Dubois' Lupus Erythematosus and Related Syndromes

Cover
Inside front cover
Front matter
	Dubois’ Lupus Erythematosus and Related Syndromes
Copyright
Dedication
Preface
Acknowledgments
Contributors
Contents
	Section 1 What is lupus?
	Section 2 Pathogenesis
	Section 3 Mechanisms of tissue injury
	Section 4 Autoantibodies
	Section 5 Clinical aspects of lupus erythematosus
	Section 6 Assessment of lupus
	Section 7 Management of lupus
	Section 8 Outcomes
1 History of lupus
	Prescientific period
	Differentiation from tuberculosis
	Recognition of systemic lupus erythematosus
	Systemic lupus erythematosus and “collagen disease”
	Serologic aspects
	Pathogenesis: Some breakthroughs
	Epidemiology
	Classification criteria and disease indices
	Management: Some breakthroughs
	Related diseases
		Antiphospholipid syndrome
		Neonatal lupus
		Lupoid hepatitis
	Prognosis: Just a few comments
	References
2 Definition and classification of lupus and lupus-related disorders
	Systemic lupus erythematosus
		Definition of systemic lupus erythematosus
		Development of the american college of rheumatology systemic lupus erythematosus classification criteria
		Constraints of the american college of rheumatology systemic lupus erythematosus classification criteria
		Systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus
		2019 European league against rheumatism/american college of rheumatology classification criteria for systemic lupus erythematosus
	Chronic cutaneous lupus
	Drug-induced lupus erythematosus
	Mixed connective tissue disease
	Undifferentiated connective tissue disease and overlap syndromes
	Antiphospholipid antibody syndrome
	Neonatal lupus
	Summary
	References
3 The epidemiology of lupus
	Introduction
	The fundamentals of epidemiology
		Case definition
		Case ascertainment
		Population at risk
	Pediatric systemic lupus erythematosus
	Cutaneous lupus erythematosus
	Other considerations
	Conclusion
	References
4 Overview of lupus pathogenesis
	Phases of SLE: Evolution of disease in susceptible persons
	Overview: The major pathways favoring development of SLE
		Stimulation of innate and adaptive immune responses by foreign and autoantigens
		Autoantibodies and immune complexes of SLE
		Regulatory mechanisms fail to control autoimmune responses
		Abnormalities in T and B lymphocytes in SLE
		Cytokines/chemokines and SLE
		Genetics and epigenetics
		Gender influences
		Environmental factors
		Complement activation and tissue damage in SLE
	Current approved and investigational therapies for SLE4
	Suggested reading
5 Genetics of SLE
	Genetic studies on SLE
		Early days of SLE genetic studies
		Genome-wide association studies
	SLE susceptibility genes in cell death and clearance of self-antigens
		Complements and nucleases
			NCF1 and NCF2
			ITGAM and SLC29A3
		Other genes involved in cell death and clearance
	Fc gamma receptors
	SLE genes in toll-like receptor and IFN-I signaling
		TLR7
		IRF5 and IRF3
		IRF7
		IFN-α
		miR-146a and USP18
		TASL and SLC15A4
		IFIH1
		STIM1
		IFN-II (IFN-γ) and IFN-III signaling
	NF-κB signaling
		TNFAIP3 and TNIP1
		UBE2L3
		RELA
		IKBKB and IKBKE
	B-cell signaling in SLE genetics
		LYN
		TNFSF13B
		TACI
		PTPN22
		CSK
		TRAF3
		CD40 and FCRL5
		TAOK3
			RASGRP1 and RASGRP3.
		IL7R
	SLE genes in T cell signaling
		HLA class II genes
		TNFSF4
		PTPRC (CD45)
		CTLA4 and CD80
		DEF6
		DUSP22
		CXCR5 and RGS1
		GRB2 and PDCD5
		WDFY4
		CD37
	IL12 and JAK/STAT signaling
		IL12A and IL12RB2
		STAT4, JAK2, and TYK2
	Transcription factors and epigenetic modifiers in SLE
		IKZF1
		BACH2 and PRDM1
		ETS1
		TET3
	Applications of the genetic findings
	Future directions
	References
6 Single gene defects and autoinflammation
	Introduction
	Type I interfons and their role in autoimmune disease
	Interferonopathies and associated molecular defects
		Aicardi-Goutières syndrome
		STING-associated vasculopathy with onset in infancy
		COPA syndrome
		Spondyloenchondrodysplasia
	Informing monogenic lupus
		Ultraviolet sensitivity and cGAS-STING
		Complement protein defects driving monogenic lupus
	Therapeutic implications of RNA/DNA sensing in monogenic autoimmune disease and future directions
	References
7 Epigenetics of lupus
	DNA methylation in SLE
		Introduction to DNA methylation
		Dysregulated DNA methylation and gene expression in SLE
		Mediators and factors contributing to dysregulated DNA methylation in SLE
	Histone modification in SLE
		Introduction to histone modification
		Dysregulated histone modification in SLE
		Mediators and factors contributing to dysregulated histone modification in SLE
	3D genome and SLE
		Introduction of 3D genome
		Genetic variants and 3D genome
		Identification of 3D genome associated with functional variants
		Dysfunctional enhancers in SLE
		3D genome as targets for SLE therapy
	RNA modification
		m6A modification
		A-to-I editing
		C-to-U editing
	miRNA in SLE
		Introduction to miRNA
			miRNA biogenesis
			miRNA regulation
		Roles of miRNAs in SLE
			Functions of miRNAs in the immune system
			Regulating the development of immune cells
			Regulating innate and adaptive immune responses
		Dysfunctional miRNAs in lupus
			Dysfunctional miRNAs in innate immunity
			Dysfunctional miRNAs in adaptive immunity
			Dysfunctional miRNAs in resident cells of target tissues
	Roles of lncRNAs in SLE
		Functions of lncRNA in the immune system
		Dysfunctional lncRNAs in lupus
	Roles of circrnas in SLE
	Translational application of epigenetics in lupus
		Prospective epigenetic biomarkers
		Epigenetic therapeutic targets
	References
8 The role of the environment and microbiome in lupus
	Interplay between environmental, genetic, and epigenetic factors
	Dietary influences on SLE
	Gut microbiome and SLE
	Environmental exposures and SLE
		Silica exposure
		Smoking
		Smoking and the role of gene-environment interactions
		Epstein-Barr virus exposure
		Vitamin D status and ultraviolet radiation exposure
		Metals
		Pesticides and persistent organic pollutants
		Air pollution
		Other environmental agents and SLE
	Methodologic considerations
		The SLE exposome
	Future considerations
	References
9 The innate immune system in SLE
	Cellular components of the innate immune system
		Monocytes, macrophages, and dendritic cells
		Neutrophils
		Plasmacytoid dendritic cells
		Natural killer cells
		Platelets
		Innate lymphoid cells
	Extracellular components of the innate immune system
	Pattern recognition receptors: Pamps, damps, and pathways of innate immune stimulation in SLE
		Toll-like receptors
		TLR7 and TLR9 in SLE
		Cytosolic sensors
		Ligands responsible for stimulating IFN-I and other inflammatory cytokines
	Innate immune detection of self versus nonself nucleic acid
	Therapeutic approaches
	References
10 B cells and generation of antibodies
	Structure of the antibody molecule
	Generation of antibody diversity
		Class switch recombination
		Somatic hypermutation
	Posttranscriptional modifications of antibodies
	Pathogenic autoantibodies
	Genetic and molecular analysis of anti-DNA antibodies
	B-cell subsets: Implications for SLE
		Innate B cells
		Follicular B cells
		Memory B cells
		Plasma cells
		Age/autoimmune-associated B cells
		Regulatory B cells
	B-cell activation
		B-cell receptor signaling
		Toll-like receptors in B-cell function
		Cytokine activation
		Plasma cell differentiation
		Germinal center and extrafollicular activation of B cells
	B-cell tolerance
		Apoptosis and autoimmunity
	Autoantibody induction
		Triggers
		Regulation of autoantibody production in the germinal center
	Therapeutic interventions
		Depleting autoreactive B cells
		Interfering with T-cell help
		Antiinflammatory therapies
		Antigen-based therapies
	Summary
	References
11 T cells
	Role of T cells in autoimmunity and inflammation
		B cell help
		Inflammation
		CD8 and double negative T cells
		Regulatory function
	Intrinsic T cell defects
		Assembly and selection of the T cell repertoire
		T cell activation and signaling
		Regulation of gene expression
		Metabolic dysfunction
		Apoptosis induction
	Acquired defects
	Concluding remarks
	References
12 Immunoregulatory cells and networks in lupus
	T-regulatory cells
		CD4⁺ T-regulatory cells
		CD4⁺ Tregs and SLE
		CD8⁺ Tregs
		CD8⁺ Tregs and SLE
	B-regulatory cells
		B-regulatory cells and SLE
	Myeloid-derived suppressor cells
		Myeloid-derived suppressor cells and SLE
	Dendritic cells
		Dendritic cells and SLE
	Natural killer cells
		NK cells and SLE
	NKT cells
		iNKT cells and SLE
	Conclusions
	References
13 Cytokines in lupus
	Properties of cytokines and their receptors
	Assessment of cytokine production
	Use of gene expression to study cytokine effects
	Activation of the immune response in systemic lupus erythematosus
	Cytokines of the innate immune response
		Type I interferons in immune responses
		Type I interferons in the pathogenesis of systemic lupus erythematosus
		Tumor necrosis factor
		Osteopontin
		Interleukin-1
		Interleukin-10
		B-lymphocyte stimulator
		Interleukin-6
		Other cytokines
	Cytokines of the adaptive immune response
		Cytokines generated in the adaptive immune response: T-cell–derived cytokines
			T helper cell cytokines
			Interleukin-2
			Interferon-γ
			T helper 2 cytokines
			Transforming growth factor-β
			Other T-cell–derived cytokines
		Cytokines generated in the adaptive immune response: B-cell–derived cytokines
			Cytokines in preclinical lupus
	Summary
	References
14 Metabolic control of immunopathogenesis in systemic lupus erythematosus
	Metabolic pathways regulate proinflammatory immune cell lineage specification via MTOR activation in SLE
	Mitochondrial oxidative stress underlie MTOR activation in SLE
	Mechanistic checkpoints of metabolic pathways represent targets for treatment in SLE
	Conclusions
	Acknowledgement
	References
15 Animal models of systemic lupus erythematosus (SLE)
	Multigenic spontaneous SLE
		NZB/BL (NZB) mice
			Clinical characteristics and autoantibodies
			B cells, T cells, and other factors
			Genetics
			Summary
		New Zealand White mice
			Clinical characteristics and autoantibodies
			Genetics
		(NZB x NZW) F1 mice (BWF1)
			Autoantibodies
			Nephritis in BWF1 females: Autoantibodies, infiltrating cells, and predisposing glomerular structures
			Neurologic tissue
			Lymphoproliferation
			Sex influences
			Hematopoietic cell abnormalities
			Interferons and TGF-β
			Abnormalities of dendritic cells in BWF1 mice
			Abnormalities of monocytes/macrophages
			Other abnormalities
			Genetic predisposition
			Summary
		New Zealand mixed mice
			Clinical and immunologic characteristics of NZM2410
			NZM2328: Clinical and immune characteristics
			NZM triple congenics (C57BL/6.NZM.Sle1.Sle2.Sle3), clinical manifestations, and immunologic features
		(SWR x NZB) F1 (SNF1) mice
			Characteristics
			Genetics
			Summary
	MRL-lpr mice and MRL/Mp (MRL⁺/⁺)
		Clinical characteristics
		Immune cell characteristics
		Genetics
		Summary
	Nonfunctional Fas ligand in GLD mice
		BXSB mice
			Clinical manifestations and autoantibodies
			Genetics
			Summary
	(NZW×BXSB) F1 model of antiphospholipid syndrome and coronary artery disease
		Disease characteristics and autoantibodies
		Other disease features
		Genetics
		Summary
	BXD2 RI model of spontaneous lupus nephritis and erosive polyarthritis (“rhupus”)
		Genetics
		Summary
	Monogenic spontaneous SLE
		Fcgr2b−/− mice
		Lyn−/− mice
		TLR7.1 mice
	Induced lupus-like disease in nonautoimmune strains
		Chronic GVHD (cGVHD) model
	Lupus induced by injection of hydrocarbon oil
		Xenobiotic-induced autoimmunity
		TLR7 agonist-induced autoimmunity
		Other induced models
		Lupus in genetically manipulated mice
			Modified genes in nonautoimmune strains
			Modified genes in lupus mice
	Therapeutic interventions in mouse models of lupus
		Immunosuppressive therapies
		Therapies targeting B cells
		Therapies targeting T cells
		Activation of suppressor networks
		Treatments targeting complement, cytokines, chemokines and their activation pathways
		Treatments targeting innate immunity
		Stem cell replacement
		Diet, gut inflammation, and the microbiome
		Manipulating sex hormones
		Target organ protection
	Lupus in domestic animals
		Spontaneous canine SLE
		SLE in cats, monkeys, and horses
	References
16 Abnormalities in clearance of immune complexes and dying cells in lupus
	Introduction
	Defective apoptotic cell clearance mechanisms in autoimmunity
	Phosphatidylserine receptors
	Role of “don’t eat me” receptors in systemic lupus erythematosus
	Role of scavenger receptors in apoptotic cell clearance
	Role of efferosome maturation in apoptotic cell clearance
	Abnormalities in immune complex clearance
	Tissue clearance mechanisms
	Complement receptors
	Role of C1q
	Fcγ receptors
	Genetic abnormalities of Fcγ receptors
	Other cell types involved in immune complex interactions
	Other tissue clearance mechanisms
	Acknowledgments
	Disclosures of interest
	Summary
	References
17 Complement and systemic lupus erythematosus
	Historical overview
		Biology of the complement system
			Complement activation pathways
			Regulators of complement activation
			Receptors for complement proteins
			Effector functions of complement
			Complements as a bridge between innate immunity and adaptive immunity
			Novel roles for complement
		Complement dysregulation and SLE
			Immune complex abnormalities, complement activation, and tissue injury
			Other potential mechanisms of complement dysregulation in SLE
		Complement defiency and SLE
			Hereditary complement deficiency and SLE
			Acquired complement deficiency and anticomplement autoantibodies
			Deficiency and dysfunction of complement regulatory proteins
			Possible mechanisms underlying the complement deficiency–SLE association
		Analyses of complement
			Measurement of complement functional activity
			Measurement of complement proteins
			Measurement of complement activation products
			Genetic testing
			Diagnostic considerations for complement dysregulation and deficiency
		Soluble complement components as biomarkers for SLE
			Soluble complement components and SLE diagnosis and activity monitoring
			Problems associated with measurement of soluble complement components
		Cell-bound complements as biomarkers for SLE
			Cell-bound complement activation products as diagnostic biomarkers
			Cell-bound complement activation products as biomarkers of disease activity
			Cell-bound complement activation products as biomarkers for predicting the development of SLE
		Complement-targeted therapeutics for SLE
		Conclusion
	References
18 Apoptosis and inflammatory forms of cell death
	Introduction and definitions
	Biochemistry of apoptosis
		Caspases
		Intrinsic apoptosis: Bcl-2 proteins and the mitochondria
			Abnormalities in the expression of Bcl-2 family members cause lupus-like autoimmunity in mice
		Intrinsic death pathways from cellular damage or stress
			Metabolic stress
			Genotoxic stress
			Endoplasmic reticulum stress
		Extrinsic signaling through death receptors
		Regulation of death receptors
		Function in immune regulation
	Deficiencies in death receptor signaling lead to systemic autoimmunity
	Removal of dead and dying cells: Tolerance versus autoimmunity
		Receptors and ligands implicated in the removal of intact dead cells by phagocytes
			How a cell dies affects the immune response
				Apoptotic cell death leads to a lack of immune response or immune suppression and tolerance.
			Defective clearance of apoptotic cells predispose to lupus-like disease in mice
				Cells that die by necrosis, pyroptosis, necroptosis, netosis or ferroptosis, stimulate inflammation and, in some cases, au ...
			The critical role of nucleases and the degradation of extracellular and intracellular nucleic acids.
	Cell death abnormalities in human SLE
		Apoptosis, clearance of apoptotic cells, and necrosis
		The pivotal role of nucleic acids in stimulation of IFN-I in SLE
			Cell death and treatment of SLE
	Conclusions
	Acknowledgments
	References
19 Tissue damage in lupus
	Introduction
	Overview of reactive oxygen and nitrogen intermediates
	Regulation of oxidant stress
	Mechanisms through which ROI can modify DNA and change transcription
	Association of ROI and RNI with SLE disease activity
	Autoantibodies
	T-cell regulation and function
	Apoptosis
	Autophagy regulation and induction
	Neutrophil net formation
	Podocyte dysfunction induced by RNI
	Fibrosis
	The role of NO• in vascular homeostasis
	Conclusion
	References
20 Lupus nephritis
	Renal anatomy and physiology
		Glomerular structure and function
			Glomerular filtration barrier
			Podocytes
			Mesangium
			Glomerular endothelial cells
		The renal tubules and the kidney interstitium
			Renal tubular epithelial cells
			Renal interstitial fibroblasts
			Resident renal immune cells
	Histologic classification of lupus nephritis
	Genetic risk for lupus nephritis
	Mouse models of lupus nephritis
		NZB/W F1 and inbred strains
		Mice overexpressing TLR7
		Fas overexpression
		Inducible models of lupus nephritis
	Mechanisms for immune complex deposition in the kidneys
		Site of immune complex deposition in SLE
		The characteristics of pathogenic autoantibodies
		Mechanisms of tissue deposition of immune complexes
	Pauci-immune glomerulonephritis
	Dissociation of immune complex deposition and/or glomerular injury from end-stage renal disease
	Effector mechanisms in the kidney
		Complement
		Fc receptors
		Innate immune receptors
		Immune cell influx
			T cells
			B cells
			Myeloid cells
		Soluble mediators of tissue injury
			Chemokines
			Cytokines
			Lipid mediators
			Hypoxia and other metabolic disturbances
			The renin-angiotensin system
			MMPs and tissue repair
		Blood vessels and endothelium
			Integrin ligands
			Heparan sulfate proteoglycan
	Progression to fibrosis and sclerosis
		Natural history of progressive lupus nephritis
		Pathways that contribute to or protect from fibrosis
			TGFβ
			Hepatocyte growth factor
			PPARγ and obesity
			LCN2 and KIM-1
	Systems biology of lupus nephritis
		Serum and urine biomarkers
		Modular signatures
		Insights from molecular profiling and single-cell RNA sequencing
	Future directions in lupus nephritis
	References
21 Pathogenesis of accelerated atherosclerosis and vascular injury in systemic lupus erythematosus
	Epidemology of cardiovascular disease in systemic lupus erythematosus
		Major adverse cardiovascular events
		Subclinical and clinical vascular damage in SLE
		Pathogenesis of atherosclerosis in the general population
	Pathogenesis of premature atherosclerosis in SLE
		The role of altered immune cell subtypes in SLE atherosclerosis
		Dysregulation of innate immune responses and SLE-related cardiovascular disease
			Monocytes/macrophages
			Plasmacytoid dendritic cells and type I interferons
			Neutrophils and low-density granulocytes
		Dysregulation of adaptive immune responses and SLE-related cardiovascular disease
			CD4+ T cells
			Th1 cells and interferon-γ
			Th17s and IL-17A
			Tregs
			Follicular helper T cells
			B cells
			Autoantibodies and immune complexes
		Cytokines and other soluble mediators
			Alarmins S100A8, S100A9, and S100A8/A9
			Tumor necrosis factor-aymor nex
			Monocyte chemotactic protein-1
			B cell activating factor/B lymphocyte stimulator
	The role of inflammatory lipids
		Oxidized low-density lipoproteins
		High-density lipoprotein structure and function
	Other factors associated with cardiovascular disease in SLE
		Homocysteine
		The PREDICTS model
		Vitamin D deficiency
		Genetic risk factors
		Potential treatments to mitigate cardiovascular disease in SLE
		Statins
		Antihypertensives
		Treatment of disease activity
		Antimalarials
		Mycophenolate mofetil
		Peptidylarginine deiminase inhibitors
		Methotrexate
		Anti–B cell therapies
		Antiinterferon therapies
	Conclusions
	Acknowledgments
	Key points
	References
22 Pathogenesis of cutaneous lupus
	Introduction
	Clinical considerations
	Epidemiology
		Triggers of cutaneous lupus erythematosus
			Ultraviolet light
			Medications
			Smoking
	Etiopathogenesis
		Genetics
		Contribution of sex bias
		Microbiome
		The importance of interferons
		Etiology of the interferon signature
		Other type II and type III interferons
		Cell death
		Immune cell populations in cutaneous lupus erythematosus
	How understanding pathogenesis is changing treatment
	References
23 Pathogenesis of neuropsychiatric lupus
	Introduction
		Neuroimmune interfaces
		Blood-brain barrier
		Blood–cerebrospinal fluid barrier
	Cell-mediated inflammation
		Autoantibodies
		Autoantibody-mediated vasculopathy
		Brain-reactive autoantibodies
		Cytokines and chemokines
	Complement-mediated immunity
		Glial cells
	Summary
	References
24 Pathogenesis of Sjögren syndrome
	Introduction
	Disease triggers
		Viruses
		Neuroendocrine axis
		Sex hormones
		Smoking
		Diet and microbiome
		Genetics
		Epigenetics
	Autoimmune epithelitis
		Salivary glands and immune system
			Innate immunity and salivary glands epithelium
			Adaptive immunity and salivary gland epithelium
			Stromal cells of salivary glands
		Mechanisms of dryness
	From a gland disease to a systemic disease
		B-cell hyperactivity
		Tertiary lymphoid structures
		Autoantibodies
		Lymphoma
	Research tools
		Animal models
		OMICs
	From pathogenesis to targeted treatment
	Major knowledge gaps
		Fatigue
		Environmental factors
		Chronic inflammation
	Conclusions
	References
25 Antinuclear antibodies, antibodies to DNA, histones, and nucleosomes
	Antinuclear antibody overview
		History
		Choice of substrate
		Patterns of immunofluorescence and links to target antigen
		Clinical interpretation
		New methods for antinuclear antibody detection
		Identification of lupus-related antibodies
		Antinuclear antibody–negative lupus
		Summary
	Antibodies to DNA, histones, and nucleosomes
		Measurement of anti-dsDNA antibodies
		Work from experimental models that emphasized the potential importance of anti-dsDNA antibodies
		How pathogenic anti-dsDNA antibodies bind to tissues: The importance of binding to nucleosomes
		Cross-reaction of anti-DNA antibodies with intracellular antigens
		Cell-penetrating anti-DNA antibodies in SLE
	Antihistone antibodies
		Structure and origin of pathogenic anti-dsDNA and antinucleosome antibodies
		Can measuring anti-dsDNA levels help manage patients with SLE?
	Acknowledgments
	Summary
	References
26 Antibodies against extractable nuclear antigens (RNP, Sm, SS-A/RO, and SS-B/La)
	Structure of the antigens
		Sm and RNP complexes
		SS-A/RO and SS-B/La ribonucleoprotein complexes
	Assays for measuring anti-ENA antibodies
	Prevalence and clinical associations in SLE
	Origins of anti-ENA autoimmunity
		Viral infections as trigger for autoimmunity
		Sequential presentation of anti-ENA antibodies and relationship of anti-ENA to other SLE-specific autoantibodies
		Role of apoptosis for the generation of anti-ENA antibodies
		Toll-like receptors as key molecules for the generation of anti-ENA antibodies
	Genetic risks and anti-ENA antibodies
	Pathogenic importance of anti-RNP and anti-Sm antibodies
	Pathogenic role of anti–SS-A/Ro and anti–SS-B/La antibodies
	Autoantibodies against other ENA
		Anti–proliferating cell nuclear antigen antibodies/anti-cyclin antibodies
	References
27 Other autoantibodies
	Introduction
	Anti-C1q antibodies
	Antilipoprotein antibodies
	Antiendothelial cell antibodies
	References
28 Pathogenesis of antiphospholipid antibody syndrome
	The clinical importance of antiphospholipid antibodies
	Epidemiology of aPL and APS
	Which aPL tests should be done and how should they be interpreted?
		Standard laboratory “criteria” assays
		Noncriteria assays
	Antiphospholipid antibody–induced mechanisms of disease
		Mechanisms of thrombosis
			Animal models
			Interactions with cell surface receptors
			Cell activation and signaling pathways leading to thrombosis
				Endothelial cells.
				Monocytes.
				Platelets.
				Neutrophils.
				Dysregulation of coagulation and complement pathways.
		Mechanisms of pregnancy morbidity
			Animal models
			Mechanisms of cellular activation leading to obstetric APS
			Dysregulation of coagulation and complement pathways
	Coronavirus disease 2019 and antiphospholipid antibodies
	Conclusions
	References
29 Drug-induced lupus
	Introduction
	Etiology
		Implicated drugs
		Genetic contributions to idiopathic and drug-induced lupus
		Roles of age and gender in idiopathic and drug-induced lupus
		Summary
	Pathogenesis
		Genetic predisposition
		Drug biotransformation
		Epigenetics and gene expression
		Epigenetics, chromatin structure, and gene expression
		Histone modification
		DNA methylation
		T cells, DNA methylation, and drug-induced lupus
		T cells, DNA methylation, and idiopathic lupus
		T cells, DNA methylation, and the environment
		Innate immune system
	Role of cytokines—evidence from biologic agents
		Interferon α (IFN-α)
			Tumor necrosis factor α (TNF-α) inhibitors
		Summary
	Clinical aspects
		Comparison of drug-induced versus idiopathic lupus
			Patient characteristics
				Hydralazine.
				Procainamide.
				Tnf-α inhibitors.
			Drug-induced subacute cutaneous lupus erythematosus
			Laboratory findings
			Clinical course
	Summary
	References
30 Overview and clinical presentation
	Clinical manifestations and racial disparities
	Chief complaint, autoantibody development, and immunologic changes
	Variations in clinical presentation
		Incomplete lupus
		Late-onset lupus
		Male lupus
	Categorization of lupus symptoms
		Fatigue
		Brain fog
		Fever
		Lymphadenopathy
		Weight loss
	References
31 Skin disease in cutaneous lupus erythematosus
	Epidemiology
	Triggers of cutaneous lupus erythematosus
	Clinical features
		Classification of cutaneous lupus erythematosus
		Lupus-specific skin lesions
			Acute cutaneous lupus erythematosus
			Subacute cutaneous lupus erythematosus
			Chronic cutaneous lupus erythematosus
				Discoid lupus erythematosus.
					Hypertrophic/verrucous DLE.
					Lupus panniculitis/lupus profundus.
				Lupus erythematosus tumidus.
					Chilblain LE.
					Lichen planus–lupus erythematosus overlap.
				Bullous SLE.
	Relationship with systemic disease features
	Pathology
	Immunopathology
	Laboratory findings
	Differential diagnosis
	Lupus-nonspecific skin lesions
		Photosensitivity
		Mucosal ulceration
		Nonscarring alopecia
		Cutaneous vascular reactions
		Vasculitis
		Vasculopathy
		Raynaud phenomenon
		Antiphospholipid antibodies
		Cryoglobulins
		Other cutaneous vascular reactions
			Urticaria
			Periungual telangiectasias
			Erythromelalgia and palmar erythema
		Other LE-nonspecific skin lesions
			Papulonodular mucinosis
			Calcinosis cutis
			Nail changes
			Anetoderma
			Interstitial granulomatous dermatitis
	Conclusion
	References
32 The musculoskeletal system and bone metabolism
	Introduction
	Arthritis
		Arthritis definition by classification criteria
		Diagnosis
			Imaging
			Synovial fluid analysis and synovial tissue pathology
			Immunologic profiles in erosive arthritis in SLE arthritis
		Jaccoud arthropathy
		Rhupus: Revisiting concepts of erosive arthritis
		Treatment
	Muscle involvement
		Lupus myositis
		Orbital myositis
		Drug-induced myopathies in SLE
		Infection-related myopathies
	Soft tissue disorders and other pain syndromes
	Musculoskeletal infections
	Avascular necrosis
		Osteoporosis
	Joint replacement in SLE
	Musculoskeletal features in outcome measures
		SLE disease activity measures
			British isles lupus assessment group
			European consensus lupus activity measurement
			Lupus activity index
			SLE activity index score
			Systemic lupus activity measure
			SLE disease activity index
		SLE damage indices
			SLICC/ACR damage index
			Lupus damage index questionnaire
			Brief index of lupus damage
	Summary
	References
33 Lupus and the cardiovascular system
	Introduction
	Epidemiology
	Pericardium
		Pericarditis
		Pericardial effusion
		Chronic pericarditis
	Myocardium
		Myocarditis
		Cardiomyopathy
	Endocardium
		Endocarditis
		Congenital heart block
		Adult conduction abnormalities
	Vasculature
		Atherosclerosis and coronary artery disease
	References
34 Pulmonary manifestations of systemic lupus erythematosus
	Introduction
	Pleural disease
		Pathogenesis
		Diagnosis
			Clinical presentation
			Imaging
			Pleural fluid analysis
		Management
	Parenchymal disease
		Acute parenchymal disease
			Acute lupus pneumonitis
			Diffuse alveolar hemorrhage
			Management of ALP and DAH
			Uncommon forms of acute parenchymal involvement in SLE
		Chronic parenchymal disease
			Interstitial lung disease
			Treatment of SLE-ILD
	Vascular disease
		Pulmonary hypertension
			Treatment of SLE-PH
		Pulmonary vasculitis
		Thromboembolic disease
		Acute reversible hypoxemia
	Diseases of the mediastinum and musculature
		Shrinking lung syndrome
			Treatment of shrinking lung syndrome
	Uncommon pulmonary involvement in SLE
		Airway disease
		Miscellaneous pulmonary disease
	Lung transplantation in SLE
	Novel treatment targets
	Summary
	References
35 Lupus and the nervous system
	Classification of NPSLE
		Attribution of neuropsychiatric events in patients with SLE
		Etiopathogenesis
	Epidemiology of NPSLE
		Risk factors for neuropsychiatric manifestations of SLE
	Clinical presentation of NPSLE
		Diffuse central nervous syndromes—neurologic
			Acute confusional state
			Aseptic meningitis
			Cognitive dysfunction
			Demyelinating syndrome
			Headache
		Diffuse central nervous system syndromes—psychiatric
			Anxiety disorders
			Mood disorders
			Psychosis
		Focal central nervous system syndromes
			Cerebrovascular disease
			Movement disorders
			Myelopathy
			Seizures
		Peripheral nervous system manifestations
			Acute inflammatory demyelinating polyneuropathy
			Autonomic disorders
			Cranial neuropathies
			Mononeuropathy
			Myasthenia gravis and related disorders
			Plexopathy
			Polyneuropathy
		Neuropsychiatric SLE in children
	Diagnostic evaluation
		Clinical laboratory tests
		Autoantibodies
			Antiphospholipid antibodies
			Anti-ribosomal P antibodies
			Anti-aquaporin 4 antibodies
			Anti-NMDAR antibodies
		Cerebrospinal fluid examination
		Electroencephalography
		Electromyography and nerve conduction studies
		Neuropsychometric tests
	Neuroimaging studies in NPSLE
		Computed tomography
		Magnetic resonance imaging
		Positron-emission tomography and single-photon emission computed tomography
		Advanced magnetic resonance imaging techniques
			Magnetization transfer imaging
			Magnetic resonance spectroscopy
			Diffusion tensor imaging
			Dynamic contrast-enhanced magnetic resonance imaging
		Functional magnetic resonance imaging
		Transcranial color doppler sonography
		Angiography
	Treatment of NPSLE
		Inflammatory pathway therapies
		Ischemic pathway therapies
	Prognosis of NPSLE
	References
36 Gastrointestinal and hepatic manifestations
	Gastrointestinal involvement
		Introduction
		Incidence and prevalence
		Manifestations
			Oral-pharyngeal ulceration, dysphagia, and esophagitis
			Anorexia, nausea, vomiting, and diarrhea
			Abdominal pain and acute abdomen
			Ascites and peritonitis
			Peptic ulcer disease
			Helicobacter pylori infection in systemic lupus erythematosus
		Pancreatitis
			Prevalence
			Clinical presentation and etiopathogenesis
			Management
		Motility disorders
		Mesenteric and intestinal vasculitis, melena, and bowel hemorrhage
			Prevalence
			Clinical presentation and etiopathogenesis
			Laboratory, radiographic, and histologic findings
			Treatment and outcome
			Mesenteric insufficiency, thromboembolism, and intestinal infarction
		Inflammatory bowel disease
			Collagenous colitis
			Celiac disease in association with systemic lupus erythematosus
			Protein-losing enteropathy and malabsorption
			Irritable bowel syndrome
	Liver manifestations of systemic lupus erythematosus
		Liver function test abnormalities: Clinicopathologic correlates
		Autoimmune liver disease in lupus
			Lupus hepatitis: Is there a distinct entity of lupus hepatitis?
			Autoimmune hepatitis and its relationship to lupus
			Overlapping syndromes in autoimmune hepatitis
			PBC and PSC overlap with SLE
		Other causes of hepatitis in systemic lupus erythematosus
			Hepatitis B infection
			Hepatitis C
			Drug-induced autoimmune hepatitis
	Biliary abnormalities: Cholecystitis, cholangitis, and biliary cirrhosis
	Hepatobiliary and pancreatic malignancies
	References
37 The gut microbiome and lupus pathogenesis
	Introduction
	Microbiome dysbiosis and the etiopathogenesis of systemic lupus disease
		Linking gut microbes with lupus etiopathogenesis
		Changes in microbial diversity
		Gut barrier impairment
		Clarifying differences between beneficial versus harmful bacteria by considering immune effects of bacterial toxins, metabolites, and antigen molecular mimicry
	Limitations of current approaches and future considerations
		Methodologic limitations and future directions
		Can we consider targeting gut microbiome dysbiosis or barrier dysfunction for therapeutic benefit in lupus disease?
	Key points and conclusions
	References
38 Hematologic and lymphoid abnormalities in SLE
	Anemia
		Anemia of chronic disease
		Iron-deficiency anemia
	Immune-mediated hemolytic anemias
		Autoimmune hemolytic anemia
		Diagnosis
		Antigen specificity of antierythrocyte antibodies
		Treatment
			General considerations
			First-line therapies
			Second-line therapies
			Third-line therapies
			Novel treatment approaches
		Bone marrow and immune-mediated hematopoietic failure in SLE
		Reactive hemophagocytic syndrome
			Diagnosis
			Treatment of autoimmune-associated hemophagocytic syndrome
	Thrombocytopenia and qualitative platelet disorders
		Pathogenesis of thrombocytopenia in SLE
		Acquired abnormalities of platelet function
		Treatment of thrombocytopenia in SLE
		Evans syndrome
		Thrombotic thrombocytopenic purpura
	White blood cell disorders
	Lymphadenopathy in SLE
	Spleen in SLE
	Bonus content for this chapter can be found online at
	References
39 Neonatal lupus
	History
	Epidemiology
	Pathogenesis
	Candidate biomarkers and new theories relating to pathogenesis
	Clinical manifestations
		Cardiac
		Dermatologic
		Gastrointestinal
		Neurologic
		Hematologic and skeletal
		Diagnosis
	Management
		Monitoring anti-SSA/Ro–exposed pregnancies and treatment approach
		Management of first-degree block
		Management of second-degree block
		Management of third-degree block
		Prevention strategies
		Postnatal assessment and treatment of neonatal lupus
	Prognosis
	References
40 Pregnancy and reproductive health issues in systemic lupus erythematosus
	Introduction
	Hormones and reproductive immunology
		Gonadal hormones and the immune system
		Female hormones and inflammatory mediators
		Complex effects of sex hormones on inflammation
		Sex hormones, immune system, and the vascular system
		Maternal–fetal immunology
		Embryologic development of the immune system
	Contraception
		Contraception use by SLE patients
		Estrogen-progestin contraception
		Progestin-only contraception
		Intrauterine devices
		Barrier methods
		Emergency contraception
		Medication interactions
	Infertility and protection against premature ovarian failure
		Preservation of fertility with cyclophosphamide therapy
		Assisted reproductive technologies
	Pregnancy in SLE
		Disease activity in pregnancy
		Diagnosing SLE flare during pregnancy
		Pregnancy outcomes
		Pregnancy loss
		Preterm birth
		Preeclampsia
		Offspring outcomes
		Long-term outcomes of SLE offspring
		Maternal mortality
	Antiphospholipid syndrome and pregnancy
		Etiologic and pathophysiologic characteristics
		Pregnancy outcomes
		Maternal outcomes
		Medications for antiphospholipid antibodies during pregnancy
	Medications in SLE pregnancy
		Nonsteroidal antiinflammatory drugs and acetaminophen
		Corticosteroids
		Hydroxychloroquine
		Azathioprine
		Mycophenolate mofetil
		Calcineurin inhibitors
		Cyclophosphamide
		Intravenous immunoglobulin
		Rituximab
		Belimumab
		Anifrolumab
	Menopause and SLE
		Postmenopausal hormone therapy
		Effect of menopausal hormone therapy on cardiovascular disease and thrombosis risk
		Effect of menopausal hormone replacement on disease activity
	Bone health and osteoporosis
		Prevention of osteoporosis
	Reproductive health care and screening
	References
41 Systemic lupus erythematosus in childhood and adolescence
	Introduction
	Epidemiology
	Diagnosis of SLE in children
		Clinical manifestations of SLE
		Renal disease
		Neuropsychiatric disease
		Pulmonary manifestations
		Musculoskeletal manifestations
		Dermatologic manifestations
		Cardiac manifestations
		Gastrointestinal manifestations
		Infection and vaccinations
		Hematologic manifestations
		Laboratory evaluation
		Clinical differences between adults and childhood-onset SLE
		Genetics of cSLE
		Standards of care of childhood-onset SLE as opposed to adult-onset SLE
	Common medications in cSLE therapy
		Other psychosocial concerns
	Summary
	References
42 Clinical aspects of antiphospholipid syndrome
	Introduction
	Epidemiology
	Risk factors for thrombosis in those with antiphospholipid antibodies
	Diagnosis and laboratory testing
	Laboratory testing
	Clinical features
		Thrombotic manifestations
		Obstetric antiphospholipid syndrome
		Neurologic manifestations
		Ocular manifestations
		Cardiovascular manifestations
		Renal manifestations
		Hematologic abnormalities
		Pulmonary involvement
		Gastrointestinal involvement
		Cutaneous manifestations of antiphospholipid syndrome
		Catastrophic antiphospholipid syndrome
	Management strategies in antiphospholipid syndrome
		Treatment of patients with prior thrombosis
		Primary thromboprophylaxis
		Obstetric antiphospholipid syndrome
		Catastrophic antiphospholipid syndrome
	Other therapies in antiphospholipid syndrome
		Hydroxychloroquine
		Statins
		Rituximab
		Eculizumab
	Conclusion
	References
43 Lupus and infections
	Prevalence of infections in SLE
	Infections as a cause of morbidity and mortality in SLE
	Risk factors for infections and serious infections in SLE
	Protean spectrum of infection in SLE
		Viruses
		Mycobacteria
		Bacteria
		Fungi
		Parasites and protozoa
	Intrinsic immune dysfunction increasing infection susceptibility in SLE
	Therapeutic toxicities
		Glucocorticoids
		Other immunosuppressive therapies
		Biologic therapies
		Hydroxychloroquine use and protection from infection
	Select genetic defects and risk of infection
	Can biomarkers be used to differentiate between infection and disease flare?
	Clinical approach to SLE patients with a suspected infection
	Acknowledgments
	Summary
	References
44 Ocular, aural, and oral manifestations of lupus
	Systemic lupus erythematosus and the eye
		Retinal vascular disease
		Subclinical retinal vascular disease
		Choroidal vascular disease
		Optic neuropathy
		Episcleritis and scleritis
		Conjunctival or corneal disease and keratitis
		Uveitis
		Orbital inflammation
		Chloroquine and hydroxychloroquine toxicity
		Antiphospholipid antibody retinopathy
	Lupus and the mouth
		Oral manifestations of lupus
		Pathology
		Treatment
		Malignant transformation
		Conditions associated with lupus
			Sjögren syndrome
			Infectious complications
			Medication toxicity
		Common oral conditions mimicking lupus
			Oral lichen planus
			Recurrent aphthous stomatitis
	Lupus and the nose
		Intranasal manifestations
		Conditions associated with lupus
			Pernio
			Relapsing polychondritis
	Lupus and the larynx
	Lupus and the ear
		Sensorineural hearing loss
		Vertigo
	Acknowledgments
	References
45 Clinical aspects of Sjögrens disease
	Introduction and epidemiology
	History
	Clinical presentation
		Overview
		Glandular manifestations
			Dry eye disease
			Salivary hypofunction
			Glandular enlargement
			Other glandular manifestations
		Extraglandular manifestations
		Skin manifestations
		Ear, nose, and throat manifestations
		Pulmonary manifestations
		Joint and muscle manifestations
		Gastrointestinal manifestations
		Gynecologic and urologic manifestations
			Pregnancy
			Kidney manifestations
			Neurologic manifestations
			Vasculitis
			Cardiovascular manifestations
			Hematologic manifestations
		Lymphoma development
		Paraclinical examinations
			Serologic findings
			Salivary gland ultrasonography (SGUS)
		Clinical forms
			Men with Sjögren’s
			Childhood Sjögren’s
			Sjögren’s in systemic lupus erythematosus
	Classification and diagnosis of Sjögren’s
	Outcome measures
		Prognosis
	Acknowledgment
	References
46 Clinical presentations of lupus in the kidney and urogenital system
	Introduction
	Lupus nephritis epidemiology and risk factors
	Clinical presentation and diagnosis of lupus nephritis
	Differential diagnosis of lupus nephritis
	Histopathologic classification of lupus nephritis
	Lupus nephritis biomarkers
	Lupus nephritis during pregnancy
	References
47 The endocrine system and hormones in lupus
	Introduction
	Role of the hypothalamic-pituitary-adrenal axis in the pathogenesis of SLE
	Role of stress in SLE
	Does prolactin function as an inflammatory cytokine?
	Sex hormones and their role in SLE
	Specific endocrine disorders in SLE
		Thyroid disease in SLE
			Epidemiology
			Hypothyroidism
			Hyperthyroidism
			Auto-immune thyroid disease
			Thyroid cancer
			Thyroid nodules
	Diabetes mellitus and SLE
	Prolactin in SLE
	Parathyroid disease in SLE
		Hypoparathyroidism
	Adrenal disease in SLE
		Addison disease
		Cushing syndrome
	Acknowledgements
	References
48 Clinical application of serologic tests, serum protein abnormalities, and other laboratory tests in systemic lupus erythematosus
	Diagnosis of SLE
	Monitoring disease activity in SLE
	Clinical significance of anti-dsDNA antibodies
		Diagnostic value
		Clinical tests for dsDNA antibodies
		Preemptive treatment of serologically active SLE
		Summary
	Anti-Sm antibodies
		Prevalence
		Anti-Sm association with organ involvement
		Anti-Sm antibodies and disease activity
	Anti–U1 ribonucleoprotein
		Clinical association of anti–U1-ribonucleoprotein antibodies
	Anti–SS-A
		Diagnostic specificity and associations
		Serial measurement of anti–SS-A antibody titer
		Summary
	Anti–SS-B antibodies
	Antihistone antibodies
		Clinical association
		Summary
	Antinucleosome antibodies in SLE
		Summary
	Anti-C1Q antibodies
	Anti–ribosomal P antibodies
		Summary
	Anti-centromere and anti–SCL-70 antibodies
		Summary
		Erythrocyte sedimentation rate
		C-reactive protein and the immune system
			Clinical significance of C-reactive protein in SLE
			C-reactive protein and cardiovascular risk in SLE
	Serum complements
		Complement activation products
		Cell-bound complement activation products
	Plasma proteins
		Globulins
		Albumin
	Serum immunoglobulins
		Immunoglobulin G
		Immunoglobulin M
		Immunoglobulin A
		Immunoglobulin E
		Common variable immunodeficiency
		Drug-related hypogammaglobulinemia
	Other serologic abnormalities in SLE
		Rheumatoid factor
		Anti–cyclic citrullinated protein antibodies
		Summary
		Cryoglobulins
		Anti–endothelial cell antibodies
		Antineutrophil cytoplasmic antibodies
			Anti-N-methyl-d-aspartate receptors
	Clustering of autoantibodies
	References
49 Differential diagnosis and disease associations
	When to suspect SLE
	Laboratory evaluation of suspected systemic lupus erythematosus
		Routine studies
		Serologic testing
	Classification criteria
	Diagnostic challenges
		Incomplete or preclinical lupus erythematosus
		Rhupus
		Undifferentiated connective tissue disease
			Mixed connective tissue disease
		Attribution to disease activity
		Differential diagnosis
			Other autoimmune diseases
				Sjögren syndrome.
				Dermatomyositis.
				Rheumatoid arthritis.
				Systemic sclerosis.
				Sarcoidosis.
				Multiple sclerosis.
			Infections
				Chronic infections.
				Acute infections.
			Malignancy
			Noninflammatory conditions
				Myalgic encephalomyelitis/chronic fatigue syndrome.
				Fibromyalgia.
	Conclusion
	References
50 Incomplete lupus, undifferentiated connective tissue disease, and mixed connective tissue disease
	Introduction and historical background
	Undifferentiated connective tissue disease and incomplete lupus syndromes
	Clinical findings in incomplete lupus erythematosus and undifferentiated connective tissue disease
	Autoantibodies and immunologic findings
	Treatment strategies
	Mixed connective tissue disease
		Historical perspective and definition
		Clinical features
			Mucocutaneous
			Joints
			Muscles
			Pulmonary system
			Gastrointestinal system
			Cardiac system
			Nervous system
			Renal disease
			Hematologic disorders
		Children
		Pregnancy
		Serologic and immunologic studies
		Pathogenesis
			Genetic factors
			Environmental factors
			B cells in pathogenesis
			T cells in pathogenesis
			Innate immunity in pathogenesis
		Course and prognosis
		Treatment
	References
51 Clinical markers, metrics, indices, and clinical trials
	Introduction
	Principles and approaches for assessing patients with lupus
	Disease activity indices
		Global indices
			SLE disease activity index and its versions
				SLEDAI-2000 (2K).
				SLEDAI-2K: 30-day version.
				Safety of estrogens in lupus erythematosus national assessment.
					Systemic lupus erythematosus disease activity index (SELENA-SLEDAI).
				Mexican version of SLEDAI (Mex-SLEDAI).
				Adjusted mean SLEDAI-2K (AMS).
				Practical considerations of SLEDAI and its modifications.
			Systemic lupus activity measure
			European consensus lupus activity measurement
			Lupus activity index
			SLE activity index score (SIS)
		SLE-disease activity score (SLE-DAS)
		Organ-specific indices
			British isles lupus assessment group index
			Renal outcome measures
			Cutaneous lupus erythematosus disease area and severity index (CLASI)
		Disease activity assessment in special circumstances
			Disease activity in childhood
			Disease activity in pregnancy
		Clinically meaningful states of disease activity
			Improvement/response
			Flare
			Remission and low disease activity
		Outcome measures in clinical trials in SLE
			Improvement and response
				SLE responder index.
				British isles lupus assessment group based combined lupus assessment (BICLA).
	Damage assessment
	Health-related quality of life
		Generic questionnaires
		Disease-specific questionnaires
	References
52 Principles of therapy, local measures, and NSAIDs
	Formulation overview
	Patient education
	General therapeutic considerations
		Rest, sleep, and the treatment of fatigue
		Exercise, physical therapy, and rehabilitation
		Tobacco smoke and alcohol
		Weather and seasons
		Pain management
			Diet
		Role of stress and trauma
			Can stress induce lupus?
			Can stress exacerbate preexisting SLE?
			Can physical trauma cause or exacerbate SLE?
	Compliance and adherence
	Nonsteroidal antiinflammatory drugs for the treatment of SLE
	Mechanisms of action
		Clinical efficacy in SLE
		Cyclooxygenase-2 inhibition
		Adverse reactions of nonsteroidal antiinflammatory drugs in SLE
			Renal system
			Gastrointestinal system
			Nervous system
			Cutaneous reactions
			Respiratory tract and infections
			Cardiovascular system
			Hematologic complications
			Bone healing
			Pregnancy
			Drug interactions and monitoring
	References
53 Antimalarial medications
	Antimalarials
	Pharmacokinetics
	Mechanism of action
		Molecular effects
			Inhibition of lysosomal activity and autophagy
			Inhibition of signaling pathways
	Efficacy of antimalarials
		Effects of AMs in pregnancy (Table 53.1)
		Effect on cardiovascular events (Table 53.2)
		Effect on diabetes mellitus
		Protective effects on infections
		Effects on damage accrual and survival
		Effects on cancer
	Adverse effects of antimalarials
		Gastrointestinal
		Cutaneous and pigmentary adverse events
		Ocular
			Screening for ocular toxicity
		Neurologic, muscular, and cardiac
		Dosage
	Summary
	References
54 Systemic glucocorticoid therapy for SLE
	Therapeutic use of glucocorticoids in sle
		Tapering of glucocorticoids
		Optimizing nonglucocorticoid therapies in lupus
	Molecular mechanisms of glucocorticoid action
		Nongenomic effects of glucocorticoids
		Genomic effects of glucocorticoids
		Antiinflammatory and immunosuppressive effects of glucocorticoids
		Mechanisms of glucocorticoid insensitivity
	Adverse effects of glucocorticoids
		Bone toxicity of glucocorticoids
		Glucocorticoid-induced diabetes
		Cardiovascular risk
		Infections
		Neuropsychiatric adverse effects
		Is there a safe dose of glucocorticoids in SLE?
	Conclusions and the future of glucocorticoid therapy in SLE
	References
55 Immunosuppressive drug therapy
	Historical perspective
		Alkylating agents
		Chlorambucil
		Cyclophosphamide
			Adverse effects of cyclophosphamide
				Hemorrhagic cystitis and carcinomas of the bladder
				Other malignancies
				Hematologic toxicity
				Gastrointestinal toxicity
				Pulmonary toxicity
				Gonadal toxicity and teratogenicity
				Infections
			Induction therapy with cyclophosphamide in lupus nephritis
				Oral cyclophosphamide
			Intravenous cyclophosphamide in nonrenal lupus
			Neuropsychiatric lupus
			Cyclophosphamide use in children
			Aggressive cyclophosphamide-containing regimens
		Azathioprine
		Mycophenolate mofetil
			Nonrenal lupus
		Calcineurin inhibitors
			Calcineurin inhibitor induction therapy of nephritis
				Cyclosporin A
				Tacrolimus
				Combined tacrolimus and mycophenolate mofetil therapy
				Voclosporin, a calcineurin inhibitor for lupus nephritis
			Calcineurin inhibitors in nonrenal lupus
			Methotrexate
			Leflunomide
		Conclusion
	References
56 Complementary and integrative health approaches
	Introduction
	Prevalence of use
	Nutritional approaches
		Diet
		Dietary supplements
			Vitamin D
			Omega 3 fatty acids
		Herbs
	Psychological approaches
		Mindfulness
		Meditation
	Physical approaches
		Massage
	Combination approaches
		Yoga
		Acupuncture
	Conclusions
	References
57 Specialized and niche therapies
	Treatment of patients with SLE and end-stage renal disease
		Incidence and prevalence
		Uremia and its reversibility
		Prognosis of end-stage renal disease
		Hemodialysis versus peritoneal dialysis
	Transplantation
		Prevalence
		Graft and patient survival
		Serologic features and disease recurrence
		Pregnancy
	Laser therapy
	Apheresis and related technologies
		Plasmapheresis and plasma exchange
			Basic science and clinical rationale
			Clinical studies in SLE
				Lupus nephritis.
				Antiphospholipid syndrome and congenital heart block.
				Other potential indications.
				Pulse synchronization therapy.
				Membrane technologies.
	Summary
		Lymphocyte depletion: Thoracic duct drainage, lymphocytapheresis, and total lymphoid irradiation
		Photopheresis
	Ultraviolet-1 radiation
	Should radiation therapy be avoided?
	Niche therapies for lupus subsets
		Antileprosy drugs
			Dapsone
			Thalidomide and lenalidomide
		Novel immunosuppressive agents
			Mizoribine
			Antilymphocyte globulin
		β-carotene and retinoids
		Intravenous, subcutaneous, and intramuscular immune globulin
	References
58 Adjunctive and preventive measures
	Infection prevention in lupus
		Immunizations in SLE
		Are there vaccinations that should be avoided with SLE?
		SARS-CoV-2 vaccination in SLE
		Should patients with SLE receive the herpes zoster (shingles) vaccine?
		Should patients with SLE receive the human papillomavirus vaccine?
		What is the risk of vaccination triggering an SLE flare or being ineffective?
	Antibiotic prophylaxis in lupus
		Are there antibiotics that patients with SLE should avoid?
	Drug allergies in patients with lupus
		Should patients with SLE and allergies consider immunotherapy?
	Vitamin D supplementation in lupus
		Should all patients with SLE be screened for vitamin D deficiency?
		What are the consequences of vitamin D deficiency for patients with SLE?
		What are the current vitamin D intake recommendation for patients with SLE?
		Management and prevention of osteoporosis
	Adherence issues in lupus
		What strategies have been shown to improve adherence?
	References
59 Management of cutaneous lupus erythematosus
	Introduction
	Photoprotection
	Topical medications
	Intralesional therapy
	Antimalarials
	Oral/intravenous corticosteroids
	Mycophenolate mofetil
	Methotrexate
	Azathioprine
	Cyclophosphamide
	Oral retinoids
	Dapsone
	Thalidomide
	Lenalidomide
	Intravenous immunoglobulin
	Biologic therapies
		Belimumab
		Rituximab
		Anifrolumab
		Anti-plasmacytoid dendritic cell therapies
	References
60 Targeted therapies in SLE
	Introduction
	B cell directed therapies
		Belimumab
			Perspectives on clinical use
		Rituximab
			Perspectives on clinical use
		Obinutuzumab
	T cell directed therapeutic approaches
		Abatacept
			Perspectives on clinical use
	Cytokine inhibition
		Anifrolumab
			Perspectives on clinical use
		Interleukin-6
		Tumor necrosis factor-α
		JAK inhibitors
			Perspectives on clinical use
	Summary
	References
61 Management of lupus nephritis
	Introduction
	Clinical manifestations of lupus nephritis
	Laboratory assessment of lupus nephritis
		Proteinuria
		Urine sediment
		Assessment of kidney function
		Biomarkers of lupus nephritis
	Kidney biopsy in the management of lupus nephritis
	Histopathologic classification of lupus nephritis
	Management of lupus nephritis
		Class 1 and 2 lupus nephritis
		Class 3 and 4 (“proliferative”) lupus nephritis
			Glucocorticoids
			Cyclophosphamide
			Mycophenolate mofetil
			Combination of calcineurin inhibitors and mycophenolate mofetil
			B-cell–directed therapies
			Other drugs for initial therapy
		Class 5 (membranous) lupus nephritis
		Class 6 lupus nephritis
	Renoprotective nonimmunosuppressive interventions
	Antimalarial drugs in lupus nephritis
	Expected results of the initial therapy
	Maintenance therapy
	Nonimmune complex-mediated kidney injury in SLE
	Resistant disease
	Long-term monitoring of lupus nephritis patients
	Pregnancy in lupus nephritis
	Progression to end-stage kidney disease
	References
62 Management of Sjögren disease syndrome
	Introduction
		Sjögren disease
	Nonmedical therapy of dryness
	Treatment of symptoms of mild-to-moderate dry eye
	Treatment of moderate-to-severe dry eye
		Blepharitis
		Topical immunomodulatory agents
		Topical steroids
		Topical lifitegrast
	Overview of treatment of dry mouth
		Saliva substitutes
		Indications for the use of sialagogues: Drugs that promote salivation
			Dose
			Choice of medication
			Pilocarpine efficacy
			Cevimeline efficacy
			Adverse effects and precautions
			Lack of benefit from sialagogues
	Treatment of systemic and extraglandular manifestations of Sjögren disease
		Cutaneous
		Arthralgia
		Cardiopulmonary manifestations
		Renal disease
		Gastrointestinal disorders
		Endocrine disorders
		Neurologic manifestations
			Peripheral neuropathies
			Autonomic neuropathy59-62
			Central nervous system manifestations64-66
		Treatment with biologic agents
			Rituximab, epratuzumab, and abatacept
			Fatigue67-71
			Endocrine factors
	Emerging therapies for the management of Sjögren disease
	Summary
	References
	Suggested reading
63 Socioeconomics, disparities, and disability
	Introduction
	Physical health and quality of life
		Measuring functional status in systemic lupus erythematosus
	Mental health and well-being
	Effect of illness on school and social support systems
	Employment and long-term disability
	Economic costs of systemic lupus erythematosus
		Direct costs
		Indirect costs
	Effects of adverse social determinants of health
	Interventions
	Conclusion
	Key take-away points
	References
64 Prognosis and mortality of systemic lupus erythematosus
	Survival rates in SLE
		Ethnic and racial variation in mortality
	Causes of death in SLE
		Prognosis and predictors of overall mortality in SLE
			Cardiovascular disease
			Renal disease
			Demographics: Sex, age, and socioeconomic status
			Disease severity, activity, and organ involvement
			Role of SLE medications
	Mortality in pediatric-onset SLE
		Evidence of improved survival in pediatric-onset SLE
		Long-term survival in pediatric-onset SLE
		Causes of death and risk factors for death in pediatric-onset SLE
	Strategies for improved mortality outcomes in SLE
	Acknowledgments
	References
65 Future directions
	Introduction
	Innate immune system targets
		Type I interferons
		Complement
	Adaptive immune system targets
		B cells
		T cells
		Plasma cells
		Cytokines
	Signaling pathways
	Cellular therapies
	Combination therapies
	Repurposed drugs
	Miscellaneous strategies
	Summary
	References
66 Expanding the opportunities to effectively treat patients
	Classification criteria and treatment guidance documents
	The relevance of lupus subsets
	Identifying relevant biomarkers and clinical determinants for precision medicine
	Preventing lupus
	Role of lupus advocacy groups
	Summary
	References
Index
	A
	B
	C
	D
	E
	F
	G
	H
	I
	J
	K
	L
	M
	N
	O
	P
	Q
	R
	S
	T
	U
	V
	W
	X
	Y
Inside back cover