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MD Consult: Books: Goldman: Cecil Medicine: Chapter 273 – URTICARIA AND ANGIOEDEMA

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 273 – URTICARIA AND ANGIOEDEMA

Stephen C. Dreskin

   URTICARIA

Urticaria (hives) are pruritic, edematous, erythematous, blanching papules that are round or oval in shape, have pale raised centers (wheals), are of several millimeters to a few centimeters in size, and are transient, lasting minutes to days ( Fig. 273-1 ). Angioedema appears as a brawny, nonpitting edema, typically without well-defined margins and without erythema. Angioedema can be accompanied by a sense of burning, pressure, or aching but not pruritus, and it is distinguished from other edematous states by often involving the lips, tongue, eyelids, hands, feet, or genitalia and rarely occurring in dependent areas of the body. Episodes (daily or almost daily symptoms) of recurrent hives and/or angioedema lasting less than 6 weeks are considered acute, and those lasting longer are said to be chronic. The terms urticaria and urticaria/angioedema are used interchangeably here to refer to illnesses in which mast cells are activated.

FIGURE 273-1  Extensive urticaria. Many presentations are more subtle.  (From Roitt I, Brostoff J, Male D [eds]: Immunology, 6th ed. London, Mosby, 2001, Figure 21-2.)

Epidemiology

Urticaria/angioedema occurs in 15 to 25% of individuals at some times during their life and can affect both genders and all races. Acute urticaria is more common in young adults and children. Chronic urticaria is more common in adults, affecting women (75% of cases) more often than men.

Pathobiology

Mast cells, the primary effector cells in urticaria/angioedema, are found in high numbers throughout the body and particularly within the subcutaneous tissue. After activation of mast cells there is a rapid release (<10 minutes) of histamine, leukotriene C4 (LTC4), and prostaglandin D2 (PGD2) leading to vasodilation, subcutaneous and intradermal leakage of plasma from postcapillary venules, and pruritus. In addition, there is a more delayed (4 to 8 hours) production and secretion of inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin-4 (IL-4), and IL-5, leading to an inflammatory infiltrate and perpetuation of longer-lived lesions. Angioedema is formed by a similar extravasation of fluid, not superficially in the skin but in the deeper dermal and subdermal sites.

Lesions of acute urticaria typically show subcutaneous edema with widened dermal papillae, swollen collagen fibers, and rare inflammatory cells. Most episodes of acute urticaria/angioedema are caused by immediate hypersensitivity reactions to drugs or foods or are a result of inflammatory processes initiated by viral illnesses. The most common drugs that cause acute urticaria/angioedema are penicillins, sulfonamides, muscle relaxants, diuretics, and nonsteroidal anti-inflammatory drugs (NSAIDs), although any drug acting as a hapten can generate an allergic response. The predominant allergenic foods are milk, egg, and peanut for children and peanut, tree nuts, fish, and shellfish for adults, although sensitization can occur to many other foods as well. These allergens cross-link immunoglobulin E (IgE) bound to the high-affinity receptor for IgE (FcεRI), leading to activation of mast cells. Some drugs (e.g., opioids, vancomycin, NSAIDs) and radiocontrast dye can activate mast cells by an IgE-independent (pseudoallergic) mechanism. Ingestion of fish contaminated with bacteria that produce histamine leads to hives as part of a toxic reaction to the histamine (scombroid food poisoning).

Lesions of chronic urticaria are characterized by similar edematous findings, with the addition of a dense perivascular inflammatory infiltrate consisting of CD4- and CD8-positive T lymphocytes, eosinophils, basophils, and neutrophils. A minority of patients have urticarial vasculitis with lesions characterized by vascular destruction with leukocytoclasis (e.g., neutrophils with ingested cellular debris).

The two largest subgroups of chronic urticaria/angioedema are autoimmune urticaria and idiopathic urticaria, each accounting for approximately 40% of cases. Patients in the autoimmune group have symptoms in the absence of a specific physical trigger, allergen exposure, or coexistent disease; autoimmune urticaria is characterized by the presence of IgG antibodies that can cross-link FcεRI. Patients with idiopathic urticaria have symptoms in the absence of specific physical triggers, allergens, coexistent disease, or evidence of autoimmunity.

Physical stimuli activate mast cells by unknown mechanisms and account for about 20% of cases of chronic urticaria. The most common of the physical urticarias is dermographism (also called dermatographism), in which wheals can be “written on the skin” by simple stroking or scratching. Cholinergic urticaria is often included as a physical urticaria, although the trigger leading to mast cell activation is related to cholinergic stimuli occurring after exposure to heat or after exercise. Other physical stimuli can cause urticaria, including cold, solar radiation, pressure, vibration, and water. Cold-induced urticaria is rarely caused by cryoglobulinemia.

In approximately 5% of patients with chronic urticaria/angioedema, symptoms appear to be caused by ingestants (e.g., foods, medications, dietary supplements), contactants (e.g., soaps, detergents, cosmetics, hair or nail products, latex), concomitant infections, hormonal changes, or systemic illnesses. A food must be consumed regularly to cause chronic urticaria. Wheat is occasionally found to be a trigger. Multicellular parasites (e.g., strongyloidiasis, filariasis) elicit strong IgE responses and are important causes of chronic urticaria in endemic areas. Rare patients report that their urticaria occurs only during their menses or is worsened by menses. Some of these patients have immediate hypersensitivity to progesterone (positive skin tests), and others may be reacting to NSAIDs taken for uterine cramping. Chronic urticaria/angioedema can be associated with flares of rheumatic conditions, other autoimmune conditions (including Hashimoto’s thyroditis), or neoplastic conditions. Occult neoplasia is exceedingly unlikely to be the cause of chronic urticaria.

Clinical Manifestations

Patients often report that the first sensation of urticaria is poorly localized pruritus that quickly develops into the typical lesions of urticaria. The intensity of the pruritus varies from a minimal inconvenience to an unbearable intensity that can lead to self-inflicted abrasion of the skin. Groups of hives often appear together over a short period, and episodes of hives can come in waves starting several times a day. Patients with cholinergic urticaria usually have a distinctive clinical presentation of diffuse erythema with elevated and pale monomorphic urticarial lesions of a few millimeters in diameter on exertion sufficient to cause sweating. The pruritus is particularly intense, and all of the symptoms are generally limited to the skin. A self-rated quality-of-life survey of patients with chronic urticaria revealed dramatic impairment in the areas of loss of sleep, fatigue, and emotional discomfort. Angioedema, when it occurs, can originate near a wheal or independently in other parts of the body. Symptoms vary from minor discomfort to an intense sense of pressure and may lead to other symptoms, such as severe shortness of breath if there is compromise of the airway.

Diagnosis

The first episode of acute urticaria/angioedema may occur in the absence of an identifiable stimulus. If hives occur within 5 to 30 minutes after ingestion of a drug or a food, the patient often can identify the association. If a physician is consulted, the best approach is to take a careful history with attention to ingestants and intercurrent illnesses. Unnecessary drugs and food supplements should be discontinued, and any recently added medication should be changed to a structurally different agent. Most often, no etiologic agent is identified, and the hives are treated symptomatically (see later discussion) for days or weeks before a spontaneous resolution occurs.

Differential Diagnosis

The differential diagnosis of chronic urticaria/angioedema includes the subgroups of urticaria discussed earlier: idiopathic, autoimmune, physical, ingestant-mediated, and associated with a variety of systemic illnesses. Other conditions that can be confused with chronic urticaria/angioedema include diffuse pruritus complicated by dermographism, flushing disorders, urticarial vasculitis, urticaria pigmentosa, systemic mastocytosis, exercise-induced anaphylaxis, exercise-induced food-associated anaphylaxis, idiopathic anaphylaxis, hereditary angioedema, acquired angioedema, and angioedema associated with angiotensin-converting enzyme (ACE) inhibitors ( Table 273-1 ).


TABLE 273-1   — 
CLASSIFICATION OF URTICARIA AND ANGIOEDEMA

   I.    Acute urticaria/angioedema

   A.    Hypersensitivity reactions

   1.    Drug allergy
   2.    Food allergy
   3.    Insect allergy
   B.    Idiopathic
   C.    Pseudoallergic reactions

   1.    Drugs
   2.    Radiocontrast dye
   D.    Toxic reactions
   E.    Immune complex

   1.    Serum sickness
   2.    Transfusion-related
   3.    Postviral
   II.  Chronic urticaria/angioedema

   A.    Autoimmune

   1.    Anti-IgE receptor (FcεRI)
   2.    Anti-IgE
   B.    Idiopathic
   C.    Physical

   1.    Dermographism
   2.    Cholinergic
   3.    Exercise-induced anaphylaxis
   4.    Delayed pressure
   5.    Solar
   6.    Cold
   7.    Vibratory
   8.    Aquagenic
   D.    Immune complex

   1.    Thyroid disease
   2.    Urticarial vasculitis
   3.    Malignancy-associated
   4.    Collagen vascular disease–associated
   III.  Urticaria pigmentosa and systemic mastocytosis
   IV.  Complement-related and kinin-mediated angioedema

   A.    Hereditary angioedema
   B.    Acquired angioedema
   C.    Angiotensin-converting enzyme inhibitor–induced angioedema

Approximately 95% of patients with urticaria/angioedema are not reacting to an ingestant and do not have another illness causing their hives. However, it is sometimes difficult for patients (and some physicians) to accept this fact, prompting an extensive, invasive, expensive, and unnecessary investigation. The best “test” to identify most of those with a specific underlying cause (i.e., physical trigger, autoimmune condition, allergen, or systemic disease) is a careful and detailed history and physical examination by a specialist knowledgeable in urticarial disease.

A good place to begin is by excluding possible physical triggers. Specific tests are available to establish the diagnosis of most physical urticarias, including scratching the skin and exposing the skin to heat, ice, vibration, pressure, ultraviolet radiation, or water. Acquired cold urticaria must be distinguished from the familial cold autoinflammatory syndrome, which is characterized by a cold-induced papular rash (not urticaria) and is now classified in the family of hereditary periodic fever syndromes. Solar urticaria must be distinguished from other types of light sensitivity, including metabolic abnormalities (e.g., erythrogenic porphyria) and photosensitivity due to drugs.

Even though foods and drugs are infrequent causes of chronic urticaria, many patients focus on ingestants and are not satisfied until these causes are ruled out. As in the evaluation of acute urticaria, the patient must discontinue all food supplements and medications that are not absolutely necessary and, if possible, change essential medications to structurally unrelated compounds. The patient then keeps a food diary to identify suspect foods that can be eliminated. Some allergists use skin tests with foods to identify “suspects.” For highly motivated patients, 2 weeks of a severely restrictive diet, often based on lamb and rice, is recommended. Antihistamines and other medications used to control the urticaria must be discontinued. If the urticaria resolves, it is critical to reintroduce foods in a controlled fashion, to identify the specific food causing the urticaria and to reinstate a healthy diet.

Chronic infections have also been considered as possible associations, including sinus infection, dental abscess, Helicobacter pylori gastric infection, cholecystitis, onychomycosis, and tinea pedis. Case reports relate resolution of urticaria after treatment of these infections, although rigorous proof of these associations is lacking. The natural history of chronic urticaria probably accounts for coincidental spontaneous improvement after treatment of these conditions, at least in some cases.

Laboratory evaluation for a patient with typical urticaria should always include a complete blood count with differential, a basic metabolic panel, liver enzymes, and a urinalysis. Specialists are not in full agreement regarding the necessity for further laboratory testing. Levels of thyroid-stimulating hormone and antithyroid antibodies may be measured in otherwise euthyroid-appearing patients to screen for occult hypothyroidism and for antithyroid autoantibodies. Skin tests for immediate hypersensitivity to foods may be ordered for patients with a suggestive history. Some specialists order no “screening” tests at all. As in vitro tests for anti-FcεRI autoantibodies become more available, it is likely that many specialists will obtain this test. The presence of a positive test for anti-FcεRI autoantibodies is useful, because this reassures the patient that the urticaria is being driven by an internal process and is not caused by an ingestant or occult illness. Also, this finding helps direct the physician toward immunomodulatory therapies. Beyond this, other tests should be ordered only as a result of positive findings in the history and physical examination.

Although not routinely indicated in every case of chronic urticaria, a skin biopsy can provide useful information. The most common indication for this procedure is to rule out urticarial vasculitis when the hives are more painful than pruritic, last longer than 24 hours, or leave discolored skin. The presence of vascular destruction, fibrinoid necrosis, and immune complex deposition on microscopic examination (including immunofluorescence) should lead to consideration of specific causes of the urticarial vasculitis (e.g., systemic lupus erythematosus) and to rapid initiation of more aggressive treatment.

Primary mast cell disorders rarely manifest as chronic urticaria (see Chapter 276 ). Systemic mastocytosis is a very rare condition resulting in increased numbers of atypical mast cells in the bone marrow, skin, and other organs. Levels of tryptase (an enzyme specific for mast cells) are usually elevated in the serum. This condition is frequently accompanied by episodic flushing, urticaria pigmentosa, prominent gastrointestinal symptoms, neuropsychiatric symptoms, and/or recurrent anaphylaxis. Urticaria pigmentosa is characterized by distinctive pigmented cutaneous lesions containing nests of mast cells and is not easily confused with urticaria/angioedema.

Hereditary angioedema, acquired angioedema, and angioedema associated with ACE inhibitors are discussed later in this chapter. Briefly, these syndromes are characterized by episodic swelling without urticaria and are best identified by a careful history, physical examination, and focused laboratory evaluation.

Treatment

Acute urticaria is usually self-limited and responds well to histamine 1 (H1)-type antihistamines. Antihistamines work better if they are taken prophylactically rather than after histamine has been released and is bound to the receptor. Patients often self-medicate with or are prescribed diphenhydramine (25 to 50 mg every 6 hours) and hydroxyzine (25 to 50 mg every 6 hours) but may experience significant sedation. Second-generation antihistamines such as cetirizine (10 mg nightly at bedtime), fexofenadine (180 mg every day), and loratadine (10 mg every day) are much better tolerated and can be effective, although doses two to three times larger than the standard doses are sometimes necessary. Occasionally, a brief course of corticosteroids is warranted to control severe symptoms. Epinephrine (0.3 mL of 1:1000, IM) will quickly (but transiently) reverse the signs and symptoms of urticaria and angioedema. Patients who have experienced potentially life-threatening angioedema or anaphylaxis should maintain ready access to epinephrine and be knowledgeable of its indications, administration, and brief duration of action. β-Blockers not only can aggravate urticaria but can interfere with the action of epinephrine. NSAIDs and codeine can lead to IgE-independent mast cell activation. These medications should all be discontinued if it is clinically safe to do so.

H1 antihistamines are the cornerstone of therapy for chronic urticaria/angioedema but are frequently inadequate to control symptoms. Certain H1 antihistamines have been proposed as “preferred” for particular subtypes of chronic urticaria, such as hydroxyzine for cholinergic urticaria or cyproheptadine (2 to 4 mg every 6 hours) for cold-induced urticaria. Some have advocated using multiple H1 antihistamines, changing or “rotating” agents, or using them in dosages well above those approved by U.S. Food and Drug Administration (FDA) labeling procedures.

Approximately 15% of histamine receptors in the skin are of the H2 subtype, and therefore the addition of an H2 antihistamine, such as ranitidine (150 mg twice daily) or famotidine (20 mg twice daily), is a logical adjunct to H1 antihistamine therapy, providing additional clinical benefit. The tricyclic antidepressant doxepin (10 to 100 mg nightly at bedtime) has highly potent H1 and H2 antihistamine activity, with an H1 receptor affinity almost 800 times that of diphenhydramine and an H2 receptor affinity six times that of cimetidine, but its use can be limited by significant sedation.

Symptoms often persist despite the use of maximal or supramaximal doses of antihistamines. This is not surprising, considering the number of vasoactive and pruritogenic mediators released by mast cells, of which histamine is only one. Antileukotriene medications, such as montelukast (10 mg every day) or zafirlukast (20 mg twice daily) may be added to antihistamines with some success. Especially severe symptoms may require systemic corticosteroids (prednisone, 10 to 60 mg every day) to achieve symptomatic control, but concerns about side effects from chronic administration limit their usefulness.

Refractory symptoms have been treated with a wide variety of other medications. Some of these medications (adrenergic agents, calcium-channel blockers) are thought to decrease the ability of mast cells to release mediators. Others drugs are anti-inflamma-tory (hydroxychloroquine, sulfasalazine, dapsone, colchicine), immunomodulatory (cyclosporine, tacrolimus, mycophenolate), or antimetabolic (azathioprine, cyclophosphamide, methotrexate). Other treatments of refractory autoimmune chronic urticaria include intravenous immunoglobulin, plasmapheresis, or both.

Evidence-Based Treatments

Multiple randomized placebo-controlled studies of chronic urticaria/angioedema have shown efficacy of both sedating and nonsedating antihistamines. If sedating antihistamines must be used, doxepin has been demonstrated to be more effective than diphenhydramine, but it must be titrated carefully to avoid significant sedation. Prednisone is generally accepted as a mainstay of therapy in difficult cases but has not been formally studied. Cyclosporine (4 mg/kg/day) was shown to be effective in a randomized, placebo-controlled, parallel study of 30 patients with autoimmune urticaria.[1] LTC4 receptor antagonists (montelukast and zafirlukast) do not provide any incremental benefit when added to an antihistamine,[2] sulfasalazine, hydroxychloroquine, dapsone, colchicine, methotrexate, azathioprine, and intravenous gamma globulin.

Prevention

As an adjunct to pharmacologic therapy, it is essential to encourage patients with chronic urticaria to accept the long-term nature of their illness and focus on achieving reasonable symptomatic control with effective treatments and the fewest possible side effects. Many patients with physical urticarias can learn to avoid or minimize triggers. The few patients with systemic illness may find relief from their urticaria if the underlying condition is appropriately treated. An excellent example is that chronic urticaria in patients with clinically apparent thyroid disease often resolves once the thyroid disease is treated. For many patients, there are other factors that can be identified as exacerbating their specific symptoms. These factors include stress or anxiety, hormonal fluctuations, aspirin and other NSAIDs, and cutaneous vasodilation (e.g., alcohol, hot baths or showers, exercise, heated waterbeds). Psychosocial stress, in particular, is a commonly reported trigger of worsening symptoms. A plausible biochemical mechanism may include increased release of cutaneous neuropeptides known to lower the threshold for mast cell degranulation.

Prognosis

The prognosis for most patients with chronic urticaria/angioedema is excellent. Spontaneous resolution occurs within 12 months in 50% of patients and within 5 years in an additional 20%. However, 10 to 20% of patients, particularly those with physical urticarias or autoimmune urticaria, continue to have symptoms for as long as 20 years. Patients who have had one episode of chronic urticaria that lasted for months or years and resolved may experience one or more similar recurrences later in life.

Future Directions

For urticaria/angioedema, the current trend is to use multiple antihistamines and other agents that block the actions of the mediators produced by mast cells. In the near future, it is likely that patients will be treated earlier with anti-inflammatory and immunomodulatory drugs. Some agents under development for asthma and rhinitis may be useful for the treatment of urticaria/angioedema, including 5-lipoxygenase inhibitors, PGD receptor antagonists, and more potent nonsedating antihistamines. Agents that decrease the sensitivity of mast cells to degranulation, such as phosphodiesterase 4 inhibitors and syk kinase inhibitors, may also find a role in the treatment of this condition.

   HEREDITARY ANGIOEDEMA AND RELATED DISEASES

Definition

Hereditary angioedema (HAE) and related illnesses are characterized by recurrent attacks of angioedema mediated by vasoactive peptides such as bradykinin.

Epidemiology

HAE affects approximately 1 in 50,000 people. It is an autosomal dominant disease and therefore affects 50% of offspring of both genders. Frequently, a history of several generations with this disease is obtained, but new mutations occur, and a negative family history is not uncommon. Acquired angioedema (AAE) is more rare and is not inherited; it affects older persons who often have paraproteinemia or malignancies such as lymphoma. Angioedema associated with ACE inhibitors occurs in 0.1 to 0.2% of treated patients.

Pathobiology

HAE and AAE are caused by either low levels or abnormal function of a regulatory protein in the plasma, C1 inhibitor (C1 INH), which exerts control of the complement, fibrinolytic, and kinin-generating pathways. Because there is one normal gene, levels of C1 INH are detectable but are not sufficient to control generation of kinins. The C1 esterase enzyme, when activated, cleaves two complement products, C4 and C2; without proper inhibition, this leads to low levels of circulating C4 and C2. C1 INH is also a critical modulator of the bradykinin pathway, and decreased C1 INH function leads to increased levels of bradykinin. Increased generation of bradykinin, and not mediators from mast cells or activation of complement, leads to capillary leakage and angioedema.

In HAE type I (85% of patients), the abnormal gene does not produce C1 INH. In HAE type II (15%), an antigenically detectable C1 INH protein is produced, but it is not functional. In HAE type III (very rare), C1 INH is present and functional, but there is a yet-to-be-defined abnormality in the generation of vasoactive compounds. In AAE, unknown factors activate C1 and deplete the C1 INH activity in plasma, or there is an autoantibody to C1 INH that interferes with its function. In ACE inhibitor–associated angioedema, the underlying problem is lack of catabolism of bradykinin; the complement pathway is unaffected.

Clinical Manifestations

Children with HAE can have attacks shortly after birth, but these tend to be mild. For most patients, the severity of the attacks worsens at puberty, with episodic attacks of swelling that can affect any external body surface, including the genitalia. Mucosal surfaces are also affected, and patients can have life-threatening swelling of the uvula and posterior pharynx leading to asphyxiation. Swelling of the submucosa of the gastrointestinal tract can cause symptoms of an “acute abdomen,” leading to unnecessary exploratory laparotomy. About half of patients report that trauma, particularly that associated with local pressure, precipitates an attack, and about half of patients note an increased frequency of attacks during times of emotional stress. Attacks in patients with AAE are clinically similar to those in patients with HAE. Patients taking ACE inhibitors may have angioedema that manifests as severe swelling or simply as a chronic cough beginning days to months after ACE inhibitor therapy is initiated.

Diagnosis

The best tests to support the diagnosis of HAE or AAE are measurements of C1 INH level, C1 INH function, and C4 level, particularly during an attack. The distinguishing features of AAE are lack of a family history, late onset, and the presence of a malignancy or paraproteinemia, as mentioned earlier. However, patients with AAE, in addition to having low C2 and C4, can have profound depressions in C1, a protein that is commonly normal in HAE. Patients with ACE inhibitor–associated angioedema can present within hours after initiation of therapy or after many months. The angioedema seen in urticaria/angioedema is distinctive in that it is usually associated with urticaria and is pruritic, responding to antihistamines, steroids, and epinephrine.

Treatment

C1 INH concentrate (500 U) is available in Europe to treat acute attacks of HAE and is the treatment of choice, but this drug has not yet been approved by the FDA. In the United States, treatment of acute attacks of angioedema is currently suboptimal. Epinephrine is only modestly effective but is the safest agent available. Treatment should include nebulized racemic epinephrine delivered in the airway (1:1000 given by nebulization) and by intramuscular injections (0.2 to 0.3 mL of 1:1000 at intervals of 20 to 30 minutes). The addition of antihistamine for sedation may be helpful. Treating physicians must be prepared to perform nasotracheal intubation, preferably in the operating room under conditions in which tracheostomy can be performed if needed. Acute attacks can be terminated by administering 2 units of fresh-frozen plasma (FFP) to supply the missing C1 INH, but in rare instances patients become more edematous, presumably reflecting increased availability of the substrates for generation of kinins. Therefore, although FFP can be useful for treating non–life-threatening acute attacks, it is not recommended for treatment of life-threatening laryngeal edema.

Patients treated prophylactically with attenuated androgens, antifibrinolytic agents, FFP, or C1-INH concentrate have fewer attacks. Attenuated androgens, such as danazol (100 to 200 mg twice daily), increase the production of C1 INH and lead to marked amelioration of symptoms. Masculinizing side effects are usually mild but can be problematic. FFP (USA) or C1 INH concentrate (Europe) should be used before surgical or dental procedures to minimize edema attack due to trauma. Symptomatic treatment of AAE is similar to that for HAE, but definitive treatment requires amelioration of the underlying disease. Treatment of angioedema associated with the use of an ACE inhibitor includes antihistamines, epinephrine, or both, as appropriate, and discontinuation of the ACE inhibitor. Rare patients also will have angioedema when taking angiotension receptor blockers. An approach to the evaluation and treatment of patients with urticaria and angioedema is summarized in Figure 273-2 .

FIGURE 273-2  Evaluation and treatment of urticaria/angioedema. Treatment of urticaria with or without angioedema (AE) is similar. Treatment of AE without urticaria depends on the cause. If the AE is caused by an angiotensin-converting enzyme (ACE) inhibitor, discontinuation of the medication is required. Treatment of AE that is caused by a deficiency or dysfunction of C1 inhibitor (C1 INH) is discussed in the text. Idiopathic AE often responds to treatments described for urticaria/angioedema. ESR = erythrocyte sedimentation rate; FcεRI = high-affinity receptor for IgE; H1 = histamine 1; H2 = histamine 2; IgE = immunoglobulin E; TSH = thyroid-stimulating hormone; UA = urinalysis; UTI = urinary tract infection.

Evidence-Based Treatments

Current therapy for HAE in the United States is directed toward prophylactic treatments, including attenuated androgens, antifibrinolytics, and FFP. Danazol was shown in a double-blind, placebo-controlled trial to significantly reduce the number of acute attacks. C1 INH has been used widely and successfully in Europe. In a study of 193 episodes of laryngeal edema treated with C1 INH concentrate, 192 responded within 60 minutes, and the remaining 1 case responded at 4 hours.[2]

Prognosis

The long-term outlook for patients with HAE depends greatly on the phenotype of the illness (more or fewer laryngeal attacks), the patient’s willingness to take attenuated androgens, and how well the patient tolerates attenuated androgens. For most patients, life expectancy should be normal. AAE usually resolves with treatment of the underlying condition, but the ultimate prognosis for the patient depends on the nature of that illness. Angioedema associated with the use of an ACE inhibitor resolves after the medication is removed.

Future Directions

For treatment of HAE and related disorders, there is a strong effort to have the C1 INH concentrate approved for use in the United States. Finally, new therapies are being developed, including kallikrein inhibitors, bradykinin receptor antagonists, and recombinant C1 INH.

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