What is the differential diagnosis for an adult patient with urticaria and no significant past medical history?

Differential Diagnosis for Urticaria

The differential diagnosis for urticaria must first distinguish between true urticaria (wheals lasting <24 hours) and urticarial-like conditions, then systematically categorize by temporal pattern, triggers, and associated features to identify mimics such as urticarial vasculitis, autoinflammatory diseases, and drug reactions.

Primary Classification by Wheal Duration

The single most critical distinguishing feature is how long individual wheals persist:

• Ordinary urticaria: Individual wheals last 2-24 hours before resolving without scarring or hyperpigmentation 1, 2
• Physical urticaria: Wheals typically resolve within 1 hour, except delayed pressure urticaria which develops in 2-6 hours and fades within 48 hours 1, 2
• Urticarial vasculitis: Wheals persist beyond 24 hours, often for days, and this mandates skin biopsy to confirm small vessel vasculitis 3, 2

If individual wheals last >24 hours, you are not dealing with ordinary urticaria—biopsy is essential to exclude vasculitis 3.

Temporal Pattern Classification

Acute Urticaria (≤6 weeks)

• Most common in all age groups, often triggered by infections, allergic reactions to foods/drugs, or physical stimuli 4, 5
• No extensive workup needed unless history suggests specific triggers 1, 2

Chronic Urticaria (>6 weeks)

Further subdivided into:

• Chronic spontaneous urticaria (CSU): Wheals appear spontaneously without identifiable physical triggers 3
• Chronic inducible urticaria (CIndU): Definite subtype-specific triggers (dermatographism, cold, heat, pressure, solar, exercise) 5, 6

Key Differential Diagnoses and Mimics

Urticarial Vasculitis

• Individual wheals persist >24 hours 3, 2
• May have systemic symptoms: fever, arthralgia, malaise 3
• Lesions may leave residual hyperpigmentation or purpura 7
• Requires biopsy for histologic confirmation 2

Autoinflammatory Diseases

• Systemic symptoms accompanying urticaria: fever, joint pain, malaise 3
• Consider cryopyrin-associated periodic syndromes, Schnitzler syndrome, Still's disease 7
• Elevated inflammatory markers (ESR, CRP) 2

Drug-Induced Reactions

• ACE inhibitors and NSAIDs are frequently implicated 3
• Aspirin can trigger or worsen urticaria 3
• Detailed medication review is mandatory 3

Physical Urticarias (Specific Subtypes)

• Delayed pressure urticaria: Strongly consider for leg-localized urticaria due to weight-bearing, sitting, standing, or tight clothing 3
• Solar urticaria: Triggered by sun exposure, must distinguish from chronic spontaneous urticaria with sun as trigger 8
• Dermatographism: Wheals induced by stroking/scratching skin 6
• Cholinergic urticaria: Small wheals triggered by heat, exercise, emotional stress 6
• Cold urticaria: Triggered by cold exposure 6

Ask specifically: "Can you make your wheals appear? Can you bring out your wheals?" to identify inducible patterns 3.

Associated Systemic Conditions

• Thyroid autoimmunity: Present in 14% of chronic urticaria patients; check thyroid autoantibodies and thyroid function tests 3, 2
• Helicobacter pylori: Chronic urticaria resolution more likely when H. pylori eradication is successful 3
• Celiac disease: Higher prevalence in children and adolescents with severe chronic urticaria 3
• Autoimmune chronic spontaneous urticaria: Approximately one-third have circulating functional autoantibodies against high-affinity IgE receptor or IgE 4

Hereditary Angioedema (HAE)

• Angioedema without urticaria, often affecting face, extremities, gastrointestinal tract 1
• C4 level has high sensitivity for C1 inhibitor deficiency; if low, confirm with quantitative and functional C1 inhibitor tests 2
• Recurrent episodes, family history 1

Other Mimics to Consider

• Urticaria pigmentosa (mastocytosis): Lesions persist and may have hyperpigmentation; Darier's sign positive 7
• Bullous pemphigoid (urticarial phase): May present with urticarial plaques before blisters develop 7
• Erythema multiforme: Target lesions, fixed location, mucosal involvement 7
• Contact urticaria: Localized to contact area, typically lasts up to 2 hours 2

Diagnostic Algorithm

Step 1: Confirm True Urticaria

• Wheals are transient, pruritic, blanching swellings 5
• Individual lesions resolve within 24 hours without residual marks 3, 2

Step 2: Determine Duration Pattern

• <6 weeks: Acute urticaria—minimal workup unless history suggests specific cause 1, 2
• >6 weeks: Chronic urticaria—proceed to further classification 5

Step 3: Identify Spontaneous vs. Inducible

• Spontaneous: No clear physical trigger; consider CSU 3
• Inducible: Specific reproducible triggers; identify subtype (pressure, cold, heat, etc.) 3, 6

Step 4: Screen for Red Flags

• Wheals >24 hours: Biopsy for urticarial vasculitis 3, 2
• Systemic symptoms (fever, arthralgia, malaise): Consider autoinflammatory disease or vasculitis 3
• Angioedema without wheals: Consider hereditary angioedema; check C4, C1 inhibitor 2
• Fixed hyperpigmented lesions: Consider mastocytosis 7

Step 5: Targeted Laboratory Testing (for Chronic Urticaria)

Useful screening tests include:

• Complete blood count with differential 2
• ESR or CRP 2
• Total IgE level 2
• IgG-anti-thyroid peroxidase (TPO) level 2
• Thyroid function tests 2

Do not perform extensive laboratory workups in all patients—investigations should be guided by clinical features 3.

For suspected autoimmune urticaria:

• Total IgE and IgG-anti-TPO ratio is the best surrogate marker 2
• Low or very low total IgE with high IgG-anti-TPO suggests autoimmune urticaria 2
• Autologous serum skin test (ASST) offers reasonably sensitive and specific screening for histamine-releasing autoantibodies 1, 2

For suspected IgE-mediated reactions:

• Skin-prick testing and CAP fluoroimmunoassay when environmental allergens suspected 2

Common Pitfalls to Avoid

• Do not dismiss wheals lasting >24 hours as "just urticaria"—this mandates biopsy to exclude vasculitis 3
• Do not overlook medication history—ACE inhibitors and NSAIDs are frequently implicated 3
• Do not assume all leg urticaria is systemic—consider localized physical triggers like delayed pressure urticaria from sitting or standing 3
• Do not perform extensive laboratory workups in all patients—investigations should be guided by clinical features suggesting specific conditions 3
• Do not confuse chronic spontaneous urticaria with chronic inducible urticaria—ask specifically about reproducible triggers 3

Special Considerations

Contact Urticaria

• Localized to area of contact with triggering substance 2
• Typically lasts up to 2 hours 2
• Can be immunologic (IgE-mediated) or non-immunologic 4

Chronic Spontaneous Urticaria (CSU) Specific Features

• Diagnosis of exclusion after ruling out physical triggers and other causes 3
• At least 30% appear to have autoimmune etiology 1
• Disease persists >1 year in most patients 5
• Greatly affects quality of life and is linked to psychiatric comorbidities 5

Note: Omalizumab (anti-IgE antibody) is FDA-approved for CSU in adults and adolescents ≥12 years who remain symptomatic despite H1 antihistamine treatment, but is not indicated for other forms of urticaria 9.