Publisher: Springer
Year: 2024
Foreword
Preface to the Third Edition
Contents
Contributors
Part I: Introduction
1: Historical Perspective of Scleroderma
Early History
Emergence of Systemic Sclerosis as a Clinical Entity
Recent History
Advances in Scleroderma Biology
Progress in Classification Natural History and Clinical Trials Methodology
References
Part II: Epidemiology, Genetics and Classification
2: Epidemiology, Environmental, and Infectious Risk Factors
Introduction
Incidence and Prevalence of SSc
Temporal Changes in Incidence Rates
Geographic Variations in SSc Occurrence
Clusters
Survival
Survival: Prognostic Factors
Risk Factors for Susceptibility of SSc
Risk Factors: Female Gender
Risk Factors: Race
Risk Factors: Age at Onset
Familial Risk
Birth Order
Risk Factors: Environmental Triggers
Silica
Solvents
Exposures and Scleroderma-Like Syndromes
Vinyl Chloride Disease
Toxic Oil Syndrome
L-Tryptophan and Eosinophilia-Myalgia Syndrome
Gadolinium and Nephrogenic Systemic Fibrosis (see Chap. 13)
Bleomycin and Pulmonary Fibrosis
Pentazocine
Infection Risk
Summary
References
3: Influence of Ethnicity and Sex Bias in Systemic Sclerosis
Ethnicity in SSc
SSc Prevalence
Genetic Risk Factors
SSc Onset
Autoantibodies, Clinical Features and Internal Organ Involvement
Mortality
Summary
Sex Bias in SSc
Epidemiology and Etiopathogenesis
Clinical Presentation and Disease Manifestations
Prognosis and Mortality
References
4: Genetic Factors
Introduction
Genetic Approaches to the Study of Polygenic Diseases
Single Nucleotide Polymorphism (SNP)
General Approaches to Genetic Studies
Genome-Wide Versus Candidate-Gene Studies
Application of Genetic Approaches to Systemic Sclerosis
Family Association Studies
Twin Studies
Genome Wide Association Studies (GWAS)
Candidate Gene Approach and Main Biological Pathways
Gene Regions Associated with SSc
Immune System Regulatory Genes
NFκB Signaling
Apoptosis and Autophagy
Fibrosis Pathways
Conclusion
References
5: Classification and Disease Subsets in Clinical Practice
Classification and Diagnosis
Clinical Cutaneous Subsets of Systemic Sclerosis
Original LeRoy Classification
Systemic Sclerosis Sine Scleroderma
Three-Subset Cutaneous Model of SSc
Early SSc Versus Undifferentiated Connective Tissue Disease
Evolution of Mixed Connective Tissue Disease into SSc
American Rheumatism Association/American College of Rheumatology Classification Criteria
Limitations
Importance of Revising the ACR Classification Criteria
The Next Generation Classification Criteria for SSc
LeRoy and Medsger Criteria
Maricq and Valter Criteria
Nadashkevich, Davis, and Fritzler Criteria
Criteria from the Canadian Scleroderma Research Group
Nailfold Capillaroscopy in the Diagnosis of SSc
Nailfold Capillaroscopic Patterns in SSc
Office Capillaroscopy
Autoantibodies and Capillaroscopic Abnormalities May Predict the Onset of SSc
Autoantibodies and Subsets of SSc
SSc-Associated Autoantibodies have Diagnostic and Prognostic Value. Consideration of Serologic Subsets
ANA and SSc-Associated Autoantibody Testing
Antibodies Associated with Diffuse Skin Thickening
Anti-Scl-70 Antibodies
Anti-RNA-Polymerase Antibodies
Anti-U3-RNP (Fibrillin) Antibodies
Anti-nucleolar Antibodies
Anti-U11/U12 Antibodies
Antibodies Associated with Limited Skin Thickening
Anticentromere Antibodies
Anti-U1-RNP Antibodies
Anti-Th/To Antibodies
Overlap Antibodies
Anti PM/Scl Antibodies
Anti-RUV-BL1/2 Antibodies
Anti-Ku Antibodies
Modern Era of Classification Criteria
Very Early Diagnosis of Systemic Sclerosis (VEDOSS)
ACR-EULAR Classification Criteria
Conclusions
References
6: Clustering and Evolving Concepts for Subclassification
Need for Classification and Subclassification in a Highly Heterogeneous Disease
Exploring New SSc Classifications
Studies Based on Skin, Organ Involvement, and Autoantibody Profiles
Overlap Syndromes
Clinical Trajectories Over Time
High-Throughput Omics Technologies
Radiomics
How Can We Integrate Data from High-Throughput Technologies?
Integrating Between Study High-Dimensional Data
Transcriptomics
cDNA Library Generation
Data Processing
Data Analysis
Integrating Data Between Studies
Integrating Multiple Omic Datasets
Toward an Integrated and Comprehensive Classification
References
7: The Clinical Aspects of Autoantibodies
Introduction
SSc-Specific and SSc-Related Autoantibodies
SSc-Specific Autoantibodies
ACA
Anti-Scl-70/Topo I Antibody
Anti-RNAP III Antibody
Anti-U3 RNP Antibody
Anti-Th/To Antibody
Anti-U11/U12 RNP Antibody
Anticentriole Antibody
Anti-eIF2B Antibody
Anti-PM-Scl Antibody
Anti-Ku Antibody
Anti-RuvBL1/2 Antibody
Anti-U1 RNP Antibody
SSc-Related Autoantibodies
ANA-Negative SSc
Screening of SSc-Specific Autoantibodies
Methods for Detection of Individual SSc-Specific Autoantibodies
Autoantibodies to Functional Molecules
Utility in SSc Diagnosis
Epidemiological Characteristics
Age at Onset
Gender
Ethnicity
Disease Subset Classification
lcSSc
dcSSc
SSc in Overlap
SSc Sine Scleroderma
Prediction of Organ Manifestations
Peripheral Vascular Manifestations
Joint Involvement
GI Involvement
Renal Crisis
Primary Heart Involvement
PAH
ILD
Cancer
Survival
Autoantibody Titer and Disease Activity
Conclusions
References
8: Systemic Sclerosis Overlap Syndromes
Definition/Classification
Epidemiology
Pathogenesis
SSc-Overlap Subgroups and Clinical Features
Further Organ Manifestation Depending on SSc Overlap Syndromes
Diagnostics
Management of SSc-Overlap Syndromes
References
9: Juvenile Localized and Systemic Scleroderma
Juvenile Localized Scleroderma
Epidemiology
Clinical Manifestations
Autoantibodies
Diagnosis and Disease Assessment
Treatment
Quality of Life
Prognosis
Juvenile Systemic Sclerosis
Clinical Presentation of Patients with Juvenile Systemic Scleroderma
Incidence and Prevalence of Juvenile Systemic Sclerosis
Classification
Diagnosis and Assessment of the Patient
Differential Diagnosis
Management
Comparison of the Largest Pediatric Cohort of jSSc with a Large Adult Cohort with Diffuse Subset jSSc
Outcome of the Patients in Two Pediatric Cohorts
Special Issues in the Care for Children with jSSc
Outcome of Pediatric-Onset Juvenile Systemic Sclerosis Patients into Adulthood
Summary
References
10: Morphea (Localized Scleroderma)
Classification and Epidemiology of Morphea
Variants and Related Entities
Epidemiology and Clinical Course
Etiology and Pathogenesis of Morphea
Genetics and Autoimmunity in Morphea
Histopathology of Morphea
Triggers and Precipitating Factors
Clinical Features of Morphea
Assessment of Disease Activity in Morphea
Stages of Morphea Lesions
Depth of Involvement
Morbidity in Morphea
Laboratory Findings in Morphea
Differential Diagnosis of Morphea
Approach to the Evaluation of the Patient with Morphea
Imaging Methods
Therapeutic Options for Morphea
Phototherapy
Vitamin D Derivatives
Immunomodulators
Antimicrobials
Treatments Not Supported by Current Evidence
Adjunctive Therapy
Surgical Therapies
Summary
References
11: Scleroderma Mimics
Differential Diagnosis of the Raynaud Phenomenon
Differential Diagnosis of Skin Thickening
Toxin-Associated Scleroderma-Like Disorders
Toxic Oil Syndrome (TOS) and Eosinophilia Myalgia Syndrome (EMS)
Nephrogenic Systemic Fibrosis
Scleredema
Scleromyxedema
Eosinophilic Fasciitis
Localized Scleroderma
Treatment Differences
References
Part III: The Biological Basis of Systemic Sclerosis
12: Introduction: The Etiopathogenesis of Systemic Sclerosis—An Integrated Overview
Introduction
Intermediate Pathophenotypes (the Triad), Disease Heterogeneity, and the Role of Heredity
The Scleroderma Triad of Intermediate Pathophenotypes
Primacy of Vascular Injury and Damage
The Immune System: Inflammation, Innate Immunity, Adaptive Immunity, and Autoimmunity
Autoantibodies in SSc: Markers of Autoimmunity—And Drivers of Disease?
Multisystem Fibrosis: The Distinguishing Hallmark of SSc
Cellular Mediators of Fibrosis
The Interplay of the Triad of Intermediate Pathophenotypes in the Pathogenesis of SSc
References
13: Pathology of Systemic Sclerosis
Introduction
Skin
Pulmonary
Renal
Cardiovascular
Gastrointestinal
Musculoskeletal
Placenta
References
14: Inflammation and Immunity in Systemic Sclerosis
T Cells
Polarized T-Cell Subsets in SSc
T-Cell Cytokines in Animal Models of Fibrosis
T Helper Cell Subsets in Human SSc
T Follicular Helper Cells in SSc
Cytotoxic CD4+ and CD8+ T Cells in SSc
Angiogenetic T Cells in SSc
Regulatory T Cells
Autoantigen-Specific T-Cell Responses in SSc
B Cells
Concluding Remarks
References
15: Autoantibodies as Markers and Possible Mediators of Scleroderma Pathogenesis
Introduction
Autoantibody Profiles as Markers of Pathogenic Events
Some Autoantibody Titers Can Change Over Time: Association with Disease Severity and Activity
Autoantigens in Target Tissues: Partners in Propagation
Autoantibodies as Clues to the Scleroderma-Cancer Interface
Autoantibodies as Possible Mediators of Scleroderma Pathogenesis
Amplification of Immune Responses
Direct Pathogenicity
Antibodies Recognizing Unidentified Cell Surface Molecules
Autoantibodies Affecting Extracellular Matrix and Its Components
Autoantibodies Stimulating Receptor Signaling
Conclusions
References
16: Mechanisms of Vascular Disease
Introduction
The Vascular Problem
The Vascular Lesion
Vascular Dysfunction in Scleroderma
Endothelin-1
Nitric Oxide
Nature of the Endothelial Injury
Microbial Triggers
Endothelial Cell Cytotoxicity, Apoptosis, and Activation
Antibody-Dependent Cellular Cytotoxicity
Antiendothelial Cell Antibodies (AECAs)
Shear Stress and SSc Vascular Disease
Reperfusion and Oxidative Injury
Agonistic Autoantibodies to the Platelet-Derived Growth Factor Receptor and Generation of ROS
Autoantibodies to Angiotensin and Endothelin Receptors
Epigenetics and SSc Vasculopathy
Defective Vascular Repair and Regeneration in SSc
Defective Angiogenesis: The Proangiogenic to Antiangiogenic Switch
Defective Vasculogenesis
The Plasminogen Activator Pathway
Microarray and Single-Cell RNA Sequencing Studies Revealing Altered Balance of Proangiogenic and Antiangiogenic Factors in SSc
Role of Perivascular Cells
Vascular Wall Remodeling in SSc
Vascular Hypoxia in the Pathogenesis of SSc
Relationship of Vasculopathy to Fibrosis
Animal Models of SSc Vasculopathy
UCD-200/206 Chickens
Chronic Graft-Versus-Host Disease (GVHD)
Endothelial Fli1-Deficient Mouse and Bleomycin-Treated Fli1-Haploinsufficient (+/−) Mouse
Klf5 and Fli1 Gene Double Heterozygous (Klf5+/−;Fli1+/−) Mouse
Fra-2 Transgenic Mouse
uPAR-Deficient Mouse
Transgenic Mouse with Endothelial Cell-Specific Inducible Expression of Constitutively Active TGF-β Receptor I
Conclusions
References
17: Biomarkers in Systemic Sclerosis
Introduction
Biomarkers as Surrogate Outcome Measures
Mechanism of Action (MOA) Biomarkers
Prognostic Biomarkers
Predictive Biomarkers
Toxicity Biomarkers
Developing Biomarkers for Clinical Applications
Sources of Biomarker Information
Diseased Tissues
Blood Biomarkers
Circulating miRNAs
Radiographic Studies
Genetic Studies
Autoantibodies
Other Biomarker Sources
Biomarkers and High-Throughput Technologies
Biomarker Performance: Correlations, Models, and ROC Curves
Biomarkers of Disease Target Organs in SSc
Skin
Pharmacodynamic Biomarkers of Skin
mRNA Biomarkers
Serum and Plasma Biomarkers
Circulating miRNA Biomarkers
Prognostic and Predictive Biomarkers of SSc Skin Disease
Biomarkers for SSc-ILD
Genetic and Epigenetic Factors
Autoantibodies
Serum/Plasma
Bronchoalveolar Lavage Biomarkers of ILD
Radiographic Studies of SSc-ILD
Clinical and Biochemical Biomarkers of Pulmonary Arterial Hypertension
Digital Ischemia, Digital Ulcers
Biomarkers of Overall Disease in SSc
Conclusion
References
Further Reading
18: Cellular and Molecular Mechanisms of Fibrosis in Systemic Sclerosis
Introduction: Cellular Determinants of Repair and Fibrosis
The Extracellular Matrix
Collagen Synthesis and Its Regulation
Effector Cells of Scleroderma Fibrosis: Fibroblasts and Myofibroblasts
Myofibroblast Origin and Heterogeneity
Pathways Regulating Myofibroblast Activation
Growth Factors: TGF-β1, PDGF, CTGF
TGF-β1
Platelet-Derived Growth Factors (PDGFs)
Connective Tissue Growth Factor (CTGF/CCN2)
Bioactive Lipids: LPA and LTB4
Lysophosphatidic Acid (LPA)
Leukotriene B4 (LTB4)
Vasoactive Peptides: Angiotensin II and Endothelin 1
Angiotensin II (Ang II)
Endothelin 1 (ET-1)
Developmental Pathways Implicated in Fibrosis: Hippo, Wnt, Jagged/Notch, and Hedgehog
Hippo
Wingless-Related Integration Site (Wnt)
Notch
Hedgehog
Feedback Amplification Loops
Mechanical Factors: Matrix Stiffness
Epigenetic Reprogramming and Noncoding RNAs in Fibrosis
Matrikines and Toll-Like Receptor (TLR) Signaling
Paracrine Mediators Released by Immune Cells, Keratinocytes, and Endothelial Cells
Monocytes/Macrophages
T Cells
B Cells
Dendritic Cells
Keratinocytes
Endothelial Cells and Pericytes
Pathways Regulating Myofibroblast Survival and Apoptosis Evasion in SSc
Biochemical, Mechanical, and Metabolic Factors
Cellular Senescence
Pathways Promoting Myofibroblast Deactivation
Interferon-γ
Nuclear Receptors: PPAR-γ, VDR, and NR4A1
Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ)
Vitamin D Receptor (VDR)
Nuclear Receptor Subfamily 4, Group A, Member 1 (NR4A1)
Soluble Guanylate Cyclase
References
19: Overview of Animal Models
Introduction
Models of SSc with Fibrosis as Predominant Clinical Feature
The Tight-Skin 1 Mouse (Tsk-1)
The Tight-Skin 2 Mouse (Tsk-2)
TGF-ß Mediated Models of Fibrosis
Inducible Expression of Activated TGF-βRI
Fibroblast-Specific Deletion of the TGF-βRII-Kinase Domain-TβRIIΔk
Fibroblast-Specific Transgenic Overexpression of Connective Tissue Growth Factor (CTGF)
Models of Fibrosis Induced by Activation of Canonical Wnt Signaling
Wnt-10b Transgenic Mice
Fibroblast-Specific Overexpression of a Constitutively Active β-Catenin
Caveolin-1-Deficient Mice
Xenograft Model of SSc Skin in SCID Mice
VEGF tg Mice
PTEN-Deficient Mice
Models of SSc with Immune and Inflammatory Deregulation and Subsequent Fibrosis
Murine Sclerodermatous Chronic Graft-Versus-Host Disease (cGvHD)
Bleomycin-Induced Inflammation and Fibrosis
Models of Reactive Oxygen Species in SSc
Topo-I Immunization Model
Type V Collagen Immunization Model
PSGL-1-Deficient Mouse
Models with SSc-Like Vascular Disease
Models of Pulmonary Arterial Hypertension (PAH)
Vascular Hyperplasia and Fibrosis in Fra-2 Transgenic Mice
Urokinase-Type Plasminogen Activator Receptor (uPAR) Deficient Mice
Allograft Arteriopathy
UCD200 Chicken
New Murine SSc Models with Fli1 Deficiency
Endothelial Cell-Specific Fli1 Knockout Mice
Epithelial Cell-Specific Fli1 Knockout Mice
Klf5+/−; Fli1+/− Mice
Myocardial Disease in Mouse Models
What Have We Learned from Analyzing Animal Models?
References
Part IV: Cardiovascular Manifestations and Management
20: Raynaud’s Phenomenon, Digital Ulcers and Nailfold Capillaroscopy
Raynaud’s Phenomenon
Clinical Features
Diagnosis and Classification of Raynaud’s Phenomenon
Epidemiology of Raynaud’s Phenomenon
Summary of the Pathogenesis of Raynaud’s Phenomenon
Raynaud’s Phenomenon in Systemic Sclerosis
Assessment of the Patient with Raynaud’s Phenomenon
History and Examination
History
Physical Examination
Investigations
Antibodies
Capillaroscopy
Other Imaging Techniques
Digital Ulcers in Systemic Sclerosis
Aetiopathogenesis
Clinical Features
Management of RP and DUs
Uncomplicated RP
General/Lifestyle Measures
Pharmacological Therapy
Complicated RP
Systemic Therapies
Digital Ulcer Wound Bed Management
Surgery
Adjunctive Therapies
Unmet Needs
Conclusion
References
21: Renal Crisis and Other Renal Manifestations
Introduction
Renal Disease in SSc: The Spectrum of Involvement
Historical Aspects of SSc Renal Disease
Scleroderma Renal Crisis
Definition
Epidemiology
Factors Predicting SRC
Clinical Presentation
Laboratory Findings
Pathogenesis
Management
Prevention
Long-term Outcomes
Interstitial Renal Disease
Glomerulonephritis
Chronic Kidney Disease (CKD) in Systemic Sclerosis
Future Perspectives
References
22: Cardiac Involvement: Evaluation and Management
Introduction
Epidemiology of Cardiac Involvement in Systemic Sclerosis
Screening and Diagnosis of Cardiac Involvement in Systemic Sclerosis
Specific Cardiac Manifestations of Systemic Sclerosis
Intrinsic Myocardial Disease: Myocardial Fibrosis and Microvascular Ischemia
Pathophysiology
Clinical Manifestations and Diagnosis
LV Systolic and Diastolic Dysfunction
RV Dysfunction
Approach to the Patient with Clinical Symptoms or Signs of Possible Myocardial Involvement
Management
Coronary Artery Disease
Pericardial Disease
Conduction Disease and Arrhythmias
Cardiac Complications of Systemic Sclerosis Therapies
Tools for the Assessment of Cardiac Dysfunction in Systemic Sclerosis
Serum Biomarkers
BNP vs. NT-proBNP in SSc
Practical Use of Natriuretic Peptides in Patients with SSc
Echocardiography
Tissue Doppler Imaging
Right Ventricular Quantification
Nuclear Imaging, Cardiac MRI, and Cardiac Computed Tomography (CT)
Cardiac Catheterization
Arrhythmia Monitoring
Emerging Tools
Speckle-Tracking Echocardiography for Measurement of Myocardial Strain
Exercise Echocardiography
Cardiopulmonary Exercise Testing
Cardiac MRI T1 Mapping (Diffuse Fibrosis Imaging)
Cardiac MRI Absolute Perfusion
Summary: Recommendations and Unanswered Questions
Conclusions
References
Part V: Pulmonary Manifestations and Management
23: Overview of Lung Involvement
Introduction
Epidemiological Considerations
Histologic Features of SSc-ILD
The Detection of SSc-ILD
Key Risk Factors for SSc-ILD in SSc Patients
Genetic and Pathogenetic Implications
Current Clinical Practice: Is Lung Disease Clinically Significant?
Monitoring of Lung Disease in SSc
Prognostic Evaluation of SSc-ILD: When Should Treatment Be Instituted?
Management Considerations
References
24: Clinical Assessment of ILD
Epidemiology and Survival
ILD is Highly Prevalent in SSc
ILD in SSc Is Associated with High Mortality
The Risk of Death Is Directly Associated with the Extent of ILD on HRCT, with Impaired Lung Function, and with ILD Progression
Screening SSc Patients for ILD
Respiratory Symptoms
Auscultation and Physical Examination
Pulmonary Function Testing (PFT)
HRCT
Chest X-Rays
Lung Ultrasound (LUS)
Screening Algorithm
ILD Diagnosis
Lung Physiology
HRCT and Chest X-Ray
BAL and Lung Biopsy
Disease Course of ILD
ILD Progression, Definitions, and Risk Factors for Progression
SSc Subtype and Skin Changes
Autoantibody Profile
Respiratory Symptoms and Functional Capacity
Clinical Findings
Pulmonary Function Tests
HRCT
Circulating Biomarkers
New Imaging Techniques
Monitoring
Conclusion and Future Perspectives
References
25: Lung Imaging Perspective in Scleroderma
Lung Imaging Perspective in Scleroderma
Introduction
HRCT in Scleroderma Lung Disease
Technique
Diagnosis of SSc-ILD on HRCT
Quantitative CT in SSc-ILD
Assessing Disease Extent
QCT as a Biomarker
QCT as Measure of Drug Rx and Disease Progression
Emerging Technologies
Ultrasound
Magnetic Resonance Imaging (MRI)
Nuclear Medicine Imaging
Optical Coherence Tomography (OCT)
Conclusion
References
26: Treatment of Interstitial Lung Disease in Systemic Sclerosis
Natural History of ILD in SSc
Who Should Be Screened?
Who Is at Increased Risk of Progressive ILD?
In Whom Should Treatment Be Considered?
What Should Be Used When Treatment Is Indicated?
Cytotoxic Therapies
Cyclophosphamide
Mycophenolate Mofetil
Biological
Rituximab
Tocilizumab
Antifibrotic
Nintedanib
Transplantation
High-Dose Immunosuppressive Therapy and Hematopoietic Stem Cell Transplantation
Lung Transplantation
Future Therapies
Pirfenidone
Other Potential Therapies
Supportive Care
Which Treatment to Which Patient?
Conclusion
References
27: Pathogenesis of Pulmonary Arterial Hypertension
Pathology of Scleroderma-Associated Pulmonary Arterial Hypertension
Comparative Pathology of CTD-PAH vs. Other Forms of PAH
Pathogenetic Insights of PAH
Genetic Basis of PAH
Pathogenic Factors and Signaling Pathways Implicated in the Development of PAH
The TGF-β/BMP Axis
Serotonin (5-HT)
Platelet-Derived Growth Factor
Inflammation in PAH
Epigenetics of PAH
Metabolism in PAH
Concluding Remarks
References
28: Clinical Assessment of Pulmonary Hypertension
Introduction
Epidemiology
Risk Factors
Screening: Why Is PAH Screening Needed in Scleroderma Patients?
How Should PAH Screening Be Accomplished in Scleroderma Patients?
Diagnosis and Evaluation
Natural History
Prognosis
Prognosis in SSc-PAH Is Worse Than in Idiopathic PAH
References
29: The Management of Pulmonary Arterial Hypertension in the Setting of Systemic Sclerosis
Definition and Classification of Pulmonary Hypertension in Systemic Sclerosis
Epidemiology of PH and Impact on Outcomes
Exercise-Induced Pulmonary Hypertension
SSc with Mildly Elevated Pulmonary Pressures
Risk Assessment in CTD-PAH
Therapy for CTD-PAH: Overview
General Measures
Anti-inflammatory Agents
Calcium Channel Blockers
Prostaglandins
Endothelin Receptor Antagonists
Phosphodiesterase Inhibitors/Soluble Guanylate Cyclase Stimulators
Combination Therapy
Lung Transplantation
Summary and Future Directions
References
Part VI: Gastrointestinal Manifestations and Management
30: Overview of Gastrointestinal Tract Involvement
Introduction
Pathogenesis
Upper GI Complications
Midgut Disease
Lower GI Complications
Recommended Approach to Gastrointestinal Tract Complications in Systemic Sclerosis
Concluding Remarks
References
31: Upper Gastrointestinal Tract: Manifestations of Systemic Sclerosis
Introduction
Oropharyngeal Cavity
Esophagus
Clinical Presentation and Complications
Relationship to Pulmonary Disease
Diagnostic Evaluation
Treatment
Stomach
Clinical Presentation
Diagnostic Evaluation
Treatment
Gastric Antral Vascular Ectasia
References
32: Lower Gastrointestinal Tract Involvement: Understanding the Interplay of Motility, the Microbiome, and Nutrition
Introduction
Anatomy and Histopathology of the Lower Bowel in SSc
Dysmotility of the Small and Large Bowel in SSc
Hypotheses for the Etiology of Dysmotility in SSc
Small Bowel Involvement in SSc and the Approach to Diagnosis and Management
Small Bowel Dysmotility
Small Intestinal Bacterial Overgrowth and Malabsorption
Pancreatic Insufficiency
Colonic Involvement in SSc and the Approach to Diagnosis and Management
Constipation
Pseudo-Obstruction
Pneumatosis (Cystoides) Intestinalis
Intestinal Pseudodiverticula
The Anorectum
Gastrointestinal Bleeding
Malnutrition
Medication Adverse Effects
Alterations in the GI Microbiome in SSc
Dysbiosis in SSc
Dysbiosis and SSc-GI Symptoms
Dysbiosis and SSc Features
The Relationship Between Nutrition and the SSc-GI Microbiome
Dietary Modifications and the GI Microbiome
Omega-3 Polyunsaturated Fatty Acids
Probiotics
Prebiotics
Antibiotics
Fecal Microbiota Transplantation
Conclusions
References
Part VII: Skin, Musculoskeletal and Other Complications
33: Evaluation and Management of Skin Disease
Phototherapy for Skin Fibrosis
Lipodystrophy
Treatment
Xerosis Cutis and Pruritus
Treatment
Telangiectasias
Treatment
Dyspigmentation
Treatment
Nail Involvement in SSc
Treatment
Orofacial Manifestations
Treatment
Ulcerations
Treatment
Future Directions
References
34: Calcinosis
Introduction
Definition of Calcinosis
Epidemiology, Distribution, and Clinical Associations of Calcinosis in Systemic Sclerosis
Clinical Presentation and Complications of Calcinosis
Composition of Calcinosis and Pathogenesis
Diagnosis
Treatment of Calcinosis
General Measures and Supportive Therapies
Medical Therapies
Vasodilators
Calcium Channel Blockers
Treprostinil
Anti-inflammatories
Triamcinolone Acetonide Injection
Minocycline
Colchicine
Intravenous Immunoglobulins
Biologic Agents
Interferes with Calcium Metabolism
Sodium Thiosulfate
Bisphosphonates
Warfarin
Nonmedical Therapies
Conclusions
References
35: Tendons, Joints, and Bone
Articular and Tendon Involvement
Tendon Involvement
Clinical Presentations
Prevalence
Enthesitis and Synovio-Entheseal Complex Involvement
Correlation with SSc Features and Prognosis
Treatment
Carpal Tunnel Syndrome
Joint Involvement
Clinical Presentation
Prevalence
Imaging Studies
Laboratory Findings
Joint Involvement as a Correlate of Prognosis in SSc
Radiologic Features: Structural Osteoarticular Lesions
Management
Pharmacological Treatments
Developing SSc-Specific MSK Outcome Measures for Future RCTs
Non-pharmacological Management Strategies
Non-articular Musculoskeletal Manifestations
Calcinosis
Acro-Osteolysis
Bone Involvement
Conclusions and Perspectives
References
36: Skeletal Muscle Involvement
Prevalence and Epidemiology
Risk Factors Associated with Skeletal Myopathy
Evaluation of Skeletal Muscle Involvement
Muscle Strength Testing
Muscle Enzymes
Electromyography (EMG) and Nerve Conduction Study (NCS)
Magnetic Resonance Imaging (MRI) of Muscles
Muscle Biopsy
Muscle Histopathology
Predominance of Muscle Fibrosis Without Inflammation or Necrosis Is a Unique Feature of Scleroderma Muscle Disease
Inflammation and Necrosis Are Prevalent Findings in Scleroderma Muscle Disease
Immunostaining of Muscle Biopsies
Autoantibodies
Novel Imaging Modalities
Treatments and Prognosis
Conclusion
References
37: Cancer in Systemic Sclerosis
Epidemiology of Cancer in SSc
Potential Risk Factors and Mechanisms That May Explain the Increased Cancer Risk
Data Suggesting That a Subset of Systemic Sclerosis Is a Paraneoplastic Disease
Genetic Alteration of Autoantigens in Malignancies May Be an Antigen Source That Triggers Scleroderma
Autoantibodies and Clinical Phenotype May Define Tumor Risk, Type, and Timing
Unique Scleroderma Immune Responses, Alone or in Combination, May Be Cancer-Protective
Implications for Cancer Screening and Scleroderma Therapeutics
Complexity of Cancer Care in Patients with SSc
Summary
References
38: Overlooked Manifestations
Oral Manifestations
Audiovestibular Disease
Thyroid Dysfunction
Liver Disease
Lower Urinary Tract
Erectile Dysfunction
Avascular Necrosis of Bone
Neurological Manifestations
Summary
References
39: Pregnancy
Sexuality in Women with Systemic Sclerosis
Fertility
Pathogenesis in SSC Pregnancies
Placental Pathology and Vasculopathy
Fetal Microchimerism
Pregnancy Outcomes
Miscarriage
Premature Delivery
Preeclampsia
Intrauterine Growth Restriction and Small for Gestational Age Infants
Neonatal Mortality
Effects of Pregnancy on Systemic Sclerosis
Renal Disease
Musculoskeletal and Gastrointestinal Disease
Raynaud’s Phenomenon and Digital Ulceration
Cardiopulmonary Disease
Pulmonary Arterial Hypertension
Pregnancy Management
Management of Renal Crisis during Pregnancy
Management of Pregnancy in Mothers with Prior Renal Crisis
Management of Pulmonary Hypertension During Pregnancy
Management of Delivery
Summary
References
40: Vaccinations in Patients with Systemic Sclerosis
The Justification for Vaccination Programmes in ARDs
Risk of Precipitating ARDs Following Vaccination
Risk of Exacerbating ARDs Following Vaccination
Risk of Sclerosing Skin Disease Following Vaccination
Impact of Immunomodulatory Treatments on Vaccine Efficacy
Re-Vaccination Following Autologous Hematopoietic Stem Cell Transplantation
Safety of Live Vaccines in ARDs
Uptake of Vaccination Programmes in Patients with ARDs
Vaccination Immunogenicity and Safety in Patients with Systemic Sclerosis
Pneumococcal Vaccination
Hepatitis B Vaccination
Influenza Vaccination
Yellow Fever Vaccination
Measles Vaccination
Varicella Vaccination
Human Papillomavirus Vaccination
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
Conclusions
References
Part VIII: Management and Outcome Assessment
41: Overview of Management and Outcome Assessment in Systemic Sclerosis
Principles of Management
Outcome Measure Development
Role of OMERACT in Development and Testing of New Outcome Measures
Defining and Quantifying Damage and Disease Activity
Systemic Sclerosis as a Multi-Compartment Disease
Composite Outcome Measures
Patient-Reported Outcomes
Biomarkers
Organ-Specific Treatment and Outcomes
Skin Assessment and Treatment
Lung Fibrosis
Pulmonary Hypertension
Gut Disease
Raynaud’s and Digital Vasculopathy
Cardiac Disease
Concluding Remarks
References
42: Management of Progressive Skin Involvement in Diffuse Scleroderma
Introduction
Clinical Features
Associated Morbidity
Risk Factors for Progressive Skin Involvement
Monitoring of Disease Progression and of Treatment Response
‘General’ Treatments
Analgesia
Treatment of Itch
Physiotherapy and Occupational Therapy
Intravenous Iloprost
Immunosuppressive Therapy
Corticosteroids
Methotrexate
Cyclophosphamide
Mycophenolate Mofetil
Targeting Therapy
Rituximab
Tocilizumab
Other Targeting Therapies
Autologous Hematopoetic Stem-Cell Transplantation
Overall Conclusions
References
43: Hematopoietic Stem Cell Transplantation
Clinical Effects of HSCT in Systemic Sclerosis
Mechanistic Effects of HSCT in Systemic Sclerosis
Patient and Societal Perspectives
Summary and Conclusions
References
44: Immune-Targeted Therapies in SSc
Introduction
Innate Immunity
Targeting Myeloid Cell
Dendritic Cell and Interferon
TLR and Inflammasome
Neutrophils
Complement Activation
Lysophosphatidic Acid Signalling
Adaptive Immune System
T-Cell-Directed Strategies
B Cell-Directed Therapies
Intravenous Immunoglobulin
IL-6 Family and Janus Kinase Signalling
Future Challenges
References
45: Physical and Occupational Therapy
Measuring Disability and Participation Restrictions
Health Assessment Questionnaire
Cochin Hand Function Scale (CHFS)
Cochin 17-Item Scleroderma Functional Scale (CSF-17)
Keitel Functional Test
Hand Functional Index (HFI)
Kapandji Index
Hand Mobility in Scleroderma (HAMIS)
Disabilities of the Arm, Shoulder, and Hand (DASH)
Mouth Handicap in Systemic Sclerosis Scale (MHISS)
Evaluation of Patient Priorities
Rehabilitation
Hand Exercises
Strengthening and General Exercise and Conditioning
Occupational Therapy
Self-Management Programs
Conclusions
References
46: Psychosocial Issues and Care for Patients with Systemic Sclerosis
Depression
Anxiety
Fatigue and Sleep
Pain
Pruritus
Body Image Distress
Sexual Dysfunction
Clinical Strategies for Psychosocial Care
Psychological Interventions in SSc
Self-help Resources
Self-Management Approaches
Support Groups
SSc-Specific Resources
References
47: Measuring Disease Activity and Outcomes in Clinical Trials
Introduction
Measurement Properties of an Instrument: Feasibility, Reliability, and Validity
Measuring Disease Activity and Damage to Assess the Severity of SSc
Disease Activity in SSc
Damage Index in SSc
Assessment of Disease Severity
Outcome Measures in SSc
Measuring Skin Disease in SSc
Measuring Musculoskeletal Involvement in SSc
Measuring Cardio-Pulmonary Disease in Scleroderma
The 6-min Walk Test in SSc-Related ILD
The 6MWT and Time to Clinical Worsening: Outcome Measures for Pulmonary Arterial Hypertension
Dyspnea Indices
Measuring Gastrointestinal Disease in SSc
Measuring Vascular Disease in SSc: Raynaud’s Phenomenon and Digital Ulcers
Measuring Digital Ulcers in SSc
Measuring Physical Function and Health-Related Quality of Life in SSc
The Short Form 36 (SF-36) and the Health Assessment Questionnaire-Disability Index (HAQ-DI)
Preference-Based Measures for HRQOL in SSc: The Short Form 6D (SF-6D)
Patient-Reported Outcomes Measurement Information System (PROMIS)
American College of Rheumatology Provisional Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis (CRISS) Index
Biomarkers for SSc
Conclusion
References
Recommended Reading
48: Evolving Clinical Trial Design and Innovative Approaches
Introduction
Historical Perspective
Considerations in Trial Design
Scleroderma Subset
Stage
Autoantibody Status and ANA Subgroups
Molecular Stratification
Biomarkers for Stratification and Pharmacodynamic Evaluation
Cohort Enrichment in Clinical Trials
Composite Endpoints
Recent Experience in Systemic Sclerosis Trials
Trials Examining a Single Disease Manifestation
Pulmonary Arterial Hypertension (PAH)
Digital Ulcers (DU)
Lung Fibrosis (SSc-ILD)
Assessing Quality of Life in Clinical Trials
Future Strategies
References
49: Drug Development and Regulatory Considerations for Systemic Sclerosis Therapies
Drug Development Overview
From Molecule to Market: Time and Risk
Cost of Drug Development
Drug Discovery Phases
Initiation of New Programs
Validation and Optimization Phase
Candidate Selection and Profiling
Initiating SSc Targeted Drug Discovery Programs
Clinical Development Phases
Exploratory Clinical Development: Phases 1 and 2a
Confirmatory Clinical Development: Phases 2b and 3
Regulatory Submission and Review
Post-approval Studies: Phase 4 and Beyond
Strategies for SSc Drug Development
Conclusion
References
Part IX: Case Studies: Approach to Complex Clinical Problems
50: Managing the Ischemic Finger in Scleroderma
Case Presentation
Initial Therapy
The Ischemic Digital Crisis
Indication for Intravenous Therapy
Indications for Digital Sympathectomy
Prevention of Recurrent Digital Ischemic Events
Key Principle Lessons of the Case
References
51: Scleroderma Renal Crisis: A Case Study
Case
Discussion
References
52: Rapid Diffuse Skin Disease with Progressive Joint Contractures
Case Presentation
Introduction and Background
Treatment Considerations
Methotrexate
Mycophenolate Mofetil (MMF)
Cyclophosphamide
Intravenous Immunoglobulin (IVIg)
Tyrosine Kinase Inhibitors
Rituximab
Abatacept
Tocilizumab
Immunoablation with Stem Cell Rescue
Rehabilitation Therapy
Key Principle Lessons of the Case
References
53: Management of the Scleroderma Patient with Pulmonary Arterial Hypertension Failing Initial Therapy
Case
Discussion
Case
Discussion
Case
Discussion
Case
Discussion
Case
Key Principle Lessons of the Case
References
54: Pseudo-obstruction with Malabsorption and Malnutrition
Case Study
Introduction
Diagnosis
Management
Conclusions
References
55: Progressive Interstitial Lung Disease Non-Responsive to Immunosuppressive Therapy
Case Presentation
Treatment Course
Discussion
References
56: Body Image Distress in Scleroderma
Case Study
Discussion
Body Image in Scleroderma
Social Impacts of Poor Body Image
Self-Esteem and Mood Impacts of Body Image Distress
Sexual Impacts of Body Image Dissatisfaction
Fear of Physical Progression
Assessments of Body Image
Clinical Strategies for Body Image Distress
Psychosocial Treatments
Cosmetic Camouflage and Surgical Options
Conclusion
References
57: Managing Complicated Digital Ulcers
The Spectrum of DU in Systemic Sclerosis
Ischaemic (Fingertip) DU
Case 1: Refractory Ischaemic Digital Ulceration
Case 2: Associated Macrovascular Disease
Case 3: Pro-coagulant Tendency
Calcinosis-associated DU
Case 4: Refractory Calcinosis-associated DU
Case 5: Inflammatory Calcinosis-associated DU
Extensor Digital Ulcers in SSc
Case 6: Extensor-aspect SSc-DU in dcSSc
Conclusions
References
58: Lower Limb Ulceration
Introduction
Case 1: Ischaemic Toe Ulceration
Discussion
Case 2: Ulceration Overlying Calcinosis
Discussion
Case 3: Ulcers Overlying the Malleoli
Discussion
Case 4: Superficial Ulceration/Erosion in Early Diffuse Cutaneous SSc
Discussion
General Approach to the Management of Lower Limb Ulceration in the Patient with Systemic Sclerosis
Conclusions
References
Index
