What is the approach to treating spontaneous recurring urticaria (hives)?

Approach to Spontaneous Recurring Urticaria (Chronic Spontaneous Urticaria)

Start with standard-dose second-generation H1-antihistamines as first-line treatment, and if symptoms persist after 2-4 weeks, increase the dose up to 4 times the standard dose before considering other therapies. 1

Step 1: Initial Assessment and Diagnosis

Before initiating treatment, confirm the diagnosis and exclude other conditions:

• Verify wheal characteristics: Individual wheals should resolve within 24 hours with surrounding erythema and itching 2
• Rule out urticarial vasculitis: If individual wheals last >24 hours, perform a lesional skin biopsy to evaluate for small-vessel vasculitis 2
• Exclude bradykinin-mediated angioedema: In patients presenting with angioedema without wheals, rule out hereditary or acquired angioedema (check C4, C1-INH levels and function) before diagnosing as chronic spontaneous urticaria 2
• Assess for autoinflammatory disease: If recurrent fever, joint/bone pain, or malaise are present, check inflammatory markers (CRP, ESR) 2

Step 2: Identify and Eliminate Aggravating Factors

• Avoid NSAIDs and aspirin: These can worsen urticaria through cyclooxygenase inhibition; the risk relates to potency and dose 2, 1
• Use ACE inhibitors cautiously: Avoid in patients with angioedema without wheals; use with caution if angioedema accompanies urticaria 2
• Minimize nonspecific triggers: Reduce overheating, stress, alcohol, and codeine exposure 2, 1
• Apply cooling measures: Use calamine or 1% menthol in aqueous cream for symptomatic relief 2

Step 3: First-Line Treatment - Standard-Dose Second-Generation Antihistamines

Begin with once-daily dosing of a second-generation H1-antihistamine 1:

• Preferred agents: Cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, bilastine, rupatadine, or ebastine 1
• Offer at least two different options: Individual responses and tolerance vary significantly between patients 2
• Avoid first-generation antihistamines as monotherapy: Due to sedation and impaired concentration, though they may be effective in select individuals 2
• Duration before reassessment: Allow 2-4 weeks to evaluate response 1

Important Antihistamine Considerations:

• Cetirizine may cause sedation, especially at higher doses 2
• Desloratadine has the longest elimination half-life (27 hours); discontinue 6 days before skin testing 2
• Mizolastine is contraindicated with cardiac disease, QT prolongation, and concurrent use of CYP450 inhibitors 2

Step 4: Second-Line Treatment - Up-Dose Antihistamines

If symptoms remain inadequately controlled after 2-4 weeks, increase the second-generation H1-antihistamine dose up to 4 times the standard dose 1, 2:

• Evidence supports up-dosing: This approach is effective in approximately 23-49% of patients who don't respond to standard dosing 3, 4
• Safety profile: Up-dosing to 4-fold shows minimal increase in adverse effects, with cetirizine being the exception (may increase sedation) 4, 5
• Specific agents with Grade A recommendation for up-dosing: Bilastine, fexofenadine, levocetirizine, and cetirizine 4
• Duration: Continue for adequate trial period before advancing to next step 1

Step 5: Third-Line Treatment - Add Omalizumab

If up-dosed antihistamines fail to control symptoms, add omalizumab 300 mg subcutaneously every 4 weeks 1, 6:

• FDA-approved dosing: 300 mg every 4 weeks for chronic spontaneous urticaria in patients ≥12 years old 6
• Dosing is NOT dependent on IgE levels or body weight for CSU (unlike asthma) 6
• Expected response rate: Approximately 70% of antihistamine-refractory patients respond 7
• Duration of trial: Allow up to 6 months to assess response before considering alternative therapies 1, 8

Critical Safety Considerations for Omalizumab:

• Anaphylaxis risk: Occurs in approximately 0.2% of patients; can happen after first dose or beyond 1 year of treatment 6
• Monitoring requirements:
  • First 3 doses: Observe for 2 hours post-injection 8
  • Subsequent doses: Observe for 30 minutes 8, 6
• Patient requirements: Prescribe epinephrine autoinjector and train in its use 8, 6
• Administration setting: Must be given in healthcare setting with staff/equipment to manage anaphylaxis 8, 6

Dose Optimization for Omalizumab:

• If breakthrough symptoms occur: Consider shortening interval to every 3 weeks or increasing dose (maximum 600 mg every 2 weeks) 2, 8
• Use Urticaria Control Test (UCT): Score <12 indicates poorly controlled disease and supports dose optimization 2, 8

Step 6: Fourth-Line Treatment - Add Cyclosporine

If omalizumab is inadequate after 6 months, add cyclosporine (up to 5 mg/kg body weight) to the antihistamine regimen 1:

• Expected response rate: Effective in 65-70% of patients unresponsive to antihistamines and omalizumab 7
• Monitoring requirements: Check blood pressure and renal function every 6 weeks 1
• Duration: Use as needed for disease control 1

Step 7: Treatment Monitoring and Step-Down

Use validated tools to assess disease control at every visit 2:

• Urticaria Activity Score (UAS7): 7-day scoring system to determine disease activity and treatment response 2
• Urticaria Control Test (UCT): Assess disease control; score ≥12 indicates well-controlled disease 2, 8
• Quality of life assessment: Monitor impact on daily functioning 2

Step-Down Protocol:

• Timing: Once complete symptom control is achieved, maintain effective dose for at least 3 consecutive months 1
• Method: Reduce daily dose by no more than 1 tablet per month 1
• If symptoms recur: Return to the last effective dose that provided complete control 1

Important Pitfalls to Avoid

• Do NOT use leukotriene receptor antagonists (montelukast): Explicitly removed from current treatment algorithms due to lack of efficacy and neuropsychiatric safety concerns 9
• Avoid chronic corticosteroids: Brief courses (3-10 days) acceptable for severe exacerbations, but chronic use causes cumulative toxicity 7
• Do NOT add H2-blockers or combine multiple antihistamines: No longer recommended due to lack of significant efficacy 7
• Do NOT retest IgE levels during omalizumab treatment: IgE remains elevated during and up to 1 year after treatment; cannot guide dosing 6

Prognosis

The prognosis for eventual recovery from chronic spontaneous urticaria is excellent, though some cases may be persistent 2. Patients should be counseled that immediate improvement may not occur and a cause is unlikely to be identified in most cases 2, 6.