Diagnosis and Management of Acute and Chronic Urticaria

Publication Date: February 1, 2014
Last Updated: September 2, 2022

Acute, Chronic and Physical Urticaria and Angioedema

Acute Urticaria and Angioedema

Acute urticaria and angioedema are differentiated from chronic urticaria and angioedema (CUA) based on duration of illness. ( D )
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Acute urticaria and angioedema should be differentiated from anaphylaxis. ( D )
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Acute urticaria and angioedema are more frequently associated with identifiable conditions. When this disorder becomes chronic, it is less likely to be associated with an identifiable cause. ( D )
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Acute urticaria and angioedema are often but not always related to mast cell and basophil activation from multiple triggers, which include IgE- and non–IgE-mediated mechanisms. ( LB )
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Although skin biopsy is not indicated in most cases of acute urticaria and angioedema, it might occasionally be useful for differentiating this condition from other inflammatory disorders. ( C )
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Common causes of acute urticaria and angioedema, including medications and foods, should be identified by a detailed history and eliminated, if possible. ( C )
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Treatment

Epinephrine should be prescribed if the diagnosis of anaphylaxis has not been excluded. ( D )
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In most cases antihistamines are efficacious for therapy of acute urticaria and angioedema. ( B )
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In severe cases oral corticosteroids might be necessary to treat acute urticaria and angioedema. In patients with poor response to antihistamines, a brief course of oral corticosteroids might also be required while attempting to eliminate suspected triggers and develop an effective treatment plan. ( C )
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Chronic Urticaria and Angioedema

CU is defined as urticaria that has been continuously or intermittently present for ≥6 weeks. ( D )
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The duration of CU varies considerably. However, physical urticarias tend to persist the longest, often for many years. ( C )
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Some patients with CU might have both urticaria and angioedema, occurring simultaneously or separately. ( C )
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Skin mast cells are the most important cells in patients with CU, and histamine is the predominant mediator, although other cells and mediators also play a key role. ( LB )
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Activation of the coagulation cascade, including increased prothrombin fragment F1 2 and D-dimer levels, has been described in patients with CU and might be a marker for CUA severity. ( C )
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Evaluation of a patient with CU should involve consideration of various possible causes. Most cases do not have an identifiable cause.

( C )
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Numerous autoimmune disorders, including SLE, dermatomyositis and polymyositis, Sjögren syndrome, type 1 diabetes, rheumatoid arthritis, celiac disease, and Still disease, have been associated with CU. ( C )
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Serology to diagnose underlying autoimmune diseases (e.g., connective tissue disease) is NOT warranted in the initial evaluation of CU in the absence of additional features suggestive of a concomitant autoimmune disease. ( B )
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Thyroid autoantibodies are frequently identified in patients with CU. ( C )
  • The clinical relevance of these tests for patients with CU has not been established.
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Chronic urticarial vasculitis, associated with low or normal complement levels, can present as a primary autoimmune disorder or develop secondary to an autoimmune disorder, such as SLE. ( B )
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Urticarial vasculitic lesions can sometimes be evanescent, lasting <24 hours, which is similar to CU. For this reason, urticarial vasculitis cannot be completely excluded based on the history of lesions spanning <24 hours. ( B )
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The co-occurrence of CU with a number of conditions, including H. pylori infection and celiac disease, has been reported. However, evidence does not support testing for these conditions in a patient with CU with an otherwise unremarkable history and physical examination. Moreover, there are no convincing data demonstrating that treatment based on abnormal test results consistent with these conditions being present leads to improvement or change in the course of CU.

( C )
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Malignancies, such as lymphoproliferative diseases and Schnitzler syndrome, can present with CU. ( C )
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Approximately 30%–50% of patients with CUε produce specific IgG antibodies against the FcR1α subunit component of the high-affinity IgE receptor. ( C )
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The utility of the autologous serum skin test (ASST) and autologous plasma skin test (APST) is unclear because evidence has not clearly demonstrated that this testing identifies a distinct subgroup of patients with CU. Current evidence does not support routine performance of ASSTs or APSTs in patients with CU. ( C )
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The pathogenesis of autoantibody-associated urticaria remains elusive, but in vitro/ex vivo studies demonstrate a role for T cells, sCD154 (sCD40 ligand), and basophil histamine responsiveness. ( LB )
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For patients with CU who present with an otherwise unremarkable history and physical examination findings, skin or in vitro testing for IgE to inhalants or foods and/or extensive laboratory testing are NOT recommended because such testing is not cost-effective and does not lead to improved patient care outcomes. ( C )
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Targeted laboratory testing based on history or physical examination findings is appropriate, and limited laboratory testing can be obtained. ()
(Grade E)
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The initial patient evaluation should be focused to determine (through history and physical examination) whether the lesions that patients describe are consistent with CU. ( D )
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The medical work-up of a patient with CU should be done, keeping in mind that CU is of undetermined cause in the majority of cases. ( C )
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After a thorough history and physical examination, no further diagnostic testing might be appropriate for patients with CU.
  • However, limited routine laboratory testing can be performed to exclude underlying causes. Targeted laboratory testing based on clinical suspicion is appropriate.
  • Extensive routine testing for exogenous and rare causes of CU or immediate hypersensitivity skin testing for inhalants or foods is NOT warranted. Routine laboratory testing in patients with CU whose history and physical examination lack atypical features rarely yields clinically significant findings.
( C )
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Screening for thyroid disease is of low yield in patients without specific thyroid-related symptoms or history of thyroid disease. Increased levels of anti-thyroglobulin or anti-thyroid antibodies in euthyroid (ie, normal TSH) subjects are commonly detected, although the clinical implications of this finding are unclear. ( C )
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Although commercial assays are now available, the utility of testing for autoantibodies to the high-affinity IgE receptor or autoantibodies to IgE has not been established. ( C )
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Patients with recurrent angioedema in the absence of coexisting urticaria should be evaluated for hereditary angioedema, acquired C1-inhibitor deficiency, or ACE inhibitor–associated angioedema before a diagnosis of idiopathic angioedema is made. ( C )
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Skin biopsy can be performed when vasculitis is suspected, such as in patients with refractory CU, or when other nonurticarial immunologic skin diseases are a consideration. Routine skin biopsy specimens are not required in most cases of CU. ( D )
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Immediate hypersensitivity skin or serologic testing for food or other allergens is rarely useful and NOT recommended on a routine basis. ( D )
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Aquagenic Urticaria

Aquagenic urticaria is a rare condition. Patients with aquagenic urticaria have hives (typically 1–3 mm in size) after direct contact of skin with any source of water independent of temperature. Aquagenic urticaria can be confirmed by the appearance of wheals at the site of challenge with a water compress at 35°C applied to the skin of the upper body for 30 minutes. ( C )
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Cholinergic Urticaria

Patients with cholinergic urticaria have hives that are "pinpoint" (1–3 mm) and surrounded by large flares in association with an increase in core body temperature. ( B )
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Common provoking factors for cholinergic urticaria include exercise, sweating, emotional factors, and hot baths or showers. ( B )
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Provocative challenges that increase core body temperature, such as exercise and hot water immersion or methacholine intradermal challenge have been considered for the diagnosis of cholinergic urticaria. However, the negative predictive value of these tests is not optimal, and lack of response cannot rule out the diagnosis. ( D )
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The severity of cholinergic urticaria ranges from mild pruritus to serious and potentially life-threatening reactions. ( C )
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Cold Urticaria

Patients with cold urticaria have pruritus and swelling with exposure of the skin to a cold stimulus. Patients with cold urticaria can have systemic reactions associated with systemic cold exposure (e.g., aquatic activities). ( B )
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The diagnosis of cold urticaria can be confirmed by applying a cold stimulus (e.g., an ice cube on the forearm) to the patients’ skin and observing a wheal-and-flare reaction during rewarming of the skin. Some forms of cold urticaria might have a negative ice cube test result. ( B )
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The primary treatment for cold urticaria is avoidance of cold exposure, as feasible; however, prescribing pharmacotherapy is also frequently advisable. ( C )
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Delayed Pressure Urticaria/Angioedema (DPUA)

Patients with DPUA have swelling (which can be painful) with a delay of 4-6 hours after exposure of the skin to a pressure stimulus. In some cases the delay can be as long as 12 or even 24 hours after pressure exposure. Common provoking factors include working with tools, sitting on a bench, or wearing constricting garments. ( B )
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DPUA can be confirmed by a challenge with 15 lbs of weight suspended over a patient’s shoulder for 10 or 15 minutes. Development of angioedema in a delayed fashion at the site of pressure is considered a positive challenge result. ( C )
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Management of DPUA differs from other types of CU/angioedema and is often very difficult to treat. Additional pharmacotherapeutic treatment is frequently required, along with avoidance measures. Conventional antihistamine dosing frequently lacks efficacy for achieving control of symptoms. ( C )
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Dermatographia

Patients with dermatographia (also known as dermatographism, dermographia, and dermographism) promptly have a wheal-and-flare response to pressure applied to the skin. Dermatographia can be confirmed by stroking the skin with a firm object, such as a tongue blade. Dermatographia is the most common form of physical urticaria and reported to be present in 2%–5% of the general population, although only a minority of patients have symptoms to a degree that prompts medical attention. ( B )
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Exercise-Induced Urticaria And Anaphylaxis (EIAN)

Urticaria provoked by exercise can occur in patients with 2 conditions: cholinergic urticaria or EIAn. ( B )
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There are 2 groups of patients with EIAn: one group can experience anaphylaxis provoked by exercise, and a second group can experience anaphylaxis with exercise temporally related to ingestion of food or medication ( C )
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Two subgroups of patients with food-dependent EIAn have been described: one group can experience anaphylaxis when exercising in temporal proximity to ingestion of any type of food, and another group can experience anaphylaxis with exercise in conjunction with prior ingestion of a specific food. ( C )
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It is important to distinguish EIAn from cholinergic urticaria. The diagnosis of EIAn can be confirmed by means of exercise challenge in a controlled environment, whereas cholinergic urticaria can be elicited by means of both exercise challenge and passive heating. ( C )
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Management depends on determining whether the patient has EIAn or cholinergic urticaria. If a food, drug, or another essential or modulating factor is identified, this should be avoided in the peri-exercise period. Patients with EIAn should carry injectable epinephrine, exercise with a partner, and wear medical identification jewelry. ( D )
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Solar Urticaria

Patients with solar urticaria promptly (generally within 1–3 minutes) experience urticaria with exposure of the skin to sunlight. ( B )
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The diagnosis of solar urticaria can be confirmed with phototesting to various wavelengths of light. ( B )
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Vibratory Angioedema

Patients with vibratory angioedema experience pruritus and swelling with exposure of the skin to a vibratory stimulus. This condition can be familial. ( B )
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Vibratory angioedema can be confirmed by demonstrating an exaggerated response after exposure of the skin to a vortex mixer. ( B )
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Differential Diagnosis

Differential Diagnosis (Table 4)

Cryoglobulinemia is often found in many conditions that result in vasculitis. ( D )
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Autoinflammatory syndromes are a group of conditions that involve aberrant activation of mediators of the innate immune response with resultant fever and other symptoms. (Table 5) ( C )
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Cryopyrin-associated periodic syndromes (also referred to as cryopyrinopathies) are a group of autoinflammatory syndromes that are characterized by abnormalities in the C1AS1 gene, which encodes for the cryopyrin protein, and are associated with an urticaria-like rash (pseudourticaria). (Table 5) ( C )
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Hypocomplementemic or normocomplementemic urticarial vasculitis is associated with decreased or normal complement (C1q, C4, and C3) levels and a biopsy that reveals vasculitis of dermal blood vessels with leukocytoclasis. (Table 5) ( C )
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Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a more severe form of this condition associated with arthralgias, glomerulonephritis, uveitis or episcleritis, recurrent abdominal pain, obstructive lung disease, and urticaria and/or angioedema. ( C )
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Swelling of the area in the medial portion of the upper eyes might be a sign of thyroid orbitopathy and misinterpreted as angioedema. (Table 6) ( C )
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Urticaria-like dermatoses can occur at various stages of pregnancy. (Table 6) ( C )
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Women who present with cyclical urticaria can have autoimmune progesterone-induced dermatitis. (Table 6) ( C )
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Episodic attacks of angioedema with weight gain are characteristic of the syndrome episodic angioedema with eosinophilia (Gleich syndrome). ( C )
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Hypereosinophilic syndrome (HES) should be considered when the peripheral total eosinophil count exceeds 1500/mL for >6 months in the absence of other causes of peripheral eosinophilia. ( C )
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Cutaneous mast cell disorders that can present with urticaria-like lesions include urticaria pigmentosa (UP), mastocytomas, and telangiectasia macularis eruptiva perstans (TMEP). ( C )
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Mast cell activation disorders can also present with urticaria and angioedema but usually have additional systemic symptoms. (Table 7) ( C )
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Erythema multiforme can resemble urticaria and might be caused by viral infections (e.g., herpes), mycoplasma infection, or medications. ( C )
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Hepatitis B or C can be associated with urticarial vasculitis and should be considered in the differential diagnosis, particularly for patients whose behaviors predispose to contracting a sexually transmitted disease, who have recently received a blood transfusion, or who have exposure to contaminated needles. ( C )
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Bullous pemphigoid can present initially with urticaria-like papules or small plaques that can be excoriated by the patient before noticeable blistering occurs. (Table 7) ( D )
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Persistent swelling of the lips without evidence of eczematous dermatitis might be a sign of cheilitis granulomatosa (Melkersson-Rosenthal syndrome). ( C )
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Polymorphous light eruption differs from solar urticaria in that onset usually occurs minutes to hours after sunlight exposure, and the eruption lasts for days compared with solar urticaria, which is short-lived between exposures. ( D )
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Recall urticaria is a condition in which urticaria is observed at the site of a previous sting or injection after re-exposure to the same inciting factor. ( C )
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Patients with Schnitzler syndrome caused by an IgM monoclonal gammopathy present with nonpruritic urticaria (that spares the face), bone pain, and intermittent fever. ( D )
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Hepatitis B or C can be associated with urticarial vasculitis and should be considered in the differential diagnosis, particularly for patients whose behaviors predispose to contracting a sexually transmitted disease, who have recently received a blood transfusion, or who have exposure to contaminated needles. ( C )
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Bullous pemphigoid can present initially with urticaria-like papules or small plaques that can be excoriated by the patient before noticeable blistering occurs. ( D )
(Table 7)
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Persistent swelling of the lips without evidence of eczematous dermatitis might be a sign of cheilitis granulomatosa (Melkersson-Rosenthal syndrome). ( C )
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Polymorphous light eruption differs from solar urticaria in that onset usually occurs minutes to hours after sunlight exposure, and the eruption lasts for days compared with solar urticaria, which is short-lived between exposures. ( D )
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Recall urticaria is a condition in which urticaria is observed at the site of a previous sting or injection after re-exposure to the same inciting factor. ( C )
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Patients with Schnitzler syndrome caused by an IgM monoclonal gammopathy present with nonpruritic urticaria (that spares the face), bone pain, and intermittent fever. ( D )
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Treatment

There are no definitive studies that demonstrate that patients with refractory CU and a positive ASST result respond differently to certain medication regimens compared with those patients with CU with a negative ASST result. ( C )
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Nonpharmacologic Therapies

NSAIDs, heat, and tight clothing can exacerbate CU in some patients, and avoidance of these factors might be beneficial. (C)
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Avoidance of pseudoallergens in the diet is NOT recommended. ( C )
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Topical Therapies

Potent topical corticosteroids can improve symptoms from delayed pressure urticaria but have limited utility in the treatment of diffuse CU. ( C )
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H1–Antihistamines

H-antagonists are effective in the majority of patients with 1CU but might not achieve complete control in all patients. ( C )
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Second-generation antihistamines are safe and effective therapies in patients with CU and are considered first-line agents. ( A )
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Higher doses of second-generation antihistamines might provide more efficacy, but data are limited and conflicting for certain agents. ( B )
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First-generation antihistamines have proved efficacy in the treatment of CU.
Efficacy of first-generation antihistamines is similar to that of second-generation antihistamines, but sedation and impairment are greater with first-generation antihistamines, especially with short-term use. ( A )
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First-generation antihistamines can be considered in patients who do not achieve control of their condition with higher-dose second-generation antihistamines. ( D )
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H2–Antihistamines

H2-antihistamines taken in combination with first- and second-generation H1-antihistamines have been reported to be more efficacious compared with H-antihistamines alone for the treatment of 1CU. ( A )
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However, this added efficacy might be related to pharmacologic interactions and increased blood levels of first-generation antihistamines. ( B )
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Because these agents are well tolerated, the addition of H-antagonists can be considered when 2CU is not optimally controlled with second-generation antihistamine monotherapy. ( D )
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Leukotriene receptor antagonists have been shown in several, but not all, randomized controlled studies to be efficacious in patients with CU. ( A )
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Leukotriene receptor antagonists are generally well tolerated. ( A )
Leukotriene receptor antagonists can be considered for patients with CU with unsatisfactory responses to second-generation antihistamine monotherapy.
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Antidepressants With H1- And H2-Antagonist Activity

Doxepin: Treatment with hydroxyzine or doxepin can be considered in patients whose symptoms remain poorly controlled with dose advancement of second-generation antihistamines and the addition of H2-antihistamines, first-generation H1-antihistamines at bedtime, and/or antileukotrienes. ( C )
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Systemic Corticosteroids

Systemic corticosteroids are frequently used in patients with refractory CU, but no controlled studies have demonstrated efficacy. In some patients short-term use (e.g., 1–3 weeks’ duration) might be required to gain control of their symptoms until other therapies can achieve control. Because of the risk of adverse effects with systemic corticosteroids, long-term use for treatment of patients with CU should be avoided as much as possible. ( D )
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Alternative Therapies In Patients With CU

Patients with CU whose symptoms are not adequately controlled on maximally tolerated antihistamine therapy (e.g., doxepin at a dose of 75–125 mg/d) might be considered to have refractory CU. ( D )
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A number of alternative therapies have been studied for the treatment of CU. These therapies merit consideration for patients with refractory CU. ( D )
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Anti-inflammatory agents, including dapsone, sulfasalazine, hydroxychloroquine, and colchicine, have limited evidence for efficacy in patients with CU, and some require laboratory monitoring for adverse effects. ( C )
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Immunosuppressant Agents

Several immunosuppressant agents have been used in patients with antihistamine-refractory CU. Cyclosporine has been studied in several randomized controlled trials. Taken in the context of study limitations, potential harms, and cost, the quality of evidence supporting use of cyclosporine for refractory CUA is low. On the basis of current evidence, this leads to a weak recommendation for use of cyclosporine in patients with CUA refractory to conventional treatment. ( A )
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Methotrexate: Experience with methotrexate in patients with CU is limited ( C )
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to small case reports and case series. ( C )
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Because of the limited evidence and potential for more serious adverse effects, use of methotrexate in patients with CU should be considered only in patients refractory to other anti-inflammatory, immunosuppressant, or other safer alternative agents. ( D )
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Biologic Agents

Omalizumab: In contrast to other alternative agents for refractory CU, the therapeutic utility of omalizumab has been supported by findings from large double-blind, randomized controlled trials and is associated with a relatively low rate of clinically significant adverse effects. On the basis of this evidence, omalizumab should be considered for refractory CU if, from an individualized standpoint, a therapeutic trial of omalizumab is favorable when balancing the potential for benefit with the potential for harm/burden and cost, and the decision to proceed is consistent with the patient’s values and preferences. ( A )
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Several biologic agents, IV immunoglobulin, and anti-TNF agents have been reported to be efficacious in patients with refractory CU. ( C )
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Phototherapy

Phototherapy might be effective for CIU as well as some physical urticarias, including solar urticaria. ( C )
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Because of limited availability and frequency of treatment, phototherapy is generally considered in patients refractory to other anti-inflammatory, immunosuppressant, or biologic agents. ( D )
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Miscellaneous Alternative Agents

Other agents have been used in patients with refractory CU, including but not limited to theophylline, attenuated androgens, anticoagulants, NSAIDs, β-agonists, cyclophosphamide, gold, plasmapheresis, cromolyn, and nifedipine. ( C )
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However, these agents should be reserved for patients with refractory urticaria whose treatment with other anti-inflammatory, immunosuppressant, or biologic agents has failed. ( D )
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Choosing Alternative Agents For Treatment Of Refractory Urticaria

Multiple factors are involved in selecting an alternative agent in patients with refractory CU, including but not limited to the presence of comorbid factors, frequency of treatment-related visits, cost, rapidity of response, adverse effects, and the patient’s values and preferences. The potential for harm and burden association with a given alternative agent is extremely important and needs to be weighed against the patient’s potential for benefit, current quality of life, and any adverse effects from current therapy for their CU. ( D )
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Therapies For Specific Conditions Associated With CU

The evidence that H. pylori eradication leads to improvement of CU outcomes is weak and conflicting, leading to a weak recommendation for routine H. pylori eradication for patients with CU. ( C )
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Thyroid Autoantibodies

Because limited data support the use of thyroid hormone therapy in euthyroid patients with CU and thyroid autoantibodies, prescribing thyroid hormone to euthyroid patients with thyroid autoimmunity remains controversial. ( C )
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Herpes Infection

Very limited data support the use of antiviral therapies in patients with CU with concomitant herpetic infections or positive viral serologies. ( C )
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Autoimmune Progesterone And Estrogen Dermatitis

Limited data are available for the use of hormonal therapies in patients with autoimmune progesterone and estrogen dermatitis. ( C )
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Unproved/Controversial Therapies

The evidence is weak that pseudoallergen-free diets improve CU. ( C )
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Given the lack of evidence and burden of adhering to these diets, their use in patients with CU is NOT recommended. ( D )
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Other unproved therapies for CU that are NOT recommended include allergen immunotherapy, herbal therapies, vitamins, supplements, and acupuncture.

( C )
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Recommendation Grading

Overview

Title

Diagnosis and Management of Acute and Chronic Urticaria

Authoring Organizations

American College of Allergy, Asthma, and Immunology

American Academy of Allergy, Asthma & Immunology

Publication Month/Year

February 1, 2014

Last Updated Month/Year

December 19, 2024

Supplemental Implementation Tools

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Inclusion Criteria

Male, Female, Adolescent, Adult, Child, Infant, Older adult

Health Care Settings

Ambulatory, Childcare center, School

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Counseling, Diagnosis, Assessment and screening, Treatment, Management, Prevention

Diseases/Conditions (MeSH)

D000080223 - Chronic Urticaria, D014581 - Urticaria

Keywords

chronic urticaria, urticaria, hives

Source Citation

Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014;133(5):1270-7.