Urticaria & Angioedema

Urticaria (also known as hives) is characterized by severely pruritic raised, erythematous, circumscribed lesions resulting from mast cell activation and subsequent release of histamine and other vasoactive mediators that lead to increased vascular permeability of postcapillary venules and subsequent edema, erythema, and pruritus. Although urticaria can last for days to weeks, each urticarial lesion typically lasts <24-48 hours and does not leave a bruise or mark.

(Source: Exanthematous Drug Eruptions. N Engl J Med 2012.)

Urticaria can be classified as acute or chronic, depending on the duration of symptoms:

• Acute urticaria (duration, <6 weeks) may have an identifiable cause, such as foods, medications (including antibiotics, aspirin, or nonsteroidal anti-inflammatory drugs [NSAIDs]), insect stings, underlying disorders (infections, Helicobacter pylori, and parasitic diseases), and malignancy (see table below).

• Chronic urticaria (duration, >6 weeks) typically does not have an underlying allergic basis; often an etiology is not found, and it is considered chronic spontaneous or chronic idiopathic urticaria (CIU):

  • CIU is associated with autoimmune disorders such as Hashimoto thyroiditis (autoimmune hypothyroidism); evidence suggests that the urticaria may be caused by autoantibodies directed against mast cells in the skin in about half of patients with CIU.

  • CIU is considered a benign and self-limiting condition and is not associated with tissue-destructive activity.

  • Nonimmunologic causes of urticaria include physical urticarias (e.g., cold-induced, pressure-induced, exercise-induced, vibration-induced, and cholinergic urticarial).

Angioedema involves a similar process as urticaria but affects the deep dermis and subcutaneous tissue and leads to nonpitting swelling. Angioedema tends to be localized, asymmetric, and often affects the face, extremities, and genitalia. Angioedema can be mast-cell-mediated or bradykinin-mediated. This section addresses mast-cell- or histamine-mediated angioedema. Bradykinin-mediated angioedema is not associated with urticaria or other histamine-mediated symptoms and is discussed in the next section.

Causes of Urticaria and Angioedema

The following table lists the possible causes of urticaria and angioedema.

(Source: Northwestern University Allergy-Immunology Syllabus 2012: Residents and Students. Providence, RI: Oceanside Publications. Copyright © 2012, OceanSide Publications, Inc. with permission.)

Evaluation of Urticaria and Angioedema

• On physical exam, urticarial lesions may be present if a flare is ongoing. Ask patients for photographs of the rash to differentiate urticaria from other skin eruptions (e.g., eczema or contact dermatitis).

• In chronic urticaria, screening tests may be indicated if a systemic disorder is suspected.

  • Specific lab tests depend on clinical suspicion but may include CBC with differential, chemistry panel, liver function tests, thyroid-stimulating hormone (TSH), ESR, serum protein electrophoresis (SPEP), and antinuclear antibodies (ANA).

• In isolated angioedema without urticaria, a C4 level is the best screening test for hereditary angioedema. However, in rare cases, patients with hereditary angioedema can have normal C4 levels. Therefore, if clinical suspicion is high, lab testing for C1 inhibitor level and function should also be sent to screen for this condition.

• Skin biopsies may be considered to evaluate for urticarial vasculitis if the hives are atypical (nonblanching, painful, purpuric, last >24 hours) or are associated with systemic symptoms (e.g., fever, uveitis, glomerulonephritis, or arthritis).

Treatment

• If a trigger is identifiable, avoidance is the first step.

• Aspirin and NSAIDs should be avoided because they can cause or exacerbate urticaria and angioedema. A selective COX-2 inhibitor (e.g., celecoxib) can be considered if needed for pain or anti-inflammatory properties.

• Antihistamines (preferably second-generation, long-acting, nonsedating H1 blockers [e.g., cetirizine or fexofenadine]) are the mainstay of treatment.

  • Higher doses (2-4 times the FDA-approved dose) are often required to control symptoms.

  • Other treatment options include doxepin, hydroxyzine, and montelukast.

  • H2 blockers can also be considered.

• In the short term, oral corticosteroids can be used to control symptoms but only for limited duration due to the adverse effect profile. Long-acting, nonsedating antihistamines should be used in conjunction with glucocorticoids to prevent recurrence once glucocorticoids are discontinued.

• Omalizumab is a monoclonal antibody that targets IgE and is approved for use in chronic idiopathic urticaria refractory to high-dose antihistamines.

• Immunomodulators such as cyclosporine have been used successfully in patients who are refractory to standard therapy and may lead to more rapid remission.

Types of Angioedema

Angioedema can be mast-cell-mediated or bradykinin-mediated (see the previous section on histamine-mediated angioedema). Bradykinin-mediated angioedema is not associated with urticaria or other histamine-mediated symptoms.

ACE-Inhibitor-Induced Angioedema

• Angiotensin converting enzyme (ACE)-inhibitor-induced angioedema is the most common cause of bradykinin-mediated angioedema and usually affects the lips, tongue, and face but can also involve the gastrointestinal tract.

• Swelling usually develops over minutes to hours, reaches a peak, and then resolves after 24 to 72 hours.

• Swelling may occur any time during the course of ACE-inhibitor therapy, from hours to years after initiation of treatment.

• Risk factors for development of ACE-inhibitor-induced angioedema include:

  • age >65 years

  • aspirin use

  • female sex

  • smoking

  • underlying hereditary angioedema

• ACE-inhibitor-induced angioedema is a clinical diagnosis based on the presence of angioedema in a characteristic anatomic site (usually lips, tongue, or throat) with the absence of itching or urticaria in a patient taking an ACE inhibitor. Lab results in these patients are usually normal.

• Some patients will have recurrent episodes after discontinuation of the ACE inhibitor, particularly during the first few weeks to months.

• Acute treatment involves discontinuing the ACE inhibitor and airway evaluation by an otolaryngologist if there are any signs of respiratory distress and consideration for intubation if there is airway compromise.

• Antihistamines, glucocorticoids, and epinephrine typically are not effective for bradykinin-mediated angioedema.

• Icatibant (a synthetic bradykinin B2-receptor antagonist) was shown to be effective for treatment of ACE-inhibitor angioedema in one small study but findings could not be replicated in subsequent studies and it is not FDA-approved for this indication. However, its use may be considered in severe cases if administered early.

• Early case reports suggested that patients with ACE-inhibitor angioedema were at risk of angioedema with angiotensin-receptor blockers(ARBs), but this is now thought to be due to the recurrent angioedema episodes even after discontinuation of the ACE inhibitor. Currently, no clear evidence suggests that ARBs should be avoided in patients with ACE-inhibitor angioedema if they are medically indicated.

• Patients should be counseled on the risk of recurrence of angioedema with an action plan, and these patients should be monitored for adverse effects.

• Given the potential for angioedema to occur weeks to months after discontinuation of the ACE inhibitor, some clinicians recommend waiting at least 4-6 weeks before starting an ARB.

Hereditary Angioedema

• Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by a deficiency or dysfunction of functional C1 esterase inhibitor (C1-INH) that leads to excessive production of the vasoactive mediator bradykinin. This causes episodic increases in vascular permeability and angioedema.

• HAE is not associated with urticaria, and an alternate diagnosis should be considered if hives are a prominent feature of presentation.

• HAE accounts for only a small fraction of cases of angioedema.

• The three subtypes of HAE are as follows:

  • type I (deficient production; C1-INH level <30% of normal)

  • type II (dysfunctional protein; C1-INH is detectable but has reduced function)

  • hereditary angioedema with normal C1-INH (previously known as type III; factor XII mutation can be present in some patients, but overall pathogenesis remains unclear)

• C4 is the best test to screen for HAE because it is low at baseline in approximately 96% of patients and during most attacks (in 99% of patients). C1-INH functional and quantitative levels can help differentiate between type I and type II HAE (see table below).

(Source: Hereditary Angioedema, N Engl J Med 2008.)

Acquired Angiodema

Acquired C1-INH deficiency or acquired angioedema can be due to consumption of complement in B-cell lymphoproliferative disorders or immune-complex disorders and generally presents during the fourth decade of life or later. The majority of patients diagnosed with acquired angioedema have an underlying disorder (e.g., lymphoproliferative disorders and B-cell malignancies, monoclonal gammopathy of uncertain significance, or other autoimmune conditions). Most (but not all) patients with acquired angioedema have identifiable autoantibodies against the C1 esterase inhibitor (C1-INH) protein.

Evaluation of acquired angioedema depends on the clinical presentation, but the following labs can be considered:

• C1q, C2, C3, total complement (CH50): can be low in acquired but not in hereditary angioedema

• ANA

• serum protein electrophoresis (SPEP)

• quantitative immunoglobulins

• serum free light chains

HAE treatment options for acute attacks include the following:

• plasma C1-inhibitor concentrate (available in intravenous and subcutaneous preparations for treatment of acute attacks and preventative therapy)

• kallikrein inhibitors (subcutaneous ecallantide)

• bradykinin receptor B2 antagonists (subcutaneous icatibant)

• anabolic steroids (e.g., danazol or stanozolol) have slower onset of action and are associated with an increased risk of adverse effects; used less often now that more-specific, targeted treatments are available

• fresh frozen plasma carries a risk of worsening angioedema; used less often now that more-specific, targeted treatments are available

HAE prophylaxis options include the following:

• purified C1-inhibitor concentrate

• subcutaneous lanadelumab (human monoclonal antibody targeting plasma kallikrein)

• attenuated androgens (adverse effects limit use; contraindicated in growing children and pregnant/lactating women)

• antifibrinolytics (generally less effective)

• oral berotralstat (plasma kallikrein inhibitor) was approved by the FDA in December 2020

(Reprinted from International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema, Allergy, Asthma, and Clin Immunol 2010. Copyright (2017), with permission from Elsevier.)