Dermatological toxicity encompasses the spectrum of cutaneous adverse drug reactions (CADRs), ranging from mild morbiliform rashes that resolve spontaneously to life-threatening conditions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. The skin is the largest organ of the body and, with its rich blood supply and high rate of cellular turnover, is particularly susceptible to drug-induced injury. Cutaneous reactions are among the most commonly reported adverse drug events, affecting approximately 2 to 3 percent of hospitalized patients and representing a frequent reason for medication discontinuation.
Mechanisms of injury vary across reaction types but commonly involve immune-mediated hypersensitivity, direct cytotoxicity, and metabolic activation. Type IV delayed hypersensitivity mediated by drug-specific T lymphocytes underlies many severe cutaneous reactions. Direct cytotoxicity can result from drug accumulation in keratinocytes or from inhibition of cellular pathways essential for skin homeostasis. Photosensitivity reactions occur when drugs absorb ultraviolet radiation and generate reactive species that damage cutaneous structures. Some drugs produce cutaneous toxicity through complement activation or through deposition of drug-antibody complexes in the skin.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent the most severe cutaneous adverse drug reactions and are medical emergencies. SJS involves less than 10 percent body surface area detachment, while TEN involves more than 30 percent, with an overlap category between these ranges. These conditions are characterized by widespread keratinocyte apoptosis leading to epidermal detachment, mucosal involvement, and systemic illness. The mortality rate ranges from 5 percent in SJS to over 30 percent in TEN. Causative drugs include allopurinol, anticonvulsants (particularly carbamazepine, lamotrigine, and phenytoin), sulfonamide antibiotics, nevirapine, and NSAIDs. The strong genetic association with HLA alleles, such as HLA-B*1502 for carbamazepine-induced SJS in Asian populations, has enabled screening strategies to prevent these reactions.
Drug rash with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction characterized by extensive rash, fever, lymphadenopathy, eosinophilia, and internal organ involvement, most commonly affecting the liver, kidneys, and lungs. The onset is typically delayed two to eight weeks after drug initiation, distinguishing it from other hypersensitivity syndromes. Common causative agents include aromatic antiepileptics, allopurinol, sulfonamides, and minocycline. DRESS carries a mortality rate of approximately 10 percent and requires prompt drug discontinuation and systemic corticosteroids.
Morbiliform drug eruptions are the most common cutaneous adverse drug reactions, presenting as symmetric, erythematous macules and papules that typically appear within one to two weeks of starting a new medication. Aminopenicillins, sulfonamides, and anticonvulsants are frequent causes. These eruptions are generally self-limited and resolve within days to weeks of drug discontinuation, though they may be difficult to distinguish from viral exanthems. Urticarial reactions and angioedema are mediated by type I hypersensitivity involving IgE-mediated mast cell degranulation and can range from mild pruritus to anaphylaxis.
Photosensitivity reactions are classified as phototoxic or photoallergic. Phototoxic reactions are more common and result from direct tissue damage by drug-derived photoproducts, presenting as an exaggerated sunburn on exposed skin. Tetracyclines, fluoroquinolones, NSAIDs, and amiodarone are common phototoxic agents. Photoallergic reactions involve a cell-mediated immune response to drug haptens activated by ultraviolet light and may persist even after drug discontinuation. Hand-foot syndrome (palmar-plantar erythrodysesthesia) occurs with chemotherapeutic agents including capecitabine, fluorouracil, liposomal doxorubicin, and tyrosine kinase inhibitors, presenting as painful erythema, swelling, and desquamation of the palms and soles.
Diagnosis and management rely on a detailed temporal relationship between drug exposure and rash onset, careful physical examination, and assessment of severity. Withdrawal of the suspected drug is the cornerstone of management. Supportive care includes antihistamines for pruritus, topical corticosteroids, and emollients. Severe reactions require hospitalization, wound care, fluid resuscitation, and ophthalmologic evaluation in cases of SJS or TEN. Prevention through genetic screening for high-risk HLA alleles and avoidance of known cross-reactive agents is increasingly integrated into clinical practice.
