Drug Eruptions

Preface
Introduction
Clinical Approach to a Patient with a Cutaneous ADR
Drug Causality in Cutaneous ADRs
Classification of the Cutaneous ADRs
Mechanistic Classification
Drug Hypersensitivity Reactions
Non-hypersensitivity
Phenotypic Classification
Contents
Contributors
Part I: General Considerations
Pharmacogenetics of Cutaneous Adverse Drug Reactions
1 Introduction
2 Abacavir Hypersensitivity and HLA-B*57:01
3 Carbamazepine Hypersensitivity
3.1 Carbamazepine Metabolism Genes
3.2 Carbamazepine and HLA Alleles
HLA-B*15:02
HLA-A*31:01
3.3 Carbamazepine and Other HLA Alleles
3.4 Carbamazepine and T Cell Receptor Variation
4 Aromatic Antiepileptics and Hypersensitivity
5 Allopurinol Hypersensitivity and HLA-B*58:01
6 Dapsone Hypersensitivity
7 Other Drugs
8 Discussion
References
Mechanisms of Drug Hypersensitivity
1 Introduction
2 Models of Drug Antigen Presentation
3 Genetic Factors in Drug Hypersensitivity
3.1 Genetic Factor in Immediate-Type Drug Hypersensitivity
3.2 Genetic Factor in Delayed-Type Drug Hypersensitivity
Allopurinol
Aromatic Anticonvulsants
Abacavir
Other Drugs
4 Drug Metabolism in SCARs
5 Immune Mechanisms in DH
5.1 Immediate-Type: IgE-Mediated DH
5.2 Delayed-Type: T Cells Mediated DH
MPE (Type Iva)
DRESS Syndrome (Type IVb)
SJS/TEN (Type IVc)
Granulysin
Perforin/Granzyme B Pathway
NK Cells
Fas–FasL Interaction
Annexin A1–FPR1 Interaction
Cytokines/Chemokines Involved in the Cell Immunity of SJS/TEN
AGEP (Type IVd)
6 T Cell Receptor (TCR) Repertoire in Drug Hypersensitivity
7 Conclusion
References
Histopathology of Cutaneous Adverse Drug Reactions
1 Introduction
2 Inflammatory Patterns in CADR
2.1 Spongiotic Reaction Pattern
2.2 Interface Dermatitis Pattern
3 Non-specific Histological Aspects of Cutaneous ADRs
4 Drug-Induced Exanthem
5 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
6 Acute Generalized Exanthematous Pustulosis (AGEP)
7 Stevens–Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN)
8 Fixed Drug Eruption (FDE)
9 Symmetrical Drug-Related Intertriginous and Flexural Exanthem (SDRIFE)
10 Problems of Differential Diagnosis in Drug Eruption Dermatopathology
References
Skin Tests in Evaluating Drug Eruptions
1 Introduction
2 Skin Tests for Immediate Drug Eruptions
3 Skin Tests for Nonimmediate Drug Eruptions
4 Other Skin Tests
5 Conclusions
References
In Vitro Drug Allergy Testing
1 Introduction
2 Immediate Drug Hypersensitivity Reactions
2.1 Acute Phase Mediators
2.2 Immunoassays
2.3 Basophil Activation Test (BAT)
3 Delayed Drug Hypersensitivity Reactions
3.1 Lymphocyte Proliferation Assay (LPA), Lymphocyte Transformation Test (LTT)
3.2 Flow Cytometry
3.3 Enzyme-Linked Immunospot (ELISpot) and Enzyme-Linked Immunosorbent Assay (ELISA)
3.4 Practical Utility of In Vitro Tests
4 Conclusions
References
Part II: Reaction Patterns
Drug-Induced Urticaria
1 Introduction
2 Pathophysiology
2.1 Immunologically Mediated Reactions
IgE Antibody-Dependent Reactions
Formation of Immune Complexes
2.2 Non-Immunological Reactions
Direct Mast Cell Degranulation
Kinin-Mediated Angioedema
Interference with the Arachidonic Metabolism
3 Evaluation of a Patient with Suspected DIU
4 Investigating DIU
4.1 In Vitro Testing
Tests to Aid Diagnosis
Tests to Help Identify Culprit Drug
4.2 In Vivo Testing
5 Management of DIU
6 Medications Associated with DIU
6.1 Aspirin and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
6.2 Opiates
6.3 Angiotensin-Converting Enzyme Inhibitors (ACEi)
6.4 Others
7 Summary
References
Exanthematous Drug Eruptions
1 Introduction
2 Pathogenesis
3 Epidemiology
4 Clinical Features
5 Offending Agents
6 Diagnosis
7 Management
8 Conclusion and Future Directions
References
Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis
1 Introduction
2 Medication Risk
3 Pathophysiology
4 Clinical Presentation
5 Management and Treatment
6 Supportive Care
7 Local Management of Skin and Mucous Membranes
8 Immunomodulatory Approaches
9 Long-Term Follow-Up
10 Tests to Identify the Culprit Drug
11 Prevention of SJS/TEN
References
Acute Generalised Exanthematous Pustulosis
1 Introduction
2 Epidemiology
3 Pathophysiology
4 Pathology
5 Culprit Drugs
6 Clinical Features
7 Differential Diagnosis
8 Investigations
9 Management
References
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
1 Introduction
2 Epidemiology
3 Drug Causality
4 Pathophysiology
5 Clinical Features
6 Histopathology
7 Long-Term Sequelae of DRESS
8 Differential Diagnosis
9 Prognosis and Management
10 Conclusion
References
Fixed Drug Eruptions and Generalized Bullous Fixed Drug Eruptions
1 Introduction
2 Epidemiology
3 Pathophysiology
3.1 Histopathology
3.2 Pathomechanism
4 Clinical Features
4.1 Clinical Presentation
4.2 Differential Diagnosis
4.3 Culprit Drugs
4.4 Prognosis
5 Investigations
6 Management
References
Lichenoid Drug Eruptions
1 Introduction
2 Epidemiology
3 Description of Features
4 Drug Causality
4.1 Biologics
4.2 Immune Checkpoint Inhibitors
5 Variations in Clinical Features of LDE
6 Histological Findings
7 Pathogenesis
7.1 Treatment
References
Drug-Induced Connective Tissue Disorders
1 Drug-Induced Lupus Erythematosus
1.1 Epidemiology
1.2 Drug Causality in Drug-Induced Lupus Erythematosus
1.3 Pathophysiology
Genetic Susceptibility
Effects on Adaptive Immunity
Effects on Innate Immunity
Clinical Features
Drug-Induced Systemic Lupus Erythematosus
Drug-Induced Subacute Cutaneous Lupus Erythematosus
1.4 Diagnosis
Serological Profile
1.5 Management
2 Drug-Induced Dermatomyositis
3 Drug-Induced Scleroderma
References
Drug-Induced Vasculitis
1 Introduction
2 Clinical Approach
3 Drugs Commonly Associated with Cutaneous Vasculitis
3.1 Antibiotics
3.2 Anti-TNF-α Agents
3.3 Propylthiouracil
3.4 Cocaine/Levamisole
3.5 Cancer Immunotherapy
4 Pathogenesis
5 Conclusion
References
Drug-Induced Autoimmune Bullous Diseases
1 Drug-Induced Pemphigus
1.1 Clinical Features
1.2 Drug Causality and Pathophysiology
2 Drug-Induced Bullous Pemphigoid (DIBP)
2.1 Clinical Presentation/Investigations
2.2 Pathophysiology
2.3 Drug Causality
3 Drug-Induced Linear IgA Bullous Dermatosis (LABD)
3.1 Clinical Presentation
3.2 Pathophysiology
3.3 Drug Causality
4 Drug-Induced Epidermolysis Bullosa Acquisita (EBA)
4.1 Management of Drug-induced Autoimmune Blistering Diseases
5 Conclusion
References
Other Drug-Induced Inflammatory Skin Reactions
1 Drug-Induced Granulomatous Reactions
1.1 Interstitial Granulomatous Drug Reaction (IGDR)
1.2 Drug-Induced Sarcoidosis
1.3 Drug-Induced Granuloma Annulare (GA)
1.4 Drug-Induced Accelerated Rheumatoid Nodulosis
2 Drug-Induced Neutrophilic Reactions
2.1 Drug-Induced Sweet’s Syndrome
3 Drug-Induced Pityriasis Rosea (PR)-like Reactions
4 Drug-Induced Panniculitis
4.1 Drug-Induced Erythema Nodosum
Clinical Features
4.2 Drug-Induced (Primarily Lobular) Neutrophilic Panniculitis
Introduction
Pathophysiology
Clinical Features
5 Drug-Induced Eczematous Reactions
6 Drug-Induced Acneiform Eruptions (Drug-Induced Acne)
References
Drug-Induced Photosensitivity
1 Introduction
2 Epidemiology
3 Pathogenesis
4 Systemic Drug Phototoxicity and Common Culprits
5 Clinical Presentation of Drug Photosensitivity
6 Wavelength Dependency
7 Investigations for Drug-Induced Phototoxicity
8 Regulatory Requirements for Photosafety Evaluation
9 Topical Photoallergy
10 Other Possible Effects of Drug Photosensitivity
11 Management
12 Practical Advice
13 Conclusions
References
Drug-Induced Pruritus Without Primary Rash
1 Definition
2 Overall Prevalence
3 Categories
4 Pathogenesis of Drug-Induced Pruritus
4.1 The Itch Pathway
4.2 Specific Drugs Inducing Pruritus
Opioids
Chloroquine
Hydroxyethyl Starch
Drugs Inducing Cholestasis
Anticancer Therapies
Other Drugs
5 Diagnosis
6 Treatment
7 Conclusion
References
Drug-Induced Nail Changes
1 Introduction
2 Human Nail Unit Anatomy with Pathophysiological Correlation
3 Approach to Nail Unit Drug Reaction
4 Common Examples of Drugs Causing Specific Clinical Findings in the Nail Unit
4.1 Nail Fold
4.2 Nail Bed
4.3 Nail Plate/Matrix
4.4 Nail Matrix Melanocytes
Entire Nail Unit
5 Management Principles for Nail Unit Drug Reactions
References
Drug-Induced Hair Changes
1 Introduction
2 The Hair Cycle and Hair Immune System
3 Clinical Assessment
4 Telogen Effluvium
5 Chemotherapy-Induced Alopecia/Anagen Effluvium
6 Chemotherapy-Induced Alopecia: Prevention and Treatments
7 Persistent Chemotherapy-Induced Alopecia
8 Targeted Therapies: Anti-tumour Necrosis Factor (Anti-TNF) Therapy
9 Targeted Oncology Therapies
10 EGFR Inhibitors
11 Tyrosine Kinase Inhibitors and Hair Pigmentation
12 Immune Checkpoint Inhibitors and Autoimmune Reactions
13 Hormone Effects on Hair Growth
14 Anti-oestrogen Therapy
15 Hirsutism, Hypertrichosis, and Trichomegaly
16 Drug-Induced Hair Colour and Texture Changes
17 Conclusions
References
Drug-Induced Pigmentary Disorders
1 Introduction
2 Pathogenesis
2.1 Drug-Induced Hyperpigmentation
2.2 Drug-Induced Hypopigmentation
3 Approach to Diagnosis of Drug Induced Pigmentary Disorders
3.1 Clinical Presentation
3.2 Differential Diagnosis
4 Common and New Drugs Inducing Hyperpigmentation
4.1 Antimalarials, e.g., Hydroxychloroquine (HCQ), Chloroquine, Mefloquine, Quinacrine
4.2 Analgesics, e.g., Non-steroidal Anti-inflammatory Drugs (NSAIDS), Paracetamol
5 Cardiac Drugs, e.g., Amiodarone, Diltiazem, Amlodipine
6 Chemotherapeutic Agents, e.g., 5-Fluorouracil, Bleomycin, Hydroxyurea, Anthracyclines
7 Antimicrobial Agents, e.g., Antibiotics, Anti-mycobacterial Agents, Anti-retrovirals
8 Metals, e.g., Bismuth, Gold, Silver, Iron
9 Psychotropic Agents, e.g., Chlorpromazine, Desipramine, Imipramine, Amitriptyline
9.1 Others
10 Common and New Drugs Inducing Hypopigmentation
11 Special Mention: Tyrosine Kinase Inhibitors
12 Conclusion
References
Part III: Special Drug Categories
Immediate and Delayed Reactions to Beta-Lactams
1 Introduction
2 BL Consumption and Sensitization Patterns over Time
3 Clinical Manifestations
3.1 Cutaneous Immediate Adverse Reactions
3.2 Cutaneous Nonimmediate Adverse Reactions
4 Diagnostic Procedure
4.1 Clinical History
4.2 Skin Tests
4.3 Drug Provocation Test
4.4 In Vitro Tests
Immediate Reactions
Detection and Quantification of Specific IgE
Basophil Activation Test
Histamine Release Test
Nonimmediate Reactions
Lymphocyte Transformation Test
Immunospot Assay (ELISpot)
5 Conclusions
References
Hypersensitivity Reactions to Iodinated Radiocontrast Media
1 Introduction
2 Classification of Hypersensitivity Reactions to RCM
3 Epidemiology and Risk Factors
4 Clinical Manifestations
5 Mechanisms of RCM Hypersensitivity
6 Diagnosis
6.1 Indication for Testing
6.2 Skin Tests
6.3 Laboratory Tests
6.4 Drug Provocation Test (DPT)
7 Management of Patients with RCM Hypersensitivity
7.1 Patients with Urgent Need of RCM Without Possibility of Immediate Testing
7.2 Management of Patients After Allergy Workup
References
Cutaneous Adverse Reactions to Biologic Agents
1 Introduction
2 General Principles/Classification
2.1 Localised Injection Site Reactions
2.2 Systemic Hypersensitivity Reactions
Immediate Hypersensitivity Reactions
Cytokine Release Syndrome
Type I Reactions: IgE Mediated
IgG Mediated
Non-immediate Hypersensitivity Reactions
Type III Reactions: Serum Sickness like Reactions (SSLR)
Delayed Type IV Reactions
2.3 Off-Target Inflammatory Cutaneous Eruptions
3 Classes of Biologic Agents and Their Reactions
3.1 Anti-tumour Necrosis Factor-α Agents (Anti-TNFs)
Hypersensitivity Reactions
Local Injection Site Reactions (ISRs)
Acute Infusion Reactions and Anaphylaxis
Off-Target Inflammatory Cutaneous Eruptions
Psoriasis/Psoriasiform Eruptions
Eczematous Reactions
Granulomatous Reactions
Lupus-like Reactions
Cutaneous Vasculitis
Hidradenitis Suppurativa
3.2 Anti-CD-20 (Rituximab)
Hypersensitivity Reactions
Off-Target Inflammatory Cutaneous Eruptions
3.3 Anti-IL 1 (Anakinra, Canakinumab)
3.4 Anti-IL 4/13 (Dupilumab)
Off-Target Inflammatory Cutaneous Eruptions
3.5 Anti-IL-5 (Mepolizumab, Reslizumab, and Benralizumab)
3.6 Anti-IL-6 (Tocilizumab)
Hypersensitivity Reactions
Off-Target Inflammatory Cutaneous Eruptions
3.7 Interleukin 17 Inhibitors
Hypersensitivity Reactions
Off-Target Inflammatory Cutaneous Eruptions
3.8 Anti IL12/23 Inhibitor (Ustekinumab)
Hypersensitivity Reactions
Off-Target Inflammatory Cutaneous Eruptions
3.9 Anti-IL23 Inhibitor (Guselkumab)
3.10 Anti-IgE (Omalizumab)
4 Management of Hypersensitivity Reactions to Monoclonal Antibodies Biologic Agents
4.1 Acute Management
4.2 Local/Injection Site Reactions
4.3 Off-Target Inflammatory Cutaneous Eruptions
4.4 Diagnostic Evaluation of Hypersensitivity Reactions
4.5 Desensitisation
4.6 Challenge
4.7 Premedication
5 Conclusion
References
Cutaneous Reactions to Oncologic Targeted Therapy
1 Introduction
2 Epidemiology
3 Pathophysiology
4 Clinical Features
4.1 EGFRi
Acneiform Eruption
Pruritus and Dry Skin (Xerosis)
Nail Changes
Hair Changes
Mucositis
4.2 Multikinase Inhibitors (MKi)
Hand-Foot Skin Reaction (HFSR)
4.3 BRAF Inhibitors (BRAFi)
Keratotic Lesions
Photosensitivity
4.4 MEK Inhibitors (MEKi)
4.5 Mammalian Target of Rapamycin Inhibitors (mTORi)
4.6 Hedgehog Signaling Pathway Inhibitors (HhSPi)
4.7 KIT Inhibitors (KITi)
Pigmentary Changes
5 Prognosis
6 Management
References
Cutaneous Reactions to Oncologic Immunotherapy
1 Introduction
2 Epidemiology
2.1 Anti-CTLA-4 Therapy: Ipilimumab
2.2 Anti-PD-1 Therapy: Nivolumab, Pembrolizumab, and Cemiplimab
2.3 Anti-PD-L1 Therapy: Atezolizumab, Avelumab, Durvalumab
2.4 Combination CTLA-4-PD-1 Inhibition Therapy
3 Clinical Features and Histopathology of Cutaneous irAE
3.1 Common Cutaneous AE
Pruritus
3.2 Morbilliform Rash
3.3 Lichenoid Reaction and Other Papulosquamous Disorders
3.4 Vitiligo-like Depigmentation
Bullous Eruptions
SCARs
3.5 Miscellaneous Reactions
4 Conclusion
References
Index