Kelley's Textbook of Rheumatology E-Book

Gary S. Firestein; Ralph Budd; Sherine E Gabriel; Iain B. McInnes; James R O'Dell

BOOK

Kelley's Textbook of Rheumatology E-Book

Gary S. Firestein | Ralph Budd | Sherine E Gabriel | Iain B. McInnes | James R O'Dell

(2012)

Additional Information

Book Details

ISBN: 978-1-4557-3767-3
Edition: 9
Language: English
Pages: 2292
Subjects: Rheumatology
Medical study & revision guides & reference material

Abstract

Kelley's Textbook of Rheumatology delivers the state-of-the-art scientific and clinical know-how you need to offer your patients the most effective diagnosis and care. This rheumatology book’s sweeping updates highlight current advances and breakthroughs that impact your practice. With Kelley's Textbook of Rheumatology, you'll be ready to handle the toughest clinical challenges you face.

Search the entire contents online at www.expertconsult.com, download all of images, and watch videos demonstrating the complete musculoskeletal exam, including abnormal findings and the arthroscopic presentation of diseased joints.

Review basic science advances and their clinical implications in one place and get dependable, evidence-based guidance with the integrated chapter format that readers of Kelley's Textbook of Rheumatology have always appreciated.

Gain a thorough understanding of the "whys" and "hows" of rheumatic disease management with detailed coverage of the very latest breakthroughs and the newest clinical algorithms.

Apply the latest therapeutic advances through new chapters in bioengineering and tissue engineering, as well as up-to-date coverage of gout and disease-modifying drugs.

Learn how the study of biomarkers across populations can help you detect diseases earlier and with greater accuracy with a new chapter on epigenetics.

Diagnose, monitor, and manage rheumatic disease more effectively with expanded information on the use of ultrasound and other imaging modalities.

Section Title	Page	Action	Price
Front cover	cover
Expert Consult page	ifcii
Kelley's Textbook of Rheumatology, 9/e	i
Copyright page	iv
Dedication	v
Contributors	ix
Preface	xxv
Table of Contents	xxvii
Duplicate half title page	xxxiii
1 Structure And Function of Bone, Joints, and Connective Tissue	1
1 Biology of the Normal Joint	1
Key Points	1
Classification of Joints	1
Developmental Biology of the Diarthrodial Joint	1
Interzone Formation and Joint Cavitation	2
Cartilage Formation and Endochondral Ossification	5
Condensation and Limb Bud Formation	5
Molecular Signals in Cartilage Morphogenesis and Growth Plate Development	6
Endochondral Ossification	6
Development of the Joint Capsule and Synovium	7
Development of Nonarticular Joints	8
Development of Articular Cartilage	8
Organization and Physiology of the Mature Joint	8
Synovium	8
Synovial Lining	9
Synovial Vasculature	10
Regulation of Synovial Blood Flow	10
Joint Innervation	10
Tendons	11
Ligaments	12
Bursae	12
Menisci	12
Mature Articular Cartilage	13
Subchondral Bone Interactions with Articular Cartilage	13
Synovial Fluid and Nutrition of Joint Structures	14
Generation and Clearance of Synovial Fluid	15
Synovial Fluid as an Indicator of Joint Function	15
Lubrication and Nutrition of the Articular Cartilage	16
Lubrication	16
Nutrition	16
Summary and Conclusion	17
Selected References	17
References	19.e1
2 Synovium	20
Key Points	20
Structure	20
Synovial Lining Cells	20
Ultrastructure of Synovial Lining Cells	20
Immunohistochemical Profile of Synovial Cells	21
Synovial Macrophages.	21
Synovial Intimal Fibroblasts.	21
Turnover of Synovial Lining Cells	22
Origin of Synovial Lining Cells	23
Subintimal Layer	23
Subintimal Vasculature	24
Subintimal Lymphatics	26
Subintimal Nerve Supply	26
Function	26
Joint Movement	26
Deformability	26
Porosity	26
Nonadherence	26
Lubrication	26
Hyaluronic Acid	27
Lubricin.	27
Formation of Synovial Fluid	27
Nutrition of Chondrocytes	29
Summary	29
References	30
3 Cartilage and Chondrocytes	33
Key Points	33
Cartilage Structure	33
Structure-Function Relationships Of Cartilage Matrix Components	35
Cartilage Collagens	35
Cartilage Proteoglycans	37
Other Extracellular Matrix and Cell Surface Proteins	37
Morphology, Classification, And Normal Function Of Chondrocytes	38
Morphology	38
Classification: Cell Origin and Differentiation	38
Normal Function of the Adult Articular Chondrocyte	39
Culture Models For Studying Chondrocyte Metabolism	41
Articular Chondrocytes	41
Cartilage Explant (Organ) Cultures	41
Monolayer Cultures	41
Three-Dimensional Culture Systems	42
Prehypertrophic and Hypertrophic Chondrocytes: Models of the Growth Plate and Terminal Differentiation	42
Chondrocyte Cell Lines	42
Interactions Of Chondrocytes With The Extracellular Matrix	43
Integrins	43
Other Cell Surface Receptors in Chondrocytes	44
Angiogenic And Antiangiogenic Factors	44
Roles Of Growth And Differentiation (Anabolic) Factors In Normal Cartilage Metabolism	45
Insulin-like Growth Factor	45
Fibroblast Growth Factor	45
Tgf-β/Bmp Superfamily	46
Transforming Growth Factor-β	46
Bone Morphogenetic Proteins	46
Receptors, Signaling Molecules, and Antagonists That Mediate Chondrocyte Responses to Growth and Differentiation Factors	47
Role Of The Chondrocyte In Cartilage Pathology	48
Cartilage Matrix–Degrading Proteinases	48
Balance of Cytokines in Cartilage Destruction	50
Interleukin-1 and Tumor Necrosis Factor	50
Cytokine Networks	51
Inhibitory Cytokines	52
Other Mediators	52
Chemokines	53
Cytokine Signaling Pathways Involved in Cartilage Metabolism	54
Role Of The Chondrocyte In Cartilage Repair	55
Aging of Articular Cartilage	55
Aging Chondrocyte	55
Markers of Cartilage Matrix Degradation and Turnover	56
Repair of Articular Cartilage	56
Summary And Conclusion	57
Selected References	57
References	60.e1
4 Biology, Physiology, and Morphology of Bone	61
Key Points	61
Structure and Composition of Bone	61
Bone Matrix	61
Bone Cells: Osteoblasts	62
Bone Cells: Osteocytes	62
Bone Cells: Osteoclasts	63
Bone Remodeling Process	64
Direct Interactions between Osteoblasts and Osteoclasts	64
Bone Remodeling by the Immune System	65
Systemic Control of Bone Remodeling by Neuroendocrine Mechanisms	65
Conclusion	66
References	66
5 Muscle:	67
Key Points	67
Structure	67
Muscle Tissue	67
Fiber Types	68
Events during Muscle Contraction	68
Neural Control	68
Neuromuscular Transmission	69
Excitation-Contraction Coupling	70
Contractile Apparatus	70
Force Generation and Shortening	72
Relaxation	73
Transmission Of Force To The Exterior	73
Cell-Matrix Adhesions	73
Myotendinous Junction	73
Energetics	73
Buffering of Adenosine Triphosphate Concentration	73
Glycolysis	74
Oxidative Phosphorylation	74
Fatigue and Recovery	75
Plasticity	76
Adaptation to Muscle Use/Disuse	76
Hormonal Control	76
Aging	76
Summary	77
References	77
6 Biomechanics	79
Key Points	79
Kinematics	80
Kinetics	82
Joint Biomechanics	84
Joint Constraint and Stability	86
References	89
7 Regenerative Medicine and Tissue Engineering	90
Key Points	90
Intrinsic Tissue Repair	91
TGF-β/BMP Signaling	91
FGF Signaling	91
Wnt Signaling	92
Other Potential Anabolic Treatments	92
Extrinsic Repair	92
Joint Resurfacing	93
Autologous Chondrocyte Transplantation	93
Additional Developments	93
Bone Regeneration	94
Regenerative Medicine In Arthritis	94
References	95
8 Proteinases and Matrix Degradation	97
Key Points	97
Extracellular Matrix Degrading proteinases	97
Aspartic Proteinases	97
Cysteine Proteinases	97
Serine Proteinases	98
Neutrophil Elastase and Cathepsin G	98
Mast Cell Chymase and Tryptase	98
Plasmin and Plasminogen Activators	98
Kallikreins	99
Metalloproteinases	99
Matrix Metalloproteinases	99
Secreted-Type Matrix Metalloproteinases	99
Collagenases (MMP-1, MMP-8, and MMP-13).	99
Gelatinases (MMP-2 and MMP-9).	101
Stromelysins (MMP-3 and MMP-10).	101
Matrilysins (MMP-7 and MMP-26).	101
Furin-Activated Matrix Metalloproteinases (MMP-11 and MMP-28).	102
Other Secreted-Type Matrix Metalloproteinases (MMP-12, MMP-19, MMP-20, MMP-21, and MMP-27).	103
Membrane-Anchored Matrix Metalloproteinases	103
Type I Transmembrane-Type MMPs.	103
ADAM and ADAMTS Families	104
Endogenous Proteinase Inhibitors	104
α2-Macroglobulin	104
Inhibitors of Serine Proteinases	104
Inhibitors of Cysteine Proteinases	105
Tissue Inhibitors of Metalloproteinases	106
Regulation Of Proteinase Activity	106
Gene Expression of Proteinases and Inhibitors	106
Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases	106
Serine Proteinases and Their Inhibitors	107
Lysosomal Cysteine and Aspartic Proteinases	107
Activation Mechanisms of the Zymogens of Matrix Metalloproteinases	108
Extracellular Activation	108
Intracellular Activation	108
Pericellular Activation	108
Pericellular Docking of Matrix Metalloproteinases	110
Joint Destruction And Proteinases	110
Degradation of Extracellular Matrix in Articular Cartilage	110
Cartilage Destruction by Proteinases in Rheumatoid Arthritis	111
Bone Resorption in Rheumatoid Arthritis	112
Cartilage Destruction by Proteinases in Osteoarthritis	112
References	113
2 Cells Involved in Autoimmune Diseases and Inflammation	117
9 Dendritic Cells	117
Key Points	117
Dendritic Cell Subsets	117
Conventional DCs (cDCs)	118
Tissue Resident cDCs	118
Langerhans Cells (LCs).	118
Dermal DCs.	118
Lymphoid Tissue DCs	119
BDCA-3+ DCs.	119
CD103+ DCs.	119
Circulating DCs	119
BDCA-1+ (CD1c) DCs.	120
Monocyte-Derived Dendritic Cells (moDCs).	120
Plasmacytoid DCs (pDCs)	120
DENDRITIC CELL Development	120
Maturation	120
Antigen Recognition	120
Receptor Upregulation	120
Cytokine and Chemokine Secretion	121
Antigen Acquisition and Recognition	121
Toll-Like Receptors (TLRs)	121
C-Type Lectin Receptors (CLRs)	122
CLRs Modulate TLR Signaling	122
CLR Signaling Independent of TLR	122
CLRs Enhance Antigen Presentation	122
Retinoic Acid Inducible Gene I (RIG-I)-Like Receptors (RLRs).	122
Nucleotide-Binding Oligomerization Domain (NOD)-Like Receptors (NLRs).	123
Apoptotic Cell Recognition Receptors	123
Fc Receptors (FcRs)	124
Antigen Presentation	124
MHC Class I Antigen Presentation	125
Cross-Presentation	125
MHC Class II Antigen Presentation	125
Lipid Presentation	126
T Cell Activation	126
B Cell Activation	126
NK Cell Activation	127
DENDRITIC CELLS and Tolerance	127
Central Tolerance	127
Peripheral Tolerance	127
Autoimmunity	128
Systemic Lupus Erythematosus	129
Rheumatoid Arthritis	129
Sjögren’s Syndrome	130
Seronegative Spondyloarthropathies (SpA) and Psoriasis	130
Selected References	131
References	133.e1
10 Mononuclear Phagocytes in Rheumatic Diseases	134
Key Points	134
Overview	134
Life History and Heterogeneity (Macrophages, Dendritic Cells, and Osteoclasts)	135
Mobilization of Mononuclear Phagocytes	137
Recognition	140
Toll-Like Receptors	140
Non–Toll-Like Receptors	140
Complement Receptors	140
Fc Receptors	142
Cytosolic Receptors	142
Damage/Danger-Associated Molecular Patterns (Damps)	145
Responses and Modulation	145
Phagocytosis and Endocytosis: Antigen Processing	145
Signaling	146
Efferent Pathways: Gene Expression and Secretion	147
Relevance to Selected Rheumatic Diseases	149
Issues for Further Investigation	149
Acknowledgments	149
References	149
11 Neutrophils	152
Key Points	152
INTRODUCTION: POLYMORPHONUCLEAR LEUKOCYTES	152
Neutrophils	152
Neutrophil Myelopoiesis and Clearance	152
Neutrophil Morphology and Content	153
Neutrophil Activation and Function	155
Stimuli and Receptors	155
G Proteins	156
Second Messengers	156
Kinases and Kinase Cascades	156
Neutrophil Adhesion	157
Diapedesis and Chemotaxis	158
Phagocytosis and Degranulation	158
Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase System	159
Nonphagocytic Bacterial Killing	160
Neutrophil Production of Proinflammatory Mediators	160
Arachidonic Acid Metabolites	160
Cytokine Production	161
Resolution of Neutrophil Infiltration and Apoptosis	161
Heritable Disorders of Neutrophil Function	162
Diseases of Diminished Neutrophil Number	162
Leukocyte Adhesion Deficiencies	162
Neutrophil Granule Defects	164
Oxidase Deficiencies—Chronic Granulomatous Disease	164
Defects of TLR Signaling	164
Neutrophil Relevance to Rheumatic Disease	164
Neutrophil-Mediated Tissue Destruction	164
Neutrophil Fc Receptor Polymorphisms	164
Gout	164
Rheumatoid Arthritis	165
Vasculitis	165
Neutrophilic Dermatoses and Familial Mediterranean Fever	166
Effects of Antirheumatic Agents on Neutrophil Functions	166
References	167
12 Eosinophils	170
Key Points	170
Eosinophil Development and Morphology	170
Eosinophil Activation and Distribution	171
Normal Eosinophil Function	171
Eosinophil Relevance to Inflammatory and Autoimmune Disease	172
Asthma	172
Rheumatic Diseases	172
Primary Eosinophilic Syndromes	172
Addison’s Disease	173
References	173
13 T Lymphocytes	174
Key Points	174
Overview	174
T Cell Development	174
Abnormalities of Human T Cell Development	178
Peripheral Migration of T Cells	178
Activation of T Cells	179
TCR and Tyrosine Kinases	179
Adaptor Proteins	180
Downstream Transcription Factors	180
Co-stimulation	181
Immunologic Synapse	181
Tolerance and Control of Autoreactive T Cells	182
Subsets and Function of Peripheral T Cells	183
CD4 Helper and CD8 Cytolytic T Cells	183
T Cells in the Innate Immune Response	183
γδ T Cells	184
Natural Killer T Cells	185
Naïve versus Memory T Cells	185
T Helper Subsets	186
Molecular Mimicry	187
Death of T Cells	187
T Cells at Sites of Inflammation	188
References	188
14 B Cells	191
Key Points	191
Overview: B Cells and Humoral Immunity	191
Immunoglobulins: Structure and Function	191
Immunoglobulin Constant Region	192
Immunoglobulin M	192
Immunoglobulin G	193
Immunoglobulin A	193
Immunoglobulin E	194
Immunoglobulin D	194
Light Chains	194
Immunoglobulin Variable Region	194
Generation of Immunoglobulin Diversity	194
B Cell Development	194
Niches of Human B Cell Lymphopoiesis	195
B Cell Ontogeny	195
Pro-B Cells	196
Pre-B Cells	196
Immature B Cells	197
Peripheral B Cell Subsets	197
Transitional B Cells	197
BAFF Family of Cytokines	197
Naïve B Cells	197
Marginal Zone B Cells	197
B1 Cells	198
Sites of B Cell Homing and Activation	198
Circulation and Homing	199
Mucosa-Associated Compartments	199
B Cell Activation and Differentiation	199
B Cell Receptor Signaling	199
Surface Co-receptors and Intracellular Regulators	200
FcγRllB	200
CD5	201
CD72	201
PIR	201
PD-1	202
Protein Tyrosine Phosphatases	202
Signal Transduction in Immature versus Mature B Cells	202
B Cell Activation	202
B1 Cell Activation	202
Marginal Zone B Cell Activation	203
Naïve B Cell Activation	203
Germinal Centers	203
Ectopic Lymphoid Structures	204
Repertoire Post antigen Activation	205
Memory B Cells	205
Plasma Cells	205
Trafficking of Postimmune Cells	205
Antigen-Independent Activation	205
Mucosal T–Independent Class Switch Recombination (CSR)	206
Repertoire Selection	206
Tolerance	206
Receptor Editing	206
Deletion	206
Anergy	207
B Cells as Immune Regulators	207
Regulation by Small Molecules	207
Vitamin D	207
Estrogens	207
Leptin	207
B Cell–Mediated Autoimmunity	207
Origin of Autoreactive B Cells	208
Autoreactivity in the Preimmune B Cell Repertoire	208
Autoreactivity in the Postimmune B Cell Repertoire	208
Molecular Triggers of Autoimmunity	208
Molecular Mimicry	208
Supraoptimal B Cell Co-stimulation	209
B Cell Signaling Thresholds	209
Summary	209
References	211
15 Fibroblasts and Fibroblast-like Synoviocytes	215
Key Points	215
What is a Fibroblast?	215
Fibroblast Identity and Microenvironments	215
Embryologic Origins	215
Origins of Fibroblasts in Tissue	216
Fibroblasts versus Mesenchymal Progenitor Cells	218
Physiologic Characteristics and Functions of Fibroblasts	218
Production of ECM Components	218
Attachment to and Interaction with Extracellular Matrix	219
Integrins	219
Syndecans	219
Immunoglobulin Superfamily Receptors	219
Cadherins	219
Degradation of Extracellular Matrix by Fibroblasts	220
Fibroblasts as Innate Immune Sentinels	221
Role of Specialized Fibroblast Subsets within Tissue Microenvironments	221
Fibroblast-like Synoviocytes in the Normal Synovium	221
Fibroblasts in Rheumatic Diseases	223
Role of Fibroblasts in Persistent Inflammation	223
Fibroblast-Like Synoviocytes in Rheumatoid Arthritis	223
Persistent Activated Fibroblast Phenotype in the Rheumatoid Arthritis Synovium	223
Interactions of Fibroblasts with Leukocytes	224
Recruitment of Inflammatory Infiltrates into the Joint	224
Fibroblast Support for Leukocyte Survival	224
Fibroblast-Mediated Retention of Leukocytes in Tissue	226
Constitutive Chemokines and Lymphoid Neogenesis	226
Role of Fibroblast Subsets in Disease	227
Lessons Learned from Cancer	227
Summary	228
References	228
16 Mast Cells	232
Key Points	232
Basic Biology of Mast Cells	232
Development and Tissue Distribution	232
Mast Cell Heterogeneity: Common Progenitor, Multiple Subsets, and Phenotypic Plasticity	233
Stem Cell Factor	234
T Lymphocytes and Other Cells	234
Different Functions for MCT and MCTC Mast Cells?	234
Mast Cell Activation	234
IgE	234
IgG and Immune Complexes	235
Soluble Mediators and Cell-Cell Contact	235
Danger and Injury	235
Inhibitory Signals for Mast Cells	235
Mast Cell Mediators	236
Granule Contents: Proteases, Amines, Proteoglycans, and Cytokines	236
Tryptase.	236
Chymase.	236
Vasoactive Amines.	236
Heparin and Chondroitin Sulfate E.	236
Pre-Formed Cytokines.	236
Newly Synthesized Mediators: Lipid Mediators, Cytokines, Chemokines, and Growth Factors	236
Lipid Mediators.	236
Cytokines, Chemokines, and Growth Factors.	237
Role of Mast Cells in Health and Disease	237
Mast Cells in Allergic Disease: Anaphylaxis, Allergic Disease, and Asthma	237
Mast Cells in Nonallergic Inflammation	238
Pathogen Defense: Mast Cells as Sentinels of Innate Immunity	238
Mast Cells and the Adaptive Immune Response	238
Neurogenic Inflammation	238
Autoimmune Disease	238
Mast Cells as Anti-Inflammatory Cells	238
Mast Cells and Connective Tissue	239
Wound Healing and Tissue Fibrosis	239
Bone	239
Angiogenesis	239
Mast Cells in Arthritis	239
Mast Cells in Acute Arthritis: Insights from Animal Models	240
Mast Cells in Chronic Arthritis	240
Conclusions	240
Selected References	241
References	244.e1
17 Platelets	245
Key Points	245
General Characteristics of Platelets	245
Function of Platelets	247
Hemostasis	247
Glycoprotein IIb-IIIa	248
Role of Platelets in the Inflammatory Response	248
Platelets and Rheumatic Diseases	249
Alterations in Platelet Numbers in Rheumatic Diseases	249
Role of Platelets in the Pathogenesis of Rheumatic Diseases	250
Inhibition of Platelet Function by Pharmacologic Agents	250
Acknowledgments	251
References	251
3 Effector Mechanisms in Autoimmunity and Inflammation	255
18 Innate Immunity	255
Key Points	255
Evolutionary Origins of Innate Immunity	255
Pathogen Recognition by the Innate Immune System	257
PAMPs and DAMPs: Patterns for Innate Immune Recognition	257
Pathogen-Associated Molecular Patterns	257
Pattern Recognition Receptors	257
Pattern Recognition Receptors of the Lectin Family	258
Pattern Recognition Receptors of the Scavenger Receptor Family	259
Pattern Recognition Receptors with Leucine-Rich Repeat Domains	259
Toll-like Receptors.	260
Toll-like Receptor 4 and the Response to Lipopolysaccharide.	260
Other Pathogen-Associated Molecular Patterns Recognized by Toll-like Receptors.	260
CARD and Pyrin Domain Proteins.	261
Effector Mechanisms of Innate Immune Responses	262
Cell Types Mediating Innate Immunity	262
Innate-like Lymphocytes	262
Antimicrobial Peptides	263
Influence of Innate Mechanisms on Adaptive Immunity	263
Disease Associations Involving Innate Immunity	264
References	266
19 Adaptive Immunity and Organization of Lymphoid Tissues	268
Key Points	268
Lymphocyte Migration Paradigms for Homing, Interstitial Navigation, and Egress	268
Multistep Paradigm for Extravasation	268
Tissue Organization and Interstitial Migration	270
Immunologic Synapses Maintain Antigen-Specific Interactions with Dendritic Cells	270
Egress from Lymph Nodes and the Thymus: Sphingosine-1-Phosphate	271
Primary Lymphoid Tissues: Sites Where T and B Cells are Generated and Self-Tolerance Mechanisms are Initiated	271
B Cell Development in the Bone Marrow	271
T Cell Development in the Thymus	271
Secondary Lymphoid Tissues: Sites Where Antigen Finds Rare Specific T and B Cells	272
Antigens from Blood Are Detected Most Efficiently in the Spleen and Liver (Portal System)	273
Antigens from Mucosal Surfaces Are Detected Most Efficiently in Peyer’s Patches and Mesenteric Lymph Nodes	273
Antigens from Other Tissues and Solid Organs Are Detected in Peripheral Lymph Nodes	275
Peripheral Tolerance Induction under Steady-State Conditions	276
Regulatory T Cells Reduce Autoreactivity by Inhibiting Immunologic Synapse Formation	276
Changes in the Lymph Node during Infection/Vaccination	276
Tissue Environment of Immature Dendritic Cells Determines T Cell Imprinting	276
Germinal Center Reactions: Sites of Antibody Affinity Maturation and Class Switch Recombination	276
Tertiary Lymphoid Tissues: Generated at Sites of Chronic Inflammation	277
Four Major Types of Effector T Cells	277
Summary	278
References	278
20 Autoimmunity	281
Key Points	281
Definition and Classification of Pathogenic Autoimmunity	281
Animal Models of Autoimmunity	282
Composition of the Innate and Adaptive Immune Systems	283
Innate Immune System Composition	284
Adaptive Immune System Composition	285
Tolerance Mechanisms	286
Clone-Specific Self-Nonself Recognition	286
Innate System and Tolerance	286
T Cell Tolerance	287
B Cell Tolerance	289
Theories of Autoimmunity	289
Defective Tolerance	290
Autoimmunity Caused by Activation of Intolerant or Partially Tolerant T Cells	291
Immunologic Mechanisms of Tissue Inflammation and Dysfunction	292
Pathophysiology of Autoimmune Rheumatic Diseases	293
Genetics of Autoimmune Diseases	294
Gender and Autoimmunity	295
Microbial and Other Environmental Triggers	295
Conclusion	296
Acknowledgments	296
Selected References	296
References	298.e1
21 Genetics of Rheumatic Diseases	299
Key Points	299
Major Histocompatibility Complex	299
Human Leukocyte Antigen Molecules and Antigen-Specific T Cell Recognition	299
Human Leukocyte Antigen Class I and Class II Molecules	299
Human Leukocyte Antigen Class I and Class II Isotypes: Functional Correlates	301
Genetic Organization of the Human Major Histocompatibility Complex	301
Human Leukocyte Antigen Molecules Are Highly Polymorphic	302
Human Leukocyte Antigen Associations with Rheumatic Diseases	303
Population-Association Studies and the Calculation of the Odds Ratio, an Estimate of Relative Risk	303
Human Leukocyte Antigen Class I Associations: HLA-B27 and Spondyloarthropathies	304
Human Leukocyte Antigen Class II Associations with Autoimmune Diseases	304
Rheumatoid Arthritis: HLA-DRB1 Associations and the “Shared Epitope”	305
HLA-DQ Associations with Autoimmune Diseases	306
Population-Association Studies: What Do They Mean?	306
Linkage Disequilibrium	307
Alternatives to the Case-Control Method for Detecting Disease Association	309
Genetics in the Era of Whole Genome Analysis	309
Estimating the Size of the Genetic Contribution to Rheumatic Diseases	310
Screening the Entire Genome for Disease Genes: Approaches Based on Linkage	310
Screening the Entire Genome for Disease Genes: Approaches Based on Association	311
Overlapping Susceptibiliy Genes and Pathways for Autoimmune Diseases: Getting to Function	312
Future Challenges of Genetics in Rheumatic Diseases	312
Selected References	313
References	315.e1
22 Epigenetics	316
Key Points	316
Epigenetic Mechanisms	316
DNA Methylation	316
Histone Modifications	317
Acetylation	317
Methylation	318
Phosphorylation	318
SUMOylation	318
Ubiquitination	319
ADP Ribosylation	319
Epigenetics and Noncoding RNAs	319
Epigenetics in Disease	319
Epigenetics and Rheumatic Diseases	320
Systemic Lupus Erythematosus	320
Rheumatoid Arthritis	321
References	322
23 Complement System	325
Key Points	325
Historical Aspects	325
Function	325
Nomenclature	326
Activation Cascades	326
Classical Pathway	326
Lectin Pathway	328
Alternative Pathway	329
Membrane Attack Complex	329
Regulators	329
Physiologic Regulation	329
Fluid-Phase and Membrane Inhibitors	330
Complement Receptors	330
Complement in the Innate and Adaptive Immune Responses	331
Innate Immunity	331
Adaptive Immunity	331
Clearance of Necrotic and Apoptotic Cells	332
Immune Complex Clearance	332
Complement Measurement	332
Complement Deficiency	333
Classical Pathway	334
Alternative Pathway	334
Lectin Pathway	334
Acquired Complement Deficiency States	335
Lupus Paradigm	335
Models of Inflammatory Disease Featuring Complement Activation	335
Deficient Animals	335
Gene-Targeted Deficiencies	336
Antiphospholipid Antibody Syndrome	336
Complement Activation in Polyarthritis	336
Human Rheumatoid Arthritis	336
Collagen-Induced Arthritis	337
K/BxN Mouse Model	337
Therapeutic Implications	337
References	337
24 Prostaglandins, Leukotrienes, and Related Compounds	340
Key Points	340
Biosynthesis of Eicosanoids	340
Phospholipases	340
Cyclooxygenase Pathway	342
Regulation of Cyclooxygenase-1 Expression	342
Regulation of Cyclooxygenase-2 Expression	343
Cyclooxygenase-3	344
Prostaglandin Synthases	344
Products of the Cyclooxygenase Pathway	344
Prostaglandins	344
Prostacyclin	345
Thromboxanes	346
Lipoxygenase Pathways	346
Products of the Lipoxygenase Pathways	347
Lipoxins	348
Isoeicosanoids	349
Isoprostanes	349
Endocannabinoids	350
Eicosanoid Receptors	351
Prostaglandin Receptors	351
Leukotriene Receptors	352
Lipoxin Receptors	352
Nuclear Receptors	352
Platelet-Activating Factor	353
Eicosanoids as Regulators of Inflammation and Immune Responses	353
Modulation of Eicosanoid Synthesis by Administration of Precursor Fatty Acids	354
References	355
25 Cell Recruitment and Angiogenesis	358
Key Points	358
Endothelial Pathophysiology In Inflammation	358
Intercellular Adhesion Molecules	358
Process of Leukocyte Extravasation in Inflammation	358
Adhesion Receptors and Ligands	359
Chemokines and Chemokine Receptors	360
Chemokine Superfamilies	360
Chemokine Receptors	360
Inflammatory and Homeostatic Chemokines: Is It a Justified Classification?	361
Angiogenesis and Vasculogenesis in Inflammation	361
Angiogenesis and Vasculogenesis	361
Angiogenic Factors	361
Vasculogenesis in Inflammatory Conditions	362
Interactions among Adhesion Receptors, Chemokines, and Angiogenesis: The “Real” Bermuda Triangle in the Regulation of Inflammatory Synovitis	362
Chemokines and Adhesion Receptors	362
Chemokines and Chemokine Receptors in Angiogenesis and Vasculogenesis	362
Adhesion Receptors, Ligands, and Proteases in Angiogenesis and Vasculogenesis	363
Targeting Cell Adhesion, Chemokines, and Angiogenesis: Possible Therapeutic Approaches in Inflammatory Arthritides	363
Inhibition of Cell Adhesion Receptors and Leukocyte-Endothelial Adhesion	363
Chemokine and Chemokine Receptor Targeting	363
Angiogenesis Targeting: Use of Angiostatic Compounds	364
Summary	366
Selected References	366
References	368.e1
26 Cytokines	369
Key Points	369
Classification of Cytokines	369
Assessing Cytokine Function in Vitro And in Vivo	369
Cytokine Receptors	370
Regulation of Cytokine Expression	371
Effector Function of Cytokines	373
Cytokines in Acute Inflammation	373
Cytokines in Chronic Inflammation	373
T Cell Effector Function in Chronic Inflammation	378
Cell-to-Cell Interactions	378
Agonist/Antagonist Cytokine Activities in Chronic Inflammation	379
Disease-Modifying Antirheumatic Drugs	379
Cellular Interactions across Diverse Tissues	379
B Cells and Cytokine Release in Chronic Inflammation	380
Innate Cell Lineages in Chronic Inflammation	380
Growth Factors in Chronic Inflammation	380
Cytokine Effects Beyond Immune Regulation	380
Summary	380
References	380
27 Cell Survival and Death in Rheumatic Diseases	382
Key Points	382
History and Concepts	382
Apoptosis	382
Programmed Cell Death	382
Autophagy	384
Necrosis	384
Pyroptosis	384
Biochemistry of Apoptosis	385
Death Ligands, Receptors, and Signals	386
Death Receptors	386
Death Receptor Signal Transduction	386
Death Ligands	386
Function in Immune Regulation	387
Intrinsic Cell Death Pathways: Initiation and Execution of Apoptosis	387
Genotoxic Injury	387
Mitochondrial Stress	387
Endoplasmic Reticulum (ER) Stress	387
Antiapoptotic Proteins: FLIP, Bcl-2, IAPs, and Akt	388
Inhibition of Death Receptors	388
Bcl-2 Family of Cell Death Regulators	388
Intracellular Inhibitors of Apoptosis (IAPs)	388
Akt	389
Caspases	389
Finding, Removing, and Responding to Dead and Dying Cells	389
Finding the Dying Cell	389
Eating the Dying Cell	389
Responding to the Dying Cell	391
Ligands (DAMPs) and Sensors for Cell Debris.	391
Laboratory Detection of Apoptosis	391
Cell Membrane Alterations	391
Loss of Mitochondrial Membrane Potential (MMP)	391
Caspase Activation	391
Chromatin Condensation and DNA Fragmentation	393
Autophagy	393
Apoptosis in Relation to Rheumatic Disorders	393
Defective Apoptosis of Immune Cells	393
Defective Uptake and Processing of Apoptotic Cells	394
Prolonged Exposure to Growth Factors	395
Tissue Injury in Organ-Specific Autoimmunity	395
Accelerated Apoptosis in Degenerative Rheumatic Disorders	396
Drugs That Affect Apoptotic Pathways	396
Anti-inflammatory Drugs	396
Immunomodulatory Drugs	396
Cytotoxic Drugs	397
Biologics	397
Other Opportunities for Therapeutic Intervention	397
Conclusions	398
Acknowledgments	398
Selected References	398
References	399.e1
28 Experimental Models for Rheumatoid Arthritis	400
Key Points	400
Arthritis Caused By Infectious Agents	401
Mycoplasma arthritides Arthritis	401
Lyme Arthritis	401
Staphylococcal Arthritis	401
Arthritis and Ankylosing Spondylitis Induced by Intracellular Bacteria	401
Arthritis Caused by Bacterial Fragments	401
Nonbacterial Adjuvant-Induced Arthritides	403
Cartilage Protein–Induced Arthritis	404
Collagen (II)-Induced Arthritis	404
Genetic Basis of Collagen-Induced Arthritis	406
Role of the Major Histocompatibility Complex	406
Autoimmunity in Collagen-Induced Arthritis	407
Induction of Arthritis with Other Cartilage and Joint-Related Proteins	407
Type XI Collagen-Induced Arthritis	407
COMP-Induced Arthritis	407
Proteoglycan (Aggrecan)-Induced Arthritis	407
Antigen-Induced Arthritis	407
Glucose-6-Phosphoisomerase–Induced Arthritis	407
Spontaneous Arthritis	407
Spontaneous Arthritis in Genetically Modified Strains	408
Using Animal Models	408
Increasing Knowledge of Disease Pathways	408
Developing New Therapeutic Strategies	409
Ethical Considerations.	409
Conclusions	409
Selected References	409
References	412.e1
29 Neural Regulation of Pain and Inflammation	413
Key Points	413
Acute Inflammation (The First 12 Hours)	414
Recognition of Foreign or Pathogenic Material: Immune and Pain Pathways	414
Peripheral Sensitization	415
Central Sensitization	415
Neuroendocrine Systemic Response	418
Intermediate Inflammation (Between 12 Hours and Several Days/Few Weeks)	420
Local Cell Accumulation in Inflamed Tissue	420
Immediate Change in Neuronal Innervation	420
Role of Catecholamines in Antigen Transport to Secondary Lymphoid Organs and Immune Response	422
Clonal Expansion of Aggressive and Regulatory T and B Cells	422
Resolution of Inflammation and Tissue Repair	422
Chronic Inflammatory Disease	423
Neuronal Influences on Chronic Inflammatory Disease in Animal Models	423
Neuronal Influence on Endothelial Cells and Angiogenesis	424
Neuronal Influences on Fibroblasts and Adipocytes	424
Neuronal Influences on Osteoclasts and Osteoblasts	424
Changes of the Nervous System in Patients with Chronic Inflammatory Diseases	425
Increased Activity of the Sympathetic Nervous System	425
Loss of Sympathetic Nerve Fibers and Sprouting of Sensory Nerve Fibers	425
Cells Positive for Neurotransmitters/Neuropeptides Appear in the Tissue	426
Summary	426
Selected References	426
References	429.e1
4 Broad Issues in the Approach to Rheumatic Disease	431
30 Principles of Epidemiology in Rheumatic Disease	431
Key Points	431
Overview of Epidemiologic Methods	431
Measures of Disease Occurrence	431
Prevalence	431
Incidence	431
Measures of Effect	432
Study Designs	432
Observational Studies	432
Ecologic Studies	432
Cross-Sectional Surveys	433
Case-Control Studies	434
Selection of Controls for Case-Control Study	434
Weaknesses of the Case-Control Design	434
Cohort Studies	435
Prospective Cohort Study	435
Retrospective Cohort Study	435
Nested Case-Control Studies	435
Registries	435
Clinical Trials	435
Noninferiority Trials	436
Comparative Effectiveness Research	436
Biases in Study Design	437
Selection Bias	437
Information Bias	437
Recall Bias	437
Confounding	437
Effect Measure Modification	437
Screening	438
Sensitivity	438
Specificity	438
Predictive Value	438
Summary	438
References	438
31 Economic Burden of Rheumatic Diseases	440
Key Points	440
Studies of the Costs of All Forms of Musculoskeletal Disease	442
Other Nations	446
Cost of Discrete Conditions	446
Rheumatoid Arthritis	447
Systemic Lupus Erythematosus	448
Osteoarthritis	448
Back Conditions	449
Other Conditions	449
Ankylosing Spondylitis	449
Fibromyalgia	449
SUMMARY AND CONCLUSIONS	449
References	450
32 Clinical Trial Design and Analysis	452
Key Points	452
Trial Design	452
Randomized Clinical Trials	452
Randomization	452
Design Considerations	453
Subject Selection	453
Informed Consent	454
Follow-up Considerations	454
Blinding	454
Choice of Outcome Variables	455
Measuring Effect	455
Sample Size and Statistical Power	456
Declaration of Helsinki	457
Place of Noninferiority Designs in Rheumatology	457
Conclusion	457
Trial Analysis	457
Hypothesis Testing	457
Intention to Treat	458
Problem of Incomplete Data	458
Presentation of Trial Results	459
Descriptive Analysis	459
Statistical Analysis	459
Statistical Significance and Clinical Relevance	460
Confounding	460
Interpretation of Safety Analyses	460
Conclusions	460
General Remarks	460
References	461
33 Assessment of Health Outcomes	462
Key Points	462
Which Health Outcomes Assessment Instruments are Available?	462
Disease-Specific Instruments: Core Sets	462
Health Status/Quality of Life	464
General Health Status.	464
Utilities: Value of Health State.	464
Symptoms.	464
Disability Scales.	465
Disease Process (Activity, Severity)	465
Damage Indices	465
Toxicity/Adverse Events (Wolfe’s “Disadvantage” Category)	465
Death	465
Dollar Costs	465
Other Outcomes of Interest	465
Self-Efficacy/Effective Consumer	465
Work Disability: Looking beyond Absenteeism	465
Nonpaid Work Roles	466
Patient-Specific Indices	466
Satisfaction with Health Outcomes	466
How TO DETERMINE WHAT to MEASURE: Defining ONE’S Measurement Need	466
What Is Worth Measuring?	466
Why Measure?	467
Who Comprises the Target Population?	467
Decision-Making Instrument for Selecting the Outcome that Can Meet THE Measurement Need	467
Step 1: Is It a Good Match with the Need?	468
Step 2: Is It Feasible to Use?	468
Step 3: Does the Instrument Look Like It Has the Right Content in Order to Measure What It Is Intended to Measure (Truth 1)?	469
Step 4: Do the Numeric Scores Make Sense? Are These Scores Behaving in Ways That a “Good” Measure of This Construct Would Behave (Truth 2)?	469
Step 5: Can This Instrument Evaluate Change over Time in a Group of Patients?	469
Test-Retest Reliability	470
Step 6: Can It Define an Important Response for an Individual Patient?	470
Benchmarking States	470
Changes in State	470
American College of Rheumatology Response Criteria.	470
Minimal Clinically Important Differences/Improvements.	471
Combined Approaches: Change and State	471
Areas of Growth in Health Outcome Assessment	471
Item Response Theory	471
Adaptation to an Ongoing Disease	472
Changing Nature of Clinical Trials	472
Conclusion: Are We There Yet?	472
Acknowledgments	472
Selected References	472
References	475.e1
34 Biologic Markers	476
Key Points	476
Inflammatory Biomarkers and Signal Molecules	477
Cytokines and Chemokines	477
Adipokines	477
EXTRACELLULAR Matrix Remodeling Biomarkers	479
Collagen Markers	479
Collagen Cross-Links	481
Collagen Synthesis	481
Proteoglycan Markers	482
Hyaluronan	482
Cartilage Oligomeric Matrix Protein	483
Metalloproteinases	483
Biologic Markers in Synovial Tissue	484
Biomarker Panels	485
“-Omics” Base Biomarkers	485
Genomics	486
Proteomics and Lipidomics	486
Metabolomics	487
Systems Biology	487
Biomarker Validation and Application	487
Conclusion	488
Selected References	489
References	492.e1
35 Occupational and Recreational Musculoskeletal Disorders	493
Key Points	493
Occupation-Related Musculoskeletal Disorders	493
Occupation-Related Rheumatic Diseases	495
Osteoarthritis	495
Other Occupational Rheumatologic Disorders	495
Recreation- And Sports-Related Musculoskeletal Disorders	496
Performing Arts–Related Musculoskeletal Disorders	499
Instrumentalists	499
Vocal Artists	501
Dancers	501
References	501
36 Cardiovascular Risk in Rheumatic Disease	505
Key Points	505
Cardiovascular Mortality	505
Rheumatoid Arthritis	505
Systemic Lupus Erythematosus	505
Cardiovascular Comorbidity	506
Rheumatoid Arthritis	506
5 Evaluation of Generalized and Localized Symptoms	559
40 History and Physical Examination of the Musculoskeletal System	559
Key Points	559
History in a Patient with Musculoskeletal Disease	559
Pain	559
Stiffness	560
Limitation of Motion	560
Swelling	560
Weakness	560
Fatigue	561
Loss of Function	561
Systematic Method of Examination	561
General Observation	561
Swelling	562
Tenderness	562
Limitation of Motion	562
Crepitation	562
Deformity	562
Instability	563
Other Aspects of the Examination	563
Recording the Joint Examination	563
INTERPRETING the Joint Examination	563
Examination of Specific Joints	563
Temporomandibular Joint	563
Cricoarytenoid Joints	564
Sternoclavicular, Manubriosternal, and Sternocostal Joints	564
Acromioclavicular Joint	564
Shoulder	564
Elbow	564
Wrist and Carpal Joints	565
Metacarpophalangeal and Proximal and Distal Interphalangeal Joints	566
Hip	568
Knee	570
Ankle	574
Foot	575
References	575
41 Acute Monoarthritis	577
Key Points	577
History	577
Examination	577
Investigations	577
Blood	577
Urine	578
Imaging Studies	578
Synovial Fluid	578
Synovial or Bone Biopsy	579
Specific Diagnoses	580
Acute Monoarthritis	580
Septic Arthritis (Bacterial)	580
Crystal Arthritis	581
Gout	581
Pseudogout	581
Acute Calcific Periarthritis	581
Calcium Phosphate Crystal Arthritis	581
Cholesterol Crystal Arthritis	581
Reactive Arthritis	581
Lyme Disease	582
Plant Thorn Synovitis	582
Other Organisms Producing Monoarthritis	582
Trauma and Internal Derangement	582
POLYARTHRITIS PRESENTING AS ACUTE Monoarthritis	582
Monoarthropathies Arising From Other Joint Diseases	583
Synovial Causes of Noninflammatory Monoarticular Pain	583
Monoarticular Arthritis in Systemic Diseases	583
Regional Differential Diagnosis of Musculoskeletal Pain	584
Monoarticular Pain Resulting From Periarticular Disorders	584
References	585
42 Polyarticular Arthritis	587
Key Points	587
Epidemiology and Societal Impact	587
Defining Polyarthritis	587
Approach to Diagnosis	588
Frequent Noninflammatory Polyarticular Scenarios	588
Fibromyalgia	588
Osteoarthritis	588
History	588
Demographics.	588
Symptom Onset.	588
Pattern of Joint Involvement.	589
Disease Course.	589
Presence of Inflammation.	589
Physical Examination	590
Arthralgia vs. Arthritis.	590
Articular vs. Periarticular.	590
Extra-articular Manifestations.	590
Laboratory Tests and Radiologic Studies	591
Laboratory Tests	591
Acute Phase Reactants	591
Serologies	591
Genetic Markers	592
Synovial Fluid Analysis	592
Imaging	593
Unique Situations	593
Undifferentiated Inflammatory Arthritis	593
The Hospitalized Patient	594
Infection and Polyarthritis	595
Polyarthritis, Rash, and Fever	595
Drug-Induced Syndromes	595
Malignancy-Related Polyarthritis	595
Pediatric Polyarthritis	595
Polyarthritis in the Elderly	596
Outcome: A Window of Opportunity	596
Conclusion	596
References	596
43 The Skin and Rheumatic Diseases	599
Key Points	599
Diagnosis of Skin Lesions Associated with Rheumatic Diseases	599
Psoriasis	599
Reactive Arthritis	600
Rheumatoid Arthritis	601
Juvenile Rheumatoid Arthritis/Still’s Disease	602
Lupus Erythematosus	602
Lupus-Specific Skin Lesions	602
Nonspecific Cutaneous Lesions	605
Neonatal Lupus Syndrome	605
Sjögren’s Syndrome	605
Dermatomyositis	605
Scleroderma and Other Sclerosing Conditions	606
Morphea	606
Systemic Scleroderma	607
Eosinophilic Fasciitis	608
POEMS Syndrome	608
Scleromyxedema	608
Nephrogenic Systemic Fibrosis	608
Primary Necrotizing Vasculitis Involving the Skin	608
Leukocytoclastic Small Vessel Vasculitis and Its Variants	608
Granulomatous Vasculitides	610
Polyarteritis Nodosa and Related Conditions	610
Large Vessel Vasculitis	610
Infections	611
Lyme Borreliosis	611
Parvovirus	611
Atypical Infections: Mycobacterium marinum	611
Panniculitis	611
Relapsing Polychondritis	612
Infiltrative Diseases and Skin/Arthritis	613
Amyloid	613
Sarcoidosis	613
Miscellaneous Skin Diseases and Arthritis	613
Behçet’s Disease	613
Familial Mediterranean Fever	614
Multicentric Reticulohistiocytosis	614
Chronic Infantile Neurologic Cutaneous and Articular (CINCA) Syndrome	614
Acknowledgment	614
References	614
44 The Eye and Rheumatic Diseases	617
Key Points	617
Ocular Anatomy and Physiology	617
Ocular Immune Response	618
Uveitis	618
Scleritis and Corneal Melt	621
Orbital Disease	622
Optic Neuritis	622
Summary	623
References	623
6 Differential Diagnosis of Regional and Diffuse Musculoskeletal Pain	625
45 Neck Pain	625
Key Points	625
Epidemiology	625
Anatomy	625
Axial Neck Pain	628
Radiculopathy and Myelopathy	629
Clinical Features	630
Patient History	630
Localization of Pain Generators	630
Clinical Examination	632
Diagnostic Evaluation	635
Differential Diagnosis and Treatment	636
References	637
46 Shoulder Pain	639
Key Points	639
Anatomy and Function	639
Diagnosis	640
Clinical Evaluation of the Shoulder	640
History	640
Physical Examination	640
Imaging	643
Radiographic Assessment	643
Scintigraphy	644
Arthrography	644
Computed Tomography	645
Ultrasonography	645
Arthroscopy	646
Magnetic Resonance Imaging	647
Electromyography and Nerve Conduction Velocity Studies	647
Injection	648
Potential Diagnostic Tests	648
Intrinsic Factors Causing Shoulder Pain	649
Periarticular Disorders	649
Shoulder Impingement and Rotator Cuff Tendinopathy	649
Calcific Tendinitis	651
Rotator Cuff Tear	652
Pathophysiology	652
Diagnosis	652
History.	652
Imaging.	652
Treatment	653
Nonsurgical Treatment.	653
Surgical Treatment.	653
Acute Tears.	653
Chronic Tears.	654
Bicipital Tendinitis and Rupture	654
Acromioclavicular Disorders	655
Glenohumeral Disorders	656
Inflammatory Arthritis	656
Osteoarthritis	657
Osteonecrosis	657
Cuff-Tear Arthropathy	657
Septic Arthritis	658
Labral Tears	658
Adhesive Capsulitis	658
Glenohumeral Instability	659
Extrinsic or Regional Factors Causing Shoulder Pain	660
Cervical Radiculopathy	660
Brachial Neuritis	660
Nerve Entrapment Syndromes	661
Sternoclavicular Arthritis	662
Reflex Sympathetic Dystrophy	662
Neoplasms	662
Miscellaneous Conditions	662
Selected References	663
References	664.e1
47 Low Back Pain	665
Key Points	665
Epidemiology	665
Anatomy	665
Clinical Evaluation	666
History	666
Physical Examination	667
Diagnostic Tests	667
Imaging	667
Electrodiagnostic Studies	669
Laboratory Studies	669
Differential Diagnosis	669
Lumbar Spondylosis	669
Disk Herniation	670
Spondylolisthesis	671
Spinal Stenosis	671
Diffuse Idiopathic Skeletal Hyperostosis	673
Nonspecific Low Back Pain	674
Neoplasm	674
Infection	674
Inflammation	675
Metabolic Disease	675
Visceral Pathology	675
Miscellaneous	675
Treatment	676
Acute Low Back Pain	676
Chronic Low Back Pain	678
Nerve Root Compression Syndromes	679
Disk Herniation	679
Spinal Stenosis	680
Spondylolisthesis	680
OUTCOME	680
Summary	681
References	681
48 Hip and Knee Pain	683
Key Points	683
Knee Pain	683
History	683
Physical Examination	684
General	684
Ligaments	685
Menisci	688
Quadriceps Tendon	689
Patella Tendon	689
Patellofemoral Pain	689
Imaging	690
Conventional Radiographs	690
Computed Tomography	691
Ultrasound	691
Nuclear Scintigraphy	691
Magnetic Resonance Imaging	691
Common Disorders in the Differential Diagnosis of Knee Pain	692
General	692
Bursitis	692
Neoplasia	692
Popliteal Cysts	693
Hip Pain	693
History	693
Physical Examination	693
Imaging	696
Conventional Radiographs	696
Computed Tomography	696
Nuclear Scintigraphy	696
Magnetic Resonance Imaging	696
Hip Arthrography	698
Common Disorders in the Differential Diagnosis of Hip Pain	698
References	698
49 Foot and Ankle Pain	700
Key Points	700
Causes of Foot and Ankle Pain	700
Functional Anatomy and Biomechanics	700
Diagnostic Evaluation	701
Physical Examination	701
Imaging	702
Common Causes of Ankle Pain	703
Anterior Ankle Pain	703
Central Joint Pain	703
Posterior Joint Pain	703
Medial and Lateral Ankle Pain	703
Common Causes of Foot Pain	704
Nonoperative Treatment	704
Operative Treatment	705
Arthrodesis	705
Arthroplasty	706
Osteotomy	706
Ostectomy	706
Synovectomy	707
Conclusion	707
References	707
50 Hand and Wrist Pain	708
Key Points	708
Patient Evaluation	708
Anatomy	708
History	708
Physical Examination	708
Imaging Studies	709
Additional Diagnostic Tests	709
Neurodiagnostic Tests	709
Injections and Aspirations	710
Arthroscopy	710
Common Etiologies for Hand and Wrist Pain	710
Wrist Pain: Palmar	710
Carpal Tunnel Syndrome	710
Ulnar Nerve Entrapment: Cubital Tunnel Syndrome	711
Ulnar Nerve Entrapment: Guyon’s Canal	711
Flexor Carpi Radialis and Flexor Carpi Ulnaris Tendinitis	711
Hamate Fracture	711
Wrist Pain: Dorsal	712
Ganglion	712
Carpal Boss	712
Extensor Tendinopathies	713
Kienböck’s Disease	713
Scapholunate Interosseous Ligament Injury	713
Gout and Inflammatory Arthritis	714
Wrist Pain: Ulnar	714
Triangular Fibrocartilage Complex Injury and Ulnocarpal Impaction Syndrome	714
Extensor Carpi Ulnaris Tendinitis and Subluxation	715
Lunotriquetral Ligament Injury	715
Pisotriquetral Arthritis	715
Wrist Pain: Radial and Base of Thumb	715
De Quervain’s Disease and Intersection Syndrome	715
Basal Joint Arthropathy	716
Volar Ganglion	717
Scaphoid Fracture and Nonunion	717
Palm	717
Trigger Finger	717
Retinacular Cysts	717
Digits	717
Mallet Finger	717
Osteoarthritis of the Digits	718
Tumors	718
Infection	718
Selected References	719
References	720.e1
51 Temporomandibular Joint Pain	721
Key Points	721
Arthritis of the Temporomandibular Joint	721
Osteoarthritis	721
Clinical Findings	721
Imaging Findings	721
7 Diagnostic Tests and Procedures in Rheumatic Diseases	753
53 Synovial Fluid Analyses, Synovial Biopsy, and Synovial Pathology	753
Key Points	753
Synovial Fluid Analysis	753
Synovial Fluid in Health	753
Accumulation of Synovial Effusions	754
Arthrocentesis	754
Gross Examination	754
Leukocyte Count	755
Synovial Fluid Cytology	755
Wet Smear Analysis by Polarized Microscopy	756
Detection of Microorganisms by Gram Stain, Culture, and Polymerase Chain Reaction Analysis of Synovial Fluid	757
Biochemical Analysis of Synovial Fluid	758
Synovial Fluid Analysis in Arthritis Research	758
Synovial Biopsy	758
Blind Percutaneous Synovial Biopsy	758
Arthroscopically Guided Synovial Biopsy	759
Processing Synovial Tissue Samples	759
Synovial Pathology	759
Synovial Membrane in Health	759
Synovial Histopathology in the Evaluation of Monoarthritis	760
Synovial Histopathology in the Evaluation of Polyarthritis	760
Synovial Immunohistology	763
Considerations Regarding Sampling and Quantitative Analysis	763
Synovial Lining Cell Layer	763
Synovial Lymphocytes and Plasma Cells	764
Synovial Sublining Macrophages and Dendritic Cells	765
Synovial Microvasculature, Endothelium, and Stromal Mesenchymal Cells	766
Synovial-Cartilage-Bone Interface	766
Synovial Biopsy and Pathology as Tools for Predicting and Assessing Response to Therapy in Inflammatory Arthritis	766
Summary	767
Selected References	767
References	769.e1
54 Arthrocentesis and Injection of Joints and Soft Tissue	770
Key Points	770
Indications and Clinical Evidence	770
Arthrocentesis	770
Therapeutic Injection	771
Inflammatory Arthritis	771
Noninflammatory Arthritis	772
Nonarticular Conditions	773
Preparations	774
Corticosteroids	774
Other Injectable Products	774
Contraindications	774
Complications	775
General Arthrocentesis Techniques	776
Materials	776
Site Preparation and Technique	776
Postprocedure Instructions and Care	777
Specific Regional Arthrocentesis Techniques	777
Cervical Spine Area	777
Anterior Chest Wall	777
Temporomandibular Joint	777
Shoulder	778
Glenohumeral Joint	778
Acromioclavicular Joint	778
Rotator Cuff Tendon and Subacromial Bursa	778
Bicipital Tendon	778
Elbow	779
Elbow Joint	779
Medial and Lateral Epicondyle	779
Olecranon Bursa and Nodules	779
Wrist and Hand	779
Radiocarpal Joint	779
Dorsal Wrist Tendons	780
de Quervain’s Tenosynovitis	780
Carpal Tunnel Syndrome	780
Ganglia	781
Thumb Carpometacarpal Joint	781
Metacarpophalangeal and Interphalangeal Joints	781
Flexor Tenosynovitis (Trigger Fingers)	781
Lumbosacral Spine Area	781
Pelvic Girdle	781
Ischiogluteal Bursitis	781
Trochanteric Pain Syndrome (Bursitis)	782
Hip (Acetabular) Joint	782
Knee	782
Knee Joint	782
Periarticular Knee Pain Syndromes	783
Ankle and Foot	783
Tibiotalar Joint	783
Subtalar Joint	784
Achilles Tendon Area	784
Tarsal Tunnel Syndrome	784
Plantar Fascia	784
Metatarsophalangeal Joints	784
Interdigital Neuroma	784
Current and Future Trends in Arthrocentesis and Joint Injection	785
Ultrasound-Guided Arthrocentesis and Injection	785
Joint Irrigation	785
Intra-articular Biologic Therapy	785
Selected References	785
References	788.e1
55 Antinuclear Antibodies	789
Key Points	789
History	789
Key Point	789
Relevance of ANTINUCLEAR ANTIBODIES to Disease Pathogenesis	790
Key Point	790
Methods of Detection	790
Key Points	790
Immunofluorescence	792
Enzyme-Linked Immunosorbent Assay	793
Anti-DNA Antibody Tests	793
Other Assays	794
Interpretation of the FLUORESCENT ANTINUCLEAR ANTIBODY (FANA) TEST	794
Key Point	794
Pattern	794
Titer	795
Diseases Associated with Antinuclear Antibodies	795
Systemic Lupus Erythematosus	795
Chromatin-Associated Antigens	796
Anti-DNA.	796
Antihistone (Nucleosome).	796
Other Chromatin-Associated Autoantigens.	796
Ribonucleoproteins	796
Anti–Small Nuclear Ribonucleoproteins.	796
Anti-Ro/SSA and La/SSB.	796
Antiribosomes	796
Other Antinuclear Antibodies in Systemic Lupus Erythematosus	797
Systemic Sclerosis (Scleroderma)	797
Antikinetochore (Centromere) and Anti–Topoisomerase I	797
Anti-RNA Polymerases	797
Anti–Polymyositis-Scleroderma (PM-Scl)	798
Other Systemic Sclerosis– Related Antinuclear Antibodies	798
Inflammatory Muscle Diseases	798
Myositis-Specific Autoantibodies	798
Myositis Overlap Autoantibodies	798
Sjögren’s Syndrome	799
Mixed Connective Tissue Disease and Overlap Syndromes	800
Other Conditions	800
Conclusion: Clinical Utility of Antinuclear Antibody Testing	800
References	801
56 Autoantibodies in Rheumatoid Arthritis	804
Key Points	804
Rheumatoid Factor	804
ANTICITRULLINATED PROTEIN AUTOANTIBODIES	805
Antikeratin Antibodies and Antiperinuclear Factor in Rheumatoid Arthritis	805
Discovery of Autoantibodies That Recognize Peptidylcitrulline	806
Anti-CCP Antibodies: Clinical Relevance	806
Kinetics of Appearance of Anti-CCP Antibodies in Rheumatoid Arthritis	807
Anticitrullinated Protein Autoantibodies	807
Antibodies Recognizing Citrullinated Fibrinogen	808
Antibodies Recognizing Citrullinated Vimentin	808
Antibodies Recognizing Citrullinated Enolase	809
Antibodies Recognizing Citrullinated Collagen Type II	809
Citrullinated Antigen Generation in Rheumatoid Arthritis	809
Peptidylarginine Deiminase Enzymes	809
Peptidylarginine Deiminase Structure, Activity, and Regulation	809
Structural and Functional Implications of Protein Citrullination	810
Peptidylarginine Deiminases in Rheumatoid Arthritis	810
Genetic Associations with Anti-Ccp/Acpas	811
OTHER AUTOANTIBODY SPECIFICITIES IN RHEUMATOID ARTHRITIS	811
Autoantibodies in Rheumatoid Arthritis: Insights into Disease Mechanism	813
Potential Environmental Factors in ACPA Production and Rheumatoid Arthritis Pathogenesis	813
Role of Autoantibodies in Rheumatoid Arthritis: Insights from Animal Models	814
Selected References	814
References	817.e1
57 Acute Phase Reactants and the Concept of Inflammation	818
Key Points	818
Acute Phase Response	819
Erythrocyte Sedimentation Rate	819
C-Reactive Protein	820
Serum Amyloid A	822
Other Acute Phase Proteins	822
Cytokines	823
Acute Phase Reactants in the Management of Rheumatic Diseases	823
Rheumatoid Arthritis	823
Systemic Lupus Erythematosus	824
Polymyalgia Rheumatica and Giant Cell Arteritis	824
Adult-Onset Still’s Disease	824
Ankylosing Spondylitis	825
Osteoarthritis	825
Other Rheumatic Diseases	825
Practical Use of Acute Phase Reactants	825
C-Reactive Protein and Health: ASSOCIATIONS with Nonrheumatologic Conditions	825
Selected References	826
References	829.e1
58 Imaging Modalities in Rheumatic Diseases	830
8 Pharmacology of Antirheumatic Drugs	871
59 Prostanoid Biology and Its Therapeutic Targeting	871
Key Points	871
History	871
Cyclooxygenase Biology and Bioactive Lipids	872
Prostaglandin Production and Action	873
Biochemistry and Structural Biology	874
Molecular Biology	876
Mechanism of Action	876
Cyclooxygenase Inhibition	876
COX-2 Selectivity	877
Cyclooxygenase-Independent Mechanisms of Action	877
Mechanism of Acetaminophen and Other Analgesic Antipyretic Drugs	877
Pharmacology and Dosing	877
Classification	877
NSAID Metabolism	880
Salicylate Metabolism and Aspirin Resistance	880
Pharmacologic Variability	880
Routes of Drug Delivery	880
Combination Drugs	880
Therapeutic Effects	881
Anti-inflammatory Effects	881
Analgesic Effects	881
Antipyretic Effects	881
Other Therapeutic Effects	881
Antiplatelet Effects	881
Cancer Chemoprevention	881
Adverse Effects	882
Gastrointestinal Tract Effects	882
Dyspepsia	883
Gastritis and Gastroduodenal Ulcer	883
Esophageal Injury	884
Small Bowel Injury	884
Colitis	884
Renal Effects	884
Sodium Excretion	884
Hypertension	884
Acute Renal Failure and Papillary Necrosis	885
Interstitial Nephritis	885
Chronic Kidney Disease	885
Cardiovascular Effects	885
Heart Failure	886
Closure of the Ductus Arteriosus	886
Hepatic Effects	886
Asthma and Allergic Reactions	886
Asthma	886
Allergic Reactions	886
Hematologic Effects	886
Effects on the Immune System	886
Central Nervous System Effects	887
Effects on Bone	887
Effects on Ovarian and Uterine Function	887
Salicylate Intoxication and NSAID Overdose	888
Adverse Effects of Acetaminophen	888
Effects of Concomitant Drugs, Diseases, and Aging	888
Drug-Drug Interactions	888
Drug-Disease Interactions	888
Drug Reactions in the Elderly	888
Colchicine	889
Mechanism of Colchicine Action	889
Adverse Effects of Colchicine	889
Choosing Anti-Inflammatory Analgesic Therapy	889
Selected References	890
References	893.e1
60 Glucocorticoid Therapy	894
Key Points	894
Characteristics of Glucocorticoids	894
Structure and Classification	894
Biologic Characteristics and Therapeutic Consequences	895
Pharmacokinetics and Pharmacology	896
Drug Interactions	897
Pregnancy and Lactation	898
Basic Mechanisms of Glucocorticoids	898
Genomic and Nongenomic Effects	898
Genomic Mechanisms	898
Glucocorticoid Effects on the Immune System	899
Leukocytes and Fibroblasts	900
Cytokines	900
Inflammatory Enzymes	901
Adhesion Molecules and Permeability Factors	901
Hypothalamic-Pituitary-Adrenal Axis	901
Pathophysiology	901
Effects of Glucocorticoids on the Hypothalamic-Pituitary-Adrenal Axis	901
Treatment with Glucocorticoids	903
Indications	903
Glucocorticoid Therapy in Rheumatoid Arthritis	903
Signs and Symptoms	903
Radiologic Joint Damage: Glucocorticoids as DMARDs	904
Prevention of Early (Rheumatoid) Arthritis Development with Glucocorticoids	905
Chronobiology	905
Other Developments to Improve the Therapeutic Ratio of Glucocorticoids	906
Alternate-Day Regimens	906
Glucocorticoid Sensitivity and Resistance	906
Glucocorticoid Withdrawal Regimens	907
Adaptations of Glucocorticoid Doses, Stress Regimens, and Perioperative Care	907
Glucocorticoid-Sparing Agents	908
Glucocorticoid Pulse Therapy	908
Intralesional and Intra-articular Glucocorticoid Injections	908
Adverse Effects and Monitoring	909
Skeletal Adverse Effects	910
Osteoporosis	910
Osteonecrosis	910
Myopathy	910
Gastrointestinal Adverse Effects	910
Peptic Ulcer Disease	910
Other Gastrointestinal Adverse Effects	911
Immunologic Adverse Effects	911
Cardiovascular Adverse Effects	911
Mineralocorticoid Effects	911
Atherosclerosis	911
Ocular Adverse Effects	911
Cataract	911
Glaucoma	911
Dermal Adverse Effects	912
Endocrine Adverse Effects	912
Glucose Intolerance and Diabetes Mellitus	912
Fat Redistribution and Body Weight	912
Dyslipidemia	912
Suppression of the Hypothalamic-Pituitary-Adrenal Axis	912
Adverse Behavioral Effects	912
Steroid Psychosis	913
Minor Mood Disturbances	913
Monitoring	913
References	913
References	916.e1
61 Traditional DMARDs:	917
9 Rheumatoid Arthritis	1059
69 Etiology and Pathogenesis of Rheumatoid Arthritis	1059
Key Points	1059
Etiology and Pathogenesis of Rheumatoid Arthritis: Roles of Innate and Adaptive Immunity	1059
Etiology of Rheumatoid Arthritis	1061
Key Points	1061
Role of HLA-DR in the Susceptibility to and Severity of Rheumatoid Arthritis	1061
Additional Polymorphisms: Cytokines, Citrullinating Enzymes, PTPN22, and Others	1062
Interactions between Genes and Environment	1063
Gender	1063
Epigenetics	1063
Changing Epidemiology of Rheumatoid Arthritis	1064
Pathogenic Mechanisms in Rheumatoid Arthritis	1064
Key Points	1064
Infectious Agents: Direct Infection and Innate Immune Responses	1064
Toll-like Receptors and the Inflammasome in the Joint	1064
Bacteria, Mycobacteria, Mycoplasma, and Their Components	1065
Epstein-Barr Virus, dnaJ Proteins, and Molecular Mimicry	1066
Parvovirus	1066
Other Viruses	1066
Autoimmunity	1067
Key Points	1067
Rheumatoid Factor	1067
Anticitrullinated Protein Antibodies (ACPAs).	1068
Autoimmunity to Cartilage-Specific Antigens	1069
Type II Collagen.	1069
gp39 and Other Cartilage-Specific Antigens.	1070
Autoimmunity to Nonarticular Antigens	1070
Glucose-6-Phosphoisomerase	1070
Heterogeneous Nuclear Ribonuceloprotein-A2 and Heavy-Chain Binding Protein.	1070
Heat Shock Proteins.	1070
Synovial Pathology and Biology	1071
Key Points	1071
Synovial Intimal Lining Cells: Type A and Type B Synoviocytes	1071
Aggressive Features of RA Fibroblast-like Synoviocytes	1073
Tumor-like Properties.	1073
Matrix Invasion.	1073
Synovial T Lymphocytes	1073
Immunohistologic Patterns	1073
Regulation of T Cell Aggregate Formation.	1074
Synovial T Cell Phenotype	1074
Co-stimulatory Molecules.	1074
Adhesion Molecules.	1074
Chemokine Receptors.	1074
T Cell Receptor Rearrangements.	1075
Determinants of T Cell Phenotype.	1075
Synovial T Cell Immunoreactivity	1075
Restoring T Cell Tolerance	1076
Synovial B Cells	1076
Cytokine Regulation of Synovial B Cells.	1076
Synovial B Cell Maturation.	1076
B Cell Depletion in RA.	1077
B Cell Contribution to Synovitis.	1077
Dendritic Cells	1077
Mast Cells, Polymorphonuclear Leukocytes, and Natural Killer Cells	1078
Bone Marrow Cells	1078
Neural Elements and Rheumatoid Synovium	1079
Synovitis in Early versus Late Rheumatoid Arthritis	1080
Animal Models as Surrogates for Rheumatoid Synovitis	1080
Synovial Fluid and the Synovial Fluid Cartilage Interface	1081
Key Points	1081
Polymorphonuclear Leukocytes	1081
Synovial Fluid Lymphocytes	1082
Platelets and Platelet Microparticles	1082
Intra-articular Immune Complexes and Complement Fixation	1082
Synovial Fluid Immune Complexes	1082
Immune Complexes Embedded in Cartilage	1083
Synovial Fluid Complement	1083
Targeting Complement in Rheumatoid Arthritis	1083
Arachidonate Metabolites	1083
Prostaglandins	1083
Leukotrienes	1084
Anti-Inflammatory Arachidonic Acid Metabolites	1084
Peripheral Blood Lymphocyte Immune Responses	1084
Role of T Cell Cytokines	1085
Key Points	1085
T Helper Type 1 Cell Cytokines	1085
T Helper Type 2 Cell Cytokines	1086
T Helper Type 17 Cytokines	1086
Regulatory T Cells (Tregs)	1086
T Helper Cell Cytokine Imbalance in RA	1087
Activation of Synovial Cells by Cell-Cell Contact with T Lymphocytes	1087
Role of Macrophage and Fibroblast Cytokines	1087
Key Points	1087
Proinflammatory Macrophage and Fibroblast Cytokines	1088
Interleukin-1 Family	1088
Interleukin-1.	1088
Interleukin-18.	1088
Interleukin-33.	1088
Tumor Necrosis Factor	1089
Interleukin-6 Family	1089
Interleukin-12 Family	1090
Interleukin-15	1090
Interleukin-32	1090
Colony-Stimulating Factors	1090
Chemokine Families	1091
Platelet-Derived Growth Factor and Fibroblast Growth Factor	1091
Suppressive Cytokines and Cytokine Antagonists	1092
Interleukin-1 Receptor Antagonist	1092
Interleukin-10	1092
Transforming Growth Factor-β	1092
Soluble Cytokine Receptors and Binding Proteins	1093
Perpetuation of Synovitis by Macrophage-Fibroblast Cytokine Networks	1093
Signal Transduction and Transcription Factors	1094
Key Points	1094
Nuclear Factor κB	1094
Activator Protein-1	1094
Mitogen-Activated Protein Kinases	1094
Janus Activated Kinases and the Signal Transducers and Activators of Transcription	1095
Interferon Regulation: IKK-Related Kinases and Interferon Regulatory Factor-3	1096
Spleen Tyrosine Kinase and Other Signaling Pathways	1096
Cell Survival and Death in Rheumatoid Synovium	1096
Key Points	1096
Reactive Oxygen and Nitrogen	1097
Apoptosis	1097
Genes Regulating Apoptosis	1097
Therapeutic Interventions That Increase Apoptosis.	1097
Tumor Suppressor Genes	1098
Blood Vessels in RHEUMATOID Arthritis	1098
Key Points	1098
Angiogenesis in Rheumatoid Arthritis: Feeding the Starved Synovium	1098
Hypoxia	1099
Angiogenic Factors	1099
Targeting Angiogenesis	1099
Adhesion Molecule Regulation	1100
Integrins and Ligands	1100
Selectins	1100
Therapeutic Potential of Blocking Adhesion Molecules	1100
Cartilage and Bone Destruction	1101
Key Points	1101
Cartilage Destruction and the Pannus-Cartilage Junction	1101
Proteases: Mediators of Joint Destruction	1102
Matrix Metalloproteinases	1102
Regulation of MMP Production.	1102
MMP Expression in Synovium.	1102
Cysteine Proteases: The Cathepsins	1103
Aggrecanases	1103
Inhibitors of Protease Activity	1104
Regulation of Bone Destruction	1104
Tissue Repair	1105
Summary	1105
Selected References	1105
References	1108.e1
70 Clinical Features of Rheumatoid Arthritis	1109
Key Points	1109
Epidemiology and the Burden of Disease	1109
Risk Factors	1109
Clinical Presentations of Early Rheumatoid Arthritis	1110
Patterns of Onset	1110
Insidious Onset	1110
Acute or Intermediate Onset	1110
Joint Involvement	1110
Early Synovitis: Which Patients Develop Rheumatoid Arthritis?	1111
Other Patterns of Disease Onset or Variants of Disease	1111
Palindromic Pattern	1111
Insidious Onset in Older Individuals	1112
Arthritis Robustus	1112
Rheumatoid Nodulosis	1112
Course and Complications of Established Rheumatoid Arthritis	1112
Involvement of Specific Joints: Effects of Disease on Form and Function	1112
Hands and Wrists	1112
Elbows	1114
Shoulders	1114
Temporomandibular Joints	1115
Cricoarytenoid Joints	1115
Sternoclavicular and Manubriosternal Joints	1115
Cervical Spine	1115
Thoracic, Lumbar, and Sacral Spine	1117
Hips	1117
Knees	1117
Ankles and Feet	1118
Extra-articular Complications of Rheumatoid Arthritis	1119
Rheumatoid Nodules	1119
Bone Density	1120
Muscle	1121
Skin	1121
Eye	1121
Host Defense and Infection	1121
Hematologic Abnormalities	1122
Vasculitis	1122
Renal Disease	1123
Pulmonary Disease	1123
Pleural Disease	1123
Interstitial Pneumonitis and Fibrosis	1124
Nodular Lung Disease	1124
Bronchiolitis	1124
Pulmonary Hypertension	1124
Small Airways Disease	1124
Pulmonary Disease due to Treatment of Rheumatoid Arthritis	1124
Cardiovascular System	1124
Atherosclerosis	1124
Pericarditis	1125
Myocarditis	1125
Endocardial Inflammation	1125
Conduction Defects	1125
Granulomatous Aortitis or Valvular Disease	1125
Diagnosis	1125
Differential Diagnosis	1127
Spondyloarthropathies (Common)	1127
Calcium Pyrophosphate Dihydrate Deposition Disease (Common)	1128
Fibromyalgia (Common)	1128
Gout (Common)	1128
Human Immunodeficiency Virus Infection (Common)	1129
Infectious Diseases (Including Viral Causes Such As Hepatitis C) (Common)	1129
Lyme Disease (Common in Endemic Areas)	1129
Osteoarthritis (Common)	1129
Polymyalgia Rheumatica and Giant Cell Arteritis (Common)	1130
Systemic Lupus Erythematosus (Common)	1130
Musculoskeletal Pain of Thyroid Disease (Common)	1130
Vasculitis (Uncommon)	1130
Adult-Onset Still’s Disease (Uncommon)	1130
Bacterial Endocarditis (Uncommon)	1131
Hemochromatosis (Uncommon)	1131
Hemophilic Arthropathy (Uncommon)	1131
Hyperlipoproteinemia (Uncommon)	1131
Hypertrophic Osteoarthropathy (Uncommon)	1131
Relapsing Seronegative Symmetric Synovitis with Pitting Edema (Uncommon)	1132
Rheumatic Fever (Uncommon)	1132
Sarcoidosis (Uncommon)	1132
Amyloidosis (Uncommon)	1132
Malignancy (Uncommon)	1132
Multicentric Reticulohistiocytosis (Rare)	1132
Pigmented Villonodular Synovitis (Rare)	1133
Outcomes	1133
Mortality	1133
Variables Related to Outcome	1134
Assessment of the Individual Patient	1135
Selected References	1135
References	1136.e1
71 Treatment of Rheumatoid Arthritis	1137
Key Points	1137
Goal of Rheumatoid Arthritis Treatment	1138
Classes of Drugs	1140
DMARDs: Methotrexate, Sulfasalazine, Hydroxychloroquine, and Leflunomide	1140
Biologic DMARDs	1140
Glucocorticoids	1140
Other Conventional DMARDs	1140
Gold Salts	1140
Immunosuppressive Agents	1141
Azathioprine	1141
Cyclosporine	1142
Minocycline and Doxycycline	1142
Nonsteroidal Anti-Inflammatory Drugs	1143
Treatment Approaches and Strategies	1143
Treatment of the DMARD-Naïve Patient	1143
The First DMARD	1145
Initiating Treatment with a Single DMARD versus Combinations of DMARDs	1145
BeSt (Dutch Acronym for Behandel-Strategieen, “Treatment Strategies”) Study	1146
Conclusions from BeSt.	1146
Treatment of Early Aggressive Rheumatoid (TEAR) Trial	1146
Conclusions from the TEAR Trial	1148
Treatment of the Patient with Active Disease despite Methotrexate	1149
Treatment of “Refractory” Patients or Those with Active Disease despite TNF Inhibition	1150
What to Do with the Patient in Remission (on DMARDs)	1151
Use of Combinations of Biologics	1152
Interpreting Radiographic Progression and the Use of Other Imaging Modalities	1152
Adjuncts to Medications	1154
Patient Education	1154
Pain Control	1154
Rest, Exercise, and Activities of Daily Living	1154
Treatment of Comorbidities and Interaction of Rheumatologist with Primary Care Physician	1155
Evidence That Patients with Rheumatoid Arthritis Are Doing Better	1156
Research Agenda: Unmet Needs	1156
Horizon	1156
Selected References	1157
References	1160.e1
72 Early Synovitis and Early Undifferentiated Arthritis	1161
Key Points	1161
What Is Early Synovitis?	1161
Early Arthritis Clinics	1161
What Is Undifferentiated Arthritis?	1162
Characteristics of Undifferentiated Arthritis	1162
Remission Rates in UNDIFFERENTIATED ARTHRITIS AND RHEUMATOID ARTHRITIS	1162
Joint Destruction in UNDIFFERENTIATED ARTHRITIS AND RHEUMATOID ARTHRITIS	1163
Biologic Mechanisms in UA and Determinants of Progression to RA	1164
Window of Opportunity	1164
Treatment of UNDIFFERENTIATED ARTHRITIS	1165
Individualized Treatment of Undifferentiated Arthritis	1165
References	1167
73 Sjögren’s Syndrome	1169
Key Points	1169
HISTORICAL PERSPECTIVE	1169
Definitions and Classification Criteria	1170
Epidemiology	1173
Genetics and Pathogenesis	1173
Clinical Features	1179
Keratoconjunctivitis Sicca	1179
Xerostomia	1181
Involvement of Other Exocrine Glands	1181
Extraglandular Manifestations	1181
Lymphoma	1184
Associated Diseases	1184
Diagnosis and Diagnostic Tests	1184
Keratoconjunctivitis Sicca and Xerostomia	1184
Labial Salivary Gland Biopsy	1185
Laboratory Evaluation	1185
Approach to Diagnosis	1185
Differential Diagnosis	1186
Treatment	1186
OUTCOME	1188
CONCLUSIONS	1189
Selected References	1189
References	1191.e1
10 Spondyloarthropathies	1193
74 Pathogenesis of Ankylosing Spondylitis and Reactive Arthritis	1193
Key Points	1193
Pathogenesis of Ankylosing Spondylitis	1193
Causes of Ankylosing Spondylitis That Are Targets of Therapies	1193
Assessment of Degree of Contribution by Environmental Versus Genetic Factors and Identification of Genetic Factors	1194
How HLA-B27 Induces Ankylosing Spondylitis	1194
Arthritogenic Peptide Hypothesis	1194
Free Heavy Chain Hypothesis	1195
Unfolded Protein Hypothesis	1195
How Non–Major Histocompatibility Complex Genes Modify HLA-B27 Physiology	1196
How Non–Major Histocompatibility Complex Genes Modify the Cytokine Network	1196
Structural Damage in Ankylosing Spondylitis	1196
Anatomic and Molecular Bases of Ankylosis	1197
Relationship between Inflammation and New Tissue Formation	1197
Pathogenesis of Reactive Arthritis	1197
Cytokines in Reactive Arthritis	1198
Innate Immunity and Reactive Arthritis	1199
Response of Reactive Arthritis to Antibiotic Treatment	1199
References	1199
75 Ankylosing Spondylitis	1202
Key Points	1202
Classification	1203
Criteria for Ankylosing Spondylitis and Axial Spondyloarthritis	1203
Epidemiology	1203
Prevalence	1203
Incidence	1204
Racial Distribution	1204
Burden of Disease	1205
Pathogenesis	1205
HLA-B27	1205
Non–Human Leukocyte Antigen Genes	1205
Autoimmunity versus Autoinflammation	1206
Structural Remodeling and Ankylosis	1206
Pathology	1206
Axial Skeleton	1206
Peripheral Skeleton	1207
Clinical Manifestations	1207
Skeletal Manifestations	1207
Low Back Pain and Stiffness	1207
Chest Pain	1207
Tenderness	1208
Joints	1208
Extraskeletal Manifestations	1208
Eye Disease	1208
Cardiovascular Disease	1208
Pulmonary Disease	1208
Neurologic Involvement	1208
Renal Involvement	1209
Osteoporosis	1209
Physical Findings	1209
Spinal Mobility	1209
Chest Expansion	1209
Enthesitis	1209
Sacroiliitis	1209
Posture	1209
Laboratory Tests	1209
Imaging Studies	1210
Conventional Radiography	1210
Computed Tomography and Magnetic Resonance Imaging	1210
Diagnosis	1211
ANKYLOSING SPONDYLITS IN MALES AND FEMALES	1212
OUTCOME	1212
Assessment and Monitoring	1213
Management	1213
Physiotherapy	1214
Medication	1216
Nonsteroidal Anti-inflammatory Drugs	1216
Second-Line Drugs	1216
Biologic Therapies	1217
Surgery	1217
Summary	1217
Selected References	1218
References	1220.e1
76 Reactive Arthritis and Undifferentiated Spondyloarthritis	1221
Key Points	1221
Definitions and Terminology	1221
Reactive Arthritis	1221
Undifferentiated Spondyloarthritis	1221
Classification Criteria for Reactive Arthritis and Undifferentiated Spondyloarthritis	1222
Incidence of Reactive Arthritis and Undifferentiated Spondyloarthritis	1224
Clinical Features and Diagnosis of Reactive Arthritis	1224
History	1224
Signs	1225
Investigations	1226
Blood Tests	1226
Tests on Synovial Fluid	1226
Microbiology	1226
Culture and Other Means of Detecting Bacteria.	1226
Serology.	1226
HLA-B27 Testing	1227
Imaging	1227
Treatment of Reactive Arthritis	1227
Control of Symptoms	1227
Disease-Modifying Drugs	1227
Biologics	1227
Antibiotics	1228
Outcome in Reactive Arthritis	1228
Diagnosis and Treatment of Undifferentiated Spondyloarthritis	1228
Diagnosis	1228
Investigations	1228
Treatment	1228
Unanswered Questions and Future Research	1229
1. How Many Patients Currently Classified as Undifferentiated Spondyloarthritis Actually Have Reactive Arthritis?	1229
2. Do Antibiotics Have Any Role in the Treatment of Established Reactive Arthritis?	1229
3. What Is the Role of HLA-B27 in Inducing Susceptibility to Reactive Arthritis, and What Other Genes Influence Susceptibility?	1229
References	1229
77 Psoriatic Arthritis	1232
Key Points	1232
Epidemiology	1232
Clinical Features	1232
Differential Diagnosis	1236
Laboratory Features	1237
Radiographic Features	1237
Plain Radiography	1237
Musculoskeletal Ultrasound	1237
Magnetic Resonance Imaging	1237
Other Imaging Modalities	1239
Diagnosis	1239
Clinical Course and Outcome	1239
Comorbidities in Psoriatic Arthritis	1240
Outcome Domains and Instruments	1240
Pathogenesis	1241
Genetic Factors	1241
Environmental Factors	1242
Animal Models	1242
Immunopathology	1242
Psoriasis Skin	1242
Psoriatic Synovium	1242
Entheseal Sites	1243
Cytokines	1243
Matrix Metalloproteinases and Cartilage Destruction	1243
Bone Remodeling	1244
Summary	1244
Treatment	1244
Traditional Agents	1245
Biologics	1247
References	1247
78 Enteropathic Arthritis	1251
Key Points	1251
Gut Biology and the Microbiota	1251
Gastrointestinal-Associated Lymphoid Tissue and Its Interactions	1252
Inflammatory Bowel Disease	1254
Epidemiology	1254
Genetics	1258
Pathogenesis	1258
Clinical Features	1259
Diagnosis	1260
Treatment	1261
Outcome	1261
Brucella Arthritis	1261
Epidemiology	1261
11 Systemic Lupus Erythematosus and Related Syndromes	1269
79 Etiology and Pathogenesis of Systemic Lupus Erythematosus	1269
Key Points	1269
Historical View of Lupus Pathogenesis	1269
Genetic Contributions to Lupus Pathogenesis	1271
Female Predominance of Systemic Lupus Erythematosus	1273
Environmental Triggers of Lupus	1274
Innate Immune System Activation in Systemic Lupus Erythematosus	1275
Adaptive Immune System Alterations in Systemic Lupus Erythematosus	1277
Autoimmunity in Systemic Lupus Erythematosus	1278
Mechanisms of Target Organ Damage	1280
Summary	1280
References	1281
80 Clinical Features of Systemic Lupus Erythematosus	1283
Key Points	1283
Classification Criteria	1283
Epidemiology	1283
Clinical Features	1283
Mucocutaneous Involvement	1284
Acute Cutaneous Lupus Erythematosus	1284
Subacute Cutaneous Lupus Erythematosus	1285
Chronic Cutaneous Lupus Erythematosus	1286
Other Systemic Lupus Erythematosus Skin Lesions	1286
Photosensitivity	1286
Alopecia	1287
Mucosal Ulcers	1287
Dermatopathology and Immunopathology	1287
Musculoskeletal	1287
Arthritis	1287
Avascular Necrosis	1288
Myositis	1288
Renal Involvement	1288
General Considerations	1288
Types of Renal Involvement in Systemic Lupus Erythematosus	1289
Laboratory Evaluation	1289
Urinalysis	1289
Measurement of Renal Function	1289
Renal Biopsy	1289
Outcome	1292
Pleuropulmonary Involvement	1292
Pleuritis	1292
Lupus Pneumonitis	1292
Chronic Interstitial Lung Disease	1293
Diffuse Alveolar Hemorrhage	1293
Pulmonary Arterial Hypertension	1293
Other	1293
Cardiovascular Involvement	1293
Pericarditis	1294
Myocarditis	1294
Valvular Abnormalities	1294
Coronary Artery Disease	1294
Neuropsychiatric Involvement	1295
General Considerations	1295
Pathogenesis	1295
Approach to Diagnosis	1295
Selected Neuropsychiatric Lupus Syndromes	1296
Gastrointestinal Involvement	1297
Ophthalmologic	1298
Hematologic	1298
Anemia	1298
Leukopenia	1298
Thrombocytopenia	1298
Lymphadenopathy and Splenomegaly	1298
Diagnosis	1299
Serologic Tests	1299
Differential Diagnosis	1300
Neonatal Lupus	1300
Selected References	1301
References	1303.e1
81 Treatment of Systemic Lupus Erythematosus	1304
Key Points	1304
Clinical Course and General Treatment Strategy	1304
Patient and Physician Preferences	1304
Drugs Used in the Treatment of Systemic Lupus Erythematosus	1305
Glucocorticoids	1305
Antimalarials and DMARD Therapy	1306
Hydroxychloroquine	1306
Methotrexate	1306
Leflunomide	1306
Cytotoxic Therapy	1306
Cyclophosphamide	1306
Pharmacology and Route of Administration.	1306
Use in Lupus Nephritis.	1308
Use in Extrarenal Disease.	1308
Other Agents	1308
Chlorambucil.	1308
Fludarabine.	1308
Antimetabolites Calcineurin Inhibitors	1308
Azathioprine	1308
Mycophenolate Mofetil	1309
Pharmacology.	1309
Use in Lupus Nephritis	1310
Induction Therapy.	1310
Maintenance Therapy.	1310
Use in Extrarenal Lupus.	1311
Cyclosporin A	1311
Pharmacology.	1311
Use in Proliferative Lupus Nephritis.	1311
Use in Membranous Lupus Nephropathy.	1311
Use in Extrarenal Lupus.	1312
Tacrolimus	1312
Biologic Therapies	1312
B Cell–Depleting Therapies	1312
Rituximab.	1312
Ocrelizumab.	1313
B Cell Inhibitors	1313
Epratuzumab.	1313
Belimumab.	1313
Atacicept.	1313
Co-stimulation Blockade	1313
CD40-Ligand Blockade.	1313
Abatacept.	1314
Anticytokine Therapy	1314
Tumor Necrosis Factor Inhibitors.	1314
Interferon Inhibition.	1314
Anti-IL-6 Therapy.	1314
Anti-IL-10 Therapy.	1314
Other Therapies	1314
Intravenous Immunoglobulin	1314
Synthetic Tolerogens	1314
Dehydroepiandrosterone	1315
Clofazimine	1315
Management of Specific Systemic Lupus Erythematosus Manifestations and Treatment Algorithms	1315
Mucocutaneous and Joint Disease	1315
Lupus Nephritis	1315
Induction Therapy	1315
Maintenance Therapy	1317
Lupus Membranous Nephropathy	1317
Treatment of Renal Flares	1317
Central Nervous System Disease	1318
Hematologic Disease	1318
Antiphospholipid Syndrome	1319
Thrombotic Antiphospholipid Syndrome	1319
Pregnancy in Antiphospholipid Syndrome	1319
Other Antiphospholipid Syndrome Manifestations	1320
ADDITIONAL Issues	1320
Treatment of Refractory Systemic Lupus Erythematosus	1320
Treatment of Lupus in Pregnancy	1320
Treatment of Pediatric Systemic Lupus Erythematosus	1321
Comorbidities in Systemic Lupus Erythematosus	1322
Infections and Immunizations	1322
Risk Factors and General Management	1322
Specific and Opportunistic Infections	1322
Tuberculosis Infection.	1322
Pneumocystis jiroveci Infection.	1323
Viral Infections.	1324
Immunizations	1324
Chronic Kidney Disease and End-Stage Renal Disease	1324
Risk Factors and Dialysis	1324
Renal Transplantation	1324
Cardiovascular Morbidity	1325
Osteoporosis	1325
Malignancy in Lupus	1325
Emergencies in Patients with Lupus	1326
Women’s Health Issues	1326
Evidence and Expert-Based Recommendations in Systemic Lupus Erythematosus	1327
Selected References	1327
References	1330.e1
82 Antiphospholipid Syndrome	1331
Key Points	1331
Epidemiology	1331
Cause	1331
Pathogenesis	1332
Clinical Features	1334
Vascular Occlusion	1334
Pregnancy Morbidity	1334
Miscellaneous and Noncriteria Manifestations	1334
Catastrophic Antiphospholipid Syndrome	1334
Diagnosis and Diagnostic Tests	1334
Laboratory Studies	1334
Imaging Studies	1335
Pathology	1335
Differential Diagnosis	1336
Treatment	1337
Thrombosis	1337
Pregnancy Morbidity	1338
Asymptomatic Antiphospholipid Antibody–Positive Individuals	1338
Antiphospholipid Antibody–Positive Individuals with Ambiguous Events	1338
Catastrophic Antiphospholipid Syndrome	1338
Antiphospholipid Antibody–Negative Individuals with a Clinical Event	1339
OUTCOME	1339
References	1339
12 Scleroderma, Inflammatory Myopathies, and Overlap Syndromes	1343
83 Etiology and Pathogenesis of Scleroderma	1343
Key Points	1343
Etiology	1343
Genetic Risk: Family Studies	1343
Genetic Association Studies: Immune Susceptibility Genes for Scleroderma	1344
Other Candidate Genes and Genome-wide Association Studies	1344
Infectious Agents: Viruses	1345
Environmental Exposures, Dietary Supplements, Drugs and Radiation	1345
Microchimerism	1345
Pathology	1346
General Features	1346
Vascular Pathology	1346
Tissue Fibrosis	1346
Organ-Specific Pathologic Findings	1346
Skin	1346
Lungs	1347
Gastrointestinal Tract	1348
Kidneys	1348
Heart	1348
Pathologic Findings in Other Organs	1348
Animal Models of Scleroderma	1348
Heritable Animal Models of Scleroderma	1350
Inducible Animal Models of Scleroderma	1350
Genetic Manipulations in Mice Giving Rise to Scleroderma-like Phenotypes	1352
Pathogenesis	1352
Integrated Overview	1352
Vasculopathy	1352
Vascular Injury and the Activated Endothelium	1352
Vascular Damage and Vasculogenesis	1353
Hypoxia	1353
Oxidative Stress and Reactive Oxygen Species	1354
Immune Dysregulation	1354
Introduction	1354
Cellular Effectors of Immune Dysregulation in Scleroderma: T Cells, B Cells, and Monocytes/Macrophages	1354
T Cell Activation	1354
Th1/Th2 Cytokine Balance and Polarized Immune Responses	1355
Other T Cell Subsets	1355
Monocytes and Macrophages	1355
Dendritic Cells	1355
Autoimmunity	1356
Autoantibodies in Scleroderma: Pathogenetic Considerations	1356
B Cells in Scleroderma	1356
Type I Interferon Signature and Innate Immune Signaling: Similarities to Systemic Lupus Erythematosus	1356
Fibrosis	1356
Overview	1356
Extracellular Matrix	1357
Regulation of Collagen Synthesis	1357
Effector Cells of Fibrosis: Fibroblasts	1358
Effector Cells of Fibrosis: Myofibroblasts, Pericytes, Endothelial Cells, and Cellular Plasticity	1358
Fibrocytes and Monocyte-Derived Mesenchymal Progenitor Cells	1358
Molecular Determinants of Fibrosis: TRANSFORMING GROWTH FACTOR-β	1359
Cellular Signaling by Transforming Growth Factor-β: Canonical Smad Pathways	1359
Noncanonical Transforming Growth Factor-β Signaling	1359
Cytokines, Growth Factors, Chemokines, and Lipid Mediators	1359
Connective Tissue Growth Factor/CCN2	1360
Platelet-Derived Growth Factor	1360
Developmental Pathways: Wnt and Notch	1360
Interleukins	1360
Chemokines	1360
Bioactive Lipids	1361
Regulation of Fibroblast Function via Innate Immune Signaling: Toll-like Receptors and the Inflammasome	1361
Negative Regulation of Extracellular Matrix Accumulation	1361
Interferon-γ	1361
Peroxisome Proliferator-Activated Receptor-γ	1362
Scleroderma Fibroblast	1362
References	1362
84 Clinical Features and Treatment of Scleroderma	1366
Key Points	1366
Historical PERSPECTIVE	1366
Epidemiology	1366
Incidence and Prevalence	1366
Survival	1367
Environmental Exposures	1367
Genetic Factors	1368
Overview of Clinical Features	1368
Diagnostic Criteria	1368
Classification and Clinical Subsets	1368
Natural History of Disease	1369
General Principles of Disease Evaluation	1370
Measuring Disease Activity and Severity	1370
Autoantibodies	1371
Clinical Manifestations and Treatment	1372
General Principles of Management	1372
Raynaud’s Phenomenon	1373
Treatment of Raynaud’s Phenomenon and Digital Ischemia	1374
Skin Involvement	1377
Gastrointestinal Involvement	1380
Oropharynx	1380
Esophagus	1380
Stomach	1383
Lower Gastrointestinal Tract	1383
Pulmonary Involvement	1383
Interstitial Lung Disease	1383
Pulmonary Hypertension	1386
Cardiac Involvement	1388
Renal Involvement	1390
Musculoskeletal Involvement	1391
Endrocrine Involvement	1393
Other Associated Manifestations	1393
Psychosocial Aspects	1394
Therapeutic Approach for Disease Modification	1395
Immunotherapy	1395
Treatment of Fibrosis	1396
Treatment of Vascular Disease	1396
Summary of Current Practical Recommendations for Treatment	1397
Localized Scleroderma	1398
Mimics of Scleroderma	1399
Selected References	1400
References	1403.e1
85 Inflammatory Diseases of Muscle and Other Myopathies	1404
Key Points	1404
History of Inflammatory Muscle Diseases	1404
Epidemiology	1404
ETIOLOGY OF MYOSITIS	1405
Genetic Risk Factors	1405
Environmental Risk Factors	1405
Mimics of Myositis	1406
Pathogenesis	1407
Humoral Immune Response	1407
Cell-Mediated Immune Response	1408
Class I Major Histocompatibility Complex	1410
Cytokines and Hypoxia	1411
Proposed Mechanisms of Muscle Damage	1411
Clinical Features	1412
Polymyositis and Dermatomyositis	1412
Skin	1412
Lungs	1414
Arthritis	1414
Heart	1414
Gastrointestinal Tract	1415
Antisynthetase Syndrome	1415
Amyopathic Dermatomyositis	1415
Juvenile Dermatomyositis	1415
Inclusion Body Myositis	1415
Myositis Associated with Malignancies	1416
Classification and Diagnostic Criteria	1416
Physical Examination	1418
Laboratory Evaluation	1418
Biochemical	1418
Immunologic	1419
Histologic	1419
Molecular	1420
Imaging	1420
Muscles	1420
Lungs	1421
Electromyography	1421
Lung Function Tests	1421
Differential Diagnosis	1421
Dystrophic Myopathies	1421
Dysferlinopathy	1421
Facioscapulohumeral Muscular Dystrophy	1422
Dystrophinopathies	1423
Proximal Myotonic Myopathy	1423
Sarcoglycanopathy	1423
Neuromuscular Disorders	1423
Motoneuron Diseases	1423
Spinal Muscular Atrophy	1423
Myasthenia Gravis	1423
Metabolic Myopathies	1423
Acid Maltase Deficiency	1423
McArdle’s Disease	1424
Mitochondrial Myopathies	1424
Endocrine Myopathies	1424
Cushing’s Syndrome	1424
Hyperthyroid and Hypothyroid Myopathy	1424
Infectious Myopathies	1424
Human Immunodeficiency Virus Myopathy	1424
HTLV-1 Myopathy	1424
Parasitic Myopathies	1424
Drug-Induced Myopathies	1424
Zidovudine Myopathy	1425
Statin Myopathy	1425
Other Drugs	1425
Management and OUTCOME	1425
Pharmacologic Treatment	1425
Nonpharmacologic Treatment	1426
Assessing Disease Activity and Outcome	1427
Muscle Examination	1427
Manual Muscle Test.	1427
Functional Index in Myositis.	1427
Extramuscular Involvement	1427
Disease Activity and Damage	1427
Selected References	1428
References	1430.e1
86 Overlap Syndromes	1431
Key Points	1431
Epidemiology	1431
Autoimmunity in Overlap Syndromes	1432
Autoimmunity to Spliceosomal Components	1432
Autoimmunity to Nucleosomal Components	1433
Autoimmunity to Proteasomal Components	1433
Generation of Autoimmunity	1433
Undifferentiated Connective Tissue Disease	1435
Scleroderma Overlaps	1435
Myositis Overlaps	1439
Mixed Connective Tissue Disease	1439
Serologic Features	1440
Clinical Features	1440
Diagnosis	1440
Early Symptoms	1440
Fever	1441
Joints	1441
Skin and Mucous Membranes	1442
Muscle	1442
Heart	1443
Lung	1444
Kidney	1444
Gastrointestinal	1444
Nervous System	1445
Blood Vessels	1445
Blood	1446
Pregnancy	1446
Juvenile Mixed Connective Tissue Disease	1446
Management of Connective Tissue Disease Overlaps	1446
OUTCOME	1448
References	1448
13 Vasculitis	1453
87 Classification and Epidemiology of Systemic Vasculitis	1453
Key Points	1453
Classification	1453
First Modern Case: “Periarteritis Nodosa”	1453
Polyarteritis Nodosa as a Reference Point	1453
Classification by Vessel Size	1454
Additional Considerations in Classification	1454
Historical Attempts at Classification and Nomenclature	1456
Sources of Confusion in Classification	1456
Epidemiology	1457
Geography	1457
Age, Gender, and Ethnicity	1458
Genes	1458
Environment	1459
Relevant Websites	1459
References	1459
88 Giant Cell Arteritis, Polymyalgia Rheumatica, and Takayasu’s Arteritis	1461
Key Points	1461
Giant Cell Arteritis and Polymyalgia Rheumatica	1461
American College of Rheumatology Criteria	1461
Definitions	1461
Giant Cell Arteritis	1461
Polymyalgia Rheumatica	1461
Epidemiology	1461
Cause, Pathology, and Pathogenesis	1463
Clinical Features	1465
Giant Cell Arteritis	1465
Classic Manifestations.	1465
Atypical Manifestations.	1466
Clinical Subsets.	1467
Polymyalgia Rheumatica	1467
Relationship between Polymyalgia Rheumatica and Giant Cell Arteritis	1468
Laboratory Studies	1468
Differential Diagnosis	1468
Diagnostic Evaluation in Giant Cell Arteritis	1470
Treatment and Course	1471
Initial Treatment for Giant Cell Arteritis	1471
Subsequent Treatment for Giant Cell Arteritis	1471
Treatment for Polymyalgia Rheumatica	1472
Takayasu’s Arteritis	1472
American College of Rheumatology Criteria	1473
Epidemiology	1473
Cause and Pathogenesis	1473
Clinical Features	1474
Symptoms and Signs	1474
Laboratory Findings	1475
Imaging Studies	1475
Diagnosis and Diagnostic Tests	1476
Treatment	1477
Medical Therapy	1477
Surgical Therapy	1478
Outcome and Prognosis	1478
References	1478
89 Antineutrophil Cytoplasm Antibody–Associated Vasculitis	1481
Key Points	1481
Classification of This Group of Vasculitides	1481
Epidemiology	1482
Genetics	1484
Clinical Features	1485
Microscopic Polyangiitis	1485
Granulomatosis with Polyangiitis	1486
Allergic Granulomatosis with Polyangiitis	1489
Diagnosis and Diagnostic Tests	1490
Treatment	1491
Induction of Remission	1491
Maintenance of Remission	1492
Adjuvant Therapy	1493
Alternative Agents	1493
Treatment of Allergic Granulomatosis with Polyangiitis	1493
Adverse Events	1494
Outcome	1494
Summary	1495
Selected References	1495
References	1497.e1
90 Polyarteritis Nodosa and Related Disorders	1498
Key Points	1498
Polyarteritis Nodosa	1498
Definition and Classification	1498
Epidemiology	1499
Etiology and Pathogenesis	1499
Pathologic Features	1500
Clinical Features	1500
Clinical Assessment of Patients	1502
Laboratory Testing	1502
Radiology	1502
Polyarteritis Nodosa in Children	1502
Microscopic Polyangiitis versus Polyarteritis Nodosa	1502
Cutaneous Polyarteritis Nodosa	1503
Hepatitis B Virus Polyarteritis Nodosa	1503
Non–Hepatitis B Virus Polyarteritis Nodosa	1503
Treatment of Polyarteritis Nodosa	1503
Outcome	1504
Cogan’s Syndrome	1504
Pathology	1504
Clinical Features	1504
Treatment	1504
Buerger’s Disease	1504
Pathology	1505
Clinical Features	1505
Treatment	1505
Susac’s Syndrome	1505
Virus-Induced Vasculitis	1505
References	1505
91 Immune Complex–Mediated Small Vessel Vasculitis	1508
Key Points	1508
Pathogenesis	1508
Arthus Reaction	1508
Immunogenicity	1508
Cutaneous Manifestations	1509
Pathologic Features	1510
Light Microscopy	1510
Direct Immunofluorescence	1511
Differential Diagnosis	1511
Clinical Syndromes	1511
Hypersensitivity Vasculitis (Cutaneous Leukocytoclastic Angiitis)	1511
Henoch-Schönlein Purpura	1513
Cryoglobulinemic Vasculitis	1513
Hypocomplementemic Urticarial Vasculitis	1515
Erythema Elevatum Diutinum	1515
Connective Tissue Disease–Associated Vasculitis	1515
Rheumatoid Vasculitis	1516
References	1516
92 Primary Angiitis of the Central Nervous System	1518
Key Points	1518
Epidemiology	1518
Genetics	1518
Clinical Features	1518
Proposed Criteria for Primary Angiitis of the Central Nervous System	1518
Clinical Subsets	1519
Granulomatous Angiitis of the Central Nervous System	1519
Atypical Central Nervous System Vasculitis	1519
Masslike Presentation.	1519
Cerebral Amyloid Angiitis.	1519
Angiographically Defined Central Nervous System Vasculitis.	1520
Spinal Cord Presentation.	1520
Nongranulomatous PACNS.	1520
Diagnosis and Diagnostic Tests	1520
Diagnostic Tests	1520
Laboratory Findings	1520
Cerebrospinal Fluid Analysis	1520
Radiologic Evaluation	1520
Brain Biopsy	1520
Differential Diagnosis	1521
Reversible Cerebral Vasoconstriction Syndromes	1521
Primary Systemic Vasculitides	1521
Connective Tissue Diseases	1522
Infections	1522
Lymphoproliferative Diseases	1522
Miscellaneous	1522
Treatment	1523
Outcome	1523
SUMMARY	1523
References	1523
93 Behçet’s Disease	1525
Key Points	1525
Epidemiology	1525
Cause and Pathogenesis	1525
Genetics	1525
Immune Mechanisms	1525
Infectious Agents	1526
Clinical Features	1526
Aphthae	1526
Cutaneous Lesions	1526
Ophthalmic Features	1527
Arthritis	1527
Other Systemic Manifestations	1527
Histopathology	1527
Diagnosis	1528
Treatment	1529
Mucocutaneous Disease	1529
Severe Mucocutaneous Disease	1530
Systemic Disease	1530
OUTCOME	1530
References	1530
14 Crystal-Induced and Inflammasome-Mediated Inflammation	1533
94 Etiology and Pathogenesis of Hyperuricemia and Gout	1533
Key Points	1533
Evolutionary Considerations	1533
Uric Acid as a Danger Signal	1533
Uric Acid and Human Evolution	1534
Uric Acid Production and Excretion: Normal Levels and Hyperuricemia	1535
Urate Production: Purine Metabolism and Intake	1535
Purine Biosynthesis	1535
Urate Formation and Purine Salvage	1536
Urate Overproduction: Primary and Secondary Causes	1537
Primary Urate Overproduction	1537
Secondary Urate Overproduction and Hyperuricemia	1538
Urate Excretion: Gastrointestinal and Renal Mechanisms	1539
Gastrointestinal Excretion of Urate	1539
Renal Excretion of Uric Acid: Normal Mechanisms	1539
Urate Resorption.	1540
Urate Secretion.	1540
Renal Causes of Hyperuricemia	1541
Primary Urate Underexcretion	1541
Secondary Causes of Renal Urate Underexcretion	1541
Age and Gender.	1541
Systemic Illnesses (Table 94-1).	1542
Drugs (Table 94-2).	1542
Toxins.	1543
Diet and Uric Acid	1543
Purine-Rich Foods	1543
Fructose	1544
Alcoholic Beverages	1544
Other Dietary Components	1545
Crystal Formation: The Transition from Hyperuricemia to Gout	1545
Acute Gout Attacks: The Inflammatory Response to Monosodium Urate Crystals	1545
Uric Acid Crystals and Complement Activation	1546
Cellular Response to Crystals	1546
Cell Recognition of Crystalline Urate	1546
Intracellular Responses to Urate Crystal Encounters	1546
Initiation and Propagation of the Acute Gouty Attack	1547
Resolution of the Acute Gouty Attack	1549
Chronic Gouty Arthritis and Tophaceous Gout	1550
Nongout Effects of Hyperuricemia	1550
Selected References	1551
References	1553.e1
95 Clinical Features and Treatment of Gout	1554
Key Points	1554
Epidemiology	1554
Environmental Factors	1555
Genetics	1555
Clinical Features	1556
Asymptomatic Hyperuricemia	1556
Acute Gouty Arthritis	1556
Intercritical Gout	1557
Chronic Gouty Arthritis	1558
Associated Conditions	1560
Renal Disease	1561
Lead Intoxication	1563
Cyclosporine-Induced Hyperuricemia and Gout	1563
Classification of Hyperuricemia and Gout	1563
Primary Gout	1563
Secondary Gout	1564
Treatment	1564
Asymptomatic Hyperuricemia	1565
Acute Gouty Arthritis	1566
Colchicine	1566
Nonsteroidal Anti-inflammatory Drugs	1567
Corticosteroids	1567
Adrenocorticotropic Hormone	1567
Prophylaxis	1567
Control of Hyperuricemia	1567
Xanthine Oxidase Inhibitors	1568
Uricosuric Agents	1569
Uricases	1570
Compliance with Treatment	1572
Management of Gout after Organ Transplantation	1572
Ancillary Factors	1572
Selected References	1573
References	1575.e1
96 Calcium Crystal Disease:	1576
Key Points	1576
Acr and EULAR Criteria for Disease	1576
Epidemiology	1576
Genetics	1577
Pathogenesis	1578
Dysregulated Inorganic Pyrophosphate Metabolism in Pathologic Articular Cartilage Calcification	1578
Role of ENPP1 and ANKH in Inorganic Pyrophosphate Metabolism in Chondrocalcinosis	1579
Effects of Imbalance of Chondrocyte Growth Factor Responses on Inorganic Pyrophosphate Metabolism in Chondrocalcinosis	1580
CPPD Deposition Disease Secondary to Primary Metabolic Disorders: Relationship to Inorganic Pyrophosphate Metabolism and Chondrocyte Differentiation	1581
Inflammation, Hypertrophic Chondrocyte Differentiation, and Transglutaminase 2 in Joint Cartilage Calcification	1581
Special Pathogenic Aspects of Articular and Periarticular Basic Calcium Phosphate Crystal Deposition	1582
Crystal-Induced Inflammation	1582
Clinical Features	1583
Calcium Pyrophosphate Dihydrate Deposition Disease	1583
Acute Synovitis	1584
Chronic Degenerative and Inflammatory Arthropathies	1584
Other Clinical Forms of Calcium Pyrophosphate Dihydrate Crystal Deposition	1586
Familial Chondrocalcinosis	1586
Clinical Features of Articular BASIC CALCIUM PHOSPHATE Crystal Disease	1586
Clinical Features of Pathologic Basic Calcium Phosphate Crystal Deposition in Joint Tissues	1586
Diagnosis and Diagnostic Tests	1588
Differential Diagnosis	1588
Differential Diagnostic Considerations for Basic Calcium Phosphate Crystal Deposition	1588
Chronic CPPD Deposition Arthropathy, BCP Crystal-Associated Arthritis, and Use of Plain Radiographs in Diagnosis	1589
High-Resolution Ultrasound and Advanced Imaging for Diagnosis of CPPD and BCP Crystal Deposition Diseases	1590
Laboratory Diagnostic Tests for CPPD and BCP Crystal Deposition Disease	1590
Treatment	1592
Calcium Pyrophosphate Dihydrate Deposition Disease	1592
Basic Calcium Phosphate Crystal Arthropathies	1592
Future Directions in Treatment	1593
Outcome	1593
Websites	1594
Selected References	1594
References	1596.e1
97 Familial Autoinflammatory Syndromes	1597
Key Points	1597
Differential Diagnosis	1597
Familial Mediterranean Fever	1599
Epidemiology	1599
Etiology	1600
Pathogenesis	1600
Clinical Features	1600
Diagnosis and Diagnostic Tests	1602
Treatment	1602
Outcome	1602
Hyper–immunoglobulin D Syndrome (Mevalonate Kinase Deficiency)	1603
Epidemiology	1603
Etiology	1603
Pathogenesis	1603
Clinical Features	1604
Diagnosis and Diagnostic Tests	1605
Treatment	1605
Outcome	1605
Tumor Necrosis Factor Receptor–associated Periodic Syndrome	1605
Epidemiology	1605
Etiology	1605
Pathogenesis	1606
Clinical Features	1606
Diagnosis and Diagnostic Tests	1607
Treatment	1607
Outcome	1607
Cryopyrin-Associated Periodic Syndrome	1607
Epidemiology	1608
Etiology	1608
Pathogenesis	1608
Clinical Features and Outcome	1609
Familial Cold Autoinflammatory Syndrome	1609
Muckle-Wells Syndrome	1609
Chronic Infantile Neurologic Cutaneous and Articular Syndrome	1610
Diagnosis and Diagnostic Tests	1610
Treatment	1611
Blau Syndrome/Early-Onset Sarcoidosis	1611
Epidemiology	1611
Etiology	1611
Pathogenesis	1611
15 Cartilage, Bone, and Heritable Connective Tissue Disorders	1617
98 Pathogenesis of Osteoarthritis	1617
Key Points	1617
Etiologic Factors in Osteoarthritis	1618
Age	1618
Joint Location	1618
Obesity	1618
Genetic Predisposition	1618
Joint Malalignment and Trauma	1619
Gender	1620
Changes in Osteoarthritis	1620
Morphologic Changes	1620
Early Reparative, Proliferative, and Hypertrophic Changes	1620
Osteophyte Formation	1621
Hypocellularity	1621
Alterations in Cartilage Matrix Metabolism	1621
Biochemical Changes	1621
Metabolic Changes	1622
Anabolic Factors (Transforming Growth Factor-β, Bone Morphogenetic Proteins) and Cartilage Repair	1622
Catabolic Factors and Cartilage Degradation	1623
Classes of Proteinases (Metalloproteinases, Aggrecanases, Serine and Cysteine Proteases)	1623
Metalloproteinases	1623
Collagenases	1624
Aggrecanases	1624
Enzyme Inhibitors (Tissue Inhibitor of Metalloproteinases, Plasminogen Activator Inhibitor-1)	1625
Alterations in Matrix Synthesis	1625
Chondrocyte Senescence	1625
Biomechanics and Disease Mechanisms of Osteoarthritis	1625
Biomechanical Changes	1625
Response of Cartilage to Mechanical Injury	1626
Mechanotransduction and Gene Expression	1627
Abnormalities of Bone	1627
Osteophyte Formation	1627
Subchondral Bone Sclerosis	1628
Bone Marrow Lesions	1628
Role of Inflammatory Mediators in Disease Progression	1628
Inflammatory Molecules Produced by Articular Cartilage	1628
Cytokines and Chemokines	1628
Proteinases	1629
Nitric Oxide	1630
Transforming Growth Factor-β	1630
Hyaluronic Acid	1630
Prostaglandins	1630
F-spondin	1631
Alterations in Bone	1631
Alterations in Synovial Tissue	1631
Biomarkers of Osteoarthritis	1632
Summary	1633
Selected References	1633
References	1635.e1
99 Clinical Features of Osteoarthritis	1636
Key Points	1636
Epidemiology of Osteoarthritis	1636
Prevalence of Radiographic Osteoarthritis	1636
Prevalence of Symptomatic Osteoarthritis	1636
Primary and Secondary Osteoarthritis	1637
Clinical Features	1637
General Symptoms and Signs	1637
Joint-Specific Symptoms and Signs: Knee	1638
Joint-Specific Symptoms and Signs: Hip	1638
Joint-Specific Symptoms and Signs: Hand	1638
Joint-Specific Symptoms and Signs: Spine	1638
Joint-Specific Symptoms and Signs: Shoulder	1639
Joint-Specific Symptoms and Signs: Other Joints	1639
Polyarticular Osteoarthritis	1639
Diagnostic Testing	1639
Diagnostic Approach	1639
Laboratory Testing	1640
Synovial Fluid	1640
Molecular Biomarkers	1640
Imaging: Conventional Radiography, General Considerations	1640
Imaging: Conventional Radiography, Specific Joint Issues	1640
Imaging: Advanced Modalities	1641
OUTCOME	1641
Performance Measures and Functional Assessment	1641
Time to Total Joint Replacement	1642
Mortality in Osteoarthritis	1642
SUMMARY	1643
References	1643
100 Treatment of Osteoarthritis	1646
Key Points	1646
Patient Assessment	1646
Source of Pain	1646
Management	1646
Nonpharmacologic Interventions	1646
Psychosocial Interventions	1646
Weight Loss	1647
Temperature Modalities	1648
Exercise	1648
Orthotics and Bracing	1648
Cane/Walking Aid	1648
Modification in Activities of Daily Living	1648
Other Interventions	1648
Pharmacologic Interventions	1649
Topical Agents	1649
Systemic Agents	1650
Non-narcotic Analgesics.	1650
Nonsteroidal Anti-inflammatory Drugs.	1650
Narcotic Analgesics.	1650
Intra-articular Agents	1651
Corticosteroids.	1651
Hyaluronic Acid Derivatives.	1651
Nutraceuticals	1652
Glucosamine	1652
Chondroitin Sulfate	1653
Other Nutraceuticals	1654
Other Potential Structure- or Disease-Modifying Therapies	1654
Surgical Intervention	1656
Summary	1656
Selected References	1657
References	1659.e1
101 Metabolic Bone Disease	1660
Key Points	1660
Osteoporosis	1660
Epidemiology and Clinical Signs	1660
Pathophysiology of Menopausal and Age-Related Bone Loss	1661
Osteoporosis in Men	1664
Osteoporosis in Rheumatic Diseases and Other Conditions	1664
Assessment of Bone Density and Osteoporotic Risk	1664
Markers of Bone Turnover	1666
Evaluation for Secondary Bone Loss	1666
Treatment	1667
Calcium	1667
Estrogen	1667
Selective Estrogen Receptor Modulators	1668
Testosterone	1668
Calcitonin	1668
Bisphosphonates	1668
RANK Ligand Inhibitor	1670
Parathyroid Hormone	1670
Vitamin D	1670
Preventive Measures	1671
Glucocorticoid-Induced Osteoporosis	1671
Osteomalacia	1672
Paget’s Disease of Bone	1674
Cause	1674
Clinical Features	1674
Laboratory Findings	1675
Diagnosis	1675
Treatment	1675
Calcitonin	1675
Bisphosphonates	1675
Other Medication-Induced Osteoporosis	1676
Selected References	1677
References	1679.e1
102 Proliferative Bone Diseases	1680
Key Points	1680
Diffuse Idiopathic Skeletal Hyperostosis	1680
Epidemiology	1681
Etiology and Pathogenesis	1681
Clinical Manifestations	1682
Treatment	1684
Hypertrophic Osteoarthropathy	1685
Etiology	1685
Pathogenesis	1685
Clinical Manifestations	1686
Treatment Considerations	1687
SAPHO Syndrome	1687
Etiology and Pathogenesis	1687
Clinical Manifestations and Imaging Findings	1688
Treatment	1688
References	1688
103 Osteonecrosis	1692
Key Points	1692
Epidemiology	1692
Etiology	1692
Clinical Features	1694
Bone Marrow Edema	1694
Bisphosphonates and Osteonecrosis of the Jaw	1695
Pathogenesis	1695
Anatomic Considerations in Trauma-Related Osteonecrosis	1695
Nontraumatic Osteonecrosis	1695
Mechanical and Vascular Considerations	1696
Osteoimmunology	1696
Osteoblast/Osteoclast Balance	1697
Apoptosis and Osteonecrosis	1698
Lipids and Osteonecrosis	1698
Coagulation and Osteonecrosis	1698
Oxidative Stress and Osteonecrosis	1699
Nitric Oxide Synthase and Osteonecrosis	1699
Multihit Hypothesis	1699
Genetic Considerations	1699
Diagnosis	1700
History and Physical Examination	1700
Radiologic Imaging	1700
Markers of Disease	1703
Treatment	1703
Surgical Treatment	1703
Nonsurgical Approaches	1707
Recent Developments	1708
Prevention versus Treatment	1708
Mesenchymal Stem Cells	1708
Outcome	1708
Summary	1709
Selected References	1709
References	1711.e1
104 Relapsing Polychondritis	1712
Key Points	1712
Epidemiology	1712
Pathology	1712
Pathogenesis	1712
Clinical Features	1713
Otorhinologic Disease	1713
Respiratory Disease	1713
Cardiovascular Disease	1713
Eye Disease	1713
Renal Disease	1713
Neurologic Disease	1714
Skin Disease	1714
Joint Disease	1714
Associated Disorders	1714
Differential Diagnosis	1715
Investigations	1715
Routine Laboratory Tests	1715
Tissue Sampling/Histopathology	1715
Pulmonary Investigations	1715
Cardiac Investigations	1716
Ocular Investigations	1716
Musculoskeletal Tests	1716
Additional Investigations	1716
Treatment	1716
OUTCOME	1716
References	1717
105 Heritable Diseases of Connective Tissue	1719
Key Points	1719
Skeletal Dysplasias	1719
Embryology	1719
Cartilage Structure	1720
Classification and Nomenclature	1720
Clinical Evaluation and Features	1720
Diagnosis and Testing	1723
Management and Treatment	1724
Achondroplasia	1725
Biochemical and Molecular Abnormalities	1725
Defects in Extracellular Structural Proteins	1725
Type II Collagen and Type XI Collagen	1725
Cartilage Oligomeric Matrix Protein	1726
Defects in Metabolic Pathways	1726
Defects in Intracellular Structural Proteins	1727
Defects in Membrane Channels	1727
Summary	1727
Osteogenesis Imperfecta	1727
Mild Osteogenesis Imperfecta (Type I)	1727
16 Rheumatic Diseases of Childhood	1741
106 Etiology and Pathogenesis of Juvenile Idiopathic Arthritis	1741
Key Points	1741
Histologic Features of Juvenile Idiopathic Arthritis Inflamed Synovium	1743
Genetics of Juvenile Idiopathic Arthritis	1743
Adaptive Immune System	1744
T Cells	1744
Antigen-Presenting Cells	1745
B Cells	1745
Innate Immune System	1745
Macrophages/Monocytes	1745
Neutrophils	1746
Stromal Cells	1746
Disease Subtype–specific PATHOGENESIS	1746
Systemic Juvenile Idiopathic Arthritis	1746
Macrophage Activation Syndrome	1747
Oligoarthritis	1747
Rheumatoid Factor–Positive Polyarthritis	1747
Rheumatoid Factor–Negative Polyarthritis	1747
Enthesitis-Related Arthritis	1748
Psoriatic Arthritis	1748
Translation from UNDERSTANDING Pathogenesis to Clinical Practice	1748
References	1748
107 Treatment of Juvenile Idiopathic Arthritis	1752
Key Points	1752
Classification Criteria for Juvenile Idiopathic Arthritis	1752
Differential Diagnosis	1752
Rheumatoid Factor–Negative Polyarthritis	1754
Clinical Manifestations and Diagnostic Features	1754
Differential Diagnosis	1754
Treatment	1754
Nonsteroidal Anti-inflammatory Drug Use in Children	1754
Intra-articular Steroid Injections	1754
Corticosteroid Use in Children with Juvenile Idiopathic Arthritis	1755
Methotrexate	1755
Tumor Necrosis Factor Inhibitors	1755
Abatacept	1757
Other Biologics	1757
Outcome	1757
Rheumatoid Factor–Positive Polyarthritis	1757
Clinical Manifestations and Diagnostic Features	1757
Differential Diagnosis	1757
Treatment	1758
Outcome	1758
Oligoarticular Juvenile Idiopathic Arthritis	1758
Clinical and Diagnostic Features	1758
Differential Diagnosis	1759
Treatment	1759
Special Considerations: Knee Monoarthritis	1760
Outcome	1760
Uveitis	1760
Clinical Manifestations and Diagnostic Features	1760
Treatment	1760
Differential Diagnosis	1760
Outcome	1761
Juvenile Psoriatic Arthritis	1761
Clinical Manifestations and Diagnostic Features	1761
Treatment	1762
Outcome	1762
Enthesitis-Related Arthritis/Juvenile Spondyloarthropathy	1762
Clinical Manifestations and Diagnostic Features	1762
Differential Diagnosis	1763
Treatment	1763
Outcome	1763
Systemic Juvenile Idiopathic Arthritis	1763
Clinical Manifestations and Diagnostic Features	1763
Differential Diagnosis	1764
Special Considerations: Macrophage Activation Syndrome	1764
Treatment	1765
Outcome	1766
IMAGING	1766
Special Considerations: Rehabilitation in Children	1767
SUMMARY	1767
Selected References	1768
References	1770.e1
108 Pediatric Systemic Lupus Erythematosus, Dermatomyositis, Scleroderma, and Vasculitis	1771
Key Points	1771
Systemic Lupus Erythematosus	1771
Definition and Classification	1771
Epidemiology	1771
Causes	1772
Genes	1772
Environment	1772
Pathology	1772
Clinical Features	1772
Diagnosis and Diagnostic Tests	1774
Treatment	1774
Immunosuppression	1774
Antimalarials	1775
Adjunctive Therapy	1775
Outcome	1775
Drug-Induced Lupus Erythematosus	1776
Neonatal Lupus Erythematosus	1776
Juvenile Dermatomyositis	1776
Definition and Criteria	1776
Epidemiology	1777
Genetics, Etiology, and Pathogenesis	1777
Clinical Features	1777
Disease Monitoring	1780
Diagnosis and Diagnostic Tests	1780
Differential Diagnosis	1781
Treatment	1781
Outcome	1782
Scleroderma	1783
Systemic Sclerosis	1783
Epidemiology	1783
Clinical Features	1783
Diagnosis and Diagnostic Tests	1784
Treatment	1784
Outcome	1784
Localized Scleroderma	1785
Epidemiology	1785
Etiology and Pathogenesis	1785
Clinical Features	1785
Diagnosis and Diagnostic Tests	1786
Treatment	1786
Disease Monitoring	1787
Outcome	1787
Eosinophilic Fasciitis	1787
Mixed Connective Tissue Disease	1787
Vasculitis	1787
Small Vessel Vasculitis	1787
Henoch-Schönlein Purpura	1787
Definition and Classification.	1788
Epidemiology.	1788
Clinical Presentation.	1788
Diagnosis and Diagnostic Tests.	1789
Treatment.	1789
Outcome.	1789
Antineutrophil Cytoplasm Antibody Vasculitis	1789
Definition and Classification	1790
Granulomatosis with Polyangiitis.	1790
Microscopic Polyangiitis.	1790
Churg-Strauss Syndrome.	1790
Epidemiology	1790
Clinical Presentation	1790
Diagnosis and Diagnostic Tests	1790
Treatment	1790
Outcome	1791
Medium-Sized Vessel Vasculitis	1791
Kawasaki Disease	1791
Definition and Classification.	1791
Epidemiology.	1791
Clinical Presentation.	1791
Diagnosis and Diagnostic Tests.	1792
Treatment.	1792
Outcome.	1792
Polyarteritis Nodosa	1792
Definition and Classification.	1793
Epidemiology.	1793
Clinical Presentation.	1793
Diagnosis and Diagnostic Tests.	1793
Treatment.	1793
Outcome.	1793
Large Vessel Vasculitis	1793
Definition and Classification	1793
Epidemiology	1794
Clinical Presentation	1794
Diagnosis and Diagnostic Tests	1794
Treatment	1794
Outcome	1795
Central Nervous System Vasculitis	1795
Definition and Classification	1795
Epidemiology	1795
Clinical Presentation	1796
Diagnosis and Diagnostic Tests	1796
Treatment	1797
Outcome	1797
Selected References	1797
References	1800.e1
17 Infection and Arthritis	1801
109 Bacterial Arthritis	1801
Key Points	1801
Epidemiology	1801
Etiology	1802
Pathogenesis	1803
Clinical Features	1804
Diagnosis and Diagnostic Tests	1805
Treatment	1807
Prosthetic Joint Infections	1809
Prevention of Prosthetic Joint Infections	1811
Outcome	1811
References	1812
110 Lyme Disease	1815
Key Points	1815
Ecology and Epidemiology of Lyme Disease	1815
Ticks and Lyme Disease	1815
Pathogenesis	1816
Borrelia burgdorferi Invasion of the Mammalian Host	1816
Pathology of Lyme Disease	1816
Immune Response to Borrelia burgdorferi	1816
Mechanisms of Spirochete Persistence	1817
Clinical Features of Lyme Disease	1817
Early Localized Infection	1817
Early Disseminated Infection	1818
Skin Disease	1818
Cardiac Disease	1818
Nervous System Involvement	1818
Other Organ System Involvement	1819
Late Disease	1819
Late Neurologic Disease	1819
Late Skin Disease	1819
Lyme Arthritis and Other Musculoskeletal Manifestations of Lyme Disease	1819
Antibiotic-Refractory Lyme Arthritis	1820
Diagnosis	1820
Serologic Testing	1821
Detection of Antibodies to Borrelia burgdorferi in Cerebrospinal Fluid	1822
Polymerase Chain Reaction	1822
Other Tests for Lyme Disease	1822
Diagnostic Imaging	1822
Treatment and OUTCOME	1822
Pregnancy and Lyme Disease	1824
Expected Outcomes	1824
Chronic Lyme Disease and Post–Lyme Disease Syndrome	1825
Prevention	1825
Summary	1826
Selected References	1826
References	1828.e1
111 Mycobacterial Infections of Bones and Joints	1829
Key Points	1829
Clinical Scenarios	1830
Direct Involvement of the Musculoskeletal System	1830
Spondylitis	1830
Tuberculous Osteomyelitis	1832
Septic Arthritis	1832
Emergence of Tuberculosis during Treatment of Rheumatic Disease	1833
Rheumatic Disorders Precipitated by Treatment of Tuberculosis	1834
Reactive Immunologic Phenomenon in the Setting of Tuberculosis	1834
Diagnosis	1835
Tuberculin Skin Test	1835
Imaging	1835
Culture	1835
Advanced Diagnostic Testing	1835
Interferon-γ Release Assays	1835
Nucleic Acid Amplification	1836
Treatment	1836
Osteoarticular Infections Caused by Nontuberculous Mycobacteria	1837
Emergence of Nontuberculous Mycobacterial Infection during the Treatment of Rheumatic Disease	1838
References	1838
112 Fungal Infections of Bones and Joints	1841
Key Points	1841
Coccidioidomycosis	1841
Blastomycosis	1842
Cryptococcosis	1842
Candidiasis	1843
Sporotrichosis	1844
Aspergillosis	1845
Histoplasmosis	1845
Scedosporiosis	1846
Treatment of Fungal Infection	1846
Fungal Infection as A Consequence of Antirheumatic Therapy	1846
References	1848
113 Rheumatic Manifestations of Human Immunodeficiency Virus Infection	1851
Key Points	1851
HIV-Associated Bone and Joint Disease	1851
HIV-Associated Arthralgia	1851
Painful Articular Syndrome	1851
HIV-Associated Arthritis	1851
Reactive Arthritis Occurring in HIV Infection	1852
Treatment	1853
Psoriasis and Psoriatic Arthritis	1853
Undifferentiated Spondyloarthritis	1854
Avascular Necrosis of Bone	1854
Hypertrophic Pulmonary Osteoarthropathy	1854
Osteopenia and Osteoporosis	1854
HIV-Associated Muscle Disease	1854
Myalgia and Fibromyalgia	1854
Noninflammatory Necrotizing Myopathy and HIV-Related Wasting Syndrome	1854
Nemaline Myopathy	1855
HIV-Associated Polymyositis	1855
Inclusion Body Myositis	1856
Myopathy Associated with Treatment	1856
Rhabdomyolysis	1856
Diffuse Infiltrative Lymphocytosis Syndrome	1856
Vasculitis Associated with HIV Infection	1858
Primary Pulmonary Hypertension	1859
HIV-Associated Musculoskeletal Infection	1859
Pyomyositis	1859
Bacterial Arthritis and Osteomyelitis	1859
Musculoskeletal Tuberculosis	1859
Atypical Mycobacterial Infection	1859
Bacillary Angiomatosis Osteomyelitis	1860
Fungal Infections	1860
Parasitic Infections	1860
Response of Other Rheumatic Diseases to HIV Infection	1860
HAART-Related Immune Reconstitution Syndrome	1861
Rheumatologic Complications of HIV Treatment	1861
Laboratory Abnormalities Associated with HIV Infection	1861
Conclusion	1861
References	1862
114 Viral Arthritis	1865
Key Points	1865
Parvovirus B19	1865
Epidemiology	1865
Pathogenesis	1865
Diagnosis	1866
Clinical Features	1866
Laboratory Tests	1866
Differential Diagnosis	1867
Treatment and Outcome	1867
Togaviruses	1867
Rubella Virus	1867
Epidemiology	1867
Pathogenesis	1867
Diagnosis	1867
Clinical Features.	1867
Laboratory Tests.	1868
Differential Diagnosis.	1868
Treatment and Outcome	1868
Alphaviruses	1868
Epidemiology	1868
Diagnosis	1869
Clinical Features.	1869
Laboratory Tests.	1869
18 Arthritis Accompanying Systemic Disease	1889
116 Amyloidosis	1889
Key Points	1889
Classification and Epidemiology	1889
Pathology and Pathogenesis of Amyloid Fibril Formation	1890
Pathologic Features	1890
Pathogenesis of Amyloid Fibril Formation	1890
Diagnosis	1891
Clinical Features and Treatment of the Systemic Amyloidoses	1892
AL Amyloidosis	1892
AA Amyloidosis	1894
Aβ2M Amyloidosis	1894
ATTR Amyloidosis	1895
Summary	1896
Acknowledgments	1896
References	1896
117 Sarcoidosis	1898
Key Points	1898
Epidemiology	1898
Immunopathogenesis	1898
Innate Immunity	1898
Acquired Immunity	1899
Etiology	1899
Genetics	1899
Diagnosing Sarcoidosis	1900
Sarcoid Arthritis	1902
Acute Sarcoid Arthritis	1902
Chronic Sarcoid Arthritis	1902
Managing Sarcoidosis: Focusing on Sarcoid Arthritis	1905
References	1905
118 Hemochromatosis	1907
Key Points	1907
Normal Iron Metabolism	1907
Genetics of Hemochromatosis	1908
Epidemiology	1908
Phenotypic Disease Expression	1909
Pathogenesis	1909
Clinical Features	1909
Extra-articular Manifestations	1909
Articular Features	1910
Differential Diagnosis	1911
Investigations	1911
Screening	1911
Management	1912
OUTCOME	1912
References	1913
119 Hemophilic Arthropathy	1915
Key Points	1915
Clinical Features	1915
Acute Hemarthrosis	1915
Subacute or Chronic Arthritis	1915
End-Stage Hemophilic Arthropathy	1915
Septic Arthritis	1916
Muscle and Soft Tissue Hemorrhage	1916
Diagnostic Imaging	1916
Radiographs	1916
Other Imaging Methods	1917
Pathologic Features and Pathogenesis	1917
Diagnosis	1918
Treatment of Hemophilia	1918
Factor VIII Replacement	1919
Factor IX Replacement	1919
Complications of Factor Replacement Therapy	1919
Inhibitor Antibodies	1919
Human Immunodeficiency Virus	1920
Viral Hepatitis	1920
Therapy for Musculoskeletal Complications of Hemophilia	1920
Acute Hemarthrosis	1920
Chronic Hemophilic Arthropathy	1920
Conservative.	1920
Synovectomy.	1921
Total Joint Replacement.	1921
Conclusion	1921
References	1922
120 Rheumatologic Manifestations of Hemoglobinopathies	1924
Key Points	1924
Clinical Biology of the Hemoglobinopathies	1924
Clinical Features of Musculoskeletal Syndromes Linked to Hemoglobinopathies	1924
Differential Diagnosis and Diagnostic Tests	1925
Treatment	1926
References	1926
121 Endocrine Diseases and the Musculoskeletal System	1927
Key Points	1927
Hypothyroidism	1927
Hyperthyroidism	1928
Hypoparathyroidism	1928
Hyperparathyroidism	1928
Adrenal Gland Disorders	1929
Musculoskeletal Manifestations and Steroid Deficiency	1929
Diabetes Mellitus	1930
Hands	1930
Shoulder	1931
Feet	1931
Muscles	1931
Diffuse Skeletal Disease	1931
References	1932
122 Musculoskeletal Syndromes in Malignancy	1934
Key Points	1934
Paraneoplastic Syndromes	1934
Carcinomatous Polyarthritis	1934
Vasculitis	1934
Cryoglobulinema	1936
Panniculitis	1936
Palmar Fasciitis	1937
Reflex Sympathetic Dystrophy	1937
Erythromelalgia	1937
Polymyalgia Rheumatica	1937
Raynaud’s Phenomenon and Digital Necrosis	1937
Remitting Seronegative Symmetric Synovitis with Pitting Edema	1938
Multicentric Reticulohistiocytosis	1938
Lupus-like Syndromes	1938
Antiphospholipid Antibodies	1938
Osteomalacia	1938
Sarcoidosis	1939
Lymphomatoid Granulomatosis	1939
Inflammatory Myopathies	1939
Risks of Developing Lymphoproliferative Disorders in Rheumatic Diseases	1940
Sjögren’s Syndrome	1940
Rheumatoid Arthritis	1941
Disease-Modifying Antirheumatic Drug Therapy	1942
Risk of Solid Tumor in Patients with Rheumatoid Arthritis	1942
Systemic Lupus Erythematosus	1943
Systemic Sclerosis	1944
Primary Tumors and Metastatic Disease	1944
Primary Musculoskeletal Tumors	1944
Metastatic Disease	1945
Postchemotherapy Rheumatism	1946
Lymphoproliferative and Myeloproliferative Diseases	1946
Leukemia	1946
Multiple Myeloma	1946
Lymphoma	1947
Angioimmunoblastic Lymphadenopathy	1947
Graft-versus-Host Disease	1947
SUMMARY	1947
Selected References	1947
References	1950.e1
123 Tumors and Tumor-like Lesions of Joints and Related Structures	1951
Key Points	1951
Non-Neoplastic Lesions	1951
Synovial and Ganglion Cysts	1951
Loose Bodies	1953
Intra-articular Ossicles	1954
Neoplasms	1954
Fatty Lesions of the Synovium	1954
Vascular Lesions of the Synovium	1956
Fibroma of Tendon Sheath	1957
Synovial Chondromatosis	1957
Chondroma of Tendon Sheath and Periarticular Structures	1960
Tenosynovial Giant Cell Tumor	1960
Tenosynovial Giant Cell Tumor of Joints and Tendon Sheaths: Diffuse Type (Synonym: Pigmented Villonodular Synovitis)	1960
Malignant Diffuse Tenosynovial Giant Cell Tumor	1963
Localized Tenosynovial Giant Cell Tumor of the Joint (Synonyms: Benign Giant Cell Synovioma, Benign Synovioma, Localized Nodular Synovitis)	1963
Localized Tenosynovial Giant Cell Tumor of the Tendon Sheath (Synonyms: Giant Cell Tumor of Tendon Sheath, Fibroxanthoma of Tendon Sheath)	1964
Malignant Tumors of the Joint	1965
Primary Sarcomas of Joints	1965
Conventional Chondrosarcoma	1965
Synovial Sarcoma	1965
Secondary Malignant Tumors of the Joint	1968
Sarcomas	1968
Metastatic Carcinoma	1968
Malignant Lymphoproliferative Disease	1968
References	1968
Index	i1
A	i1
B	i10
C	i13
D	i22
E	i24
F	i27
G	i30
H	i33
I	i37
J	i41
K	i42
L	i43
M	i47
N	i52
O	i55
P	i58
Q	i66
R	i66
S	i71
T	i80
U	i85
V	i86
W	i87
X	i88
Y	i88
Z	i88

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