Firestein & Kelley’s Textbook of Rheumatology, 2-Volume Set, 12e (Oct 23, 2024)_(0323935400)_(Elsevier).pdf

Cover FIRESTEIN & KELLEY’S Textbook of Rheumatology Copyright Dedication Contributors Preface Contents 1 1. Developmental Biology, Organization, and Function of the Synovial Joints Classification of Joints ? Onset of Limb Skeletogenesis Determination of Joint Site and Interzone Formation Interzone Roles and Regulation Cavitation Articular Cartilage Genesis, Morphogenesis, and Endurance Growth Plates and Ossification Centers Organization and Physiology of the Mature Joint Synovium Synovial Lining (Intima) Synovial Sublining (Subintima) Synovial Innervation Synovial Fluid Generation and Clearance of Synovial Fluid Synovial Fluid as an Indicator of Joint Health and Disease Lubrication and Nutrition of the Articular Cartilage Mature Articular Cartilage Subchondral Bone Tendons Ligaments Bursae Menisci Conclusion 2 2. Synovium Structure Synovial Lining Cells Ultrastructure of Synovial Lining Cells ? Immunohistochemical Profile of Synovial Cells Synovial Macrophages. Synovial macrophages and fibroblasts express lineage-specific molecules that can be detected by immunohist... Turnover of Synovial Lining Cells Origin of Synovial Lining Cells Subintimal Layer Subintimal Vasculature Subintimal Lymphatics Subintimal Nerve Supply Function Joint Movement Deformability Porosity Nonadherence Lubrication Synovial Fluid Formation Chondrocyte Nutrition Conclusion 3 3. Cartilage and Chondrocytes Introduction Cartilage Structure ? Structure–Function Relationships of Cartilage Matrix Components Cartilage Collagens Cartilage Proteoglycans Other Extra-cellular Matrix and Cell Surface Proteins Morphology Classification: Cell Origin and Differentiation Normal Function of the Adult Articular Chondrocyte Interactions of Chondrocytes With the Extra-cellular Matrix Integrins Other Cell Surface Receptors on Chondrocytes Angiogenic and Antiangiogenic Factors Roles of Growth and Differentiation (Anabolic) Factors in Normal Cartilage Metabolism Insulin-like Growth Factor Fibroblast Growth Factor Transforming Growth Factor-β/Bone Morphogenetic Protein Superfamily Transforming Growth Factor-β Bone Morphogenetic Proteins Epigenetic Regulation of Cartilage Homeostasis Role of the Chondrocyte in Cartilage Pathology Cartilage Matrix–Degrading Proteinases Cytokines in Cartilage Destruction Interleukin-1 and Tumor Necrosis Factor Cytokine Networks Other Mediators Cytokine Signaling Pathways Involved in Cartilage Metabolism Aging of Articular Cartilage Chondrocyte Aging Markers of Cartilage Matrix Degradation and Turnover Repair of Articular Cartilage Conclusion 4 4. Development and Biology of Bone Structure and Composition of Bone Bone Vasculature ? Bone Matrix Bone Cells Osteoblasts Osteocytes Osteoclasts Bone Remodeling Fracture Repair Regulation of Bone Remodeling Direct Interactions Between Osteoblasts and Osteoclasts Systemic Control of Bone Remodeling by Neuroendocrine Mechanisms Interactions of Immune System and Bone Cells: Osteoimmunology Osteoimmunology in Rheumatoid Arthritis Osteoimmunology in Psoriatic Arthritis Osteoimmunology in Post-menopausal Osteoporosis Osteoimmunology in Osteoarthritis Conclusion 5 5. Muscle Anatomy, Physiology, and Biochemistry Introduction Structure Sarcomere Myotendinous Junction ? Muscle Spindle Golgi Tendon Organ Peripheral Nerves and Neurons Motor and Sensory Neurons Neuromuscular Junctions Muscle Architecture Physiology Motor Control Motor Units Size Principles of Motor Control Physiology of the Neuromuscular Junction Excitation–Contraction Coupling Troponin, Tropomyosin, and the Cross-Bridge Cycle Length–Tension Force–Velocity Force Transmission Energy and Biochemistry ATP-Phosphocreatine Energy System Glycolytic Energy System Aerobic Energy System Fatigue Plasticity Atrophy and Hypertrophy Denervation Fatigue Resistance Aging Conclusion 6 6. Biomechanics Introduction ? Kinematics Kinetics Statics Dynamics Joint Mechanics Joint Constraint and Stability Mechanical Loading on Tendon Mechanical Loading on Bursae Conclusion 7 7. Regenerative Medicine and Tissue Engineering Introduction Extrinsic Repair: Current Therapeutic Interventions Joint Surface Defects ? Autologous Chondrocyte Implantation Stem Cell–Based Approaches Osteochondral Repair Regeneration of Other Joint-Related Structures Menisci Tendons Cell Therapy for Osteoarthritis Intrinsic Repair Genetic Basis of Tissue Repair Signaling Pathways Orchestrating Joint Homeostasis and Surface Repair Parathyroid Hormone–Related Protein Signaling Transforming Growth Factor-β/Bone Morphogenetic Protein Signaling Fibroblast Growth Factor Signaling Wnt Signaling Agrin ROR-2 Blockade CXCR2 Signaling Joint-Resident Stem and Progenitor Cells Events Leading to Joint Surface Repair Immediate Molecular Response Activation and Attraction of Mesenchymal Progenitors Patterning, Differentiation, Integration, and Remodeling Emerging Clinical Applications That Target Endogenous Repair Targeting Fibroblast Growth Factor Signaling Targeting Wnt Signaling Targeting Integrin Signaling Conclusion 8 8. Proteinases and Matrix Degradation Introduction Extra-cellular Matrix–Degrading Proteinases Aspartic Proteinases ? Cysteine Proteinases Serine Proteinases Neutrophil Elastase and Cathepsin G Mast Cell Chymase and Tryptase Plasmin and Plasminogen Activators Kallikreins Metalloproteinases Matrix Metalloproteinases ADAM and ADAMTS Families Regulation of Proteinase Activity Gene Expression Matrix Metalloproteinases Serine Proteinases Lysosomal Cysteine and Aspartic Proteinases Inhibition of Proteinases by Endogenous Inhibitors α2 Macroglobulin Inhibitors of Serine Proteinases Inhibitors of Cysteine Proteinases Tissue Inhibitors of Metalloproteinases Activation Mechanisms of Matrix Metalloproteinase Zymogens Extra-cellular Activation Intra-cellular Activation Cell Surface Activation Endocytosis of ECM-Degrading Metalloproteinases Joint Tissue Destruction in Arthritis Cartilage Destruction in Rheumatoid Arthritis Bone Resorption in Rheumatoid Arthritis Cartilage Degradation in Osteoarthritis Conclusion 9 9. Dendritic Cells Introduction Dendritic Cell Subsets and Development ? Conventional Dendritic Cells Plasmacytoid Dendritic Cells Inflammatory Dendritic Cells Summary of Developments in Dendritic Cell Classification Emergence of DC3 Subset Transitional AS-DC Subset Legitimacy of pDCs Removal of LCs From DC Classification Dendritic Cell Maturation and Activation Pattern-Recognition Receptors and Dendritic Cell Maturation RLRs and Intra-cellular DNA Sensors TLRs NLRs CLRs Fc Receptors Antigen Processing and Presentation Major Histocompatibility Complex Class I Antigen Presentation Cross-Presentation Major Histocompatibility Class II Antigen Presentation T Cell Activation B Cell Activation Cross-Talk Between Dendritic Cells and Innate Lymphoid Cells Activation of Other Elements of the Immune System Impairment of Dendritic Cell Biology in Diseases Dendritic Cells and Autoimmunity Dendritic Cells in Human Immunodeficiency Subversion of Dendritic Cell Function by Pathogens Dendritic Cell Dysfunction in Tumors Immunotherapeutic Strategies and Clinical Trials Cancer Infectious Disease Autoimmunity Conclusion 10 10. Mononuclear Phagocytes Introduction Macrophage Origin: Nature Versus Nurture ? Macrophage Plasticity Studying Mononuclear Phagocyte Heterogeneity at Single-Cell Resolution Mononuclear Phagocytes in Rheumatoid Arthritis Synovial Macrophages in the Mouse Synovial Macrophages in the Human Human Synovial Macrophages During Rheumatoid Arthritis Remission and Relapse Human Macrophage Heterogeneity: Where Do We Go From Here 11 11. Neutrophils Introduction Neutrophils: Basic Principles Development and Clearance ? Morphology and Contents Primary Granules Secondary Granules Tertiary Granules: Gelatinase and Secretory Vesicles Neutrophil Functions Adhesion Diapedesis Chemotaxis Degranulation Phagocytosis Oxidative or Respiratory Burst/Reactive Oxygen Species Production Neutrophil Extra-cellular Traps Heterogeneity Systemic Lupus Erythematosus Anti-neutrophilic Cytoplasmic Antibody–Associated Vasculitis Rheumatoid Arthritis Antiphospholipid Antibody Syndrome Idiopathic Inflammatory Myositis Psoriasis Gout Other Diseases Targeting Neutrophils and Neutrophil Extra-cellular Traps in Systemic Autoimmune Diseases Conclusion 12 12. T Lymphocytes Introduction T Cell Development ? Immunodeficiencies Resulting From Defects in T Cell Development Peripheral Migration and Homeostatic Proliferation of T Cells Activation of T Cells Metabolic Switch TCR Signal Regulation Adaptor Proteins Downstream TCR Signaling Co-stimulation Immunologic Synapse Tolerance and Control of Autoreactive T Cells Regulatory T Cells T Cell Subsets CD4+ Helper and CD8+ Cytolytic T Cells CD4 T Helper Subsets Naive Versus Memory T Cells Nonconventional and Innate T Cells γδ T Cells NKT Cells MAIT Cells Inflammation Mediated by T Cells Termination of T Cell Responses Conclusion 13 13. B Cells Introduction Immunoglobulins: Structure and Function ? Immunoglobulin Heavy Chain Constant Region Immunoglobulin M Immunoglobulin G Immunoglobulin A Immunoglobulin E Immunoglobulin D Immunoglobulin Light Chains Immunoglobulin Variable Region Generation of Immunoglobulin Diversity Glycosylation B Cell Development Niches for Human B Lymphopoiesis B Cell Ontogeny Pro-B Cells Pre-B Cells Immature B Cells Transitional B Cells Mature B Cells Peripheral Naïve B Cell Subsets and Their Homing Follicular B Cells Marginal Zone B Cells B1 Cells B Cell Activation and Differentiation B Cell Receptor Signaling Phosphatases Co-receptors CD19 CD22 FcγRllB CD5 CD72 Paired Ig-like Receptor Programmed Cell Death Protein-1 BCR Signal Transduction in Immature and Mature B Cells Toll-like Receptors Tumor Necrosis Factor Superfamily Receptors CD40 BAFF-R, TACI, BCMA B Cell Activation B1 Cell Activation Marginal Zone B Cell Activation Follicular B Cell Activation Germinal Centers Ectopic Lymphoid Structures Mucosa-Associated Compartments B Cell Differentiation Memory B Cells Plasma Cells Metabolic Changes During Differentiation Nonconventional B Cell Activation Mucosal T–Independent Class Switch Recombination Repertoire Selection Tolerance Receptor Editing Deletion Anergy B Cells as Immune Regulators Regulation by Small Molecules Vitamin D Estrogens Leptin B Cell–Mediated Autoimmunity Origin of Autoreactive B Cells Autoreactivity in the Preimmune B Cell Repertoire Autoreactivity in the Postimmune B Cell Repertoire Molecular Triggers of Autoimmunity Molecular Mimicry Supraoptimal B Cell Co-stimulation B Cell Signaling Thresholds Conclusion 14 14. Fibroblasts andFibroblast-like Synoviocytes Introduction What Is a Fibroblast Fibroblast Identity and Microenvironments ? Embryologic Origins Origin of Fibroblasts in Tissue Fibroblasts and Mesenchymal Progenitor Cells Production of ECM Components Integrins Syndecans Immunoglobulin Superfamily Receptors Cadherins Adhesion Molecule-Mediated Signaling Degradation of Extra-cellular Matrix by Fibroblasts Fibroblasts as Innate Immune Sentinels Role of Specialized Fibroblast Subsets Within Tissue Microenvironments Fibroblast-like Synoviocytes in the Normal Synovium Role of Fibroblasts in Persistent Inflammation Fibroblast-like Synoviocytes in Rheumatoid Arthritis Persistent Activated Fibroblast Phenotype in the Rheumatoid Arthritis Synovium Interactions of Fibroblasts With Leukocytes Recruitment of Inflammatory Infiltrates Into the Joint Fibroblast Support for Leukocyte Survival Fibroblast-Mediated Retention of Leukocytes in Tissue Constitutive Chemokines and Lymphoid Neogenesis Fibroblast Subsets Epigenetic Regulation of Fibroblast Gene Expression microRNAs and Fibroblast-like Synoviocytes Lessons Learned From Cancer Conclusion 15 15. Mast Cells and Basophils Introduction Mast Cells and Basophils in Ancient Innate Immunity ? Mast Cells Morphology Natural History and Regulation of Development Effects of Stem Cell Factor, Interleukin-3, and Other Cytokines Positive and Negative Regulation of Function Activation by Mrgprb2 (in Mice)/MRGPRX2 (in Humans) Lipid Mediators Other Regulators of Mast Cell Function Products and Mediators Basophils Morphology Natural History and Regulation of Development Positive and Negative Regulation of Function Products and Mediators IgE-Dependent Upregulation of FcεRI Expression and FcεRI-Dependent Function Mast Cell and Basophil Heterogeneity Genetic Approaches for Analyzing Mast Cell and Basophil Function Immunoregulatory Functions of Mast Cells and Basophils Roles in IgE-Associated Allergic Responses Roles in Host Defense in Innate and Adaptive Immune Responses Roles in Other Immunologic Disorders Systemic Lupus Erythematosus Inflammatory Arthritis Multiple Sclerosis/Experimental Autoimmune Encephalomyelitis Conclusion 16 16. Innate Lymphoid Cells and Natural Killer Cells Introduction Distinguishing Human ILCs and NK Cells ? Target Recognition by NK Cells and Killer Immunoglobulin-like Receptors Biology of ILCs and NK Cells ILC Development NK Cell Development NK Cell Function Regulation of NK Cell Activation, Licensing, and Missing Self The Evolution of Missing Self ILC Functions Role of NK Cells in Rheumatic Disease NK Cell Correlates With Rheumatologic Diseases Rheumatoid Arthritis and NK Cells Systemic Lupus Erythematosus and NK Cells Juvenile Idiopathic Arthritis and NK Cells Macrophage Activation Syndrome/Hemophagocytic Lymphohistiocytosis and NK Cells Multisystem Inflammatory Syndrome in Children, Kawasaki Disease, and NK Cells Association of KIR/HLA With Autoimmune Disease Role of ILCs in Rheumatic Disease 17 17. Platelets and Megakaryocytes Introduction Platelet Structure ? Platelet Production Platelets and Hemostasis Signaling Pathways in Platelet Activation The Platelet as an Immune Cell The Megakaryocyte as an Immune Cell Rheumatoid Arthritis Systemic Lupus Erythematosus Other Rheumatic Diseases Conclusion 18 18. Principles of Signaling Introduction Receptors With Enzymatic Activity ? Immunoreceptors: T Cell Receptor, B Cell Receptor, and FcRs Co-stimulatory Receptors Cytokine Receptors Adhesion Molecules Seven-Transmembrane Domain Receptors G Protein–Coupled Receptors Wingless-Type Signaling Pathways Sphingosine 1-Phosphate Innate Receptor Signaling Intra-cellular Receptor Signaling Adaptor Molecules Transmembrane Adaptor Proteins Grb2 Family Tumor Necrosis Factor Receptor Signaling Adaptor Molecules Myeloid Differentiation Primary Response Gene 88 and IL-1R Associated Kinase TIR-Domain-Containing Adaptor-Inducing Interferon-β TRAM and TIRAP Second Messengers Phospholipase C Signaling: Calcium Flux and Protein Kinase C Activation PI3K/Akt Pathway Metabolite Sensing Signaling Pathways JAK/STAT Pathway Mammalian/Mechanistic Target of Rapamycin Pathway MAPK Pathway IRAK Transcription Factors Nuclear Factor-κB Activator Protein-1 NFAT CREB/CREM Conclusion 19 19. Innate Immunity Introduction Evolutionary Origins of Innate Immunity ? Pathogen Recognition by the Innate Immune System Pathogen-Associated Molecular Patterns Pattern Recognition Receptors Pattern Recognition Receptors of the Lectin Family Pattern Recognition Receptors of the Scavenger Receptor Family Pattern Recognition Receptors With Leucine-rich Repeat Domains Nod-like Receptors (NLRs) as Cytosolic Sensors for Innate Immunity Other Cytosolic Sensors for Innate Responses to Nucleic Acids Effector Mechanisms of Innate Immune Responses Cell Types Mediating Innate Immunity Innate-like Lymphocytes Anti-microbial Peptides Influence of Innate Mechanisms on Adaptive Immunity Trained Immunity: Blurring the Distinction Between Innate and Adaptive Responses Disease Associations Involving Innate Immunity Conclusions Connection to the Clinic 20 20. Adaptive Immunity Introduction Phylogenetic Appearance of the Adaptive Immune System ? Specificity/Diversity Tolerance Expansion/Contraction Memory Cells of the Adaptive Immune System B Cells and Humoral Immunity Contrasting the BCR With the TCR T Cell–Mediated Immunity Development of Adaptive Immune Cells Primary Lymphoid Organs B Cell Development in the Bone Marrow T Cell Development in the Thymus Secondary Lymphoid Organs Spleen Lymphatics Lymph Nodes and Mucosal Lymphoid Tissue Tertiary Lymphoid Structures Trafficking of Adaptive Immune Cells Egress From the Thymus and Lymph Nodes Lymphocyte Migration and Circulation to SLOs and Peripheral Tissues Cell-to-Cell Interactions That Support Development of an Immune Response Consequences of Failed Development or Activation of the Adaptive Immune System B Cell Deficiency and Hyperactivity T Cell Deficiency and Hyperactivity Conclusion 21 21. Immune Tolerance and Autoimmunity Introduction Definition and Classification of Pathogenic Autoimmunity ? Animal Models of Autoimmunity Tolerance Mechanisms Clone-Specific Self/Nonself Recognition The Innate System and Tolerance T Cell Tolerance B Cell Tolerance Theories of Autoimmunity Defective Tolerance Autoimmunity Caused by Activation of Nontolerant or Partially Tolerant T Cells Immunological Mechanisms of Tissue Inflammation and Dysfunction Pathophysiology of Autoimmune Rheumatic Diseases Genetics of Autoimmune Diseases Sex and Autoimmunity Microbial and Other Environmental Triggers Conclusion 22 22. Pre-clinical Autoimmunity Introduction Defining Pre-classification Autoimmunity: More Than Just Semantics ? Population Epidemiology of Autoimmunity Type 1 Diabetes as a Paradigm for Pre-classification Autoimmunity Rheumatoid Arthritis Systemic Lupus Erythematosus Systemic Sclerosis Sjögren’s Disease Axial Spondyloarthritis Multiple Sclerosis Conclusion 23 23. The Microbiome in Rheumatic Diseases Introduction ? Microbiome by Location The Gut Microbiome The Oral Microbiome The Lung Microbiome The Skin Microbiome Microbiome Analyses Sequencing and Omics Approaches Culture-Based Approaches Gnotobiotics Emerging Technologies The Microbiota in Rheumatic Diseases Spondyloarthritis Gut and Joints Are Interconnected in Spondyloarthritides Microscopic Gut Inflammation and Its Implications Intestinal Dysbiosis in Spondyloarthritis Rheumatoid Arthritis Systemic Lupus Erythematosus Other Rheumatic Diseases Microbiota Therapies Conclusion 24 24. Genetics of Rheumatic Diseases Introduction Evidence for a Genetic Component to Rheumatic Diseases ? Study Design Linkage Studies Population Association Studies Choice of Genetic Marker to Test Candidate Gene Versus Genome-wide Association Studies Genome-wide Association Studies Linkage Disequilibrium Common Versus Rare Variants Interpreting Statistical Association From Case-Control Studies Susceptibility Genes in Rheumatic Disease Rheumatoid Arthritis Human Leukocyte Antigen Class I and Class II Isotypes: Functional Correlates Juvenile Idiopathic Arthritis Psoriatic Arthritis Ankylosing Spondylitis Systemic Lupus Erythematosus—the Interferon Pathway Osteoarthritis Clinical Translation Identification of Drug Targets—Lessons From Genetics Prognosis Treatment Response Identification of High-Risk Groups 25 25. Epigenetics of Rheumatic Diseases Introduction Epigenetic Regulation ? Epigenetics and the Immune Response Challenges Faced in Translational Epigenetics Research Epigenetics in Rheumatic Diseases Systemic Lupus Erythematosus DNA Methylation Regulation and Candidate Gene Studies in Lupus T Cells Genome-wide DNA Methylation Studies in Lupus Genetic–Epigenetic Interaction in Lupus Histone Modifications in Lupus MicroRNAs and the Pathogenesis of Lupus Rheumatoid Arthritis Primary Sjögren’s Syndrome Systemic Sclerosis Behçet’s Disease Osteoarthritis Integration of Epigenetic Data Streams and Clinical Applications Conclusion 26 26. Complement System Introduction Functions of the Complement System ? Terminology to Describe Complement and Its Activation Fragments Activation Pathways Regulation of Complement Activation Functions of the Complement System Innate Immune Responses Clearing Immune Complexes and Apoptotic Material Regulating Adaptive Immune Responses Noncanonical Functions of Complement Measuring Complement Activation Complement Deficiency Primary Complement Deficiency Secondary Complement Deficiency Targeted Complement Therapeutics Complement in Rheumatic Diseases Systemic Lupus Erythematosus Rheumatoid Arthritis Other Systemic Rheumatic Conditions Conclusion 27 27. Prostaglandins, Leukotrienes, and Related Compounds Introduction Biosynthesis of Eicosanoids Phospholipases ? Cyclooxygenase Pathway Regulation of Cyclooxygenase-1 Expression Regulation of Cyclooxygenase-2 Expression Cyclooxygenase-3 and Other Variants Prostaglandin Synthases Products of the Cyclooxygenase Pathway Prostaglandins Prostacyclin Thromboxanes Lipoxygenase Pathways Products of the Lipoxygenase Pathways Lipoxins and Resolution of Inflammation Isoeicosanoids Isoprostanes Endocannabinoids Eicosanoid Receptors Prostaglandin Receptors Leukotriene Receptors Lipoxin Receptors Nuclear Receptors Platelet-Activating Factor Eicosanoids as Regulators of Inflammation and Immune Responses Modulation of Eicosanoid Synthesis by Administration of Precursor Fatty Acids Anandamide N-Arachidonylglycine and 2-Arachidonoylglycerol Synthetic Cannabinoids CP-55,940. The effects of a synthetic CB agonist CP-55,940 (systemic 3 mg) on PG levels in female mouse brain regions was studie... 28 28. Angiogenesis Introduction Endothelial Cells Endothelial Permeability Endothelial Injury and Regeneration Angiogenesis ? Sprouting Angiogenesis Endothelial Subtypes Tip-Stalk Cell Lateral Inhibition Vessel Stabilization and Maturity Regulators of Angiogenesis Growth Factors Cytokines and Chemokines Matrix Remodeling: The Role of Adhesion Molecules Hypoxia, Cell Metabolism, and Angiogenesis Hypoxia Cell Metabolism Macroscopic Morphology and Microscopic Blood Vessel Stability Influence of Joint Environment and Metabolism on Angiogenesis Single-Cell RNA Sequencing Demonstrates Differential Endothelial Cell Clusters Targeting Angiogenesis Conclusion 29 29. Cytokines and Chemokines Introduction Cytokines Classification of Cytokines Assessing Cytokine Function In Vitro and In Vivo ? Cytokine Receptors Regulation of Cytokine Expression Effector Function of Cytokines Chemokines Defining Membership of the Chemokine Family Chemokine Nomenclature System Inflammatory and Homeostatic Chemokine Model Chemokine Receptors Atypical Chemokine Receptors Chemokines in an Evolutionary Context How Do Chemokines Attract Cells to Specific In Vivo Destinations Chemokines in the Leukocyte Adhesion Cascade Chemokine Functions Within a Tissue Chemokines and Their Receptors in Disease Immune and Inflammatory Diseases HIV Pathogenesis Cancer Conclusion 30 30. Neuronal Mechanisms of Pain and Inflammation Introduction ? Peripheral Pain Pathways Somatosensory Neurons Dorsal Root Ganglia Contain the Cell Bodies of Sensory Neurons Nociceptor Subsets Are Associated With Distinct Pain Modalities The Nociceptive Pathway Peripheral Sensitization Hyperalgesia and Allodynia Are Behavioral Manifestations of Sensitization of the Nociceptive Pathway Mediators of Peripheral Sensitization Structural Neuroplasticity in the Joint Peripheral Musculoskeletal Tissues Neuroimmune Interactions Within the Nervous System Pain-Resolving Pathways in the Periphery Interactions Between Peripheral Pain Pathways and the CNS Systemic Factors Contributing to Pain Heterogeneity in Rheumatic Diseases Sex as a Modifier of Pain Genetics of Pain Obesity Efferent Actions of Nociceptive Pathways Clinical Scenarios Inflammatory Arthritis Osteoarthritis Fibromyalgia Ehlers–Danlos Syndromes and Hypermobility Spectrum Disorder Conclusions 31 31. Clinical Research Methods in the Rheumatic Diseases Data Sources for Research in Rheumatology Electronic Health Records ? Administrative Claims Databases Registry Data Vital Statistics Data Survey Data Wearables Measures of Occurrence Prevalence Incidence Measures of Association Risk-Based Measures Odds-Based Measures Rate-Based Measures Study Designs Observational Studies Clinical Trial Considerations Common Sources of Bias Selection Bias Information Bias Confounding Types of Confounding Assessing for Confounding Dealing With Confounding Effect Measure Modification, Interaction, and Heterogeneity Surveillance and Screening 32 32. Epidemiology and Impact of Rheumatic Diseases Prevalence Overall and by Selected Sociodemographic and Health Characteristics ? Risk Factors for Arthritis Osteoarthritis Gout Systemic Lupus Erythematosus Rheumatoid Arthritis Arthritis and Physical Activity Arthritis Impact Disability Severe Joint Pain Physical Function Mental Health Employment Opioid Use Joint Replacement Hospitalizations Falls Mortality Arthritis-Attributable Costs Direct and Indirect Costs Public Health Approaches to Arthritis Self-Management Physical Activity Self-Management Interventions Conclusion 33 33. Assessment of Health Outcomes Introduction Types of Outcomes ? Evaluation and Endorsement of Outcomes Validity Content Validity Construct Validity Reliability and Reproducibility Test/Retest Reliability Intra-/Inter-rater Reliability Internal Consistency Responsiveness Feasibility Meaningful States or Changes Thresholds of “States” Minimally Important Differences/Changes Minimal Detectable Change Floor and Ceiling Effects Outcome Measures in Rheumatology (OMERACT) and Other Organizations Review of Disease-Specific Outcomes Rheumatoid Arthritis and Peripheral Psoriatic Arthritis American College of Rheumatology Response Criteria Disease Activity Score in 28 Joints Simplified Disease Activity Index Clinical Disease Activity Index Routine Assessment of Patient Index Data Patient Activity Scale Systems Boolean Remission Disease Activity in Psoriatic Arthritis Axial Spondyloarthritis and Enthesitis Bath Ankylosing Spondylitis Disease Activity Index Ankylosing Spondylitis Disease Activity Score Leeds Enthesitis Index Systemic Lupus Erythematosus Systemic Lupus Erythematosus Disease Activity Index British Isles Lupus Assessment Group Index Cutaneous Lupus Erythematosus Disease Area and Severity Index Safety of Estrogens in Lupus National Assessment–Systemic Lupus Erythematosus Disease Activity Index Flare Index Systemic Lupus Erythematosus Responder Index British Isles Lupus Assessment Group–Based Composite Lupus Assessment Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index Systemic Sclerosis European Scleroderma Study Group Activity Index Medsger Disease Severity Scale Scleroderma Clinical Trials Consortium Damage Index Scleroderma Health Assessment Questionnaire Modified Rodnan Skin Score Scleroderma Skin PRO Vasculitis Birmingham Vasculitis Activity Score Vasculitis Damage Index Gout Gout Assessment Questionnaire Gout Activity Score Gout Flare Knee and Hip Osteoarthritis Knee Osteoarthritis Outcome Score Hip Osteoarthritis Outcome Score Measures That Address Symptoms and Individual Health Domains PROMIS (Patient-Reported Outcome Measurement Information System) Pain Function Fatigue Depression and Anxiety Imaging and Biomarker Outcomes Health Outcomes in Real-World Settings 34 34. Biomarkers in Rheumatology Biomarker Definitions and Applications Defining Patient Heterogeneity ? Challenges With Biomarker Discovery and Qualification Biomarker Assay Qualification and Validation Sample Matrices and Assay Interference Impact of Patient Selection on Validation of Biomarkers Pre-analytical Variables Surrogate Biomarkers Companion Diagnostics Versus CLIA Regulatory Routes Safety Biomarkers Biomarkers in Rheumatic Diseases Biomarkers in Osteoarthritis Biochemical Biomarkers Imaging Biomarkers in Rheumatoid Arthritis Autoantibodies in Rheumatoid Arthritis Prognostic and Diagnostic Biomarkers of Structural Damage in Rheumatoid Arthritis Genetics Protein Biomarkers Imaging Emerging Rheumatoid Arthritis Biomarkers Biomarkers in Synovial Biopsies Blood Transcriptomic Biomarkers Biomarkers in Systemic Lupus Erythematosus Type 1 Interferon Pathway Biomarkers in Systemic Lupus Erythematosus Emerging Biomarkers in Systemic Lupus Erythematosus Next Horizons for Biomarkers Reclassifying Disease Enabling Personalized Health Care 35 35. Occupational, Environmental, and Recreational Musculoskeletal Disorders Introduction Occupation-Related Musculoskeletal Disorders ? Occupation-Related Rheumatic Diseases Osteoarthritis Other Occupational Rheumatologic Disorders and Environmental Risks Recreation- and Sports-Related Musculoskeletal Disorders Performing Arts–Related Musculoskeletal Disorders Instrumentalists Vocal Artists Dancers 36 36. Cardiovascular Risk in Inflammatory Rheumatic Disease Introduction Biologic Mechanisms: Relationship Between Inflammation and Cardiovascular Disease ? Rheumatoid Arthritis Ischemic Heart Disease in Rheumatoid Arthritis Heart Failure in Rheumatoid Arthritis Cardiovascular Mortality in Rheumatoid Arthritis Systemic Lupus Erythematosus Ischemic Heart Disease in Systemic Lupus Erythematosus Heart Failure in Systemic Lupus Erythematosus Cardiovascular Mortality in Systemic Lupus Erythematosus Risk Factors for Cardiovascular Disease Traditional Cardiovascular Risk Factors in Rheumatoid Arthritis: Occurrence and Impact Disparities in Cardiovascular Risk Smoking in People With Rheumatoid Arthritis Hypertension in Rheumatoid Arthritis Blood Lipids in People With Rheumatoid Arthritis Diabetes Mellitus and Metabolic Syndrome in Rheumatoid Arthritis Body Composition/Obesity in Rheumatoid Arthritis Impact of Rheumatoid Arthritis Disease Activity on Cardiovascular Comorbidity Medications and Cardiovascular Risk Traditional and Nontraditional Cardiovascular Risk Factors in Systemic Lupus Erythematosus Ankylosing Spondylitis Psoriasis and Psoriatic Arthritis Giant Cell Arteritis, Takayasu’s Arteritis, and Polymyalgia Rheumatica Anti-neutrophil Cytoplasmic Antibodies (ANCA)–Associated Vasculitis Dermatomyositis and Polymyositis Osteoarthritis Pediatric-Onset Rheumatologic Diseases Coordinating Care: Cardiology and Rheumatology Cardiovascular Disease Risk Assessment