Overview

Chronic spontaneous urticaria (CSU) is a mast-cell–driven skin disorder defined by recurrent wheals (hives), angioedema, or both for >6 weeks without a specific external trigger, with a point prevalence around 0.5–1% and a female predominance; median disease duration is ~2–5 years, but a subset persists longer and markedly impairs quality of life and work productivity. Autoimmune mechanisms (type I “autoallergic” IgE-mediated and type IIb IgG-autoantibody–mediated) account for a large fraction of cases, and comorbidities include atopy, autoimmune thyroid disease, and anxiety/depression.

Aetiology & Risk factors

Aetiology

• Autoimmune mechanisms: type I autoallergic (IgE to self-antigens) and type IIb autoimmunity (anti-FcεRIα/anti-IgE) with basophil activation and low total IgE
• Non-specific mast-cell hyper-reactivity: neuropeptides (substance P), MRGPRX2 agonists, innate signals.

Risk factors

• Female sex
• Middle age onset
• Personal/family atopy
• Autoimmune thyroid disease and other autoimmunity
• NSAID-exacerbated cutaneous disease; stress, infections; obesity and metabolic syndrome reported in some cohorts

Pathophysiology 

• In chronic urticaria, mast cells and basophils become abnormally sensitive and overactive, often due to autoimmune mechanisms.
• In some patients, IgE autoantibodies bind self-antigens, while in others IgG autoantibodies target FcεRI (the high-affinity IgE receptor) or IgE itself on mast cells and basophils.
• This leads to activation of these cells through FcεRI cross-linking or related immune pathways, sometimes with contribution from complement.
• Activated mast cells and basophils then release histamine, tryptase, leukotrienes, prostaglandins, and other inflammatory mediators.
• Histamine acts on H1 and H2 receptors in the skin vasculature, causing vasodilation, increased vascular permeability, and sensory nerve stimulation, which produce erythema, edema, and itch.
• When this vascular leakage occurs in the superficial dermis, it causes urticarial wheals; when it occurs in the deeper dermis and subcutaneous tissue, it causes angioedema.
• The inflammatory response is further amplified by cytokines such as IL-4, IL-5, IL-13, IL-31, and TNF, which promote ongoing immune activation and increase mast-cell responsiveness.
• Neuropeptides and signals from the coagulation/fibrinolytic system may also contribute, helping explain why some patients have more severe or persistent disease, sometimes with an elevated D-dimer.

Clinical manifestations

• Intensely pruritic wheals of variable size/shape, migrating, each lesion <24 h
• Angioedema in ~40–50%.
• Course: daily or near-daily flares >6 weeks
• Symptoms are worse at night causing sleep disturbance, anxiety/depression, work/school impairment.
• Triggers/exacerbators (not causal): NSAIDs, stress, heat/pressure/tight clothing, infections; some foods may exacerbate but no consistent allergen like in acute urticaria

Diagnosis

Clinical diagnosis: recurrent wheals/angioedema on most days for >6 weeks without consistent external trigger; exclude differentials 

Differential diagnosis

• Chronic inducible urticarias: reproducible by specific stimuli (cold, heat, pressure, cholinergic, solar) → confirm with provocation tests
• Urticarial vasculitis: lesions >24–48 h, painful/burning, bruising/hyperpigmentation, raised CRP/ESR; biopsy with leukocytoclastic vasculitis
• Bradykinin-mediated angioedema (ACE-i/HAE): angioedema without itch/wheals, prolonged, antihistamine/steroid-resistant
• Mastocytosis/MCAS: recurrent flushing, systemic mediator symptoms, elevated baseline tryptase

Treatment 

• Education & general measures
  • reassure chronic but benign course
  • avoid NSAIDs (if exacerbating)
  • heat/tight clothing
  • optimise sleep/stress
  • trigger diaries
    
• Step 1 — First-line: Second-generation, non-sedating H1-antihistamine daily (cetirizine, levocetirizine, fexofenadine, bilastine, loratadine, desloratadine) at standard dose
  
• Step 2 — Up-dosing: if uncontrolled after 2–4 weeks, increase to as much as 4-fold the standard dose (e.g., fexofenadine up to 720–960 mg/day in divided doses) within label/regional guidance; avoid chronic first-generation agents due to anticholinergic/CNS effects
  
• Step 3 — Add biologic: Omalizumab 300 mg SC q4w (some patients respond to 150 mg); up-dosing or interval shortening (e.g., 300–600 mg q2–4w) for partial responders under specialist care
  
• Step 4 — Add immunosuppressant: Cyclosporine (≈3–5 mg/kg/day) when omalizumab fails/contraindicated, with BP/renal monitoring; often effective in type IIb endotype
  
• Rescue for severe flares: short oral corticosteroid burst (e.g., ≤10 days) may be used sparingly; avoid repeated/long courses
  
• Emerging/near-future: BTK inhibitors (e.g., remibrutinib) show promising phase-3 efficacy; ligelizumab has mixed phase-3 results; dupilumab shows benefit in trials/real-world cohorts for antihistamine-refractory CSU but guideline positioning varies by jurisdiction.
  

Complications & Prognosis

Complications

• Sleep disturbance
• Anxiety/depression
• Presenteeism/absenteeism; steroid toxicity if mismanaged; ED visits for angioedema flares.

Prognosis
~50% remit within 1–3 years; many within 5 years, but a subset persists longer; type IIb, angioedema-predominant, high baseline activity (UAS7), elevated CRP/ESR, and low total IgE predict more severe/refractory disease.

References 

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2. Zuberbier T, Maurer M, Weller K, et al. Definition, classification, diagnosis, and management of chronic urticaria: A GA²LEN position paper. Allergy. 2018;73(7):1393–1414.
   
3. Sánchez-Borges M, Ansotegui IJ, Baiardini I, et al. Diagnosis and treatment of urticaria and angioedema: 2022 WAO/EAACI consensus. World Allergy Organ J. 2022;15(12):100733.
   
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