What is the treatment for chronic spontaneous urticaria (CSU) in adults?

Treatment of Chronic Spontaneous Urticaria

Start immediately with a standard-dose second-generation H1-antihistamine (cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, or mizolastine), and if symptoms remain inadequately controlled after 2-4 weeks, increase the dose up to 4-fold; if still uncontrolled, add omalizumab 300 mg subcutaneously every 4 weeks. 1, 2

First-Line Treatment: Second-Generation Antihistamines

• Begin treatment with a standard daily dose of a second-generation H1-antihistamine 1, 2, 3
• Offer patients at least two different antihistamine options, as individual responses and tolerance vary significantly between agents 2, 3
• Avoid first-generation antihistamines (diphenhydramine, hydroxyzine, chlorpheniramine) as primary therapy due to significant sedation and anticholinergic effects, though they may be added at bedtime for additional symptom control if needed 2, 4

Dose Escalation Strategy

• If symptoms remain inadequately controlled after 2-4 weeks (or earlier if symptoms are intolerable), increase the antihistamine dose up to 4 times the standard dose 1, 2, 3
• For example, fexofenadine can be increased from 180 mg daily to 360 mg, then up to 720 mg daily (4× standard dose) if needed 3
• Patients should complete at least 3 consecutive months of complete control before attempting to step down from higher-than-standard dosing 1
• When stepping down, reduce the daily dose by no more than 1 tablet per month 1

Common Pitfall: Many clinicians hesitate to exceed manufacturer-recommended doses, but up-dosing to 4-fold is well-supported by guidelines and has a favorable safety profile, with only 20% of patients reporting side effects (primarily somnolence at 17%) 5

Second-Line Treatment: Omalizumab

• For patients with inadequate control despite 4-fold antihistamine dosing, add omalizumab (anti-IgE monoclonal antibody) 300 mg subcutaneously every 4 weeks 1, 2, 3, 6
• The dose can be increased to 600 mg every 2 weeks in patients with insufficient response 1
• Allow up to 6 months for patients to respond to omalizumab before considering it a treatment failure 1, 2, 3
• Omalizumab is effective in approximately 70% of antihistamine-refractory patients 7
• Omalizumab dosing for CSU is NOT dependent on serum IgE level or body weight, unlike its use in asthma 6

Critical Safety Warning for Omalizumab

• Anaphylaxis can occur after omalizumab administration, even after the first dose or beyond 1 year of treatment 6
• Initiate omalizumab therapy in a healthcare setting and observe patients for an appropriate period after administration 6
• Healthcare providers must be prepared to manage life-threatening anaphylaxis 6

Third-Line Treatment: Cyclosporine

• For patients who fail both high-dose antihistamines and omalizumab, add cyclosporine at 4-5 mg/kg body weight daily for up to 2 months 1, 2, 3
• Cyclosporine is effective in approximately 65-70% of patients with severe autoimmune urticaria 2, 7
• Monitor blood pressure and renal function every 6 weeks due to potential nephrotoxicity and hypertension 3, 7

Role of Corticosteroids

• Oral corticosteroids should be restricted to short courses (3-10 days) for severe acute exacerbations only 1, 4, 7
• Never use systemic corticosteroids as maintenance therapy for chronic urticaria due to cumulative toxicity including adrenal suppression, osteoporosis, diabetes, hypertension, and immunosuppression 4

Common Pitfall: Clinicians often resort to repeated corticosteroid courses when antihistamines fail, but this should be avoided—escalate to omalizumab instead 4, 7

Adjunctive Measures and Trigger Avoidance

• Identify and minimize aggravating factors: overheating, stress, alcohol, tight clothing, and hot showers 3, 4, 8
• Avoid NSAIDs and aspirin in all urticaria patients, as they can worsen symptoms 3, 4
• Discontinue ACE inhibitors if angioedema is present 3, 4
• Apply cooling antipruritic lotions (calamine or 1% menthol in aqueous cream) for symptomatic relief 1, 4
• Use emollients regularly for any associated dry skin 4

Monitoring Disease Control

• Use the Urticaria Control Test (UCT) to assess disease control; scores ≤16 indicate inadequate control requiring treatment escalation 1, 3
• The goal is complete disease control with no wheals, no angioedema, and no pruritus 1

Special Population Considerations

Renal Impairment

• Avoid acrivastine in moderate renal impairment 2, 3
• Halve the dose of cetirizine, levocetirizine, and hydroxyzine in moderate renal impairment 2, 3
• Avoid cetirizine, levocetirizine, and alimemazine in severe renal impairment 2, 3

Hepatic Impairment

• Avoid mizolastine in significant hepatic impairment 2, 3
• Avoid alimemazine, chlorphenamine, and hydroxyzine in severe liver disease 2, 3

Pregnancy

• Avoid antihistamines during pregnancy if possible, especially during the first trimester 2, 3
• If necessary, choose chlorphenamine due to its long safety record 2, 3
• Loratadine and cetirizine are FDA Pregnancy Category B drugs 3

Diagnostic Workup

• Perform differential blood count, C-reactive protein or ESR, total IgE, and IgG-anti-thyroid peroxidase (TPO) levels 2
• Patients with autoimmune CSU typically have low or very low total IgE levels and elevated IgG-anti-TPO 2
• A high ratio of IgG-anti-TPO to total IgE is the best surrogate marker for autoimmune CSU 2
• Routine extensive laboratory investigation is not cost-effective unless clinical features suggest autoimmune disease 8

Agents NOT Recommended

• H2-antihistamines (cimetidine, ranitidine) add little benefit and are no longer recommended 7
• Leukotriene antagonists lack significant efficacy and are no longer recommended 7
• Topical crotamiton cream or capsaicin are not supported by evidence 4

Key Algorithmic Approach: Standard-dose sgAH → 4-fold sgAH (2-4 weeks) → Add omalizumab 300 mg every 4 weeks (up to 6 months) → Add cyclosporine 4-5 mg/kg daily 1, 2, 3