eMedicine Specialties > Dermatology > Allergy & Immunology

Urticaria, Chronic

Author: Daniel J Hogan, MD, Affiliate Teaching Faculty, Sun Coast Hospital; Investigator, Hill Top Research, Florida Research Center
Contributor Information and Disclosures

Updated: Jul 28, 2008

Introduction

Background

Chronic urticaria, defined as urticaria that persists for longer than 6 weeks, is a frustrating condition for both patients and caregivers. Urticaria is not a single disease but a reaction pattern that represents cutaneous mast cell degranulation, resulting in extravasation of plasma into the dermis. Urticaria is characterized by hives or wheals, which are edematous pruritic papules or plaques. The variety of potential triggers of urticaria, especially for acute urticaria, can make the approach to diagnosis and treatment a challenge. Patients with chronic urticaria may not improve or may depend on medication for years to relieve symptoms.

The primary subgroups of chronic urticaria include physical urticaria (ie, symptomatic dermatographism, cholinergic urticaria, pressure urticaria), urticaria secondary to an underlying medical condition, and chronic idiopathic urticaria (CIU). Physical urticaria, which is reproducible with the appropriate stimuli, can be identified with a thorough history and challenge testing. For more information, see the following eMedicine articles on the various types of urticaria:

• Urticaria, Acute
• Urticaria, Cholinergic
• Urticaria, Contact Syndrome
• Urticaria, Dermographism
• Urticaria, Pressure
• Urticaria, Solar

Traditionally, the approach in patients with chronic urticaria (when physical etiology has been excluded) has been to order a panel of laboratory tests to uncover an occult medical condition responsible for the skin findings. In many patients, an extensive workup does not uncover an etiology. Urticaria rarely is the sole manifestation of an underlying medical problem. Patients in whom no explanation for the urticaria is established are said to have CIU; however, findings suggest that in 25-45% of patients, CIU is not idiopathic but is an autoimmune disease termed chronic autoimmune urticaria.¹

An important entity in the differential diagnosis of chronic urticaria is urticarial vasculitis. A forme fruste of leukocytoclastic vasculitis, urticarial vasculitis may be associated with hypocomplementemia and systemic symptoms (see Urticarial Vasculitis).

The Medscape Allergy Resource Center may be helpful.

Pathophysiology

The mast cell is the primary agent in the pathogenesis of urticaria. Mast cell stimulation results in the release of both preformed (histamine) and newly formed (prostaglandins) mediators from cytoplasmic granules, which cause wheal formation, vasodilatation, and erythema. Mast cells also release chemoattractants for other cells (eg, neutrophils) that also are involved in wheal formation. A number of mediators may be involved in the pathogenesis of urticaria, which may explain why antihistamines are not always effective therapy.

Immunoglobulin G autoantibodies to the alpha subunit of the Fc receptor of the immunoglobulin E (IgE) molecule or, less commonly, anti-IgE autoantibodies, can activate basophils to release histamine. This response may be augmented by complement activation and production of C5a. Unlike pulmonary mast cells, cutaneous mast cells have C5a receptors. C5a not only brings about mast cell activation, but is also a neutrophil and eosinophil chemoattractant, leading to accumulation of these cells in lesional skin. 
 
Dermal mast cells secrete preformed mediators, including histamine (mainly the cause of pruritus.), proteases, interleukin 1, and tumor necrosis factor-alpha. The cytokines cause increased expression of adhesion molecules by endothelium of postcapillary venules.
 
Approximately one third of patients with chronic urticaria have either or both antithyroglobulin antibody and antimicrosomal antibody, and up to one fifth have abnormal thyroid function. A positive functional anti-FcεR test result supports an autoimmune basis. A positive test result does not indicate which autoantibody (anti-IgE, anti-FcεRI, or anti-FcεRII) is present. Affected patients may be categorized as having autoimmune chronic urticaria.

Other non–IgE-mediated mast cell degranulators include radiocontrast media, morphine, codeine, and vancomycin. Approximately  one third of patients with chronic urticaria may develop angioedema after administration of aspirin or other nonsteroidal anti-inflammatory drugs.²

Approximately 85% of histamine receptors in the skin are of the H1 subtype, with the remaining 15% being H2 receptors. The addition of an H2 receptor antagonist to an H1 receptor antagonist augments the inhibition of a histamine-induced wheal-and-flare reaction once histamine-receptor blockade has been maximized. The combination of H2 receptor antagonists with an H1 receptor antagonist provides small additional benefit. Doxepin blocks both types of histamine receptors and is a much more potent inhibitor of H1 receptors than diphenhydramine or hydroxyzine.

Food allergy is rarely the basis of chronic urticaria.

Frequency

United States

Chronic urticaria is less common than acute urticaria. Urticaria affects 15-20% of the population at some point in their lives, but the urticaria persists daily or almost daily for more than 6 weeks in only approximately 1% of the population.

International

The incidence is the same as in the United States.

Mortality/Morbidity

Unlike angioedema, which may affect the airway, urticaria is not a life-threatening disease; however, chronic urticaria has been shown to have a negative impact on the quality of life of affected patients.³ In a study by O'Donnell et al,⁴ the effects of chronic urticaria on the activities of daily living, social interactions, rest, and work were found to be similar to those experienced by patients with heart disease.

Race

Urticaria affects persons of all races.

Sex

Both sexes are affected; however, urticaria is more common in women, especially in middle-aged women. CIU occurs twice as often in women as in men.

Age

Chronic urticaria is reported to be more common in adults, while acute urticaria is more common in children.

Clinical

History

An important historical characteristic of urticarial lesions is their transient nature. An individual wheal typically lasts for less than 24 hours. Pruritus is the most common associated symptom. If lesions last longer and are associated with pigmentary changes or symptoms (eg, pain or burning), consider performing a biopsy to exclude urticarial vasculitis.

Individual wheals last less than 1 hour in persons with physical urticaria, except for delayed pressure urticaria, in which individual wheals last at least 8-48 hours, especially on the palms and soles.

Physical

The typical lesion of urticaria is a pale-to-red, well-demarcated papule or plaque. Lesions may be round, oval, annular, arcuate, serpiginous, or generalized. They resolve without postinflammatory pigmentary changes or scaling.

• Primary lesion: They are edematous erythematous papules or plaques with a pale center (wheal) and surrounding erythema (flare).
• Distribution of lesions: Lesions can be localized or generalized.
• Color of lesions: Depending on background skin color, lesions may be pale to red.
• Differentiation: Stroking the skin firmly tests for symptomatic dermatographism. Exercise testing can confirm cholinergic urticaria. Application of an ice cube to the skin may test for cold urticaria.

Causes

A number of factors have been reported to cause chronic urticaria, and these include the following:

• Medications: Urticaria may be caused or exacerbated by a number of drugs. More common culprits include aspirin, other nonsteroidal anti-inflammatory drugs, opioids, ACE inhibitors, and alcohol.
• Contactants: Contact urticaria syndrome refers to the onset of urticaria within 30-60 minutes of contact with an inciting agent. The lesions may be localized or generalized. Precipitating factors include latex (especially in health care workers), plants, animals (eg, caterpillars, dander), medications, and food (eg, fish, garlic, onions, tomato).
• Foods and food additives: Some patients report the onset of acute urticaria associated with the consumption of certain foods, such as shellfish, eggs, nuts, strawberries, or certain baked goods.
• Arthropod assault: Arthropod assault is the most common cause of papular urticaria. Although patients who are bitten by mosquitoes are likely to be aware of the source of the problem, patients with scabies, bedbug bites, fleabites, or other similar problems may not be aware. Ask patients about exposure to animals, recent moves, hobbies, travel, or the presence of a similar skin condition in other members of the household.
• Infections: Urticaria has been reported to be associated with a number of infections; however, these associations are not strong and may be spurious. Infectious agents reported to cause urticaria include hepatitis B virus, Streptococcus and Mycoplasma species, Helicobacter pylori,^5,6 Mycobacterium tuberculosis, and herpes simplex virus.
• Autoimmune disease: Urticaria has been associated with a number of autoimmune diseases, including systemic lupus erythematosus, cryoglobulinemia, juvenile rheumatoid arthritis, and autoimmune thyroid disease (patients may be euthyroid but respond to replacement therapy).
• Autoinflammatory diseases: Urticaria is a feature of Muckle-Wells syndrome (amyloidosis, nerve deafness, and urticaria) and Schnitzler syndrome⁷ (fever, joint/bone pain, monoclonal gammopathy, and urticaria).
• Malignancies: Little evidence exists to support the concern that chronic urticaria is a cutaneous sign of occult internal malignancy. In a study of 1155 patients with chronic urticaria in Sweden, Sigurgeirsson⁸ found no association with cancer, although acquired angioedema associated with C1 inhibitor depletion may be associated with malignancy.
• Physical factors: Physical factors are the most commonly identified etiologies of chronic urticaria, accounting for approximately 20% of cases. The various types of physical urticaria are diagnosed by challenge testing. Several types exist, and finding that a single patient has more than 1 type is not uncommon. Below is a list of some types of physical urticaria and their causes.
• Dermatographism/dermographism - Firm stroking
• Delayed pressure urticaria - Pressure
• Cold urticaria - Cold
• Aquagenic urticaria - Water exposure
• Cholinergic urticaria - Heat, exercise, or stress
• Solar urticaria - Sun exposure
• Vibratory urticaria - Vibration
• Emotional factors: Psychological factors are reported to play a role in a number of patients. Reports exist of improvement of symptoms using hypnotism; however, the role of emotional factors remains controversial.
• Genetic: Hereditary angioedema is characterized by recurrent attacks of angioedema (without urticaria) involving the skin, GI tract, respiratory tract, and mucous membranes in a patient with a positive family history. The disorder is autosomal dominant, and it is caused by a functional deficiency of the C1 inhibitor protein.

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