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