INTRODUCTION — Physical urticarias are disorders in which urticaria (ie, hives or wheals) are induced by environmental stimuli, such as heat, cold, pressure applied to the skin, exercise, water, vibration, and sunlight. The term "inducible urticaria" was preferred by a 2018 international guideline . These disorders probably result from heightened sensitivity by the mast cell to environmental conditions, although the exact pathogenesis is unknown.
An urticarial lesion is an intensely pruritic, circumscribed, raised, erythematous plaque, which can range in diameter from a few millimeters to many centimeters (picture 1 and picture 2). Urticaria may enlarge, sometimes developing central pallor, and coalesce with other adjacent lesions. They usually appear in crops and are typically short-lived, expanding and then resolving over a few hours without leaving residual marks on the skin (unless there is trauma from scratching).
Inducible urticarias, except cold urticaria, will be discussed in this topic review. Other disorders of acute and chronic spontaneous urticaria and cold urticaria are reviewed separately. (See "New-onset urticaria" and "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history" and "Chronic spontaneous urticaria: Standard management and patient education" and "Cold urticaria".)
GENERAL POINTS ABOUT INDUCIBLE URTICARIAS — Before discussing individual syndromes, it is helpful to review some observations about the inducible urticaria disorders as a group.
Inducible urticarias are considered subtypes of chronic urticaria. In some patients, a specific physical stimulus is the only trigger for hives, whereas in others, a physical stimulus is an identifiable factor in a case of otherwise idiopathic chronic urticaria (also called chronic spontaneous urticaria). A minority of patients have hives triggered by multiple physical stimuli.
Prevalence — The inducible urticarias, considered as a group, are present in a subset of patients with chronic urticaria, which afflicts approximately 1 percent of adults. Inducible urticarias are present in 20 to 30 percent of adults with chronic urticaria and also occur in children, although there are fewer reports about this population . The overall prevalence in the general population is not well-defined, and many cases may be mild and easily managed in the primary care setting. In contrast, most published reports are based upon patient populations referred to specialty centers, and so they may overestimate the severity and persistence of these disorders.
Classification — There are differences among experts concerning the best manner of classifying the inducible urticarias. Guidelines for classification and diagnosis have been published by an international expert panel . The material in this topic review is similar, although not identical.
Variations in clinical presentation and severity — Inducible urticarias vary widely in severity. The symptoms of each syndrome can range from mild to disabling, with some patients experiencing potentially dangerous systemic symptoms.
Testing — Specific testing procedures are presented in the discussions of each disorder below and summarized in the table (table 1) . However, there are some general points to consider in performing challenge procedures for inducible urticarias.
Precautions — Physical challenges are not always needed for diagnosis, although they are sometimes invaluable in clarifying or confirming the diagnosis. These challenges are usually performed by allergy specialists with training in the management of the systemic allergic reactions that could conceivably result in anaphylaxis. Proper access to the staff and equipment necessary to treat a potentially life-threatening allergic reaction is essential. This is especially true if the patient has experienced systemic symptoms in the past (eg, bronchospasm or hypotension).
During these challenges, physical stimuli are applied to the skin for a specified amount of time (usually a few minutes) and then removed. Urticaria typically develops after removal of the stimulus. Leaving the stimulus in contact with the skin until urticaria or angioedema actually appear can result in excessive exposure and systemic symptoms. Similarly, exposure time may need to be reduced in patients who describe unusual levels of sensitivity.
When to refer — Patients suspected of having a syndrome of inducible urticaria should be referred to an allergy or dermatology specialist with experience in these disorders in the following situations:
●The diagnosis is not apparent.
●The condition does not respond adequately to initial therapy.
Referral is usually appropriate if a challenge procedure is being considered. Patients with past systemic reactions/anaphylaxis should be referred to allergists specifically because there is potential risk involved in challenging such patients and because they can educate patients about how to manage possible recurrent anaphylaxis, including use of an epinephrine autoinjector. (See "Long-term management of patients with anaphylaxis", section on 'Preparing the patient to treat possible recurrences'.)
OVERVIEW OF TREATMENT APPROACH — The treatment of inducible urticarias should be approached in a stepwise manner. Avoidance of the physical stimuli that induce symptoms should always be considered initially, although complete avoidance may not be possible or practical.
Pharmacologic therapy is often required but variably successful. Certain types of inducible urticarias (eg, dermographism) are responsive to antihistamines, while other forms (eg, local heat urticaria) are typically resistant. However, therapy must be individualized in each case, often by trial and error. In addition, most studies of therapy in these disorders were performed with first-generation, sedating H1 antihistamines, and the relative effectiveness of the newer second-generation drugs has not been evaluated.
Antihistamines — In patients with an inducible urticaria disorder who cannot avoid the stimulus, a trial of antihistamines is warranted. The approach outlined here is opinion-based, since trials comparing different regimens are lacking.
●Second-generation H1 antihistamine – We usually begin with a second-generation H1 antihistamine at standard doses but quickly increase to double the standard dose (eg, cetirizine 10 mg twice daily, fexofenadine 180 mg twice daily, or loratadine 10 mg twice daily), if needed. In chronic spontaneous urticaria, doses up to four times the standard have been shown to be safe and effective, and this can be applied to more difficult cases of inducible urticaria also .
●H2 antihistamine – If symptoms are not controlled, we add an H2 antihistamine at standard dose (eg, famotidine 20 mg twice daily). If there is no detectable improvement, the H2 antihistamine can be discontinued.
●Hydroxyzine – Hydroxyzine may be dosed once at bedtime or alternatively in divided doses throughout the day. Adults may be given 10 or 25 mg initially at bedtime and increased in weekly increments as tolerated, typically up to a maximum of 100 mg as a single dose before bedtime. Alternatively, total daily doses of up to 100 to 200 mg may be given, divided into three or four doses in a 24-hour period. Sedating antihistamines may be used cautiously in children. Children ≥6 years of age may be given up to 50 to 100 mg per day in divided doses.
●Doxepin – Doxepin is a tricyclic antidepressant with antihistaminergic properties at low doses. In adults, doxepin may be initiated at 10 or 25 mg and increased in weekly increments up 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. (See "Chronic spontaneous urticaria: Standard management and patient education", section on 'H1 antihistamines'.)
Symptoms refractory to antihistamines — The US Food and Drug Administration (FDA) approval of the monoclonal antibody omalizumab in 2014 for patients with chronic idiopathic urticaria refractory to antihistamines has given providers a new option for disease management. Patients who fail to respond to avoidance of the triggering stimulus combined with safe and practical doses of a second-generation antihistamine should be considered candidates for chronic therapy with omalizumab. A number of case series or case reports have demonstrated that omalizumab is safe and effective in patients with a wide variety of inducible urticarias. The most impressive data have been found for patients with dermatographism, cold urticaria, delayed-pressure urticaria, and solar urticarias . Data are more limited for other types of inducible urticarias, but omalizumab should remain an option for these patients. Nonresponders sometimes occur despite the therapy. Other therapies for refractory disease, depending upon the specific disorder, include glucocorticoids, phototherapy, physical desensitization protocols, and immunomodulatory agents (eg, cyclosporine, dapsone).
Case reports for each type of inducible urticaria are discussed in the appropriate sections below. It is the practice of the authors to use omalizumab for inducible urticaria in patients who have failed to respond adequately to a trial of avoidance of the offending trigger combined with a safe and practical dose of a second-generation antihistamine (ie, typically four times the standard dose). Newer biologic agents may offer additional options in the near future. Dupilumab showed effectiveness in a case report for a patient with cholinergic urticaria .
Oral glucocorticoids may be used for short-term treatment and are usually very effective. This is most commonly appropriate for the persistent symptoms of delayed-pressure urticaria, as the urticarial lesions of many of the other types of inducible urticarias are short-lived. We typically continue antihistamines and begin glucocorticoid therapy with prednisone, 0.5 to 1.0 mg/kg daily. Symptoms usually improve within days. The dose can then be tapered gradually over two to four weeks to discontinuation or at least to <10 mg per day. If the prednisone cannot be reduced to <10 mg per day after two to four weeks or stopped entirely within two to three months, then an alternate, steroid-sparing agent should be considered, as the long-term side effects of glucocorticoids make chronic therapy undesirable. (See "Major side effects of systemic glucocorticoids".)
Agents that have been found to be useful for particular inducible urticaria syndromes are discussed in the sections below, as are alternate therapies for refractory disease. The treatment of chronic spontaneous urticaria is reviewed in detail separately. (See "Chronic spontaneous urticaria: Standard management and patient education" and "Chronic spontaneous urticaria: Treatment of refractory symptoms".)
DERMOGRAPHISM — Dermographism (also called dermatographism, urticaria factitia, or dermographic urticaria) literally means to "write on the skin." Patients with this condition develop the rapid onset of a wheal-and-flare reaction after firm stroking, scratching, or the application of pressure to the skin. Dermographism is the most common of the inducible urticarias and is often an incidental finding in the evaluation of other skin conditions, most commonly atopic dermatitis, chronic spontaneous urticaria, and the other inducible urticarias discussed in this topic.
●Simple dermographism is the more common disorder, in which raised urticarial welts form on the skin with scratching or other stroking, but the skin is not pruritic.
●Symptomatic dermographism is less common. In this disorder, the affected skin shows urticarial welts and is pruritic.
Epidemiology — Simple dermographism is thought to occur in approximately 2 to 5 percent of the general population [7,8]. The symptomatic forms of dermographism are much less common and usually occur sporadically, although there is a single case report of familial dermographism .
Clinical features — In simple dermographism, a wheal is provoked by stroking, scratching, or rubbing the skin. The wheal typically appears within 6 to 7 minutes and begins to fade 15 to 30 minutes later . Symptomatic dermographism is only slightly different, with lesions appearing in less than 5 minutes and lasting 30 minutes . In addition to classic wheals, variants of symptomatic dermographism have been described in which the reactions are follicular  or inflamed and swollen (red dermographism) .
Although a purposeful stroking of the skin is the most common way to elicit symptoms, patients often are unaware of the inciting action. Occasionally, idiopathic pruritus or pruritus caused by dry skin can be the event that elicits scratching and subsequent dermographism. In this setting, the wheals are typically linear. Simple actions, such as scratching, leaning against a solid object, or irritation from clothes or bed sheets, may provoke whealing. In one case series, dermographism could be exacerbated by hot water, emotion, exercise, or cold exposure .
Dermographism is typically idiopathic and begins without a clear inciting event. However, inflammatory perturbations may occasionally precede onset, as cases have been described in which symptomatic dermographism appeared to be triggered by infections with bacteria, fungi, viruses, and scabies [14,15] or after receiving penicillin  or famotidine .
Pathogenesis — The cause of dermographism is unknown. The release of vasoactive mediators from cutaneous mast cells is assumed to be involved, and elevated levels of serum histamine have been demonstrated after a whealing episode . Experiments in which serum from a dermographic patient injected intradermally into a monkey transferred dermographism suggest that the reaction may be immunoglobulin (Ig)E-mediated, although no allergen has been identified [18,19].
Diagnostic testing — In simple dermographism, a wheal is provoked by stroking the skin with a clean, firm object (table 1). The wheal typically appears within 6 to 7 minutes and begins to fade 15 to 30 minutes later . Special testing devices are available [3,20]. The patient should refrain from taking antihistamines for several days before the test.
Treatment — Simple dermographism that is nonpruritic requires no therapy, and treatment involves avoidance of inciting triggers. If the skin appears dry, emollients (such as hydrated petrolatum applied daily immediately after bathing) can be helpful.
Therapies for symptomatic dermatographism:
●H1 antihistamines have been shown to be effective for treatment of pruritus and reduction of whealing and are the initial drug of choice. Both first-generation antihistamines, such as hydroxyzine, and second-generation H1 antihistamines, such as cetirizine, have demonstrated benefit, although studies comparing different antihistamine regimens are lacking [12,21-23].
It is the authors' practice to initiate therapy for symptomatic dermographism with second-generation H1 antihistamines as described above. (See 'Overview of treatment approach' above.)
●The addition of an H2 antihistamine was beneficial in several studies [22,24,25], although not all concluded that there was an additive effect . A trial of combination therapy with an H1 and H2 antihistamine is warranted if the response to H1 antihistamines alone is inadequate.
●Some patients report that sun exposure improves the condition, and one uncontrolled study of 43 patients reported that 39 improved or cleared with ultraviolet B light treatment . Such aggressive therapy could be considered in a patient refractory to standard medications and with a severe decrease in quality of life (eg, poor sleep, poor performance at work or school, negative effect on social life).
DELAYED-PRESSURE URTICARIA/ANGIOEDEMA — Delayed-pressure urticaria/angioedema (which is sometimes classified as a delayed form of symptomatic dermographism) presents most commonly as an erythematous swelling of the skin that develops four to six hours after sustained pressure has been applied to the area.
Clinical manifestations — The leading presentation is erythematous swelling of the skin 4 to 6 hours after the application of pressure, although the time to onset of symptoms may be as little as 30 minutes or as long as 12 hours. Less often, patients develop urticaria with prominent swelling. The amount of pressure that is needed to induce symptoms varies among different individuals. Patients often describe burning and pain instead of, or in addition to, pruritus, and the swelling can last several hours to several days [3,7]. There may be accompanying arthralgias .
Activities that typically induce symptoms in patients with delayed-pressure angioedema include wearing tight clothing (affecting areas of constriction), sitting for prolonged periods of time on a hard surface (affecting the buttocks), an extended period of walking (affecting the soles and feet), or carrying heavy bags of groceries (affecting the palms and hands). Some patients will wake up with facial swelling on the side of the face that was compressed against the pillow.
Diagnosis — Delayed-pressure urticaria/angioedema can often be accurately diagnosed based upon historical features alone. Devices called dermographometers have been used in research protocols in the past but are not widely available [28,29]. Diagnostic maneuvers are not standardized, and the amount of weight used varies, but one approach is to attach a sling to a 10-pound weight and place this over the patient's arm for 20 minutes . Alternatively, a 5-kg rod may be laid across the patient's forearms for 20 minutes . Once the weight is removed, the patient is instructed to observe the compressed skin for symptoms over the next 24 hours (table 1). The delayed appearance of erythematous palpable swelling is a positive result. The patient should refrain from taking antihistamines for several days before the test.
Treatment — Delayed-pressure urticaria/angioedema can be challenging to treat, and symptoms often do not respond to antihistamines alone. Antileukotriene agents have also shown utility [31-33].
In a randomized trial of 36 patients with delayed-pressure urticaria confirmed by challenge with a dermographometer (18 of whom had concomitant chronic spontaneous urticaria), patients were assigned to one of three treatment groups :
●Oral desloratadine (5 mg once daily) plus oral placebo
●Oral placebo alone
Subjects were rechallenged after two weeks of therapy. Patients in both active treatment groups showed a significant reduction in the mean diameter of the induced wheals compared with placebo, and patients in the group receiving montelukast were significantly better than those receiving desloratadine alone, with fewer episodes and reduced symptoms. The use of other antihistamines in combination with montelukast has not been studied, although different agents are probably also effective.
Other agents that have been used with some success to manage this disorder include montelukast, dapsone, chloroquine, sulfasalazine, intravenous immune globulin, nonsteroidal anti-inflammatory drugs, tumor necrosis factor inhibitors, and omalizumab [31,36-42].
CHOLINERGIC URTICARIA — Cholinergic urticaria (sometimes called generalized heat urticaria) describes hives with a characteristic appearance that are precipitated by active or passive heating of the body, exercise, strong emotions, and bathing in hot water . Some classification systems do not include cholinergic urticaria with other forms of inducible urticaria, because the trigger is internal rather than environmental .
Epidemiology — Cholinergic urticaria is believed to account for approximately 30 percent of all cases of inducible urticaria and approximately 5 percent of all cases of chronic spontaneous urticaria . Cholinergic urticaria typically has its onset during the second or third decade of life [45-47]. Whereas one study noted a predominance in male patients , others have found that both sexes are affected equally [46,47]. Familial cases are rare but have been reported (in which all affected individuals were male) .
Clinical features — The classic initial appearance of cholinergic urticaria is that of numerous, small (1 to 3 mm) punctate wheals surrounded by large flares (picture 5). Many patients note a tingling, itching, or burning sensation of the skin before the appearance of the hives . As the response progresses, the flares may coalesce to form large areas of erythema. The wheals typically begin on the trunk and neck and spread distally to involve the face and extremities, although lesions may begin anywhere on the body. Uncommonly, cholinergic urticaria may progress to include systemic symptoms, such as hypotension, angioedema, and bronchospasm [45,49-51]. In a series of 19 patients with cholinergic urticaria associated with anaphylaxis, the majority of patients were young women. Patients experienced a mean of nine episodes per year, triggered most consistently by high ambient temperatures, strenuous exertion, and stress .
Any trigger that results in an elevation of core body temperature may provoke the onset of cholinergic urticaria. Exercise and hot, humid environments are some of the most common triggers. Other typical inciting factors for cholinergic urticaria include hot baths or showers, strong emotional feelings, and ingestion of spicy or hot foods [45,46]. In one study, a patient with pre-existing cholinergic urticaria experienced a flare of his condition while undergoing dialysis treatments . A decrease in the patient's dialysate temperature by 1.5°C (2.7°F) led to resolution of his symptoms, and rechallenge with fluid at a higher temperature reproduced his urticaria.
Theories of pathogenesis — As with many of the other inducible urticarias, a variety of pathogenetic mechanisms have been postulated in cholinergic urticaria, and there may be different mechanisms at work in different patients. Elevated levels of histamine have been detected in the serum during an attack . The precise trigger for the onset of urticaria is not clear.
●One theory of pathogenesis proposed that urticaria in this condition was caused by the cholinergic nervous system . In some patients, the injection of methacholine intradermally induces urticaria, which can be reversed by administration of atropine [45,53,54]. Patients with cholinergic urticaria have been shown to have an increased number of muscarinic receptors on cutaneous mast cells in areas that demonstrate hives .
●The presence of a more typical antigen-antibody reaction or a transferable serum factor has been investigated in a series of passive transfer experiments using sera from patients with cholinergic urticaria that were injected into the skin of a primate . When the primate was subsequently injected with acetylcholine, a cutaneous reaction was observed with 7 of 16 patient sera. (See 'Diagnosis and testing' below.)
●Many of the triggers for cholinergic urticaria also lead to increased sweating, and it is possible that the immediate trigger for urticaria formation is something that occurs during sweating, rather than shifts in core body temperature .
Several studies have suggested that cholinergic urticaria might be caused by an IgE-mediated allergy to some component of human sweat [58-61]. Some patients demonstrate immediate reactions to skin testing with their own diluted sweat [58,61,62]. An IgE-mediated mechanism was also implicated in a case report of a patient successfully treated with anti-IgE therapy . Another found that a group of 18 patients with cholinergic urticaria appeared to have two separate mechanisms for their condition . One subset of patients had positive skin test results to his/her own sweat and had a positive acetylcholine skin test, whereas these tests were negative in the other patients.
●There have been several reports of patients with cholinergic urticaria that was associated with hypohidrosis [63,64]. An explanation was proposed that occlusion of the pores of the stratum corneum could cause hypohidrosis and subsequent abnormal leakage of inflammatory sweat materials into the upper dermis, resulting in a whealing reaction .
Diagnostic testing — The presentation of the lesions of classic cholinergic urticaria in the context of typical inciting triggers is often sufficient to make the diagnosis, and a clinical diagnosis is usually all that is required in routine practice. However, several methods of provocation testing have been proposed, which are largely used in research settings (table 1):
●Passive heat challenge – Another diagnostic strategy used in research protocols involves nonexertional elevation of the patient's core body temperature. Patients may have one or both arms submerged in a 40°C (104°F) hot water bath until the core body temperature has increased at least 0.7°C (33.3°F) . The appearance of generalized urticaria (ie, not limited to the water-exposed skin) confirms the diagnosis of cholinergic urticaria.
●Exercise challenge – One group has described the measurement of both core temperature and skin temperature while subjects perform 30 minutes of exercise on a stationary bicycle to achieve a specified heart rate . In a group of 10 patients with cholinergic urticaria, onset of urticaria was found to correlate with sweating, rather than rise in temperature. These results warrant replication in larger numbers of patients.
●Combination challenges – A two-step approach to differentiating cholinergic urticaria from exercise-induced urticaria has been proposed . This involves first performing an exercise challenge (treadmill or stationary bicycle) to the point of sweating and for 15 minutes beyond. Wearing warm clothing and/or keeping the room warm facilitates the elicitation of symptoms. A positive test consists of the appearance of suggestive skin changes. If the exercise challenge is positive, then the next step is to perform a passive heat challenge. This should take place no earlier than 24 hours later. For this step, the patient's torso and limbs are submerged in a 42°C (107.6°F) bath for up to 15 minutes while recording body temperature to ensure a rise of ≥1°C (≥33.8°F). The development of symptoms with both types of challenge is diagnostic of cholinergic urticaria, while the elicitation of symptoms only with exercise is diagnostic of exercise-induced urticaria.
●Intradermal methacholine – An intradermal injection of 0.01 mg of methacholine in 0.1 mL saline that produces a local area of hives is diagnostic. However, only about one-third of patients with cholinergic urticaria demonstrate a positive test, so this procedure cannot be used to exclude the diagnosis [45,53]. In addition, there are no injectable forms of methacholine commercially available in the United States.
Differential diagnosis — Cholinergic urticaria/anaphylaxis may be confused with exercise-induced urticaria or anaphylaxis if other triggers are not considered. However, the two conditions can usually be distinguished because a variety of triggers precipitate cholinergic urticaria, including passive heating of the body, while exercise or exertion is the primary trigger for exercise-induced urticaria or anaphylaxis. (See 'Exercise-induced urticaria/anaphylaxis' below.)
Treatment — Identification and avoidance of known triggers are the first steps in controlling cholinergic urticaria. Bathing in hot water and performing strenuous exercise during hot weather are to be avoided.
The following pharmacotherapies have been studied:
●Medical therapy consists predominantly of oral H1 antihistamines. Typically, these are taken daily, although as-needed administration is possible if triggers are easy to identify in advance. We usually initiate therapy with a second-generation antihistamine, as described previously. Cetirizine, a less sedating metabolite of hydroxyzine, has shown efficacy at doses twice normal (10 mg twice daily). (See 'Overview of treatment approach' above.)
●If cetirizine at twice normal dose is not effective, we typically change to the first-generation antihistamine, hydroxyzine, which has been used successfully for decades [8,46]. This agent is highly sedating for some patients. Therapy should be initiated with a low dose, which is increased gradually until the urticaria is controlled. This typically occurs at doses of 100 to 200 mg divided over 24 hours. Studies comparing the hydroxyzine with cetirizine have not been performed, but clinical experience suggests that some patients who do not respond to cetirizine do respond to hydroxyzine.
●Oral anticholinergic agents have also been evaluated. An initial report described no consistent benefit with atropine and hexamethonium . However, in two case reports, scopolamine butylbromide (10 mg orally, three times daily) was effective in combination with antihistamines [69,70].
●The anabolic steroid, danazol, can be effective [71,72]. This agent is postulated to correct the low blood levels of protease inhibitors that occur in some patients with cholinergic urticaria . Given its potential for adverse effects, however, this medication should be reserved only for severe cases refractory to antihistamines.
Desensitization may be possible, as patients will sometimes experience a period of latency after an episode of cholinergic urticaria. In most cases, these relatively symptom-free periods lasted only a few hours but could last more than 24 hours if the initial episode was severe. One study described two patients who treated themselves on a nightly basis using a dose of antihistamine that was followed three hours later by a hot bath .
Prognosis — The prognosis for cholinergic urticaria is generally favorable. One study reported only 31 percent of patients with a persistence of symptoms greater than 10 years . Another estimated that the average duration of symptoms is 7.5 years (range, 3 to 16 years) .
EXERCISE-INDUCED URTICARIA/ANAPHYLAXIS — Urticaria with exercise has been shown to occur in two distinct situations.
●Cholinergic urticaria – Patients with cholinergic urticaria develop hives after exercising or after experiencing any other trigger that elevates core body temperature. Systemic symptoms are uncommon but can occur. (See 'Cholinergic urticaria' above.)
●Exercise-induced anaphylaxis – Urticaria with exercise may also be an early manifestation of exercise-induced anaphylaxis. Unlike in cholinergic urticaria, exercise is the only trigger in exercise-induced anaphylaxis, and passively raising the core body temperature is not sufficient to induce symptoms. In addition, the hives of exercise-induced anaphylaxis are typically larger in size than those of cholinergic urticaria. This disorder is reviewed in detail elsewhere. (See "Exercise-induced anaphylaxis: Clinical manifestations, epidemiology, pathogenesis, and diagnosis".)
COLD URTICARIA — There are several disorders that can present with cold-induced urticaria or cold-induced cutaneous changes. They are discussed in detail separately. (See "Cold urticaria" and "Cryopyrin-associated periodic syndromes and related disorders" and "Autoinflammatory diseases mediated by miscellaneous mechanisms", section on 'PLAID/APLAID'.)
LOCAL HEAT URTICARIA — Local heat urticaria describes a rare disorder in which a warm stimulus must come into direct contact with the skin and results in the formation of a wheal at the heated site within minutes . The pathogenesis involves histamine release, implicating the mast cell in the cause of this condition . Passive transfer experiments, however, have been negative. There is one case report of a familial, delayed-type variant of local heat urticaria .
Diagnostic testing is conducted by the application of a test tube containing water at 44°C (111.2°F) to the arm for four to five minutes . Other protocols use a cylinder heated to 50 to 55°C (122 to 131°F) (table 1) . A localized hive should develop within a few minutes after removal of the heated object. The patient should refrain from taking antihistamines for several days before the test. Occasionally, a positive test can only be obtained on specific areas of skin that have displayed symptoms in the past .
Therapy using antihistamines and oral cromolyn has generally not been effective for local heat urticaria . However, there may be individual patients who respond to the combination of H1 and H2 antihistamines . Desensitization using daily hot baths was successful in one patient but carries some risk for a systemic reaction .
AQUAGENIC URTICARIA — Aquagenic urticaria is a rare condition in which urticaria develop as a result of direct skin contact with water.
Epidemiology — There are fewer than 100 cases of aquagenic urticaria reported in the medical literature [10,80-86]. Females seem to have a slightly higher incidence than males, and, in most cases, the age of onset is during or slightly after puberty. Aquagenic urticaria can be sporadic (or acquired) or familial [10,80-86]. In one report, the condition existed across three generations of a single family .
Clinical features — In aquagenic urticaria, hives appear rapidly after direct contact with various sources of water (ie, distilled, tap, or saline), regardless of the temperature of the water. The lesions of aquagenic urticaria are characteristically small, punctate (1 to 3 mm), perifollicular wheals that may occur on all parts of the body, although generally not on the palms and soles. They are indistinguishable in appearance from the wheals of cholinergic urticaria.
In some patients, salinity appears to be important. One patient experienced urticaria after exposure to tap water, snow, and sweat but did not develop symptoms after exposure to sea water . Another developed hives on exposure to sea water but not fresh water, although over time, she also became sensitive to tap water as well . Bodily fluids may induce hives in some patients . Hive formation is not influenced by the temperature or pH of the water . Alcohol and other liquid organic solvents applied to the skin do not lead to wheal formation [83,86]. However, they can potentiate the reaction to water, possibly by enhancing the permeability of the skin .
Wheals appear rapidly within 20 to 30 minutes following exposure to water. Once the water source is removed from the skin, the wheals generally fade within 30 to 60 minutes . Systemic symptoms are rare but have been reported and may be induced by either exposure of the skin to water or by drinking water [80,82,90]. A refractory period lasting several hours has been demonstrated after an attack . Repeated, short, purposeful exposures to water can lead to exhaustion of the wheal response .
Aquagenic urticaria is occasionally associated with other forms of inducible urticaria. Case reports describe patients with aquagenic urticaria and coexisting dermographism [82,92], cholinergic urticaria [83,91,92], or cold urticaria .
Pathogenesis — The pathogenesis of this condition is poorly understood and may not be the same in all patients. Several theories have been proposed based upon studies in small numbers of subjects. Serum histamine levels are variable from patient to patient, as is the response to pretreatment with oral antihistamines. The studies reviewed below were performed before the publication of those implicating hypersensitivity to sweat allergens in cholinergic urticaria, and comparative mechanistic studies of the two conditions have not been undertaken. (See 'Cholinergic urticaria' above.)
The following mechanisms have been postulated:
●Several researchers have proposed that water is primarily acting as a solvent in aquagenic urticaria, solubilizing an antigen that then permeates the skin and activates dermal mast cells. Water may interact with sebum (the oily substance produced by sebaceous glands in the skin) to form a substance capable of acting as a direct mast cell degranulator, resulting in histamine release . One study demonstrated that patch testing with a patient's sweat produced only erythema, whereas testing with sweat and sebum produced marked urticaria . Others have proposed that the causative antigen(s) normally resides at the epidermal layer of the skin, and solubilization in water allows this antigen to diffuse more deeply into the skin . It is possible that different antigens in different skin layers are involved.
In another study, removal of the stratum corneum layer of the skin enhanced reactivity upon contact with water . Similarly, pretreatment of the skin with organic solvents enhanced wheal formation to water. These investigators concluded that enhancing the ability of water to penetrate the stratum corneum layer of the skin increases the wheal-provoking effects of water in these patients.
●Another theory suggested that activation of the cholinergic pathway was essential for the formation of aquagenic urticaria, based upon the ability of scopolamine (an acetylcholine antagonist) to suppress wheal formation when applied to the skin before water exposure in two patients . However, other studies did not find evidence for a cholinergic mechanism, as pretreatment with atropine did not suppress subsequent wheal formation . In addition, methacholine injection testing, often positive in cholinergic urticaria, was negative in a series of patients with aquagenic urticaria .
Diagnostic testing — The standard test for aquagenic urticaria is the application of a compress or towel of 35°C (95°F) water or physiologic saline to the upper body for 30 to 40 minutes (table 1). The challenge is considered positive if urticaria are present at the test site 10 minutes after removal of the towel/compress . Although water of any temperature can provoke aquagenic urticaria, using ambient-temperature water avoids confusion with cold-induced or local heat urticaria. The upper body is chosen as the preferred site because other areas, such as the extremities, are affected less commonly in aquagenic urticaria . The patient should refrain from taking antihistamines for several days before the test.
In some case reports, rinsing specific areas of the body with water or performing direct bath and shower challenges has been attempted. Use of these approaches may be required when localized testing using a small water compress is negative, although it should be avoided in patients with a history of significant systemic symptoms.
Differential diagnosis — Aquagenic pruritus, cholinergic urticaria, cold-induced urticaria, and local heat urticaria may have inciting factors that can be confused with those of aquagenic urticaria.
●Aquagenic pruritus is itching of the skin upon contact with water, without the development of actual hives or other objective findings .
●Cholinergic urticaria can be elicited by sweating, exercise, heat, and strong emotions, whereas aquagenic urticaria requires the skin to be in direct contact with water. (See 'Cholinergic urticaria' above.)
●Cold-induced urticaria can be differentiated from aquagenic urticaria by the history of reactions upon exposure to cold air and tolerance of warm or hot water. (See "Cold urticaria".)
●Local heat urticaria can be distinguished from aquagenic pruritus by reactions to warm but dry triggers (heating pad or test tube filled with warm water). (See 'Local heat urticaria' above.)
Treatment — A trial of second-generation H1 antihistamines is warranted in all patients as an initial intervention [89,96,97]. In a systematic review of 77 patients, standard doses of H1 antihistamines were reported in 39 patients and resulted in complete or marked control in 28 . The dose may be increased up to four times standard dosing if standard doses are ineffective . Other reported therapies include the following:
●Omalizumab was used successfully in a patient with refractory aquagenic urticaria who responded after only two doses and remained symptom-free even when all other medications were discontinued . Other cases report similar success .
●Ultraviolet B light treatments twice per week in a child with coexisting aquagenic urticaria, cholinergic urticaria, and dermographism resulted in improvement by 20 weeks . Two reports have documented the benefits of psoralen plus ultraviolet A therapy [80,103,104].
●Stanozolol was effective in a patient with HIV infection, hepatitis C virus infection, and aquagenic urticaria, who had failed therapy with oral antihistamines . Symptoms recurred when stanozolol was stopped.
●Barrier creams were reported to be effective in a small number of patients, although this may only be practical in very specific circumstances [89,94,105].
SOLAR URTICARIA — Solar urticaria involves the induction of urticaria, most commonly following direct exposure of the skin to sunlight . The number of patients affected by this condition is small, and most data are case reports and small series [108-111]. The largest series included 87 cases confirmed by phototesting .
Epidemiology — Retrospective reviews of patients with urticaria found that only approximately 0.5 percent were classified as solar urticaria [108,109]. There is a higher incidence in women [110,112]. Patient age at onset, atopic history, and the wavelength of light responsible for the reaction may vary significantly. Geographic and racial differences have not been described.
Clinical features — Solar urticaria generally presents with classic-appearing urticarial lesions, developing within minutes after exposure to direct sunlight and occurring on skin that was uncovered (picture 6). However, in the series of 87 cases, 76 and 83 percent developed symptoms through thin clothing and glass, respectively . Limited exposures provoke only itching or burning erythema, while more prolonged exposures lead to typical wheals. A more delayed onset of symptoms (several hours after light exposure) has been reported in a few patients [113,114].
The severity of the symptoms generally increases with the intensity of the sun exposure. Areas of skin that frequently are exposed to sunlight are less sensitive than areas that are usually covered . The exact mechanism of this "hardening" phenomenon remains unknown . A more severe reaction may be provoked by purposeful sunbathing rather than by normal daily sunlight exposure. Systemic anaphylactic reactions are possible if the exposed body surface area is large enough .
When the patient is removed from the sun exposure, symptoms usually fade rapidly. Most patients note disappearance of the urticaria within 24 hours.
Pathogenesis — It has been hypothesized that solar urticaria is dependent on the presence in the skin of a precursor molecule that is activated by exposure to a particular wavelength of light and becomes a photoallergen. This antigen can be activated in vivo or in vitro by irradiating a sample of the patient's serum . The origin of the precursor molecule has not been determined. The fact that passive transfer is not always successful could indicate that there are different photoallergens at work in different patients. Different classification systems have been proposed . One group has suggested that the disorder be divided into two subtypes: type I solar urticaria, due to IgE antibodies directed against an abnormal photoallergen present only in affected patients and type II solar urticaria, due to circulating IgE antibodies against a normal photoallergen present in most people .
Diagnosis and testing — Clinical history may be sufficient to differentiate solar urticaria from other conditions. If there is clinical uncertainty, the diagnosis can be established using phototesting (table 1). The patient should refrain from taking antihistamines for several days before the test.
A simple form of testing may be performed by exposing a small area of the patient's skin to natural sunlight, which induces erythema or urticaria. The reaction generally fades quickly after the test is halted. However, patients with cholinergic or local heat urticaria might react to this type of testing as well.
More formal evaluation is performed with light sources that emit specific wavelengths of light. Ultraviolet A (UVA) and ultraviolet B (UVB) light sources are available for this purpose. In certain instances, it may be necessary to evaluate visible light sources as well . Most patients demonstrate a threshold wavelength at which symptoms develop, which is referred to as the action spectrum. In some patients, testing with monochromatic light failed to provoke urticaria, although exposure to other light sources, such as natural sunlight, high-intensity ultraviolet light, or slide-projector light, did cause symptoms . These methods are unlikely to be practical for most clinicians but are mentioned for academic and research interest.
In some patients, there is a spectrum of light (an inhibition spectrum), which when applied to the skin during or immediately after the action spectrum, inhibits the development of wheals . However, application of the inhibition spectrum before the action spectrum does not prevent symptoms , so this phenomenon has no immediate clinical utility.
Differential diagnosis — A variety of photosensitive disorders has been described. The symptoms of solar urticaria could initially be mistaken for common sunburn. However, the lesions of solar urticaria develop within minutes of sun exposure. Two other disorders that can present with symptoms similar to solar urticaria are polymorphous light eruption and erythropoietic protoporphyria:
●Polymorphous light eruption – In this idiopathic condition, which is far more common than solar urticaria, pruritic, papular, and papular-vesicular lesions appear on sun-exposed areas, although there is less of a predilection for the face (picture 7 and picture 8). In northern climates, patients may develop symptoms with the first full sun exposure of the season. The lesions of polymorphous light eruption tend to last two to six days, which usually allows differentiation from solar urticaria, in which lesions resolve within 24 hours. (See "Polymorphous light eruption".)
●Erythropoietic protoporphyria – Erythropoietic protoporphyria (EPP) can present as acute, nonblistering induration and swelling of sun-exposed skin, although the skin is typically painful (often extremely so) rather than pruritic. EPP usually presents in early childhood, and there may be a family history of the disorder. The cutaneous lesions of EPP can develop within minutes of sun exposure, and diffuse edema of the skin in sun-exposed areas may resemble angioedema. Petechiae and purpuric lesions may be seen (picture 9). With time, the skin may become lichenified and leathery, with labial grooving and nail changes. This disorder is reviewed separately. (See "Erythropoietic protoporphyria and X-linked protoporphyria".)
●Drug-induced phototoxicity – Phototoxicity results from direct tissue or cellular damage following ultraviolet irradiation of a phototoxic agent that has been ingested or applied to the skin. The reaction is not immune-mediated and can occur in any individual in whom the threshold concentration of the chemical or drug has been reached. Common culprits include tetracyclines and thiazides. Phototoxic reactions appear as an exaggerated sunburn (picture 10A-C). In severe cases, vesicles or bullae may form. The reaction usually evolves within minutes to hours of sun exposure and is restricted to exposed skin. Drug-induced toxicity can usually be distinguished from solar urticaria, as patients with the former are taking a photosensitizing medication and complain of burning rather than pruritus. In some situations, phototesting may be necessary to differentiate between the two disorders. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity'.)
●Photoallergic reactions – Photoallergic reactions are a form of contact dermatitis caused by an antigen that has become allergenic as a result of exposure to ultraviolet radiation. Photoallergic reactions are typically pruritic, eczematous eruptions in sun-exposed areas of skin. The responsible mechanism is delayed-type hypersensitivity, with symptoms developing 24 to 48 hours after sun exposure, which is significantly more delayed than solar urticaria. Photoallergic reactions are most common with topical agents (eg, sunscreen, antimicrobials), although systemic agents (eg, quinidine) can also cause these reactions (picture 11). (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Photoallergy'.)
●Cutaneous lupus erythematosus – Cutaneous forms of systemic lupus erythematosus (SLE) may develop initially after exposure to ultraviolet light and appear years before other manifestations of the disease. Cutaneous SLE most commonly presents with a characteristic facial eruption (butterfly rash) or (less commonly) as a generalized eruption. Biopsy of affected skin can distinguish this from solar urticaria. In addition, lesions of cutaneous lupus are more persistent than solar urticaria. (See "Overview of cutaneous lupus erythematosus".)
●Brachioradial pruritus – Brachioradial pruritus presents as localized pruritus involving the proximal dorsolateral forearm. The pathogenesis is unclear, although it is often thought to be a localized neuropathic pruritus of the arms and forearms that can also involve the shoulders and neck. Symptoms may be intermittent, unilateral, or bilateral. Sun exposure may be a contributing factor, as affected individuals often state that sun exposure provokes the disease. People with brachioradial pruritus complain of burning and stinging rather than pruritus and do not have any cutaneous lesions, only the discomfort. (See "Pruritus: Etiology and patient evaluation", section on 'Brachioradial pruritus'.)
Treatment — H1 antihistamines provide symptomatic treatment and can be used orally or topically. These medications are effective in reducing pruritus and wheal formation but may not eliminate the erythema. In most of the initial studies, terfenadine was used, and higher than standard doses often were required to achieve symptom relief [119,121]. Whether this finding is true for all antihistamines, including some of the newer agents, remains to be determined. Topical and systemic glucocorticoids can be used if antihistamines are insufficient. (See 'Overview of treatment approach' above.)
When antihistamines provide inadequate relief, other treatment approaches may be considered:
●Omalizumab (anti-IgE therapy) has been shown to be of benefit in multiple studies [35,122-125]. Solar urticaria can be particularly difficult to treat as sun avoidance is extremely difficult to manage, and antihistamines are often of limited benefit. With its high likelihood of benefit and low risk of adverse effects compared with other agents, the use of omalizumab should be considered early in the treatment plan.
●Desensitization may be useful in some cases . It has been demonstrated that skin that is regularly exposed to sunlight becomes less reactive than that which is usually covered . Patients may be repeatedly exposed to ultraviolet light sources, although the desensitized state typically lasts only a few days.
●The use of psoralen plus ultraviolet A (PUVA) radiation and narrowband UVB has been shown to induce a longer-lasting effect, although the potential long-term adverse effects are greater [121,127].
●Plasmapheresis has been used alone and in conjunction with PUVA therapy [131-133]. This modality has been reported to improve symptoms in the few patients included in these studies. One study failed to demonstrate a lasting benefit with plasmapheresis . The effectiveness of this therapy may depend on the characteristics of the specific photoallergen at work (ie, circulating antigen versus cutaneous antigen).
●Future possible therapeutic options include a melanocyte-stimulating hormone that has shown an ability to decrease hive formation under laboratory conditions .
Prognosis — The long-term outlook for patients with solar urticaria has been uncertain because of the small number of cases. A review of 87 patients found that 25 percent of 60 subjects who were available for follow-up reported complete resolution of their conditions . An additional 32 percent reported improvement, whereas 35 percent were unchanged, and 8 percent believed that their conditions had worsened. Most of the original case reports indicated that the condition was persistent, and although many experienced overall improvement in symptoms, few patients experienced complete resolution.
VIBRATORY ANGIOEDEMA AND URTICARIA — Vibratory angioedema refers to the development of pruritus and swelling after the application of a vibratory stimulus to the skin. Hives are usually not observed in this syndrome. Vibratory urticaria, in which patients do have distinct hives, sometimes accompanied by systemic symptoms, has also been described .
Epidemiology — Vibratory angioedema and urticaria are rare disorders. Familial forms of the condition, with autosomal dominant inheritance, have been reported [137,138]. Other case reports describe patients with vibratory symptoms that are not familial but rather related to the subject's occupation.
Clinical features — Common triggers for vibratory angioedema or urticaria include mowing the lawn, riding a motorcycle, horseback riding, or mountain biking. At-risk occupations include jackhammer operator, machinist , carpenter , and metal grinder . Patients generally complain of local pruritus, erythema, and swelling arising within a few minutes after exposure to vibration and affecting the area that was most exposed to the stimulus (often the hands). There are rare cases of delayed-onset symptoms beginning 1 to 2 hours after exposure . Symptoms peak in severity at 4 to 6 hours and typically resolve by 24 hours. In some episodes, the symptoms may persist for several days. The severity and duration of the symptoms may vary and seem to be proportional to the intensity and duration of the applied vibratory stimulus and to the area of exposed body surface. An early report described systemic symptoms of headache and generalized erythema . Another report described a severe case with accompanying dizziness, tachycardia, and hypotension . One patient developed carpal tunnel syndrome and slowed median nerve conduction that was documented only during episodes of edema .
In autosomal dominant vibratory urticaria, a mutation was found in three unrelated Lebanese families with multiple members exhibiting vibratory urticaria symptoms . All patients experienced localized, pruritic urticaria in response to repetitive mechanical stimulation of the skin. Some patients also experienced facial flushing, headache, or the sensation of a metallic taste. All patients tested negative for dermographism using standard protocols.
Pathogenesis — The pathogenesis of sporadic vibratory angioedema has not been satisfactorily elucidated. Elevated levels of serum histamine and mast cell degranulation have been documented during symptomatic episodes [139,141,143]. Most investigators favor a nonimmunologic reaction (eg, direct mast cell stimulation from the vibration causes degranulation and local release of histamine), and passive transfer experiments have been negative [137,143]. In a study of vibration exercise in 37 healthy subjects, approximately one-half developed a pruritic erythematous eruption .
In autosomal dominant vibratory urticaria, a gain-of-function mutation in the gene ADGRE2 (adhesion G protein-coupled receptor E2, also called EMR2) has been implicated . ADGRE2 encodes a cell surface receptor that is normally inhibitory on mast cells, but the mutated form renders the cell susceptible to degranulation following exposure to vibration. This receptor may be a component of an innate immune response to noxious physical stimuli.
Diagnostic testing — Several methods for reproducing the vibratory stimulus and classifying the reaction have been used in the literature . The patient should refrain from taking antihistamines for several days before the test. The subject's arm is held on a level plane, and a vortex mixer is placed in contact with the skin (table 1). The vibratory stimulus is applied for 10 minutes, although this may need to be reduced for very sensitive patients, and the site is observed for five to six hours. The test is considered positive if the area becomes erythematous, pruritic, and edematous around the full circumference of the arm, although one study found that this test also induced a positive response in 7 of 20 normal volunteers , suggesting that this response may not be entirely abnormal. In patients with vibratory urticaria the same protocol is used to elicit characteristic wheals. Dermographism should be excluded using the appropriate tests. At the present time, testing for the novel genetic mutation is not commercially available. (See 'Dermographism' above and 'Delayed-pressure urticaria/angioedema' above.)
Treatment — Patient avoidance of specific vibratory stimuli is the first line of therapy, although this may not be possible in occupational cases.
H1 antihistamines have been used successfully . In another report, symptoms were refractory to multiple antihistamines, antileukotriene agents, dapsone, cyclosporine, prednisone, and omalizumab but eventually responded partially to ketotifen, a strong antihistamine and mast cell stabilizer. This was given at a dose of 1 to 2 mg twice daily. Ketotifen (not available in the United States) is highly sedating for some patients.
A state of tolerance was achieved in one patient by using twice daily vibration challenges until symptoms were delayed in onset and reduced in duration . The patient eventually attained complete control of her symptoms by using a five-minute desensitization protocol every five to seven days. However, a state of tolerance could not be induced in another case report .
POSTURAL URTICARIA — Urticaria induced by positional changes, which is referred to as postural urticaria, has been described in a small number of case reports [147,148]. In these cases, urticaria repeatedly developed on the lower extremities within 10 to 20 minutes after rising from a seated position. The hives resolved spontaneously after several hours. In one case, the hives responded poorly to high-dose antihistamine therapy but responded moderately well to omalizumab . It is uncertain how prevalent this condition is, but it may be a newly-recognized form of physical urticaria.
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 info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Inducible hives (The Basics)")
●Beyond the Basics topic (see "Patient education: Hives (urticaria) (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Definition of inducible urticaria – Inducible urticarias are forms of chronic urticaria in which hives (sometimes with angioedema) are elicited by physical or environmental stimuli. These syndromes often occur in children and adults with chronic spontaneous urticaria. (See 'General points about inducible urticarias' above.)
●Common types – The more common inducible urticaria syndromes include dermographism, cholinergic urticaria, and delayed-pressure urticaria/angioedema. (See 'Dermographism' above and 'Delayed-pressure urticaria/angioedema' above and 'Cholinergic urticaria' above.)
●Rare types – Rare disorders include urticaria/angioedema following exposure to heat, exercise, water, sunlight, or vibration. (See 'Local heat urticaria' above and 'Exercise-induced urticaria/anaphylaxis' above and 'Aquagenic urticaria' above and 'Solar urticaria' above and 'Vibratory angioedema and urticaria' above.)
●Diagnosis – Inducible urticarias can often be diagnosed based upon history and physical examination. In some cases, physical challenge procedures are needed to clarify or confirm the responsible trigger (table 1). (See 'Testing' above.)
●Trigger avoidance and antihistamines – The management of inducible urticaria begins with accurate identification and avoidance of the triggering stimulus. (See 'Overview of treatment approach' above.)
•For initial pharmacotherapy for the majority of patients with an inducible urticaria, we suggest a less sedating, second-generation antihistamine (Grade 2C). Options include cetirizine (10 mg daily), loratadine (10 mg daily), or fexofenadine (180 mg daily). Many patients will require a doubling of the standard dose to impact symptoms significantly (eg, cetirizine, 10 mg twice daily). (See 'Overview of treatment approach' above.)
•If symptoms do not respond adequately to antihistamines, management proceeds in a stepwise manner and includes H2 antihistamines, first-generation H1 antihistamines, and in some cases, limited courses of systemic glucocorticoids. (See 'Overview of treatment approach' above.)
●Biologic therapies – Patients who fail to respond to avoidance of the triggering stimulus combined with safe and practical doses of a second-generation antihistamine should be considered candidates for chronic therapy with omalizumab. Other therapies for refractory disease, depending upon the specific disorder, include phototherapy, physical desensitization protocols, and immunomodulatory agents. (See 'Symptoms refractory to antihistamines' above.)
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