Sjögren's Syndrome and Oral Health: Disease Characteristics and Management of Oral Manifestations

Description

This book provides a thorough update on Sjögren’s syndrome (SS) and its adverse impacts on oral health. The opening section focuses on the clinical and laboratory characteristics of SS and its current management. Here, readers will find information on diagnostic criteria, pharmacotherapy, dental management, and the importance of saliva in oral health and SS. Attention then turns to the immunopathogenesis of SS, which includes the mechanisms of secretory dysfunction, myoepithelial cell functions in salivary gland physiology and disease, dysregulated innate and adaptive immunity, and B-cell expansion and neoplasia. The final section details important advances in SS diagnosis and therapy. The differential diagnoses of recurrent glandular swelling, glandular irrigation and sialendoscopy, and salivary gland ultrasound for SS in children are explained, along with the pharmacological management for SS, clinical care for dry eyes, and gene therapy. This book will be of interest to not only dental practitioners and researchers but also rheumatologists and pathologists. Preface Living with Sjögren’s Syndrome What Is Sjögren’s Disease to Me? My Journey with Sjögren’s Syndrome When Dry Mouth Was Jeopardizing My Career Contents Part I: Clinical/Laboratory Characteristics and Current Dental Management 1: Introduction, Diagnostic Criteria, Pharmacotherapy, and Dental Management 1.1 Introduction 1.1.1 History 1.1.2 Definitions 1.1.3 Prevalence 1.1.4 Disease Spectrum 1.2 Diagnosis 1.2.1 Signs and Symptoms 1.2.2 Diagnostic Criteria 1.2.3 Chairside Clinical Observations Indicative of Possible Hyposalivation 1.2.4 Chairside Patient Questions to Aid the Detection of Hyposalivation and SS Diagnosis [18, 19] 1.2.5 Xerostomia, Salivary Hypofunction, and Sialometry 1.2.6 Lab/Serological Testing 1.2.7 Labial Salivary Gland Biopsy 1.2.8 Salivary Gland Enlargement and Lymphoma 1.2.9 Sialendoscopy 1.3 Pharmacotherapy 1.3.1 Caries Prevention and Home Care 1.3.2 Agents for Caries Prevention: Fluoride 1.3.3 Agents for Caries Prevention: Non-Fluoride Remineralizing Agents 1.3.4 Antimicrobial Agent for Caries Prevention: Chlorhexidine 1.3.5 Prescription Sialogogues 1.3.5.1 Pilocarpine 1.3.5.2 Cevimeline 1.3.5.3 Electrostimulation 1.3.6 Medication-Induced Hyposalivation 1.3.7 Conventional Systemic Pharmacotherapy 1.4 Dental Management 1.4.1 Caries Prevention and Management: Patient Counseling 1.4.2 Management of Oral Candidiasis 1.4.3 Review of Periodontal Disease in Sjögren’s Syndrome Patients 1.4.4 Review of Periodontal Disease in Secondary Sjögren’s (sSS) with Rheumatoid Arthritis 1.4.5 Review of Orofacial Function and TMD in Sjögren’s Syndrome 1.4.6 Restorative Considerations 1.4.7 Dental Implants 1.4.8 Quality of Life 1.5 Extraglandular Manifestations 1.6 Outcomes Assessments 1.7 Conclusion References 2: Saliva and Its Importance in Sjögren’s Syndrome 2.1 Introduction 2.2 The Exocrine System 2.3 Salivary Gland Anatomy and Physiology 2.4 Salivary Components and Their Functions 2.5 Saliva Organic Constituents 2.6 Protective Functions of Saliva 2.7 Speech, Digestion, and Related Functions 2.8 Salivary Flow and Oral Health 2.9 Sjögren’s Syndrome References Part II: Immunopathogenesis of SS 3: Mechanisms of Secretory Dysfunction in Autoimmune Sjögren’s Syndrome 3.1 Introduction 3.1.1 Autoimmune Sjögren’s Syndrome (SS) 3.1.2 Neural Regulation of Secretion 3.2 Factors Influencing Secretion in SS 3.2.1 Cytokines 3.2.1.1 Potential Mechanisms of Secretory Dysfunction by Inflammatory Cytokines 3.2.1.2 Proinflammatory Cytokines in SS 3.2.2 Autoantibodies 3.2.2.1 Anti-Ro/SSA and Anti-La/SSB 3.2.2.2 Anti-Nuclear Antibodies (ANA) 3.2.2.3 Rheumatoid Factor (RF) 3.2.2.4 Autoantibodies to Aquaporins (Anti-AQP5) 3.2.2.5 Autoantibodies to Carbonic Anhydrase 6 (CA6), Salivary Protein 1 (SP1), and Parotid Secretory Protein (PSP) 3.2.2.6 Anti-Muscarinic Type 3 Receptor (M3R) Autoantibodies 3.2.2.6.1 Detection of Anti-M3R Autoantibodies in Patient Sera 3.2.2.6.2 Anti-M3R Autoantibodies in SS Studies with Animal Models 3.2.3 MicroRNAs (miRNAs) 3.2.3.1 Roles of miRNA in Dry Mouth 3.2.3.2 Roles of miRNA in Dry Eyes 3.2.4 Reactive Oxygen Species (ROS) 3.2.4.1 Roles of ROS in Salivary Dysfunction of SS Patients 3.2.4.2 Roles of ROS in Dry Eyes of SS Patients 3.2.5 Calcium Signaling in SOCE 3.2.5.1 Overview 3.2.5.2 Calcium Signaling for Saliva Secretion 3.2.5.3 Mechanisms and Physiological Relevance of SOCE 3.2.5.4 Impaired Ca2+Signaling in SS 3.3 Other Conditions Contributory to SS Secretory Dysfunction 3.3.1 Effect of Sex Hormones in SS 3.3.2 Meibomian Gland Dysfunction in SS 3.3.3 Conjunctival Disease in SS 3.4 Conclusion References 4: Myoepithelial Cell Function in Salivary Gland Physiology and Disease 4.1 Introduction 4.2 General Morphology of Human Salivary Glands 4.3 General Histology of the Salivary Glands 4.4 Salivary Secretion 4.4.1 Salivary Secretion Flow Rate 4.4.2 Autonomic Control of Salivary Fluid and Protein Secretion 4.4.3 Salivary Secretion Modification 4.5 Myoepithelial Cells 4.5.1 Development and Structure 4.5.2 Functions of Myoepithelial Cells 4.5.3 Myoepithelial Cells in Salivary Gland Pathology 4.5.4 Recent Advances 4.6 Summary and Conclusion References 5: Innate Immune Dysregulation in Sjögren’s Syndrome 5.1 Introduction 5.2 Innate Immune Pathways Mediate Disease 5.2.1 Toll-like Receptor Signaling: Murine Studies 5.2.2 Human Studies Corroborate Findings in Mouse Models 5.2.3 Inflammasome Activation Is Implicated in pSS 5.2.4 Emerging Work Describes a Role for Additional Innate Immune Sensors in pSS Pathogenesis 5.3 Underlying Causes of Innate Immune Activation 5.3.1 PAMPs Contribute to the Development and Progression of pSS 5.3.2 Evidence for DAMPs in Innate Immune Activation in pSS 5.3.3 Innate Immune Dysfunction Is Influenced by Genetics in pSS 5.3.4 Sex Hormones May Contribute to the Striking Female Disease Prevalence Observed in pSS 5.3.5 The Microbiome Modulates the Innate Immune Response and Is Dysregulated in Autoimmunity 5.4 Current and Emerging Therapeutics That Target Innate Immune Activation in pSS 5.4.1 Hydroxychloroquine (HCQ) Blocks Endosomal-Mediated TLR Signaling 5.4.2 Blockade of TLRs Pathways Shows Promise in Clinical Trials 5.4.3 Cytokine Inhibitors Mitigate Innate Immune Activation 5.4.4 Depletion of pDCs May Have Therapeutic Efficacy in pSS 5.4.5 Targeting of the Microbiome May Represent a Novel Therapeutic Approach to Diminish Innate Immune Activation in pSS 5.5 Conclusion References 6: Dysregulation of Adaptive Immunity in Sjögren’s Syndrome 6.1 Introduction 6.2 Initiation of Adaptive Immune Responses 6.3 Th1 Cells and Cytokines 6.3.1 IFNγ 6.3.2 TNFα 6.3.3 IL-7 6.3.4 IL-12 and IL-18 6.4 Th2 Cells and Cytokines 6.4.1 IL-4 6.4.2 IL-13 6.5 Th17 Cells and Cytokines 6.5.1 IL-17 (IL-17A) and IL-23 6.5.2 IL-22 6.6 TFH Cells and IL-21 6.7 Immune-Regulatory Lymphocytes and Cytokines 6.7.1 Tregs 6.7.2 IL-10 6.7.3 Tfr Cells 6.8 B Cells 6.8.1 Major B Cell Subsets in the Target Exocrine Glands of SjS 6.8.2 B Cells in Ectopic Germinal Centers 6.8.3 B Cell-Activating Factor (BAFF) 6.9 Biological Therapies Targeting Adaptive Immunity in SjS 6.10 Conclusions References 7: B Cell Expansion and Neoplasia in Sjögren’s Syndrome 7.1 Introduction 7.2 Salivary Gland Inflammation in SS 7.3 Extranodal Lymphomas in SS 7.3.1 Frequency of SS Among Patients with Salivary Gland-Associated MZL 7.3.2 Case 1: 58-Year-Old Woman with SS and Persistent Right Parotid Swelling 7.4 Lymphocytic Interstitial Pneumonia and B Cell Neoplasia 7.4.1 Case 2: 50-Year-Old Female Non-Smoker with SS and Multiple Pulmonary Nodules 7.4.2 Lymphoproliferation in SS Lung 7.5 Other Forms of Lymphoma in SS 7.5.1 DLBCL 7.5.2 Follicular Lymphoma 7.5.3 Case 3: 79-Year-Old Woman with SS and Probable Follicular Lymphoma 7.6 RF B Cells, Cryoglobulins, and Lymphoma Risk 7.6.1 Cryoglobulins and Preferential Immunoglobulin Heavy Chain (VH) Gene Usage 7.6.2 Role of Infection in Pathogenesis of HCV-Induced MZL 7.7 Risk Factors for Lymphomagenesis in SS 7.8 Prevalence of B Cell Lymphoma in Primary Compared with Secondary SS 7.9 Therapy of Extranodal B Cell Lymphoma in SS 7.9.1 Therapy of DLBCL 7.10 Conclusion References Part III: Improved SS Diagnosis and Therapeutics 8: Recurrent Vs. Persistent Salivary Gland Swelling in Differential Diagnosis of Sjögren’s Syndrome 8.1 Introduction 8.2 Idiopathic 8.2.1 Chronic Recurrent Non-Specific Parotitis 8.2.2 Juvenile Recurrent Parotitis 8.2.3 Sarcoidosis 8.3 Reactive 8.3.1 Sialadenosis 8.3.1.1 Alcohol Sialadenosis (Alcohol Sialosis) 8.3.1.2 Bulimia/Malnutrition-Related Sialadenosis 8.3.2 Radiation Sialadenitis 8.3.3 Obstructive 8.3.3.1 Sialolithiasis 8.4 Developmental 8.4.1 Lymphangiomas 8.4.2 Arteriovenous Malformations 8.4.3 Hemangiomas 8.5 Inflammatory/Immune Mediated 8.5.1 Immunoglobulin G4-Related Sialadenitis 8.6 Infectious 8.6.1 Bacterial Sialadenitis 8.6.1.1 Streptococcal/Staphylococcal Sialadenitis 8.6.1.2 Parotid Tuberculosis (TB) 8.6.2 Viral Sialadenitis 8.6.2.1 Mumps 8.6.2.2 Epstein–Barr Virus-Related Parotid Gland Lesions 8.6.2.3 HIV-Associated Sialadenitis 8.6.2.3.1 HIV-Related Bilateral Parotid Gland Lymphoepithelial Cysts 8.7 Neoplastic Lesions 8.7.1 Pleomorphic Adenoma of the Parotid Gland 8.7.2 Warthin Tumor 8.7.3 Adenocarcinomas of the Parotid Gland 8.7.4 Primary Parotid Lymphoma 8.8 Conclusion References 9: Efficacy of Glandular Irrigation and Sialendoscopy in Salivary Glands Affected by Sjögren’s Syndrome 9.1 Introduction 9.2 Intraglandular Irrigation 9.3 Sialendoscopy 9.3.1 Instruments Used in Sialendoscopy 9.3.2 Procedure 9.3.3 Sialendoscopy in Sjögren’s Syndrome Patients 9.4 Conclusion References 10: Salivary Gland Ultrasonography for Primary Sjögren’s Syndrome and Juvenile Sjögren’s Syndrome 10.1 Introduction 10.2 Normal Salivary Gland Sonographic Anatomy 10.2.1 Parotid Glands (PGs) 10.2.2 Submandibular Glands (SMGs) 10.2.3 Sublingual Glands (SLGs) 10.3 Scanning Technique 10.4 Abnormal Salivary Gland Ultrasound Findings in Sjögren Syndrome 10.5 Salivary Gland Ultrasound Scoring Systems 10.5.1 Salivary Gland Ultrasound Scoring System and the Diagnosis of pSS/jSS 10.5.2 Salivary Gland Ultrasound Scoring System and Salivary Gland Biopsy 10.5.3 Salivary Gland Ultrasound Scoring System and Autoantibodies 10.5.4 Salivary Gland Ultrasound Scoring System and Sialometry 10.6 SGUS Mimicking Sjögren’s Syndrome 10.6.1 Juvenile Recurrent Parotitis (JRP) 10.6.2 Mumps 10.6.3 Chronic Bacterial Infection 10.6.4 IgG4-Related Disease 10.6.5 Sarcoidosis 10.6.6 Systemic Immunoglobulin Light-Chain Amyloidosis (AL Amyloidosis) 10.6.7 HIV Infections 10.6.8 Lymphoma 10.6.9 Postradiotherapy 10.7 Other Imaging for Primary Sjögren’s Syndrome and Juvenile Sjögren’s Syndrome 10.7.1 Plain Radiograph 10.7.2 Sialography 10.7.3 Salivary Gland Scintigraphy 10.7.4 Computed Tomography (CT) 10.7.5 Magnetic Resonance Imaging (MRI) and Magnetic Resonance Sialography (MR Sialography) 10.8 Conclusion References 11: Pharmacological Management of Sjögren’s Syndrome 11.1 Introduction 11.2 Treatment of Salivary Gland Involvement 11.2.1 Dry Mouth 11.2.1.1 Pilocarpine Hydrochloride 11.2.1.2 Cevimeline Hydrochloride 11.2.1.3 Other Strategies 11.2.2 Salivary Gland Swelling 11.2.3 Salivary Dysfunction-Related Problems 11.2.3.1 Frictional Oral Ulcer 11.2.3.2 Candidiasis 11.2.3.3 Dental Caries 11.3 Treatment of Lacrimal Gland Involvement 11.4 Treatment of Other Xeroses 11.4.1 Dry Cough 11.4.2 Vaginal Dryness 11.5 Treatment of Extraglandular Involvement 11.5.1 Evidence for the Use of Antirheumatic Drugs and Biologics 11.5.2 Articular Manifestations 11.5.3 Cutaneous Purpura/Ulcers 11.5.4 Annular Erythema 11.5.5 Interstitial Lung Disease 11.5.6 Pulmonary Arterial Hypertension 11.5.7 Renal Involvement 11.5.8 Interstitial Cystitis 11.5.9 Peripheral Nerve Involvement 11.5.10 Central Nerve Involvement 11.5.11 Fatigue 11.5.12 Hematologic Involvement 11.5.13 Muscular Involvement 11.6 Conclusion References 12: Gene Therapy for Sjögren’s Syndrome 12.1 Why Gene Therapy 12.2 Gene Delivery Strategies 12.2.1 Nonviral Gene Therapy 12.2.2 Viral Gene Therapy 12.3 Biosafety for Current Gene Therapy 12.4 What to Deliver 12.4.1 Cytokines 12.4.2 Receptors 12.4.3 Intracellular Regulators 12.4.4 Intracellular Proteins 12.5 How to Control Expression 12.6 SS-like Animal Models Used in Preclinical Studies 12.6.1 Inducers of Autoimmune Epithelitis in SS 12.6.1.1 Loss of Epithelial Hemeostasis 12.6.1.2 Autoimmune Epithelitis by Virus Infection 12.6.1.3 Autoimmune Epithelitis by Immune Cells Activation/Deletion 12.6.1.3.1 T Cell-Targeted 12.6.1.3.2 Dendritic Cell (DC)-Targeted 12.6.1.3.3 B Cell-Targeted 12.6.1.3.4 Autoantigens 12.6.1.4 Epithelial Function-Associated Gene 12.6.2 Spontaneous Models 12.7 Preclinical Gene Therapies Studies in Mice 12.7.1 Immunomodulatory Gene Therapies 12.7.1.1 Targeting Cytokines 12.7.1.1.1 Blocking Pro-inflammatory Cytokine: Tumor Necrosis Factor-α (TNF-α) 12.7.1.1.2 Overexpressing Protective Cytokine: IL-10 12.7.1.2 Targeting Co-Stimulatory Molecules 12.7.1.2.1 Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) 12.7.1.2.2 CD40 12.7.1.2.3 Intercellular Adhesion Molecule-1 (ICAM-1) 12.7.1.3 Targeting Th17 Cells 12.7.1.3.1 IL-17 12.7.1.3.2 IL-27 12.7.1.4 Targeting B Cells 12.7.1.4.1 B Cell-Activating Factor 12.7.1.4.2 Transmembrane Activator and CAML Interactor (TACI) 12.7.1.5 Targeting Neuroendocrine-Immune Regulator 12.7.1.5.1 Vasoactive Intestinal Peptide (VIP) 12.7.2 Non-immunomodulatory Gene Therapies 12.7.2.1 AQP1 12.8 Future Therapeutic Targets in Gene Therapy 12.9 Concluding Thoughts References 13: Clinical Management of Dry Eye in Sjögren’s Syndrome 13.1 Diagnosis of Dry Eye 13.2 Treatment of Dry Eye in Sjögren’s Syndrome 13.2.1 Lubricant 13.2.2 Secretagogues 13.2.3 Topical Corticosteroid 13.2.4 Cyclosporine A 13.2.5 Lifitegrast 13.2.6 Blood Derivatives 13.2.7 Bandage Contact Lens 13.2.8 Tear Retention 13.2.9 Essential Fatty Acids 13.3 Summary References