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Disclosures: David A Khan, MD Speaker's Bureau: Genentech [asthma (omalizumab)]; Merck [asthma (montelukast)]. 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 1 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".)
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".)
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.
Chronic urticaria and chronic idiopathic urticaria — The terms "chronic urticaria" and "chronic idiopathic urticaria" are used interchangeably in this review and in the medical literature. These terms refer to CU in which appearance of lesions is not triggered by consistent or identifiable factors. However, physical urticaria syndromes are variably included in CU. Physical urticarias are disorders in which urticaria is induced by one or more environmental stimuli, such as heat, cold, pressure applied to the skin, exercise, water, vibration, and sunlight. The inclusion of physical urticaria in the definition of CU is based upon the observation that some patients with CU have symptoms triggered by a physical stimulus on some occasions, while most of the symptoms are spontaneous.
Chronic spontaneous urticaria — The term "chronic spontaneous urticaria" is increasingly used instead of CU. This term refers to CU in which appearance of lesions is not triggered by consistent or identifiable factors, and it specifically excludes the physical urticaria syndromes.
Chronic autoimmune urticaria — 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'.)
GUIDELINES — Treatment guidelines and practice parameters for the management of chronic urticaria (CU) have been published by professional allergy and dermatology groups worldwide [3-9]. In all cases, management begins with a careful clinical history to detect and minimize aggravating factors, followed by initial treatment with H1 antihistamines. If symptoms persist, most guidelines suggest increasing the dose of H1 antihistamine, changing agents, or both. When symptoms are refractory to these measures, guidelines differ somewhat as to the next steps, although most suggest addition of an H2 antihistamine or antileukotriene agents. The approach described here is consistent with the 2014 American practice parameter .
Aggravating factors for CU symptoms are discussed elsewhere. (See "Chronic urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history", section on 'Aggravating factors'.)
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:
●Patients need to understand that CU is rarely permanent and that almost 50 percent of patients experience remission within one year .
●While acute urticaria and angioedema may be manifestations of allergic reactions that can be life threatening, CU is a different disorder that rarely puts the patient at any acute risk.
●The symptoms of CU can be successfully managed in the majority of patients.
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:
●Physical factors – A substantial subset of patients with CU have some flares that are triggered by physical stimuli. Educating patients about this can help them avoid these stimuli or simply make sense of their symptoms. As an example, heat (hot showers, extreme humidity) is a common trigger for many CU patients, and tight clothing or straps can also aggravate symptoms. In contrast, patients in whom physical factors are the main trigger for symptoms are more appropriately diagnosed as having a physical urticarial syndrome, such as cholinergic urticaria or delayed-pressure urticaria. Physical urticarias are reviewed separately. (See "Physical urticarias" and "Cold urticaria".)
●Antiinflammatory medications and alcohol – Nonsteroidal antiinflammatory drugs (NSAIDs) and alcohol worsen symptoms in many patients.
Dietary manipulations — For most patients with CU, dietary manipulations are not indicated . 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. Immunoglobulin E (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' and "Allergic and asthmatic reactions to food additives", section on 'Patients with chronic urticaria'.)
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 naturally-occurring aromatic compounds in certain foods (many fruits and vegetables, seafood, others), as well as artificial preservatives and dyes in processed foods. Diets free of pseudoallergens are difficult to follow because the array of foods that must be avoided is so broad (table 1).
We do not routinely advise CU patients to adopt pseudoallergen-free diets and this approach is not supported by most practice parameters . However, if a patient is very motivated to try these diets, we do not object. The utility of pseudoallergen-free diets in CU has been evaluated in uncontrolled studies. One prospective 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 .
AGENTS AND EFFICACY STUDIES — 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 [1,4,14-16]. 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 [15,17,18].
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) [2,19-22]. 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) [24,25].
●Cetirizine was significantly more likely to induce clearance of hives (52 versus 4 percent) with a similar rate of improvement of hives (37 versus 42 percent) in 117 patients, compared with fexofenadine .
Rupatadine is a newer second-generation antihistamine (not available in the United States) that also has anti-platelet-activating factor (PAF) effects. Randomized trials comparing levocetirizine and rupatadine have shown that rupatadine is more effective and better tolerated [30,31].
Dosing — Doses of second-generation antihistamines as high as four times the standard dose are advocated in American and most other guidelines on CU [4,15,32,33]. However, there are a limited number of published studies specifically evaluating higher doses and a clear increase in efficacy and benefit has not been demonstrated for all agents [18,19,34]. The evidence for higher doses is strongest for levocetirizine and desloratadine, mixed for cetirizine, and weak for fexofenadine. In the United States, it can be very difficult to get insurance approval for high doses of prescription second-generation antihistamines. The author most commonly recommends higher doses of cetirizine as it is inexpensive and available without a prescription.
Studies of specific agents include the following:
●Levocetirizine and desloratadine may be more effective at higher doses and do not cause clinically significant sedation. In a randomized trial of 80 patients referred to a tertiary center for refractory CU, subjects were assigned to either levocetirizine or desloratadine . Subject were initially treated with 5 mg of either drug, and doses were doubled at weekly intervals if symptoms had not responded (with response defined as >50 percent improvement), up to maximal doses of 20 mg by week 3. If subjects did not respond to 20 mg of one drug, they were then changed to 20 mg of the other during week 4. Increased somnolence was not observed with either agent.
Response rates were slightly higher to levocetirizine than desloratadine. Among those patients who responded (as defined previously), improvement was achieved in 52, 65, and 74 percent with 5, 10, and 20 mg of levocetirizine respectively, and 41, 56, and 63 percent with the same doses of desloratadine. There were seven subjects who did not respond to 20 mg of desloratadine, but did respond to 20 mg of levocetirizine. There were no patients who responded to desloratadine after failing levocetirizine. Approximately 15 percent failed to respond to the highest doses of either drug, and overall, only about one-half of patients achieved complete control of symptoms by the conclusion of the trial.
Of note, there was no placebo arm in this trial and there were 13 patients who became symptom free on standard 5 mg doses of either medication, raising the issue of whether these "refractory" subjects had been adherent with previous therapies. Despite these limitations, this study suggests that higher doses of either desloratadine or levocetirizine may be more effective than standard doses. In addition, the approach of doubling the dose stepwise in patients whose symptoms are not controlled appears to be safe and well tolerated.
●Studies of cetirizine updosing for CU are conflicting and methodologically less rigorous, and information about sedation at higher doses is lacking. A small observational study evaluated 21 CU patients with inadequate response after one to two weeks of cetirizine 10 mg daily for improvement with cetirizine 10 mg twice daily for an additional one to two weeks . Subjects were then randomized to continue at a dose of either 20 mg daily or reduce to 10 mg daily for an additional two weeks. Both groups had improved urticarial scores on cetirizine 20 mg daily, but only the group that remained on the higher dose had continued improvement, with worsening symptoms in the group whose cetirizine dose was reduced. Thus, this study suggested that the higher dose was more effective. However, in another small observational study, increasing cetirizine from 10 mg once daily to 10 mg three times daily improved disease control in only 1 of 22 patients .
●Fexofenadine has not been shown to be more effective at higher doses. A multicenter randomized trial of 418 patients treated with fexofenadine at doses of 20 mg, 60 mg, 120 mg, or 240 mg twice daily found that the three higher doses provided better disease control than the lowest dose (which was below the lowest recommended adult dose), but there were no significant differences in effectiveness among the higher doses . Another study of very similar design, also using fexofenadine, 20 mg, 60 mg, 120 mg, or 240 mg twice daily, found no difference in efficacy among the three highest doses . Thus, evidence is lacking that doses higher than 60 mg twice daily are more useful for patients with CU. A caveat of these studies is that the patients enrolled were not considered refractory to recommended doses of second-generation antihistamines.
Importance of regular dosing — Most clinicians prescribe nonsedating H1 antihistamines to be taken regularly and advise patients to minimize day-to-day changes in their medication regimen, and clinical trials demonstrating the efficacy of H1 antihistamines in this disorder involve regularly-dosed antihistamines. However, in reality, the symptoms of CU fluctuate, and patients may try taking their medications only as needed. A small number of studies have evaluated the efficacy of as-needed antihistamines, and found it to be inferior to regular administration.
●In a study of over 100 patients with CU, subjects were randomized to desloratadine 5 mg daily with placebo if needed for symptom control, or placebo daily with desloratadine as needed for symptom control . At four and eight weeks, there was a statistically significant difference in quality of life scores, in favor of regular desloratadine.
Thus, patients should be encouraged to take their prescribed regimen of H1 antihistamines regularly for maximal benefit.
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 [39-41]. 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 [13,42].
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 [1,42]. However, in a randomized, double-blind crossover study of 24 patients with CU, this approach (ie, 15 mg levocetirizine in the day, with 50 mg hydroxyzine at night) was compared with second-generation agents alone (10 mg levocetirizine twice daily) for periods of five days . Wheals and pruritus were reduced by both treatments and sleep quality was similar, however, daytime somnolence was statistically reduced in patients in the levocetirizine monotherapy group, but remained unchanged from baseline in the hydroxyzine group. The clinical relevance of this change is unknown and the assessment of daytime somnolence was not validated. In addition, given the long half-life of hydroxyzine, five days is likely an insufficient time to study its efficacy or tolerance. Furthermore, the initial starting dose of 50 mg of hydroxyzine is higher than is typically recommended. The American practice parameters recommend dose advancement of evening doses of first-generation antihistamines in those that have failed higher doses of second-generation antihistamines and/or H2 antihistamines and leukotriene-receptor antagonists.
H2 antihistamines — Patients whose symptoms are not adequately controlled on H1 antihistamines alone may experience modest improvement with the addition of an H2-antagonist antihistamine. A metaanalysis concluded that there was insufficient evidence upon which to make recommendations about the use of H2 antagonists in CU because the available studies were old and at risk for bias . Most of the studies demonstrating benefit used the combination of hydroxyzine and cimetidine [45-48]. These two drugs are metabolized by the same liver enzymes, and the benefit may be due to increased serum concentrations of one or both drugs, rather than a true synergistic effect [49,50]. The same effect was not observed with cimetidine and cetirizine , whereas the combination of ranitidine and famotidine, which do not affect liver enzymes, was shown to be helpful in other studies [52,53]. Thus, until more conclusive data are available, a trial of H2 antihistamines can be considered as additive therapy in patients whose symptoms do not respond adequately to H1 antihistamines alone. If not effective, the H2 antagonist should be discontinued.
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 [4,14,15]. 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 short-term control' 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 [56-58]. 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. 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.
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 [61,62]. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions".)
●Case reports described the use of montelukast to block acute urticaria secondary to NSAIDs [63,64], and another described a patient with NSAID-exacerbated CU, who responded to both zafirlukast and zileuton .
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:
●Montelukast (10 mg once daily), either alone or in combination with antihistamines, has demonstrated efficacy in randomized-controlled trials [46,60,65,68,69]. However, not all trials were positive [70,71], and one found montelukast to be less effective than desloratadine for 160 patients with relatively mild CU .
●Studies of zafirlukast are mixed as well. The combination of zafirlukast and cetirizine was shown to be superior to cetirizine alone in a randomized trial of patients with a positive autologous serum skin test (ASST), but not in patients with a negative ASST . This distinction was not confirmed in a separate open trial . A second randomized trial was negative, showing no statistical difference between zafirlukast and placebo in 52 CU patients .
●Zileuton has not been formally studied in the treatment of CU. The only published experience with pranlukast described two patients who experienced an exacerbation during therapy . No head-to-head studies have compared different leukotriene modifiers in the treatment of CU.
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 [77,78]. 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 [80-82]. 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 [80,83]. (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) [80,81,83-86]. 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 stepwise approach is advocated by the 2014 American guidelines  and is similar, although not identical, to guidelines from groups in the United Kingdom and Europe [4,9]. All doses mentioned are for adults, unless otherwise noted.
Systemic glucocorticoids for short-term control — 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) treatment with systemic glucocorticoids 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 or longer courses (eg, three weeks).
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 — Administer a second-generation antihistamine at standard therapeutic dose as initial therapy (adult dosing shown). (see 'H1 antihistamines' above):
●Cetirizine, 10 mg once daily
●Levocetirizine, 5 mg once daily
●Fexofenadine, 180 mg once daily
●Loratadine, 10 mg once daily
●Desloratadine, 5 mg once daily
Patients should also be counseled to avoid nonsteroidal antiinflammatory drugs (NSAIDs) and any other triggers relevant to that individual. (See 'Avoidance of exacerbating factors' above.)
Step 2 — If step 1 does not control symptoms adequately within one to two weeks, therapy may be increased by making one or more of the changes described below. There are no controlled studies comparing the efficacy of these different interventions:
●Advance the dose of the second-generation antihistamine. Dosing up to four times standard doses with desloratadine or levocetirizine has been shown to be helpful, although data for other agents are either lacking (cetirizine and loratadine) or do not support the use of higher doses (fexofenadine), as previously discussed. (See 'Dosing' above.)
●Add a different second-generation antihistamine. This can be particularly helpful for patients who find cetirizine sedating.
●Add an H2 antihistamine, such as one of the following (adult dosing shown):
•Ranitidine, 150 mg twice daily
•Famotidine, 20 mg twice daily
•Cimetidine, 400 mg twice daily
Studies of the efficacy of H2 antihistamines are discussed above. (See 'H2 antihistamines' above.)
●Add a leukotriene-receptor antagonist (adult dosing shown):
•Montelukast, 10 mg once daily
•Zafirlukast, 20 mg twice daily
●Add a first-generation H1 antihistamine at bedtime. (See 'Dosing of first-generation agents' above.)
•Hydroxyzine is commonly used in this setting, beginning (in adults) with 10 to 25 mg as a single dose before bed. In children up to 12 years of age, we start with a dose of 0.5 mg/kg. For children >12 years of age, 10 mg can be given initially.
•Doxepin (in adults), may be initiated at 10 or 25 mg given at bedtime. Doxepin is generally avoided in children <12 years of age due to limited clinical experience. (See 'Dosing of first-generation agents' above.)
•Cyproheptadine can be helpful for children, starting with a dose of 2 mg for children six years of age and younger, 4 mg for older children, and increasing to 8 mg before bed.
Step 3 — If the measures in step 2 do not result in adequate control of symptoms, the dose of the first-generation H1 antihistamine may be advanced gradually. It is also important to discontinue any medications that were added in step 2 that did not appear to benefit the patient.
●Hydroxyzine – Adults may be given 10 or 25 mg initially at bedtime, and increased in weekly increments as tolerated. Total daily doses of up to 100 to 200 mg may be given, divided into three or four doses in a 24-hour period. In children, the maximum single dose for children <6 years of age is 12.5 mg; for those 6 to 12 years of age: 25 mg, and for those >12 years of age: 100 mg. Children ≥6 years of age may be given up to 50 to 100 mg per day in divided doses.
●Doxepin – Doxepin (in adults), may be initiated at 10 or 25 mg and increasing in weekly increments to 100 to 150 mg, given once at bedtime or alternatively in divided doses throughout the day. Doxepin is generally avoided in children <12 years of age due to limited clinical experience.
Step 4 — Patients whose symptoms are not controlled by step 3 therapies, or who are intolerant of dose advancement of first-generation H1 antihistamines, are considered to have refractory CU, according to the 2014 American practice parameters . There are several therapies that may be considered for such patients, including omalizumab and various immunomodulatory and immunosuppressive agents. These are presented separately. (See "Chronic urticaria: Treatment of refractory symptoms".)
ASSESSING CONTROL OF SYMPTOMS — Questionnaires have been developed and validated for monitoring patients with urticaria, although the minimal important change remains to be defined .
Maintenance therapy — Many patients with chronic urticaria (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:
●Symptoms that were present for years, were very severe, or were difficult to control
●Concomitant physical urticarias, which tend to be longer lasting than simple CU
●Symptoms that are mostly controlled, but still present at a low level
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.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topic (see "Patient information: Hives (urticaria) (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Patients with chronic urticaria (CU) are often frustrated and anxious. Although no external cause is identified in most patients, numerous factors can aggravate the condition. Understanding these triggers and learning to avoid those that are relevant to the individual patient are critical components of successful management. Education should begin as soon as the diagnosis is made. (See 'Patient education' above and 'Information for patients' above.)
●We recommend H1 antihistamines as initial therapy for all patients with CU (Grade 1A). We recommend less sedating second-generation agents (eg, cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine), rather than first-generation agents (eg, hydroxyzine, diphenhydramine, chlorpheniramine, or mizolastine) (Grade 1B). (See 'H1 antihistamines' above and 'Step 1' above.)
●Systemic glucocorticoids should be reserved for short-term control of refractory symptoms. (See 'Systemic glucocorticoids for short-term control' above.)
●Up to one-half of patients may not achieve complete control of symptoms using standard doses of second-generation H1 antihistamines alone. For these patients, a stepwise approach to increasing therapy is appropriate. As doses are increased or different agents are introduced, it is important to discontinue any that have not been beneficial, so that medications do not accumulate. (See 'Stepwise approach to treatment' above.)
•Increasing the dose of the second-generation H1 antihistamine to two to four times the standard dose
•Adding a different second-generation antihistamine
•Adding an H2 antagonist
•Adding a leukotriene-receptor antagonist
•Adding a first-generation H1 antihistamine at bedtime
●For patients whose symptoms persist, we suggest increasing the dose of first-generation H1 antihistamine starting at low doses and gradually increasing (Grade 2C). The patient should be informed about sedation and anticholinergic side effects. (See 'Step 3' above.)
●Patients whose symptoms persist despite step 3 therapy, or who are intolerant of dose advancement of first-generation H1 antihistamines, are considered to have refractory disease. There are several therapies that may be considered for such patients, including omalizumab and various immunomodulatory and immunosuppressive agents. These are presented separately. (See 'Step 4' above and "Chronic urticaria: Treatment of refractory symptoms".)
●Once symptoms are controlled, we continue the drug(s) required for control for a minimum of one to three months before attempting to taper doses or discontinue medications. We extend this maintenance period even longer in patients whose disease was particularly difficult to suppress. (See 'Maintenance therapy' above.)
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