Neuropsychiatric Systemic Lupus Erythematosus (eBook)

Shunsei Hirohata - Shunsei Hirohata graduated from The University of Tokyo School of Medicine in 1980. After the 2-year residency, he joined the Department of Medicine & Physical Therapy, The University of Tokyo. He moved to Teikyo University School of Medicine in 1992 (Associated professor), to Kitasato University School of Medicine in 2006 (Professor), and to Nobuhara Hospital in 2017 (Vice Director). His research topics include neuro-Behcet's disease, neuropsychiatric SLE and bone marrow abnormalities in rheumatoid arthritis. He also works as a visiting professor in Kitasato University School of Medicine.

Preface 5
Contents 6
Chapter 1: Epidemiology of Neuropsychiatric Systemic Lupus Erythematosus 8
1.1 Introduction 8
1.2 Classification 9
1.3 Demographic Features of NPSLE 11
1.3.1 Prevalence 11
1.3.2 Age of Onset and Ethnicity 13
1.3.3 Risk Factors 13
1.4 The Limitations of 1999 ACR Nomenclatures and Definitions 14
1.5 NPSLE in Childhood 15
1.6 Steroid Induced Psychosis 15
1.7 Mortality 16
1.8 Emerging Problems from the Epidemiological Studies 16
1.9 Summary 17
References 18
Chapter 2: Genetics 21
2.1 Introduction 21
2.2 Genetics of Overall SLE 22
2.2.1 Major Histocompatibility Complex (MHC) Region 22
2.2.2 Type I Interferon Pathway and Nucleic Acid Response Genes 26
2.2.3 Defective Clearance of Dying Cell Nucleic Acids 27
2.2.4 Signaling Molecules in Immune System Cells 28
2.3 Genetics of Neuropsychiatric SLE 28
2.3.1 TREX1 28
2.3.2 Other Candidate Genes 29
2.4 Summary 30
References 30
Chapter 3: Immunopathology of Neuropsychiatric Systemic Lupus Erythematosus 34
3.1 Introduction 34
3.2 Autoantibodies Implicated in the Pathogenesis of NPSLE 35
3.2.1 Anti-Phospholipid Antibodies 35
3.2.2 Anti-Ribosomal P Antibodies 36
3.2.3 Anti-NMDA Receptor NR2 Subunit Antibodies 37
3.2.4 Anti-Sm Antibodies 37
3.2.5 Anti-Neuronal Antibodies 38
3.2.6 Other Autoantibodies 39
3.3 Intrathecal Ig Production and Blood-Brain Barrier Damages in NPSLE 39
3.3.1 Intrathecal Ig Production 39
3.3.2 Blood-Brain Barrier Damages in NPSLE 40
3.4 Roles of Complements and Microglia in the Pathogenesis of NPSLE 41
3.4.1 Complements 41
3.4.2 Microglia 41
3.5 Summary 42
References 43
Chapter 4: Pathology of Neuropsychiatric Systemic Lupus Erythematosus 48
4.1 Introduction 48
4.2 Overall Characteristic Features in Pathology in NPSLE 49
4.3 The Pathogenesis of Vasculopathy in NPSLE 50
4.4 Diffuse Psychiatric/Neuropsychological Syndromes 51
4.4.1 Acute Confusional State 51
4.4.2 Non-ACS Diffuse NPSLE 54
4.5 Neurologic Syndromes 55
4.5.1 Cerebrovascular Disease and Reversible Focal Neurological Deficits 55
4.5.2 Seizures 55
4.5.3 Cranial Neuropathy 55
4.5.4 Myelopathy 56
4.5.5 Peripheral Neuropathy 58
4.6 Other Pathological Features in NPSLE 58
4.6.1 Choroid Plexus 58
4.6.2 Microglia 58
4.6.3 Perivenous Changes 59
4.7 Summary 60
References 60
Chapter 5: Clinical Features 64
5.1 Introduction 65
5.2 Classification 65
5.3 Case Definition and Clinical Significance 66
5.3.1 Diffuse Psychiatric/Neuropsychological Syndromes 66
5.3.1.1 Acute Confusional State 67
5.3.1.2 Anxiety Disorder 68
5.3.1.3 Cognitive Dysfunction 69
5.3.1.4 Mood Disorder 69
5.3.1.5 Psychosis 70
5.3.2 Neurologic Syndromes of CNS 71
5.3.2.1 Aseptic Meningitis 71
5.3.2.2 Cerebrovascular Disease 72
5.3.2.3 Demyelinating Syndrome. 72
5.3.2.4 Headache 73
5.3.2.5 Movement Disorder (Chorea) 74
5.3.2.6 Myelopathy 74
5.3.2.7 Seizures and Seizure Disorders 75
5.3.3 Neurologic Syndromes of PNS 75
5.3.3.1 Neuropathy, Cranial 76
5.3.3.2 Acute Inflammatory Demyelinating Polyradiculoneuropathy (Guillain-Barré Syndrome) 76
5.3.3.3 Autonomic Disorder 76
5.3.3.4 Mononeuropathy (Single/Multiplex) 76
5.3.3.5 Myasthenia Gravis 77
5.3.3.6 Plexopathy 77
5.3.3.7 Polyneuropathy 77
5.4 Summary 77
Reference 78
Chapter 6: Cytokines and Chemokines 82
6.1 Introduction 82
6.2 The Blood-Brain Barrier 83
6.3 Cytokines 84
6.4 Cytokines as Biomarkers 84
6.4.1 Tumor Necrosis Factor 84
6.4.2 Interleukin-10 86
6.4.3 Interferon-? 86
6.4.4 Interleukin-6 87
6.4.5 Granulocyte-Colony Stimulating Factors 89
6.5 Chemokines 89
6.6 Chemokines as Biomarkers 90
6.6.1 Monocyte Chemoattractant Protein-1/CCL2 (A Ligand of CCR2) 90
6.6.2 Regulated Upon Activation, Normal T-Cell Expressed and Secreted (RANTES)/CCL5 (A Ligand of CCR1, CCR3, and CCR5) 91
6.6.3 Interleukin-8/CXCL8 (A Ligand of CXCR1 and CXCR2) 91
6.6.4 Interferon-Gamma Inducible Protein-10/CXCL10 (A Ligand of CXCR3) 92
6.6.5 Fractalkine/CX3CL1 (a Ligand of CX3CR1d) 92
6.6.6 Ratio of Two Different Chemokine Levels (The IP-10/MCP-1 Ratio) 93
6.7 Cytokines and Chemokines as Pathogenic Factors 93
6.7.1 Cytokines as Pathogenic Factors 93
6.7.2 Chemokines as Pathogenic Factors 94
6.8 Summary 94
References 95
Chapter 7: Diagnosis and Differential Diagnosis 98
7.1 Introduction 99
7.2 Classification of NPSLE 99
7.3 Risk Factors for NPSLE 99
7.4 SLE Disease Activity 100
7.5 Diagnostic Approach of NPSLE 101
7.6 Clinical and Laboratory Examination for the Diagnosis of NPSLE 102
7.6.1 Clinical and Laboratory Tests 102
7.6.2 Autoantibodies 103
7.6.3 CSF Tests 104
7.6.3.1 Routine CSF Tests 104
7.6.3.2 CSF Immunologic Tests 104
7.6.3.3 CSF Autoantibodies 105
7.6.3.4 CSF Cytokine and Chemokine 105
7.6.4 Neuroimaging Studies 105
7.6.5 Electroencephalography 106
7.7 Guidelines for Diagnosis of NPSLE 106
7.7.1 Headache 108
7.7.2 Cerebrovascular Disease 109
7.7.3 Cognitive Dysfunction 109
7.7.4 Seizure Disorders 110
7.7.5 Movement Disorders 110
7.7.6 Acute Confusional State 110
7.7.7 Psychosis 111
7.7.8 Myelopathy 111
7.7.9 Cranial Neuropathy 111
7.7.10 Peripheral Nervous System Disorders 112
7.8 The Important Diseases for Differential Diagnosis 112
7.8.1 Psychiatric Manifestations after Steroid Therapy 112
7.8.2 Neuromyelitis Optica 113
7.8.3 Reversible Posterior Leukoencephalopathy Syndrome 113
7.8.4 Progressive Multifocal Leukoencephalopathy 113
7.9 Summary 114
References 114
Chapter 8: Imaging of Neuropsychiatric Systemic Lupus Erythematosus 118
8.1 Introduction 119
8.2 Computed Tomography (CT) 119
8.3 Magnetic Resonance Imaging (MRI) 121
8.3.1 Parenchymal Lesion 122
8.3.2 White Matter Hyperintensity (WMH) 124
8.3.3 Gray Matter Hyperintensity (GMH) 126
8.3.4 Atrophic Lesion 127
8.3.5 Meningeal Lesion 127
8.4 Advanced Techniques of MRI 128
8.4.1 Magnetic Resonance Spectroscopy (MRS) 128
8.4.2 Diffusion Tensor Imaging (DTI) 128
8.4.3 Magnetization Transfer Imaging (MTI) 129
8.5 Single Photon Emission Computed Tomography (SPECT) 129
8.6 Positron Emission Tomography (PET) 129
8.7 Summary 130
References 130
Chapter 9: Psychiatric Symptoms 133
9.1 Introduction 134
9.2 Primary and Secondary NPSLE 134
9.3 SLE-Associated Psychiatric Syndromes 136
9.3.1 Psychiatric Disorders 136
9.3.1.1 Psychosis 136
9.3.1.2 Mood Disorder 137
9.3.1.3 Anxiety Disorder 138
9.3.2 Acute Confusional State (Delirium) 138
9.3.3 Cognitive Dysfunction 139
9.3.4 Other Psychiatric Symptoms and Conditions 140
9.3.4.1 Catatonia 140
9.3.4.2 Suicide Ideation and Attempts 140
9.4 Special Consideration of Corticosteroid-Induced Psychiatric Disorder 141
9.5 Summary 142
References 142
Chapter 10: Treatment of Neuropsychiatric Systemic Lupus Erythematosus 145
10.1 Introduction 145
10.2 Pathogenesis of NPSLE 146
10.3 Treatment of NPSLE: Overviews 147
10.4 Management of the Main Neuropsychiatric Manifestations 148
10.4.1 Acute Confusional State 148
10.4.2 Mood Disorder, Anxiety Disorder, and Psychosis 149
10.4.3 Cognitive Dysfunction 149
10.4.4 Seizures 150
10.4.5 Headache 150
10.4.6 Movement Disorder 150
10.4.7 Cerebrovascular Disease 151
10.5 Immune-Modulating Drugs Used for NPSLE 151
10.5.1 Corticosteroids 151
10.5.2 Cyclophosphamide 152
10.5.3 Hydroxychloroquine 153
10.5.4 Intravenous Immunoglobulin 153
10.5.5 Plasmapheresis 153
10.5.6 Mycophenolate Mofetil (MMF) 153
10.5.7 Azathioprine 154
10.5.8 Rituximab 154
10.5.9 Belimumab 154
10.6 Summary 155
References 155
Chapter 11: Promising Treatment Alternatives 159
11.1 Introduction 160
11.2 Anti-CD20 Antibodies (Rituximab) 160
11.2.1 Clinical Trials and Cohort Studies of Rituximab 160
11.2.2 Regimen and Efficacy of Rituximab in Patients with NPSLE 161
11.2.3 Case Report 1: The Efficacy of Rituximab in 33-Year Old Woman with NPSLE 164
11.2.4 Case Report 2: The Efficacy of Rituximab in 38-Year Old Woman with NPSLE 165
11.2.5 Mechanism of Action of Rituximab 166
11.2.6 Rituximab as Potential Future Therapies 167
11.3 Potential Future Therapies Other than Rituximab 167
11.3.1 Anti-CD22 Antibodies (Epratuzumab) 167
11.3.2 B Cell Stimulator Targets 168
11.3.2.1 Anti-BLyS Antibodies (Belimumab, Tabalumab and Blisibimod) 168
11.3.2.2 BLyS and APRIL Receptor (Atacicept) 168
11.3.3 Cytokine and Chemokine Targets 168
11.3.3.1 Anti-IL-6 Receptor Antibodies (Tocilizumab) 169
11.3.3.2 Anti-IFN-? Antibodies (Sifalimumab and Rontalizumab) 169
11.3.4 Complement Targets: Anti-Terminal Complment Component C5a And C5b-9 Antibodies (Eculizumab) 169
11.4 Summary 170
References 170
Chapter 12: Prognosis of Neuropsychiatric Systemic Lupus Erythematosus 173
12.1 Introduction 173
12.2 Mortality in Patients with NPSLE 174
12.3 Evaluation of NP Symptoms and Irreversible NP Damages in SLE 176
12.4 Prognosis of Overall/Specific Manifestations of NPSLE 178
12.4.1 Cerebrovascular Disease 178
12.4.2 Cognitive Dysfunction 179
12.4.3 Acute Confusional State (ACS) 181
12.5 Treatment that Impact Prognosis of NPSLE 181
12.5.1 Inflammatory NPSLE 181
12.5.2 Ischemic NPSLE 182
12.5.3 Corticosteroid-Induced Psychosis or NPSLE? 183
12.6 Summary 184
References 185
Index 188