Cholinergic Urticaria

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Background

Cholinergic urticaria is one of the physical urticarias brought on by a physical stimulus. Although this stimulus might be considered to be heat, the actual precipitating cause is sweating. The definition and diagnostic testing of cholinergic urticaria has been the subject of consensus panel recommendations. (See Etiology, Presentation, and Workup.)[1]

Cholinergic urticaria can be divided into the following four subtypes[2] :

See also the Medscape Drugs & Diseases articles Acute Urticaria; Chronic Urticaria; Contact Urticaria Syndrome; Dermographism Urticaria; Papular Urticaria; Pressure Urticaria; and Solar Urticaria.

Pathophysiology

Autonomic functions are normal in cholinergic urticaria. In one study of cholinergic urticaria, muscarinic receptors were reduced, but binding was normal. Thermography ostensibly shows the areas of involvement.

Elevation of histamine levels can be detected at 5 minutes after exercise, reaching a peak of 25 ng/mL at 30 minutes in persons with cholinergic urticaria. Treadmill exercise produces a sensation of generalized skin warmth, followed by pruritus, erythema, urticaria, and transient respiratory tract symptoms consisting of shortness of breath, wheezing, or both. Statistically significant decreases have been observed in 1 second forced expiratory volumes, maximal midexpiratory flow rates, and specific conductance. An increase in residual volume may also detected. (See Presentation and Workup.)

Etiology

Mast cells seem to be critically involved in cholinergic urticaria. In fact, cholinergic urticaria has been used to study mast cell activity.[4] Serum histamine, the principal mediator, rises in concentration with experimentally induced exercise, accompanied by eosinophil and neutrophil chemotactic factors and tryptase. A reduction of the alpha1-antichymotrypsin level, as seen in some other forms of urticaria, is present. The eruption is improved with danazol. These findings have prompted some to argue for proteases as a cause of histamine release.

Although mast cell release seems to be involved in cholinergic urticaria, less eosinophilic major basic protein is present than in many other forms of urticaria.

Possible allergy-based etiology

Several factors, including an increased incidence in patients with atopic dermatitis (AD), a marked sensitivity in some patients with anaphylactic and anaphylactoid reactions, and an immediate reactivity in some patients, suggest an allergic basis for cholinergic urticaria.[5]

One report showed positive immediate sensitivity to sweat with passive transfer.[6] Some investigators, but not others, have documented positive passive transfer. Another group has delineated a follicular pattern of cholinergic urticaria in sweat-sensitized patients, but not in patients without prominent sensitivity.

Patients with atopic dermatitis and those with cholinergic urticaria develop skin reactions and histamine release of basophils in response to autologous sweat.[7, 8] Most patients demonstrate immediate-type skin responses to their own sweat and satellite wheals after acetylcholine injection. The rest have positive autologous serum skin tests.[9] The pathogenesis may involve disordered immune responses to products of skin flora that are soluble in human sweat. Patients with atopic dermatitis and cholinergic urticaria demonstrate elevated immunoglobulin E against the fungal protein MGL1304 produced by Malassezia globosa.[10]

Body temperature

A crucial point in cholinergic urticaria is not the actual temperature of the skin surface, the average skin temperature, or even the core temperature, but an increase or a decrease in the weighted average body temperature. An increase in core body temperature may trigger cholinergic urticaria; some patients appear unaffected by exercise and other activity in the summer.[11]

Seasonal temperature

It has been suggested that 2 conditions are required to provoke seasonal cholinergic urticaria: heat induced by various cholinergic stimuli and a low ambient temperature. Indeed, some persons who report cholinergic urticaria symptoms only during the winter months apparently have a reaction only when exposed to heat or heat-producing exercise while not acclimatized to heat.

In cholinergic urticaria, whether skin lesions are provoked by passive heating of the body at rest (eg, saunalike conditions) or by active heating at a low ambient temperature is basically related to the thermoregulatory process.

Other associated factors

The prevalence of cholinergic urticaria is definitely higher in persons with urticaria; cholinergic urticaria affected 11% of a population with chronic urticaria in one study and 5.1% of persons with urticaria in another.

The prevalence is also higher in persons with atopic conditions (eg, asthma, rhinitis, atopic eczema), but this is by no means exclusive. A rare, familial form of cholinergic urticaria has also been reported.

Cholinergic urticaria may also occur in the setting of acquired forms of generalized absence or decrease in sweating. Some patients with acquired idiopathic generalized hypohidrosis are theorized to have a defect in the nerve-sweat gland junction.[12] Superficial obstruction of the acrosyringium has sometimes been associated with acquired generalized hypohidrosis.[13]

Aspirin aggravated the urticaria in 52% of patients with cholinergic urticaria, which is similar to other forms of urticaria.

Epidemiology

The prevalence of cholinergic urticaria is variable. Moore-Robinson and Warin found that about 0.2% of patients in an outpatient dermatologic clinic had cholinergic urticaria.[14] However, many published series have found cholinergic urticaria to be common. The prevalence of cholinergic urticaria is definitely higher in persons with urticaria.

The overall prevalence of cholinergic urticaria in one survey of 600 medical and engineering students in western India was 4%.[15]

Although the disorder occurs in both sexes, it seems to be more common in males than in females. In one study, almost 96% of patients with cholinergic urticaria were men.

Cholinergic urticaria usually first develops in people aged 10-30 years, with an average age at onset of 16 years in one study and a mean age of 22 years in another survey.

Patient Education

For patient education information, see the Allergies Center and the Skin Conditions and Beauty Center, as well as Hives and Angioedema.

History

Cholinergic urticaria appears rather rapidly, usually within a few minutes after the onset of sweating, and lasts from a half hour to an hour or more, with a mean duration of about 80 minutes.

Cholinergic urticaria symptoms are sufficiently uncomfortable to cause many patients to change their patterns of activity to prevent attacks.

Exercise is the most common precipitating event for cholinergic urticaria, but any stimulus that causes sweating, including elevated environmental temperature, hot food, sauna baths, immersion in hot water, gustatory stimuli, emotional stress, and hemodialysis,[16] can bring on an urticarial attack in some persons. Exercise and hot baths exacerbate pruritus and provoke lesions in previously unaffected areas.

Symptoms

Often in cholinergic urticaria, itching, burning, tingling, warmth, or irritation precedes the onset of numerous small (1-4mm in diameter), pruritic wheals with large, surrounding flares. (See the image below.)



View Image

Close-up view shows small urticarial wheals within large erythematous flares.

Cholinergic urticaria may appear anywhere on the body, except on the palms or the soles and rarely in the axillae. Sometimes, flares are the only presentation.

Patients who are more severely affected with cholinergic urticaria may experience systemic symptomatology, such as the following:

Hepatocellular injury, angioedema,[17] asthma, anaphylactoid reactions, and even anaphylactic reactions are also reported. The angioedema may be palpebral.[18]

Persons with cardiorespiratory symptoms include patients with increased pulmonary resistance with acetylcholine challenge, which may be a limiting factor in certain occupations (eg, those relating to aerospace).

One form of cholinergic urticaria, sometimes called cholinergic erythema, is believed to show persistent and individual macules of short duration, but with new macules continually appearing at adjacent sites.

Duration

Cholinergic urticaria persists for a number of years. Most patients retain a tendency to develop it for many years. It may improve after botulinum toxin injection for axillary hyperhidrosis.[19]

In one series of 22 persons, the average duration of cholinergic urticaria was 7.5 years, with a range of 3-16 years. In 7 patients on follow-up study, however, some retained the cholinergic urticaria tendency for 30 years.

In a large series from an urticaria clinic, however, cholinergic urticaria had the shortest course from onset to 50% remission (34 months).[20]

Cholinergic urticaria may be associated with anaphylaxis with upper and/or lower airway obstructive symptoms, gastrointestinal involvement, and cardiovascular manifestations. Cholinergic urticaria with anaphylaxis has been characterized as underrecognized.[21]

Physical Examination

The most reliable way to reproduce cholinergic urticaria is to cause the patient to sweat from a stimulus, such as during exercise (eg, walking or running on a treadmill).

Cholinergic dermographism occurs in the form of localized distribution of typical tiny wheals that appear after stroking the skin of some patients with cholinergic urticaria.

A localized form of cholinergic urticaria with a presentation with cold-induced urticarial lesions may occur.[22] Patients with this condition were found to experience a generalized reaction to cold ambient air and cold water, but a negative response to the ice-cube test. Cold urticaria and cold-induced cholinergic urticaria may be seen in about 1% of patients with cold urticaria.

Approach Considerations

Traditionally, an intradermal injection of either 0.05 mL of 0.002% carbamylcholine chloride (carbachol) or 0.05 mL of 0.02% (0.01 mg) methacholine has been used to produce a flare-up of cholinergic urticaria containing characteristic wheals, often with satellites. This outcome occurs in about 51% of patients. The same flare-up may occur in persons without this condition, but it is usually smaller and without whealing.

Nicotinic acid has also been used at a dilution of 1:500,000 or 1:100,000. Lesions of cholinergic urticaria have even been reproduced by curare derivatives such as D-tubocurarine.

Cholinergic dermographism can be reproduced by stroking the skin, by using methyl acetylcholine, or by using other stimuli that cause sweating.

The demonstration of sweat-specific immunoglobulin E in cholinergic urticaria patients who are unable to provide sufficient sweat may be facilitated by use of iontophoresis with pilocarpine nitrate.[26]

Approach Considerations

Traditional treatment options for cholinergic urticaria are antihistamines, leukotriene inhibitors, and immunosuppressives.[26, 27] However, cholinergic urticaria in some patients may be refractory.

Sometimes, an attack of cholinergic urticaria can be aborted by rapid cooling. Ultraviolet (UV) light has been beneficial in some patients with the condition, but one must be circumspect about contraindications to UV light.

Rapid desensitization with autologous sweat has been reported in patients resistant to conventional therapy who have sweat hypersensitivity.[28]

In evaluating any response to therapy, one must always consider that cholinergic urticaria can clear spontaneously.

Diet

Modifying one's diet may be helpful because cholinergic urticaria attacks can sometimes result from hot foods and beverages, highly spiced foods, and alcohol.

Deterrence/prevention

Patients with cholinergic urticaria should avoid the precipitating factors. These factors, in some persons, include exercise and any activity that causes sweating, such as elevated environmental temperature, hot food, sauna baths, immersion in hot water, gustatory stimuli, emotional stress, and hemodialysis.

Long-term monitoring

A quality-of-life questionnaire has been developed for cholinergic urticaria.[29]

Pharmacologic Therapy

Antihistamines, including cetirizine, are helpful for cholinergic urticaria. Second-generation antihistamines are generally regarded as first-line therapy.[30] The response to cetirizine is important because some of the antihistaminic effect has been attributed to antimuscarinic activity. Some data suggest that a combination of H1 and H2 blockers is more effective than combining different H1 blockers.[31] The antimuscarinic cholinergic methanthelinium bromide has also been suggested as a therapeutic option.[32]

For patients with both cold urticaria and cholinergic urticaria, ketotifen (where available) may be helpful. About 62% of patients experience a reduction in wheals, and 68% of patients report reduced itching. Cardiorespiratory symptoms also reportedly respond to ketotifen.

Danazol is another agent that can be beneficial for patients with cholinergic urticaria, ostensibly because it elevates antichymotrypsin levels.

Beta-blockers, such as propranolol, have also been reported to be useful in treating the disease.[33]

Topically applied benzoyl scopolamine and oral scopolamine butylbromide, where available, may be helpful in blocking the appearance of cholinergic urticaria lesions after challenge.[34]

Medication Summary

As previously mentioned, antihistamines, including cetirizine, are used in the treatment of cholinergic urticaria. The response to cetirizine is important because some of the antihistaminic effect has been attributed to antimuscarinic activity. Loratadine and desloratadine are other antihistamines that can be employed in therapy.

Treatment approaches to cholinergic urticaria also include anti–immunoglobulin E therapy and combination therapy (eg, cetirizine, montelukast, propranolol).[35, 36] Use of omalizumab for refractory cholinergic urticaria has been advocated[37]  and evaluated as safe and effective.[38, 39]

Cetirizine (Zyrtec)

Clinical Context:  Cetirizine is a second-generation antihistamine that forms a complex with histamine for H1-receptor sites in the blood vessels, the gastrointestinal (GI) tract, and the respiratory tract.

Levocetirizine (Xyzal)

Clinical Context:  Levocetirizine is an H1-receptor antagonist, an active enantiomer of cetirizine. It is a second-generation prescription antihistamine.

Loratadine (Claritin, Alavert)

Clinical Context:  Loratadine selectively inhibits peripheral histamine H1 receptors.

Desloratadine (Clarinex)

Clinical Context:  Desloratadine is a long-acting tricyclic histamine antagonist that is selective for the H1 receptor. It is a major metabolite of loratadine, which, after ingestion, is extensively metabolized to the active metabolite 3-hydroxydesloratadine.

Class Summary

These agents may control itching by blocking the effects of endogenously released histamine.

Danazol

Clinical Context:  Danazol treatment elevates several protease inhibitors, particularly antichymotrypsin, which has been reported previously to be low in cholinergic urticaria. The use of danazol gives rise to the improvement in the eruption experienced in cholinergic urticaria.

Class Summary

Agents from this class may suppress pituitary secretion of follicle-stimulating hormone and luteinizing hormone.

Propranolol (Inderal)

Clinical Context:  Beta-blockers, such as propranolol, have also been reported to be useful in treating the disease.

Propranolol hydrochloride (Inderal LA, InnoPran XL)

Clinical Context:  This is a nonselective beta-adrenergic receptor blocker. After primary treatment with an alpha-receptor blocker, propranolol hydrochloride has membrane-stabilizing activity of some cells.

Class Summary

Beta-blockers may prevent migraines by blocking vasodilators, decreasing platelet adhesiveness and aggregation, stabilizing the membrane, and increasing the release of oxygen to tissues.

Scopolamine (Transderm Scop Patch, Scopace)

Clinical Context:  Scopolamine blocks the action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the central nervous system (CNS). It antagonizes histamine and serotonin action.

Class Summary

Some agents in this class antagonize histamine effects.

What is cholinergic urticaria?What are the subtypes of cholinergic urticaria?What is the pathophysiology of cholinergic urticaria?What is the role of mast cells in the etiology of cholinergic urticaria?What is the allergy-based etiology of cholinergic urticaria?What is the role of seasonal temperature in the etiology of cholinergic urticaria?What are risk factors for cholinergic urticaria?What is the prevalence of cholinergic urticaria?Where can patient education resources for cholinergic urticaria be found?Which clinical history findings suggest cholinergic urticaria?What are symptoms of cholinergic urticaria?What are cardiorespiratory symptoms of cholinergic urticaria?What is the duration of cholinergic urticaria?What is included in the physical exam of cholinergic urticaria?How are other forms of urticaria differentiated from cholinergic urticaria?What are the differential diagnoses for Cholinergic Urticaria?Which tests are performed in the workup of cholinergic urticaria?What are the treatment options for cholinergic urticaria?What is the role of dietary modifications in the treatment of cholinergic urticaria?How is cholinergic urticaria prevented?What tool is available for the long-term monitoring of patients with cholinergic urticaria?What is the role of pharmacologic therapy in the treatment of cholinergic urticaria?Which medications are used in the treatment of cholinergic urticaria?Which medications in the drug class Anticholinergic Agents are used in the treatment of Cholinergic Urticaria?Which medications in the drug class Beta-Blockers are used in the treatment of Cholinergic Urticaria?Which medications in the drug class Androgens are used in the treatment of Cholinergic Urticaria?Which medications in the drug class Antihistamines are used in the treatment of Cholinergic Urticaria?

Author

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Jerri Hoskyn, MD Private Practice, River City Dermatology

Disclosure: Nothing to disclose.

Mark G Lebwohl, MD Chairman, Department of Dermatology, Mount Sinai School of Medicine

Mark G Lebwohl, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Amgen/Pfizer Honoraria Consulting; GlaxoSmithKline Honoraria Consulting; Novartis Honoraria Consulting; Ranbaxy Honoraria Lectures; Pfizer Honoraria Consulting; BioLineRX, Ltd. Honoraria Consulting; Celgene Corporation Consulting; Clinuvel None Investigator; Eli Lilly & Co. None Investigator; Genentech Honoraria Consulting

Christen M Mowad, MD Associate Professor, Department of Dermatology, Geisinger Medical Center

Christen M Mowad, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association

Disclosure: Nothing to disclose.

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Close-up view shows small urticarial wheals within large erythematous flares.

Close-up view shows small urticarial wheals within large erythematous flares.