Systemic Lupus Erythematosus: Basic, Applied and Clinical Aspects

Chapter 1 - History of systemic lupus erythematosus with an emphasis on certain recent major issues
	History of clinical observations
		The age of dermatology
		Transition of lupus erythematosus to systemic lupus erythematosus
	History of laboratory investigations
		Development of clinical tests
	History of genetics of SLE
	History of therapy in SLE with an emphasis on the use of steroids
	History of classification criteria for SLE
	References
Chapter 2 - The patient
	Improve the interactions with your patients
		Do not make your patient wait
		Smile as you enter the patient’s room
		Make a visible show of hand washing
		Shake hands
		Acknowledge and greet others in the room
		Ask open-ended questions
		Provide a mechanism for your patient to set the agenda
		Speak in nonmedical terms
		Be honest
		Learn to be empathetic
		Always examine your patient
		End the visit with, “Do you have any other concerns or questions?”
		Consulting in the hospital
	Improving adherence
	Disability
	Patient education
	The lupus secrets
	References
Chapter 3 - A plea of a young patient to the lupus experts
	Reference
Chapter 4 - Epidemiology
	Introduction
	Incidence and prevalence
		Distribution according to gender
		Distribution according to age
		Distribution according to ethnic/racial group
		Distribution around the world
	Factors that affect the course of SLE
		Impact of race/ethnicity
		Impact of gender
		Mortality and survival in SLE
	References
Chapter 5 - Measuring disease activity
	References
Chapter 6 - Disease development and outcome
	Historical perspective
	Clinical manifestations
	Assessment of disease activity
	Disease damage
	Patient reported outcomes
	Mortality
	Causes of death
	Treatment guidelines and quality indicators
	Conclusions
	References
Chapter 7 - Socioeconomic aspects of SLE
	Introduction
	Sociodemographic determinants of health in SLE
		Gender as a construct in risk and morbidity
		Race/ethnicity as a multidimensional determinant of outcomes
		Age and aging
		Income, poverty, and educational attainment
	Healthcare access and utilization
		Health literacy
		Health insurance
	The economic burden of SLE
		Work and disability
		Individual and societal costs
	Conclusion
	References
Chapter 8 - Biomarkers in systemic lupus erythematosus
	Introduction
		Biomarker definition and validation
	Biomarkers for diagnosis of SLE
		Cell-bound complement activation products
		Interferon-α and interferon-α-inducible genes
		T-cell gene expression assays
		DNA methylation
		Plasma thermograms
	Biomarkers for measuring SLE disease activity
		Cell-bound complement activation proteins
		Interferon-α and interferon-α-inducible genes
		B-lymphocyte stimulating factor/B-cell activating factor
		MicroRNAs
		Tumor necrosis factor α
		CD27high plasma cells
		CD44+ T cells
	Biomarkers to detect specific organ involvement
		Lupus nephritis biomarkers
			Antibodies to complement C1q
			Monocyte chemoattractant protein-1
			Neutrophil gelatinase-associated lipocalin
			Urinary TWEAK
			MicroRNAs
			Hepcidin
			Urinary biomarker panels
		Central nervous system biomarkers
			Anti-NMDA receptor antibody
			Antiribosomal P antibody
			Antiphospholipid antibodies
			Platelet-bound C4d
			Other
		Cardiovascular system biomarkers
		Respiratory system biomarkers
		Lupus arthritis biomarkers
		Genetic susceptibility and theranostics
	Conclusions
	References
Chapter 9 - Overview of the pathogenesis of systemic lupus erythematosus
	Genetics
	Epigenetics
	Gender
	Environment
	Immune dysregulation
	Tissue damage
	Conclusions
	References
Chapter 10 - System lupus erythematosus and the environment
	Introduction
	Infectious agents, dysbiosis the microbiome, and SLE
	Cigarette smoking, alcohol and SLE
	Cosmetics, chemicals, and risk of SLE
	Ultraviolet radiation, vitamin D, and SLE
	Drugs, vaccines, and SLE
	Geography, socioeconomics, and SLE
	Conclusion
	References
Chapter 11 - Genes and genetics in human SLE
	Introduction
	Transcription factors
	Clearance of apoptotic cells and immune complexes
	Autophagy
	Type I IFN pathway
	NFkB pathway
	Neutrophils and NETosis
	T cell signaling
	B cell signaling
	Genes and phenotypes
	SLE risk genes as therapeutic targets
	Drug repositioning and predicting clinical outcomes
	Conclusions
	References
Chapter 12 - Monogenic lupus
	Introduction
	Complement deficiency
	Deficiencies in DNA damage repair and clearance
		DNase1L3
		DNase II
		DNase III/TREX1
	Abnormalities of DNA sensing
		Stimulator of interferon genes (STING)
		IFIH1
	Other interferonopathies
	Apoptosis
		Fas/FasL
	Cell signaling
		PKCδ
		Ras
		STAT1
	Implications for SLE as a whole
	Conclusion
	References
Chapter 13 - Hormones
	Sex hormones
	Estrogen-estrogen receptor signaling
		Estrogen and the immune response
	Innate immune response
	Adaptive immune response
		B cells
		T cells
	Estrogen and SLE
	Other hormones
	Hormone therapy
	Conclusions
	References
Chapter 14 - Clinical aspects of the complement system in systemic lupus erythematosus
	Introduction
		General comments
		Historical notes
	Complement testing and its interpretation
		Serum levels and hemolytic activities for C4 and C3
		Interpretation of C4 and C3 complement tests in SLE
			Consumption versus biosynthesis
			Chronically low C4 and C3: How to interpret?
			When C4 and C3 are discrepant
				Cryoglobulins
				Cold activation
				Copy-number variation (CNV)
				Alternative pathway activation
		New developments
		Assessing a therapeutic response
			Interpretation
			Renal biopsy
	New connections for lupus and complement
		Local synthesis
		Activation by local proteases
		Intracellular complement activation
		Exogenous coating with opsonic fragments leads to endogenous consequences
	Conclusions
		Lupus develops among complement deficient subjects
		To treat or not to treat SLE with a complement inhibitor
			Cons
			Pros
		Future considerations
	References
Chapter 15 - T cells
	Mechanisms through which T Cells promote SLE
		B cell help
		Proinflammatory activities
		Defective regulation
		Signaling and gene expression in SLE T cells
		Apoptosis defects
	References
Chapter 16 - B cells in SLE
	Introduction
	B lineage cell abnormalities in SLE indicating disturbances of B cell differentiation
	Functional abnormalities of SLE B lineage cells
	B cell signaling in “post-activated B cells” in SLE
	Conclusions
	References
Chapter 17 - Neutrophils in systemic lupus erythematosus
	Introduction
	Neutrophil dysfunction in SLE
	NETosis in the pathogenesis of SLE
	Low-density granulocytes (LDGs) in SLE
	DNA methylation changes in SLE neutrophils and LDGs
	Conclusion
	References
Chapter 18 - The role of dendritic cells in systemic lupus erythematosus
	Dendritic cell origins, subsets, and functions
		Origins
		Subsets/functions
			Conventional/myeloid DCs
			Plasmacytoid DCs
			Monocyte-derived DCs (Mo-DCs)
		DCs and tolerance
			DCs in central tolerance
			DCs in peripheral tolerance
	DCs and SLE
		Myeloid DCs
			Number/activation status
			Implication for T-cell activation
			Implication for B-cells activation
		pDCs
			Number/activation status
			Implication for T-cell activation
			Implication for B-cells activation
	Amplifying mechanisms promoting IFN-α secretion in SLE and activation of DCs
		NK cell help
		Platelet help
		Neutrophil help
	Overall picture of DC implication in SLE pathogenesis
	References
Chapter 19 - Cytokines
	Cytokines in SLE
		IL-2
		IL-17
		IL-6
		TNF
		IFN-α
		BAFF and APRIL
	Conclusions
	References
Chapter 20 - RNA/DNA sensing in SLE—Toll-like receptors and beyond
	Introduction
	Toll-like receptor family (TLRs)
	Toll-like receptor 7 (TLR7)
		TLR7 expression in SLE
		TLR7 in murine lupus
		TLR7 polymorphisms in SLE
	Toll-like receptor 8 (TLR8)
		TLR8 in murine lupus
		TLR8 polymorphisms in SLE
	Toll-like receptor 9 (TLR9)
		TLR9 expression in SLE
		TLR9 in murine lupus
		TLR9 polymorphisms and copy number in SLE
	Cytosolic RNA and DNA sensors
		Activation of cytosolic RNA/DNA sensors
		cGAS and RLRs in SLE
	Conclusions
	References
Chapter 21 - The role of interferons in systemic lupus erythematosus
	Introduction
	The interferon families
	Regulation of interferon production
	Interferons and the immune system
	Interferons in systemic lupus erythematosus
		Impact of interferons in pathogenesis and disease heterogeneity
		Genetic factors
		Measuring IFNs in blood
		Targeting the interferon system in lupus
	Conclusion
	References
Chapter 22 - Fcγ receptors in autoimmunity and end-organ damage
	Introduction
	FcγRs structure
	IgG and FcγR interactions
	FcγRs and complement
	Activating and inhibitory FcγR signaling
	Regulation of FcγR affinity for ligand
	Roles of FcγR in SLE
		Maintenance of peripheral tolerance
		Immune complex clearance
	FcγR-mediated leukocyte recruitment
	Activation of immune cell effector functions
	Roles of FcγRs in lupus nephritis pathogenesis
	FcγR polymorphisms and copy number variation in lupus
	Future directions
	References
Chapter 23 - Apoptosis, autophagy, and necrosis
	Definition
	Apoptosis
		Pathways: intrinsic versus extrinsic
		Apoptosis and SLE
		NETosis, a special case of cell death
	Autophagy
		Autophagy and SLE
	Necrosis
	References
Chapter 24 - Infections in early systemic lupus erythematosus pathogenesis
	Introduction
	Pathogens associated with lupus autoimmunity and clinical disease
	Epstein–Barr virus as a model infection in the etiology of SLE
		Molecular mimicry and epitope spreading
		Functional mimicry
		Disruption of gene regulatory networks
	Pathogen exposures that may protect against lupus autoimmunity
	Conclusion
	Acknowledgements
	References
Chapter 25 - Microbiota influences on systemic lupus erythematosus and Sjögren’s syndrome
	Introduction
		Microbiota effects on the host immune system
		Host effects on the microbiota
	Microbiota in mouse models of SLE and pSS
		Evidence for a role of the microbiota in SLE models
		Antibiotic studies in TLR-sensitive models—focus on TLR4 and TLR7
		Evidence for a role of the microbiota in models for Sjögren’s syndrome
	Human host-microbiome studies in SLE and pSS
		Mechanistic host-microbiota studies in SLE
			Translocation of pathobionts
			Microbial ortholog cross-reactivity in SLE
		Associative microbiome studies in Sjögren’s syndrome
	Conclusions/Outlook
	References
Chapter 26 - Origin of autoantibodies
	B cell tolerance in SLE
	Altered BCR signaling in lupus
	Properties of lupus autoantibodies
	GC versus extrafollicular origin of autoantibodies
		Role of GC
		Role of extrafollicular responses
		GC versus extrafollicular origin of human autoantibodies
	Role of TLR signaling
		TLRs in serological memory
		Importance of the antigens
	Intracellular accumulation nucleic acids promotes autoantibody production
	How does IFN-I promote autoantibody production?
	Association of autoantibodies with abnormal clearance of apoptotic cells
		Phosphatidylserine (PtdSer) receptors
		Role of complement proteins
	References
Chapter 27 - Anti-DNA antibodies
	Introduction
	Cellular source of anti-DNA antibodies
	Contribution of antigen selection
	Triggers: chromatin and environmental exposures
	Mechanisms of injury in the kidney and brain
	Immune complexes and myeloid cell activation
	Summary
	References
Chapter 28 - Antihistone and antispliceosome antibodies
	Histones are key protein components of chromatin
	Anti-histone antibodies
	Assays for anti-histone antibodies
	Solid phase assays for anti-histone antibodies
	Problems and discrepancies in measuring anti-histone antibodies
	Prevalence and disease association of anti-histone and anti-nucleosome antibodies
	Anti-histone in SLE
	Anti-histone in drug-induced lupus
	Anti-snRNP antibodies
	Cellular localization and function of snRNP
		Components of snRNPs
	Reactivity of anti-snRNPs autoantibodies
	History of detection of autoantibodies to snRNPs and potential problems
	Detection of antibodies to snRNPs in clinical practice
	Clinical significance of antibodies to snRNPs
		Distribution and coexistence of anti-U1RNP and anti-Sm antibodies
		Clinical association of anti-Sm and -U1RNP antibodies
	Other anti-snRNPs antibodies
	Mechanism of production
	References
Chapter 29 - Immune complexes in systemic lupus erythematosus
	Introduction
	Basic immunochemistry of ICs
	Generation of autoantibodies and ICs in SLE
	IFN-α production from pDCs induced by ICs through TLRs
	Vicious cycle between NETs and ICs
	FcγRs and clearance of ICs
	Role of FcγRs and ICs in each hematopoietic cell in SLE
	Complement activation by ICs
	Clearance of ICs by complement
	Depositions of ICs in lupus nephritis
	Detection of ICs in the tissue and serum
	Treatment for SLE based on ICs
	Summary
	References
Chapter 30 - MicroRNA in systemic lupus erythematosus
	Introduction
	The biology of miRNAs
	Role of miRNAs in SLE
		Genetic risk factors associated with miRNAs in SLE
		MiRNAs in innate immunity of SLE
		MiRNAs in adaptive immunity of SLE
	MiRNAs in target tissues of SLE
		MiRNAs as biomarkers for SLE
		MiRNAs as therapeutic targets for SLE
	Conclusion
	References
Chapter 31 - Metabolic control of lupus pathogenesis: central role for activation of the mechanistic target of rapamycin
	Introduction
	Accumulation of dysfunctional mitochondria is the source of oxidative stress in T cells
	Extramitochondrial generation of oxidative stress
	Oxidative stress emanates from the liver in SLE
	Oxidative stress due to diminished reducing power
	Biomarkers of oxidative stress reflect disease activity in SLE
	Oxidative stress is a target for treatment in SLE
	NAC-responsive accumulation of kynurenine is a trigger of mTOR pathway activation in SLE
	Acknowledgments
	References
Chapter 32 - Epigenetics
	Introduction
	DNA methylation in T Cells from SLE patients
		Receptors and coreceptors
		Cytokine and cytolysine genes
	DNA hydroxymethylation
	Histone modifications
		Receptors and coreceptors
		Cytokine genes
	MicroRNAs in SLE
	Molecular mechanisms of pathological epigenetic pemodeling in SLE
		Transcription factors mediate epigenetic changes in SLE T cells
		The extracellular signal-regulated kinase pathway and reduced DNA methylation in SLE T cells
		GADD45α, AID, and MBD4 mediate reduced DNA methylation in SLE
		DNA hydroxymethylation in SLE T cells
	Epigenetic modification as promising targets for future treatment
		Epigenetics as targets of already existing treatments
		Epigenetic alterations as targets for potential future strategies in SLE therapy
	Conclusions
	References
Chapter 33 - What do mouse models teach us about human SLE?
	Commonly used murine lupus models
	Conditional knockout system of lupus models helps delineate the cell-intrinsic mechanisms of autoimmunity and lupus development
	Murine lupus strains constitute excellent models for defining the genetic architecture of SLE
	Mouse models help validate GWAS-identified lupus risk alleles
	The contribution of antiDNA autoantibodies
	The pathogenic role of leukocytes in lupus
		B cells: more than just a source of autoantibodies
		T cells: manifold contributions to lupus
		Macrophage: the complex roles of macrophage subtypes in SLE
		DCs: tipping the balance from immune tolerance towards autoimmunity
	Multiple cytokines and chemokines also contribute to lupus pathogenesis
	Lessons from therapeutic studies in murine lupus models
	Concluding thoughts
	References
Chapter 34 - Genes and genetics of murine systemic lupus erythematosus
	Introduction
	Mouse models of lupus used in genetic studies
	Predisposing loci and genes in natural-occurring lupus models
	Lupus predisposing variants that promote lupus in nonautoimmune mice
	Genes affecting susceptibility to end-organ pathology
	Susceptibility genes affect several key stages in lupus pathogenesis
	Comparison with human SLE genes
	Conclusion
	Acknowledgment
	References
Chapter 35 - Mechanisms of renal damage in systemic lupus erythematosus
	Introduction
		Autoimmunity and end-organ damage
		Lessons learned from the mouse model NZM2328
		Silent LN
		Human genetics on lupus susceptibility genes
		Origin of SLE-related auto-Abs
		A useful model for the pathogenesis of SLE with protean initial clinical presentations and relapses
		dsDNA is not the only auto-Ag in LN
		Anti-dsDNA Abs may not be the Abs that initiate LN
		Multiple cells and cytokines are involved in the pathogenesis of LN
	Kidney disease in lupus is not always “lupus nephritis”
	Regeneration and fibrosis are keys to recovery from LN.
	Concluding remarks
	Acknowledgements
	References
Chapter 36 - Mechanisms of vascular damage in systemic lupus erythematosus
	Epidemiology of vascular damage in systemic lupus erythematosus
	Risk of vascular damage: traditional versus nontraditional factors
	Role of cytokines in vascular damage in SLE
		Type I interferons
		Role of other cytokines
	Autoantibodies and immune complexes
	Cellular mediators
		Adaptive immune responses
			Innate immune responses
		Oxidized lipoproteins
		Modulation of CV risk in SLE
	References
Chapter 37 - The mechanism of skin damage
	Introduction
	Clinical aspects
	Pathogenesis of skin damage
		Ultraviolet radiation and skin damage
			Photosensitivity and photoprovocation
			UV-triggered apoptotic cells
		Immune cells, cytokines, and chemokines
			Dendritic cells and T-cell subtypes
			Type 1 interferon and tumor necrosis factor
			Other cytokines and chemokines
		The genetic and epigenetic mechanisms for skin damage in CLE
	References
Chapter 38 - Pathogenesis of tissue injury in the brain in patients with systemic lupus erythematosus
	The challenge of neurolupus
	Models of neurolupus
	Genetics of brain disease
	The pathological substrates of lupus brain disease
	Mechanisms of accelerated cerebrovascular disease
	Antibody-mediated brain disease in lupus: antineuronal antibodies
	Antibody-mediated brain disease in lupus: anti glial antibodies
	Cytokine pathways: Type I interferon
	Other cytokines pathways
	Inflammatory cells
		Future Challenges
	References
Chapter 39 - Constitutional symptoms and fatigue in systemic lupus erythematosus
	Introduction
	Fatigue
		Management of fatigue in SLE
	Fever
	Lymphadenopathy
	Splenomegaly
	Weight loss
	Conclusion
	References
Chapter 40 - The musculoskeletal system in SLE
	Arthritis
		Nonerosive arthritis
		Erosive arthritis (rhupus)
		Jaccoud’s arthropathy
		Tendons and entheses
		Treatment
	Myalgia/myopathy/myositis
		Fibromyalgia
		Medication-related myopathy
		Myositis
		Histologic features
		Treatment
	Osteonecrosis
		Clinical impact
		Epidemiology
		Pathogenesis
		Risk factors
		Diagnosis
		Treatment
	Osteoporosis
		Epidemiology of osteopenia and osteoporosis
		Risk factors and pathophysiology of bone loss
		Glucocorticoids
		Other factors
		Treatment
	References
Chapter 41 - Cutaneous lupus erythematosus
	Epidemiology
	Classification criteria for SLE
	Photosensitivity
	Cutaneous manifestations
	Scores in cutaneous lupus erythematosus
	Subtypes of cutaneous lupus erythematosus
		Acute cutaneous lupus erythematosus
		Subacute cutaneous lupus erythematosus (SCLE)
		Chronic cutaneous lupus erythematosus (CCLE)
		Discoid lupus erythematosus (DLE)
		Lupus erythematosus profundus/panniculitis (LEP)
		Chilblain lupus erythematosus (CHLE)
		Intermittent cutaneous lupus erythematosus (ICLE)
			Lupus erythematosus tumidus (LET)
	Conclusion
	Acknowledgment
	References
Chapter 42 - The clinical evaluation of kidney disease in systemic lupus erythematosus
	Introduction
	The scope of lupus nephritis
	The diagnosis of lupus nephritis
	Evaluation of kidney function
	Evaluation of the urine
	Evaluation of proteinuria
	The kidney biopsy
	Antiphospholipid syndrome and the kidney
	Pregnancy and lupus nephritis
	Childhood lupus nephritis
	Conclusion
	References
Chapter 43 - The pathology of lupus nephritis
	Introduction
	Introduction to nephropathology
	Introduction to the nephropathology of SLE
	Renal biopsy and SLE
	The lesions of lupus nephritis
		Glomeruli
		Tubulointerstitium
		Vessels
	Classification of lupus nephritis
		Class I (Minimal mesangial LN)
		Class II (mesangial proliferative LN)
		Class III (Focal LN)
		Class IV (Diffuse LN)
		Class V (Membranous LN)
		Class VI (Advanced sclerosing LN)
	Selected topics in classification
		Distinction between classes IV-S and IV-G
		Fibrinoid necrosis and karyorrhexis
		Glomerulosclerosis
		Reproducibility of classification
		Treatment and transformation
		Activity, chronicity, plasticity, and prognosis
	Selected clinco-pathologic topics
		“Silent” LN
		ANCA, crescentic GN and LN
		Lupus podocytopathies
		Other renal diseases and SLE
		Transplantation
	References
Chapter 44 - Cardiovascular disease in systemic lupus erythematosus: an update
	Burden of cardiovascular disease in lupus
	Traditional risk factors for cardiovascular disease in SLE
	SLE-specific risk factors for cardiovascular disease
	Atherogenesis
	Biomarkers for atherosclerosis
	Imaging strategies for early detection of cardiovascular disease
	Treatment of cardiovascular disease in SLE
	Summary
	References
Chapter 45 - The lung in systemic lupus erythematosus
	Introduction
	Role of inflammation in SLE lung
		IFN-driven autoimmune lung inflammation
		Immune complex involvement
		Neutrophils and NETosis
	Clinical presentations of lung involvement in SLE
		Pulmonary infection
		Nonpulmonary involvement as a cause of respiratory symptoms
		Pleural disease
	Parenchymal disease
		Acute lupus pneumonitis
		Pulmonary hemorrhage/diffuse alveolar hemorrhage
		Chronic interstitial lung disease
		Shrinking lung syndrome
	Pulmonary vascular disease
		Pulmonary hypertension
		Pulmonary Thromboembolism
		Acute reversible hypoxia syndrome
		Airway disease
	Overlap syndromes
	COPA syndrome and SAVI: Interferonopathies with lung involvement
		COPA syndrome
		SAVI syndrome
	A case for screening for Lung Disease In SLE
	Summary
	Acknowledgment
	References
Chapter 46 - Gastrointestinal, hepatic, and pancreatic disorders in systemic lupus erythematosus
	Introduction
	The gastrointestinal tract in SLE
		Buccal cavity
		Esophagus
		Stomach
		Small intestine
			Mesenteric/Intestinal vasculitis/lupus enteritis
			Mesenteric insufficiency
			Intestinal pseudo-obstruction
			Malabsorption and celiac disease
			Protein-losing gastroenteropathy
			Infective and eosinophilic enteritis
			Ascites and peritonitis
		Large intestine
			Lupus colitis and inflammatory bowel disease
			Infective and collagenous colitis
	The liver in SLE
		Subclinical liver disease
		Autoimmune hepatitis
		Viral and drug-induced hepatitis
		Nodular regenerative hyperplasia
		Other liver diseases
	Biliary tract disease in SLE
	The pancreas in SLE
	Acute abdominal pain in SLE
	Intestinal microbiome in SLE
	Conclusions
	References
Chapter 47 - Systemic lupus erythematosus and infections
	Introduction
	Epidemiology of SLE infections
	Immunologic pathogenesis of infections in systemic lupus erythematosus
	Treatment-associated immunosuppression and infection risk
	Types of infections
		Clinical considerations
	Preventative strategies
	References
Chapter 48 - Malignancies in systemic lupus erythematosus
	Introduction
	Hematologic cancers
	Lung cancers
	Cervical cancer
		Increased risk of other cancers in SLE
	Breast, ovarian, and endometrial cancers
		Prostate cancers
	Conclusions
	References
Chapter 49 - The nervous system in systemic lupus erythematosus
	Introduction
	Classification of neurolupus
	Mechanisms of neurolupus
	Clinical approach
	Investigations
		Routine laboratory tests
		Brain-reactive antibodies
		Conventional neuroimaging
		CSF examination
		Neurophysiology
		Neuropathology
	Central nervous system disease in people with lupus
		Neurovascular disease—large vessel
		Neurovascular disease—small vessel
		CNS vasculitis
		Seizures
		Movement disorder
		Cognitive dysfunction
		PRES
		Psychiatric disease
		Spinal cord disease
		Meningeal disease
		Progressive multifocal leukoencephalopathy
		Functional neurological disorder
	Peripheral nervous system disease in people with lupus
		Peripheral neuropathy
		Optic neuropathy
	Questionable clinical syndromes
		Lupus headache
		Demyelinating syndrome
		Acute confusional state
	Treatment of neurolupus
	Conclusion
	References
Chapter 50 - Overlap syndromes
	Introduction
	Clinical and laboratory manifestations of overlap syndromes
	Immunology of overlap syndromes
	Genetics
	Animal models
	Treatment
	References
Chapter 51 - Systemic lupus erythematosus and the eye
	Introduction
	The role of ophthalmic features in the criteria for classification and disease activity
	Clinical presentation
		Anterior segment
			Keratoconjunctivitis sicca
			Other corneal disease
			Episcleritis
			Scleritis
			Other anterior segment complications
		Orbits and lids
			Lid disease
			Orbital disease
		Posterior segment
			Classic lupus retinopathy
			Severe vaso-occlusive retinopathy (“retinal vasculitis”)
			Arteriole and venule occlusions
			Other retinal manifestations
			Lupus choroidopathy
		Neuro-ophthalmic complications
			Optic nerve disease
			Ocular motility abnormalities
			Retrochiasmal
	Investigations
		General
		Ophthalmic
			Anterior segment
			Posterior segment
	Treatment
		General
		Ophthalmic
			Anterior segment
			Posterior segment
			Neuro-ophthalmic
		Ophthalmic complications of systemic therapy
	Conclusion
	References
Chapter 52 - Fertility and pregnancy in systemic lupus erythematosus
	Systemic lupus erythematosus—A manual
	Fertility and SLE
		Etiology of infertility in subsets of SLE patients
		Preservation of fertility
		Assisted reproductive techniques
	Pregnancy in SLE patients
		Pregnancy impact on SLE disease activity
		Preeclampsia and SLE flare
		SLE impact on pregnancy outcome
		Pregnancy loss
		Preterm birth and intrauterine growth restriction
	Management of SLE during pregnancy
		Medication management
		Biological agents
		Other medications
		Medication summary
	Conclusions
	References
Chapter 53 - Neonatal lupus: Clinical spectrum, biomarkers, pathogenesis, and approach to treatment
	Introduction
	Risk of cardiac NL and population prevalence
	Transient clinical manifestations of NL: cutaneous, hepatic, hematologic, and neurologic
	Immutable manifestations of NL: cardiac
	Factors contributing to mortality
	Seeking biomarkers: the candidate autoantibodies
	Linking antibody to tissue damage and fibrosis: accounting for antigen target accessibility
	Guidelines for monitoring antiSSA/Ro-exposed pregnancies and approach to cardiac NL
	Translating pathogenesis to prevention
	References
Chapter 54 - Incomplete lupus syndromes
	Definition
	Significance
	Epidemiology
	Clinical manifestations
	Transition to SLE
	Treatment
	References
Chapter 55 - Lupus in children
	Epidemiology
	Clinical m‑anifestations
	Familial SLE
	Morbidity and mortality
	Therapeutic considerations in children
		Medication toxicity
		Fertility
		Vaccinations
		Malignancy risk
		Psychosocial issues
	References
Chapter 56 - Drug-induced lupus
	Introduction and historical perspective
	Diagnosis of drug-induced lupus
	Lupus-inducing drugs with specific clinical features
	Distinguishing DIL from idiopathic SLE
	Treatment and management of DIL
	Lupus-inducing drugs
	The expanding breadth of lupus-inducing drugs
	Epidemiology of DIL
	Genetic factors in DIL
		Human leukocyte antigens
		Complement
		Acetylator phenotype
	Drug metabolism in the etiology of DIL
	Pathogenesis of DIL
	Proposed mechanisms underlying DIL
		Drug-altered self-molecules induce autoimmunity
		Cell death caused by reactive drug metabolites initiates autoimmunity
		Drugs cause nonspecific lymphocyte activation
		Drug metabolites disrupt central T cell tolerance
		Mechanism underlying DIL related to immune-modulating biologics
	Conclusions
	References
Chapter 57 - Vasculitis in lupus
	Prevalence and associated features of vasculitis in lupus
	Cutaneous vasculitis
	Lupus mesenteric vasculitis
	Large vessel vasculitis
	Other forms of vasculitis
	References
Chapter 58 - Pathogenesis of antiphospholipid syndrome
	Introduction
	Pathogenic mechanisms of aPL
		aPL and the coagulation system
		aPL and the fibrinolytic system
		Interaction of aPL with cells
	Cell receptors for aPL interaction
	Signaling pathways of aPL-mediated cell activation
	aPL and atherothrombosis
	aPL and oxidative stress
	aPL and complement activation
	Conclusion
	Acknowledgment
	References
Chapter 59 - Antibodies and diagnostic tests in antiphosholipid syndrome
	Antiphospholipid syndrome as an autoantibody–mediated disease
	Classification laboratory assays
		Lupus anticoagulant
		Anticardiolipin antibodies
		Anti-β2 glycoprotein I antibodies
	Nonclassification laboratory assays
		Antiβ2 glycoprotein I domain I antibodies
		Anti-cardiolipin and antiβ2 glycoprotein I antibody IgA
		Antiprothrombin antibodies
		Antibodies against phosphatidylethanolamine
		Antibodies against anionic phospholipids other than cardiolipin
		Annexin A5 resistance assay
	Other autoantibodies in antiphospholipid syndrome
		Antibodies possibly involved in thrombosis
			Antibodies against proteins involved in hemostasis
				Antibodies against protein C and S
				Antibodies against coagulation factors
				Antibodies against tissue type plasminogen activator
				Antibodies against annexin A2
			Antiplatelet antibodies
	3-Anti-endothelial cell antibodies
		Autoantibodies not involved in thrombosis
			Antimitochondrial antibodies
			Antinuclear antibodies
			Antired blood cell antibodies
			Antithyroid antibodies
			Antibodies against plasma lipoproteins
	Complement activation
	References
Chapter 60 - Clinical manifestations
	Introduction
		Vascular thrombosis
		Pregnancy morbidity
		Catastrophic APS
	Features associated with aPL
		Cardiac manifestations
		Hematological manifestations
		Renal manifestations
		Neurological manifestations
		Skin manifestations
		Pulmonary manifestations
	References
Chapter 61 - Nonsteroidal antiinflammatory drugs in systemic lupus erythematosus
	Introduction
	Inhibitory role of NSAIDs
	Effects on the kidneys
	Gastrointestinal side effects
	Increased cardiovascular risk: What is the Verdict?
	Central nervous system (aseptic meningitis) side effects
	Effects on reproduction
	Conclusion
	References
Chapter 62 - Value of antimalarial drugs in the treatment of lupus
	Introduction
	Pharmacokinetics and pharmacodynamics of antimalarials
	Mechanisms of action
		Modification of the lysosome pH
		Blockade of Toll-like receptors
		Nonimmunological effects of antimalarials
	The beneficial effects of antimalarials in SLE
	Practical aspects related to the use of antimalarials
	Screening for glucose-6-phosphate dehydrogenase deficiency
	Nonophthalmologic adverse effects of antimalarial agents
	Ophthalmologic adverse effects of antimalarial agents
	Use of antimalarials in pregnancy and lactation
	References
Chapter 63 - Systemic glucocorticoids
	Introduction
	Nomenclature
	Rationale and mechanism of action of glucocorticoids in SLE
		Mechanism of action of glucocorticoids
		Antiinflammatory and immunosuppressive effects of glucocorticoids
	Forms and mode of administration of systemic corticosteroids
		Forms of synthetic steroids
		Mode of administration of systemic corticosteroids
			Topical, intraarticular and intralesional glucocorticoids
			Oral glucocorticoids
			Intravenous glucocorticoids
			Intramuscular therapy
	Approach for the use of glucocorticoids based on organ system involvement
		Mucocutaneous
		Musculoskeletal
		Cardiopulmonary
		Renal
		Hematologic
		Neuropsychiatric
	Tapering and withdrawal of glucocorticoids
	Side effects of glucocorticoids
	Future direction
	References
Chapter 64 - Cytotoxic drug treatment
	Introduction
	Alkylating agents
		Cyclophosphamide
			Mechanism of action and pharmacokinetics
			Use in renal disease
			Use in extra-renal disease
			Adverse effects
	Nucleotide synthesis inhibitors
		Azathioprine
			Mechanism of action and pharmacokinetics
			Use in renal disease
			Use in extra-renal disease
			Adverse effects
		Mycophenolate mofetil/mycophenolate acid (MMF/MPA)
			Mechanism of action and pharmacokinetics
			Use in renal disease
			Use in extra-renal disease
			Adverse effects
	Calcineurin inhibitors
		Cyclosporine A
			Mechanism of action and pharmacokinetics
			Use in renal disease
			Use in extra-renal disease
			Adverse effects
		Tacrolimus
			Mechanism of action and pharmacokinetics
			Use in renal disease
			Use in extra-renal disease
			Adverse effects
		Voclosporin
			Mechanism of action
			Use in renal disease
	General issues in lupus patients on cytotoxic- immunosuppressive drug treatment
		Infections
		Immunizations
		Malignancy
		Pregnancy
	References
Chapter 65 - Treatment of antiphospholipid syndrome
	Introduction
	Primary thromboprophylaxis
	Prevention of recurrent thrombosis
	Alternative therapies for refractory and difficult cases
	Other therapies
	Pregnancy
	Recurrent early miscarriage
	Fetal death
	Management of pregnancy in patients with APS and previous thrombosis
	Management of refractory obstetric APS
	Postpartum period
	References
Chapter 66 - New treatments of systemic lupus erythematosus
	Cytokines
		B lymphocyte-activating factor (BAFF)
		Interferon-α
		Interferon-γ
		Interleukin-23/Interleukin-17
		Interleukin-2 (IL-2)
	Complement
	Costimulatory pathways
		CD154-CD40
		CD28-CD80/86
		ICOS-B7RP
	Cell surface molecules
		CD20
		CD22
		CD19
	Intracellular molecules
		Bruton’s tyrosine kinase (Btk)
		Cereblon
		Calcineurin
		Mammalian target of rapamycin (mTOR)
		JAK/STAT
		Proteasome
	Conclusion
	References
Chapter 67 - Repositioning drugs for systemic lupus erythematosus
	Why try to repurpose/reposition drugs for SLE patients?
	Strategies for drug repurposing/repositioning in SLE
	Current and future repurposing/repositioning efforts
	Summary
	References