AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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. 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

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Melkersson-Rosenthal syndrome

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

Elicit a history and perform a physical examination and challenge testing for physical causes in patients with chronic urticaria. Direct the selection of laboratory tests using the information elicited from the history and physical examination.

• Complete blood cell count with differential: Patients with parasitic infections, especially in developing countries, or patients experiencing a drug reaction may have an elevated eosinophil count. The absence of blood eosinophilia may obviate the necessity for stool examination for ova.
• Erythrocyte sedimentation rate: It may be elevated in persons with urticarial vasculitis.
• Hepatitis B and C titers: Both hepatitis B and C may be associated with cryoglobulinemia, which is associated with some forms of cold-induced urticaria and urticarial vasculitis. In addition, an association has been reported between hepatitis C and chronic urticaria.⁹
• Antinuclear antibody titers: These are indicated in patients in whom urticarial vasculitis is suggested.
• Erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, and rheumatoid factor: Testing should be performed if an underlying rheumatologic disorder is suspected.
• Stool ova and parasites: Consider this test in patients with GI tract symptoms, an elevated eosinophil count, or a positive travel history.
• Serum cryoglobulins: Cryoglobulinemia is associated with some forms of cold-induced urticaria.
• Complement studies: C3 (associated with pulmonary involvement in a subset of patients with urticarial vasculitis), C4 (may be low in hereditary angioedema), and C1-esterase inhibitor (hereditary angioedema) functional assays may be performed.
• Thyroid function, antithyroid microsomal, and peroxidase antibody titers: Patients with urticaria unresponsive to antihistamines or steroids may have elevated titers, which may respond to thyroid hormone therapy.¹⁰ Patients may be euthyroid. Urticaria is also more common in patients with Hashimoto thyroiditis. If antithyroglobulin and antimicrosomal antibodies are present, this supports the diagnosis of chronic immunologic urticaria. The plasma level of thyrotropin helps screen for thyroid dysfunction.

Other Tests

• Challenge testing: Challenge testing may be required to exclude a physical urticaria.
• Skin biopsy: Histologic examination is not necessary for the diagnosis urticaria. A biopsy is necessary for the diagnosis of urticarial vasculitis or a neutrophil-predominant pattern of urticaria that may not respond well to antihistamines. A skin biopsy is indicated when individual urticarial lesions persist for more than 24 hours or have associated petechiae or purpura and in patients with systemic symptoms such as fever, arthralgia, or arthritis. Histological evidence of leukocytoclasia (neutrophilic infiltration with fragmentation of nuclei) is a characteristic feature of urticarial vasculitis. The presence of neutrophils may indicate potential benefit from treatment with dapsone or colchicine.
• Prick or radioallergosorbent assay testing: This might be useful if contact urticaria is suggested.
• Skin prick testing: Results may help identify a food allergy, which is a rare cause of chronic urticaria.

Histologic Findings

Dermal edema, blood vessel dilatation, and mild perivascular infiltrate predominantly consisting of monocytes and CD4⁺ lymphocytes are characteristic findings; some forms exist in which neutrophils predominate.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

Avoidance of mental stress, overtiredness, alcohol, nonsteroidal anti-inflammatory drugs, and tight-fitting garments is recommended. Nocturnal pruritus may be reduced by lukewarm bathing and keeping the ambient temperature of the bedroom cool. Application of lotions with menthol and phenol (Sarna) provide prompt relief of pruritus for some patients.
 
Nonsedating antihistamines remain the mainstay of treatment. Many patients find pruritus less troublesome during the daytime, with pruritus maximized at night when there are fewer distractions. An additional nocturnal dose of a sedative antihistamine such as hydroxyzine or doxepin may be added to the morning dose of a low-sedation anti-H1 antihistamine. Doxepin should not be used in patients with glaucoma and should be used with extreme caution in elderly patients or those with heart disease. Doubling the labeled dose of low-sedating antihistamines may benefit some patients, and increasing the dose of these antihistamines is often the safest therapeutic approach for patients who do not have an adequate response to the conventional dose of these medications.

Patients who respond poorly to antihistamine therapy or who are known to have urticaria in which the inflammatory infiltrate is neutrophil predominant may require the addition of colchicine (0.6 mg twice daily) or dapsone (50-150 mg once daily) to the treatment regimen (except patients with glucose-6-phosphate dehydrogenase [G-6-PD] deficiency). Patients with autoimmune urticaria may benefit from methotrexate or cyclosporine.

Consultations

A consultation with an allergist is recommended when the eliciting factor seems to be food sensitivity

Diet

Advise patients to avoid foods containing salicylate if they are allergic to salicylic acid Additionally, advise patients with known food allergies to avoid those foods.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Antihistamines
 
The mainstay of pharmacotherapy for chronic urticaria is low-sedation anti-H1 antihistamines, which have a low incidence of adverse effects. Low-sedating antihistamines such as loratadine, cetirizine, levocetirizine, and fexofenadine decrease the intensity of hives and pruritus in patients with mild, chronic urticaria and are considered first-line therapy. Crossover studies comparing the suppression of skin papule and erythema formation induced by intradermal histamine injection following a single antihistamine dose suggest the following order of inhibitory effect: (1) levocetirizine, (2) cetirizine, (3) terfenadine, (4) fexofenadine, and (5) loratadine.

Skin concentration—not plasma concentration—correlates to drug potency in inhibiting wheal and erythema formation response to intradermal histamine injection. Sedation and impairment of performance are concerns when using sedating antihistamines, yet these adverse effects may diminish after 1-2 weeks of therapy.
 
Pregnancy
 
Cetirizine and loratadine are category B; nevertheless, a first-generation antihistamine, such as chlorpheniramine, may be considered the drug of choice because the cumulative experience of use of this agent in pregnant women is greater.
 
Kidney or liver impairment
 
For cetirizine, 60% is eliminated via the kidneys. For levocetirizine, the figure is 85%. Most H1 or H2 antihistamines undergo presystemic metabolism in the liver via cytochrome P-450. A reduction in dose of low-sedating antihistamines is advised in patients with liver or renal failure. 
 
Children
 
Cetirizine and fexofenadine  are approved by the US Food and Drug Administration for chronic urticaria in children aged 6 months and older. Desloratadine is approved for chronic urticaria in children aged 1 year and older. Loratadine is approved for chronic urticaria in children aged 2 years and older. Levocetirizine is approved for chronic urticaria in children aged 6 years and older. Hydroxyzine has been used to alleviate pruritus in children with atopic dermatitis and is an appropriate second-line agent in children with chronic urticaria refractory to low-sedating antihistamines.
 
Antileukotrienes^{11, 12}
 
Leukotriene antagonists have been shown to be superior to placebo in the treatment of patients with chronic urticaria but are considered less effective than nonsedating antihistamines; however, the agents can be combined. Montelukast at 10 mg/d may be particularly helpful for patients experiencing flare-ups due to aspirin or other nonsteroidal anti-inflammatory drugs. Montelukast is approved for perennial allergic rhinitis in children aged 6 months and older.

Cyclosporine
 
Cyclosporine at 4-6 mg/kg/d has been shown in randomized double-blind studies to be effective for chronic urticaria. Cyclosporine therapy should be limited to 3 months or less for chronic urticaria. A sustained remission is observed in approximately one third of patients treated with his medication.
 
Systemic corticosteroids
 
Systemic corticosteroids are usually effective when antihistamines are not adequate. In the rare situation when systemic corticosteroid treatment is needed to treat chronic urticaria, a low dose daily or alternate-day dosing of corticosteroids is advised, and the dose should be titrated to the lowest effective level. Patients receiving long-term corticosteroid therapy should be routinely monitored for bone density changes and adverse ocular effects. 
 
Levothyroxine

Some patients with chronic urticaria and antithyroid antibodies have been shown to benefit from levothyroxine treatment, perhaps by suppression of thyroid activity and, possibly, the autoimmune process. The goal of treatment is to maximally suppress thyrotropin without rendering the patient clinically hyperthyroid. The urticaria may respond within 2 weeks of initiation of adequate treatment. Some patients may maintain a sustained remission after 3-6 months of treatment, at which point the levothyroxine can be tapered and then discontinued. 

Drug Category: Antihistamines, first generation

Compete with histamine at tissue receptor level, preventing it from carrying out its mediator functions in urticaria.

Drug Category: Anti-inflammatory agents

Modify the immune response to diverse stimuli.

Drug Category: Sulfones

May reduce inflammation.

Drug Category: Antihistamines, second generation

Also known as less-sedating antihistamines, these drugs produce less sedation than traditional H1 blockers because they are less lipid soluble and only cross the blood-brain barrier in small amounts. Also have longer half-lives, allowing for less-frequent dosing.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Deterrence/Prevention

If a precipitating factor is identified, patients should be advised to avoid it. Certain medications, such as aspirin and nonsteroidal anti-inflammatory drugs, are reported to exacerbate urticaria in patients with chronic urticaria resulting from other causes.

Complications

Lesions of urticaria should resolve without complication; however, patients with severe pruritus may develop scratch purpura and excoriations that may become secondarily infected. Additionally, antihistamine use may cause somnolence and dry mouth. Finally, patients with severe disease may be impacted by quality-of-life issues.

Prognosis

Most patients with CIU have resolution of symptoms within 3 years from the onset of symptoms; 86% are symptom free at 5 years. The presence of anti–immunoglobulin G or antithyroid antibodies may worsen the prognosis. Chronic urticaria impairs quality of life to the extent experienced by persons with severe coronary artery disease. Chronic urticaria can lead to significant psychological stress, and the converse is also recognized. A possible mechanism is through stress-induced release of corticotrophin-releasing hormone (CRH), which is known to be expressed in the skin. Up-regulation occurs of the CRH-R1 receptor that mediates CRH-dependent cutaneous mast cell degranulation in chronic urticaria.

Patient Education

For excellent patient education resources, visit eMedicine's Allergy Center and Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Hives and Angioedema.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

A potential pitfall is the failure to consider a diagnosis of urticarial vasculitis in patients with lesions lasting longer than 24 hours, in patients with lesions associated with pain more than with itching, and in patients with lesions resolving with pigmentary changes or scaling.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Dr Dina Strachan, to the development and writing of this article. The authors and editors of eMedicine would also like to gratefully acknowledge the contributions of previous Chief Editor, William D. James, MD, to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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Article Last Updated: Jun 25, 2008