BOOK
Kelley and Firestein's Textbook of Rheumatology E-Book
Gary S. Firestein | Ralph Budd | Sherine E Gabriel | Iain B. McInnes | James R O'Dell
(2016)
Additional Information
Book Details
Abstract
Consult the definitive resource in rheumatology for an in-depth understanding of scientific advances as they apply to clinical practice. Masterfully edited by Drs. Gary S. Firestein, Ralph C. Budd, Sherine E. Gabriel, Iain B. McInnes, and James R. O'Dell, and authored by internationally renowned scientists and clinicians in the field, Kelley and Firestein’s Textbook of Rheumatology, 10th Edition, delivers the knowledge you need for accurate diagnoses and effective patient care. From basic science, immunology, anatomy, and physiology to diagnostic tests, procedures, and specific disease processes, this state-of-the-art reference provides a global, authoritative perspective on the manifestations, diagnosis and treatment of rheumatic diseases.
- An ideal balance of the basic science you need to know and how to apply that information to clinical practice.
- An integrated chapter format allows you to review basic science advances and their clinical implications in one place and get dependable, evidence-based guidance for the full range of rheumatologic diseases and syndromes.
- Consult this title on your favorite e-reader, conduct rapid searches, and adjust font sizes for optimal readability.
- Metabolic Regulation of Immunity, Principles of Signaling, Research Methods in the Rheumatic Diseases, Novel Intracellular Targeting Agents, and IgG4-Related Diseases.
- New and expanded chapter topics on small molecule treatment, biologics, biomarkers, epigenetics, biosimilars, and cell-based therapies.
- More schematic diagrams clearly summarize information and facilitate understanding.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| 9780323414944v1_WEB.pdf | 1 | ||
| Front Cover | 1 | ||
| Inside Front Cover | 2 | ||
| Kelley and Firestein's Textbook of Rheumatology, 2-Volume Set | 3 | ||
| Copyright Page | 6 | ||
| Dedication | 7 | ||
| Acknowledgement | 9 | ||
| Contributors | 11 | ||
| Preface | 27 | ||
| Table Of Contents | 29 | ||
| I Structure and Function of Bone, Joints, and Connective Tissue | 33 | ||
| 1 Biology of the Normal Joint | 33 | ||
| Key Points | 33 | ||
| Classification of Joints | 33 | ||
| Developmental Biology of the Diarthrodial Joint | 33 | ||
| Interzone Formation and Joint Cavitation | 34 | ||
| Cartilage Formation and Endochondral Ossification | 35 | ||
| Condensation and Limb-Bud Formation | 36 | ||
| Molecular Signals in Cartilage Morphogenesis and Growth Plate Development | 37 | ||
| Endochondral Ossification | 38 | ||
| Development of the Joint Capsule and Synovium | 39 | ||
| Development of Nonarticular Joints | 39 | ||
| Development of Articular Cartilage | 39 | ||
| Organization and Physiology of the Mature Joint | 40 | ||
| Synovium | 40 | ||
| Synovial Lining | 41 | ||
| Synovial Vasculature | 41 | ||
| Regulation of Synovial Blood Flow | 42 | ||
| Joint Innervation | 42 | ||
| Tendons | 43 | ||
| Ligaments | 43 | ||
| Bursae | 44 | ||
| Menisci | 44 | ||
| Mature Articular Cartilage | 44 | ||
| Subchondral Bone | 45 | ||
| Synovial Fluid and Nutrition of Joint Structures | 46 | ||
| Generation and Clearance of Synovial Fluid | 46 | ||
| Synovial Fluid as an Indicator of Joint Function | 47 | ||
| Lubrication and Nutrition of the Articular Cartilage | 48 | ||
| Lubrication | 48 | ||
| Nutrition | 48 | ||
| Conclusion | 49 | ||
| Selected References | 49 | ||
| References | 52 | ||
| 2 Synovium | 56 | ||
| Key Points | 56 | ||
| Structure | 56 | ||
| Synovial Lining Cells | 56 | ||
| Ultrastructure of Synovial Lining Cells | 56 | ||
| Immunohistochemical Profile of Synovial Cells | 57 | ||
| Synovial Macrophages. | 57 | ||
| Synovial Intimal Fibroblasts. | 57 | ||
| Turnover of Synovial Lining Cells | 59 | ||
| Origin of Synovial Lining Cells | 59 | ||
| Subintimal Layer | 60 | ||
| Subintimal Vasculature | 61 | ||
| Subintimal Lymphatics | 61 | ||
| Subintimal Nerve Supply | 61 | ||
| Function | 61 | ||
| Joint Movement | 62 | ||
| Deformability | 63 | ||
| Porosity | 63 | ||
| Nonadherence | 63 | ||
| Lubrication | 63 | ||
| Hyaluronic Acid. | 64 | ||
| Lubricin. | 64 | ||
| Synovial Fluid Formation | 64 | ||
| Chondrocyte Nutrition | 66 | ||
| Conclusion | 66 | ||
| References | 67 | ||
| 3 Cartilage and Chondrocytes | 70 | ||
| Key Points | 70 | ||
| Cartilage Structure | 70 | ||
| Structure-Function Relationships of Cartilage Matrix Components | 72 | ||
| Cartilage Collagens | 72 | ||
| Cartilage Proteoglycans | 74 | ||
| Other Extra-cellular Matrix and Cell Surface Proteins | 75 | ||
| Structure, Classification, and Normal Function of Chondrocytes | 75 | ||
| Structure | 75 | ||
| Classification: Cell Origin and Differentiation | 75 | ||
| Normal Function of the Adult Articular Chondrocyte | 77 | ||
| Culture Models for Studying Chondrocyte Metabolism | 78 | ||
| Articular Chondrocytes | 78 | ||
| Cartilage Explant (Organ) Cultures | 78 | ||
| Monolayer Cultures | 78 | ||
| Three-Dimensional Culture Systems | 79 | ||
| Interactions of Chondrocytes with the Extra-cellular Matrix | 79 | ||
| Integrins | 79 | ||
| Other Cell Surface Receptors in Chondrocytes | 81 | ||
| Angiogenic and Antiangiogenic Factors | 81 | ||
| Roles of Growth and Differentiation (Anabolic) Factors in Normal Cartilage Metabolism | 81 | ||
| Insulin-like Growth Factor | 81 | ||
| Fibroblast Growth Factor | 82 | ||
| TGF-β/BMP Superfamily | 82 | ||
| Transforming Growth Factor-β | 83 | ||
| Bone Morphogenetic Proteins | 83 | ||
| Receptors, Signaling Molecules, and Antagonists that Mediate Chondrocyte Responses to Growth and Differentiation Factors | 83 | ||
| Role of the Chondrocyte in Cartilage Disease | 84 | ||
| Cartilage Matrix–Degrading Proteinases | 85 | ||
| Balance of Cytokines in Cartilage Destruction | 87 | ||
| Interleukin-1 and Tumor Necrosis Factor | 87 | ||
| Cytokine Networks | 88 | ||
| Other Mediators | 88 | ||
| Cytokine Signaling Pathways Involved in Cartilage Metabolism | 89 | ||
| Role of the Chondrocyte in Cartilage Repair | 91 | ||
| Aging of Articular Cartilage | 91 | ||
| Aging Chondrocyte | 91 | ||
| Markers of Cartilage Matrix Degradation and Turnover | 92 | ||
| Repair of Articular Cartilage | 92 | ||
| Conclusion | 93 | ||
| Selected References | 93 | ||
| References | 96 | ||
| 4 Biology, Physiology, and Morphology of Bone | 99 | ||
| Key Points | 99 | ||
| Structure and Composition of Bone | 99 | ||
| Bone Matrix | 99 | ||
| Bone Cells: Osteoblasts | 100 | ||
| Bone Cells: Osteocytes | 100 | ||
| Bone Cells: Osteoclasts | 101 | ||
| Bone Remodeling Process | 102 | ||
| Direct Interactions between Osteoblasts and Osteoclasts | 103 | ||
| Bone Remodeling by the Immune System | 103 | ||
| Systemic Control of Bone Remodeling by Neuroendocrine Mechanisms | 104 | ||
| Conclusion | 104 | ||
| References | 104 | ||
| 5 Muscle | 105 | ||
| Key Points | 105 | ||
| Structure | 105 | ||
| Muscle Tissue | 105 | ||
| Fiber Types | 106 | ||
| Events during Muscle Contraction | 107 | ||
| Neural Control | 107 | ||
| Neuromuscular Transmission | 108 | ||
| Excitation-Contraction Coupling | 108 | ||
| Contractile Apparatus | 108 | ||
| Force Generation and Shortening | 110 | ||
| Relaxation | 111 | ||
| Transmission of Force to the Exterior | 111 | ||
| Cell-Matrix Adhesions | 111 | ||
| Myotendinous Junction | 112 | ||
| Energetics | 113 | ||
| Buffering of Adenosine Triphosphate Concentration | 113 | ||
| Glycolysis | 113 | ||
| Oxidative Phosphorylation | 113 | ||
| Fatigue and Recovery | 113 | ||
| Plasticity | 114 | ||
| Adaptation to Muscle Use/Disuse | 114 | ||
| Hormonal Control | 114 | ||
| Aging | 114 | ||
| Conclusion | 115 | ||
| References | 115 | ||
| 6 Biomechanics | 117 | ||
| Key Points | 117 | ||
| Kinematics | 117 | ||
| Kinetics | 120 | ||
| Joint Biomechanics | 123 | ||
| Joint Constraint and Stability | 124 | ||
| Mechanical Loading on Tendon | 127 | ||
| References | 128 | ||
| 7 Regenerative Medicine and Tissue Engineering | 129 | ||
| Key Points | 129 | ||
| Intrinsic Repair Mechanisms | 129 | ||
| Genetic Basis of Tissue Repair | 129 | ||
| Signaling Pathways | 131 | ||
| Transforming Growth Factor-β/Bone Morphogenetic Protein Signaling | 131 | ||
| Fibroblast Growth Factor Signaling | 131 | ||
| Wnt Signaling | 131 | ||
| Growth Hormone/Insulin-like Growth Factor Axis | 132 | ||
| Stem Cell Niches | 132 | ||
| Targeting Homeostasis of the Joint | 134 | ||
| Cellular and Molecular Mechanisms of the Homeostatic Response | 134 | ||
| Immediate Molecular Response. | 134 | ||
| Activation and Attraction of Mesenchymal Progenitors. | 134 | ||
| Patterning and Differentiation. | 135 | ||
| Extrinsic Repair: Current Therapeutic Interventions | 135 | ||
| Joint Surface Defects | 135 | ||
| Autologous Chondrocyte Transplantation | 135 | ||
| Stem Cell–Based Approaches | 137 | ||
| Osteochondral Repair | 137 | ||
| Bone Regeneration | 138 | ||
| Regeneration of Other Joint-Related Structures | 139 | ||
| Menisci | 139 | ||
| Tendons | 140 | ||
| Regenerative Medicine and Tissue Engineering in Arthritis | 140 | ||
| Conclusion | 141 | ||
| Selected References | 141 | ||
| References | 145 | ||
| 8 Proteinases and Matrix Degradation | 149 | ||
| Key Points | 149 | ||
| Extra-cellular Matrix–Degrading Proteinases | 149 | ||
| Aspartic Proteinases | 149 | ||
| Cysteine Proteinases | 150 | ||
| Serine Proteinases | 150 | ||
| Neutrophil Elastase and Cathepsin G | 150 | ||
| Mast Cell Chymase and Tryptase | 151 | ||
| Plasmin and Plasminogen Activators | 151 | ||
| Kallikreins | 151 | ||
| Metalloproteinases | 151 | ||
| Matrix Metalloproteinases | 151 | ||
| Secreted-Type Matrix Metalloproteinases | 152 | ||
| Collagenases (MMP-1, MMP-8, and MMP-13). | 152 | ||
| Gelatinases (MMP-2 and MMP-9). | 153 | ||
| Stromelysins (MMP-3 and MMP-10). | 153 | ||
| Matrilysins (MMP-7 and MMP-26). | 154 | ||
| Furin-Activated Matrix Metalloproteinases (MMP-11 and MMP-28). | 155 | ||
| Other Secreted-Type Matrix Metalloproteinases (MMP- 12, MMP-19, MMP-20, MMP-21, and MMP-27). | 155 | ||
| Membrane-Anchored Matrix Metalloproteinases | 156 | ||
| ADAM and ADAMTS Families | 156 | ||
| Endogenous Proteinase Inhibitors | 156 | ||
| α2 Macroglobulin | 156 | ||
| Inhibitors of Serine Proteinases | 156 | ||
| Inhibitors of Cysteine Proteinases | 157 | ||
| Tissue Inhibitors of Metalloproteinases | 158 | ||
| Regulation of Proteinase Activity | 158 | ||
| Gene Expression of Proteinases and Inhibitors | 158 | ||
| Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases | 158 | ||
| Serine Proteinases and Their Inhibitors | 159 | ||
| Lysosomal Cysteine and Aspartic Proteinases | 160 | ||
| Activation Mechanisms of the Zymogens of Matrix Metalloproteinases | 160 | ||
| Extra-cellular Activation | 160 | ||
| Intra-cellular Activation | 160 | ||
| Pericellular Activation | 161 | ||
| Pericellular Docking and Recycling of Matrix Metalloproteinases | 162 | ||
| Joint Destruction and Proteinases | 162 | ||
| Degradation of Extra-cellular Matrix in Articular Cartilage | 162 | ||
| Cartilage Destruction by Proteinases in Rheumatoid Arthritis | 163 | ||
| Bone Resorption in Rheumatoid Arthritis | 164 | ||
| Cartilage Destruction by Proteinases in Osteoarthritis | 165 | ||
| References | 165 | ||
| II Cells Involved in Autoimmune Diseases and Inflammation | 169 | ||
| 9 Dendritic Cells | 169 | ||
| Key Points | 169 | ||
| Dendritic Cell Subsets | 169 | ||
| Conventional Dendritic Cells | 170 | ||
| Tissue Resident cDCs | 171 | ||
| Langerhans Cells. | 171 | ||
| Dermal Dendritic Cells. | 171 | ||
| CD14+ Dendritic Cells. | 171 | ||
| CD1a+ Dermal DCs. | 172 | ||
| Circulating Dendritic Cells | 172 | ||
| CD1c+/BDCA-1+ Dendritic Cells. | 172 | ||
| CD141++/BDCA-3+ Dendritic Cells. | 172 | ||
| Inflammatory Monocyte-Derived Dendritic Cells | 172 | ||
| Plasmacytoid DCs | 172 | ||
| Lymphoid Tissue–Associated Dendritic Cells | 173 | ||
| Dendritic Cell Development | 173 | ||
| Dendritic Cell Maturation | 173 | ||
| Phagocytosis and Autophagy | 174 | ||
| Homeostatic Maturation | 174 | ||
| Pattern-Recognition Receptors and Dendritic Cell Maturation | 174 | ||
| Dendritic Cell Maturation and Toll-like Receptors. | 174 | ||
| C-Type Lectin Receptors. | 175 | ||
| Nod-like and Retinoic Acid-Inducible Gene I–like Receptors. | 176 | ||
| Fc Receptors. | 176 | ||
| Apoptotic Cell Recognition Receptors. | 176 | ||
| Antigen Presentation | 177 | ||
| Class I Major Histocompatibility Complex Antigen Presentation | 177 | ||
| Class I Cross-Presentation. | 177 | ||
| Class II Major Histocompatibility Complex Antigen Presentation | 178 | ||
| Class II Cross-Presentation. | 178 | ||
| Lipid Presentation | 178 | ||
| T Cell Activation | 179 | ||
| B Cell Activation | 179 | ||
| Natural Killer Cell Activation | 180 | ||
| Dendritic Cells and Tolerance | 180 | ||
| Central Tolerance | 180 | ||
| Peripheral Tolerance | 180 | ||
| Autoimmunity | 181 | ||
| Dendritic Cells in Psoriasis | 181 | ||
| Dendritic Cells in Systemic Lupus Erythematosus | 182 | ||
| Dendritic Cells in Rheumatoid Arthritis | 183 | ||
| Dendritic Cells in Sjögren’s Syndrome | 184 | ||
| Conclusions and Future Directions | 184 | ||
| Inflammation Resolution | 184 | ||
| Immune Response Activation and Co-stimulation | 185 | ||
| Vaccines and Cellular Immunotherapy | 185 | ||
| Selected References | 185 | ||
| References | 188 | ||
| 10 Mononuclear Phagocytes | 194 | ||
| Key Points | 194 | ||
| Overview | 194 | ||
| Life History and Heterogeneity (Macrophages, Dendritic Cells, and Osteoclasts) | 196 | ||
| Mobilization of Mononuclear Phagocytes | 199 | ||
| Recognition | 201 | ||
| Toll-Like Receptors | 201 | ||
| Non–Toll-Like Receptors | 202 | ||
| Complement Receptors | 202 | ||
| Fc Receptors | 204 | ||
| Cytosolic Receptors | 204 | ||
| Damage/Danger-Associated Molecular Patterns | 205 | ||
| Responses and Modulation | 207 | ||
| Phagocytosis and Endocytosis: Antigen Processing | 207 | ||
| Signaling | 208 | ||
| Efferent Pathways: Gene Expression and Secretion | 209 | ||
| Macrophage Plasticity | 213 | ||
| Relevance to Selected Rheumatic Diseases | 214 | ||
| Issues for Further Investigation | 215 | ||
| Selected References | 215 | ||
| References | 218 | ||
| 11 Neutrophils | 221 | ||
| Key Points | 221 | ||
| Neutrophil Development, Morphology, and Content | 221 | ||
| Neutrophil Myelopoiesis and Clearance | 221 | ||
| Neutrophil Morphology and Contents | 222 | ||
| Primary Granules | 222 | ||
| Secondary Granules | 223 | ||
| Gelatinase Granules and Secretory Vesicles | 224 | ||
| Neutrophil Activation and Signal Transduction | 224 | ||
| Stimuli and Receptors | 224 | ||
| Guanosine Triphosphate–Binding Proteins | 225 | ||
| Second Messengers | 225 | ||
| Kinases and Kinase Cascades | 226 | ||
| Neutrophil Function | 226 | ||
| Adhesion | 226 | ||
| Selectins and Sialylated Glycoproteins | 226 | ||
| Integrins and Intercellular Adhesion Molecules | 227 | ||
| Diapedesis and Chemotaxis | 227 | ||
| Diapedesis | 227 | ||
| Chemotaxis | 227 | ||
| Phagocytosis and Degranulation | 228 | ||
| Phagocytosis | 228 | ||
| Degranulation | 228 | ||
| Respiratory Burst | 229 | ||
| Nonphagocytic Mechanisms of Neutrophil Action | 229 | ||
| Neutrophil Extra-cellular Traps | 229 | ||
| Microparticles | 230 | ||
| Neutrophil Production of Pro-inflammatory Mediators | 231 | ||
| Arachidonic Acid Metabolites | 231 | ||
| Cytokine Production | 231 | ||
| Role of Neutrophils in Thrombosis | 231 | ||
| Resolution of Neutrophil Infiltration | 231 | ||
| Resolvins | 231 | ||
| Lipoxins | 232 | ||
| Other Inflammation-Resolving Molecules | 232 | ||
| Role of Apoptotic Neutrophils in Resolving Inflammation | 233 | ||
| Heritable Disorders of Neutrophil Function | 233 | ||
| Diseases of Diminished Neutrophil Number | 233 | ||
| Leukocyte Adhesion Deficiencies | 233 | ||
| Granule Defects | 233 | ||
| Oxidase Deficiencies—Chronic Granulomatous Disease | 234 | ||
| Defects of TLR Signaling | 235 | ||
| Neutrophil Relevance to Rheumatic Disease | 235 | ||
| Neutrophil-Mediated Tissue Destruction | 235 | ||
| Neutrophil Fc Receptor Polymorphisms | 235 | ||
| Gout | 235 | ||
| Rheumatoid Arthritis | 235 | ||
| Systemic Lupus Erythematosus | 236 | ||
| Vasculitis | 236 | ||
| Neutrophilic Dermatoses and Familial Mediterranean Fever | 236 | ||
| Effects of Anti-rheumatic Agents on Neutrophil Functions | 237 | ||
| Glucocorticoids | 237 | ||
| Disease-Modifying Anti-rheumatic Drugs | 237 | ||
| Colchicine | 237 | ||
| Biologic Agents | 237 | ||
| Conclusion | 238 | ||
| Selected References | 238 | ||
| References | 241 | ||
| 12 T Lymphocytes | 244 | ||
| Key Points | 244 | ||
| T Cell Development | 244 | ||
| Abnormalities of Human T Cell Development | 248 | ||
| Peripheral Migration and Homeostatic Proliferation of T Cells | 249 | ||
| Activation of T Cells | 249 | ||
| TCR and Tyrosine Kinases | 249 | ||
| Adaptor Proteins | 250 | ||
| Downstream Transcription Factors | 250 | ||
| Co-Stimulation | 251 | ||
| The Immunologic Synapse | 251 | ||
| Tolerance and Control of Autoreactive T Cells | 252 | ||
| T Cell Subsets | 253 | ||
| CD4+ Helper and CD8+ Cytolytic T Cells | 253 | ||
| T Cells in the Innate Immune Response | 254 | ||
| γδ T Cells | 255 | ||
| Natural Killer T Cells | 255 | ||
| Naïve Versus Memory T Cells | 255 | ||
| T Helper Subsets | 256 | ||
| Molecular Mimicry | 257 | ||
| Death of T cells | 257 | ||
| T Cells at Sites of Inflammation | 258 | ||
| References | 258 | ||
| 13 B Cells | 262 | ||
| Key Points | 262 | ||
| Immunoglobulins: Structure and Function | 262 | ||
| Immunoglobulin Heavy Chain Constant Region | 263 | ||
| Immunoglobulin M | 263 | ||
| Immunoglobulin G | 264 | ||
| Immunoglobulin A | 264 | ||
| Immunoglobulin E | 265 | ||
| Immunoglobulin D | 265 | ||
| Light Chains | 265 | ||
| Immunoglobulin Variable Region | 265 | ||
| Generation of Immunoglobulin Diversity | 265 | ||
| B Cell Development | 266 | ||
| Niches for Human B Lymphopoiesis | 266 | ||
| B Cell Ontogeny | 266 | ||
| Pro-B Cells | 267 | ||
| Pre-B Cells | 267 | ||
| Immature B Cells | 268 | ||
| Peripheral Naïve B Cell Subsets | 268 | ||
| Transitional B Cells | 268 | ||
| BAFF Family of Cytokines | 268 | ||
| Mature B Cells | 268 | ||
| Marginal Zone B Cells | 269 | ||
| B1 Cells | 269 | ||
| Sites of B Cell Homing and Activation | 270 | ||
| Circulation and Homing | 270 | ||
| Mucosa-Associated Compartments | 270 | ||
| B Cell Activation and Differentiation | 270 | ||
| B Cell Receptor Signaling | 271 | ||
| Surface Co-Receptors | 271 | ||
| FcγRllB | 272 | ||
| CD5 | 272 | ||
| CD72 | 272 | ||
| PIR | 273 | ||
| PD-1 | 273 | ||
| Phosphatases | 273 | ||
| Signal Transduction in Immature versus Mature B Cells | 273 | ||
| B Cell Activation | 273 | ||
| B1 Cell Activation | 273 | ||
| Marginal Zone B Cell Activation | 273 | ||
| Follicular B Cell Activation | 274 | ||
| Germinal Centers | 275 | ||
| Ectopic Lymphoid Structures | 276 | ||
| B Cell Differentiation | 276 | ||
| Memory B Cells | 276 | ||
| Plasma Cells | 277 | ||
| Trafficking of Postimmune Cells | 278 | ||
| Nonconventional B Cell Activation | 278 | ||
| Mucosal T–Independent Class Switch Recombination | 278 | ||
| Repertoire Selection | 278 | ||
| Tolerance | 278 | ||
| Receptor Editing | 279 | ||
| Deletion | 279 | ||
| Anergy | 279 | ||
| B Cells as Immune Regulators | 279 | ||
| Regulation by Small Molecules | 279 | ||
| Vitamin D | 279 | ||
| Estrogens | 280 | ||
| Leptin | 280 | ||
| B Cell–Mediated Autoimmunity | 280 | ||
| Origin of Autoreactive B Cells | 280 | ||
| Autoreactivity in the Preimmune B Cell Repertoire | 280 | ||
| Autoreactivity in the Postimmune B Cell Repertoire | 280 | ||
| Molecular Triggers of Autoimmunity | 280 | ||
| Molecular Mimicry | 280 | ||
| Supraoptimal B Cell Co-Stimulation | 281 | ||
| B Cell Signaling Thresholds | 282 | ||
| Conclusion | 282 | ||
| Selected References | 283 | ||
| References | 286 | ||
| 14 Fibroblasts and Fibroblast-like Synoviocytes | 289 | ||
| Key Points | 289 | ||
| What Is a Fibroblast? | 289 | ||
| Fibroblast Identity and Microenvironments | 289 | ||
| Embryologic Origins | 290 | ||
| Origins of Fibroblasts in Tissue | 290 | ||
| Fibroblasts versus Mesenchymal Progenitor Cells | 292 | ||
| Physiologic Characteristics and Functions of Fibroblasts | 292 | ||
| Production of ECM Components | 292 | ||
| Attachment to and Interaction with Extra-cellular Matrix | 293 | ||
| Integrins | 293 | ||
| Syndecans | 293 | ||
| Immunoglobulin Superfamily Receptors | 293 | ||
| Cadherins | 293 | ||
| Adhesion Molecule-Mediated Signaling | 293 | ||
| Degradation of Extra-cellular Matrix by Fibroblasts | 294 | ||
| Fibroblasts as Innate Immune Sentinels | 295 | ||
| Role of Specialized Fibroblast Subsets within Tissue Microenvironments | 295 | ||
| Fibroblast-like Synoviocytes in the Normal Synovium | 295 | ||
| Fibroblasts in Rheumatic Diseases | 297 | ||
| Role of Fibroblasts in Persistent Inflammation | 297 | ||
| Fibroblast-Like Synoviocytes in Rheumatoid Arthritis | 297 | ||
| Persistent Activated Fibroblast Phenotype in the Rheumatoid Arthritis Synovium | 297 | ||
| Interactions of Fibroblasts with Leukocytes | 298 | ||
| Recruitment of Inflammatory Infiltrates into the Joint | 298 | ||
| Fibroblast Support for Leukocyte Survival | 298 | ||
| Fibroblast-Mediated Retention of Leukocytes in Tissue | 299 | ||
| Constitutive Chemokines and Lymphoid Neogenesis | 301 | ||
| Role of Fibroblast Subsets in Disease | 301 | ||
| Epigenetic Regulation of Fibroblast Gene Expression in Rheumatic Disease | 302 | ||
| MicroRNAs and Fibroblast-like Synoviocytes | 303 | ||
| Lessons Learned from Cancer | 303 | ||
| Conclusion | 304 | ||
| Selected References | 304 | ||
| References | 308 | ||
| 15 Mast Cells | 312 | ||
| Key Points | 312 | ||
| Basic Biology of Mast Cells | 312 | ||
| Development and Tissue Distribution | 312 | ||
| Mast Cell Heterogeneity: Common Progenitor, Multiple Subsets, and Phenotypic Plasticity | 313 | ||
| Stem Cell Factor | 314 | ||
| T Lymphocytes and Other Cells | 314 | ||
| Different Functions for MCT and MCTC Mast Cells | 314 | ||
| Mast Cell Activation | 315 | ||
| Immunoglobulin E | 315 | ||
| Immunoglobulin G and Immune Complexes | 315 | ||
| Soluble Mediators and Cell-Cell Contact | 315 | ||
| Danger and Injury | 315 | ||
| Inhibitory Signals for Mast Cells | 315 | ||
| Mast Cell Mediators | 316 | ||
| Granule Contents: Proteases, Amines, Proteoglycans, and Cytokines | 316 | ||
| Tryptase. | 316 | ||
| Chymase. | 316 | ||
| β-Hexosaminidase. | 316 | ||
| Vasoactive Amines. | 316 | ||
| Heparin and Chondroitin Sulfate E. | 316 | ||
| Pre-Formed Cytokines and Chemokines. | 317 | ||
| Newly Synthesized Mediators: Lipid Mediators, Cytokines, Chemokines, and Growth Factors | 317 | ||
| Lipid Mediators. | 317 | ||
| Cytokines, Chemokines, and Growth Factors. | 317 | ||
| Role of Mast Cells in Health and Disease | 317 | ||
| Mast Cells in Allergic Disease: Anaphylaxis, Allergic Disease, and Asthma | 317 | ||
| Mast Cells in Nonallergic Inflammation | 318 | ||
| Pathogen Defense: Mast Cells as Sentinels of Innate Immunity | 318 | ||
| Mast Cells and the Adaptive Immune Response | 318 | ||
| Neurogenic Inflammation | 319 | ||
| Autoimmune Disease | 319 | ||
| Mast Cells as Anti-Inflammatory Cells | 319 | ||
| Mast Cells and Connective Tissue | 319 | ||
| Wound Healing and Tissue Fibrosis | 319 | ||
| Bone | 320 | ||
| Angiogenesis | 320 | ||
| Mast Cells in Arthritis | 320 | ||
| Mast Cells in Acute Arthritis: Insights from Animal Models | 321 | ||
| Mast Cells in Chronic Arthritis | 321 | ||
| Therapeutic Potential of Mast Cell Antagonism in Rheumatic Disease | 322 | ||
| Mast Cell Protease Inhibition | 322 | ||
| SCF/c-Kit Antagonism | 322 | ||
| Signaling Pathways | 322 | ||
| Conclusion | 323 | ||
| Selected References | 323 | ||
| References | 326 | ||
| 16 Platelets | 330 | ||
| Key Points | 330 | ||
| Platelet Structure | 330 | ||
| Platelet Production | 331 | ||
| Platelets and Hemostasis | 331 | ||
| Signaling Pathways in Platelet Activation | 333 | ||
| The Platelet as an Inflammatory Cell | 334 | ||
| Platelets and Rheumatic Diseases | 334 | ||
| Rheumatoid Arthritis | 334 | ||
| Systemic Lupus Erythematosus | 335 | ||
| Other Rheumatic Diseases | 337 | ||
| Conclusion | 337 | ||
| Selected References | 337 | ||
| References | 340 | ||
| III Effector Mechanisms in Autoimmunity and Inflammation | 343 | ||
| 17 Innate Immunity | 343 | ||
| Key Points | 343 | ||
| Evolutionary Origins of Innate Immunity | 343 | ||
| Pathogen Recognition by the Innate Immune System | 345 | ||
| Pamps and Damps: Patterns for Innate Immune Recognition | 345 | ||
| Pathogen-Associated Molecular Patterns | 345 | ||
| Pattern Recognition Receptors | 345 | ||
| Pattern Recognition Receptors of the Lectin Family | 346 | ||
| Pattern Recognition Receptors of the Scavenger Receptor Family | 347 | ||
| Pattern Recognition Receptors with Leucine-Rich Repeat Domains | 348 | ||
| Toll-Like Receptors. | 348 | ||
| Toll-Like Receptor 4 and the Response to Lipopolysaccharide. | 349 | ||
| Other Pathogen-Associated Molecular Patterns Recognized by Toll-Like Receptors. | 349 | ||
| CARD and Pyrin Domain Proteins. | 349 | ||
| Effector Mechanisms of Innate Immune Responses | 350 | ||
| Cell Types Mediating Innate Immunity | 350 | ||
| Innate-like Lymphocytes | 350 | ||
| Anti-microbial Peptides | 351 | ||
| Influence of Innate Mechanisms on Adaptive Immunity | 351 | ||
| Disease Associations Involving Innate Immunity | 353 | ||
| Future Directions | 354 | ||
| Connection to the Clinic | 354 | ||
| References | 354 | ||
| 18 Adaptive Immunity and Organization of Lymphoid Tissues | 357 | ||
| Key Points | 357 | ||
| Lymphocyte Migration Paradigms for Homing, Interstitial Navigation, and Egress | 357 | ||
| Multistep Paradigm for Extravasation | 358 | ||
| Tissue Organization and Interstitial Migration | 359 | ||
| Immunologic Synapses Maintain Antigen-Specific Interactions with Dendritic Cells | 360 | ||
| Egress from Lymph Nodes and the Thymus: Sphingosine 1 Phosphate | 360 | ||
| Primary Lymphoid Tissues: Sites Where T and B Cells are Generated and Self-Tolerance Mechanisms are Initiated | 360 | ||
| B Cell Development in the Bone Marrow | 360 | ||
| T Cell Development in the Thymus | 361 | ||
| Secondary Lymphoid Tissues: Sites Where Antigen Finds Rare Specific T and B Cells | 361 | ||
| Antigens from Blood Are Detected Most Efficiently in the Spleen and Liver (Portal System) | 362 | ||
| Antigens from Mucosal Surfaces Are Detected Most Efficiently in Peyer’s Patches and Mesenteric Lymph Nodes | 363 | ||
| Antigens from Other Tissues and Solid Organs Are Detected in Peripheral Lymph Nodes | 363 | ||
| Peripheral Tolerance Induction under Steady-State Conditions | 364 | ||
| Regulatory T Cells Reduce Autoreactivity by Inhibiting Immunologic Synapse Formation | 364 | ||
| Changes in the Lymph Node during Infection/Vaccination | 365 | ||
| Tissue Environment of Immature Dendritic Cells Determines T Cell Imprinting | 365 | ||
| Germinal Center Reactions: Sites of Antibody Affinity Maturation and Class Switch Recombination | 366 | ||
| Tertiary Lymphoid Tissues are Generated at Sites of Chronic Inflammation | 366 | ||
| Five Major Types of Effector T Cells | 367 | ||
| Conclusion | 367 | ||
| References | 367 | ||
| 19 Autoimmunity | 370 | ||
| Key Points | 370 | ||
| Definition and Classification of Pathogenic Autoimmunity | 370 | ||
| Animal Models of Autoimmunity | 371 | ||
| Tolerance Mechanisms | 374 | ||
| Clone-Specific Self/Nonself Recognition | 374 | ||
| The Innate System and Tolerance | 375 | ||
| T Cell Tolerance | 375 | ||
| B Cell Tolerance | 377 | ||
| Theories of Autoimmunity | 377 | ||
| Defective Tolerance | 378 | ||
| Autoimmunity Caused by Activation of Intolerant or Partially Tolerant T Cells | 379 | ||
| Immunologic Mechanisms of Tissue Inflammation and Dysfunction | 381 | ||
| Pathophysiology of Autoimmune Rheumatic Diseases | 381 | ||
| Genetics of Autoimmune Diseases | 382 | ||
| Gender and Autoimmunity | 383 | ||
| Microbial and Other Environmental Triggers | 383 | ||
| Conclusion | 384 | ||
| Selected References | 384 | ||
| References | 387 | ||
| 20 Metabolic Regulation of Immunity | 392 | ||
| Key Points | 392 | ||
| Overview | 392 | ||
| Metabolic Rewiring in Innate Immunity | 392 | ||
| Macrophage Metabolism | 392 | ||
| Dendritic Cell Metabolism | 393 | ||
| Metabolic Rewiring in Adaptive Immunity | 394 | ||
| T Cell Metabolism | 394 | ||
| T Cell Activation | 394 | ||
| T Cell Differentiation | 394 | ||
| B Cell Metabolism | 395 | ||
| Mitochondria and Immunity | 395 | ||
| Mitochondria and NOD-Like Receptor Signaling | 395 | ||
| Mitochondria and RIG-I-Like Signaling | 396 | ||
| Mitochondria and Toll-Like Receptor Signaling | 396 | ||
| Mitochondria as a Source of Danger Signals | 396 | ||
| Metabolic Interplay in the Immune Microenvironment | 396 | ||
| Metabolic Antagonism in Immunity | 397 | ||
| Metabolic Symbiosis in Immunity | 397 | ||
| Conclusion | 397 | ||
| References | 397 | ||
| 21 Genetics of Rheumatic Diseases | 401 | ||
| Key Points | 401 | ||
| Evidence for a Genetic Component to Rheumatic Diseases | 401 | ||
| Study Design | 401 | ||
| Linkage Studies | 402 | ||
| Population-Association Studies and the Calculation of the Odds Ratio, an Estimate of Relative Risk | 403 | ||
| Family-Based Versus Case-Control Approaches | 404 | ||
| Choice of Genetic Marker to Test | 404 | ||
| Candidate Gene Versus Genome-wide Association Studies | 404 | ||
| Genome-wide Association Studies | 405 | ||
| Linkage Disequilibrium | 405 | ||
| Common Versus Rare Variants | 407 | ||
| Interpreting Statistical Association from Case-Control Studies | 407 | ||
| Rheumatoid Arthritis Susceptibility Genes | 408 | ||
| Class I and Class II Human Leukocyte Antigen Isotypes: Functional Correlates | 408 | ||
| Rheumatoid Arthritis: HLA-DRB1 Associations and the “Shared Epitope” | 408 | ||
| The Genome-Wide Association Studies Era of Rheumatoid Arthritis Genetics | 409 | ||
| Juvenile Idiopathic Arthritis | 411 | ||
| Psoriatic Arthritis | 412 | ||
| Ankylosing Spondylitis | 412 | ||
| Systemic Lupus Erythematosus: Identification of the Interferon Pathway | 413 | ||
| Osteoarthritis | 413 | ||
| Clinical Translation | 414 | ||
| Identification of Drug Targets: Lessons from Rheumatoid Arthritis Genetics | 414 | ||
| Prognosis | 414 | ||
| Treatment Response | 414 | ||
| Identification of High-Risk Groups | 415 | ||
| References | 415 | ||
| 22 Epigenetics of Rheumatic Diseases | 418 | ||
| Key Points | 418 | ||
| Epigenetic Regulation | 418 | ||
| Epigenetics and the Immune Response | 419 | ||
| Epigenetics in Rheumatic Diseases | 420 | ||
| Systemic Lupus Erythematosus | 420 | ||
| DNA Methylation Regulation and Candidate Gene Studies in Systemic Lupus Erythematosus T Cells | 420 | ||
| Genome-wide DNA Methylation Studies in Systemic Lupus Erythematosus T Cells | 421 | ||
| Genetic–Epigenetic Interaction in Systemic Lupus Erythematosus | 422 | ||
| Histone Modifications in Systemic Lupus Erythematosus | 422 | ||
| MicroRNAs and the Pathogenesis of Systemic Lupus Erythematosus | 423 | ||
| Rheumatoid Arthritis | 423 | ||
| Primary Sjögren’s Syndrome | 424 | ||
| Systemic Sclerosis | 424 | ||
| Behçet’s Disease | 425 | ||
| Osteoarthritis | 425 | ||
| Future Directions | 425 | ||
| References | 426 | ||
| 23 Complement System | 429 | ||
| Key Points | 429 | ||
| Functions of the Complement System | 429 | ||
| Terminology Used to Describe Complement and Its Activation Fragments | 429 | ||
| Activation Pathways | 430 | ||
| Regulation of Complement Activation | 431 | ||
| Receptors for Complement Fragments | 432 | ||
| Functions of the Complement System | 433 | ||
| Innate Immune Responses | 433 | ||
| Clearing Immune Complexes and Apoptotic Material | 433 | ||
| Regulating Adaptive Immune Responses | 434 | ||
| Measuring Complement Activation | 434 | ||
| Complement Deficiency | 434 | ||
| Primary Complement Deficiency | 434 | ||
| Secondary Complement Deficiency | 435 | ||
| Targeted Complement Therapeutics | 435 | ||
| Complement in Rheumatic Diseases | 436 | ||
| Systemic Lupus Erythematosus | 436 | ||
| Rheumatoid Arthritis | 436 | ||
| Other Systemic Rheumatic Conditions | 437 | ||
| Conclusion | 437 | ||
| References | 437 | ||
| 24 Prostaglandins, Leukotrienes, and Related Compounds | 440 | ||
| Key Points | 440 | ||
| Biosynthesis of Eicosanoids | 440 | ||
| Phospholipases | 440 | ||
| Cyclooxygenase Pathway | 442 | ||
| Regulation of Cyclooxygenase-1 Expression | 442 | ||
| Regulation of Cyclooxygenase-2 Expression | 443 | ||
| Cyclooxygenase-3 | 444 | ||
| Prostaglandin Synthases | 444 | ||
| Products of the Cyclooxygenase Pathway | 444 | ||
| Prostaglandins | 444 | ||
| Prostacyclin | 445 | ||
| Thromboxanes | 446 | ||
| Lipoxygenase Pathways | 446 | ||
| Products of the Lipoxygenase Pathways | 447 | ||
| Lipoxins | 448 | ||
| Isoeicosanoids | 449 | ||
| Isoprostanes | 449 | ||
| Endocannabinoids | 450 | ||
| Eicosanoid Receptors | 451 | ||
| Prostaglandin Receptors | 451 | ||
| Leukotriene Receptors | 451 | ||
| Lipoxin Receptors | 452 | ||
| Nuclear Receptors | 452 | ||
| Platelet-Activating Factor | 453 | ||
| Eicosanoids as Regulators of Inflammation and Immune Responses | 453 | ||
| Modulation of Eicosanoid Synthesis by Administration of Precursor Fatty Acids | 454 | ||
| Selected References | 455 | ||
| References | 458 | ||
| 25 Cell Recruitment and Angiogenesis | 461 | ||
| Key Points | 461 | ||
| Endothelial Pathophysiology in Inflammation | 461 | ||
| Endothelial Permeability | 461 | ||
| Endothelial Injury and Regeneration | 461 | ||
| Cell Adhesion Molecules | 462 | ||
| Integrins | 462 | ||
| Immunoglobulin Superfamily Members | 463 | ||
| Selectins | 463 | ||
| Cadherins | 463 | ||
| Other Adhesion Receptors | 463 | ||
| Chemokines and Chemokine Receptors | 463 | ||
| Chemokine Superfamilies and Their Receptors | 463 | ||
| CXC Chemokines in Arthritis | 464 | ||
| CC Chemokines in Rheumatoid Arthritis | 464 | ||
| C and CX3C Chemokines in Rheumatoid Arthritis | 464 | ||
| Chemokine Receptors in Arthritis | 464 | ||
| Angiogenesis in Inflammation | 465 | ||
| Angiogenic Process | 465 | ||
| Mediators of Angiogenesis in Rheumatoid Arthritis | 465 | ||
| Vasculogenesis in Arthritis | 467 | ||
| Cellular and Molecular Regulation of Leukocyte Recruitment and Angiogenesis | 467 | ||
| Process of Leukocyte Extravasation in Inflammation | 467 | ||
| Interactions among Chemokines, Adhesion Receptors, and Angiogenic Factors | 467 | ||
| Targeting Cell Adhesion, Chemokines, Angiogenesis, and Vasculogenesis in Inflammatory Rheumatic Disease | 467 | ||
| Inhibition of Cell Adhesion Receptors | 467 | ||
| Chemokine and Chemokine Receptor Targeting | 468 | ||
| Angiogenesis Targeting: Use of Angiostatic Compounds | 469 | ||
| Restoration of Impaired Vasculogenesis | 469 | ||
| Conclusion | 469 | ||
| Selected References | 469 | ||
| References | 473 | ||
| 26 Cytokines | 478 | ||
| Key Points | 478 | ||
| Classification of Cytokines | 478 | ||
| Assessing Cytokine Function in Vitro and in Vivo | 478 | ||
| Cytokine Receptors | 479 | ||
| Regulation of Cytokine Expression | 480 | ||
| Effector Function of Cytokines | 482 | ||
| Cytokines in Acute Inflammation | 482 | ||
| Cytokines in Chronic Inflammation | 486 | ||
| T Cell Effector Function in Chronic Inflammation | 486 | ||
| Cell-to-Cell Interactions | 486 | ||
| Agonist/Antagonist Cytokine Activities in Chronic Inflammation | 487 | ||
| Disease-Modifying Anti-rheumatic Drugs | 487 | ||
| Cellular Interactions Across Diverse Tissues | 487 | ||
| B Cells and Cytokine Release in Chronic Inflammation | 488 | ||
| Innate Cell Lineages in Chronic Inflammation | 488 | ||
| Growth Factors in Chronic Inflammation | 488 | ||
| Cytokine Effects Beyond Immune Regulation | 488 | ||
| Conclusion | 488 | ||
| References | 489 | ||
| 27 Principles of Signaling | 490 | ||
| Key Points | 490 | ||
| Receptors with Enzymatic Activity | 490 | ||
| Receptors That Recruit Molecules with Enzymatic Activity | 491 | ||
| Cytokine Receptors | 491 | ||
| JAK/STAT Pathway | 491 | ||
| Tumor Necrosis Factor Receptor Signaling | 492 | ||
| G Protein–Coupled Receptors | 493 | ||
| Immunoreceptors: T Cell Receptor, B Cell Receptor, and FcRs | 494 | ||
| PI3K/Akt Pathway | 494 | ||
| Phospholipase C Signaling: Calcium Flux and Protein Kinase C Activation | 495 | ||
| MAP Kinase Pathway | 495 | ||
| Co-stimulatory Receptors | 496 | ||
| Adhesion Molecules | 497 | ||
| Innate Receptor Signaling | 497 | ||
| Intra-cellular Receptor Signaling | 497 | ||
| Conclusion | 498 | ||
| References | 499 | ||
| 28 Immunologic Repercussions of Cell Death | 500 | ||
| Key Points | 500 | ||
| Types of Cell Death | 500 | ||
| Apoptosis | 500 | ||
| Necrosis—Classical or Noncanonical? | 501 | ||
| Pyroptosis | 501 | ||
| Autophagy | 501 | ||
| Molecular Mechanisms of Cell Death | 502 | ||
| Apoptosis | 502 | ||
| Caspase Substrates of Note | 502 | ||
| Caspase Regulation: Activation and Inhibition | 502 | ||
| Caspase Inhibitors (Inhibitors of Apoptosis Proteins) | 502 | ||
| Caspase Recruitment Domains and Death Effector Domains—Activation Platforms of the Initiator Caspases | 503 | ||
| The Inflammasome-Activation Platform for Procaspase-1 and -11 | 503 | ||
| The PIDDosome Activation Platform for Procaspase-2 | 503 | ||
| The Death-Inducing Signaling Complex Activation Platform for Procaspase-8 | 504 | ||
| The Apoptosome-Activation Platform for Procaspase-9 | 504 | ||
| Mitochondria and Apoptosis— Intrinsic Apoptosis | 504 | ||
| Release of Intermitochondrial Regulators to Activate Caspases | 504 | ||
| Mitochondrial Outer Membrane Permeabilization and Apoptosis | 504 | ||
| Regulation of Mitochondrial Outer Membrane Permeabilization | 504 | ||
| Post-Translational Regulation of Bcl-2 Protein Function | 506 | ||
| Alternative/Additional Roles of Bcl-2 Proteins | 508 | ||
| Is MOMP Really the End of It All? | 508 | ||
| Death Receptor–Associated Signaling Events—Extrinsic Apoptosis | 508 | ||
| Molecular Interaction with the Mitochondrial Pathway—Caspase-8/BID | 509 | ||
| Noncanonical Forms of Caspase-Mediated Cell Death | 509 | ||
| Cell Death, Inflammasomes, and Caspase-1 Activation | 509 | ||
| Canonical NLRP3 Inflammasome | 511 | ||
| NLRC4 (IPAF or CARD12 Inflammasome) | 514 | ||
| NLRP1b Inflammasome | 515 | ||
| NLRP6 Inflammasome | 515 | ||
| AIM2 (Pyrin) Inflammasome | 515 | ||
| Noncanonical Inflammasome | 516 | ||
| Nonapoptotic Cell Death Signaling Pathways | 516 | ||
| Necrosis and Secondary Necrosis | 516 | ||
| Necrosis and the Mitochondrial Permeability Transition | 516 | ||
| Poly-ADP-Ribose Polymerase and Necrosis (Parthanatos) | 517 | ||
| Excitotoxicity and Necrosis | 517 | ||
| Ferroptosis | 518 | ||
| Programmed Necrosis or Necroptosis | 518 | ||
| Were We Missing Something? | 518 | ||
| Molecular Regulation of Programmed Necrosis | 519 | ||
| RIPK1—Apoptosis, Necroptosis, or Survival—Take Your Pick | 519 | ||
| RIPK1-Independent Necroptosis | 520 | ||
| Pro-inflammatory Effects of Programmed Necrosis | 520 | ||
| Autophagy | 522 | ||
| Molecular Mechanisms of Autophagy | 522 | ||
| Overeating Is Good for You—Autophagy and the Immune System | 524 | ||
| Mitophagy | 524 | ||
| Mitophagy and Immune Function | 525 | ||
| “Like All Successful Relationships, It’s Complex”—Interaction between Cell Death and Immune Function | 525 | ||
| Conclusion | 526 | ||
| Caspase Inhibitors | 527 | ||
| Necroptosis Inhibitors | 527 | ||
| BH3 Mimetics and BCL-2/MCL-1 Inhibitors | 527 | ||
| IAP Inhibitors | 527 | ||
| Autophagy Regulators | 527 | ||
| Selected References | 527 | ||
| References | 531 | ||
| 29 Experimental Models for Rheumatoid Arthritis | 537 | ||
| Key Points | 537 | ||
| Arthritis Caused by Infectious Agents | 538 | ||
| Mycoplasma Arthritides | 538 | ||
| Lyme Arthritis | 538 | ||
| Staphylococcal Arthritis | 538 | ||
| Arthritis and Ankylosing Spondylitis Induced by Intra-cellular Bacteria | 540 | ||
| Arthritis Caused by Bacterial Fragments | 540 | ||
| Adjuvant-induced Arthritis | 541 | ||
| Cartilage Protein-Induced Arthritis | 542 | ||
| Collagen (II)-Induced Arthritis | 542 | ||
| Genetic Basis of Collagen-Induced Arthritis | 543 | ||
| Autoimmunity Associated with the Major Histocompatibility Complex in Collagen-Induced Arthritis | 544 | ||
| Induction of Arthritis with Other Cartilage and Joint-Related Proteins | 545 | ||
| Type XI Collagen-Induced Arthritis | 545 | ||
| Cartilage Oligomeric Matrix Protein-Induced Arthritis | 545 | ||
| Proteoglycan (Aggrecan)-Induced Arthritis | 545 | ||
| Antigen-Induced Arthritis | 545 | ||
| Glucose-6-Phosphate Isomerase-Induced Arthritis | 545 | ||
| Spontaneous Arthritis | 545 | ||
| Spontaneous Arthritis in Genetically Modified Strains | 545 | ||
| Use of Animal Models | 546 | ||
| Increasing the Knowledge of Disease Pathways | 546 | ||
| Developing New Therapeutic Strategies | 546 | ||
| Ethical Considerations | 547 | ||
| Conclusion | 547 | ||
| References | 547 | ||
| 30 Neuronal Regulation of Pain and Inflammation | 549 | ||
| Key Points | 549 | ||
| Primary Afferent Fibers | 550 | ||
| Skin | 550 | ||
| Joint Afferents | 550 | ||
| Fascia | 550 | ||
| Muscle | 550 | ||
| Mechanically Sensitive Afferents— “Silent Nociceptors” | 550 | ||
| Sensitization | 550 | ||
| Efferent Functions of Primary Afferent Fibers | 551 | ||
| Neurogenic Inflammation | 551 | ||
| Neurogenic Anti-Inflammation | 552 | ||
| Dorsal Root Reflex | 552 | ||
| Pain Transmission in the Dorsal Horn | 553 | ||
| Descending Modulation | 553 | ||
| Neuronal Regulation of Inflammation in Acute Inflammatory Models | 555 | ||
| Neuronal Regulation of Inflammation in Chronic Models of Inflammation | 556 | ||
| Sympathetic Effects on Peripheral Inflammation are Time Dependent | 557 | ||
| Parasympathetic Effects on Peripheral Inflammation | 557 | ||
| Role of Pain in Inflammatory Disease | 558 | ||
| Selected References | 560 | ||
| References | 563 | ||
| IV Broad Issues in The Approach to Rheumatic Disease | 566 | ||
| 31 Clinical Research Methods in Rheumatic Disease | 566 | ||
| Key Points | 566 | ||
| Measures of Disease Occurrence | 566 | ||
| Incidence | 566 | ||
| Measures of Effect | 567 | ||
| Clinical Research Study Designs | 567 | ||
| Observational Studies | 567 | ||
| Ecological Studies | 569 | ||
| Cross-Sectional Surveys | 569 | ||
| Case-Control Studies | 569 | ||
| Selection of Controls for Case-Control Study | 569 | ||
| Weaknesses of the Case-Control Design | 569 | ||
| Cohort Studies | 570 | ||
| Prospective Cohort Study | 570 | ||
| Retrospective Cohort Study | 570 | ||
| Nested Case-Control and Case-Cohort Studies | 570 | ||
| Clinical Trials | 570 | ||
| General Principles of Clinical Trial Design | 570 | ||
| Noninferiority Trials | 572 | ||
| Pragmatic Clinical Trials | 572 | ||
| Cluster Randomized Implementation Trials | 572 | ||
| Comparative Effectiveness Research and Patient-Centered Outcomes Research | 573 | ||
| Patient-Reported Outcomes | 573 | ||
| Biases in Study Design | 573 | ||
| Selection Bias | 573 | ||
| Information and Recall Bias | 573 | ||
| Confounding | 574 | ||
| Confounding by Indication and Channeling in Observational Studies of Therapeutics | 574 | ||
| Analytic Methods to Address Confounding by Indication | 574 | ||
| Effect Measure Modification | 574 | ||
| Screening | 575 | ||
| Sensitivity | 575 | ||
| Specificity | 575 | ||
| Predictive Value | 575 | ||
| Conclusion | 575 | ||
| References | 575 | ||
| 32 Economic Burden of Rheumatic Diseases | 577 | ||
| Key Points | 577 | ||
| Studies of the Costs of All Forms of Musculoskeletal Disease | 579 | ||
| Other Nations | 581 | ||
| Cost of Discrete Conditions | 581 | ||
| Rheumatoid Arthritis | 581 | ||
| Systemic Lupus Erythematosus | 582 | ||
| Osteoarthritis | 583 | ||
| Back Conditions | 583 | ||
| Ankylosing Spondylitis | 584 | ||
| Fibromyalgia | 584 | ||
| Gout | 584 | ||
| Conclusions | 584 | ||
| References | 585 | ||
| 33 Assessment of Health Outcomes | 587 | ||
| Key Points | 587 | ||
| What Types of Outcomes are Typically Measured in Arthritis? | 588 | ||
| Arthritis/Disease Specific Instruments: The Core Outcome Sets | 588 | ||
| Indicators of Pathophysiologic Manifestations of the Disease | 588 | ||
| Life Impact of the Disease | 588 | ||
| General Health Status. | 588 | ||
| Utilities: Value of Health State. | 590 | ||
| Symptoms | 590 | ||
| Disability Scales | 590 | ||
| Self-Efficacy/Effective Consumer. | 590 | ||
| Work Disability: Looking Beyond Absenteeism | 590 | ||
| Nonpaid Work Roles. | 590 | ||
| Patient-Specific Indices. | 591 | ||
| Toxicity/Adverse Events | 591 | ||
| Death | 591 | ||
| Resource Utilization (Costs) | 591 | ||
| How Do You Know What You Need to Measure? Defining Your Measurement Needs | 591 | ||
| What Do You Want to Measure? | 591 | ||
| Why Are You Measuring? | 592 | ||
| Who Comprises the Target Population? | 592 | ||
| Decision-Making Instrument for Selecting the Outcome That Can Meet Your Measurement Needs | 592 | ||
| Step 1: Is It a Good Match with Your Needs? | 593 | ||
| Step 2: Is It Feasible to Use? | 593 | ||
| Content Validity | 593 | ||
| Step 3: Do Its Numeric Scores Make Sense? (Construct Validity) | 593 | ||
| Item onto Scale (Only for Multi-item Reflective Scales): Structural Validity | 593 | ||
| Score Level Analysis: Construct Validity | 594 | ||
| Step 4: Can This Instrument Evaluate Change during a Period of Time in a Group of Patients? | 594 | ||
| Test-Retest Reliability | 594 | ||
| Step 5: are Thresholds of Meaning Defined for This Scale? | 595 | ||
| Benchmarking States | 595 | ||
| Changes in State | 595 | ||
| American College of Rheumatology Response Criteria | 595 | ||
| Minimal Clinically Important Differences/Improvements | 596 | ||
| Combined Approaches: Change and State | 596 | ||
| Areas of Growth in Health Outcome Assessment | 596 | ||
| Systematic Reviews of Measurement Properties | 596 | ||
| The Message Could Be in the Subgroups: The Rise of Cluster Analysis to Uncover Patterns of Responses | 596 | ||
| Adaptation to an Ongoing Disease | 596 | ||
| Conclusion | 597 | ||
| References | 597 | ||
| 34 Biologic Markers in Clinical Trials and Clinical Care | 600 | ||
| Key Points | 600 | ||
| Molecular Biomarkers | 600 | ||
| Characteristics of Biomarker Measurement | 600 | ||
| Biomarker Validation | 601 | ||
| Biomarker Timing | 602 | ||
| Mechanistic and Descriptive Biomarkers | 602 | ||
| Biologic Sample Sources for Biomarker Assays | 602 | ||
| Biomarker Discovery | 603 | ||
| Biomarker Profiles | 603 | ||
| Application of Biomarkers in Clinical Practice and Drug Development | 603 | ||
| Diagnosis of Established Disease | 603 | ||
| Diagnosis of Pre-clinical or Asymptomatic Disease | 603 | ||
| Assessment of Disease Activity and Prognosis | 603 | ||
| Pharmacodynamic Biomarkers | 604 | ||
| Assessing Response to Therapy | 604 | ||
| Assessing Toxicity | 604 | ||
| Predictive Biomarkers | 604 | ||
| Mechanistic Biomarkers | 605 | ||
| Cytokines | 605 | ||
| Autoantibodies | 605 | ||
| Epigenetic Biomarkers | 606 | ||
| Metabolomics | 607 | ||
| Tissue Degradation Product Biomarkers | 607 | ||
| Conclusion | 608 | ||
| References | 608 | ||
| 35 Occupational and Recreational Musculoskeletal Disorders | 611 | ||
| Key Points | 611 | ||
| Occupation-Related Musculoskeletal Disorders | 611 | ||
| Occupation-Related Rheumatic Diseases | 613 | ||
| Osteoarthritis | 613 | ||
| Other Occupational Rheumatologic Disorders | 613 | ||
| Recreation- and Sports-Related Musculoskeletal Disorders | 614 | ||
| Performing Arts–Related Musculoskeletal Disorders | 618 | ||
| Instrumentalists | 618 | ||
| Vocal Artists | 620 | ||
| Dancers | 620 | ||
| References | 621 | ||
| 36 Cardiovascular Risk in Inflammatory Rheumatic Disease | 624 | ||
| Key Points | 624 | ||
| Biologic Mechanisms: Relationship between Inflammation and Cardiovascular Disease | 624 | ||
| Cardiovascular Morbidity in Rheumatoid Arthritis and Systemic Lupus Erythematosus | 625 | ||
| Rheumatoid Arthritis | 625 | ||
| Ischemic Heart Disease in Rheumatoid Arthritis | 625 | ||
| Heart Failure in Rheumatoid Arthritis | 625 | ||
| Systemic Lupus Erythematosus | 626 | ||
| Ischemic Heart Disease in Systemic Lupus Erythematosus | 626 | ||
| Heart Failure in Systemic Lupus Erythematosus | 627 | ||
| Cardiovascular Mortality in Rheumatoid Arthritis and Systemic Lupus Erythematosus | 627 | ||
| Rheumatoid Arthritis | 627 | ||
| Systemic Lupus Erythematosus | 627 | ||
| Risk Factors for Cardiovascular Disease | 628 | ||
| Traditional Cardiovascular Risk Factors in Rheumatoid Arthritis: Occurrence and Impact | 628 | ||
| Smoking in Persons with Rheumatoid Arthritis | 628 | ||
| Hypertension in Rheumatoid Arthritis | 628 | ||
| Dyslipidemia in People with Rheumatoid Arthritis | 629 | ||
| Diabetes Mellitus and Metabolic Syndrome in Rheumatoid Arthritis | 630 | ||
| Body Composition/Obesity in Rheumatoid Arthritis | 630 | ||
| Nontraditional Cardiovascular Risk Factors in Rheumatoid Arthritis: Occurrence and Impact | 630 | ||
| The Impact of Rheumatoid Arthritis Disease Activity and Severity on Cardiovascular Co-Morbidity | 630 | ||
| Medications as Cardiovascular Risk Factors | 631 | ||
| Traditional and Nontraditional Cardiovascular Risk Factors in Systemic Lupus Erythematosus | 631 | ||
| Cardiovascular Mortality, Morbidity, and Risk Factors in Other Rheumatic Diseases | 631 | ||
| Ankylosing Spondylitis | 631 | ||
| Psoriasis and Psoriatic Arthritis | 631 | ||
| Giant Cell Arteritis and Polymyalgia Rheumatica | 632 | ||
| Dermatomyositis and Polymyositis | 632 | ||
| Osteoarthritis | 632 | ||
| Pediatric-Onset Rheumatological Diseases | 632 | ||
| Cardiovascular Risk Assessment | 632 | ||
| Connection to the Clinic | 633 | ||
| Risk Scores and Risk Markers: Biomarkers and Tests for Subclinical Disease | 633 | ||
| Translating Knowledge into Clinical Practice | 633 | ||
| Managing CVD Risk in Patients with Rheumatic Disease | 634 | ||
| Patient Awareness of Cardiovascular Disease Risk | 634 | ||
| Future Directions | 635 | ||
| Selected References | 635 | ||
| References | 638 | ||
| 37 Cancer Risk in Rheumatic Diseases | 643 | ||
| Key Points | 643 | ||
| Malignancy in Autoimmune Rheumatic Diseases | 643 | ||
| Rheumatoid Arthritis | 644 | ||
| Systemic Lupus Erythematosus | 645 | ||
| Systemic Sclerosis (Scleroderma) | 646 | ||
| Idiopathic Inflammatory Myopathy | 646 | ||
| Sjögren’s Syndrome | 647 | ||
| Vasculitis | 647 | ||
| Seronegative Spondyloarthritis | 648 | ||
| Cancer Risks Associated with Anti-rheumatic Drug Therapies | 648 | ||
| Nonbiologic Disease-Modifying Anti-rheumatic Drug Therapy | 648 | ||
| Methotrexate | 649 | ||
| Azathioprine | 649 | ||
| Cyclosporine | 649 | ||
| Alkylating Agents | 649 | ||
| Biologic Therapeutic Agents | 650 | ||
| Anti–Tumor Necrosis Factor Agents | 650 | ||
| Rituximab | 651 | ||
| Abatacept | 652 | ||
| Tocilizumab | 652 | ||
| Anakinra | 652 | ||
| Tofacitinib | 652 | ||
| Cancer Screening in Patients with Rheumatic Disease | 652 | ||
| Conclusion | 652 | ||
| References | 653 | ||
| 38 Introduction to Physical Medicine, Physical Therapy, and Rehabilitation | 656 | ||
| Key Points | 656 | ||
| Brief History of Rehabilitation in Rheumatology | 656 | ||
| Goals of Rehabilitation, Rehabilitation Team Members, and Models of Team Care | 656 | ||
| International Classification of Functioning, Disability, and Health: A Framework for Rehabilitation Management | 657 | ||
| Assessment Tools and the Rehabilitation Cycle | 658 | ||
| What Do Current Guidelines Suggest for Rehabilitation Management of Select Rheumatologic Conditions? | 658 | ||
| Nonpharmacologic Interventions to Manage Rheumatologic Conditions | 658 | ||
| Principles Guiding Rehabilitation in People with Rheumatologic Conditions | 661 | ||
| Rehabilitation of Select Rheumatologic Conditions | 661 | ||
| Rheumatoid Arthritis and Inflammatory Arthritis | 661 | ||
| Systemic Lupus Erythematosus | 663 | ||
| Osteoarthritis | 663 | ||
| Ankylosing Spondylitis | 664 | ||
| Strategies to Increase Adherence to Exercise and Rehabilitation | 664 | ||
| Conclusion | 664 | ||
| References | 664 | ||
| 39 Pregnancy and Rheumatic Diseases | 668 | ||
| Key Points | 668 | ||
| Interplay of Rheumatic Disease and Pregnancy Physiology | 668 | ||
| General Principles of Pregnancy and Rheumatic Disease: Pre-pregnancy Assessment | 669 | ||
| Severe Disease Damage | 669 | ||
| Disease Activity | 669 | ||
| Medication Review | 669 | ||
| Assessment of Autoantibodies | 669 | ||
| Counseling | 669 | ||
| Systemic Lupus Erythematosus | 669 | ||
| Maternal Outcomes | 670 | ||
| Fetal and Neonatal Outcomes | 670 | ||
| Management | 670 | ||
| Mixed Connective Tissue Disease and Undifferentiated Connective Tissue Disease | 671 | ||
| 9780323414944v2_WEB | 1344 | ||
| Front Cover | 1344 | ||
| Kelley and Firestein's Textbook of Rheumatology, 2-Volume Set | 1345 | ||
| Copyright Page | 1348 | ||
| Dedication | 1349 | ||
| Acknowledgement | 1351 | ||
| Contributors | 1353 | ||
| Preface | 1369 | ||
| Table Of Contents | 1371 | ||
| IX Rheumatoid Arthritis | 1375 | ||
| 69 Etiology and Pathogenesis of Rheumatoid Arthritis | 1375 | ||
| Key Points | 1375 | ||
| How Rheumatoid Arthritis Begins | 1375 | ||
| Etiology | 1377 | ||
| Role of Human Leukocyte Antigen-DR in the Disease Susceptibility and Severity | 1378 | ||
| Additional Polymorphisms: Cytokines, Citrullinating Enzymes, PTPN22, and Others | 1378 | ||
| Interactions between Genes and Environment | 1379 | ||
| Microbiome | 1380 | ||
| Sex | 1380 | ||
| Epigenetics | 1381 | ||
| Changing Epidemiology | 1382 | ||
| Pathogenic Mechanisms | 1382 | ||
| Infectious Agents: Direct Infection and Innate Immune Responses | 1383 | ||
| Toll-like Receptors and the Inflammasome in the Joint | 1383 | ||
| Bacteria, Mycobacteria, Mycoplasma, and Their Components | 1383 | ||
| Epstein-Barr Virus, dnaJ Proteins, and Molecular Mimicry | 1384 | ||
| Parvovirus | 1384 | ||
| Other Viruses | 1385 | ||
| Autoimmunity | 1385 | ||
| Anti-citrullinated Protein Antibodies | 1385 | ||
| Antibodies to Other Modified Antigens: Anti-carbamylated Peptide Antibodies | 1387 | ||
| Rheumatoid Factor | 1387 | ||
| Autoimmunity to Cartilage-Specific Antigens | 1388 | ||
| Type II Collagen. | 1388 | ||
| gp39 and Other Cartilage-Specific Antigens. | 1388 | ||
| Autoimmunity to Nonarticular Antigens | 1388 | ||
| Glucose-6-Phosphoisomerase | 1388 | ||
| Heterogeneous Nuclear Ribonucleoprotein-A2 and Heavy-Chain Binding Protein. | 1389 | ||
| Heat Shock Proteins. | 1389 | ||
| Synovial Disease and Biology | 1389 | ||
| Synovial Intimal Lining Cells: Type A and Type B Synoviocytes | 1389 | ||
| Aggressive Behavior of RA Fibroblast-like Synoviocytes | 1391 | ||
| Tumor-like Properties. | 1391 | ||
| Matrix Invasion. | 1391 | ||
| Synovial T Lymphocytes | 1392 | ||
| Immunohistologic Patterns | 1392 | ||
| Regulation of T Cell Aggregate Formation. | 1392 | ||
| Synovial T Cell Phenotype | 1393 | ||
| Co-stimulatory Molecules. | 1393 | ||
| Adhesion Molecules. | 1393 | ||
| Chemokine Receptors. | 1393 | ||
| T Cell Receptor Rearrangements. | 1393 | ||
| Determinants of T Cell Phenotype. | 1393 | ||
| Synovial T Cell Immunoreactivity | 1393 | ||
| Activation of Synovial Cells by Cell-Cell Contact with T Lymphocytes | 1394 | ||
| Restoring T Cell Tolerance | 1394 | ||
| Regulatory T Cells | 1394 | ||
| Synovial B Cells | 1395 | ||
| Cytokine Regulation of Synovial B Cells | 1395 | ||
| Synovial B Cell Maturation | 1395 | ||
| Role of B Cells in RA: Clinical Improvement after B Cell Depletion | 1396 | ||
| Dendritic Cells | 1396 | ||
| Mast Cells, Polymorphonuclear Leukocytes, and Natural Killer Cells | 1397 | ||
| Bone Marrow Cells | 1398 | ||
| Synovitis in Pre- versus Early-Stage versus Late-Stage Rheumatoid Arthritis | 1398 | ||
| Synovial Fluid and the Synovial Fluid Cartilage Interface | 1399 | ||
| Polymorphonuclear Leukocytes | 1399 | ||
| Synovial Fluid Lymphocytes | 1400 | ||
| Platelets and Platelet Microparticles | 1400 | ||
| Intra-articular Immune Complexes and Complement Fixation | 1400 | ||
| Synovial Fluid Immune Complexes | 1400 | ||
| Immune Complexes Embedded in Cartilage | 1400 | ||
| Synovial Fluid Complement | 1401 | ||
| Targeting Complement | 1401 | ||
| Arachidonate Metabolites | 1401 | ||
| Prostaglandins | 1401 | ||
| Leukotrienes | 1402 | ||
| Anti-inflammatory Arachidonic Acid Metabolites | 1402 | ||
| Peripheral Blood Lymphocytes | 1402 | ||
| Role of T Cell Cytokines | 1402 | ||
| Type 1 T Helper Cell Cytokines | 1403 | ||
| Type 2 T Helper Cell Cytokines | 1404 | ||
| Type 17 T Helper Cytokines | 1404 | ||
| T Helper Cell Cytokine Imbalance | 1404 | ||
| Role of Macrophage and Fibroblast Cytokines | 1405 | ||
| Pro-inflammatory Macrophage and Fibroblast Cytokines | 1405 | ||
| Interleukin-1 Family | 1405 | ||
| Interleukin-1. | 1405 | ||
| Interleukin-18. | 1405 | ||
| Interleukin-33 and Other Alarmins. | 1406 | ||
| Tumor Necrosis Factor and the Tumor Necrosis Factor Superfamily | 1406 | ||
| Interleukin-6 Family | 1406 | ||
| Interleukin-12 Family | 1407 | ||
| Interleukin-15 | 1407 | ||
| Interleukin-32 | 1407 | ||
| Colony-Stimulating Factors | 1407 | ||
| Interferons | 1408 | ||
| Chemokines | 1408 | ||
| Platelet-Derived Growth Factor and Fibroblast Growth Factor | 1409 | ||
| Immunosuppressive Cytokines and Cytokine Antagonists | 1409 | ||
| Interleukin-1 Receptor Antagonist | 1409 | ||
| Interleukin-10 | 1409 | ||
| Transforming Growth Factor-β | 1409 | ||
| Soluble Cytokine Receptors and Binding Proteins | 1410 | ||
| Perpetuation of Synovitis by Cytokine Networks | 1410 | ||
| Signal Transduction and Transcription Factors | 1411 | ||
| Nuclear Factor-κB | 1411 | ||
| Activator Protein-1 | 1411 | ||
| Mitogen-Activated Protein Kinases | 1412 | ||
| Janus Kinases and the Signal Transducers and Activators of Transcription | 1413 | ||
| Interferon Regulation: IKK-Related Kinases and Interferon Regulatory Factors | 1413 | ||
| Spleen Tyrosine Kinase | 1414 | ||
| PI3 Kinases and Other Signaling Pathways | 1414 | ||
| Cell Survival and Death in Rheumatoid Synovium | 1414 | ||
| Reactive Oxygen and Nitrogen | 1414 | ||
| Apoptosis and Autophagy | 1414 | ||
| Genes Regulating Apoptosis | 1414 | ||
| Genes Regulating Autophagy | 1415 | ||
| Possible Therapeutic Interventions that Increase Apoptosis | 1415 | ||
| Tumor Suppressor Genes | 1415 | ||
| Blood Vessels and the Synovial Vasculature | 1416 | ||
| Angiogenesis: Feeding the Starved Synovium | 1416 | ||
| Hypoxia | 1416 | ||
| Angiogenic Factors | 1417 | ||
| Targeting Angiogenesis | 1417 | ||
| Adhesion Molecule Regulation | 1417 | ||
| Integrins and Their Ligands | 1418 | ||
| Therapeutic Potential of Blocking Adhesion Molecules | 1418 | ||
| Cartilage and Bone Destruction | 1418 | ||
| Cartilage Destruction and the Pannus-Cartilage Junction | 1418 | ||
| Proteases: Mediators of Joint Destruction | 1419 | ||
| Matrix Metalloproteinases | 1419 | ||
| Regulation of MMP Production. | 1420 | ||
| MMP Expression in Synovium. | 1420 | ||
| Cysteine Proteases: The Cathepsins | 1420 | ||
| Aggrecanases | 1421 | ||
| Endogenous Protease Inhibitors | 1421 | ||
| Regulation of Bone Destruction | 1422 | ||
| Tissue Repair | 1423 | ||
| Conclusion | 1423 | ||
| Selected References | 1423 | ||
| References | 1427 | ||
| 70 Clinical Features of Rheumatoid Arthritis | 1434 | ||
| Key Points | 1434 | ||
| Epidemiology and Disease Burden | 1434 | ||
| Disease Frequency | 1434 | ||
| Disease Outcomes | 1434 | ||
| Pre-clinical Rheumatoid Arthritis | 1435 | ||
| Diagnosis | 1435 | ||
| Clinical Presentations of Early Rheumatoid Arthritis | 1439 | ||
| Patterns of Onset | 1439 | ||
| Insidious Onset | 1439 | ||
| Acute or Intermediate Onset | 1439 | ||
| Atypical Onset | 1439 | ||
| Other Patterns of Onset | 1440 | ||
| Palindromic Rheumatism. | 1440 | ||
| Arthritis Robustus. | 1440 | ||
| Extra-articular Disease as Initial Presentation. | 1440 | ||
| Course and Complications of Established Rheumatoid Arthritis | 1440 | ||
| Articular Manifestations | 1440 | ||
| Hands and Wrists | 1440 | ||
| Feet and Ankles | 1442 | ||
| Cervical Spine | 1443 | ||
| Intermediate and Large Peripheral Joints | 1444 | ||
| Temporomandibular, Cricoarytenoid, Sternoclavicular and Manubriosternal Joints | 1445 | ||
| Extra-articular Manifestations | 1445 | ||
| Mucocutaneous | 1445 | ||
| Ocular | 1446 | ||
| Bone | 1447 | ||
| Muscle | 1447 | ||
| Hematologic | 1447 | ||
| Vasculitis | 1448 | ||
| Pulmonary | 1449 | ||
| Pleural Disease. | 1449 | ||
| Interstitial Lung Disease. | 1449 | ||
| Obstructive Lung Disease. | 1450 | ||
| Nodular Lung Disease. | 1450 | ||
| Cardiovascular | 1450 | ||
| Atherosclerosis. | 1450 | ||
| Pericarditis. | 1450 | ||
| Myocarditis. | 1450 | ||
| Conduction Defects. | 1450 | ||
| Endocardial Inflammation and Granulomatous Aortitis. | 1450 | ||
| Prognosis and Individual Patient Follow-up | 1450 | ||
| References | 1451 | ||
| 71 Treatment of Rheumatoid Arthritis | 1454 | ||
| Key Points | 1454 | ||
| Goal of Rheumatoid Arthritis Treatment | 1455 | ||
| Classes of Drugs | 1457 | ||
| Disease-Modifying Anti-rheumatic Drugs | 1457 | ||
| Methotrexate, Sulfasalazine, Hydroxychloroquine, Leflunomide, and Azathioprine | 1457 | ||
| Biologic Disease-Modifying Anti-rheumatic Drugs | 1458 | ||
| Glucocorticoids | 1458 | ||
| Other Conventional Disease-Modifying Anti-rheumatic Drugs | 1458 | ||
| Azathioprine. | 1458 | ||
| Cyclosporine. | 1459 | ||
| Minocycline and Doxycycline | 1459 | ||
| Nonsteroidal Anti-inflammatory Drugs | 1460 | ||
| Treatment Approaches and Strategies | 1460 | ||
| Treatment of the Disease-Modifying Anti-rheumatic Drug–Naïve Patient | 1461 | ||
| Initial Therapy—The First Disease-Modifying Anti-rheumatic Drug | 1462 | ||
| Initiating Treatment with a Single Disease-Modifying Anti-rheumatic Drug versus Combinations of Disease-Modifying Anti-rheumatic Drugs | 1463 | ||
| The BeSt Study | 1463 | ||
| Conclusions from the BeSt Study | 1465 | ||
| Treatment of Early Aggressive Rheumatoid (TEAR) Trial | 1465 | ||
| Conclusions from the TEAR Trial | 1466 | ||
| Treatment of Patients with Active Disease Despite Treatment with Methotrexate | 1467 | ||
| Rheumatoid Arthritis: Comparison of Active Therapies Trial | 1468 | ||
| Conclusions from the RACAT Trial | 1469 | ||
| Treatment of “Refractory” Patients or Those with Active Disease Despite TNF Inhibition | 1469 | ||
| The Niche for Tofacitinib and Potentially Other Janus Kinase Inhibitors | 1470 | ||
| How to Manage Patients in Remission Who Are Taking Disease-Modifying Anti-rheumatic Drugs | 1470 | ||
| Use of Combinations of Biologic Agents | 1471 | ||
| Interpreting Radiographic Progression and the Use of Other Imaging Modalities | 1471 | ||
| Adjuncts to Medications | 1473 | ||
| Patient Education | 1473 | ||
| Pain Control | 1473 | ||
| Rest and/or Exercise and Activities of Daily Living | 1474 | ||
| Treatment of Rheumatoid Arthritis Comorbidities and the Interactions of Rheumatologists with Primary Care Physicians | 1474 | ||
| Evidence That Patients with Rheumatoid Arthritis are Doing Better | 1475 | ||
| Research Agenda: Unmet Needs | 1475 | ||
| The Horizon | 1476 | ||
| Selected References | 1476 | ||
| References | 1480 | ||
| 72 Early Synovitis and Early Undifferentiated Arthritis | 1485 | ||
| Key Points | 1485 | ||
| What is Early-Stage Synovitis? | 1485 | ||
| Early-Stage Arthritis Clinics | 1485 | ||
| What is Undifferentiated Arthritis? | 1486 | ||
| Characteristics of Early-Stage Undifferentiated Arthritis | 1486 | ||
| Remission Rates in Early-Stage Undifferentiated Arthritis and Rheumatoid Arthritis | 1486 | ||
| Joint Destruction in Early-Stage Undifferentiated Arthritis and Rheumatoid Arthritis | 1487 | ||
| Biologic Mechanisms in Undifferentiated Arthritis and Determinants of Progression to Rheumatoid Arthritis | 1488 | ||
| Window of Opportunity | 1489 | ||
| Treatment of Undifferentiated Arthritis | 1489 | ||
| Individualized Treatment of Undifferentiated Arthritis | 1489 | ||
| References | 1491 | ||
| 73 Sjögren’s Syndrome | 1493 | ||
| Key Points | 1493 | ||
| Historic Perspective | 1493 | ||
| Definitions and Classification Criteria | 1494 | ||
| Epidemiology | 1497 | ||
| Etiology and Pathogenesis | 1497 | ||
| Genetics | 1498 | ||
| Adaptive and Innate Immunity | 1499 | ||
| Autoantibodies | 1501 | ||
| Glandular Epithelium | 1501 | ||
| Clinical Features | 1502 | ||
| Keratoconjunctivitis Sicca | 1502 | ||
| Xerostomia | 1502 | ||
| Involvement of Other Exocrine Glands | 1505 | ||
| Extraglandular Manifestations | 1505 | ||
| Fatigue | 1505 | ||
| Raynaud’s syndrome | 1505 | ||
| Skin | 1505 | ||
| Joints | 1506 | ||
| Lung | 1506 | ||
| Kidney | 1506 | ||
| Gastrointestinal | 1507 | ||
| Nervous System | 1507 | ||
| Vasculitis | 1508 | ||
| Risk for Cardiovascular Disease | 1508 | ||
| Lymphoma | 1508 | ||
| Associated Diseases | 1509 | ||
| Diagnosis and Diagnostic Tests | 1509 | ||
| Keratoconjunctivitis Sicca and Xerostomia | 1509 | ||
| Labial Salivary Gland Biopsy | 1510 | ||
| Laboratory Evaluation | 1510 | ||
| Approach to Diagnosis | 1510 | ||
| Differential Diagnosis | 1511 | ||
| Treatment | 1511 | ||
| Outcome | 1513 | ||
| Conclusion | 1513 | ||
| Selected References | 1514 | ||
| References | 1517 | ||
| X Spondyloarthropathies | 1521 | ||
| 74 Etiology and Pathogenesis of Spondyloarthritis | 1521 | ||
| Key Points | 1521 | ||
| Etiology of Spondyloarthritis | 1521 | ||
| Genetics | 1521 | ||
| Environment | 1522 | ||
| Pathogenesis of Spondyloarthritis | 1523 | ||
| Functional Genomics | 1523 | ||
| HLA-B27 | 1523 | ||
| Arthritogenic Peptides | 1523 | ||
| HLA-B27 Misfolding | 1524 | ||
| Free Heavy Chain Dimers and Monomers | 1524 | ||
| ERAP1 | 1525 | ||
| Genetic Susceptibility Distinct from the Major Histocompatibility Class I Pathway | 1525 | ||
| IL-23 and the Spondyloarthritis Phenotype | 1525 | ||
| Cytokines and Cytokine-Producing Cells in Spondyloarthritis | 1527 | ||
| Structural Damage in Ankylosing Spondylitis | 1527 | ||
| Bone Homeostasis and Aberrant Bone Formation | 1527 | ||
| Inflammation and New Bone Formation in Spondyloarthritis | 1528 | ||
| Current and Future Therapeutic Targets in Spondyloarthritis | 1529 | ||
| Targeting the IL-23/IL-17 Axis | 1529 | ||
| Selected References | 1529 | ||
| References | 1532 | ||
| 75 Ankylosing Spondylitis | 1536 | ||
| Key Points | 1536 | ||
| Classification | 1536 | ||
| Criteria for Ankylosing Spondylitis and Axial Spondyloarthritis | 1536 | ||
| Epidemiology | 1538 | ||
| Prevalence | 1538 | ||
| Incidence | 1538 | ||
| Racial Distribution | 1538 | ||
| Burden of Disease | 1538 | ||
| Genetics | 1538 | ||
| Major Histocompatibility Complex Associations with Ankylosing Spondylitis | 1538 | ||
| Non–Major Histocompatibility Complex Associations of Ankylosing Spondylitis | 1539 | ||
| Aminopeptidase Genes and Ankylosing Spondylitis | 1539 | ||
| Interleukin-23 Pathway Genes and Ankylosing Spondylitis | 1541 | ||
| Lymphocyte Development and Activation Genes | 1541 | ||
| Pathogenesis | 1541 | ||
| HLA-B27 | 1541 | ||
| ERAP1 and Other Aminopeptidases | 1542 | ||
| IL-23 Signaling Pathway | 1542 | ||
| Structural Remodeling and Ankylosis | 1542 | ||
| Clinical Manifestations | 1543 | ||
| Skeletal Manifestations | 1543 | ||
| Low Back Pain and Stiffness | 1543 | ||
| Chest Pain | 1543 | ||
| Tenderness | 1543 | ||
| Joints | 1543 | ||
| Extraskeletal Manifestations | 1544 | ||
| Eye Disease | 1544 | ||
| Cardiovascular Disease | 1544 | ||
| Pulmonary Disease | 1544 | ||
| Neurologic Involvement | 1544 | ||
| Renal Involvement | 1544 | ||
| Osteoporosis | 1544 | ||
| Physical Examination | 1545 | ||
| Spinal Mobility | 1545 | ||
| Chest Expansion | 1545 | ||
| Enthesitis | 1545 | ||
| Sacroiliitis | 1545 | ||
| Posture | 1545 | ||
| Laboratory Tests | 1545 | ||
| Imaging Studies | 1545 | ||
| Conventional Radiography | 1545 | ||
| Computed Tomography and Magnetic Resonance Imaging | 1546 | ||
| Diagnosis | 1547 | ||
| Ankylosing Spondylitis in Males and Females | 1548 | ||
| Outcome | 1548 | ||
| Assessment and Monitoring | 1549 | ||
| Management | 1549 | ||
| Physiotherapy | 1550 | ||
| Pharmacotherapy | 1552 | ||
| Nonsteroidal Anti-inflammatory Drugs | 1552 | ||
| Second-Line Drugs | 1552 | ||
| Biologic Therapies | 1553 | ||
| Anterior Uveitis | 1554 | ||
| Surgery | 1554 | ||
| Osteoporosis | 1555 | ||
| Conclusion | 1556 | ||
| Selected References | 1556 | ||
| References | 1560 | ||
| 76 Undifferentiated Spondyloarthritis | 1565 | ||
| Key Points | 1565 | ||
| Epidemiology | 1565 | ||
| Genetics, Pathogenesis, and Etiology | 1566 | ||
| Clinical Features | 1567 | ||
| Laboratory, Radiographic, and Advanced Imaging Findings | 1568 | ||
| Diagnosis | 1568 | ||
| Treatment | 1568 | ||
| References | 1568 | ||
| 77 Psoriatic Arthritis | 1570 | ||
| Key Points | 1570 | ||
| Epidemiology | 1570 | ||
| Clinical Features | 1571 | ||
| Differential Diagnosis | 1575 | ||
| Laboratory Features | 1575 | ||
| Radiographic Features | 1575 | ||
| Plain Radiography | 1575 | ||
| Musculoskeletal Ultrasound | 1575 | ||
| Magnetic Resonance Imaging | 1577 | ||
| Other Imaging Modalities | 1577 | ||
| Diagnosis | 1578 | ||
| Clinical Course and Outcome | 1578 | ||
| Comorbidities in Psoriatic Arthritis | 1579 | ||
| Outcome Domains and Instruments | 1580 | ||
| Pathogenesis | 1581 | ||
| Genetic Factors | 1581 | ||
| Environmental Factors | 1582 | ||
| Animal Models | 1582 | ||
| Immunopathology | 1583 | ||
| Psoriasis Skin | 1583 | ||
| Psoriatic Synovium | 1583 | ||
| Entheseal Sites | 1583 | ||
| Cytokines | 1584 | ||
| Matrix Metalloproteinases and Cartilage Destruction | 1584 | ||
| Bone Remodeling | 1584 | ||
| Conclusion | 1585 | ||
| Treatment | 1585 | ||
| Traditional Agents | 1585 | ||
| Biologics | 1589 | ||
| Selected References | 1590 | ||
| References | 1594 | ||
| 78 Enteropathic Arthritis | 1598 | ||
| Key Points | 1598 | ||
| Gut Mucosa Biology | 1598 | ||
| Gut Microbiota | 1599 | ||
| Gastrointestinal-Associated Lymphoid Tissue | 1601 | ||
| Inflammatory Bowel Disease | 1604 | ||
| Epidemiology | 1604 | ||
| Genetics | 1605 | ||
| Pathogenesis | 1605 | ||
| Clinical Features | 1607 | ||
| Diagnosis | 1609 | ||
| Treatment | 1609 | ||
| Outcome | 1609 | ||
| Brucella Arthritis | 1609 |