Chronic Urticaria

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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 if lesions recur for longer than 6 weeks. Mast cell degranulation results in extravasation of plasma into the dermis, forming characteristic hives—edematous pruritic pink wheals of variable size and shape, with or without accompanying angioedema. In angioedema, the swelling is deeper than wheals and may affect mucosal surfaces. Erythema is often absent in angioedema, and typical sites of predilection include the eyelids, lips, and tongue.

In the majority of patients with chronic urticaria, no external cause or underlying disease process can be identified. Several theories regarding the pathogenesis of chronic urticaria exist but none has been conclusively established. It is a disease that can be frustrating to treat for both patients and caregivers, and it can have a detrimental effect on quality of life.

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:

See Clinical Presentation for more detail.

Diagnosis

The diagnosis of chronic urticaria is largely clinical and based on a thorough history and physical examination. A limited set of laboratory studies may be indicated for some patients in the diagnosis of chronic urticaria, and these include the following:

A skin biopsy is necessary in cases of suspected urticarial vasculitis or in cases of urticaria with atypical features on history and examination. 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. A neutrophil-predominant pattern of urticaria on biopsy may represent a subtype that does not respond well to antihistamines.

See Workup for more detail.

Management

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

See Treatment and Medication for more detail.

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 caused by or related to various factors, which trigger cutaneous mast cell degranulation and resulting 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 chronic urticaria, and large number of cases without known cause, can make the approach to diagnosis and treatment a challenge. Patients with chronic urticarial may not improve or may depend on medication for years to relieve symptoms.



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Urticaria developed after bites from an imported fire ant.



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Urticaria associated with a drug reaction.

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

About 20% of patients with chronic urticaria have physical urticaria, in which the appearance of lesions is triggered by a consistent identifiable factor. Physical urticaria is reproducible with the appropriate stimuli, and it can be identified with a thorough history, physical examination, and challenge testing. Some examples of direct triggers include mechanical stimuli, temperature changes, sweating, stress, sun exposure, and water contact.

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. In systematic review of 6462 patients with chronic urticaria, a causative internal medical condition was found in only 1.6% of patients[6] .Urticaria rarely is the sole manifestation of an underlying medical problem.

The largest subset of patients with chronic urticaria encompasses patients in whom no explanation for their urticaria is definitively established. Traditionally, these patients were said to have chronic idiopathic urticaria; however, findings suggest that about 20-45% of such patients may have an underlying autoimmune process driving their disease, and this specific cohort of patients is said to have chronic autoimmune urticaria. Chronic spontaneous urticaria is a newer label used to refer to all patients with either chronic idiopathic urticaria (55%) or chronic autoimmune urticaria (45%).[7]

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. If urticarial lesions persist for more than 24 hours, biopsy should be performed to rule out this entity histologically.

Pathophysiology

The mast cell is the primary agent in the pathogenesis of urticaria. Dermal mast cell stimulation results in the release of both preformed (histamine) and newly formed (prostaglandin) mediators, as well as cytokines (interleukin [IL]–1, tumor necrosis factor-α [TNF-α]) from cytoplasmic granules, which cause wheal formation, vasodilatation, and erythema. Mast cells also release chemoattractants for other cells (eg, neutrophils) involved in wheal formation. A complex interplay of varied proinflammarory cytokines, chemokines, and adhesion molecules that regulate vasoactivity and the dynamics of cellular infiltration ultimately evolves to form a lymphocyte- and granulocyte-mediated hypersensitivity reaction in the skin.

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.

Further, on a molecular level, it has been shown that there is an increased cis-to-trans urocanic acid ratio in the epidermis of patients with chronic urticaria, which is postulated to enhance mast cell degranulation.[8]

The complex nature of the pathogenesis of urticaria beyond the release of histamine from dermal mast cells may explain why antihistamines alone are not always effective therapy. The signals that activate mast cells in urticaria are ill-defined and varied. A number of triggers can result in degranulation of mast cells and initiation of the cascade that results in urticaria formation.

An autoimmune origin is one hypothesis for mast cell activation. IgE- and IgG-dependent mechanisms include autoantibodies encompassing either IgG autoantibodies to the alpha subunit of the Fc receptor of the IgE molecule (35-40% of patients with chronic urticaria)—that is, anti-FcεR—or, less commonly, anti-IgE autoantibodies (5-10% of patients with chronic urticaria), both of which can activate mast cells or basophils to release histamine.[9] A positive functional anti-FcεR test result does not indicate which autoantibody (anti-IgE, anti-FcεRI, or anti-FcεRII) is present, but it does support an autoimmune basis. Affected patients may be categorized as having autoimmune chronic urticaria.

Mast cells may also be degranulated through an IgE- and IgG-independent mechanism in chronic urticaria.[10] 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).[11]

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.

Etiology

A number of different etiologic factors have been reported as proposed causes of chronic urticaria.

Autoimmunity is thought to be one of the most frequent causes of chronic urticaria. Various autoimmune or endocrine diseases have been associated with urticaria, including systemic lupus erythematosus, cryoglobulinemia, juvenile rheumatoid arthritis, and autoimmune thyroid disease (eg, Graves disease).[12, 13]

Several cross-sectional studies have investigated whether patients with chronic urticaria are more prone to autoimmune disorders. Ryhal et al compared 25 patients with urticaria with 75 subjects being treated for other conditions and found that antibodies to thyroid peroxidase (also known as thyroid microsomal antibody) and rheumatoid factor were more common in patients with chronic urticaria (P <.01 and P <.05, respectively) compared with controls.[14] However, no difference was reported in the prevalence of other autoantibodies, such as anti-sDNA, anti-Ro/anti-La ribonucleic acid antibodies, anti-cardiolipin, anti–β2-glycoprotein 1, antimyeloperoxidase, anti–proteinase 3, anti–smooth muscle, and antinuclear antibodies, between the two groups. These data imply that broad nonspecific autoantibodies are not commonly found in patients with chronic urticaria.

There is a significant association of chronic urticaria with thyroid autoimmunity, and antithyroid autoantibodies are significantly increased in patients with chronic urticaria. The prevalence of thyroid autoimmunity among chronic urticaria patients varies from 4.3% to 57% in the literature, and about 5-10% of chronic urticaria patients have abnormal thyroid function.[15] In one study comparing 70 patients with chronic urticaria with 70 healthy controls, it was found that 23-30% of patients with chronic urticaria had either or both antithyroglobulin antibody (anti-Tg) and antimicrosomal antibody (antithyroid peroxidase [TPO]), and as many as 5-10% had abnormal thyroid function.[15] A case control study detected similar rates of thyroid antibodies in chronic urticaria patients, detecting anti-TG positivity in 22% and anti-TPO positivity in 27% of chronic urticaria patients; 93% of patients had normal thyroid function.[16]

Although thyroid autoantibodies are identified more frequently in patients with chronic urticaria compared with the general population, there is no clear evidence that management of chronic urticaria or the course of chronic urticaria differs in this subgroup, nor is there persuasive evidence that administration of thyroid hormone supplementation in such cases is associated with improved outcomes. Because the clinical relevance of these autoantibodies for evaluation and treatment of patients with chronic urticaria has not been established, routine testing for thyroid autoantibodies is not recommended.[9]

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.

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 and C viruses, Streptococcus and Mycoplasma species, Helicobacter pylori,[17, 18] Mycobacterium tuberculosis, and herpes simplex virus (HSV).

There is limited evidence that if H pylori colonization is present, eradication may result in an improvement in chronic urticaria symptoms and thus, screening for H pylori is not recommended.[19]

The nematode Anisakis simplex is often the cause of chronic urticaria in areas where the population frequently consumes raw or marinated fish. A report of adults seen at an allergy center in Bari, Italy, found that 106 (50%) of 213 patients with chronic urticaria had A simplex hypersensitivity; 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.[20] Chronic urticaria disappeared in 82 (77%) of 106 patients who gave up raw fish for 6 months; the condition cleared up in only one (2%) of 42 patients who did not give up raw fish. Additionally, 88% who returned to eating raw fish after their condition disappeared had a relapse of chronic urticaria, compared with 14% of those who remained on the diet.[20]

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. However, food allergy is rarely the basis of chronic urticaria.

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 healthcare workers), plants, animals (eg, caterpillars, dander), medications, and food (eg, fish, garlic, onions, tomato).

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 is a feature of some autoinflammatory diseases, such as Muckle-Wells syndrome (characterized by amyloidosis, nerve deafness, and urticaria) and Schnitzler syndrome[21] (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, although acquired angioedema associated with C1 inhibitor depletion may be associated with malignancy.[22] In a population-based cohort study in Taiwan, a slightly increased risk of cancer, especially hematologic malignant tumor, was observed among patients with chronic urticarial.[23] However, evidence is not sufficient to suggest any causality. Routine screening for malignancies in chronic urticaria is not suggested; it is only warranted if patient history dictates.

In approximately 20% of cases, physical factors can be identified as a consistent cause or trigger for chronic urticaria. 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 one type. The following are some of the types of physical urticaria, along with their triggers:

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.[24]

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.

Epidemiology

In the general population, the prevalence of chronic urticaria is estimated to be around 0.5-5%. Chronic urticaria is more frequently seen in females.[9]

Patients with chronic urticaria have a strong association with HLA-DR4 and the associated allele HLA-DQ8 compared with a control population.[25]

Prognosis

The primary manifestations of urticaria are rash and pruritus. The course of the disease is unpredictable, and it may last months to years. About 50% of patients experience remission within 1 year.[26] Only rarely does permanent hyperpigmentation or hypopigmentation occur. The only long-term consequences of chronic urticaria are anxiety and depression.

The prognosis in chronic urticaria depends on the comorbid disease causing the urticaria and the patient’s response to therapy. Several diseases associated with chronic urticaria can be associated with significant morbidity and mortality (eg, malignancies, systemic lupus erythematosus). Chronic urticaria can affect the patient’s quality of life, owing to the associated pruritus and loss of sleep. It can lead to anxiety and depression, with rare reports of suicide.

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.

In persons with physical urticaria, individual wheals last less than 1 hour. The exception to this rule is delayed pressure urticaria, in which individual wheals last at least 8-48 hours, especially on the palms and soles.

Physical Examination

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. Examination should focus on the following:

Complications

Unlike angioedema, which may affect the airway, urticaria is not a life-threatening disease. As a rule, lesions of urticaria should resolve without complications; 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, severe chronic urticaria has been shown to have a negative impact on the quality of life of affected patients.[27]

In a study by O’Donnell et al, 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.[28] These findings were confirmed by a subsequent French-German study, which suggested that physicians should discuss the emotional aspect of chronic urticaria with patients if time allows.[29]

Laboratory Studies

The information elicited from the history and physical examination is used to direct the selection of laboratory tests. While in most cases no diagnostic testing may be necessary, targeted laboratory testing based on clinical suspicion is appropriate. In most patients, the only screening tests that are recommended to be performed are a complete blood cell (CBC) count with differential, erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP), liver enzymes, and thyrotropin (TSH).[9]

A CBC count with differential should be done. In patients with parasitic infections, especially in developing countries, or patients experiencing a drug reaction, the eosinophil count may be elevated.

Examination of the stool for ova and parasites should be considered in patients with gastrointestinal (GI) tract symptoms, an elevated eosinophil count, or a positive travel history. The absence of blood eosinophilia may render stool examination for ova unnecessary.

The ESR may be elevated in persons with urticarial vasculitis. Antinuclear antibody (ANA) titers are indicated when urticarial vasculitis is suspected. ESR, CRP, ANA, and rheumatoid factor (RF) testing should be performed if additional features of an underlying rheumatologic disorder are found.

Hepatitis B and C titers may be helpful. 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.[31]

Serum cryoglobulin and complement assays may be useful. Cryoglobulinemia is associated with some forms of cold-induced urticaria. 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 may also be useful. Patients with urticaria unresponsive to antihistamines or steroids may have elevated titers, which may respond to thyroid hormone therapy.[1] Patients may be euthyroid. Urticaria is also more common in patients with Hashimoto thyroiditis. The presence of antithyroglobulin and antimicrosomal antibodies supports the diagnosis of chronic immunologic urticaria. The plasma thyrotropin level helps screen for thyroid dysfunction.

The Chronic Urticaria (CU) Index is not widely available and is only performed at a few reference laboratories. Patients with a chronic form of urticaria who have a positive functional test result for autoantibody to the Fc receptor of IgE—that is, anti-FcεR—likely have an autoimmune basis for their disease. A positive result does not indicate which autoantibody (anti-IgE, anti-FcεRI, or anti-FcεRII) is present. This test is usually combined with thyroid function testing, antithyroid microsomal titers, and peroxidase antibody titers.

Other Tests

Other tests that may be required include challenge testing. Testing to cold, pressure, heat, ultraviolet light, and visible light may be required to exclude a physical urticaria.[32]

Prick or radioallergosorbent assay testing may be useful if contact urticaria is suggested. Skin prick test results may help identify a food allergy, which is a rare cause of chronic urticaria.

Although histologic examination is not necessary for the diagnosis of urticaria, 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. A skin biopsy is indicated for patients in whom individual urticarial lesions persist for more than 24 hours or are associated with petechiae or purpura and for patients with systemic symptoms such as fever, arthralgia, or arthritis.

Histologic Findings

Characteristic histologic findings include dermal edema, blood vessel dilatation, and a mild perivascular infiltrate predominantly consisting of monocytes and CD4+ lymphocytes; some forms exist in which neutrophils predominate.

Histologic 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.

Approach Considerations

Nonsedating anti-H1 antihistamines remain the mainstay of treatment for chronic urticaria. If these agents are ineffective, higher dosages may be tried (up to four times the standard recommended dosage), or other agents may be substituted (see below).

Elimination of suspected triggers should be advocated. Avoidance of mental stress,[32] overtiredness, alcohol, nonsteroidal anti-inflammatory drugs (NSAIDs), and tight-fitting garments is recommended. Psychological stress can trigger or increase itching.[32] Nocturnal pruritus may be reduced by lukewarm bathing and keeping the ambient temperature of the bedroom cool. Application of lotions with menthol and phenol provide prompt relief of pruritus for some patients.

Pharmacologic Therapy

Antihistamines

The mainstay of pharmacotherapy for chronic urticaria is the administration of low-sedation anti-H1 antihistamines (eg, loratadine, cetirizine, levocetirizine, and fexofenadine), which have a low incidence of adverse effects.[33, 34] Quality of life appears to be improved more by daily therapy than by therapy administered on an “as needed” basis.[35]

Low-sedation antihistamines 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 after a single antihistamine dose suggest the following order of inhibitory effect: (1) levocetirizine, (2) cetirizine, (3) terfenadine, (4) fexofenadine, and (5) loratadine.

The potency of an antihistamine in inhibiting wheal and erythema formation response to intradermal histamine injection is correlated with the skin concentration of the drug rather than the plasma concentration. Sedation and impairment of performance are concerns when sedating antihistamines are used, but these adverse effects may diminish after 1-2 weeks of therapy.

Many patients find that pruritus is less troublesome during the day but is 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-sedation 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 doses of these medications. Increasing the dosage up to 4-fold is recommended by expert groups such as the European Academy of Allergy and Clinical Immunology (EAACI).[32]

As many as 75% of patients with chronic urticaria referred to tertiary care centers may require higher than conventional antihistamine doses.[36] These higher nonsedating antihistamine doses improved quality of life but did not increase somnolence.[36]

If high-dose nonsedating antihistamine therapy is not effective, switching to a different nonsedating antihistamine or adding a leukotriene antagonist (see below) to the antihistamine regimen may be considered.[32] Patients who do not respond to 20 mg of desloratadine may benefit from 20 mg of levocetirizine.[36]

Use in pregnant women

Cetirizine and loratadine are category B agents; nevertheless, a first-generation antihistamine such as chlorpheniramine may be considered the drug of choice in pregnant women because the cumulative experience with use of such agents in this population is greater.

Use in patients with kidney or liver impairment

For cetirizine, 60% of an administered dose 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. Accordingly, reduction of low-sedation antihistamine doses is advised in patients with liver or renal failure.

Use in children

Cetirizine and fexofenadine are approved by the US Food and Drug Administration (FDA) 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 that is refractory to nonsedating antihistamines.

Leukotriene antagonists

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[2, 3] ; however, the two classes of agents can be combined. Montelukast 10 mg/day may be particularly helpful for patients experiencing flare-ups due to aspirin or other NSAIDs. Montelukast is approved for treatment of perennial allergic rhinitis in children aged 6 months and older.

Colchicine and dapsone

Patients who respond poorly to antihistamine therapy or who are known to have urticaria in which the inflammatory infiltrate is neutrophil-predominant (except those with glucose-6-phosphate dehydrogenase [G6PD] deficiency) may require the addition of colchicine (0.6 mg twice daily) or dapsone (50-150 mg once daily) to the treatment regimen.

Systemic corticosteroids

Systemic corticosteroids are usually effective when antihistamines are not adequate. In the rare situation where systemic corticosteroid treatment is needed to treat chronic urticaria, a low daily dose or alternate-day dosing is advised, and the dose should be titrated to the lowest effective level. In general, long-term systemic corticosteroids are not recommended.[32] Patients receiving long-term corticosteroid therapy should be routinely monitored for bone density changes and adverse ocular effects.

Cyclosporine and methotrexate

Patients with autoimmune urticaria may benefit from administration of methotrexate or cyclosporine.[5, 4] Cyclosporine 4-6 mg/kg/day has been shown in randomized double-blind studies to be effective for chronic urticaria. Cyclosporine has a better risk-to-benefit ratio than systemic corticosteroids.[32]

Cyclosporine is recommended only for patients with severe disease refractory to high doses of oral antihistamines. Cyclosporine therapy for chronic urticaria should be limited to 3 months or less. A sustained remission is observed in approximately one third of patients treated with this medication.

Levothyroxine

Some patients with chronic urticaria and antithyroid antibodies benefit from levothyroxine treatment, perhaps because of suppression of thyroid activity and, possibly, the autoimmune process. The goal of treatment is to suppress thyrotropin maximally 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.

Monoclonal antibodies

Omalizumab (Xolair) was approved by the US Food and Drug Administration (FDA) in March 2014 for chronic idiopathic urticaria in adults and children aged 12 years or older who remain symptomatic despite anti-H1 antihistamine treatment. It is a monoclonal antibody that selectively binds to immunoglobulin E (IgE) and inhibits binding to IgE receptors on the surface of mast cells and basophils. The efficacy and safety of omalizumab for chronic idiopathic urticaria was demonstrated in 2 clinical studies that showed omalizumab significantly improved the mean weekly itch severity score (ISS) from baseline by 9.4-9.6 in the 300-mg treatment arm, by 6.4-6.7 in the 150-mg treatment arm, and by 5.9-6.5 in the 75-mg treatment arm, compared with an improvement of 3.6-5.1 in patients on placebo.[37, 38]

Vitamin D

High-dose vitamin D add-on therapy may provide relief in some patients with chronic urticaria. In a 12-week prospective study of 42 patients with chronic therapy receiving standard triple-drug therapy (cetirizine, ranitidine, and montelukast), those randomized to supplementation with high-dose vitamin D3 (4,000 IU/d) had a trend toward lower total symptom severity scores at the end of the trial (significant reduction in hive body distribution and duration, improved pruritus, and improved sleep quality) compared with patients randomized to low-dose vitamin D3 supplements.[39, 40]

Although baseline total Urticaria Symptom Severity (USS) scores were similar between the 2 groups, and each group had a 33% reduction in total USS scores on triple-drug therapy at 1 week follow-up, by 12 week follow-up, the high-dose vitamin D3 group showed an additional 40% decrease in total USS scores that was not seen in the low-dose group.[2, 3] Despite an increase in levels of serum 25-hydroxyvitamin D with high-dose vitamin D3 supplementation, there was no corresponding association between 25-hydroxyvitamin D levels and USS scores. No adverse events were reported, and medication use in both groups remained similar.[39, 40]

Autologous whole blood injection (AWBI)

AWBI may be an alternative to treat adults with refractory chronic urticaria. In a study of 19 patients in which AWBI was performed on a weekly basis for 8 weeks, a significant improvement was seen in urticaria symptoms and quality-of-life scores.[41]

Consultations

Referral a dermatologist or allergy and immunology specialist should be considered. A consultation with an allergist is recommended when the eliciting factor seems to be food sensitivity.

Clinical Guidelines

The American Academy of Allergy, Asthma, and Immunology (AAAAI) and the European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA2LEN)/European Dermatology Forum (EDF)/World Allergy Organization (WAO) have both updated their guidelines for managing chronic urticaria.[42] While some differences in their recommendations exist, the core recommendations remain similar.

A brief summary and highlights of the AAAAI guidelines are as follows:

A brief summary and highlights of EAACI/GA2LEN/EDF/WAO guidelines are as follows:

In March 2015, the Standards of Care Committee of the British Society for Allergy and Clinical Immunology published guidelines on treatment of chronic urticaria.[43] Management must include the identification and exclusion of possible triggers, patient education, and a personalized management plan.

Often, food allergy can be excluded as a cause of urticaria if no temporal relationship exists to a particular food trigger, by either ingestion or contact. Food additives rarely cause chronic urticaria. Certain drugs may cause or aggravate chronic urticaria; therefore, a detailed drug history is mandatory.

Up to 50% of chronic urticaria cases in older children and adults are reported to be autoimmune in nature, and these may be associated with other autoimmune conditions such as thyroiditis. Autoimmune and some inducible wheals can follow a more protracted course and may be more resistant to treatment.

Antihistamine doses at higher than normal levels may be required to control severe urticaria. An increased dose of a single antihistamine is preferred over mixing different antihistamines.

For adult patients with wheals, check that symptomatic episodes have not followed ingestion of an NSAID (eg, aspirin, ibuprofen). Provide an explanation for the symptoms and reassure that the histamine-induced chronic urticaria symptoms do not involve the respiratory tract or cardiovascular system, such as occurs in anaphylaxis. Note that very rare exceptions to this rule do exist. A once-daily dose of a long-acting, nonsedating antihistamine should be given, as necessary, if symptoms are infrequent. If necessary, double the antihistamine dose (usually given at night), and/or add a second antihistamine. Consider (1) further increases of antihistamine doses (≤ 4 times recommended), (2) adding one or more second-line drugs, and/or (3) short-term oral corticosteroid rescue treatment.

For chronic urticaria in children, the primary strategy should be avoidance of known provoking stimuli. The mainstay of treatment for children with chronic urticaria is nonsedating antihistamines; up to 4 times the recommended dose may be required for adequate symptom control. In patients who do not respond to high-dose antihistamine therapy, consider the possibility of an underlying diagnosis such as vasculitis.

For chronic urticaria in pregnancy and breastfeeding, antihistamine treatment can possibly be reduced, as chronic urticaria often improves in pregnancy. Note, however, that in some rare cases it deteriorates. While the risks of prenatal urticaria treatment are small, pregnant women should be informed that no drug can be considered absolutely safe. Antihistamines should only be used if clearly needed. If an antihistamine is required in pregnancy, the lowest dose of chlorphenamine, cetirizine, or loratadine should be used. In breastfeeding mothers, either cetirizine or loratadine at the lowest effective does is recommended and chlorphenamine should be avoided.  

Medication Summary

Medications used to treat chronic urticaria include antihistamines (first- and second-generation), anti-inflammatory agents, and sulfones.

Cetirizine (Zyrtec)

Clinical Context:  Cetirizine forms a complex with histamine for H1-receptor sites in blood vessels, the gastrointestinal (GI) tract, and the respiratory tract. It is available as a 5- or 10-mg tablet and as a syrup containing 1 mg/mL (5 mg/5 mL [tsp]).

Fexofenadine (Allegra)

Clinical Context:  Fexofenadine competes with histamine for H1 receptors in the GI tract, blood vessels, and the respiratory tract, reducing hypersensitivity reactions. It does not sedate. Fexofenadine is available as a 30-, 60-, or 180-mg tablet. The Allegra ODT tablet is formulated for disintegration in the mouth immediately after administration. Each orally disintegrating tablet contains 30 mg of fexofenadine hydrochloride. The Allegra oral suspension contains 6 mg/mL of fexofenadine hydrochloride (30 mg/5 mL).

Loratadine (Claritin, Alavert)

Clinical Context:  Loratadine selectively inhibits peripheral histamine H1 receptors. It is available in 10-mg tablets or 10-mg RediTabs; the syrup is 5 mg/5 mL (tsp).

Desloratadine (Clarinex)

Clinical Context:  Desloratadine is a long-acting tricyclic histamine antagonist that is selective for H1 receptors. It relieves nasal congestion and alleviates the systemic effects of seasonal allergy. Desloratadine is a major metabolite of loratadine, which, after ingestion, is extensively metabolized to the active metabolite 3-hydroxydesloratadine. The tablet is 5 mg; the syrup is 0.5 mg/mL (2.5 mg/5 mL [tsp]); and the RediTabs (orally disintegrating desloratadine tablets) are 2.5 mg and 5 mg.

Levocetirizine (Xyzal)

Clinical Context:  Levocetirizine is an H1-receptor antagonist, an active enantiomer of cetirizine. It is a second-generation prescription antihistamine.

Class Summary

Second-generation antihistamines, also known as less-sedating or low-sedation antihistamines, produce less sedation than traditional H1 blockers because they are less lipid-soluble and only cross the blood-brain barrier in small amounts. They also have longer half-lives, allowing less frequent dosing.

Diphenhydramine (Benadryl, Diphenhist, Allerdryl)

Clinical Context:  Diphenhydramine is given for symptomatic relief of symptoms caused by release of histamine in allergic reactions.

Hydroxyzine (Vistaril)

Clinical Context:  Hydroxyzine antagonizes H1 receptors in the periphery. It may suppress histamine activity in subcortical region of the central nervous system (CNS). Hydroxyzine is available in 10-, 25-, and 50-mg tablets or capsules and in a 100-mg capsule. The suspension is 25 mg/5 mL, and the syrup is 10 mg/5 mL (tsp).

Class Summary

First-generation antihistamines compete with histamine at the tissue-receptor level, preventing it from carrying out its mediator functions in urticaria.

Montelukast (Singulair)

Clinical Context:  Montelukast is a selective competitive inhibitor of the cysteinyl leukotriene receptor. Montelukast is the last agent introduced in its class. The advantages are that it is chewable, it has a once-a-day dosing, and it has no significant adverse effects.

Class Summary

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 2 classes of agents can be combined. Montelukast 10 mg/day may be particularly helpful for patients experiencing flare-ups due to aspirin or other NSAIDs. Montelukast is approved for treatment of perennial allergic rhinitis in children aged 6 months and older.

Prednisone

Clinical Context:  Prednisone is an immunosuppressant used to treat autoimmune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity. It stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Colchicine (Colcrys)

Clinical Context:  Colchicine decreases leukocyte motility and phagocytosis in inflammatory responses.

Class Summary

Anti-inflammatory agents modify the immune response to diverse stimuli.

Cyclosporine (Gengraf, Neoral, Sandimmune)

Clinical Context:  Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions, such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease for a variety of organs. For children and adults, base the dosing on ideal body weight. Cyclosporine 4-6 mg/kg/day has been shown in randomized double-blind studies to be effective for chronic urticaria. Cyclosporine has a better risk-to-benefit ratio than systemic corticosteroids.

Cyclosporine is recommended only for patients with severe disease refractory to high doses of oral antihistamines. Cyclosporine therapy for chronic urticaria should be limited to 3 months or less. A sustained remission is observed in approximately one third of patients treated with this medication.

Methotrexate (Rheumatrex, Trexall)

Clinical Context:  Methotrexate has an unknown mechanism of action in the treatment of inflammatory reactions; it may affect immune function. Methotrexate ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). It is an antimetabolite that inhibits deoxyribonucleic acid (DNA) synthesis and it may suppress immune system. Adjust the dose gradually to attain a satisfactory response.

Class Summary

These agents inhibit immune reactions that result from diverse stimuli. Patients with autoimmune urticaria may benefit from the administration of methotrexate or cyclosporine.

Omalizumab (Xolair)

Clinical Context:  Omalizumab is a recombinant humanized monoclonal antibody administered by SC injection every 4 weeks. It selectively binds to IgE and inhibits binding to IgE receptors on the surface of mast cells and basophils. It is indicated for chronic idiopathic urticaria in adults and children aged 12 years or older who remain symptomatic despite anti-H 1 antihistamine treatment.

Class Summary

Monoclonal antibodies directed to immunoglobulin E (IgE) binding may reduce the release of mediators that provoke an allergic response. These agents may be considered when H 1 -receptor antagonists are ineffective.

Doxepin

Clinical Context:  Doxepin inhibits histamine and acetylcholine activity and has proven useful in the treatment of allergic dermatologic disorders. The oral form is marketed as an antidepressant but is used also for its antihistaminic/antipruritic effects. The dosage is 10-25 mg at night in adults; if necessary, this can be gradually increased to a maximum dose of 75 mg/d for dermatoses.

Class Summary

Agents in this class antagonize the histamine (H1) receptor, preventing histamine from causing urticaria. The tricyclic antidepressant doxepin is used in urticaria for its sedative and antihistaminic properties. Oral doxepin may be considered if oral antihistamines are not helpful.

Dapsone

Clinical Context:  The mechanism of action of dapsone is similar to that of sulfonamides, in which competitive antagonists of para-aminobenzoic acid (PABA) prevent formation of folic acid. The effects of this agent on inflammatory reactions are unknown.

Class Summary

Certain antibiotics may modulate the immune system.

Levothyroxine (Levothroid, Levoxyl, Synthroid, Unithroid)

Clinical Context:  In active form, levothyroxine influences the growth and maturation of tissues. It is involved in normal growth, metabolism, and development.

Some patients with chronic urticaria and antithyroid antibodies benefit from levothyroxine treatment, perhaps because of suppression of thyroid activity and, possibly, the autoimmune process. The goal of treatment is to suppress thyrotropin maximally 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.

Class Summary

Thyroid hormones may be used to suppress thyroid activity and possibly the immune process.

Author

Marla N Diakow, MD, Resident Physician, Department of Dermatology, State University of New York Downstate College of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Jeannette Rachel Jakus, MD, MBA, Clinical Assistant Professor, Director of Clinical Research, Assistant Program Director, Department of Dermatology, SUNY Downstate Medical Center; Dermatologist, Brody Dermatology

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

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: nakedbiome<br/>Received income in an amount equal to or greater than $250 from: elsevier;webMD<br/>editor in chief for: statpearls.

Additional Contributors

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

Disclosure: Nothing to disclose.

Acknowledgements

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.

Urticaria developed after bites from an imported fire ant.

Urticaria associated with a drug reaction.