Systemic Lupus Erythematosus (eBook)

Foreword 25
Preface 27
Introduction 29
Section I. Pathogenesis 33
1. Autoimmunity and Autoimmune Diseases like Systemic Lupus Erythematosus 35
The Nature of Autoimmunity 35
What Leads from Autoimmunity to an Autoimmune State? 36
Which Diseases Are Really Autoimmune Ones? 36
Classification of Autoimmune Diseases 39
The Mosaic of Autoimmunity or Why Are Autoimmune Diseases so Diversified? 40
The Kaleidoscope of the Autoimmune Mosaic 41
Why Do Patients Differ from Each Other? 43
Physiologic and Pathologic Autoimmunity 44
Mechanisms of Autoimmunity 44
Breaking Peripheral Tolerance 44
Autoimmunity Induction by the Idiotype–Anti-idiotype Interaction 45
Role of Cytokines in the Induction of Autoimmunity 46
Autoimmunity and MHC: Dissecting the Molecular Basis 48
Apoptosis and Its Role in Autoimmunity 48
Using the Principles of Autoimmunity to Design Therapeutics 49
Modulation of the Idiotypic Network as a Possible Treatment Approach to Autoimmune Diseases 49
Intravenous Gamma Globulin Infusion 49
Oral Tolerance 51
Hemopoietic Stem Cell Transplantation in Autoimmune Diseases 51
Peptide Immunotherapy 52
What Are We Expecting in the Future? 53
2. Overview of Cellular Immune Function in Systemic Lupus Erythematosus 61
Introduction 61
Monocyte/Macrophage Function 62
Dendritic Cells 63
T Lymphocytes 63
Lymphocyte Numbers 63
T Lymphocyte CD4 Epitope Deficiency 64
Functional Features of Anti-T-Cell Antibodies 64
Activated T Lymphocytes 65
T Suppressor Lymphocyte Function 65
T Helper Lymphocyte Function 66
Double Negative T Cells in SLE 66
Heat Shock Proteins in Lupus Immune Cell Biology 67
T-Cell Clones in the Study of the Pathogenesis of Lupus 68
T-Cell Antigen Receptor Gene Repertoire in SLE 69
Lymphokines 70
IL-2 70
IL-2 Inhibitor 70
Soluble IL-2 Receptors 70
IFN-g 71
IL-6 71
IL-10 71
IL-12 72
Tumor Necrosis Factor 72
TGF-b 72
Other Cytokines 72
Polarization of the Lymphokine Production Response 73
Proliferative Responses 73
Antigens and Mitogens 73
Alloantigens 73
Autologous Mixed Lymphocyte Reaction 73
Skin Tests 74
Responses to Anti-CD3 Antibody 74
Biochemical and Molecular Abnormalities of SLE T Cells 74
Capping of Surface Molecules 74
Oncogenes in SLE 74
T-Cell Signaling Abnormalities 75
Abnormalities of Elf-1 Expression 77
Mechanisms of Increased TCR/CD3-Mediated [Ca2_]i Response in SLE 78
FceRIg Chain Replaces the Defective TCR z Chain 78
Increased Membrane Lipid Raft Association of theResidual TCR z Chain 78
Deficient Protein Kinase A Activity 79
Abnormalities in Transcription Factor Expression 79
Deficient p65-Rel A Subunit of NF-kB in SLE T Cells 79
Increased CREM Binding to the –180 Site of the IL-2 Promoter 79
Abnormal Nuclear Translocation of RIIb Subunit 80
Impaired Protein Translation 80
Abnormal Immune Cell Signaling and Autoimmunity 80
Antigen-Presenting Cell Function 80
Costimulation in Lupus 81
B7-CD28 81
CD40-CD40 Ligand 82
Lymphocyte Trafficking 83
Cytotoxic Responses 83
Natural Killer Cells 83
Specific Cytotoxicity 84
Antibody-Dependent Cell-Mediated Cytotoxicity 84
Nonantigen-Specific Cell Cytotoxicity 84
B Lymphocytes 84
B-Cell Repertoire in Lupus 84
B Lymphocyte Subsets 85
Phenotypic Changes 85
Spontaneously Ig-Secreting B Cells 85
Mitogen-Induced Ig Secretion 86
Lymphokines in Lupus B-Cell Function 86
Aberrant B-Cell Antigen Receptor Signal Transduction 87
B-Cell Surface Receptors That Provide Negative Regulation 87
What Causes B-Cell Hyperactivity? 88
Hypogammaglobulinemia in SLE 88
Regulation of Immune Responses by Complement 89
Complement Receptor Expression 89
Complement Receptor Ligands 89
Apoptosis 90
Biochemistry and Molecular Biology 90
Apoptosis in Murine Lupus-Prone Mice 90
Apoptosis in Human Lupus 90
Apoptosis of Keratinocytes 91
Soluble Fas Antigen 91
Canale–Smith Syndrome 91
Structural Defects of Fas and Fas Ligand Molecules in Human Lupus 91
Activation-Induced Cell Death 91
Altered Mitochondrial Hyperpolarization, Reactive Oxygen Intermediates 92
Effect of Treatment on the Function of Lupus Cells 92
General Considerations 92
Cyclophosphamide 93
Plasmapheresis 93
Total Lymphoid Irradiation 93
Drugs in the Pathogenesis of SLE 93
Sex Hormones in Cellular Immune Responses 94
From Pathogenesis to the Development of Novel Treatments 95
Gene Therapy for SLE 96
Pathogenesis: An Overview 97
3. Etiopathogenesis of Systemic Lupus Erythematosus: The Itineraries of Three Troikas 125
The First Troika: Etiology 125
Genetic Factors in SLE 126
Hormonal Factors in SLE 129
Environmental Factors in SLE 130
The Second Troika: Etiopathogenesis 130
T-Cell Dysfunction 130
Polyclonal B-Cell Activation 131
Cytokines 131
The Third Troika: Pathogenesis 132
Immune Complex-Mediated Damage 133
Direct Damaging Effects by Autoantibodies 133
Functional Effects of Autoantibodies 133
Summary 134
4. MHC Class II and Non-MHC Genes in the Pathogenesis of Systemic Lupus Erythematosus 141
Introduction 141
Familial Aggregation in Systemic Lupus Erythematosus 141
Family Studies 142
Studies Of Candidate Genes In Sle 148
Genes of the Major Histocompatibility Complex 148
Non-MHC Genes in Predisposition to SLE (Table 4, Fig. 3) 157
Conclusion 168
5. Genetic Susceptibility and Class III Complement Genes 185
Introduction 185
Fourth Component of Complement (C4) 187
Structure 187
Function 188
C4A and C4B 189
Serum C4 Concentration 190
C2 and Factor B 191
Partial C4 Deficiency and Susceptibility to Systemic Lupus Erythematosus 192
Acquired C4 And/Or C2 Deficiency and Susceptibility to Systemic Lupus Erythematosus 194
Partial C2 Deficiency and Susceptibility to SLE 194
Immune Complex Processing and the Complement System 195
Targeted Gene Knockouts 195
C4 195
Factor B/C2 197
C1q 197
Further Speculation on the Association Between Systemic Lupus Erythematosus and Complement Deficiency 197
Detection of Complement Deficiency 198
6. Complement Deficiency and Systemic Lupus Erythematosus 205
The Complement System 205
Classical Pathway Activation 206
Alternate Pathway Activation 207
Mannan-Binding Lectin Activation Pathway 208
Membrane Attack Complex Activation 208
Regulation and Control of Complement Activation and Cell Lysis 209
Biological Activities of the Complement System 210
Genetics of Complement Components 211
Genetics of Complement Regulatory Molecules 213
Deficiencies of the Complement System and Disease 214
Susceptibility to Infection 214
Autoimmune Manifestations of Complement Deficiencies 216
Atypical Cutaneous Lupus Erythematosus: A Hallmark of Deficiencies of Early Complement Components 216
Hereditary C1q Deficiency 216
Hereditary C1r–C1s Deficiency 217
Hereditary C4 Deficiency 217
Hereditary C2 Deficiency 218
Hereditary C3, C5, C6, C7, and C8 Deficiencies 219
Hereditary C9 Deficiency 219
Hereditary MBL Deficiencies 220
Combined Hereditary Complement Deficiencies 221
Acquired Deficiencies of Complement 221
Deficiencies of Regulatory Molecules 222
Speculation on the Role of Early Complement Component Deficiency in Systemic Lupus Erythematosus 225
7. Gender and Age in Systemic Lupus Erythematosus 235
Late-Onset Systemic Lupus Erythematosus 235
Introduction 235
Clinical Presentation of the Aged Patient with SLE 235
Race 236
Course and Therapy in the Older Patient 236
Comments on the Elderly SLE Patient 236
Gender And SLE 237
Murine Models of Autoimmunity and the Sex Hormones 237
Gonadotropin Effects 239
Sex Steroids and Human SLE 239
Summary 247
Section II. Animal Models 255
8. Genes and Genetics of Murine Systemic Lupus Erythematosus 257
Mouse Models of Lupus 257
Predisposing Genes in Spontaneous Lupus Mouse Models 258
MHC Region 258
Fas and Fas Ligand 259
SHP-1 259
Yaa Gene 259
Loci Predisposing to Spontaneous SLE in Lupus Mouse Models 262
Loci Derived from NZB and NZW Crosses 262
Loci in MRL-Faslpr Crosses 264
Loci in BXSB Crosses 264
Conclusions from Studies on Susceptibility Loci in Spontaneous Lupus Strains 265
Systemic Autoimmunity in Normal Background Gene Knockout/Mutated and Transgenic Mice 265
B-Cell Activation Genes 265
T-Cell Activation Genes 269
Apoptosis Genes 271
Enhanced Antigen Presentation 272
Complement Genes 273
Cytokine Ligand and Receptor Genes 273
Cell Cycle-Related Genes 274
Glycosylation Enzymes 274
Miscellaneous 275
Gene Knockout and Transgenic Lupus Background Mice 275
B-Cell-Related Genes 275
T-Cell-Related Genes 277
Costimulatory Molecules 278
Cytokine Genes 278
Cell-Signaling Molecules 279
Complement Components 280
Local Immune and Inflammatory Response Regulation 280
Miscellaneous Genes 280
Conclusions 281
9. Systemic Lupus Erythematosus in Domestic Animals 297
Introduction 297
Canine Systemic Lupus Erythematosus 297
Introduction 297
Clinical Signs 297
Immunological Findings 302
Epidemiology of Canine SLE: Lessons for Human SLE 306
Diagnosis of SLE in Dogs 307
Treatment 308
Systemic Lupus Erythematosus in Cats 308
Introduction 308
Clinical Signs 308
Diagnosis and Therapy 309
Systemic Lupus Erythematosus in Horses 310
Conclusions 310
Section III. Autoantibodies and Antigens 313
10. Anti-DNA Antibodies: Structure, Assembly and Diversity 315
Detection of Anti-DNA Antibodies 318
Cellular Origin of Anti-DNA Antibodies 318
Structure of Anti-DNA Antibodies 320
Idiotypes of Anti-DNA Antibodies 321
Antigenic Cross-Reactivity of Anti-DNA Antibodies 322
Pathogenic Potential of Anti-DNA Antibodies 323
Hypothesis 1: Circulating Immune 324
Hypothesis 2: Cross-Reactivity with Renal Antigen 324
Hypothesis 3: Planted Antigen 325
Activation of Anti-dsDNA B Cells 325
Immunogenicity of DNA 326
Epitope Spreading 329
T Cells Involved in Anti-DNA Antibody Production 329
Regulation of Anti-dsDNA B Cells 330
Tolerance Induction 330
Anti-DNA Antibody Transgenic Mice 330
Genes That Regulate B-Cell Tolerance 331
Therapy 333
Summary 334
11. Anticytoplasmic Antibodies in SLE: Antibodies to Cytoplasmic Antigens 347
Antibodies to Ro and La: Methods of Detection 347
Clinical Associations 349
ANA-Negative SLE 349
Differences between SLE Patients with Anti-Ro/SSA and Those with Both Anti-Ro/SSA and Anti-La/SSB 349
Subacute Cutaneous Lupus Erythematosus 350
Homozygous C2 = C4 Deficiency 351
Neonatal SLE 351
Serologic Phenomena in SLE Patients with Antibodies to Ro/SSA and La/SSB 351
Molecular Biology Of Ro/SSA And La/SSB Antigens 352
Heterogeneity of Ro/SSA Antigen and Anti-Ro/SSA 352
Antibodies to Ribosomes 353
Antibodies to the Ribosomal P Proteins 353
Significance of the Autoimmune Response to Cytoplasmic Constituents 353
12. Antihistone Antibodies 357
Historical Perspective 357
Histone Structure and Function 358
Primary Structures and Histone Variants 358
Higher Order Structure Comprising the Nucleosome 359
Domain Structure of Histones 360
Assays for Antihistone Antibodies 361
Prevalence and Specificity of Antihistone Antibodies 362
Overall Disease Association 362
Associations with Clinical Disease Activity and Symptoms 364
Isotypes of Histone-Reactive Antibodies 365
Fine Specificities of Autoantibodies to Individual Histones 365
Significance of Antihistone Antibody Fine Specificity 368
Artifactual Antihistone Antibodies 368
Cross-Reactions of Antihistone Antibodies 369
Murine Experimental Models with Antihistone Antibodies 370
Histone-Reactive T Cells 370
Pathogenic Potential of Antihistone Antibodies 371
13. Antibodies to Non-Histone Agents in Systemic Lupus Erythematosus 381
Introduction 381
Nomenclature and Molecular Biology of Nonhistone Autoantigens 383
RNA 383
Proteins 383
Biochemical and Clinical Aspects of Nonhistone Antigen/Antibody Systems 384
Sm 384
LSm4 and LSm Complex 386
U1RNP 386
Heterogeneous RNP 387
U2 RNP, RNase P, and Other nRNP 387
SS-A/Ro 388
SS-B/La 390
Proliferating Cell Nuclear Antigen 391
Ku, Sp1 391
Ki/SL 392
Ribosomal RNP and P Proteins 393
High Mobility Group Proteins 393
Ubiquitin and Proteasome 394
Nuclear Lamins 394
Mitotic Spindle Apparatus 395
Other Antigens 395
Summary: SLE is Characterized by Distinct Autoantibody Profiles 396
14. Immune Complexes 409
Characteristics of Immune Complexes 409
Antigens 409
Antibodies 411
Nature of the Antigen–Antibody Union 411
Biologic Properties of Immune Complexes 413
Complement Activation by Immune Complexes 413
Interaction of Immune Complexes with Cell Receptors: Binding and Functional Consequences 414
Fate of Circulating Immune Complexes 417
Tissue Deposition of Immune Complexes 419
Localization of Immune Complexes in Glomeruli 419
Localization of Immune Complexes in Other Organs 422
Measurement of Immune Complexes and Use of These Tests in Patients With SLE 423
Physical Methods 423
Methods Based on Biologic Properties 424
Tests for Immune Complexes and Clinical Activity of SLE 425
Development of Therapies Based on the Immune Complex Model 426
15. Origins of Antinuclear Antibodies 433
Diagnostic Importance of Antinuclear Antibodies 433
Autoantigens are Usually Macromolecular Complexes 434
Characterization of Autoimmune Responses to Multicomponent Antigens 436
Anti-Sm and nRNP Autoantibodies Recognize the U1 snRNP 437
Immune Response to Macromolecular Complexes 439
Autoantibodies to Components of the U1 snRNP: A Prototype-Linked Set 439
Intermolecular–Intrastructural Help 440
Role of T-Cell Defects in Autoantibody Production 441
T-Cell-Dependent vs -Independent Autoantibody Production 441
Self-tolerance in T Cells 441
T-Cell Costimulation in Autoimmunity 442
Role of T-Cell Subsets in Autoantibody Formation 443
Role of B-Cell Defects in Autoantibody Production 444
B-Cell Activation 444
Self-tolerance in B Cells 444
Abnormal B-Cell Activation Promotes Autoimmunity 445
Role of Antigen-Presenting Cells 446
Innate Immunity 446
Innate Immunity and Autoantibody Formation 446
Central Role of IFN-a in Linking Innate and Adaptive Immunity 446
Autoimmunity with Abnormal Clearance of Apoptotic Cells 447
Cytokine Dependence of Autoantibody Formation 447
TNF-a and Related Molecules 447
Other Cytokines Produced by APC 448
Cytokines Produced by T Cells 448
The Basis Of Antigen Selectivity 449
Altered Antigen Processing 449
Induction of Autoimmunity by Complexes of Self and Nonself Proteins 449
Induction of Autoantibodies by Haptens 450
Apoptosis 450
Somatic Mutation of Autoantigens 450
Molecular Mimicry 451
Future Directions 451
Section IV. Clinical Approach to Diagnosis 465
16. The Clinical Presentation of Systemic Lupus Erythematosus in Adults 467
Introduction 467
General Symptoms 467
Criteria for Lupus 468
General Considerations Regarding Lupus 468
Musculoskeletal System 470
Clinical Involvement of the Renal System 471
Clinical Involvement of the Central Nervous System 472
Clinical Presentation of Cardiovascular Lupus 473
Pulmonary Disease and Lupus 474
Hematology of SLE 475
Clinical Presentation of Lupus of the Skin 475
Gastrointestinal Tract and Liver Disease in SLE 476
The Eye And SLE 476
Miscellaneous Organ Involvement 476
17. Neonatal Lupus Syndromes 481
Introduction 481
Passively Acquired Heart Block: An Irreversible Manifestation of Neonatal Lupus Syndromes 482
Cardiac Histopathology 482
Congenital Heart Block Occurs in an Anatomically Developed Heart and Coincides with Placental Transport 483
Classification of Heart Block 484
The Transient Skin Rash 485
Less Commonly Encountered Manifestations of NLS 486
Candidate Antigen–Antibody Systems in NLS 487
Target Autoantigens of the SSA/Ro-SSB/La System 487
Novel Antigen/Antibody Systems 489
Evaluation of the Fine Specificities of the Maternal SSA/Ro-SSB/La Autoantibody Response 489
Proposed Mechanisms of Immune Injury 491
Accessibility of Fetal Antigen to Maternal Antibody 491
Complement Regulatory Proteins 495
Arrhythmogenicity of Maternal Autoantibodies and Perturbation of L-Type Calcium Channels 496
Murine Model of CHB 498
Lessons from Monozygotic and Dizygotic Twins 498
Immunogenetics of the Mother And Host 499
Maternal Disease at Identification of Neonatal Lupus And Progression 501
Identification and Management of the High-Risk Pregnancy 502
Prenatal Considerations 502
Breast Feeding 505
Treatment of Cutaneous Manifestations 505
Recurrence Rates 506
Fetal Outcome 506
Long-Term Follow-up of Children with Varied Manifestations of NLS 507
Conclusions 508
18. Systemic Lupus Erythematosus in Childhood 517
Incidence 517
Manifestations of Childhood SLE 517
Mode of Onset 519
Clinical Manifestations 519
Laboratory Findings 526
Clinical Course And Prognosis 527
Discoid Lupus Erythematosus in Children 527
Drug-Induced Lupus Erythematosus in Children 528
Mixed Connective Tissue Disease in Childhood 528
Juvenile Sjögren’s Syndrome 530
Antiphospholipid Antibody Syndrome 530
General Approach to Management of Children With SLE 531
Treatment of Specific Problems and Long-Term Complications 532
Abdominal Crises 532
Hypertension and Renal Disease 532
Chronic Renal Failure 533
Special Considerations in the Adolescent with SLE 533
19. Imaging of Systemic Lupus Erythematosus: State of the Art 547
Imaging of Musculoskeletal SLE 547
General Radiographic Features 547
Subchondral Cysts and Erosions 549
Acral Sclerosis–Tuft Resorption and Periarticular Calcifications 550
Sacroiliitis 551
Abnormalities of the Tendon and Ligaments 552
Complications of Treatment of SLE 555
Imaging of Dermatologic SLE 562
Imaging of Pleuropulmonary SLE 567
Pleural Effusions 567
Lupus Pneumonitis 568
Pulmonary Infarcts 571
Pulmonary Hemorrhage 571
Pulmonary Hypertension 573
Hilar Adenopathy 573
Imaging of Cardiovascular SLE 575
Pericardial Disease 575
Cardiac Abnormalities 575
Endocardial Lesions 577
Myocardial Functional and Anatomic Abnormalities 580
Coronary Artery Disease 581
Aortic, Great Vessel, and Peripheral Arterial Occlusive Disease 581
Peripheral Venous Occlusive Disease 582
Imaging of Gastrointestinal SLE 586
Acute Reversible Lupus Gastrointestinal Ischemia 587
Chronic Gastrointestinal Lupus 589
Ascites 590
Hepatic Abnormalities in SLE 591
Imaging of the Reticuloendothelial System in SLE 591
Lymphadenopathy 591
Splenic Abnormalities 595
Imaging of Genitourinary SLE 596
Renal Manifestations 596
Bladder Abnormalities 598
Renal Allografts and Their Complications 603
The First Week after Transplantation 603
Imaging of Obstetric SLE 608
Intrauterine Cardiac Abnormalities of Neonatal Lupus 608
Placental Abnormalities and Intrauterine Growth Retardation 609
Imaging of Nervous System SLE 610
Central Nervous System Lupus 611
Cerebral and Subdural Hemorrhage in SLE 611
Cerebral Atrophy in SLE 611
Cerebral Calcifications in SLE 613
Lupus Cerebritis 613
Vasculitis of Cerebral Lupus 619
Parkinsonism in SLE 621
Lupus Cerebritis and Progressive Multifocal Leukoencephalopathy 621
Ophthalmic and Orbital Involvement in SLE 621
Cerebral Lymphoma in SLE 622
Complications of Therapy in SLE 622
Spinal Cord and Associated DURA in SLE 624
Conclusions 625
20. Monitoring Patients and Systemic Lupus Erythematosus 651
Introduction 651
Clinical Assessment 651
Constitutional Symptoms 652
Mucocutaneous Manifestations 652
Ocular Manifestations 653
Lymphoreticular Manifestations 653
Cardiopulmonary Manifestations 653
Gastrointestinal Manifestations 654
Musculoskeletal Manifestations 654
Neuropsychiatric Manifestations 655
Laboratory Monitoring 655
Hematologic 655
Renal 656
Autoantibodies 656
Immune Complexes 657
Complement Components 657
Acute-Phase Reactants 657
Disease Activity Indices 657
Assessment of Organ Damage 658
Monitoring Drug Toxicity 658
21. Laboratory Evaluation of Patients with Systemic Lupus Erythematosus 665
Introduction 665
Antinuclear Antibodies 665
Performance of the ANA Assay 665
Diseases Associated with a Positive ANA 666
Anti-DNA Antibodies 668
Anti-Smith Antibodies and Anti-RNP Antibodies 670
Anti-Ro/Anti-SSA Antibodies 671
Nucleosome-Specific Autoantibodies 673
Anti-hnRP Antibodies 674
Anti-PCNA Antibodies 674
Antibodies to Ribosomal P Proteins 674
Other Autoantibodies 676
Antiphospholipid Antibodies 676
False-Positive Serologic Test for Syphilis 676
Lupus Anticoagulants 676
Anticardiolipin Antibodies 677
Anti-b2 Glycoprotein I Antibodies 677
Antiprothrombin Antibodies 677
Prevalence of Antiphospholipid Antibodies 677
Associated Disorders 677
Immunoglobulins 678
Immune Complexes 678
Complement 678
Measurement of Complement 678
Acute-Phase Reactants 679
Clinical Relevance of Acute-Phase Reactants 679
Comparison of ESR and CRP 679
Hematological Abnormalities 680
Anemia 680
Leukopenia 681
Thrombocytopenia 681
Renal Function 682
Synovial Fluid 682
Pleural Fluid 682
Pericardial Fluid 682
Cerebrospinal Fluid 683
22. Systemic Lupus Erythematosus Pregnancy 691
Normal and Abnormal Pregnancy 691
Definition of Pregnancy 691
Special Issues 691
Physiologic Adaptations in Pregnancy Influencing the Course of Lupus 692
Non-SLE Pregnancy Complications: Maternal 693
The Pregnant Lupus Patient 697
Planning for Pregnancy 697
Measurement of Flare in Pregnancy 700
Management of Pregnancy: Mother 702
Monitoring 702
Treatment of Lupus during Pregnancy 702
Pregnancy Complications in Patients Entering Pregnancy with Preexisting Abnormalities 702
Drug Treatment in Lupus Pregnancy 704
Physiology of Drug Metabolism during Pregnancy 704
Common Drugs Used during Pregnancy (Non-SLE) 704
Drugs Used for Treating Lupus 705
Drugs Used for Pregnancy 706
Management: Treatment of Fetus During Pregnancy 706
Fetal Monitoring 706
Long-Term Outcomes of Lupus Children 708
The Puerperium 708
Route of Delivery 708
Treatment in the Peripartum Period 708
Placentae 709
Breast Feeding 709
Antiphospholipid Antibody Syndrome 711
Identification of the Patient at Risk 711
Effect of Pregnancy on the Course of Antiphospholipid Antibody Syndrome 711
Mechanism of Antiphospholipid Antibody Pregnancy Loss 712
Monitoring the Mother during Pregnancy 712
Monitoring the Fetus during Pregnancy and the Puerperium 712
Treatment 713
Patients with Prior Thrombotic events Thrombocytopenic Patients
Treatment for Infertility in Antiphospholipid Antibody Syndrome Patients 715
Postpartum Treatment Abortion
Medico-legal Considerations 715
Counseling and Other Issues 716
What to Tell Prospective Parents 716
Lupus-Like Disease 717
In Vitro Fertilization and Related Topics 717
Infertility, Male and Female 717
Assisted Reproductive Techniques 717
Treatment Regimens Used in Assisted Reproduction 718
Alternatives To Assisted Reproduction 718
23. Epidemiology of Systemic Lupus Erythematosus 729
Classification Criteria 729
Morbidity Data 730
Prevalence 730
Incidence 731
Effects of Age, Gender, and Race on Morbidity Rates 732
Mortality Data 733
Prognosis and Survivorship 735
Factors Associated with Survival Outcomes 735
Overall Disease Activity as a Predictor for Mortality in SLE 737
Reasons for Improved Survival 738
Causes of Death 738
Morbidity Outcome 738
Etiologic Factors 739
Endocrine–Metabolic Factors 739
Environmental Factors 739
Genetic Factors 740
Summary 741
24. Overlap Syndromes: Mixed Connective Tissue Disease and Sjögren’s Syndrome 749
Concept of Overlap Syndrome 749
Mixed Connective Tissue Disease 750
Historical Overview 750
Clinical Features 751
Laboratory Features 757
Histopathology and Immunopathology 758
Immunogenetics 761
Controversy of MCTD as a Distinct Entity 761
Model for Pathophysiology 761
T Cells in MCTD 762
Distinctive Clinical, Immunologic, and Genetic Features 763
Model of Disease: A Synthesis 763
Treatment and Prognosis 764
Relationship of MCTD to SLE 765
Sjögren’s Syndrome 766
Clinical Features 766
Laboratory Features 768
Histopathology 768
Immunogenetics 768
Relationship of Sjögren’s Syndrome to Lupus 768
Other Overlap Syndromes 768
25. Systemic Lupus Erythematosus and Fibromyalgia 777
Abstract 777
Introduction 777
Clinical Classification of Fibromyalgia 777
Prevalence of Fibromyalgia in the General Population and in Systemic Lupus Erythematosus 778
Pathophysiology of Pain and Fatigue in Fibromyalgia 778
Biopsychosocial Model of Chronic Pain and Fatigue 779
Psychological Stress in Fibromyalgia 779
Does Psychological Stress Cause or Exacerbate Systemic Lupus Erythematosus? 780
Stress and Immune Responses in Systemic Lupus Erythematosus 781
Fibromyalgia and its Impact on Health Outcomes and Quality of Life in Systemic Lupus Erythematosus 781
Relevance of Stress, Distress, and Fibromyalgia to Neuropsychiatric Manifestations of Systemic Lupus Erythematosus 782
Conclusions 783
Section V. Organs Affected by Systemic Lupus Erythematosus 787
26. Neuropsychiatric Systemic Lupus Erythematosus 789
Introduction 789
Prevalence of NPSLE Syndromes Using the American College of Rheumatology Case Definitions 789
Pathogenesis of NPSLE Syndromes 790
Non-Immune-Mediated Mechanisms 792
Murine Neurobehavioral SLE 792
Murine Strains with Spontaneous Disease 792
Murine Strains with Accelerated or Induced Disease 793
Clinical Features 794
Diagnosis and Management of Individual Syndromes 794
Risk Factors for Development of NPSLE Syndromes 800
Neurodiagnostic Npsle 800
Imaging 800
Electroencephalography 801
Cerebrospinal Fluid Evaluation 801
Autoantibody Testing 801
Prognosis of Patients with NPSLE Syndromes 801
Treatment of Patients with NPSLE Syndromes 802
Acute Inflammatory Demyelinating Polyradiculoneuropathy (Guillain-Barré Syndrome) 803
Aseptic Meningitis 804
Autonomic Disorder 804
Cerebrovascular Disease 804
Demyelinating Syndrome 804
Headache 805
Peripheral and Cranial Neuropathies 805
Movement Disorders 805
Myasthenia Gravis 806
Seizures 806
Cognitive Dysfunction 806
Psychiatric Disease 806
27. Psychiatric Aspects of Systemic Lupus Erythematosus 817
Introduction 817
Pathogenesis of Psychiatric Manifestations of Systemic Lupus Erythematosus 817
Direct Pathophysiologic CNS Effects of SLE (Primary Neuropsychiatric SLE) 818
Secondary Causes of Neuropsychiatric Symptoms in SLE: Infection, Other CNS or Systemic Illness, or Drug-Induced Side Effects 820
Psychological Impact of Illness 821
Stressful Aspects of SLE 821
Psychological Reactions to Having SLE 821
Psychological Factors Affecting Onset and Course of Systemic Lupus Erythematosus, and Adherence to Treatment 822
Stress: Its Role in the Onset and Exacerbations of SLE 822
Premorbid Personality Styles and Response to Having SLE 823
Classification of Psychiatric Disorders in Systemic Lupus Erythematosus 824
Cognitive Dysfunction 825
Depression 826
Anxiety 827
Mania 827
Psychosis 828
Acute Confusional State (Delirium) 828
Personality Change 828
Prevalence 828
Corticosteroid-Induced Psychiatric Symptoms 829
Corticosteroid Withdrawal Syndrome 831
Pediatric and Adolescent Systemic Lupus Erythematosus: Psychiatric Aspects 831
Relationships, Sexual Intimacy, and Pregnancy in Systemic Lupus Erythematosus: Psychiatric Aspects 833
Marriage and Family Relationships 833
Sexuality 833
Pregnancy 833
Diagnosis of Psychiatric Syndromes 834
Mental Status Exam and Neuropsychiatric Testing 834
Laboratory Workup 834
Electroencephalogram (EEG) 835
Neuroimaging 835
Limitations to the Use of Laboratory Tests in Diagnosing Neuropsychiatric Lupus 837
Summary of Diagnostic Approach 837
Differential Diagnosis 838
Psychiatric Syndromes in Other Collagen–Vascular, Autoimmune, or Multisystem Diseases 838
Somatization Disorder (“Psychogenic Pseudolupus” and Psychogenic Symptoms in SLE) 839
Factitious SLE 840
Treatment 840
Inpatient vs Outpatient Treatment 840
Suicidal Patients 840
Treatment Modalities 840
28. Cognitive Dysfunction in Systemic Lupus Erythematosus 859
Overview 859
Diagnosis and Classification of Nervous System Involvement in Systemic Lupus Erythematosus 860
Neuropsychological Assessment 860
Background and General Considerations 860
Sensitivity of Neuropsychological Assessment 861
Goals of Neuropsychological Assessment 861
Neuropsychological Studies in Systemic Lupus Erythematosus 862
Methodology 862
Prevalence of Cognitive Impairment in SLE 863
Types of Cognitive Deficit in SLE 864
Course of Cognitive Function in SLE 865
Interpretation of Cognitive Impairment 866
Pathogenesis of Cognitive and Behavioral Abnormalities in Systemic Lupus Erythematosus 869
Common Lymphocyte/Brain Antigens 869
Bacterial and Other Nonprotein Antigens 869
Specific Antigens on Neuroglia and Lymphocytes 870
Brain Cross-Reactive Antigens in Other Diseases 870
Phospholipid Antigens 870
Other Mechanisms: Apoptosis 871
Behavioral Abnormalities in Lupus-Prone Mice 871
Neuropsychological Correlates of Specific Anti-Brain Antibodies 872
Therapeutic Implications of Cognitive Dysfunction in Systemic Lupus Erythematosus 873
Medical Intervention for Acute CNS Involvement 873
Long-Term Functional Issues 873
Future Directions for Cognitive Studies in Systemic Lupus Erythematosus 874
Summary 875
29. Systemic Lupus Erythematosus and the Skin 887
Introduction 887
Cutaneous Forms of Lupus Erythematosus 887
Clinical and Immunopathologic Correlation 887
Chronic Cutaneous Lupus Erythematosus 888
Discoid Lupus Erythematosus 888
Lupus Tumidus 891
Lupus (Profundus) Panniculitis 892
Subacute Cutaneous Lupus Erythematosus 893
Definition 893
Clinical Findings 893
Relationship with SLE 894
Immunopathology 894
Prognosis 894
Neonatal LE 894
Acute Cutaneous Lupus Erythematosus 895
Definition 895
Clinical Findings 895
Immunopathology 896
Prognosis 896
Pathogenesis of Cutaneous Lupus Erythematosus 897
Other Clinical Presentations 897
30. Systemic Lupus Erythematosus and the Kidney 909
Introduction 909
Definitions and Manifestations of Lupus Renal Disorders 909
Clinical Syndromes and Laboratory Manifestations 909
Urinalysis 910
Renal Function Tests 911
Renal Biopsy 912
Pathology of Lupus Nephritis 913
Normal or Minimal Mesangial Abnormality (Class I) 914
Mesangial Nephropathy (Class II) 914
Focal (Class III) and Diffuse Proliferative (Class IV) Lupus Nephritis 915
Membranous Lupus Nephropathy (Class V) 917
Sclerosing Nephropathy (Class VI) 919
Activity and Chronicity Indexes 920
Pathogenesis of Lupus Nephritis 921
Course of Proliferative Lupus Nephritis 923
Course of Lupus Membranous Nephropathy 925
Prognostic Indicators 925
Approaches to Treatment of Lupus Nephritis 926
Evidence From Controlled Trials of Therapy for Lupus Nephritis 926
Corticosteroids 928
Azathioprine 928
Cyclophosphamide 928
Pulse Cyclophosphamide 928
Mycophenolate Mofetil 929
Plasmapheresis 930
Treatment of Proliferative Lupus Nephritis 930
Treatment of Lupus Membranous Nephropathy 931
Monitoring Patients with Lupus Nephritis 933
Remission 934
Relapse 934
Hypertension 935
Hyperlipidemia and Cardiovascular Risks 935
Thrombotic Diathesis 935
Renal Vasculopathies on Lupus Nephritis 936
Pregnancy and Lupus Nephritis 936
Lupus Nephritis in Children 936
Chronic Renal Insufficiency 937
End-Stage Renal Disease 938
Dialysis 938
Renal Transplantation 938
Referral Guidelines and Use of Consultants 939
Future Directions and Experimental Therapies 939
31. Cardiovascular Systemic Lupus Erythematosus 945
Cardiac Manifestations of Active Systemic Lupus Erythematosus 945
Pericarditis 945
Myocarditis 948
Left Ventricular Dysfunction 950
Valvular Disease 951
Arrythmias and Conduction Disturbances 954
Coronary Arteritis 954
Prevalence 954
Pulmonary Hypertension 955
Hypertension 956
Coronary Atherosclerosis in SLE 957
Management of Myocardial Infarction 962
Cardiovascular Mortality 963
Cardiovascular Surgery 963
Summary 963
32. Systemic Lupus Erythematosus and the Cardiovascular System: Vasculitis 975
Pathogenesis of Vasculitis in Systemic Lupus Erythematosus 975
The Spectrum of Vasculitis in Systemic Lupus Erythematosus 978
Cutaneous Vasculitis 978
Central Nervous Systems and Peripheral Nervous System Vasculitis 980
Pulmonary Vasculitis 982
Gastrointestinal Vasculitis 982
Vasculitis of the Heart 984
Vasculitis of the Genitourinary System 984
Large-Vessel Disease 985
Vasculitis of the Placenta 985
Differential Diagnosis of SLE Vasculitis 985
Management 985
33. Systemic Lupus Erythematosus and the Lung 993
Primary Pulmonary Involvement in Systemic Lupus Erythematosus 993
Diaphragmatic Involvement 993
Pleural Involvement 994
Parenchymal Lung Involvement 995
Pulmonary Vascular Involvement 999
Pulmonary Disorders Associated with SLE 1000
Other Associated Conditions 1000
34. Nonhepatic Gastrointestinal Manifestations of Systemic Lupus Erythematosus 1007
Oral Cavity 1007
Clinical Features 1007
Discoid Lesions 1009
Ulcers 1009
Erythematous Lesions 1009
Other Oral Lesions 1010
Esophagus 1010
Clinical Features 1010
Pathology–Pathophysiology 1011
Diagnosis 1011
Therapy 1011
Stomach And Duodenum 1011
Clinical Features 1011
Pathology–Pathophysiology 1011
Diagnosis 1012
Therapy 1012
Other Gastric Manifestations 1012
Small and Large Intestine 1012
Vasculitis 1012
Other SLE-Related Intestinal Diseases 1014
Peritoneal Cavity 1016
Clinical Features 1016
Pathology–Pathophysiology 1016
Diagnosis 1017
Therapy 1017
Pancreas 1017
Clinical Features 1017
Pathology–Pathophysiology 1017
Diagnosis 1017
Therapy 1017
Gallbladder 1018
Spleen 1018
Drug-Related Pathology 1018
Conclusions 1018
35. Hepatic Disease and Systemic Lupus Erythematosus: Coincidence or Converence 1025
Abstract 1025
Introduction 1025
Liver Disease and Lupus Erythematosus 1025
The Logic of Naming and Diagnosis of Disease and Establishing Causality 1026
Chronic Active and Lupoid Hepatitis: Early Descriptions 1026
Diagnostic Criteria: Systemic Lupus Erythematosus and Autoimmune Hepatitis 1027
Criteria for Systemic Lupus Erythematosus 1027
Criteria for Autoimmune Hepatitis 1027
World Congress of Gastroenterology (WCG) Working Party, 1994 1028
Autoimmune Hepatitis: Contemporary Clinical Appraisal 1029
Description of the Disease 1029
Extrahepatic Manifestations of Autoimmune Hepatitis 1029
Subtypes of Autoimmune Hepatitis 1029
Autoimmune Overlap Syndromes Involving the Liver 1029
The Liver in Systemic Lupus Erythematosus: Clinical Analysis 1031
Autoimmune Hepatitis: The Vision of the Histopathologist 1032
Histopathology: The Deviation of Hepatitis and Lupus 1032
The Histopathology of Autoimmune Hepatitis 1032
Histopathology of the Liver in SLE 1033
Autoimmune Hepatitis: The Vision of the Serologist 1034
Serologic Reactions in Type 1 Autoimmune Hepatitis 1034
Serologic Reactions in Type 2 Autoimmune Hepatitis 1038
Hepatitis C Virus and Autoimmune Serologic Reactions 1040
How Close Is the Serologic Overlap for Autoimmune Hepatitis and SLE? 1041
T-Cell Reactivity in Autoimmune Hepatitis 1041
Immunogenetics Predisposition 1041
General Comments 1041
MHC (HLA) Alleles 1041
Non-MHC Alleles 1042
Environmental Agents 1042
Conclusions 1043
36. The Cellular Hematology of Systemic Lupus Erythematosus 1051
Anemia 1051
Anemias Due to Decreased Red Cell Production 1051
Autoimmune Hemolytic Anemia 1053
Other Causes of Anemia 1055
Thrombocytopenia 1055
Qualitative Platelet Defects 1058
LEUKOPENIA 1059
Neutropenia 1059
Lymphocytes 1060
Monocytes 1060
Natural Killer Cells 1060
Bone Marrow Disease in Systemic Lupus Erythematosus 1061
Lymphadenopathy 1061
Myeloid and Lymphoid Malignancies in SLE 1061
37. Articular Manifestations of Systemic Lupus Erythematosus 1069
Abstract 1069
Introduction 1069
“Lupus Hand” 1070
Jaccoud’s Arthropathy 1070
Pathogenesis of Lupus Hand 1071
Clinical Findings of Lupus Hand 1071
Arthropathy of the Feet, Sacroiliac Joint, And Spine 1073
The Foot in SLE 1073
Sacroiliac Joint Abnormalities in SLE 1073
Spinal Abnormalities in SLE 1073
Less Frequently Encountered Articular and Periarticular Manifestations of Systemic Lupus Erythematosus 1073
The Shoulder, Hip, and Knee 1073
Periarticular Manifestations 1074
Nodules and Soft Tissue Calcifications 1074
Synovial Fluid and Tissue in Systemic Lupus Erythematosus 1075
Synovial Fluid 1075
Synovial Tissue 1075
Treatment of Systemic Lupus Erythematosus Arthropathy 1076
Salicylates 1076
Nonsteroidal Anti-inflammatory Drugs 1076
Antimalarial Drugs 1076
Corticosteroids 1076
Osteonecrosis and Systemic Lupus Erythematosus 1077
Epidemiology of Osteonecrosis in SLE 1077
Pathogenesis of Osteonecrosis 1078
Diagnosis Studies 1080
Staging and Classification for Osetonecrosis of the Femoral Head 1081
Treatment of Osteonecrosis of the Femoral Head 1083
Osteonecrosis of Other Sites 1087
38. Osteoporosis and Metabolic Bone Disease in Systemic Lupus Erythematosus 1097
Osteoporosis 1097
Introductiona 1097
Epidemiology of Bone Loss and Fractures in Systemic Lupus 1097
Fractures 1098
Pathophysiology of Low Bone Mass and Osteoporosis in Patients with Systemic Lupus 1098
Risk Factors of Osteoporosis in Patients with Systemic Lupus 1099
Abnormal Vitamin D Metabolism 1099
Ovarian Dysfunction 1099
Other Hormonal Factors 1099
Physical Activity and Bone Mass 1100
Lupus and Glucocorticoid-Induced Osteoporosis 1100
Pathophysiology of Glucocorticoid-Induced Osteoporosis in Patients with Lupus 1100
Drug-Induced Osteoporosis in Lupus 1100
Osteomalacia in Patients with Lupus 1101
Bone Mineral Density Measurement 1101
Central Techniques 1101
Peripheral Techniques 1102
Therapy of Osteoporosis in Patients with Systemic Lupus 1102
Alendronate 1103
Risedronate 1103
Calcitonin 1104
Meta-analysis of Therapy 1104
Parathyroid Hormone Therapy 1104
ACR Guidelines 1104
Unapproved Therapies for Glucocorticoid-Induced Osteoporosis 1105
Therapy of Osteomalacia and Drug-Induced Osteomalacia 1105
Renal Tubular Acidosis 1105
Renal Osteodystrophy 1106
Glucocorticoid-Induced Osteonecrosis 1106
Clinical Manifestations of Osteonecrosis 1106
Radiographic Evaluation 1106
Staging 1106
Treatment 1107
Pathogenesis of Glucocorticoid-Induced Osteonecrosis 1107
Conclusion 1107
Section VI. Specific Syndromes 1111
39. Immunology of Antiphospholipid Antibodies and Co-factors 1113
Historical Background 1113
Phospholipids 1114
Anti-Phospholipid Antibodies (Apls) and Their Cofactors 1115
Anti-cardiolipin Antibodies (aCLs) and b2-Glycoprotein I (b2-GPI) 1115
Lupus Anticoagulant (LA) and Its Cofactors 1120
Other APS-Related Autoantibodies 1122
Pathogenesis of Anti-Phospholipid Antibodies 1124
Platelet Interaction 1124
Endothelial Cell Interaction 1124
Involvement of Apoptosis 1126
Arterial Diseases and Atherosclerosis 1126
Pregnancy Morbidity 1127
40. The Clinical Aspects of the Antiphospholipid Syndrome 1139
Diagnostic Approach to the Antiphospholipid Syndrome 1139
Clinical Features 1140
Thrombosis 1140
Central Nervous System Manifestations 1141
Skin Manifestations 1143
Heart Manifestations 1145
Kidney Manifestations 1146
Lung Manifestations 1147
Hematologic Manifestations 1147
Obstetric Manifestations 1147
Catastrophic Antiphospholipid Syndrome 1148
Other Manifestations 1148
Epidemiology 1148
41. The Catastrophic Antiphospholipid Syndrome 1157
Introduction 1157
Definition 1157
Pathogenesis 1158
General Characteristics 1158
Specific Triggering Factors 1159
Clinical Manifestations 1160
General Characteristics 1160
Specific Organ Involvement 1161
Serology 1162
Diagnosis 1163
Clinical Diagnosis 1164
Laboratory Diagnosis 1165
Differential Diagnosis 1166
Thrombotic Thrombocytopenic Purpura 1166
Heparin-Induced Thrombocytopenia 1167
Disseminated Intravascular Coagulation 1167
Treatment 1167
First Line Therapies 1167
Second Line Therapies 1168
Other Therapies 1168
Unusual Therapies 1168
Intensive Care Therapies 1169
42. Hematology: Coagulation Problems 1171
Lupus Anticoagulants 1171
Laboratory Diagnosis of Lupus Anticoagulants 1171
Prevalence of Lupus Anticoagulants and Anti-Cardiolipin Antibodies in Systemic Lupus Erythematosus 1173
Prevalence of Thrombosis in Patients with Lupus Anticoagulants or Elevated Anti-Cardiolipin Antibodies 1173
Mechanisms 1174
Lupus Anticoagulants, Anti-Cardiolipin Antibodies and Related Antibodies as Risk Factors for Thrombosis 1175
The Role of Genetic Risk Factors in the Thrombotic Risk in Patients with Lupus Anticoagulants and Anti-Cardiolipin Antibodies 1176
Treatment of Thrombosis in Systemic Lupus Erythematosus Patients with Lupus Anticoagulants or Anti-Cardiolipin Antibodies 1178
Anticoagulation 1178
Steroid and Other Immunosuppressive Therapy 1179
Treatment of Cerebrovascular Events 1180
Treatment of Recurrent Fetal Loss 1181
Other Possible Risk Factors for Thrombosis 1181
Coagulation Factor Inhibitors and Bleeding in Systemic Lupus Erythematosus 1182
43. The Antiphospholipid Syndrome: Pathogenesis and Implications for Systemic Lupus Erythematosus 1193
Abstract 1193
Introduction 1193
Primary Secondary Antiphospholipid Syndrome: Is There a Fundamental Difference or Is the Antiphospholipid 1194
Pathogenesis of the Antiphospholipid Syndrome: Overview of a Complex Disorder 1195
An Explanation for the Association between “Lupus Anticoagulants” and a Thrombotic Clinical Syndrome: 1195
Anti-phospholipid Antibodies Primarily Target Either b2-Glycoprotein I or Prothrombin: Is There a Role for Phospholipid? 1197
Pathogenic Mechanism for the Antiphospholipid Syndrome: Autoantibodies Interfere with Protein 1199
There Are Many Autoantibodies, but Few Are Thrombotic 1202
Phospholipids Tie Together a Complex Disease Model 1202
Pathogenesis of the Antiphospholipid Syndrome: Clues from the Association with SLE. The Coagulopathy Is 1202
C4b-Binding Protein: A link between Protein C, Its Cofactor Protein S, and the Complement System 1203
Implications for Lupus 1205
Pathophysiologic Implications for Lupus 1205
Clinical Implications for Lupus: Integrating an Evolving Pathophysiologic Model into Current (Albeit Limited) 1205
Clinical Predictors of Outcome 1205
44. Pathophysiology of Drug-Induced Systemic Lupus Erythematosus 1217
Pathophysiology of Drug-Induced Lupus 1217
Structures of Drugs Causing Drug-Induced Lupus 1217
Anti-Drug Antibodies 1217
Drug–DNA Interactions 1219
Drug–Histone Interactions and Anti-Histone Antibodies 1219
Abnormal Immune Regulation 1219
Genetic Factors 1220
Human Leukocyte Antigen and Complement 1220
Acetylator Phenotype and DIL 1221
Acetylator Phenotype and Idiopathic SLE 1222
Neutrophil-Mediated Oxidative Metabolism 1222
Epigenetic Mechanisms 1223
ADP-Ribosylation and DIL 1223
T-Cell DNA Hypomethylation and DIL 1223
T-Cell DNA Methylation in Idiopathic Lupus 1225
Animal Models 1226
Early Animal Models 1226
Recent Animal Models 1227
Xenobiotics 1228
Foods and Dietary Supplements 1229
Heavy Metals 1230
Gold 1230
Mercury 1230
Cadmium 1231
Vinyl Chloride and Industrial Solvents 1231
Silica, Silicon, and Silicones 1232
Hair Dye and SLE 1232
Conclusions 1232
45. Drug and Environmental Systemic Lupus Erythematosus: Clinical Manifestations and Differences 1243
Introduction 1243
History 1244
Definition 1244
Prevalence 1245
Demographic Features 1245
Clinical Features 1245
Laboratory Findings 1246
Differential Diagnosis 1248
Therapy 1248
Comments on Certain Drugs Associated with Drug-Related Lupus 1248
Hydralazine 1249
Procainamide 1249
Isoniazid 1250
Quinidine 1250
Anticonvulsants 1250
Chlorpromazine 1251
Beta Blockers 1251
ACE Inhibitors 1251
Sulfasalazine 1251
Minocycline 1253
Lipid Lowering Agents 1254
d-Penicillaimine 1255
Hormonal Factors 1255
Biological Agents 1255
Tumer Necrosis Factor Alpha Inhibitors 1256
Environmental Agents 1257
Chemical Agents 1258
Heavy Metals 1260
Dietary Factors 1261
Conclusion 1261
Section VII. Therapy of Systemic Lupus Erythematosus 1271
46. Corticosteroid Use in Systemic Lupus Erythematosus 1273
General Biochemistry, Pharmacology, Physiology 1273
Structure of Glucocorticoids 1273
Secretion and the Hypothalamic-Pituitary Axis 1275
Special Situations 1276
Selective Steroid Compounds 1276
Mechanisms and Actions 1277
Overview 1277
Metabolic Effects 1279
Anti-inflammatory Effects 1279
Immunosuppressive Effects 1280
Immunosuppression-Pulse Therapy 1281
Clinical Applications 1281
Preparations and Routes of Administration 1282
Therapeutic Situations 1283
Dose Response Modifiers: Genetics, Disease States, and Drug Interactions 1287
Side Effects 1288
47. Antimalarials and Immunosuppresive Therapies 1305
Antimalarials 1305
Alkylating Agents 1308
Mechlorethamine 1308
Cyclophosphamide 1308
Chlorambucil 1311
Antimetabolite Immunosuppresants 1311
Azathioprine 1311
Mycophenolate Mofetil 1313
Methotrexate 1313
Leflunomide 1314
Macrolide Immunosuppressants 1315
Cyclosporine 1315
Tacrolimus 1316
48. Unproven and Experimental Therapies 1327
Introduction 1327
Overview 1327
Evaluating New Therapies for SLE 1327
Challenges in SLE Therapy 1328
Unproven and Experimental Therapies: An Overview 1328
Nonimmunosuppressive Immunomodulatory Treatments 1328
Intravenous Immunoglobulin 1328
LJP394: DNA-Toleragen 1330
Nonpharmacological Immunosuppressive Approaches 1331
Plasmapheresis 1331
Total Lymphoid Irradiation (TLI) 1332
High-Dose and Myeloablative Chemotherapy 1332
Higher-Than-Conventional Dosages of Cyclophosphamide 1332
Bone-Marrow and Stem-Cell Transplantation 1333
Hormonal Therapies 1333
Dehydroepiandrosterone (DHEA) 1334
Other Hormonal Therapies 1336
Monoclonal Antibodies and Other Biological Treatments 1337
Cell-Directed Biological Therapies 1337
Cytokines and Cytokine Antagonists 1337
Second Signal Blockade 1338
Other Biological Agents 1338
Novel Immunosuppressive and Immunomodulatory Pharmacological Agents 1339
Mycophenolate Mofetil 1339
Other Immunosuppressive Agents 1339
Immunomodulators 1340
Arachidonic Acid Derivatives and Their Inhibitors 1340
Prophylactic Use of Corticosteroids 1340
UV-A1 Light Therapy 1340
“Alternative Therapies” 1341
Chinese Herbs and Other Herbal Therapies 1341
Nutritional Therapies 1341
Antioxidants 1342
Acupuncture 1342
Other Alternative Therapies 1342
Conclusion 1342
Index 1353