What is the treatment for hives (urticaria)?

Treatment of Urticaria (Hives)

Start with a second-generation non-sedating H1 antihistamine at standard dose, and if symptoms persist after 2-4 weeks, increase up to 4 times the standard dose before considering omalizumab as second-line therapy. 1

First-Line Treatment: Second-Generation Antihistamines

Second-generation non-sedating H1 antihistamines are the cornerstone of urticaria management for both acute and chronic presentations. 1, 2 The recommended options include:

• Cetirizine (has the shortest time to maximum concentration, advantageous for rapid relief) 3
• Desloratadine 1
• Fexofenadine 1
• Levocetirizine 1
• Loratadine 1
• Mizolastine 1

Offer patients at least two different non-sedating antihistamines to trial, as individual responses and tolerance vary significantly. 1, 3 This is critical because what works for one patient may be ineffective for another.

Dose Escalation Strategy

If standard dosing provides inadequate symptom control after 2-4 weeks, increase the antihistamine dose up to 4 times the standard dose when potential benefits outweigh risks. 1, 3 This updosing strategy is supported by evidence showing that 4 tablets/day exceeds the response of 3, which exceeds 2, which exceeds 1. 4 The maximum effective dose corresponds to what was previously used with first-generation antihistamines (6 tablets/day). 4

Second-Line Treatment: Omalizumab

For chronic spontaneous urticaria unresponsive to high-dose antihistamines, omalizumab (anti-IgE monoclonal antibody) should be initiated at 300 mg every 4 weeks. 5, 1 This recommendation is based on robust double-blind placebo-controlled studies demonstrating approximately 75% response rates. 5, 4

Omalizumab Dosing Algorithm

• Starting dose: 300 mg subcutaneously every 4 weeks 5, 1
• For insufficient response: Updose by shortening the interval and/or increasing the dosage 5, 1
• Maximum recommended dose: 600 mg every 14 days 5, 1
• Duration before reassessment: Allow up to 6 months for patients to respond before considering alternative treatments 5, 1, 3

Higher doses are particularly beneficial in patients with high body mass index. 5 The risk-benefit profile of high-dose omalizumab is superior to cyclosporine, with a safety spectrum similar to standard dosing. 5

Third-Line Treatment: Cyclosporine

For patients who do not respond to high-dose antihistamines and omalizumab within 6 months, cyclosporine should be added to the antihistamine regimen. 1, 3 Cyclosporine is effective in approximately 65-75% of patients with severe autoimmune urticaria. 1, 4

Cyclosporine Dosing and Monitoring

• Dose: 4-5 mg/kg body weight daily for up to 2 months 1, 3
• Response rate: Approximately 75% 4
• Required monitoring: Blood pressure and renal function (blood urea nitrogen, creatinine, urine protein) every 6 weeks 1, 4

Critical Safety Considerations

Cyclosporine carries significant risks that must be monitored: 5

• Hypertension
• Renal failure
• Epilepsy in predisposed patients
• Hirsutism
• Gum hypertrophy

Even long-term low-dose cyclosporine has been shown safe in small patient groups, but vigilant monitoring is essential. 5

Role of Corticosteroids

Oral corticosteroids should be restricted to short courses (3-10 days) for severe acute exacerbations only and should never be used chronically due to cumulative toxicity. 3, 6 If steroids are necessary, use no more than 10 mg/day with weekly reduction of 1 mg. 4 The evidence for their benefit in urticaria is questionable, and toxicity limits their utility. 6, 4

Adjunctive Measures

Trigger Identification and Avoidance

Identify and minimize aggravating factors: 1, 3

• Overheating
• Stress
• Alcohol
• Aspirin and NSAIDs (especially in aspirin-sensitive patients)
• Codeine
• ACE inhibitors (avoid in patients with angioedema without wheals) 1

Symptomatic Relief

• Cooling antipruritic lotions (calamine or 1% menthol in aqueous cream) can provide symptomatic relief 1, 3
• First-generation antihistamines (hydroxyzine, chlorpheniramine) may be added at night for additional symptom control and sleep aid, but sedating effects must be considered 3, 6

Special Population Considerations

Renal Impairment

• Moderate impairment: Avoid acrivastine; halve the dose of cetirizine, levocetirizine, and hydroxyzine 1
• Severe impairment: Avoid cetirizine, levocetirizine, and alimemazine 1

Hepatic Impairment

• Significant impairment: Avoid mizolastine 1
• Severe liver disease: Avoid alimemazine, chlorphenamine, and hydroxyzine 1

Pregnancy

• Avoid antihistamines if possible, especially during first trimester 1
• If necessary: Choose chlorphenamine due to long safety record 1
• Loratadine and cetirizine are FDA Pregnancy Category B 1

Children

• Use age-appropriate dosing of second-generation antihistamines (cetirizine, loratadine, fexofenadine) 6
• Can increase up to 4 times standard dose if symptoms persist, though this exceeds manufacturer's recommendations 6
• Short courses of oral prednisolone (3 days, adjusted for children) for severe acute urticaria or angioedema affecting the mouth 6

Emergency Management

For anaphylaxis or severe laryngeal angioedema, intramuscular epinephrine is life-saving. 6, 7 Epinephrine acts on alpha and beta-adrenergic receptors to alleviate pruritus, urticaria, and angioedema through smooth muscle relaxation effects. 7

Pediatric Epinephrine Dosing

• 15-30 kg: 150 µg intramuscularly 6
• >30 kg: 300 µg intramuscularly 6

Diagnostic Workup for Chronic Spontaneous Urticaria

When patients fail to respond to H1 antihistamines, obtain: 5

• Differential blood count
• C-reactive protein level and/or ESR
• Total IgE levels
• IgG-anti-thyroid peroxidase (TPO) levels

A high ratio of IgG-anti-TPO to total IgE is currently the best surrogate marker for autoimmune chronic spontaneous urticaria. 5 Patients with autoimmune urticaria are more likely to have low or very low total IgE levels and elevated IgG-anti-TPO. 5 These biomarkers are prognosticators for treatment outcomes with omalizumab or cyclosporine. 5

Common Pitfalls to Avoid

• Do not use first-generation antihistamines as first-line monotherapy due to sedating properties that impair daily activities 6
• Do not continue corticosteroids beyond short courses due to cumulative toxicity 6
• Do not add leukotriene antagonists or H2 receptor antagonists as second-line therapy—these are of little utility despite older guidelines 4
• Do not expect routine laboratory investigations to reveal a cause in chronic idiopathic urticaria—they are consistently disappointing unless suggested by history 8
• The majority of patients with urticaria are undertreated—the more H1-receptors blocked, the better the results 8

Prognosis

Approximately 50% of patients with acute urticaria presenting with wheals alone will be clear by 6 months. 6 All urticarias eventually resolve spontaneously, and all treatment is palliative. 8 Refractoriness to both omalizumab and cyclosporine is expected in less than 5% of patients. 4