Rheumatology, 2-Volume Set

Cover
Rheumatology
Copyright
Dedication
Contributors
Preface​
Acknowledgments​
Contents
Volume I
01
1 The synovium
Definitions
Embryology
Structure
Cell Types Found in the Synovium as Revealed by Single-Cell Analysis
Intimal Cells
Synovial Macrophages
Synovial Fibroblasts and the Stroma
Intimal Matrix
Vascular Network
Cell Origins and Recruitment
Function
Maintenance of the Tissue Surface
Lubrication
Chondrocyte Health and Nutrition
Synovium as a Target for Immune-Mediated Disease
Summary
Acknowledgment
References
02
2
The articular cartilage
Overall Tissue Organization
Aggrecan
Collagen Fibrillar Networks
Fibers With Collagen Type II as the Main Constituent
Collagen type XI
Collagen type IX
Molecules Regulating Collagen Fiber Assembly
Cartilage oligomeric matrix protein
Decorin
Fibromodulin and lumican
Other leucine-rich repeat proteins
Heparin and heparan sulfate proteoglycans
Fibers and Networks With Collagen Type VI as the Main Constituent
Collagen type VI
Biglycan and decorin
Matrilins
A module cross-linking to other matrix constituents
Molecules Interacting at the Cell Surface and Modulating Chondrocyte Behavior
Integrin-Binding Proteins
Chondroadherin
Fibronectin
Discoidin Domain 2–Containing Receptor
Hyaluronan
Ligands for Heparin Sulfate/Syndecans
Other Molecular Functions
Binding and Sequestering Growth Factors in the Extracellular Matrix
Transforming growth factor-β
Fibroblast growth factor
Other Molecules in the Extracellular Matrix
Matrix Protein Fragments as Indicators of Disease
Repair and Regeneration of Cartilage
Replacing Cartilage
Microfracture
Implanted Cell-Based Therapies
Autologous Chondrocyte Implantation
Stem/Progenitor Cells of Other Tissues
Progenitor Cells of Articular Cartilage
Tissue-Engineered Cartilage
Acknowledgment
References
03
3
Bone structure and function
Introduction
Organization of Bone
Macroscopic (Organ) Level
Microscopic (Tissue) Level
Composition of Bone
Proteoglycans
Osteocalcin
Osteopontin
Osteonectin
Alkaline Phosphatases and Ectonucleotide Pyrophosphatase and Phosphodiesterases
Thrombospondins 1 and 2
Proteins Involved in Mineralization
Fibroblast growth factor 23
PHEX
Dentin matrix protein-1
Matrix extracellular phosphoglycoprotein
Growth Factors
Insulin-like growth factors
Bone morphogenetic protein family
Fibroblast growth factors
Transforming growth factor-β
Platelet-derived growth factor and vascular endothelial growth factor
Bone Cells
Osteoclasts
Osteoclast morphology and function
Osteoclast formation and differentiation
Osteoclast apoptosis
Regulation of osteoclast generation and survival
Osteoblasts
Osteoblast function
Osteoblast formation and differentiation
Osteoblast apoptosis
Regulation of osteoblast generation and apoptosis
OSTEOCYTES
Osteocyte apoptosis: Consequences and regulation
Preservation of osteocyte viability by mechanical stimuli
Osteocyte apoptosis and aging
Hormonal regulation of osteocyte life span
Regulation of bone formation by osteocytes: Sclerostin
Osteocytes as mediators of the anabolic actions of canonical Wnt signaling in bone
Regulation of bone resorption by osteocytes: RANKL and osteoprotegerin
Osteocytes and the bone-remodeling compartment
Growth, Modeling, Remodeling, and Repair
Growth
Modeling
Remodeling
Repair
References
04
4 Tendons and ligaments
Introduction
Classification of Disease Affecting Tendons and Ligaments
Etiology of Tendinopathy, Enthesopathy, and Desmopathy
Pathophysiology of Tendon and Ligaments
Inflammation Activation Pathways Show Plasticity in Tendon Disease
Fibroblast Activation in Tendon Disease
Diseased Tendons Show Dysregulated Resolution Responses
Pain and Neuropeptides
Extracellular Matrix Turnover in Health and Disease
Treatment of Tendon and Ligament Pathology
Medical Treatments
Surgical Treatments
Recent Evidence from Randomized Controlled Trials of Tendon Therapies
Conclusions
References
05
5
Biomechanics of peripheral joints and spine
Introduction
Biomechanics of Whole Joints and Spine
Whole-Joint Movement
Mechanical Function of the Spine
Spinal Movements
Statics and Dynamics
Example of static analysis
Limitations of static analysis
Joint Lubrication
Modes of lubrication
Lubrication in diarthrodial joints
Biomechanics of Tissues
Structural and Material Properties
Stress and Strain
Viscoelasticity
Forces Acting on the Spine
Muscle Forces
Intraabdominal Pressure
Diurnal Variation
Measurement of Spinal Loading in Vivo
Intervertebral Disk Mechanics
Resistance to Compression, Shear, Torsion, and Bending
Acknowledgment
References
06
6
Scientific basis of pain
Nociception and Pain
Types of Pain
The Peripheral Basis of Pain
Structure and Dual Function of Peripheral Nociceptors
Sensory Function of Nociceptors
Sensitization of Nociceptors (Peripheral Sensitization)
Molecular Mechanisms of Peripheral Stimulus Transduction and Peripheral Sensitization
Peripheral Mechanisms of Neuropathic Pain
The Central Basis of Pain
Nociceptive Spinal Cord Neurons
Generation of the Conscious Pain Response in the Thalamocortical System
Central Sensitization (Especially Spinal Sensitization)
Neuroplasticity at the Thalamocortical Level
Reduction of Endogenous Descending Pain Inhibition
Integrative View of Pain
Local Pathological Processes in the Tissue
Systemic/General Factors
Conclusions
References
07
7
Principles of innate immunity
Introduction
Sensing by Innate Immunity
Signaling Sensors
Toll-like receptors
Cytosolic signaling sensors
Internalizing Sensors
Lectin
Soluble Sensors
Complement system
Phylogenetic Comparison of the Recognition System
Critical Functions of Innate Immunity
Induction of Inflammation
Activation of Adaptive Immunity on Infection
Antiviral Responses
Molecular Mechanism of Sensor Signaling
Sensors and Diseases
Toll-Like Receptors and Autoimmunity
Type I Interferonopathies
Toll-Like Receptors and Metabolic Diseases
NOD-Like Receptors and Inflammation
Conclusion
Acknowledgments
References
08
8 Principles of adaptive immunity
Introduction
The Adaptive Immune System
Clonal Selection and Expansion of Lymphocytes
Antigen Receptors of Lymphocytes
Generation of Diversity of Antigen Receptors
B Cells and Humoral Immunity
Development of B Cells
B-Cell Activation and Functions
T Cells and Cell-Mediated Immunity
Recognition of Antigens by T Cells
Processing of Antigens for Presentation to T Cells
T-Cell Development
T-Cell Activation
T-Cell Function
Immunologic Tolerance and Autoimmunity
Conclusion
References
09
9
Signal transduction in immune cells
Introduction
Membrane-Permeable Ligands That Bind Intracellular Receptors
Steroid Hormone Receptors With Ligand-Binding, Dna-Binding, and Transactivation Domains
Receptors With Intrinsic Enzymatic Activity
Receptors That Associate With Enzymes
Type I/II Cytokine Receptors
Antigen Receptors and FC Receptors: The Multichain Immune Recognition Receptor Family
Tumor Necrosis Factor Receptor Superfamily
Innate Recognition of Pathogens
G Protein–Coupled Receptors
Summary
References
10
10
Cytokines
Introduction
Interleukin-1 Receptor Family
Ligand and Receptor Structure
Family Members and their Action
Interleukin-1α and interleukin-1β
Negative regulation of interleukin-1α and interleukin-1β
Interleukin-18
Interleukin-33
Interleukin-36 members and interleukin-36 receptor antagonist
Interleukin-37 and interleukin-38
Signal Transduction
Tumor Necrosis Factor Receptor Superfamily
Ligand and Receptor Structure
Tumor Necrosis Factor–Family Receptor Signaling
Tumor Necrosis Factor Receptor Family Members and their Actions
Type I and II Cytokine Receptors: Hematopoietin and Interferon Receptors
Cytokines that use Glycoprotein 130: Interleukin-6 as a Prototype
Cytokine Receptors Using the β Chain: Interleukin-3, Interleukin-5, and Granulocyte-Macrophage Colony-Stimulating Factor
Cytokine Receptors Using the γ Chain: Interleukin-2, Interleukin-4, Interleukin-7, Interleukin-9, Interleukin-15, and Inter ...
Homodimeric Receptors
Heterodimeric Cytokines
Interferons
Interleukin-10 Family
Signaling by Type I/II Cytokine Receptors
Interleukin-17 Receptors
Transforming Growth Factor-β Receptor Family Cytokines
Signaling
Receptor Tyrosine Kinases
Other Cytokines
Chemokines
Ligand and receptor organization
Family Members and their Actions
Chemokines and immune cell development
Chemokines in lymphoid organs
Sphingosine 1 phosphate
Chemokines in inflammation and HIV infection
Signaling
References
11
11
Inflammation and its chemical mediators
Introduction
The Cells of Inflammation
Endothelial Cell Activation and Leukocyte Adhesion
Granulocytes
Neutrophils
Neutrophil extracellular traps
Eosinophils and basophils
Mast cells
Macrophages
Inflammasomes
Platelets
Regulation and Modulation of Inflammatory Cells
Metabolic Regulation of Inflammation
Trained Immunity, or Innate Immune Memory
Inflammatory Mediators
The Complement System
Lipid Mediators of Inflammation
Arachidonic acid derivatives
Cyclooxygenase products
Lipoxygenase products
Platelet-activating factor
Vasoactive amines
Histamine
Serotonin
Reactive oxygen species and nitric oxide
Reactive oxygen species
Nitric oxide
The Nervous System in Inflammation
Autonomic Influence on Inflammation
The parasympathetic nervous system: a largely antiinflammatory pathway
The sympathetic nervous system
Neuroendocrine mechanisms
Neuropeptides
Substance P
Calcitonin gene-related protein
Neuropeptide Y
Vasoactive intestinal peptide
The Resolution of Inflammation
Elimination Of The Inciting Stimulus And Proinflammatory Signals
Removal of Inflammatory Cells
Lipoxins, Resolvins, and Other Antiinflammatory Mediators
Immune Activity After Resolution of Inflammation
The Aging Inflammatory System: Immunosenescence and Inflammaging
Acknowledgments
References
12
12
The complement system
Classical Pathway
Mannose-Binding Lectin Pathway
Alternative Pathway
Anaphylatoxins
Regulation of the Complement System
Complement in Disease
Complement in Autoimmunity
Complement in Inflammatory Diseases
Strategies for Therapeutically Targeting Complement
Conclusions
References
13
13
Osteoimmunology
Introduction
Current Concepts in Osteoimmunology
Osteoclasts as Triggers of Arthritic Bone Erosions
Molecular and Cellular Mechanisms of Inflammatory Bone Erosion
Intraarticular and Systemic Bone Loss in Rheumatic Disease
Osteoimmunologic Aspects of Bone Formation in Rheumatic Disease
Bone Marrow as a Niche for B-Cell Differentiation and Autoantibody Formation
Conclusion
References
14
14
Joint tissue destruction and proteolysis
Introduction
Proteolytic Pathways of Connective Tissue Breakdown
Extracellular Proteolysis
Matrix Metalloproteinases
MMP regulation—from transcription to inhibition
Regulation of MMP transcription
Epigenetic regulation
Regulation by activation
Regulation by inhibition
Endocytic regulation
Regulation of MMPs and Their Inhibitors by the ECM
Other Proteinases Involved in Pathological Joint Destruction
ADAM and ADAMTS proteinase families
Serine Proteinases
Intracellular Pathways
Osteoclastic Bone Resorption
Model Systems of Joint Destruction
Proteinase Deficiency in Murine Models of Arthritis
Therapeutic Inhibition of Proteinases
Repair of Connective Tissue Matrix
Acknowledgments
References
15
15
Principles of tissue engineering and cell- and gene-based therapy
Introduction
Tissue Engineering
Autologous Chondrocyte Implantation
Mesenchymal Stem Cells
Intraarticular Injection of Mesenchymal Stem Cells
Cell Concentrates
Bone marrow aspirate concentrate
Stromal vascular fraction
Matrix-Guided Application of Mesenchymal Stem Cells
Synthetic scaffolds
Natural scaffolds
Fabrication methods
Trophic and Immunosuppressive Effects of Mesenchymal Stem Cells
Gene Transfer Strategies
Rheumatoid Arthritis
Osteoarthritis
References
16
16 Big Data analysis
What Is Big Data?
Sources of Big Data in Rheumatology
Clinical Data
Challenges and Considerations in the Analysis of Big Clinical and Health Data
Traditional analytical approaches to Big Data
Machine learning approaches to Big Data
Supervised machine learning
Unsupervised machine learning
“Garbage in, garbage out”
Data heterogeneity and integration
Biological Data
Challenges of generation and storage of big biological data
Application and the Future of Big Data
Ethics
References
17
17
Principles and techniques in molecular biology
Introduction
The Human Genome Sequence and Biomedical Research
Basic Manipulation of DNA: Cloning Vectors and Cutting and Pasting DNA Using Enzymes
Polymerase Chain Reaction
DNA Sequencing
Gene Transcription
Gene Expression Profiling
DNA Chip Microarrays
Massively Parallel Sequencing of RNA
Single Cell RNA Sequencing
Regulation of Gene Expression and Protein–DNA Interactions
Analysis of Gene Function
Genetic Manipulation of Mice
Transgenic Mice
Knockout Mice
Mice with cre/lox-Directed Targeted Disruption
CRISPR-Cas9 and Genome Editing
Analysis of Proteins
Proteomics
Molecular Biology: The New Pathology for Practicing Rheumatologists?
References
18
18
Proteomics
Proteomics—A Powerful New Tool for Personalized Medicine
How Does a Mass Spectrometer Work?
Main Proteomics Technologies
Expression Proteomics
Interaction Proteomics
Thermal Shift Proteomics
Post-translational Modification Proteomics
Yeast Two-Hybrid Assay
Mammalian-Membrane Two-Hybrid Assay
How Can Proteomics Help Rheumatology?
Nucleic Acid Programmable Protein Arrays
Recent Advances in Data Acquisition of Mass Spectra
Outlook
References
19
19
Metabolomics
We Are What We Eat: Metabolism Has Driven Our Development
Metabolism Underpins Musculoskeletal Function
Inflammation Perturbs Metabolism
Metabolism and Immune Inflammation
Metabolism in Rheumatology
Metabolomics
Acquiring Metabolomics Data
Making Sense of the Data
Applications of Metabolomics in Rheumatology
Osteoarthritis
Rheumatoid Arthritis
Metabolomics and Other Rheumatic Diseases
Systemic Metabolic Effects
Responses to Therapy
Conclusions
References
20
20
Epigenetics
What Is Epigenetics?
Transcriptional Control Through Epigenetic Mechanisms
Molecular Epigenetics—The Basic Mechanisms
Histone Modifications
Histone acetylation
Histone methylation and citrullination
Histone SUMOylation
DNA Modifications
Epigenetics in Disease
The Origin of Epigenetic Alterations
Rheumatic Diseases and Epigenetic Changes
Systemic lupus erythematosus
Rheumatoid arthritis
Other rheumatic diseases
References
21
21
Precision medicine and pharmacogenomics in rheumatology
Pharmacogenomics
Experimental Approaches and Considerations Regarding Study Design and Data Interpretation
Synthetic Disease-Modifying Antirheumatic Drugs
Methotrexate
Azathioprine
Sulfasalazine
Biologic Disease-Modifying Antirheumatic Drugs
Conclusion
Acknowledgments
References
22
22
The microbiome in rheumatic diseases
Introduction
The Microbiome
Mucosal Barriers and Host-Immune Interactions
Physiologic intestinal inflammation and homeostasis in health
Dysbiosis as a trigger for autoimmunity
Research Methods for Study of the Human Microbiome
The Microbiome in Animal Models of Inflammatory Arthritis
The Microbiome in Human Inflammatory Arthritis
Spondyloarthritis
Inflammatory bowel disease–related arthropathy
Psoriatic arthritis and psoriasis
Rheumatoid Arthritis
The intestinal microbiome in rheumatoid arthritis
The oral microbiome in rheumatoid arthritis
The Microbiome in Systemic Lupus Erythematosus
Pharmacomicrobiomics
Manipulating the Microbiome to Modulate Autoimmune Disease
Conclusion
References
23
23
Principles of epidemiology
Introduction
What Is Epidemiology?
What Can Epidemiologic Methods Accomplish?
What Will Be Covered in This Chapter?
How to Study and Define Populations
Defining the Pieces of an Epidemiologic Study
Defining Exposure
Defining Outcome
Descriptive Epidemiology
Analytic Epidemiology
Traditional Study Designs
Other Study Designs
Measures
Some Notes About Measures and Modeling
Types of Bias
Confounding
Selection Bias
Immortal Time
Misclassification
Generalizability
Summary
References
24
24
Principles of clinical outcome assessment
Introduction
Purpose of Measuring a Clinical Outcome
Sensibility
Validity
Reliability
Responsiveness
Quality assessment of methods in studies of measurement properties and its statistics
Variations in outcome measurement
Interpretability
Examples of Clinical Outcome Assessement
Global assessments
Multidimensional Health Status Instruments
Assessment of Adverse Reactions
Measurement in Clinical Trials
References
25
25
Principles of health economics
Introduction
Concepts of Health Economic Analysis
Types of Costs
Perspectives
Types of Economic Analyses
Cost analysis
Cost–benefit analysis
Cost-effectiveness analysis
Cost–utility analysis
Quality of Life
Time Horizon and Discounting
Reference Case
Health Technology Assessment
Decision Analysis Modeling
Cost-Effectiveness Thresholds
Budgets
Economic Applications in Rheumatic Diseases
Rheumatoid Arthritis
Multiple Technology Analysis
Biosimilar Drugs
Resource Impact
Recommendation
Conclusion
References
26
26
Principles of genetic epidemiology
Introduction
Complex Rheumatic Diseases
Rationale for Investigating the Genetic Basis of Rheumatic Diseases
Approaches for Identifying Disease Genes
Association Studies
Selection of cases and control participants
Power and effect sizes
Selection of genetic markers
Analysis and interpretation of results
Successful Examples of Candidate Association Studies
Protein Tyrosine Phosphatase N22
Whole-Genome Association Studies of Rheumatologic Conditions
New Horizons
References
27
27
Interpreting the medical literature for the rheumatologist
Introduction
Levels of Evidence
Randomized Controlled Trials or Observational Studies?
Critical Appraisal I: Issues Pertaining to Randomized Controlled Trials
Internal Validity and External Validity
Efficacy vs Effectiveness
Superiority Trials and Noninferiority Trials
Statistical Power
Intention-to-Treat Analysis
Subgroup Analyses
Critical Appraisal II: Issues Pertaining to Observational Studies
Types of Cohorts
Healthy cohorts
Clinical cohorts
Use of registries
Selection Bias
Left-censorship bias
Right-censorship bias
Confounding by indication
Critical Appraisal III: Issues Pertaining to Randomized Controlled Trials and Observational Studies
Generalizability
Missing Data
Data Interpretation
The Statistical Test
Conflict of interests
Conclusion
References
28
28
Ethics in clinical trials
Introduction
“Ethical Guardrails” in Clinical Research
Key Principles for Ethical Clinical Trials
Selected Challenges in Clinical Trial Ethics
Conclusion
Acknowledgment
References
29
29
History and physical examination
Introduction
Screening Assessment
Screening History
Screening Examination
Assessing a Musculoskeletal Problem
Aims and Key Principles
The Consultation to Assess a Musculoskeletal Problem: Key Components
History
What are the symptoms?
Pain
What are the site and distribution of the pain?
What are its characteristics?
What precipitates, worsens, or improves the pain?
Stiffness
Swelling and deformity
Weakness and instability
Loss of movement or function
Fatigue and malaise
Anxiety and depression
What are the mode of onset, pattern, and chronology of the various symptoms?
Associated symptoms, preceding factors, red flags, and other clues
Previous health interventions and symptom response
What is its impact?
Social history and occupation
General examination
Regional examination of the musculoskeletal system
Posture
Gait
Identifying and characterizing any abnormalities
Inflammation
Damage
Deformity
Biomechanical abnormalities
What other features are of diagnostic importance?
Examination
Method of examination
Look
Attitude and spontaneous movement
Swelling and deformities
Skin
Wasting
Feel
Warmth
Tenderness
Swelling
Move
Stress
Documentation
Joint problems
Regional pain problems
Generalized pain problems
Neck or back problems
Muscle problems
Bone disorders
Systemic problems with musculoskeletal symptoms
Communicating the findings
Interpretation
References
30
30
Laboratory tests in rheumatic disorders
Introduction
Laboratory Tests in Rheumatic Diseases
Blood Cell Counts
White blood cells
Platelets
Red blood cells
Biochemical Testing
Liver Function Tests
Alkaline Phosphatase
Kidney Function Tests and Urinalysis
Uric acid
Calcium and vitamin D
Acute-phase reactants
Serologic Testing
Autoantibodies
Rheumatoid factor
Antibodies to citrullinated protein and peptide antigens
Antinuclear antibodies
Anti-double-stranded DNA antibodies
Anti-Sm and anti-U1 ribonucleoprotein antibodies
Anti-Ro (SS-A) and anti-La (SS-B) antibodies
Anticentromere and anti-Scl-70 antibodies
Autoantibodies in idiopathic inflammatory myopathies
Antiphospholipid antibodies
Antineutrophil cytoplasmic antibodies
Complement
Conclusion
References
31
31
Aspiration and injection of joints and periarticular tissue and intralesional therapy
Indications for Aspirating or Injecting Musculoskeletal Tissues
Aspiration of Fluid or Diagnostic or Therapeutic Purposes
Key Practice Issues
Procedure
External landmark-guided aspiration
Ultrasound-guided aspiration and injection
Aftercare
Contraindications
Corticosteroid Injections
Complications of corticosteroid injections23
Other Therapeutic Injections
Viscosupplementation
Synoviorthesis
Other Injections
Wrist and Hand
Finger and Metacarpophalangeal Joints
First Carpometacarpal Joint
Wrist (Radiocarpal and Midcarpal Joints, Distal Radioulnar Joint)
Trigger Finger and Trigger Thumb
Digital Flexor Tenosynovitis
Carpal Tunnel Syndrome57
De Quervain Tenosynovitis59
Wrist Extensor Tenosynovitis
Ganglia
Elbow Region
Elbow (Joint)
Olecranon Bursa
Lateral Epicondylar Syndrome, or Tennis Elbow, and Medial Epicondylar Syndrome, or Golfer’s Elbow61,62
Shoulder Region
Shoulder (Glenohumeral Joint)
Acromioclavicular Joint
Subacromial Bursa
Rotator Cuff Calcific Tendinopathy
Long Head of The Biceps Brachii Tendon
HIP Region
HIP joint66
Iliopsoas Bursa
Trochanteric Syndrome
Knee Region
Knee (Joint)
Baker Cyst
Medial Knee Pain and Pes Anserinus Syndrome
Ankle and Foot
Ankle (Joint)
Subtalar Joint
Metatarsophalangeal Joints
Retrocalcaneal Bursa
Posterior Tibialis Tendon (Ptt), Peroneal Tendon, Extensor and Flexor Tendon Sheath
Plantar Fascia Calcaneal Enthesis73,74
Intermetatarsal Bursae
Morton Neuroma76
Intralesional Corticosteroid Treatment
Acknowledgments
References
32
32
Synovial fluid analysis
Macroscopic Characterization
Microscopic Analysis
Wet-Preparation Microscopy
Cell Counts
Crystal Detection
MSU Crystals
CPP Crystals
BCP Crystals
Lipids
Glucocorticoid Crystals
Other Crystalline Contents Of Sf
Noncrystalline Particulate Matter
Ragocytes
Cytocentrifuge Preparation
Bacterial and Septic Arthritis
Nonbacterial Infections
Synovial Fluid Cytology
Summary
References
33
33
Minimally invasive procedures
Introduction
Arthrocentesis
Biopsies
Skin and Subcutaneous Tissue
Abdominal Fat Pad Fine-Needle Aspiration
Temporal Artery
Muscle and Fascia
Salivary Glands
Synovium
Blind (or closed) needle biopsy
Arthroscopic biopsy and joint lavage
Ultrasound-guided synovial biopsy
Acknowledgment
References
34
34
The skin in rheumatic disease
Introduction
Approach to the Patient
Major Systemic Connective Tissue Disorders
Systemic Lupus Erythematosus
Dermatomyositis
Systemic Sclerosis
Sjögren Syndrome (Sicca Syndrome)
Other Systemic Rheumatic Diseases
Rheumatoid Arthritis
Juvenile Idiopathic Arthritis
Relapsing Polychondritis (Atrophic Polychondritis, Systemic Chondromalacia, Polychondropathia)
Psoriatic Arthritis
References
35
35
Ocular manifestations of rheumatic diseases
Introduction
UVEITIS
Management
Scleral Disease
Management
Retinal Vascular Disease
Optic Nerve Disease
Orbital Disease
Corneal Disease
Keratoconjunctivitis Sicca
References
36
36
The cardiovascular system in rheumatic disease
Introduction and Overview
Coronary Artery Disease
Prevention of Coronary Events in Rheumatologic Conditions
Atypical Coronary Disease in SARDs
Coronary Arteritis
Functional Coronary Artery Disorders
Hypertension
Heart Failure and Direct Myocardial Involvement
Valvular Heart Disease
Pericarditis
Arrhythmias
Pulmonary Hypertension
Medication and the Heart
Conclusion
References
37
37
The lungs in rheumatic disease
Introduction
Interstitial Lung Disease
Pathologic and Radiologic Features in Interstitial Lung Disease
Evaluation of Patients With Interstitial Lung Disease in the Rheumatic Diseases
Radiographic Studies
Pulmonary Function Testing
Bronchoscopy
Surgical Lung Biopsy
Ancillary Studies
Lung Involvement in Rheumatic Diseases
Systemic Sclerosis
Rheumatoid Arthritis
Dermatomyositis and Polymyositis
Systemic Lupus Erythematosus
Sjögren Syndrome
Interstitial Pneumonia With Autoimmune Features
Drug-Induced Lung Injury
Lung and Vasculitic Syndromes
Treatment of Interstitial Lung Disease Associated With the Rheumatic Diseases
Conclusion
References
38
38
The gastrointestinal tract in rheumatic disease
Introduction
Inflammatory Bowel Disease: Crohn’s Disease and Ulcerative Colitis
Extraintestinal Manifestations of Inflammatory Bowel Disease
Peripheral Arthritis and Arthralgia Associated With Inflammatory Bowel Disease
Axial Arthritis Associated With Inflammatory Bowel Disease
Bacterial Enteritis
Celiac Disease
Whipple’s Disease
Polyarteritis Nodosa
Henoch-Schönlein Purpura
Behçet Disease
Microscopic Colitis
Conclusion
Acknowledgments
References
39
39
The kidneys in rheumatic diseases
Introduction
Approach to the Patient with Rheumatologic Disease and Suspected Kidney Disease
Acute Versus Chronic Kidney Disease
Glomerular Disease: Nephrotic Versus Nephritic
Diagnostic Tools for Identification of Kidney Disease
Glomerular Filtration Rate
Serum Creatinine
Proteinuria: Urinary Albumin or Protein Excretion Rate
Hematuria
Leukocyturia, Eosinophiluria, and Urinary Casts
Electrolytes and Acid–Base Status
Plasma Complement Levels
Imaging Studies
Kidney Biopsy
Kidney Involvement In Rheumatologic Diseases (Table 39.3)
Rheumatoid Arthritis
Infection-Related Rheumatic Diseases
Infectious arthritis (bacterial, viral, mycobacterial, fungal, parasitic, tickborne)
Acute rheumatic fever
Reactive arthritis
Spondyloarthritis and Psoriatic Arthritis
Axial spondyloarthritis/ankylosing spondylitis
Psoriatic arthritis
Systemic Lupus Erythematosus and Related Diseases
Systemic lupus erythematosus
Sjögren syndrome
Mixed connective tissue disease
Antiphospholipid syndrome
Thrombotic microangiopathy
Systemic Sclerosis/Scleroderma
Systemic sclerosis/scleroderma
Inflammatory Muscle Disease
Polymyositis and dermatomyositis
Vasculitides
Polyarteritis nodosa
Antineutrophil cytoplasmic autoantibody-associated vasculitis
Takayasu arteritis
Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA)
Behçet disease
Kawasaki disease
Immunoglobulin A vasculitis and Henoch-Schönlein purpura
Cryoglobulinemia
Other Systemic Illnesses
Adult-onset Still’s disease
Sarcoidosis
Relapsing polychondritis
Amyloidosis
Immunoglobulin G4-related disease
Nephrogenic systemic fibrosis
Osteoarthritis
Crystal-Related Arthropathies
Gout
Pseudogout
Nephrotoxicity of Antirheumatologic Pharmacologic Therapy
Nonsteroidal Antiinflammatory Drugs
Functional effects
Interstitial nephritis and nephrotic syndrome
Analgesic nephropathy and papillary necrosis
Calcineurin Inhibitors: Cyclosporine and Tacrolimus
Acute kidney injury
Systemic arterial hypertension
Chronic kidney disease
Hemolytic-uremic syndrome
Disease-Modifying Antirheumatic Drugs and Biologic Agents
Rheumatologic Complications of Kidney Disease
Etiologic Factors Specific to Kidney Failure and Their Associated Rheumatic Syndromes
β2-microglobulin amyloidosis
CKD-mineral and bone disorder (CKD-MBD): calcium, phosphorus, vitamin D, fibroblast growth factor 23 (FGF23), and parathyro ...
Oxalate deposition
Hydroxyapatite arthropathy
Clinical Features of CKD-MBD: Bone Disorder and Turnover
Renal osteodystrophy
Other arthropathies in dialysis patients
Rheumatologic-Associated Issues Postkidney Transplantation
Metabolic bone disease
Calcineurin-induced pain syndrome
Renal replacement therapy with transplantation
Acknowledgment
References
40
40
The nervous system in rheumatic disease
Introduction
Peripheral Nervous System
Distal Neuropathy
Cranial Neuropathy
Optic Neuropathy
Trigeminal Neuropathy
Facial Palsy
Multiple Mononeuropathies
Non-Length-Dependent Neuropathy
Central Nervous System
Meningitis
Encephalitis
Myelitis
Conclusion
References
41
41
The muscles in rheumatic disease
Introduction
Skeletal Muscle Anatomy and Architecture
Normal Muscle Contractile Function
Muscle Involvement in Rheumatologic Conditions
Idiopathic Inflammatory Myopathies
Metabolic Myopathies
Cachexia Associated With Rheumatological Diseases
Drug-Induced Myopathy
Generalized Myalgia
Clinical Assessment of Skeletal Muscle
Neurophysiology
Muscle Biopsy
Magnetic Resonance Imaging
Manual Muscle Testing
Acknowledgment
References
42
42
Multimorbidity
Introducing The Concept of Multimorbidity
Assessment and Screening of Multimorbidity
Impact of Multimorbidity
Health Economic Implications
Mortality
Disease-Related Outcomes
Prevalence of Multimorbidity
Impact of Distinct Morbid Conditions
Cardiovascular Disease
Cancer
Depression
Respiratory Diseases
Venous Thromboembolic Disease
Other Important Morbid Conditions
Conclusion
References
43
43
Conventional radiography and computed tomography
Conventional Radiography
Uses
Projection views
Hand and wrist
Sacroiliac joints
Knees
Choice of Joints
Techniques and Physics
Magnification radiography
Digital radiography
Computerized x-ray image analysis methods—Computer-aided detection
Interventional techniques
Computed Tomography
Multidetector Computed Tomography
Applications in Rheumatology
Bone
Peripheral and axial joints
Soft tissues and vessels
Dual-Energy Computed Tomography
References
44
44
Magnetic resonance imaging
Introduction
Basic Principles
T2 Relaxation
T1 Relaxation
Magnetic Resonance Imaging Contrast
Image Quality
Conventional Magnetic Resonance Imaging Methods
Two-Dimensional Fast Spin-Echo Imaging
Three-Dimensional Gradient-Echo Techniques
Advanced Magnetic Resonance Imaging Techniques
Double-Echo Steady-State Imaging
Parallel Imaging
Balanced Steady-State Free Precession Imaging
Three-Dimensional Fast Spin-Echo Imaging
High-Field Magnetic Resonance Imaging
Cartilage Thickness and Volume Mapping
Magnetic Resonance Imaging to Demonstrate Physiologic Activity
Contrast-enhanced imaging
T2 relaxation time mapping
T1rho mapping
Delayed contrast-enhanced imaging
Sodium magnetic resonance imaging
Positron Emission tomography and Magnetic Resonance Imaging
Artificial Intelligence, Machine Learning, and Super-Resolution
Conclusion
Acknowledgments
References
45
45
Functional magnetic resonance imaging
fMRI in Understanding the Mechanism of Pain
fMRI in evaluation of experimental or acute pain
Sensory–discriminative aspect of pain
Affective and cognitive aspects of pain
fMRI in understanding chronic pain
Task-based fMRI
Resting-state fMRI
fMRI in Patient Evaluation and Pain Management
fMRI in therapeutic evaluation
prediction of response to treatment and placebo
Future of fMRI in Clinical Application
Summary
References
46
46
Musculoskeletal ultrasonography
Introduction
Musculoskeletal Ultrasound Imaging
Basic Principles of Ultrasonography
Ultrasound Equipment
Education and Training
Standard Views and Artifacts
Anisotropy
Refractile shadowing and edge artifact
Acoustic shadowing
Acoustic enhancement
Reverberation
Power Doppler scanning technique artifacts
Doppler imaging artifacts
Musculoskeletal Ultrasonography in Rheumatology
Synovial Tissue and the Synovial Joint
Tendon and Enthesis
Dactylitis
Muscle
Bone Erosion and Osteophyte
Cartilage
Soft Tissue Calcification and Crystal-Induced Arthritis
Noninflammatory Soft Tissue Disorders
Spine and Sacroiliac Joint
Intervention
Nonmusculoskeletal Tissue Ultrasonography in Rheumatology
Peripheral Nerves
Vasculitis
Parotid and Salivary Glands
Skin
Conclusion
References
47
47
Bone scintigraphy and positron emission tomography
Introduction
Bone Scintigraphy
Principles
Single-photon emission computed tomography
Uses
Positron Emission Tomography
Background
Uses
Positron Emission Tomography/Computed Tomography
Applications of 18F-Fluorodeoxyglucose Positron Emission Tomography in Inflammatory Diseases
Large-vessel vasculitis
Systemic lupus erythematosus
Sarcoidosis
Arthritis
Fever of unknown origin
IgG4-related disease
Practical Issues
References
48
48
Dual x-ray absorptiometry and measurement of bone
Introduction
Diagnosis of Osteoporosis
Skeletal Sites to Measure
Using Non-Dual X-ray Absorptiometry Technologies for Osteoporosis Diagnosis
Technical Aspects of DXa
Indications for Bone Mineral Density Testing
Vertebral Fracture Assessment
Fracture Risk Assessment
Bone Mineral Density
Clinical Risk Factors and Fracture Risk Assessment Tool (10-Year Fracture Risk Tool)
Bone Turnover Markers
Other Modalities for Fracture Risk Assessment
Quantitative ultrasonography
Quantitative computed tomography
Recent emerging technologies for fracture risk assessment
Monitoring of Therapy
Quantitative Computed Tomography and Peripheral Computed Tomography
Quantitative Ultrasonography
Biochemical Bone Turnover Markers
Bone Turnover Markers After Discontinuing Therapy
Evaluation of Cortical and Trabecular Bone
High-Resolution Peripheral Quantitative Computed Tomography
Finite Element Analysis
High-Resolution Magnetic Resonance Imaging
Bone Material Strength as Measured by Microindentation
Bone Biopsy
Conclusions
References
49
49
Use of imaging as an outcome measure in clinical trials
Introduction
General Aspects for Clinical Trials
Different Phases of Drug Development
Readers
Assessment of Reader Agreement
Grouping of Films—Read Sessions
Blinding Time Sequence
Presentation of Data
Statistical Handling of Missing Data
Statistical Analyses
Minimum Duration of Trial
Placebo Versus Active Comparator
Rheumatoid Arthritis
Conventional Radiography
Films of hands and feet
Scoring Methods
Sharp’s method
Genant’s modification of Sharp’s method
van der Heijde’s modification of Sharp’s method
Magnetic Resonance Imaging and Ultrasonography
Magnetic resonance imaging sum scores
Ultrasonography
HR-pQCT
Psoriatic Arthritis
Conventional Radiography
Typical lesions and site of lesions
Scoring Methods
Psoriatic arthritis scoring method based on the Sharp scoring method for rheumatoid arthritis
Sharp–van der Heijde modified scoring method for psoriatic arthritis
Magnetic Resonance Imaging and Ultrasonography
Axial Spondyloarthritis
Conventional Radiography
Scoring methods
Assessment of the spine
Modified Stoke Ankylosing Spondylitis Spine Score
Low-dose CT
Magnetic Resonance Imaging and Ultrasonography
Scoring methods
Sacroiliac joints
Spine
References
50
50
The patient perspective
Key Points
Introduction
Patients’ Perception of Remission and Flares
Patient-Centered Care
Holistic Approach
Patient-Reported Outcomes
Shared Decision Making
Self-Management
Multidisciplinary Team Care
Organization of Care
Patient Education
Conclusion
References
51
51
Treatment recommendations and “treat to target”
General Treatment Approaches to Rheumatic Diseases
Taking an Integrated Chronic Disease Management Approach (Icdm)
Definition of chronic disease management
Multidisciplinary team-based care
Treating the whole patient: assessing and addressing comorbidities
Incorporating Patient Preferences Through Shared Decision Making (SDM)
Treat-to-Target Concept
Treat-to-Target For Rheumatoid Arthritis
Imaging as the target in treat-to-target strategies
Adherence to treat-to-target strategies in rheumatoid arthritis
Treat-to-Target for Psoriatic Arthritis
Treat-to-Target for Axial Spondyloarthritis
Treat-to-Target for Systemic Lupus Erythematosus
Treat-to-Target for Osteoarthritis
Treat-to-Target for Gout
References
52
52
Arthritis patient education, self-management, and health promotion
Introduction
Patient Education During the Clinical Encounter
Factors Affecting Patient Adherence to Treatments
Designing Patient Education Self-Management Programs
Structure and Content of Arthritis Education and Self-Management Programs
Health Literacy and Cultural Considerations in Patient Education
Evidence for the Effectiveness of Self-Management Education Programs
Team Care, Team Roles, and Approaches to Management
Public Health Approaches to Patient Education In Arthritis
Technology and the Future of Arthritis Patient Education
References
53
53
Principles of rehabilitation: physical and occupational therapy
Rehabilitation and its Role in People with Disability Caused by Rheumatic Diseases
Rehabilitation Adopts A Biopsychosocial Approach To Patients And Their Needs
Patient-Centered Care is a Central Tenet of Rehabilitation
Education of Patients and Caregivers is Important to Facilitate Self-Management and Adherence to Treatment Recommendations
Adherence to an Individualized Structured Exercise Program is Fundamental to Self-Management
Patients Should be Encouraged and Supported to Maintain or Increase Their General Physical Activity Levels
Aids, Adaptive Devices, and Environmental Modifications Can Maximize Functional Independence
Joint Protection and Energy Conservation are Important to Minimize Symptoms
Occupational Rehabilitation is Important for Patients of Working Age
Regular Monitoring and Follow-Up are Important
References
54
54
Multidisciplinary approaches to managing chronic pain in arthritis
Introduction
Prevalence of Pain in Musculoskeletal and Rheumatologic Conditions
Measurement of Pain
Psychological Factors and Pain
Psychological Factors Associated with Outcome
Interventions
Physical Activity for the Relief and Self-Management of Pain
Lifestyle Management of Rheumatologic Pain
Joint Protection Programs
Arthritis Self-Management Programs
Splinting for the Painful Hand
Sleep
Activity Pacing
Relaxation
Work
Patient Education and E-Health
Novel Interventions for Pain Relief
Graded Motor Imagery (GMI) Programme
Visual Illusions
Conclusion
Acknowledgment
References
55
55
Placebo, nocebo, caring, and healing in rheumatology
Introduction
Definition
Biological Mechanisms
Conclusions
References
56
56
Complementary and alternative medicine
Overview
Who Seeks Complementary and Alternative Medicine and Why
Widely Used Complementary and Alternative Medicine Systems and Their Therapies
Traditional Chinese Medicine and Acupuncture
Philosophy and history
Treatment
Evidence
Herbal Medicine
Philosophy and history
Treatment
Evidence
Topical capsaicin
Curcumin
Ginger
Devil’s claw
Boswellia serrata
Nutraceuticals and Dietary Supplements
Glucosamine and chondroitin
S-adenosylmethionine
Avocado/soybean unsaponifiables
Omega-3 and omega-6 fatty acids
Homeopathy
Referral and Professional Practice
References
57
57
Outcomes and perioperative management of patients with inflammatory arthritis and systemic lupus erythematosus undergoi ...
Key Points
Introduction
Outcomes and Adverse Events
Rheumatoid Arthritis
Spondyloarthritis
SLE
Perioperative Management
Anesthesia in Patients With Rheumatic Disease
Perioperative Management of Comorbid Medical Conditions
Cardiovascular Disease
Venous Thromboembolism
Antiphospholipid Syndrome
Pulmonary Disease
Management of Antirheumatic Therapy
Chronic Glucocorticoid Therapy
Prevention of Postoperative Infection
Conclusion
References
58
58
Indications for and long-term complications of total hip and knee arthroplasty
Introduction
Indications
Osteoarthritis Is the Most Common Indication for TJA
Clinical Presentation
Contraindications for TJA
Age and TJA
BMI and TJA
Outcomes
Complications
Nonorthopedic Complications
Orthopedic Complications
Impact Of BMI On Complications
Impact of Age on Complications
Conclusion
References
59
59
Medication management during preconception, pregnancy, and lactation
Introduction
Pregnancy
Rheumatic Diseases And Pregnancy
Aspirin And Other Nonsteroidal Antiinflammatory Drugs
Glucocorticoids
Antimalarials
Sulfasalazine
Immunosuppressive Agents
Azathioprine
Cyclosporine
Mycophenolate Mofetil
Tacrolimus
Methotrexate
Leflunomide
Cyclophosphamide
Intravenous Immunoglobulin
Tumor Necrosis Factor-α Blockade And Inhibitors
Rituximab, Other Biologic Agents, And Small Molecules
Inadvertent Teratogenic Medication Exposure
Paternal Medications Pre- And Postconception
Conclusion
References
60
60
Principles of pharmacologic pain management
Introduction
Opioid Mechanisms
The Evidence
Patient Selection and Medication Management
Risk Assessment
Prescription Drug Monitoring Plans
Informed Consent
Dosing
Drug Monitoring
Adverse Drug Effects
Driving and Opioids
Older Adults and Chronically Ill Patients
Acute-on-Chronic Pain
Dual-Action Opioids
Alternative Medications for Chronic Musculoskeletal Pain
Tricyclic Antidepressants, Selective Serotonin Reuptake Inhibitors, and Calcium Channel Blockers (Gabapentinoids)
Topical Analgesics
Cannabinoids
References
61
61
Nonsteroidal antiinflammatory drugs
Introduction
Mechanism of Action
Cyclooxygenase Isozyme Selectivity
Pharmacokinetics and Drug Interactions
Clinical Efficacy
Adverse Effects
Gastrointestinal
Cardiovascular
Renal
Respiratory
Hepatic
Rational Selection of Nonsteroidal Antiinflammatory Drug Therapy
References
62
62
Systemic glucocorticoids in rheumatology
Nomenclature and Pharmacology
Preparations and Structure
Dosing
Bioequivalence and Bioavailability
Metabolism and Drug Interactions
Clearance and Dose Timing
Mechanisms of Glucocorticoid Action
Efficacy
Efficacy in Rheumatoid Arthritis
Efficacy in Systemic Connective Tissue Disorders and Vasculitis
Efficacy in Polymyalgia Rheumatica and Large-Vessel Vasculitis
Adverse Effects
Bone and Muscle
Cardiovascular
Dermatologic and Appearance
Gastrointestinal
Infectious Diseases
Metabolic and Endocrine
Neuropsychiatric
Ophthalmologic
Use in Pregnancy
Practical Recommendations
Evidence-Based Treatment Guidelines
Perioperative and Stress-Dose Considerations
Glucocorticoids in Children
Glucocorticoid Withdrawal Regimens and Alternate-Day Therapy
References
63
63
Methotrexate
Introduction
Pharmacology
Mechanism of Action
Efficacy in Rheumatoid Arthritis
Initial Use
Efficacy Compared With Other Disease-Modifying Antirheumatic Drugs
Efficacy in Combination With Other Disease-Modifying Antirheumatic Drugs
Effect of Methotrexate on Structural Damage
Long-Term Studies
Predictors of Response to Methotrexate
Effect on Mortality
Adverse Effects
Common Adverse Effects
Hepatic Toxicity
Pulmonary Toxicity
Vaccination
Other Adverse Effects
Teratogenicity
Folic Acid Supplementation
Methotrexate Use in Rheumatoid Arthritis: Recommendations
Methotrexate in Other Rheumatic Diseases (Table 63.3)
Psoriatic Arthritis
Juvenile Idiopathic Arthritis
Other Rheumatic Diseases
Conclusions
Acknowledgment
References
64
64
Synthetic disease-modifying antirheumatic drugs and leflunomide
Introduction
Parenteral Gold
Introduction
Pharmacology
Mode of Action
Efficacy
Toxicity
Dosage and Monitoring
Bucillamine
Introduction
Pharmacology
Mode of Action
Efficacy
Adverse Effects
Dosage and Monitoring
Sulfasalazine
Introduction
Pharmacology
Mode of Action
Efficacy
Toxicity
Dosage and Monitoring
Hydroxychloroquine
Introduction
Pharmacology
Mode of Action
Efficacy
Rheumatoid arthritis
Systemic lupus erythematosus
Metabolic effects
Toxicity
Dosing of hydroxychloroquine
Leflunomide
Introduction
Pharmacology
Mode of Action
Efficacy in Rheumatoid Arthritis
Monotherapy
Combination therapy
Combination therapy with biologic agents
Efficacy in Other Rheumatologic Conditions
Safety and Tolerability
Tetracycline Derivatives: Minocycline and Doxycycline
Introduction
Randomized controlled trials of minocycline
Randomized controlled trials (RCTs) of doxycycline in RA and OA
Metaanalysis of minocycline and doxycycline for rheumatoid arthritis
Doxycycline for the Treatment of Osteoarthritis
References
65
65
Immunosuppressive agents: cyclosporine, cyclophosphamide, azathioprine, mycophenolate mofetil, and tacrolimus
Introduction
Mechanisms of Action
Azathioprine
Cyclophosphamide
Cyclosporine
Mycophenolate Mofetil
Tacrolimus
Pharmacokinetics
Azathioprine
Cyclophosphamide
Cyclosporine
Mycophenolate Mofetil
Tacrolimus
Efficacy, Toxicity, and Therapeutic Use
Azathioprine
Efficacy
Toxicity
Therapeutic use
Cyclophosphamide
Efficacy
Toxicity
Therapeutic use
Cyclosporine
Efficacy
Toxicity
Therapeutic use
Mycophenolate Mofetil
Efficacy
Toxicity
Therapeutic use
Tacrolimus
Efficacy
Toxicity
Therapeutic use
Acknowledgment
References
66
66
Kinase inhibitors and other synthetic agents
Introduction
Tyrosine Kinases
Tyrosine Kinase Inhibitors
JAK Inhibitors for Rheumatoid Arthritis
Tofacitinib
Baricitinib
Safety and tolerability of the approved JAK inhibitors
Position of JAK inhibitors in the treatment of RA
JAK Inhibitors for Other Rheumatological Indications
Psoriatic arthritis
Systemic lupus erythematosus and other connective tissue diseases
Other JAK inhibitors
Other Kinase Inhibitors
References
67
67
Overview of biologic agents
Introduction
Antibodies and the Humoral Immune Response
Antibody Structure
Structural Characterization of Approved Antibody Therapeutics
Mechanisms of Action
Placental Transfer of Biological Drugs
Immunogenicity
Specific MoA of Biological Drugs: Relating Structure to Function
Targeting Cytokines: TNF-α as an Example
Cell Depletion: B Cells as an Example
Targeting Cell–Cell Interactions
Future Directions
Alternative Structures
Using Multiple Antibodies and Bispecific Molecules
References
68
68
Interleukin-1 inhibitors
Interleukin-1 Family
Ligands and Receptors
Interleukin-1 Plays a Critical Role in Inflammation
Regulation of Interleukin-1β Maturation by the Inflammasome
Therapeutic Inhibitors of Interleukin-1 in Rheumatic Diseases
Rheumatoid Arthritis
Recombinant interleukin-1 receptor antagonist (anakinra, Kineret)
Soluble interleukin-1 receptors
Monoclonal antibodies
Inhibition of interleukin-1β production
Ankylosing Spondylitis
Psoriatic Arthritis
Systemic Lupus Erythematosus
Osteoarthritis
Crystal-Induced Arthritis
Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still’s Disease
Interleukin-1 Inhibition for Periodic Fever Syndromes
Other Autoinflammatory Disorders
General Comments on Available Interleukin-1 Inhibitors
References
69
69
Interleukin-6 inhibitors
Tocilizumab
Mechanism of Action
Use, Recommended Dose, and Dose Adjustment
Intravenous administration
Subcutaneous administration
Pharmacokinetics
Intravenous administration
Subcutaneous administration
Use in Specific Populations
Pregnancy and nursing
Use in older adults
Hepatic or renal impairment
Clinical Trial Results in Rheumatoid Arthritis
Safety
Infections
Gastrointestinal perforation
Malignancies
Cardiovascular events
Infusion reactions
Hematology
Transaminase elevations
Lipids
Use in Other Rheumatoid Diseases
Large-vessel vasculitis (Takayasu and giant cell arteritis)
Juvenile idiopathic arthritis
Adult-onset Still disease
Systemic lupus erythematosus
Scleroderma
Spondyloarthritis
Upcoming Agents
Sarilumab
Olokizumab
Clazakizumab
Sirukumab
Acknowledgment
References
70
70
Tumor necrosis factor inhibitors
Introduction
Mechanism of Action
Biologic Effects
Approved Indications and Practical Use
Adalimumab (Humira)
Pharmacology
Indications and Use
Adalimumab in Rheumatoid Arthritis Pivotal Trials
Etanercept (Enbrel)
Pharmacology
Indications and Use
Etanercept in Rheumatoid Arthritis Pivotal Trials
Infliximab (Remicade)
Pharmacology
Indications and Dosing
Clinical Efficacy of Infliximab in Rheumatoid Arthritis
Certolizumab Pegol (Cimzia)
Pharmacology
Indications and Dosing
Clinical Efficacy of Certolizumab Pegol in Rheumatoid Arthritis
Golimumab (Simponi)
Pharmacology
Indications and Dosing
Clinical Efficacy of Golimumab in Rheumatoid Arthritis
Dose Reduction or Withdrawal of Anti–Tumor Necrosis Factor Therapy
Immunogenicity
Switching Between Anti–Tumor Necrosis Factor Agents
Expanded Indications
Ankylosing Spondylitis
Psoriatic Arthritis
Other Orphan Disorders
Granulomatous Disease
Antineutrophil Cytoplasmic Antibody–Associated Granulomatous Vasculitis
Giant Cell Arteritis
Polymyalgia Rheumatica
Sarcoidosis
Pyoderma Gangrenosum
Hidradenitis Suppurativa
Takayasu Arteritis
Inflammatory Eye Disease or Uveitis
Behçet Syndrome
Baseless Use of Tumor Necrosis Factor Inhibitors
Tumor Necrosis Factor Inhibitors in Early Rheumatoid Arthritis
Tumor Necrosis Factor Inhibitors in Children
Tumor Necrosis Factor Inhibitors in Older Adults
Pregnancy and Lactation
Safety of Anti–Tumor Necrosis Factor Therapy
Infusion Reactions
Injection Site Reactions
Infectious Risk
Tuberculosis
Other Opportunist Infections
Malignancy
Autoimmune Responses
Demyelinating Syndromes
Congestive Heart Failure
Interstitial Lung Disease
Cytopenias
Hepatotoxicity
Cutaneous Reactions
Unusual Toxicities
Vaccinations
Monitoring
Conclusion
References
71
71
Interleukin-17, interleukin-12, and interleukin-23 inhibitors
Potential Cytokine Targets in Rheumatic Diseases
Interleukin-17
Description, Receptor, and Function
Interleukin-17 in Rheumatic Disease
Clinical Trials
Interleukin-23
Description, Receptor, and Function
Interleukin-12 and Interleukin-23 in Rheumatic Diseases
Clinical Trials
Significant Points
Conclusion
References
72
72
Inhibitors of T-cell costimulation
Rationale for Targeting T Cells in Rheumatoid Arthritis
Costimulatory Signal in T-Cell Activation
Abatacept
Clinical Efficacy
Intravenous abatacept
Comparison with tumor necrosis factor inhibitors
Treatment of early rheumatoid arthritis
Subcutaneous abatacept
Combination with methotrexate
Comparison with tumor necrosis factor inhibitors
Drug-free remission
Safety
Infusion-related reaction
Infection
Tuberculosis
Vaccination
Malignancy
Subcutaneous abatacept
Safety of Abatacept in Routine Clinical Practice
Immunogenicity
Real-World Effectiveness And Safety
Biologic Effects
Summary of the Efficacy and Safety of Abatacept
New Costimulatory Inhibitors
Conclusions
References
73
73
Inhibitors of B cells
Introduction
Roles of B Cells in Rheumatic and Musculoskeletal Diseases
Targeting CD20
Rituximab
Rituximab Biosimilars
Other Type 1 and 2 Anti-Cd20 Molecules
Efficacy for Rheumatoid Arthritis
Radiographic Outcomes
Outcome of Repeat Cycles
Effect Of Rituximab Dose
Retreatment Of Nonresponse
Concomitant Conventional Synthetic Disease Modifying Antirheumatic Drugs
Antibody status
Type 1 interferon
Interleukin-33
Peripheral blood B-cell studies
Genetic studies
Factors Predicting Response to Rituximab
Rituximab: Use in Connective Tissue Diseases
Anca-Associated Vasculitis (AAV)
Systemic Lupus Erythematosus
Primary Sjögren Syndrome
Safety of Rituximab
Screening Before Therapy
Infusion Reactions
Infections
Low Immunoglobulin Levels Before And After Rituximab
Vaccination Responses And Immunization Following Rituximab
Progressive Multifocal LEUKOENCEPHALOPATHY (Pml)
Immunogenicity
Rituximab In Chronic Lung Disease
Malignancy
Inhibition of B-Cell Survival Factors
Efficacy of Belimumab in Systemic Lupus Erythematosus
Summary
References
74
74
Emerging therapeutic targets
Introduction
Anti-cytokines (Table 74.1)
Granulocyte–Macrophage Colony-Stimulating Factor
Interferon-Alpha
Interleukin-17 AXIS
BAFF/TACI/APRIL
IL-4/IL-13
T CELLS (Table 74.2)
VIB4920
Signaling Pathways (Table 74.3)
Bruton Tyrosine Kinase Inhibition
Other Signaling Pathways
Adhesion
E6011
Asp5094
Glucocorticoid Analogues (Table 74.6)
AZD-9567
ABBV-3373
AP1189
Immunoregulation
Cells as Therapies (Table 74.4)
Vagal Nerve Stimulation
Microbiome Manipulation
Targeting Stroma
RO7123520/RG6125 (Secara)
R-Roscovitine (Seliciclib)
Miscellaneous Interventions (Table 74.6)
ABX464
MBS2320
CF101
CR6086
Complement C5a
Autotaxin
Proteasome Inhibitors
Cannabinoid Receptors
References
75
75
Biosimilars in rheumatology
Definitions
Biosimilars
Biomimics
“Second-Generation” Biopharmaceuticals
Development of Biosimilars
Demonstration of Biosimilarity
Biosimilars for Inflammatory Diseases
Approved Biosimilars
Biosimilars in Development
Immunogenicity
Extrapolation of Indications
Interchangeability
Nomenclature
Cost
References
76
76
Infections in rheumatoid arthritis: biologic therapy and JAK inhibitors
Rheumatoid Arthritis and Burden of Infection
Prednisone
Biologic Therapies and Risk for Infection
Tumor Necrosis Factor Antagonists and Risk for Infection
Opportunistic Infections with Anti–Tumor Necrosis Factor Therapy
Abatacept, Rituximab, Tocilizumab, and Anakinra
Risk for Serious Bacterial and Opportunistic Infections
JAK Inhibitors
Prevention of Infection in Patients Treated with Biologics or Jak Inhibitors: Screening and Vaccination
Intracellular Pathogens
Conclusion
Acknowledgment
References
77
77
Neck pain
Introduction
Epidemiology
Incidence and Prevalence
Risk Factors
Pathogenesis of Neck Pain
Clinical Assessment
History
Clinical Examination
Onset of pain
Quality of pain
Frequency and duration of episodes of pain
Site, radiation, and source of pain
Associated features
Neurologic abnormalities
Clinical Examination
General Examination
Neurologic Examination
Neck Movement
Cervical Nerve Root Compression
Clinical Features
Clinical Examination
Investigations
Imaging
Radiographs
Computed tomography
Magnetic resonance imaging
Isotope scans
Blood Tests
Investigations Targeting Pain
Zygapophyseal joint blocks
Other anesthetic blocks
Provocation diskography
Treatment of Neck Pain
Nonspecific Treatments
Analgesics
Exercises
Physical therapy
Manual therapy or manipulation
Pillows and posture correction
Specific Treatments
Zygapophyseal joints
Intervertebral disks
Treatment—Cervical Nerve Root Compression
Natural History
Treatment Modalities
Corticosteroid injections
Surgery
Whiplash
Biomechanics
Pathology
Imaging
Natural History
Treatment of Acute Whiplash Injury
Treatment of Chronic Whiplash
Conclusion
References
78
78
Low back pain
Epidemiology
Occurrence
Impact
Risk Factors
Clinical Evaluation
Introduction
History
Site of pain
Aggravating and relieving factors
Physical Examination
General examination
Spinal examination
Lumbar range of motion
Manual muscle testing
Neurologic examination
Sensory examination
Deep tendon reflexes
Provocative maneuvers
Root tension signs
Gait analysis
Nonorganic physical signs
Investigations
Imaging
Plain radiographs
Radionuclide bone scintigraphy
Computed tomography
Magnetic resonance imaging
Correlation between magnetic resonance imaging and clinical findings
Comparison between magnetic resonance imaging and other modalities
Other imaging techniques
Clinical Laboratory Tests
Electrodiagnostic Studies
Concerning Causes of Low Back Pain (Box 78.3)
Cauda Equina Compression
Abdominal Aortic Aneurysm
Infections
Vertebral osteomyelitis
Disk infection
Pyogenic sacroiliitis
Herpetic Neuralgia
Neoplasms
Osteoid osteoma
Other primary spinal tumors
Multiple myeloma
Skeletal metastases
Rheumatologic Causes
Primary Bone Disorders
Referred Pain
Pain referred from other visceral organs
Pain referred from the hip joint
Centrally mediated pain
Mechanical Causes of Low Back Pain
Spondylolysis and Spondylolisthesis
Intervertebral Disk Disorder and Vertebrogenic Low Back Pain
Mechanisms of pain
Clinical features
Investigations
Treatment
Zygapophyseal (Facet) Joint Syndrome
Lumbar Spinal Stenosis
Etiology and pathogenesis
Clinical features
Investigations
Differential diagnosis
Management of Lumbar Spine Disorders
Conservative Approaches
Physical modalities
Exercise
Oral Drug Therapy
Analgesics
Nonsteroidal antiinflammatory drugs
Muscle relaxants
Neuropathic pain agents
Injection Therapy
Epidural injections
Facet joint injection
Complementary/Integrative Therapies
Surgical Treatment
Neuromodulation
References
79
79
The shoulder
Functional Anatomy
The Glenohumeral Joint
The glenohumeral ligaments
Coracohumeral and coracoacromial ligaments
Rotator cuff and long head of biceps tendon
Acromioclavicular Joint
Scapulothoracic Joint
Sternoclavicular Joint
Bursae
Nerve and Blood Supply
History and Physical Examination
History
Examination
Inspection
Palpation
Movements
Special tests
Hypermobility
Glenohumeral joint instability
Differential Diagnoses
Rotator Cuff Tears, Tendinopathy, and Impingement
Pathology
Clinical Features
Investigations
Management
Calcific Tendonitis
Pathology
Clinical Features
Investigations
Management
Biceps Pathology and SLAP Tears
Pathology
Clinical Features
Investigations
Management
Frozen Shoulder
Pathology
Clinical Features
Investigations
Management
Glenohumeral Joint Instability
Pathology
Clinical Features
Investigations
Management
Glenohumeral Arthritis
Pathology
Clinical Features
Investigations
Management
Acromioclavicular Joint Instability
Pathology
Clinical Features
Investigations
Management
Acromioclavicular Arthritis
Pathology
Clinical Features
Investigations
Management
Lateral Clavicular Osteolysis
Scapular Winging
Scapulothoracic Crepitus
Sternoclavicular Disorders
References
80
80
The elbow
Anatomy of the Elbow
Clinical Evaluation
Investigations
Elbow Disorders
Soft Tissue Elbow Conditions
Bone And Joint Conditions
References
81
81
The wrist and hand
Introduction
Clinical Evaluation
History
Physical Examination
Resting Posture
Swelling And Deformity
Differential Diagnosis of Joint Swelling
Other hand findings
Range of motion
Differential Diagnosis of Wrist and Hand Pain
Specific Disorders of the Wrist and Hand
Tenosynovitis
De Quervain Syndrome
Intersection Syndrome
Trigger Finger or Thumb (Stenosing Digital Tenosynovitis)
Ganglions of the Wrist and Hand
Carpal Tunnel Syndrome
Dupuytren Disease
References
82
82
The hip
Functional Anatomy
Bony Structures
Joint Capsule
Hip Musculature
Bursae
Blood Supply
Clinical Evaluation
History
Physical Examination
Gait examination
General inspection
Palpation
Range of motion
Special tests
Patrick (FABER) test
Thomas test
Stinchfield test
Apprehension tests
McCarthy test
Leg length measurement
Radiographic Evaluation
Plain Radiographs
Other Imaging
Role Of Imaging In Clinical Practice
Specific Hip Disorders
Hip Dysplasia
Femoroacetabular Impingement
Clinical features
Imaging
Treatment
Periarticular Soft Tissue Problems
Bursitis
Trochanteric bursitis
Iliopsoas bursitis
Ischiogluteal bursitis
Abductor tendon tears
Acknowledgment
References
83
83
The knee
Structure of the Knee Joint
Skeletal Anatomy
Distal femur
Proximal tibia
Patella
Soft Tissue Anatomy
Superficial Musculature
Extensor mechanism
Deep structures
Ligaments
Medial collateral ligament
Lateral collateral ligament
Anterior and posterior cruciate ligaments
Posterior structures
Neurovascular Supply
Menisci
Clinical Evaluation of a Patient With Knee Symptoms
History
Examination
Observation
Palpation
Range of motion
Ligamentous stability
Patellofemoral joint stability
Imaging
Specific Disorders of the Knee
Early Childhood
Referred hip pain
Infection
Septic arthritis
Osteomyelitis
Discoid meniscus
Malignancy and hematologic conditions
Inflammatory disease of the knee
Adolescence
Osgood-Schlatter disease
Sinding-Larsen-Johansson disease
Osteochondritis dissecans
Anterior cruciate ligament rupture
ADULTS
Anterior knee pain
Chondromalacia patellae
Patellofemoral maltracking, subluxation, and dislocation
Traumatic ligamentous injuries
Anterior cruciate ligament injuries
Posterior cruciate ligament injuries
Medial collateral ligament injuries
Lateral collateral ligament injuries
Bursitis
Patellar tendonitis
Iliotibial band syndrome
Disorders Occurring Across the Age Spectrum from Adolescence
Popliteal cysts
Synovial chondromatosis
Pigmented villonodular synovitis
Meniscal injuries
Extensor mechanism injuries
Isolated cartilage defects
Osteoarthritis
References
84
84
The ankle and foot
Introduction
Epidemiology of Foot and Ankle Problems
Anatomy of the Ankle and Foot
Ankle
Foot
Examination of the Foot and Ankle
Imaging
OTHER ASSESSMENTS
Local Ankle and Foot Problems
Ankle Sprains
Impingement Syndromes
Achilles Tendinopathy
Tibialis Posterior Tendon Dysfunction and Acquired Adult Flatfoot
Flatfeet (Pes Planus) and High-Arched Feet (Pes Cavus)
Nerve Entrapments
Morton neuroma
Tarsal tunnel syndrome
Heel Pain
Midfoot Pain
Forefoot Pain
Foot Problems Secondary to Systemic Conditions
Rheumatoid Arthritis
Psoriatic Arthritis and Seronegative Diseases
Juvenile Idiopathic Arthritis
Osteoarthritis
Connective Tissue Diseases
Crystal Arthropathies
Hypermobility Syndrome
Acknowledgments
References
85
85
The temporomandibular joint
Epidemiology, Etiology, and Classification
Functional Anatomy
Clinical Features
Management
Nonsurgical Management
Surgical Management
Relationship to Other Chronic Pain Disorders
References
86
86
Entrapment neuropathies and compartment syndromes
Introduction
Upper Extremity
Thoracic Outlet Syndrome
Anatomy
Etiology
Clinical features
Diagnosis
Treatment
Ulnar Nerve Compression Syndromes
Cubital Tunnel Syndrome
Anatomy
Etiology
Clinical features
Diagnosis
Treatment
Ulnar Tunnel Syndrome
Anatomy
Etiology
Clinical features
Diagnosis
Treatment
Median Nerve Compression Syndromes (Forearm Entrapment)
Anterior Interosseous Nerve Syndrome
Pronator Teres Syndrome
Carpal Tunnel Syndrome
Anatomy
Etiology
Clinical Features
Tests
Diagnosis
Treatment
Splinting
Local injection of corticosteroid
Nonsteroidal antiinflammatory drugs and other agents
Surgery
Radial Nerve Compression Syndrome
Posterior Interosseous Nerve Syndrome
Anatomy
Etiology
Clinical features
Diagnosis
Treatment
Lower Extremity
Piriformis Syndrome
Anatomy
Etiology
Clinical features
Diagnosis
Treatment
Meralgia Paresthetica
Anatomy
Etiology
Clinical Features
Diagnosis
Treatment
Peroneal Nerve Entrapment
Anatomy
Etiology and Clinical Features
Diagnosis
Treatment
Tarsal Tunnel Syndrome
Anatomy
Etiology
Clinical Features
Diagnosis
Treatment
Morton Metatarsalgia (Morton Neuroma, Interdigital Neuritis)
Anatomy
Etiology
Clinical Features
Diagnosis
Treatment
Compartment Syndromes
Acute Compartment Syndrome
Chronic Compartment Syndrome
Acknowledgments
References
87
87
Complex regional pain syndrome
Introduction
History of CRPS
The establishment of pain as a “5th vital sign”
Triggers
Pathogenesis
Inflammation
Autoimmunity
Neurological System Abnormalities
A Psychological Component to Crps
Biomarkers
Criteria for the Diagnosis of CRPS
The Orlando Criteria
Component factor analysis and the creation of symptom groups
Attempts to validate the Orlando criteria
The Budapest Criteria
Validation of the Budapest criteria
Incidence of CRPS Based on Evolving Criteria
Confusion with Other Diagnoses
CRPS in Children
Treatment of CRPS
Nonpharmaceutical, Nonsurgical Approaches to Crps
Physiotherapy
Psychotherapy
Medications
Nonsteroidal antiinflammatory agents
Calcitonin
Bisphosphonates
Free radical scavengers
Corticosteroids
Isosorbide dinitrate
Antidepressants
Anticonvulsants
Ketamine
Sympathetic blocking agents
Opioids
Surgical Intervention
Sympathetic blockade
Amputation
Integrative Medicine (IM) and Complementary and Alternative Medicine (CAMS)
Acupuncture
Peripheral Nerve Stimulation
Controversial or Potentially Dangerous Therapies
Electroconvulsive therapy
Hyperbaric oxygen therapy
CRPS in the Courtroom
Parallels with the Opioid Epidemic
Conclusions
References
88
88
Fibromyalgia and related syndromes
Introduction
Pathophysiology and Pathogenesis
Risk Factors
Clinical Features
Differential Diagnosis
The Continuum of Fibromyalgia to Fibromyalgianess
Treatment
General Approach
Pharmacologic therapies
Nonpharmacologic therapies
Natural History
References
89
89
Classification and epidemiology of rheumatoid arthritis
Classification of Rheumatoid Arthritis
Disease Occurrence
Incidence
Prevalence
Geographic Variation
Time Trends
Environmental Factors
Lifestyle Factors
Nutrition
Medications
Infectious Agents
Socioeconomic Status and Occupation
Urban and Industrialized Environments
Host Factors
Reproductive and Endocrine Factors
Birth Weight
References
90
90
Clinical features of rheumatoid arthritis
Introduction
Clinical Evaluation
History
Examination and Clinical Features of Specific Joints
Diagnosis
Natural History
Disease Onset
Patterns Of Onset
Gradual onset
Slow, monoarticular onset
Abrupt, acute polyarthritis
Acute monoarthritis
Palindromic rheumatism
Remitting seronegative symmetrical synovitis with pitting edema
Local extraarticular features
Systemic extraarticular features
Patterns of Progression
Clinical Course—Morbidity and Mortality
Acute-onset pattern
Gradual-onset pattern
Assessment of disease activity
Prognosis
References
91
91
Extraarticular features of rheumatoid arthritis
Introduction
Skin Disease
Hematologic Abnormalities
Felty Syndrome
Hepatic Abnormalities
Pulmonary Involvement
Cardiac Disease
Ocular Involvement
Neurologic Impairment
Muscular Involvement
Renal Abnormalities
Amyloidosis
Rheumatoid Vasculitis
Acknowledgment
References
92
92
Common comorbidities in rheumatoid arthritis
Introduction
Measurement of Comorbidity
Cardiovascular Disease and Cardiovascular Risk Factors
Venous Thromboembolism
Malignancy
Metabolic Disease
Osteoporosis and Osteopenia
Mental Health
Fibromyalgia and Central Pain Sensitization
Frequent Infections
Gastrointestinal Disease
Chronic Obstructive Pulmonary Disease
Chronic Kidney Disease
Screening and Management of Comorbidities in Patients with RA
Conclusion
References
93
93
Imaging of rheumatoid arthritis
Introduction
Approach to Imaging and General Imaging Features
Imaging Modalities
Conventional Radiography
Hands and wrists
Feet and ankles
Large joints
Pelvis and hips
Knees
Shoulders
Elbows
Cervical spine
Arthrography
Ultrasonography
Computed Tomography
Magnetic Resonance Imaging
Emerging Imaging Modalities
Final Points
Acknowledgment
References
94
94
Genetics of rheumatoid arthritis
Introduction
Strength of Genetic Contribution
Role of Major Histocompatibility Complex Genes
History
Refining the Amino Acid Sites Driving RA Susceptibility
Biologic Function of HLA-DRB1 Risk Alleles
Genetic Association Between Human Leukocyte Antigen Alleles and Anti–Cyclic Citrullinated Peptide–Positive and–Negative Rhe ...
Major Histocompatibility Complex: Disease Susceptibility or Severity?
Role of Non–Major Histocompatibility Complex Genes
Candidate Gene Association Studies in Rheumatoid Arthritis
PTPN22
PADI4
CTLA4
STAT4
Genome-Wide Association Studies in Rheumatoid Arthritis
Ethnic Differences in Rheumatoid Arthritis Susceptibility
Insight into the Pathogenesis of Rheumatoid Arthritis from Non–Major Histocompatibility Complex Genetic Studies
Gene and Environment Interactions
Conclusion
Summary
References
95
95
Animal models of rheumatoid arthritis
Introduction
Mechanisms of Induction of Experimental Arthritis
Immunization With Cartilage Components
Response to Nonspecific Immunologic Stimuli
Adjuvant- and pristane-induced arthritis
Components of Infectious Agents
Streptococcal cell wall arthritis
Antigen-induced arthritis
Flares of arthritis
Immune Complex–Induced Arthritis
K/BxN and serum transfer models
Anticitrullinated Protein Antibodies and Arthritis Models
Gene Manipulation and Transgenic Models
The 3 R’s
Conclusions
References
96
96
Autoantibodies in rheumatoid arthritis
Introduction
Rheumatoid Factors
Role as Diagnostic and Prognostic Markers
Pathogenetic Involvement
Anticitrullinated Protein/Peptide Antibodies
Citrullinated Autoantigens
Role of ACPA as Diagnostic and Prognostic Markers
Role in Disease Etiology and Pathogenesis
Antibodies to Carbamylated (Homocitrullinated) Antigens
Anti-RA33 Antibodies
Anticollagen Antibodies
Antibodies to Other Posttranslational Modifications
Additional Antibodies
The Impact of Immunoglobulin Glycosylation on Arthritis
Autoantibodies and Disease Pathogenesis
References
97
97
Pathogenesis and pathology of rheumatoid arthritis
Introduction
Normal Synovium
Synovium in Rheumatoid Arthritis
Pannus
Histologic Subtypes of RA Synovium
Mechanisms of Chronic Synovitis in Rheumatoid Arthritis
Cellular Immunology of Rheumatoid Arthritis
New Technologies in the Study of Rheumatoid Arthritis
Cells of Rheumatoid Synovium
Macrophages
Synovial Fibroblasts
T Cells
B Cells
Neutrophils
Other Leukocytes: Dendritic Cells, Mast Cells, NK Cells, and Other Innate Cell Types
Chondrocytes
Molecular Mediators in Rheumatoid Synovium
Tumor Necrosis Factor
Tumor Necrosis Factor Superfamily
Interleukin-1
Interleukin-6
Interleukin-18 and Other IL-1 Family Members
Interferon-γ and Canonical T-Cell–Derived Cytokines: Interleukin-2, -4, -5
Interleukin-10
Interleukin-17
Interleukin-21 and Interleukin-22
Interleukin-12 and Interleukin-23
Interleukin-15
Transforming Growth Factor-β
Granulocyte-Monocyte Colony-Stimulating Factor
Other Secreted Proteins
Chemokines
Arachidonic Acid Metabolites
Ligands for Toll-Like Receptors
Complement and Immune Complexes
Angiogenesis in Rheumatoid Arthritis
Vasculogenesis
Regulatory Networks in Synovial Angiogenesis
Angiostatic Compounds
Perspectives on Targeting Angiogenesis
Joint Destruction
Matrix Metalloproteinases
Collagenases
Stromelysins
Other Matrix Metalloproteinases and Related Enzymes
Role of Matrix Metalloproteinases in Inflammation
Protease Inhibitors
Cysteine and Serine Proteases
Bone Destruction
New Horizons in RA Pathogenesis Research
Genetics and Autoimmunity
Seronegative Rheumatoid Arthritis
T Cells in the Initiation and Propagation of Rheumatoid Arthritis
Cell–Cell and Cytokine Interactions in the Perpetuation of Inflammation in Rheumatoid Arthritis
Unifying Hypothesis
Conclusion
Acknowledgment
References
98
98
Preclinical rheumatoid arthritis
Introduction and Overview of Rheumatoid Arthritis Development
The Pathophysiology of Rheumatoid Arthritis Development Before Clinically Apparent Inflammatory Arthritis
Autoantibody Abnormalities Precede Clinically Apparent Inflammatory Arthritis
Epitope Spreading Occurs in pre-RA
Other Autoantibody Changes in Preclinical Rheumatoid Arthritis
Systemic Inflammation in Pre-RA
Other Immune Features in pre-RA
Genes and Environment in pre-RA
Putting It All Together: When, Where, and How Does RA-Related Autoimmunity Develop?
Caveats to the Model of RA Development
“Autoimmune-Opathy” Preceding Inflammatory Arthritis In RA
Nomenclature
Prediction of Future Rheumatoid Arthritis
Prevention of Rheumatoid Arthritis
Conclusion
Acknowledgment
References
99
99
Assessment of the patient with rheumatoid arthritis and the measurement of outcomes
Introduction
2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis
Disease Process (“Disease Activity”) and Its Consequence (“Disease Outcome”)
Evaluation Versus Prognostication
Individual Measures Versus Composite Indices
Definition and Evaluation of Treatment Targets in Clinical Practice
Assessment Strategies in Clinical Trials
Instruments for Assessing Disease Activity
Core Sets of Disease Activity Variables
Swollen and tender joint counts
Pain
Patient and evaluator assessment of global disease activity
Acute-phase reactants
Composite Indices of Disease Activity
Improvement Criteria
Remission Criteria
Instruments for Assessing Physical Function
Instruments for Assessing Structural Progression
Scoring of Radiographs
Other Imaging Modalities
Other Instruments: Fatigue, Work Productivity, and Comorbidity
Conclusion
References
100
100
Management of rheumatoid arthritis in csDMARD-naïve patients
Introduction
Early Diagnosis and Treatment
Treating to Target
DISEASE MODIFYING ANTIRHEUMATIC DRUG (DMARD) THERAPY
Conventional Synthetic DMARDs
Glucocorticoids
csdmard Strategies—Initial Monotherapy vs Combination Therapy
Biologic/Targeted Synthetic DMARD Induction Strategies
Biologic Dmard Induction Followed by Tapering
Treatment Stratification in Early RA
Non-Dmard and Non-pharmacological Management
References
101
101
Management of rheumatoid arthritis in patients with prior exposure to conventional synthetic disease-modifying antirhe ...
Introduction
Therapeutic Overview
Guiding Principles of Treatment
Adjusting Therapy to Achieve Targets
Comparative Efficacy of Targeted DMARDs (tDMARDs)
Treatment Withdrawal
General Safety Monitoring of DMARD Therapies
Non-class-Specific Adverse Events With Targeted Therapies
Infections and immunizations
Malignancies
Other non-class-specific adverse events with targeted therapies
Potential Class-Specific Adverse Events With tDMARDs
Fertility and Pregnancy
Comorbid Disease
Cardiovascular Disease
Interstitial Lung Disease
Conclusions
References
102
102
Multidisciplinary nonpharmacologic approach to rheumatoid arthritis
Introduction
Coping—Balancing Needs and Resources
Patient Education and Counseling
Exercise Therapy
Hands-on Techniques and Physical Modalities
Orthoses, Insoles, and Shoes
Assistive Technology
Nutrition
Interventions Preventing Job Loss and Work Disability
Multidisciplinary Team Care
Digital Health Interventions
Acknowledgment
References
Volume II
103
103
Evaluation of children with rheumatologic complaints
History Taking for the Musculoskeletal System in Children
General Approach
Constitutional Features
Joint Pain
Joint Swelling And Stiffness
Examination of the Musculoskeletal System
General Examination
Joint Assessment
Cervical spine and temporomandibular joints
Elbows and shoulders
Hands and wrists
Hips
Knees
Feet and ankles
Spine and gait
Differential Diagnosis
Septic Arthritis
Reactive or Postinfectious Arthritis
Musculoskeletal Syndromes and Benign Limb Pains
Regional Syndromes: Hip
Transient (Toxic) Synovitis (Irritable Hip)
Legg-Calvé-Perthes Disease
Imaging
Pathophysiology
Treatment
Prognosis
Long-term follow-up
Slipped Capital Femoral Epiphyses
Clinical findings
Imaging
Treatment
Idiopathic Chondrolysis
Imaging
Treatment and prognosis
Acetabular Dysplasia, Impingement, And Developmental Dysplasia Of The Hip
Clinical findings
Imaging
Treatments
Regional Syndromes: Knee
Patellofemoral Dysfunction
Chondromalacia Patellae
Bone Lesions That Mimic Mechanical Knee Disease
Osgood-Schlatter Disease
Other Knee Disorders
Regional Syndromes: Foot
Acknowledgments
References
104
104
Classification and epidemiology of juvenile idiopathic arthritis
Classification of Childhood Arthritis
History of Childhood Arthritis Classification
Role of the International League of Associations for Rheumatology Classification
Validity of the International League of Associations for Rheumatology Criteria
Descriptive Epidemiology
Incidence and Prevalence
Geographic and Ethnic Variation
Time Trends
Descriptive Epidemiology of the Different Disease Categories
Risk Factors
Genetic Factors
Familial risk
Role of HLA
Role of non–human leukocyte antigen genes
Environmental factors
Summary
Course and Prognosis
Mortality
Outcome
References
105
105
Clinical features of juvenile idiopathic arthritis
Introduction
General Clinical Features
Laboratory Investigations
Imaging
Clinical Features of Different Categories of Juvenile Idiopathic Arthritis (Table 105.3)
Systemic Arthritis
Oligoarthritis, Persistent and Extended
Polyarthritis
Rheumatoid factor–negative polyarticular juvenile idiopathic arthritis
Rheumatoid factor–positive polyarticular juvenile idiopathic arthritis
Psoriatic Arthritis
Enthesitis-Related Arthritis
Undifferentiated Arthritis
Special Problems of Arthritis in Children
Multidimensional Outcome
Mortality, Cancer, and Severe Morbidity
Continuous Activity, Inactivity, and Remission
Risk Factors for Continuous Activity and Damage
Articular and Skeletal Damage
Joint destruction
Local growth disturbances
Knee
Ankle
Wrist and hand
Hip
Cervical spine
Temporomandibular joint
Bone health and osteopenia
General growth disturbance
Pubertal delay
Endocrine Damage
Ophthalmologic Complications and Damage
Physical Disability
Quality of Life
Pain
Fatigue and sleep disturbance
Psychosocial health
Participation
Transition of Care
References
106
106
Etiology and pathogenesis of juvenile idiopathic arthritis
Introduction
Etiology
Genetic Factors
Human leukocyte antigen region
Non–human leukocyte antigen genes
Environmental Factors
Microbes
Pathogenesis
Pathology
Pathogenesis of Oligo- and Poly-Juvenile Idiopathic Arthritis
Enthesitis-Related Arthritis
Systemic Juvenile Idiopathic Arthritis
Conclusion
Acknowledgment
References
107
107 Management of juvenile idiopathic arthritis
Surgical Management
Other Issues of Management
Introduction
Treatment Recommendations for Juvenile Idiopathic Arthritis (Table 107.3)
Oligoarthritis
Polyarthritis Course (Regardless of Onset)
Systemic Arthritis
Macrophage Activation Syndrome
Enthesitis-Related Arthritis
Active Sacroiliac Arthritis
Psoriatic Arthritis
Uveitis
Nonsteroidal Antiinflammatory Drugs
Corticosteroids
Methotrexate
Other Disease-Modifying Antirheumatic Drugs and Immunosuppressive Medications (Table 107.4)
Biologic-Modifying Medications
Tumor Necrosis Factor Inhibitors
Abatacept
Anti–Interleukin (IL)-1 Medications
Anti–Interleukin (IL)-6
Intravenous Immunoglobulin
Rituximab
Janus Kinase (JAK) Inhibitors
Secukinumab
Stem Cell Transplantation
Studies of Disease-Modifying Antirheumatic Drug vs Biologic Combination Therapy for Juvenile Idiopathic Arthritis
Management of Pain
Rehabilitation
Management of Growth Retardation
Complementary and Alternative Therapies
Surgical Interventions
Synovectomy
Arthroplasty
Adjunct Nonsurgical and Surgical Treatment of Temporomandibular Joint Deformities
Conclusion
References
108
108
The juvenile-onset spondyloarthropathies
Classification and Epidemiology
Clinical Manifestations
Genetics
Pathophysiology
Evaluation of Disease Phenotype and Disease Activity
Treatment Considerations
Outcomes
Conclusions
References
109
109
Systemic autoimmune rheumatic diseases in children
Introduction
Juvenile-Onset Systemic Lupus Erythematosus
Epidemiology
Etiopathogenesis
Clinical Presentation
Assessment Of Disease Severity And Monitoring Of Outcome
Management
Management And Prevention Of Comorbidities
Clinical Severity And Outcome
Neonatal Lupus Syndrome
The Pediatric Inflammatory Myopathies: Juvenile Dermatomyositis
Epidemiology
Etiopathogenesis
Clinical Presentation
Assessment And Monitoring
Treatment And Outcome
Sjögren Disease In Children
Epidemiology
Etiopathogenesis
Clinical Presentation And Features
Making The Diagnosis
Management
Prognosis And Outcomes—More Questions Than Answers
Scleroderma
Epidemiology
Etiopathogenesis
Clinical Presentation
Localized scleroderma
Systemic sclerosis
Diagnosis And Management
Treatment And Outcome
Localized scleroderma treatment and outcome
Systemic sclerosis treatment and outcome
Prognosis
References
110
110
Rehabilitation and psychosocial issues in juvenile idiopathic arthritis
Key Points
Introduction
Impacts
Pain
Structural Damage
Hand and Wrist
Lower Extremities
Bone Mineralization
Limitations in Daily Living
Psychosocial Implications
Childhood
Adolescence
Adulthood
Evaluation
Pain Scales
Range of Motion and Muscle Strength
Function, Quality of Life, and Health Status
Goals of Treatment: Evidence-Based Treatment and Outcome
Conclusion
References
111
111
Bacterial native joint arthritis
Introduction
Epidemiology, Origins of Arthritis, and Related Microbiology
Clinical Presentation, Patients’ History, and Diagnosis
Laboratory Diagnoses
Management of Bacterial Arthritis
Degree of Emergency for Lavage/Drainage
Combined surgical and medical therapy
Techniques for lavage/drainage
Resection, Arthrodesis, or Amputation
Antibiotic Treatment
Total Duration of Antibiotic Therapy and of Its Parenteral Part
Supportive Therapy and Research for the Future
Outcomes of Therapy
Acknowledgment
References
112
112
Mycobacterial, brucellar, fungal, and parasitic arthritis
Introduction
Tuberculous Arthritis
Epidemiology
Pathophysiology
Musculoskeletal Manifestations
Spondylitis (Pott’s Disease)
Peripheral Arthritis
Osteomyelitis
Reactive Arthritis (ReA) (Poncet Disease)
Soft Tissue Abscess And Panniculitis
Diagnosis
Imaging
Spondylitis
Peripheral arthritis
Osteomyelitis
Treatment
Prevention
Leprosy and Other Mycobacterial Infections
Epidemiology
Microbiology
Clinical Characteristics
Diagnosis
Treament
Brucellosis
Epidemiology
Microbiology
Clinical Manifestations
Diagnosis
Treatment
Prevention
Fungal Musculoskeletal Infections
Histoplasmosis
Clinical manifestations
Treatment
Blastomycosis
Clinical manifestations
Treatment
Paracoccidioidomycosis
Clinical manifestations
Treatment
Coccidioidomycosis
Clinical manifestations
Treatment
Cryptococcosis
Clinical manifestations
Treatment
Aspergillosis
Clinical manifestations
Therapy
Candidiasis
Clinical manifestations
Treatment
Sporotrichosis
Clinical manifestations
Treatment
Parasitic Arthritis
Protozoans
Diagnosis
Helminths
Cestodes
Diagnosis
Nematodes
Diagnosis
Trematodes
Diagnosis
Treatment
References
113
113
Viral infections
Other Viruses
Introduction
Human Immunodeficiency Virus
Principles of Management of Inflammatory Diseases in the Setting of HIV
Special Situations in Evaluating and Treating Patients With HIV and Rheumatic Disorders
Osteoporosis
Immune reconstitution syndrome
Avascular necrosis
Parvovirus B19
Virology
Clinical Manifestations
Laboratory Investigation
Treatment
Hepatitis B Virus
Virology
Clinical Manifestations
Hepatitis C Virus
Clinical Manifestations
Coexistent arthropathy
Hepatitis C virus–associated arthritis
Arthritis in hepatitis C virus–associated cryoglobulinemic vasculitis
Chikungunya and Other Alphaviruses
Clinical Manifestations
Acute phase (<10 days)
Subacute phase (>10 days–3 months)
Chronic phase (>3 months)
Laboratory Investigation
Treatment
Human T-Cell Lymphotropic Virus Type I
Other Viruses
References
114
114
Lyme and other tickborne diseases
History
Epidemiology
Etiologic Agent
Pathogenesis
Clinical Manifestations
Skin
Nervous System
Cardiac System
Joints
Diagnosis
Other Tickborne Diseases
Differential Diagnosis
Treatment
Post–Lyme Disease Symptoms
Prevention
References
115
115
Acute rheumatic fever
Introduction
Epidemiology
Rheumatic Fever Risk Factors
Streptococcus Factors
Environmental Factors
Host Factors
HLA class II antigens
B-cell alloantigen
Gene polymorphisms
Pathophysiology
Relationship Between Gabhs And Rheumatic Fever
Molecular Mimicry and Epitope Spreading
Humoral Immune Response
Cellular Immune Response
Cytokine balance
Pathology
Myocarditis
Endocarditis
Pericarditis
Arthritis
Chorea
Clinical Manifestations
Major Manifestation
Arthritis
Carditis
Transition from acute to chronic heart disease
Subclinical carditis
Chronic rheumatic heart disease
Sydenham Chorea
Erythema Marginatum
Subcutaneous Nodules
Other Clinical Features
Minor Manifestation
Investigations
Throat Cultures
Rapid Antigen Detection Test
Streptococcal Antibody Tests
Acute-Phase Reactants
Other Laboratory Findings
Echocardiography
Diagnosis
Treatment
Primary Prevention: Gas Vaccine
Primary Prevention (Pharyngitis Treatment)
Acute Rheumatic Fever
Streptococcus eradication
Arthritis, fever, and rash
Acute carditis
Sydenham Chorea
Secondary Prevention
Endocarditis Prophylaxis
Emergency Valve Procedure
References
116
116
Reactive arthritis
Introduction
Innate Immunity and Reactive Arthritis
Too much immunity or too little?
Self–Nonself Complexities
Chlamydia-Induced Reactive Arthritis
Reactive Arthritis: The Noncanonical Septic Arthritis
Chlamydial persistence: pathogenicity or symbiosis?
Mediators of Susceptibility to Chlamydia-Induced Reactive Arthritis
Importance of Innate Immunity in Chlamydia-Induced Reactive Arthritis
Macrophages as Key Players in Chlamydia-Induced Reactive Arthritis
Classification Criteria
Genetic Factors
Epidemiology
Clinical Features
Arthritis
Extraarticular features
Atypical Aspects of Reactive Arthritis
Sapho
Clostridium Difficile and Giardia Lamblia
Streptococcal Infections
Human Immunodeficiency Virus and Reactive Arthritis
Investigations
Laboratory Testing
Radiology
Treatment
Triggering Infection
Acute Arthritis
Extraarticular Symptoms
Skin and Mucosal Lesions
Chlamydia-Induced Reactive Arthritis
Disease-Modifying Antirheumatic Drugs
Biologic Agents in the Treatment of Reactive Arthritis
Prophylaxis
Prognosis and Natural History
Summary: Key Elements of the Clinical Approach to Reactive Arthritis182 (Box 116.4)
References
117
117
Classification and epidemiology of spondyloarthritis
The Historical Concept of Spondyloarthritis
The Evolution of Axial Spondyloarthritis
Diagnosis and Classification of Axial Spondyloarthritis
Classification of Peripheral Spondyloarthritis
Prevalence of Spondyloarthritis
Impact of Gender
Conclusion
References
118
118
Enthesopathies
Introduction
History
Anatomy and Pathology
Anatomy
Fibrocartilage
Related structures
Histopathologic Features and Cellular Basis for Enthesitis
Enthesitis and the Pathogenesis of Spondyloarthritis
A Universal Hallmark of Spondyloarthritis
Enthesitis and Osteitis
Enthesitis and Anatomically Similar Structures
An Enthesitis-Based Model
Sites of Enthesitis
Symptoms and Signs
Differential Diagnosis
Imaging
Magnetic Resonance Imaging
Conventional Radiography
Ultrasonography
Clinical Scores for Enthesitis Assessment
Management
First-Line Therapy
Disease-Modifying Therapy for Enthesitis
References
119
119
Inflammatory back pain
Introduction
Inflammatory Back Pain Criteria
Inflammatory Back Pain in the Population
Patient Referral Strategies
Inflammatory Back Pain in Diagnosis
Acknowledgment
References
120
120
Clinical features of axial spondyloarthritis
Introduction
Clinical Features
Chronic Back Pain
Arthritis
Enthesitis
Dactylitis
Extra-musculoskeletal manifestations
Uveitis
Inflammatory bowel disease
Psoriasis
Other
Cardiac manifestations
Pulmonary manifestations
Renal manifestations
Neurologic manifestations
Psychosocial manifestations
Constitutional symptoms
Osteoporosis and spinal fractures
Fibromyalgia
Structural damage
Physical Examination Findings
Laboratory and Imaging Investigations
Diagnosis and Classification
Clinical Assessment of axspa
Burden of Disease and Prognosis
Acknowledgments
References
121
121
Pathogenesis and pathophysiology of axial spondyloarthritis
Introduction
Axial Spondyloarthritis: A Polygenic Disease with a Predominant Autoinflammatory Nature
Key Inflammatory Mediators in Spondyloarthritis
Histopathology and New Bone Formation
References
122
122
Genetics of axial spondyloarthritis
Genetic Epidemiology of Ankylosing Spondylitis
Major Histocompatibility Complex Genes
HLA-B27 and B27 Subtypes
Other Major Histocompatibility Complex Genes
Non–Major Histocompatibility Complex Genes
Genetics of Acute Anterior Uveitis
Ankylosing Spondylitis in East Asians
Ankylosing Spondylitis in Africans
Summary and Conclusions
Acknowledgment
References
123
123
Animal models of spondyloarthritis
Introduction
HLA-B27 Transgenic Animals
HLA-B27 Transgenic Mice
HLA-B27 Transgenic rats
TNF Overexpression Models
Human TNF-Transgenic Mice
TNFΔARE MICE
tmTNF Transgenic Mice
IL-23/IL-17 Pathway
Beta-Glucan Induced Disease In Skg Mice
Mechanical Loading
Selective A20 Deficiency
Microbiome
Conclusion
References
124
124
Imaging in spondyloarthritis
Introduction
Technical Aspects Of Imaging In Axial Spondyloarthritis
Importance Of Imaging Of The Sacroiliac Joints In Axial Spondyloarthritis
Conventional Radiology
Computed Tomography
Scintigraphy
Magnetic Resonance Imaging
Technical aspects of MRI
Definition of a positive magnetic resonance imaging of the sacroiliac joint in axial spondyloarthritis
Differential Diagnoses For Involvement Of The Sacroiliac Joint
Imaging Of The Spine In Axial Spondyloarthritis
Conventional Radiographs
Magnetic Resonance Imaging
Definition Of A Positive Magnetic Resonance Imaging Of The Spine In Axial Spondyloarthritis
Differential Diagnoses For Involvement Of The Spine
Cauda Equina Syndrome
Extravertebral Manifestations Of Axial Spondyloarthritis
Future Directions
References
125
125
Management of axial spondyloarthritis
Historical Perspective
Current Perspectives
Assessment Of Efficacy Of Treatment Of Axial Spondyloarthritis
Pooled Indices
Assessment of SpondyloArthritis international Society instruments
Bath indices
Specific Clinical And Laboratory Markers
Laboratory tests
Spinal mobility
Imaging
Physical Therapy
Nonbiologic Pharmacologic Therapy
Nonsteroidal Antiinflammatory Drugs
Nonsteroidal antiinflammatory drugs as disease modifiers
Corticosteroids
Systemic corticosteroids
Intraarticular corticosteroids
Conventional Synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs)
Sulfasalazine
Methotrexate
Other csDMARDs
Targeted Synthetic Disease-Modifying Antirheumatic Drugs (tsDMARDs)
Biologic DMARDs (Table 125.4)
Tumor Necrosis Factor-α–Blocking Agents
Biologic basis
Treatment of early axial spondyloarthritis with tumor necrosis factor blockers
Can a good response to tumor necrosis factor blockers be predicted?
Treatment targeting the interleukin-23–interleukin-17 pathway
bDMARDs for peripheral arthritis and enthesitis
Switching after failure of the first biologic
Management Of Extraarticular Manifestations
Anterior Uveitis
Psoriasis and inflammatory bowel disease in patients with ankylosing spondylitis
Tumor necrosis factor blockers for the treatment of juvenile spondyloarthritis
Adverse events associated with biologic therapy
Osteoporosis
Surgical Intervention In Ankylosing Spondylitis
Hip Replacement
Spinal Surgery
Acknowledgment
References
126
126
Classification and epidemiology of psoriatic arthritis
Introduction
Diagnosis
Epidemiology of Psoriatic Arthritis
Prevalence and Incidence of Psoriatic Arthritis Among Patients in the General Population
Prevalence and Incidence of Psoriatic Arthritis Among Patients with Psoriasis
Risk Factors for PsA Among Patients with Psoriasis
Classification
Classification Versus Diagnosis
Comorbidities Among Patients with PsA
Conclusions
References
127
127
Clinical features of psoriatic arthritis
Introduction
History, Epidemiology, and Criteria
Epidemiology
Principles of the Diagnosis of PsA
Classification Criteria Used in PsA Trials
Key Clinical Features: Skin and Joints
Skin Psoriasis
Nail involvement
Peripheral Joint Involvement
Other Musculoskeletal Features
Dactylitis
Enthesitis
Axial Involvement
Other Extraarticular Features
Rare Forms of PsA
Synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome
Psoriatic onychopachydermoperiostitis
Evaluation and Follow-Up
Prognosis
Natural History
Comorbidities
Investigations
Laboratory Investigations
Imaging Investigations
Peripheral joint structural changes as seen on radiographs
Other Imaging Modalities of the Peripheral Joints
Entheseal imaging
Spinal imaging
Acknowledgment
References
128
128
Extraarticular manifestations and comorbidities in psoriatic arthritis
Introduction
Extraarticular Manifestations
Psoriasis
Prevalence and incidence
Classification and clinical manifestations of psoriasis
Psoriasis risk factors for PsA transition
Pathologic mechanisms proposed
Screening and management recommendations
Inflammatory Bowel Disease
Prevalence, incidence, and clinical implications
Pathologic mechanisms proposed
Screening and management recommendations
Ocular Manifestations
Prevalence, incidence, and clinical implications
Pathologic mechanisms proposed
Management recommendations
Comorbidities
Cardiovascular Disease
Prevalence, incidence, and clinical implications
Pathologic mechanisms proposed
Screening and management
Cardiovascular Risk Factors: Metabolic Syndrome, Obesity, Diabetes Mellitus, Dyslipidemia, and Hypertension
Prevalence, incidence, and clinical implications
Pathologic mechanisms proposed
Screening and management recommendations
Malignancy
Prevalence, incidence, and clinical implications
Screening and management recommendations
Liver Disease
Prevalence, incidence, and clinical implications
Pathologic mechanisms proposed
Liver disease and PsA medications
Screening and management recommendations
KIDNEY DISEASE
Prevalence, incidence, and clinical implications
Kidney disease and PsA medications
Infections
Prevalence, incidence, and clinical implications
Infections and PsA medications
Osteoporosis
FIBROMYALGIA
Depression AND ANXIETY
Gout
References
129
129
Etiology and pathogenesis of psoriatic arthritis
Introduction
Genetic Factors
Epigenetics
Environmental Factors
Infection
Trauma, Severity of Psoriasis, Obesity, and Diet
Cells, Cytokines, and Pathways Involved in Skin and Joint Tissue Inflammation
Immunopathology
Psoriatic Plaque
Nail Disease
Synovium
Enthesis
Dactylitis
Links Between Skin and Musculoskeletal Inflammation
Pathologic Cartilage Resorption and Altered Bone Remodeling
Cartilage Resorption
Altered Bone Remodeling
Conclusion
References
130
130
Animal models of psoriatic arthritis
Animal Model Strategies and Concept
Challenges in the Development of Animal Models for Psoriatic Disease
Animal Models of Psoriatic Arthritis
Spontaneous Models of Psoriatic Arthritis
Transgenic Approaches Towards Psoriatic Arthritis Models
Induced Models of Psoriatic Arthritis
Lessons Learned and Future Perspectives
References
131
131
Management of psoriatic arthritis
Introduction
Is Psoriatic Arthritis an Important Pathology?
Assessment of Disease Activity and Outcome of Psoriatic Arthritis
Is there a need for novel treatments in psoriatic arthritis?
Nonsteroidal Antiiinflammatory Drugs and Glucocorticoids
Conventional Synthetic Disease-Modifying Antirheumatic Drugs
Methotrexate
Sulfasalazine
Leflunomide
Cyclosporine
Biologic Disease-Modifying Antirheumatic Drugs
Tumor Necrosis Factor Inhibitors
Etanercept
Infliximab
Adalimumab
Golimumab
Certolizumab
Health Benefits of Tumor Necrosis Factor Inhibitors in Psoriatic Arthritis
Other Biologic Disease-Modifying Antirheumatic Drugs
Costimulatory Blockade Agents
Anti–Interleukin-12 and -23 Agents
Anti–Interleukin-17
Small-Molecule Inhibitors
Treatment Recommendations
Conclusion
Acknowledgments
References
132
132
Epidemiology and classification of systemic lupus erythematosus
Introduction
Classification of Systemic Lupus Erythematosus for Clinical Studies and Trials
Systemic Lupus Erythematosus Heterogeneity and Subtypes
Descriptive Epidemiology of Systemic Lupus Erythematosus
Prevalence and Incidence in the United States
Ethnicity and Geography
Sex
Age
Risk Factors for Systemic Lupus Erythematosus
Hormonal/Reproductive Factors
Cigarette Smoking, Alcohol Consumption, and Obesity
Environmental Contaminants
Nutritional Factors and Ultraviolet Light
Psychosocial Stressors
Infections and Immunizations
Epidemiology of Major Adverse Outcomes Among Patients with Systemic Lupus Erythematosus
Conclusions
Acknowledgment
References
133
133
Preclinical features of systemic lupus erythematosus
Introduction
Importance of Understanding and Identifying Preclinical Lupus
Healthy Individuals with Antinuclear Autoantibodies
Clinical and Serologic Features of Healthy Individuals who Transition to Systemic Lupus Erythematosus
Risk Factors for Transition in Relatives of Patients with Systemic Lupus Erythematosus
Environmental Exposures and Life Experiences in the Preclinical Period which Associate with Future SLE Development
Clinical Manifestations and Transition of Patients with Incomplete, Potential, or Latent Lupus
Transition of Patients with Undifferentiated Connective Tissue Disease to Systemic Lupus Erythematosus
Development of Systemic Lupus Erythematosus in Patients with Another Systemic Autoimmune Disease
Conclusions
Acknowledgments
References
134
134
Clinical features of systemic lupus erythematosus
Introduction
Clinical Features
General Manifestations
Cutaneous Manifestations
Musculoskeletal Features
Renal Manifestations
Neuropsychiatric Manifestations
Gastrointestinal Involvement
Lymphatic And Hematologic Involvement
Pulmonary Involvement
Cardiac Manifestations Of Systemic Lupus Erythematosus
Accelerated Atherosclerosis
Endocrine
Eye, Ear, Nose, Throat
Malignancies
Infections
Acknowledgment
References
135
135
Genetics of systemic lupus erythematosus
Introduction
Female Dominance of Lupus
Rare Presentations of Lupus
TREX1
Early Complement Components
Genetic Association
Genomic Mechanisms
Risk Loci Identified in Cohort Association Studies
Human Leukocyte Antigen Locus at 6p21
HLA-DRB1 and HLA-DQB1
TNFAIP3
ITGAM
ETS1
IRF5 (AND TNPO3)
STAT4 (and STAT1)
CD44
TLR7
IRAK1 (and MECP2)
The Promise of Genetics
References
136
136
Immunopathology of systemic lupus erythematosus
Introduction
Pathology
Characteristic Lesions
Hematoxylin bodies
Libman-Sacks endocarditis
Cutaneous Immunopathology
Vascular Immunopathology
Immunopathology of Lymphoid Organs
Renal Immunopathology
Approach to classification
Prognostic features
Pathogenetic mechanisms
Central Nervous System Immunopathology
Cardiac Immunopathology
Pulmonary Immunopathology
Properties of Immune Complexes
Antibodies and Antigens
Critical Properties of Immune Complexes
Pathogenic Mechanisms
Biology of Immune Complex Handling
Role of Complement in Immune Complex Handling
Receptors for the Fc Region of Immunoglobulin G
Structure and function
Fcγ receptors and systemic lupus erythematosus
Complement and Fcγ Receptor Function: Targets for Treatment
References
137
137
Animal models of systemic lupus erythematosus
Introduction
Spontaneous Mouse Models
New Zealand Black
(NZB × NZW)F1
New Zealand Mixed Strains
SNF1
MRL/LPR AND GLD
BXSB
Induced Models
Pristane-Induced Lupus
Engineered Mouse Models
References
138
138
Autoantibodies in systemic lupus erythematosus
Introduction
Antinuclear Antibodies
Fluorescent ANA Assay
Techniques for Detecting ANA Specificity
Antinuclear and Anticytoplasmic Autoantibodies
“Antiphospholipid” Autoantibodies
Cell Membrane Antigens
Autoantibodies as the Initial Manifestation of Autoimmunity
Mechanisms of Autoantibody Production in Lupus
How are lupus autoantigens selected?
How do autoantibodies cause disease?
References
139
139
Pathogenesis of systemic lupus erythematosus
Genetic Susceptibility and Gender and Environmental Triggering Factors
Innate Immune Responses
Type I Interferons and other Cytokines
Neutrophils and Neutrophil Extracellular Traps (Nets)
Dendritic Cells and other Antigen-Presenting Cells
Adaptive Immune Responses
B Cells and the Production of Autoantibodies
T Cells and Regulation of the Immune Response
Local Factors Involved in Lupus Pathogenesis
Concluding Remarks
References
140
140
Drug-induced lupus
Introduction
Etiology
Drugs Implicated
Genetic Contributions to Idiopathic and Drug-Induced Lupus
Age and Gender Contributions to Drug-Induced and Idiopathic Lupus
Summary
Pathogenesis
Epigenetics and Gene Expression
Epigenetics, chromatin structure, and gene expression
Histone modifications
DNA methylation
ROLE OF DNA METHYLATION IN T CELLS
T cells, DNA methylation, and idiopathic lupus
T cells, DNA methylation, and the environment
Recombinant Biologic Agents
Interferon-αα
Tumor necrosis factor inhibitors
Summary
Clinical Aspects
Idiopathic Lupus in Younger Versus Older Adults
Gender aspects
Clinical and serologic features
Drug-Induced Lupus Versus Idiopathic Lupus
Patient characteristics
Clinical Features
Autoantibodies
Summary
References
141
141 Assessing disease activity and outcome in systemic lupus erythematosus
Introduction
Global Disease Activity Indices
Systemic Lupus Erythematosus Disease Activity Index (Sledai)
Systemic Lupus Activity Measure
SLE Disease Activity Score (SLE-DAS)
Organ-Specific Indices
British Isles Lupus Assessment Group Disease Activity Index (Bilag)
Renal Outcome Measures
Cutaneous Outcome Measures
Measures of Change in Disease Activity
Composite Responder Indices
Measurement of Low Disease Activity State
Measurement of Flare
Measurement of Damage
Health-Related Quality of Life
Generic Questionnaires
Disease-Specific Hrqol Questionnaires
Fatigue Measures
Miscellaneous
Patient and Physician Global Assessment of SLE Activity
Glucocorticoid Background Therapy
Critique of SLE Outcomes and Trial Designs
Conclusion
References
142
142
Management of nonrenal and non–central nervous system lupus
Introduction
Recommended Assessment and Monitoring of SLE Patients with Nonrenal/Non–Central Nervous System Manifestations
Management of Musculoskeletal Manifestations
Arthritis
Avascular Necrosis
Myositis
Management of Cutaneous Manifestations
General Nonpharmacologic Measures
Topical Treatment
Systemic Therapy
Biologic Therapies and Experimental Drugs
Hematologic Involvement
Management of Cardiopulmonary Manifestations
Management of other Nonrenal/Non-CNS Manifestations
Future Perspectives: Treat to Target in Systemic Lupus Erythematosus
References
143
143
Management of central nervous system lupus
Etiology of Neuropsychiatric Systemic Lupus Erythematosus
Clinical Manifestations of Selected Neuropsychiatric Events
Headache
Psychosis, Mood Disorders, and Anxiety
Cerebrovascular Disease
Seizures
Demyelination, Transverse Myelopathy, and Chorea
Peripheral Nervous System Disease
Acute Confusional State
Neurocognitive Disorders
Diagnosis of Neuropsychiatric Systemic Lupus Erythematosus
Neuroimaging in Neuropsychiatric Systemic Lupus Erythematosus
Treatment of Neuropsychiatric Events in Patients with Systemic Lupus Erythematosus
Ischemic-Mediated Injury
Inflammation-Mediated Injury
Pharmacologic Treatment and Rehabilitation of Neurocognitive Disorders
References
144
144
Management of renal lupus
Introduction
Therapeutic Agents in Lupus Nephritis
Cyclophosphamide (High- and Low-Dose Regimens)
Mycophenolate Mofetil/Mycophenolic Acid
Calcineurin Inhibitors
Biologic Agents
Rituximab
Belimumab
Treatment Options and Recommendations
Proliferative Lupus Nephritis
Initial (“induction”) treatment
Mild-moderate disease
Severe disease
Subsequent (“maintenance”) treatment
Class V Lupus Nephropathy
Monitoring and Targets of Therapy
Renal response and nonresponding/refractory disease
Renal relapses
Adjunct Treatment
End-Stage Renal Disease and Kidney Replacement Modalities
References
145
145 Systemic lupus erythematosus in pregnant patients and neonatal lupus
Introduction
Prepregnancy Evaluation and Counseling
Medication Use in Pregnancy
Maternal and Fetal Complications During Pregnancy
Distinguishing Changes of Normal Pregnancy From Lupus Flares
Lupus Nephritis and Preeclampsia
Antiphospholipid Antibodies
Neonatal Lupus
Pregnancy and Systemic Lupus Erythematosus Management
Monitoring
Labor and Delivery
Lactation
References
146
146
Sjögren syndrome
History
Epidemiology
Glandular Pathology
Clinical Features
Glandular Involvement
Ocular manifestations
Oral manifestations
Extraglandular Manifestations
Overview
Primary versus secondary disease
Constitutional symptoms
Cutaneous involvement
Musculoskeletal involvement
Pulmonary involvement
Gastrointestinal and hepatic involvement
Renal involvement
Gynecologic involvement
Neurologic involvement
Endocrine involvement
Systemic vasculitis
Hematologic abnormalities
Systemic Autoimmunity
Association with other Autoimmune Diseases
Lymphoproliferative Disease
Natural History
Classification Criteria
Diagnostic Evaluation
Ophthalmologic Examination
Major Salivary Glands
Labial Gland Biopsy
Assessment of Disease Activity
Differential Diagnosis
Pathogenesis
Genetic Susceptibility
Environmental Factors
Role of the target tissue
Immune Pathways
Interferons and TLR activation
T cells
B cells and B cell–activating factor
Lymphomagenesis
Management
Glandular Manifestations
Extraglandular Manifestations
Lymphoma
References
147
147
Antiphospholipid syndrome: pathogenesis, diagnosis, and management
Antiphospholipid Syndrome: Definition and History
Epidemiology
Pathogenesis
Mechanisms of Thrombosis
Mechanisms of Pregnancy Loss
Clinical Features
Overview
Venous Thrombosis
Arterial Thrombosis
Pregnancy Complications
Nervous System Abnormalities
Cardiac Valve Abnormalities
Skin Manifestations
Thrombocytopenia and Hemolytic Anemia
Renal Manifestations
Catastrophic Antiphospholipid Syndrome
Laboratory Diagnosis
Serologic Assays Used in the Diagnosis of Antiphospholipid Syndrome
Anticardiolipin test
Lupus anticoagulant test
Anti β2-GPI test
Novel Serologic Assays for Antiphospholipid Syndrome
Seronegative APS
Importance of Scoring Systems in APS
Thrombotic risk assessment
Irreversible damage assessment
Management
Management of Thrombosis
Secondary thromboprophylaxis
Non-VKA oral anticoagulants (NOACs)
Primary thromboprophylaxis
Pregnancy Management
General Pregnancy Care in Women With Obstetric Antiphospholipid Syndrome (Oaps)
Pharmacologic Management of Antiphospholipid Syndrome During Pregnancy
Recurrent Early (Preembryonic or Embryonic) Miscarriage
Fetal Death or Prior Early Delivery Due to Severe Preeclampsia or Placental Insufficiency
Antiphospholipid Syndrome With Thrombosis
Postpartum Period
Management of Other Manifestations of Antiphospholipid Syndrome
Alternative Therapies for Refractory and Difficult Cases
Hydroxychloroquine
Statins
Rituximab
Complement Inhibition
Future Treatments
References
148
148
Classification and epidemiology of systemic sclerosis
Introduction
Disease Classification
Very Early Disease Subset
Epidemiology
Prevalence and Incidence
Disease Risk Factors
Influence of Age, Gender, Ethnicity
Age
Gender
Ethnicity
Sur vival
Survival Prognosis Factors
Summary and Conclusion
References
149
149
Clinical and serologic features of systemic sclerosis
Introduction
Diagnosis and Classification
Clinical Features
Skin
Musculoskeletal
Gastrointestinal Tract
Heart
Arrhythmias and conduction defects
Myocarditis
Cardiac fibrosis
Valvular heart disease
Systolic and diastolic dysfunction
Lungs
Upper airways
Parenchymal lung disease
Pleural and pericardial disease
Pulmonary vascular disease
Renal Scleroderma
Digital Vasculopathy
Neurologic Manifestations of Systemic Sclerosis
Calcinosis
Sexual Dysfunction
Psychological and Social Impact of Systemic Sclerosis
Serologic Features of Systemic Sclerosis
Autoimmune Serology
Other Serologic Markers in Systemic Sclerosis
Risk Stratification
Conclusions
References
150
150
Etiology and pathogenesis of systemic sclerosis
Introduction
Etiology
Genetic Studies in Systemic Sclerosis
Functional SNP activity
Whole-exome and whole-genome sequencing
Epigenetic changes in systemic sclerosis
Analysis of gene expression patterns in systemic sclerosis: distinct molecular subsets
Noncoding RNAs in SSc
Single Cell Analyses are Revealing the Complexity of Cell Phenotypes in SSc
Infectious Etiologic Agents in Systemic Sclerosis
Environmental Exposure, Drugs, and Radiation
Pathology
Vascular Pathology
Tissue Fibrosis
Organ-Specific Pathology
Skin
Lungs
Cardiac disease
Gastrointestinal tract
Kidneys
Pathologic features of SSc in other organs
Pathogenesis: Immunity, Vascular Injury, and Fibrosis
Inflammation and Immunity
The immune response in systemic sclerosis
Innate immunity in systemic sclerosis
Monocyte and macrophage activation in fibrosis
Toll-like and nucleic acid receptor in systemic sclerosis
The inflammasome in systemic sclerosis
Oxidative stress
Endoplasmic reticulum stress, autophagy, and the unfolded protein response
Cellular senescence
Humoral immunity in the pathogenesis of systemic sclerosis
Autoantibodies associated with nucleic acids in systemic sclerosis
Neoantigens as autoimmune targets in systemic sclerosis
Autoantibodies implicated in tissue damage in systemic sclerosis
Toll-like receptor activation and autoreactive B cells
Cellular immunity in systemic sclerosis
Adaptive T-cell responses in fibrotic disease
Type 2 helper T-cell immune skewing and fibrosis
Innate lymphoid cells in systemic sclerosis
Proinflammatory mediators in SSc (Table 150.2)
Interferon
Interleukin-4 and interleukin-13
Interleukin-6
Adenosine
Tumor necrosis factor-α
Chemokines
Vascular Injury and Vasculopathy in Systemic Sclerosis
Endothelial cell injury and apoptosis
Cytotoxic factors in endothelial apoptosis
Vascular spasm, reactive oxygen species, and hypoxia
Endothelium-dependent relaxation and nitric oxide
Endothelin-1
Intimal hyperplasia
Endothelial–mesenchymal transformation
Circulating endothelial cells and vascular progenitor cells
Platelet activation and coagulation
Tissue Fibrosis
Pathogenesis of fibrosis: cellular and molecular determinants
Cellular determinants of fibrosis
Fibroblasts
Myofibroblasts
Pericytes
Cellular fate transitions in systemic sclerosis
Bone marrow–derived mesenchymal progenitor cells in SSc
Molecular determinants of fibrosis
Regulation of collagen production
Cell-autonomous regulation of collagen synthesis
Peroxisome proliferator–activated-γ: the interface between adipogenesis and fibrosis
Biomechanical signaling
Fibrogenic Growth Factors and Chemokines
Transforming growth factor-β is a master regulator of connective tissue remodeling
Connective tissue growth factor or CCN2
Platelet-derived growth factors
Wnt–β-catenin signaling
Paracrine mediators with antifibrotic activity
Cultured systemic sclerosis fibroblasts show cell-autonomous persistent activation ex vivo
Animal Models of Systemic Sclerosis
Heritable Animal Models of Scleroderma
Tight skin 1 mouse
Tight skin 2 mice
Constitutive transforming growth factor-β receptor 1 signaling
Inducible Animal Models of Scleroderma
Bleomycin-induced scleroderma in the mouse
Immunologically Induced Mouse Models of Systemic Sclerosis
Topoisomerase I immunization-induced scleroderma in mice
Type V collagen immunization-induced scleroderma in rabbits
Sclerodermatous chronic graft-versus-host disease
References
151
151
Outcomes measures in systemic sclerosis
Introduction
Measuring Disease Activity, Damage, and Severity in Scleroderma
Disease Activity in Scleroderma
Assessment of Disease Damage
Assessment of Disease Severity
Outcome Measures in Scleroderma
Measuring Skin Disease in Scleroderma
Measuring Musculoskeletal Involvement in Scleroderma
Measuring Cardiopulmonary Disease in Scleroderma
The 6-minute walk test—an outcome measure for pulmonary arterial hypertension
Composite outcome endpoints
Dyspnea indices
Measuring Gastrointestinal Tract Disease in Scleroderma
Measuring Vascular Disease in Scleroderma: Raynaud Phenomenon and Digital Ulcers
Measuring ischemic digital ulcers in scleroderma
Measuring Physical Function and Health-Related Quality of Life
Patient-Reported Outcomes Measurement Information System®
COMPOSITE ENDPOINTS
American College of Rheumatology Provisional Composite Response Index for Clinical Trials in Early Diffuse Cutaneous System ...
Biomarkers for Scleroderma
Conclusion
Acknowledgments
References
152
152
Management of systemic sclerosis
Introduction
Principles of Effective Management
Clinical Trials in Systemic Sclerosis
Disease-Modifying Therapies for Systemic Sclerosis
Organ-Based Assessment and Treatments
Raynaud Phenomenon
Critical digital ischemia and ulceration
Musculoskeletal Complications
Skin Thickening
Other Skin Manifestations
Gastrointestinal Complications
Lung Disease
Pulmonary fibrosis
Pulmonary vascular disease
Pulmonary arterial hypertension
Macrovascular Disease
Cardiac Disease
Renal Scleroderma
Summary
References
153
153
Emerging therapies for systemic sclerosis
Introduction
Skin Fibrosis as Outcome for Clinical Trials
Change in Clinical Trial Design for Emerging Therapies in SSc
Development of Targeted Therapies for SSc
Randomized Clinical Trials From 2018–2021 To Identify Emerging Therapies In Ssc
Ild As The Primary Outcome
Skin As The Primary Outcome
Composite Response Index Criss As The Primary Outcome
Pulmonary Hypertension As The Primary Outcome
Gastrointestinal Symptoms As The Primary Outcome
Translation of The Emerging Therapies Into Clinical Use
Summary
References
154
154
Raynaud phenomenon
History
Nomenclature
Epidemiology And Etiology
Pathophysiology
Neural Abnormalities And Mechanisms
Vascular Abnormalities And Mechanisms
Intravascular Abnormalities And Mechanisms
Clinical Features
Investigations
Confirming RP
Investigations For Secondary Causes
Management
General Measures
Drug Treatment
Calcium channel blockers
Other vasodilators
Prostaglandin treatment
Other medical therapies
Surgery
Conclusion
Acknowledgment
References
155
155
Localized scleroderma and scleroderma-like syndromes
Localized Forms of Scleroderma
Morphea
Deep morphea or morphea profunda
Generalized or diffuse morphea
Linear Scleroderma
Conditions that Mimic Scleroderma
Scleromyxedema
Nephrogenic Systemic Fibrosis
Scleredema
Eosinophilic Fasciitis
Chronic Graft-Versus-Host Disease
References
156
156
Clinical features, classification, and epidemiology of inflammatory muscle disease
Epidemiology
Classification Criteria
Incidence and Prevalence by Age, Race, and Sex
Environmental Factors
Genetic Factors
Clinical Features
Constitutional
Skeletal Muscle
Skin
Calcinosis
Joints
Lung
Heart
Gastrointestinal Tract
Peripheral Vascular System
Kidney
Differential Diagnosis
Noninflammatory Myopathies
Other Inflammatory Myopathies
Malignancy and Myositis
Investigations
General Concepts
Serum Muscle Enzymes
Electromyography
Muscle Biopsy
Magnetic Resonance Imaging
Skin
Serum Autoantibodies
Overview of the Natural History and Disease Prognosis
Prognostic Considerations
Survival
Disability
References
157
157
Etiology and pathogenesis of inflammatory muscle disease (myositis)
Introduction
Muscle Biology and Physiology
Muscle Development and Regeneration
Etiology
Genetic Factors
Environmental Factors
Infections
Ultraviolet Light and Vitamin D Deficiency
Drugs
Smoking
Malignancy
Pathogenesis
Muscle Histopathologic Features
Immunopathologic Features
Cytokines and Chemokines
Immune Mechanisms and Muscle Function
Mechanisms of cell damage
Indirect effects of molecules from the immune system (cytokines and others) on muscle metabolism and function
Involvement of the microvasculature in inflammatory myopathies
Humoral Mechanisms
Inclusion Body Myositis
Conclusion
References
158
158
Clinical significance of autoantibodies in inflammatory muscle disease
Introduction
Myositis-Associated Autoantibodies
Anti–PM-SCL
Anti-RO/SSA And Anti-LA/SSB
Anti-KU
Anti–U1-SNRNP
Anti-PUF60
Myositis-Specific Autoantibodies
ANTI-ARS
Dermatomyositis-Specific Autoantibodies
Anti–MI-2
Anti-MDA5
Anti–TIF-1γ
Anti-SAE
Anti-NXP2
Inclusion Body Myositis–Associated Antibody
Anti-MUP44
Immune-Mediated Necrotizing Myopathy–Associated Antibodies
Anti-SRP
Anti-HMGCR/ANTI-200/100
Conclusion
References
159
159
Management of inflammatory muscle disease
General Principles
Assessing Disease Activity and Damage
Drug Therapies
Corticosteroids
Adrenocorticotropic Hormone Gel
Methotrexate
Azathioprine
Intravenous Immunoglobulin
Mycophenolate Mofetil
Cyclosporine and Tacrolimus
Cyclophosphamide
Antimalarials
Rituximab
Anti–Tumor Necrosis Factor Agents
Anakinra
Janus Kinase Inhibitors
Other Therapies
Nonpharmacologic Treatments
Patient and Family Education
Rehabilitation
Management of Extramuscular Manifestations
Interstitial Lung Disease
Cardiac Involvement
Gastrointestinal Involvement
Skin Involvement
Calcinosis
Inclusion Body Myositis
Statin-Associated Necrotizing Myopathy
Future Directions
Acknowledgments
References
160
160
Metabolic, drug-induced, and other noninflammatory myopathies
Key Points
Metabolic Myopathies
Glycogen and glucose metabolism (Fig. 160.1)
Defects of glucose and glycogen metabolism
Myophosphorylase deficiency (McArdle disease, glycogenosis type V)
Phosphofructokinase deficiency (glycogen storage disease type VII, Tarui disease)
Debrancher deficiency (Cori-Forbes disease, glycogenosis type III)
Acid maltase deficiency (glycogenosis type II, Pompe disease)
Lipid metabolism
Fatty acid oxidation disorders
Carnitine palmitoyltransferase II deficiency
Very-long-chain acyl-CoA dehydrogenase deficiency
Long-chain acyl-CoA dehydrogenase deficiency and trifunctional protein deficiency
Mitochondrial myopathies
Myoadenylate deaminase deficiency
Drug- and Toxin-Induced Myopathies
Statins
Colchicine
Hydroxychloroquine
Glucocorticoids
Alcohol
Endocrine Myopathies
Thyroid disorders
Cushing syndrome
Diabetes
Muscular Dystrophies
Duchenne muscular dystrophy
Becker muscular dystrophy
Emery-dreifuss muscular dystrophy
Limb-girdle muscular dystrophies
Myotonic dystrophy
Proximal myotonic myopathy
Infectious Myopathies
Pyomyositis
Gas gangrene
Psoas abscess
Influenza
Human immunodeficiency virus
Parasites
References
161
161
Classification and epidemiology of vasculitis
Introduction
Classification, Definitions, and Diagnostic Criteria for Vasculitis
Historical Background
American College of Rheumatology 1990 Classification Criteria
Chapel Hill Consensus Conferences
European Medicines Agency Algorithm
ACR/EULAR Criteria
Criteria for Childhood Vasculitis
Large-Vessel Vasculitis
Medium-Vessel Vasculitis
Polyarteritis Nodosa
Kawasaki Disease
Small-Vessel Vasculitis
ANCA Vasculitis
Immune Complex Vasculitis
Cryoglobulinemic vasculitis
Immunoglobulin A vasculitis (Henoch–Schönlein purpura)
Hypocomplementemic urticarial vasculitis
Other Types of Vasculitides
Behçet disease
Diagnostic Criteria for Vasculitis
Current Position
Epidemiology of Vasculitis
Vasculitides Predominantly Affecting Large Vessels
Giant Cell Arteritis
Takayasu Arteritis
Vasculitides Predominantly Affecting Medium-Sized Vessels
Polyarteritis Nodosa
Kawasaki Disease
Vasculitides Predominantly Affecting Small Vessels
ANCA-Associated Vasculitis
Incidence
Prevalence
Influence of race and ethnicity
Genetic influences
Other environmental factors
Immunoglobulin A Vasculitis (Henoch–Schönlein Purpura)
Anti–Glomerular Basement Membrane Disease (Goodpasture Syndrome)
Hypocomplementemic Urticarial Vasculitis
Behçet Disease
Secondary Vasculitides
Current Status
References
162
162
Biology and immunopathogenesis of vasculitis
Introduction
The Endothelium
Endothelial Cell Activation
Leukocyte–Endothelial Cell Interaction
Role Of Aging In Leukocyte–Endothelial Cell Interaction
Endothelium, Coagulation, And Inflammation
Damage And Repair: Angiogenesis
Immunopathogenesis Of Small-Vessel Vasculitis
Immune Complex–Mediated Small-Vessel Vasculitides
Immunoglobulin A vasculitis (Henoch Schönlein purpura)
Anti–glomerular basement membrane disease
Cryoglobulinemic vasculitis
Hypocomplementemic urticarial vasculitis (anti-C1q vasculitis)
Antineutrophil Cytoplasmic Antibody–Associated Vasculitides
Immunopathogenesis Of Major Small-Vessel Vasculitides
Granulomatosis with polyangiitis
Microscopic polyangiitis
Eosinophilic granulomatosis with polyangiitis
Immunopathogenesis of Vasculitides of Medium- and Small-Sized Arteries
Polyarteritis Nodosa
Kawasaki Disease
Immunopathogenesis of Large-Vessel Vasculitides
Giant Cell Arteritis
Takayasu Arteritis
Conclusion
References
163
163
Polyarteritis nodosa and Cogan syndrome
Key Points
Introduction
Polyarteritis Nodosa
Definition
Classification
Epidemiology
Environmental factors
Genetics
Clinical Features
Cutaneous lesions
Musculoskeletal features
Neurologic features
Renal involvement
Gastrointestinal involvement
Cardiac involvement
Orchitis
Other features
Secondary polyarteritis nodosa
Limited forms of polyarteritis
Pathology
Investigations
Differential Diagnosis
Management
Prognosis
Cogan Syndrome
Definition
Classification
Typical and atypical Cogan syndrome
Epidemiology
Environmental factors
Pathogenesis
Clinical Features
Ocular
Vestibuloauditory
Vasculitis
Other systemic features
Associations with other diseases
Assessment Of Disease Activity And Investigations
Blood and cerebrospinal fluid
Assessment of organ involvement
Ocular
Vestibuloauditory
Cardiovascular
Neurologic
Differential Diagnosis
Management
Main principles
Ocular disease
Vestibuloauditory disease
Systemic vasculitis
Prognosis
Conclusion
References
164
164
Antineutrophil cytoplasm antibody–associated vasculitis
Definition
Etiology and Pathogenesis
Epidemiology
Classification and Definitions
Clinical Features
Investigations and Differential Diagnosis Of Antineutrophil Cytoplasm Antibody–Associated Vasculitis
Pathology
Clinical Assessment of Vasculitis
Disease Activity
Damage in Vasculitis
Other Scores
Assessing Function
Therapies
Treatments
No Treatment
Topical And Other Treatment Of Upper And Lower Airways
Systemic Glucocorticoid Therapy
Immunosuppressive Agents
Rituximab
Other Immunosuppressive Agents
Outcomes
References
165
165
Takayasu arteritis
History
Epidemiology
Clinical Features
Investigations
Diagnosis And Monitoring Of Disease Activity
Laboratory Investigations
Radiographic Studies
Differential Diagnosis
Pathology And Pathogenesis
Management
General Principles
Immunosuppressive Therapy
Glucocorticoids
Methotrexate
Azathioprine
Cyclophosphamide
Other conventional immunosuppressive agents
Biologic Therapies
Antiplatelet Therapy
Nonmedical Interventions
Management of Comorbid Features
Outcome
Pregnancy
References
166
166
Polymyalgia rheumatica and giant cell arteritis
Introduction
Epidemiology and Diagnosis
Relationship Between Polymyalgia Rheumatica And Giant Cell Arteritis
Pathology
Pathogenesis
Role of Infectious Agents
Immunogenetics
Innate And Adaptive Immune Mechanisms
Clinical Findings
Giant Cell Arteritis
Cranial Symptoms
Visual symptoms
Cerebrovascular ischemic events
Constitutional symptoms
Large-vessel vasculitis
Musculoskeletal symptoms and polymyalgia
Other less frequent manifestations
Polymyalgia Rheumatica
Laboratory Findings
Imaging
Polymyalgia Rheumatica
Giant Cell Arteritis
Ultrasonography
Computed tomography and computed tomography angiography
Magnetic resonance imaging and magnetic resonance angiography
Digital subtraction angiography
18F-Fluorodeoxyglucose positron emission tomography
Differential Diagnosis
Treatment
Giant Cell Arteritis
Polymyalgia Rheumatica
References
167
167
Behçet disease
Introduction
Epidemiology
Pathogenesis
Clinical Features
Mucocutaneous Features
Eye Involvement
Musculoskeletal Features
Cardiovascular Involvement
Neurologic Involvement
Gastrointestinal Involvement
Lung Involvement
Others
Laboratory Features
Disease Course and Prognosis
Differential Diagnosis
Management
References
168
168
Kawasaki disease
History
Epidemiology
Clinical Features
Laboratory Assessments
Pathologic Features
Etiology And Pathogenesis
Treatment And Management
References
169
169
IgA vasculitis (Henoch–Schönlein purpura)
Definition
Epidemiology
Classification
Etiology and Pathogenesis
Environmental Factors
Immunologic Factors
Genetic Background
Clinical Findings
Cutaneous Involvement
Joint Involvement
Gastrointestinal Involvement
Renal Involvement
Genitourinary Involvement
Neurologic Involvement
Pulmonary Involvement
Malignancy
Pregnancy
Diagnosis
Differential Diagnosis
TreatmeNt
Treatment of Henoch–Schönlein Purpura–Associated Nephritis
Moderate nephritis
Rapidly progressive glomerulonephritis
Renal transplantation
Outcome and Prognosis
References
170
170
Cutaneous vasculitis and panniculitis
Classification
Vasculitis
Panniculitis
Pathologic, Clinical, and Systemic Features
Cutaneous Vasculitides
Histopathologic features
Palpable purpura
Urticarial lesions
Other cutaneous lesions
Systemic manifestations
Vasculitic syndromes with prominent cutaneous disease
Acute hemorrhagic edema of infancy
Hypocomplementemic urticarial vasculitis
Vasculitis associated with paraproteinemia
Paraneoplastic vasculitis
Cutaneous polyarteritis nodosa
Erythema elevatum diutinum
Cutaneous vasculitis in patients with rheumatic diseases
Cocaine- or levamisole-associated vasculitis and vasculopathy syndrome
Panniculitides
Erythema nodosum
Idiopathic neutrophilic lobular panniculitis
α1-Antitrypsin deficiency–associated panniculitis
Pancreatic panniculitis
Calcifying panniculitis of renal failure
Poststeroid panniculitis
Lipoatrophic panniculitis
Histiocytic cytophagic panniculitis or subcutaneous panniculitis–like T-cell lymphoma
Lupus erythematosus panniculitis (lupus profundus)
Sclerosing panniculitis (lipodermatosclerosis)
Factitial panniculitis
Investigations
Cutaneous Vasculitis
Panniculitis
Differential Diagnosis
Cutaneous Vasculitis
Panniculitis
Management
Cutaneous Vasculitis
Panniculitis
Conclusion
References
171
171
Cryoglobulinemia
Epidemiology
Clinical Manifestations
Skin Manifestations
Joint Manifestations and Weakness
Renal Manifestations
Nervous Manifestations
Liver Manifestations
Lymphoproliferation
Other Manifestations
Outcome
Diagnosis and Classification
Pathogenesis
Therapy
References
172
172
Primary angiitis of the central nervous system
History
Case Definition and Criteria
Clinical Syndromes of Cerebral Vasculitis
Clinical Findings
Pathogenesis
Pathology
Laboratory Investigations
Brain Imaging
Biopsy Findings
Differential Diagnosis
Reversible Cerebral Vasoconstriction Syndromes
Cerebral Amyloid Angiitis
Paraneoplastic Angiitis
Diagnostic Approach
Treatment and Outcome
References
173
173
Adult-onset Still disease
Introduction
Epidemiology
Pathogenesis
Genetic Predisposition
Environmental Factors
Immune Dysregulation
Clinical Presentation
Fever
Arthritis
Rash
Other Frequent Findings
Infrequent Findings
Laboratory Findings
Classification and Diagnosis
Management
First-Line Treatment: Nonsteroidal Antiinflammatory Drugs and Glucocorticoids
Second-Line Therapy: Immunosuppressants
Third-Line Therapy: Biologic Agents
Tumor necrosis factor inhibitors
Anakinra
Tocilizumab
Other biologic agents
Special Issues Regarding Treatment
Pregnancy
Macrophage activation syndrome
AA amyloidosis
Prognosis and Functional Outcome
References
174
174
Monogenic autoinflammatory diseases
Key Points
Introduction
The Hereditary Episodic Fever Syndromes
Familial Mediterranean Fever
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Laboratory investigations
Treatment
Mevalonate Kinase Deficiency (Previously Hyperimmunoglobulinemia D with Periodic Fever Syndrome)
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Clinical findings
Laboratory investigations
Treatment
TNF-Receptor–Associated Periodic Syndrome
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Laboratory investigations
Treatment
Neutrophilic Urticaria (The Cryopyrin-Associated Periodic Syndrome, Familial Cold Autoinflammatory Syndrome, Muckle-Wells S ...
Background
Genetics and Pathophysiology
The NLRP3 Inflammasome and IL-1β Activation and Secretion
Clinical Features And Laboratory Findings
Familial Cold Autoinflammatory Syndrome
Muckle-Wells Syndrome
Neonatal-Onset Multisystem Inflammatory Disease or Chronic Infantile Neurologic Cutaneous And Arthritis Syndrome
Laboratory investigations of cryopyrin-associated periodic syndromes
Treatment of cryopyrin-associated periodic syndromes
Variable Rashes, High Serum Interleukin-18, and Variable Predisposition to Macrophage Activation Syndrome
NLRC4-Related Autoinflammatory Syndromes
Background
Genetics and pathophysiology
Clinical features and laboratory findings
CDC42-mediated autoinflammatory disease
IL-18PAP-MAS
Treatment of high IL-18 states
NLRP1-Associated Autoinflammation with Arthritis and Dyskeratosis
Background
Genetics and Pathophysiology
Clinical features and laboratory findings
Treatment
Pustular Skin Rashes and Episodic Fevers
Interleukin-1–Mediated Pyogenic Disorders with Sterile Osteomyelitis
Deficiency of the IL-1-receptor antagonist
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Majeed syndrome
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Partially Interleukin-1–Mediated Pyogenic Disorders
Pyogenic Sterile Arthritis, Pyoderma Gangrenosum, and Acne Syndrome
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
HA20: Haploinsufficiency of A20 (Monogenic Form of Behçet’s Disease)
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Pyogenic Disorders Caused by Non–Interleukin-1 Cytokine Dysregulation
Deficiency of Interleukin 36 Receptor Antagonist
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
CARD14-Mediated Psoriasis
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
AP1S3-Mediated Pustular Psoriasis
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Early-Onset Inflammatory Bowel Disease
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Vasculopathy and Panniculitis/Lipoatrophy Syndromes
Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature Syndrome Or Proteasome-Associated Auto ...
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Otulin-Related Autoinflammatory Syndrome
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Nemo Deleted Exon 5-Autoinflammatory Syndrome (NEMO-NDAS) and SAMD9L-Associated Autoinflammatory Disease (SAMD9L-SAAD)
Vasculopathy and/or Vasculitis with Livedo Reticularis Syndromes
Without Significant Central Nervous System Disease
Sting-associated vasculopathy with onset in infancy
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
With Severe Central Nervous System Disease
Deficiency of adenosine deaminase 2
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Aicardi-Goutières syndromes
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Spondyloenchondrodysplasia with immune dysregulation
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Autoinflammatory Disorders with Granulomatous Skin Diseases
Without Significant Immunodeficiency
Blau syndrome/early onset sarcoidosis (pediatric granulomatous arthritis)
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Laboratory investigations
Complications of untreated disease
Treatment
With Variable Features of Immunodeficiency
PLCG2-associated antibody deficiency and immune dysregulation
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Other Autoinflammatory Syndromes
LACC1-Mediated Monogenic Still Disease
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Familial Cold-Induced Autoinflammatory Syndrome 2 (FCAS2)
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Syndromes Presenting with a Wider Clinical Phenotype
Sideroblastic Anemia, B-Cell Immunodeficiency, Periodic Fevers, and Developmental Delay Syndrome
Background
Genetics and pathophysiology
Clinical features and laboratory findings
RIPK1 Deficiency (Cleavage-Resistant RIPK1-Induced Autoinflammatory Syndrome)
Cherubism
Autoinflammation and Immunodeficiency
Acknowledgment
References
175
175
Sarcoidosis
History
Epidemiology
Prevalence and Incidence
Risk Factors
Immunopathogenesis
Step 1: Lymphocytic Alveolitis
Step 2: Granuloma Formation
Step 3: Granuloma Resolution
Diagnostic Investigations
Laboratory Tests
Imaging
Biopsy
Additional Tests
Differential Diagnosis
Clinical Features
Respiratory Involvement
Ophthalmologic Involvement
Cutaneous Involvement
Cardiac Involvement
Nervous System Involvement
Musculoskeletal Involvement
Articular
Osseous
Muscular
Other Organ System Involvement
Childhood Sarcoidosis
Sarcoidosis Associations
Natural History and Prognosis
Management
Monitoring of Therapy
Acknowledgment
References
176
176
Relapsing polychondritis
HISTORY
Epidemiology
Clinical Features
Otorhinolaryngeal Disease
Respiratory Disease
Musculoskeletal Symptoms
Cardiovascular Disease
Ocular Symptoms
Renal Disease
Dermatologic Disease
Neurologic Disease
Miscellaneous Features
Diagnosis And Investigations
Differential Diagnosis
Pathogenesis
Management
Acknowledgments
References
177
177
The systemic amyloidoses
Introduction
Amyloidogenesis In Vivo
Aggregation
Tissue Deposition
Tissue Compromise
Host Responses
Clinical Epidemiology
AA Amyloid
Clinical Features
Diagnosis
Treatment
Aβ2-Microglobulin Amyloidosis (Aβ2m) (Dialysis Related Amyloidosis, DRA)
Clinical Features
Diagnosis
Treatment
AL (Immunoglobulin L-Chain Amyloidosis)
Epidemiology
Clinical Features
Diagnosis
Treatment
The Transthyretin Amyloidoses (ATTR)
Epidemiology
Hereditary autosomal dominant ATTR
ATTR pV50M
ATTR pV142I
ATTRwt (senile systemic amyloidosis)
Clinical Features
ATTR hereditary polyneuropathy
ATTR hereditary and sporadic cardiomyopathy
Diagnosis
Treatment
Attacking the Deposits
References
178
178
IgG4-related disease
History and Overview
Epidemiology
Clinical Features
IgG4-related type 1 autoimmune pancreatitis and sclerosing cholangitis
IgG4-related ophthalmic disease and sialoadenitis
IgG4-related kidney disease
IgG4-related lung disease
IgG4-related retroperitoneal fibrosis (RPF) and periaortitis
Other Organ Manifestations
Laboratory and Image Findings
Blood Test Findings
Histopathologic Findings
Radiologic Imaging
Pathogenesis45
Autoantigens
Innate Immunity
T-Cell Populations
B Cells
Diagnosis
The 2020 Revised Comprehensive Diagnostic (RCD) Criteria for IgG4-RD61
The 2019 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Classification Criteria For IgG4 ...
Differential Diagnosis
Management
References
179
179
Immune-mediated complications of checkpoint inhibitors
Introduction
Mechanism of Action/Review of T-Cell Activation
Normal T-Cell Activation Background Data
Ctla-4 Antagonist
Pd-1 Inhibition
Immune-Related Adverse Events
Overview of IrAE Toxicity Grades
Endocrine
Gastrointestinal
Hepatic
Pulmonary
Neurologic
Dermatologic
Rheumatic IrAEs (fig. 179.3)
Sicca syndrome
Vasculitis
SLE/nephritis
Inflammatory arthritis
Polymyalgia rheumatica
Pathophysiology
Treatment of Rheumatic IrAEs
Guidelines
Targeted therapies
Anti-Tumor Necrosis Factor Directed Therapies
Anti-Interleukin-6 Directed Therapies
Anti-B-Cell Directed Therapies
Anti-T-Cell Directed Therapies
Other Targeted Therapies
Potential Adverse Effects From Glucocorticoids
Use of Checkpoint Inhibitors In Patients With Preexisting Autoimmune Disease
Conclusion
References
180
180
The epidemiology of coronavirus disease 2019 (COVID-19) and rheumatic disease
Introduction
Rheumatic Diseases and Risk of Covid-19 and Related Outcomes
Risk of Covid-19
Covid-19-Related Outcomes
Use of Antirheumatic Medications for the Management of Covid-19
Antimalarials
Glucocorticoids
Interleukin-6 Inhibitors
Interleukin-1 Inhibitors
Tumor Necrosis Factor Inhibitors
Colchicine
Janus Kinase (Jak) Inhibitors
Autoimmune/Inflammatory Manifestations of Covid-19
Multisystem Inflammatory Syndrome In Children and Adults
Thrombotic Events
New Onset Arthritis In Covid-19
Post-Covid Syndrome
Impact of the Covid-19 Pandemic On People With Rheumatic Disease
References
181
181
Epidemiology and classification of osteoarthritis
Introduction
Definitions of Osteoarthritis
Radiographic Osteoarthritis: Definitions
Prevalence of radiographic osteoarthritis
Prevalence of radiographic hip osteoarthritis
Prevalence of radiographic knee osteoarthritis
Prevalence of radiographic hand osteoarthritis
Prevalence of radiographic osteoarthritis in other sites
Incidence and progression of radiographic osteoarthritis
Incidence and progression of radiographic hip osteoarthritis
Incidence and progression of radiographic knee osteoarthritis
Symptomatic Osteoarthritis: Definitions
Prevalence of symptomatic knee/hip osteoarthritis
Prevalence of symptomatic hip osteoarthritis
Prevalence of symptomatic knee osteoarthritis
Prevalence of symptomatic hand osteoarthritis
Prevalence of symptomatic osteoarthritis in other sites
Incidence and progression of symptomatic osteoarthritis
Incidence of joint replacement
Mortality Rate In Osteoarthritis
Conclusion
References
182
182
Local and systemic risk factors for incidence and progression of osteoarthritis
Introduction
Systemic Risk Factors For Knee Osteoarthritis
Age
Sex
Body Weight
Race/Ethnicity
Bone Mineral Density
Occupational Activity
Nonoccupational Physical Activity
Nutritional And Dietary Factors
Smoking
Local Risk Factors For Knee Osteoarthritis
Injury
Knee Tissue Abnormalities
Local Neuromuscular And Mechanical Factors
Hip Osteoarthritis
Developmental Abnormalities
Hand Osteoarthritis
Hand Osteoarthritis Progression
Risk Factors For Pain In Osteoarthritis
Radiographic Disease
Tissue Lesions Detected By Mri
Psychological Factors
Body Weight
Risk Factors For Function Limitation And Disability In Osteoarthritis
Pain, Strength, Self-Efficacy, Depression, And Physical Activity
Knee Confidence, Instability, And Falls
Body Weight
References
183
183
Clinical features of osteoarthritis
Introduction
Definition
Symptoms (Box 183.1)
Pain
The joint as a driver of osteoarthritis pain
Biopsychosocial aspects of osteoarthritis pain
Joint Deformity and Swelling
Stiffness
Mechanical Symptoms
Signs (BOX 183.1)
Crepitus
Joint Swelling
Observable Deformity
Gait
Somatosensory Alterations
Clinical Presentations
Knees
HIPS
Hands
Shoulders
Feet
Spine
Other Sites
Miscellaneous Osteoarthritis Syndromes
Generalized osteoarthritis
Erosive osteoarthritis
Diffuse idiopathic skeletal hyperostosis
Evaluation
Patient-Reported Outcome Measures
Mortality
Conclusion
References
184
184
Animal models of osteoarthritis
Introduction
Why do we need osteoarthritis models?
How do we Model Osteoarthritis in Animals?
What components of disease are being modeled?
Osteoarthritis Models: A Historical Perspective
How Good are the Osteoarthritis Models as Models of Human Disease?
Current Rodent Osteoarthritis Models
Spontaneous Osteoarthritis
Chemical Induction of Osteoarthritis
Surgical Induction of Osteoarthritis
Meniscectomy
Anterior cruciate ligament transection
Destabilization of the medial meniscus
Genetic Modification
Generation of Genetically Modified Mice
How to ensure maximum value from in vivo studies
Animal Model Limitations
Conclusion
References
185
185
Pathogenesis and pathology of osteoarthritis
Introduction
The Normal Joint: Anatomy, Physiology, and Function
Joint Pathology in Osteoarthritis
Cartilage Pathology
Bone Pathology
Synovial Pathology
Meniscal Pathology
Staging and Grading of Cartilage and Bone Pathology in Osteoarthritis
Grading of Synovial Membrane Alterations in Osteoarthritis
Imaging of Joint Pathology in Osteoarthritis
Pathogenetic Concepts in Osteoarthritis
Animal Models of Osteoarthritis
Cartilage Matrix Degradation
Chondrocyte Activation, Differentiation, and Loss
Disease Risk Factors Inform Pathogenesis
Aging
Oxidative stress and mitochondrial dysfunction
Cellular senescence and the senescence-associated secretory phenotype
Autophagy
Biomechanics and Loading
Mechanoreceptors
The pericellular matrix
Neuromuscular function and proprioception
Obesity and Metabolic Disease
Load
Metabolic derangement and inflammation
Other metabolic/associated conditions
Genetics and Epigenetics
Genetics
Epigenetics
Integration of “omics”
Synovial and Bone Response in OA
Synovial membrane and synovitis in OA
Synovial inflammation and pain sensitization in OA
Bone remodeling and pain in OA
Conclusion
Acknowledgment
References
186
186
Genetics and epigenetics of osteoarthritis
Introduction
Early Heritability Studies
Traits and Outcomes Studied in the Genetics Of Osteoarthritis
Twin and Family Studies
Twin Studies
Familial Aggregation Studies
Familial Disorders Associated with Osteoarthritis
Candidate Gene Studies in Osteoarthritis
Genome-Wide Association Studies in Osteoarthritis
Epigenetics of Osteoarthritis
Introduction to Epigenetics
Candidate Gene Dna Methylation Studies in Osteoarthritis
Genome-Wide Epigenetic Studies in Osteoarthritis
Epigenetics as a Modulator of Genetic Risk
Conclusions
Acknowledgments
References
187
187
Imaging of osteoarthritis
Introduction
Conventional Radiography
Radiographic Procedures
What Pathologic Features can Conventional Radiography Assess in Osteoarthritis?
Osteophytes
Subchondral sclerosis, erosions, and cysts
Joint space narrowing
Bone remodeling and attrition
Subchondral trabecular bone analysis
Joint morphology
Conventional radiography and osteoarthritis symptoms
Conventional radiography and early osteoarthritis
Conventional radiography in advanced osteoarthritis
Conventional radiography: quantification and scoring methods
Hip conventional radiography
Hand conventional radiography
Knee conventional radiography
Magnetic Resonance Imaging
What Pathologic Features can Magnetic Resonance Imaging Assess in Osteoarthritis?
Cartilage abnormalities
Synovitis and joint effusion
Fibrocartilage and ligament abnormalities
Subchondral bone marrow lesions and cysts
Bone attrition
Osteophytes
Bone erosion
Three-dimensional bone shape
Muscle
Magnetic Resonance Imaging: Quantification and Scoring Methods
MRI semiquantitative evaluation: knee
MRI semiquantitative evaluation: hand
MRI semiquantitative evaluation: hip
MRI semiquantitative evaluation: foot
Quantitative MRI Analysis
Ultrasound
What Pathologic Features can Ultrasound Assess in Osteoarthritis?
Synovitis
Cartilage
Osteophytes
Menisci
Ultrasound: Quantification and Scoring Methods
Other Imaging Modalities
Scintigraphy
Computed Tomography and Computed Tomographic Arthrography
Positron Emission Tomography
Considerations for Osteoarthritis Imaging in Clinical Practice
Considerations for Future Research in Osteoarthritis Imaging
Summary
References
188
188
Assessment of the patient with osteoarthritis and measurement of outcomes
Introduction
Biomedical Versus Biopsychosocial Perspective in Assessment of Patients with Osteoarthritis
Fundamental Differences between Patient Assessment in Clinical Research Versus Routine Clinical Practice
The World Health Organization’s International Classification Of Functioning, Disability, And Health
Selection of Measures for Evaluation of Patients with Osteoarthritis
Assessment of Impairments in Osteoarthritis
Examination of physical signs of osteoarthritis
Symptom reporting using standardized questionnaires
Assessment of pain
Assessment of fatigue
Assessment of sleep
Assessment of mood
Assessment of Activity Limitations and Participation Restrictions in Osteoarthritis
Measurement of activity limitations using standardized questionnaires
Performance-Based Assessment of Impairments and Activity Limitations
Assessment of Participation Restrictions
Evaluation of Key Contextual Factors
Responsiveness and Interpretation of Change in Patient Status
Responsiveness of Measure Scores
Interpretation of Changes in Measure Scores
Conclusion
Acknowledgment
References
189
189
Preclinical and early osteoarthritis
Definition of Preclinical and Early Osteoarthritis
Evidence for Preclinical and Early Osteoarthritis
Detection of Preclinical and Early Osteoarthritis
Progression of Osteoarthritis
Triggering Mechanisms
Treatment Paradigms
Potential Benefits to an Early Diagnosis of Osteoarthritis
Summary
References
190
190
Management of osteoarthritis
Introduction
Core Principles in Osteoarthritis Management
Education
Exercise
Individualized Treatment
Multidisciplinary Approach
Behavioral, Psychosocial, and Physical Interventions
Weight Loss
Orthoses, Braces, and Assistive Devices
Other Behavioral, Psychosocial, and Physical Interventions
Pharmacologic Treatments
Topical Agents
Oral Agents
Nonsteroidal antiinflammatory drugs
Other Oral Agents
Acetaminophen
Duloxetine
Glucosamine sulfate and chondroitin sulfate
Opioids
Intraarticular Therapy
Glucocorticoids
Hyaluronate Preparations
Surgical Interventions
Issues Specific to the Management of Hand Osteoarthritis
Core Principles of Hand Osteoarthritis Management
Pharmacologic Treatments
Surgical Interventions
Acknowledgment
References
191
191
Emerging treatments for osteoarthritis
Emerging Symptomatic Treatments (Fig. 191.1)
Drugs Targeting the Nerve Growth Factor Pathway
Anti-NGF antibodies
Tanezumab
Fasinumab
TrkA inhibitors
LEVI-O4
MEDI-7352
Botulinum Toxin
Capsaicin
LMWF5
Resiniferatoxin
Emerging Dmoads (Fig. 191.1 and Table 191.1)
Cartilage as the Target
Cartilage catabolism as the main target
ADAMTS-5 inhibitor
Cartilage anabolism as the main target
Sprifermin or rhFGF18
Inhibition of the Wnt pathway
OP-1/BMP-7
TPX100
Engedi1000
SB-061
LNA043
LRX712
KA34
Bone
Systemically
Cathepsin K inhibitor (MIV711)
Bisphosphonates
Denosumab
Inflammation and Immunomodulators
Anti-IL-1
Anti-TNF
Anti-IL-6
Anti-granulocyte-macrophage colony-stimulating factor (GM-CSF)
APPA
IκB kinase inhibitor
Drugs Targeting Cellular Senescence
UBX101 (unity technology)
Cell and Cell-Derived Therapies
Mesenchymal Stem Cells
Cell-Derived Concentrate
Platelet rich plasma (PRP)
nSTRIDE Autologous Protein Solution (APS) Kit
Research Avenues in Therapeutics
References
192
192
Epidemiology and classification of gout
Historical Perspective
Westernization And Gout Trends
Case Definitions And Classification Criteria
Prevalence of Gout
Incidence of Gout
Risk Factors for Hyperuricemia and Gout
Nonmodifiable Factors: Demographics: Sex, Age, Ethnicity/Race, and Genetics
Modifiable Factors: Obesity, Insulin Resistance, Lifestyle, and Others
Obesity, insulin resistance, and cardiovascular comorbidities
Dietary factors
Alcoholic beverages
Sugar-sweetened beverages
Coffee, teas, and caffeine
Medications and supplements
Environmental and Ambient Exposure
Key Mediating Mechanisms Of Lifestyle Factors: Purine And Insulin Resistance
Cardiovascular-Metabolic Conditions and Other Disorders
References
193
193
Etiology and pathogenesis of gout
Urate Physiology
Forms of Urate
Urate Production and Excretion
Urate Balance
Purine Metabolism and Urate Production
Urate Excretion
Extrarenal urate excretion
Renal urate excretion
Urate transporters
Glucose transporter 9
Urate transporter 1
Other urate transporters
Hyperuricemia
Conditioning Factors
Classification of Hyperuricemia
Monosodium Urate Crystal Formation
Proteins Binding to Monosodium Urate Crystals
The Gout Flare
NLRP3 Inflammasome Activation
Priming signal
Assembly signal
Other Inflammatory Mediators
Neutrophil Activation
Termination of the Gout Flare
Advanced Gout
Tophus Formation
Joint Damage
The Genetics of Gout
Transporter Genes
Metabolic Genes
Genes Influencing Crystal Formation and Crystal-Triggered Inflammation
Rare Genetic Disorders
Purine metabolism syndromes
Autosomal dominant kidney diseases caused by UMOD pathogenic variants (ADTKD-UMOD)
Summary
Acknowledgment
References
194
194
Clinical features of gout
Asymptomatic Hyperuricemia
Acute Gout Flares
Intervals Between Gout Flares
Advanced Tophaceous Gout
References
195
195
Management of gout and hyperuricemia
Treatment of Arthritis and Hyperuricemia in Gout
Therapeutic Targets For Acute Gouty Arthritis
Primary Treatment Objectives
Choice of Drug and Treatment Regimens
Nonsteroidal antiinflammatory drugs
Corticosteroids and adrenocorticotropic hormone (Acth)
Colchicine
Clinical pharmacology of colchicine and drug–drug interactions
Mechanism of action
Evidence basis and colchicine dosing for treatment of acute gout
Side effects
Colchicine And Other Antiinflammatory Drugs For Prophylaxis Of Acute Gout
Interleukin-1 Inhibition for Treatment And Prophylaxis of Gouty Arthritis
Treatment of Hyperuricemia in Gout
Nonpharmacologic Measures
Indications For Pharmacologic Oral Urate-Lowering Therapy For Gout And Drug Choices
The Advantages Of The “Treat To Target” Ult Strategy For Outcomes In Gout
Treating Hyperuricemia In Severe Gout Refractory To First- And Second-Line Therapy
Allopurinol
Clinical pharmacology and mechanism of action
Side Effects
Severe allopurinol hypersensitivity reaction: clinical features and risk management
Allopurinol dosing and factors influencing response to allopurinol, including in chronic kidney disease
Febuxostat
Probenecid
Mechanism of action
Dosing recommendations and side effects
Pegloticase For Refractory Hyperuricemia In Severe, Chronic Gout
Recent developments
Acknowledgments
References
196
196
Calcium pyrophosphate deposition disease (pseudogout)
Introduction
Nomenclature
Epidemiology
Clinical Presentation
Asymptomatic Chondrocalcinosis
Acute Calcium Pyrophosphate Crystal Arthritis (Pseudogout)
Osteoarthritis with Acute Attacks
Osteoarthritis Without Acute Attacks
Polyarticular Inflammatory Arthritis
Neuropathic Arthritis
Other Forms of Calcium Pyrophosphate Deposition Disease
Spinal Involvement
Crowned Dens Syndrome
Extraarticular Calcium Pyrophosphate Deposition Disease Deposits (Tophaceous Calcium Pyrophosphate Deposition Disease)
Involvement of other Mineralized Tissues
Triggers of Acute Attacks of Calcium Pyrophosphate Crystal Arthritis
Intraarticular Hyaluronic Acid Administration
Bisphosphonates
The Postoperative State
Other Triggers
Associated Diseases
Hyperparathyroidism
Hemochromatosis
Hypomagnesemia
Hypophosphatasia
Gout
Rheumatoid Arthritis
Familial Forms of Calcium Pyrophosphate Deposition Disease
Diagnostic Strategies
Synovial Fluid Analysis
Imaging
Conventional radiography
Computed tomography
Magnetic resonance imaging
Diagnostic ultrasonography
Advanced imaging techniques
Pathology
Pathogenesis
Step 1: crystal formation
Step 2: crystal effects
Mechanical consequences
Treatment
Acute Calcium Pyrophosphate Crystal Arthritis (Box 196.4)
Conclusions
Acknowledgments
References
197
197
Basic calcium phosphate crystal deposition disease
History
Calcific Periarthritis
Intraarticular Basic Calcium Phosphate Crystal Deposition
Epidemiology
Calcific Periarthritis
Articular Calcification
Clinical Features
Calcific Periarthritis
Large-joint destructive arthropathies
Additional clinical manifestations
Investigations
Imaging
Biochemical
Synovial or Bursal Fluid
Identification and Characterization of Basic Calcium Phosphate Crystals
Differential Diagnosis
Structure and Function
Nature of the Crystals
Etiology
Pathogenesis
Calcific Periarthritis
Tumoral Calcinosis
Basic Calcium Phosphate Crystals and Osteoarthritis
Management
Calcific Periarthritis
Tumoral Calcinosis
Articular Basic Calcium Phosphate Crystals
Conclusion
References
198
198
Epidemiology and classification of osteoporosis
Key Points
Introduction
History
Definition of Osteoporosis
Classification of Osteoporosis
Assessment of Fracture Risk
Prevalence and Incidence
Risk Factors
Impact of Osteoporotic Fracture
Mortality
Morbidity
Bone Mineral Density and Fracture
Fracture Epidemiology
Hip Fracture
Secular trends in hip fracture
Vertebral Fracture
Distal Forearm Fracture
Prior Fracture and the Risk of Subsequent Fracture
Economic Burden of Fracture
Implications for Prevention
Secondary Prevention: Treating Those Who Have Already Had a Fracture
Primary Prevention: Starting Treatment in Individuals at High Fracture Risk
Future Projections
Conclusion
References
199
199
Clinical evaluation and clinical features of osteoporosis
Key Points
Osteoporosis: Definition And Diagnosis
Clinical Evaluation
Bone Health Optimization Prior to Elective Orthopedic Surgery
History
History of a Patient on Therapy
Physical Examination
Investigations
Bone Mineral Density Testing
Vertebral Fracture Assessment
Trabecular Bone Score
Plain Radiography
Repeat Dual-Energy X-Ray Absorptiometry
Risk Algorithms
Bone Turnover Markers
Laboratory Studies
Diagnosis
Differential Diagnosis
Natural History
Morbidity And Mortality
Osteoporosis In Men
Conclusion
Acknowledgment
References
200
200
Pathophysiology of osteoporosis
Introduction
Determinants of Peak Bone Mass
Genetic Factors Affecting Bone Mass
Monogenic osteoporosis
Ethnic differences
Nutrition Effects on Bone Mass
Exercise Effects on Bone Mass
Gonadal Function Effects on Peak Bone Mass
Determinants of Bone Loss
Nutrition: Calcium and Vitamin D Effects on Bone Loss
Nutrition: other dietary factors
Alcohol and Smoking Effects on Bone Loss
Physical Activity Effects on Bone Loss
Chronic Diseases and Medications
Pathogenesis of Bone Loss
Bone Remodeling
Osteoclast Activation and Resorption
Osteoblast-Mediated Bone Formation and Osteocytes
Gender and other Influences on Remodeling
Effects of Remodeling on Cancellous Bone
Effects of Remodeling on Cortical Bone
References
201
201 Biochemical markers of bone turnover in postmenopausal osteoporosis
Introduction
Bone Turnover
Bone Remodeling
Bone Turnover Assessment
Bone Cells
Practical Aspects
Choice of Bone Turnover Markers
Variability
Overview
Age and sex
Reference BTM intervals
Weight
Circadian
Day to day
Exercise
Immobilization
Nutrition
Surgical menopause
Diseases And Drugs
Osteoporosis
Prediction of Bone Loss
Prediction of Fractures
Diagnosis of Osteoporosis
Treatment of Osteoporosis
Treatment response to drugs given for osteoporosis
Bisphosphonates
Denosumab
Selective estrogen receptor modulators
Anabolic treatment
Selection of therapy
Harm caused by therapy
Offset monitoring
Bone Turnover Markers in Men
Conclusion
References
202
202
Management of osteoporosis
Key Points
Introduction
Recommendations For Treatment
Evaluation for Secondary Osteoporosis
Treatment
Nonpharmacologic Approaches
Physical therapy and balance training
Calcium and Vitamin D Supplementation
Other Lifestyle Modifications
Prevention of Falls
Hip Pads and Other Assistive Devices
Pharmacologic Interventions
Hormone Replacement Therapy
Mechanism of action
Fracture prevention
Side effects
Estrogen Agonist-Antagonists
Mechanism of action
Fracture reduction
Side effects
Newer Estrogen Agonist-Antagonists
Calcitonin
Bisphosphonates
Mechanism of action
Pharmacologic properties
Fracture reduction in clinical trials
Etidronate
Alendronate
Risedronate
Ibandronate
Zoledronate
Denosumab
Mechanism of action
Fracture reduction
Side Effects of Antiresorptive Agents
Parathyroid Hormone
Mechanism of action
Fracture reduction
Teriparatide (Anabolic Therapy) Vs Antiresorptive Therapy
Abaloparatide (PTHrP 1-34)
Mechanism of action
Fracture reduction
Side effects
Romosozumab
Strontium Ranelate
Mechanism of action
Fracture reduction
Side effects
Summary
Mangement of Vertebral Fractures
Operative Management
References
203
203
Glucocorticoid-induced osteoporosis
Key Points
Introduction
Pathophysiology of Glucocorticoid Bone Loss
Epidemiology
Investigations
Bone Mineral Density
Trabecular Bone Score
Advanced Imaging
Biochemical Markers
Management
Risk Stratification
Current Recommendations
Calcium And Vitamin D
Calcitonin
Bisphosphonates
Risedronate
Parathyroid Hormone
Rankl Inhibition: Denosumab
Sclerostin Inhibitor: Romosozumab
Care Gap in the Screening, Prevention, and Treatment of Glucocorticoid-Induced Osteoporosis
Conclusion
References
204
204
Osteomalacia, rickets, and renal osteodystrophy
Introduction
Calcium, Phosphorous, and Vitamin D Metabolism
Effect of Vitamin D on Bone Metabolism
Causes of Osteomalacia and Rickets
Consequences of Vitamin D Deficiency on Bone Mineralization, Mineral Ion Homeostasis, and Growth
Definition of vitamin D deficiency and insufficiency
Calcium Deficiency
Phosphate Deficiency: Heritable and Acquired Disorders
Fanconi Syndrome and Renal Tubular Acidosis
Aluminum, Fluoride, And Heavy Metal Toxicity
Drugs
Clinical Evaluation of Osteomalacia and Rickets
Imaging
Biochemistry
Clinical Findings
Strategies for the Treatment and Prevention of Osteomalacia
Renal Osteodystrophy
Altered Calcium, Phosphate, and Vitamin D Metabolism in Ckd-Mbd
The Skeletal Defects of Renal Osteodystrophy
Strategies for the Treatment of Ckd-Mbd
Acknowledgment
References
205
205
Paget disease of bone
Key Points
Introduction
History
Epidemiology
Pathogenesis
Genetic Factors
Environmental Factors
Histopathology
Clinical Features
Signs And Symptoms
Skeletal Sites
Imaging
Laboratory Findings
Differential Diagnosis
Complications and Natural History
Treatment
Bisphosphonates
Other Drugs
Supportive Therapy
Surgery
Follow-Up and Retreatment
Conclusion
Acknowledgment
References
206
206
Diffuse idiopathic skeletal hyperostosis
History
Epidemiology
Criteria and Characteristic Description
Criteria
Characteristic bone changes
Spectrum of bone changes
General Findings
Clinical Features
Investigations
Differential Diagnosis
Etiology and Pathogenesis
Pathology
Metabolic Factors
Diabetes and obesity
Bone growth factors
Other metabolic factors
Management
Primary Prevention
Specific Interventions
References
207
207
Neuropathic arthropathy
History
Etiology
Diabetes Mellitus
Syringomyelia
Tabes Dorsalis
Leprosy
Congenital Indifference To Pain
Meningomyelocele (Spinal Dysraphism)
Drug-Induced Neuropathic Arthropathy
Other
Clinical Features
Imaging
Plain Radiography
Other Imaging Techniques
Laboratory Investigations and Histologic Analysis
Differential Diagnosis
Pathogenesis
Management
Acute Neuropathic Arthritis
Reduction of weight bearing
Bisphosphonates
Chronic Neuropathic Arthropathy
Conclusion
References
208
208
Osteonecrosis
Introduction
Epidemiology
Glucocorticoids
Alcohol
Systemic Lupus Erythematosus
Coagulopathies and Hemoglobinopathies
Medication-Induced Osteonecrosis of the Jaw
Pathologic Features
Pathogenesis
Altered fat metabolism
Intravascular coagulation
Elevated intraosseous pressure
Intramedullary hemorrhage
Osteocytotoxicity
Other participatory processes
Clinical Features
Imaging
Radiography
Radionuclide Bone Scans
Computed Tomography
Magnetic Resonance Imaging
Staging Systems
Diagnosis
Differential Diagnosis
Specific Variants Of Osteonecrosis
Bone infarct
Subchondral insufficiency fracture
Osteonecrosis during pregnancy
Idiopathic transient osteoporosis of the hip
Management
Role of Conservative Management
Core Decompression
Other Orthopedic Interventions for Osteonecrosis
Arthroplasty
Experimental and Empirical Therapies
References
209
209
Rheumatoid manifestations of endocrine and metabolic diseases and treatments
Acromegaly
Clinical Features
Diabetes Mellitus
Thyroid Disease
Hyperparathyroidism
Adrenal Disorders
Ochronosis
Lipid Disorders
Statin Drug–Associated Muscle Syndromes
Other Drug-Associated Musculoskeletal Manifestations
Aromatase Inhibitors—Musculoskeletal Manifestations
Acknowledgments
References
210
210
Hemophilia-associated arthritis
Hemophilia
History
Epidemiology
Classification
Etiology
Von Willebrand Disease
Hemophilic Arthritis
Clinical Features
Acute hemarthrosis
Differential diagnosis of acute hemarthroses
Subacute arthritis
Chronic arthritis
Non–Joint-Related Disorders
Muscle hemorrhage
Hemophilic pseudotumors
Diagnosis
Imaging
Pathogenesis of Hemophilic Arthritis
Management
Primary Prevention
Management of Arthritis
Acute hemarthroses
Subacute hemophilic arthritis
Chronic arthritis
Complications of Hemophilic Arthritis
Osteoporosis
Chronic pain
Management of Joint Bleeding at Specific Sites
Orthopedic surgery
Knee
Ankle
Elbow
Hip
Exercise and sports
Current Issues in Treatment of Hemophilia
Blood Product–Transmitted Infections
Coagulation Factor Inhibitors
Future Treatment Options
Summary
References
211
211
Rheumatologic manifestations of hemoglobinopathies
Introduction
Sickle Cell Disease
Diagnosis
Clinical
Acute painful crisis
Dactylitis
Osteonecrosis
Soft tissue
Orofacial pain
Infections
Sequelae of chronic hemolysis
Association with rheumatic diseases
Imaging
Treatment
Thalassemia
Clinical
Osteopenia and osteoporosis
Growth
Autoimmune disease
Treatment-induced complications
Imaging
Treatment
References
212
212
Hemochromatosis
Introduction
The Hemochromatosis Arthropathy
Chondrocalcinosis
Spinal Involvement
Radiologic Appearance
Pathophysiology
Osteoporosis
Diagnosis
Treatment
Iron Depletion
General Management
Acknowledgment
References
213
213
Gaucher disease
Epidemiology
Etiology
Biochemistry
Molecular Biology And Genetics
Pathogenesis
Clinical Features
Hematologic Manifestations And Other Extraskeletal Disorders
Skeletal Involvement
Investigations
Biochemical Studies
Imaging
Differential Diagnosis
Management
Enzyme Replacement Therapy
Substrate Reduction Therapy
Symptomatic Treatments
Bone remodeling–targeted treatments and vitamin D
Splenectomy
Orthopedic treatments
Experimental Therapies
References
214
214
Digital clubbing and hypertrophic osteoarthropathy
History
Epidemiology
Classification
Clinical Features
Symptoms
Physical Findings
The Primary Form
Investigations
Differential Diagnosis
Clinical Significance
Pathology
Etiology And Pathogenesis
Prostaglandins And Primary Hypertrophic Osteoarthropathy
Management
References
215
215
Miscellaneous arthropathies
Key Points
Cancer-Related Musculoskeletal Syndromes
Associations of Rheumatologic Diseases with Cancer
Musculoskeletal Manifestations of Cancer
Synovial sarcoma
Cartilaginous tumors
Metastatic disease
Paraneoplastic syndromes
Inflammatory manifestations associated with myelodysplastic syndromes
Carcinomatous polyarthritis
Hypertrophic osteoarthropathy
Palmar fasciitis and polyarthritis syndrome
Oncogenic osteomalacia
Neoplastic Conditions That Mimic Rheumatologic Disease
Acute lymphoblastic leukemia
Hairy cell leukemia
Angioimmunoblastic T-cell lymphoma
Multiple myeloma
Musculoskeletal Side Effects of Oncologic Drugs
Aromatase inhibitors
Immune checkpoint inhibitors
Other Systemic Syndromes With Rheumatologic Features
Multicentric Reticulohistiocytosis
Castleman Disease
Poems Syndrome
Whipple Disease
Syndromes With Predominantly Musculoskeletal Involvement
Bypass arthritis
Intermittent hydrarthrosis
Palindromic Rheumatism
Fibroblastic Rheumatism
SAPHO Syndrome
Diabetic Muscle Infarction
Retroperitoneal Fibrosis
Foreign Body Synovitis
Silicone Synovitis
Pigmented Villonodular Synovitis and Tenosynovitis
Primary Synovial Osteochondromatosis
Synovial Hemangioma
Lipoma Arborescens
Musculoskeletal Syndromes Associated With Chronic Kidney Disease
Arthritis And Periarthritis
β2-Microglobulin Amyloidosis
Gadolinium-Induced Fibrosis (Nephrogenic Systemic Fibrosis)
Use Of Antirheumatic Drugs In Patients Receiving Dialysis
References
216
216
Heritable connective tissue disorders
Key Points
Introduction to Genetic Disorders of the Skeleton and Associated Soft Tissues
Disorders of Bone Density
Skeletal Dysplasias
Marfan Syndrome (MIM154700) and Related Conditions
Clinical Features of Marfan Syndrome
Cardiovascular disease
Ocular disease
Skeletal involvement
Respiratory system
Diagnosis of Marfan Syndrome
Ehlers-Danlos Syndrome
Disorders of Bone Density
Osteopetrosis
Osteoscleroses
Skeletal Dysplasias and Related Conditions
Osteogenesis Imperfecta (Brittle Bone Syndrome)
Diagnosis of osteogenesis imperfecta
Treatment
Chondrodysplasias
Fibroblast growth factor receptor 3–related disorders
Achondroplasia (MIM100800)
Hypochondroplasia (MIM146000)
Thanatophoric dwarfism (MIM187600)
Type 2 Collagenopathies
Multiple epiphyseal dysplasias
Other forms of chondrodysplasia
Dysostoses
Craniosynostoses
Other Miscellaneous Conditions
Fibrodysplasia Ossificans Progressiva (MIM135100)
Abnormalities in the G Protein Signaling System
Activating Mutations IN GNAS1
Enzyme Defects and the Skeleton
Hypophosphatasia
Alkaptonuria (MIM203500)
Mucopolysaccharidoses
References
217
217
Hypermobility syndrome
Introduction
Epidemiology And Genetics
Diagnostic Criteria For Conditions Presenting To Rheumatology With Associated Hypermobility
Diagnosing Generalized Hypermobility
Classification Of The Ehlers-Danlos Syndromes
Hypermobile Ehlers-Danlos Syndrome (hEDS)
Marfan Syndrome
Clinical Musculoskeltal Associations With Joint Laxity (Known And Postulated)
Musculoskeletal Pain
Reduced Proprioception And Muscle Weakness
Pes Planus
Genu Recurvatum
Dislocations And Subluxations
Recurrent Patellar Dislocation
Osteoarthritis
Extraarticular Associations
Fatigue
Gastrointestinal
Autonomic Dysfunction
Postural Orthostatic Tachycardia Syndrome
Hernias
Varicose veins
Uterine prolapse and voiding dysfunction
Psychological Problems
Differentiating Between Chronic Widespread Pain Conditions (Including Fibromyalgia) And Hypermobile Joints With Associated ...
Rehabilitation
Musculoskeletal Rehabilitation
Pain Management
Summary
References
218
218
Bone tumors
Introduction
Metastatic Tumors
Hematologic Malignancies In Bone
Primary Bone Tumors
Metastatic Carcinoma To Bone
Radiographic Appearance
Histologic Appearance
Hematologic Malignancies
Multiple Myeloma
Investigations
Treatment
Malignant Lymphoma
Histologic appearance
Treatment and prognosis
Primary Bone Tumors
Bone Cysts
Aneurysmal bone cyst
Simple bone cysts
Bone-Forming Neoplasms
Incidental bone islands
Osteoid osteoma
Osteoblastoma
Osteosarcoma
Parosteal osteosarcoma
Cartilage Neoplasms
Chondroblastoma
Chondromyxoid Fibroma
Enchondroma
Osteochondroma
Periosteal Chondroma
Chondrosarcoma
Fibrous-Like Neoplasms
Nonossifying fibroma
Fibrous Dysplasia
Undifferentiated High-Grade Pleomorphic Sarcoma
Giant Cell Tumor
Ewing Sarcoma
Osteofibrous Dysplasia And Adamantinoma
Vascular Neoplasms
Hemangiomas
Epithelioid hemangioendotheliomas
Angiosarcomas
Chordoma
References
Appendix:
Classification and Diagnostic Criteria
Classification And Diagnostic Criteria
Acute Rheumatic Fever
Adult-Onset Still Disease
Antiphospholipid Syndrome
Complex Regional Pain Syndrome
Diffuse Idiopathic Skeletal Hyperostosis
Fibromyalgia
Gout
Hypermobility
Igg4-Related Disease
Inflammatory Muscle Disease
Idiopathic Inflammatory Myopathies
Inclusion Body Myositis
Polymyositis And Dermatomyositis
Juvenile Idiopathic Arthritis
Kashin-Beck Disease
Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis
Osteoarthritis
Psoriatic Arthritis
Reactive Arthritis
Relapsing Polychondritis
Rheumatoid Arthritis
Sjögren Syndrome
Spondyloarthritis
Axial
Peripheral
Systemic Lupus Erythematosus
Systemic Sclerosis And Scleroderma
Vasculitis
Antineutrophil Cytoplasmic Antibody–Associated Vasculitis
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
Granulomatosis with polyangiitis
Childhood Wegener granulomatosis
Polyarteritis Nodosa
Childhood polyarteritis nodosa
Behçet Disease
Cryoglobulinemia
Henoch-Schönlein Purpura And Immunoglobulin A Vasculitis
Childhood Henoch-Schönlein purpura
Hypersensitivity Vasculitis
Kawasaki Disease
Polymyalgia Rheumatica And Giant Cell Arteritis
Polymyalgia rheumatica
Giant cell arteritis
Takayasu Arteritis
Childhood Takayasu arteritis
Primary Angiitis Of The Central Nervous System
Periodic Fever Syndromes
Familial Mediterranean Fever
References