Urticaria and Angioedema

GENERAL PRINCIPLES

Definition

• Urticaria (hives) are raised, erythematous, well-demarcated pruritic skin lesions. Central clearing can cause an annul ar lesion and is often seen after antihistamine use.

• Angioedema is swelling of the deep dermis and subcutaneous tissue. It is often painful rather than pruritic and generally lasts less than 48 hours. It can be found anywhere on the body but most often involves the tongue, lips, eyelids, throat, bowels, and/or genitals.

Classification

• Acute urticaria (with or without angioedema) is defined as the occurrence of hives and/or angioedema lasting 6 weeks. There are many possible causes of chronic urticaria and angioedema, including medications, autoimmunity, self-care products, and physical triggers. However, the etiology remains unidentified in >80% of cases.

Epidemiology

• Urticaria is a common condition that affects 15%-24% of the US population at some time in their life. Chronic idiopathic urticaria occurs in approximately 1% of the US population, and there does not appear to be an increased risk in persons with atopy.¹⁴

• Angioedema occurs in 40%-50% of patients with urticaria.

Etiology

• IgE-mediated: drugs, foods, stinging and biting insects, latex, inhalant, or contact allergens

• Non-IgE-mediated: narcotics, muscle relaxants, radiocontrast, vancomycin, NSAIDs, ACE inhibitors

• Transfusion reactions

• Infections (i.e., viral, bacterial, parasitic)

• Systemic disorders: autoimmune diseases, malignancy, mastocytosis, HES, cryoglobulinemia, and hereditary diseases

• Physical urticaria: dermographism, cold, cholinergic, pressure, vibratory, solar, and aquagenic

• Idiopathic

Pathophysiology

Most forms of urticaria and angioedema are caused by the degranulation of mast cells or basophils and the release of inflammatory mediators.

DIAGNOSIS

Diagnosis is based on complete history and physical examination with characteristic skin lesions.

Clinical Presentation

• Patients with an acute urticaria episode present with history of pruritic, raised, erythematous lesions. Individual lesions resolve over a period of 1-24 hours.

• Angioedema usually presents with painful swelling without pruritus. The swelling can take up to 72 hours to resolve.

• Physical urticaria is induced by environmental or physical stimuli. The common triggers are cold, heat, sweating, exercise, pressure, vibration, and sunlight. Dermographism, literally “skin writing,” is the most common form of physical urticaria. It affects approximately 4% of the population and can be elicited by briskly stroking or scratching skin.

HISTORY

• A detailed history should elicit identifiable triggers and rule out any systemic causes. When the individual skin lesion lasts longer than 48 hours, the diagnosis of urticarial vasculitis must be investigated by a skin biopsy.

• Any changes in environmental exposures, foods, medications, personal care products, etc. should be determined.

• It is important to differentiate from anaphylaxis, which affects organs other than the skin, as this will be treated differently (see “Anaphylaxis” section).

PHYSICAL EXAMINATION

• Complete examination of the affected and nonaffected skin.

• Urticaria appears as erythematous, raised lesions that blanch with pressure.

• Angioedema appears as swelling; can often involve the face, tongue, extremities, or genitalia; and may be asymmetric.

Differential Diagnosis

• IgE-mediated allergic reaction to drugs, foods, insects, inhalant, or contact allergen.

• Non-IgE-mediated drug and food reactions (i.e., medications including NSAIDs, vancomycin, radioactive iodine, opiates, muscle relaxants, foods including tomatoes and strawberries).

• Pruritic urticarial papules and plaques of pregnancy.

• Mast cell release syndromes (i.e., systemic mastocytosis, cutaneous mastocytosis including urticaria pigmentosa).

• Cutaneous small-vessel vasculitis (i.e., urticarial vasculitis, systemic lupus erythematosus).

• HES.

• Toxic drug eruptions.

• Allergic contact dermatitis (i.e., poison ivy, poison oak).

• Cryopyrin-associated periodic syndromes including familial cold autoinflammatory syndrome and Muckle-Wells syndrome.

• Angioedema without urticaria should lead to consideration of specific entities.

๎ Use of ACE inhibitors or angiotensin II receptor blockers (ARBs) can be associated with angioedema at any point in the course of therapy and can occur up to 6 weeks after last exposure.

๎ HAE, or C1 INH deficiency, is inherited in an autosomal dominant pattern; 25% of cases arise from de novo mutations.

๎ Acquired C1 INH deficiency presents similarly to HAE but is typically associated with an underlying lymphoproliferative disorder, connective tissue disease, or other neoplasias.

Diagnostic Testing

Epicutaneous skin testing and patch testing are only indicated when symptoms are associated with specific triggers.

LABORATORIES

• Routine laboratory testing in the absence of a clinical history is rarely helpful in determining an etiology in chronic urticaria. Evaluation for systemic disease associated with chronic urticaria includes CBC with differential, CRP or ESR, thyroid-stimulating hormone, renal and hepatic profiles.

• Autologous serum skin testing, assays for basophil histamine release, and autoantibodies to IgE and the high-affinity IgE receptor are available, but the utility of these tests has not been established.

• All patients with angioedema without urticaria should be screened with a C4 level, which is reduced during and between attacks of HAE. If the C4 level is reduced, a quantitative and functional C1 INH assay should be performed. Measuring C1 INH levels alone is not sufficient because 15% of patients have normal levels of a dysfunctional C1 INH protein; therefore, it is important to also obtain the functional assay.

• Acquired C1 INH deficiency patients have reduced C1q, C1 INH level and function, and C4 levels due to an autoantibody to C1 INH.

DIAGNOSTIC PROCEDURES

• A skin biopsy should be performed if individual lesions persist for >24 hours to rule out urticarial vasculitis.

TREATMENT

• The ideal treatment of acute urticaria with or without angioedema is identification and avoidance of specific causes. All potential causes should be eliminated. Most cases of acute urticaria are selfญlimited and resolve spontaneously.

• Careful consideration should be given to the elimination or substitution of each prescription or over- the-counter medication or supplement. If a patient reacts to one medication in a class, the reaction likely will be triggered by all medications in that class. Exacerbating agents (e.g., NSAIDs, opiates, vancomycin, and alcohol) should be avoided because they may induce nonspecific mast cell degranulation and exacerbate urticaria caused by other agents.

Medications

If acute urticaria is associated with additional systemic symptoms such as hypotension, laryngeal edema, or bronchospasm, treatment with epinephrine (0.3-0.5 mL of a 1:1000 solution IM) should be administered immediately. See “Anaphylaxis” section for additional information.

ACUTE URTICARIA AND/OR ANGIOEDEMA

• Second-generation antihistamines such as cetirizine, fexofenadine, or loratadine should be administered to patients until the hives have cleared. Higher than conventional, US FDA-approved doses may provide more efficacy. A first-generation antihistamine such as hydroxyzine may be added as an evening dose if needed to obtain control in refractory cases. H₂ antihistamines, such as ranitidine, may also be added to the above treatment.

• Oral corticosteroids should be reserved for patients with moderate to severe symptoms. Corticosteroids will not have an immediate effect but may prevent relapse.

• If a patient presents with systemic symptoms, self-administered epinephrine should be prescribed for use in the case of anaphylaxis.

CHRONIC URTICARIA

• Use of a second-generation H₁ antihistamine once or twice daily (up to four times daily).

• If no response, then can add H₂ antihistamine, leukotriene receptor antagonist, and/or first-generation H₁ antihistamine or doxepin to be taken at bedtime.

• If continued urticaria, then can choose an alternative such as omalizumab (FDA approved for patient with chronic urticaria that fail H₁ antihistamine therapy), cyclosporine, hydroxychloroquine, dapsone, or other immunosuppressants.

• Optimal duration of therapy has not been established; tapering medications after 3-6 months of symptom control has been suggested.

HEREDITARY AND ACQUIRED ANGIOEDEMA (DISORDER OF C1 INHIBITOR)

• Acute attacks: C1 inhibitor concentrate, icatibant, and ecallantide are first-line agents. If none of the first-line agents are available, fresh frozen plasma can be used. Also pursue symptomatic therapy and rehydration.

• Preventative medications include C1 inhibitor replacement via IV or SC, lanadelumab, berotralstat, attenuated androgens, and antifibrinolytics.

Referral

All patients with chronic urticaria or a history of anaphylaxis should be referred to an allergy specialist for evaluation to identify potential allergic and autoimmune triggers.