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Disclosures: David A Khan, MD Speaker's Bureau: Genentech (asthma). Sarbjit Saini, MD Grant/Research Support: Novartis (asthma). Consultant/Advisory Boards: Novartis; Genentech; Regeneron; MedImmune; Kendle (allergic disease, urticaria). Jeffrey Callen, MD, FACP, FAAD Consultant/Advisory Boards: Xoma; Amgen [psoriasis (etanercept)]; Lilly; Steifel, a GSK company; Auxilium. Equity Ownership/Stock Options: Celgene; Pfizer; 3M; Johnson & Johnson; Merck; Abbott; Abbvie; Proctor & Gamble. Equity Ownership/Stock Options (spouse): 3M; Abbott; Abbvie; Amgen; Johnson & Johnson; Proctor & Gamble. Anna M Feldweg, MD Employee of UpToDate, Inc.
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INTRODUCTION — Chronic urticaria (CU) is defined by the presence of urticaria (hives) on most days of the week, for a duration of longer than six weeks. The prevalence of this disorder is up to one percent of the general population in the United States, and is believed similar around the world . Associated angioedema occurs in about 40 percent of patients with CU and usually affects the lips, cheeks, periorbital areas of the face, extremities, and genitals .
The management of CU in most patients, as well as counseling of individuals with this disorder, will be discussed here. Treatment of CU that is refractory to standard management and the diagnosis, pathogenesis, and prognosis of CU are presented separately. (See "Chronic urticaria: Treatment of refractory symptoms" and "Chronic urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)
Terminology — In this review, the term CU refers to patients with isolated chronic idiopathic urticaria (CIU), as well as those with both urticaria and angioedema. Disorders involving isolated angioedema, urticarial vasculitis, and specific physical forms of CU (such as delayed pressure urticaria, cholinergic urticaria, or cold urticaria) are discussed separately. (See "An overview of angioedema: Pathogenesis and causes" and "Urticarial vasculitis" and "Physical urticarias" and "Cold urticaria".)
Chronic autoimmune urticaria — In the discussion below, the terms CU and CIU are used synonymously. Some studies distinguish between patients with and without positive autologous serum skin tests (ASSTs) or other laboratory indicators of an autoimmune process. This distinction is mentioned in the text only if a study found a difference between these two patient groups. The interpretation of a positive ASST in patients with CU is reviewed elsewhere. (See "Chronic urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history", section on 'Autoimmune theory'.)
PATIENT EDUCATION — Chronic urticaria (CU) causes marked distress to patients because it is physically uncomfortable, waxes and wanes unpredictably, interferes with work/school and sleep, and is often difficult to treat. The severity and duration of symptoms vary among individuals, and the underlying cause is not known in most cases. Furthermore, it can be misinterpreted by others to be infectious and patients may stay home to avoid embarrassment. All of these factors contribute to patient frustration and anxiety.
Reassurance — Patients with CU are often frustrated and fearful, and reassurance is an important component of successful management. There are three important concepts to relay to patients with CU:
Avoidance of exacerbating factors — No external cause can be identified in 80 to 90 percent of people affected by CU/angioedema. The evaluation and diagnosis of a patient with persistent urticaria are reviewed separately. (See "Chronic urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)
Once the diagnosis of chronic idiopathic urticaria (CIU)/angioedema has been established, the clinician should begin educating the patient about management, including avoidance of things that can aggravate the condition, including:
Dietary manipulations — It is particularly important to explain to patients that an undiscovered allergy to food or food additives is not likely to be responsible for their symptoms. IgE-mediated food reactions are not a cause of CU and testing for food allergy is not necessary . (See "Chronic urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history", section on 'Foods and food additives'.)
Although CU is not a manifestation of IgE-mediated food allergy, food can cause fluctuations in the symptoms of CU that are noticeable to patients. This is believed to be due to the presence of "pseudoallergens," which are substances in food that exacerbate CU. Pseudoallergens include artificial preservatives and dyes in processed foods, as well as naturally-occurring aromatic compounds in certain foods (many fruits and vegetables, seafood, others). Diets free of pseudoallergens are difficult to follow because the array of foods that must be avoided is so broad (table 1).
The utility of pseudoallergen-free diets in CU has been evaluated in uncontrolled studies. One study concluded that adherence to a diet low in pseudoallergens was helpful, since 73 percent of 64 CU patients had either cessation or a significant reduction of symptoms within two weeks of adopting a pseudoallergen-free diet . However, only 19 percent of those who improved developed symptoms when subsequently challenged with individual pseudoallergens on provocation tests, suggesting that no one substance was responsible, and that benefit was dependent upon the strict avoidance of multiple foods. In contrast to the high rates of response in this study, a subsequent larger study of 140 patients placed on a pseudoallergen-free diet found that only 28 percent had a strong or partial response . The foods and other substances that are prohibited in a pseudoallergen-free diet are listed in the table (table 1). Several weeks of adherence to this diet may be necessary for clinical improvement.
The limited clinical relevance of pseudoallergens in CU is also supported by the observation that patients in whom CU has remitted are able to eat anything without recurrence of urticaria .
In summary, we do not routinely advise CU patients to adopt pseudoallergen-free diets. However, if a patient is very motivated to try these diets, we do not object.
AGENTS AND EFFICACY — Most patients with chronic urticaria (CU) are initially treated with antihistamines, often in conjunction with limited courses of oral glucocorticoids for refractory symptoms. However, long-term systemic glucocorticoids are associated with significant adverse effects, and persistent symptoms should be treated instead with other immunosuppressive, immunomodulatory, or steroid-sparing agents.
The different medications used in the management of CU and studies of efficacy are discussed in this section. A stepwise approach to therapy, including recommended dosing and monitoring, is presented subsequently. (See 'Stepwise approach to treatment' below.)
H1 antihistamines — H1 antihistamines are the cornerstone of pharmacotherapy for CU and control symptoms to at least some degree in most patients [1,8-10]. Patients show variable responsiveness to antihistamines. The magnitude of effect is difficult to generalize, although in various reports, 50 to 95 percent of patients achieved satisfactory disease control with one or a combination of antihistamines, without other agents [9,11,12].
Several randomized, placebo controlled trials have demonstrated that both the first and second generation H1 antihistamines reduce the major symptoms of CU, (ie, pruritus, wheal (hive) formation, and disruption of sleep and daily activities) [2,13-16]. A systematic review concluded that nonsedating antihistamines improve quality of life for patients with CU .
The newer second generation agents (eg, cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine) are generally as effective and better tolerated (ie, less sedative and anticholinergic effects) than moderate doses of the older, first generation antihistamines (eg, hydroxyzine, diphenhydramine, chlorpheniramine, or mizolastine) [18,19].
Dosing of second generation agents — As mentioned above, the second generation H1 antihistamines (eg, cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine) are generally as effective and better tolerated than the first generation agents.
Doses of second generation antihistamines as high as four times the recommended dose are advocated in international guidelines on CU, based largely upon expert opinion [9,10,25,26]. However, the limited number of published studies evaluating this approach has not demonstrated a clear increase in efficacy [12,13,27]:
Studies of other second generation antihistamines have not shown improved efficacy at higher doses [13,27]:
Thus, the evidence for higher doses of second generation antihistamines is mixed and varies for different antihistamines. To summarize :
Dosing of first generation agents — Higher doses of first generation antihistamines have been recommended by several authors, particularly when second generation antihistamines do not produce an adequate response . The primary concern with higher dose therapy is sedation and performance impairment, and clinicians should inform patients specifically about this side effect.
In children younger than two years of age, first generation, sedating antihistamines should be avoided, as these drugs can cause paradoxical agitation and over-the-counter cold remedies containing them have been linked to a small number of deaths in this age group. (See "The common cold in children: Treatment and prevention", section on 'Treatment'.)
Studies of first generation antihistamines in adults, at usual doses, have shown tolerance to performance impairment after three to five days of therapy [31-33]. Studies in patients with CU given higher doses are lacking, although many patients with CU seem to tolerate high doses without difficulty. Based upon this information, some authors suggest a gradual titration of first generation antihistamines. As an example, hydroxyzine can be started at 10 to 25 mg daily and increased in 10 to 25 mg increments every five to seven days to a maximum of 25 to 50 mg four times daily [7,34].
Another approach is to administer first generation antihistamines as a single dose in the evening, in combination with a second generation antihistamine given in the morning [1,34]. First generation antihistamines typically have long half-lives and a single nighttime dose may reduce daytime sedation compared to frequent daytime dosing; however these proposed regimens have not been compared in terms of either efficacy or adverse effects in patients with CU.
H2 antihistamines — Patients whose symptoms are not adequately controlled on H1 antihistamines alone may experience modest improvement with the addition of H2 antihistamines [35,36]. Some studies of H1 and H2 antihistamine combinations have used agents that are metabolized by the same liver enzymes, raising the possibility that the benefit was largely due to increased serum concentrations of one or both drugs, rather than a true synergistic effect . Thus, a trial of H2 antihistamines can be considered as additive therapy in patients whose symptoms do not respond adequately to H1 antihistamines alone.
Topical agents — While there are isolated, anecdotal reports that suggest benefit of some topical agents for CU, routine use is discouraged as they rarely result in sustained improvement and are rarely used as intended outside of clinical trials. Some of the agents that have been used include emollients that contain menthol, phenol or pramoxine, substances that are benign but minimally effective. Others contain high-potency topical corticosteroids, which can cause dermal atrophy, or topical antihistamines (eg, doxepin-containing preparations), which can cause contact sensitization .
Systemic glucocorticoids — Systemic (usually oral) glucocorticoids are effective in controlling symptoms in most patients with CU. However, administration beyond several weeks is not justified for a disorder that, in itself, has an excellent long-term prognosis, since glucocorticoids have predictable and significant adverse effects. In addition, a retrospective study found that the addition of glucocorticoids to antihistamines during the initial weeks of treatment did not hasten the time required to achieve control of symptoms, compared with treatment with antihistamines alone . Thus, there is no evidence that glucocorticoids have a disease modifying effect. We view glucocorticoids as rescue therapy that should be used to attain temporary control of severe symptoms. (See "Major side effects of systemic glucocorticoids".)
Most guidelines suggest that oral glucocorticoids be considered as an initial additive therapy for patients with symptoms refractory to one or more antihistamines at full dose [8-10]. Optimal dosing has not been formally studied, although our approach is described below. In many cases, symptoms recur as glucocorticoids are tapered or discontinued, and these agents are not believed to alter the long-term course of the disease. (See 'Systemic glucocorticoids for rescue therapy' below.)
Leukotriene modifiers — Leukotrienes are believed involved in the pathogenesis of urticaria. Activated mast cells generate and release leukotrienes in addition to histamine, and intradermally injected leukotriene D4 causes a strong wheal and flare response [40-42]. Antileukotriene medications include the leukotriene receptor antagonists, montelukast and zafirlukast, as well as the 5-lipoxygenase inhibitor zileuton.
Available evidence suggests that these agents may be useful either as monotherapy or add-on therapy in some patients with CU. One subgroup that may respond more predictably to these agents is patients with CU that is exacerbated by ingestion of aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs), since abnormal leukotriene regulation is believed to be important in the pathogenesis of this type of urticaria [43,44]. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions".)
Patients with the rare disorder of antihistamine-induced urticaria  might also benefit from antileukotriene agents. A case report described four such patients, three of whom responded to montelukast .
In unselected populations of patients with CU, the data in support of leukotriene modifiers are less robust:
Choice of agent and time to response — The preferred agents are montelukast and zafirlukast, because these drugs are widely available and require no monitoring of laboratory studies. In contrast, zileuton use requires that liver function tests be followed. Time to benefit can be fairly rapid in some patients, while others appear to require several weeks of treatment . One study suggested persistent drug-free remission , although most studies did not observe this outcome.
OTHER THERAPIES FOR SPECIFIC CLINICAL SITUATIONS
Patients with concomitant borderline or elevated blood pressure — Dihydropyridine calcium channel blockers may reduce the proliferation of stimulated T-lymphocytes and inhibit mast cell mediator release [61,62]. A small, randomized, controlled, crossover trial of 10 patients with chronic idiopathic urticaria (CIU) treated with nifedipine (up to 20 mg three times daily) demonstrated benefit in seven patients, with mild adverse effects . Other evidence consists of case reports.
Advantages of this agent include a relatively rapid therapeutic response, familiarity of clinicians with this class of drug, and wide availability. Thus, a trial of calcium channel blockers may be reasonable for patients who can tolerate the hemodynamic effects, or for those with concomitant hypertension.
In addition, there is preliminary evidence that the presence of systemic hypertension is associated with longer chronic urticaria (CU) duration, as discussed elsewhere. (See "Chronic urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history", section on 'Natural history and prognosis'.)
Patients with thyroid autoantibodies — Thyroid autoimmunity, as determined by the presence of elevated levels of thyroid peroxidase antibodies or antithyroglobulin antibodies, is found in patients with CU at a greater than expected frequency [64-66]. However, the patient's thyroid status does not necessarily correlate with the presence of urticaria. Patients with CU/angioedema and evidence of thyroid autoimmunity may be euthyroid, hypothyroid, or hyperthyroid [64,67]. (See "Chronic urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)
Patients with thyroid autoantibodies and laboratory evidence of clinical hypothyroidism may benefit from thyroid hormone replacement. In contrast, the treatment of euthyroid patients with CU is controversial. There are several reports of apparently successful treatment of euthyroid patients with thyroid hormone at doses that suppress the level of thyroid stimulating hormone (TSH) [64,65,67-70]. A proposed mechanism of action is reduction in complement activation by the complement controller domain of thyroperoxidase . We have seen some euthyroid patients with thyroid autoantibodies respond to thyroxine therapy without adverse effects, but the results are mixed and unpredictable. If this therapy is used, the uncertain benefits must be balanced with potential risks of iatrogenic hyperthyroidism and osteoporosis .
Pregnant or lactating women — Pregnant women with urticaria with/without angioedema should be treated with the least amount of medication possible. Most patients can be treated with H1 antihistamines alone, with occasional short courses of oral glucocorticoids for severe flares. The safety of different antihistamines, leukotriene modifying drugs, and other agents in pregnancy and lactation is discussed separately. (See "Recognition and management of allergic disease during pregnancy", section on 'Urticaria and angioedema'.)
STEPWISE APPROACH TO TREATMENT — This section describes an approach to the treatment of chronic urticaria (CU) using the different medications discussed previously. This approach represents that of the author and editors of UpToDate. Practice Parameters for the management of CU have been published by expert panels of allergists/immunologists and/or dermatologists in the United States, United Kingdom, and Europe [8-10]. The approach described herein is relatively consistent with these practice parameters, although there are differences among these parameters and the best approach is not known. All doses listed are for adults, unless otherwise noted.
Systemic glucocorticoids for rescue therapy — Systemic glucocorticoids may be required periodically to gain temporary control of symptoms during severe exacerbations of urticaria that significantly impair quality of life. These rescue courses of glucocorticoids may be required at any point in therapy and are generally added on to the medications that the patient is already taking. However, long-term (eg, months to years) of systemic glucocorticoid therapy should be avoided, as discussed previously. (See 'Systemic glucocorticoids' above.)
The optimal dose and duration of glucocorticoids used for CU exacerbations has not been systematically studied, and recommendations vary among urticaria specialists. In addition, patients differ in their responsiveness to glucocorticoids in both the dose and duration of treatment required to control symptoms.
We prefer to use relatively brief (ie, 3 to 10 day) courses of prednisone, and typically begin with a dose of 20 mg twice daily for two to three days. Occasional patients require higher initial doses.
Once symptoms are controlled, the dose should be tapered down to 10 mg daily or less, which can typically be done in increments of 10 mg. Rebound worsening of urticaria may occur with tapering or discontinuation of systemic glucocorticoids and if this occurs, we return to the last effective dose and then try to taper again more gradually. Some authors suggest that once the dose has been reduced to 20 mg daily, the frequency of administration may be changed to every other day, and then the dose tapered further.
Step 1: Second generation H1 antihistamine — We administer a second generation antihistamine at standard therapeutic dose as initial therapy. We prefer cetirizine 10 mg once daily, but the following other agents are appropriate alternatives (see 'H1 antihistamines' above):
Step 2: Increase dose — We instruct patients to increase the dose of the second generation antihistamine to twice daily if once daily does not control symptoms adequately within several days. Another option is to add a different second generation antihistamine (eg, fexofenadine 180 mg in the morning, and cetirizine 10 mg at night). This can be particularly helpful when patients develop increased sedation from higher doses of certain agents, such as cetirizine. Dosing up to four times standard doses may be considered with some agents, such as desloratadine and levocetirizine, although it is not useful with fexofenadine. (See 'Dosing of second generation agents' above.)
Step 3: Add or substitute other types of antihistamines — If increased doses of a second-generation H1 antihistamine do not control symptoms, we then either add or substitute a first generation H1 antihistamine at bedtime, or add an H2 antihistamine.
We prefer to add one of the following potent H1 receptor antagonists:
Step 4: Leukotriene modifier — If symptoms are refractory to high-doses or combinations of H1 antihistamines and/or H2 antihistamines, or if patients experience excessive sedation or anticholinergic side effects, we then consider non-antihistamine therapies.
Our preferred initial add-on therapy is a leukotriene modifier. We usually prescribe montelukast 10 mg daily, while maintaining the patient on the highest tolerated dose of H1 antihistamines. We allow at least four weeks to gauge the effect of the leukotriene modifier. If there is no improvement, we discontinue the medication. (See 'Leukotriene modifiers' above.)
Step 5: Consider immunomodulatory and immunosuppressive agents — For patients whose symptoms are refractory to the measures discussed so far in this review, additional therapies should be considered and are presented separately. (See "Chronic urticaria: Treatment of refractory symptoms".)
Maintenance therapy — Many patients with CU require multiple medications to control symptoms fully. Once symptoms have come under control, the patient should be maintained on those agent(s) for a period of time before withdrawal of medications is considered.
The optimal duration of maintenance therapy in a variable disease like CU has not been studied. Patients whose symptoms were easily and completely controlled with one or two agents may begin to taper therapy after a month or two of well-controlled symptoms. For the majority of patients, we generally recommend three months of good control prior to tapering therapies, and we extend this longer for patients with one or more of the following characteristics:
We typically discontinue agents that have been deemed ineffective, including antihistamines in patients who are completely antihistamine resistant. In patients responsive to antihistamine therapy, we gradually reduce antihistamine doses every two to four weeks, beginning with first generation agents. Other agents can be tapered in a similar fashion. In patients dependent on systemic glucocorticoids, we reduce the dose as quickly as possible once their urticaria has been stabilized.
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