Urticaria and angioedema

LERGY AND

CLINICAL VOLUME

IMMUNOLOGY

72

NUMBER

Continuing

Medical

1

Education

This continuing medical education self-assessment program is sponsored by The American Academy of Allergy and Immunology and supported by a grant-in-aid from Fisons Corporation.

Urticaria Kenneth

and angioedema

P. Mathews,

M.D. Ann Arbor,

Becausetheir common occurrence hasled to familiarity with the diseaseby the general public, patients themselves often make a correct diagnosis of urticaria. The lesionsconsist of circumscribed, slightly elevated swellings that usually are multiple #andvary in size from 1 to 2 mm to many centimetersin diameter. Of particular diagnostic significance is that individual lesions seldom last longer than 24 to 48 hr, although new lesions commonly arise as older ones fade away. Also, hives almost always itch. Angioedemais frequently discussedalong with urticaria becausethe two conditions often occur together; for example, in Champion’s experience in referral practice, 40% of patients with either or both conditions had urticaria alone, 11% had angioedemaalone, and 49% had both.’ However, a much smallerpercentage of children is reported to have both types of lesions.’ Since angioedematousswellingsdevelop in the subcutaneous tissueswhere there are fewer sensory nerve endings, these lesions present clinically as diffuse swellings with little or no pruritus. They are especially apt to develop in areaswith loose subcutaneous tissue, suchasthe eyelids and lips. In contrast to other

From the Division of Allergy, Department of Internal Medicine, University of Michigan, Ann Arbor. Reprint requests: Kenneth P. Mathews, M.D., Division of Allergy, University of Michigan Medical Center, Box 027, D3259 SACB, Ann Arbor, MI 48109.

Mich.

forms of edema, angioedematousswellings do not characteristically occur in dependentareas,they often are asymmetrically distributed, they are transient (but often recurrent), and asjust noted, they often are associated with urticaria. Urticaria and/or angioedema that occur continuously or frequently for longer than about 6 wk are consideredto be chronic. Since the diseaseoften is transient and of minor significance, it is difficult to estimate reliably the cumulative prevalence of urticaria and/or angioedema. In a survey of 1424 students at the University of Michigan, 15.7% reported having had at least one bout of hives. In an earlier survey by Swinny3 of 1000 personsof all agesin Virginia, the cumulative prevalence was 23.6%. On the other hand, lower cumulative prevalanceshave beenreported in Europe. At one point in time, 0.11% of males and 0.14% of females in a survey of 36,475 personsin Sweden objectively exhibited hives.4 U&aria and angioedemaoccur in all age groups, but chronic urticaria and/or angioedemaare more common in middle age, especially in women. As discussedbelow, certain types of these conditions appear to occur more often in atopic persons, but the majority of casesoccur in nonatopic individuals. PATHOLOGY

AND PATHOPHYSIOLOGY

Skin biopsiesof most urticarial lesionsshow edema in the upper dermis, vascular dilatation, and minimal 1

2 Mathews

Abbreviutions

MW: Ci INH: P-K: PUVA: q.i.d.: t.i.d.: SLE: HAE:

used

Molecular weight Ci inhibitor Prausnitz-Kiistner Psoralens and ultraviolet A Four times a day Three times a day Systemic lupus erythematosus Hereditary angioedema

to moderatecellular infiltrate in the dermis, especially about small venules. Theseinfiltrates consistpredominantly of mononuclear cells accompanied in occasional casesby eosinophils; mast cells often are increased in chronic urticaria.” Immunofluorescent staining of theselesionsusually showsno evidence of immunoglobulin, complement, or fibrin deposition. However, in a small subgroup of patients with urticaria associated with vasculitis, the findings are much more striking. Here one finds a leukocytoclastic inflammatory responsecharacterized by polymorphonuclear cell infiltration (particularly about the venules), leukocytoclasis with nuclear dust, endothelial proliferation, fibrinoid deposits, and sometimesextravasation of red blood cells.6-Y In these instances, immunofluorescent staining often shows immunoglobulin and complement deposition in the walls of small venulesin the sameareaswhere inflammation is presentby light microscopy, but occasionally theseimmunoreactantsare observed in a granular pattern at the dermal-epidermal junction. C3, fibrin, and IgM are the agentsmost often detected by immunofluorescence.’ Electron microscopy of such lesions shows electron-densedepositsbetween endothelial cells and pericytes within the basementmembraneof postcapillary venules. However, it should be emphasizedthat leukocytoclastic vasculitis is found in only a minority of casesof urticaria (e.g., one of 43 patients recently reported by Natbony et al.5). Historically, efforts to delineatethe pathogenesisof urticaria initially focused on a possible role for histamine. lntracutaneous injections of histamine in humans reproduce the pruritic wheal-and-flare reaction typical for urticaria; although some of the other candidate mediators discussedbelow produce swelling and redness, the itching, wheal, and flare may be absent. Although the capacity of antihistaminic drugs to inhibit urtication in many instancesis suggestive, it doesnot firmly prove a role for histamine, sincemost of these drugs have additional pharmacologic effects (anticholinergic, local anesthetic, central nervous system effects, etc.). Some of the most impressiveevidence in support of a role for histamine in urticaria

comesfrom the study of physical urticarias. Numbers of investigators have found that if one placesthe distal extremity of a patient with cold urticaria in cold water, there is a transient elevation of histaminelevels in venous plasma from the chilled extremity as it is rewarmed. Interestingly, venous plasma histamine in the opposite extremity usually is normai, in accord with the fact that the biological half-life of histamine in the human intravascular compartment is well under 1 min. This also probably explains why plasma histamine levels are usually normal in other forms of urticaria and angioedemawhere there is not such a massiveand rapid releaseof histamine asin challenging patients with physical stimuli. In addition to cold urticaria, transient elevations in plasma histamine have been found after challenging somepatients with solar urticaria, dermographism,cholinergic urticaria, vibratory angioedema,and aquagenicurticaria. Chilling the blood of patients with cold urticaria in vitro does not result in basophil histaminerelease, but histamine releasedoes occur after chilling (and rewarming) skin biopsies from these patients.lO However, it should be noted that these observations do not prove that histamine actually is causing the skin lesions. since other mast cell products also can be found in these venous effluents. Indeed. a high-molecularweight neutrophil chemotactic factor was originally discovered in these sera,” and more recently Wassermanet al.‘” have found three types of eosinophil chemotactic factors in theseeffluents: The ECF-A tetrapeptides, a highly acidic 1000 to 3000 MW fraction that is chemotactic for monocytes as well as for eosinophils, and a lessacidic 1000 to 3000 MW fraction that attracts only eosinophils. In contrast to physical urticarias, plasmahistamine hasbeen reported to be normal but whole blood histamine and basophil counts decreased in other allergic urticarias. I” This would be in accord with histaminereleasefrom circulating basophils in these patients, with subsequent rapid clearance of histamine from the plasma. It is more difficult to explain recent observations that skin histamineI or the histamine content of vesicles induced over urticarial lesionsi is elevated in patients with chronic urticaria, although usually the histamine levels are higher in uninvolved than involved skin. However, thesechemical measurementsare in accord with recent observationsindicating increasednumbers of mast cells in the skin of chronic urticaria patients.” One might speculatethat thesepatients have “leaky ” mast cells and/or basophils, but there actually is decreased histamine release by heterologous anti-IgE antibodiesfrom peripheral blood basophilsof chronic urticaria patients ascompared with normal controls. ” Possibly an in vivo “desensitization” has occurred,

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since thesecells respondnormally to chemical histamine releasers.Eosinophil chemotactic factor release by anti-IgE also is impaired in chronic urticaria.” Sir Thomas Lewis’* in particular called attention to the possiblerole of histamine in the pathogenesisof urticaria during the 1920sin an era when the concept also had evolved that allergic symptoms were due to histamine. Accordingly the deduction was reached that urticaria must be due to allergy, a concept that completely dominated thinking about urticaria for decades. Although the concept is valid for many cases of acute urticaria, it gradually became apparent that no IgE-mediated allergy could be discovered in the large majority of cases of chronic urticaria or angioedema. Accordingly, other pathogenetic mechanisms must be considered. One possibility is that histamine release may occur as a result of nonimmunologic mechanismsor by immune processesnot involving IgE. An example of the former is cholinergic urticaria. Patients afflicted with this disorder have hives featuring tiny wheals surroundedby large areas of erythema, and the lesionsare brought on by exertion, exercise, or emotional stress. Studies of these patients by British investigators almost 50 yr ago led to the conclusion that acetycholine derived from cutaneous cholinergic nerve endings seemed to be involved in producing the lesions, although histamine releasemay be the final step in the process.I9 Modern studies*”in which cholinergic urticaria is provoked by having patients in plastic occlusive suitsexerciseon a treadmill indicate that the expected sweating, pruritus, and urticaria may be accompaniedby wheezing, airways obstruction, and increasedplasmahistamine, neutrophil chemotactic activity, and eosinophil chemotactic activity. Trauma is another mechanismfor nonimmunologichistaminerelease.Examples include welts resulting from a whip lash or the urtication that develops when one rubs cutaneouslesionsof urticaria pigmentosa, which are benign mast cell tumors. In addition, pharmacologists have known for decades that there are a large number of compounds which produce histamine release the first time that animal tissuesare perfused with them.*’ These include many drugs used clinically, including morphine, codeine, meperidine, d- tubocurarine, polymyxin antibiotics, and thiamine. Indeed, it is a common practice to use codeine as a positive control in performing ordinary allergy skin testing, since almost all normal humans give a wheal-and-erythema responseto this agent. Thus one may conceptualize a final pathway leading to urticaria from mast cell mediator releaseinto which there may be both nonimmunologic and immunologic inputs.22 The possiblerole of complementhasbeen assessed

3

in an attempt to account for urticaria or angioedema not explicable on an IgE-mediated allergic basis. Since the C5a, C3a, and C4a anaphylatoxins all are known to be very potent histamine releasersfrom mast cells, their generation would provide a means whereby complement activation could result in urticaria. As indicated by the following list, some cryoglobulins are capable of activating complement both in vitro and in vivo: Complement abnormalities in acquired urticaria and angioedema Cryoglobulinemia Connective tissue disease (e.g., SLE) Leukocytoclastic vasculitis Drugs (rarely): lidocaine; procarbazine Localized heat urticaria (sometimes)

AcquiredCi INH deficiency Idiopathic

urticaria or angioedema (rarely)

In a few clinical casesthis processis associatedwith urticaria rather than the more usualpurpuric lesions.*” An increased incidence of urticaria in patients with SLE has been documented,24and an associationwith complement activation by immune complexes is likely in urticaria accompanying this and other connective tissue diseases,including polymyositis and Sjagren’s syndrome. As discussedabove, there also are a number of reports of urticaria occurring as a cutaneous manifestation of leukocytoclastic vasculitis. Of particular interest are casesof hypocomplementemic urticarial vasculitis” featuring low levels of Clq, C4, C2, C3, normal Clr, Cls, factor B, factor D, and terminal complement components, and 7s proteins that precipitate with Clq. Complement activation also hasbeen reported in rare casesof urticaria associatedwith drugs and in one caseof localized heat urticaria. Its role in hereditary and acquired forms of angioedemais discussedbelow. Aside from thesespecific situations, there hasbeen only a small number of complement abnormalities uncovered in surveying large numbersof patients with chronic idiopathic urticaria and/or angioedema.Ballow et al.25found decreasedC3 levels in four of 150 suchcases,and Laurel1et al .*’ found decreasedC3 or C4 in five of 150 patients. In my experience, none of 125 patients with chronic urticaria has had decreased C3 or C4 levels, two of 217 had a low Clq level, and one of 186 had reduced factor B. On the other hand, Mathison et al.” found evidence of either classicalor alternative pathway activation in 10 of 72 cases. It should be noted, however, that there could be biologically significant cleavage of complement componentswithout a grossreduction in complementlevels. In addition to histamine and complement, other biologically active substancessuch as kinins, arachi-

4 Mathews donic acid metabolites, plasmin, or serotonin could play a pathogenetic role in some cases of urticaria and/or angioedema. Stimulation of mast cells can lead to kinin generation secondarily, as a result of either the secretion of mast cell kallikrein or the cleavage of kininogen after its escape into connective tissue consequent to increased vascular permeability produced by histamine or other mediators. Indeed, as discussed below, a kinin-like substance is thought to be the immediate cause of the swelling in patients with HAE. A primary role in urticaria seems less likely in that the injection of bradykinin into human skin produces swelling and redness but not a typical pruritic, wheal-and-flare reaction. However, European investigators have reported that patients with chronic urticaria or angioedema have increased intracutaneous responses to kallikrein and bradykinin.“’ Since plasmin may be capable of cleaving kinin-like substances from precursors and also can cleave complement components, it is tempting to speculate that plasmin also could produce swelling. Since aspirin or other cyclooxygenase inhibitors often exacerbate chronic urticaria and angioedema, it is possible that certain arachidonic acid metabolite(s) may play a pathogenic role in these conditions. For example, leukotriene Dd causes increased vascular permeability in human skin at very low concentrations. Rare cases of urticaria accompanied by increased levels of plasma serotonin also have been reported, but it should be noted that in contrast to many other mammalian species, human mast cells are devoid of serotonin. Finally, there is recent evidence that substance P. a neuropeptide, is a histamine liberator and may be responsible for the “flare” surrounding urticarial wheals. ‘!’ Another plausible approach to explaining idiopathic cases of urticaria and angioedema is to postulate a deficiency of an inhibitor of some urticariogenic or permeability-increasing substance. As discussed below, the documented role of Ci INH deficiency in HAE lends credence to this possibility. However, my studies of a large number of sera from patients with chronic idiopathic urticaria and angioedema have shown very infrequent subnormal values of the major serum protease inhibitors: alpha,-protease inhibitor, alpha,-antichymotrypsin, alpha,-macroglobulin, antithrombin III, inter-alpha inhibitor, Ci INH, or alpha,-plasmin inhibitor. Most other investigators also have not found consistent abnormalities in these inhibitory substances,:‘O, ‘j’ although it is possible that there could be small subgroups in which deficiencies of these substances might be significant. An example of the latter is a reported single family afflicted with

serum carboxypeptidase N (anaphylatoxin Inactivator) deficiency.“’ It is presumed that impaired breakdown of the C5a, C3a. and C4a anaphylatoxins or bradykinin predisposed the propositus of this family to the frequent attacks of angiocdema which he ha% had for the past 17 years. In addition to these factors that might play an underlying role in urticaria and angioedema. there alho are a number of modulating t’actors which often are rather conspicuous clinically. These include agents that produce cutaneous vasodilation, such BL heat, exertion, alcoholic drinks, fever. emotional upsets. and hyperthyroidism: ‘)‘I Other endocrine Factors also may play a modulating role either by regulating mediator secretion or by direct effects on blood vessels. Obvious examples would be beta- and alphaadrenergic agents. In addition, some women have striking premenstrual exacerbations of their chronic urticaria, and in a few cases lesions appear only at such times. Antibodies to progesterone might play a role in some cases.“.’ Finally, as discussed below. genetic factors also are involved in the pathogenesis of some types of angioedema or urticaria. CLINICAL

ASSESSAllENT

In a few instances the appearance of the lesions gives a clue to pathogenesis: cholinergic urticaiia has been described above; linear wheals suggest dermographism; lesions limited to exposed areas suggest possible solar or cold urticaria; hives mainly on the lower extremities suggest urticarial vasculitis or papular urticaria; small perifollicular hives occur in aquagenic urticaria; and in urticaria pigmentosa there are persistent, pigmented, macular, papular, or nodular lesions which urticate when rubbed. Unfortunately, however, in the vast majority of cases the appearance of the lesions gives no indication of the cause of urticaria or angiocdema. The search for possible clues about pathogenesis is appropriately initiated by the types of questions used to assess patients with other types of potentially allergic disease. When and where does the patient have symptoms? What has the patient suspected to cause difficulty’? As indicated previously. one is more likely to be able to ascertain a cause for acute urticaria or angioedema than for chronic problems. Thus, especially vigorous “detective work” is more likely to be productive in acute or intermittent cases, although at the outset one can not differentiate acute urticaria and angioedema from the beginning of chronic. idiopathic disease. Even in chronic cases the patient merits a reasonable effort at trying to identify a specific -etiulogy, but the low yield of success in such instances

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argues against an exhaustive and expensive assessment that is most likely to yield only frustration. Possibilities to be considered are as follows**: Alleged causes of urticaria and angioedema Drugs and foreign sera Contact urticaria Connective tissue diseases Foods and food additives Neoplasms Infection Psychic factors Physical agents Inhalants Genetic types Miscellaneous Bites and stings Drugs

and

foreign

sera

These are someof the most commonly identifiable causesof urticaria or angioedema. Most often IgE antibodiesto a drug metabolite are presumedto cause the reaction, but as discussedabove, somedrugs are pharmacologic histamine liberators.21Sometimesurticaria or angioedema are part of a serum sickness syndrome. These cutaneousmanifestationsmight be due either to complement activation associatedwith the immune complex vasculitis or to the development of IgE antibodiesalong with IgG and IgM antibodies. The penicillins have been the drugs that most often produce urticaria or angioedema,but numerousother medicationsalso have been implicated. A careful history of all drugs taken by all possibleroutes of administration remains the cornerstonefor diagnosing drug allergy. In addition to drugs actually causing the difficulty, it is noteworthy that aspirin is said to causeexacerbations in up to 40% of casesof chronic urticaria and/or angioedema, even though these patients continue to have difficulty when aspirin is assiduouslyavoided. Accordingly, it is common to advise patients with chronic urticaria and angioedema that they should avoid this drug or, at the very least, to forewarn them of possible difficulty from this source. In rare cases the aspirin intolerance may be due to IgE antibodies, particularly if the drug is contaminated with the reactive aspirin anhydride derivative. As in the case of aspirin intolerance manifestedby asthma, however, it is more likely that the adverse effect of aspirin in some way is related to its activity in blocking the cyclooxygenase pathway of arachidonic acid metabolism. This leadsto enhancedreleaseof histamine and SRS-A as well as other potentially harmful effects. Accordingly, other drugs that inhibit cyclooxygenase, such as indomethacin, phenylbutasone, and other nonsteroidal anti-inflammatory agents, also have the potential for flaring urticaria and angioedema.In addition, as discussedbelow, tartrazine yellow dye, which is used as a coloring agent in many medications, might causedifficulty in this group of patients.

5

Foods and food additives In the community at large, many casesof acute urticaria or angioedemaare causedby food allergy. Fish, seafood, nuts, peanuts, and egg are among the most common offenders, although numerous other foods also are culprits at times. Since this relationship is widely known to the public, patients often make the correct diagnosis without medical assistance.This type of urticaria or angioedemaappearsto be more frequent in atopic than in nonatopic individuals, presumably becauseit is IgE mediated. As a causefor chronic urticaria or angioedema, however, food allergy only rarely can be implicated. A retrospective food diary is of value in making the diagnosisin acute sporadic cases, whereas elimination diets are employed when symptoms are frequent or continuous. In addition to the food antigens themselves, there has been much recent interest in the possibility that food additives may causeurticaria or angioedema.An example is the use of sodium or potassiumsulfite or metabisulfite as antioxidants in such foods as lettuce, shrimp, or wines.a5 Vegetable gums such as acacia, gum arabic, tragacanth, quince, carob seed, or caregeenanalso have been known as occasional allergensfor many years. In addition to its presencein drugs, tartrazine yellow dye (FD&C No. 5) is added to a large variety of foodstuffs-particularly colored soft drinks. Several investigators have reported exacerbations of chronic urticaria or angioedemawhen patients are fed tartrazine. However, the deduction that this dye is a major and common cause of these conditions appears doubtful, particularly since the amount of dye required to provoke a responseoften substantially exceedsthe amount likely to be encountered in an ordinary diet. Another reasonfor concern is that it is very difficult to determine whether the development of new lesionsin patients with frequent or continuous hives can validly be ascribed to the introduction of a test material. It also is noteworthy that someelimination diets commonly usedto rule out food allergy are essentially tartrazine free, thus indicating that the usual failure to improve speaksagainst tartrazine reactivity as well asto food allergy. Similar concerns apply to the question of whether other azodyes, benzoic acid, 4-hydroxybenzoic acid, and salicylates in foods are as important as claimed by someinvestigators. Infection Clinically, urticaria rather frequently seemsto be associatedwith virus infections in children. In the prodromal phaseof hepatitis B virus infections, there may be a vasculitis due to complement activation by

6 Mathews immune complexes and manifested by arthralgias, arthritis, and fever.“” Occasionally the cutaneous manifestation of this process is urticaria, which usually disappears with the onset of jaundice. Although less well documented, it is likely that immune complexes with other virus antigens also can lead to the same outcome. An association of urticaria with parasitic infection has been quite well demonstrated in a few cases, but routinely testing stool specimens for ova and parasites in temperate areas has a very low yield of helpful information. An area of even greater uncertainty relates to whether chronic, focal pyogenic infection might be of etiologic importance. This concept dominated speculation about the causes of urticaria and angioedema 50 yr ago, just as it was thought to be related to a wide variety of obscure neurologic and rheumatic conditions in the early years of the century. It is of importance because it determines whether one should expend considerable money and effort in ruling out infection in such sites as the paranasal sinuses, teeth, gums, tonsils, gallbladder, and genitourinary tract. However, in a careful study of 106 hospitalized patients with chronic urticaria and/or angioedema by Rorsman,‘” evidence of chronic focal infection was found in 78, but only four of 64 improved after treatment-a result in accord with my experience. On the other hand, Jacobson et al.:” found abnormal sinus X-rays in 17% of patients with chronic urticaria or angioedema. In rather rare cases, these lesions have been associated with cutaneous fungus infections, but the efficacy of ridding the gastrointestinal tract of Cundidu requires further confirmation. In summary, the possibility that infection might be causingor contributing to urticaria or angioedema requires that a thorough general medicinal history and physical examination be performed, but an expensive and exhaustive researchfor inapparentinfection appearsunwarranted. Even when infection is found, treatment thereof may or may not help the cutaneousproblem. Psychic factors It is common clinical experience to observeexacerbationsof urticaria during periodsof emotional stress. A pathophysiologic explanation for this observation is that urticaria is likely to worsen when blood flow to the skin is increased(seeabove). This possibility was documented many years ago by the observations of Graham and Wolf.“” They found that bringing up stressful material during psychiatric interviews can lead to increased skin temperature, changes in the cutaneous reactive hyperemia threshold, and sometimes the concomitant development of dermatographism or urticaria in susceptiblesubjects. However, this still doesnot explain why somepatients develop hives

rather than tension headaches,functional gastroinrestinal symptoms, or a variety of other psychosomatic complaints. In addition, psychiatrists ha\,e nor been able to agreeon a personality profile charauter.istict‘;il patients with urticaria. Accordingly. it appearslikeI>. that urticaria may be aggravated by emotional btrcsy. but to passoff the entire problem as a ps~~&osomatic illness is to blame patients’ psyches for phjslcians. currently incomplete understanding of the disease Inhalants Urticaria or angioedema occasionally may bc caused by inhaled allergens, but in these cases the cutaneous eruption almost invariably ih associated with upper or lower respiratory tract symptoms. A relatively common example would be symptoms of this type on exposure to cats or horses. More rarely. one may observe seasonalurticaria associatedwith hay fever. Bites and stings Urticaria and angioedema are the most common manifestationsof anaphylactic reactions to Hymenoptera stings. Occasionally fire ants, deer flies, black flies, mosquitos,or kissing bugs(Triatoma protracmj may induce similar reactions. The term papular urticaria is used to describe urticaria-like lesions most often seenon the lower extremities of children as a result of bites from such insects as bedbugs, fleas. or sometypes of mites. These lesions, however. tend to be more persistentthan ordinary hives. Contact urticaria The usual allergic responseof the skin to contact with allergens, allergic contact dermatitis (e.g., to poison ivy or nickel), represents primarily a cellmediatedform of hypersensitivity. However, in some casesan urticarial responsemay be elicited. Rather often the offending agentsactually penetrate the skin and inject mediator-releasing substances.Examples are nettles, cat scratches, various forms of sea life such as Portugueseman-of-war and sea nettles, and insect-derived materials such as moth or butterfly scales,tarantula hairs, and caterpillar foot processes. Epidemic urticaria has been described aboard ships where the cargo was heavily contaminated with moths. In addition there are some casesof urticaria arising through contact with apparently intact skin. Causative agents include drugs, occupationally employed chemicals, and foods.“” Connective

tissue disease

As discussedabove, urticaria may occur in association with SLE, Sjagren’s syndrome, polymyositis, and various forms of hypersensitivity or leukocyto-

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and

angioedema

elastic vasculitis. Although palpable purpura is a more common cutaneous manifestation of these diseases, u&aria may occur particularly in serum sickness, essential mixed cryoglobulinemia, and hypocomplementemic vasculitis.” The latter patients also may have arthralgias, arthritis, fever, neurologic abnormalities, pseudotumor cerebri, asthma, conjunctivitis, episcleritis, uveitis, angioedema, Raynaud’s phenomenon, lymphadenopathy, weakness,abdominal pain, chronic obstructive pulmonary disease, or renal involvement. These occurrences provide additional, cogent reasonsfor doing a thorough, general medical work-up and appropriate screeninglaboratory studies, particularly if the urticaria or angioedemais chronic.

Transient forms Delayed dermatographism Delayed-pressure urticaria Immediate-pressure urticaria 2. Thermal Cold Acquired Idiopathic Associated with cryoglobulinemia, cryofibrinogenemia, or cold hemolysins Transient forms associated with other factors Delayed cold-induced urticaria Familial cold urticaria

Neoplasms

3. Light Solar urticaria Probably allergic types Associated with abnormal protoporphyrin lism Idiopathic types

There are a number of reports of urticaria associated with neoplasms, especially lymphomas, but since both types of lesionsare common, the relationship at times may be coincidental. More recently, however, a number of instanceshave beenreported of lymphomas or carcinomas associated with angioedema where there was an acquired Ci INH deficiency. ‘O In contrast to patients with hereditary angioedema (seebelow), these patients have decreased Clq levels in addition to low C4 and Ci INH. Hence, these measurementsshould be made in all patients with neoplasmsassociatedwith angioedema, not only for diagnostic reasonsbut also becausethey may respondto treatment usually employed in hereditary angioedema. In patients without a known neoplasm, prudence again calls for a thorough history, physical examination, and screeninglaboratory studies. Neoplasmespecially needsto be excluded in patients found to have a cryoproteinemia. In the absence of any suggestionof a neoplasm, currently available information does not warrant an exhaustive study for an inapparent neoplasm in every patient presenting with hives. Genetic types These are discussedbelow. Physical agents Increasing attention is being paid to the following as causesfor urticaria or angioedema: Physical

agents

producing

I. Mechanical Dermatographism Primary Idiopathic Allergic Secondary Cutaneous mastocytosis

urticaria

7

Heat Cholinergic Localized heat urticaria Familial localized heat urticaria of delayed type

metabo-

Dermatographism (dermographism,dermographia, skin writing) is present in about 2% to 5% of the populace. It is more readily elicited by stroking the back than the forearm and should be routinely tested for in casesof urticaria. Since excessivepressurewill produce a wheal in normal skin, various mechanical devices have been suggestedfor semiquantitating the dermographic stimulus for investigative purposes. Plasmahistamine elevations can be induced by rubbing large skin areas.Although it has beenpresumed that in many instancesdetiographism is due simply to mechanicaldisruption of cutaneousmastcells with mediator release,the dermographismsometimescan be transferred by the P-K technique. Newcomb and Nelson4’ showed that it is the IgE fraction of serum which is responsiblefor theseP-K reactions. As in the caseof the other physical urticarias, the nature of this IgE is not known; antibody to altered or exposed skin antigensresulting from trauma is one possibility. As might be expected, dermographism is especially likely to occur in patients with increasednumbersof cutaneousmast cells. Urtication from rubbing the lesions of urticaria pigmentosa has been mentioned previously, and it also may be seenin patients with more diffuse cutaneous mastocytosis. Subjects with this latter condition may have thickened skin with accentuation of the skin folds, or sometimesthe skin may have a fairly normal gross appearance.Another secondary form of dermographismis its occurrence after allergic reactions to drugs, especially penicillin. Investigationally it can be induced in human skin by the topical application of tetrahydrofurfuryl nicotinate (Trafuril). In recent years there also has been an in-

8 Mathews creasing awareness of combined forms of physical urticaria in some patients, including dermographism with cholinergic urticaria or cold allergy. Sometimes symptomatic dermographism provides an explanation for all the patient’s difficulty with itching wheals, whereas in other cases it may be coincidental or only a minor aspect of the problem. Delayed dermographism features whealing and erythema about 6 to 8 hr after the skin is stroked. It is a rare condition which may or may not coexist with immediate dermographism. Deluged-pressure urticariu is a sometimes disabling condition that may occur alone but more often is an added feature of chronic idiopathic urticaria and angioedema.” Typically these patients develop deep, painful swelling about 4 to 6 hr after pressure is applied to the skin, with the palms, soles, and buttocks being most often involved. Common examples would be swelling of the hands after shovehng or swollen soles of the feet after walking on a hard surface. There frequently are associated constitutional symptoms such as malaise, fever, chills, arthralgia, and headache. and leukocytosis may develop during attacks. A useful confirmatory diagnostic test is to attach two sandbags or jugs of fluid with a combined weight of 15 lb to either end of a strap and apply this over the shouider or thigh for 10 to 1.5 min. Then the site is observed for a number of hours for the development of linear wheals. Biopsy of these lesions shows predominantly mononuclear cells with or without an infiltrate of eosinophils; immunofluorescent staining is negative.‘?. “I This condition is refractory to antihistamine therapy, the more severely afflicted patients usually requiring intermittent or low-dose prednisone. Sussman et al.1’ recently reported that 80% of 17 patients responded to treatment with nonsteroidal anti-inflammatory drugs. There also are rare cases of immediate-pressure urticaria, and these are more easily managed. This condition is similar to the recently described red dermographism, which is elicited by rubbing the skin. Temperature changes also induce urticaria or angioedema with significant frequency. As discussed below, there are two genetic forms of cold urticaria. Acquired cold urticaria has been reported to occur transiently in association with the administration of drugs such as griseofulvin or with infections such as infectious mononucleosis. It also may be associated with other physical allergies such as cholinergic urticaria or dermographism. In fact, there have been recently described patients in whom cold exposure has induced lesions typical of cholinergic urticaria4’ and cases of cold dependent dermatographism. Cold reflex urticaria also has been described. In addition, cold urticaria may occur secondarily to cryoglobulin-

emia, cryofibrinogenemia (rarely), heparin-precipitable cryoprecipitate (very rarely). or cold hemolysins (very rarely). Accordingly, blood from patients with this diagnosis should be (properlyj tested for at least the first two of these cryoproteins. allowing 5 days for the precipitation of cryoglobulins. If present, they can be washed, redissolved in warm buffer. quantitated.. and characterized as to type. Cryofibrinogens ‘ire more often observed in patients with connective tix-sue, malignant, or hematopoietic disease than with urticaria. Heparin-precipitable cryoprecipitare con-sists of cold-insoluble globulin (fibronectinb and fibrinogen and is most often increased in patients with inflammatory connective tissue diseases. but it has been observed in association with cold onicaria. If cold urticaria is associated with hemolysis or cold hemoglobinuria, serologic tests for congenital or tertiary syphilis should be carried out and the diagnosis confirmed by the Donath-Landsteiner test. in which hemolysis is observed after chilled blood is rcwarmed. However, this disease now is almost extinct. Cold urticaria also has been reported in a patient with complement C2 deficiency, By far the most common form of cold urticaria or angioedema is the acquired. idiopathic type. The diagnosis generally is apparent from the history of lesions developing on exposed surfaces with changes in air temperature or on contact with cold water. Recognition of the diagnosis is important because it has been responsible for deaths from swimming in cold water, with massive mediator release, syncope. and drowning. The diagnosis often can be confirmed by the simple ice cube test: place an ice cube on an extremity for 3 to 5 min and then observe the area for the development of a pruritic welt. surrounded by erythema, which mimics the exact size and shape of the ice cube as the skin rewarms over the following 5 to 15 min. This test, however, is not invariably positive, and more sophisticated procedures for determining the erythematous response to the applications of chilled metal devices have been described. ” As in the case of other physical allergies, cold urticaria sometimes can be passively transferred to normal skin by the P-K test. Generally it is the IgE in serum that confers this passive sensitization, although occasionally IgM has been reported to be responsible. Data of Kaplan et al. lo largely exclude the possibility that aggregation of serum IgE by the cold is responsible for this phenomenon. The hypothesis that IgE antibodies are generated to skin proteins exposed or modified by the cold remains neither substantiated nor refuted. In addition to P-K testing, as discussed above the study of venous effluents from the previously chilled extremities of patients with cold urticaria has

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provided a productive clinical model for studying mediator release from human skin.“6, 47 Hrut urticaria is caused by the opposite thermal stimulus, heat, which is often an aggravating factor in chronic idiopathic urticaria and a dominant factor in causing cholinergic urticaria (along with exercise and emotional tension). In addition to the previously described rather characteristic appearance of the lesions of cholinergic urticaria, this diagnosis often can be confirmed by having the patient exercise. Wearing a wet suit or plastic occlusive suit while exercising on a treadmill is especially provocative.‘o The British investigators’” who originally described cholinergic urticaria almost 50 years ago reproduced the lesions by immersing both legs for 40 min in water maintained at about 44” C. Another test used to confirm the diagnosis is to inject 0.01 mg of methacholine in 0.05 ml of saline intracutaneously and look for satellite wheals in the area surrounding the injection, but this procedure is associated with many false negative responses. Cholinergic urticaria needs to be differentiated from exercise-induced anaphylaxis.4x The latter condition typically features pruritus, larger urticarial lesions, collapse, and elicitation by exercise but not by heat, but a few cases have features of both. In addition to the systemic effects of heat, there also is localized heat urticaria, which, however, is much less common than cold urticaria. The diagnosis is confirmed by eliciting prompt whealing by holding a test tube containing warm water against the skin. Passive transfer has not been achieved, but release of histamine has been noted from an extremity submerged in warm water. Localized heat urticaria and cold urticaria have been reported in the same individual, and a family has been described featuring localized heat urticaria of delayed type. Solar urticaria is one of the less common adverse effects of sunlight on human skin. Usually the diagnosis is evident from the history and distribution of the skin lesions, and, if desired, the diagnosis can be confirmed by controlled exposure to light. Uncommon as it may be, solar urticaria has been divided up into several subgroups by various investigators on the basis of the wavelength of light eliciting the reaction.“Y One type results from a genetic abnormality in protoporphyrin IX metabolism and is diagnosed by finding abnormal protoporphyrin levels in red cells or feces. Two other types appear in some way to be immunologically mediated in that they can be passively transferred by the P-K technique, IgE being the serum fraction responsible for this. Histamine release after ultraviolet light irradiation also can be demonstrated. The mechanism(s) involved in the other types is totally unknown.

Urticaria

Miscellaneous

and

angioedema

9

types

Aquagenic urticaria consists of tiny, perifollicular urticarial lesions developing in areas of contact between the skin and water at body temperature. The diagnosis is confirmed by the “tepid towel test’ ‘: application of a towel soaked in 37” C water for 30 min. The lesions may result from formation of a histamine-liberating substance by the action of water on sweat or sebum: mast cells in the water-challenged skin are degranulated and plasma histamine may be transiently elevated. However, cholinergic mechanisms may be additionally involved,“O and aquagenic urticaria has been reported in association with cholinergic urticaria.“’ Familial cases have been reported. Urticaria also has been reported to be caused by implanted materials such as Vitallium cups or nails, tantalum staples, analgam fillings, or retained myelographic contrast medium. Other cases have been reported in association with hyperthyroidism, polycythemia Vera, the hemolytic-uremic syndrome, and pregnancy and resulting from direct electric current stimulation. DIAGNOSTK

PROCEDURES

Needless to say, if the history or physical examination gives any clues about the cause(s) of the patient’s urticaria or angioedema, these should be pursued by the appropriate tests. 22 This might include dietary intervention, tests for SLE, exercise test for cholinergic urticaria, ice cube test, delayed-pressure test, e INH and C4 measurements, etc. Skin tests with atopic allergens are likely to be helpful only in exceptional patients with suspected inhalant allergy or in some cases of suspected food allergy where the history is not diagnostic. In the many cases of chronic urticaria and angioedema where the history provides no clues about etiology, a major objective of the evaluation is to exclude important underlying diseases. Accordingly, it is reasonable to supplement the complete physical examination (which should include testing for dermographism) with a complete and differential blood count, urinalysis, sedimentation rate, and antinuclear antigen test. In sporadic cases it is simple enough to have patients retroactively keep a diary of foods ingested within 6 to 12 hr of their attacks. Beyond this point, the physician faces a difficult dilemma: there are many additional tests that may be helpful in a few patients, but the cost effectiveness of these procedures is very poor when applied routinely to patients with chronic urticaria or angioedema.“7 At some point in time, the judicious physician must call a halt to diagnostic testing, accepting the fact that these conditions often have no known cause in our present state of knowledge. Endless testing not only is waste-

10 Mathews ful but also leads to increasing frustration on the part of both the patient and physician. Indeed, in cases of chronic urticaria and angioedema, it generally is advisable to tell the patient at the outset that no specific cause is likely to be found (though an effort will be made) but that usually the diseasecan be controlled symptomatically until a spontaneousremissionoccurs. Among the additional teststo be considered,a trial of a food elimination diet in patients with frequent or persistent symptoms is not costly but hasa low yield of success.Having the patient drink the orange drink “Tang,” which contains tartrazine yellow dye, is an easy way to assessthe potential importance of this food additive. One is more inclined to searchfor ova and parasitesin the stoolsof patients with prominent eosinophilia, high IgE levels, gastrointestinal symptoms, or recent travel to tropical countries. Physical findings suggestive of hyperthyroidism would justify appropriate tests, and chest and/or sinus roentgenograms often are obtained. Many other tests-skin biopsy with immunofluorescentstaining, complement levels, hepatitis B antigen and antibodies, cryoglobulins, and other testsfor immunecomplexes (Clq binding, Raji cell)-are directed particularly toward the possibility of an underlying cutaneousvasculitis. The presence of joint symptoms, fever, other systemic symptoms, or a high sedimentationrate would especially encouragethis type of investigation. Finally, a simple clinical maneuver in dealing with patients who have not changedtheir environment since the onsetof chronic urticaria or angioedema is to determine whether getting away from home, as well as from work, on their next vacation period influences the course of the disease.This gives some indication of whether extrinsic environmental factors are likely to be important.

TREATMENT Obviously the preferred form of treatment for urticaria and angioedemais avoidance of the causative agent(s) when these can be identified and when avoidance is feasible. This generally is the casewhen allergy to drugs, foods, inhalants, insects,and contactants is involved. In casesof papular urticaria due to insect bites, the family pets also may require therapy. An explanation of the diseaseprocessand its triggers should be helpful for patients with cholinergic urticaria, dermatographism, and perhapsdelayed-pressure urticaria. Patients with cold allergy should be forewarned about the dangers of swimming in cool water and should never swim alone. Such common sensemeasuresas wearing warm socks and gloves help to protect against cold air, but in extreme cases wrapping most of the face in a scarf or wearing a ski face mask or even a mask over the nose and mouth

may be necessary. In cases of mild solar urticarla, simple precautionary measures such ;I:, uearing broad-brimmed hats and long sleevesmay suf‘fice. !r! more severe cases sun screens contaming par+ aminobenzoic acid help to protect against light in the 28.5to 320 nm wavelengths. and chloroquine hashecn reported to be helpful in someinstances.Of course. ?i an underlying infection. parasitic infestation. ronncctive tissue disease, vasculitis. or neoplasm ha:, been identified, therapy should be focused on thebe pncesses. Genetic counsellinp should be oi‘rcreti to families with the hereditary forms of these disease? describedbelow. In addition to avoidance of possiblecausative iiictors, patients with chronic urticaria or angioedemaarc appropriately advised to avoid, to the extent feasible, previously mentioned potentiating factors such as alcoholic drinks, heat, exertion, and aspiri:t, Reassuranceis another important aspectof therapy, since the cutaneouslesionsoften are more frightening in appearancethan the generally favorable prognosis warrants. In reassuringpatients, however, the physician should observe two caveats. One is the threat of laryngeal edema, particularly in patients who already have experienced swelling in the throat. At the least. patients should be aware that this should prompt an immediatevisit to the nearestemergency room. and in cases of recurrent symptoms, prescribing an emergency kit (e.g., ANA-KIT) containing epinephrine i> appropriate. To be effective, this requiresteaching the patient how to usethe kit by demonstrationand practicing self-administration of saline. Alternatively, one may prescribe an Epi-Pen, which is easierto use but more expensive. However, it should be indicated that actual fatalities from laryngeal edema have been limited almost exclusively to casesof hereditary angioedema (see below) and edema after Hymenoptera stings. Thus one shouldbe careful to avoid generating undue anxiety about laryngeal edema. The other caveat concerns the possible presenceof a significant underlying disorder, such as a connective tissue disease, which is not apparent when the patient is first seen. Accordingly, periodic follow-up i\ important even though the skin lesions may be under control with suitable medications. Desensitization or immunotherapy has little role in the management of patients with urticaria or angioedema.The main exception would be patients with Hymenoptera sensitivity together with occasional casesof prophylactic desensitizationto penicillin, insulin, or equine antisera. There also may be rare indications for immunotherapy with inhalar.ts v;hen urticaria accompaniesrespiratory allergy. Proceduresto desensitize to cold and light are cumbersome and generally not very successful, although good results

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72 1

with Psoralen-ultraviolet A treatment have been reported recently. Graded exercise or artificial heat acclimatization during the winter may benefit some patients with cholinergic urticaria. Fortunately most patients respond to some extent to symptomatic therapy for urticaria or angioedema, although regrettably there is a small residue of cases in which neither a cause nor effective symptomatic treatment can be established. Symptomatic treatment is appropriate when the lesions are causing significant symptoms and the causative factors either have not been determined or cannot be adequately avoided. Several types of urticaria respond well to antihistamines of the H, inhibitor type. Among these hydroxyzine is very potent in its capacity to inhibit urtication. However, because of the frequent occurrence of drowsiness, especially at the outset of therapy, it is prudent often to start at a relatively small dose (e.g., 10 mg q.i.d. or 2.5 mg t.i.d.), which is titrated upward until either relief is obtained or excessive sedation occurs. An even more potent H, antagonist in vitro is doxepin, an antidepressant, which also is being tried (75 mg at bedtime) in refractory urticaria, although its usefulness in some patients may be limited by sedation. Cyproheptadine, which has several pharmacologic properties in addition to its action as an H, blocker, is another commonly effective antihistamine and is regarded by some as the drug of choice in cold urticaria, where it is most effectively used prophylactically. However, weight gain due to appetite stimulation and pituitary effects can cause concern if cyproheptadine is used for prolonged periods. When excessive sedation is a problem with these drugs, other antihistamines commonly used for treating hay fever with less sedation often are effective, particularly for acute urticaria. Angioedema may be less responsive to all these drugs. Recently there has been much interest in supplementing the use of H, blockers with cimetidine, an H, antagonist, in a dose of 300 mg q.i.d. for adults. Contrary to earlier suppositions, there is (conflicting) evidence that the skin vasculature has some H, as well as Hi receptors, and thus in some cases a combination of H, and H, blockers may be more effective than an Hi antagonist alone.“2 It should be emphasized that prescribing cimetidine alone not only is likely to be ineffective but may even make some patients worse, perhaps by blocking the negative feedback loop or by inhibiting histamine N-methyl transferase. Unless there are specific cardiovascular contraindications, subcutaneously administered epinephrine (0.3 ml of 1 : 1000 solution for adults) remains the drug of choice for the treatment of acute, severe urticaria or angioedema. Prior to the development of antihistamines, ephedrine was widely used for treat-

and

angioedema

11

ing milder urticaria, and some physicians still prescribe this drug (25 mg q.i.d.) or other sympathomimetic agents such as terbutaline (2.5 to 5 mg t.i.d.) as a supplement to antihistamines when patients are not responding well to the latter drugs alone. Because of its capacity to limit mast cell secretion, one might expect theophylline to be effective in treating urticaria or angioedema, but the results often are disappointing. Large oral doses of cromolyn have helped to control symptoms of some patients with systemic mastocytosis, but this has not been extensively evaluated in chronic idiopathic urticaria. Indomethatin has been reported to be helpful in some cases of urticarial vasculitis .33 If the disease is severe and not responding to other forms of treatment, corticosteroids sometimes are resorted to. They are the drugs of choice in severe serum sickness, particularly if neurologic or renal manifestations are developing. They also are often used in some types of urticaria with vasculitis or connective tissue disease and in some cases of severe delayed-pressure urticaria. On the other hand, treating patients with chronic idiopathic urticaria or angioedema with large daily doses of corticosteroids would place the patient more at risk from treatment than from the disease. However, there are a small number of patients with extremely severe chronic urticaria or angioedema who respond well only to corticosteroids. Treatment of this group with small doses every other day-if successful-could be justified. Additionally, there are innumerable other drugs that have been used for treating urticaria or angioedema in past years. Some more recent suggestions have included doxantrazole and dapsone (for urticaria associated with SLE). However, in view of the tendency for these conditions to undergo spontaneous remission over a period of time, proposed therapeutic regimens need to be assessed by carefully controlled studies. At least 35 previously recommended drugs for treating urticaria have been abandoned.“4 The prognosis for early spontaneous remission of chronic urticaria or angioedema is least favorable for patients who already have had the disease for a prolonged period. A review of 554 cases by Champion et al.‘” in England revealed the mean duration of urticaria alone was 6 mo, angioedema alone lasted an average of about 1 yr, and urticaria together with angioedema had an average course of about 5 yr. HEREDITARY ANGIOEDEMA Genetic forms listed below:

FORMS

OF URTICARIA

of urticaria

HAE

Vibratory angioedema

AND

and angioedema are

12

Mathews

Urticaria. deafness, and amyloidosia Familial cold “urticxia” Delayed cold-induced urticaria Familial localized heat urticaria of delayed type Erythropoietic protoporphyria with solar urticaria C:, inhihitor deficiency

All are rare and all appear to be transmitted as autosomal dominant traits. By far the most important, and common. of these is HAE, or hereditary angioedema.;‘” It is important to recognize this entity both because of its potentially serious prognosis without treatment and its different mode of therapy. Although its onset typically is in youth or early adulthood, symptoms may develop at a relatively advanced age, and there is not always a family history of HAE. Particularly noteworthy are the absence of associated urticaria and a common history of attacks of abdominal pain. In the past, up to 25% of these patients died of laryngeal edema. HAE appears to occur with increased frequency in patients with SLE but does not seem to be linked to the HLA complex. The cause for this disease is a genetically determined partial deficiency of an alpha,-glycoprotein that inhibits the activated first component of complement (Cl INH or Cis inhibitor). Consequently there is an excessive consumption of C4, with low levels of this component during attacks of HAE and usually between attacks as well. In addition, Ci INH inhibits Clr, kallikrein, Hageman factor fragments, plasmin, and activated thromboplastin antecedent. The actual cause of the swellings is thought by some investigators to be a kinin cleaved from C2 by plasmin (C2 kinin).“’ although more recent data suggest kallikrein-generated cleavage products are involved.“” The diagnosis is established by finding low levels of CT INH and C4. Where available, hemolytic C2 measurements also will be found to be decreased during attacks. In about 15% of cases, however, Ci INH levels are reported to be normal by immunologic measurement (nepholometry, radial diffusion), but functional assays show low activity with inhibitor present but functionally impaired. Establishing a diagnosis of HAE calls for measuring C4 and Ci INH in other family members, explanation of the disease, and perhaps genetic counseling. it should be made clear that symptoms of developing laryngeal edema mandate an immediate emergency room visit where intubation or tracheostomy sometimes may be necessary. Wearing a Medic Alert Emblem or other means of communicating the diagnosis may be desirable, and patients should be certain to inform surgeons or dentists about the diagnosis, particularly if the oropharyngeal area is to be operated on. No further treatment may be needed in intelligent patients whose attacks of angioedema are infre-

quent and mild. In more severe cases, the trequency of attacks can be markedly reduced by treatment with an attenuated androgren. most often dartazol kfi stanozolol.

the

latter

being

substantially

ics.~ expen-

sive.“” Surprisingly. these drugs actually ittcrease the Ci INH level. but it is not necessary to keep this v-alum in the normal range to prevent attacks. 4 .ommtm dosage schedule would be to start with 3, rug Tut stanozolol every 6 hr until the attacks are ,urested. Then the dose should be reduced to the smallest daily dose (initially 2 mg with further reductions if tolcrated) required to keep the patient essentially free 01 attacks regardless of the measured Ci INH or (I’4 levels. However, if elective surgery is needed. ihe fuil therapeutic dose should be resumed for a week prcoperatively, with monitoring of the C4 and Cl INH levels. The most common side effects from stanozolol have been menstrual abnormalities and some virihzation in women and elevated creatine phosphokinasc levels in men. Patients treated with danazol may ex-perience these effects as well as myositis. headache, weight gain, and hematuria. Plasmin inhibitors such as epsilonaminocaproic acid and tranexamic acid also provide effective treatment, but they have significant toxicity, especially at high doses. If an untreated patient requires emergency surgery, the administration of 2 U of fresh frozen plasma is recommended preoperatively. If an attack of angioedema has already started, however, plasma administration is controversial because it provides not only Ci INH but aisn complement components that could worsen the attack. Accordingly, the best treatment for the acute attack is simply vigilance in maintaining the airway and intravenous fluids and supplying opiates, if necessary, for severe abdominal pain. Partially purified Cl INH is effective in terminating prolonged attacks of HAE, but this material is not available in most countries.“” Concerning the other genetic types of urticaria or angioedema listed, vibratory angioedema has characteristics implied by its name and is associated with increased plasma histamine levels during attacks. The recently described dermodistortive urticaria may bc the same disease. About 78 cases of u&aria. deafness, and amyloidosis (Muckle-Wells syndrome) have been reported. ‘I There is evidence of. amyloidosis in only about 25% of these cases, but the association of the urticarial attacks with malaise. limb pains. fever, and leukocytosis merit emphasis. Other features may include nephrotic syndrome. pes cavus, increased erythrocyte sedimentation rate and serum globulins, urinary reducing substance. hyperglycinuria, and malabsorption. Familial cold “urticaria” really is a misnomer in that these patients experience a

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maculopapular eruption a number of hours after exposure to cold, the attacks are associated with leukocytosis and fever, and intravenous endotoxin inhibits the response to cold. Several families have been reported with delayed cold-induced urticaria.62 As implied by its name, these patients develop swelling several hours after spontaneous cold exposure or ice cube tests. Familial localized heat urticaria of delayed type is extremely rare; acetylcholine release may be an initiating event. Erythropoietic protoporphyria with solar urticaria was noted above. Finally, an extensively studied patient with C3 inactivator deficiency and increased urinary histamine excretion has been reported with nonpruritic urticaria, particularly after taking hot showers. These findings are in addition to his difficulties with infection.

REFERENCES 1. Warin RP, Champion RH: Urticaria. Philadelphia, 1974, W. B. Saunders Co. 2. Harris A, Twarog FJ, Geha RS: Chronic urticaria in children. J ALLERGY CLIN IMMUNOL 69:109, 1982. 3. Swinny B: The atopic factor in u&aria. South Med J 34:855, 1941. 4. Hellgren L: The prevalence of urticaria in the total population. Acta Allergol 27:236, 1972. 5. Natbony SF, Phillips ME, Elias JM, Godfrey HP, Kaplan AP: Histologic studies of chronic idiopathic urticaria. J ALLERGY CLIN IMMUNOL 71:177, 1983. 6. Schwartz HR, McDuffie FC, Black LF, Schroeter AL, Conn DL: Hypocomplementemic urticarial vasculitis. Mayo Clin Proc .57:231, 1982. 7. Monroe EW, Schulz CL, Maize JC, Jordan RE: Vasculitis in chronic urticaria: an immunolopathologic study. J Invest Dermatol 76:103, 1981. 8. Zeiss CR, Burch FX, Marder RJ, Fumey NL, Schmid FR, Gewurz H: A hypocomplementemic vasculitic urticarial syndrome. Report of four new cases and definition of the disease. Am J Med 68:867, 1980. 9. Soter NA: Chronic urticaria as a manifestation of necrotizing vasculitis. N Engl J Med 2961440, 1977. 10. Kaplan AP, Garofalo J, Sigler R, Hauber T: Idiopathic cold urticaria: in vitro demonstration of histamine release upon challenge of skin biopsies. N Engl J Med 305:1074, 1981. 11. Wasserman SI, Soter NA, Center DM, Austen KF: Cold urticaria: recognition and characterization of a neutrophil chemotactic factor which appears in serum during experimental cold challenge. J Clin Invest 60:189, 1977. 12. Wasserman SI, Austen KF, Soter NA: The functional and physicochemical characterization of three eosinophilotactic activities released into the circulation by cold challenge of patients with cold u&aria. Clin Exp ImmunoI47:570, 1982. 13. Rorsman H: Basophilic leukopenia in different forms of urticaria. Act Allergo 17:168, 1962. 14. Phanuphak P, Schocket AC, Arroyave LM, Kohler PF: Skin histamine in chronic urticaria. J ALLERGY CLIN IMMUNOL 65:371, 1980. 15. Kaplan AP, Horakovaz Z, Katz SI: Assessment of tissue fluid histamine levels in patients with urticaria. J ALLERGY CLIN IMMUNOL 61:350, 1978.

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LM: Defective histamine release in 16. Kern F, Lichtenstein chronic urticaria. J Clin invest 57:1369, 1976. 17. Czametzki BM, Kern F, Lichtenstein LM: Defective release of eosinophil chemotactic factor from peripheral leukocytes in patients with chronic urticaria. J Invest Dermatol 67:276, 1976. 18. Lewis T: The blood vessels of the human and their responses. London, 1927, Shawn & Sons, Ltd. 19. Grant RT, Pearson RSB, Comeau WJ: Observations on urticaria provoked by emotion, by exercise and by warming the body. Clin Sci 2:253, 1936. 20. Soter NA, Wasserman SJ, Austen KF, McFadden ER: Release of mast cell mediators and alterations of lung function in patients with cholinergic urticaria. N Engl J Med 302:604, 1980. 21. Paton WDM: Histamine release by compounds of simple chemical structure. Pharmacol Rev 9:269, 1957. 22. Mathews KP: Management of urticaria and angioedema. J ALLERGY CLIN IMMUNOL 66~347, 1980. 23. Costanzi JJ, Coltman CA, Donaldson VH: Activation of complement by a monoclonal cryoglobulin associated with cold urticaria. J Lab Clin Med 74:902, 1969. 24. Becker LC: Allergy in systemic lupus erythematosus. Johns Hopkins Med J 133:38, 1973. 25. Ballow M, Ward GW, Gershwin WE, Day NF: Cl-bypass complement-activation pathway in patients with chronic urticaria and angioedema. Lancet 2:248, 1975. 26. Laurel1 A-B, Martensson U, Sjoholm AG: Studies of Cl subcomponents in chronic urticaria and angiocdema. Int Arch Allergy Appl Immunol 54:434, 1977. 27. Mathison DA, Arroyare CM, Bhat KN, Hurewitz DS, Mamell DJ: Hypocomplementemia in chronic idiopathic urticaria. Ann Intern Med 86:534, 1977. 28. Juhlin L, Michaelsson G: Cutaneous reactions to kallikrein, bradykinin and histamine in healthy subjects and in patients with urticaria. Acta Derm Venereol 49:26, 1969. 29 Bernstein JE, Swift RM, Soltanik, Lorincz AL: Inhibition of axon reflex vasodilatation by topically applied capsaicin. J Invest Dermatol 76:394, 198 1. 30 Eftekhari N, Ward AM, Allen R, Greaves MW: Protease inhibitor profiles in urticaria and angioedema. Br J Dermatol 103:33, 1980. 31 Chodirker WB, Bauman W, Komar RR: Immunological parameters and alpha, antitrypsin in chronic urticaria. Clin Allergy 9:201, 1979. 32. Mathews KP, Pan PM, Gardner NJ, Hugh TE: Familial serum carboxypeptidase N deficiency. Ann Intern Med 93:443. 1980. 33 Isaacs NJ, Ertel NH: Urticaria and pruritus: uncommon manifestations of hyperthyroidism. J ALLERGY CLIN IMMUNOL 48:73, 1971. 34 Farah FS, Shbakln Z: Autoimmune progesterone u&aria. J ALLERGY CLIN IMMUNOL 48:257, 1971. 35 Prenner BM, Stevens JJ: Anaphylaxis after ingestion of sodium bisulfite. Ann Allergy 37: 180, 1976. 36 Alpert E, Isselbacher KJ, Schur PH: The pathogenesis of arthritis associated with viral hepatitis. N Engl J Med 285: 185, 1971. 37. Jacobson KW, Branch LB, Nelson HS: Laboratory tests in chronic urticaria. JAMA 243:1644, 1980. 38. Graham DT, Wolf S: Pathogenesis of urticaria. Experimental study of life situations, emotions and cutaneous vascular reactions. JAMA 143:13%, 1950. 39. Fisher AA: Contact u&aria due to medicaments, chemicals and foods. Cutis 30:171, 1982. 40. Gelfand JA, Boss GR, Conley CC, Reinhart R, Frank MM:

14

41, 42. 43. 44.

45.

46.

47. 48.

49.

50.

5 1,

52.

June

CME

examination

answers

Acquired Cl esterase inhibitor deficiency and angioedema: a review. Medicine 58:321, 1979. Newcomb RW, Nelson HS: Dermographia mediated by IgE. Am J Med 54~174, 1973. Sussman CL, Harvey RP, Schocket AL: Delayed pressure urticaria. J ALLERGY CLIN IMMUNOI 70:337, 1982. Ryan TJ. Shim-Young N, Turk JL: Delayed pressure urticaria. Br J Dermatol S&485. 1968. Kaplan AP, Garofalo J: Identification of a new physically induced urticaria: cold-induced cholinergic urticaria. J ALLERGY CLIN IMMUNOL f&438. 198 I. Pasricha JS, Nayyar KL: An exaggerated erythema response to a cold pressure test in patients with cold unicaria. Br J Dermatol 89:587, 1973. Soter NA, Wasserman Sl: Physical urticariaiangioedema: an experimental model of mast cell activation in humans. J ALLERGY CLIE~ IMMUNOL 66:358. 1981. Mathews KP: Exploiting the cold-urticaria model. N Engl J Med 305:1090, 1981. Sheffer AL, Soter NA, McFadden ER, Austen KF: Exerciseinduced anaphylaxis: a distinct form of physical allergy. J ALLERGY CLIN IMMUNOL 71:311, 1983. Ravits M, Armstrong RB, Harber LC: Solar urticaria: clinical features and -wave length dependence. Arch Dermatol 118: 228, 1982. Sibbald RG. Black AK, Eady RA, James M. &eaves MW: Aquagenic urticaria: evidence of cholinergic and histaminergic basis. Br J Dermatol 105:297, 19X 1. Davis RS, Remigio LK, Schocket AL, Bock SA: Evaluation of a patient with both aquagenic and cholinergic urticaria. J ALLERGY CLIN IMMUNOL 68:479, 1981. Monroe EW, Cohen SH, Kalbfleisch J, Schulz CI: Combined

Answers

for June CME examindon

Fearon DT: Complement.

Hl and HZ antihistamine therapy in chronic urticuna Arch Dermatol 117:404, 198 I 53. Milins JL, Randle HW, Solley GO, Dicken CH. The therapcu tic response of urticarial vasculitis to intlomcrh;r:i;1. .! ht?r Acad Dermatol 3:349. 1980. 54. Sheldon JM. Mathewb KP. Love11 RC: The lcring u~f~n+t problem: present concepts of etiology and management. J Alergy 25:525. 1954. 55. Champion RH. Roberts SDB. Carpenter RG. e: :ii i:mcaria and angioedema. A review of 554 patients. Br .i Detmatol

81588, 1969 56. Frank MM. Gelfand JA, Atkinson JP: Hereditar! angloedema: the climcai syndrome and its management. Ann Intern Med 84:580. 1976, 57. Donaldson VH. Rosen FS, Bing DH: Role of tb second cornponent of complement (C2) and plasmin in kimn release in hereditary angioneurotic edema (H.A.N.E.) plasma Trdns Assoc Am Physicians 90: 174. 1977 58. Schapira M, Silver LD, Scott 0’. Prograis LJ. (:urtl JG, Colman RW, Prekallikrein and high molecular weight kininogen in hereditary angioedema. Blood 58:226a, 198 I 59. Sheffer AL, Fearon DT, Austen KF: Clinical and biochemical effects of stanozolol therapy for hereditary an&edema J ALLERGY CLIN IMMUNOL 68: IX I , 198 I. 60. Gadek JE. Hosea SW, G&and JA. et al: Replacement therapy in hereditary angioedemd. N Engl J Med 3@&542. 1980. 61. Muckle TJ: The Muckle-Wells syndrome. Br J Dermatal

lCKk87, 1979 62. Soter NA, Jo&l NP, Twarog FJ, et al: Delayed cold-Induced urticaria: a dominantly inherited disorder. 3 Al.1 ERGY CI IN IMMVNOI. 59~294. 1977

Wentification

J ALLERGY CLIN IMMUNOL 71520-524,

Questions l-3 1. c 2. a 3. b In membranoproliferative glomerulonephritis there is persistent activation of the alternative complement pathway and therefore low C3 levels but normal C4 concentration in serum. Some patients also have an acquired decreasedbiosynthesis of C3, the cause of which is not known. Many of these patients have partial lipodystrophy and an autoantibody, termed “C3 nephritic factor, ” that binds to and stabilizes the amplification C3 convertase C3b,Bb. The biologic activity of this unusualautoantibody is responsiblefor the systemic activation of the alternative pathway that occurs in these patients. In proriferative glomerulonephritis of lupus, systemic activation of complement is causedby the high

No. 068301

1983.

levels of immune complexes and therefore occurs through the classical pathway. This circumstanceresults in hypercatabolism of both C4 and C3. In poststreptococcal glomerulonephritis, patients may have low serum C3 either with or without evidence of classical pathway activation in the form oflow serumC4 levels. There is someevidence to indicate that circulating immune complexes in these patients initially are activating C3 through the classical pathway, but the mechanismof alternative pathway activation in thesepatients is not known. References I. Sissons JGP, West RJ, Fallows J, Williams DG. Boucher BJ, Amos N, Peters DK: Complement abnormalities IR lipodystrophy. N Engl J Med 294~461, 1976. 2. Lachmann PJ, Peters DK: Complement. In Lachman PJ, Peters DK, editors: Clinical aspects of immunology. London, 1982. Blackwelt Scientific Publications, pp. 18-49.