Urticaria Management
Treatment Algorithm
Start with second-generation non-sedating H1 antihistamines at standard doses, escalate up to 4 times the standard dose if needed, then add omalizumab 300 mg every 4 weeks for refractory cases, and reserve cyclosporine for patients who fail omalizumab after 6 months. 1, 2
First-Line Treatment: Second-Generation Antihistamines
Initial Approach
- Begin with second-generation non-sedating H1 antihistamines (cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, or mizolastine) as the foundation of therapy for both acute and chronic urticaria 2, 3
- Offer patients a choice of at least two different non-sedating antihistamines, as individual responses and tolerance vary significantly between agents 2, 3
- Cetirizine reaches maximum concentration fastest, making it advantageous when rapid symptom relief is needed 4
- Administer antihistamines on a regular scheduled basis, not just after hives appear 5
Dose Escalation Strategy
- If symptoms remain inadequately controlled at standard doses, increase the antihistamine dose up to 4 times the standard dose when potential benefits outweigh risks 2, 3, 4
- This updosing approach is supported by the most recent international guidelines and represents a streamlined 3-step treatment algorithm 1
- First-generation sedating antihistamines (hydroxyzine, diphenhydramine) may be added at nighttime for additional symptom control and to help patients sleep, but should not be used as first-line monotherapy due to sedating properties 3, 6
Second-Line Treatment: Omalizumab
When to Initiate
- Add omalizumab for chronic spontaneous urticaria that remains unresponsive to high-dose (up to 4x standard) antihistamines 1, 2, 3
- Omalizumab is effective in approximately 70% of antihistamine-refractory patients 6
Dosing Protocol
- Start with omalizumab 300 mg subcutaneously every 4 weeks, based on robust double-blind placebo-controlled studies demonstrating efficacy 1, 2
- For insufficient response, consider updosing by shortening the interval and/or increasing the dosage, particularly in patients with high body mass index 1
- The maximum recommended dose is 600 mg every 14 days 1, 2
- Allow up to 6 months for patients to respond to omalizumab before declaring treatment failure and moving to third-line therapy 1, 2, 3
Important Safety Consideration
- Omalizumab carries a risk of anaphylaxis (presenting as bronchospasm, hypotension, syncope, urticaria, and/or angioedema), which can occur after the first dose or beyond 1 year of treatment 7
- Initiate therapy in a healthcare setting and closely observe patients for an appropriate period after administration 7
Third-Line Treatment: Cyclosporine
Indications and Efficacy
- Reserve cyclosporine for patients who do not respond to higher than standard doses of omalizumab after 6 months 1, 2
- Cyclosporine is effective in approximately 65-70% of patients with severe autoimmune urticaria unresponsive to antihistamines 2, 3, 6
Dosing and Monitoring
- Administer cyclosporine at 4 mg/kg daily (up to 5 mg/kg) for up to 2 months 2, 3
- Treatment duration of 16 weeks is superior to 8 weeks for reducing therapeutic failures 3
- Monitor blood pressure and renal function regularly (every 6 weeks) due to potential nephrotoxicity, hypertension, and other side effects including epilepsy in predisposed patients, hirsutism, and gum hypertrophy 1, 2, 3
- The risk-benefit profile of high-dose omalizumab is superior to cyclosporine, which is why cyclosporine is reserved for omalizumab failures 1
Role of Corticosteroids
Limited Use Only
- Restrict oral corticosteroids to short courses (3-10 days) for severe acute urticaria or severe exacerbations 3, 6
- Use corticosteroids for angioedema affecting the mouth or airway 3
- Do not use corticosteroids chronically due to cumulative dose- and time-dependent toxicity 6
- Most patients respond to doses equivalent to 40 mg prednisone daily when needed 5
- Recent evidence shows that adding corticosteroids (prednisone) to antihistamines (cetirizine/levocetirizine) did not improve symptoms of acute urticaria compared to antihistamine alone in two out of three randomized controlled trials 8
Identifying and Managing Aggravating Factors
Factors to Avoid
- Identify and minimize aggravating factors including overheating, stress, alcohol, and certain medications (aspirin, NSAIDs, codeine) 2, 3, 4
- Avoid NSAIDs in aspirin-sensitive patients with urticaria 2, 3, 4
- Avoid ACE inhibitors in patients with angioedema without wheals 2, 3, 4
Symptomatic Relief Measures
- Cooling antipruritic lotions (calamine or 1% menthol in aqueous cream) can provide symptomatic relief 2, 4
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
Hepatic Impairment
- Avoid mizolastine in significant hepatic impairment 2, 3
- Avoid alimemazine, chlorphenamine, and hydroxyzine in severe liver disease 2
- Hydroxyzine should be avoided in severe liver disease 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 2
Diagnostic Workup for Chronic Spontaneous Urticaria
Essential Testing
- Obtain thorough history and physical examination, including review of pictures of wheals and/or angioedema 1
- Perform basic tests including differential blood count, C-reactive protein level and/or ESR, total IgE, and IgG-anti-thyroid peroxidase (TPO) levels 1
- Testing for IgG-anti-TPO and total IgE helps clarify whether patients have autoallergic or autoimmune-mediated chronic spontaneous urticaria 1
- Patients with autoimmune chronic spontaneous urticaria are more likely to have low or very low total IgE levels and elevated IgG-anti-TPO 1
- A high ratio of IgG-anti-TPO to total IgE is currently the best surrogate marker for autoimmune chronic spontaneous urticaria 1
Additional Testing for Antihistamine Non-Responders
- Obtain a chronic urticaria index in patients not responsive to H1 antihistamines to determine presence of antibodies directed against IgE, FcεRI, or anti-FcεRII, or alternate histamine-releasing factors 1
- These biomarkers are prognosticators for treatment outcomes with omalizumab or immunosuppressants such as cyclosporine 1
Emergency Management
Life-Threatening Presentations
- Administer intramuscular epinephrine 0.5 mL of 1:1000 (500 µg) immediately for severe urticaria with anaphylaxis or angioedema affecting the airway 3
- Prescribe fixed-dose epinephrine auto-injectors (300 µg for adults) for patients at risk of life-threatening attacks 3
Common Pitfalls to Avoid
- Do not use antihistamines only after hives appear; they must be administered on a regular scheduled basis for optimal efficacy 5
- Do not re-test IgE levels during omalizumab treatment to guide dosing, as total IgE levels remain elevated during treatment and up to one year after discontinuation 1
- Do not add H2-receptor blockers or leukotriene antagonists, as the literature does not support significant efficacy and they add little benefit 6
- Do not use chronic corticosteroid therapy due to cumulative toxicity 6
- Do not declare omalizumab failure before allowing 6 months for response 1, 2