Cutaneous Drug Eruptions

Adverse drug reaction of the skin

Aetiology

Immunologically mediated reactions ('allergic')

• Not dose dependent

• Type I: anaphylactic reactions, urticaria

• Type II: cytotoxic reactions, pemphigus and pemphigoid

• Type III: immune complex mediated reactions, purpura/rash

• Type IV: T cell mediated delayed hypersensitivity reactions, erythema/rash

Non immunological reactions ('non-allergic')

Risk factors for drug eruptions

• Young adults greater risk than infants/elderly

• More common in females

• Genetic influence

• Concomitant disease - viral infections (HIV, EBV, CMV), cystic fibrosis

• Immune status - previous drug reaction or positive skin test

• Chemistry - β-lactam compounds, NSAIDS, high molecular weight/hepten-forming drugs

• Topical route

• Higher dose/longer half life

Exanthematous drug eruptions

• Most common type of drug eruption (90%)

• Type IV reaction

• Usually mild and self limiting but can progress to a severe life-threatening reaction

• Most commonly associated drugs include antibiotics (beta-lactams, sulfonamides), NSAIDs, anti-epileptics (carbamazepine, phenytoin), alopurinol and chloramphenicol

Clinical presentation

• Onset 4-21 days after first taking drug

• Widespread symmetrically distributed rash

• Usually no involvement of mucous membranes

• Pruritus common

• Mild fever common

Indicators of a potentially severe reaction

• Involvement of mucous membrane and face

• Facial erythema and oedema

• Widespread confluent erythema

• Fever >38.5℃

• Blisters, purpura, necrosis

• Skin pain

• Lymphadenopathy, arthralgia

• Dysnpnoea, wheezing

Urticarial drug reactions

• Usually an immediate IgE-mediated (type I) hypersensitivity reaction after rechallenge with drug
• Commonly β-lactam antibiotics, carbamazepine, many others

• Can also be due to a direct release of inflammatory mediators from mast cells on first exposure
• Commonly aspirin, opiates, NSAIDs, muscle relaxants, vancomycin, quinolones

Pustilar or bullous drug eruptions

• Acneiform: glucocorticoids (steriod acne), androgens, lithium, isoniazid, phenytoin

• Acute generalised exanthematous pustulosis (AGEP): rare, antibiotics, calcium channel blockers, antimalarials

• Drug-induced bullous pemphigoid: ACE inhibitors, penicillin, furosemide

• Linear IgA disease can be triggered by drugs e.g. vancomycin

Fixed drug eruptions

• Well demarcated round/ovoid plaques which recur at the same site each time a drug is taken and resolves with persistent pigmentation when drug stops

• Can present as eczematous lesions, papules, vesicles or urticaria

• Red, painful

• Occur on hands, genitalia, lips, occasionally oral mucosa

• Can re-occur at same site on re-exposure to drug

• Usually mild when restricted to a single lesion

• Associated drugs include antibiotics (tetrecycline, doxycycline), paracetamol, NSAIDs and carbamazepine

Severe cutaneous adverse drug enlargement

• Severe mucocutaneous disorders that are considered variants of a disease spectrum

• They are characterised by varying extents of blistering/epidermal detachment and mucosal ulceration

• Both associated with sulfonamides, cephalosporins, carbamazepine, phenytoin, NSAIDs, nevirapine, lamotrigine, sertraline, pantoprazole, tramadol

• Widespread erythema, facial oedema, fever, lymphadenopathy and hepatosplenomegaly which usually starts 2-6 weeks after initial exposure

• Associated with sulfonamides, anticonvulsants, allopurinol, minocycline, dapsone, NSAIDs, abacavir, nevirapine, vancomycin

• Widespread rash with numerous small, non-follicular, sterile pustules around the neck, axillae and groin

• Usually starts a few days after drug exposure and resolves with peeling

Phototoxic cutaneous drug reactions

• Non-immunological skin reaction arising in an individual exposed to enough photo-reactive drug and light of the appropriate wavelength

• Common causative drugs include NSAIDs, diuretics, amiodarone, tetracyclines and ciprofloxin

• Drug metabolites interact with UV light (usually triggered by UVA) → free radical release → direct tissue or cell injury → severe rash

Drugs associated with phototoxicity

• Immediate prickling with delayed erythema and pigmentation - chlorpromazine, amiodarone

• Exaggerated sunburn - quinine, thiazides, demeclocycline

• Exposed telangiectasia - calcium channel blockers

• Delayed 3-5 days erythema and pigmentation - psoralens

• Increased skin fragility - nalidixic acid, tetracyclines, naproxen, amiodarone

• Others - fluoroquinolones, doxycycline, NSAIDs, polyphorins, BRAF inhibitors (vemurafenib), antifungals (voriconazole), immunosuppressants

Investigations

• History and physical examination usually sufficient to spot likely drug

• In less clear situations:
• Phototesting for suspected phototoxic drug reactions
• Biopsies - can identify type of drug reaction and exclude other diseases
• Patch and photopatch tests e.g. for suspected allergic contact dermatitis (type IV)
• Skin prick/intradermal test for specific drugs e.g. suspected allergic reactions (Type I)

• Skin prick testing is not indicated for serum sickness reactions (Type III) or for Type IV reactions
• Skin prick testing can potentially trigger SJS, TEN and DRESS
• Not indicated in those with severe cutaneous adverse drug reactions

Management

• Discontinue the drug (if possible), use an alternative

• Topical corticosteroids may be useful

• Antihistamines may help if type I or with symptoms of itch

• Allergy bracelets are useful for some drugs

• Immunocompromised patients more likely to suffer a severe cutaneous reactions