis Osteoporosis Joint replacement in SLE Musculoskeletal features in outcome measures SLE disease activity measures British isles lupus assessment group European consensus lupus activity measurement Lupus activity index SLE activity index score Systemic lupus activity measure SLE disease activity index SLE damage indices SLICC/ACR damage index Lupus damage index questionnaire Brief index of lupus damage Summary References 33 Lupus and the cardiovascular system Introduction Epidemiology Pericardium Pericarditis Pericardial effusion Chronic pericarditis Myocardium Myocarditis Cardiomyopathy Endocardium Endocarditis Congenital heart block Adult conduction abnormalities Vasculature Atherosclerosis and coronary artery disease References 34 Pulmonary manifestations of systemic lupus erythematosus Introduction Pleural disease Pathogenesis Diagnosis Clinical presentation Imaging Pleural fluid analysis Management Parenchymal disease Acute parenchymal disease Acute lupus pneumonitis Diffuse alveolar hemorrhage Management of ALP and DAH Uncommon forms of acute parenchymal involvement in SLE Chronic parenchymal disease Interstitial lung disease Treatment of SLE-ILD Vascular disease Pulmonary hypertension Treatment of SLE-PH Pulmonary vasculitis Thromboembolic disease Acute reversible hypoxemia Diseases of the mediastinum and musculature Shrinking lung syndrome Treatment of shrinking lung syndrome Uncommon pulmonary involvement in SLE Airway disease Miscellaneous pulmonary disease Lung transplantation in SLE Novel treatment targets Summary References 35 Lupus and the nervous system Classification of NPSLE Attribution of neuropsychiatric events in patients with SLE Etiopathogenesis Epidemiology of NPSLE Risk factors for neuropsychiatric manifestations of SLE Clinical presentation of NPSLE Diffuse central nervous syndromes—neurologic Acute confusional state Aseptic meningitis Cognitive dysfunction Demyelinating syndrome Headache Diffuse central nervous system syndromes—psychiatric Anxiety disorders Mood disorders Psychosis Focal central nervous system syndromes Cerebrovascular disease Movement disorders Myelopathy Seizures Peripheral nervous system manifestations Acute inflammatory demyelinating polyneuropathy Autonomic disorders Cranial neuropathies Mononeuropathy Myasthenia gravis and related disorders Plexopathy Polyneuropathy Neuropsychiatric SLE in children Diagnostic evaluation Clinical laboratory tests Autoantibodies Antiphospholipid antibodies Anti-ribosomal P antibodies Anti-aquaporin 4 antibodies Anti-NMDAR antibodies Cerebrospinal fluid examination Electroencephalography Electromyography and nerve conduction studies Neuropsychometric tests Neuroimaging studies in NPSLE Computed tomography Magnetic resonance imaging Positron-emission tomography and single-photon emission computed tomography Advanced magnetic resonance imaging techniques Magnetization transfer imaging Magnetic resonance spectroscopy Diffusion tensor imaging Dynamic contrast-enhanced magnetic resonance imaging Functional magnetic resonance imaging Transcranial color doppler sonography Angiography Treatment of NPSLE Inflammatory pathway therapies Ischemic pathway therapies Prognosis of NPSLE References 36 Gastrointestinal and hepatic manifestations Gastrointestinal involvement Introduction Incidence and prevalence Manifestations Oral-pharyngeal ulceration, dysphagia, and esophagitis Anorexia, nausea, vomiting, and diarrhea Abdominal pain and acute abdomen Ascites and peritonitis Peptic ulcer disease Helicobacter pylori infection in systemic lupus erythematosus Pancreatitis Prevalence Clinical presentation and etiopathogenesis Management Motility disorders Mesenteric and intestinal vasculitis, melena, and bowel hemorrhage Prevalence Clinical presentation and etiopathogenesis Laboratory, radiographic, and histologic findings Treatment and outcome Mesenteric insufficiency, thromboembolism, and intestinal infarction Inflammatory bowel disease Collagenous colitis Celiac disease in association with systemic lupus erythematosus Protein-losing enteropathy and malabsorption Irritable bowel syndrome Liver manifestations of systemi