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Cutaneous Drug Reactions

Chapter 63 | Part 2 – Cardinal Manifestations & Presentation · Part 2 – Cardinal Manifestations & Presentation · Chapter 63

Key Clinical Points

  1. Cutaneous reactions are the most frequent adverse drug reactions (10–15%), ranging from benign to life-threatening.
  2. Morbilliform eruptions are the most common reaction (91% of acute cases in hospitalized patients).
  3. Severe Cutaneous Adverse Reactions (SCARs) include SJS/TEN, DRESS, and AGEP; incidence is between 1 in 1000 and 2 per million users.
  4. HLA-B*57:01 screening has a 100% negative predictive value for abacavir hypersensitivity (AHS).
  5. Specific HLA alleles are associated with severe reactions: HLA-B15:02 (carbamazepine), HLA-B58:01 (allopurinol), HLA-B13:01 (dapsone/sulfonamides), and HLA-A32:01 (vancomycin).
  6. Immune-mediated reactions are categorized by pathway: Type I (IgE), Type II (Cytotoxic), Type III (Immune Complex), and Type IV (T-cell mediated).
  7. Type IV is further subdivided into IVa (macrophage/cytotoxic), IVb (eosinophil), and IVc (neutrophil) pathways.
  8. Nonimmunologic reactions include photodermatitis, pigmentation changes, hair loss, and nail disorders.
  9. Warfarin-induced skin necrosis occurs in 0.01–0.1% of patients, typically in women, between days 3–10 of therapy.
  10. Immune Checkpoint Inhibitors (ICIs) cause immune-related adverse events (irAEs) in 30–60% of patients.
  11. Morbilliform eruptions are rarely assisted by laboratory testing or skin biopsy; absence of enanthems supports drug etiology.

DEFINITION & CLASSIFICATION

• Overview: Cutaneous reactions are the most frequent adverse drug reactions (10–15%). • Clinical Significance: Most are benign; however, some (SCARs) are life-threatening and require prompt recognition. • Mechanism Basis: Reactions are categorized as immunologic or nonimmunologic. • Immune Pathway Classification: Based on Table 63-1, reactions are classified by the primary immune mediator:

Table 63-1: Revised Classification of Adverse Drug Reactions Based on Immune Pathway • Type I (IgE-mediated): IgE, B cells, T2, ILC2; Mast cells, basophils → Acute urticaria, angioedema, anaphylaxis. • Type II (Cytotoxic): IgG, B cells, IgM; Phagocytes, neutrophils, macrophages → Drug-induced cytopenia (e.g., hemolysis, thrombocytopenia). • Type III (Immune Complex): IgG + antigen (immune complexes); B cells, IgM, IgG; Complement, basophils, mast cells, platelets, Neutrophils, monocytes, macrophages → Serum sickness, Arthus reaction, drug-induced vasculitis and lupus. • Type IVa (T-cell mediated macrophage/cytotoxic): T1, ILC1, Tc1, NK; IFN-γ, TNF-α, granzyme B, perforins, granulysin; Macrophages → SJS/TEN, erythema multiforme, allergic contact dermatitis, fixed drug eruption. • Type IVb (T-cell mediated eosinophil): T2, ILC2, Tc2, NK-T; IL-4, IL-5, IL-9, IL-13, IL-31; Eosinophils, B cells, mast cells/basophils → DIHS/DRESS, Morbilliform eruption. • Type IVc (T-cell mediated neutrophil): TH17, ILC3, Tc17; IL-17, IL-22, IL-23, CXCL8, GM-CSF; Neutrophils → AGEP.

EPIDEMIOLOGY

• Incidence: • 2.2 to 10 per 1000 hospitalized patients experience acute cutaneous reactions. • Morbilliform rash (91%) and urticaria (6%) are the most frequent skin reactions. • Severe hypersensitivity reactions (SCARs) occur in between 1 in 1000 and 2 per million users, depending on reaction type. • Common Culprits: Antimicrobials, radiocontrast, and nonsteroidal anti-inflammatory drugs (NSAIDs). • Risk Factors: • Elderly patients, patients with autoimmune disease, and hematopoietic stem cell transplant recipients. • Infections: EBV or HIV. Individuals with advanced HIV (CD4+ <200 cells/μL) have a 40- to 50-fold increased risk of reactions to sulfamethoxazole and higher overall risk for severe hypersensitivity.

ETIOLOGY & PATHOPHYSIOLOGY

• Nonimmunologic Mechanisms: • Pigmentation: Due to dermal accumulation or altered hair follicles (e.g., minocycline, amiodarone). • Mast Cell Activation: Non-IgE-mediated; can occur on first exposure; dose-related (e.g., NSAIDs, fluoroquinolones, vancomycin). • IgE-Mediated: Requires prior sensitization; often due to haptenated products or excipients (e.g., penicillin, cephalosporins). • Immunologic Mechanisms: • Immediate Reactions: Urticaria/anaphylaxis via IgE or direct mast cell activation (MRGPRX2). • Delayed Reactions: T-cell mediated; involves specific CD4+ and CD8+ T-cell clones. • SCARs Pathophysiology: Driven by MHC-restricted T-cell recognition of drug-peptide complexes. • Genetic Factors: • HLA-B*57:01: Associated with abacavir hypersensitivity (AHS); 100% negative predictive value. • HLA-B*15:02: Associated with carbamazepine-induced SJS/TEN in Han Chinese populations. • HLA-B*58:01: Associated with allopurinol-induced DRESS/SJS/TEN in Han Chinese populations. • HLA-B*13:01: Associated with dapsone or sulfonamide-induced SJS/TEN. • HLA-A*32:01: Associated with vancomycin-induced DRESS/SJS/TEN. • Metabolism Factors: e.g., CYP2C9*3 slow metabolism → risk of phenytoin-induced morbilliform eruption, DRESS, and SJS/TEN.

CLINICAL FEATURES

• Photosensitivity Eruptions: • Mechanism: Typically phototoxic; resembles sunburn. • Common Drugs: Fluoroquinolones, tetracyclines, trimethoprim/sulfamoxazole, thiazides, NSAIDs. • Severe Cases: Voriconazole (risk of cancer/accelerated aging); Hydrochlorothiazide (nonmelanoma risk). • Pigmentation Changes: • Minocycline/Amiodarone: Blue-gray pigmentation. • Phenothiazine/Gold/Bismuth: Gray-brown pigmentation. • Quinacrine: Yellow discoloration. • Antimalarials: Hyperpigmentation of face, mucous membranes, pretibial area. • Drug-Induced Hair Disorders: • Anagen Effluvium: Occurs within days (e.g., antimetabolites, chemotherapy). • Telogen Effluvium: Delay of 2–4 months after initiation (e.g., carbamazepine, valproate). • Hirsutism/Hypertrichosis: Caused by androgens or other agents (e.g., minoxidil, cyclosporine A). • Drug-Induced Nail Disorders: • Timing: Usually involves all 20 nails; months to resolve. • Types: Beau lines, onycholysis, onychomadesis, pigmentation, paronychia. • Common Drugs: Tetracyclines, fluoroquinolones, retinoids, chemotherapy agents. • Warfarin Necrosis of Skin: • Incidence: 0.01–0.1% of patients; typically women; days 3–10 of therapy. • Sites: Breurs, thighs, buttocks. • Mechanism: Tissue hypercoagulability in protein C or S deficiency → microvascular thrombosis. • Toxic Erythema of Chemotherapy (TEC): • Palmar Erythema: Edematous eruption of palms/soles; caused by citarabine, doxorubicin, methotrexate, hydroxyurea, fluorouracil, capecitabine. • Exacerbation of Dermatologic Diseases: • Includes psoriasis, bullous pemphoid, and cutaneous neoplasms.

DIFFERENTIAL DIAGNOSIS

• Viral Exanthem vs. Drug Eruption: • Differentiation based on timing of onset and presence/absence of enanthems. • Graft-versus-Host Disease: • Must be considered in transplant patients with cutaneous reactions.

DIAGNOSTIC APPROACH

  1. Clinical Assessment of Timing (Latency):
  2. Identify duration from first ingestion to symptom onset.
  3. <6 hours → Suggests IgE-mediated or non-IgE mast cell activation.
  4. 2–3 weeks → Typical for DRESS/SJS/TEN.
  5. 24–48 hours → Typical for AGEP (unless associated with hydroxychloroquine, which may take up to 3 weeks).
  6. Morphological Identification:
  7. Morbilliform eruption → Common drug reaction; no specific severity indicator.
  8. Target-like lesions → Suggests Erythema Multiforme or SJS.
  9. Bullae/Erosion → Potential SCAR (SJS/TEN).
  10. Pustules on erythematous base → AGEP.
  11. Laboratory Evaluation:
  12. Eosinophil count: >1000/μL suggests DRESS.
  13. Leukocyte count: Check for leukopenia or atypical lymphocytes.
  14. Organ function: Assess liver/kidney function in suspected SCARs.
  15. Genetic Screening:
  16. HLA-B*57:01 → Perform before starting abacavir.
  17. HLA-B15:01 / HLA-B58:01 → Consider for carbamazepine/allopurinol in high-risk populations.

MANAGEMENT & TREATMENT

  1. Morbilliform Drug Eruption:
  2. Step 1: Identify and withdraw offending drug.
  3. Step 2: Symptomatic treatment (antihistamines, emollients).
  4. Urticaria/Angioedema/Anaphylaxis:
  5. Step 1: Immediate management of airway and circulation.
  6. Step 2: Antihistamines for cutaneous symptoms.
  7. Pruritus:
  8. Step 1: Topical agents or systemic antihistamines.
  9. Severe Cutaneous Adverse Reactions (SCARs):
  10. Step 1: Immediate drug withdrawal.
  11. Step 2: Supportive care (fluids, etc.).
  12. Step 3: Systemic corticosteroids for severe cases.
  13. Immune Checkpoint Inhibitor (ICI) irAEs:
  14. Management depends on severity of the specific organ involvement.

PROGNOSIS & COMPLICATIONS

• Resolution and Sequelae: • Morbilliform eruptions typically resolve after drug withdrawal. • SJS/TEN can lead to permanent scarring or mucosal damage. • Warfarin necrosis results in significant tissue loss. • Hair and nail changes may take months to resolve. • Risk Populations: • Elderly, immunocompromised (HIV), and transplant patients are at higher risk for severe reactions.

SPECIAL CONSIDERATIONS

• Genetic Screening Utility: - HLA-B57:01 screening is highly effective regardless of population. - Targeted screening (e.g., HLA-B15:02) is cost-effective in specific populations like Han Chinese.

KEY PEARLS & CLINICAL TRAPS

• Morbilliform eruptions are the most common drug reaction (91%). • SJS/TEN is characterized by mucosal involvement and extensive skin detachment (SJS ≤10% body surface area; TEN >30%). • DRESS involves eosinophilia, atypical lymphocytosis, and organ involvement. • AGEP presents with hundreds of non-follicular pustules within 24–48 hours. • Warfarin necrosis is a rare but severe reaction occurring in days 3–10. • HLA-B*57:01 has 100% negative predictive value for abacavir hypersensitivity.

Reference Tables

TABLE 63-1 Revised Classification of Adverse Drug Reactions Based on Immune Pathway TYPE Antibody Mediated Type I

Harrison's 22e, p.417

TYPE KEY PATHWAY KEY IMMUNE MEDIATORS ADVERSE DRUG REACTION TYPE
Antibody Mediated
Type I IgE, immediate IgE, B cells, T2, ILC2
H
(IL-4,IL-5, IL-9, IL-13)
Mast cells, basophils		 Acute urticaria, angioedema, anaphylaxis
IgG-mediated cytotoxicity IgG, B cells, IgM
Phagocytes, neutrophils, macrophages
Complement-dependent cytotoxicity, NK (antibody-
dependent cellular cytotoxicity)
Type III Immune complexes IgG + antigen (immune complexes)
B cells, IgM, IgG
Complement, basophils, mast cells, platelets,
Neutrophils, monocytes, macrophages		 Serum sickness, Arthus reaction, drug-induced
vasculitis and lupus
Cell-Mediated (T-cell mediated) (Delayed Hypersensitivity)
T lymphocyte–mediated macrophage
inflammation and cytotoxic functions
of T cells		 T1 cells, ILC1, Tc1, NK
H
(IFN-γ, TNF-α, granzyme B, perforins, granulysin)
Macrophages (granulomas)
Type IVb
(T2)		 T lymphocyte–mediated eosinophil
inflammation		 T2 cells, ILC2, Tc2, NK-T
H
(IL-4, IL-5, IL-9, IL-13, IL-31)
Eosinophils, B cells, mast cells/basophils		 DIHS/DRESS
Morbilliform eruption
T lymphocyte–mediated neutrophil
inflammation		 TH17, ILC3, Tc17 (IL17, IL-22, IL-23, CXCL8, GM-CSF)
Neutrophils

TABLE 63-2 Clinical and Laboratory Findings Suggestive of Severe Cutaneous Adverse Drug Reaction Cutaneous Generalized…

Harrison's 22e, p.426

  • Cutaneous
  • Generalized rash
    Dusky or target-like lesions
    Purpura
    Blisters or epidermal detachment
    Positive Nikolsky sign
    Skin pain
    Skin necrosis
    Erosions of the mucous membranes
    Facial or acral edema
    Swelling of the lips or tongue
  • General
  • Fever
    Enlarged lymph nodes
    Arthralgias or arthritis
    Tachycardia, hypotension
    Shortness of breath, hoarseness, wheezing
  • Laboratory Results
  • Eosinophil count >1000/μL
    Leukopenia or leukocytosis with atypical lymphocytes
    Abnormal liver or kidney function tests

TABLE 63-3 Clinical Features of Severe Cutaneous Drug Reactions DIAGNOSIS Stevens-Johnson syndrome (SJS)

Harrison's 22e, p.427

DIAGNOSIS MUCOSAL LESIONS TYPICAL SKIN LESIONS FREQUENT SIGNS AND
SYMPTOMS		 MOST COMMON CULPRIT
DRUGS
Stevens-Johnson syndrome
(SJS)		 Erosions usually of two
or more sites		 Dusky macules or atypical targets
evolve into small blisters; rare areas
of confluence; detachment ≤10% body
surface area		 Most cases involve fever Trimethoprim-sulfamethoxazole,
allopurinol, anticonvulsants,
β-lactam antibiotics,
nonsteroidal anti-inflammatory
drugs (NSAIDs)
Erosions usually of two
or more sites		 Individual lesions like those in SJS
evolving into confluent dusky erythema;
large sheets of necrotic epidermis; total
detachment of >30% body surface area		 Fever, leukopenia
Drug-induced hypersensitivity
syndrome/drug rash with
eosinophilia and systemic
symptoms (DIHS/DRESS)		 Mucositis reported in
up to 30%		 Diffuse, deep red morbilliform eruption
with facial involvement; facial and acral
swelling		 Fever, lymphadenopathy;
eosinophilia, atypical
lymphocytosis, hepatitis,
nephritis, myocarditis		 Anticonvulsants, sulfonamides,
allopurinol, minocycline,
vancomycin
Oral erosions in
perhaps 20%		 Diffuse erythematous eruption;
innumerable pinpoint pustules with
preference for body folds; superficial
peeling or erosions		 High fever, leukocytosis
(neutrophilia), hypocalcemia
Serum sickness or serum
sickness–like reaction		 Absent Urticarial rash, often serpiginous or
polycyclic; purpuric eruption along
the sides of the feet and hands is
characteristic		 Fever, arthralgias,
lymphadenopathy		 Antithymocyte globulin,
anti-toxins, rituximab, other
monoclonal antibodies;
cefaclor, penicillin, amoxicillin,
trimethoprim-sulfamethoxazole
Infrequent Purpura and necrosis, especially of
central, fatty areas		 Ischemic pain in affected areas
Angioedema Often involved Swelling, erythema, and discomfort of
skin and subcutaneous tissue, generally
associated with urticaria		 Stridor, respiratory distress,
cardiovascular collapse		 Angiotensin-converting enzyme
(ACE) inhibitors, NSAIDs,
contrast dye