BOOK
Dubois' Lupus Erythematosus and Related Syndromes E-Book
Daniel Wallace | Bevra Hannahs Hahn
(2012)
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Book Details
Abstract
Recognized for more than 45 years as the definitive text in the field, Dubois’ Lupus Erythematosus and Related Syndromes strikes the perfect balance between basic science and clinical expertise, providing the evidence-based findings, treatment consensuses, and practical clinical information you need to confidently diagnose and manage SLE.
- Broaden your understanding with comprehensive coverage of every aspect of cutaneous and systemic lupus erythematosus, including definitions, pathogenesis, autoantibodies, clinical and laboratory features, management, prognosis, and patient education.
- Experience clinical scenarios with vivid clarity through a heavily illustrated, full-color format which includes fundamental images of lupus rashes as well as graphs, algorithms, and differential diagnosis comparisons.
- Discover the latest in systemic lupus erythematosus with new chapters on important emerging topics such as socioeconomic and disability aspects; and rigorously updated chapters that include expanded coverage of the nervous system, and the most in-depth discussion of immunity and regulatory cells.
- Learn from the very best. World-renowned rheumatologists Drs. Daniel Wallace and Bevra Hannahs Hahn, along with new associate editors Drs. Michael Weisman, Ronald Van Vollenhoven, Nan Shen, and David Isenberg, present definitive coverage on new and rapidly changing areas in the field.
- Rely on it anytime, anywhere! Access the full text, image bank, and bonus online-only chapters at www.expertconsult.com.
Dubois’ Lupus Erythematosus was first published in 1966. For the past forty years, the product has distinguished itself internationally as the go-to reference on lupus and related diseases.
For rheumatologists and internal medicine practitioners who need a comprehensive clinical reference on systemic lupus erythematosus (SLE) and related disorders, this product delivers a complete arsenal of information on SLE, connective tissue diseases, and the antiphospholipid syndromes.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Front cover | cover | ||
| Inside front cover | ifc_i | ||
| Dubois' Lupus Erythematosus and Related Syndromes | i | ||
| Copyright page | iv | ||
| Contributors | v | ||
| Preface | xi | ||
| Table of Contents | xiii | ||
| I What is Lupus? | 1 | ||
| 1 Definition and Classification of Lupus and Lupus-Related Disorders | 1 | ||
| Systemic Lupus Erythematosus | 1 | ||
| Definition of SLE | 1 | ||
| Development of the SLE Classification Criteria | 1 | ||
| Constraints of the Current SLE Classification Criteria | 3 | ||
| Future Directions | 3 | ||
| Chronic Cutaneous Lupus | 3 | ||
| Drug-Induced Lupus Erythematosus | 3 | ||
| Mixed Connective Tissue Disease | 4 | ||
| Undifferentiated Connective Tissue Disease and Overlap Syndromes | 5 | ||
| Antiphospholipid Antibody Syndrome | 5 | ||
| Neonatal Lupus | 5 | ||
| Summary | 5 | ||
| References | 6 | ||
| 2 The Epidemiology of Lupus | 8 | ||
| The Fundamentals of Epidemiology | 8 | ||
| Case Definition | 8 | ||
| Case Ascertainment | 8 | ||
| Population at Risk | 9 | ||
| Pediatric Systemic Lupus Erythematosus | 15 | ||
| Cutaneous Lupus | 15 | ||
| Other Considerations | 15 | ||
| Environmental Epidemiology in Lupus | 15 | ||
| Smoking | 16 | ||
| Alcohol Consumption | 22 | ||
| Occupational Exposures and Chemicals | 22 | ||
| Ultraviolet Light Exposure and Lupus | 22 | ||
| Summary | 23 | ||
| Conclusion | 23 | ||
| References | 23 | ||
| II The Pathogenesis of Lupus | 25 | ||
| 3 The Pathogenesis of SLE | 25 | ||
| The Phases of Sle: Evolution of Disease in Susceptible Persons | 25 | ||
| Overview: The Major Immune Pathways Favoring Autoantibody Production | 25 | ||
| Stimulation of Innate and Adaptive Immune Responses by Autoantigens | 25 | ||
| Autoantibodies and Immune Complexes of SLE | 25 | ||
| Regulatory Mechanisms Fail to Control Autoimmune Responses | 26 | ||
| Abnormalities in T and B Lymphocytes in SLE | 26 | ||
| Cytokines/Chemokines and SLE | 28 | ||
| Genetics and Epigenetics | 28 | ||
| Gender Influences | 29 | ||
| Environmental Factors | 32 | ||
| Tissue Damage in SLE | 32 | ||
| Current Approved and Investigational Therapies for SLE | 34 | ||
| Suggested Reading | 34 | ||
| 4 Genetics of Human SLE | 35 | ||
| Monogenic Deficiencies and Rare Mutations with SLE | 35 | ||
| Complement Deficiency | 35 | ||
| TREX1 | 35 | ||
| TRAP | 35 | ||
| DNASE 1 | 35 | ||
| Polygenic Common Variants in SLE | 36 | ||
| Genome-Wide Linkage Studies | 36 | ||
| Candidate Gene Studies | 36 | ||
| Genome-Wide Association Studies | 36 | ||
| Human Leukocyte Antigen | 36 | ||
| Major Histocompatibility Complex Structure | 36 | ||
| HLA Class II Region and SLE | 39 | ||
| HLA Class III Region and SLE | 39 | ||
| Summary | 39 | ||
| Innate Immunity Genes | 39 | ||
| IRF5 | 39 | ||
| STAT4 | 40 | ||
| PHRF1/IRF7 | 40 | ||
| TLR7/TLR8 | 40 | ||
| IRAK1 and MECP2 | 40 | ||
| TNFAIP3 and TNIP1 | 40 | ||
| PRKCB | 40 | ||
| Adaptive Immunity Genes | 40 | ||
| PTPN22 | 41 | ||
| TNFSF4 | 41 | ||
| CD44 | 41 | ||
| BLK, BANK1, and LYN | 41 | ||
| ETS1 and PRDM1 | 41 | ||
| IKZF1 | 42 | ||
| IL10 | 42 | ||
| IL21 | 42 | ||
| Immune Complex Clearance | 42 | ||
| Common Genetic Variants of Complement Components | 42 | ||
| Fcγ Receptor Genes | 42 | ||
| ITGAM | 42 | ||
| Other Genes | 42 | ||
| Correlation of Genotypes with Disease Phenotypes in SLE | 43 | ||
| Gene-Gene Interactions among Susceptibility Loci in SLE | 43 | ||
| Common Loci among Autoimmune Diseases | 43 | ||
| Conclusion | 43 | ||
| References | 43 | ||
| 5 Epigenetics of Lupus | 46 | ||
| DNA Hypomethylation in SLE | 46 | ||
| Histone Modification Changes in SLE | 46 | ||
| microRNAs in SLE | 46 | ||
| miRNA Biogenesis | 47 | ||
| Novel Functions of miRNA in the Immune System | 47 | ||
| Dicer−/− | 49 | ||
| miR-155 | 49 | ||
| Depletion of miR-155 Causes Severe Immune Deficiency | 49 | ||
| miR-155 Is a Multifunctional Regulator in Toll-Like Receptor Signaling | 50 | ||
| Involvement of miR-155 in Inflammation | 50 | ||
| miR-146a: A Critical Immunomodulator | 50 | ||
| Other miRNAs | 50 | ||
| miRNAs in Immune Cell Differentiation and Maturation | 50 | ||
| miRNAs in Immune Response | 50 | ||
| Roles of miRNA in SLE | 51 | ||
| miRNA Profiling in SLE | 51 | ||
| Dysfunction of miRNAs in Lupus Pathogenesis | 51 | ||
| miRNA-Mediated Hyperactivation of the Interferon Pathway in SLE | 51 | ||
| Roles of miRNAs in DNA Hypomethylation in Lupus CD4+ T Cells | 52 | ||
| Dysregulation of miRNAs as a Causal Factor of Abnormal Cytokine/Chemokine Production | 52 | ||
| Interaction of miRNAs with Genetic Factors in Lupus | 52 | ||
| Conclusions and Future Perspectives | 54 | ||
| References | 54 | ||
| 6 The Innate Immune System in SLE | 57 | ||
| What Constitutes an Autoantigen? | 57 | ||
| The Endosomal Nucleic Acid–Sensing PRRs | 57 | ||
| TLR7 and TLR9 in SLE | 58 | ||
| In Vivo Support for TLR Associations with SLE | 58 | ||
| Potential Sources of Autoantigen | 59 | ||
| The Cytosolic Nucleic Acid–Sensing PRRs | 60 | ||
| Defects in DNA and RNA Degradation | 60 | ||
| Summary and Potential Therapies: Implication for Targeting PRR Pathways | 60 | ||
| References | 60 | ||
| 7 Cytokines and Interferons in Lupus | 62 | ||
| Properties of Cytokines and Their Receptors | 62 | ||
| Assessment of Cytokine Production | 62 | ||
| Use of Microarray to Study Cytokine Effects | 64 | ||
| Activation of the Immune Response in SLE | 64 | ||
| Cytokines of the Innate Immune Response | 64 | ||
| Type I Interferons | 65 | ||
| Tumor Necrosis Factor | 67 | ||
| Osteopontin | 68 | ||
| Interleukin-1 | 68 | ||
| Interleukin-10 | 68 | ||
| B-Lymphocyte Stimulator (BLyS) | 68 | ||
| Interleukin-6 | 68 | ||
| Other Cytokines | 69 | ||
| Cytokines of the Adaptive Immune Response | 69 | ||
| Cytokines Generated in the Adaptive Immune Response: T-Cell–Derived Cytokines | 69 | ||
| The Th1/Th2 Paradigm | 69 | ||
| Interleukin-2 | 69 | ||
| Interferon-γ | 69 | ||
| Th2 Cytokines in SLE | 70 | ||
| TGF-β | 70 | ||
| Additional T-Cell–Derived Cytokines | 70 | ||
| Cytokines Generated in the Adaptive Immune Response: B-Cell–Derived Cytokines | 70 | ||
| Summary | 70 | ||
| References | 71 | ||
| 8 The Structure and Derivation of Antibodies and Autoantibodies | 76 | ||
| Structure of the Antibody Molecule | 76 | ||
| Antibody Assembly | 77 | ||
| Generation of Antibody Diversity | 78 | ||
| Somatic Hypermutation | 79 | ||
| B-Cell Subsets: Implications for SLE | 80 | ||
| Toll-Like Receptors in B-Cell Function | 81 | ||
| Pathogenic Autoantibodies | 82 | ||
| Genetic and Molecular Analysis of Anti-DNA Antibodies | 83 | ||
| Autoantibody Induction | 83 | ||
| B-Cell Tolerance | 85 | ||
| Therapeutic Interventions | 87 | ||
| Non–Antigen-Specific Therapies | 87 | ||
| Depleting Autoreactive B Cells | 87 | ||
| Interfering with T-Cell Help | 87 | ||
| Antigen-Based Therapies | 88 | ||
| Summary | 88 | ||
| References | 89 | ||
| 9 T Cells | 96 | ||
| Role of T Cells in Autoimmunity and Inflammation | 96 | ||
| Help to B Cells | 96 | ||
| Promotion of Inflammation | 96 | ||
| CD8+ and Double-Negative T Cells | 97 | ||
| Regulatory Function | 97 | ||
| Intrinsic T-Cell Defects | 98 | ||
| Assembly and Selection of the T-Cell Repertoire | 98 | ||
| T-Cell Activation and Signaling | 98 | ||
| Regulation of Gene Expression | 98 | ||
| Mitochondrial Dysfunction and mTOR Signaling | 100 | ||
| Apoptosis Induction | 100 | ||
| Conclusion | 100 | ||
| References | 100 | ||
| 10 Regulatory Cells in SLE | 104 | ||
| Regulatory T Cells | 104 | ||
| CD4+ Regulatory T Cells | 104 | ||
| CD4+ Tregs and SLE | 106 | ||
| CD8+ Tregs | 106 | ||
| CD8+ Tregs and SLE | 106 | ||
| Regulatory B Cells | 107 | ||
| Regulatory B Cells and SLE | 107 | ||
| Myeloid-Derived Suppressor Cells | 107 | ||
| Myeloid-Derived Suppressor Cells and SLE | 107 | ||
| Dendritic Cells | 108 | ||
| Dendritic Cells and SLE | 108 | ||
| Natural killer Cells | 108 | ||
| NK Cells and SLE | 109 | ||
| Invariant NKT cells | 109 | ||
| Invariant NKT Cells and SLE | 109 | ||
| Conclusions | 110 | ||
| References | 110 | ||
| 11 Apoptosis, Necrosis, and Autophagy | 115 | ||
| Definitions | 115 | ||
| Apoptosis | 115 | ||
| Necrosis | 115 | ||
| Autophagy | 115 | ||
| Other Forms of Cell Death | 115 | ||
| Biochemistry of Apoptosis | 116 | ||
| Caspases | 116 | ||
| Inhibition of Caspases—Intracellular Inhibitors of Apoptosis | 117 | ||
| Nucleases and the Degradation of Cellular DNA and RNA | 117 | ||
| The Bcl-2 Family: Central Regulators of Apoptosis | 118 | ||
| Abnormalities in the Expression of Bcl-2 Family Members Cause Lupus-Like Autoimmunity in Mice | 119 | ||
| Initiation and Pathways of Apoptosis | 119 | ||
| Extrinsic Signaling Through Death Receptors | 119 | ||
| Regulation of Death Receptors | 120 | ||
| Function in Immune Regulation | 121 | ||
| Deficiencies in Death Receptor Signaling Lead to Systemic Autoimmunity | 121 | ||
| Intrinsic Death Pathways from Cellular Damage or Stress | 121 | ||
| The Mitochondria as an Integrator of Cell Metabolism and Apoptosis | 121 | ||
| Metabolic Stress | 121 | ||
| Genotoxic Stress | 121 | ||
| Endoplasmic Reticulum Stress | 122 | ||
| Removal of Apoptotic Cells | 122 | ||
| Receptors and Ligands | 122 | ||
| Function in Immune Regulation | 123 | ||
| Defective Clearance of Apoptotic Cells Predisposes to Lupus-Like Disease in Mice | 123 | ||
| Apoptosis Abnormalities in Human SLE | 123 | ||
| Is the Process of Cell Death Normal in SLE? | 123 | ||
| Is the Response to Dying Cells Abnormal? | 123 | ||
| Do Patients with SLE Have Reduced Clearance of Apoptotic Cells? | 124 | ||
| Conclusions | 124 | ||
| Acknowledgments | 124 | ||
| References | 124 | ||
| 12 Abnormalities in Immune Complex Clearance and Fcγ Receptor Function | 127 | ||
| The Role of the Mononuclear Phagocyte System in the Clearance of Immune Complexes | 127 | ||
| Mechanisms of Immune Complex Clearance | 127 | ||
| Complement Mechanisms: Immune Adherence and the Erythrocyte CR1 System | 127 | ||
| Fcγ Receptor Mechanisms | 128 | ||
| Abnormal Immune Complex Clearance in SLE | 129 | ||
| Human Models of Immune Complex Clearance | 129 | ||
| Analysis of the Clearance of IgG-Sensitized Autologous Erythrocytes | 129 | ||
| Analysis of Clearance of Infused Soluble Immune Complexes | 130 | ||
| Biology of Human Fcγ Receptors | 131 | ||
| Structure and Distribution | 131 | ||
| Ligands | 132 | ||
| FcγR Signal Transduction | 133 | ||
| FcγR-Mediated Effector Functions | 133 | ||
| Inherited Differences in FcγRs | 133 | ||
| Abnormalities in Fcγ Receptors in SLE | 134 | ||
| Strategies for Modulating FcγR-Mediated Immune Complex Clearance and Receptor Function | 135 | ||
| Acknowledgments | 136 | ||
| References | 136 | ||
| 13 Neural-Immune Interactions: | 141 | ||
| The Immune System | 141 | ||
| Central Nervous System Regulation of Immunity | 141 | ||
| The Neuroendocrine System | 142 | ||
| The Stress Response | 143 | ||
| Sex Hormones | 143 | ||
| Interactions between the HPA and HPG Axes | 143 | ||
| Molecular Mechanisms of Steroid Hormone Actions | 143 | ||
| Impact of Neuroendocrine Factors on Immunity | 143 | ||
| Glucocorticoid Modulation of the Immune System | 144 | ||
| Effects of Sex Hormones on Immunity | 145 | ||
| Autonomic and Peripheral Nervous System Regulation of Immunity | 145 | ||
| Sympathetic Nervous System Effects on Inflammation and the Immune System | 145 | ||
| Parasympathetic Nervous System and Immunity | 145 | ||
| Peripheral Nervous System Effects on Inflammation and the Immune System | 146 | ||
| Physiologic Impact of Miscommunications between the CNS and Immune System | 146 | ||
| Glucocorticoid Resistance | 146 | ||
| Effects of Stress in SLE | 146 | ||
| Neuroendocrine Mechanisms in SLE | 147 | ||
| Autonomic and Peripheral Nervous System Activity in SLE | 147 | ||
| Summary | 147 | ||
| References | 147 | ||
| 14 Complement and SLE | 152 | ||
| Historical Overview | 152 | ||
| Biology of the Complement System | 152 | ||
| Complement Activation Pathways | 152 | ||
| Regulators of Complement Activation | 154 | ||
| Receptors for Complement Proteins | 155 | ||
| Effector Functions of Complement | 156 | ||
| Complement: An Important Bridge between Innate Immunity and Adaptive Immunity | 156 | ||
| Complement and SLE | 156 | ||
| Immune Complex Abnormalities, Complement Activation, and Tissue Injury | 156 | ||
| Complement Deficiency and SLE | 156 | ||
| Possible Mechanisms Underlying the Complement Deficiency–SLE Association | 157 | ||
| Analyses of Complement | 158 | ||
| Measurement of Complement Functional Activity | 158 | ||
| Measurement of Complement Proteins | 158 | ||
| Measurement of Complement Activation Products | 159 | ||
| Proteomics Approaches for Complement Analyses | 159 | ||
| Soluble Complement Components as Biomarkers for SLE | 159 | ||
| Soluble Complement Components and SLE Activity | 159 | ||
| Complement Measurement in Lupus Nephritis | 160 | ||
| Problems Associated with Measurement of Soluble Complement Components | 160 | ||
| Cell-Bound Complement as a Biomarker for SLE | 160 | ||
| Rationale for Cell-Bound Complement Biomarkers | 160 | ||
| Investigational Studies of Cell-Bound Complement Activation Products | 161 | ||
| Clinical Applications of Cell-Bound Complement Activation Products as Lupus Biomarkers | 161 | ||
| Cell-Bound Complement Activation Products as Diagnostic Biomarkers for SLE | 161 | ||
| Cell-Bound Complement Activation Products as Biomarkers for SLE Disease Activity | 162 | ||
| Cell-Bound Complement Activation Products as Biomarkers for Stratifying Clinical Subsets of SLE Patients | 162 | ||
| Anticomplement Therapeutics for SLE | 162 | ||
| Conclusion | 163 | ||
| References | 163 | ||
| 15 Mechanisms of Acute Inflammation and Vascular Injury in SLE | 166 | ||
| Epidemiology of Premature Vascular Damage in SLE | 166 | ||
| Subclinical and Clinical Vascular Damage in SLE | 166 | ||
| Mechanisms of Atherosclerosis Development in the General Population | 166 | ||
| Mechanisms of Endothelial Inflammation, Injury, and Atherosclerosis in SLE | 167 | ||
| Type I Interferons and SLE-Related Cardiovascular Disease | 168 | ||
| Induction of an Imbalance of Vascular Damage and Repair by Type I Interferons | 168 | ||
| IFN-α and Plaque Formation | 169 | ||
| Platelet Abnormalities Induced by IFN-α | 169 | ||
| Neutrophil Extracellular Traps | 169 | ||
| Other Cytokines | 170 | ||
| T Cells | 170 | ||
| Complement and Immune Complexes | 171 | ||
| Oxidative Stress | 171 | ||
| Lupus-Related Dyslipidemias | 171 | ||
| Antiphospholipid Antibodies | 171 | ||
| Other Autoantibodies | 172 | ||
| Conclusion | 172 | ||
| References | 172 | ||
| 16 Mechanisms of Tissue Damage—Free Radicals and Fibrosis | 175 | ||
| Free Radicals and Oxidative Stress | 175 | ||
| Free Radicals, Antioxidant Enzymes, and Lipid Peroxidation | 175 | ||
| Detection of Radicals | 175 | ||
| Radical Chemistry—A Brief Outline | 175 | ||
| Reactive Oxygen Species | 175 | ||
| Interaction of Reactive Oxygen Species with Lipids | 176 | ||
| Interaction of Reactive Oxygen Species with Proteins | 176 | ||
| Reactive Nitrogen Species | 176 | ||
| Oxidation and Immune Response | 177 | ||
| Oxidative Damage and Oxidative Modification of Proteins in Autoimmune Disease | 178 | ||
| Free Radical Damage in SLE | 178 | ||
| Increased Oxygen Free Radical Production in SLE | 178 | ||
| Altered Antioxidant Enzyme and Antioxidant Levels in SLE | 179 | ||
| Antibodies to Catalase, Superoxide Dismutase, and Oxidized Low-Density Lipoprotein | 179 | ||
| Lipid Peroxidation | 180 | ||
| Protein Modification and Antibodies against Modified Proteins | 181 | ||
| Antibodies against Oxidatively Modified Proteins | 181 | ||
| Oxidative Modification of DNA | 181 | ||
| Reactive Nitrogen Species in SLE | 181 | ||
| Nitration and NO in SLE | 181 | ||
| Animal Models of SLE and Oxidative Damage | 182 | ||
| Animal Models of SLE and Reactive Oxygen Species | 182 | ||
| Animal Models of SLE and Reactive Nitrogen Species | 183 | ||
| Therapy in SLE | 184 | ||
| Fibrosis in SLE | 184 | ||
| Renal Fibrosis in Lupus Nephritis | 184 | ||
| Pulmonary Fibrosis in SLE | 185 | ||
| Fibrotic Lupus Pneumonitis (Chronic Interstitial Lung Disease) | 185 | ||
| Pulmonary Arterial Hypertension | 186 | ||
| Drug-Induced Pulmonary Fibrosis | 186 | ||
| Cirrhosis or Periportal Hepatitis in SLE | 186 | ||
| Retroperitoneal Fibrosis | 186 | ||
| Mechanisms of Fibrosis in SLE | 186 | ||
| Conclusion | 187 | ||
| References | 187 | ||
| 17 Animal Models of SLE | 190 | ||
| Clinical Disease, Autoantibodies, Immunologic Abnormalities, and Genetics in Spontaneous Multigenic Murine SLE | 190 | ||
| New Zealand Mice | 190 | ||
| NZB/BL (NZB) Mice | 190 | ||
| Clinical Characteristics and Autoantibodies | 190 | ||
| Abnormalities of Stem Cells and B Cells | 191 | ||
| Abnormalities of Dendritic Cells | 193 | ||
| Abnormalities of Thymus and T Cells | 194 | ||
| Genetics | 194 | ||
| Summary | 194 | ||
| New Zealand White Mice | 194 | ||
| Clinical Characteristics and Autoantibodies | 194 | ||
| Genetics | 195 | ||
| (NZB/NZW) F1 Mice (BWF1) | 195 | ||
| Clinical Characteristics and Autoantibodies | 196 | ||
| Nephritis in BWF1 Females: the Autoantibodies, the Infiltrating Cells, and the Predisposing Glomerular Structures | 196 | ||
| Neurologic Tissue | 198 | ||
| Lymphoproliferation | 198 | ||
| Sex Hormone Influences on Lupus in BWF1 Mice | 198 | ||
| Interferons and SLE in BWF1 Mice | 198 | ||
| Abnormalities of Hematopoietic Cells in BWF1 Mice | 198 | ||
| Abnormalities of Thymus and T Cells | 199 | ||
| Abnormalities of Monocytes/Macrophages | 199 | ||
| The Role of Defective Regulatory Cells in BWF1 Lupus (CD4+CD25+, CD8+, NK T Cells, B-1 B Cells) | 199 | ||
| Abnormalities of Dendritic Cells in BWF1 Mice | 199 | ||
| Genetic Predisposition | 199 | ||
| III Autoantibodies | 256 | ||
| 19 Immune Tolerance Defects in Lupus | 256 | ||
| Immune Tolerance | 256 | ||
| Lymphocyte Homeostasis and Immune Tolerance | 256 | ||
| Mechanisms Underlying T-Cell Tolerance | 257 | ||
| Thymic Selection | 257 | ||
| Induction of Anergy | 257 | ||
| Immune Deviation | 259 | ||
| Regulatory, Suppressor, or Inhibitory T cells | 259 | ||
| Mechanism of B-Cell Tolerance | 259 | ||
| Immune Tolerance Defects in Lupus | 261 | ||
| Abnormalities at the Level of Autoantigens in Causing Tolerance Breakdown | 261 | ||
| Impairment of Antigen-Presenting Cell Function in Tolerance Breakdown | 261 | ||
| T-Cell Abnormalities Contributing to Tolerance Breakdown | 262 | ||
| Impaired Clonal Deletion of Lupus Autoreactive T-Helper Cells | 262 | ||
| Neonatal and Adult Tolerance to Exogenously Administered Peptide Antigens in Lupus | 262 | ||
| Intact Central Tolerance but Impaired Peripheral T-Cell Control Mechanisms | 262 | ||
| T Cell–Signaling Defects in SLE | 262 | ||
| Expansion of Follicular Helper T Cells in Lupus | 264 | ||
| B-Cell Abnormalities Contributing to Tolerance Breakdown | 264 | ||
| Breaking the B-Cell Tolerance Checkpoints | 264 | ||
| B-Cell Receptor Signaling Defects, Hyperactivation, and Loss of Tolerance in SLE | 265 | ||
| Role of B Cells in Breaking T-Cell Tolerance | 266 | ||
| Impairments of Regulatory T Cells and Factors as Mechanisms of Loss of Tolerance | 266 | ||
| Strategies to Reestablish Tolerance in Lupus | 267 | ||
| Tolerizing DNA-Specific B Cells | 267 | ||
| Tolerizing Lupus Th Cells | 267 | ||
| Non–Antigen-Specific Approaches to Reestablishing Immune Tolerance in SLE | 267 | ||
| Stem Cell Transplantation to Reset Immune Tolerance in SLE | 267 | ||
| Looking Beyond Immune Tolerance in Lupus | 268 | ||
| Synthesis | 268 | ||
| References | 268 | ||
| 20 Autoantibodies | 273 | ||
| Part A Antibody Structure, Function, and Production | 273 | ||
| Antibody Structure and Function | 273 | ||
| Antibody Production and the Generation of Diversity | 273 | ||
| References | 274 | ||
| Part B Antibodies to DNA, Histones, and Nucleosomes | 274 | ||
| Anti-DNA Antibodies in Lupus: Historical Overview | 274 | ||
| Measurement of Anti-dsDNA Antibodies | 275 | ||
| Work from Experimental Models Emphasing the Potential Importance of Anti-dsDNA Antibodies | 275 | ||
| How Pathogenic Anti-dsDNA Antibodies Bind to Tissues: The Importance of Binding to Nucleosomes | 275 | ||
| Cross-Reaction of Anti-DNA Antibodies with Intracellular Antigens | 276 | ||
| Antihistone Antibodies | 276 | ||
| Structure and Origin of Pathogenic Anti-dsDNA and Antinucleosome Antibodies | 276 | ||
| Can Measuring Anti-dsDNA Levels Help Us Manage Patients with SLE? | 277 | ||
| Summary | 277 | ||
| References | 277 | ||
| Part C Anti-lipoprotein and Anti–Endothelial Cell Antibodies | 278 | ||
| Anti–Endothelial Cell Antibodies | 278 | ||
| References | 279 | ||
| Part D Anti-C1q Antibodies | 279 | ||
| Antigenic Specificity and Methods of Detection of Anti-C1q | 279 | ||
| Clinical Associations | 279 | ||
| Do Levels of Anti-C1q Follow Disease Activity in Lupus (Nephritis)? | 280 | ||
| Pathogenic Role of Anti-C1q Autoantibodies | 280 | ||
| Conclusion | 280 | ||
| References | 280 | ||
| Part E Antibodies against the Extractable Nuclear Antigens RNP, Sm, Ro/SSA, and La/SSB | 281 | ||
| Structure of the Antigens | 281 | ||
| Sm/RNP Complex | 281 | ||
| Ro/SSA and La/SSB RNP Complex | 281 | ||
| Assays for Measuring Anti-ENA Antibodies | 281 | ||
| Prevalence and Clinical Associations in SLE | 282 | ||
| Virus Infections as Triggers for Autoimmunity | 282 | ||
| Sequential Presentation of Anti-ENA Antibodies and Relationship of Anti-ENA to Other Lupus-Specific Autoantibodies | 283 | ||
| Role of Apoptosis for the Generation of Anti-ENA Antibodies | 283 | ||
| Toll-Like Receptors as Key Molecules for the Generation of Anti-ENA Antibodies | 283 | ||
| Genetic Risks and Anti-ENA Antibodies | 283 | ||
| Pathogenic Importance of Anti-RNP and Anti-Sm Antibodies | 284 | ||
| Pathogenic Role of Anti-Ro/SSA and Anti-La/SSB Antibodies | 284 | ||
| References | 284 | ||
| 21 Autoantigenesis and Antigen-Based Therapy and Vaccination in SLE | 286 | ||
| Autoantigenesis: Mechanisms that Make an Antigen an Autoantigen | 286 | ||
| Defective Apoptosis | 286 | ||
| Impaired Removal of Apoptotic Cells | 286 | ||
| Mutations | 286 | ||
| Genetic Polymorphisms | 287 | ||
| Alternative Splicing | 287 | ||
| Posttranslational Modifications | 287 | ||
| Altered Antigen Processing | 287 | ||
| Molecular Mimicry | 287 | ||
| Defective Sensing and Uptake of Autoantigen | 287 | ||
| Chronic Inflammation as a Trigger of Autoantigenesis | 289 | ||
| Mechanisms by which Autoantigens May Contribute to the Development of Disease | 289 | ||
| Induction of Effector T cells | 289 | ||
| Reduced Activation of Regulatory, Inhibitory, or Suppressor T Cells | 290 | ||
| Activation of Toll-Like Receptors | 290 | ||
| Autoantigens as Chemoattractants | 290 | ||
| Altered Recognition of Autoantigens | 290 | ||
| Autoantigen Ro52 | 290 | ||
| Common Autoantigens in Lupus | 290 | ||
| Identification of Autoantigenic Epitopes in Lupus | 291 | ||
| Studies in Animal Models | 291 | ||
| Nucleosome Core Histone Peptides as Th Autoepitopes | 291 | ||
| Self-Ig Peptides as Autoantigenic Epitopes | 291 | ||
| T-Cell Pepscan of U1-70K snRNP Autoantigen | 292 | ||
| Screening Phage Display Library to Identify Peptidomimetics That Bind Anti-DNA Antibody | 292 | ||
| Identification of Self-Epitopes in Human SLE | 292 | ||
| Autoantigen-Based Vaccination and Peptide Therapies in Lupus | 293 | ||
| Preclinical Animal Studies | 293 | ||
| Gene Vaccination for SLE | 295 | ||
| Human Studies and Clinical Trials | 295 | ||
| Mechanisms of Peptide-Based Therapies in Lupus | 297 | ||
| Neonatal Peptide Tolerance: Can Peptide Vaccines Worsen Lupus? | 297 | ||
| Induction of “Direct” Tolerance in Th Cells: Induction of Apoptosis | 297 | ||
| Modulation of T-Cell Subsets: Increased Regulatory but Decreased Follicular T Helper, Th1, and Th17 Cells | 297 | ||
| Modulation of PD-1 | 297 | ||
| Role of Dendritic Cells in Facilitating Peptide-Induced Tolerance | 297 | ||
| Modulation of Cytokine Production: Reduced Proinflammatory but Increased Regulatory Cytokines | 297 | ||
| Modulation of Molecules Associated with B-Cell Survival and Function | 298 | ||
| Modulating Determinant Spreading | 298 | ||
| Inhibiting T-Cell Chemotaxis | 298 | ||
| Inhibiting Autoantibody Binding to Extracellular Matrix | 298 | ||
| Induction of Cytotoxic T Lymphocytes That Ablate Autoreactive B Cells | 298 | ||
| Alteration of Autophagic Process and MHC Class II Stability | 298 | ||
| Will Peptide-Specific Treatment Ever Be a Reality in Patients with SLE? | 298 | ||
| Synthesis | 299 | ||
| References | 299 | ||
| IV Clinical Aspects of SLE | 304 | ||
| 22 Overview and Clinical Presentation | 304 | ||
| History | 304 | ||
| Chief Complaint | 304 | ||
| Variations in Clinical Presentation | 304 | ||
| Incomplete Lupus | 304 | ||
| Late-Onset Lupus | 306 | ||
| Male Lupus | 307 | ||
| Constitutional Symptoms | 308 | ||
| Fever | 308 | ||
| Lymphadenopathy | 308 | ||
| Weight Loss | 308 | ||
| Malaise and Fatigue | 308 | ||
| References | 308 | ||
| 23 Pathomechanisms of Cutaneous Lupus Erythematosus | 310 | ||
| Clinical Photosensitivity in Lupus | 310 | ||
| Action Spectrum of Cutaneous Lupus Erythematosus | 310 | ||
| Role of Ultraviolet Light in the Exacerbation of SLE | 310 | ||
| A Selective Sensitivity to Ultraviolet Light in LE? | 310 | ||
| Responses to Ultraviolet Light in Cutaneous Lupus Erythematosus | 310 | ||
| Ultraviolet Light, Cell Death, and the Skin | 311 | ||
| Cell Death in Cutaneous Lupus Erythematosus | 311 | ||
| Ultraviolet Light as Inflammatory Stimulus | 313 | ||
| Humoral Factors in Cutaneous Lupus Erythematosus | 313 | ||
| Immunopathology of Cutaneous Lupus Erythematosus | 313 | ||
| Ro/SSA Autoantibodies and LE Photosensitivity | 313 | ||
| Cellular Factors | 314 | ||
| Immunogenetics | 314 | ||
| Immune Cells and Murine Models of Cutaneous Lupus Erythematosus | 314 | ||
| Role of Activated T Cells in Human Cutaneous Lupus Erythematosus | 314 | ||
| Cofactors in Cutaneous Lupus Erythematosus | 315 | ||
| Ultraviolet Effects on Cutaneous Vasculature | 315 | ||
| Vascular Activation | 315 | ||
| Cytokines | 315 | ||
| TNF-α and IL-18 | 315 | ||
| IL-17 | 315 | ||
| Type 1 and Type 3 Interferons | 315 | ||
| A Model of Pathogenesis of Cutaneous Lupus Erythematosus | 316 | ||
| Acknowledgments | 316 | ||
| References | 317 | ||
| 24 Skin Disease in Cutaneous Lupus Erythematosus | 319 | ||
| History | 319 | ||
| Epidemiology | 319 | ||
| Triggers of CLE | 319 | ||
| Clinical Features | 319 | ||
| Classification of Cutaneous LE | 319 | ||
| Lupus-Specific Skin Lesions | 319 | ||
| Acute Cutaneous LE | 319 | ||
| Subacute Cutaneous LE | 320 | ||
| Chronic Cutaneous LE | 322 | ||
| Hypertrophic/Verrucous DLE. | 322 | ||
| Lupus Panniculitis/Lupus Profundus. | 323 | ||
| Mucosal DLE. | 323 | ||
| LE Tumidus/Papulomucinous LE. | 323 | ||
| Chilblain LE | 323 | ||
| Lichen Planus–Lupus Erythematosus Overlap. | 323 | ||
| Additional Variants | 324 | ||
| Bullous LE. | 324 | ||
| Neonatal LE. | 324 | ||
| Relationship with Systemic Disease Features | 324 | ||
| Pathology | 324 | ||
| Immunopathology | 324 | ||
| Laboratory Findings | 325 | ||
| Differential Diagnosis | 325 | ||
| Treatment | 325 | ||
| Topical Therapy | 325 | ||
| Systemic Therapy | 325 | ||
| Lupus-Nonspecific Skin Lesions | 325 | ||
| Photosensitivity | 326 | ||
| Alopecia | 326 | ||
| Cutaneous Vascular Reactions | 326 | ||
| Vasculitis | 326 | ||
| Vasculopathy | 327 | ||
| Ischemic Vasculopathy | 327 | ||
| Raynaud Phenomenon | 327 | ||
| Thromboembolic Vasculopathy and Antiphospholipid Antibodies | 328 | ||
| Cryoglobulins | 328 | ||
| Cholesterol Crystals | 328 | ||
| Calcium Deposits | 328 | ||
| Other Cutaneous Vascular Reactions | 328 | ||
| Urticaria | 328 | ||
| Periungual Telangiectasias | 329 | ||
| Erythromelalgia and Palmar Erythema | 329 | ||
| Other LE-Nonspecific Skin Lesions | 329 | ||
| Cutaneous Mucinosis | 329 | ||
| Calcinosis Cutis | 329 | ||
| Nail Changes | 329 | ||
| Anetoderma | 330 | ||
| Interstitial Granulomatous Dermatitis | 330 | ||
| Conclusion | 330 | ||
| References | 330 | ||
| 25 The Musculoskeletal System and Bone Metabolism | 333 | ||
| Arthritis | 333 | ||
| Soft Tissue Disorders and Other Pain Syndromes | 333 | ||
| Muscle Involvement | 334 | ||
| Musculoskeletal Infections | 334 | ||
| Avascular Necrosis of Bone | 334 | ||
| Osteoporosis | 336 | ||
| Summary | 338 | ||
| References | 338 | ||
| 26 Pathogenesis and Treatment of Atherosclerosis in Lupus | 341 | ||
| Introduction | 341 | ||
| Subclinical Measures of Atherosclerosis | 341 | ||
| Traditional and SLE-Specific Risk Factors for Atherosclerosis in SLE | 341 | ||
| Traditional Risk Factors | 341 | ||
| SLE-Specific Risk Factors | 342 | ||
| Disease Activity, Duration, and Damage | 342 | ||
| Renal Disease | 342 | ||
| Glucocorticoid Therapy | 342 | ||
| Antiphospholipid Antibodies | 343 | ||
| Novel Biomarkers/“Non-traditional” Cardiac Risk Factors | 343 | ||
| Inflammation and the Pathogenesis of Atherosclerosis | 343 | ||
| Monocyte and T-Cell Recruitment to the Arterial Wall | 343 | ||
| Low-Density Lipoproteins and the Development of Foam Cells | 343 | ||
| HDL Clears Ox-LDL from the Endothelium | 343 | ||
| Innate Immunity in Atherosclerosis | 344 | ||
| Potential Biomarkers for Atherosclerosis in SLE | 344 | ||
| Oxidized Low-Density Lipoproteins | 344 | ||
| Lipoprotein(a) | 344 | ||
| High-Density Lipoproteins: Function and Structure | 345 | ||
| Proinflammatory HDL | 345 | ||
| Apolipoprotein A-I and Antibodies to It | 345 | ||
| Paraoxonase | 345 | ||
| Adipocytokines | 345 | ||
| Markers of Endothelial Dysfunction | 345 | ||
| C-Reactive Protein | 345 | ||
| Homocysteine | 346 | ||
| Strategies for Prevention of Cardiovascular Complications in SLE | 346 | ||
| Minimizing Framingham Risk Factors | 346 | ||
| Hypertension | 346 | ||
| Dyslipidemia: Statin Use | 346 | ||
| Modulators of Lupus Disease Activity | 347 | ||
| Antimalarial Therapy | 347 | ||
| Azathioprine | 347 | ||
| Glucocorticoids | 347 | ||
| Mycophenolate Mofetil | 347 | ||
| Summary | 347 | ||
| References | 347 | ||
| 27 Cardiopulmonary Disease in SLE | 352 | ||
| Cardiopulmonary Manifestations | 352 | ||
| Serositis: Pleurisy and Pericarditis | 352 | ||
| Acute Lupus Pneumonitis | 352 | ||
| Pulmonary Hemorrhage | 353 | ||
| Chronic Diffuse Interstitial Lung Disease | 354 | ||
| Pulmonary Embolism | 355 | ||
| Reversible Hypoxemia | 355 | ||
| Pulmonary Hypertension | 355 | ||
| Shrinking Lung Syndrome | 355 | ||
| Airway Obstruction | 356 | ||
| Infections and the Lung in SLE | 356 | ||
| Myocardiac Involvement | 356 | ||
| Valvular Heart Disease | 357 | ||
| Diagnostic Challenges | 358 | ||
| Treatment | 358 | ||
| Pleuropericarditis | 359 | ||
| Pneumonitis and Alveolar Hemorrhage | 359 | ||
| Interstitial Lung Disease | 360 | ||
| Bronchiolitis | 360 | ||
| Pulmonary Thromboembolism | 360 | ||
| Pulmonary Arterial Hypertension | 360 | ||
| Shrinking Lung Syndrome | 360 | ||
| Myocarditis | 360 | ||
| Heart Valve Disease | 360 | ||
| References | 361 | ||
| 28 Pathogenesis of the Nervous System | 363 | ||
| Vascular Mechanisms | 363 | ||
| Central Nervous System Mechanisms | 363 | ||
| Cytokines and Chemokines | 363 | ||
| Autoantibodies | 364 | ||
| Blood-Brain Barrier | 364 | ||
| Peripheral Nervous System Mechanisms | 365 | ||
| Summary | 365 | ||
| References | 365 | ||
| 29 Clinical Aspects of the Nervous System | 368 | ||
| Classification | 368 | ||
| Clinical Presentations | 368 | ||
| Frequency of Manifestations | 368 | ||
| Etiopathogenesis | 368 | ||
| Clinical Manifestations | 369 | ||
| Central Nervous System | 369 | ||
| Acute Confusional State | 369 | ||
| Cognitive Dysfunction | 369 | ||
| Headache | 370 | ||
| Aseptic Meningitis | 370 | ||
| Cerebrovascular Disease | 370 | ||
| Myelopathy | 371 | ||
| Movement Disorders | 371 | ||
| Demyelinating Syndrome | 372 | ||
| Seizures | 372 | ||
| Psychiatric Disorders | 372 | ||
| Psychosis | 372 | ||
| Mood and Anxiety Disorders | 372 | ||
| Peripheral Nervous System | 372 | ||
| Cranial Neuropathies | 372 | ||
| Peripheral Polyneuropathies | 373 | ||
| Autonomic Disorders | 373 | ||
| Myasthenia Gravis and Related Disorders | 373 | ||
| Neuropsychiatric Systemic Lupus Erythematosus in Children and Older Adults | 374 | ||
| Secondary Causes of Central Nervous System Dysfunction in Systemic Lupus Erythematosus | 374 | ||
| Clinical and Laboratory Evaluation | 374 | ||
| Clinical Laboratory Tests | 374 | ||
| Autoantibodies | 375 | ||
| Antiphospholipid Antibodies | 375 | ||
| Anti–Ribosomal P Antibodies | 376 | ||
| Antineuronal and Neural Antigen-Specific Antibodies | 377 | ||
| Cerebrospinal Fluid Tests | 377 | ||
| Routine Cerebrospinal Fluid Tests | 377 | ||
| Cerebrospinal Fluid Immunologic Tests | 377 | ||
| Cerebrospinal Fluid Antineuronal Antibodies | 377 | ||
| Miscellaneous Determinations | 377 | ||
| Summary | 377 | ||
| Neuroimaging Studies | 377 | ||
| Angiography | 378 | ||
| Electroencephalography | 378 | ||
| Treatment | 378 | ||
| Central Nervous System Manifestations | 378 | ||
| Difficult Clinical Situations | 379 | ||
| Peripheral Nervous System Manifestations | 379 | ||
| Prognosis | 379 | ||
| References | 380 | ||
| 30 Psychopathology, Neurodiagnostic Testing, and Imaging | 382 | ||
| Introduction | 382 | ||
| Classification of Neuropsychiatric Systemic Lupus Erythematosus | 382 | ||
| Frequency and Attribution of Neuropsychiatric Systemic Lupus Erythematosus | 382 | ||
| Psychiatric Disorders | 382 | ||
| Acute Confusional State (Delirium) | 382 | ||
| Anxiety Disorders | 383 | ||
| Mood Disorders | 383 | ||
| Psychosis | 384 | ||
| Cognitive Function in Systemic Lupus Erythematosus | 384 | ||
| Etiology of Cognitive Impairment in Systemic Lupus Erythematosus | 385 | ||
| Cognitive Function, Global Systemic Lupus Erythematosus Disease Activity, and Overt Neuropsychiatric Systemic Lupus Erythematosus | 385 | ||
| Cognitive Function and Psychiatric Morbidity | 385 | ||
| Cognitive Function and Medication | 386 | ||
| Cognitive Function and Immunologic Variables | 386 | ||
| Neuroimaging | 386 | ||
| Differences between Brain Structure and Function | 386 | ||
| Clinical Structural Imaging Methods: Computed Tomography and Magnetic Resonance Imaging | 387 | ||
| Computed Tomography | 387 | ||
| Magnetic Resonance Imaging | 387 | ||
| Clinical Functional Imaging | 387 | ||
| Electroencephalogram | 387 | ||
| Positron Emission Tomography and Single-Photon Emission Computed Tomography | 387 | ||
| Nonconventional Magnetic Resonance Imaging | 388 | ||
| Functional Magnetic Resonance Imaging | 388 | ||
| Magnetic Resonance Relaxometry | 388 | ||
| Magnetization Transfer Imaging | 388 | ||
| Diffusion Tensor Imaging | 389 | ||
| Magnetic Resonance Spectroscopy | 389 | ||
| Treatment of Psychiatric Disorders and Cognitive Impairment in Systemic Lupus Erythematosus | 389 | ||
| Summary | 390 | ||
| Acknowledgments | 390 | ||
| References | 390 | ||
| 31 Ocular, Aural, and Oral Manifestations | 393 | ||
| Systemic Lupus Erythematosus and the Eye | 393 | ||
| Retinal Vascular Disease | 393 | ||
| Choroidal Vascular Disease | 393 | ||
| Optic Neuropathy | 393 | ||
| Episcleritis and Scleritis | 394 | ||
| Corneal Disease and Keratitis | 395 | ||
| Uveitis | 395 | ||
| Orbital Inflammation | 395 | ||
| Chloroquine and Hydroxychloroquine Toxicity | 395 | ||
| Antiphospholipid Antibody Retinopathy | 396 | ||
| Oral Manifestations | 396 | ||
| Nasal Septal Disease | 397 | ||
| Relapsing Polychondritis | 397 | ||
| Laryngeal Involvement | 398 | ||
| Temporomandibular Joint | 398 | ||
| Ear Involvement and Lupus | 398 | ||
| Ear Involvement in Lupus | 398 | ||
| Mechanisms of Immune-Mediated Inner Ear Disease | 398 | ||
| Acknowledgments | 398 | ||
| References | 398 | ||
| 32 Management of Sjögren Syndrome in Patients with SLE | 401 | ||
| History | 401 | ||
| Clinical Presentation | 401 | ||
| Glandular Manifestations | 401 | ||
| Extraglandular Manifestations | 401 | ||
| Lymphoma Development | 401 | ||
| Serologic Findings | 402 | ||
| Classification and Diagnosis of Sjögren Syndrome | 404 | ||
| Pathogenesis | 405 | ||
| Genetic Factors | 405 | ||
| Hormonal Factors | 405 | ||
| Glandular Infiltration | 406 | ||
| Sjögren Syndrome in Patients with Lupus | 407 | ||
| Management of Glandular Manifestations | 407 | ||
| Management of Ocular Manifestations | 408 | ||
| Preventive Measures | 408 | ||
| Symptomatic Treatment | 408 | ||
| Management of Oral Manifestations | 408 | ||
| Preventive and General Measures for Oral Complications | 408 | ||
| Local Salivary Stimulation | 408 | ||
| Systemic Salivary Stimulation | 409 | ||
| Symptomatic Treatment | 409 | ||
| Prevention and Treatment of Oral Candidiasis | 410 | ||
| Management of Dry Surfaces Other than the Mouth and Eyes | 411 | ||
| Outcome Measures | 411 | ||
| Management of Extraglandular Disease | 411 | ||
| Antiinflammatory and Disease-Modifying Drugs | 411 | ||
| Treatment Strategies in Severe Extraglandular Manifestations | 411 | ||
| Nephritis | 411 | ||
| Neurologic Manifestations | 411 | ||
| Vasculitis | 411 | ||
| Hematologic Complications | 411 | ||
| Mucosa-Associated Lymphoid Tissue Lymphoma | 411 | ||
| Biological Agents in the Treatment of Sjögren Syndrome | 412 | ||
| Interferon-Alpha | 412 | ||
| Anti-CD20 Therapy | 412 | ||
| Future Perspectives | 412 | ||
| References | 412 | ||
| 33 Gastrointestinal and Hepatic Manifestations | 415 | ||
| Gastrointestinal Involvement | 415 | ||
| Prevalence | 415 | ||
| Pharyngitis, Dysphagia, and Esophagitis | 415 | ||
| Anorexia, Nausea, Vomiting, and Diarrhea | 415 | ||
| Motility Disorders | 415 | ||
| Abdominal Pain and Acute Abdomen | 416 | ||
| Peptic Ulcer Disease | 416 | ||
| Helicobacter pylori Infection in Systemic Lupus Erythematosus | 417 | ||
| Inflammatory Bowel Disease | 417 | ||
| Ulcerative Colitis | 417 | ||
| Regional Ileitis | 417 | ||
| Collagenous Colitis | 417 | ||
| Celiac Disease in Association with Systemic Lupus Erythematosus | 417 | ||
| Protein-Losing Enteropathy and Malabsorption | 417 | ||
| Ascites and Peritonitis | 418 | ||
| Pancreatitis | 418 | ||
| V The Reproductive System & Hormones | 455 | ||
| 36 Pregnancy in Women with SLE | 455 | ||
| Immunobiologic Implications of Pregnancy | 455 | ||
| Physiologic Alterations of Pregnancy | 455 | ||
| Immunologic Mechanisms of Pregnancy | 455 | ||
| Systemic Lupus Erythematosus Activity in Pregnancy | 456 | ||
| Types of Systemic Lupus Erythematosus Activity and Their Impact on Pregnancy Outcomes | 456 | ||
| Predictors of Systemic Lupus Erythematosus Activity | 456 | ||
| Pregnancy Outcomes in Systemic Lupus Erythematosus with Mediators of Complications | 456 | ||
| Pregnancy Loss | 456 | ||
| Preterm Birth | 457 | ||
| Preeclampsia | 457 | ||
| Offspring Outcomes | 457 | ||
| Maternal Mortality Rate | 457 | ||
| Types of Disease Activity | 457 | ||
| Lupus Nephritis | 458 | ||
| Frequency in Pregnancy | 458 | ||
| Impact on Pregnancy Outcomes | 458 | ||
| Differentiating Lupus Nephritis from Preeclampsia | 458 | ||
| Antiphospholipid Syndrome | 458 | ||
| Etiologic and Pathophysiologic Characteristics | 458 | ||
| Pregnancy Outcomes | 459 | ||
| Maternal Outcomes | 459 | ||
| Impact of Medications | 459 | ||
| Medications in Systemic Lupus Erythematosus Pregnancy | 459 | ||
| Nonsteroidal Antiinflammatory Drugs and Acetaminophen | 459 | ||
| Corticosteroids | 459 | ||
| Hydroxychloroquine | 460 | ||
| Azathioprine | 460 | ||
| Mycophenolate Mofetil | 461 | ||
| Cyclosporin | 461 | ||
| Cyclophosphamide | 461 | ||
| Intravenous Immunoglobulin | 461 | ||
| Rituximab | 461 | ||
| Belimumab | 461 | ||
| Discussion | 461 | ||
| References | 461 | ||
| 37 Neonatal Lupus Erythematosus | 464 | ||
| Etiologic Factors and Pathogenesis | 464 | ||
| Maternal Autoantibodies in Congenital Heart Block | 464 | ||
| Clues to Pathogenic Mechanisms in Congenital Heart Block from Experimental Models | 465 | ||
| Targets for Maternal Antibodies in the Fetal Heart | 466 | ||
| Additional Risk Factors in Congenital Heart Block Development | 466 | ||
| Cardiac Manifestations | 467 | ||
| Cutaneous Manifestations | 467 | ||
| Other Manifestations | 468 | ||
| Hematologic Abnormalities | 468 | ||
| Liver Abnormalities | 468 | ||
| Neurologic Abnormalities | 468 | ||
| Chondrodysplasia Punctata | 469 | ||
| Fetal Screening and Surveillance | 469 | ||
| Cardiac Involvement | 469 | ||
| Screening for Other Features of Neonatal Lupus Erythematosus | 469 | ||
| Prevention and Therapy | 469 | ||
| Steroids | 469 | ||
| Intravenous Immunoglobulin | 470 | ||
| Hydroxychloroquine | 470 | ||
| Sympathomimetic Medications | 470 | ||
| Long-Term Outcomes | 470 | ||
| References | 470 | ||
| 38 Reproductive and Hormonal Issues in Women with Autoimmune Diseases | 473 | ||
| Introduction | 473 | ||
| Hormones and Reproductive Immunology | 473 | ||
| Gonadal Hormones and the Immune System | 473 | ||
| Female Hormones and Inflammatory Mediators | 473 | ||
| Complex Effects of Sex Hormones on Inflammation | 473 | ||
| Sex Hormones and the Immune and Vascular Systems | 474 | ||
| Maternal-Fetal Immunology | 474 | ||
| Embryologic Development of the Immune System | 474 | ||
| Reproductive Issues in Women with Systemic Lupus Erythematosus and Related Autoimmune Disorders | 475 | ||
| Contraception | 475 | ||
| Estrogen-Containing Contraception | 476 | ||
| Progestin-Only Hormonal Contraception | 476 | ||
| Intrauterine Devices | 476 | ||
| Barrier Methods | 477 | ||
| Infertility and Protection against Premature Ovarian Failure | 477 | ||
| Assisted Reproductive Technologies | 477 | ||
| Recurrent Pregnancy Loss | 477 | ||
| Antiphospholipid Antibody–Mediated Recurrent Pregnancy Loss | 478 | ||
| Treatment of Antiphospholipid Antibody–Mediated Recurrent Pregnancy Loss | 478 | ||
| Menopause and Disease Activity | 478 | ||
| Postmenopausal Hormone Replacement | 479 | ||
| Hormone Therapy and Cardiovascular Disease and Thromboses | 479 | ||
| Effect of Menopausal Hormone Replacement on Disease Activity | 479 | ||
| Bone Health and Osteoporosis | 480 | ||
| Prevention of Osteoporosis | 480 | ||
| Androgen Therapy with Dehydroepiandrosterone | 481 | ||
| Reproductive Health Care and Screening | 481 | ||
| References | 482 | ||
| VI Special Considerations, Subsets of SLE and Lupus-Related Syndromes | 484 | ||
| 39 Drug-Induced Lupus: | 484 | ||
| Etiology | 484 | ||
| Drugs Implicated | 484 | ||
| Genetic Contributions to Drug-Induced and Idiopathic Lupus | 485 | ||
| Age and Gender Contributions to Drug-Induced and Idiopathic Lupus | 486 | ||
| Summary | 486 | ||
| Pathogenesis | 486 | ||
| Epigenetics and Gene Expression | 486 | ||
| Epigenetics, Chromatin Structure, and Gene Expression | 486 | ||
| Histone Modifications | 487 | ||
| DNA Methylation | 487 | ||
| T Cells, DNA Methylation, and Drug-Induced Lupus | 487 | ||
| T Cells, DNA Methylation, and Idiopathic Lupus | 489 | ||
| T Cells, DNA Methylation, and the Environment | 489 | ||
| Recombinant Biologic Agents | 490 | ||
| Interferon-Alpha | 490 | ||
| Tumor Necrosis Factor Inhibitors | 490 | ||
| Summary | 490 | ||
| Clinical Aspects | 490 | ||
| Idiopathic Lupus in Younger versus Older Adults | 490 | ||
| Patient Characteristics | 490 | ||
| Clinical and Serologic Features | 490 | ||
| Drug-Induced Lupus versus Idiopathic Lupus | 491 | ||
| Patient Characteristics | 491 | ||
| Clinical Features | 491 | ||
| Autoantibodies | 491 | ||
| Summary | 491 | ||
| References | 492 | ||
| 40 SLE in Childhood and Adolescence | 495 | ||
| Epidemiology | 495 | ||
| Diagnosis | 495 | ||
| Clinical Manifestations | 495 | ||
| Renal Disease | 495 | ||
| Central Nervous System Manifestations | 497 | ||
| Psychosocial Concerns | 498 | ||
| Pulmonary Manifestations | 498 | ||
| Musculoskeletal Manifestations | 498 | ||
| Dermatologic Manifestations | 499 | ||
| Cardiac Manifestations | 499 | ||
| Gastrointestinal Manifestations | 499 | ||
| Infection | 500 | ||
| Hematologic Manifestations | 500 | ||
| Laboratory Evaluation | 500 | ||
| Pharmaceutical Therapies | 501 | ||
| Prognosis | 502 | ||
| Summary | 503 | ||
| References | 504 | ||
| 41 Mixed Connective Tissue Disease and Undifferentiated Connective Tissue Disease | 506 | ||
| Mixed Connective Tissue Disease | 506 | ||
| Historical Perspective | 506 | ||
| Definition | 506 | ||
| Clinical Features | 507 | ||
| General Features | 507 | ||
| Epidemiologic Characteristics | 507 | ||
| Sex Distribution | 507 | ||
| Skin | 507 | ||
| Joints | 508 | ||
| Muscles | 508 | ||
| Pulmonary System | 508 | ||
| Gastrointestinal System | 508 | ||
| Cardiac System | 509 | ||
| Nervous System | 509 | ||
| Renal Disease | 509 | ||
| Hematologic Disorders | 509 | ||
| Miscellaneous Systemic Features | 509 | ||
| Children | 509 | ||
| Pregnancy | 510 | ||
| Serologic and Immunologic Studies | 510 | ||
| Immunopathologic Considerations | 511 | ||
| Pathogenesis | 511 | ||
| Genetic Factors | 511 | ||
| Environmental Factors | 512 | ||
| B Cells in Pathogenesis | 512 | ||
| T Cells in Pathogenesis | 512 | ||
| Innate Immunity in Pathogenesis | 513 | ||
| Tissue Injury in Pathogenesis | 513 | ||
| Course and Prognosis | 513 | ||
| Treatment | 513 | ||
| Undifferentiated Connective Tissue Disease and Overlap Syndromes | 514 | ||
| Undifferentiated Connective Tissue Disease | 515 | ||
| Overlap Syndromes | 515 | ||
| Synthetase Syndromes | 515 | ||
| Polymyositis and Limited Scleroderma | 515 | ||
| Ku Antigen | 515 | ||
| RNA Polymerase II | 515 | ||
| Co-Existing Rheumatic Diseases | 515 | ||
| References | 516 | ||
| 42 Clinical Aspects of the Antiphospholipid Syndrome | 518 | ||
| Introduction | 518 | ||
| Epidemiology | 518 | ||
| Classification Criteria | 518 | ||
| Pathogenesis | 518 | ||
| Clinical Features | 518 | ||
| Thrombotic Manifestations | 518 | ||
| Neurologic Manifestations | 519 | ||
| Ocular Manifestations | 519 | ||
| Cardiovascular Manifestations | 519 | ||
| Dermatologic Manifestations | 519 | ||
| Pulmonary Manifestations | 520 | ||
| Other Manifestations | 520 | ||
| Pregnancy Complications | 520 | ||
| Catastrophic Antiphospholipid Syndrome | 520 | ||
| Laboratory Diagnosis | 521 | ||
| Lupus Anticoagulant Test | 521 | ||
| Solid-Phase Assays | 521 | ||
| Management | 521 | ||
| Treatment of Patients with Prior Thrombosis | 521 | ||
| Primary Thromboprophylaxis | 521 | ||
| Obstetric Antiphospholipid Syndrome | 522 | ||
| Catastrophic Antiphospholipid Syndrome | 522 | ||
| Other Therapies | 522 | ||
| Statins | 522 | ||
| Rituximab | 522 | ||
| Future Targets | 522 | ||
| Conclusion | 522 | ||
| References | 522 | ||
| VII Assessment of Lupus | 526 | ||
| 43 Clinical Application of Serologic Tests, Serum Protein Abnormalities, and Other Clinical Laboratory Tests in SLE | 526 | ||
| Diagnosis of Systemic Lupus Erythematosus | 526 | ||
| Monitoring Disease Activity in Systemic Lupus Erythematosus | 527 | ||
| Clinical Significance of Anti–Double Stranded DNA Antibodies | 528 | ||
| Diagnostic Value | 528 | ||
| Clinical Tests for Anti–Double Stranded DNA | 528 | ||
| Preemptive Treatment of Serologically Active Systemic Lupus Erythematosus | 528 | ||
| Summary | 528 | ||
| Anti-Smith Antibodies | 528 | ||
| Prevalence | 529 | ||
| Anti-Smith Antibody Association with Organ Involvement | 529 | ||
| Anti-Smith Antibodies and Disease Activity | 529 | ||
| Anti-U1 Ribonucleoprotein | 529 | ||
| Clinical Association of Anti–U1 Ribonucleoprotein Antibodies | 529 | ||
| Serum Antibody Titer | 529 | ||
| Anti–Sjögren Syndrome Antigen A | 529 | ||
| Diagnostic Specificity and Associations | 530 | ||
| Serial Measurement of Anti–Sjögren Syndrome Antigen A Titer | 530 | ||
| Summary | 530 | ||
| Anti-SSB/La Antibodies | 530 | ||
| Antihistone Antibodies | 531 | ||
| Clinical Association | 531 | ||
| Summary | 531 | ||
| Antinucleosome Antibodies in Systemic Lupus Erythematosus | 531 | ||
| Anticomplement 1q Antibodies | 531 | ||
| Anti–Ribosomal P Antibodies | 531 | ||
| Anticentromere and Antiscleroma 70-kD Antibodies | 532 | ||
| Erythrocyte Sedimentation Rate | 532 | ||
| C-Reactive Protein and the Immune System | 532 | ||
| Clinical Significance of C-Reactive Protein in Systemic Lupus Erythematosus | 532 | ||
| C-Reactive Protein and Cardiovascular Risk in Systemic Lupus Erythematosus | 532 | ||
| Anti–C-Reactive Protein and Antipentraxin Antibodies | 533 | ||
| Serum Complement | 533 | ||
| Plasma Proteins | 533 | ||
| Serum Protein Electrophoresis | 533 | ||
| Albumin | 534 | ||
| Gamma Globulins | 534 | ||
| Serum Immunoglobulins | 534 | ||
| Immunoglobulin G | 534 | ||
| Immunoglobulin M | 535 | ||
| Immunoglobulin A | 535 | ||
| Immunoglobulin E | 535 | ||
| Common Variable Immunodeficiency | 535 | ||
| Drug-Related Hypogammaglobulinemia | 535 | ||
| Circulating Plasma Cells in Systemic Lupus Erythematosus | 536 | ||
| Other Serologic Abnormalities in Systemic Lupus Erythematosus | 536 | ||
| Rheumatoid Factor | 536 | ||
| Anti–Cyclic Citrullinated Peptide Antibodies | 536 | ||
| Cryoglobulins | 537 | ||
| Antiendothelial Cell Antibodies | 537 | ||
| Antineutrophil Cytoplasmic Antibodies | 537 | ||
| Clustering of Autoantibodies | 538 | ||
| References | 538 | ||
| 44 Differential Diagnosis and Disease Associations | 541 | ||
| Is It Really Systemic Lupus Erythematosus? | 541 | ||
| Misdiagnosis of Lupus | 541 | ||
| Positive Antinuclear Antibody Testing: How Often Is it Systemic Lupus Erythematosus? | 542 | ||
| Antinuclear Antibody–Negative Lupus | 542 | ||
| Undifferentiated Connective-Tissue Disease | 543 | ||
| Incomplete Lupus | 543 | ||
| Rheumatoid Arthritis | 543 | ||
| Clinical Differentiation | 543 | ||
| Extraarticular Differentiation | 543 | ||
| Laboratory and Serologic Differentiation | 543 | ||
| Rhupus | 543 | ||
| Juvenile Idiopathic Arthritis | 544 | ||
| Vasculitis | 544 | ||
| Polymyositis and Dermatomyositis | 544 | ||
| Scleroderma and Other Fibrosing Syndromes | 544 | ||
| Serum Sickness | 545 | ||
| Kikuchi Disease | 545 | ||
| Fibromyalgia | 545 | ||
| Crystal-Induced Arthropathies | 545 | ||
| Dermatitis Herpetiformis | 546 | ||
| Sarcoidosis | 546 | ||
| Amyloid | 546 | ||
| Seronegative Spondyloarthropathies and Psoriasis | 546 | ||
| Association of Systemic Lupus Erythematosus with Other Disorders | 546 | ||
| Porphyria | 546 | ||
| Angioimmunoblastic Lymphadenopathy with Dysproteinemia and Autoimmune Lymphoproliferative Syndrome | 547 | ||
| Carcinoma | 547 | ||
| Infectious Diseases | 547 | ||
| Viral Infections | 547 | ||
| Bacterial Infections | 548 | ||
| Parasites | 548 | ||
| Miscellaneous Disorders | 548 | ||
| Key Points | 548 | ||
| References | 548 | ||
| 45 SLE and Infections | 555 | ||
| Mortality and Infections in Systemic Lupus Erythematosus | 555 | ||
| Prevalence of Infections in Systemic Lupus Erythematosus | 555 | ||
| Identifying Independent Risk Factors for Infection in Systemic Lupus Erythematosus | 555 | ||
| Factors that Influence Infection Susceptibility in Systemic Lupus Erythematosus | 556 | ||
| Systemic Lupus Erythematosus Intrinsic Immune Dysfunction | 556 | ||
| Macrophages | 556 | ||
| Neutrophils | 556 | ||
| T Cells and Natural Killer Cells | 556 | ||
| B Cells and Immunoglobulin | 557 | ||
| Reticuloendothelial System Defects | 557 | ||
| Therapeutic Toxicities | 557 | ||
| Glucocorticoids | 557 | ||
| Other Immunosuppressive Systemic Lupus Erythematosus Therapies | 557 | ||
| Hydroxychloroquine Use and Protection from Infection | 559 | ||
| Select Genetic Defects and Risk of Infection | 559 | ||
| Mannose-Binding Lectin | 559 | ||
| Fc-Gamma Receptors | 559 | ||
| Complement Components | 559 | ||
| Protean Spectrum of Infection in Systemic Lupus Erythematosus | 559 | ||
| Bacteria | 559 | ||
| Mycobacterium | 559 | ||
| Viruses | 560 | ||
| Fungal | 560 | ||
| Parasitic and Protozoan | 560 | ||
| Using Systemic Lupus Erythematosus Biomarkers to Differentiate Between Infection and Disease Flare | 560 | ||
| Clinical Approach to Patients with Systemic Lupus Erythematosus and a Suspected Infection | 560 | ||
| Summary | 560 | ||
| Acknowledgments | 561 | ||
| References | 561 | ||
| Online-Only Supplementary References | 562.e1 | ||
| 46 Clinical Measures, Metrics, and Indices | 563 | ||
| Principles for Assessing Patients with Lupus | 563 | ||
| Approaches to Clinical Measurement in Lupus | 563 | ||
| Disease Activity Indices | 563 | ||
| Global Indices | 563 | ||
| Systemic Lupus Erythematosus Disease Activity Index and Its Versions | 563 | ||
| Mexican Version of SLEDAI | 564 | ||
| SELENA-SLEDAI | 564 | ||
| SLEDAI-2000 | 566 | ||
| SLEDAI-2K: 30-Day Version | 566 | ||
| Systemic Lupus Activity Measure | 566 | ||
| European Consensus Lupus Activity Measurement | 567 | ||
| Lupus Activity Index | 567 | ||
| SLE Activity Index Score | 567 | ||
| Organ-Specific Indices | 567 | ||
| British Isles Lupus Assessment Group | 567 | ||
| Renal Outcome Measures | 569 | ||
| Cutaneous Lupus Erythematosus Disease Area and Severity Index | 569 | ||
| Measures of Disease Activity over Time | 569 | ||
| Adjusted Mean SLEDAI-2K | 569 | ||
| Responder Measures | 569 | ||
| Flares | 569 | ||
| Improvement | 570 | ||
| Responder Index for Lupus Erythematosus. | 570 | ||
| SLE Responder Index. | 570 | ||
| SLEDAI-2K Responder Index 50. | 570 | ||
| Disease Activity in Childhood | 570 | ||
| Disease Activity in Pregnancy | 575 | ||
| Clinically Meaningful Change in Disease Activity Measures | 575 | ||
| Improvement | 575 | ||
| Flare | 575 | ||
| Damage | 575 | ||
| Health-Related Quality of Life | 578 | ||
| Generic Questionnaires | 578 | ||
| Disease-Specific Questionnaires | 578 | ||
| Costs and Economic Impact Events | 579 | ||
| Adverse Events | 579 | ||
| References | 579 | ||
| VIII Management of SLE | 582 | ||
| 47 Principles of Therapy, Local Measures, and Nonsteroidal Medications | 582 | ||
| Formulation Overview | 582 | ||
| Educational Session | 582 | ||
| General Therapeutic Considerations | 582 | ||
| Rest, Sleep, and the Treatment of Fatigue | 582 | ||
| Exercise, Physical Therapy, and Rehabilitation | 583 | ||
| Tobacco Smoke and Alcohol | 584 | ||
| Weather and Seasons | 584 | ||
| Pain Management | 585 | ||
| Role of Stress and Trauma | 585 | ||
| Can Stress Induce Lupus? | 585 | ||
| Can Stress Exacerbate Preexisting Systemic Lupus Erythematosus? | 585 | ||
| Can Physical Trauma Cause or Exacerbate Systemic Lupus Erythematosus? | 585 | ||
| How Important ARE Patient Compliance and Treatment Adherence? | 585 | ||
| Sun Avoidance and Phototoxicity | 585 | ||
| Which Sunscreen Should Be Used in Lupus? | 586 | ||
| Sun Protection and Safe Sun Habits | 586 | ||
| Local Therapy for Cutaneous Lupus Erythematosus | 586 | ||
| Topical Corticosteroid Preparations | 586 | ||
| Other Steroid Delivery Systems: Occlusive Patches and Dressings, Intralesional Therapy, and Intradermal Injections | 587 | ||
| Topical Calcineurins for Cutaneous Lupus and Other Approaches | 587 | ||
| Can Patients with Lupus Undergo Topical Cosmetic Procedures? | 587 | ||
| Nonsteroidal Antiinflammatory Drugs for the Treatment of Systemic Lupus Erythematosus | 587 | ||
| Mechanisms of Action | 587 | ||
| Clinical Efficacy in Systemic Lupus Erythematosus | 588 | ||
| Cyclooxygenase-2 Inhibition | 588 | ||
| Adverse Reactions of Nonsteroidal Antiinflammatory Drugs in Systemic Lupus Erythematosus | 588 | ||
| Renal System | 588 | ||
| Gastrointestinal System | 588 | ||
| Nervous System | 588 | ||
| Cutaneous Reactions | 589 | ||
| Cardiovascular System | 589 | ||
| Hematologic Complications | 589 | ||
| Pregnancy | 589 | ||
| Drug Interactions and Monitoring | 589 | ||
| References | 589 | ||
| 48 Systemic Glucocorticoid Therapy in SLE | 591 | ||
| Endogenous and Synthetic Glucocorticoids | 591 | ||
| Molecular Mechanisms of Glucocorticoid Action | 591 | ||
| Antiinflammatory and Immunosuppressive Effects | 592 | ||
| Glucocorticoid Resistance | 593 | ||
| Pharmacokinetics and Drug Interactions | 593 | ||
| General Principles of Glucocorticoid Therapy | 593 | ||
| Pulse-Glucocorticoid Therapy | 596 | ||
| Use of Depot Glucocorticoid Agents | 596 | ||
| Glucocorticoid Use During Pregnancy and Lactation | 596 | ||
| Use of Glucocorticoids During Stress | 597 | ||
| Adverse Effects of Glucocorticoids | 597 | ||
| Bone Toxicity | 597 | ||
| Cardiovascular Effects | 598 | ||
| Infections | 598 | ||
| Neuropsychiatric Adverse Effects | 598 | ||
| Other Adverse Effects | 598 | ||
| References | 598 | ||
| 49 Antimalarial Medications | 601 | ||
| Introduction | 601 | ||
| Pharmacokinetics of Antimalarial Medications | 601 | ||
| Hydroxychloroquine | 601 | ||
| Chloroquine | 601 | ||
| Quinacrine | 601 | ||
| Mechanisms of Action | 601 | ||
| Efficacy of Antimalarial Medications | 602 | ||
| Controlled Studies Assessing Efficacy | 602 | ||
| Efficacy during Pregnancy | 603 | ||
| Antithrombotic Effects | 604 | ||
| Effects on Dyslipidemia and Atherosclerosis | 604 | ||
| Effects on Diabetes Mellitus | 604 | ||
| Protective Effects on Infections | 604 | ||
| Effects on Cancer | 604 | ||
| Effects on Damage Accrual and Survival | 605 | ||
| Adverse Effects of Antimalarial Therapy | 605 | ||
| Gastrointestinal Adverse Effects | 605 | ||
| Cutaneous and Pigmentary Adverse Events | 605 | ||
| Ocular Effects | 605 | ||
| Screening for Ocular Toxicity | 605 | ||
| Neurologic, Muscular, and Cardiac Adverse Effects | 606 | ||
| Adverse Events of Antimalarial Medications during Pregnancy and Breast-Feeding | 606 | ||
| Other Rare Adverse Events | 606 | ||
| Doses and Dosage Schedule | 606 | ||
| Summary | 606 | ||
| References | 606 | ||
| 50 Immunosuppressive Drug Therapy | 609 | ||
| Alkylating Agents | 609 | ||
| Cyclophosphamide | 609 | ||
| Hemorrhagic Cystitis and Carcinomas of the Bladder | 610 | ||
| Other Malignancies | 610 | ||
| Hematologic Toxicity | 610 | ||
| Gastrointestinal Toxicity | 610 | ||
| Pulmonary Toxicity | 610 | ||
| Gonadal Toxicity and Teratogenicity | 611 | ||
| Infections | 611 | ||
| Clinical Trials Administering Cyclophosphamide for Lupus Nephritis | 611 | ||
| Intravenous Bolus Cyclophosphamide for the Treatment of Lupus Nephritis | 611 | ||
| Relationship of Efficacy and Toxicity to the Effective Dose of Intravenous Cyclophosphamide | 611 | ||
| Advantage of Maintenance Immunosuppression Therapy after Intravenous Cyclophosphamide Induction Therapy | 611 | ||
| Concomitant Daily Corticosteroids | 612 | ||
| Combining Bolus Methylprednisolone with Intravenous Cyclophosphamide | 612 | ||
| Racial Differences in Response to Intravenous Cyclophosphamide | 612 | ||
| Sequential Therapy for Lupus Nephritis | 612 | ||
| Induction Therapy: Comparisons of Intravenous Cyclophosphamide with Other Agents | 614 | ||
| Intravenous Cyclophosphamide versus Mycophenolate Mofetil | 614 | ||
| Pulse Cyclophosphamide versus Intravenous Immunoglobulin | 614 | ||
| Oral Cyclophosphamide | 614 | ||
| Daily Oral CyX for Induction | 614 | ||
| Guidelines for Treating Lupus Nephritis | 615 | ||
| Intravenous Cyclophosphamide in Nonrenal Lupus | 615 | ||
| Neuropsychiatric Lupus | 615 | ||
| Other Disease Manifestations | 615 | ||
| Bolus Cyclophosphamide in Children | 616 | ||
| Aggressive Cyclophosphamide-Containing Regimens | 616 | ||
| Summary of Cyclophosphamide Therapy for Lupus | 616 | ||
| Chlorambucil | 616 | ||
| Summary of Chlorambucil Therapy for Lupus | 617 | ||
| Azathioprine | 617 | ||
| Summary of Azathioprine Therapy for Lupus | 618 | ||
| Cyclosporine and Tacrolimus | 618 | ||
| Induction Therapy of Nephritis | 618 | ||
| Maintenance of Remission after Treatment of Lupus Nephritis with Cyclophosphamide | 619 | ||
| Nonrenal Lupus | 619 | ||
| Tacrolimus | 619 | ||
| Tacrolimus for Induction Therapy of Lupus Nephritis | 619 | ||
| Combined Tacrolimus and Mycophenolate Mofetil Therapy | 619 | ||
| Calcineurin Inhibitors for Skin Disease | 619 | ||
| Summary of Calcineurin Inhibitors | 619 | ||
| Methotrexate | 619 | ||
| Summary of Methotrexate Therapy for Lupus | 620 | ||
| Mycophenolate Mofetil | 620 | ||
| Animal Studies | 621 | ||
| Nonrenal Lupus | 621 | ||
| Summary of Mycophenolate Mofetil Therapy for Lupus | 621 | ||
| Leflunomide | 621 | ||
| Summary of Leflunomide Therapy for Lupus | 622 | ||
| Conclusion | 622 | ||
| References | 623 | ||
| 51 Specialized Treatment Approaches and Niche Therapies for Lupus Subsets | 626 | ||
| Treatment of Patients with Systemic Lupus Erythematosus and End-Stage Renal Disease | 626 | ||
| Incidence and Prevalence | 626 | ||
| Uremia and Its Reversibility | 626 | ||
| Prognosis of End-Stage Renal Disease | 626 | ||
| Hemodialysis versus Peritoneal Dialysis | 626 | ||
| Transplantation | 626 | ||
| Prevalence | 626 | ||
| Graft and Patient Survival | 626 | ||
| Serologic Features and Disease Recurrence | 626 | ||
| Pregnancy | 627 | ||
| Laser Therapy | 627 | ||
| Apheresis and Related Technologies | 627 | ||
| Lymphocyte Depletion: Thoracic Duct Drainage, Lymphocytapheresis, and Total Lymphoid Irradiation | 627 | ||
| Photopheresis | 627 | ||
| Plasmapheresis and Plasma Exchange | 627 | ||
| Basic Science and Clinical Rationale | 627 | ||
| Clinical Studies in Systemic Lupus Erythematosus | 628 | ||
| Lupus Nephritis | 628 | ||
| Antiphospholipid Syndrome and Congenital Heart Block | 628 | ||
| Other Potential Indications | 628 | ||
| Pulse Synchronization Therapy | 628 | ||
| Membrane Technologies | 628 | ||
| Summary | 628 | ||
| Ultraviolet UVA-1 IRRadiation | 628 | ||
| Should Radiation Therapy Be Avoided? | 628 | ||
| Niche Therapies for Lupus Subsets | 629 | ||
| Antileprosy Drugs | 629 | ||
| Dapsone | 629 | ||
| Thalidomide and Lenalidomide | 629 | ||
| Clofazimine | 629 | ||
| Novel Immune Suppressive Agents | 629 | ||
| Immunophylins: Tacrolimus and Rapamycin | 629 | ||
| Antimetabolites | 629 | ||
| Gold | 629 | ||
| Antilymphocyte Globulin | 629 | ||
| Beta Carotene and Retinoids | 629 | ||
| Miscellaneous Hormonal Interventions | 630 | ||
| Danazol | 630 | ||
| Testosterones | 630 | ||
| Dehydroepiandrosterone | 630 | ||
| Bromocriptine | 630 | ||
| Gamma Globulin and Intravenous Immunoglobulin | 630 | ||
| Vasodilators as Disease-Modifying Agents | 631 | ||
| Agents to Avoid and Failed Agents | 631 | ||
| References | 631 | ||
| For Further Reading: References for the OnLine Version | 632.e1 | ||
| Dialysis and End-Stage Renal Disease | 632.e1 | ||
| Uremia and Its Reversibility | 632.e1 | ||
| Prognosis of End-Stage Renal Disease | 632.e1 | ||
| Hemodialysis versus Peritoneal Dialysis | 632.e1 | ||
| Transplantation | 632.e1 | ||
| Graft and Patient Survival | 632.e2 | ||
| Serologic Features and Disease Recurrence | 632.e2 | ||
| Pregnancy | 632.e2 | ||
| Laser Therapy | 632.e2 | ||
| Apheresis and Related Technologies | 632.e3 | ||
| Photopheresis | 632.e3 | ||
| Plasmapheresis and Plasma Exchange: Basic Science and Clinical Rationale | 632.e3 | ||
| Plasmapheresis and Plasma Exchange: Clinical Studies in Systemic Lupus Erythematosus | 632.e3 | ||
| Lupus Nephritis | 632.e3 | ||
| Antiphospholipid and Congenital Heart Block | 632.e4 | ||
| Other Potential Indications | 632.e4 | ||
| Pulse Synchronization Therapy | 632.e4 | ||
| Membrane Technologies | 632.e5 | ||
| Summary | 632.e5 | ||
| Ultraviolet-1 Radiation | 632.e5 | ||
| Should Radiation Therapy Be Avoided? | 632.e5 | ||
| Antileprosy Drugs | 632.e5 | ||
| Thalidomide and Lenalidomide | 632.e6 | ||
| Clofazimine | 632.e6 | ||
| Novel Immune Suppressives | 632.e7 | ||
| Antimetabolites | 632.e7 | ||
| Gold | 632.e7 | ||
| Antilymphocyte and Antithymocyte Globulin | 632.e7 | ||
| Beta Carotene and Retinoids | 632.e7 | ||
| Miscellaneous Hormonal Interventions | 632.e8 | ||
| Testosterones | 632.e8 | ||
| Dehydroepiandrosterone | 632.e8 | ||
| Bromocriptine | 632.e9 | ||
| Gamma Globulin and Intravenous Immunoglobulin | 632.e9 | ||
| Vasodilators as Disease Modifying Agents | 632.e10 | ||
| Agents to Avoid and Failed Agents | 632.e10 | ||
| 52 Adjunctive and Preventive Measures | 633 | ||
| Immunizations and Prevention of Infection in Lupus | 633 | ||
| Are There Vaccinations That Should Be Avoided with Systemic Lupus Erythematosus? | 633 | ||
| Should Patients with Systemic Lupus Erythematosus Receive the Varicella Zoster Vaccine? | 633 | ||
| What Is the Risk of a Vaccination Triggering a Lupus Flare or Being Ineffective? | 633 | ||
| Antibiotic Prophylaxis in Lupus | 634 | ||
| Are There Specific Infections of Concern Requiring Prophylaxis in Patients with Systemic Lupus Erythematosus? | 634 | ||
| Are There Antibiotics That Patients with Systemic Lupus Erythematosus Should Avoid? | 635 | ||
| Allergies in Patients with Lupus | 635 | ||
| Should Patients with Systemic Lupus Erythematosus and Allergies Consider Immunotherapy? | 635 | ||
| Vitamin D Supplementation in Lupus | 635 | ||
| Should All Patients with Systemic Lupus Erythematosus Be Screened for Vitamin D Deficiency? | 635 | ||
| What Are the Consequences of Vitamin D Deficiency for Patients with Systemic Lupus Erythematosus? | 635 | ||
| What Are the Current Vitamin D Intake Recommendations for Patients with Systemic Lupus Erythematosus? | 636 | ||
| Complementary and Alternative Medicine in Lupus | 636 | ||
| What Are the Most Common Types of Complementary and Alternative Therapies Used by Patients with Systemic Lupus Erythematosus? | 636 | ||
| Are There Types of Complementary and Alternative Therapies That Should Be Avoided by Patients with Systemic Lupus Erythematosus? | 636 | ||
| Adherence Issues in Lupus | 636 | ||
| What Are the Consequences of Nonadherence in Patients with Systemic Lupus Erythematosus? | 636 | ||
| What Strategies Have Been Shown to Improve Adherence? | 637 | ||
| References | 637 | ||
| 53 Novel Therapies for SLE: | 640 | ||
| Introduction | 640 | ||
| Belimumab | 640 | ||
| Rituximab | 642 | ||
| Rituximab in Nonrenal Systemic Lupus Erythematosus | 644 | ||
| Rituximab in Lupus Nephritis | 644 | ||
| Rituximab in Systemic Lupus Erythematosus: Conclusions | 645 | ||
| Recommendations for the Clinician | 645 | ||
| Safety of Rituximab | 645 | ||
| Anti–Tumor Necrosis Factor Agents | 645 | ||
| Abatacept | 645 | ||
| References | 646 | ||
| 54 Critical Issues in Drug Development for SLE | 648 | ||
| Introduction | 648 | ||
| Systemic Lupus Erythematosus Disease Characteristics Critical for Drug Development | 648 | ||
| Systemic Lupus Erythematosus Is a Chronic Nonlethal Disease | 648 | ||
| Systemic Lupus Erythematosus Is Associated with Significant and Incompletely Understood Detrimental Effects on Quality of Life | 648 | ||
| Systemic Lupus Erythematosus Is Highly Heterogeneous in its Clinical Expression and Probably in its Underlying Pathophysiology | 649 | ||
| Systemic Lupus Erythematosus Exhibits a Bewildering Variation in its Long-Term Course | 650 | ||
| Outcomes and Endpoints for Clinical Trials and the Regulatory Environment | 650 | ||
| References | 651 | ||
| 55 Socioeconomic and Disability Aspects | 653 | ||
| Physical and Mental Functioning | 653 | ||
| Physical Functioning | 653 | ||
| Mental Functioning | 654 | ||
| Interventions | 654 | ||
| Schooling and Family Life | 654 | ||
| Employment and Work Disability | 654 | ||
| Employment | 655 | ||
| Work Disability | 655 | ||
| Costs of Illness | 655 | ||
| Direct Costs | 656 | ||
| Indirect Costs | 656 | ||
| Summary | 657 | ||
| Acknowledgments | 657 | ||
| References | 657 | ||
| IX Outcomes and Future Considerations | 659 | ||
| 56 Investigational Agents and Future Therapy for SLE | 659 | ||
| Trials and Their Design | 659 | ||
| Potential New Therapeutic Targets in Systemic Lupus Erythematosus | 659 | ||
| Antigen-Presenting Cells, Dendritic Cells, and Toll-Like Receptors | 659 | ||
| T Cells and Co-Stimulation | 660 | ||
| Regulatory T Cells | 660 | ||
| B Cells | 661 | ||
| Stem Cell Transplantation | 662 | ||
| Tolerogens | 662 | ||
| Intracellular Targets and Signal Transduction | 662 | ||
| Janus Kinase Inhibitors | 662 | ||
| Proteasome Inhibitor Bortezomib (PS-341; Janssen Cilag) | 663 | ||
| MicroRNAs (miRNAs) | 663 | ||
| Mediators of Inflammation | 663 | ||
| Interleukin Blockers | 663 | ||
| Interferon Blockers | 663 | ||
| Complement | 663 | ||
| Extracorporeal Removal of Autoantibodies and Immune Complexes | 663 | ||
| Summary | 663 | ||
| References | 664 | ||
| 57 Mortality in SLE | 666 | ||
| Survival Rates in Systemic Lupus Erythematosus | 666 | ||
| Five-Year Survival | 666 | ||
| Longer-Term Survival | 667 | ||
| Standardized Mortality Rates in Systemic Lupus Erythematosus | 667 | ||
| Causes of Death in Systemic Lupus Erythematosus | 668 | ||
| Co-Morbidities as Predictors of Overall Mortality in Systemic Lupus Erythematosus | 669 | ||
| Cardiac Disease | 669 | ||
| Renal Disease | 669 | ||
| Other Important Baseline Factors: Demographics, Organ Involvement, and Medications | 669 | ||
| Demographics: Sex, Age, and Socioeconomic Status | 669 | ||
| Organ Involvement | 670 | ||
| Drug Use | 670 | ||
| Mortality in Pediatric-Onset Systemic Lupus Erythematosus | 670 | ||
| Evidence of Improved Survival in Pediatric-Onset Systemic Lupus Erythematosus | 671 | ||
| Long-Term Survival | 671 | ||
| Causes of Death and Risk Factors for Death in Pediatric-Onset Systemic Lupus Erythematosus | 672 | ||
| Strategies for Improved Mortality Outcomes in Systemic Lupus Erythematosus | 672 | ||
| References | 673 | ||
| Lupus Resource Materials | 676 | ||
| What Organizations Provide Patient Support in the United States? | 676 | ||
| Historical Background of Discoid and SLE | e1 | ||
| Prescientific Period | e1 | ||
| Differentiation from Tuberculosis | e1 | ||
| Recognition of Systemic Lupus Erythematosus | e3 | ||
| Lupoid Hepatitis | e5 | ||
| Serologic Aspects | e5 | ||
| Epidemiology | e6 | ||
| Systemic Lupus Erythematosus and “Collagen Disease” | e6 | ||
| Photosensitivity | e7 | ||
| Drug-Induced and Aggravated Lupus Erythematosus | e7 | ||
| Diagnostic Criteria | e7 | ||
| Relationship of Discoid Lupus Erythematosus to Systemic Lupus Erythematosus | e8 | ||
| Four Subsets of Lupus Erythematosus | e8 | ||
| Antiphospholipid Syndrome | e8 | ||
| Lupus Erythematosus Profundus | e8 | ||
| Subacute Cutaneous Lupus Erythematosus | e8 | ||
| Neonatal Lupus Erythematosus | e8 | ||
| How Did Systemic Lupus Erythematosus Evolve from the Realm of Dermatology to Internal Medicine? | e8 | ||
| References | e8 | ||
| Patient Guide to Lupus Erythematosus | e12 | ||
| Purpose of this Guide | e12 | ||
| Brief History of Lupus Erythematosus | e12 | ||
| What Is Systemic Lupus Erythematosus? | e12 | ||
| Frequency of Lupus Erythematosus | e13 | ||
| What Causes Lupus Erythematosus? | e13 | ||
| Diagnosis | e13 | ||
| Diagnostic Criteria and Autoantibody Testing | e13 | ||
| Resemblance to Other Diseases | e13 | ||
| Symptoms and Course | e14 | ||
| Symptoms of the Disorder | e14 | ||
| General Symptoms | e14 | ||
| Other Considerations | e15 | ||
| Childbearing | e15 | ||
| Contraception | e15 | ||
| Hormonal Replacement Therapy | e16 | ||
| Treatment of Lupus Erythematosus | e16 | ||
| Aspirin and Nonsteroidal Antiinflammatory Drugs | e16 | ||
| Antimalarial Drugs | e16 | ||
| Corticosteroidal Drugs | e16 | ||
| Immune Suppressive Agents | e17 | ||
| Coping with Systemic Lupus Erythematosus: How Can You Help Yourself? | e17 | ||
| Physical Measures | e17 | ||
| Develop Preventive Coping Strategies | e17 | ||
| Is There Hope of Conquering Systemic Lupus Erythematosus? | e18 | ||
| Glossary | e18 | ||
| Index | 679 | ||
| A | 679 | ||
| B | 681 | ||
| C | 682 | ||
| D | 684 | ||
| E | 684 | ||
| F | 685 | ||
| G | 685 | ||
| H | 686 | ||
| I | 686 | ||
| J | 687 | ||
| K | 687 | ||
| L | 688 | ||
| M | 688 | ||
| N | 689 | ||
| O | 690 | ||
| P | 690 | ||
| Q | 691 | ||
| R | 691 | ||
| S | 692 | ||
| T | 693 | ||
| U | 694 | ||
| V | 694 | ||
| W | 694 | ||
| Index | e21 | ||
| A | e21 | ||
| B | e23 | ||
| C | e24 | ||
| D | e26 | ||
| E | e26 | ||
| F | e27 | ||
| G | e27 | ||
| H | e28 | ||
| I | e28 | ||
| J | e29 | ||
| K | e29 | ||
| L | e30 | ||
| M | e30 | ||
| N | e31 | ||
| O | e32 | ||
| P | e32 | ||
| Q | e33 | ||
| R | e33 | ||
| S | e34 | ||
| T | e35 | ||
| U | e36 | ||
| V | e36 | ||
| W | e36 |