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Chronic Urticaria

  • Author: Daniel J Hogan, MD; Chief Editor: William D James, MD  more...
Updated: Apr 02, 2015

Practice Essentials

Urticaria is not a single disease but a reaction pattern that represents cutaneous mast cell degranulation, with the condition being defined as chronic when it persists for longer than 6 weeks. The mast cell degranulation results in extravasation of plasma into the dermis; urticaria is characterized by hives or wheals, which are edematous, pruritic papules or plaques.

Signs and symptoms

Urticarial lesions are transient in nature, with individual wheals typically lasting for less than 24 hours. Pruritus is the most common associated symptom of chronic urticaria.

Lesions typically can be described as follows:

  • Primary lesions are edematous, erythematous papules or plaques with a pale center (wheal) and surrounding erythema (flare)
  • Lesions may be pale to red (depending on background skin color)
  • Lesions can be localized or generalized
  • Lesions may be round, oval, annular, arcuate, serpiginous, or generalized
  • Lesions resolve without postinflammatory pigmentary changes or scaling

See Clinical Presentation for more detail.


Laboratory studies used in the diagnosis of chronic urticaria include the following:

  • Complete blood count (CBC) with differential: The eosinophil count may be elevated in patients with parasitic infections, especially in developing countries, or in patients experiencing a drug reaction
  • Examination of the stool for ova and parasites: Should be considered in patients with gastrointestinal tract symptoms, an elevated eosinophil count, or a positive travel history
  • Erythrocyte sedimentation rate (ESR): May be elevated in persons with urticarial vasculitis
  • Antinuclear antibody (ANA) titers: Indicated when urticarial vasculitis is suspected
  • Hepatitis B and C titers: Hepatitis B and C may be associated with cryoglobulinemia, which is associated with some forms of cold-induced urticaria and urticarial vasculitis
  • Serum cryoglobulin and complement assays: Cryoglobulinemia is associated with some forms of cold-induced urticaria
  • Complement assays: C3 (associated with pulmonary involvement in a subset of patients with urticarial vasculitis), C4 (sometimes low in hereditary angioedema), and C1-esterase inhibitor (associated with hereditary angioedema) functional assays may be performed
  • Thyroid function testing and antithyroid microsomal and peroxidase antibody titers: Patients with urticaria unresponsive to antihistamines or steroids may have elevated titers [1] ; the plasma thyrotropin level helps screen for thyroid dysfunction
  • Chronic Urticaria (CU) Index: Patients with a chronic form of urticaria who have a positive functional test result for autoantibody to the Fc receptor of immunoglobulin E (IgE)—that is, anti-FceR—likely have an autoimmune basis for their disease

A skin biopsy is necessary for the diagnosis of urticarial vasculitis or a neutrophil-predominant pattern of urticaria that may not respond well to antihistamines. It is also indicated for patients in whom individual urticarial lesions persist for more than 24 hours or are associated with petechiae or purpura, as well as for patients with systemic symptoms such as fever, arthralgia, or arthritis.

See Workup for more detail.


The following medications can be used in the treatment of chronic urticaria:

  • Low-sedation antihistamines: The mainstay of pharmacotherapy for chronic urticaria; they decrease the intensity of hives and pruritus in patients with mild chronic urticaria
  • Leukotriene antagonists: Shown to be superior to placebo in the treatment of patients with chronic urticaria but considered less effective than nonsedating antihistamines [2, 3] ; however, the 2 classes of agents can be combined
  • Colchicine and dapsone: May help patients who respond poorly to antihistamine therapy or who are known to have urticaria in which the inflammatory infiltrate is neutrophil-predominant
  • Systemic corticosteroids: Usually effective when antihistamines are not adequate
  • Cyclosporine and methotrexate: May benefit patients with autoimmune urticaria [4, 5]
  • Levothyroxine: May benefit some patients with chronic urticaria and antithyroid antibodies

See Treatment and Medication for more detail.



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 (see images below), 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.

Urticaria developed after bites from an imported f Urticaria developed after bites from an imported fire ant.
Urticaria associated with a drug reaction. Urticaria associated with a drug reaction.

Chronic urticaria may be divided into 3 primary subgroups, as follows:

Physical urticaria, which is reproducible with the appropriate stimuli, can be identified with a thorough history and challenge testing.

When a physical etiology has been excluded, the traditional approach 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 chronic idiopathic urticaria; however, findings suggest that in 25-45% of patients, chronic idiopathic urticaria is not actually idiopathic but is an autoimmune disease termed chronic autoimmune urticaria.[6]

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.



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 (prostaglandin) 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.

Once the physical urticarias and urticarial vasculitis are eliminated, chronic urticaria can be divided into autoimmune chronic urticaria (45%) and idiopathic chronic urticaria (55%).[7] Either immunoglobulin G (IgG) autoantibodies to the alpha subunit of the Fc receptor of the immunoglobulin E (IgE) molecule (35-40%)—that is, anti-FcεR—or, less commonly, anti-IgE autoantibodies (5-10%) 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 (the main cause of pruritus), proteases, interleukin-1 (IL-1), and tumor necrosis factor alpha (TNF-α). The cytokines cause increased expression of adhesion molecules by the endothelium of postcapillary venules.

Approximately one third of patients with chronic urticaria have either or both antithyroglobulin antibody and antimicrosomal antibody, and as many as 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.

Mast cells may be degranulated through an IgE- and IgG-independent mechanism in chronic urticaria.[8] 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 (NSAIDs).[9]

About 85% of the histamine receptors in the skin are H1 receptors, 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 receptor types and is a much more potent inhibitor of H1 -receptors than diphenhydramine or hydroxyzine is.

Food allergy is rarely the basis of chronic urticaria.



A number of different factors have been reported to cause chronic urticaria.

Urticaria may be caused or exacerbated by a number of drugs. Among the more common culprits are aspirin and other NSAIDs, opioids, angiotensin-converting enzyme (ACE) inhibitors, and alcohol.

Contactants may give rise to contact urticaria syndrome, a term referring to the onset of urticaria within 30-60 minutes of contact with an inciting agent. The lesions may be localized or generalized. Precipitating agents include latex (especially in health care workers), plants, animals (eg, caterpillars, dander), medications, and food (eg, fish, garlic, onions, or tomato).

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.

The nematode Anisakis simplex is often the cause of chronic urticaria in areas where the population frequently consumes raw or marinated fish, according to researchers. The report, on adults seen at an allergy center in Bari, Italy, found that 106 out of 213 patients (50%) with chronic urticaria had A simplex hypersensitivity. It was also determined that all of the hypersensitive patients regularly ate marinated fish. In comparison, only 16% of a control population without chronic urticaria had sensitization to A simplex.[10]

The investigators also found that chronic urticaria disappeared in 82 out of 106 (77%) patients with the disease who gave up raw fish for 6 months; the condition cleared up in only 1 out of 42 patients (2%) with chronic urticaria who did not give up raw fish. Additionally, 88% who returned to eating raw fish after their condition disappeared suffered a relapse of chronic urticaria, compared with 14% of those who remained on the diet.[10]

Arthropod bites or stings are 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, flea bites, 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.

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 (HBV), Streptococcus and Mycoplasma species, Helicobacter pylori,[11, 12] Mycobacterium tuberculosis, and herpes simplex virus (HSV).

Various autoimmune diseases have been associated with urticaria, including systemic lupus erythematosus, cryoglobulinemia, juvenile rheumatoid arthritis, and autoimmune thyroid disease (eg, Graves disease).[13, 14] Patients may be euthyroid but respond to replacement therapy, or they may respond to treatment of hyperthyroidism with carbimazole.

Urticaria is a feature of some autoinflammatory diseases, such as Muckle-Wells syndrome (characterized by amyloidosis, nerve deafness, and urticaria) and Schnitzler syndrome[15] (characterized by fever, joint or bone pain, monoclonal gammopathy, and urticaria).

Little evidence exists to support the concern that chronic urticaria may be a cutaneous sign of occult internal malignancy. In a study of 1155 patients with chronic urticaria in Sweden, Sigurgeirsson found no association with cancer, though acquired angioedema associated with C1 inhibitor depletion may be associated with malignancy.[16]

Physical factors are the most commonly identified causes of chronic urticaria, accounting for approximately 20% of cases. The various types of physical urticaria are diagnosed by challenge testing. Several types exist, and it is not uncommon to find that a single patient has more than 1 type. The following are some of the types of physical urticaria, along with 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

Neurologic factors may play a causative role. An Italian study reported an association between chronic urticaria and fibromyalgia, and the authors suggested that chronic urticaria may be a consequence of fibromyalgia-neurogenic skin inflammation.[17]

Emotional and psychological factors are reported to play a role in a number of patients. Some reports cite improvement of symptoms with hypnotism; however, the role of emotional factors remains controversial.

Hereditary angioedema is characterized by recurrent attacks of angioedema (without urticaria) involving the skin, gastrointestinal (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.

Contributor Information and Disclosures

Daniel J Hogan, MD Clinical Professor of Internal Medicine (Dermatology), Nova Southeastern University College of Osteopathic Medicine; Investigator, Hill Top Research, Florida Research Center

Daniel J Hogan, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Contact Dermatitis Society, Canadian Dermatology Association

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.


Warren R Heymann, MD Head, Division of Dermatology, Professor, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Warren R Heymann, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Dina D Strachan, MD Assistant Clinical Professor, Department of Dermatology, St Vincent's Medical Center

Dina Strachan, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association

Disclosure: Nothing to disclose.

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Urticaria developed after bites from an imported fire ant.
Urticaria associated with a drug reaction.
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