PRESENTED AT THE ROUNDTABLE, "CURRENT MANAGEMENT OF URTICARIA AND ANGIOEDEMA," SUPPORTED BY AN EDUCATIONAL GRANT FROM MARION MERRELL DOW INC.

Acute and chronic urticaria and angioedema Nicholas A. Soter, MD, New York, New York Urticaria and angioedema are clinical manifestations of various immunologic and inflammatory mechanisms, or they may be idiopathic. The respiratory and gastrointestinal tracts as well as the cardiovascular system may be involved in any combination. Patients with urticaria andjor angioedema can be classified based on pathophysiologic mechanisms into those with IgE-dependent or complement-mediated immunologic disorders, those with nonimmunologic disorders in which there is a direct effect on the mast cell or on arachidonic acid metabolism, and those whose condition is idiopathic. Evaluation of patients should focus on a thorough history. Laboratory tests provide minimal additional information. About one half of patients with urticaria alone and 25% with urticaria and angioedema or angioedema alone are free of lesions within 1 year. With urticaria, angioedema, or both, 20% of patients experience episodes for more than 20 years. (J AM ACAD DERMATOL 1991;25:146-54.)

CLINICAL MANIFESTATIONS OF URTICARIA AND/OR ANGIOEDEMA

Urticaria and angioedema rnay occur as clinical manifestations of various immunologic and inflammatory mechanisms, or they may be idiopathic. Either form of cutaneous swelling may occur after an immediate type of immunologic reaction resulting from the antigen-induced release of biologically active materials from mast cells or basophils, after direct mast ceil degranulation caused by various eliciting agents, or in association with abnormalities of the arachidonic acid metabolic pathways, the complement system, or the Hageman factor-dependent pathways. The respiratory and gastrointestinal tracts as well as the cardiovascular system also may be involved in any combination. Although persons of any age may experience urticaria and angioedema, the incidence is highest in young adults. 1n·a study of 554 patients, 50% experienced both urticaria and angioedema, 40% only urticaria, and 10% only angioedema. 1 About 50% of patients with urticaria are free of lesions within 1 year, but 20% continue to experience episodes for more than 20 years. When angioedema accompanies urticaria, 75% of patients have symptoms and signs for more than 1 year and 20% for more than 20 years. l

Circumscribed, raised, erythematous, usually pruritie, evanescent areas of edema that involve the superficial portions of the dermis are known as urticaria (Fig. 1). When the edematous process extends into the deep dermis or subcutaneous and submucosal layers, it is known as angioedema (Fig. 2). Urticaria and angioedema may occur in any location, together or individually, Table I outlines a current classification of urticaria and angioedema based on pathophysiologic mechanisms. The individual lesions of urticaria arise suddenly, usually persist for less than 24 hours, and may continue to recur for indefinite periods. Angioedema may persist for several days. Episodes of lesions lasting less than 6 to 8 weeks are considered acute, whereas those persisting longer are termed chronic. Recurrent episodes of urticaria andlor angioedema lasting more than 3 months are more prevalent in women than in men. 2 Headache, arthralgias, the sensation of a lump in the throat, hoarseness, shortness of breath, wheezing, nausea, vomiting, abdominal pain, and diarrhea may occur as concomitant systemic manifestations.

From the Department of Dermatology, New York University School of Medicine.

IMMUNOLOGIC URTICARIA: IgE-DEPENDENT URTICARIA AND/OR ANGIOEDEMA

Reprint requests: Nicholas A. Soter, MD, Department of Dermatology, New York University Medical Center, 550 First Ave., New York, NV 10016. 16/11/29709

146

Specific antigen sensitivity. Specific antigens that provoke urticaria andjor angioedema include foods such as shellfish, nuts, and chocolate, drugs and

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Urticaria and angioedema 147

Fig. 1. Typical circumscribed, erythematous lesions of urticaria. Fig 2. Lesions of angioedema indicate that the edematous process extends more deeply into the dermis than it does in urticaria. Fig. 3. Cholinergic urticaria is manifested as distinctive 1 to 2 mm wheals.

therapeutic agents, notably penicillin, aeroallergens, and Hymenoptera venom. Although urticaria and/ or angioedema in patients with helminthic infestations has been attributed to 19E-dependent processes, proof of this mechanism is often lacking. Atopic. Patients with a personal or family history of asthma, rhinitis, or eczema may also have a history of acute urticaria and/or angioedema. In clinical practice, however, one rarely observes urticaria and/or angioedema accompanying an exacerbation of asthma, rhinitis, or eczema. The prevalence of chronic urticaria and/or angioedema is not greater in atopic persons.

Physical. Various forms of physical urticaria and/or angioedema have been described (Table II).3,4 Dermographism appears as a wheal with a flare at a site in which skin is subjected to mechanical trauma. Its configuration depends on the eliciting stimulus. Dermographism with substantial degrees of pruritus has been called symptomatic dermographism. A transient, pruritic, or asymptomatic wheal with erythema appears rapidly and usually fades within 30 minutes. The prevalence of dermographism was 1.5% and 4.2%, respectively, in two separate studies. 5, 6 In patients with dermographism, the prevalence of the

Journal of the American Academy of Dermatology

148 Soter

Table I. Classification of urticaria and/or angioedema 1. Immunologic urticaria/angioedema A. IgE-dependent urticaria/angioedema

1. Specific antigen sensitivity 2. Atopic diathesis 3. Physical urticaria/angioedema: Dermographism, vibratory, cold, light, and cholinergic 4. Contact urticaria/angioedema B. Complement-mediated urticaria/angioedema 1. Serum sickness 2. Hereditary angioedema 3. Acquired angioedema with malignant disorders and systemic lupus erythematosus 4. Necrotizing venulitis 5. Reactions to blood products

II. Nonimmunologic urticaria/angioedema A. Direct mast cell-releasing agents 1. Opiates 2. Polymyxin B 3. Curare, d-tubocurarine 4. Radiocontrast media B. Agents that presumably alter arachidonic acid metabolism 1. Aspirin and nonsteroidal antiinflammatory agents 2. Azo dyes and benzoates III. Idiopathic urticaria/angioedema

atopic diathesis does not differ from that in control populations. 7 Rare forms of dermographism include a delayed type that develops 3 to 6 hours after stimulation either with or without an immediate reaction,s,9 a form that occurs only after cold exposure, 10 and one that appears as punctate wheals and is known as cholinergic dermographism. 11 Pressure urticaria often accompanies dermographism and episodes of chronic urticaria. It appears as erythematous, deep, and often painful swellings that arise immediately or within 4 to 6 hours after sustained pressure has been applied to the skin. 12-15 The delayed form may occur without an immediate swelling, and it may be associated with fever, chills, and arthralgia,13 as well as with an elevated erythrocyte sedimentation rate and leukocytosis. 14 Vibratory angioedema may occur as an acquired idiopathic disorder, 16, 17 with cholinergic urticaria, 18 or after several years of occupational exposure to vibration. 19 Ithas been described in a family with an autosomal dominant pattern of inheritance. 2o There are both acquired and inherited forms of cold-induced urticaria and/or angioedema. Idiopathic, acquired cold-induced urticaria may be associated with headache, hypotension, syncope, and wheezing. Attacks occur within minutes after

direct cold contact or changes in ambient temperature. Ifthe entire body is cooled such as in swimming, hypotension and collapse, a potentially lethal event, may occur. Acquired cold urticaria has rarely been associated with underlying cryoglobulins, cryofibrinogens, cold agglutinins, and cold hemolysins, especially in patients with infections, notably infectious mononuc1eosis. 21-23 Two forms of dominantly inherited familial cold urticaria have been described. 24-26 An immediate form, known as familial cold urticaria, occurs as erythematous patches rather than as wheals, associated with pyrexia, arthralgias, and neutrophils in the blood and skin. A delayed form occurs as erythematous, deep swellings arising 9 to 18 hours after cold challenge without an immediate phase. Exposure to the sun or artificial light sources may be followed by pruritus and erythema with the formation of wheals, angioedema, and occasionally bronchospasm or syncope. 27-30 Solar urticaria may be associated with systemic lupus erythematosus or erythropoietic protoporphyria. Persons may respond to more than one portion ofthe light spectrum. Rare instances of a delayed form of light-induced urticaria have been reported. 3I, 32 Cholinergic urticaria develops after an increase in core body and skin temperature, such as occurs dur-

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Urticaria and angioedema

149

Table II. Physical urticaria and/or angioedema Stimulus and type of response

Mechanical trauma Dermographism Immediate Delayed Pressure Immediate Delayed Vibration Temperature Cold Immediate Delayed Familial Heat Cholinergic Local Light Solar Stress Adrenergic Water Aquagenic

Clinical presentation

Mediators

Erythema, wheal Erythema, wheal, nodules

Histamine Unknown

Erythema, deep local swelling Erythema, deep local swelling, fever, chills, arthralgia Angioedema

Histamine Histamine, LTB4, RETE Histamine

Erythema, wheal, angioedema, headache, hypotension, syncope, wheezing Erythema, deep local swelling Erythema, fever, arthralgia, leukocytosis

Histamine, ECFs, NCF, PGD 2 , PGE2 LTE4, PAP Unknown Unknown

Erythema, small wheal, dizziness, headache, syncope, wheezing, nausea, vomiting, diarrhea Erythema, wheal

Histamine, RCFs, NCF Histamine, PGDz, NCF, complement

Erythema, wheal, angioedema, syncope, wheezing

Histamine, ECFs, NCF

Erythema, wheal with halo

Unknown

Erythema, small wheal

Histamine, NCF

ECF, Eosinophil chemotactic factor; HETE, hydroxyeicosatetraenoic acid; LTB4, leukotriene B4; LTE4, leukotriene E 4; NCF, neutrophil chemotactic factor; PAF, platelet·activating factor. PGD z, prostaglandin D2; PGE2, prostaglandin E2.

ing a warm shower, exercise, or episodes of pyrexia. The eruption appears as distinctive, pruritic, I to 2 mm wheals that are surrounded by large areas of erythema (Fig. 3). Wheezing and tightening of the chest with alterations in pulmonary function tests have been documented during experimental exercise challenge. 33 Heightened bronchial reactivity was demonstrated by increased pulmonary resistance after acetylcholine inhalation. 34 Other systemic features include dizziness, headache, shortness of breath, nausea, vomiting, and diarrhea. Intracutaneous injection of cholinergic agents, such as methacholine chloride, locally elicits the lesion in approximately one third of patients. 35 Exercise-induced anaphylaxis is a disorder in which warmth, pruritus, and urticaria and/or angioedema occur with vascular collapse and pulmonary manifestations. 36 Although urticaria that is

similar to cholinergic urticaria has been reported,37 exercise-induced anaphylaxis is a distinct syndrome without alterations in pulmonary function tests. 38 Heat urticaria is a rare disorder in which wheals develop within minutes after exposure to locally applied heat.39·41 A familial delayed form of local heat urticaria has been described. 42 Adrenergic urticaria occurs as urticaria surrounded by a characteristic white halo that develops during emotional stress. 43 Clinically, the lesions can be elicited by the intracutaneous injection of nonadrenaline. Contact ofthe skin with water of any temperature may result in pruritus alone44 ,45 or rarely urticaria. 46,47 The eruption consists of small wheals resembling cholinergic urticaria. Aquagenic urticaria has been reported in two members of the

Journal of the American Academy of Dermatology

150 Soter Table III. Investigation of chronic idiopathic urticaria and/or angioedema In all patients History and physical examination Provocative tests for physical urticarias Complete blood count with differential analysis Erythrocyte sedimentation rate Urinalysis In certain patients Stool examination for ova and parasites Blood chemistry profile Antinuclear factor Hepatitis B virus surface antigen and antibody Skin tests for IgE-mediated reactions, RAST Thyroid microsomal antibody

CHso*

Cyroproteins Circulating immune complexes Skin biopsy *Measurement of the amount of complement for erythrocytes.

50%

hemolysis of

same family.48 Aquagenic pruritus also occurs in elderly persons with dry skin 49 and in patients with polycythemia vera. 50 Contact urticaria also may occur after direct contact with various substances. 51 Agents such as stinging nettles, arthropod hairs, and chemicals may directly release histamine from mast cells. IMMUNOLOGIC URTICARIA: COMPLEMENT-MEDIATED URTICARIA AND/OR ANGIOEDEMA Hereditary and acquired angioedema. Hereditary angioedema is a dominantly inherited disorder characterized by recurrent episodes of edema involving the skin and mucous membranes as well as the respiratory and gastrointestinal tracts. 52,53 Urticaria is not a manifestation. The episodes of angioedema are self-limited and subside within 72 hours. Involvement of the upper airways is associated with death by asphyxiation in 25% of patients. Abdominal pain is a prominent feature. There is a functional deficiency of the inhibitor of the activated first component of the complement system (CIINH). Depletion of CIINH has been noted in patients with acquired angioedema and certain malignant disorders 54 and in systemic lupus erythematosus. 55 This form of acquired angioedema can be distinguished from hereditary angioedema by the absence of complement abnormalities in family members and by the reduced

levels of the first component of complement, which is present in normal concentrations in patients with hereditary angioedema. Necrotizing venulitis. Chronic urticaria may rarely be a manifestation of underlying cutaneous necrotizing venulitis and is associated with arthralgia, abdominal pain, diffuse glomerulonephritis, benign intracranial hypertension, iritis, and obstructive pulmonary disease. 56 , 57 This type of urticaria has been described variously as hypocomplementemic vasculitis, atypical erythema multiforme, and unusual systemic lupus erythematosus-like syndromes. Low levels of serum complement and Clq precipitins have been reported in some patients; however, serum complement levels are often normal. An urticarial form of necrotizing venulitis may also occur in patients with serum sickness, connective tissue disorders, such as systemic lupus erythematosus58 and Sjogren's syndrome,59 during the prodrome of hepatitis B virus infection,60 and in macroglobulinemia. 6J Reactions to administration of whole blood, plasma, or immunoglobulins. Urticaria may be observed after the administration of blood products. These reactions are the result of immune complex formation and complement activation. Numerous reports have identified aggregates of IgG, capable of fixing complement, as responsible for such reactions. 62 Urticaria occurring after the administration of "(-globulin may depend on IgG antibody to IgA.63 An uncommon mechanism is the transfusion of IgE of donor origin directed toward an antigen to which the recipient is then exposed or the transfusion of a soluble antigen present in the donor preparation into a previously sensitized recipient. Activated Hageman factor fragments have been implicated in urticarial transfusion reactions. NONIMMUNOLOGIC URTICARIA Direct mast cell-releasing agents. Several therapeutic and diagnostic agents have been associated with urticaria and/or angioedema without specific antibody. As many as 5% to 8% of patients receiving radiocontrast media experience such reactions. 64 Opiates, polymyxin B, curare and d-tubocurarine, and radiocontrast media have been documented to release histamine directly from mast cells and basophils. 65,66 Mast cell degranulation in an organ culture of human foreskin keratinocytes can be abrogated by antibody to tumor necrosis factor £x, suggesting that

Volume 25 Number I, Part 2 July 1991

this cytokine may be involved in the formation of wheals. 67

Presumed abnormalities of arachidonic acid metabolism. Urticaria and/or angioedema and ana-

phylactic responses may occur after exposure to aspirin and nonsteroidal antiinflammatory agents. The frequency of these reactions is approximately 1% in an outpatient population68 and has a familial basis. 69 Intolerance to aspirin manifested as bronchospasm occurs primarily in patients with asthma, whereas urticaria and/or angioedema occurs primarily in normal persons or patients with rhinitis. The incidence of aspirin intolerance in patients with chronic urticaria ranges from 20% to 50%.70,7 J Patients who cannot tolerate aspirin may also react to indomethacin or nonsteroidal antiinflammatory agents; in addition, patients have been reported to react to azo dyes, notably tartrazine,n and benzoates used as preservatives,?3 Clinical manifestations of intolerance to these agents may appear from 15 minutes to 20 hours after ingestion. Urticaria and/or angioedema may accompany asthma or occur independently; in the latter case the onset of urticaria may be delayed as long as 20 hourS. 71 IDIOPATHIC URTICARIA

In at least 70% of patients, the cause of chronic episodes of urticaria and/ or angioedema is unknown. I Because this clinical entity is common, follows a capricious course, and is easily recognized, it is frequently associated with concomitant events. Such attributions must be interpreted with caution. Although idiopathic urticaria and/ or angioedema is the most common form of urticaria, angioedema or both, the diagnosis is reached by exclusion. LABORATORY FINDINGS

The antigenic specificity of IgE can be recognized

in vivo by prick skin testing or formerly by passive transfer reaction to humans or monkeys. Routine prick skin testing in patients with chronic idiopathic urticaria has had minimal value. In vitro techniques to assess the presence of specific IgE antibodies include the radioallergosorbent test (RAST), as well as research techniques involving the release of histamine from leukocytes of sensitive persons on antigen challenge or the ability of patients' sera to passively sensitize normal tissues in vitro, such as leukocytes, for the subsequent antigen-induced release of mediators. RAST determinations have not proved to be valuable in uncovering elusive causes of urticaria

Urticaria and angioedema 151 and/or angioedema. The release of histamine from peripheral leukocytes remains a research technique. Mean serum levels of IgE in patients with chronic idiopathic urticaria are normal. . PATHOLOGIC FINDINGS

On histologic examination, edema involving the superficial portion of the dermis is characteristic of urticaria; angioedema involves the deeper dermis and subcutaneous tissue. Both disorders are associated with dilation of the venules. In chronic idiopathic urticaria and/or angioedema, the dermal infiltrating inflammatory cells may be sparse or dense and include various numbers of lymphocytes, neu· trophils, and eosinophils. 74, 75 Major basic protein, a cytotoxic molecule derived from the eosinophil granule, has been demonstrated about blood vessels and dispersed in the dermis in lesions of chronic urticaria76 and delayed pressure urticaria. 77 Mast cell degranulation has been noted in most forms of urticaria and/or angioedema. PATIENT EVALUATION

Evaluation of patients with urticaria and/or an· gioedema begins with a thorough history, with particular emphasis on the recognized causes of urticaria and/or angioedema and a physical examination (Table Ill). (Also see the article by Dr. Kevin Cooper in this supplement.) Some types of urticaria may be identified by their characteristic appearance, such as the small wheals with a large erythematous flare of cholinergic urticaria, the linear wheals in dermographism, and the localization of lesions to exposed areas suggestive of light-induced or cold-induced urticaria. The physical examination in all patients with urticaria should include tests for physical urticaria, such as a brisk stroke to identify dermographism, and application of a warm or cold stimulus for cold-induced urticaria and localized heat ur~ ticaria. Exercise, such as running in place, is useful to elicit cholinergic urticaria. Elicitation of solar urticaria requires instruments available in certain dermatology departments. In most patients with chronic urticaria and/or angioedema, no underlying pathologic disorder can be discerned. Moreover, laboratory tests provide little additional information. 78 ,79 A complete blood count with differential analysis, an erythrocyte sedimentation rate, and a urinalysis may be useful initial tests. The yields in such analyses are low, but certain findings may indicate diagnostic directions.

152 Soter For example, eosinophilia may suggest IgE-mediated allergic disorders or drug reactions, and an elevated erythrocyte sedimentation rate may suggest necrotizing venulitis and indicate patients in whom a skin biopsy test may prove diagnostic. Further diagnostic studies should be selected on the basis of findings elicited by history and physical examination and by results ofscreening tests. A stool examination may show ova and parasites. Abnormal liver function tests and the presence of hepatitis B surface antigen document viral infection. 8o Cryoproteins should be sought in patients with acquired cold urticaria. The presence of thyroid microsomal antibodies may point to patients with thyroid disease and urticaria and/or angioedema. 81 Assessment of serum complement proteins may be helpful to identify not only necrotizing venulitis but also hereditary and acquired dINH deficiency. In transfusion reactions, immunoglobulin analysis may detect an IgA deficiency. The search for antinuclear factor, especially in women, may uncover systemic lupus erythematosus. Skin biopsy tests of chronic urticarial lesions generally are unrewarding and should be undertaken only to identify suspected urticarial vasculitis. There is little role for routine screening by prick skin testing in the diagnosis of specific IgE-mediated antigen sensitivity in chronic urticaria and/or angioedema. Ifa particular antigen is suspected in the genesis of the lesions of a particular patient, prick skin testing may prove diagnostic. The tests should not be performed in patients with dermographism. The routine use of the RAST should be discouraged. Controversy surrounds the role of foods and occult infection in the pathogenesis of chronic urticaria. The yield of sinus79 and dental radiographs is low, and routine tomographic or scintigraphic examinations are not advocated. Tests for the role of foods in urticaria must be rigorously controlled, must be associated with clinical improvement on withdrawal of and exacerbation on reintroduction of the food, and must be verified by double-blind food challenge. Most patients do not manifest this sensitivity when studied in an objective and double-blind fashion. The role for elimination diets is uncertain, and any effect of such a diet is open to question as a potential placebo response. Some patients are reported to benefit from the avoidance of yeasts. 82

Journal of the American Academy of Dermatology

REFERENCES I. Champion RH, Roberts SOB, Carpenter RG, et al. Urticaria and angio-oedema: a review of 554 patients. Br J Dermatol 1969;81:588-97. 2. Juhlin L. Recurrent urticaria: clinical investigation of 330 patients. Br J Dermatol 1981;104:369-81. 3. Soter NA. Physical urticaria/angioedema. Semin Dermatal 1987;6:302-12. 4. Casale TB, Sampson HA, Hanifin J, et al. Guide to physical urticarias. J Allergy Clin Immunol 1988;82:758-63. 5. Ebken RK, Bauschard FA, Levine MI. Dermographism: its definition, demonstration, and prevalence. J Allergy 1968;41 :338-43. 6. Kirby JD, Matthews CNA, James J, et al. The incidence and other aspects of factitious wealing (dermographism). Br J Dermatol 1971 ;85:331-5. 7. Breathnach SM, Allen R, Ward AM, et al. Symptomatic dermographism: natural history, clinical features, laboratory investigations and response to therapy. Clin Exp Dermatol 1983;8:463-75. 8. Kalz F, Bower CM, Pritchard H, et al. Delayed and persistent dermographia. Arch Dermatol Syphilol 1950;61: 772-80. 9. Baughman RD, Jillson OF. Seven specific types ofurticaria: with special reference to delayed persistent dermographism. Ann Allergy 1963;21:248-55. 10. Kaplan AP. Unusual cold-induced disorders: cold-dependent dermatographism and systemic cold urticaria. J Allergy Clin Immunol 1984;73:453-6. II. Mayou SC, Kobza-Black A, Eady RAF, et al. Cholinergic dermographism. Br J DermatoI1986;115:371-7. 12. Ryan TJ, Shim-Young N, TurkJL, etal. Delayed pressure urticaria. Br J Dermatol 1968;80:485-90. 13. Sussman GL, Harvey RP, Schocket AL, et al. Delayed pressure urticaria. J Allergy Clin Immunol 1982;70:33742. 14. Czarnetski BM, Meentken J, Rosenbach T, et al. Clinical, pharmacological and immunological aspects of delayed pressure urticaria. Br J Dermatol 1984;111 :315-23. IS. Lawlor F, Kobza-Black A, Milford WardA, etal. Delayed pressure urticaria: objective evaluation of a variable disease using a dermatographometer and assessment of treatment using colchicine. Br J DermatoI1989;120:403-8. 16. Ting S, Reimann BEF, Rauls DD, et al. Nonfamilial vibration-induced angioedema. J Allergy Clin Immunol 19R3 :71 :546-51 . 17. Lawlor F, Kobza BlackA, Breathnach AS, et al. Vibratory angioedema: lesion induction, clinical features, laboratory and ultrastructural findings and response to therapy. Br J Dermatol 1989;120:93-9. 18. Kaplan AP, Beaven MA. In vivo studies of the pathogenesis of cold urticaria, cholinergic urticaria and vibration-induced swelling. J Invest Dermatol 1976;67:327-32. 19. Wener MH, Metzger WJ, Simon RA, et al. Occupationally acquired vibratory angioedema with secondary carpal tunnel syndrome. Ann Intern Med 1983;98:44-6. 20. Patterson R, Mellies CJ, Blankenship ML, et al. Vibratory angioedema: a hereditary type of physical hypersensitivity. J Allergy Clin Immunol 1972;50: 174-82. 21. Tyson Cl, Czrney D. Cold-induced urticaria in infectious mononucleosis. Med J Aust 1981;1:33-5. 22. Lemanske RF Jr, Bush RK. Cold urticaria in infectious mononucleosis. JAMA 1982;247:1604. 23. Wu LYF, Mesko JW, Peterson BH, et al. Cold urticaria

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24. 25. 26. 27. 28. 29. 30. 31. 32. 33.

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COMMENTARY AND DISCUSSION

Initial evaluation of patients with urticaria Dr. Ellis. Dr. Soter, do you classify all your patients based largely on history, or for example, do you do coded challenges of compounds in blinded capsules? Dr. Soter. The main assessment is done by history. It is the single most important way to evaluate individuals with urticaria-more valuable than any laboratory study-and it is one thing that so many people do not do. Dr. Schwartz. In addition to the patient's history, you have to remember to ask about the family history. About half of all patients with urticaria will have some type of family history. Dr. Ellis. Everybody always says to obtain a history, but it is also true that each time you see the patient you have

Journal of the American Academy of Dermatology to requestion in many areas because new information comes out, and patients give you new information that they denied before. For example, patients classically misreport their drug history. The first time you see a patient, they might say they never take aspirin. However, the second time you see them, they are chewing gum, and it turns out to be Aspergum. Dr. Soter, After we take the history, we seek forms of physical urticaria in anyone with chronic idiopathic disease. It is interesting how often physical urticaria has not been uncovered, even though almost all the patients I see are referred. We do not do aspirin challenges because they are potentially hazardous. Thus our approach includes the history, seeking physical urticarias, and certain laboratory studies depending on the problem. Dr. Greaves. We are a little more adventurous than you. We do challenge with aspirin because we take a very careful history initially, and we routinely do a single-blind study. We give patients 36 capsules, 18 of which contain lactose. The other 18 capsules contain all the different tartrazines and so on, even a low dose of aspirin. Dr. Soter. Do you keep them in the clinic for observation? Dr. Greaves. No, we do not. We send them home. Dr. Soter. You are not worried about a serious reaction? Dr. Greaves. We have had no problems so far, because we take such a careful history to detect potential aspirin reactions. Dr. Ellis. You see predominantly the skin manifestations and not an asthmatic reaction? Dr. Greaves. Yes, that is right. We have patients with diathesis of nasal polyps, asthma, and urticaria, and we certainly would not challenge those people with aspirin. Dr. Cooper. A crucial question when evaluating patients with urticaria is how extensive testing should be and when such testing should begin. Dr. Greaves. In deciding whether you are going to begin a detailed investigation in patients with urticaria, it is crucial to set a cutoff point. I believe a patient must have urticaria for 3 months, every day ofthe week, or most days of the week, before I will actually begin an extended investigation. Dr. Cooper. With patients whose disease is very severe, you are pressed into a workup much sooner. In addition, in patients who are having a poor response to treatment or who are very anxious about possible underlying internal causes, you would be triggered to begin a thorough screening workup sooner. On the other hand, if you have been managing a case empirically for 6 months and it is going well, you would simply continue empiric treatment.