What are the current pharmacologic treatments for Chronic Spontaneous Urticaria (CSU) and when are they used?

Pharmacologic Treatment of Chronic Spontaneous Urticaria

Start with standard-dose second-generation H1-antihistamines, uptitrate to 4-fold if needed after 2-4 weeks, add omalizumab 300mg every 4 weeks if antihistamines fail, and reserve cyclosporine as third-line therapy for refractory cases. 1

First-Line Treatment: Second-Generation H1-Antihistamines

Begin with standard-dose second-generation (non-sedating) H1-antihistamines as monotherapy. 1 These are preferred over first-generation antihistamines due to superior safety profiles and reduced sedation. 1

Specific Agent Selection

• Offer at least two different non-sedating antihistamines to each patient, as individual responses and tolerance vary significantly between agents. 2
• Available options include: cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, mizolastine, bilastine, rupatadine, and ebastine. 2, 3
• Cetirizine has the shortest time to maximum concentration, which may be advantageous when rapid symptom control is needed. 2
• Desloratadine has the longest elimination half-life (27 hours) and should be discontinued 6 days before skin prick testing. 2

When to Use Standard Dosing

• Use standard dosing for all newly diagnosed CSU patients as initial therapy. 1
• Continue for 2-4 weeks before considering dose escalation. 1, 3

Second-Line Treatment: Up-Dosed Antihistamines

If symptoms remain inadequately controlled after 2-4 weeks of standard-dose treatment, increase the dose of second-generation H1-antihistamines up to 4 times the standard dose. 1, 2

Evidence for Up-Dosing

• Bilastine, fexofenadine, levocetirizine, and cetirizine have Grade A evidence supporting up-dosing to 4-fold conventional doses. 4
• Desloratadine and ebastine have Grade B evidence for up-dosing. 4
• Up-dosing is effective in approximately 23-49% of patients who fail standard dosing. 5
• No dose-dependent increase in adverse effects occurs with up-dosing, except cetirizine may cause dose-related sedation. 4

Practical Considerations

• Adjust timing of medication to ensure highest drug levels coincide with anticipated urticaria activity. 2
• Some patients may benefit from doses higher than 4-fold (median 8-fold, range 5-12), which appears safe and effective in 49% of cases. 5
• Higher-than-fourfold dosing showed only 10% side effect rate, primarily mild somnolence. 5

Special Populations

Renal impairment: Halve the dose of cetirizine, levocetirizine, and hydroxyzine; avoid acrivastine in moderate impairment (creatinine clearance 10-20 mL/min); avoid cetirizine, levocetirizine, and alimemazine in severe impairment (creatinine clearance <10 mL/min). 2

Hepatic impairment: Avoid mizolastine, alimemazine, chlorphenamine, and hydroxyzine in severe liver disease. 2

Pregnancy: Avoid all antihistamines, especially in first trimester; if necessary, chlorphenamine is often chosen due to long safety record; loratadine and cetirizine are FDA Pregnancy Category B. 2

Children: All licensed antihistamines are safe in children ≥12 years; consult product data sheets for younger children. 2

Third-Line Treatment: Omalizumab

Add omalizumab 300mg subcutaneously every 4 weeks if symptoms remain inadequately controlled despite up-dosed antihistamines. 1, 2, 6

When to Use Omalizumab

• For adults and adolescents ≥12 years who remain symptomatic despite H1-antihistamine treatment. 6
• Omalizumab is effective in approximately 70% of antihistamine-refractory patients. 7
• In clinical trials, 36% of patients achieved complete symptom control (UAS7=0) at 300mg dosing. 6

Dosing Considerations

• Standard starting dose is 300mg every 4 weeks. 2, 1, 6
• Allow up to 6 months for patients to demonstrate response before considering treatment failure. 2, 1
• If insufficient response, consider up-dosing by shortening interval and/or increasing dosage, with maximum recommended dose of 600mg every 2 weeks. 2, 3
• Dosing is NOT dependent on serum IgE level or body weight for CSU (unlike asthma). 6

Safety Monitoring

• Risk of anaphylaxis (0.2% of patients) requires observation for 30 minutes after established therapy (beyond first three doses). 8, 6
• Patients should have access to epinephrine autoinjector and training in its use. 8
• Most common adverse effects are headache and upper respiratory infections, generally mild. 8

Fourth-Line Treatment: Cyclosporine

Add cyclosporine (up to 5mg/kg body weight) to the second-generation H1-antihistamine regimen if inadequate control persists with omalizumab after 6 months. 1, 3

When to Use Cyclosporine

• For patients unresponsive to both high-dose antihistamines and omalizumab. 7
• Effective in approximately 65-70% of patients with severe autoimmune urticaria. 2, 7
• Optimal patient selection includes those with positive autologous serum skin test (ASST), though some ASST-negative patients also respond. 2

Monitoring Requirements

• Monitor blood pressure and renal function every 6 weeks due to potential nephrotoxicity and hypertension. 1, 3
• Treatment duration of 16 weeks shows fewer therapeutic failures than 8 weeks. 2
• Only 25% of responders remain clear 4-5 months after discontinuation, indicating need for prolonged therapy. 2

Adjunctive Therapies

Antileukotrienes

• Add montelukast to H1-antihistamine for poorly controlled urticaria, though evidence for monotherapy is limited. 2
• More likely to benefit aspirin-sensitive and ASST-positive CSU patients, though response is unpredictable. 2

H2-Antihistamines

• May provide additional benefit when added to H1-antihistamines (Quality of evidence II), though in practice may be more helpful for accompanying dyspepsia. 2
• No longer routinely recommended as literature does not support significant efficacy. 7

Corticosteroids

Restrict oral corticosteroids to short courses (3-10 days) for severe acute exacerbations only. 3, 7

• Long-term oral corticosteroids should NOT be used in chronic urticaria except in very selected cases under regular specialist supervision. 2
• Short courses may shorten duration of acute urticaria (e.g., prednisolone 50mg daily for 3 days in adults). 2
• Chronic use causes cumulative toxicity that is dose and time dependent, including hypertension, hyperglycemia, osteoporosis, and gastric ulcer exacerbation. 8, 7

Treatment Monitoring and Step-Down

Disease Control Assessment

• Use the Urticaria Control Test (UCT) to assess disease control, with scores ranging 0-16 (higher scores indicate better control). 1, 8
• Monitor weekly urticaria activity score (UAS7, range 0-42), which combines weekly itch severity score (0-21) and weekly hive count score (0-21). 6

Step-Down Protocol

• Once complete symptom control is achieved, maintain effective dose for at least 3 consecutive months before considering step-down. 1
• Reduce daily dose by no more than 1 tablet per month during step-down. 1
• If symptoms recur during step-down, return to the last effective dose that provided complete control. 1

Common Pitfalls to Avoid

• Do not use first-generation sedating antihistamines as monotherapy due to concerns about reduced concentration and performance, though they may be added at night for sleep. 2
• Do not combine multiple antihistamines at standard doses before up-dosing a single agent to 4-fold. 1
• Do not use leukotriene antagonists as monotherapy—they should only be added to antihistamines. 2
• Do not use epinephrine for angioedema caused by C1-inhibitor deficiency—it is not considered helpful. 2
• Avoid potential triggers including NSAIDs, aspirin, codeine, alcohol, and stress. 1, 3
• Distinguish CSU from urticarial vasculitis (lesions lasting >24 hours) as management differs. 1