What is the recommended workup and treatment for a patient presenting with urticaria?

Urticaria Workup and Treatment

Initial Clinical Assessment and Classification

The workup for urticaria should be guided by clinical classification rather than extensive routine testing, as the diagnosis is primarily clinical and most cases remain idiopathic despite thorough evaluation. 1, 2

Key Clinical Features to Document

• Duration of individual wheals: Wheals lasting 2-24 hours suggest ordinary urticaria, while lesions persisting >24 hours indicate possible urticarial vasculitis requiring skin biopsy 1, 2
• Presence of angioedema: Document whether angioedema occurs with or without wheals, as isolated angioedema requires different evaluation (particularly C4 screening for C1 inhibitor deficiency) 1, 3
• Pattern of occurrence: Distinguish between acute (<6 weeks), chronic (≥6 weeks continuous activity), or episodic (intermittent recurrent) patterns 1, 2
• Physical triggers: Assess for reproducible induction by mechanical, thermal, or other physical stimuli 1
• Review patient photo documentation of wheals and angioedema 1

Diagnostic Testing Strategy

Acute Urticaria

No routine testing is recommended unless the patient's history suggests a specific underlying cause requiring confirmation of an allergic etiology. 1

Chronic Spontaneous Urticaria (CSU)

The 2022 international guidelines emphasize the "7 Cs" framework for diagnostic workup 1:

Basic laboratory tests recommended for all CSU patients:

• Differential blood count 1
• C-reactive protein level or erythrocyte sedimentation rate 1
• Total IgE level 1
• IgG anti-thyroid peroxidase (anti-TPO) antibodies 1

Rationale for IgE and anti-TPO testing: Patients with autoimmune CSU typically have low or very low total IgE levels and elevated IgG anti-TPO levels; a high ratio of IgG anti-TPO to total IgE is the best surrogate marker for autoimmune CSU 1

Additional testing for antihistamine-refractory cases:

• CU index to determine presence of antibodies against IgE, FcεRI, or anti-FcεRII 1
• Autologous serum test may be considered for auto-reactive disease, though relevance is limited 1

Chronic Inducible Urticaria

Testing is limited to confirmation of diagnosis by provocation testing and subsequent trigger threshold assessment. 1

Critical Rule-Outs

For angioedema without wheals:

• Immediately order serum C4 level, which has high sensitivity for C1 inhibitor deficiency 3
• If C4 is low, confirm with quantitative and functional C1 inhibitor assays 3

For suspected urticarial vasculitis (wheals >24 hours):

• Lesional skin biopsy is mandatory 2
• Full vasculitis screen including serum complement assays 2

Disease Activity and Control Monitoring

Use validated patient-reported outcome measures (PROMs) to guide treatment decisions:

• Urticaria Control Test (UCT): For patients with wheals ± angioedema; cutoff for well-controlled disease is ≥12 points 1, 3
• Angioedema Control Test (AECT): For patients with angioedema ± wheals; cutoff for well-controlled disease is ≥10 points 1, 3
• Urticaria Activity Score (UAS7): Weekly composite score (range 0-42) combining itch severity (0-21) and hive count (0-21) 4

Treatment Algorithm

First-Line Treatment

Begin with second-generation H1 antihistamines at standard dosing (cetirizine, fexofenadine, loratadine, desloratadine, levocetirizine) 3, 5

• Cetirizine reaches maximum concentration fastest, advantageous for rapid symptom relief 5
• Continue for 2-4 weeks before determining inadequate response 3

Second-Line Treatment

If inadequate control after 2-4 weeks, escalate to up to 4 times the standard daily dose of the second-generation antihistamine. 3, 5

• Continue high-dose antihistamine for 2-4 weeks before advancing therapy 3

Third-Line Treatment

For inadequate control on high-dose antihistamines, add omalizumab 300 mg subcutaneously every 4 weeks. 3

• Allow up to 6 months to demonstrate response before considering treatment failure 3
• In clinical trials, 36% of CSU patients achieved complete symptom control (UAS7=0) at week 12 with omalizumab 300 mg versus 9% with placebo 4
• Once complete symptom control is achieved, maintain effective dose for at least 3 consecutive months before attempting step-down 3

Adjunctive Therapies

For resistant cases on high-dose antihistamines:

• Consider adding H2 antihistamines (ranitidine or cimetidine) 5
• First-generation sedating antihistamines (hydroxyzine) may be added at night for additional symptom control and sleep aid 5
• Leukotriene receptor antagonists may benefit a small subgroup 6

Role of Corticosteroids

Restrict oral corticosteroids to short courses (3-10 days) only for severe acute urticaria or life-threatening angioedema affecting the mouth. 3, 5

• Never use prolonged corticosteroids as maintenance therapy due to significant cumulative toxicity without addressing underlying disease mechanism 3, 5

Refractory Chronic Urticaria

For patients unresponsive to omalizumab, cyclosporine and tacrolimus have been used successfully 6

Trigger Identification and Avoidance

Common aggravating factors to avoid:

• NSAIDs and aspirin (particularly in aspirin-sensitive patients) 3, 5
• Codeine 3, 5
• Alcohol 3, 5
• Overheating and stress 5

ACE inhibitors must be avoided in patients with angioedema without wheals and used with caution when angioedema accompanies urticaria. 3

Special Dosing Considerations

Renal impairment:

• Avoid acrivastine in moderate renal impairment 5
• Halve the dose of cetirizine, levocetirizine, and hydroxyzine 5

Hepatic impairment:

• Avoid mizolastine in significant hepatic impairment 5
• Avoid hydroxyzine in severe liver disease 5

Prognosis

• Approximately 50% of patients with wheals alone will be clear by 6 months 5
• Patients with both wheals and angioedema have poorer outlook, with >50% still having active disease after 5 years 5
• Over 40% of patients show good response to antihistamines 5
• More than one-half of patients with chronic urticaria will have resolution or improvement within one year 7

Critical Pitfalls to Avoid

• Never confuse isolated urticaria with anaphylaxis: Check for systemic symptoms (hypotension, bronchospasm, airway angioedema) before diagnosing simple urticaria 5
• Never use antihistamines or corticosteroids in place of epinephrine for anaphylaxis: Antihistamines take 30-120 minutes to reach peak plasma concentrations and lack vasoconstrictive, bronchodilatory, and mast cell stabilization properties 5
• Avoid extensive routine laboratory testing in acute urticaria or chronic urticaria without specific clinical indicators, as most cases are idiopathic and testing rarely changes management 1, 2
• Do not continue ineffective treatments indefinitely: The primary treatment aim is complete disease control, requiring treatment adjustments based on UCT/AECT scores 1