Systemic Retinoids

Systemic retinoids (isotretinoin, acitretin, alitretinoin, bexarotene, and oral tretinoin in acute promyelocytic leukaemia) are synthetic vitamin A derivatives with effects on epidermal differentiation, sebaceous gland activity and cell proliferation. Isotretinoin is used for severe acne; acitretin for severe psoriasis and disorders of keratinisation; alitretinoin for severe chronic hand eczema. They are teratogenic and carry strict prescribing rules.

Mechanism. Binding to RAR and RXR nuclear receptors regulates transcription: isotretinoin reduces sebum production by shrinking sebaceous glands and induces apoptosis of sebocytes; acitretin normalises keratinocyte proliferation and differentiation; alitretinoin binds both RAR and RXR.

Pharmacokinetics. Isotretinoin: oral absorption increases with food, half-life 10 to 20 hours, highly lipophilic. Acitretin: half-life about 50 hours, but alcohol converts it to etretinate (half-life about 120 days), so teratogenic risk persists for 3 years after stopping in women. Alitretinoin: half-life 2 to 10 hours.

• Isotretinoin: severe, nodular or scarring acne; acne resistant to other therapy; gram-negative folliculitis; rosacea (severe, off-label).
• Acitretin: severe plaque, pustular and erythrodermic psoriasis; Darier disease; congenital ichthyoses; palmoplantar pustulosis; prevention of skin cancer in transplant recipients.
• Alitretinoin: severe chronic hand eczema unresponsive to potent topical steroids.
• Bexarotene: cutaneous T-cell lymphoma (specialist use).

Representative regimens.

• Isotretinoin: 0.5 mg/kg daily (about 10 to 40 mg) with food, increasing to 1 mg/kg daily if tolerated, for 16 to 24 weeks, aiming for a cumulative dose of 120 to 150 mg/kg. Low-dose regimens (10 to 20 mg daily) are used for moderate acne and in those who cannot tolerate full doses. Review at each monthly visit.
• Acitretin: 25 to 30 mg daily with the main meal, adjusted to 10 to 50 mg daily (up to 0.5 mg/kg, maximum 75 mg) depending on response and tolerability; response takes 3 to 6 months. Often combined with phototherapy.
• Alitretinoin: 10 or 30 mg once daily with food for 12 to 24 weeks.

Selection. Reserve for severe disease or failure of conventional treatment, prescribed by or with a dermatologist where possible.

Contraindications. Pregnancy and breastfeeding; women of childbearing potential unless a pregnancy prevention programme is followed; severe hepatic or renal impairment; uncontrolled hyperlipidaemia; hypervitaminosis A; concurrent tetracyclines or methotrexate.

Pregnancy prevention. Negative pregnancy test before starting, monthly during treatment and 5 weeks after isotretinoin; effective contraception (preferably two methods, one highly effective) from 1 month before until 1 month after isotretinoin and for 3 years after acitretin; no alcohol with acitretin and for 2 months after; no blood donation during and for 3 years after acitretin.

Serious effects. Teratogenicity (craniofacial, cardiac, CNS defects); hepatotoxicity; hypertriglyceridaemia with pancreatitis; cheilitis, xerosis, epistaxis, dry eyes; bone and joint pain, hyperostosis and premature epiphyseal closure with prolonged acitretin; raised intracranial pressure (avoid tetracyclines); mood change and depression (association debated, monitor); photosensitivity; muscle pain and raised creatine kinase; inflammatory bowel disease reports.

Interactions. Tetracyclines (intracranial hypertension), methotrexate (hepatotoxicity), vitamin A supplements, alcohol, progestogen-only micro-dose contraceptives (unreliable), carbamazepine.

Monitoring. Liver tests and fasting lipids at baseline, after 1 month, and then every 3 months; pregnancy tests; mood and visual symptoms; bone imaging with long-term acitretin.

Special groups. Children: weight-based dosing with growth monitoring in prolonged courses. Region: contraception access, regular testing and availability vary in East Africa; the pregnancy prevention programme is a condition of prescribing.