- Author: Daniel J Hogan, MD; Chief Editor: William D James, MD more...
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  ; 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
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.
Chronic urticaria may be divided into 3 primary subgroups, as follows:
Urticaria secondary to an underlying medical condition
Chronic idiopathic urticaria
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.
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%). 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. 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).
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.
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.
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 (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.
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.
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.
Dreyfus DH, Schocket AL, Milgrom H. Steroid-resistant chronic urticaria associated with anti-thyroid microsomal antibodies in a nine-year-old boy. J Pediatr. 1996 Apr. 128(4):576-8. [Medline].
Ellis MH. Successful treatment of chronic urticaria with leukotriene antagonists. J Allergy Clin Immunol. 1998 Nov. 102(5):876-7. [Medline].
Spector S, Tan RA. Antileukotrienes in chronic urticaria. J Allergy Clin Immunol. 1998 Apr. 101(4 Pt 1):572. [Medline].
[Guideline] Powell RJ, Du Toit GL, Siddique N, et al. BSACI guidelines for the management of chronic urticaria and angio-oedema. Clin Exp Allergy. 2007 May. 37(5):631-50. [Medline].
Morgan M, Khan DA. Therapeutic alternatives for chronic urticaria: an evidence-based review, part 1. Ann Allergy Asthma Immunol. 2008 May. 100(5):403-11; quiz 412-4, 468. [Medline].
Tong LJ, Balakrishnan G, Kochan JP, Kinet JP, Kaplan AP. Assessment of autoimmunity in patients with chronic urticaria. J Allergy Clin Immunol. 1997 Apr. 99(4):461-5. [Medline].
Kaplan AP, Greaves M. Pathogenesis of chronic urticaria. Clin Exp Allergy. 2009 Jun. 39(6):777-87. [Medline].
Bossi F, Frossi B, Radillo O, et al. Mast cells are critically involved in serum-mediated vascular leakage in chronic urticaria beyond high-affinity IgE receptor stimulation. Allergy. 2011 Dec. 66(12):1538-1545. [Medline].
Mathelier-Fusade P. Drug-induced urticarias. Clin Rev Allergy Immunol. 2006 Feb. 30(1):19-23. [Medline].
Ventura MT, Napolitano S, Menga R, Cecere R, Asero R. Anisakis simplex Hypersensitivity Is Associated with Chronic Urticaria in Endemic Areas. Int Arch Allergy Immunol. 2013. 160(3):297-300. [Medline].
Tebbe B, Geilen CC, Schulzke JD, Bojarski C, Radenhausen M, Orfanos CE. Helicobacter pylori infection and chronic urticaria. J Am Acad Dermatol. 1996 Apr. 34(4):685-6. [Medline].
Valsecchi R, Pigatto P. Chronic urticaria and Helicobacter pylori. Acta Derm Venereol. 1998 Nov. 78(6):440-2. [Medline].
Heymann WR. Chronic urticaria and angioedema associated with thyroid autoimmunity: review and therapeutic implications. J Am Acad Dermatol. 1999 Feb. 40(2 Pt 1):229-32. [Medline].
Bansal AS, Hayman GR. Graves disease associated with chronic idiopathic urticaria: 2 case reports. J Investig Allergol Clin Immunol. 2009. 19(1):54-6. [Medline].
Baty V, Hoen B, Hudziak H, Aghassian C, Jeandel C, Canton P. Schnitzler's syndrome: two case reports and review of the literature. Mayo Clin Proc. 1995 Jun. 70(6):570-2. [Medline].
Sigurgeirsson B. Skin disease and malignancy. An epidemiological study. Acta Derm Venereol Suppl (Stockh). 1992. 178:1-110. [Medline].
Torresani C, Bellafiore S, De Panfilis G. Chronic urticaria is usually associated with fibromyalgia syndrome. Acta Derm Venereol. 2009. 89(4):389-92. [Medline].
Yosipovitch G, Greaves M. Chronic idiopathic urticaria: a "Cinderella" disease with a negative impact on quality of life and health care costs. Arch Dermatol. 2008 Jan. 144(1):102-3. [Medline].
O'Donnell BF, Lawlor F, Simpson J, Morgan M, Greaves MW. The impact of chronic urticaria on the quality of life. Br J Dermatol. 1997 Feb. 136(2):197-201. [Medline].
Maurer M, Ortonne JP, Zuberbier T. Chronic urticaria: a patient survey on quality-of-life, treatment usage and doctor-patient relation. Allergy. 2009 Apr. 64(4):581-8. [Medline].
Brodell LA, Beck LA. Differential diagnosis of chronic urticaria. Ann Allergy Asthma Immunol. 2008 Mar. 100(3):181-8; quiz 188-90, 215. [Medline].
Kanazawa K, Yaoita H, Tsuda F, Okamoto H. Hepatitis C virus infection in patients with urticaria. J Am Acad Dermatol. 1996 Aug. 35(2 Pt 1):195-8. [Medline].
Zuberbier T, Asero R, Bindslev-Jensen C, Walter Canonica G, Church MK, Giménez-Arnau A, et al. EAACI/GA(2)LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria. Allergy. 2009 Oct. 64(10):1417-26. [Medline].
[Guideline] Powell RJ, Leech SC, Till S, Huber PA, Nasser SM, Clark AT. BSACI guideline for the management of chronic urticaria and angioedema. Clin Exp Allergy. 2015 Mar. 45(3):547-65. [Medline].
Egan CA, Rallis TM. Treatment of chronic urticaria with ketotifen. Arch Dermatol. 1997 Feb. 133(2):147-9. [Medline].
Jauregui I, Ferrer M, Montoro J, et al. Antihistamines in the treatment of chronic urticaria. J Investig Allergol Clin Immunol. 2007. 17 Suppl 2:41-52. [Medline].
Grob JJ, Auquier P, Dreyfus I, Ortonne JP. How to prescribe antihistamines for chronic idiopathic urticaria: desloratadine daily vs PRN and quality of life. Allergy. 2009 Apr. 64(4):605-12. [Medline].
Staevska M, Popov TA, Kralimarkova T, Lazarova C, Kraeva S, Popova D, et al. The effectiveness of levocetirizine and desloratadine in up to 4 times conventional doses in difficult-to-treat urticaria. J Allergy Clin Immunol. 2010 Mar. 125(3):676-82. [Medline].
Maurer M, Rosén K, Hsieh HJ, Saini S, Grattan C, Gimenéz-Arnau A, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med. 2013 Mar 7. 368(10):924-35. [Medline].
Brooks M. FDA OKs Omalizumab (Xolair) for Chronic Hives. Medscape Medical News. Mar 21 2014. [Full Text].
Rorie A, Goldner WS, Lyden E, Poole JA. Beneficial role for supplemental vitamin D3 treatment in chronic urticaria: a randomized study. Ann Allergy Asthma Immunol. 2014 Feb 5. [Medline].
Janeczko LL. High-dose vitamin D supplements may benefit people with chronic urticaria. Reuters Health Information. February 24, 2014. [Full Text].