What is the differential diagnosis for urticaria?

Differential Diagnosis for Urticaria

Primary Distinction: Duration and Characteristics of Lesions

The duration of individual wheals is the single most important clinical feature for distinguishing urticaria from its mimics: ordinary urticaria wheals last 2-24 hours and resolve without scarring, whereas lesions persisting beyond 24 hours strongly suggest alternative diagnoses, particularly urticarial vasculitis. 1, 2

Key Temporal Patterns by Diagnosis:

• Ordinary urticaria: 2-24 hours per wheal 1, 2
• Contact urticaria: Up to 2 hours 1
• Physical urticaria: Within 1 hour (except delayed pressure urticaria) 1, 2
• Delayed pressure urticaria: Develops in 2-6 hours, fades within 48 hours 1, 2
• Urticarial vasculitis: Wheals persist for days 1, 2
• Angioedema: May last up to 3 days without treatment 1

Major Differential Diagnoses

Urticarial Vasculitis

When wheals are painful, persist beyond 24 hours, and resolve with bruising or hyperpigmentation, urticarial vasculitis must be excluded through lesional skin biopsy. 1, 3, 4

• Presents with urticaria clinically but shows small vessel vasculitis histologically (leucocytoclasia, endothelial cell damage, perivascular fibrin deposition, red cell extravasation) 1
• May include systemic features: joint involvement, renal disease, fever, asthenia 1, 4
• Requires full vasculitis screen including C3 and C4 levels to distinguish normocomplementemic from hypocomplementemic disease (worse prognosis) 1
• Lesions may show bilateral symmetrical distribution and leave marks upon resolution 4

Angioedema Without Wheals

Angioedema occurring without wheals requires immediate evaluation for C1 esterase inhibitor deficiency or ACE inhibitor-induced angioedema, as these have distinct pathophysiology and treatment implications. 1

• May be caused by ACE inhibitors (bradykinin-mediated mechanism) 1
• C1 esterase inhibitor deficiency (hereditary or acquired) 1
• Screen with serum C4 level (sensitivity >95% but low specificity when <30% mean normal) 1
• If C4 low, confirm with quantitative and functional C1 inhibitor assays 1, 2
• Type I HAE: both immunochemical and functional C1 inhibitor low 1
• Type II HAE: only functional activity low 1
• Acquired C1 inhibitor deficiency: C1q also reduced 1
• May present with abdominal pain without obvious angioedema 1

Autoinflammatory Syndromes

In patients with recurrent urticarial plaques accompanied by fever, elevated inflammatory markers (CRP, leukocytosis), and negative connective tissue serologies, autoinflammatory disorders must be considered. 3

• Typically develop spontaneous wheals with pyrexia and malaise 1
• Include cryopyrin-associated periodic syndromes (e.g., Muckle-Wells syndrome with renal amyloidosis and sensorineural deafness) 1
• Schnitzler syndrome and familial cold autoinflammatory syndrome 2 3
• Inherited patterns usually present in early childhood 1
• ESR always raised in autoinflammatory syndromes 1
• Serum protein electrophoresis should be checked to rule out monoclonal gammopathy 3

Contact Urticaria

Contact urticaria occurs exclusively when the eliciting substance is absorbed percutaneously or through mucous membranes—it is never spontaneous. 1

• May result in localized or systemic reaction 1
• Can progress to anaphylaxis in highly sensitized individuals (e.g., latex allergy) 1
• Wheals typically last up to 2 hours 1
• Confirmed by skin-prick testing and CAP fluoroimmunoassay when environmental allergens suspected 1, 2

Physical Urticarias

Physical urticarias are distinguished by their specific triggers (pressure, cold, heat, exercise, dermographism) and rapid resolution within 1 hour, except for delayed pressure urticaria. 1, 5

• May occur alone or coexist with ordinary urticaria 1
• Cholinergic urticaria: triggered by stimuli that induce sweating (raised core temperature), not overheating per se 6
• Specific challenge testing required for diagnosis 1

Additional Differential Considerations

Systemic Diseases Presenting with Urticarial Lesions:

• Connective tissue diseases (systemic lupus erythematosus—look for leucopenia) 1, 4
• Hematologic diseases 4
• Mast cell disorders 3
• Hypereosinophilic syndrome (check eosinophilia on differential) 1, 3
• Pemphigoid 3
• Polymorphous eruption of pregnancy 3

Other Mimics:

• Drug eruptions 7
• Viral eruptions 7
• Urticaria pigmentosa 7

Clinical Pitfalls and Red Flags

When to Suspect Alternative Diagnosis:

• Wheals lasting >24 hours → consider urticarial vasculitis 1, 2, 3
• Painful rather than pruritic lesions → urticarial vasculitis 3
• Resolution with bruising or hyperpigmentation → urticarial vasculitis 3, 4
• Fever and elevated inflammatory markers → autoinflammatory syndromes 3
• Bilateral symmetrical distribution → systemic disease 4
• Angioedema without wheals → C1 inhibitor deficiency or ACE inhibitor effect 1
• Abdominal pain without obvious angioedema → C1 inhibitor deficiency 1

Investigation Strategy:

The diagnosis of urticaria is primarily clinical; investigations should be guided by history and not performed routinely in all patients. 1, 2

For acute/episodic urticaria: No investigations required except where history suggests specific trigger 1, 2

For chronic urticaria with severe disease or poor antihistamine response:

• Full blood count and differential (detect eosinophilia, leucopenia) 1, 2
• ESR or CRP (normal in ordinary urticaria, raised in vasculitis and autoinflammatory syndromes) 1, 2
• Thyroid autoantibodies and function tests 1, 2
• Consider autologous serum skin test (ASST) in experienced centers 1, 2

For suspected urticarial vasculitis: Lesional skin biopsy is essential 1, 2

For angioedema without wheals: Serum C4 as initial screen, then C1 inhibitor quantitative and functional assays if low 1, 2