Firestein & Kelley's Textbook of Rheumatology

Firestein & Kelley’s Textbook of Rheumatology
Copyright
Dedication
Contributors
Preface
Part 1: Structure and Function of Bone, Joints, and Connective Tissue
Chapter 1: Biology of the Normal Joint
Classification of Joints
Developmental Biology of the Diarthrodial Joint
Interzone Formation and Joint Cavitation
Cartilage Formation and Endochondral Ossification
Condensation and Limb Bud Formation
Molecular Signals in Cartilage Morphogenesis and Growth Plate Development
Endochondral Ossification
Development of Articular Cartilage
Development of the Joint Capsule, Synovial Lining, Menisci, and Intracapsular Ligaments
Development of Nonarticular Joints
Organization and Physiology of the Mature Joint
Synovium
Synovial Lining
Synovial Vasculature
Regulation of Synovial Blood Flow
Joint Innervation
Synovial Fluid and Nutrition of Joint Structures
Generation and Clearance of Synovial Fluid
Synovial Fluid as an Indicator of Joint Function
Lubrication and Nutrition of the Articular Cartilage
Lubrication
Nutrition
Mature Articular Cartilage
Subchondral Bone
Tendons
Ligaments
Bursae
Menisci
Conclusion
Chapter 2: Synovium
Structure
Synovial Lining Cells
Ultrastructure of Synovial Lining Cells
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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
Chapter 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, and Normal Function of Chondrocytes
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
Receptors, Signaling Molecules, and Antagonists That Mediate Chondrocyte Responses to Growth and Differentiation Factors
Epigenetic Regulation of Cartilage Homeostasis
Role of the Chondrocyte in Cartilage Pathology
Cartilage Matrix–Degrading Proteinases
Balance of 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
Chapter 4: Biology, Physiology, and Morphology of Bone
Structure and Composition of Bone
Bone Vasculature
Bone Matrix
Bone Cells: Osteoblasts
Bone Cells: Osteocytes
Bone Cells: Osteoclasts
Bone Remodeling Process
Direct Interactions Between Osteoblasts and Osteoclasts
Bone Remodeling by the Immune System
Systemic Control of Bone Remodeling by Neuroendocrine Mechanisms
Conclusion
Chapter 5: Muscle: Anatomy, Physiology, and Biochemistry
Introduction
Structure
Muscle Tissue
Fiber Types
Events During Muscle Contraction
Neural Control
Neuromuscular Transmission
Excitation-Contraction Coupling
Contractile Apparatus
Force Generation and Shortening
Relaxation
Transmission of Force to the Exterior
Cell-Matrix Adhesions
Myotendinous Junction
Energetics
Buffering of Adenosine Triphosphate Concentration
Glycolysis
Oxidative Phosphorylation
Fatigue and Recovery
Plasticity
Adaptation to Muscle Use/Disuse
Hormonal Control
Aging
Conclusion
Chapter 6: Biomechanics
Introduction
Kinematics
Kinetics
Joint Biomechanics
Joint Constraint and Stability
Mechanical Loading on Tendon
Chapter 7: Regenerative Medicine and Tissue Engineering
Introduction
Intrinsic Repair
Genetic Basis of Tissue Repair
Signaling Pathways Orchestrating Joint Homeostasis and Surface Repair
PTHrP Signaling
Transforming Growth Factor-β/Bone Morphogenetic Protein Signaling
Fibroblast Growth Factor Signaling
Wnt Signaling
Growth Hormone/Insulin-like Growth Factor Axis
Joint Resident Stem Cells
The Role of Inflammation and the Immune System
Events Leading to Joint Surface Repair
Immediate Molecular Response
Activation and Attraction of Mesenchymal Progenitors
Patterning, Differentiation, Integration, and Remodeling
Emerging Clinical Applications Targeting Endogenous Repair
Targeting FGF Signaling
Targeting Wnt Signaling
Extrinsic Repair: Current Therapeutic Interventions
Joint Surface Defects
Autologous Chondrocyte Transplantation
Stem Cell–Based Approaches
Osteochondral Repair
Bone Regeneration
Regeneration of Other Joint-Related Structures
Menisci
Tendons
Regenerative Medicine and Tissue Engineering in Arthritis
Conclusion
Chapter 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 the Zymogens of Matrix Metalloproteinases
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
Part 2: Cells Involved in Autoimmune Diseases and Inflammation
Chapter 9: Dendritic Cells
Introduction
Dendritic Cell Subsets and Development
Conventional Dendritic Cells
Plasmacytoid Dendritic Cells
Inflammatory Dendritic Cells
Langerhans Cells
New Developments in Dendritic Cell Classification
Dendritic Cell Maturation and Activation
Pattern-Recognition Receptors and Dendritic Cell Maturation
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
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
Future Directions
Chapter 10: Mononuclear Phagocytes
Introduction
Steady-State Development of Synovial Macrophages
Transcriptional Regulation of Synovial Macrophages
Synovial Macrophage Production of Cytokines and Chemokines
The M1 and M2 Paradigm Revisited
Macrophages in Murine Models of Inflammatory Arthritis
Monocyte and Macrophage Contribution to Synovial Hyperplasia
Synovial Macrophages as a Possible Predictor of Disease Activity
Conclusion
Chapter 11: Neutrophils
Overview
Neutrophil Development, Morphology, and Content
Neutrophil Myelopoiesis and Clearance
Neutrophil Morphology and Contents
Neutrophil Activation and Signal Transduction
Stimuli and Receptors
Guanosine Triphosphate-Binding Proteins
Second Messengers
Kinases and Kinase Cascades
Neutrophil Function
Adhesion
Diapedesis and Chemotaxis
Phagocytosis and Degranulation
Respiratory Burst
Neutrophil Production of Pro-inflammatory Mediators
Neutrophil NETs and Microparticles
Resolution of Neutrophil Inflammation
Heritable Disorders of Neutrophil Function
Diseases of Diminished Neutrophil Number
Leukocyte Adhesion Deficiencies
Granule Defects
Oxidase Deficiencies—Chronic Granulomatous Disease
Defects of TLR Signaling
Neutrophil Relevance to Rheumatic Disease
Neutrophil-Mediated Tissue Destruction
Neutrophil Fc Receptor Polymorphisms and Rheumatic Disease
Gout
Rheumatoid Arthritis
Systemic Lupus Erythematosus
Vasculitis
Neutrophilic Dermatoses and Familial Mediterranean Fever
Effects of Anti-rheumatic Agents on Neutrophil Functions
Conclusion
Selected References
Chapter 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
TCR Signal Regulation
Adaptor Proteins
Downstream TCR Signaling
Co-stimulation
The 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
Naïve Versus Memory T Cells
Nonconventional and Innate T Cells
γδ T Cells
Natural Killer T Cells
Inflammation Mediated by T Cells
Termination of T Cell Responses
Future Directions
Selected References
Chapter 13: B Cells
Introduction
Immunoglobulins: Structure and Function
Immunoglobulin Heavy Chain Constant Region
Immunoglobulin M
Immunoglobulin G
Immunoglobulin A
Immunoglobulin E
Immunoglobulin D
Light Chains
Immunoglobulin Variable Region
Generation of Immunoglobulin Diversity
B Cell Development
Niches for Human B Lymphopoiesis
B Cell Ontogeny
Pro-B Cells
Pre-B Cells
Immature B Cells
Peripheral Naïve B Cell Subsets
Transitional B Cells
Mature B Cells
Marginal Zone B Cells
B1 Cells
Sites of B Cell Homing and Activation
Circulation and Homing
Mucosa-Associated Compartments
B Cell Activation and Differentiation
B Cell Receptor Signaling
Co-receptors
FcγRllB
CD5
CD72
Paired Ig-like Receptor
Programmed Cell Death Protein-1
Phosphatases
Signal Transduction in Immature Versus Mature B Cells
B Cell Activation
B1 Cell Activation
Marginal Zone B Cell Activation
Follicular B Cell Activation
Germinal Centers
Ectopic Lymphoid Structures
B Cell Differentiation
Memory B Cells
Plasma Cells
Trafficking of Postimmune Cells
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
Chapter 14: Fibroblasts and Fibroblast-like Synoviocytes
What Is a Fibroblast
Fibroblast Identity and Microenvironments
Embryologic Origins
Origins of Fibroblasts in Tissue
Fibroblasts Versus Mesenchymal Progenitor Cells
Physiologic Characteristics and Functions of Fibroblasts
Production of ECM Components
Attachment to and Interaction With Extra-cellular Matrix
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
Fibroblasts in Rheumatic Diseases
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
Role of Fibroblast Subsets in Disease
Epigenetic Regulation of Fibroblast Gene Expression in Rheumatic Disease
MicroRNAs and Fibroblast-like Synoviocytes
Lessons Learned From Cancer
Conclusion
Chapter 15: Mast Cells
Introduction
Basic Biology of Mast Cells
Development and Tissue Distribution
Mast Cell Heterogeneity: Common Progenitor, Multiple Subsets, Phenotypic Plasticity
Stem Cell Factor
T Lymphocytes and Other Cells
Different Functions for MCT and MCTC Mast Cells
Mast Cell Activation
Immunoglobulin E
Immunoglobulin G and Immune Complexes
Soluble Mediators and Cell-Cell Contact
Danger and Injury
Inhibitory Signals for Mast Cells
Mast Cell Mediators
Granule Contents: Proteases, Amines, Proteoglycans, and Cytokines
Newly Synthesized Mediators: Lipid Mediators, Cytokines, Chemokines and Growth Factors
Role of Mast Cells in Health and Disease
Mast Cells in Allergy: Anaphylaxis, Allergic Disease, and Asthma
Mast Cells in Nonallergic Inflammation
Pathogen Defense: Mast Cells as Sentinels of Innate Immunity
Mast Cells and the Adaptive Immune Response
Neurogenic Inflammation
Autoimmune Disease
Mast Cells as Anti-inflammatory Cells
Mast Cells and Connective Tissue
Wound Healing and Tissue Fibrosis
Bone
Angiogenesis
Mast Cells in Arthritis
Mast Cells in Acute Arthritis: Insights From Animal Models
Mast Cells in Chronic Arthritis
Therapeutic Potential of Mast Cell Antagonism in Rheumatic Disease
Mast Cell Protease Inhibition
SCF/c-Kit Antagonism
Signaling Pathways
Conclusions
Chapter 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 (KIRs)
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 Health and 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
KIR/HLA and Their Association With Autoimmune Disease
ILCs and Potential Contributions to Rheumatologic Disease
Chapter 17: Platelets and Megakaryocytes
Introduction
Platelet Structure
Platelet Production
Platelets and Hemostasis
Signaling Pathways in Platelet Activation
The Platelet as an Inflammatory Cell
The Megakaryocyte as an Inflammatory Cell
Rheumatoid Arthritis
Systemic Lupus Erythematosus
Other Rheumatic Diseases
Conclusion
Part 3: Effector Mechanisms in Autoimmunity and Inflammation
Chapter 18: Principles of Signaling
Introduction
Receptors With Enzymatic Activity
Receptors That Recruit Molecules 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
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
TRIF
TRAM and TIRAP
Second Messengers
Phospholipase C Signaling: Calcium Flux and Protein Kinase C Activation
PI3K/Akt Pathway
Signaling Pathways
JAK/STAT Pathway
Mammalian/Mechanistic Target of Rapamycin (mTOR) Pathway
MAPK Pathway
IRAK
Transcription Factors
Nuclear Factor (NF)-κB
Activator Protein (AP)-1
NFAT
CREB/CREM
Conclusion
Chapter 19: The Immunologic Repercussions of Cell Death
Introduction
Types of Cell Death
Apoptosis
Necrosis—Classic or Noncanonical
Pyroptosis
Autophagy
Molecular Mechanisms of Caspase Activation
Caspases and Apoptosis
Caspase Substrates of Note
Caspase Regulation: Activation and Inhibition
Caspase Inhibitors (IAPs)
Playing CARDS (and DEDs)—Activation Platforms of the Initiator Caspases
The Inflammasome—Activation Platform for Procaspase-1
The DISC—Activation Platform for Procaspase-8
The Apoptosome—Activation Platform for Procaspase-9
Mitochondria and Apoptosis—INTRINSIC Apoptosis
Caspase-dependent apoptosis is broadly defined as two pathways that, for the most part, proceed independently of one another—the...
Regulation of Mitochondrial Outer Membrane Permeabilization (MOMP)
Post-translational Regulation of Bcl-2 Protein Function
Alternative/Additional Roles of Bcl-2 Proteins
Death Receptor–Associated Signaling Events—EXTRINSIC Apoptosis
Molecular Interaction With the Mitochondrial Pathway—Caspase-8 and BID
Caspases and Pyroptosis
The NLRP3 Inflammasome
The NLRC4 Inflammasome
The NLRP1b Inflammasome (Fig. 19.3C)
The NLRP6 Inflammasome
The AIM2 Inflammasome
Noncanonical Inflammasomes
Molecular Pathways of Regulated Necrosis
Necrosis and Secondary Necrosis
Necrosis and the Mitochondrial Permeability Transition
PARP and Necrosis (Parthanatos)
Ferroptosis
Necroptosis
An Unanticipated Finding of a Caspase Needed for Cell Survival
Molecular Regulation of Programmed Necrosis
RIPK1—Apoptosis, Necroptosis, or Survival
RIPK1-Independent Necroptosis
Pro-inflammatory Effects of Programmed Necrosis
Cell Death and Immunity
“Like All Successful Relationships, It’s Complex”
Strategies to Inhibit Cell Death Pathways
Conclusion and Clinical Potential
Caspase Inhibitors
Necroptosis Inhibitors
Pyroptosis Inhibitors
BH3 Mimetics
IAP Inhibitors
Chapter 20: 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
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
Future Directions
Connection to the Clinic
Chapter 21: 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
Chapter 22: Autoimmunity and Tolerance
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 Non- or Partially Tolerant T Cells
Immunologic Mechanisms of Tissue Inflammation and Dysfunction
Pathophysiology of Autoimmune Rheumatic Diseases
Genetics of Autoimmune Diseases
Sex and Autoimmunity
Microbial and Other Environmental Triggers
Conclusion
Chapter 23: The Microbiome in Health and Disease
The Human Microbiome
What Is the Microbiome
Principles of Host-Microbiome Interaction
What Affects the Microbiome
How Is the Microbiome Determined From a Sample
How Are Microbiome Data Interpreted
What Can the Microbiome Be Used for Today
What Microbiome Principles From Other Areas of Medicine or Biology Can Be Applied to Rheumatology
How Will the Microbiome Be Useful to Rheumatologists in the Future
Chapter 24: Metabolic Regulation of Immunity
Introduction
Metabolic Rewiring in Innate Immunity
Macrophage Metabolism
Dendritic Cell Metabolism
Metabolic Rewiring in Adaptive Immunity
T Cell Metabolism
T Cell Activation
T Cell Differentiation
B Cell Metabolism
Mitochondria and Immunity
Mitochondria and NOD-like Receptor Signaling
Mitochondria and RIG-I-like Signaling
Mitochondria and Toll-like Receptor Signaling
Mitochondria as a Source of Danger Signals
Metabolic Interplay in the Immune Microenvironment
Metabolic Antagonism in Immunity
Metabolic Symbiosis in Immunity
Conclusion
Chapter 25: 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
Rheumatoid Arthritis Susceptibility Genes
Human Leukocyte Antigen Class I and Class II Isotypes: Functional Correlates
Rheumatoid Arthritis: HLA-DRB1 Associations and the “Shared Epitope”
The Genome-wide Association Studies Era of Rheumatoid Arthritis Genetics
Juvenile Idiopathic Arthritis
Psoriatic Arthritis
Ankylosing Spondylitis
Systemic Lupus Erythematosus—Identification of the Interferon Pathway
Osteoarthritis
Clinical Translation
Identification of Drug Targets—Lessons From Genetics
Prognosis
Treatment Response
Identification of High-Risk Groups
Chapter 26: 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 Systemic Lupus Erythematosus
Genetic–Epigenetic Interaction in Lupus
Histone Modifications in Systemic Lupus Erythematosus
MicroRNAs and the Pathogenesis of Lupus
Rheumatoid Arthritis
Primary Sjögren’s Syndrome
Systemic Sclerosis
Behçet’s Disease
Osteoarthritis
Epigenetic Modifications as Biomarkers of Rheumatic Disease
Future Directions
Chapter 27: Complement System
Introduction
Functions of the Complement System
Terminology Used to Describe Complement and Its Activation Fragments
Activation Pathways
Regulation of Complement Activation
Receptors for Complement Fragments
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
Chapter 28: 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
Chapter 29: Chemokines and Cellular Recruitment
Introduction
Defining Membership of the Chemokine Family
The Chemokine Nomenclature System
The Inflammatory and Homeostatic Chemokine Model
The Chemokine Receptor Family
Atypical Chemokine Receptors
Chemokines in an Evolutionary Context
How Chemokines Attract Cells to Particular 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
Chapter 30: 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
Transendothelial Leukocyte Recruitment During Angiogenesis
Leukocyte Extravasation in Inflammation
Regulation of Leukocyte Migration by Chemokines During Angiogenesis
Hypoxia, Cell Metabolism, and Angiogenesis
Hypoxia
Cell Metabolism
Targeting Angiogenesis
Chapter 31: Cytokines
Introduction
Classification of Cytokines
Assessing Cytokine Function In Vitro and In Vivo
Cytokine Receptors
Regulation of Cytokine Expression
Effector Function of Cytokines
Agonist/Antagonist Cytokine Activities in Chronic Inflammation
B Cells and Cytokine Release in Chronic Inflammation
Innate Cell Lineages in Chronic Inflammation
Growth Factors in Chronic Inflammation
Cytokine Effects Beyond Immune Regulation
Conclusion
Chapter 32: Experimental Models for Rheumatoid Arthritis
Introduction
Arthritis Caused by Infectious Agents
Mycoplasma Arthritides
Lyme Arthritis
Staphylococcal Arthritis
Arthritis and Ankylosing Spondylitis Induced by Intra-cellular Bacteria
Arthritis Caused by Bacterial Fragments
Adjuvant-Induced Arthritis
Cartilage Protein-Induced Arthritis
CII-Induced Arthritis
Genetic Basis of Collagen-Induced Arthritis
Induction of Arthritis With Other Cartilage and Joint-Related Proteins
CXI-Induced Arthritis
Cartilage Oligomeric Matrix Protein-Induced Arthritis
Proteoglycan (Aggrecan)-Induced Arthritis
Antigen-Induced Arthritis
Glucose-6-Phosphate Isomerase–Induced Arthritis
Spontaneous Arthritis
Spontaneous Arthritis in Genetically Modified Strains
Use of Animal Models
Increasing the Knowledge of Disease Pathways
Developing New Therapeutic Strategies
Ethical Considerations
Conclusion
Chapter 33: Neuronal Regulation of Pain and Inflammation
Introduction
Primary Afferent Fibers
Skin
Joint Afferents
Bone
Fascia
Muscle and Tendon
Sensitization
Pain Prior to Clinical Inflammation
Persistent Pain Despite Suppression of Inflammation
Efferent Functions of Primary Afferent Fibers
Neurogenic Inflammation
Neurogenic Anti-inflammation
Dorsal Root Reflex
Pain Transmission in the Dorsal Horn
Descending Modulation
Neuronal Regulation of Inflammation in Acute Inflammatory Models
Neuronal Regulation of Inflammation in Chronic Models of Inflammation
Sympathetic Effects on Peripheral Inflammation Are Time Dependent
Parasympathetic Effects on Peripheral Inflammation
Role of Pain in Inflammatory Disease
Part 4: Broad Issues in the Approach to Rheumatic Disease
Chapter 34: Clinical Research Methods in Rheumatic Disease
Introduction
Measures of Disease Occurrence
Incidence
Measures of Effect
Data Sources for Research in Rheumatology
Clinical Research Study Designs
Observational Studies
Ecological Studies
Cross-Sectional Surveys
Case-Control Studies
Selection of Controls for Case-Control Study
Weaknesses of the Case-Control Design
Cohort Studies
Prospective Cohort Study
Retrospective Cohort Study
Nested Case-Control, Case-Cohort, and Case-Cohort Studies
Self-Controlled Study Designs
Clinical Trials
General Principles of Clinical Trial Design
Noninferiority Trials
Pragmatic and Adaptive Design Clinical Trials
Cluster (Group)-Randomized Implementation Trials
Comparative Effectiveness Research and Patient-Centered Outcomes Research
Patient-Reported Outcomes
Biosensors in Clinical Research
Biases in Study Design
Selection Bias
Information and Recall Bias
Collider Stratification Bias
Confounding
Confounding by Indication and Channeling in Observational Studies of Therapeutics
Analytic Methods to Address Confounding by Indication
Effect Measure Modification
Screening
Sensitivity
Specificity
Predictive Value
Conclusion
Chapter 35: Economic Impact of Arthritis and Rheumatic Conditions
Introduction
Arthritis and Rheumatic Conditions
Direct Costs
Cost Sharing
Indirect Costs
Musculoskeletal Conditions
Cost of Specific Arthritis Types
Rheumatoid Arthritis
Systemic Lupus Erythematosus
Connective Tissue Disease (Including Systemic Lupus Erythematosus)
Osteoarthritis
Gout
Back Conditions
Ankylosing Spondylitis
Fibromyalgia
Psoriatic Arthritis
Summary
Chapter 36: Assessment of Health Outcomes
Introduction
Health Outcome Assessments
What Needs to Be Measured: Defining Measurement Needs
The Target Population
Defining the Reason for Measuring
What Do You Want to Measure
Outcome Measures in Arthritis
Deciding on an Instrument for a Health Outcome Assessment
Signaling Question 1: Is It a Good Match With the Target Domain
Signaling Question 2: Is It Feasible to Use
Signaling Question 3: Do the Numeric Scores Make Sense
Checking Whether the Items Fit Onto the Intended Scale
Evidence Supporting the Validity of the Numeric Score in Setting
Signaling Question 4: Can It Discriminate Between Groups of Interest
Test-Retest Reliability
Responsiveness
Discrimination Between Treatment Arms in a Trial/Cohort
Thresholds of Meaning
Is the Instrument Good Enough
Examples of Arthritis Instruments
Indicators of Pathophysiologic Manifestations of the Disease
Symptoms
Life Impact of the Disease
General Health Status
Utilities: Value of Health State
Physical Functioning Scales
Self-Efficacy/Effective Consumer
Social Role Functioning
Patient-Specific Indices
Resource Utilization and Costs
Toxicity/Adverse Events
Systematic Reviews of Measurement Properties
Adaptation to an Ongoing Disease
Conclusion
Chapter 37: 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
Chapter 38: Occupational and Recreational Musculoskeletal Disorders
Introduction
Occupation-Related Musculoskeletal Disorders
Occupation-Related Rheumatic Diseases
Osteoarthritis
Other Occupational Rheumatologic Disorders
Recreation- and Sports-Related Musculoskeletal Disorders
Performing Arts–Related Musculoskeletal Disorders
Instrumentalists
Vocal Artists
Dancers
Chapter 39: 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
Smoking in People With Rheumatoid Arthritis
Hypertension in Rheumatoid Arthritis
Lipids in People With Rheumatoid Arthritis
Diabetes Mellitus and Metabolic Syndrome in Rheumatoid Arthritis
Body Composition/Obesity in Rheumatoid Arthritis
Nontraditional Cardiovascular Risk Factors in Rheumatoid Arthritis: Occurrence and Impact
The Impact of Rheumatoid Arthritis Disease Activity and Severity on Cardiovascular Co-morbidity
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
Antineutrophil Cytoplasmic Antibodies (ANCA)-Associated Vasculitis
Dermatomyositis and Polymyositis
Osteoarthritis
Pediatric-Onset Rheumatologic Diseases
Managing Cardiovascular Risk in Rheumatic Disease
Coordinating Care: Cardiology and Rheumatology
Cardiovascular Disease Risk Assessment
Risk Calculators
Risk Scores and Risk Markers: Biomarkers and Tests for Subclinical Disease
Managing CVD Risk in Patients With Rheumatic Disease
Patient Awareness of Cardiovascular Disease Risk
Conclusion
Chapter 40: Cancer Risk in Rheumatic Diseases
Introduction
Malignancy in Autoimmune Rheumatic Diseases
Rheumatoid Arthritis
Systemic Lupus Erythematosus
Systemic Sclerosis (Scleroderma)
Idiopathic Inflammatory Myopathy
Sjögren Syndrome
Vasculitis
Seronegative Spondyloarthritis
Cancer Risks Associated With Anti-rheumatic Drug Therapies
Nonbiologic DMARD Therapy
Methotrexate
Azathioprine
Cyclosporine
Alkylating Agents
Biologic Response Modifiers
Anti–tumor Necrosis Factor Agents
Rituximab
Abatacept
Tocilizumab
Anakinra
Tofacitinib
Cancer Screening in Patients With Rheumatic Disease
Conclusion
Chapter 41: Introduction to Physical Medicine and Rehabilitation
Introduction
Rehabilitation Interventions
Rest
Exercise
Physical Modalities
Orthoses
Assistive Devices and Home/Environmental Modifications
Procedural Interventions
Patient Education
Vocational Aspects
Specific Disorders
Rheumatoid Arthritis
Shoulder Rheumatoid Arthritis
Elbow Rheumatoid Arthritis
Wrist Rheumatoid Arthritis
Hand Rheumatoid Arthritis
Hip Rheumatoid Arthritis
Knee Rheumatoid Arthritis
Foot and Ankle Rheumatoid Arthritis
Cervical Spine Rheumatoid Arthritis
Osteoarthritis
Hip and Knee Osteoarthritis
Shoulder Osteoarthritis
Hand Osteoarthritis
Foot Osteoarthritis
Spondyloarthropathies
Systemic Lupus Erythematous
Juvenile Idiopathic Arthritis
Alternative, Innovative, and Emerging Therapeutic Approaches
Conclusion
Chapter 42: Pregnancy and Rheumatic Diseases
Introduction
Interplay of Rheumatic Disease and Pregnancy Physiology
General Principles of Pregnancy and Rheumatic Disease: Pre-pregnancy Assessment
Severe Disease Damage
Disease Activity
Medication Review
Assessment of Autoantibodies
Counseling
Systemic Lupus Erythematosus
Maternal Outcomes
Fetal and Neonatal Outcomes
Management
Overlap Syndromes and Undifferentiated Connective Tissue Disease
Maternal Outcomes
Fetal and Neonatal Outcomes
Sjögren’s Syndrome
Maternal Outcomes
Fetal and Neonatal Outcomes
Management
Antiphospholipid Antibody
Maternal Outcomes
Fetal and Neonatal Outcomes
Management
Inflammatory Arthritis
Rheumatoid Arthritis
Maternal Outcomes
Fetal and Neonatal Outcomes
Psoriatic Arthritis and Ankylosing Spondylitis
Management
Inflammatory Myositis
Maternal Outcomes
Fetal and Neonatal Outcomes
Management
Systemic Sclerosis
Maternal Outcomes
Fetal Outcomes
Management
Vasculitis
Large Vessel Vasculitis: Takayasu’s Arteritis
Medium Vessel Vasculitis: Polyarteritis Nodosa
Anti-neutrophil Cytoplasmic Antibody–Associated Vasculitis
Behçet’s Disease
Medications During Pregnancy and Breastfeeding
Aspirin, Nonsteroidal Anti-inflammatory Medications, and Cyclooxygenase-2 Inhibitors
Glucocorticoids
Anti-malarial Agents
Sulfasalazine
Immune Modulating Therapies
Intravenous Immunoglobulin
Tumor Necrosis Factor Inhibitors
Other Biologic Agents
Other Medications
Paternal Medication Use
Pregnancy-Related Issues for Rheumatic Disease Patients
Contraception
Contraceptive Methods
Fertility and Assisted Reproductive Techniques
Conclusion
Part 5: Evaluation of Generalized and Localized Symptoms
Chapter 43: History and Physical Examination of the Musculoskeletal System
History in a Patient With Musculoskeletal Disease
Pain
Stiffness
Limitation of Motion
Swelling
Weakness
Fatigue
Loss of Function
Systematic Method of Examination
General Observation
Swelling
Tenderness
Limitation of Motion
Crepitus
Deformity
Instability
Other Aspects of the Examination
Recording the Joint Examination
Interpreting the Joint Examination
Examination of Specific Joints
Temporomandibular Joint
Cricoarytenoid Joints
Sternoclavicular, Manubriosternal, and Sternocostal Joints
Acromioclavicular Joint
Shoulder
Elbow
Wrist and Carpal Joints
Metacarpophalangeal and Proximal and Distal Interphalangeal Joints
Hip
Knee
Ankle
Foot
Chapter 44: Ultrasound in Rheumatology
Introduction
Technical Aspects
Physics
Knobology
Artifacts
Examination Technique
Transducer Positioning
Conventions for Imaging Orientation
Examiner Positioning
Patient Positioning
Limited Versus Comprehensive Studies
Ultrasound in Rheumatology Definitions
Rheumatoid Arthritis
Diagnosis
Monitoring
Predicting Outcome
Osteoarthritis
Diagnosis
Monitoring
Predicting Outcome
Crystalline Arthropathy
Gout
Diagnosis
Monitoring
Predicting Outcome
Diagnosis
Monitoring
Predicting Outcome
Spondyloarthropathy
Diagnosis
Monitoring
Predicting Outcome
Polymyalgia Rheumatica
Diagnosis
Giant Cell Arteritis
Sjögren’s Syndrome
Monitoring
Predicting Outcome
Sclerosing Diseases
Use in Diagnosis, Monitoring, and Predicting Outcome
Non-inflammatory Conditions
Nerves
Tendon
Bursa
Fascia
Plantar fasciitis is a common cause of heel pain and results from micro-trauma due to repetitive overload of the plantar connect...
Nodules
Pediatric Rheumatology
Ultrasound in Rheumatology Intervention
Pitfalls
Accuracy
Efficacy
Procedural Pain
Conclusion
Chapter 45: Evaluation of Monoarticular and Polyarticular Arthritis
Introduction
Approach to the Patient With Arthritis
Monoarthritis Versus Oligo- and Polyarthritis
History
Physical Examination
Laboratory Investigation
Urine
Genetic Testing
Synovial Fluid Analysis
Imaging and Additional Diagnostic Procedures
Synovial or Bone Biopsy
Differential Diagnosis
Bacterial Infections
Lyme Disease
Plant Thorn Synovitis
Mycobacteria
Whipple’s Disease
Viral Infections
Malignancy-Associated Polyarthritis
Crystal-Associated Polyarthritis
Gout
Calcium Phosphate Crystal Arthritis
Cholesterol Crystal Arthritis
Degenerative Arthritis
Benign Tumors Causing Arthritis
Trauma and Internal Derangement
Metabolic Diseases
Diabetic Cheiroarthropathy
Autoimmune Diseases
Drug-Induced Arthritis and Serum Sickness
Formal Criteria and Their Role in Clinical Diagnosis
Preliminary Diagnoses, Working Diagnoses, Presumptive Treatments, Reassessments, and Future Perspectives
Chapter 46: Skin and Rheumatic Diseases
Diagnosis of Skin Lesions Associated With Rheumatic Diseases
Psoriasis
Reactive Arthritis
Rheumatoid Arthritis
Juvenile Rheumatoid Arthritis/Still’s Disease
Lupus Erythematosus
Lupus-Specific Skin Lesions
Nonspecific Cutaneous Lesions
Neonatal Lupus Syndrome
Sjögren’s Syndrome
Dermatomyositis
Cutaneous Manifestations of Dermatomyositis
Autoantibodies in Dermatomyositis
Diagnosis and Management
Morphea, Systemic Sclerosis, and Other Sclerosing Conditions
Morphea
Systemic Sclerosis
Eosinophilic Fasciitis
Scleromyxedema
Scleredema
Nephrogenic Systemic Fibrosis
Primary Vasculitis Involving the Skin
Nomenclature and Classification for Cutaneous Vasculitis
Cutaneous Vasculitis Involving Predominantly Small-Sized Vessels
ANCA-Associated Vasculitis
Immune Complex Vasculitis
Cutaneous Vasculitis Involving Predominantly Medium-Sized Vessels: Polyarteritis Nodosa
Large Vessel Vasculitis
Infections
Lyme Borreliosis
Parvovirus
Atypical Infections: Mycobacterium marinum
Panniculitis
Relapsing Polychondritis
Infiltrative Diseases
Amyloid
Sarcoidosis
Miscellaneous Skin Diseases and Arthritis
Behçet’s Disease
Familial Mediterranean Fever
Multicentric Reticulohistiocytosis
Cryopyrin-Associated Periodic Syndromes
Interferon-Associated Genetic Syndromes
Chapter 47: The Eye and Rheumatic Diseases
Introduction
Ocular Anatomy and Physiology
Ocular Immune Response
Uveitis
Scleritis and Corneal Melt
Orbital Disease
Optic Neuritis
Medication-Related Ocular Toxicity
Conclusion
Part 6: Differential Diagnosis of Regional and Diffuse Musculoskeletal Pain
Chapter 48: Neck Pain
Epidemiology
Anatomy
Axial Neck Pain
Radiculopathy and Myelopathy
Infection and Neoplasm
Clinical Features
Patient History
Localization of Pain Generators
Clinical Examination
Diagnostic Evaluation
Differential Diagnosis and Treatment
Chapter 49: Shoulder Pain
Introduction
Anatomy and Function
Diagnosis
Clinical Evaluation of the Shoulder
History
Physical Examination
Imaging
Radiographic Assessment
Scintigraphy
Arthrography
Computed Tomography
Ultrasonography
Magnetic Resonance Imaging
Arthroscopy
Electromyography and Nerve Conduction Velocity Studies
Injection
Diagnostic Tests
Intrinsic Factors Causing Shoulder Pain
Periarticular Disorders
Shoulder Impingement and Rotator Cuff Tendinopathy
Calcific Tendinitis
Rotator Cuff Tear
Pathophysiology. Spontaneous tear of the rotator cuff in an otherwise healthy person is rare.17 It can occur in patients with RA...
Bicipital Tendonitis and Rupture
Acromioclavicular Disorders
Glenohumeral Disorders
Inflammatory Arthritis
Osteoarthritis
Osteonecrosis
Cuff-Tear Arthropathy
Septic Arthritis
Labral Tears
Adhesive Capsulitis
Glenohumeral Instability
Extrinsic or Regional Factors Causing Shoulder Pain
Cervical Radiculopathy
Brachial Neuritis
Nerve Entrapment Syndromes
Sternoclavicular Arthritis
Reflex Sympathetic Dystrophy
Neoplasms
Miscellaneous Conditions
Chapter 50: Low Back Pain
Epidemiology
Anatomy
Clinical Evaluation
History
Physical Examination
Diagnostic Tests
Imaging
Electrodiagnostic Studies
Laboratory Studies
Differential Diagnosis
Lumbar Spondylosis
Disk Herniation
Spondylolisthesis
Spinal Stenosis
Diffuse Idiopathic Skeletal Hyperostosis
Nonspecific Low Back Pain
Neoplasm
Infection
Inflammation
Metabolic Disease
Visceral Pathology
Miscellaneous
Treatment
Acute Low Back Pain
Chronic Low Back Pain
Spine Patient Outcomes Research Trial
Disk Herniation
Spinal Stenosis
Spondylolisthesis
Outcome
Conclusion
Chapter 51: Hip and Knee Pain
Introduction
Knee Pain
History
Physical Examination
General
Ligaments
Menisci
Quadriceps Tendon
Patella Tendon
Patellofemoral Pain
Imaging
Conventional Radiographs
Computed Tomography
Ultrasound
Nuclear Scintigraphy
Magnetic Resonance Imaging
General
Bursitis
Neoplasia
Popliteal Cysts
Hip Pain
History
Physical Examination
Imaging
Conventional Radiographs
Computed Tomography
Nuclear Scintigraphy
Magnetic Resonance Imaging
Ultrasound
Hip Arthrography
Common Disorders in the Differential Diagnosis of Hip Pain
Chapter 52: Foot and Ankle Pain
Introduction
Functional Anatomy and Biomechanics
Diagnostic Evaluation
Physical Examination
Imaging
Differential Diagnosis of Ankle Pain
Anterior Ankle Pain
Central Joint Pain
Posterior Ankle and Hindfoot Pain
Medial and Lateral Ankle Pain
Differential Diagnosis of Foot Pain
Nonoperative Treatment
Operative Treatment
Arthrodesis
Arthroplasty
Osteotomy
Ostectomy
Synovectomy
Conclusion
Chapter 53: Hand and Wrist Pain
Introduction
Patient Evaluation
Anatomy
History
Physical Examination
Imaging Studies
Additional Diagnostic Tests
Neurodiagnostic Tests
Injections and Aspirations
Arthroscopy
Common Causes of Hand and Wrist Pain
Wrist Pain: Palmar
Carpal Tunnel Syndrome
Ulnar Nerve Entrapment: Cubital Tunnel Syndrome
Ulnar Nerve Entrapment: Guyon’s Canal
Flexor Carpi Radialis and Flexor Carpi Ulnaris Tendinitis
Hamate Fracture
Wrist Pain: Dorsal
Ganglion
Carpal Boss
Extensor Tendinopathies
Kienböck’s Disease
Scapholunate Interosseous Ligament Injury
Gout and Inflammatory Arthritis
Wrist Pain: Ulnar
Triangular Fibrocartilage Complex Injury and Ulnocarpal Impaction Syndrome
Extensor Carpi Ulnaris Tendinitis and Subluxation
Pisotriquetral Arthritis
Wrist Pain: Radial and Thumb
De Quervain’s Disease and Intersection Syndrome
Basal Joint Arthropathy
Thumb Metacarpophalangeal Joint Injuries and Instability
Volar Ganglion
Scaphoid Fracture With Nonunion
Distal Radius Fractures
Palm
Trigger Finger
Retinacular Cysts
Digits
Mallet Finger
Osteoarthritis of the Digits
Tumors
Infection
Chapter 54: Temporomandibular Joint Pain
Introduction
Arthritis of the Temporomandibular Joint
Osteoarthritis
Clinical Findings
?
Imaging Findings
Diagnosis
Treatment
Rheumatoid Arthritis
Clinical Findings
Imaging Findings
Diagnosis
Treatment
Spondyloarthropathies
Psoriatic Arthritis
Ankylosing Spondylitis
Reactive Arthritis
Traumatic Arthritis
Infectious Arthritis
Clinical Findings
Imaging Findings
Treatment
Metabolic Arthritis
Gout
Pseudogout
Internal Derangements
Clinical Findings
Etiology
Imaging Findings
Treatment
Neoplasms
Myofascial Pain and Dysfunction
Etiology
Clinical Findings
Diagnosis
Treatment
Conclusion
Chapter 55: Fibromyalgia
Introduction
Historical Perspective
Diagnostic Criteria
Epidemiology
Clinical Features
Differential Diagnosis and Comorbidities
Assessment of Severity
Mechanisms of Disease
Genetic Risk
Central Pain Amplification and Peripheral Pain Generators
Stress Response Systems
Social and Psychological Factors
Life Stress and Socioeconomic Factors
Personality, Cognitive, and Psychological Factors
Treatment Approaches
Education and Self-Management
Exercise and Body-Based Therapies
Cognitive Behavioral Therapy
Pharmacologic Approaches
Practical Advice
Outcome
Part 7: Diagnostic Tests and Procedures in Rheumatic Diseases
Chapter 56: Synovial Fluid Analyses, Synovial Biopsy, and Synovial Pathology
Introduction
Synovial Fluid Analysis
Synovial Fluid in Health
Accumulation of Synovial Effusions
Arthrocentesis
Gross Examination
Leukocyte Count
Synovial Fluid Cytology
Wet Smear Analysis by Polarized Microscopy
Biochemical Analysis of Synovial Fluid
Synovial Fluid Analysis in Arthritis Research
Synovial Biopsy
Blind Percutaneous Synovial Biopsy
Arthroscopically Guided Synovial Biopsy
Ultrasound Guided Synovial Biopsy
Processing Synovial Tissue Samples
Synovial Pathology
Synovial Membrane in Healthy Individuals
Synovial Histopathology in the Evaluation of Monoarthritis
Synovial Histopathology in the Evaluation of Polyarthritis
Synovial Immunohistology
Sampling Error and Quantitative Analysis
Synovial Lining Cell Layer
Synovial Lymphocytes and Plasma Cells
Synovial Sublining Macrophages and Dendritic Cells
Synovial Microvasculature, Endothelium, and Stromal Mesenchymal Cells
Synovium-Cartilage-Bone Interface
Synovial Biopsy and Pathology as Research Tools for Clinical Biomarker Development
Conclusion
Chapter 57: Arthrocentesis and Injection of Joints and Soft Tissues
Introduction
Indications, Contraindications, and Potential Complications of Arthrocentesis and Soft Tissue Injections
Drugs and Preparations Used for Injection
Procedures Description
Upper Limb Injections
Proximal Interphalangeal Joint
Metacarpophalangeal (MCP) Joint
Wrist Joint
Elbow Joint Injection
Shoulder Joint (Glenohumeral) Injection
Acromioclavicular Joint
Lower Limbs Injections
Metatarsophalangeal Joint
Midfoot Joints (Talonavicular and Navicular Cuneiform)
Ankle (Tibiotalar) Joint
Subtalar Joint
Knee Joint
Soft Tissue Injections: Upper Limbs
Tendon Sheath and Trigger Finger
Carpal Tunnel
De Quervain’s Tendonitis
Tennis Elbow Injection
Subacromial Bursa
Soft Tissue Injections: Lower Limbs
Morton’s Neuroma Injection
Plantar Fascia Injection
Retrocalcaneal Bursa
Tibialis Posterior and Peroneal Tendon-Sheaths
Tarsal Tunnel Syndrome Injection
Trochanteric Bursa
Conclusion
Chapter 58: Anti-nuclear Antibodies
Introduction
History
Relevance of Anti-nuclear Antibodies to Disease Pathogenesis
Methods of Detection
Immunofluorescence
Enzyme-Linked Immunosorbent Assay
Anti-DNA Antibody Tests
Other Assays
Interpretation of the FANA
Pattern
Titer
Diseases Associated With Anti-nuclear Antibodies
Systemic Lupus Erythematosus
Chromatin-Associated Antigens
Ribonucleoproteins
Systemic Sclerosis (Scleroderma)
Anti-kinetochore (Centromere) and Anti-topoisomerase I
Anti-RNA Polymerases
Anti–polymyositis Scleroderma
Other SSc-Related ANAs
Inflammatory Muscle Diseases
Myositis-Specific Autoantibodies
Myositis Overlap Autoantibodies
Primary Sjögren’s Syndrome
Overlap Syndromes
Other Conditions
Clinical Utility of Anti-nuclear Antibody Testing
Chapter 59: Autoantibodies in Rheumatoid Arthritis
Introduction
Citrullination-Associated Autoantibodies
Antibodies to Citrullinated Proteins
Discovery of Autoantibodies to Citrullinated Antigens
The Anti–cyclic Citrullinated Peptide (Anti-CCP) Antibody Assay
Anti-citrullinated Protein Autoantibodies (ACPA)
Clinical Relevance of Antibodies to Citrullinated Proteins
Pre-clinical Detection of Antibodies to Citrullinated Proteins
Citrullinated Autoantigen Generation in Rheumatoid Arthritis
Peptidylarginine Deiminase Enzymes
Peptidylarginine Deiminase Structure, Activity, and Regulation
Peptidylarginine Deiminases in Rheumatoid Arthritis
Antibodies to Peptidylarginine Deiminase Enzymes
The Etiology and Pathogenesis of Citrullination-Associated Autoantibodies
Genetic Factors Linked to the Development of Citrullination-Associated Autoantibodies
Environmental Factors Linked to the Development of Citrullination-Associated Autoantibodies
Origin and Pathogenesis of Citrullination-Associated Antibodies
Mechanisms for Citrullination-Associated Autoantigen Production in the Rheumatoid Joint
Antibodies to Chemically Modified Antigens
Antibodies to Carbamylated Proteins (Anti-CarP)
Antibodies to Malondialdehyde-Acetaldehyde Adducts (Anti-MAA)
Mechanistic Implications of Antibodies to Post-translationally Modified Proteins
Nonspecific Rheumatoid Arthritis Autoantibodies
Rheumatoid Factor
Anti-RA33 Autoantibodies
Anti-glucose-6-Phosphate Isomerase Antibodies
Conclusion
Chapter 60: Acute Phase Reactants
Introduction
Acute Phase Response
Erythrocyte Sedimentation Rate
C-Reactive Protein
Procalcitonin
Calprotectin
Other Acute Phase Proteins
Cytokines
Acute Phase Reactants in the Management of Rheumatic Diseases
Rheumatoid Arthritis
Systemic Lupus Erythematosus
Polymyalgia Rheumatica and Giant Cell Arteritis
Adult-Onset Still’s Disease
Axial Spondyloarthritis
Osteoarthritis
Other Rheumatic Diseases
Practical Use of Acute Phase Reactants
C-Reactive Protein and Health: Associations with Nonrheumatologic Conditions
Chapter 61: Imaging in Rheumatic Diseases
Introduction
Radiography
Technical Aspects
Rheumatoid Arthritis
Spine
Use in Diagnosis, Monitoring, and Prognosis
Ankylosing Spondylitis
Sacroiliac Joints
Spine
Use in Diagnosis, Monitoring, and Prognosis
Psoriatic Arthritis
Use in Diagnosis, Monitoring, and Prognosis
Gout
Use in Diagnosis, Monitoring, and Prognosis
Calcium Pyrophosphate Dihydrate Crystal Deposition Disease
Septic Arthritis
Use in Diagnosis, Monitoring, and Prognosis
Osteoarthritis
Use in Diagnosis, Monitoring, and Prognosis
Juvenile Idiopathic Arthritis (JIA)
Use in Diagnosis, Monitoring, and Prognosis
Computed Tomography
Technical Aspects
Rheumatoid Arthritis
Use in Diagnosis, Monitoring, and Prognosis
Ankylosing Spondylitis/Axial Spondyloarthritis
Use in Diagnosis, Monitoring, and Prognosis
Psoriatic Arthritis
Use in Diagnosis, Monitoring, and Prognosis
Gout
Use in Diagnosis, Monitoring, and Prognosis
Calcium Pyrophosphate Dihydrate Crystal Deposition Disease
Septic Arthritis
Osteoarthritis
Use in Diagnosis, Monitoring, and Prognosis
Juvenile Idiopathic Arthritis
Magnetic Resonance Imaging
Technical Aspects
Rheumatoid Arthritis
Use in Diagnosis, Monitoring, and Prognosis
Ankylosing Spondylitis/Axial Spondyloarthritis
Use in Diagnosis, Monitoring, and Prognosis
Psoriatic Arthritis
Use in Diagnosis, Monitoring, and Prognosis
Gout
Use in Diagnosis, Monitoring, and Prognosis
Calcium Pyrophosphate Dihydrate Crystal Deposition Disease
Septic Arthritis
Osteoarthritis
Use in Diagnosis, Monitoring, and Prognosis of Osteoarthritis
Juvenile Idiopathic Arthritis
Use in Diagnosis, Monitoring, and Prognosis
Other Imaging Modalities
Digital X-Ray Radiogrammetry (DXR)
Nuclear Medicine
Bone Scintigraphy (Planar)
Single-Photon-Emission Computer Tomography (SPECT) and SPECT-CT
Positron Emission Tomography (PET)
Conclusion
?Full references for this chapter can be found on ExpertConsult.com
Part 8: Pharmacology of Anti-rheumatic Drugs
Chapter 62: Therapeutic Targeting of Prostanoids
Introduction
History
Mechanism of Action
Cyclooxygenase Inhibition
COX-2 Selectivity
Cyclooxygenase-Independent Mechanisms of Action
Mechanism of Acetaminophen and Other Analgesic Antipyretic Drugs
Pharmacology and Dosing
Classification
NSAID Metabolism
Salicylate Metabolism and Aspirin Resistance
Pharmacologic Variability
Routes of Drug Delivery
Combination Drugs and Prodrugs
Therapeutic Effects
Anti-inflammatory Effects
Analgesic Effects
Antipyretic Effects
Disease and Symptom-Modifying Effects
Other Therapeutic Effects
Anti-platelet Effects
Cancer Chemoprevention
Adverse Effects
Gastrointestinal Tract Effects
Major Gastrointestinal Toxicity
Dyspepsia
Gastritis and Gastroduodenal Ulcer
Esophageal Injury
Small Bowel Injury
Colitis
Renal Effects
Electrolyte Effects
Hypertension
Acute Renal Failure and Papillary Necrosis
Interstitial Nephritis
Chronic Kidney Disease
Cardiovascular Effects
Heart Failure
Closure of the Ductus Arteriosus
Hepatic Effects
Asthma and Allergic Reactions
Asthma and Aspirin-Exacerbated Respiratory Disease
Allergic Reactions
Hematologic Effects
Central Nervous System Effects
Effects on Bone
Effects on Ovarian and Uterine Function
Salicylate Intoxication and Nonsteroidal Anti-inflammatory Drug Overdose
Adverse Effects of Acetaminophen
Effects of Concomitant Drugs, Diseases, and Aging
Drug-Drug Interactions
Drug-Disease Interactions
Drug Reactions in Elderly People
Choosing Anti-inflammatory Analgesic Therapy
Conclusion
Chapter 63: Glucocorticoid Therapy
Introduction
Characteristics of Glucocorticoids
Structure
Classification
Activation
Genomic and Nongenomic Modes of Action
Genomic Mechanisms
Nongenomic Mechanisms
Hypothalamic-Pituitary-Adrenal Axis and Inflammation
Tertiary Adrenal Insufficiency
Glucocorticoid Effects on the Immune System
Leukocytes and Fibroblasts
Cytokines
Pro-inflammatory Enzymes
Adhesion Molecules and Permeability Factors
Pharmacology and Clinical Considerations
Pharmacokinetics
Glucocorticoid Resistance
Drug Interactions
Glucocorticoid Therapy
Indications
Glucocorticoid Therapy in Rheumatoid Arthritis
Glucocorticoid Pulse Therapy
Glucocorticoid Tapering Regimens
Stress Regimens and Perioperative Care
Pregnancy and Lactation
Intralesional and Intra-articular Glucocorticoid Injections
Improving the Therapeutic Ratio of Glucocorticoids
Alternate-Day Regimens
Glucocorticoid-Sparing Agents
Modified-Release Prednisone
Other Developments: Selective Glucocorticoid Receptor Agonists and Liposomes
Adverse Effects and Monitoring
Infections
Cardiovascular Adverse Effects
Mineralocorticoid Effects
Atherosclerosis and Dyslipidemia
Mortality
Skeletal Adverse Effects
Osteoporosis
Osteonecrosis
Myopathy
Gastrointestinal Adverse Effects
Peptic Ulcer Disease
Other Gastrointestinal Adverse Effects
Ocular Adverse Effects
Cataract
Glaucoma
Dermal Adverse Effects
Endocrine Adverse Effects
Glucose Intolerance and Diabetes Mellitus
Increased Body Weight and Altered Fat Redistribution
Suppression of the Hypothalamic-Pituitary-Adrenal Axis
Adverse Behavioral Effects
Steroid Psychosis
Minor Mood Disturbances
Monitoring
Future Directions
Chapter 64: Traditional DMARDs: Methotrexate, Leflunomide, Sulfasalazine, Hydroxychloroquine, and Combination Therapies
Methotrexate
Introduction
Chemical Structure
Actions of Methotrexate
Pharmacology
Absorption and Bioavailability
Distribution and Half-Life
Elimination
Indications
Dose and Drug Administration
Geriatric Patients
Pediatric Patients
Toxicity
Gastrointestinal and Hepatic Side Effects
Hematologic Side Effects
Pulmonary Side Effects
Mucocutaneous Side Effects
Malignancies
Miscellaneous
Fertility, Pregnancy, and Lactation
Toxicity Monitoring
Drug Interactions and Contraindications
Drug Interactions
Contraindications
Leflunomide
Chemical Structure
Actions of Leflunomide
Pharmacology
Absorption and Bioavailability
Distribution and Half-Life
Elimination
Indications
Dose and Drug Administration
Geriatric Patients
Pediatric Patients
Toxicity
Gastrointestinal and Hepatic Side Effects
Cardiovascular Side Effects
Miscellaneous
Fertility, Pregnancy, and Lactation
Toxicity Monitoring
Drug Interactions and Contraindications
Drug Interactions
Contraindications
Sulfasalazine
Chemical Structure
Actions of Sulfasalazine
Pharmacology
Absorption and Bioavailability
Distribution and Half-Life
Elimination
Indications
Spondyloarthropathies
Psoriatic Arthritis. A recently published systematic review of therapies for psoriatic arthritis looked at six randomized contro...
Ankylosing Spondylitis. A recent meta-analysis reviewed 11 trials that included 895 patients with AS treated with SSZ or placebo...
Reactive Arthritis. Most cases of reactive arthritis (ReA) resolve spontaneously; others become chronic with peripheral or axial...
Inflammatory Bowel–Associated Arthritis. SSZ has been used effectively to treat ulcerative colitis and distal Crohn’s disease. N...
Dosing
Geriatric Patients
Pediatric Patients
Toxicity
Gastrointestinal and Hepatic
Hematologic
Dermatologic
Pulmonary
Miscellaneous
Fertility, Pregnancy, and Lactation
Toxicity Monitoring
Drug Interactions and Contraindications
Drug Interactions
Contraindications
Anti-malarials
Chemical Structure
Actions of Hydroxychloroquine
Pharmacology
Absorption and Bioavailability
Distribution and Half-Life
Elimination
Indications
Dosing
Geriatric Patients
Pediatric Patients
Toxicity
Ophthalmologic
Dermatologic
Neuromuscular
Cardiovascular
Gastrointestinal
Metabolic
Fertility, Pregnancy, and Lactation
Toxicity Monitoring
Drug Interactions and Contraindications
Drug Interactions
Contraindications
Combination DMARD Therapy in Rheumatoid Arthritis
History of Combination DMARD Therapy
Early Rheumatoid Arthritis
Patients With Active Disease Despite Methotrexate
Corticosteroids in DMARD Combinations
Biologic Agents in DMARD Combinations
Selecting the Right Patients for the Right Combination Therapy
Chapter 65: Immunosuppressive Drugs
Introduction
Cyclophosphamide
Structure
Mechanisms of Action
Pharmacology
Absorption and Distribution
Metabolism and Elimination
Pharmacokinetic Considerations
Clinical Indications
Dosage and Route of Administration
Toxicity
Hematologic
Infection
Urologic
Malignancy
Reproduction
Pulmonary
Miscellaneous
Strategies to Minimize Toxicity
Pregnancy and Lactation
Drug Interactions
Azathioprine
Structure
Mechanisms of Action
Pharmacology
Absorption and Distribution
Metabolism and Elimination
Dosage
Clinical Indications
Toxicity
Hematologic
Gastrointestinal
Malignancy
Hypersensitivity
Other Toxicities
Strategies to Minimize Toxicity
Drug Interactions
Pregnancy and Lactation
Mycophenolate Mofetil
Structure
Mechanism of Action
Pharmacology
Dosage
Clinical Indications
Toxicity
Pregnancy and Lactation
Drug Interactions
Cyclosporine and Tacrolimus
Structure
Mechanism of Action
Pharmacology
Absorption and Distribution
Metabolism and Elimination
Dosage
Clinical Indications
Toxicity
Hypertension
Nephrotoxicity
Gastrointestinal
Malignancy
Other Toxicities
Strategies to Minimize Toxicity
Pregnancy and Lactation
Drug Interactions
Conclusion
Chapter 66: Anti-cytokine Therapies
Introduction
Tumor Necrosis Factor
TNF and Inflammation
Mechanism of Action of TNF Inhibitors
TNF Inhibitors
Infliximab
Etanercept
Adalimumab
Golimumab
Certolizumab
Efficacy of the TNF Inhibitors
Rheumatoid Arthritis
Psoriatic Arthritis
Ankylosing Spondylitis
Treatment of Other Immune-Mediated Inflammatory Disorders
Toxicity
Infusion and Injection Site Reactions
Antigenicity
Infection
Malignancy
Autoimmune Disorders
Demyelinating Syndromes
Cardiovascular Risk and Lipid Profile
Congestive Heart Failure
Paradoxical Psoriasis
Interleukin-1
IL-1 and Inflammation
Interleukin-1 Inhibitors
Anakinra
Rilonacept
Canakinumab
Efficacy
Rheumatoid Arthritis
Autoinflammatory Diseases
Gout
Other Disorders
Toxicity
Interleukin-6
IL-6 and Inflammation
IL-6 Agents
Tocilizumab
Sarilumab
Anti-IL-6 Antibody
Toxicity
Drug Interactions
Interleukin-12/23
IL-12 and IL-23 in Inflammation
Anti-IL12/23 Antibodies
Toxicity
Drug Interactions
Anti-IL-23
Interleukin-17
IL-17 and Inflammation
IL-17 Mechanism of Action
Anti-IL-17 Antibodies
Ixekizumab
Toxicity
Dual Cytokine Inhibition
JAK-STAT Pathway
Therapies Directed at Cytokines That Regulate B Cells
Monitoring When Treating With Cytokine Blockade
Pregnancy and Breastfeeding
Vaccinations
Conclusion
Chapter 67: Cell-Targeted Biologics and Emerging Targets: Rituximab, Abatacept, and Other Biologics
Introduction
Targeting B Cells
Rituximab and Rheumatoid Arthritis
Clinical Studies
Disease Modification
Safety Issues
Duration of Benefit
Current Role
Rituximab in Other Rheumatic Conditions
Targeting Co-stimulatory Molecules
Abatacept and Rheumatoid Arthritis
Clinical Studies
Safety Issues
Current Role
Implications for the Pathogenesis of Rheumatoid Arthritis
Abatacept in Other Rheumatic Conditions
Targeting T Cells
Clinical Studies
Future Directions
Conclusion
Chapter 68: Intra-cellular Targeting Agents in Rheumatic Disease
Introduction
Signal Transduction Pathways
p38 MAPK Inhibitors
MEK Inhibitors
Spleen Tyrosine Kinase Inhibitors
Janus Kinase Inhibitors
JAK Selectivity
JAK Inhibitors for Treatment of Rheumatoid Arthritis
JAK Inhibitor Pharmacology
JAK Inhibitor Clinical Development and Efficacy
JAK Inhibitors Versus Adalimumab
Radiographic Outcomes
Patient-Reported Outcomes
Efficacy Summary: JAK Inhibitors
JAK Inhibitor Safety
Tofacitinib
Baricitinib
Safety Summary: JAK Inhibitors
Laboratory Evaluation With JAK Inhibitors
Real-World Experience With JAK inhibitors
JAK Inhibitors for Other Rheumatic Diseases
Psoriatic Arthritis
Systemic Lupus Erythematosus
Pre-clinical Studies
Baricitinib
Ankylosing Spondylitis
BTK Inhibitors
PI3K Inhibitors
Sphingosine-1-Phosphate Modulators
Phosphodiesterase Inhibitors
Conclusion
Chapter 69: Urate-Lowering Therapy
Introduction
Nonpharmacologic Treatment of Hyperuricemia
Patient Selection, Timing of Treatment Initiation, and Asymptomatic Hyperuricemia
Duration of Urate-Lowering Therapy
Target Serum Urate Goals
Anti-inflammatory Prophylaxis With Urate-Lowering Therapy Administration
Urate-Lowering Therapy Adherence
Xanthine Oxidase Inhibition
Allopurinol
Role in Rheumatic Disease and Indications
Chemical Structure and Mechanism of Action
Pharmacology
Dose and Drug Administration
Toxicity
Fertility, Pregnancy, and Lactation
Drug Interactions and Contraindications
Febuxostat
Role in Rheumatic Diseases and Indications
Chemical Structure and Mechanism of Action
Pharmacology
Dose and Drug Administration
Toxicity
Fertility, Pregnancy, and Lactation
Drug Interactions and Contraindications
Uricosurics
Role in Rheumatic Disease and Indications
Mechanism of Action
Pharmacology
Dose and Drug Administration
Toxicity
Fertility, Pregnancy, and Lactation
Drug Interactions and Contraindications
Uricases
Pegloticase
Role in Rheumatic Disease and Indications
Chemical Structure and Mechanism of Action
Pharmacology
Dose and Drug Administration
Toxicity
Fertility, Pregnancy, and Lactation
Drug Interactions and Contraindications
Future Directions
Chapter 70: Bisphosphonates
Introduction
Clinical Pharmacology
Chemistry of Bisphosphonates
Pharmacokinetics
Absorption
Distribution and Metabolism
Molecular Mechanism of Action
Mechanism of Action at the Cell and Tissue Level
Mechanism of Action on Bone Strength
Treatment Effects and Indications
Osteoporosis
Paget’s Disease of Bone
Adverse Effects and Tolerability
Gastrointestinal
Acute Phase Response Reactions
Osteonecrosis of the Jaw
Atypical Femoral Fracture
Other Bisphosphonate Adverse Effects
Atrial Fibrillation
Uveitis
Fracture Nonunion
Renal Toxicity
Use in Children and Pregnancy Considerations
Duration of Therapy and “Drug Holidays”
Chapter 71: Analgesic Agents in Rheumatic Disease
Introduction
Physiology of Pain Perception (the “Pain Experience”)
Pain Classification
Pharmacologic Treatment of Chronic Pain
Opioids
Opiate Receptor Classes
Opiate Receptor Distribution and Mechanisms of Opioid-Induced Analgesia
Tolerance
Physical Dependence
Addiction
Opioid Pharmacology
Morphine
Methadone
Fentanyl
Oxycodone and Oxymorphone
Hydromorphone
Meperidine
Hydrocodone
Codeine
Tramadol
Tapentadol
Toxicity
Respiration
Sedation
Neuroendocrine Effect
Miosis
Myoclonus and Seizure
Nausea and Vomiting
Constipation
Biliary Spasm
Urinary Retention
Pruritus
Immunosuppression
Sweating
Anti-depressants
Tricyclic Anti-depressants
Side Effects
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
Side Effects
Anti-convulsants
Mechanism of Action
Pharmacology of Gabapentin and Pregabalin
Gabapentin
Pregabalin
Toxicity of Gabapentin and Pregabalin
Muscle Relaxants
Antispasmodic Medications
Baclofen
Dantrolene
Tizanidine
Diazepam
Muscle Relaxants
Cyclobenzaprine
Carisoprodol
Methocarbamol
Metaxalone
Chlorzoxazone
Orphenadrine
Efficacy
Topical Pain Medications
Emerging Targets
Opioids
Nerve Growth Factor Inhibitors
Cannabinoid Agonists
AMPA/Kainate Antagonists
Angiotensin II Type 2 Receptor Antagonists
Mirogabalin
Chapter 72: Nutrition and Rheumatic Diseases
Introduction
Nutrition and Inflammation
Omega-3 Fatty Acids
Fatty Acid Biochemistry
?
Pro-inflammatory Actions of Eicosanoids
Effect of n-3 Fatty Acids on Pro-inflammatory Cytokine Production
Effects of n-3 Fatty Acids on Major Histocompatibility Expression
Effect of n-3 Fatty Acids on Adhesion Molecule Expression
Effect of n-3 Fatty Acids on Degradative Enzymes
Importance of the Balance of n-3 and n-6 Fatty Acids in Inflammation
Specialized Proresolving Mediators and N-3 Fatty Acids
Vitamin D and the Inflammatory Process
Reactive Oxygen Species/Antioxidants
Obesity
Gut and Oral Microbiome and Inflammation
Conclusion
Rheumatoid Arthritis
Omega-3 Fatty Acid Consumption
Red Meat and Protein Consumption
Tea and Coffee Consumption
Alcohol Consumption
Sugar-Sweetened Beverages
Vitamin D
Obesity and Rheumatoid Arthritis
Gout
Dietary Factors and Gout
Fasting and Gout
Obesity and Gout
Osteoarthritis
Nutrition in the Management of Rheumatic Diseases
Rheumatoid Arthritis
Dietary n-3 Fatty Acids in the Management of Rheumatoid Arthritis
Antioxidants in the Management of Rheumatoid Arthritis
Dietary Omega-3 Fatty Acids as a Potential Preventive for Rheumatoid Arthritis
Vitamin D and the Management of Rheumatoid Arthritis
Dietary Restriction in Rheumatoid Arthritis—Fasting, Vegetarian, and Elimination Diets
Interactions Among Diet, Obesity, and Disease-Modifying Anti-rheumatic Drugs
Gout
Osteoarthritis
Conclusion
Chapter 73: Evaluation and Management of Early Undifferentiated Arthritis
Introduction
Changing Definitions of Classifiable and Undifferentiated Arthritis
Definition of “Early” Arthritis
Facilitating Access to Rheumatologists
Predicting Outcomes in Clinical-Undifferentiated Inflammatory Arthritis
Predicting Outcomes in Imaging–Undifferentiated Inflammatory Arthritis
Management of Early Undifferentiated Arthritis
Traditional Disease-Modifying Anti-rheumatic Drugs
Biologic Therapy
Glucocorticoid Therapy
Nonpharmacologic Approaches
Management of Imaging-Only Synovitis
Part 9: Rheumatoid Arthritis
Chapter 74: Etiology of Rheumatoid Arthritis
Introduction
How Rheumatoid Arthritis Begins
Genetic Risk
Role of Human Leukocyte Antigen-DR in the Disease Susceptibility and Severity
Additional Polymorphisms: Cytokines, Citrullinating Enzymes, PTPN22, and Others
Epigenetics
Interactions Between Genes and Environment
Sex
Autoimmunity and Innate Immunity
Anti-citrullinated Protein Antibodies
Antibodies to Other Modified Proteins
Rheumatoid Factor
Autoimmunity to Cartilage-Specific Antigens
Autoimmunity to Nonarticular Antigens
Innate Immunity: Toll-like Receptors and the Inflammasome in the Joint
Infectious Agents and the Microbiome
Bacteria, Mycobacteria, Mycoplasma, and Their Components
Epstein-Barr Virus, DnaJ Proteins, and Molecular Mimicry
Parvovirus
Other Viruses
Microbiome
Changing Epidemiology
Chapter 75: Pathogenesis of Rheumatoid Arthritis
Introduction
Synovial Disease and Biology
Synovial Intimal Lining Cells: Macrophage-like and Fibroblast-like Synoviocytes
Aggressive Behavior of Rheumatoid Arthritis Fibroblast-like Synoviocytes
Synovial T Lymphocytes
Immunohistologic Patterns
Synovial T Cell Phenotype
Co-stimulatory Molecules. RA synovial T lymphocytes exhibit an activated surface phenotype, with high expression of HLA-DR, CD69...
Adhesion Molecules. Synovial lymphocytes also express adhesion molecules of very late activation antigen (VLA) and lymphocyte fu...
Chemokine Receptors. Synovial T cells in RA express characteristic receptors to specific chemokines. The chemokine receptor CCR5...
T Cell Receptors. In some patients, a pattern emerged suggesting an increased number of T cells expressing Vβ3, Vβ14, and Vβ17, ...
Metabolic Mechanisms Contributing to T Cell Accumulation. The number of T cells in the joint could increase due to cell prolifer...
Synovial T Cell Immunoreactivity and Activation
Cell-Cell Contact-Mediated T Lymphocyte Activation
Re-establishing Immune Homeostasis
Treg Cells and Innate Lymphoid Cells
Synovial B Cells
Cytokine Regulation of Synovial B Cells
Synovial B Cell Maturation and Clonality
Clinical Improvement After B Cell Depletion
Dendritic Cells
Mast Cells
Polymorphonuclear Leukocytes
Natural Killer Cells
Bone Marrow Cells
Synovial Biology in Pre- Versus Early-Stage Versus Late-Stage Rheumatoid Arthritis
Synovial Fluid and the Synovial Fluid Cartilage Interface
Synovial Fluid Neutrophils
Synovial Fluid Lymphocytes
Synovial Fluid Platelets and Platelet Microparticles
Synovial Fluid Immune Complexes
Immune Complexes Embedded in Cartilage
Synovial Fluid Complement
Targeting Complement
Arachidonate Metabolites
Prostaglandins
Leukotrienes
Anti-inflammatory Arachidonic Acid Metabolites
Peripheral Blood Lymphocytes
Role of T Cell Cytokines
Type 1 T Helper Cell Cytokines
Type 2 T Helper Cell Cytokines
Type 17 T Helper Cytokines
Type 9 Helper T Cell and Innate Lymphoid Cell (ILC) Cytokines
T Helper Cell Cytokine Imbalance
Macrophage and Fibroblast Cytokines
Pro-inflammatory Macrophage and Fibroblast Cytokines
IL-1 Family
Tumor Necrosis Factor and the Tumor Necrosis Factor Superfamily
Interleukin-6 Family
Interleukin-12 Family
Interleukin-15
Interleukin-32
Colony-Stimulating Factors
Interferons
Chemokines
Platelet-Derived Growth Factor and Fibroblast Growth Factor
Immunosuppressive Cytokines and Cytokine Antagonists
Interleukin-1 Receptor Antagonist
Interleukin-10
Transforming Growth Factor-β
Soluble Cytokine Receptors and Binding Proteins
Perpetuating Synovitis by Cytokine Networks
Signal Transduction and Transcription Factors
Janus Kinases and the Signal Transducers and Activators of Transcription
Mitogen-Activated Protein Kinases
Nuclear Factor-κB
Activator Protein-1
Interferon Regulation: IKK-Related Kinases and Interferon Regulatory Factors
Spleen Tyrosine Kinase
PI3 Kinases and Other Signaling Pathways
Cell Survival and Death in Rheumatoid Synovium
Reactive Oxygen and Nitrogen
Apoptosis and Autophagy
Genes Regulating Apoptosis
Genes Regulating Autophagy
Interventions to Increase Apoptosis in Arthritis Models
Tumor Suppressor Genes
The Synovial Vasculature
Angiogenesis: Feeding the Starved Synovium
Hypoxia
Angiogenic Factors
Targeting Angiogenesis in Models of Arthritis
Adhesion Molecule Regulation
Integrins and Their Ligands
Therapeutic Potential of Blocking Adhesion Molecules
Cartilage and Bone Destruction
Proteases: Mediators of Joint Destruction
Matrix Metalloproteinases
Cysteine Proteases: The Cathepsins
Aggrecanases
Endogenous Protease Inhibitors
Regulation of Cartilage Destruction
Regulation of Bone Destruction
Tissue Repair
Conclusion
Chapter 76: Clinical Features of Rheumatoid Arthritis
Epidemiology and Disease Burden
Disease Frequency
Pre-clinical Rheumatoid Arthritis
Clinical Presentations of Early Rheumatoid Arthritis
Patterns of Onset
Insidious Onset
Acute or Intermediate Onset
Atypical Onset
Other Patterns of Onset
Diagnosis
Articular Manifestations
Hands and Wrists
Feet and Ankles
Cervical Spine
Intermediate and Large Peripheral Joints
Temporomandibular, Cricoarytenoid, Sternoclavicular, and Manubriosternal Joints
Extra-articular Manifestations
Mucocutaneous
Ocular
Bone
Muscle
Hematologic
Malignancy
Vasculitis
Pulmonary
Cardiovascular
Disease Outcomes and Prognosis
Disease Outcomes
Prognosis
Temporal Trends in Outcomes
Chapter 77: Treatment of Rheumatoid Arthritis
Introduction
Goal of Rheumatoid Arthritis Treatment
Classes of Drugs
Disease-Modifying Anti-rheumatic Drugs
Methotrexate, Sulfasalazine, Hydroxychloroquine, Leflunomide, and Azathioprine
Biologic Disease-Modifying Anti-rheumatic Drugs
Glucocorticoids
Other Conventional Disease-Modifying Anti-rheumatic Drugs
Minocycline and Doxycycline
Nonsteroidal Anti-inflammatory Drugs
Treatment Approaches and Strategies
Treatment of the Disease-Modifying Anti-rheumatic Drug–Naïve Patient
Initial Therapy—The First Disease-Modifying Anti-rheumatic Drug
Initiating Treatment With a Single Disease-Modifying Anti-rheumatic Drug Versus Combinations of Disease-Modifying Anti-rheumatic...
The BeSt Study
Conclusions From the BeSt Study
Treatment of Early Aggressive Rheumatoid (TEAR) Trial
Conclusions From the TEAR Trial
Treatment of Patients With Active Disease Despite Treatment With Methotrexate
Rheumatoid Arthritis: Comparison of Active Therapies Trial
Conclusions From the RACAT Trial
Treatment of “Refractory” Patients or Those With Active Disease Despite TNF Inhibition
The Niche for JAK Inhibitors
Biosimilars: Why Have We Been Slow to Adopt
Managing Patients in Remission Who Are Taking Disease-Modifying Anti-rheumatic Drugs
Use of Combinations of Biologic Agents
Interpreting Radiographic Progression and the Use of Other Imaging Modalities
Adjuncts to Medications
Patient Education
Pain Control
Rest and/or Exercise and Activities of Daily Living
Comorbidities and the Interactions of Rheumatologists With Primary Care Physicians
Perioperative Management of Rheumatoid Arthritis Medications
Patients With Rheumatoid Arthritis Are Doing Better
Research Agenda: Unmet Needs
The Horizon
Chapter 78: Sjögren’s Syndrome
Historical Perspective
Definitions and Classification Criteria
Epidemiology
Etiology and Pathogenesis
Genetics
Adaptive and Innate Immunity
Autoantibodies
Glandular Epithelium
Clinical Features
Keratoconjunctivitis Sicca
Xerostomia
Involvement of Other Exocrine Glands
Extraglandular Manifestations
Fatigue
Raynaud’s Syndrome
Skin
Joints
Lung
Kidney
Gastrointestinal
Nervous System
Vasculitis
Risk for Cardiovascular Disease
Lymphoma
Associated Diseases
Diagnosis and Diagnostic Tests
Keratoconjunctivitis Sicca and Xerostomia
Ultrasound and Other Imaging Tests
Salivary Gland Biopsy
Laboratory Evaluation
Approach to Diagnosis
Differential Diagnosis
Treatment
Outcome
Conclusion
Part 10: Spondyloarthritis
Chapter 79: Etiology and Pathogenesis of Spondyloarthritis
Introduction
Etiology of Spondyloarthritis
Genetics
Environment
Pathogenesis of Spondyloarthritis
Functional Genomics
HLA-B27
Arthritogenic Peptides
HLA-B27 Misfolding
Free Heavy Chain Dimers and Monomers
Endoplasmic Reticulum Aminopeptidase-1
Genetic Susceptibility Is Distinct From the Class I Major Histocompatibility Pathway
Interleukin-23 and the Spondyloarthritis Phenotype
Cytokines and Cytokine-Producing Cells in Spondyloarthritis
Structural Damage in Ankylosing Spondylitis
Bone Homeostasis and Aberrant Bone Formation
Inflammation and New Bone Formation in Spondyloarthritis
Targeting the Interleukin-23/Interleukin-17 Axis
Chapter 80: Ankylosing Spondylitis and Other Forms of Axial Spondyloarthritis
Introduction
Classification
Criteria for Ankylosing Spondylitis and Axial Spondyloarthritis
Epidemiology
Prevalence
Incidence
Racial Distribution
Burden of Disease
Genetics
Major Histocompatibility Complex Associations With Ankylosing Spondylitis
Non–major Histocompatibility Complex Associations of Ankylosing Spondylitis
Aminopeptidase Genes and Ankylosing Spondylitis
Interleukin-23 Pathway Genes and Ankylosing Spondylitis
Lymphocyte Development and Activation Genes
Pathogenesis
HLA-B27
ERAP1 and Other Aminopeptidases
IL-23 Signaling Pathway
Mucosal Immunity and the Microbiome
Structural Remodeling and Ankylosis
Clinical Manifestations
Skeletal Manifestations
Low Back Pain and Stiffness
Chest Pain
Tenderness
Joints
Extramusculoskeletal Manifestations
Eye Disease
Cardiovascular Disease
Pulmonary Disease
Neurologic Involvement
Renal Involvement
Osteoporosis
Physical Examination
Spinal Mobility
Chest Expansion
Enthesitis
Sacroiliitis
Posture
Laboratory Tests
Imaging
Conventional Radiography
Computed Tomography and Magnetic Resonance Imaging
Diagnosis
Ankylosing Spondylitis in Males and Females
Outcome
Assessment and Monitoring
Treatment
Pharmacologic Therapy
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
Anchor 995
Glucocorticoids
Conventional Synthetic DMARDs
Tumor Necrosis Factor inhibitors
Consideration of Extramusculoskeletal Manifestations
Stable Disease on TNF Inhibitor Therapy
Interleukin 17A Inhibitors
Janus Kinase (JAK) Inhibitors
Other Agents
Failed Biologic Trials
Treat-to-Target
Non-pharmacologic Therapy
Surgical Approach
Treatment Summary
Osteoporosis
Conclusion
Chapter 81: Reactive Arthritis
Reactive Arthritis
Introduction and Historical Background
Epidemiology
Etiology and Triggering Organisms
Clinical Features
Laboratory, Radiographic, and Advanced Imaging Findings
Diagnosis
Treatment
Conclusion
Undifferentiated Spondyloarthritis
Introduction and Historical Background
Epidemiology
Genetics, Pathogenesis, and Etiology
Clinical Features
Laboratory, Radiographic, and Advanced Imaging Findings
Diagnosis
Treatment
Chapter 82: Psoriatic Arthritis
Introduction
Epidemiology
Clinical Features
Differential Diagnosis
Laboratory Features
Radiographic Features
Plain Radiography
Musculoskeletal Ultrasound
Magnetic Resonance Imaging
Other Imaging Modalities
Diagnosis and Classification Criteria
Clinical Course and Outcome
Comorbidities in Psoriatic Arthritis
Cardiovascular Disease
Diabetes Mellitus and Metabolic Syndrome
Other Comorbidities
Outcome Domains and Instruments
Pathogenesis
Genetic Factors
Environmental Factors
Animal Models
Immunopathology
Skin
Synovium
Enthesis
Cytokines
Matrix Metalloproteinases and Cartilage Destruction
Bone Remodeling
Pathogenesis Summary
Treatment
Traditional Agents (csDMARDs)
Biologics (boDMARDs and bsDMARDs)
Small Molecules (tsDMARDs)
Therapies Currently in Development
Treat to Target
Conclusion
Chapter 83: Inflammatory Bowel Disease–Associated Arthritis and Other Enteropathic Arthropathies
Introduction
Inflammatory Bowel Disease-Associated Arthritis
Overview of the Gut Environment in Health
Maintaining Balance in the Gut
Barrier Disruption
Dysbiosis in Inflammatory Bowel Disease and Spondyloarthritis
From the Gut to the Joint
Shared Genetics
The Th17 Pathway and the Implications for Development of Spondyloarthritis
Role of Dysbiosis in Stimulating Joint Disease
Clinical Manifestations
Diagnosis
Screening for Spondyloarthritis Among Patients With Inflammatory Bowel Disease
Assessing and Monitoring Disease Activity
Management
Nonsteroidal Anti-inflammatory Drugs
Role of Glucocorticoids
Synthetic Disease Modifying Anti-rheumatic Drugs
Tumor Necrosis Factor Inhibitors
Other Biologics
Probiotics
Other Enteropathic Arthropathies
Whipple’s Disease
Brucellosis
Celiac Disease
Bowel-Associated Dermatosis-Arthritis Syndrome
Other Conditions
Part 11: Systemic Lupus Erythematosus and Related Syndromes
Chapter 84: Etiology and Pathogenesis of Systemic Lupus Erythematosus
Introduction
Historic View of Lupus Pathogenesis
Genetic Contributions to Lupus Pathogenesis
Female Predominance of Systemic Lupus Erythematosus
Environmental Triggers of Lupus
Innate Immune System Activation in Systemic Lupus Erythematosus
Adaptive Immune System Alterations in Systemic Lupus Erythematosus
Autoimmunity in Systemic Lupus Erythematosus
Mechanisms of Target Organ Damage
Conclusion
Chapter 85: Clinical Features of Systemic Lupus Erythematosus
Introduction
Epidemiology
Clinical Features
Mucocutaneous Involvement
Acute Cutaneous Lupus Erythematosus
Subacute Cutaneous Lupus Erythematosus
Chronic Cutaneous Lupus Erythematosus
Other Systemic Lupus Erythematosus Skin Lesions
Photosensitivity
Alopecia
Mucosal Ulcers
Dermatopathology and Immunopathology
Musculoskeletal Involvement
Arthritis
Osteonecrosis
Myositis
Renal Involvement
General Considerations
Types of Renal Involvement in Systemic Lupus Erythematosus
Laboratory Evaluation
Urinalysis
Measurement of Renal Function
Renal Biopsy
Outcome
Pleuropulmonary Involvement
Pleuritis
Lupus Pneumonitis
Chronic Interstitial Lung Disease
Diffuse Alveolar Hemorrhage
Pulmonary Hypertension
Other
Cardiovascular Involvement
Pericarditis
Myocarditis
Valvular Abnormalities
Coronary Artery Disease
Neuropsychiatric Involvement
General Considerations
Pathogenesis
Approach to Diagnosis
Selected Neuropsychiatric Lupus Syndromes
Gastrointestinal Involvement
Ocular Involvement
Hematologic Involvement
Anemia
Leukopenia
Thrombocytopenia
Lymphadenopathy and Splenomegaly
Diagnosis
Serologic Tests
Differential Diagnosis
Neonatal Lupus
Chapter 86: Treatment of Systemic Lupus Erythematosus
Clinical Course and General Treatment Strategy
Patient and Physician Preferences
Drugs Used in the Treatment of Systemic Lupus Erythematosus
Glucocorticoids
Anti-malarial Drugs
Immunosuppressive and Cytotoxic Drugs
Methotrexate
Cyclophosphamide
Azathioprine
Mycophenolate Mofetil
Use in Lupus Nephritis
Induction Therapy. Several RCTs have demonstrated equal or even superior efficacy of MMF versus CYC in inducing renal response i...
Maintenance Therapy. Meta-analysis of RCTs comparing MMF versus AZA as maintenance therapy in PLN showed comparable rates of ren...
Calcineurin Inhibitors
Tacrolimus
Other Nonbiologic Therapies
Intravenous Immunoglobulin
Biologic Therapies
Belimumab
Rituximab
Interferon Inhibition
Ustekinumab
Epratuzumab
Janus Kinase Inhibition
BAFF Inhibition Beyond Belimumab
Management of Specific Systemic Lupus Erythematosus Manifestations and Treatment Algorithms
Mucocutaneous and Joint Disease
Lupus Nephritis
Induction and Maintenance Therapy
Treatment of Renal Flares—Relapsing Disease
Central Nervous System Disease
Hematologic Disease
Antiphospholipid Syndrome
Special Issues: Treat-to-Target, Refractory Disease and Lupus in Pregnancy
Treat-to-Target in Systemic Lupus Erythematosus
Treatment of Refractory Systemic Lupus Erythematosus
Treatment of Lupus in Pregnancy
Comorbidities
Infections and Immunizations
Risk Factors and General Management
Immunizations
Risk Factors and Dialysis
Renal Transplantation
Cardiovascular Morbidity
Osteoporosis
Malignancy in Lupus
Women’s Health Issues
Evidence and Expert-Based Recommendations in Systemic Lupus Erythematosus
Current Trends and Future Perspectives
Chapter 87: Antiphospholipid Syndrome
Introduction
Epidemiology
Etiology
Pathogenesis
Target Receptors and Intra-cellular Signal Transduction
Activation of Complement Cascade
Activated Protein C Resistance
Other Mechanisms
Clinical Features
Vascular Occlusion
Pregnancy Morbidity
Miscellaneous and Noncriteria Manifestations
Catastrophic Antiphospholipid Syndrome
Diagnosis and Diagnostic Tests
Laboratory Studies
Imaging Studies
Pathology
Differential Diagnosis
Treatment
Thrombosis
Pregnancy Morbidity
Asymptomatic Antiphospholipid Antibody–Positive Individuals
Antiphospholipid Antibody-Positive Individuals With Ambiguous or “Noncriteria” Events
Catastrophic Antiphospholipid Syndrome
Antiphospholipid Antibody-Negative Individuals With a Clinical Event
Outcome
Part 12: Systemic Sclerosis, Inflammatory Myopathies, and Overlap Syndromes
Chapter 88: Etiology and Pathogenesis of Systemic Sclerosis
Introduction
Etiology
Genetic Risk: Family Studies
Genetic Association Studies
Other Candidate Genes, Genome-wide Association, and Whole Exome Sequencing
Epigenetic Factors
Infectious Agents and Viruses
Environmental Exposures, Dietary Factors, Drugs, and Radiation
Microbiome Alterations in Scleroderma or Systemic Sclerosis
Microchimerism
Pathology
General Features
Vascular Pathology
Tissue Fibrosis
Organ-Specific Pathologic Findings
Skin
Lungs
Gastrointestinal Tract
Kidneys
Heart
Pathologic Findings in Other Organs
Animal Models of Scleroderma
Heritable Animal Models of Scleroderma
Inducible Animal Models of Scleroderma
Genetic Manipulations in Mice Giving Rise to Scleroderma-like Phenotypes
Pathogenesis
Integrated Overview
Vasculopathy
Vascular Injury and the Activated Endothelium
Vascular Damage and Failure of Compensatory Vascular Repair
Hypoxia
Oxidative Stress and Reactive Oxygen Species
Inflammation and Immune Dysregulation in the Pathogenesis of Systemic Sclerosis
Cellular Effectors of Dysregulated Immunity
T Cell Subsets and Activation
T Helper 1/T Helper 2 Cytokine Balance and Polarized Immune Responses
Other T Cell Subsets in Scleroderma or Systemic Sclerosis
Monocytes and Macrophages
Dendritic Cells
Mast Cells and Innate Lymphoid Cells
Humoral Autoimmunity and B Cells
Autoantibodies in Systemic Sclerosis: Pathogenetic Considerations
B Cells in Systemic Sclerosis
Fibrosis
Extra-cellular Matrix
Regulation of Collagen Synthesis
Effector Cells of Fibrosis: Fibroblasts
Effector Cells of Fibrosis: Myofibroblasts, Pericytes, Endothelial Cells, and Cellular Plasticity
Fibrocytes and Monocyte-Derived Mesenchymal Progenitor Cells
Cellular Senescence and Fibrosis in Scleroderma or Systemic Sclerosis
Molecular Determinants of Fibrosis: Transforming Growth Factor-β
Cellular Signaling by Transforming Growth Factor-β: Canonical Smad Pathways
Noncanonical Transforming Growth Factor-β Signaling in Fibrosis
Cytokines, Growth Factors, Chemokines, and Lipid Mediators
Connective Tissue Growth Factor (CTGF)/CCN2
Platelet-Derived Growth Factor
Developmental (Morphogen) Pathways: Wnt, Hedgehog, and Notch
Interleukins
Chemokines
Angiotensin II
Bioactive Lipids
Regulation of Fibroblast Function via Innate Immune Signaling: Toll-like Receptors, Endogenous Ligands, and the Inflammasome
Matrix Regulation of Fibrosis via Mechanosensing and Mechanotransduction
Negative Regulation of Myofibroblast Activity and Matrix Accumulation
Interferon-γ
Peroxisome Proliferator-Activated Receptor-γ
The Scleroderma Fibroblast
Conclusion
Chapter 89: Clinical Features and Treatment of Scleroderma
Historical Perspective
Epidemiology
Incidence and Prevalence
Survival
Environmental Exposures
Clinical Features
Diagnostic Criteria
Classification and Clinical Subsets
Natural History of Disease
General Principles of Disease Evaluation
Measuring Disease Activity and Severity
Autoantibodies
Clinical Manifestations
General Principles
Raynaud’s Phenomenon
Treatment of Raynaud’s Phenomenon and Digital Ischemia
Skin Involvement
Gastrointestinal Involvement
Oropharynx
Esophagus
Stomach
Lower Gastrointestinal Tract
Pulmonary Involvement
Interstitial Lung Disease
Pulmonary Hypertension
Cardiac Involvement
Renal Involvement
Musculoskeletal Involvement
Endocrine Involvement
Other Associated Manifestations
Psychosocial Aspects
Treatment
Immunotherapy
Treatment of Fibrosis
Treatment of Vascular Disease
Conclusion of Current Practical Recommendations for Treatment
Chapter 90: Inflammatory Diseases of Muscle and Other Myopathies
Introduction
Epidemiology
Etiology of Myositis
Genetic Risk Factors
Environmental Risk Factors
Mimics of Myositis
Pathogenesis
Humoral Immune Response
Cell-Mediated Immune Response
Class I Major Histocompatibility Complex Expression
Cytokines and Hypoxia
Proposed Mechanisms of Muscle Damage
Clinical Features
Polymyositis and Dermatomyositis
Skin
Lungs
Arthritis
Heart
Gastrointestinal Tract
Anti-synthetase Syndrome
Clinically Amyopathic Dermatomyositis
Juvenile Dermatomyositis
Inclusion Body Myositis
Immune-Mediated Necrotizing Myopathies
Statin Myopathy
Myositis Associated With Malignancies
Classification and Diagnostic Criteria
Physical Findings
Laboratory Findings
Biochemical Tests
Histopathology
Imaging
Muscles
Lungs
Electromyography
Pulmonary Function Tests
Differential Diagnosis
Dystrophic Myopathies
Dysferlinopathy
Facioscapulohumeral Muscular Dystrophy
Dystrophinopathies
Proximal Myotonic Myopathy
Sarcoglycanopathy
Neuromuscular Disorders
Motoneuron Diseases
Spinal Muscular Atrophy
Myasthenia Gravis
Metabolic Myopathies
Acid Maltase Deficiency
McArdle’s Disease
Mitochondrial Myopathies
Endocrine Myopathies
Cushing’s Syndrome
Hyperthyroid and Hypothyroid Myopathy
Infectious Myopathies
Human Immunodeficiency Virus Myopathy
Human T-Lymphotropic Virus I Myopathy
Parasitic Myopathies
Drug-Induced Myopathies
Management and Outcome
Pharmacologic Treatment
Nonpharmacologic Treatment
Assessing Disease Activity and Outcome
Muscle Examination
Extramuscular Involvement
Chapter 91: Overlap Syndromes
Introduction
Historical Background
Immunogenetics of Overlap Syndromes
Autoantibodies in Overlap Syndromes
Mixed Connective Tissue Disease
The Controversy
Phenotypic Stability
Epidemiology and Classification
Clinical Features
Joint Involvement
Skin Involvement
Pulmonary Manifestations
Kidney
Cardiovascular System
Gastrointestinal Tract
Muscle Involvement
Neurologic Disease
Patients Presenting With Undifferentiated Rheumatic Disease
Undifferentiated Connective Disease: A Stable Phenotype
Early Undifferentiated Systemic Sclerosis
Overlap Syndromes With Dominant Features of Scleroderma
Overlap Syndromes With Dominant Features of Myositis
Sjögren’s Syndrome and Autoimmune Thyroid Disease
Treatment of Overlap Connective Tissue Disease Syndromes
Part 13: Vasculitis
Chapter 92: Classification and Epidemiology of Systemic Vasculitis
Introduction
Classification of Vasculitis
Introduction to the Concept of Classification
A Framework for Classification of Vasculitis: Vessel Size Versus Pathogenesis
Small-Vessel Vasculitis
Anti-neutrophil Cytoplasmic Antibody-Associated Vasculitis
Immune Complex-Mediated Small-Vessel Vasculitis
Medium-Vessel Vasculitis
Polyarteritis Nodosa
Kawasaki’s Disease
Large-Vessel Vasculitis
Giant Cell Arteritis
Takayasu’s Arteritis
Other Classifications
Variable-Vessel Vasculitis: Behçet’s Disease and Cogan’s Syndrome
Single-Organ Vasculitis
Secondary Causes of Vasculitis
Epidemiology of Vasculitis
Geography
Age, Sex, and Ethnicity
Genetics
Environment
Chapter 93: Giant Cell Arteritis, Polymyalgia Rheumatica, and Takayasu’s Arteritis
Introduction
American College of Rheumatology Classification Criteria
Definitions
Giant Cell Arteritis
Polymyalgia Rheumatica
Epidemiology
Etiology, Pathology, and Pathogenesis
Clinical Features
Giant Cell Arteritis
Polymyalgia Rheumatica
Laboratory Studies
Differential Diagnosis
Diagnostic Evaluation in Giant Cell Arteritis
Treatment and Outcome
Initial Treatment for Giant Cell Arteritis
Subsequent Treatment for Giant Cell Arteritis
Treatment for Polymyalgia Rheumatica
Takayasu’s Arteritis
American College of Rheumatology Classification Criteria
Epidemiology
Etiology and Pathogenesis
Clinical Features
Laboratory Studies
Imaging
Diagnosis and Diagnostic Tests
Treatment
Medical Therapy
Surgical Therapy
Outcome
Chapter 94: Anti-neutrophil Cytoplasmic Antibody–Associated Vasculitis
Introduction
Classification Criteria and Nomenclature
Epidemiology
Triggering Factors
Genetics
Clinical Manifestations
Granulomatosis With Polyangiitis
Microscopic Polyangiitis
Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss Syndrome)
Diagnostic Testing
Treatment
Induction of Remission for Granulomatosis With Polyangiitis and Microscopic Polyangiitis
Maintenance of Remission for Granulomatosis With Polyangiitis and Microscopic Polyangiitis
Adjunctive and Alternative Agents
Treatment of Eosinophilic Granulomatosis With Polyangiitis
Outcome
Pathogenesis
Conclusion
Chapter 95: Polyarteritis Nodosa and Related Disorders
Polyarteritis Nodosa
Definition and Classification
Epidemiology
Etiology and Pathogenesis
Pathologic Features
Clinical Features
Clinical Assessment of Patients
Laboratory Testing
Imaging
Polyarteritis Nodosa in Children
Microscopic Polyangiitis Versus Polyarteritis Nodosa
Dermatologic Forms of Vasculitis
Cutaneous Polyarteritis Nodosa
Hepatitis B Virus Polyarteritis Nodosa
Non–hepatitis B Virus Polyarteritis Nodosa
Outcome
Cogan’s Syndrome
Pathology
Clinical Features
Treatment
Buerger’s Disease
Pathology
Clinical Features
Treatment
Susac’s Syndrome
Virus-Induced Vasculitis
Infections and Vasculitis
Chapter 96: Immune Complex–Mediated Small Vessel Vasculitis
Introduction
Pathogenesis
Arthus Reaction
Immunogenicity
Cutaneous Manifestations
Pathology Features
Light Microscopy
Direct Immunofluorescence
Differential Diagnosis
Clinical Syndromes
Hypersensitivity Vasculitis
IgA Vasculitis (Henoch-Schönlein Purpura)
Cryoglobulinemic Vasculitis
IgG4-Related Vasculitis
Hypocomplementemic Urticarial Vasculitis
Erythema Elevatum Diutinum
Autoimmune Disease Associated Vasculitis
Rheumatoid Vasculitis
References
Chapter 97: Primary Angiitis of the Central Nervous System
Introduction
Epidemiology
Genetics
Clinical Features
Proposed Criteria for Primary Angiitis of the Central Nervous System
Clinical Subsets
Granulomatous Angiitis of the Central Nervous System
Other Forms of Central Nervous System Vasculitis
Mass-like Presentation
Cerebral Amyloid Angiitis
Angiographically Defined Central Nervous System Vasculitis
Spinal Cord Presentation
Nongranulomatous Primary Angiitis of the CNS
Diagnosis and Diagnostic Tests
Diagnostic Tests
Laboratory Findings
Cerebrospinal Fluid Analysis
Radiologic Evaluation
Brain Biopsy
Differential Diagnosis
Reversible Cerebral Vasoconstriction Syndromes
Primary Systemic Vasculitides
Systemic Autoimmune Diseases
Infections
Lymphoproliferative Diseases
Miscellaneous
Treatment
Outcome
Conclusion
References
Chapter 98: Behçet’s Disease
Introduction
Epidemiology
Pathogenesis
Genetics
Immunologic Mechanisms
Infection
Clinical Features
Mucocutaneous Manifestations
Ophthalmologic Manifestations
Vascular Manifestations
Articular Manifestations
Other Systemic Manifestations
Diagnosis
Diagnostic Criteria
Histopathology
Treatment
Mucocutaneous Disease
Systemic Disease
Prognosis
References
Part 14: Crystal-Induced and Inflammasome-Mediated Inflammation
Chapter 99: Pathogenesis of Inflammasome-Mediated Diseases
Introduction
Inflammasome Biology
Inflammasome Structure and Assembly
Inflammasome Triggers
Inflammasome Regulation
Inflammasomes and Autoinflammation
NLRP1
NLRP1 in Autoinflammatory Disease
NLRP3
NLRP3 in Autoinflammatory Disease
The Pathogenesis of Tumor Necrosis Factor Associated Periodic Syndrome
NLRP3 in More Common Diseases
Pyrin
Pyrin in Autoinflammatory Disease
The Pathogenesis of Mevalonate Kinase Deficiency
NLRC4
NLRC4 in Autoinflammatory Disease
Other Inflammasomes
NLRP6
NLRP7
NLRP12
PYHIN Proteins
Inflammasomes in Autoimmunity
Genetic Variants in Inflammasome Genes and Autoimmunity
Ex Vivo Studies of Inflammasomes and Autoimmunity
Inflammasome-Targeted Therapies
Conclusion
Selected References
References
Chapter 100: Etiology and Pathogenesis of Hyperuricemia and Gout
Introduction
Evolutionary Considerations
Uric Acid as a Danger Signal
Uric Acid and Human Evolution
Determinants of Serum Urate Levels
Uric Acid Production and Excretion: Normal Levels and Hyperuricemia
Uric Acid Production: Purine Metabolism and Intake
Purine Biosynthesis
Urate Formation and Purine Salvage
Urate Overproduction: Primary and Secondary Causes
Primary Urate Overproduction
Secondary Urate Overproduction and Hyperuricemia
Urate Excretion: Gastrointestinal and Renal Mechanisms
Gastrointestinal Excretion of Urate
Renal Excretion of Uric Acid: Normal Mechanisms
Urate Resorption
Urate Secretion
Renal Causes of Hyperuricemia
Primary Urate Underexcretion
Secondary Causes of Renal Urate Underexcretion
Age and Sex
Systemic Illnesses
Medications
Toxins
Diet and Uric Acid
Purine-Rich Foods
Fructose
Alcoholic Beverages
Other Dietary Components
Crystal Formation: The Transition From Hyperuricemia to Gout
Acute Gout Flares: The Inflammatory Response to Monosodium Urate Crystals
Uric Acid Crystals and Complement Activation
Cellular Response to Crystals
Cell Recognition of Urate Crystals
Intra-cellular Responses to Urate Crystal Encounters
Initiation and Propagation of the Acute Gouty Flare
Resolution of the Acute Gouty Flare
Chronic Gouty Arthritis and Tophaceous Gout
Asymptomatic Hyperuricemia
Selected Reference
References
Chapter 101: Clinical Features and Treatment of Gout
Classification
Clinical Features of Gout
Introduction
Epidemiology
Prevalence and Incidence of Gout
Risk Factors for Developing Gout
Clinical Risk Factors for Flares in Patients With Gout
Associated Comorbid Conditions
Clinical Presentations of Gout
Investigations for Gout
Microscopic Analysis for Monosodium Urate Crystals
Blood and Urine Testing
Plain Radiography
Ultrasound
Dual Energy Computed Tomography
Magnetic Resonance Imaging
Diagnosis
Gout Management
Gout Management Guidelines
Gout Flare Treatment
Principles of Gout Flare Management
Corticosteroids and Related Medications
Nonsteroidal Anti-inflammatory Drugs
Colchicine
Anti-IL-1 Biologic Therapy
Urate-Lowering Therapy
Principles of Urate-Lowering Therapy for Gout Management
Allopurinol
Febuxostat
Uricosuric Agents
Pegloticase
Novel Urate-Lowering Drugs
Anti-inflammatory Prophylaxis When Initiating Urate-Lowering Therapy
Role of Dietary/Lifestyle Interventions
Comorbidity Assessment and Management in Patients With Gout
Outcome
Strategies to Improve Gout Care
Selected References
References
Chapter 102: Calcium Crystal Disease: Calcium Pyrophosphate Dihydrate and Basic Calcium Phosphate
Introduction
Epidemiology
Genetics
Etiology and Pathogenesis
Dysregulated PPi Metabolism in Pathologic Articular Cartilage Calcification
Role of ENPP1 and ANKH in PPi Metabolism in Chondrocalcinosis
Imbalance of Chondrocyte Growth Factor Responses Affects PPi Metabolism in Calcium Pyrophosphate Dihydrate Crystal Deposition Disease
Calcium Pyrophosphate Dihydrate Crystal Deposition Disease Secondary to Primary Metabolic Disorders: Relationship to PPi Metabolism and Chondrocyte Differentiation
Inflammation and Hypertrophic Chondrocyte Differentiation in Chondrocalcinosis
Special Pathogenic Aspects of Articular and Periarticular Basic Calcium Phosphate Crystal Deposition
Crystal-Induced Inflammation
Clinical Features
Calcium Pyrophosphate Dihydrate Crystal Deposition Disease
Acute Calcium Pyrophosphate Dihydrate Crystal-Associated Synovitis (Pseudogout)
Chronic Degenerative and Inflammatory Arthropathies
Other Clinical Forms of Calcium Pyrophosphate Dihydrate Crystal Deposition Disease
Familial Calcium Pyrophosphate Dihydrate Crystal Deposition Disease
Articular Basic Calcium Phosphate Crystal Disease
Diagnosis and Diagnostic Tests
Differential Diagnosis
Differential Diagnostic Considerations for Basic Calcium Phosphate Crystal Deposition
Plain Radiographs
High-Resolution Ultrasound and Advanced Imaging
Laboratory Diagnostic Tests
Treatment
Calcium Pyrophosphate Dihydrate Crystal Deposition Disease
Basic Calcium Phosphate Crystal Arthropathies
Future Directions in Treatment
Outcome
Conclusion
Selected References
Websites
References
Chapter 103: Familial Autoinflammatory Syndromes
Introduction
Differential Diagnosis
The Four ‘Classic’ Hereditary Autoinflammatory Syndromes
Familial Mediterranean Fever
Epidemiology
Etiology and Pathogenesis
Clinical Features
Diagnosis and Diagnostic Tests
Treatment
Outcome
Expanding Spectrum of Pyrin-Associated Disorders
Mevalonate Kinase Deficiency (Previously Known as Hyper-IgD Syndrome)
Epidemiology
Etiology and Pathogenesis
Clinical Features
Diagnosis and Diagnostic Tests
Treatment
Outcome
Tumor Necrosis Factor Receptor–Associated Periodic Syndrome (TRAPS)
Epidemiology
Etiology and Pathogenesis
Clinical Features
Diagnosis and Diagnostic Tests
Treatment
Outcome
Cryopyrin-Associated Periodic Syndrome
Epidemiology
Etiology and Pathogenesis
Clinical Features and Outcome
Diagnosis and Diagnostic Tests
Treatment
Other Hereditary Autoinflammatory Syndromes
Blau Syndrome/Early Onset Sarcoidosis
Epidemiology
Etiology and Pathogenesis
Clinical Features and Outcome
Diagnosis
Treatment
Pyogenic Sterile Arthritis, Pyoderma Gangrenosum, and Acne Syndrome
Epidemiology
Etiology and Pathogenesis
Clinical Features and Outcome
Diagnosis
Treatment
Deficiency of the IL-1 Receptor Antagonist (DIRA)
Deficiency of Adenosine Deaminase 2
Interferonopathies
Deficiency of the IL-36 Receptor Antagonist (DITRA)
CARD14 Mediated Psoriasis
Monogenic Autoinflammatory Disorders Associated With Immunodeficiency
NLRC4-Associated Autoinflammatory Disorder
A20 Haploinsufficiency
Otulinopenia
NLRP12-Associated Autoinflammatory Disorder
NLRP1-Associated Autoinflammatory Disorder
Conclusion
Selected References
References
Part 15: Cartilage, Bone, and Heritable Connective Tissue Disorders
Chapter 104: Pathogenesis of Osteoarthritis
Introduction
Etiology
Age
Joint Location
Obesity
Gut Microbiome
Genetic Predisposition
Joint Malalignment and Trauma
Sex
Pathology
Morphologic Changes
Early Reparative, Proliferative, and Hypertrophic Changes in Cartilage
Osteophyte Formation
Cartilage Hypocellularity
Alterations in Cartilage Matrix Metabolism
Biochemical Changes
Metabolic Changes
Anabolic Factors (TGF-β, Bone Morphogenic Proteins) and Cartilage Repair
Catabolic Factors and Cartilage Degradation
Proteinases
Metalloproteinases
Collagenases
Cathepsins
Aggrecanases
Proteinase Inhibitors
Alterations in Matrix Synthesis
Chondrocyte Senescence
Biomechanics and Disease Mechanisms
Biomechanical Changes
Muscle Weakening in Mechanical Loading
Response of Cartilage to Mechanical Injury
Mechanotransduction and Gene Expression
Bone Abnormalities
Osteophyte Formation
Subchondral Bone Sclerosis
Bone Marrow Lesions
Role of Inflammatory Mediators in Disease Progression
Inflammatory Molecules Produced by Articular Cartilage
Cytokines and Chemokines
Proteinases
Nitric Oxide
Transforming Growth Factor-β
Hyaluronic Acid
Prostaglandins
F-Spondin
Inflammatory Mediators in Bone
Abnormalities of Synovium
Conclusion
Selected References
References
Chapter 105: Clinical Features of Osteoarthritis
Introduction
Epidemiology of Osteoarthritis
Prevalence of Radiographic Osteoarthritis
Prevalence of Symptomatic Osteoarthritis
Racial Differences in Osteoarthritis Prevalence
Primary and Secondary Osteoarthritis
Clinical Features
General Signs and Symptoms
Joint-Specific Signs and Symptoms: Knee
Joint-Specific Signs and Symptoms: Hip
Joint-Specific Signs and Symptoms: Hand
Joint-Specific Signs and Symptoms: Spine
Joint-Specific Signs and Symptoms: Shoulder
Joint-Specific Signs and Symptoms: Other Joints
Polyarticular Osteoarthritis
Nodal Osteoarthritis and Genetics
Diagnostic Testing
Laboratory Testing
Synovial Fluid
Molecular Biomarkers
Imaging: Conventional Radiography and General Considerations
Imaging: Conventional Radiography of Specific Joints
Imaging: Advanced Modalities
Magnetic Resonance Imaging
Ultrasound
Computed Tomography
Nuclear Medicine
Outcome
Pain and Functional Status Assessment
Self-Reported Measures of Pain and Function
Performance-Based Assessment
Quality of Life
Time to Total Joint Replacement
Responder Criteria
Mortality in Osteoarthritis
Conclusion
References
Chapter 106: Treatment of Osteoarthritis
Introduction
Therapeutic Pain Targets in Osteoarthritis
Approach to Management of Osteoarthritis
General Considerations
Physical Modalities and Mind-Body Approaches
Patient Education and Self-Management
Weight-Management
Physical Activity
Exercise
Therapies to Modulate Joint Loading
Cognitive-Behavioral Therapy (CBT)
Manual Therapy
Complementary and Integrative Therapies
Pharmacologic Management: Knee, Hip, Hand
Local Therapies
Topical Therapies
Lidocaine
Intra-articular Agents
Glucocorticoids
Viscosupplementation
Platelet-Rich Plasma, Mesenchymal Stem Cell Therapy, Prolotherapy, Botulinum Toxin
Systemic Therapies
Oral NSAIDs, Including COX-2 Inhibitors
Opioids
Duloxetine and Other Centrally Acting Agents
Other Pharmacologic Agents Tested in OA
Supplements/Nutraceuticals
Glucosamine and Chondroitin
Fish Oil/Omega-3 Polyunsaturated Fatty Acids
Surgical Management of Osteoarthritis
Arthroscopic Procedures
Joint Arthroplasty
Other Surgical Approaches
Experimental Osteoarthritis Therapies
Selected References
References
Chapter 107: Metabolic Bone Disease
Introduction
Osteoporosis
Epidemiology and Clinical Signs
Pathophysiology of Menopausal and Age-Related Bone Loss
Osteoporosis in Men
Osteoporosis in Rheumatic Diseases and Other Conditions
Assessment of Bone Density and Osteoporotic Risk
Markers of Bone Turnover
Evaluation for Secondary Bone Loss
Treatment
Calcium
Estrogen
Selective Estrogen Receptor Modulators
Testosterone
Calcitonin
Anti-resorptive Drugs
Bisphosphonates
RANK Ligand Inhibitor
Adverse Events Associated With Potent Anti-resorptive Agents
Parathyroid Hormone
Abaloparatide
Recently Approved Medications
Romosozumab
Vitamin D
Preventive Measures
Glucocorticoid-Induced Osteoporosis
Osteomalacia
Paget’s Disease of Bone
Etiology
Clinical Features
Laboratory Findings
Diagnosis
Treatment
Bisphosphonates
Osteoporosis Induced by Other Medications
Selected References
References
Chapter 108: Proliferative Bone Diseases
Introduction
Diffuse Idiopathic Skeletal Hyperostosis
Epidemiology
Etiology and Pathogenesis
Genetic Factors
Metabolic Factors
Other Bone Formation–Promoting Pathways
Clinical Manifestations
Spinal Involvement
Extraspinal Involvement
Fracture Risk and Heterotropic Ossification
Treatment
Hypertrophic Osteoarthropathy
Etiology
Primary Hypertrophic Osteoarthropathy
Secondary Hypertrophic Osteoarthropathy
Pathogenesis
Clinical Manifestations
Treatment
SAPHO Syndrome
Etiology and Pathogenesis
Clinical Manifestations and Imaging
Treatment
Selected References
References
Chapter 109: Osteonecrosis
Introduction
Epidemiology
Etiology
Steroid-Related Osteonecrosis
Alcohol and Smoking
Transplantation
Dysbaric Osteonecrosis
Infection
Radiation and Osteonecrosis
Coagulopathy and Osteonecrosis
Clinical Variants
Osteonecrosis
Bone Marrow Edema
Bisphosphonates, Denosumab, and Osteonecrosis of the Jaw
Osteonecrosis in Children
Staging Osteonecrosis
Pathogenesis
Traumatic Osteonecrosis
Anatomic Considerations in Trauma-Related Osteonecrosis
Nontraumatic Osteonecrosis
Vascular and Mechanical Considerations
Osteoimmunologic Factors
Osteoblast/Osteoclast Balance
Apoptosis
The Role of Lipids
The Role of Coagulopathy in Osteonecrosis
Oxidative Stress
Nitric Oxide Synthase
The Multi-hit Theory of Osteonecrosis
The Microbiome in Osteonecrosis
Genetics, Epigenetics, and Osteonecrosis
Diagnosis
History and Physical Examination
Imaging
Pathology
Biomarkers of Disease
The Natural History of Osteonecrosis
Treatment of Osteonecrosis
Surgery
Nonsurgical Approaches
Prevention Versus Treatment
Stem Cell Transplantation
Conclusion
Selected References
References
Chapter 110: Relapsing Polychondritis
Introduction
Epidemiology
Pathology
Normal Cartilage
Relapsing Polychondritis Cartilage
Pathogenesis
Clinical Features
Otorhinologic Disease
Respiratory Disease
Cardiovascular Disease
Eye Disease
Renal Disease
Neurologic Disease
Mucocutaneous Disease
Joint Disease
Associated Disorders
Differential Diagnosis
Diagnostic Tests
Routine Laboratory Tests
Tissue Sampling and Histopathology
Pulmonary Studies
Cardiac Studies
Ophthalmologic Studies
Imaging
Additional Studies
Treatment
Outcome
Conclusion
References
Chapter 111: Heritable Diseases of Connective Tissue
Introduction
Skeletal Dysplasias
Embryology
Cartilage Structure
Classification and Nomenclature
Clinical Evaluation and Features
Diagnosis and Testing
Management and Treatment
Biochemical and Molecular Abnormalities
Defects in Extra-cellular Structural Proteins
Type II Collagen and Type XI Collagen
Cartilage Oligomeric Matrix Protein
Osteogenesis Imperfecta
Mild Osteogenesis Imperfecta (Type I OI)
Molecular Pathology
Lethal Osteogenesis Imperfecta (Type II OI)
Molecular Pathology
Severely Deforming Osteogenesis Imperfecta (Type III OI)
Molecular Pathology
Osteogenesis Imperfecta of Moderate Severity (Type IV OI)
Molecular Pathology
Type V Osteogenesis Imperfecta
Histopathology of Bone in Osteogenesis Imperfecta
Treatment
Ehlers-Danlos Syndrome
Ehlers-Danlos Syndrome (Classic Type)
Clinical Features
Ehlers-Danlos Syndrome (Hypermobility Type)
Structural and Molecular Pathology of the Classic and Hypermobile Types of Ehlers-Danlos Syndrome
Ehlers-Danlos Syndrome (Vascular Type)
Molecular Pathology
Therapy in the Classic, Hypermobility, and Vascular Types of Ehlers-Danlos Syndrome
Arthrochalasia Type
Molecular Pathology
Ehlers-Danlos Syndrome (Dermatosparaxis Type)
Ehlers-Danlos Syndrome (Kyphoscoliosis Type)
Molecular Pathology
Marfan Syndrome
Clinical Features
Differential Diagnosis
Homocystinuria
Molecular Biology of Marfan Syndrome
Treatment
Loeys-Dietz Syndrome
Congenital Contractural Arachnodactyly
Conclusion
Selected References
References
Part 16: Rheumatic Diseases of Childhood
Chapter 112: Etiology and Pathogenesis of Juvenile Idiopathic Arthritis
Introduction
Epidemiology
Histopathology
Synovium
Skin
Eye
Bone Marrow
Secondary Immune Organs
Environmental Triggers of Disease
Host Triggers of Disease
Genetics
Immune System
Adaptive Immunity
T-Cell
B-cell
Innate Immunity
Antigen Presenting Cells
Macrophages/Monocytes
Neutrophils
Subtype-Specific Pathogenesis
Systemic
Macrophage Activation Syndrome
Oligoarticular
Uveitis
Polyarticular
Enthesitis-Related and Psoriatic
Conclusion
References
Chapter 113: Clinical Features and Treatment of Juvenile Idiopathic Arthritis
Introduction
Classification Criteria for Juvenile Idiopathic Arthritis and Differential Diagnosis
Oligoarticular Juvenile Idiopathic Arthritis
Rheumatoid Factor–Negative Polyarticular Juvenile Idiopathic Arthritis
Rheumatoid Factor–Positive Polyarticular Juvenile Idiopathic Arthritis
Juvenile Spondyloarthritis and Enthesitis-Related Arthritis
Juvenile Psoriatic Arthritis
Systemic Juvenile Idiopathic Arthritis
Special Considerations: Macrophage Activation Syndrome
Treatment
Nonsteroidal Anti-inflammatory Drug Use in Children
Intra-articular Steroid Injections
Corticosteroid Use in Children With Juvenile Idiopathic Arthritis
Methotrexate
Biologic Agents
Tumor Necrosis Factor Inhibitors
Abatacept
IL-1 Inhibitors
IL-6 Inhibitors
Other Drugs and Biologic Agents
Biosimilars
Treatment of Juvenile Idiopathic Arthritis Subtypes
Oligoarticular-Course Arthritis
Polyarticular-Course Arthritis
Juvenile Spondyloarthritis
Juvenile Psoriatic Arthritis
Systemic Juvenile Idiopathic Arthritis
Clinical Features and Management of Juvenile Idiopathic Arthritis-Associated Uveitis
Imaging
Outcome
Oligoarticular Juvenile Idiopathic Arthritis
Rheumatoid Factor–Negative Polyarticular Juvenile Idiopathic Arthritis
Rheumatoid Factor–Positive Polyarticular Juvenile Idiopathic Arthritis
Juvenile Spondyloarthritis
Juvenile Psoriatic Arthritis
Systemic Juvenile Idiopathic Arthritis
Special Considerations in Children
Conclusion
Selected Reference
References
Chapter 114: Childhood-Onset Systemic Lupus Erythematosus, Drug-Induced Lupus in Children, and Neonatal Lupus
Childhood-Onset Systemic Lupus Erythematosus
Definition and Classification
Epidemiology
Genetics and Pathogenesis
Clinical Features
Lupus Nephritis
Neuropsychiatric Systemic Lupus Erythematosus (NPSLE)
Antiphospholipid Antibody Syndrome
Macrophage Activation Syndrome
Diagnosis and Diagnostic Tests
Treatment and Management
Hydroxychloroquine
Photoprotection
Glucocorticoids
Steroid-Sparing Agents: Disease-Modifying Anti-rheumatic Drugs
Steroid-Sparing Agents: Biologics
Other Treatments
Approach to Treating Lupus Nephritis
Approach to Treating Neuropsychiatric Lupus
Management of Antiphospholipid Syndrome
Adherence to Treatment in Childhood-Onset Systemic Lupus Erythematosus
Opportunities for Prevention
Infection Prevention
Optimizing Bone Health
Cardiovascular Risk Reduction
Reproductive Health
School Concerns
Mental Health Concerns
Transition to Adult Care
Outcomes in Childhood-Onset Systemic Lupus Erythematosus
Drug-Induced Lupus
Definition and Classification
Genetics and Pathogenesis
Clinical Manifestations
Treatment
Neonatal Lupus
Definition and Classification
Genetics and Pathogenesis
Clinical Features
Treatment
Conclusion
References
Chapter 115: Juvenile Dermatomyositis, Scleroderma, Vasculitis, and Autoimmune Brain Disease
Juvenile Dermatomyositis
Definition and Classification
Epidemiology
Genetics
Etiology and Pathogenesis
Maternal Microchimerism
Infectious and Environmental Triggers
Clinical Features
Characteristic Rash
Proximal Muscle Weakness
Systemic Manifestations
Lung Disease
Heart Disease
Amyotrophic Dermatomyositis
Malignancy
Diagnosis and Diagnostic Tests
Autoantibody Profiles
Muscle Pathology
Peripheral Blood Phenotyping in Juvenile and Adult Dermatomyositis
Differential Diagnosis
Treatment
Standard Therapies
Therapy for Refractory Disease
Consensus Protocols
Non-pharmacologic Treatment
Outcome
Conclusion
Pediatric Scleroderma: Systemic and Localized Forms
Epidemiology
Genetics
Pathogenesis (Shared Between Localized Scleroderma and Systemic Sclerosis)
Systemic Sclerosis
Classification
Clinical Features
Vascular Manifestations
Cutaneous Manifestations
Gastrointestinal Manifestations
Pulmonary Involvement
Musculoskeletal Involvement
Cardiac Involvement
Renal Dysfunction
Neurologic Involvement
Diagnosis and Diagnostic Tests
Evaluation/Disease Monitoring of the Patient With JuvenileSystemic Sclerosis
Treatment
Outcome
Localized Scleroderma
Classification
Clinical Features
Cutaneous Manifestations
Disease Activity and Damage Features: Clinical and Histologic Findings
Extracutaneous Manifestations
Diagnosis and Diagnostic Tests
Diagnosis
Disease Monitoring
Treatment
Other Therapies
Outcome
Conclusion: Localized Scleroderma and Systemic Sclerosis
Pediatric Vasculitis
Small-Vessel Vasculitis: Henoch-Schönlein Purpura
Definition and Classification
Epidemiology
Etiology and Pathogenesis
Clinical Features
Diagnosis and Diagnostic Tests
Treatment
Outcome/Prognosis
Medium-Vessel Vasculitis: Kawasaki’s Disease
Classification
Epidemiology
Clinical Features
Diagnosis and Diagnostic Tests
Treatment
Outcome
Anti-neutrophil Cytoplasm Antibody–Associated Vasculitis, Polyarteritis Nodosa, and Takayasu’s Arteritis
Definition and Classification
Anti-neutrophil Cytoplasm Antibody-Associated Vasculitis
Epidemiology
Clinical Features
Diagnosis and Diagnostic Tests
Treatment
Polyarteritis Nodosa
Classification
Clinical Features
Diagnostic Testing and Treatment
Takayasu’s Arteritis
Classification and Epidemiology
Clinical Features
Treatment and Outcome
Autoimmune Brain Disease
Central Nervous System Vasculitis
Epidemiology and Etiology
Central Nervous System Vasculitis
Definition and Classification
Clinical Features
Diagnostic Testing
Treatment
Outcome
Definition/Classification
Epidemiology
Clinical Manifestations
Diagnostic Evaluation
Treatment
Autoimmune Encephalitis Clinical Syndromes
Anti-NMDA Receptor Encephalitis
Clinical Manifestations
Diagnosis
Treatment
Prognosis
Limbic Encephalitis
Clinical Manifestations
Diagnosis
Treatment
Prognosis
Hashimoto’s Encephalopathy
Clinical Manifestations
Diagnosis
Treatment
Other Forms of Autoimmune Encephalitis
Acquired Demyelinating Syndromes
Acute Disseminated Encephalomyelitis
Neuromyelitis Optica Spectrum Disorder
Myelin Oligodendrocyte Glycoprotein (MOG) Antibody-Associated Demyelination
Selected References
References
Part 17: Infection and Arthritis
Chapter 116: Bacterial Arthritis
Epidemiology
Etiology
Pathogenesis
Clinical Features
Diagnosis and Diagnostic Tests
Treatment
Prosthetic Joint Infections
Prevention of Prosthetic Joint Infections
Conclusion
Selected References
References
Chapter 117: Lyme Disease
Introduction
Ecology and Epidemiology of Lyme Disease
Ticks and Lyme Disease
Pathogenesis
Borrelia burgdorferi Invasion of the Mammalian Host
Pathology of Lyme Disease
Immune Response to Borrelia burgdorferi
Mechanisms of Spirochete Persistence
Clinical Features
Early Localized Infection
Early Disseminated Infection
Skin Disease
Cardiac Disease
Nervous System Involvement
Other Organ System Involvement
Late Disease
Neurologic Disease
Skin Disease
Lyme Arthritis and Other Musculoskeletal Manifestations of Lyme Disease
Post-antibiotic Lyme Arthritis
Diagnosis
Culture
Serologic Testing
Antibodies to Borrelia burgdorferi in Cerebrospinal Fluid
Polymerase Chain Reaction
Other Tests
Imaging
Treatment and Outcome
Pregnancy and Lyme Disease
Outcome
Chronic Lyme Disease and Post–Lyme Disease Syndrome
Prevention
Conclusion
Selected References
References
Chapter 118: Mycobacterial Infections of Bones and Joints
Introduction
Clinical Scenarios
Direct Involvement of the Musculoskeletal System
Spondylitis
Tuberculous Osteomyelitis
Septic Arthritis
Emergence of Tuberculosis During Treatment of Rheumatic Diseases
Rheumatic Disorders Precipitated by the Treatment of Tuberculosis
Reactive Immunologic Phenomena in the Setting of Tuberculosis
Diagnosis
Tuberculin Skin Test
Interferon-γ Release Assays
Imaging
Culture
Polymerase Chain Reaction
Treatment
Osteoarticular Infections Caused by Nontuberculous Mycobacteria
Emergence of Nontuberculous Mycobacterial Infections During the Treatment of Rheumatic Diseases
References
Chapter 119: Fungal Infections of Bones and Joints
Introduction
Coccidioidomycosis
Blastomycosis
Cryptococcosis
Candidiasis
Sporotrichosis
Aspergillosis
Histoplasmosis
Scedosporiosis
Treatment of Fungal Infection
Fungal Infection as a Consequence of Anti-rheumatic Therapy
Selected References
References
Chapter 120: Rheumatic Manifestations of HIV Infection
Introduction
HIV-Associated Bone and Joint Disease
HIV-Associated Arthralgia
Painful Articular Syndrome
HIV-Associated Arthritis
Reactive Arthritis Occurring in HIV Infection
Treatment
Psoriasis and Psoriatic Arthritis
Undifferentiated Spondyloarthritis
Avascular Necrosis of Bone
Hypertrophic Pulmonary Osteoarthropathy
Osteopenia and Osteoporosis
HIV-Associated Muscle Disease
Myalgia and Fibromyalgia
Non-inflammatory Necrotizing Myopathy and HIV-Related Wasting Syndrome
Nemaline Myopathy
HIV-Associated Polymyositis
Inclusion Body Myositis
Myopathy Associated With Treatment
Rhabdomyolysis
Diffuse Infiltrative Lymphocytosis Syndrome
Vasculitis Associated With HIV Infection
Primary Pulmonary Hypertension
HIV-Associated Musculoskeletal Infection
Pyomyositis
Bacterial Arthritis and Osteomyelitis
Musculoskeletal Tuberculosis
Atypical Mycobacterial Infection
Bacillary Angiomatosis Osteomyelitis
Fungal Infections
Parasitic Infections
Response of Other Rheumatic Diseases to HIV Infection
Highly Active Anti-retroviral Therapy-Related Immune Reconstitution Syndrome
Rheumatologic Laboratory Abnormalities Associated With HIV Infection
Conclusion
References
Chapter 121: Viral Arthritis
Introduction
Examples of Arthritogenic Viruses
Parvovirus B19
Rubella Virus
Chikungunya Arthritogenic Alphavirus
Epstein-Barr Virus (EBV)
Hepatitis C Virus (HCV) and Other Flaviviruses
Arthritogenic Viruses Hijack the Innate Interferon-Type I Response to Favor Persistence
Arthritogenic Viruses Engage a Trojan Horse Scenario to Avoid Adaptive Immunity
Other Mechanisms Favoring Viral Persistence Inside Synovial Tissues
Mechanisms Involved in Chronic Painful Arthralgias
Mechanisms Involved in Chronic Inflammatory Viral Arthritis That Resemble Rheumatoid Arthritis
Treatment and Prevention
Conclusion
Selected References
References
Chapter 122: Rheumatic Fever and Post-streptococcal Arthritis
Introduction
Rheumatic Fever and Rheumatic Heart Disease
Etiologic Agent (S. pyogenes)
Epidemiology
Clinical Manifestations
Acute Rheumatic Fever
Pharyngitis
Arthritis
Acute Carditis
Transition From Acute to Chronic Heart Disease
Indolent Carditis
Subclinical Carditis
Rheumatic Heart Disease
Sydenham’s Chorea
Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections
Fever
Erythema Marginatum
Subcutaneous Nodules
Genetic Associations
Innate Immunity
Adaptive Immunity
Pathologic Effector Mechanisms and Autoimmunity
Immune Complex
Molecular Mimicry and Epitope Spreading
Immune Mechanisms and Disease Manifestations
Arthritis
Sydenham’s Chorea
Rheumatic Heart Disease
Cytokines and the Inflammatory Process
Diagnostic Tests
Throat Cultures
Rapid Antigen Testing
Streptococcal Antibody Tests
Acute-Phase Reactants
Other Laboratory Tests
Chest Radiography
Electrocardiography
Echocardiography
Diagnosis
Treatment
Primary Prophylaxis
Acute Rheumatic Fever Treatment
Eradication of Streptococcus
Acute Carditis
Heart Failure
Emergency Valve Surgery
Arthritis and Fever
Chorea
Rheumatic Heart Disease Management
Secondary Prophylaxis
Infective Endocarditis Prophylaxis
Vaccine Development
Post-streptococcal Arthritis
Conclusion
References
Part 18: Arthritis Accompanying Systemic Disease
Chapter 123: Amyloidosis
Introduction
AA Amyloidosis
Pathogenesis
Epidemiology
Incidence
Risk Factors and Underlying Conditions
Genetics
Clinical Features
Other Types of Systemic Amyloidosis
Systemic Light Chain (AL) Amyloidosis
β2 Microglobulin Amyloidosis
Wild-type Transthyretin Amyloidosis (ATTR)
Hereditary Amyloidosis
Diagnosis and Diagnostic Tests
Imaging, Including SAP Scintigraphy
Treatment of AA Amyloidosis
Principles of Treatment
General Supportive Management
Systemic Treatment
Renal Transplantation
Novel Treatments
Outcome
Conclusion
References
Chapter 124: Sarcoidosis
Introduction
Classification Criteria
Epidemiology
Etiology
Genetics
Pathogenesis
Clinical Features
Acute Sarcoid Arthritis
Chronic Sarcoid Arthritis
Diagnosis and Diagnostic Tests
Treatment
General Approach
Management of Sarcoid Arthritis
Outcome and Prognosis
Conclusion
References
Chapter 125: Hemochromatosis
Introduction
Iron Metabolism in Health and Disease
Genetics
Other Inherited Iron-Overload Syndromes
Epidemiology
Influence of Other Genes and Environment
Pathogenesis
Clinical Features
Extra-articular Manifestations
Articular Features
Differential Diagnosis
Diagnostic Tests
Screening
Population Screening
Screening People With a Positive Family History
Screening in Patients With Related Diseases
Treatment
Outcome
Conclusion
References
Chapter 126: Hemophilic Arthropathy
Introduction
Clinical Features
Acute Hemarthrosis
Synovitis
Hemophilic Arthropathy
Muscle and Soft Tissue Hemorrhage
Pseudotumor
Osteoporosis
Diagnosis
Conventional Radiography
Magnetic Resonance Imaging
Ultrasonography
Biochemical Markers
Pathogenesis
Synovial Inflammation and Proliferation
Cartilage Degeneration
Bone Changes
Treatment of Hemophilia
Complications of Treatment
Inhibitors
Viral Infections
Treatment of Musculoskeletal Complications
Comprehensive Care
Acute Hemarthrosis
Chronic Synovitis
Hemophilic Arthropathy
Conclusion
Selected References
References
Chapter 127: Rheumatic Manifestations of Hemoglobinopathies
Introduction
Thalassemias
Sickle Cell Anemia and Related Disorders
Diagnosis
Treatment
Musculoskeletal Involvement: Sickle Cell Disease
Vaso-occlusive Crisis of Bone
Dactylitis
Osteomyelitis
Acute Synovitis and Septic Arthritis
Growth Disturbance
Osteopenia and Osteoporosis
Osteonecrosis
Iron Metabolism
Musculoskeletal Involvement: Thalassemias
Decreased Bone Density and Osteoporosis
Extramedullary Hematopoiesis
Iron Metabolism
Comorbid Rheumatic Disease
Autoimmune Disorders
Gout
Conclusion
References
Chapter 128: IgG4-Related Disease
Introduction
Epidemiology
Classification Criteria
Pathology Features
Morphologic Change of Affected Organs
Histologic Features
Immunostaining
Serum IgG4 Concentrations
Dramatic IgG4 Elevations in a Minority
IgG4: The Tissue/Serum Paradox
IgG4 as a Biomarker of Disease Activity
Serum IgG4 in Other Conditions
Pathophysiology
Is the IgG4 Molecule Central to Disease?
B Cell Lineage
T Cells
T Follicular Helper Cells
CD4+ Cytotoxic T Lymphocytes
Clinical Manifestations
Constitutional and Musculoskeletal Symptoms
Orbits
Nervous System Disease
Salivary Glands
Ear, Nose, and Throat
Thyroid Gland
Lymphadenopathy
Thoracic Aorta, Branches of the Aorta, and Coronary Lesions
Chronic Periaortitis and Retroperitoneal Fibrosis
Lung
Kidney
Pancreas
IgG4-Related Sclerosing Cholangitis and Cholecystitis
Other Manifestations
Differential Diagnosis
Treatment
References
Chapter 129: Arthritis Accompanying Endocrine and Metabolic Disorders
Introduction
Adrenal Gland Disorders
Acromegaly
Bone Mass and Quality in Acromegaly
Hypothalamic-Gonadal Axis
Androgens in Rheumatoid Arthritis
Ligamentous Injuries and Estrogen
Diabetes Mellitus
Shoulder
Hands
Feet
Muscles
Diffuse Idiopathic Skeletal Hyperostosis
Hyperthyroidism
Hypothyroidism
Chronic Autoimmune Thyroiditis
Thyroid Disorders in Patients With Rheumatic Disease
Systemic Lupus Erythematosus
Polymyalgia Rheumatica and Giant Cell Arthritis
Fibromyalgia
Rheumatoid Arthritis and Psoriatic Arthritis
Sjögren’s Syndrome
Scleroderma and Overlap Syndromes
Juvenile Idiopathic Arthritis
Spondyloarthritis
Hypoparathyroidism
Similarities to Other Rheumatic Diseases
Systemic Lupus Erythematosus
Hyperparathyroidism
Lipid Disorders
Tendinopathy
Arthritis
Selected References
References
Chapter 130: Rheumatic Paraneoplastic Syndromes—Links Between Malignancy and Autoimmunity
Introduction
Paraneoplastic Arthritis (PA)
Palmar Fasciitis and Polyarthritis Syndrome (PFPAS)
Remitting Seronegative Symmetrical Synovitis With Pitting Edema (RS3PE)
Pancreatic Panniculitis and Polyarthritis (PPP)
Erythromelalgia
Paraneoplastic Vasculitis
Cancer-Associated Myositis (CAM)
Hypertrophic (Pulmonary) Osteoarthropathy (HOA)
Tumor-Induced Osteomalacia (TIO)
Conclusion
References
Chapter 131: Tumors and Tumor-like Lesions of Joints and Related Structures
Introduction
Non-neoplastic Lesions
Synovial and Ganglion Cysts
Loose Bodies
Intra-articular Ossicles
Neoplasms
Fatty Lesions of the Synovium
Vascular Lesions of the Synovium
Fibroma of Tendon Sheath
Synovial Chondromatosis
Chondroma of Tendon Sheath and Periarticular Structures
Tenosynovial Giant Cell Tumor
Tenosynovial Giant Cell Tumor of Joints and Tendon Sheaths: Diffuse Type (Pigmented Villonodular Synovitis)
Malignant Diffuse Tenosynovial Giant Cell Tumor
Localized Tenosynovial Giant Cell Tumor of the Joint (Synonyms: Benign Giant Cell Synovioma, Benign Synovioma, Localized Nodular Synovitis)
Localized Tenosynovial Giant Cell Tumor of the Tendon Sheath (Giant Cell Tumor of Tendon Sheath or Fibroxanthoma of Tendon Sheath)
Malignant Tumors of the Joint
Primary Sarcomas of Joints
Conventional Chondrosarcoma
Synovial Sarcoma
Secondary Malignant Tumors of the Joint
Sarcomas
Metastatic Carcinoma and Melanoma
Malignant Lymphoproliferative Disease
Selected References
References
Chapter 132: Autoimmune Complications of Immune Checkpoint Inhibitors for Cancer
Introduction
Immune Checkpoint Inhibitor Mechanism of Action
Other Types of Cancer Immunotherapy
Immune Checkpoint Inhibitors and Their Uses in Oncology
Immune-Related Adverse Events (irAEs)
Clinical Spectrum of Immune-Related Adverse Events
Potential Mechanisms Underlying Immune-Related Adverse Events
The Relationship Between Immune-Related Adverse Events and Tumor Response
Rheumatologic Immune-Related Adverse Events
Epidemiology
Inflammatory Arthritis
Polymyalgia Rheumatica/Giant Cell Arteritis
Sicca Syndrome
Myositis
Other Vasculitis
Scleroderma
Sarcoidosis-like Disease
Others
Treatment of Rheumatologic Immune-Related Adverse Events
General Treatment Principles
Inflammatory Arthritis Treatment
Specific Treatments in Other Syndromes
Concerns With Immunosuppression
Multidisciplinary Care
Pre-existing Autoimmune Disease and Immune Checkpoint Inhibitor Use
Concurrent Immunosuppression
References
Chapter Acknowledgments