Urticaria (hives) consists of transient, pruritic wheals with or without angioedema due to mast cell activation and histamine release. It is classified by duration into acute (<6 weeks) and chronic (≥6 weeks), and by triggers into spontaneous and inducible (physical) types. Angioedema involves deeper dermal/subcutaneous swelling, may occur with urticaria, and can be histaminergic or bradykinin-mediated (e.g., ACE inhibitor–induced, hereditary angioedema) with distinct management. First-line therapy for chronic urticaria is non-sedating H1 antihistamines up-titrated above standard doses; refractory disease responds to omalizumab or cyclosporine. Bradykinin-mediated angioedema requires targeted therapies and avoidance of epinephrine/corticosteroids as primary treatments.
Epidemiology
- Lifetime prevalence of acute urticaria ~15–20%; chronic spontaneous urticaria (CSU) point prevalence ~0.5–1%.
- Female predominance in CSU; peak in middle age.
- Inducible urticarias: dermographism most common; others include cold, cholinergic, delayed pressure, solar, vibratory.
Pathophysiology
- Histaminergic urticaria: IgE- or autoantibody-mediated mast cell degranulation; multiple mediators including histamine, leukotrienes.
- Autoimmune CSU subset: IgG autoantibodies to FcεRIα or IgE; basophil anomalies; elevated D-dimer in some.
- Angioedema:
- Histaminergic: often accompanies urticaria.
- Bradykinin-mediated: C1-inhibitor deficiency (hereditary or acquired), ACE inhibitor–induced; no wheals, poor response to antihistamines/steroids.
Clinical Features
- Wheals: pruritic, pink edematous papules/plaques with central pallor; individual lesions resolve within 24 hours without residual scale or bruising.
- Angioedema: non-pitting swelling of lips, eyelids, tongue, genitalia, extremities; may involve airway or GI tract (abdominal pain).
- Red flags: systemic symptoms, anaphylaxis (hypotension, wheeze), bruising/painful lesions lasting >24–48h (consider urticarial vasculitis).
Differential Diagnosis
- Urticarial vasculitis, autoinflammatory syndromes (cryopyrinopathies), mastocytosis, drug eruptions, contact urticaria, erythema multiforme, anaphylaxis.
Diagnostic Workup
- Acute urticaria: usually clinical; targeted evaluation for triggers (infections, drugs, foods).
- CSU: limited labs unless suggested by history—CBC, ESR/CRP, TSH/anti-TPO in select patients; test for inducible types with provocation (e.g., ice cube test for cold, dermographometer).
- Angioedema without wheals or recurrent abdominal attacks: measure C4, C1-inhibitor level and function; consider C1q (for acquired C1-INH deficiency). Review ACE inhibitor use.
Management
- Immediate safety
- Suspected anaphylaxis: intramuscular epinephrine, airway support, adjunctive antihistamines and corticosteroids; observe for biphasic reactions.
- Acute urticaria
- Remove triggers; non-sedating H1 antihistamines (cetirizine, fexofenadine, loratadine, bilastine).
- Short oral corticosteroid burst for severe flares; avoid prolonged courses.
- Chronic urticaria (stepwise)
- Step 1: Standard-dose second-generation H1 antihistamine daily.
- Step 2: Up-titrate up to 4× standard dose (e.g., fexofenadine 180 mg up to 720 mg/day) as tolerated.
- Step 3: Add-on omalizumab 300 mg every 4 weeks (consider 150–600 mg and q2–4 week intervals based on response, per real-world data).
- Step 4: Cyclosporine (2–4 mg/kg/day) as add-on in refractory cases; monitor BP/renal function.
- Adjuncts: H2 blockers and leukotriene receptor antagonists have limited benefit; sedating H1 antihistamines at night for sleep itching.
- Avoid first-generation antihistamines for routine daytime use due to cognitive/motor impairment.
- Inducible urticarias
- Trigger avoidance and provocation threshold modification; high-dose antihistamines; omalizumab effective in many inducible subtypes; cyclosporine for refractory cases.
- Cold urticaria: carry epinephrine autoinjectors; avoid sudden cold exposure or aquatic immersion.
- Angioedema
- Histaminergic: treat as urticaria; epinephrine if airway compromise.
- Bradykinin-mediated (HAE, ACEI-induced):
- On-demand: icatibant (bradykinin B2 antagonist), C1-INH concentrate (plasma-derived/recombinant), ecallantide (kallikrein inhibitor, region-specific).
- Long-term prophylaxis (HAE): lanadelumab (anti-kallikrein), berotralstat (oral kallikrein inhibitor), scheduled C1-INH; short-term pre-procedural prophylaxis when needed.
- Discontinue ACE inhibitors permanently; consider ARBs with caution.
Prognosis
- Acute urticaria resolves within days to weeks.
- CSU: ~50% remit within 1–5 years; course fluctuates.
- HAE is lifelong; modern prophylaxis markedly reduces attack burden and mortality.
References (recent guidelines and key reviews)
- EAACI/GA2LEN/WAO International Guideline for Urticaria, 2022–2024 updates.
- AAAAI/ACAAI Parameter for Urticaria and Angioedema, 2023–2024.
- WAO/EAACI Guideline for the Diagnosis and Management of Hereditary Angioedema, 2023–2024.
- Real-world evidence for omalizumab and cyclosporine in CSU, 2021–2024.