INFLAMMATORY AND IMMUNE-MEDIATED SKIN DISORDERS

Urticaria

Etiology and risk factors

• Acute triggers include viral infection, foods, medications, insect stings, and contact exposures. Chronic spontaneous urticaria often has no external trigger and may involve functional autoantibodies or autoimmune mast-cell activation (Gohara et al., 2012; Pincus & McCalmont, 2019).
• Inducible forms follow pressure, cold, heat, exercise/cholinergic stimulation, vibration, water, sunlight, or scratching. Acute is less than 6 weeks; chronic is 6 weeks or longer (Gohara et al., 2012; Pincus & McCalmont, 2019).

Pathophysiology

• Mast-cell degranulation releases histamine and other mediators, causing superficial dermal vasodilation and increased permeability. Local edema forms a wheal with surrounding erythema (Norris, 2020; Pincus & McCalmont, 2019).
• Deeper dermal/subcutaneous mediator effects cause angioedema. Bradykinin-mediated angioedema is a different pathway and usually occurs without hives or pruritus (Norris, 2020; Pincus & McCalmont, 2019).

Clinical manifestations

• Abrupt raised, blanching, intensely pruritic wheals of variable size and shape that move or disappear within hours. No primary scale, crust, vesicle, or pigment remains (Gohara et al., 2012; Pincus & McCalmont, 2019).
• Angioedema causes deeper, often painful swelling of lips, eyelids, tongue, hands, feet, genitalia, or airway. Anaphylaxis adds respiratory compromise, hypotension, or significant multisystem symptoms (Gohara et al., 2012; Pincus & McCalmont, 2019).

Findings that argue against or redirect

• A fixed lesion lasting more than 24 hours, pain/burning, purpura, fever, joint/renal symptoms, or residual pigment suggests urticarial vasculitis or another inflammatory disease (Gohara et al., 2012; Pincus & McCalmont, 2019).
• Fixed target lesions favor EM; contact-distribution vesicles favor dermatitis; nonpruritic angioedema without wheals suggests bradykinin-mediated disease (Gohara et al., 2012; Pincus & McCalmont, 2019).
• Normal testing does not exclude chronic spontaneous urticaria, which is a clinical diagnosis (Gohara et al., 2012; Pincus & McCalmont, 2019).

Diagnostic evaluation

• Confirm the duration of each lesion, total disease duration, triggers, medications including NSAIDs and ACE inhibitors, physical stimuli, infection symptoms, and anaphylaxis features. Photographs help when lesions have resolved (Pincus & McCalmont, 2019; Zuberbier et al., 2026).
• Do not order routine testing for uncomplicated acute spontaneous urticaria unless the history suggests a specific allergy or drug reaction. For chronic spontaneous urticaria, use a limited evaluation such as CBC with differential and CRP or ESR, then add tests only when the history and examination indicate a specific cause or comorbidity (Pincus & McCalmont, 2019; Zuberbier et al., 2026).
• Consider complement and C1-inhibitor testing for recurrent angioedema without wheals and biopsy lesions that persist longer than 24 hours, are painful or purpuric, or leave residual pigment when urticarial vasculitis is suspected (Pincus & McCalmont, 2019; Zuberbier et al., 2026).

Expected diagnostic and laboratory findings

• Clinical finding: transient blanching wheal with no epidermal surface change. Biopsy, rarely needed, shows dermal edema and sparse perivascular inflammation without primary epidermal injury (Gohara et al., 2012; Pincus & McCalmont, 2019).
• Elevated tryptase can support recent systemic mast-cell activation when collected at the correct time, but a normal result does not exclude anaphylaxis (Gohara et al., 2012; Pincus & McCalmont, 2019).
• Low complement or vasculitic histology redirects toward urticarial vasculitis (Gohara et al., 2012; Pincus & McCalmont, 2019).

Differential diagnosis

• Urticarial vasculitis: lesions persist over 24 hours, hurt/burn, may be purpuric, and leave residual pigment; biopsy shows vasculitis (Gohara et al., 2012; Pincus & McCalmont, 2019).
• Erythema multiforme: fixed target lesions lasting days (Gohara et al., 2012; Pincus & McCalmont, 2019).
• Allergic contact dermatitis: delayed exposure-linked eczematous/vesicular surface change (Gohara et al., 2012; Pincus & McCalmont, 2019).
• Hereditary/ACE-inhibitor angioedema: deeper nonpruritic swelling without wheals; complement/medication history helps distinguish (Gohara et al., 2012; Pincus & McCalmont, 2019).

Treatment and management

• Avoid an identified trigger and begin a second-generation H1 antihistamine. If control is inadequate, increase the dose of the same agent up to fourfold under clinician direction rather than combining multiple H1 antihistamines (Pincus & McCalmont, 2019; Zuberbier et al., 2026).
• Add omalizumab for chronic spontaneous urticaria that remains uncontrolled on high-dose second-generation H1 antihistamine. Cyclosporine may be considered by a specialist for severe disease refractory to antihistamines and omalizumab (Pincus & McCalmont, 2019; Zuberbier et al., 2026).
• Avoid long-term systemic corticosteroids. A brief rescue course, generally no longer than 10 days, may be considered for a severe acute exacerbation (Pincus & McCalmont, 2019; Zuberbier et al., 2026).
• Epinephrine is first-line for anaphylaxis or threatened airway or circulation; antihistamines do not replace epinephrine. Stop an offending medication when clinically safe and appropriate (Pincus & McCalmont, 2019; Zuberbier et al., 2026).

Additional complications and red flags

• Angioedema without hives requires evaluation for bradykinin-mediated causes because antihistamines/epinephrine may not address the underlying pathway, although airway management remains urgent (Pincus & McCalmont, 2019; Zuberbier et al., 2026).

---

---

References

Gohara, M. A., Schaffer, J. V., Abbasi, N. R., Kingsley, M. M., Sheehan, J. M., & Arndt, K. A. (2012). Inflammatory dermatoses (rashes). In M. C. Henderson, L. M. Tierney, Jr., & G. W. Smetana (Eds.), The patient history: An evidence-based approach to differential diagnosis (2nd ed.). McGraw-Hill.

Norris, T. L. (2020). Porth’s essentials of pathophysiology (5th ed.). Wolters Kluwer.

Pincus, L. B., & McCalmont, T. H. (2019). Diseases of the skin. In G. D. Hammer & S. J. McPhee (Eds.), Pathophysiology of disease: An introduction to clinical medicine (8th ed.). McGraw-Hill Education.

Zuberbier, T., Ansari, Z. A. H., Abdul Latiff, A. H., Abuzakouk, M. M., Agcaoili-De Jesus, M. S., Agondi, R. C., Al-Ahmad, M., Alangari, A. A., Alhameli, H., Alonso Bello, C. D., Alshareef, S., Al-Tamemi, S., Altrichter, S., Al Wahshi, H., Aquilina, S., Araújo, M., Arnaout, R., Asero, R., Ballmer-Weber, B., . . . Giménez-Arnau, A. M. (2026). The international guideline for the definition, classification, diagnosis and management of urticaria. Allergy, 81(8), 2582–2632. https://doi.org/10.1111/all.70210