Review

URTICARIA/ANGIOEDEMA A CONSIDERATION OF PATHOGENESIS AND CLINICAL MANIFESTATIONS

NICHOLAS A. SOTER, M.D. AND STEPHEN I. WASSERMAN, M.D.

Urticaria and angioedema are recognized as evanescent, often erythematous, areas of cutaneous edema. Although the cause of urticaria/angioedema is usually unknown, its pathogenesis is felt to be in some way related to the activation of mast ceils and/or basophilic leukocytes and the release of their products. The antigen-induced release of biologically active materials from mast cells or basophilic leukocytes sensitized with specific IgE antibody is termed an immediate type of immunologic reaction (Type I, anaphylactic, or IgE-dependent hypersensitivity). The clinical symptoms and signs occur rapidly after the exposure of a sensitive individual to the appropriate antigen. The sites of clinical involvement include the skin (urticaria/angioedema), the respiratory and gastrointestinal tracts, and the cardiovascular system. Although these sites may be involved singly or in any combination, this review will focus entirely on the cutaneous manifestations. Simiiar symptoms and signs may occur after mast cell degranulation without IgE antibody caused by drugs or in association with activation of the arachidonic acid-prostaglandin system or complement pathways.

Address for reprints: Nicholas A. Soter, M.D., Seeley G. Mudd Building Room 610, Harvard Medica! School, 25& Longwood Avenue, Boston, MA 02115.

From tbe Departments of Dermatology and Medicine, Harvard Medical School; Divisions of Dermatology, Departments of Medicine, Robert B. and Peter Bent Brigham Divisions of tbe Affiliated Hospitals Center, Boston, Massachusetts

Complement factors may also cause the release of mediators from mast ceils or basophilic leukocytes. This paper discusses these cells, mediators dependent on their activation, mediators which directly influence their function, the interrelationships of these mediators, and the clinical manifestations of urticaria/ angioedema. Epidemiology

Urticaria and angioedema are rather common and may occur at any age. The lesions occur most frequently after adolescence with the highest incidence being in young adults. Ofagroup of college students, 15to 20% had experienced urticaria/angioedema,^ whereas only 1 to 2% of the patients in general dermatology practice were seen because of urticaria/angioedema.2 Angioedema, with the notable exception of hereditary angioedema, is often associated with urticaria. In a study of

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patients with urticaria/angioedema, 49% had both, 11 % presented with angioedema alone, and the remainder had only urticaria.^ The natural history of urticaria/angioedema is inadequately documented. In one study of patients with only urticaria, 50% were free of lesions by one year, but 20% continued to experience lesions for more than 20 years; in patients with angioedema alone, half of the patients continued to develop lesions after a year; and with both urticaria and angioedema, three-quarters of patients had symptoms beyond the first year, half for more than five years and 20% for more than 20 years.^ Age, race, sex, occupation, geographic location and season of year can be implicated in IgE-dependent hypersensitivity reactions only insofar as they m ight contribute to exposure to the eliciting agent. The incidence of these reactions to any antigens in a sensitized population is unknown. Parenteral rather than oral administration of an antigen is more likely to precipitate clinical symptoms and signs. Previous studies of mast eel l-dependent reactions occurring after exposure to penicillin or Hymenoptera venoms have suggested an increased risk of anaphylaxis in atopic persons; recent information"* indicates, however, that the risk of such reactions is not greater in atopic individuals. Pathogenesis

Antigen Materials known to elicit specific IgE antibodies and subsequent mast cell/basophildependent reactions in humans include proteins, polysaccharides and haptens. There are no common structural features shared by antigens capable of inducing production of IgE antibody. The major antigens encountered in medical practice are haptens and include examples from every class of diagnostic and therapeutic agents. These reactions may follow the administration of antigen by any route.

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Antibody IgE is the immunoglobulin responsible for immediate-type hypersensitivity reactions in humans. Its molecular weight is 190,000 and it is rich in carbohydrate. The mean serum concentration of IgE is ~ 100 lU/ml. IgE levels are under genetic control and tend to be higher in atopic individuals. The B-!ymphocytes and plasma cells that synthesize IgE are directed by immune response genes and by subpopulations of T-lymphocytes. Mast cells and basophils process receptors on their membranes for the Fc portion of IgE. In the serum of a sensitized individual as much as one-half of the IgE may be directed toward a single antigen,^ presumably explaining the absence of elevated levels of IgE in some allergic individuals.

Mast Cells and Basophiiic Leukocytes The skin is rich in mast cells; the mean number is 7,000 to 12,000/^.^ Mast cells vary with respect to size and shape and contain unilobed nuclei, well-defined nucleoli and numerous spheroidal cytoplasmic granules surrounded by a membrane. Human skin mast cells have been distinguished from respiratory tract mast cells by prominent villous extensions of the plasma membrane, granules that contain crystalline lattices and numerous microfilaments.^ The metachromatic staining property of mast cells is due to the heparin in their granules. The basophil, a polymorphonuclear leukocyte derived from the bone marrow, is unrelated to the mast cell. The basophil circulates in the peripheral blood of normal individuals and is present in increased numbers in atopic persons.^ It is not found in normal skin, but is found to infiltrate the skin in allergic contact dermatitis.* The metachromatic staining property of basophils is due to the content of chondroitin and dermatan sulfates in their granules.

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Mast Cell/Basophil Activation (Table 1) Antigen-dependent activation and secretion in basophils or mast cells require the bridging of at least two IgE molecules and involves calcium ion flux as well as energydependent processes. These biochemical events are modulated by the cyclic nucleotides, 3'5'-cyclic adenosine monophosphate (c-AMP) and 3'5'-cyclic guanidine monophosphate (c-GMP). Elevated levels of c-AMP inhibit mediator release, and decreased levels of c-AMP or increased levels of c-GMP augment mediator release.'" In some instances, heat stable skin-sensitizing IgG has been implicated. Activation of mast cells and basophils may proceed independent of immunoglobulin. Activation may be induced by complement factors C3a and C5a, by kinins, by insect venoms, by highly charged polyanions such as polymyxin and by radiocontrast media. Physical stimuli such as light, heat, cold, pressure and trauma may be operative via IgE or by unknown mechanisms. The antigen-induced release of histamine can be demonstrated in vitro in skin" after passive sensitization with IgE-rich serum. Histamine release from human skin is optimal from 29 to 37C; this fact is noteworthy since peripheral skin temperatures are generally variable and range from 34 to 37C.^^ Chemical Mediators Mast cell and basophil-derived mediators are best understood when considered in relation to their biologic function, including the capacity to alter venular permeability, to contract smooth muscles in a variety of organs, to influence the motility of leukocyte populations, to modulate the release of biologically active substances from other cell types, and to elaborate enzymes capable of degrading protein and glycosaminoglycan substrates. Proteoglycans comprise the structural matrix of the granule. Although the function of each

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Table 1. Mast Cell Activation 1. Immunoglobulin-Dependent A. IgE B. IgG (?) 11. Non-lmmunoglobulin-Dependent A. C3a B. C5a C. Kinins D. Venoms E. Charged polyanions F. Radiocontrast media IM. Physical Stimuli A. Heat B. Cold C. Light D. Pressure E. Trauma F. X-ray

mediator has been inferred from the study of individual agents, complex biologic interactions undoubtedly exist. Both mast cells and basophils possess certain of these mediators preformed in their granules or generate them directly or indirectly through their interactions with other cell types. Structural and Functional Characteristics of Mast Cell/BasophiI'Derived Products (Table 2) Smooth muscle contraction and vasoactive activity. Mast cells and basophils contain the preformed amine histamine in their granules. It is formed from L-histidine and enzymatically degraded by diamine oxidases (histaminase) or by histamine methyltransferase. Two tissue receptors, classified as HI and H2," mediate the biologic activity of histamine. HI effects include smooth muscle contraction, increases in airway resistance, and augmentation of leukocyte motility. H2 effects include inhibition of T-lymphocyte functions, depression of leukocyte chemotaxis, suppression of mast cell and basophil mediator release, increased cardiac

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rate and force of contraction, and augmentation of gastric acid secretion. As the human skin vasculature contains both types of histamine receptors/^ dermal vascular permeability may depend on the effect of histamine on both. Slow-reacting substance of anaphylaxis (SRS-A) is an acidic lipid-like substance of approximately 400 molecular weight that is inactivated by arylsulfatases and which increases vascular permeability and contracts smooth muscle.1^ Platelet activating factors (PAF)^« are phospholipid-like materials which alter vascular permeability indirectly by a direct action on platelets to cause the secretion of serotonin. Platelet aggregation in vitro and local platelet accumulation in vivo may also be mediated by the action of PAF. Prostaglandins may be generated by mast cell and basophil membrane enzymes. The stable end-products include PGF2a and PGE i, the latter of which causes cutaneous erythema lasting up to ten hours.^^ Other prostaglandin Intermediates and products may also be generated, but their functional relevance remains to be elucidated. Chemotactic factors. Chemotactic factors with specificity for eosinophiiic and neutrophilic leukocytes are derived from mast cells and basophils. These factors mediate the directed migration (chemotaxis) of cells as well as their unresponsiveness (deactivation) to subsequent chemotactic stimulation. The mast cell-derived eosinophil chemotactic factor of anaphylaxis (ECF-A) occurs as two acidic tetrapeptides with different N-terminal amino acids. The tetrapeptides can induce the accumulation of eosinophils in skin.'« Larger oligopeptides also possess preferential chemotactic activity for eosinophils.'^ The eosinophil chemotactic factors derived from human basophils have not been characterized sufficiently to define their relation to the mast cell-derived products. A highmoiecuiar-weight-neutrophil chemotactic factor (HMW-NCF) has been identified in the

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serum of patients with gold urticaria subsequent to the activation of mast cells.^" This neutral molecule chemotactically attracts and deactivates neutrophlMc leukocytes. Mast cells also have the capacity to elaborate defined metabolites of arachidonic acid that are derived from both the lipooxygenase and cyclooxygenase pathways and tha possess chemotactic activity for human neutrophils and eosinophils.'^^ Granular enzymes. Mast cells contain proteolytic enzymes with both chymotryptic (chymase)" and tryptic (kallikrein) specificities.''^ The former may play a role in dermal inflammation caused by immediate hypersensitivity reactions while the latter can generate bradykinin from kininogen and can cleave and thereby activate Hageman factor. Additional mast cell granule enzymes include arylsulfatases, j8-glucuronidase and hexosaminidase. These three in concert may degrade ground substance, whereas arylsulfatases alone can inactivate SRS-A." While it is presumed that similar enzymes are present in the basophil, only kallikrein and arylsulfatases have been identified. Structural components. Heparin is the proteoglycan present in the mast cell granule. Heparin may inhibit complement activation, and it interacts with antithrombin 111 to generate anticoagulant activity. Whereas mast cells contain predominantly heparin, chondroitin sulfates comprise the proteoglycans of basophilic leukocytes. No functional role in skin for these materials has been proved. In Vivo Observations The participation of mast cells or basophils in vivo can be inferred from morphologic analysis or by quantitation and identification of mediators in tissues or biologic fluids. The intracutaneous injection of specific antigen or anti-lgE and the passive transfer of igE-mediated hypersensitivity to normal recipients (Prausnitz-Kustner reaction) have provided experimental models for the analysis of the role of IgE and its interaction

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with the mast cell. Clinically these sites demonstrate a biphasic response with a transient pruritic wheal-and-flare reaction followed by a painful, deep, erythematous, poorly demarcated area of swelling that persists for 24 hours.25 The histologic studies of the early phase show mast cell degranulation and edema; those of the late phase show edema, infiltrating polymorphonuclear and mononuclear cells, and endothelial cell damage. Mast cell degranulation has been noted in some forms of urticaria/angioedema; however, this morphologic alteration isdifflcuitto observe in routinely processed specimens. Models of basophil participation in cutaneous disease include contact sensitivity in humans and experimental animals. Morphologic analysis has demonstrated basophil accumulation and granule extrusion in these lesions.^ Antigenic challenge of basophil-rich delayed hypersensitivity sites in animals has been associated with marked increases in dermal edema and concomitant histamine release.^^ Elevated levels of circulating histamine occur in patients with certain forms of physical urticaria2^-28 Q^ after the administration of agents which directly degranulate mast cells.2^ Increased amounts of histamine have also been noted in the skin or blister fluids of patients with various forms of urticaria.^" Factors chemotactic for neutrophils and eosinophils have been recognized in serum after experimental mast cell activation in patients with physical urticaria.^o-^s ^ decrease in the content or releasability of histamine and eosinophil chemotactic activity has been noted in peripheral blood basophils of some patients with chronic idiopathic urticaria.^^ The intradermal injection of histamine induces erythema, whealing, and pruritus, and venular dilatation with interendothelial cell gaps. A single, rapid intravenous injection of histamine into humans is followed by generalized erythematous flushing with pruritic wheals. C3a and C5a induce local erythema, wheals, and pruritus with mast cell degranulation that may be accompanied in

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time by the appearance of neutrophilic leukocytes.^^ The Complement System The complement system consists of a group of serum proteins which, when activated, generate enzymes and principles that may enhance vascular permeability, alter cell movement, participate in the adherence of particles to cells, enhance phagocytosis, damage membranes and interact with other inflammatory systems. The complement system may be activated by altered immunoglobulins, antigen-antibody complexes, polysaccharide constituents of cell walls or organisms, and proteolytic enzymes. The role of complement in disorders with urticaria/ angioedema varies and thus will be discussed in relation to disease entities.

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Table 3. Classification of Urticaria /Angioedema I. igE-Dependent Urticaria A. Atopic diathesis B. Specific antigen sensitivity C. Physical II. Complement-Mediated Urticaria A. Hereditary angioedema B. Acquired angioedema with lymphoproliferative disorders C. Necrotizing venulitis D. Serum sickness E. Reactions lo blood products Ml. Direct Mast Cell-Releasing Agents IV. Agents which Presumably Alter Arachidonic Acid Metabolism V. Idiopathic Urticaria

tion or arachidonic acid/prostaglandin activation, and those that are idiopathic (Table 3).

Clinical Manifestations

IgE-dependent Urticaria/Angioedema

Urticaria is manifested by circumscribed raised erythematous, usually pruritic, areas of edema that involve the superficial portions of the dermis. When the edematous process extends into the deep dermis and/or subcutaneous and submucosal layers, it is known as angioede^ia and can be recognized as localized erythematous areas of deep nonpittingedema with diffuse borders. Urticaria and angioedema may occur in any location together or individually. Angioedema commonly affects the face or a portion of an extremity. Involvement of the larynx, which leads to hoarseness, stridor and dyspnea, may be fatal. The individual lesions arise suddenly, rarely persist longer than 24 to 48 hours, but may recur for indefinite periods. Episodes of lesions of less than one month's duration are acute, whereas those persisting longer may be termed chronic. Urticaria/angioedema may be classified, based upon current concepts of its pathophysiology, into those types that are IgE-dependent or complement-dependent, those due to direct mast ceil/basophil activa-

Atopy. In individuals with a personal or family history of asthma, rhinitis or eczema, a history of urticaria/angioedema is elicited with some frequency. Although such urticaria/angioedema is presumed to be IgEdependent, in clinical practice urticaria/ angioedema seldom accompanies exacerbations of asthma, rhinitis, or eczema. Specific antigen sensitivity. Definitive demonstration of IgE-dependent mechanisms in the pathogenesis of urticaria/angioedema has been accomplished in atopic and nonatopic individuals. Examples of specific antigens provoking reactions include foods, such as milk, eggs, wheat, soy, yeast, peanuts and nuts; drugs and therapeutic agents, notably penicillin, pollens and Hymenoptera venom. In some instances of food-related urticaria/angioedema, vasoactive constituents of the food or chemical additives may be responsible ratherthan IgE-dependent processes. Urticaria/angioedema in patients with helminthic infestations also has been attributed to IgE-dependent processes; how-

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ever, proof of this relationship is generally lacking. Physical. The IgE-dependent nature of certain but not all forms of physical urticaria has been demonstrated by passive transfer. Physical urticaria occurs after a variety of stimuli, and the clinical types are discussed below. /. Dermographism: Dermographism has a prevalence of 4.2% in the normal population.^^ It appears as a linear wheal with a flare at sites in which skin is briskly stroked or traumatized with a firm object. The transient, pruritic or asymptomatic wheal appears rapidly and usually fades within 30 minutes. This response has been passively transferred to the skin of normal subjects with serum and IgE,^" and elevations in blood histamine levels have been documented in some patients after extensive experimental scratching." A rare form of dermographism, of unknown pathophysiology, occurs three to six hours after stimulation, may be preceded by an immediate reaction, and lasts up to 48 hours.

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transient rise in plasma histamine occurred after an experimentally induced attack. 4. Cold-induced urticaria: Inherited and acquired forms of cold-induced urticaria have been described. Acquired cold-induced urticaria usually is dependent upon IgE and rarely occurs in association with cryoproteins. Within minutes after exposure to one or more precipitating events, including cold foods or liquids, the application of ice, and changes in ambient temperature, patients experience a burning pruritic urticarial eruption that may evolve into angioedema and rarely syncope or wheezing. The skin lesions generally clear rapidly, but extensive exposure may induce swelling which persists for 24 to 72 hours. If the entire body of a patient is cooled, as in swimming, hypotension and collapse may occur, a potentially lethal event.

In IgE-dependent acquired cold-induced urticaria, passive transfer to the skin of a normal recipient has been documented." The release into the serum of the mast cell-derived mediators histamine, ECF, and HMW-NCF 2. Pressure urticaria: Pressure urticaria, has been observed.^'^-''^ In skin, the histologic which often accompanies dermographism demonstration of degranulation of mast cells and episodes of chronic urticaria, appears as without infiltrating cells after cold challenge erythematous deep local swellings, often has been noted.^^ There is no evidence for painful, that arise immediately or from four to the participation of complement factors six hours^^ after the application of sustained or bradykinin. pressure to the skin. Spontaneous episodes In rare instances, acquired cold urticaria are frequently noted under shoulder straps may be secondary to complement activation and belts as well as on the feet after running. in serum due to the presence of underlying Histamine levels are elevated in experimental cryoproteins such as cryoglobulins, cryofiblisters between four and eight hours coincibrinogens, and cold hemolysins. The latter may dent with the urticaria! lesion.^" While this be associated with tertiary syphilis. The form of urticaria/angioedema often accompathogenetic relevance of cold agglutinins in panies proved IgE-dependent processes, this this syndrome remains unproved. The fremechanism may not explain all instances of quent finding of cold agglutinins in the abpressure urticaria. sence of cold-induced urticaria militates 3. Vibratory angioedema: Angioedema against this cryoprotein as a cause. occurring after the application of a vibratory An immediate and a delayed form of famistimulus, such as a laboratory vortex mixer, is lial cold urticaria have been described, each termed vibratory angioedema. This disorder of which is dominantly inherited.^^-'"* In the may be familial with an autosomal dominant immediate form, the eruption occurs usually pattern of inheritance^^ or may accompany as erythematous burning macules, rather than cholinergic urticaria. In the latter instance a wheals, and with fever and arthralgias. Neu-

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trophilic leukocytosis and dermal neutrophilic infiltration accompany the clinical presentation. Passive transfer with serum has been negative. In the delayed form erythematous, edematous deep swellings occur nine to 18hours after coldchallenge. Lesional biopsy shows edema with minima! numbers of mononuclear cells; mast cells are not degranulated and complement proteins, immunoglobulins, and fibrin are not detected. Cold immersion does not release histamine, and the condition cannot be passively transferred. 5. Light urticaria: Pruritus, erythema, urticaria/angioedema, and occasionally syncope may occur immediately after exposure to the sun or to artificial light sources. In some instances, a delayed papular response occurs 18 to 72 hours later." Light urticaria rarely is associated with systemic lupus erythematosus and erythropoietic protoporphyria. Classification of light urticaria into subtypes has been based on the urticarial response to specific portions of the light spectrum.^^-^^ In two of the types, those elicited by wavelengths of 285 to 320 nm and 400 to 500 nm, the response can be passively transferred. A serum factor induced by irradiation has been implicated in the development of the lesions in some instances.^^ It should be noted that this disorder is extraordinarily uncommon, with fewer than 100 cases reported.

gic agents into the skin reproduces locally the skin lesions in some patients, the pathogenetic role of the cholinergic nervous system remains speculative. After challenge by exercise, elevations in plasma histamine and chemotactic factors have been noted.^^ The urticarial response has been passively transferred. 7. Heat urticaria: In a rare form of urticaria, wheals develop within minutes after exposure to locally applied heat. Passive transfer has been unsuccessful. In one instance, heat-induced urticaria has been associated with activation in serum of the alternative complement pathway without mast cell activation.*^ It is critical to the eval uation of patients with chronic urticaria to recognize the common association of several types of physical urticaria. For example, chronic idiopathic urticaria is frequently accompanied by dermographism and/or pressure urticaria. Cold urticaria has been noted to occur in association with dermographism, cholinergic, and, rarely, light urticaria. These clinical associations imply but do not prove common pathobiologic mechanisms.

6. Cholinergic urticaria: Known also as generalized heat urticaria, this develops after an increase in core body temperature, such as during a warm bath or shower, exercise, episodes of pyrexia, or perhaps emotional stress. The eruption is preceded by a sensation of warmth and appears as pruritic wheals one to two mm in size surrounded by macular areas of erythema; occasionally the wheals may become confluent and thus may be confused with other types of urticaria. Wheezing has been reported in some instances of cholinergic urticaria and alterations in pulmonary function documented after experimental induction of the clinical syndrome.'** Although the injection of choliner-

Hereditary angioedema. Hereditary angioedema {HAE) is a disorder characterized by recurrent episodes of edema of the skin and of the upper respiratory and gastrointestinal tracts due to the functional absence of the serum inhibitor (Cl INH) of the activated fi£st component of the complement system (Cl). The cutaneous swelling is sometimes accompanied by vague local symptoms and rarely by serpiginous or mottled erythema and may occur over any area of the body, most commonly a portion of the face or an extremity. The swelling may progress for 24 to 48 hours, but each area subsides within 72 hours. The angioedema does not pit; pruritus is absent. Ordinary urticaria is not a manifestation of

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HAE. Swelling of the face or buccal mucosa may progress to involve the larynx with the danger of death by asphyxiation. The severity of abdominal pain, vomiting and diarrhea occasionally mimic surgical abdominal conditions. Symptoms and signs of cutaneoous, respiratory, or gastrointestinal involvement may occur together or independently. Although HAE is transmitted as an autosomal dominant trait and afflicted individuals are therefore heterozygotes, the absence of a confirmatory family history does not exclude the diagnosis. There are two forms of th^ inherited disease, one in which both C1INH protein and its function are lacking^^ arid another in which normal serum levels of Cl INH protein without function are present.^^ The absence of Cl INH provides a genetic marker for HAE and introduces the possibility that the functional lack of this complement control factor is involved in the pathogenesis of the clinical attacks. Evidence suggesting that uncontrolled Cl is present in HAE includes the persistently reduced levels of its substrate the fourth complement component (C4). In addition, circulating levels of C4 and the second complement component (C2) fall during clinical attacks. Except for posttraumatic attacks, the reasons for the episodic activation of Cl remain an enigma. It is speculated that the angioedema is a result of a smooth muscle-contracting heatstable polypeptide derived by the action of plasminon a complement fragment produced by the action of Cl on C4 and C2.^^ In tissue trauma, the activation of Hageman factor might_be poorly controlled in the absence of the C1INH, which may account for the frequency of attacks occurring after trauma to an extremity or surgery in the region of the oropharynx. The Hageman factor-dependent activation of plasminogen to plasmin which subsequently activates Cl could contribute to the attack. Urinary histamine levels are increased during attacks of HAE, which may reflect the activation of mast cells or basophils by C3a anaphylatoxin.

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Acquired angioedema v/ith lympho-: proliferative disorders. The acquired depletion of the cTlNH sometimes associated with angioedema has been observed primarily in patients with different types of lymphoproliferative disorders.^*_[n addition to low serum levels of C4 and ClINH, Cl and Clq levels are reduced, thus permitting its differentiation from HAE. Moreover, there are no abnormalities of the ClINH in other family members. Cutaneous necrotizing venuHtis. Recurrent episodes of angioedema/urticaria and arthralgias may be associated with a striking reduction in the early components of the complement system.^"-^^ Biopsy specimens of urticarial lesions in such patients exhibit cutaneous necrotizing venulitis,^^ and it is assumed that mediator generation or release accounts for the presentation of angioedema/ urticaria. The recurrent skin lesions have been described to occur as erythematous macules, circumscribed wheals, localized angioedema of the extremities and face, and foci of purpura. This array of cutaneous lesions may have led to the description of similar patients under the terms erythema multiforme, lupus erythematosus-like syndrome, and hypocomplementic-vasculitis-urticaria syndrome.""^" Although some patients are hypocomplementemic with circulating Clq precipitins, others are not. Mast cells are de-^ granulated both in the hypocomplementemic form in which neutrophils are predominant in the necrotizing lesions and in the normocomplementemic form in which lymphocytes or neutrophils are predominant.^* Serum sickness. Serum sickness occurs seven to 12 days after the administration of heterologous serum or drugs and is manifested by fever, urticaria, lymphadenopathy, myalgia, arthralgia, or arthritis. Symptoms are usually self-limited and last four to five days. An accelerated reaction may occur one to three days after exposure of previously sensitized individuals. Over 70% of patients with serum sickness manifest urticaria often preceded by pruritus and erythema. The initial

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manifestation of urticaria often appears at the site of injection. The pathogenetic mechanism by which urticaria occurs in serum sickness has not been proved. In experimental animals, circulating antigen-antibody complexes and depressed serum hemolytic complement levels can be demonstrated just prior to and during the acute illness.^^ Fixation of immune reactants in blood vessel walls in a variety of tissues has also been documented. Urticaria in serum sickness may thus be a manifestation of immune complex-induced necrotizing vasculitis. The activation of the complement system may provide anaphylatoxins which directly induce mast cell degranulation. It is possible, however, that IgE-dependent mechanisms may be operative in some individuals, particularly those who manifest anaphylactic reactions to foreign proteins or drugs. Reactions to administration of blood products. Urticaria is a commonly observed complication of the administration of whole blood, serum or immunoglobulin. An uncommon mechanism for this reaction is the transfusion of IgE of donor origin directed towards an antigen to which the recipient is subsequently exposed. A second mechanism may be the transfusion of an antigen in the donor preparation into a sensitized recipient. More commonly, however, both the urticarial and the anaphylactic reactions seen with transfusion of blood or serum and administration of IgG are the result of immune complex formation and complement activation. This mechanism has been clearly delineated in patients with antibodies to IgA. Such antibodies form complexes with donor IgA and may activate complement. Inasmuch as IgA is present in preparations of IgG, such reactions may occur in patients receiving replacement immunoglobulin therapy." Urticarial or anaphylactic reactions to the administration of gammaglobulin do not require antibody to IgA. Numerous reports have identified aggregates of IgG, capable of fixing complement, as responsible for such reactions. The administration of IgG treated to

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remove aggregates is not associated with urticaria or anaphylaxis. Intradermal administration of aggregated IgG to humans leads to development of swelling and erythema by ten minutes which becomes tender after several hours and persists up to 48 hours. Biopsy specimens of these reactions show intense neutrophilic infiltrates at six and 24 hours with a mononuctear infiltrate appearing at 24

Direct Mast Cell-releasing Agents Opiates, antibiotics (notably polymyxin B), curare, and d-tubocurarine as well as radiocontrast media have been documented to directly release histamine from mast cells and basophils. As many as 5 to 8% of patients receiving radiocontrast media experience urticarial reactions, most commonly following intravenous administration. These contrast media may activate the alternative pathway of complement as well as induce elevations in plasma histamine^^*^" both in normal individualsand in patients experiencing an urticarial response. /Agents Which Presumably Alter Arachidonic Acid Metabolism Urticaria/angioedema in response to administration of aspirin or related nonsteroidal anti-inflammatory agents occurs with a frequency of approximately 1 % and appears to have a familial basis. The incidence of aspirin intolerance in patients with chronic urticaria is 20 to 50%. Patients intolerant to aspirin also react to indomethacin and frequently to a variety of nonsteroidal anti-inflammatory agents; in addition, up to 15 to 20% of such patients react to azo dyes, notably tartrazine, and some patients manifest responses to benzoates used as preservatives.^^ Such intolerance is often unrecognized and may only be documented by challenge studies. The clinical manifestations of intolerance may begin from 15 minutes to 20 hours after ingestion.^^ Although initially considered to be immunologic, reactions to aspirin do not occur

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after exposure to structurally unrelated compounds such as sodium salicylate or choline salicylate, whereas the structurally related nonsteroidal anti-inflammatory agents and tartrazine do precipitate the clinical symptoms. Skin testing is of no diagnostic value, passive transfer reactions are negative, and neither IgG nor IgE antibodies have been associated with clinical disease. A common feature shared by aspirin and the nonsteroidal anti-inflammatory agents is their ability to inhibit cyclo-oxygenase, an enzyme operative in the generation of prostaglandins from arachidonic acid. Whether mediators other than prostaglandins play a role is unclear. The mechanisms by which alterations in prostaglandin synthesis may elicit the characteristic clinical manifestations include inherited or acquired sensitivity to normal metabolites or, less likely, the generation of an abnormal product. Idiopathic Urticaria In more than 80% of instances, chronic urticaria/angioedema is of unknown cause.^ Since 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 fungal or bacterial infections, foods, medications, metabolic and hormonal abnormalities, malignant conditions, and emotional factors have been claimed as causes, proof of their etiologic relation usually is lacking. In some patients abnormalities of the complement system have been described ^^; however, the examination of skin biopsy specimens to describe the tissue alterations was not reported in most instances. In other patients elevations of histamine in lesional and clinically normal skin were detected.30 Laboratory Findings

Laboratory evaluation of acute episodes of urticaria/angioedema is seldom needed and is usually not helpful. Historical information

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and physical findings offer better diagnostic clues. It is important, however, to recognize that acute urticaria may be present as a prodromal manifestation of hepatitis B viral disease. In such instances, liver functional abnormalities or presence of hepatitisassociated antigen may be diagnostic. In those patients whose acute urticaria/ angioedema suggests an IgE-mediated allergic process prick skin testing or in vitro assessment of specific IgE antibody may be indicated. Prick skin testing with protein antigens or with penicillin analogues and metabolites has been of value, but this technique has not been helpful with regard to other drugs and carries with it the hazard of anaphylaxis. Prick skin testing is unreliable in the presence of dermographism. Of great precision is the radio-allergosorbent test (RAST) used to quantitate nanogram amounts of specific IgE antibody. This test has allowed the diagnosis of sensitivity to a variety of antigens, including foods, pollens, insect venom and animal danders. In instances of chronic urticaria/angioedema, tests that may be of val ue i ncl ude total eosinophil count, erythrocyte sedimentation rate and a search for cryoproteins. Although mean levels of IgE in the serum of patients with chronic urticaria/angioedema are normal, the RAST or skin tests may, in rare instances, prove helpful. Assessment of the complement system in serum may be of value in detecting patients with hereditary and acquired forms of angioedema and necrotizing vascuiitis. Because there are two genetic forms of HAE, serum from suspected patients should be assessed by immunochemical measurements of both ClINH and C4 proteins. If the ClINH protein level is normal and the C4 low, then a functional assessment of ClINH may be performed to confirm the diagnosis. The serum levels of Cl and C3 are normal in HAE. The acquired forms of angioedema associated with adenocarcinoma or lymphoproliferative disorders can be distinguished from HAE by the absence of affected family

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members and by the reduced levels of C l . The serum complement profilejhows low levels of C l , Clq, C4, C2, and ClINH with normal levels of C3. In patients with chronic idiopathic urticaria/angioedema, the finding of an elevated erythrocyte sedimentation rate should prompt a search for underlying cutaneous necrotizing venulitis by examination of a lesional skin biopsy specimen. In some of these patients associated hypocomplementemia may be detected with low levels of C l , C4, C2, and occasionally C3, if classical pathway activation is marked, or low C3 levels with normal levels of C l , C4, and C2 in circumstances associated with activation of the alternative pathway. As not all such patients manifest hypocomplementemia the sedimentation rate has proven to be a more sensitive screening test. If cutaneous necrotizing venulitis is present, a thorough evaluation of the patient must be undertaken to determine the extent of vasculitis in other organ systems.

Pathology

Edema involving the superficial portion of the dermis is characteristic of all forms of urticaria, whereas angioedema involves the deeper dermis and subcutaneous tissue. Both are associated with dilatation of the venules and with tissue infiltration by various numbers of lymphocytes and/or eosinophilic and neutrophilic polymorphonuclear leukocytes. Care should be taken to differentiate such infiltrates from true instances of necrotizing venuiitis in which fibrinoid necrosis of the venular wall is present. In patients with HAE, light microscopic examination of skin, larynx and jejunum shows subcutaneous or submucosal edema without infiltrating inflammatory cells in any of these lesional sites. Interendothelial gaps in cutaneous venules are noted by electron microscopy. Systematic studies of the histopathologic alterations have not been reported in most forms of urticaria/ angioedema.

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Diagnosis and Differential Diagnosis

Urticaria and angioedema are easily recognizable disorders. Urticaria! eruptions are episodic and evanescent, with multiple lesions occurring in various stages of evolution and resolution. Seldom do individual urticarial or angioedematous lesions persist more than 24 hours. Several disorders are included in the differential diagnosis. Papular urticaria consists of small wheals inflicted by insect bites, usually in children, which involve any area of the body. Papulovesicular or butlous eruptions with mucosal involvement and typical iris lesions characterize erythema multiforme. Urticaria pigmentosa is a generalized, pigmented, papular or even nodular mast ceil infiltration in which the skin lesions become urticarial upon rubbing. The syndrome of perceptive deafness, fever with urticaria, and renal insufficiency consequent to amyloidosis is readily excluded. Several other disorders are included in the differential diagnosis of angioedema. Contact dermatitis may occur as recurrent episodes of eyelid and facial swelling. Historical information, the additional cutaneous changes of exudation or scaling, and patch tests are useful in establishing the diagnosis. Cellulitis and erysipelas may at times resemble angioedema. Lymphedema may occur after cutaneous pyoderma or surgery, and the skin may become thick. Congestive heart failure, renal insufficiency, obstruction of the superior vena cava, myxedema, thrombophlebitis, and stasis may produce recurrent swelling. The Melkersson-Rosenthal syndrome consists of facial paralysis fissured tongue, and swelling of the lips. Prevention and Treatment

In those instances in which urticaria/ angioedema is due to a known agent, avoidance is mandatory. Inasmuch as patients with urticaria/angioedema respond to the administration of placebos,^^ and since the disease tends to spontaneously remit, the

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evaluation of therapeutic intervention is difficult. However, avoidance of aspirin^' or food additives has been claimed to improve 50% of patients with chronic idiopathic urticaria/angioedema. Recurrent episodes of idiopathic urticaria/angioedema without systemic manifestations are most effectively treated by the continual therapeutic and prophylactic administration of antihistaminic agents. The administration of both H1 and H2 antihistaminesmay prove of additional benefit but studes are presently unavailable. Epinephrine is required rarely in such patients, and the chronic systemic administration of corticosteroid preparations creates risks considered out of proportion to the therapeutic benefits. The treatment of various forms of physical urticaria includes avoidance of the precipitating stimulus and the administration of antihistamines. Cyproheptadine has been reported to be of particular usefulness in cold urticaria and hydroxyzine is thought to be beneficial in cholinergic urticaria. Effective therapy for the prevention of urticaria/angioedema due to radiocontrast media is undefined; the administration of corticosteroids or antihistamines has proved beneficial in some instances. Treatment of HAE must be addressed to the acute episode, preoperative prophylaxis, and long-term prevention of spontaneous attacks. No specific therapeutic measures have been consistently able to interrupt spontaneous attacks. Preoperative preparation of patients with antifibrinolytic agents, such as e-aminocaproic acid (EACA) or tranexamic acid, or with plasma infusion appears to suppress both intra- and postoperative attacks of angioedema. Long-term prophylactic treatment with EACA or tranexamic acid is effective in preventing recurrent episodes. Methyltestosterone and "non-androgenic" anabolic steroids are also effective in reducing the frequency of spontaneous attacks.^"^ Methyltestosterone and the impeded androgens augment cTlNH synthesis, and the increased ClINH levels are apparently sufficient to control C l , thereby preventing attacks. The

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administration of impeded androgens has been used successfully to treat the acquired Cl INH deficiency and recurrent angioedema in a patient with lymphoproliferative disorder.^^ There is no proved effective treatment for the angioedema/urticaria that occurs as a manifestation of underlying necrotizing venulitis. Drug Names cyproheptadine: Periactin E-aminocaproic acid: Amicar hydroxyzine: Atarax, Vistaril indomethacin: Indocin tranexamic acid: Amikapron

References 1. Mathews, K. P., Hemphill, F. M., Lovell, R. G., Forsythe, W. E., and Sheldon, J. M.: Controlled study on use of parenteral and oral antihistamines in preventing penicillin reactions. J. Allergy 27:1, 1956. 2. Hallgren, L., and Hersle, K.: Acute and chronic urticaria. A statistical investigation on clinical and laboratory data in 1,204 patients and matched healthy controls. Acta Allergol. 19:406, 1964. 3. Champion, R. H., Roberts, S. O. B., Carpenter, R. G., and Roger, |. H.: Urticaria and angio-oedema: a revievi- of 554 patients. Br. ). Dermatol, 81:588, 1969. 4. Setlipane, G. A., Klein, D. E., and Boyd, G. K.: Relationship of atopy and anaphylactic sensitization: a bee sting allergy model. Clin. Allergy 8:259, 1978. 5. Gleich, G. )., and Jacob, G. L.: Immunoglobulin E antibodies to pollen allergens account for high percentages of total immunoglobulin E proteins. Sci-. ence 190:1106, 1975. 6. Soter, N. A., Mihm, M. C, jr., Dvorak, H. F., and Austen, K. F.: Cutaneous necrotizing venulitis: a sequential analysis of the morphologic alterations occurring after mast cell degranulation ina patient with a unique syndrome. Clin. Exp. Immunol. 32:46,1978. 7. Trolter, C. M.,andOrr, T. S.C.: A fine structure study of some cellular components in allergic reactions. II. Mast cells in normal and atopic human skin. Clin. Allergy 4:421, 1974. 8. Hirsch, S. R., and Kalbfleisch, J. H.: Circulating basophils in normal subjects and in subjects u^ith hay fever. J. Allergy Clin. Immunol. 58:676, 1976. 9. Dvorak, H. F., and Mihm, M. C, Jr.: Basophilic leukocytes in allergic contact dermatitis. |. Exp. Med.. 135:235,1972. 10. Austen, K. F., and Orange, R. P.: Bronchial asthma: the possible role of the chemical mediators of immediate hypersensitivity in the pathogenesis of subacute chronic disease. Am. Rev. Resp. Dis. 112:423, 1975. 11. Greaves, M. W., Yamamoto, S., and Fairley, V. M.: IgE-mediated hypersensitivity in human skin studied

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using a new in vitro method. Immunology 23:239, 1972. 12. Crissey, ).T.,FergasonJ. L., and Bettenhausen, J. M.: Cutaneousthermography with liquid crystals. |. Invest. Dermalol. 45:329, 1965. 13. Black, J. W., Duncan, W. A. M., Durant, C. J., Ganellin, C. R., and Parsons, E. M.: Definition and antagonism of histamine Hi-receptors. Nature 236:385, 1972. 14. Greaves, M., Marks, R., and Robertson, I.; Receptors for histamine in human skin blood vessels: a review. Br. J. Dermatol. 97:225, 1977. 15. Brocklehurst, W. E.i Slow reacting substance and related compounds. Prog. Allergy 6:539, 1962. 16. Benveniste, J.: Platelet-activating factor, a new mediator of anaphylaxis and immune complex deposition from rabbit and human basophils. Nature 249:581, 1974. 17. Solomon, L. M., Juhlin, L., and Kirschenbaum, M. B.: Prostaglandin on cutaneous vasculature. ). Invest. Dermatol. 51:280, 1968. 18. Turnbull, L. W., Evens, D. P.. and Kay, A. B.: Human eosinopHils, acidic tetrapeptides (ECF-A) and histamine: interactions in vitro and in vivo. Immunology 32:57, 1977. 19. Boswell, R. N., Austen, K. F., and Goetzl, E. J.: Intermediate molecular weight eosinophil chemotactic factors in rat peritoneal mast cells: immunologic release, granule association, and demonstration of structural heterogeneity. J. Immunol. 120:15, 1978. 20. Wasserman, S. I., Soter, N. A., Center. D. M., and Austen, K. F.: Cold urticaria: recognition and characterization of a neutrophil chemotactic factor which appears in serum during experimental cold challenge. ). Clin. Invest. 60:189, 1977. 21. Goetzl, E. J., Woods, |. M., and Gorman, R. R.: Stimulation of human eosinophil and neutrophil polymorphonuclear leukocyte chemotaxis and random migration by 1 2-L-hydroxy-5,8,1 0,1 4eicosatetraenoic acid (HETE). |. Clin. Invest. 59:179, 1977. 22. Yurt, R., and Austen, K. E.: Preparative purification of the rat mast cell chymase: characterization and interaction with granule components. ). Exp, Med. 146:1405, 1977. 23. Newball, H. H., and Berninger, R. W.: Characterization of human basophil and lung kinin-generating esterases. Fed. Proc. 37:1667, 1978. 24. Wasserman, S. I., and Austen, K. F.: Identification and characterization of arylsulfatase A and B of the rat basophil leukemia tumor. J. Biol. Chem. 252:7074, 1977. 25. Solley, G. O., Gleich, G. J., Jordon, R. E., and Schroeter, A. L.:The late phase of the immediate wheal and flare skin reaction: its dependence upon IgE antibodies. |. Clin. Invest. 58:408, 1976. 26. Askenase, P. W., Debernardo, R., Tauben, D., and Kashgarian, M.: Cutaneous basophil anaphylaxis: immediate vasopermeability increases and anaphylactic degranulation of basophils and delayed hypersensitivity reactions challenged with additional antigen. Immunology 35:741, 1978. 27. Rose, B.: Studies on blood histamine in cases of

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allergy. I. Blood histamineduring wheal formation.). Allergy 12:327, 1941. 28. Soter, N. A., Wasserman, S. I., and Austen, K. F.: Cold urticaria: release into the circulation of histamine and eosinophil chemotactic factor of anaphyiaxis during cold challenge. N. Engl. ). Med. 294:687, 1976. 29. Lasser, E. G.: Basic mechanism of contrast media reactions. Radiology 91:63, 1968. 30. Kaplan, A. P., Horakova, Z., and Katz, S. 1.: Assessment of tissue fluid histamine levels in patients with urticaria. |. Allergy Clin. Immunol. 61:350, 1978. 31. Kern, F.,and Lichtenstein, L. M.: Defective histamine release in chronic urticaria. J. Clin. Invest. 57:1369, 1976. 32. Wuepper, K. D., Bokisch, V. A., Muller-Eberhard, H. J., and Stoughton, R. B.: Cutaneous responses to human C3 anaphylatoxin in man. Clin. Exp. Immunol. 11:13, 1972. 33. Kirby, J. D., Mathews, C. N. A., James, |., Duncan, E. H. L., and Warin, R. P.: The incidence and other aspects of factitious whealing (dermographism). Br. J. Dermatol. 85:3 34. Newcomb, R. W., and Nelson, H.: Dermographia mediated by immunoglobulin E. Am. J. Med. 54:174, 1973. 35. Ryan, T. J., Shim-Young, N., and Turk, J. L.: Delayed pressure urticaria. Br. ). Dermatol. 80:485, 1968. 36. Patterson, R., Mellies, C. J., Blankenship, M. L., and Pruzansky, J. J.: Vibratory angioedema: a hereditary type of physical hypersensitivity. J. Allergy Clin. Immunol. 50:174, 1972. 37. Sherman, W. B., and Seebohm, P. M.: Passive transfer of cold urticaria. J. Allergy 21:414, 1950. 38. Center, D. M., Wasserman. S. I.. 5oter, N. A., and Austen. K. F.: In vivo deactivation of human neutrophils to a subsequent in vitro chemotactic stimulus. Clin. Res. 25:355A, 1977. 39. Tindall,). P., Becker, S. K., and Rosse, W. F.: Familial cold urticaria: a generalized reaction involving leukocytosis. Arch. Intern. Med. 124:129, 1969. 40. Soter, N. A., Joshi, N. P., Twarog, F.)., Zeiger, R. S., Rothman, P. M., and Colten, H. R.: Delayed coldinduced urticaria: a dominantly inherited disorder. ]. Allergy Clin. Immunol. 59:294, 1977. 41. Ive, H., Lloyd, J., and Magnus, I. A.: Action spectra in idiopathic solar urticaria: a study of 1 7 cases with a monochromator. Br. |. Dermatol. 77:229, 1965. 42. Harber, L. C, Holloway, R. M., Wheatley, V. R., and Baer, R. L.: Immunologic and biophysical studies in solar urticaria. ). Invest. Dermatol. 41:439, 1963. 43. Horio, T.: Photoallergic urticaria induced by visible light: additional cases and further studies. Arch. Dermatol. 114:1761, 1978. 44. Soter, N. A., Wasserman, S. 1., Austen, K. F., and McFadden, E. R., )r.: Mast cell mediator release in vivo and alterations in lung function in patients with cholinergic urticaria. Clin. Res. 27:245A, 1979. 45. Daman, L., Lieberman, P., Ganier, M., and Hashimoto, K.: Localized heat urticaria. ]. Allergy Clin. Immunol. 61:273, 1978. 46. Donaldson, V. H., and Evans, R. R.: A biochemical abnormality in hereditary angioneurotic edema: ab-

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senceofseruminhibitorofC'i-esterase. Am.J.Med. 35:37, 1963. Rosen, F. S., Charache, P., Pensky, J., and Donaldson, V.: Hereditary angioneurotic edema: two genetic variants. Science 148:957, 1965. Donaldson. V. H., Merler, E., and Rosen, F. S.: Polypeptide kinin from hereditary angioneurotic edema plasma. In: Clinical Aspects of the Complement System. Stuttgart, Thieme, in press. Caldwell, J. R., Ruddy, S., Schur, P. H., and Austen, K. F.: Acquired Cl inhibitor deficiency in lymphosarcoma. Clin. Immunol. Immunopathol. 1:39, 1972. McDuffie, E. C. Sams, W. M., jr., Maldonaldo. J. E., Andreini, P. H., Conn, D. L., and Samayoa, E. A.: Hypocomplementemia with cutaneous vasculitis and arthritis: possible immune complex syndrome. Mayo Clin. Proc. 48:340, 1973. Soter, N. A.: Chronic urticaria as a manifestation of necrotizing venulitis. N. Eng. |. Med. 296:1440, 1977. Agnello, V., Koffler, D., Eisenberg,). W., Winchester, R.J.,andKunkel, H. G.: Clq precipitins in the sera of patients with systemic lupus erythematosus and other hypocomptementemic states: characterization of high and low molecular weight types. |. Exp. Med. 134:228s, 1971. Oishi, M., Takano, M.. Miyachi, K., Ichikawa. Y., and Homma, M.: A case of unusual SLE related syndrome characterized by erythema multiforme, angioneurotic edema, marked hypocomplementemia and Clq precipitins of the low molecular weight type. Int. Arch. Allergy Appl. Immunol. 50:463, 1976. Marder, R. |., Burch, F. X., Schmid, F. R., Zeiss, C. R., and Gewurz, H.: Low molecular weight Clqprecipitins in hypocomplementemic vasculitisurticaria syndrome: partial purification and characterization as immunoglobulin. J. Immunol. 121:6]3, 1978.

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55. Soter. N. A., Mihm, M. C, Jr., Gigli, I., Dvorak, H. E., and Austen, K. F.: Two distinct cellular patterns in cutaneous necrotizing angiitis. J. Invest. Dermatol.' 66:344, 1976. 56. Dixon, E. J., Vagquez, J. |., Weigle, W. O., and Cochrane, C. G.: Pathogenesis of serum sickness. Arch. Pathol. 65:18. 1958. 57. Ellis, H, F., and Henney, C. S.: Adverse reactions following administration of human gamma globulin. I. Allergy 43:45. 1969. 58. Christian, C. L.: Studies of aggregated y-globulin. II. Effect in vivo. ]. Immunol. 84:117, 1960. 59. Brasch, R. C, Rochoff, S. D., Kuhn, C, and Chraphlyvy, M.: Contrast media as histamine releasers. Invest. Radiol. 5:510, 1970. 60. Arroyave, C. M., Bhat, K. N., and Crown, R.: Activation of the alternative pathway of the complement system by radiographic contrast media. |. Immunol. 117:1866, 1976. 61. Ros, A. -M., Juhtin, L., and Michaelsson, G.: A follow-up study of patients with recurrent urticaria and hypersensitivity to aspirin, benzoates, and azo dyes. Br. J. Dermatol. 95:19, 1976. 62. Mathison, D. A., Arroyave, C M., Bhat, K. N., Hurewitz, D. S.. and Marnell, D. J.: Hypocomplementemia in chronic idiopathic urticaria. Ann. Intern. Med. 86:534, 1977. 63. Rudzki, E., Borkowski, W., and Czabalski. K.: The suggestive effect of placebo on the intensity of chronic urticaria. Acta Allergy (Kobenhavn) 25:70, 1970. 64. Erank. M. M., Gelfand, J. A., and Atkinson, J. P.: Hereditary angioedema: the clinical syndrome and its management. Ann. Intern. Med. 84:580. 1976. 65. Hauptmann, G., Mayer, S., Lang, J. -M., Oberling, F., and Mayer, G.: Treatment of acquired Cl-inhibitor deficiency with danazol. Ann. Intern. Med. 87:577, 1977.

Sign of Leser Trelat

The sudden appearance of seborrheic keratosis on the trunk of our patient, which resolved after the subsequent diagnosis and removal of a bronchogenic carcinoma of the lung, suggeststhesignofLeser-Trelat. This skin manifestation is named in recognition of two surgeons, one Erench, Uiysse Trelat, and the other German, Edmund Leser, whose names are associated with a belief that the sudden onset of numerous seborrheic keratoses might be a marker of internal malignant disease. Since then, the relationship between keratosis and cancer has been controversial.—Doll, D. C, McCagh, M. F., and Welton, W. A.: Sign of ieser-Trelat. JAMA 238:236, 1977.