Version May 2024
INTRODUCTION — Chronic spontaneous urticaria (CSU) is defined by the presence of recurrent urticaria (also called hives or wheals), angioedema, or both, for a period of six weeks or longer [1]. Associated angioedema occurs in approximately one-half of patients with CSU and usually affects the lips, cheeks, periorbital areas of the face, extremities, and genitals [2,3].
This topic will discuss the initial and most commonly used therapies for CSU, as well as counseling of individuals with this disorder. Treatment of CSU that is refractory to standard management and the diagnosis, pathogenesis, and prognosis of CSU are presented separately. (See "Chronic spontaneous urticaria: Treatment of refractory symptoms" and "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)
Disorders involving isolated angioedema, urticarial vasculitis, and specific physical forms of CSU (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 (inducible) forms of urticaria" and "Cold urticaria".)
TERMINOLOGY — In this review, the term "chronic spontaneous urticaria" (CSU) refers to patients with isolated chronic idiopathic urticaria (CIU), as well as those with both urticaria and angioedema. There are several closely related terms that are used in the urticaria literature.
Chronic idiopathic urticaria and chronic spontaneous urticaria — The terms "chronic urticaria," "chronic idiopathic urticaria," and "chronic spontaneous urticaria" have been used interchangeably. "Chronic urticaria" is the most general term, although it has been used less in the literature over time because it is nonspecific and sometimes is applied to patients with various forms of inducible urticaria (ie, hives triggered by physical stimuli).
The term "chronic spontaneous urticaria" is preferred by the 2018 international guidelines [1]. CSU is not triggered by identifiable factors, and the inclusion of "spontaneous" specifically excludes physical urticaria syndromes or other inducible forms of urticaria.
Some studies distinguish between patients with and without positive autologous serum skin tests (ASSTs) or other laboratory indicators of an autoimmune process [4]. The terms "chronic autoimmune urticaria" or "autoantibody associated urticaria" are variably used. In this review, this distinction is mentioned only if a study found a difference between these two patient groups. The performance and interpretation of an ASST is reviewed separately. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history", section on 'Autoimmune theory'.)
Inducible urticaria — Urticaria can be triggered by physical stimuli, such as heat, cold, pressure applied to the skin, exercise, water, vibration, and sunlight. These disorders are referred to as physical urticaria or "inducible urticaria." A patient can have only CSU or only inducible urticaria or a combination of these disorders. Inducible urticaria syndromes are discussed in detail separately. (See "Physical (inducible) forms of urticaria".)
GUIDELINES — Treatment guidelines and practice parameters for the management of chronic urticaria have been published by professional allergy and dermatology groups worldwide [1,5-12]. In all cases, management begins with a careful clinical history to detect and minimize aggravating factors, followed by initial treatment with nonsedating, second-generation 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 (algorithm 1) [13]. The approach described here is consistent with the American practice parameters [5], although the recommendations of the international guidelines are noted also.
PATIENT EDUCATION — CSU 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 [14]. 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 [15].
Reassurance — Patients with CSU are often frustrated and fearful, and reassurance is an important component of successful management. There are several important concepts to relay to patients with CSU:
●CSU is rarely a sign of another underlying disease. When it is, the hives are usually accompanied by other systemic symptoms that are noticeable to the patient and/or the clinician.
●CSU is rarely permanent. Almost 50 percent of patients experience remission within one year [16]. However, for those in whom the disorder persists beyond one year, approximately 14 percent will still have symptoms beyond five years [17,18].
●CSU is not an allergic reaction, and it rarely puts the patient at any acute risk. This can be confusing to patients because acute urticaria and angioedema are manifestations of allergic reactions, which can be life-threatening. However, CSU is limited to the skin and mucosal tissues and does not involve other organ system as an allergic reaction can. Also, the angioedema that sometimes accompanies CSU tends to be milder and rarely compromises the airway.
●CSU symptoms can be adequately controlled in the majority of patients.
Goal of therapy — It is helpful to explain to patients that treatments for CSU are intended to reduce or eliminate symptoms for as long as the condition lasts, using one or more medications that do not cause significant side effects for that individual. The majority of available therapies have not been shown to cure CSU (although symptoms may be eliminated) or impact how long the underlying disorder persists. In most patients, CSU spontaneously resolves in two to five years, although it may recur or persist in a significant minority. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history", section on 'Natural history and prognosis'.)
Avoidance of exacerbating factors — CSU, by definition, has no external cause or triggering stimulus that explains all episodes. However, there are various factors that can exacerbate CSU. The evaluation and diagnosis of persistent urticaria are reviewed separately. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)
Once the diagnosis of CSU/angioedema has been established, the clinician should begin educating the patient about management, including avoidance of factors that can aggravate the condition (table 1):
●Physical factors – A substantial subset of patients with CSU 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 CSU 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 inducible urticaria (previously referred to as a physical urticarial syndrome), such as cholinergic urticaria or delayed-pressure urticaria. (See "Physical (inducible) forms of urticaria" and "Cold urticaria".)
●Anti-inflammatory medications – Nonsteroidal anti-inflammatory drugs (NSAIDs) worsen symptoms in many patients, and patients with CSU should be advised to avoid them, especially if there is any concern they may be exacerbating their urticaria [1]. After the ingestion of NSAIDs, patients may develop worsening of urticaria as quickly as 15 minutes or as delayed as 24 hours, although most patients report symptoms within 1 to 4 hours. In a study of 68 children with CSU and no history of previous reactions to NSAIDs, challenge-proven aspirin sensitivity was found in 10 to 24 percent, most often manifesting as lip angioedema [19]. In adults with CSU, 20 to 40 percent will experience worsening symptoms after ingesting NSAIDs [20,21]. Once the NSAID is stopped, most patients return to the baseline state in a few hours to two days, although some may continue to have increased symptoms for up to two weeks [22-24].
●Foods – Patients may notice that some foods seem to aggravate their symptoms, although food allergy is not a cause of CSU. The role of diet is reviewed below. (See 'Dietary manipulations (controversial)' below.)
STEPWISE APPROACH TO TREATMENT — A stepwise approach is advocated by all major guidelines [1,5]. The approach of the 2014 American practice parameters is similar, although not identical, to the 2018 international guideline and other guidelines (algorithm 1) [1,6,12,13]. All doses mentioned in this section are for adults, unless otherwise noted. More detailed information about dosing and efficacy for the agents discussed in this section is found below. (See 'Agents and efficacy studies' below.)
Step 1 — For initial therapy, administer a second-generation antihistamine at standard therapeutic dose (adult dosing shown) (see 'H1 antihistamines' below):
●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
Several other agents are available outside of the United States, including bilastine, ebastine, olopatadine, and rupatadine. (See "New-onset urticaria", section on 'Second-generation agents'.)
Patients should also be counseled to avoid nonsteroidal anti-inflammatory drugs and any other triggers relevant to that individual that can be avoided (table 1). (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 directly comparing these different interventions:
●Increase the dose of the second-generation antihistamine. This is the approach preferred by the 2018 international guidelines and the author [1]. In a systematic review, dosing up to four times standard doses with desloratadine or levocetirizine has been shown to be helpful with pruritus, although higher doses did not consistently reduce the number of wheals [25]. In addition, higher doses do not appear to be more effective for all antihistamines. (See 'Up-dosing of second-generation agents' below.)
A difference between the 2018 international guidelines and the 2014 American practice parameters is the preference of the international guidelines to use a single antihistamine for up-dosing [13]. In contrast, the American guidelines suggest combining two different second-generation antihistamines when up-dosing. Comparative studies have not been done, although a retrospective study suggested that more patients could be controlled by combining high doses (eg, fourfold doses) of two antihistamines compared with high doses of single antihistamines [26].
If up-dosing over the course of a few weeks does not control symptoms, international guidelines suggest omalizumab as a next step based on clearly demonstrated efficacy (algorithm 1) [1]. American guidelines suggest that the agents described below may also be tried and may be more practical in some settings. Omalizumab is discussed in detail separately. (See "Chronic spontaneous urticaria: Treatment of refractory symptoms", section on 'Omalizumab'.)
●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):
•Famotidine, 20 mg twice daily
•Cimetidine, 400 mg twice daily
Studies of the efficacy of H2 antihistamines are discussed below. (See 'H2 antihistamines' below.)
●Add a leukotriene-receptor antagonist (adult dosing shown):
•Montelukast, 10 mg once daily
•Zafirlukast, 20 mg twice daily
We usually add montelukast and allow at least four weeks to assess the impact. (See 'Leukotriene modifiers' below.)
●Add a first-generation H1 antihistamine at bedtime. (See 'Use of first-generation agents' below.)
•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 'Use of first-generation agents' below.)
•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. International guidelines do not advocate the use of sedating antihistamines, unless there are no other options [1]. The author finds these drugs convenient and helpful in some patients but avoids them in children and older adults, particularly because of the association between dementia and anticholinergic medications in that latter age group. (See "Risk factors for cognitive decline and dementia", section on 'Medications'.)
●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 increased 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 CSU [5]. There are several therapies that may be considered for such patients, including omalizumab, cyclosporine, and various anti-inflammatory and immunosuppressive agents. These are presented separately. (See "Chronic spontaneous urticaria: Treatment of refractory symptoms".)
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 [1]. 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. (See 'Systemic glucocorticoids' below.)
The optimal dose and duration of glucocorticoids used for CSU 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. The following are example regimens:
●We typically give prednisone at a dose of 40 mg daily (in the morning, with food) for two to three days. 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.
●Other experts suggest a prednisone dose of 35 to 40 mg initially, given once daily (with food) for five to seven days, followed by tapering by 5 mg every two to three days. Occasionally, patients require higher initial doses or longer courses (eg, three weeks).
Rebound worsening of urticaria may occur with tapering or discontinuation of systemic glucocorticoids. 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.
ASSESSING CONTROL OF SYMPTOMS — Control of symptoms should be assessed at each visit.
Validated questionnaires — Questionnaires have been developed and validated for monitoring patients with urticaria. We favor the four question Urticaria Control Test (UCT) for both accuracy and simplicity (table 2) [27]. Answers are assigned a value of 0 to 4, from most severe to least severe, such that a higher score indicates better symptom control. Scores can range from 0 to 16. A score of <12 on the UCT identifies patients with poorly controlled chronic urticaria, and a score of ≥12 identifies those with well-controlled symptoms. An improvement in 3 points is a minimal response [28]. A different tool, the Urticaria Activity Score (UAS7) is favored by the international guidelines, although it requires the patient to complete the questionnaire over seven days prior to evaluation [29].
Maintenance therapy — Many patients with CSU 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.
For the majority of patients, we generally recommend three months of good control prior to tapering therapies. The optimal duration of maintenance therapy in a variable disease like CSU has not been studied, and we would alter this suggestion for specific situations. For example, patients whose symptoms were easily and completely controlled with one or two agents may begin to taper therapy after one or two months of well-controlled symptoms. We extend the period of control further than three months 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 CSU
●Symptoms that are mostly controlled but still present at a low level
Discontinuing therapy — At any point in therapy, we 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 upon systemic glucocorticoids, we reduce the dose as quickly as possible once their urticaria has been stabilized.
WHEN TO REFER — Patients with CSU should be referred for specialist care in the following circumstances:
●An underlying disorder is suspected (refer to an allergist/immunologist or other appropriate specialist).
●Signs or symptoms suggest urticarial vasculitis, such as urticarial lesions that have a purpuric quality, leave residual ecchymotic markings, or are accompanied by fever or joint pain (refer to a specialist capable of performing skin biopsies).
●Symptoms are not controlled with steps 1, 2, or 3 or the patient is requiring repeated or prolonged treatment with glucocorticoids (refer to an allergist/immunologist or dermatologist). (See "Chronic spontaneous urticaria: Treatment of refractory symptoms".)
AGENTS AND EFFICACY STUDIES — Most patients with CSU 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, anti-inflammatory, or steroid-sparing agents.
The different medications used in the management of CSU and studies of efficacy are discussed in this section.
H1 antihistamines — H1 antihistamines are the cornerstone of pharmacotherapy for CSU and control symptoms to at least some degree in most patients [6,30-33]. Patients show variable responsiveness to antihistamines. Eosinopenia (ie, an absolute eosinophil count of <50 cells/microL) with or without basopenia was found in one large study to be a marker of more severe disease and poor response to second generation antihistamines [34]. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history", section on 'Laboratory evaluation'.)
Several randomized, placebo-controlled trials have demonstrated that both the first- and second-generation H1 antihistamines reduce the major symptoms of CSU (ie, pruritus, wheal [hive] formation, and disruption of sleep and daily activities) [2,35-41]. A systematic review concluded that nonsedating antihistamines improve quality of life for patients with CSU [42]. 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 [32,43-45].
The newer second-generation agents (eg, cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine) are preferred because they are 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) [46,47]. A systematic review of randomized trials concluded that there was insufficient evidence to make recommendations for any specific second-generation agent over another when each was used at approved doses [48]. In the absence of additional data, it is the author's practice to initiate therapy with cetirizine in most patients. Of note, most patients require higher than approved doses, and the data addressing "up-dosing" are reviewed below. (See 'Up-dosing of second-generation agents' below.)
Rupatadine is a newer second-generation antihistamine (not available in the United States) that also has antiplatelet-activating factor effects. Randomized trials comparing levocetirizine and rupatadine have shown that rupatadine is more effective and better tolerated [49,50]. Olopatadine (not available in the United States) is also promising [51].
Up-dosing of second-generation agents — Doses of second-generation antihistamines as high as four times the standard dose are advocated in American and most other guidelines [1,6,32,52,53]. The effectiveness of this approach varies between studies. One study estimated overall efficacy of the second-generation agents and found that the standard dose of second-generation antihistamines controlled symptoms in only 18 percent of patients with CSU, whereas doses as high as four times the standard dose achieved control of symptoms in 74 percent [54]. Consistent with this, a systematic review found that higher doses were helpful in controlling pruritus, although not wheal number, in approximately 63 percent of patient who did not respond adequately to standard dose therapy [25].
Not all agents are more effective at higher doses. The evidence for higher doses is strongest for levocetirizine and desloratadine, mixed for cetirizine, and weak for fexofenadine [25,35,44,55,56]. The author most commonly starts with cetirizine (10 mg twice daily) or levocetirizine (5 mg twice daily) in patients who have already failed once daily. If symptoms continue, doses can be increased up to four times daily at one- to two-week intervals. One difference between the 2018 international guidelines and recommendations from American experts is that the international guidelines discourage use of more than one different nonsedating antihistamine, while this is relatively common practice in the United States, and studies comparing the two approaches are lacking [1].
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 CSU, subjects were assigned to either levocetirizine or desloratadine [44]. 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 being symptom-free for the last three days of the interval), 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 above), 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. Another open-label study of levocetirizine reported similar results [56].
●Studies of cetirizine up-dosing for CSU are conflicting and methodologically less rigorous, and information about sedation at higher doses is lacking. A small observational study evaluated 21 CSU patients with inadequate responses after one to two weeks of cetirizine 10 mg daily [57]. Cetirizine was increased to 10 mg twice daily for an additional one to two weeks, and then subjects were 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 suggests that the higher dose is 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 [55].
●Fexofenadine has not been shown to be more effective at doses higher than 60 mg twice daily. 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 [35]. 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 [58]. A caveat of these studies is that the patients enrolled were not considered refractory to recommended doses of second-generation antihistamines.
●An open-label study of 29 adults with CSU refractory to other antihistamines evaluated up-dosing of bilastine (not available in the United States) at 20, 40, and 80 mg daily [59]. The dose of bilastine was doubled every two weeks, and at each step, significantly more patients achieved control of their symptoms. However, at the 80 mg dose, 11 patients still had moderate disease activity, consistent with studies of other second-generation antihistamines.
Importance of a regular regimen — 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 CSU 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 CSU, subjects were randomized to desloratadine 5 mg daily with placebo if needed for symptom control or to placebo daily with desloratadine as needed for symptom control [60]. At four and eight weeks, there was a statistically significant difference in quality of life scores in favor of regular desloratadine.
●In a double-blind trial of 29 patients with CSU, a single dose of desloratadine (either 5 or 20 mg) had relatively little effect on existing wheals [61].
Thus, patients should be encouraged to take their prescribed regimen of H1 antihistamines regularly for maximal benefit.
Use of first-generation agents — The use of first-generation antihistamines is suggested by the American practice parameters as an option for adults when second-generation antihistamines do not provide adequate control, although not by international guidelines [12]. The first-generation antihistamines are similarly effective compared with newer second-generation antihistamines but with more adverse effects.
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: Management and prevention", section on 'Over-the-counter medications'.)
The primary concern with first-generation agents is sedation and performance impairment, and clinicians should inform patients specifically about this side effect [62]. First-generation antihistamines, including hydroxyzine, doxepin, and diphenhydramine, can enhance the QTc-prolonging effect when combined with other QTc-prolonging agents (eg, antiarrhythmic drugs, macrolides, fluoroquinolones) (table 3). Therefore, combinations of such drugs should be avoided (when possible), particularly in patients at elevated risk (eg, those with congenital long QT syndrome, electrolyte abnormalities, recent myocardial infarction, or uncompensated heart failure). High doses of doxepin are potentially cardiotoxic and should be avoided in susceptible individuals with heart disease. It is the author's approach to use extra caution in older adults chronically taking first-generation antihistamines at doses greater than 50 mg daily and to obtain a baseline electrocardiogram in such individuals. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)
Studies of first-generation antihistamines in adults at usual doses have shown tolerance to performance impairment after three to five days of therapy [63-65]. Studies in patients with CSU given higher doses are lacking, although many patients with CSU 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 [66,67].
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 [30,67]. However, in a randomized, double-blind crossover study of 24 patients with CSU, 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 [68]. 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 patients who have failed higher doses of second-generation antihistamines and/or H2 antihistamines and leukotriene-receptor antagonists, while the international guidelines do not [1,5].
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, although data are conflicting, and international guidelines do not include H2 antihistamines as an option [1,12]. If not effective, the H2 antagonist should be discontinued.
A meta-analysis concluded that there was insufficient evidence upon which to make recommendations about the use of H2 antihistamines in CSU because the available studies were old and at risk for bias [69]. Most of the studies demonstrating benefit used the combination of hydroxyzine and cimetidine [70-73]. 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 [74,75]. However, the combined use of ranitidine (no longer available in the US) and terfenadine (no longer available), which are not metabolized by the same liver enzymes, was shown to be helpful in another study [76]. In contrast, improved symptom control was not observed by combining cetirizine with either cimetidine [77] or ranitidine (no longer available in the US) [78]. 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, but if no improvement is noted within two to four weeks, other therapies should be considered.
Systemic glucocorticoids — Systemic (usually oral) glucocorticoids are effective in controlling symptoms in most patients with CSU. 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. Further, there is no evidence that glucocorticoids have a disease-modifying effect. 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 [79]. We view glucocorticoids as rescue therapy that should be used to attain temporary control of severe symptoms. (See "Major adverse effects of systemic glucocorticoids".)
Most guidelines suggest that oral glucocorticoids be considered as a temporary additive therapy for patients with symptoms refractory to one or more antihistamines at full dose, for the purpose of gaining control of severe symptoms [1,6,31,32]. Optimal dosing has not been formally studied, although our approach is described above. 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' above.)
Leukotriene modifiers — Leukotrienes are believed to be 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 [80-82]. Antileukotriene medications include the leukotriene-receptor antagonists, montelukast and zafirlukast, as well as the 5-lipoxygenase inhibitor, zileuton. Amongst these agents, montelukast is the most commonly used for CSU. We do not recommend the use of zileuton in CSU given the absence of controlled studies, higher cost, need for laboratory monitoring, and potential adverse effects (eg, liver toxicity). The 2018 international guidelines excluded leukotriene modifiers from the stepwise approach based on limited evidence of efficacy [1].
In unselected populations of patients with CSU, the data in support of leukotriene modifiers are relatively weak:
●Montelukast (10 mg once daily), either alone or in combination with antihistamines, has demonstrated efficacy in randomized-controlled trials [71,83-86]. However, not all trials were positive [87,88], and one found montelukast to be less effective than desloratadine for 160 patients with relatively mild CSU [89].
●Studies of zafirlukast are mixed as well. In a double-blind, placebo-controlled, crossover study, 52 patients with CSU were randomized to 20 mg zafirlukast twice daily or placebo for 12 weeks [90]. There was no statistical difference between zafirlukast and placebo. In another randomized trial, the combination of zafirlukast and cetirizine was superior to cetirizine alone in patients with a positive autologous serum skin test (ASST) but not in patients with a negative ASST [91].
Patients with CSU that is exacerbated by ingestion of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) may respond more predictably to antileukotriene medications, since abnormal leukotriene regulation is believed to be important in the pathogenesis of this type of urticaria [92,93]. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions".)
●Case reports described the use of montelukast to block acute urticaria secondary to NSAIDs [94,95], and another report described a patient with NSAID-exacerbated CSU who responded to both zafirlukast and zileuton [92].
●Two small randomized trials found montelukast to be superior to cetirizine and placebo in patients with NSAID-exacerbated CSU [83,84].
Topical agents — Routine use of topical agents for CSU is discouraged, as they rarely result in sustained improvement. Some of these agents include emollients that contain menthol, phenol, or pramoxine, which are 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 [96].
OTHER THERAPIES
Vitamin D — A small number of studies have examined the impact of vitamin D supplementation on chronic urticaria [97-100]. In a prospective, double-blinded study, 42 subjects with CSU were randomized to high (4000 international units daily) or low (600 international units daily) vitamin D3 supplementation for 12 weeks and also received a standardized three-drug regimen (cetirizine, ranitidine [no longer available in the US], and montelukast) and a written action plan. Three-drug therapy decreased total urticaria symptom severity (USS) scores by 33 percent in the first week. There was a further significant decrease (40 percent) in total USS scores in the high but not low vitamin D3 treatment group by week 12. Sleep quality and pruritus scores improved in the high-dose group. However, serum 25-hydroxyvitamin D levels did not correlate with USS scores, and there was no reduction in medication use between the high and low supplementation groups. Therefore, the clinical significance of vitamin D supplementation remains unclear, although it may be an option for patients who wish to minimize other medications or prefer nontraditional therapies.
Dietary manipulations (controversial) — We do not routinely advise CSU patients to modify their diets for the purpose of controlling CSU symptoms, because adherence to the proposed diets is difficult, benefit has not been demonstrated in controlled trials, and dietary modifications are not supported by most guidelines [5]. A 2019 systematic review concluded that the quality of the evidence in support of dietary interventions including pseudoallergen-free and low histamine diets for CSU was low [101]. The most recent international guidelines state these diets are "controversial and as yet unproven" [1]. However, if a patient is very motivated to try these diets, we do not object. A pseudoallergen-free diet avoids naturally occurring aromatic compounds in certain foods such as many fruits and vegetables, seafood, and artificial preservatives (table 4). It is recommended that a trial of a minimum of two to three weeks is required to see benefit.
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 (Ig)E-mediated food reactions are not a cause of CSU, and testing for food allergy is not necessary [5]. (See "Chronic spontaneous 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'.)
SPECIAL POPULATIONS
Children — CSU can occur in infants and children, and the approach to therapy is the same as that in adults, although avoidance of first-generation, sedating antihistamines is particularly emphasized [1]. Nonsedating antihistamines that have been shown to be safe in children include cetirizine, levocetirizine, loratadine, desloratadine, fexofenadine, and outside the United States, bilastine and rupatadine [1,102-108]. Most are available in orally-dissolving or chewable tablets or syrups for ease of administration. While up-dosing second-generation antihistamines has been recommended in guidelines for children with CSU, the safety and efficacy of this approach has not been well-studied [109].
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 second-generation H1 antihistamines alone, with occasional short courses of oral glucocorticoids for severe flares. Among second-generation antihistamines, cetirizine (10 mg once daily), levocetirizine (5 mg once daily), fexofenadine (180 mg once daily) and loratadine (10 mg once daily) may be considered the antihistamines of choice in pregnancy [110-112]. No studies have evaluated the safety or efficacy of high-dose antihistamines in pregnancy. We have used twofold higher doses of single agents or two separate antihistamines at approved doses after a careful discussion with the patient about these issues. Omalizumab has been used safely for refractory CSU in pregnant women, as discussed separately. (See "Chronic spontaneous urticaria: Treatment of refractory symptoms", section on 'Safety'.)
Additional information on the safety of antihistamines, leukotriene-modifying drugs, and other agents in pregnancy and lactation is discussed separately. (See "Recognition and management of allergic disease during pregnancy".)
Patients with concomitant hypertension — For patients with concomitant hypertension, dihydropyridine calcium channel blockers may help with both disorders. These drugs appear to reduce the proliferation of stimulated T lymphocytes and inhibit mast cell-mediator release [113,114]. A small, randomized-controlled crossover trial of 10 patients with chronic idiopathic urticaria treated with nifedipine (up to 20 mg three times daily) demonstrated benefit in seven patients, with mild adverse effects [115]. 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 duration, as discussed separately. (See "Chronic spontaneous 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 CSU at a greater than expected frequency [116-118]. However, the patient's thyroid status does not necessarily correlate with the presence of urticaria, and patients with CSU/angioedema and evidence of thyroid autoimmunity may be euthyroid, hypothyroid, or hyperthyroid [116,119]. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)
Patients with thyroid autoantibodies and laboratory evidence of clinical hypothyroidism may benefit from thyroid-hormone replacement [120]. In contrast, the treatment of euthyroid patients with CSU is controversial. There are several reports of apparent success treating euthyroid patients with thyroid hormone at doses that suppress the level of thyroid-stimulating hormone [116,117,119,121-123]. A proposed mechanism of action is reduction in complement activation by the complement controller domain of thyroperoxidase [124]. 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 [125].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Urticaria and angioedema (excluding hereditary angioedema)".)
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 education" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Hives (The Basics)" and "Patient education: Chronic hives (The Basics)")
●Beyond the Basics topic (see "Patient education: Hives (urticaria) (Beyond the Basics)")
PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Chronic urticaria".)
SUMMARY AND RECOMMENDATIONS
●Patient support and education – Patients with chronic spontaneous urticaria (CSU) are often frustrated and anxious. Although no external cause is identified in most patients, numerous factors can aggravate the condition (table 1). 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.)
●Minimally-sedating antihistamines – We recommend H1 antihistamines as initial therapy for all patients with CSU (Grade 1A). We recommend less-sedating, second-generation agents (eg, cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine), rather than older first-generation agents (eg, hydroxyzine, diphenhydramine, chlorpheniramine, or mizolastine) (Grade 1B). (See 'H1 antihistamines' above and 'Step 1' above.)
●Increase therapy for uncontrolled symptoms – 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. There are minor differences in the stepwise approaches advocated by American and European expert panels (algorithm 1). (See 'Stepwise approach to treatment' above.)
●Next steps – For patients whose symptoms persist, we suggest one or more of the following interventions, which have not been compared in head-to-head studies (Grade 2C) (see 'Step 2' above):
•Increasing the dose of the second-generation H1 antihistamine to up to four times the standard dose (after which, international guidelines suggest adding omalizumab)
•Adding a different second-generation antihistamine
•Adding an H2 antagonist
•Adding a leukotriene-receptor antagonist
•Adding a first-generation H1 antihistamine at bedtime
●Use of sedating antihistamines – For patients whose symptoms persist, we suggest increasing the dose of first-generation H1 antihistamine gradually (Grade 2C). The patient should be informed about sedation and anticholinergic side effects. (See 'Step 3' above.)
●Systemic glucocorticoids for short-term control – Systemic glucocorticoids should be reserved for short-term control of refractory symptoms. (See 'Systemic glucocorticoids for short-term control' above.)
●Refractory disease – 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 anti-inflammatory and immunosuppressive agents. These are discussed separately. (See 'Step 4' above and "Chronic spontaneous urticaria: Treatment of refractory symptoms".)
●Maintenance therapy – 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 symptoms were particularly difficult to suppress. (See 'Maintenance therapy' above.)
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