Urticaria and angioedema.

0025-7125/92 $0.00 + .20

CLINICAL ALLERGY

URTICARIA AND ANGIOEDEMA David P. Huston, MD, and Robert B. Bressler, MD

Urticaria and angioedema affect approximately 20% of the population. I? Urticaria is a well-demarcated skin reaction clinically characterized by erythematous palpable lesions that blanch with pressure, often have pale centers, and are usually pruritic. Angioedema is clinically characterized by swelling of the subcutaneous or submucosal tissues, often with normal appearing skin and a tingling or burning sensation rather than pruritus. 53 Acute urticaria and angioedema are defined by the fleeting nature of attacks, with resolution of any given lesion within hours, and by characteristic histology. Although acute urticaria and angioedema attacks usually recur for less than 6 weeks, attacks may recur for extended time periods, such as with some of the physical urticarias. Acute attacks are more common in children and young adults and are often attributable to an allergic reaction or infection. Histologic examination of acute urticarial lesions reveals dilatation and engorgement of minute cutaneous blood vessels, dilated lymphatics of the superficial dermis, widening of the dermal papillae, flattening of the rete pegs, swelling of collagen fibers, and an absent or minimal perivascular infiltrate that may predominantly contain eosinophils. 52 . 53 Acute angioedema is histologically similar, except that these changes are located in the deep dermis and subcutaneous or submucosal tissues. The triple response of Lewis is basic to the understanding of these findings: initial redness due to capillary dilatation; secondary flare produced by arteriolar dilatation mediated by nerve axon reflexes; and, finally, the wheal caused by extravasation of fluid due to increased vascular permeability. 52. 53. 91 These reactions are reproducible by intradermal injection of various vasoactive mediators common to the mast cell, which is considered to have a major role in most causes of urticaria and angioedema. Mast cell activation and degranulation may be the consequence of antigen cross-linking of Fc receptor-bound IgE (anaphylactic) or non-IgE-mediated (anaphylactoid) mechanisms, such as with the complement anaphylatoxins (C3a, C5a), and nonimmunologic causes, such as certain chemicals (e.g., ionic radiocontrast dye) or physical stimuli (e.g., temperature changes) (Table 1). 52. 53

From the Departments of Medicine and Microbiology and Immunology, Baylor College of Medicine and The Methodist Hospital, Houston, Texas THE MEDICAL CLINICS OF NORTH AMERICA VOLUME 76' NUMBER 4' JULY 1992

805

806

HUSTON & BRESSLER

Table 1. MAST CELL SECRETAGOGUES FCERI-mediated Allergens (antigen) Anti-lgE antibody Anti·FcERI antibody Lectins Anaphylatoxins C3a, C5a Neuropeptides Substance P Histamine-releasing factors Major basic protein Cytokines IL-1 IL-3 IL-8 GM-CSF Platelet factor 4

Drugs Morphine sulfate Codeine Polymyxin B Vancomycin d-tubocurarine Adriamycin Hyperosmolarity Radiocontrast media Physical factors Cold Heat Pressure Exercise Vibration Water Light Hydrogen peroxide Chemical reagents Compound 48/80 Calcium ionophore (A23187) f·Met-Leu-Phe

Chronic urticaria and angioedema lesions are histologically characterized by a tenfold increase in mast cells, a fourfold increase in mononuclear cells, and a nonnecrotizing perivascular lymphocytic infiltrate. 52, 53 Although eosinophils are not prominent, deposition of eosinophil major basic protein (MBP) has been shown. R6 The lesions are less fleeting than those with acute urticaria, with any given lesion persisting for up to 24 hours and recurrences usually continuing for more than 6 weeks. 52, 53 Chronic urticaria and angioedema are also more common in middle-aged adults, and a specific etiology is not identified in 80% or more of patients. 17, ,52, 53 Confounding efforts to classify urticarias and angioedemas are some forms whose time course and histology are typical of late-phase reactions, such as delayed pressure urticaria, or whose clinical course and histology are that of immune complex disorders. Rarely, urticaria or angioedema syndromes are the consequence of a hereditary disorder. The most common of these are the hereditary forms of angioedema caused by Cl esterase inhibitor (Cl-INH) deficiency, which must be distinguished from acquired Cl-INH deficiency disorders, as well as mast cell causes of angioedema, for the purposes of instituting appropriate therapy. PATHOGENESIS OF URTICARIA AND ANGIOEDEMA Brief Overview of Mast Cell Biology

The mast cell has long been recognized as the primary effector cell in allergic disease. However, mast cells also have an important role in many nonIgE-mediated disease processes. Indeed, mast cells are favorably positioned to exert important physiologic influences throughout the body. They are scattered throughout most connective tissue and solid organs and are especially prominent in those tissues that are in close contact with body cavities or the external

URTICARIA AND ANGIOEDEMA

807

environment, such as the skin, lungs, and gastrointestinal tract. In addition, mast cells have a predilection for proximity to small blood vessels and nerves (i.e., cutaneous venules and sensory neurons).91, 92 This enables molecules released by mast cells to interact closely with and affect neuromuscular and vascular response systems. Mast cells are derived from bone marrow precursors, and they do not circulate in mature form. In vitro, interleukin (lL)-3 and fibroblasts both promote human mast cell growth. 23, 3.5, 73. 111 The latter's effect is demonstrated by mast cell growth from precursor cells that have been cocultured with 3T3 fibroblasts. 35. 73. 111 Similar to the murine model, there appear to be two major populations of human mast cells distinguished histochemically by the protease content of their granules. 35 • 73. 91.111 Mast cells containing tryptase and no chymase are designated MCT, and those containing both tryptase and chymase are designated MCTc.73, 91 MC' and MC'c differ in many ways, including tissue distribution, granule characteristics, and histamine release in response to stimuli.73. 91 Dermal mast cells are mostly MCrc .73. 112 Classical mast cell activation occurs by functional cross-linkage of two high-affinity IgE Fc receptors (FcERI).91, 92 In allergic disease, this is caused by antigen ligation of antigenspecific IgE bound to FCERI on the mast cell surface. Mast cell activation is followed by an explosive degranulation process, with release of preformed mediators and generation of lipid-derived metabolites (Table 2).52,53,91,92.111,112 Certain preformed mediators are packaged within the matrix of the mast cell granules. 91, 92. 112 Proteoglycans, such as heparin, form the backbone of the granule structure and are tightly associated with histamine and proteases. In the acidic granule environment, proteases remain intact but inactive, whereas exposure to the extracellular environment following degranulation leads to enzymatic activation. 73. 91. 92. 112 With degranulation, histamine is rapidly dissociated from the granules and diffuses rapidly, with peak plasma levels occurring within minutes after mast cell activation. Tryptase diffuses more slowly, and serum levels peak at 1 hour. The effects of heparin are local, and systemic anticoagulation does not occur. Activation of arachidonic acid metabolism is coupled to degranulation and histamine release with FCERI activation, but in other mechanisms of mast cell activation, such as by substance P, histamine release without prostaglandin (PG) D2 production may occur. 9. 91, 92,112 Lipidderived mediators include PG, leukotrienes (LT), and platelet-activating factor. 91 . 92, III 112 In mast cells, activation of the cyclo-oxygenase pathway leads almost exclusively to production of PGD 2, and activation of the lipoxygenase pathway leads to production of LTC 4, D4 , and E4 , with lesser amounts of LTB4 .91, 92,112 Platelet-activating factor, also with potent inflammatory properties, is produced by metabolism of lyso-platelet-activating factor. 91 , 92, 112 Studies with murine mast cells demonstrate that activation by FCERI or nonimmunologic stimuli induces production of mRNA for multiple cytokines and secretion of IL-l, IL3, IL-4, IL-6, tumor necrosis factor (TNF)-alpha, and granulocyte-macrophage colony-stimulating factor (GM-CSF), which may have an autocrine or paracrine effect on mast cells. 23,41, 95 Mast cell activation with histamine release, arachidonic acid metabolism, and production of cytokines also may be stimulated by many non-IgE-mediated mechanisms. s4 , 91 4(1,

Acute Urticaria and Angioedema

Lesions in acute urticaria are characterized by rapid onset (usually within minutes) and resolution within several hours. 52, 53 Lesions are variable in size

808

HUSTON & BRESSLER

Table 2. MAST CELL MEDIATORS Mediator(s)

Preformed Histamine

Neutral proteases Tryptase Chymase Carboxypeptidase A Heparin Eosinophil chemotactic factor Neutrophil chemotactic factor Acid hydrolases (beta-hexosaminidase, beta-glucuronidase, arylsulfatase) Oxidative enzymes Newly generated Prostaglandins PGD 2 Leukotrienes LTC.,D.,E. LTB. Platelet-activating factor

Thromboxane A2 Adenosine Oxygen metabolites

Biologic Effects

Pruritus, vasodilation, vascular permeability, smooth muscle contraction, mucous secretion, leukocyte chemokinesis, prostaglandin production, gastric acid secretion, immunoregulation Cleavage of C3, fibrinolysis, inactivation of high molecular weight kininogen Type IV collagen degradation, inhibit angiotensin I Enzymatic degradation Anticoagulation, inhibition of complement activation, neutralization of MBP Eosinophil chemotaxis Neutrophil chemotaxis Enzymatic degradation

Cellular toxicity, LTC4 inactivation Vasodilatation, vascular permeability, smooth muscle contractility, inhibition of platelet aggregation Vascular permeability, vasoactive, smooth muscle contractility, mucous secretion Neutrophil chemotaxis, adherence, activation and degranulation, vascular permeability Vasopermeability, vasoactive, platelet aggregation, mucous secretions, smooth muscle contraction, eosinophil and neutrophil chemotaxis and activation Smooth muscle contraction, platelet aggregation Smooth muscle contraction, vasoactive Cellular cytotoxicity

(ranging from several millimeters to centimeters) and shape (round or serpiginous in configuration) and individual or confluent (Fig. 1). They typically have a clear center and blanch with pressure, indicative of tissue edema. Urticaria and angioedema may occur alone or together, and lesions can be localized, scattered, or generalized, with angioedema having a predilection for the face and extremities. The most feared complication of acute angioedema is laryngeal edema, which can cause airway obstruction. Pathophysiology

Biopsy of acute urticarial lesions reveals interstitial edema and endothelial cell swelling, and is notable for lack of cellular infiltrate (Fig. 1).52,53 The histologic presentation of angioedema is similar, except that the subcutaneous or submucosal tissues are involved. These reactions are the consequence of either IgE-mediated or non-IgE-mediated mast cell activation (see Table 1).


809

Figure 1. Acute urticaria and angioedema. A, Acute urticaria. B, Histopathology demonstrating interstitial edema and minimal cellular infiltrate. C, Acute angioedema.

This results in degranulation with release of preformed mediators and secretion of newly formed mediators that have potent inflammatory properties (Table 2).52,53,91,92,111,112 Although some of these mediators, including LTC4 and plateletactivating factor, are more potent on a molar basis than histamine at inducing a wheal and flare reaction, histamine is probably the most important mediator because of its greater concentration in tissues following degranulation. 52, 91,112 Neurogenic responses to histamine are also important in the pathogenesis of cutaneous inflammation. Histamine stimulation of cutaneous sensory nerves generates an impulse that travels toward the spinal cord and on to the central nervous system (CNS), where it is perceived as pruritus. In addition, at the neuronal bifurcation in the periphery, the same impulse generates a stimulus back along unmyelinated sensory nerve branches in an antidromic fashion to the cutaneous nerve endings from which substance P and other neuropeptides are released. 52 These nerve endings are in close proximity to small cutaneous blood vessels and mast cells, generating a flare response and causing degranulation, respectively, thereby potentially amplifying the initial allergic response. 9,84

Patient Evaluation

Because of the rapid onset and limited duration, historical identification of the cause of acute urticaria and angioedema is far more successful than in chronic urticaria and angioedema. The list of potential etiologies is exhaustive (Table 3), and careful detailed history taking is essential because no laboratory studies are characteristically abnormal in acute urticaria or angioedema.

810

HUSTON & BRESSLER

Table 3. POTENTIAL CAUSES OF URTICARIA AND ANGIOEDEMA Idiopathic Food allergy Food additives and preservatives-benzoic acid derivatives, dyes (especially tartrazine), etc. Drug reactions Antibiotics-penicillin, cephalosporins, sulfa derivatives, vancomycin, etc. Cyclo-oxygenase inhibitors-aspirin, NSAIDs Over-the-counter medications-vitamins, cold formulas, etc. Antihypertensive agents-angiotensin-converting enzyme inhibitors, beta-blockers, diuretics, etc. Psychotropics-sedatives, tranquilizers, etc. Hyperosmolar radiocontrast media Opiates-morphine-sulfate, codeine Muscle relaxants-d-tubocurarine Hormonal-birth control pills, thyroid replacement, synthetic ACTH, insulin Chemotherapeutic medications-doxorubicin (Adriamycin) Intravenous gamma globulin Protamine Enzymes-papain Vaccines Antisera Immunotherapy injections Insect bites and stings Hymenoptera-wasp, honey bee, yellow jacket, hornet, fire ant Others-caterpillar, spider Physical Dermatographism Cholinergic Localized heat Cold Delayed pressure Exercise-induced anaphylaxis Solar Vibratory Aquagenic Endocrine disorders Thyroid disease-hypo-thyroidism or hyperthyroidism, thyroiditis Diabetes mellitus Progesterone hypersensitivity Hyperparathyroidism Collagen vascular diseases-particularly systemic lupus erythematosus, rheumatoid arthritis, Sjbgren's syndrome Infection Viral-hepatitis B, infectious mononucleosis Bacterial Parasitic-invasive helminths, giardiasis Fungal Malignancy-lymphoma, solid tumors, myeloproliferative disorders Vasculitis Idiopathic hypocomplementemic Idiopathic normocomplementemic Associated with systemic diseases Serum sickness-heterologous protein administration, drugs Schnitzler's syndrome C, esterase inhibitor deficiency syndromes (angioedema only) Hereditary angioedema Acquired angioedema Contact-latex, animals, food, plants, sea nettles Inhalant atopy Transfusion reaction Rare miscellaneous C3 b inactivator deficiency Familial cold urticaria Amyloidosis with nerve deafness Episodic angioedema with eosinophilia Carboxypeptidase N deficiency


811

Food allergy is an important cause of acute urticaria and angioedema. 17, If a clear-cut cause and effect relationship to a specific food is recorded in association with multiple acute reactions, testing may not be required. In uncertain instances, allergy skin testing may be helpful when a specific food is suspected. A positive skin test is supportive evidence for specific food allergy, whereas a negative skin test makes allergy to that specific food highly unlikely. Positive skin tests without a corroborative history are nondiagnostic. If necessary, open or double-blinded food challenges can be performed to confirm a suspected food allergy. However, they should be performed only under appropriate medical supervision, and the risk of potential life-threatening anaphylaxis should be recognized in highly sensitive patients. Drugs are another important consideration, especially when patients are taking multiple medications. 17. 52. 53 Penicillin is the most common offender, but other antibiotics, including sulfa derivatives, cephalosporins, and tetracyclines, as well as diuretics, antihypertensive agents, tranquilizers, analgesics, muscle relaxants, and cold medications may be responsible. Most acute urticaria and angioedema reactions caused by antibiotics are IgE-mediated, with the exception of polymixin B and vancomycin ("red man" syndrome), which cause direct mast cell degranulation. 45 Morphine, codeine, doxorubicin (Adriamycin), certain muscle relaxants such as d-tubocurarine, and ionic radiocontrast media all cause mast cell degranulation (see Table 1).45 57,76,84 The mechanism for urticaria and angioedema due to aspirin and other cyclo-oxygenase inhibitors is unknown but may be due to a resultant imbalance between prostaglandin and leukotriene production. Acute reactions to protamine are predominantly IgEmediated and are important in heparin anticoagulation reversal following cardiopulmonary bypass. Egg-containing vaccines may cause acute reactions in egg-allergic individuals. Antisera administration can cause acute urticaria and angioedema by an anaphylactic reaction or as a manifestation of acute serum sickness. IgA-deficient individuals who receive blood products containing IgA, including intravenous gamma globulin, may experience acute urticaria or angioedema due to an anaphylactoid reaction from IgG-anti-IgA immune complex activation of complement or due to a classic anaphylactic reaction. Particularly interesting is the role of angiotensin-converting enzyme inhibitors in causing angioedema. 9, 103 The mechanism of these reactions is probably through decreased degradation and, thus, accumulation of bradykinin. Angioedema is most frequent during the initial weeks of angiotension-converting enzyme therapy, and, rarely, life-threatening laryngeal edema may occur. IQ3 The usefulness of allergy skin testing for drugs other than penicillin is not well defined and, when utilized, should be interpreted with particular caution. Acute urticaria and angioedema also may be caused by stinging insects; this is usually readily apparent, especially with Hymenoptera. Wasp, hornet, yellow jacket, honeybee, and fire ant skin testing can be used for diagnostic confirmation and guidance of therapy. Papular urticaria is characterized by small wheals surrounding insect bites and is more common in young children. 53 Inhaled allergens are less likely than ingested substances to cause urticaria or angioedema, but in those patients, other signs of allergic disease, such as rhinitis, are also usually present. Localized urticaria is suggestive of a contact phenomenon (when phYSical factors are not involved), and suspected agents can be tested by application to the skin and noting the development of hives over a 30-minute period. 52,53

Treatment

The best treatment against recurrence of acute urticaria or angioedema is avoidance of the offending substance when it can be identified. Because acute

812

HUSTON & BRESSLER

urticaria and angioedema are self-limiting processes, medical intervention is usually limited to the use of H, receptor (H,R) antagonists. Epinephrine should immediately be given if there is clinical indication of laryngeal involvement or systemic anaphylaxis. For non-life-threatening cases of urticaria and angioedema, epinephrine should be used with extreme caution, especially in the elderly population because of potential adverse effects on the cardiovascular system. In progressive acute angioedema involving the larynx, maintaining a patent airway is of paramount importance, and intubation or tracheostomy should be performed if necessary. Corticosteroids should not be given routinely because they do not inhibit mast cell degranulation and are not useful in most instances of acute urticaria and angioedema. However, patients who have persistent or recurrent attacks of acute urticaria or angioedema may have additional contributory factors that are steroid responsive, and a rapidly tapering course of corticosteroids may be efficacious. When the recurrence of acute urticaria or angioedema is likely despite attempts at avoidance, patients should be instructed on the proper use of injectable epinephrine for selfadministration in emergency situations. The use of beta-adrenergic receptor antagonists should be avoided in these patients when possible because of their potential to exacerbate symptoms and to interfere with the therapeutic effects of epinephrine!

Chronic Urticaria and Angioedema The clinical appearance of chronic and acute urticaria or angioedema lesions is usually indistinguishable, except that resolution of individual chronic lesions is longer, typically lasting a minimum of several hours and up to 24 hours (Fig.

Figure 2. Chronic idiopathic urticaria. A, Typical hives. B, Histopathology demonstrating perivascular mononuclear cell infiltrate.


813

2). Size, number, and distribution of hives are highly variable and are typically very pruritic. Chronic hives are often exacerbated by alcohol and physical factors, such as heat, exercise, and pressure. Pressure-related hives in chronic urticaria are different from lesions in delayed pressure urticaria and have the same clinical and histologic characteristics as spontaneously occurring chronic hives. When hives are painful instead of pruritic, last longer than 24 hours, leave residual pigmentation, or are resistant to corticosteroid tapering, urticarial vasculitis should be considered. The natural history of chronic urticaria and angioedema is poorly defined. The mean duration for chronic urticaria has been reported as 3 to 4 years, although some cases persist for years, whereas others resolve within months. The potential morbidity of this disease cannot be understated because lesions may be disfiguring, embarrassing, and interfere with the patient's personal, business, and social life. Pathophysiology

IgE-mediated pathogenic mechanisms are difficult to establish in chronic urticaria and angioedema. Nonetheless, the mast cell has an important role. Evidence in support of this includes the demonstration of mast cell degranulation in lesional skin, increased histamine content in induced blister fluid from lesional and nonlesional skin, increased histamine release in nonlesional skin, and an approximately tenfold increase in mast cell density in lesional skin biopsies from patients with chronic idiopathic urticaria.>' 13, 52, 53, 61, 69 Multiple stimuli may singly or in concert have a role in this heightened level of mast cell activity. A central role in this process may belong to the perivascular mononuclear cell infiltrate that accompanies the mast cell hyperplasia found in chronic urticaria lesions (Fig. 2). These mononuclear cells are mostly activated T cells, 52, 53 Monocyte numbers are also increased, and B cells are notably absent. 52, 53 Both T cells and monocytes produce multiple cytokines capable of activating mast cells and causing degranulation (Fig. 3), Histamine-releasing factors from T cells have been shown to cause basophil degranulation, and, presumably, similar molecules also cause mast cell degranulation. 52, 109 Activated T cells are also capable of producing several cytokines, including IL-3 and GMCSF, which have been demonstrated to cause basophil and murine mast cell degranulation. 23, 44, 81, III IL-3 might also act as a mast cell growth factor in these lesions. Monocytes produce histamine-releasing factor activity and GM-CSF as well as IL-8, which can cause basophil degranulation, and IL-I, which in high concentrations has been demonstrated to cause human mast cell degranulation, 23, 52, 81, 107, III The prO-inflammatory effects of IL-I are numerous and include increasing CD25 expression on T cells, activating monocytes and endothelial cells, and inducing production of multiple pro-inflammatory cytokines, including IL-8, GM-CSF, and IL-6!' 23, 62, 81 Other cytokines produced by these cells include TNF-alpha, IL-2, IL-4, and interferon-gamma, which have potent proinflammatory properties, including activation and upregulation of T cells, monocytes, eosinophils, endothelial cells, and fibroblasts!, 23, 62, 81 The importance of these cells and their relationship to mast cells in the pathogenesis of urticaria lesions is indicated by the efficacy of systemic corticosteroids in suppression of chronic idiopathic urticaria. Corticosteroids do not affect mast cell degranulation, but effects on T cells and monocytes include inhibition of migration, down-regulating cell activation, and inhibition of the production of inflammatory mediators and cytokines, including IL-I.'>' 81 Cytokine production by mast cells may similarly contribute to the disease process (Fig. 3), IL-3 or GM-CSF can cause "self-degranulation" of mast cells.

~ Physical and

,,

Nonlmmunologlc

lTYi

Stimuli,

Type 11 Reaction III Reaction

,,

,

\

Complemen~ C5a--

Pathway

Activation

Cla - - . .

•• • • • • • • • ..: •:.

.. .. .....

..;... : •..•.

_---I----..,..

~ TNF-(' _Il-'. Il- 4. Il- 6

Il- 3 Arachidonic Acid Metabolism

~

~

I Upoxygenas.

I

Preformed Mediators

I

c:~~ge"'Tryptasel/Heperin

Pathway

II

I

E1CF '1F HI·1Iamin ...... R.I::.. lTC4lD4E4 , Neuropeplklel Neutrophil (e.g. Substance P) Recruitment

Inhibit Coagulation

Eos"no hO'

Rec~:e~t

Pruritus Vasodilatation • Vascular Permeability

+

Axon Flare Vascular Vascular Permeabfltty Permeability Vasoactive

I

V

Activation

\

Upregulation

I

Cyclooxygenese Pathway

I

PGD2

PAF

Vasodilatation Vascular

Perme_1Iy

1 1

Permeability

Vascular

Vasoactive

Eosinophil

Recruitment and Activation

Figure 3. Mast cell activation and degranulation in urticaria and angiodema. MC = mast cell; T = T cell; M = monocyte; EOS = eosinophil; ENDO = endothelial cell; MBP = major basic protein; HRF = histamine-releasing factor; GM-CSF = granulocyte macrophage-colony stimulating factor; PAF = platelet-activating factor; LT = leukotriene; IL = interleukin; NCF = neutrophil chemotactic factor; ECF = eosinophil chemotactic factor; ).. = antibody; - = antigen; - - --> = degranulation stimulus.


815

IL-3 may also function as an autocrinelike growth stimulus, whereas GM-CSF activates infiltrating monocytes and eosinophils. TNF-alpha is a potent stimulus to T cells, monocytes, and endothelial cells."1 Activation of endothelial cells by TNF-alpha with increased adhesion molecule expression and cytokine production may represent one important physiologic effect of the close physical relationship between mast cells and endothelial cells. IL-4 and IL-6 produced by mast cells promote T cell activation and proliferation, and IL-4 has recently been reported to activate endothelial cells. 23, 47, 81 Although IL-4 is a potent stimulus for IgE production, the absence of B cells in involved tissue and relative lack of evidence for IgE in the pathogenesis of most instances of chronic urticaria makes this biologic effect unlikely to contribute significantly to this disease. 81 Cytokine-induced mast cell degranulation stimuli may also serve as an activation signal for promoting further cytokine production and thereby provide a positive feedback loop for both mediator and cytokine production by mast cells. These conditions may further serve to "prime" mast cells, resulting in a lowered threshold for degranulation, which may be important in chronic idiopathic urticaria and in the pathogenesis of some of the physical urticarias. In summary, cytokine production by mast cells may have an important role in the pathogenesis of chronic urticaria by promoting activation of T cells, monocytes, eosinophils, endothelial cells, and fibroblasts; stimulating T cell proliferation; causing self-degranulation of mast cells; and causing autocrine mast cell growth. Eosinophils may conspire with mast cells in contributing to chronic urticaria and angioedema. Despite the lack of prominence of eosinophils in most chronic urticarial reactions, degranulated eosinophils can be identified by electron microscopy, and MBP deposition can be demonstrated by immunofluorescence in blood vessel walls and is scattered throughout the dermis.67, 86 Thus, even though the degree of eosinophil migration into affected skin may be a variable phenomenon and more prominent early in the course of disease, persistence of MBP may serve as a chronic inflammatory stimulus. Potential stimuli for eosinophil attraction include eosinophil chemotactic factor, histamine, and platelet-activating factor produced by mast cells. Eosinophil activation leads to the release of granule constituents, including MBP, eosinophil cationic protein, and eosinophil-derived neurotoxin, each of which can cause a wheal and flare reaction. 67, 79 Activated eosinophils also produce IL-3 and GM-CSF, whose potential effects on mast cells have been discussed previously. 55 In addition, they produce large quantities of platelet-activating factor and LTC4, which are potent mediators of vascular permeability.67 Complement pathway activation may have a role in chronic urticaria and is especially important in the pathogenesis of urticarial vasculitis. Anaphylatoxins (C3a and C5a) generated by classic and alternate pathway complement activation are potent inducers of mast cell degranulation and neutrophil chemotaxis. 52, 53, 84 C3a also can be generated by cleavage of C3 by mast cell tryptase. 91 Autoantibodies to IgE have been reported in a few patients with chronic urticaria. These autoantibodies presumably could serve as a chronic mast cell stimulus by cross-linking IgE bound to mast cells. Theoretically, autoantibodies to the FCER! could provide a similar chronic stimulus to mast cells. Patient Evaluation

The differential diagnosis of chronic urticaria is extensive and includes most of the causes of acute urticaria (Table 3). As is true in acute urticaria, the

816

HUSTON & BRESSLER

most important aspect of evaluating patients with chronic urticaria is a detailed history and physical examination. Screening tests for physical urticarias should be performed as indicated by the patient's history and physical examination. Foods are an uncommon cause of chronic urticaria and angioedema. 52 , 53 However, food additives (e.g., benzoates) and dyes (e.g., tartrazine) may be important subtle causes of chronic urticaria, although their true incidence is unknown. 52, 53 Elimination of suspected foods may be tried, and if this offers no improvement, a strict elimination diet consisting of lamb or chicken, rice, and water for 2 to 3 weeks may be tried. If symptoms do not improve, ingested food substances are unlikely as the cause of urticaria. If there is improvement, foods can gradually be added back until a normal diet is obtained. Such a plan is both tedious and difficult to maintain and has no assurance of providing useful information. A careful medication history is important and should include documentation of all over-the-counter medications, even those being taken sporadically. Penicillin, sulfa derivatives, and cephalosporins are potential causes when taken as chronic therapy. Aspirin may cause urticaria in 1% of the general population and exacerbations in 20% or more of patients with chronic urticaria. 53 This is presumably related to inhibition of the cyclo-oxygenase pathway, because other nonsteroidal anti-inflammatory drugs (NSAIDs) can also cause exacerbations in these patients. 53 In approximately 15% to 20% of aspirin sensitive patients, tartrazine may also exacerbate urticaria. 17, 53 Discontinuation of the responsible medication should result in improvement of the urticaria within several days. Chronic urticaria, especially in the elderly population, may be indicative of underlying systemic disease. Urticaria has been reported in association with autoimmune thyroiditis, hyperthyroidism, hypothyroidism, and thyroid replacement therapy. 53, 66, 83 The actual incidence of thyroid disease in patient populations with chronic urticaria is disputed, as is the usefulness of routine screening with thyroid function tests or for thyroid autoantibodies. 54 , 65 However, thyroxine replacement therapy may cause dramatic improvement of urticaria or angioedema in some patients with subclinical thyroiditis. 65 Urticaria or angioedema may persist for an extended period of time after the euthyroid state has been achieved, particularly in autoimmune thyroiditis. 52 Chronic urticaria also may be associated with collagen vascular diseases, particularly systemic lupus erythematosus, rheumatoid arthritis, and Sjogren's syndrome. 52 Urticaria may present during remission, when it may be an early manifestation of disease exacerbation, or it may occur during active disease. Chronic urticaria and angioedema, particularly in the elderly, also has been reported in association with malignancy, including myeloproliferative disorders, lymphoma (particularly Hodgkins), and solid tumorsY' 53, 65 Occult infections have often been touted as important causes of chronic urticaria, but this relationship is probably overestimated. 52, 53 However, certain viral, bacterial, fungal, and parasitic infections should be considered. 52, 53 Inhalant substances are probably rare causes of chronic urticaria and are even more rarely positively identified. In patients with seasonal occurrences of hives or in a patient exposed repeatedly to aerosolized substances, this should be considered. These patients may also have rhinitis or pulmonary symptoms coexistent with the urticaria. Urticaria pigmentosa is dermal mastocytosis and is readily distinguished from other urticarias. It mayor may not be accompanied by internal organ mast cell disease or systemic symptoms, such as flushing, headache, nausea, vomiting, and diarrhea. Lesions in urticaria pigmentosa are typically brownishred, persist for years, and urticate with light trauma (Darier's sign).


817

In patients in whom the history and physical examination do not indicate a possible causative factor for chronic urticaria, extensive laboratory work-ups are singularly unrewarding. Routine dental and gallbladder radiographs searching for occult infection are decidedly unproductive and cost ineffective and should not be performed unless there is clinical suspicion of disease. Similarly, stool tests for ova and parasites are not performed unless there is significant blood eosinophilia, recurrent diarrhea, or other evidence of parasitic infection. Determination of severe IgE levels is not diagnostically useful. In greater than 80% of patients, chronic urticaria is considered idiopathic for lack of an identifiable cause. 5', 53 Most nonidiopathic cases are diagnosed as a result of limited laboratory screening and clinical suspicion followed by more specific testing. Treatment

Known causative agents and potentially aggravating factors, such as heat, exercise, alcohol, and aspirin, should be avoided. Treatment of underlying systemic disease may result in resolution of the urticaria. In patients with chronic idiopathic urticaria, therapy is virtually always required and often needed for extended periods of time. The initial treatment is with the maximum tolerated doses of an H1R antagonist needed for disease control (Table 4). Second-generation H,R antagonists are attractive alternatives to the first-generation H,R antagonists because they are nonsedating, require less frequent dosing, have fewer anticholinergic side effects, and are at least as efficacious. YS 100.114 If the desired effect is not obtained, these medications can be interchanged. Refractory conditions may benefit from the combined use of H,R antagonists from different chemical classes. The addition of an H,R antagonist also may be of benefit." Of these, cimetidine has more potential side effects and alters metabolism of some drugs by its effect on hepatic microsomal cytochrome P 450. Therefore, ranitidine or famotidine may be preferable. Some patients require corticosteroid therapy, which dramatically decreases disease activity. Long-term, daily corticosteroid administration results in serious adverse effects and should be avoided. However, judicious corticosteroid therapy can offer complete symptomatic relief and may induce remission or resolution of urticaria. Various corticosteroid regimens have been suggested. 53 Typically, one might initiate therapy at a 0.5 to 1.0 mg prednisone equivalent! kg daily followed by a gradual taper over several weeks to the lowest effective daily or alternate day dose. In severe urticaria, brief courses of corticosteroid therapy invariably offer only temporary relief and are ineffective in long-term Table 4. CHEMICAL CLASSES OF H,R ANTAGONISTS AND REPRESENTATIVE EXAMPLE(S)

Class

Generic Name

Alkylamine

Chlorpheniramine Brompheniramine Diphenhydramine Clemastine Tripelennamine Hydroxyzine Cetirizine* Cyproheptadine Doxepen Astemizole* Terfenadine*

Ethanolamine Ethylenediamine Piperazine Piperidine Tricyclic Unclassified *Second-generation antihistamines.

818

HUSTON & BRESSLER

Table 5. CLINICAL FEATURES OF URTICARIAL VASCULITIS

Lesion characteristics Persistence of individual lesions for greater than 24 hours Lesions are painful or burning in sensation in addition to or rather than pruritic Pronounced central clearing or dusky coloration Residual pigmentation following resolution Concurrent systemic symptoms Fever, malaise, headache, arthralgias, serositis Coexistence of palpable purpura, livedo-reticularis Moderate to marked elevation of ESR Hypocomplementemia Onset in patients with known collagen vascular disease, malignancy, infection, cryoglobulinemia or serum sickness

suppression of disease activity. The length of time that corticosteroid therapy is required varies, but in some patients it may be necessary for extended periods of time. Urticarial Vasculitis

The spectrum of urticarial vasculitis ranges from chronic, relatively benign disease to an aggressive multisystem visceral illness. I, B, 70, 89 Certain criteria are helpful in differentiating urticarial vasculitis from other forms of chronic urticaria (Table 5) but are not by themselves diagnostic. I, 8, 89 Thus, when urticarial vasculitis is suspected clinically, a lesional biopsy is required for confirmatory diagnosis. I, B, 70, B9 Urticarial vasculitis is typically a necrotizing or nonnecrotizing, leukocytoclastic vasculitis involving venules but not arterioles (Fig. 4). I, 8, 29, 68, 70, 104 Hypogranulated mast cells, indicative of recent activation and degranulation, also may be present. 104 Immunofluorescent staining is often positive for immunoglobulin (mostly IgM) and complement, particularly when hypocomplementemia is present. I, 8, 6B, 70, 89 Patients with idiopathic normocomplementemic vasculitis usually do not have accompanying systemic disease manifestations, and, when present, they are typically not severe. B9 In idiopathic hypocomplementemic urticarial vasculitis, multisystem involvement is common. 29, B9, 93 Urticarial vasculitis may also occur in association with collagen vascular disease and may antedate or develop concurrently with malignancy or infections, particularly those of viral etiology (e.g., hepatjtis B antigenemia).47, 65, B9 Urticarial vasculitis is also a common manifestation of acute serum sickness. 51, 58 Schnitzler's syndrome is characterized by chronic urticaria, typically with vasculitis, and high levels of monoclonal IgM. Familial cold urticaria is a rare, hereditary, cold-induced urticarial vasculitis described with the physical urticarias. Therapy for urticarial vasculitis should be individualized depending on the severity of and presence or absence of underlying disease. Antihistamines may be tried initially but are usually only partially effective. NSAIDs, dapsone, and, particularly, colchicine may be effective in some patients. I, 8, 14, 30, 74 In serum sickness, a brief course of corticosteroids may be used initially because of the limited clinical course and beneficial role of corticosteroids in ameliorating accompanying systemic symptoms. 51 Idiopathic hypocomplementemic urticarial vasculitis presents a challenging therapeutic problem. Corticosteroid therapy is


819

Figure 4. Urticarial vasculitis. A, Indurated lesion of urticarial vasculitis (arrow) with accompanying histopathology of leukocytoclastic vasculitis (8).

almost always required, and in severe cases, even daily dosing with 1 to 2 mg prednisone equivalent/kg daily may be inadequate. s, 14 In patients who require long-term daily corticosteroid therapy for control of disease activity, a second medication, such as dapsone or colchicine, should be considered for steroidsparing effect, and in severe cases, azathioprine or cyclophosphamide may be indicated. s,I4 Physical Urticaria and Angioedema Syndromes

The onset of physical urticarial and angioedema syndromes is usually spontaneous, and they can be initiated reproducibly by specific physical stimuli (Table 6 and Fig. 5).16,53,97 Many physical urticarias might be considered to be acute forms of urticarias, because the onset of lesions is usually rapid, with resolution within hours, despite the recurrence of symptoms for months to years. 52 Dermatographism

Dermatographism is the most common of the physical urticarias, affecting approximately 2% to 5% of the general population, but in most cases is usually a mild disease. 97 Diagnosis is made by the application of linear pressure. 16, so, 97 HIR antagonists may be beneficial in patients requiring therapy. Cholinergic Urticaria

The physical stimulus for cholinergic urticaria is an increased core body temperature that may be caused by factors such as exercise, a hot shower, and anxiety. 16, 53, 97 Increased plasma histamine levels after exercise challenge can be demonstrated readily.I6, 4S, 53, 97 Lesions are mostly punctate, intensely pruritic wheals surrounded by a 'large area of erythema. In severe cases, systemic anaphylaxis may develop.I6, 53, 97 Methacholine skin testing is positive in only approximately one third of patients and is not always reproducible. 16, 53, 97

820

HUSTON & BRESSLER

Table 6. TESTS USEFUL FOR THE DIAGNOSIS OF THE PHYSICAL URTICARIAS Type of Urticaria Dermatographism Delayed dermatographism Cholinergic

Exercise-induced anaphylaxis Cold urticarias Primary Secondary (associated with systemic disease) Exercise cold-induced Systemic Cold-induced dermatograph ism Delayed pressure Solar

Vibratory Aquagenic

Test

Positive Result

Application of pressure to the skin with a narrow object Same

Linear wheal and flare (2-5 minutes) Linear wheal and flare (3-8 hours) Characteristic satellite lesions or urticaria

1. Methacholine skin test 2. Increase core body temperature 0.7 to 1.0°C by or immersion in warm water or exercise Exercise challenge Localized cold challenge (i.e., ice cube test) Not indicated or recommended

Urticaria Pruritus and urticaria or angioedema within 5 minutes of rewarming None

Exercise in cold temperature 1. Generalized cold exposure 2. Local cold challenge Chilling lightly scratched skin

Urticaria 1. Generalized urticaria 2. Negative Linear wheal and flare

Application of a 15-lb weighted sling to shoulder for 20 minutes 1. Monochrometer testing with specific wavelengths of light 2. Testing for porphyrins for type 6 Vibration to forearm for 5 minutes Room temperature water compress to upper back for 30 minutes

Painful swelling 4-12 hours later Hives over light-exposed area Elevated erythrocyte protoporphyrin Localized urticaria Localized urticaria

Increasing the core body temperature by 0.7 to 1.0°C by immersion in a warm (40 to 42°C) bath or exercise results in urticaria. '6, 97 Activities that increase core body temperature should be avoided. Because hydroxyzine appears to be more effective than other antihistamines, cetirizine, its carboxylated metabolite, may be particularly effective. Cooling may decrease the length and severity of an acute attack, and induction of tolerance may be possible in some patients. 16,97 Localized Heat Urticaria

Although systemic symptoms may occur in severe localized heat urticaria, urticaria remains localized to the area of heat contact. Application of a heated cylinder (50 to 55°C) on the forearm for 5 minutes results in characteristic lesions. 16,97 Antihistamines are only partially effective. '6,97 Therapeutic induction of tolerance has been reported.'6


20000

821

r----:--------.....

o ~~

::>a:: oc( ""i t= o a:: 5::> zU

U

E W z

I

10000

5000

~

1000

ow U

::>c( 0za:: .(S w_ CJ)I-a:: ~::> w

~

3000

~

w

2000

~

1000

~

:I:

0

8

4

12 16

~

o

6

12 18 24 Minutes

30

36

Figure 5. Evidence for mast cell degranulation in physical urticarias. Rise in plasma histamine levels in draining venous blood following ice cube test (A), stroking the skin (B), and exercise (C).

Exercise-Induced Anaphylaxis

In exercise-induced anaphylaxis, urticarial lesions appear 5 to 30 minutes after the onset of exercise. '6 Initially, this condition may be difficult to differentiate from cholinergic urticaria because exercise is a potent stimulus for both disorders .'6 However, raising the core body temperature without exercise does not precipitate exercise-induced anaphylaxis, and the hives are usually larger than in cholinergic urticaria .97 A negative response to exercise does not necessarily rule out exercise-induced anaphylaxis because it is not always reproducible,,7 Therapy with a combination of H,R and H2R antagonists may be partially effective. 16 Cold Urticaria and Angioedema

Primary (essential) cold urticaria is acquired and is not associated with underlying systemic disease or identifiable cold reactive proteins. 16, 77, 97 Symptoms are usually localized to the area of cold exposure, although generalized

822

HUSTON & BRESSLER

cold exposure, such as with swimming, can result in systemic anaphylaxis with severe hypotension and even death. 53 Intense pruritus and wheal formation occur usually within minutes of re warming of the cold-challenged area and are accompanied by peak plasma histamine levels in draining venous blood. 48 53. 77. 07 Cyproheptadine and ketotifen appear to be especially effective, and induction of therapeutic tolerance is possible in some patients. lb. 48. 97 In patients with secondary cold urticaria, urticaria and angioedema are associated with an underlying systemic disease (e.g., cryoglobulinemia) in which a cold-precipitating protein (usually an antibody) is present. 53. 77. 97 Treatment of the underlying disease usually results in improvement in urticaria or angioedema. Physical testing with cold is not indicated and is, in fact, dangerous because it may lead to vascular occlusion and tissue ischemia. Lesions in exercise cold-induced urticaria (cold-induced cholinergic urticaria) are similar to those in cholinergic urticaria but occur only when the patient exercises in a cold environment. 16. 53 Neither cold nor exercise alone is a sufficient stimulus. In patients with systemic cold urticaria, generalized rather than localized hives and angioedema develop in response to systemic but not local cold challenge. '6 . 56. 97 Thus, an ice cube test is negative, and there is no relationship to exercise. Lesions associated with cold-dependent dermatographism occur with cooling skin that has been lightly traumatized (i.e., stroked).l6 Exercise, ice cube challenge, and systemic cold exposure tests are all negative. Familial cold urticaria is an autosomal dominant disorder. 97 Following generalized cold exposure, burning, erythematous papular lesions develop, which last 24 to 48 hours and may be accompanied by fever, headache, arthralgias, abdominal pain, leukocytosis, and an elevated erythrocyte sedimentation rate (ESR). Biopsy reveals a leukocytoclastic vasculitis. 16. 97 Oelayed Pressure Urticaria

In delayed pressure urticaria, the onset of lesions usually occurs 4 to 8 hours following sustained pressure, such as walking, sitting, use of hand tools, or wearing tight clothes. 16. lOS Lesions are diffuse, tender, and painful rather than pruritic, usually appear as angioedema rather than urticaria, and typically resolve in 24 to 48 hours. 16. 07. 108 Flulike symptoms, including fever and arthralgias, and an elevated ESR may be present. 16. 07. 108 Chronic idiopathic urticaria is common in these patients. 10S Application of a IS-pound weight for 20 minutes results in painful swelling approximately 4 to 6 hours later. 16. 97. 108 Antihistamines have a very limited effect, and NSAIDs may offer partial relief but may cause exacerbation of accompanying chronic urticaria. 97 • 108 Most patients require corticosteroid therapy, and in some patients prolonged corticosteroid therapy is needed. 108 High-dose cetirizine (30 mg/day) has been reported to be effective. 50 60 Solar Urticaria

Solar urticaria is classified based on causative wavelength ranges of light (action spectra): type I (280 to 320 nm), type II (320 to 400 nm), type III (400 to 500 nm), type IV (400 to 500 nm), type V (280 to 500 nm), and type VI (400 nm). Passive transfer tests are positive for the most part in types I and IV.53. 07 In type VI, the photoallergen is protoporphyrin IX, but, otherwise, photoallergens remain to be identified. 53


823

Within a few minutes of light exposure to the appropriate wavelength, pruritus occurs followed by morbilliform erythema and then urticaria over exposed areas. 16, 53, 97 Anaphylaxis may occur with exposure of a large body surface. Specific wavelength light challenge can be performed using a monochromator.16, 07 Antihistamines and sunscreens (e.g., para-aminobenzoic acid) may be useful in selected patients. 16, 75, 97 Therapeutic tolerance may be induced in some patients by repetitive phototherapy, psoralen with ultraviolet A light therapy, or sunlight exposure. 16, 97 When a circulating photoallergen is present, plasmapheresis may induce temporary or prolonged remission. M Miscellaneous Syndromes

Aquagenic urticaria occurs at the site of water exposure and can be elicited by application of a compress of room temperature water applied for 30 minutes to the back.16, 97 Antihistamines may be effective, and application of oil-based lotions may minimize water contact to the skin. 1b, 97 In vibratory urticaria, lesions (usually angioedema) typically occur 1 to 5 minutes following stimuli such as lawn mowing and motorcycle riding, with resolution occurring 1 to 24 hours later. 16 Vibratory stimulus to the forearm for 5 minutes leads to the development of lesions.16 53 Antihistamine therapy may be partially effective, and therapeutic tolerance can be induced. lb , 53 Episodic angioedema with eosinophilia is characterized by recurrent urticaria and angioedema, fever, and weight gain. 40 Leukocytosis and an elevated ESR are usually present. Biopsy reveals dermal infiltration of eosinophils with a high degree of degranulation. Disease will spontaneously regress over 7 to 10 days, but treatment with corticosteroids leads to rapid defervescence and diuresis. Polymorphic eruption of pregnancy occurs in approximately 0.5% of pregnancies and usually begins in the last 5 weeks, occurs almost exclusively in primigravidas, and does not typically recur with subsequent pregnancies. 90 Biopsy reveals a perivascular lymphocytic infiltrate without vasculitis. Laryngopathia gravidarum affects mostly multigravidarum women. 90 An acute form of the disease develops just before parturition, whereas chronic disease occurs earlier and has a tendency to recur with subsequent pregnancies. The disease consists of angioedema primarily limited to the larynx and epiglottis with sparing of the true vocal cords. Systemic symptoms are absent, but leukocytosis and an elevated ESR are frequently found. Biopsy reveals edema with a mild inflammatory submucosal infiltrate consisting primarily of lymphocytes and plasma cells. C3b inactivator deficiency is characterized by spontaneous activation of the alternate complement pathway with unchecked generation of C3a. 53 Urticaria and amyloidosis (Muckle-Wells syndrome) is characterized by urticaria, amyloidosis, nerve deafness, and limb pain.53 Carboxypeptidase N deficiency leads to the unchecked generation of the anaphylatoxins C3a, C4a, and C5a. Brief Overview of Second-Generation Antihistamines

Treatment with first-generation antihistamines has been severely limited by their sedative and anticholinergic side effects. In addition, to obtain maximal efficacy, most of these preparations necessitate frequent dosing schedules,

824

HUSTON & BRESSLER

which is both inconvenient and often results in poor compliance. A major advance in antihistamine therapy has been the development of second-generation antihistamines. Terfenadine and astemizole are available for general use, whereas loratadine and cetirizine are awaiting approval by the United States Food and Drug Administration (FDA). These drugs have in common several important characteristics, including excellent oral absorption, lack of sedation and anticholinergic effects, lack of potentiation and interaction with ethanol, valium, and other psychotropic compounds, and sufficiently long half-lives to permit once-a-day dosing. % 98, JOO, 114 The low incidence of CNS effects is probably due to poor penetration into the CNS.9sI00 Binding to H1R is with high specificity and affinity, and the dissociation rate is slow, which explains, at least in part, why the duration of action is much longer than one would expect from the serum half-life of these drugs. 9s Terfenadine, astemizole, and loratadine are all metabolized by the hepatic P 450 cytochrome pathway, whereas cetirizine undergoes very little metabolism. 100 In addition to the half-life, dosage is a very important factor in the efficacy of these drugs as demonstrated by effects on wheal and flare response to histamine injection. The relative effectiveness of a single dose of astemizole, cetirizine, loratadine, and terfenadine on histamineinduced wheal formation over 24 hours is as follows: cetirizine (10 mg) > terfenadine (60 mg) > loratadine (10 mg) > astemizole (10 mg) (Table 7).99 However, this does not take into account repetitive dosing.99 Thus, after several weeks of daily therapy, astemizole may result in at least comparable wheal suppression (up to 97% reported) in comparison with the other secondgeneration antihistamines. 99 As a general rule, the half-life of these drugs is less in children and longer in elderly patients. 9s ]00 Tachyphylaxis does not develop with any of these medications with at least 8 weeks of therapy and most likely does not occur with long-term therapy.9s, 1011 Adverse effects in normal persons are largely doserelated and occur in patients with liver disease or in those taking drugs that inhibit the cytochrome P 450 pathway; therefore, appropriate dose adjustments should be made for terfenadine, astemizole, and loratadine. The half-life of cetirizine is prolonged in renal failure. 98 Even though these drugs are "nonsedating," occasionally, patients may experience decreased mental acuity even with standard doses. 1011 None of these drugs has been proved to be safe in pregnancy, and all H]R antagonists are secreted in breast milk. 98 1011 Terfenadine is extensively biotransformed to its principal metabolite, terfenadine metabolite I, which has an elimination half-life of 17 to 20 hours and is excreted mostly in the urine (40%) and feces (60%).98, lOO,]]4 A single 60-mg dose leads to suppression of wheal for 12 hours and 120 mg for 24 hours. 99 , lOO Thus, once-a-day dosing can be clinically effective. Torsades de pointes has been reported with overdose and in association with ketoconazole therapy, presumably by its inhibitory effect on cytochrome P 450. 98, 100 Astemizole undergoes extensive first-pass metabolism and has an elimination half-life of 9 to 10 days.98 100, 114 Excretion is primarily in the feces. 98 Contrary to early reports, absorption does not appear to be significantly inhibited by food. IOU The drug binds with extreme avidity to H,R, and dissociation is extremely slow. Maximum clinical effect may not be immediately apparent on initiation of a 10-mg daily regimen because of drug pharmacokinetics. 99 100,114 Steady state plasma concentrations are not reached until 4 to 8 weeks of 10-mg daily therapy. Wheal and flare suppression persists for weeks after discontinuation, which should be considered in patients in whom pregnancy is a possibility or when subsequent allergy skin testing may be needed. 9s lOO, 114 Weight gain has been reported to occur in as many as 3.5% of patients. 9S Overdose may cause torsades de pointes. lOo

Table 7. CHARACTERISTICS OF SECOND-GENERATION H,R ANTAGONISTS

Drug

Single Dose (mg)

Terienadinet

60

17-20 hours

Astemizolet

10

9.5 days

Loratadine

10

7.8-11 hours

Cetirizine

10

7.4 hours

Serum Elimination Half-life

Significant Wheal Suppression' (hours after dose) Onset

Maximum

Resolution

Maximum Wheal Suppression (% of baseline)

2

6

12

79 ± 12

Hepatic cytochrome P 450 system

6

24

86

± 15


8

12

51 ± 13


5

24

94 ± 9

Minimally metabolized

4

'Dose-dependent. tTerfenadine metabolite I. :j:lncludes desmethylastemizole. Adapted from Simons FER, Simons KJ: Second generation H,-receptor antagonists. Ann Allergy 66:5, 1991.

00

N

U1

Metabolism

826

HUSTON & BRESSLER

Loratadine is rapidly metabolized and is excreted in the urine and feces. 9B, The terminal elimination half-life is 11 hours for the parent compound and 17 to 24 hours for the principal metabolite. 9B, '00, 114 Prolongation of the halflife of the active metabolite may be particularly prominent in some elderly patients. '00 Cetirizine is the carboxylic acid metabolite of hydroxyzine. 96, 9B.'00, 114 Metabolism is minimal, and within 72 hours, 70% is excreted unchanged in the urine. The elimination half-life is 7 hours for children, 7 to 10 hours for adults, 11 to 12 hours for the elderly, and up to 19 hours in renal failure. 9B In addition to H,R blockade, cetirizine has been reported to inhibit eosinophil chemotaxis into antigen-stimulated late-phase reactions in the skin and to inhibit the late-phase reaction. 2B, 96 The significance of the last effect seems substantiated by the reported efficacy of cetirizine in delayed pressure urticaria. 59, 60 Whether it will be of particular usefulness in other physical urticarias, such as cholinergic urticaria, remains to be determined. '00, 114

Other Medications for Treatment of Chronic Urticaria

Ketotifen has been shown to be effective in the treatment of some patients .with physical urticarias, chronic idiopathic urticarias, and systemic mastocytosis. Pharmacologic properties include H,R antagonism, mast cell stabilization, and calcium channel blockade. Nifedipine, a calcium channel blocker, has been reported to be effective in refractory chronic idiopathic urticaria.'2 A possible mechanism for this effect is inhibition of calcium-dependent mast cell degranulation. However, a more likely possibility is an as yet undetermined effect on the inflammatory function(s) of the mononuclear cell infiltrate, which characterizes the lesions of chronic idiopathic urticaria. Side effects included headache, peripheral edema, dizziness, and fatigue, which were usually either tolerated or decreased with continued therapy. However, in some patients, these symptoms necessitated discontinuation of the medication. Additional classes of medications may become available in the future that may be important in the treatment of chronic urticarias. These include inhibitors of neuropeptides (particularly substance P), platelet-activating factor, and the lipoxygenase pathway of arachidonic acid metabolism. C1 ESTERASE INHIBITOR DEFICIENCY

Deficiency of C1-INH is manifest as recurrent angioedema. 24, 32, 97 Clinically and histologically, the angioedema is indistinguishable from other causes, although attacks may be more severe. Urticaria does not occur as a consequence of C1-INH deficiency. As a non-mast cell disorder, angioedema resulting from C1-INH deficiency is nonpruritic. Virtually all patients eventually experience angioedema of the extremities, and most have involvement of the gastrointestinal tract. Approximately two thirds of the patients have orofacial and laryngeal swelling, which may cause asphyxiation in severe cases (Fig. 6). Hypotension and tachycardia result from intravascular volume depletion secondary to extravasation of plasma into involved skin and mucosal tissues, as well as emesis and diarrhea. Hemoconcentration is evident by an increased hematocrit and prerenal azotemia. Attacks usually crescendo over several hours and spontaneously resolve over several days. Exacerbation of attacks has been associated with menstruation, whereas there is a reported decrease in attacks during the


827

Figure 6. Oropharyngeal angioedema causing laryngeal obstruction necessitating emergency intubation in a woman with hereditary angioedema. This attack evolved over 4 hours.

last trimester of pregnancy and after menopause. CNS symptoms suggestive of focal cerebral edema, such as headaches, hemiparesis, or seizures, may also occur. Distinction of intra-abdominal angioedema from an acute surgical abdomen is paramount, but difficult. Angioedema accompanied by fever, leukocytosis out of proportion to hemoconcentration, and an elevated ESR each indicate the need to search for an underlying infection. Cl Esterase Inhibitor Structure and Function

Cl esterase inhibitor is an alpha-2-neuraminoglycoprotein normally present in serum at a concentration of approximately 18 to 22 mg/dL. 85 The genomic and biophysical characteristics of Cl-INH are provided in Table 8 and Figure 7. The gene encoding Cl-INH is located on chromosome 11 and is codominantly expressed. lO• 15, 25 As a serine protease inhibitor, Cl-INH is a member of the Table 8. CHARACTERISTICS OF C1 ESTERASE INHIBITOR Genetics

Encoded by eight exons on chromosomes 11 .2-q13, interrupted by introns with highdensity Alu repeat clusters mRNA = 2.1 kb Member of the serpin gene family

Structure

478 residue single-chain polypeptide (53 kd), glycosylated to yield an alpha-2neuraminoglycoprotein (104 kd)

Synthesis

Liver (also synthesized by fibroblasts, monocytes, megakaryocytes, placenta) Upregulated by androgens, interferon-gamma, IL-6

Function

Inhibit active serine proteases of the contact-activated (intrinsic) fibrinolytic and kiningenerating pathways and of activated C 1rand C1 s

828

HUSTON & BRESSLER

5'

• 1

I 1

11

I

I

C1-INH Gene (Chromosome 11)

3'

C1-INH Glycoprotein Figure 7. C1-INH genomic and protein structure. The C1-INH gene is located on chromosome 11 as eight exons. The translated C1-INH protein is 104 kd and consists of 478 amino acids. Approximately half its molecular mass is due to carbohydrate residues (0). The binding site for C1-INH ligand/substrate interactions is within the 442-453 residues that are part of the serpin-reactive loop. (Adapted from Bock SC, Skriver K, Nielsen E, et al: Human C1 inhibitor: Primary structure, cDNA cloning, and chromosomal localization. Biochemistry 25:4296, 1985; with permission, and Skriver K, Radjiejewska E, Silberman JA, et al: CpG mutations in the reactive site of human C1 inhibitor. J Bioi Chem 264:3071, 1989; with permission.)

serpin gene family.l02, 110 The C1-INH gene is 17 kilobases long, with a coding region of approximately 1800 base pairs, with eight exons interrupted by seven introns. In vivo synthesis is primarily in the liver, but other cells, including peripheral blood monocytes, also synthesize C1-INH, thereby providing readily accessible tissue for in vitro studies of C1-INH biosynthesis. 50, 63 Up to 49% of the apparent molecular mass of the circulating protein is accounted for by posttranslational modification, with carbohydrate groups located predominantly on the carboxy terminal end. The serine protease inhibitory activity is the consequence of a C1-INH conformational change that occurs when the serpin-reactive loop moves from its surface location to an internal location upon binding with an appropriate s,erine protease. Subsequently, a 94 kd inactive form of C1-INH is generated,115 Thus, three forms of C1-INH can exist, a normal 104 kd species, a high molecular weight complexed species, and a 94 kd inactive species. Physiologically, C1-INH is a highly competitive substrate for activated complement components Clr and C1s and for factors XIIa, XIIf, and kallikrein of the contact activation pathway for the intrinsic coagulation and kinin-forming systems (Fig. 8).54 As such, C1-INH inhibits the proteolytic activation of C2 and C4 along the classical complement pathway. Within the fibrinolytic pathway, Cl-INH inhibits the amplification pathway for factor XII proteolysis, the generation of plasmin, which can activate C1r, and the formation of bradykinin from kininogen. Biochemistry of Cl Esterase Inhibitor Deficiency

A decrease in serum C1-INH functional activity to less than approximately 38% of normal is associated with a risk for angioedema. 105 Serum C4 is markedly


C1-INH REGULATION OF FIBRINOLYTIC PATHWAY

r:

XII C1r

1[>4,~,

t

C1r

HMXlla

T

Xllf'y"

-"'"

C2

N

f

ACE REGULATION OF BRADYKININ K"Inlnogen

prekallikrein.i.Kallikrein""""'j XI - . Xla Coagulation ~ Pathway

Angiotensin I

Pla5min~Plasminogen

Fibr~Degradation f ~

c1sLc15 C4

t'

Contact Activation Factors

-
-+- C3 Convertase

C2b _

829

' Inactive Peplldes

t Angiotensin Converting Enzyme (Kininase 11)

C2 Kinin . . ANGIOEDEMA

Figure 8. Pathophysiology of angioedema due to C1-INH deficiency. Sites of C1-INH

activity are denoted by lines with crossbars ( """"'). Enzymes inhibited by C1-INH are in bold type. Sites of ACE inhibitor activity are denoted by lines with X's (-.-).

reduced between attacks and may be un detectable during an attack. Serum C2 may be normal between attacks but is reduced during an attack. Also, there are reductions during attacks in factor XII serum levels coupled with an increase in kallikrein activity and in plasmin-alpha-2-antiplasmin complexes. 46 , 78 These serologic findings are all consistent with activation of both the classical complement pathway and the contact system for fibrinolysis and kinin formation. During attacks, patients with CI-INH also have increased urinary histamine levels. 42 However, histamine is not considered to be central in the pathogenesis of the angioedema, because the patients do not experience pruritus, and antihistamines neither prevent nor ameloriate the angioedema. The source of histamine is most likely to be from mast cells activated by C3a and C5a anaphylatoxins generated as a consequence of the unabated cascade of the classical complement pathway. Kinins, on the other hand, are mole-for-mole of equal potency to histamine and cause histologic lesions similar to histamine, but without pruritus, making them attractive etiologic molecules for the angioedema of CI-INH deficiency. 54 Two products generated from the complement activation and contactactivated fibrinolytic pathways have kinin activity. The more controversial is a degradation product of C2b that has kininlike activity,27 A more likely candidate molecule in the pathogenesis of the angioedema attacks is bradykinin, a vasoactive peptide generated by the proteolytic effect of kallikrein on kininogen. 105 During an attack, there is an increase in kallikrein activity and production of bradykinin. Activation of the classical complement pathway with CI-INH deficiency may be the consequence of unabated fluid phase proteolysis, the activation of Clr by factor XIIf, and the activation of Cls by plasmin, which is generated by the action of factors XIIa, XIIf, Xla, and kallikrein on plasminogen. 54 These diverse mechanisms for complement activation, as well as the physiologic role of CI-INH, provide the link between the complement and the fibrinolytic and kinin-generating pathways. Through this linkage, the determination of complement profiles has been diagnostically useful.

830

HUSTON & BRESSLER

Pathophysiology of C1 Esterase Inhibitor Deficiency

The original description of hereditary C1-INH deficiency is a ttribu ted to OsIer in 1888. 82 The associated biochemical abnormalities of the serum complement profile enable this inherited clinical disorder to be divided into two subsets now referred to as hereditary angioedema (HAE) type I and HAE type H.39 88 Approximately 20 years ago, an apparently acquired angioedema (AAE) secondary to C1-INH deficiency was described in association with cryoglobulinemia and has subsequently been observed in some patients with underlying Iymphoproliferative disorders.22. 3(' These patients lacked a family history of recurrent angioedema and usually had the onset of symptoms after the fourth decade of life in association with a B-Iymphocyte malignancy or autoimmune disorder. Within the past 5 years, a second form of AAE (type H) due to C1INH deficiency has been described. 3 . 49 AAE type H is secondary to an autoantibody with specificity for C1-INH, rendering it nonfunctional. The complement profiles of HAE type I, HAE type II, AAE type 1, and AAE type H are shown in Table 9 and are contrasted with the complement profiles characteristic of immune complex vasculitis and allergic or idiopathic angioedemas. The prevalence of HAE is approximately 1:150,000. HAE type I accounts for more than 80% of C1-INH deficiencies and is the consequence of a change in the genomic sequence of the CI-INH gene that impairs either mRNA transcription or translation for a functional CI-INH protein. 5. 19. 20. 31. 71 106 HAE type II accounts for approximately 15% of C1-INH-deficient patients and is the consequence of a change in the genomic sequence of the C1-INH gene such that mRNA transcription and translation occur but yield a nonfunctional C1INH protein. b. 19. 101 Restriction fragment length polymorphism analysis of genomic DNA and DNA sequence analysis of cloned C1-INH genes or polymerase chain reaction amplified C1-INH cDNA have all been used to elucidate the molecular basis for HAE. Deletions, rearrangements, or single-base mutations of the C1-INH gene have all been described. 6. 101 Of particular importance is the presence of intronic Alu repeats (repetitive DNA sequences), which are "hot spots" for DNA rearrangements or deletions by homologous recombination and may account for the spontaneous appearance of HAE within an extended pedigree. 2b Analysis of mRNA isolated from peripheral blood monocytes indicates that in HAE type I and type II, there is a 50% reduction in full-length C1-INH Table 9. COMPLEMENT PROFILES WITH ANGIOEDEMA

Type HAE I HAE II AAE I AAE 11 Immune complex vasculitis Allergicl idiopathic

C1-INH (Antigenic)

C1-INH (Functional) C1 C4 C3

1

CH SOl 100

Paraprotein

Anti-C1-INH Ab

N N

N* N

1 1 1 1

,j,

,j,

N N N* N*

N* N* N* N*

N

1 1 1 1 1 1

1

No No Yes No No

No No No Yes No

N

N

N

N

N

N

No

No

N

1

N = Normal. 'Small decrease may be seen.

1


831

mRNA, as would be predicted with heterozygosity for a codominantly expressed allele."3 However, the serum levels of Cl-INH in these patients are often 5% to 30% that of normals. The less than expected Cl-INH serum level is due to post-translational consumption of the protein during or after secretion as reflected by a modest increase in the fractional catabolic rate of Cl-INH.72 Additional evidence for increased turnover of Cl-INH in HAE is the increase in the proportion of the total Cl-INH in the 94 kd inactive form (28%) in comparison with normals (1.2% ).115 In contrast to HAE, the Cl-INH genes are completely normal in patients with either type of AAE, as is Cl-INH gene transcription and translation and Cl-INH protein secretion. Serologically, both types of AAE are distinguished from HAE by markedly reduced Clq, Ch, and Cls levels and functional activity.3. 37. 49. 72 AAE type I is serologically distinguishable from AAE type II by a markedly reduced Cl-INH antigenic level. In AAE type I, Cl-INH catabolism is markedly increased as reflected by a twice normal fractional catabolic rate and by the proportion of total Cl-INH in the 94 kd inactive form (92 %) in comparison with normals (1.2%)/2 In patients with an underlying B cell lymphoproliferative disorder, the B cells can massively activate Cl, leading to direct consumption of Clq, r, s, and secondary consumption of Cl-INH. The putative mechanism by which such Cl activation occurs is the formation of immune complexes consisting of anti-idiotypic antibodies and the idiotype of the monoclonal immunoglobulin produced by the malignant B cells. 36 Acquired angioedema type II is serologically characterized by only a modest reduction in the quantity of Cl-INH (60% to 70% of normal) but a marked reduction in Cl-INH functional activity. The pathogenesis of AAE type II is the presence of autoantibodies whose specificity is for Cl-INH.3.49 These antiCl-INH antibodies may be monoclonal but in different individuals recognize different epitopes on Cl-INH. These autoantibodies prevent thejJinding of ClINH to activated Cls, presumably by binding to or near the Cls binding site of Cl-INH. The anti-Cl-INH antibodies do not bind to Cl-INH molecules already comple~d with Cls:... The inability of the autoantibody Cl-INH complex to inactivate Cls allows Cls to cleave Cl-INH to yield an inactive 96 kd molecule. 3 The majority of antigenic Cl-INH in these patients circulates as the 96 kd form bound by the autoantibody in an approximately 400-kd immune complex. Anti-Cl-INH autoantibodies have been reported as IgG and IgA isotypes. The serum of the patients also usually contains unbound anti-ClINH autoantibodies, presumably as an antibody excess state. The true incidence of AAE type II has yet to be established.

Therapy For all types of HAE and AAE, acute management of an angioedema attack is similar (Table 10). Foremost is maintenance of the airway. Patients with airway involvement should be monitored closely in a hospital setting until the attack resolves. Intravenous fluids are indicated to maintain intravascular volume. Narcotics may be necessary to control abdominal pain, and nasogastric suction may be needed to control emesis. Gastric hyperacidity has been observed with Cl-INH deficiency and can be managed with H2R antagonists. 21 No evidence exists for either efficacy or adverse consequences from epinephrine, H1R antagonists, or corticosteroids in managing an acute angioedema attack secondary to Cl-INH deficiency. Recent reports suggest that intravenous infusion of 500 to 1000 U of purified Cl-INH will attenuate attacks. 4 11.34 Purified

832

HUSTON & BRESSLER

Table 10. TREATMENT OF C1 ESTERASE INHIBITOR DEFICIENCY

Acute Attacks· Maintain airway Maintain intravascular volume Medication for pain C1-INH concentratet

Preventative and Maintenance

Special Considerations for

AAE

AAE type I: Treat Attenuated underlying androgens (current neoplasm agents of choice) AAE type 11: Antifibrinolytics ImmunoC1-INH concentratet suppression ± Fresh frozen plasma plasmapheresis

Future Considerations Recombinant cytokine activation of C1-INH genes Recombinant C1-INH . Recombinant product of a serpine gene mutated for greater C1-INH activity Designer molecules with C1-INH activity Gene therapy

"Epinephrine, corticosteroids, and antihistamines are commonly used but have no proven efficacy. tNot currently approved by the FDA.

C1-INH is lyophilized to have a shelf-life longer than 1 year but is expensive and has not yet been approved by the FDA. The alternative available source of C1-INH for passive replacement therapy is fresh frozen plasma, which has the less desirable features of infection transmission and transfusion reactions. Important in the management of acute attacks is the distinction of angioedema symptoms from alternative or additional diagnoses that could require surgical therapy or antibiotics. Also, patients with C1-INH deficiency are as likely as other individuals to experience mast cell-mediated causes of angioedema. Preventative and maintenance therapy for HAE types I and 11 are similar (Table 10). Postpuberty, an attenuated androgen is the drug of choice. 38. 95 Androgens have an anabolic effect on productive C1-INH alleles, thereby causing increased transcription, translation, and secretion of C1-INH (Fig. 9). The most widely used attenuated androgens are danazol and stanozolol, the latter being less expensive and having less masculinizing side effects (Table 11). There is a direct correlation of androgen dose and the enhanced synthesis of C1-INH. However, normalization of functional C1-INH serum levels is not necessary to prevent attacks. Usually, 50% of normal C1-INH function is sufficient to achieve clinical efficacy. Treatment with 400 to 600 mg of danazol or 4 to 6 mg of stanozolol daily will usually result in a substantial reduction in the frequency and severity of attacks. A particular dose of androgen will result in stable C1-INH serum levels within 7 to 14 days. Some patients require high doses of androgen, but many can be managed with as little as 50 mg of danazol or 2 mg of stanozolol daily. Alternate-day therapy is occasionally possible. It is not uncommon for clinical efficacy to be achieved despite the failure to observe an increment of the serum C4 level or C1-INH antigenic level and functional activity. Treatment should be directed by clinical response and not by laboratory values. The masculinizing side effects of attenuated androgens are minimal at the doses used, and only rarely are menstrual cycles affected. Periodic determination of serum transaminase levels is used to monitor patients for androgeninduced hepatitis. Patients have been treated with attenuated androgens for as many as 15 years, usually with no major complications. IS In children with HAE, androgen therapy is generally not used unless attacks are severe and frequent, and then only in consultation with an endocrinologist. If available, purified C1-INH can be used on a weekly basis


HAE TYPE I

HAE TYPE 11

// //

Nontranslated Abnormal Allele Q)

>

.3 I Z

,

.....

()

I

Translated Abnormal Allele

833

ME TYPE 1/11

//

//

Normal AIIeles

Functional

Rx

Rx

Rx TIME

Figure 9. Potential effects of androgen therapy on antigenic and functional levels of C1INH.

for maintenance therapy in both adults and children with HAE.4, 11, 34 In any patient with HAE scheduled for a traumatic procedure, preventative management may include an increment in androgen dose for the preceding 2 weeks or infusion of purified CI-INH or fresh frozen plasma within 24 hours of the procedure. Tranexamic acid and epsilon-aminocaproic acid are antifibrinolytic drugs that have been used successfully to treat HAE.33, 94 Tranexamic acid is approximately ten times more potent. Both drugs are competitive inhibitors of plasminogen activation and plasmin activity. Both drugs are also effective in preventing angioedema due to CI-INH deficiency, although there is no associated improvement in C4- or CI-INH serum levels. The potential side effects of these agents have diminished their use in favor of attenuated androgens. However, the lowest efficacious doses of tranexamic acid or epsilon-aminocaTable 11. PROFILE OF AGENTS MOST COMMONLY USED TO TREAT C1 ESTERASE INHIBITOR DEFICIENCY Agent Attenuated androgens Stanozolol Danazol Antifibrinolytics epsilon-ami nocaproic acid Tranexamic acid C1-INH concentrate Fresh frozen plasma

Dose

1-4 mg/d 50-400 mg/d 7-10 g/d 1-2 g/d

500-1000 U/5 d 250-500 mU1-2 d

Mechanism

Side Effects

Anabolic for C1-INH gene

Virilization Hepatitis

Inhibit plasminogen

Vascular thrombosis Myonecrosis

Passive replacement Passive replacement

None reported Infection transfusion reaction

834

HUSTON & BRESSLER

proic acid are used as maintenance therapy in some severely affected children or in adults who do not tolerate androgens. If used, these anti fibrinolytic drugs should be discontinued before traumatic procedures in favor of alternative prophylaxis against angioedema because of their potential for increasing the risk of thrombotic complications. Acquired angioedema types I and II each require special therapeutic considerations (Table 10). Diagnosis of AAE type I necessitates a rigorous workup for an underlying neoplasm, primarily a B cell lymphoma. Occasionally, AAE type I can be clinically evident years before the neoplasm is clinically apparent. Treatment to prevent the angioedema attacks is similar to that for HAE. However, higher doses of androgens may be required. A reduction in tumor load by surgical excision and chemotherapy increases the efficacy of androgen therapy by reducing the rate of Cl-INH consumption by the tumor to below the rate of androgen-induced Cl-INH synthesis. The few reports on the treatment of AAE type II indicate poor response to androgens, presumably due to the high rate of Cl-INH consumption by the anti-Cl-INH autoantibody.4 Likewise, antifibrinolytic agents have not been effective. Purified Cl-INH infusion has been transiently effective only in those patients with lower titers of Cl-INH autoantibody. Theoretically, treatment of AAE type II will require immunosuppression of the autoantibody production. Contraindicated in any patient with Cl-INH deficiency is the use of drugs that inhibit angiotensin-converting enzyme. 2 These inhibitors are clinically used in the management of hypertension. 113 However, angiotension-converting enzyme, which is also known as kininase II, is enzymatically active in the degradation of bradykinin (see Fig. 8). Therefore, the use of angiotensinconverting enzyme inhibitors to prevent cleavage of angiotensin I to angiotensin II also prevents the proteolytic degradation of bradykinin. Because bradykinin is considered to be a pathogenically critical mediator of angioedema in Cl-INH deficiency, inhibition of its degradation would be predicted to exacerbate the severity and frequency of attacks. This has been observed clinically with lifethreatening angioedema and hypotensive shock occurring within hours of treatment with angiotensin-converting enzyme inhibitors.

SUMMARY

Urticaria and angioedema are usually the clinical consequence of vasoactive mediators derived from mast cells in the skin or mucosal tissues. Efforts to classify mast cell-mediated causes of urticaria and angioedema have generally been frustrated by their diverse pathogenesis and clinical course. The term acute is typically used to describe fleeting lesions whose recurrence does not extend beyond 6 weeks. Chronic is the term used to describe lesions that persist for more than a few hours but usually less than a day, and recurrences extend for more than 6 weeks. These definitions do not take histology into account. Skin biopsies of fleeting lesions demonstrate a paucity of inflammatory cells, whereas more persistent lesions display a spectrum of perivascular cuffing by predominantly T cells and monocytes. The presence of leukocytoclastic vasculitis in persistent lesions indicates an underlying immune complex disease. Many of the physical urticarias have fleeting lesions that can be induced with the appropriate stimulus for years. This review article has emphasized the clinical course and histology of urticaria and angioedema lesions in an effort to


835

provide a more complete understanding of the pathogenesis and appropriate treatment. Clearly, avoidance of an identifiable inciting stimulus is optimum management, although most patients have no etiology defined or the cause is not realistically avoidable. At present, treatment options for these patients rely on antihistamines to control the immediate consequence of mast cell degranulation. Corticosteroids are reserved for the treatment of patients whose urticaria or angioedema lesions persist, reflecting the increasing involvement of mononuclear cells in the disease process. For leukocytoclastic vasculitis, corticosteroids are indicated, and cytotoxic drugs may be required for adequate treatment. Future treatments of urticaria and angioedema will evolve based on elucidation of the relevant cells and soluble mediators and will include counterregulatory or antagonistic peptides and drugs. Cl esterase inhibitor deficiency is a relatively uncommon cause of angioedema but is important to understand because of its ability to clinically mimic mast cell-mediated angioedemas and its unique pathogenesis and treatment. HAE can be divided into two serologic subtypes that simply reflect the location of the defect in one of the codominantly expressed CI-INH genes on chromosome 11. AAE can be divided into two serologic subtypes. AAE type I is due to massive consumption of C1-INH, presumably by tumor-related immune complexes. AAE type H is due to an anti-C1-INH autoantibody. Acute management of angioedema in any patient with C1-INH deficiency is directed toward maintenance of a patent airway, hemodynamic stability, relief of pain, and identification of causes precipitating the attack. Patients with HAE can be treated prophylactically with attenuated androgens, antifibrinolytic agents, or C1-INH infusions. Although these same agents may be of some benefit in patients with AAE, therapy for these patients is directed toward the underlying disease with AAE type I and immunosuppression with AAE type H. Future approaches to the treatment of CI-INH deficiency will include recombinant C1-INH for passive replacement as well as exploration of the potential for gene therapy. ACKNOWLEDGMENT The authors thank Kathy Jolivette and Tammy Kocurek for their patience and expert secretarial assistance in the preparation of the manuscript.

References 1. Aboobaker 1, Greaves MW: Urticarial vasculitis. Cl in Exp Dermatol 11:436, 1986 2. Agostoni A, Cicardi M: Contraindications to the use of ACE inhibitors in patients with Cl esterase inhibitor deficiency. Am J Med 90:278, 1991 3. Alsenz 1, Bork K, Loos M: Autoantibody-mediated acquired deficiency of Cl inhibitor. N Engl J Med 316:1360, 1987 4. Alsenz 1, Lambris JD, Bork K, et al: Acquired Cl inhibitor (C1-INH) deficiency type II: Replacement therapy with C1-INH and analysis of patients' C1-INH and anti-C1INH autoantibodies. J Clin Invest 83:1794, 1989 5. Ariga T, Igaraski T, Ramesh N, et al: Type I Cl inhibitor deficiency with a small messenger RNA resulting from deletion of one exon. J Clin Invest 83:1888, 1989 6. Aulak KS, Pemberton PA,Rosen FS, et al: Dysfunctional Cl inhibitor (At), isolated from a type II hereditary angioedema plasma, contains a PI reactive centre (Arg444_ His) mutation. Biochem J 253:615, 1988 7. Bedard PM, Brunet C, Pelletier G, et al: Increased compound 48/80 induced local

836

8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

HUSTON & BRESSLER

histamine release from nonlesional skin of patients with chronic urticaria. J Allergy C1in Immunol 78:1121, 1986 Berg RE, Kantor GR, Bergfield WF: Urticarial vasculitis. Int J Dermatol 27:468, 1988 Black AK, Greaves MW, Champion RH, et al: The urticarias 1990. Br J Dermatol 124:100, 1991 Bock Se, Skriver K, Nielsen E, et al: Human Cl inhibitor: Primary structure, cDNA cloning, and chromosomal localization. Biochem 25:4292, 1985 Bork K, Witzke G: Long-term prophylaxis with Cl-inhibitor (Cl INH) concentrate in patients with recurrent angioedema caused by hereditary and acquired C1inhibitor deficiency. J Allergy C1in Immunol 83:677, 1989 Bressler RB, Sowell K, Huston DP: Therapy of chronic idiopathic urticaria with nifedipine: Demonstration of a beneficial effect in a double-blinded, placebo controlled, crossover trial. J Allergy C1in Immunol 83:756, 1989 Brunet e, Bedard PM, Hebert J: Analysis of compound 48/80-induced skin histamine release and leukotriene production in chronic urticaria. J Allergy C1in Immunol 82:398, 1988 Callen JP, Kaebfleish 5: Urticarial vasculitis: A report of nine cases and review of the literature. Br J Dermatol 107:87, 1982 Carter PE, Dunbar B, Fothergill JE: Genomic and cDNA cloning of the human Cl inhibitor: Intron-exon junctions and comparison with other serpins. Eur J Biochem 173:163, 1988 Casale TB, Sampson HA, Hanifin J, et al: Guide to physical urticarias. J Allergy C1in Immunol 82:758, 1988 Champion RH, Roberts SOB, Carpenter RG, et al: Urticaria and angioedema: A review of 554 patients. Br J Dermatol 81:588, 1969 Cicardi M, Bergamaschini L, Cugno M, et al: Long-term treatment of hereditary angioedema with attenuated androgens: A survey of a 13-year experience. J Allergy C1in Immunol 87:768, 1991 Cicardi M, Igaraski T, Kim MS, et al: Restriction fragment length polymorphism of the Cl inhibitor gene in hereditary angioneurotic edema. J Clin Invest 80:1640, 1987 Cicardi M, Igaraski T, Rosen FS, et al: Molecular basis for the deficiency of complement 1 inhibitor in type I hereditary angioneurotic edema. J C1in Invest 79:698, 1987 Collen MJ, Lewis JH, Deschner WK, et al: Abdominal pain in hereditary angioedema: The role of acid hypersecretion. Am J Gastroenterol 84:873, 1989 Constanzi JJ, Donaldson VH: Activation of complement by a mono clonal cryoglobulin associated with antiidiotypic antibody to monoclonal immunoglobulins. N Engl J Med 312:534, 1985 Costa JJ: Mast cells and cytokines: New insights into the pathogenesis of allergic diseases. Insigh ts in Allergy 5(6), 1990 Davis AE: Cl inhibitor and hereditary angioneurotic edema. Ann Rev Immunol 6:595, 1988 Davis AE Ill, Whitehead AS, Harrison RA, et al: Human inhibitor of the first component of complement Cl: Characterization of cDNA clones and localization of the gene to chromosome 11. Proc Natl Acad Sci USA 83:3161, 1986 Dominique SL, Carter PE, Meo T, et al: Clusters of intragenic A1u repeats predispose the human Cl inhibitor locus to deleterious rearrangements. Proc Natl Acad Sci USA 87:1551, 1990 Donaldson VH, Rosen FS, Bing OH: Role of the second component of complement (C2) and plasmin in kinin release in hereditary angioneurotic edema: Plasma. Trans Assoc Am Physicians 40:174, 1977 Fadel R, David B, Rassemont R: Eosinophilic infiltration: Effects of H j antihistamines. JAm Acad Dermatol 24:1094, 1991 Feig PU, Soter NA, Yager HM, et al: Vasculitis with urticaria, hypocomplementemia and multisystem involvement. JAMA 236:2065, 1976 Fortson JS, Zone JJ, Hammond ME, et al: Hypocomplementemic urticarial vasculitis syndrome responsive to dapsone. JAm Acad Dermatol 15:1137, 1986


837

31. Frangi 0, Cicardi M, Sica A, et al: Nonsense mutations affect Cl inhibitor messenger RNA levels in patients with type I hereditary angioneurotic edema. J Clin Invest 88:755, 1991 32. Frank MM, GeIfand JA, Atkinson JP: Hereditary angioedema: The clinical syndrome and its management. Ann Intern Med 84:580, 1976 33. Frank MM, Sergent JS, Kane MA, et al: Epsilon aminocaproic acid therapy of hereditary angioneurotic edema: A double-blind study. N Engl J Med 286:808, 1972 34. Gadek JE, Hosea SW, GeIfand JA, et al: Replacement therapy in hereditary angioedema: Successful treatment of acute episodes of angioedema with partly purified Cl inhibitor. N Engl J Med 302:542, 1980 35. Galli SJ: New insights into the "riddle of the mast cells": Microenvironmental regulation of mast cell development and phenotypic heterogeneity. Lab Invest 62:5, 1990 36. Geha RS, Quinti I, Austen KF, et al: Acquired Cl-inhibitor deficiency associated with antiidiotypic antibody to monoclonal immunoglobulins. N Engl J Med 312:534, 1985 37. Gelfand JA, Boss GR, Conley CL, et al: Acquired Cl esterase inhibitor deficiency and angioedema: A review. Medicine 58:321, 1979 38. GeIfand JA, Sherins RI, Ailing DA, et al: Treatment of hereditary angioedema with danazol: Reversal of clinical and biochemical abnormalities. N Engl J Med 295:1444, 1976 39. Glass DN, Fearon DT, Austen KF: Inherited abnormalities of the complement system. In Stanbury JB, Wyngaarden JB, Fredrickson DS, et al (eds): The Metabolic Basis of Inherited Disease, ed 5. New York, McGraw-Hill, 1983, p 1934 40. Gleich GJ, Schroeter AL, Marcoux JP: Episodic angioedema associated with eosinophilia. N Engl J Med 310:1621, 1984 41. Gordon JR, Burd PR, Galli SJ: Mast cells as a source of multifunctional cytokines. Immunology Today 11:458, 1990 42. Granerus G: Studies on the histamine metabolism and complement system in hereditary angioneurotic edema. Acta Med Scand 182:11, 1967 43. Greer jM, Longley 5, Edwards N, et al: Vasculitis associated with malignancy. Medicine 67:220, 1988 44. Haak-Frendscho M, Arai N, Arai K, et al: Human recombinant granulocytemacrophage colony-stimulating factor and interleukin 3 cause basophil histamine release. J Clin Invest 82:17, 1988 45. Healy DP, Sahai JV, Fuller SH: Vancomycin-induced histamine release and "red man syndrome": Comparison of 1 and 2 hour infusions. Antimicrob Agents Ch em other 34:550, 1990 46. Hentges F, Humbel R, Dicato M, et al: Acquired Cl esterase-inhibitor deficiency: Case report with emphasis on complement and kallikrein activation during two patterns of clinical manifestations. J Allergy Clin Immunol 78:860, 1986 47. Howells G, Pham P, Taylor D, et al: Interleukin 4 induces interleukin 6 production by endothelial cells: Synergy with interferon '/. Eur J Immunol 21:97, 1991 48. Huston DP, Bressler RB, Kaliner M, et al: Prevention of mast cell degranulation by kelotifen in patients with physical urticarias. Ann Intern Med 104:507, 1986 49. Jackson I, Sim RB, Whelan A, et al: An IgG autoantibody which inactivates C1inhibitor. Nature 323:722, 1986 50. Johnson AM, Alper CA, Rosen FS, et al: Cl inhibitor: Evidence for decreased hepatic synthesis in hereditary angioneurotic edema. Science 173:553, 1971 51. Kantor FS: Serum sickness. In Wyngaarden JB, Smith LH (eds): Cecil Textbook of Medicine. Philadelphia, WB Saunders, 1982, p 1615 52. Kaplan AP: Acute and chronic urticarias. Insights in Allergy 4(3), 1989 53. Kaplan AP: Urticaria and angioedema. In Middleton E, Reed CE, Adkinson NF, et al (eds): Allergy: Principles and Practice. St. Louis, CV Mosby, 1988, P 1341 54. Kaplan AP, Silverberg M: The coagulation-kinin pathway of human plasma. Blood 70:1, 1987 55. Kita H, Ohnishi T, Okubo Y, et al: Granulocyte/macrophage colony-stimulating factor and interleukin 3 release from human peripheral blood eosinophils and neutrophils. J Exp Med 174:745, 1991

838

HUSTON & BRESSLER

56. Kivity S, Schwartz Y, Wolf R, et al: Systemic cold-induced urticaria-clinical and laboratory characterization. J Allergy Clin Immunol 85:52, 1990 57. Klugmann FB, Decorti G, Crivellato e, et al: Effect on Iysosomotropic and membrane active substances on adriamycin uptake and histamine release. Anticancer Res 10:1571, 1990 58. Knox JP, Welykyi SE, Gradini R, et al: Procainamide-induced urticarial vasculitis. Cutis 42:469, 1988 59. Kontou-Fili K, Maniatakou G, Demaka P, et al: Therapeutic effects of cetirizine in delayed pressure urticaria: Clinicopathologic findings. J Am Acad DermatoI24:1090, 1991 60. Kontou-FiIi K, Maniatakou G, Paleologos G, et al: Cetirizine inhibits delayed pressure urticaria. Part 2. Skin biopsy findings. Ann Allergy 65:520, 1990 61. Krause LB, Shuster S: Enhanced wheal and flare response to histamine in chronic idiopathic urticaria. Br J Clin Pharmacol 20:486, 1985 62. Kupper TS: Immune and inflammatory processes in cutaneous tissues. J Clin Invest 86:1783, 1990 63. Lappin DF, McPhaden AR, Yap P-L, et al: Monocyte Cl-inhibitor synthesis in patients with Cl-inhibitor deficiency. Eur J Clin Invest 19:45, 1989 64. Leenutaphong V, Holzle E, Plewig G, et al: Plasmapheresis in solar urticaria. Dermatologica 182:35, 1991 65. Lewis JE: Urticarial vasculitis occurring in association with visceral malignancy. Acta Derm Venereol 70:345, 1990 66. Leznoff A, Sussman GL: Syndrome of idiopathic chronic urticaria and angioedema with thyroid immunity: A study of 90 patients. J Allergy Clin Immunol 84:66, 1989 67. Lieferman KM: A current perspective on the role of eosinophils in dermatologic diseases. J Am Acad Dermatol 24:1101, 1991 68. Matheson DA, Amagave CM, Bhat KN, et al: Hypocomplementemia in chronic idiopathic urticaria. Ann Intern Med 86:534, 1977 69. Maxwell DL, Atkinson BA, Spur BW, et al: Skin responses to intradermal histamine and leukotrienes C" D" and E4 in patients with chronic idiopathic urticaria and in normal subjects. J Allergy Clin Immunol 86:759, 1990 70. McDuffie Fe, Sams WM, Maldonado JE, et al: Hypocomplementemia with cutaneous vasculitis and arthritis. Mayo Clin Proc 48:340, 1973 71. McPhaden AR, Bimie GD, Whaley K: Restriction fragment length polymorphism analysis of the Cl-inhibitor gene in hereditary Cl-inhibitor deficiency. Clin Genet 39:161, 1991 72. Melamed J, Alper CA, Cicardi M, et al: The metabolism of Cl inhibitor and C1q in patients with acquired Cl inhibitor deficiency. J Allergy Clin Immunol 77:322, 1986 73. Miller J, Schwartz LB: Heterogeneity of human mast cells. In Tauber AI, Wintroub BU, Simon AS (eds): Biochemistry of the Acute Allergic Reactions: Fifth International Symposium. New York, AIan R Liss, 1989, P 115 74. Muramatsu e, Tanabe E: Urticarial vasculitis: Response to dapsone and colchicine [letter]. JAm Acad Dermatol 13:1055, 1985 75. Murphy GM, Hawk JLM: Broadening of action spectrum in a patient with solar urticaria. Clin Exp Dermatol 12:455, 1987 76. Narth Fe, Kettlekamp N, Hirshman CA: Comparison of cutaneous and in vitro histamine release by muscle relaxants. Anesthesiology 66:543, 1987 77. Neittaanmaki H: Cold urticaria. J Am Acad Dermatol 13:636, 1985 78. Nilsson T, Back 0: Elevated plasmin-Ci2-antiplasmin complex levels in hereditary angioedema: Evidence for the in vivo efficiency of the intrinsic fibrinolytic pathway. Thromb Res 40:817, 1985 79. O'Donnell Me, Ackerman SJ, Gleid GJ, et al: Activation of basophil and mast cell histamine release by eosinophil granule major basic protein. J Exp Med 157:1981, 1983 80. Olson Je, Esterly NB: Urticarial vasculitis and lyme disease. J Am Acad Dermatol 6:1114, 1990 81. Oppenheim JJ, Ruscetti FW, Faltynek C: Cytokines. In Stites DP, Terr AL (eds): Basic and Clinical Immunology. Norwalk, CT, Appleton and Lange, 1991, p 78


839

82. Osier W: Hereditary angioneurotic edema. Am J Med Sci 93:362, 1988 83. Pandya AG, Tharp MD: Chronic urticaria associated with exogenous thyroid use [letter]. Arch Dermatol 126:1238, 1990 84. Pearce FL: Non-lgE mediated mast cell stimulation. In Mast Cells and the Allergic Response. (Ciba Foundation Symposium) Chichester, Wiley, 1989, p 74 85. Pensky I. Schwick HG: Human serum inhibitor of Cl esterase: Identity with Ct 2 neuraminoglycoprotein. Science 163:698, 1969 86. Peters MS, Schroeter AL, Kephart GM, et al: Localization of eosinophil granule major basic protein in chronic urticaria. J Invest Dermatol 81:39, 1983 87. Plaut M, Pierce JH, Watson q, et al: Mast cells produce Iymphokines in response to cross-linkage of FCER1 or to calcium ionophores [letter]. Nature 339:64, 1989 88. Rosen FS, Charache P, Pensky I. et al: Hereditary angioneurotic edema: Two genetic variants. Science 148:957, 1965 89. Sanchez NP, Winklemann RK, Schroeter AL, et al: The clinical and histological spectrums of urticarial vasculitis. J Am Acad Dermatol 7:599, 1982 90. Schatz M, Hoffman CP, Zeiger RS, et al: The course and management of asthma and allergic diseases during pregnancy. In Middleton E, Reed CE, Ellis EF, et al (eds): Allergy: Principles and Practice. St. Louis, CV Mosby, 1988, P 1140 91. Schwartz LB, Austen KF: The mast cell and mediators of immediate hypersensitivity. In Samter M, Talmage DW, Frank MM, et al (eds): Immunologic Diseases. Boston, Little, Brown, 1988, p 157 92. Serafin WE, Austen KF: Mediators of immediate hypersensitivity reactions. N Engl J Med 317:30, 1987 93. Sessons JGP, Peters DK, Williams DG, et al: Skin lesions angio-oedema and hypocomplementemia. Lancet 2:1350, 1974 94. Sheffer AL, Austen KF, Rosen FS: Tranexamic acid therapy in hereditary angioneurotic edema. N Engl J Med 287:452, 1972 95. Sheffer AL, Fearon DT, Austen KF: Clinical and biochemical effects of stanozolol therapy for hereditary angioedema. J Allergy Clin Immunol 68:181, 1981 96. Sheffer AL, Samuels LL: Cetirizine: Antiallergic therapy beyond traditional antihistamines. J Allergy Clin Immunol 86:1040, 1990 97. Sibbald RG: Physical urticaria. Dermatol Clin 3:57, 1984 98. Simons FER: New H 1-receptor antagonists: Clinical pharmacology. Clin Exp Allergy 20(suppl 2):19, 1990 99. Simons FER, McMillan JL, Simons KJ: A double-blind, single-dose crossover comparison of cetirizine, terfenadine, loratadine, astemizole, and chlorpheniramine versus placebo: Suppressive effects on histamine-induced wheals and flares during 24 hours in normal subjects. J Allergy Clin Immunol 86:540, 1990 100. Simons FER, Si mons KJ: Second generation H1-receptor antagonists. Ann Allergy 66:5, 1991 101. Skriver K, Radjiejewska E, Silberman JA, et al: CpG mutations in the reactive site of human Cl inhibitor. J Bioi Chem 264:3066, 1989 102. Skriver K, Wikoff WR, Patston PA, et al: Substrate properties of Cl inhibitor Ma. J Bioi Chem 266:9216, 1991 103. Slater EE, Merrill DD, Guess HA, et al: Clinical profile of angioedema associated with angiotensin converting-enzyme inhibition. JAMA 260:967, 1988 104. Soter NA, Mihm MC, Gigli I, et al: Two distinct cellular patterns in cutaneous necrotizing vasculitis. J Invest Dermatol 66:344, 1976 105. Spath PI. Wuthrich B, Butler R: Quantification of Cl-inhibitor functional activities by immunodiffusion assay in plasma of patients with hereditary angioedemaevidence of a functionally critical level of Cl-inhibitor concentration. Complement 1:147, 1984 106. Stoppa-Lyonnet D, Tosi M, Laurent J, et al: Altered Cl inhibitor genes in type I hereditary angioedema. N Engl J Med 317:1, 1987 107. Subramanian N, Bray MA: Interleukin 1 releases histamine from human basophils and mast cells in vitro. J Immunol 138:271, 1987 108. Sussman GL, Harvey RP, Schocket AL: Delayed pressure urticaria. J Allergy Clin Immunol 70:337, 1982 109. Thueson DO, Speck LS, Lett-Brown MA: Histamine releasing activity (HRA):

840

110. 111. 112. 113. 114. 115.

HUSTON & BRESSLER

Production by mitogen or antigen stimulated mononuclear cells. J Immunol 123:626, 1979 Tosi M, Duponchel C, Bourgarel P, et al: Molecular cloning of human Cl inhibitor: Sequence homologies with cd-antitrypsin and other members of the serpins superfamily. Gene 42:265, 1986 Wasserman SI: Mast cell biology. J Allergy Clin Immunol 86:590, 1990 Wasserman SI: Mediators of inflammation. In Stites DP, Terr AL (eds): Basic and Clinical Immunology. Norwalk, CT, Appleton and Lange, 1991, p 159 Williams GH: Converting-enzyme inhibitors in the treatment of hypertension. N Engl J Med 319:1517, 1988 Woodward JK: Pharmacology of antihistamines. J Allergy Clin Immunol 86:606, 1990 Zuraw BL, Curd JG: Demonstration of modified inactive first component of complement (Cl) inhibitor in the plasmas of Cl inhibitor-deficient patients. J Clin Invest 78:567, 1986

Address reprint requests to David P. Huston, MD Baylor College of Medicine and the Methodist Hospital 6565 Fannin, M.S. F-501 Houston, TX 77030

Urticaria and angioedema.

Urticaria, angioedema, and anaphylaxis.

[Angioedema and urticaria].

[Histaminergic angioedema and chronic urticaria].

Acute and chronic urticaria and angioedema.

Diagnostic testing in chronic urticaria and angioedema.

Diagnostic testing in chronic urticaria and angioedema.

Studies of C1 subcomponents in chronic urticaria and angioedema.

Case of angioedema and urticaria induced by lenalidomide.

Bringing your "A" game to urticaria and angioedema.

angioedema and its treatment.

Urticaria and angioedema induced by low-molecular-weight heparin.

angioedema: a consideration of pathogenesis and clinical manifestations.

Wheels within wheals: the burden of urticaria and angioedema.

angioedema.

angioedema does not evolve into chronic urticaria: a 12-year follow-up study.

Quality of life in patients with urticaria and angioedema: assessing burden of disease.

A 60-year-old woman with recurrent episodes of flushing, urticaria, and angioedema.

angioedema in Spanish and Han Chinese populations.

Hypersensitivity to procarbazine associated with angioedema, urticaria, and low serum complement activity.

Urticaria and Angioedema Secondary to Methylphenidate Exposure in a Young Child.

Angioedema is not just 'deep urticaria' but an entity of its own.

angioedema.

A patient with steroids and antihistaminic drug allergy and newly occurred chronic urticaria angioedema: what about omalizumab?