NSAID Exacerbated Cutaneous Disease

NSAID-exacerbated cutaneous disease is the worsening of chronic spontaneous urticaria, with new wheals and angio oedema, after taking aspirin or other COX-1 inhibiting NSAIDs. It occurs in a minority of patients with chronic urticaria.

Pathophysiology. COX-1 inhibition shifts arachidonic acid metabolism towards leukotrienes and lowers protective prostaglandin E2, so mast cell activity and cysteinyl leukotriene release rise. The mechanism is pharmacological, not IgE-mediated, and all strong COX-1 inhibitors cross-react.

About 10 to 30% of patients with chronic spontaneous urticaria have a cutaneous flare after NSAIDs, and the reaction may be dose dependent.

Selective COX-2 inhibitors and paracetamol at low doses are usually tolerated.

• Wheals and angio oedema within 30 minutes to 6 hours of an NSAID
• Reaction to aspirin, ibuprofen, diclofenac, naproxen and other COX-1 inhibitors
• Existing chronic spontaneous urticaria (wheals for over 6 weeks)
• Lip, eyelid and tongue swelling
• Rarely wheeze or hypotension
• Reaction at any time during the course of chronic urticaria, and not at every exposure

• History: timing of wheals, which NSAIDs were involved, and urticaria activity at the time of exposure.
• Urticaria activity score (UAS7) to measure control.
• Exclusion of other triggers: infection, physical urticaria, autoimmune disease (thyroid antibodies, antinuclear antibody), food.
• Oral challenge with aspirin in graded doses (for example 50 mg, 100 mg, 300 mg and 500 mg at 90 minute intervals) in a monitored setting, only when urticaria is controlled, to confirm.
• Challenge with an alternative (celecoxib 100 to 200 mg) to confirm a safe drug.

Differential diagnosis.

• Selective NSAID-induced urticaria and anaphylaxis (single drug IgE-mediated)
• NSAID-induced urticaria and angio oedema in people without chronic urticaria
• NSAID-exacerbated respiratory disease
• Chronic inducible urticaria
• Urticarial vasculitis and mastocytosis
• Hereditary angio oedema and ACE inhibitor angio oedema

• Avoid COX-1 inhibiting NSAIDs, including aspirin, until urticaria is controlled and tolerance is proven.
• Safe analgesia: paracetamol 500 mg to 1 g orally up to four times daily (maximum 4 g daily; 3 g daily if under 50 kg or hepatic impairment), or celecoxib 100 to 200 mg orally twice daily (maximum 400 mg daily) after a supervised challenge.
• Treat the urticaria:
  • A second generation antihistamine daily, such as cetirizine 10 mg once daily, increased up to four times the licensed dose (up to 40 mg daily) if wheals persist.
  • Omalizumab 300 mg subcutaneously every 4 weeks for urticaria that persists on high dose antihistamine.
  • Ciclosporin 3 to 5 mg/kg orally daily in specialist care for refractory disease, with blood pressure and creatinine monitoring.
• Acute severe reaction: oral prednisolone 40 mg daily for 3 days in adults, and adrenaline 0.5 mg intramuscularly (children 0.01 mg/kg, maximum 0.5 mg) for anaphylaxis.
• Patients who need aspirin (for example after a coronary event) can have desensitisation or continue under cover of controlled urticaria, in specialist care.
• Medical alert listing the drugs to avoid and the tolerated alternatives.

Special groups.

• Patients with cardiovascular indication for aspirin: urticaria is stabilised first, and then aspirin is introduced in a monitored setting.

Monitoring. UAS7 at each visit. Review every 3 months, with an attempt to step down the antihistamine when controlled for 3 to 6 months. Annual review of NSAID tolerance.

Referral and escalation. Refer to allergy or dermatology for chronic urticaria not controlled by high dose antihistamine, or for reactions with systemic features. Emergency for airway swelling or anaphylaxis.