Abstract
Urticaria, characterized by transient but recurrent swelling of the skin or mucosa, is a common dermatologic disorder. It can sometimes last for years and cause significant distress. Determining the cause and distinguishing from other urticarial dermatoses require comprehensive history, clinical examination, and sometimes thorough workup. Treatment aims at removal of the cause when possible and symptomatic control with anti-histamines, anti-inflammatory, or immunosuppressive agents.
Keywords
Acquired angioedema, Angioedema, Anti-histamines, Cryopyrin-associated periodic syndromes (CAPS), Hereditary angioedema, Omalizumab, Physical urticaria, Urticaria, Urticarial vasculitis
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Urticaria is characterized by development of wheals and/or angioedema of the skin or mucosa. Individual lesions have a transient nature lasting less than 24 hours.
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Infection, drugs, chemicals, foods, inhalants, contactants, and physical stimuli are several recognizable triggers of urticaria. Urticaria can also be associated with endocrinopathies, autoimmune connective tissue diseases, and malignancies. However, in many cases, the cause of urticaria can remain unexplained despite extensive work-up, especially in chronic urticaria.
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Lesions that last longer than 24 hours are urticarial. On cursory clinical examinations, a few diseases, such as urticarial vasculitis, bradykinin-mediated angioedema, and mast cell disorders, can be mistaken as urticaria.
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Treatments of urticaria aim at eliminating the triggers as well as symptomatic control. Antihistamines, anti-inflammatory and immunosuppressive agents have demonstrated efficacy.
Urticaria is characterized by wheals (hives) and/or angioedema. It affects up to 20% of the population at some point and occurs across the age spectrum. Wheals are well-demarcated swelling of the superficial dermis surrounded by a reflex erythema ( Fig. 10-1, A ). The size and number of the lesions vary. It is associated with an itching or burning sensation. Lesions typically come and go within 24 hours, although the overall condition may persist with fresh crops of wheals occurring in other areas. Angioedema is characterized by sudden pronounced swelling in the deeper dermis, subcutaneous or submucosal tissue. It appears as brawny nonpitting edema. It is less well demarcated than wheals and often painful rather than pruritic. It lasts for 2 to 3 days. Lips, tongues, eyelids, genitalia, and rarely bowels are affected ( Fig. 10-1, B ).
Acute urticaria is defined as occurrence of spontaneous wheals, angioedema, or both for less than 6 weeks. If an allergic cause is suggested by the patient’s history, such as medications or food, occasionally skin testing or immunoassays to identify the triggers for acute urticaria can be useful. It is important to exclude anaphylaxis in patients presenting with acute urticaria, as they may have common triggers. Involvement of respiratory (wheezing and cough), gastrointestinal (diarrhea and vomiting), neurologic (dizziness and loss of consciousness), or cardiac (change in heart rate and blood pressure) systems are concerning and could progress to anaphylaxis.
Episodes of urticaria and/or angioedema lasting longer than 6 weeks are designated as chronic. Duration can vary from months to many years. In 90% to 97% of patients with chronic urticaria, the cause is found. Fifty percent of patients with chronic urticaria for 6 months will have active disease 10 years later.
Pathogenesis
Urticaria and angioedema may be a final common pathway for a number of immunologic or nonimmunologic reactions that lead to cutaneous vasodilatation with extravasation of edema fluid in response to perivascular inflammation. It is believed that the vascular reaction in most patients with urticaria results from the release of proinflammatory mediators from mast cells and basophils. The most important mediator is histamine. Others include heparin, tryptase, platelet-activating factor, prostaglandins, leukotrienes, eosinophil chemotactic factor of anaphylaxis, neutrophil chemotactic factor, serotonin, and cytokines, such as tumor necrosis factor-alpha (TNF-α). Mediators produce vascular permeability with extravasation of plasma into the dermis or subcutaneous tissue. The delayed reaction produces tissue infiltration with eosinophils, neutrophils, and monocytes.
IgE-mediated immediate hypersensitivity reaction is a classical mechanism of mast cell activation. IgE antibody is produced in response to an antigen. IgE binds to mast cell or basophil Fc receptors. Exposure to the antigen results in Fab binding and crosslinking of IgE molecules, initiating a cascade of calcium-dependent processes that leads to release of proinflammatory mediators. Categories of antigen that may produce urticaria by a presumed IgE-dependent mechanism are listed in Table 10-1 . Physical stimuli may produce antigens that react with IgE and lead to the release of mast cell-derived mediators, giving rise to a subtype of urticaria, physical urticaria.
| Infections |
| Bacterial infections |
| Dental abscess |
| Sinusitis |
| Otitis |
| Pneumonitis |
| Gastritis |
| Hepatitis |
| Cholecystitis |
| Cystitis |
| Vaginitis |
| Fungal infections |
| Dermatophytes |
| Candida |
| Other infections/infestations |
| Scabies |
| Helminth |
| Protozoa |
| Trichomonas |
| Drugs and Chemicals |
| Salicylates |
| Indometacin and other, newer nonsteroidal anti-inflammatory agents † |
| Opiates † |
| Radiocontrast material † |
| Penicillin (medication, milk, blue cheese) |
| Sulfonamides |
| Sodium benzoate |
| Douches |
| Ear drops or eye drops |
| Insulin |
| Menthol (cigarettes, toothpaste, iced tea, hand cream, lozenges, candy) |
| Tartrazine (vitamins, birth control pills, antibiotics, FDC yellow #5) |
| Foods |
| Nuts |
| Berries † |
| Fish |
| Seafood |
| Shellfish † |
| Bananas |
| Grapes |
| Tomatoes |
| Eggs † |
| Cheese |
| Inhalants |
| Animal danders |
| Pollen |
| Contactants |
| Wool |
| Silk |
| Occupational exposure |
| Potatoes |
| Antibiotics |
| Cosmetics |
| Dyes |
| Hairspray |
| Nail polish |
| Mouthwash |
| Toothpaste |
| Perfumes |
| Hand cream |
| Soap |
| Insect repellent |
| Physical Stimuli |
| Light |
| Pressure |
| Heat |
| Cold |
| Water |
| Vibration |
| Endocrinopathies |
| Thyroid disease |
| Diabetes mellitus |
| Pregnancy |
| Menstruation |
| Menopause |
| Systemic Diseases |
| Rheumatic fever |
| Connective tissue diseases (lupus erythematosus, Sjögren’s syndrome, rheumatoid arthritis, Still’s disease, dermatomyositis, polymyositis, other) |
| Leukemia |
| Lymphoma |
| Acquired immunodeficiency disease |
| Ovarian tumors |
∗ Partial list of most frequently described causes in each category.
† May be mediated by nonimmunologic mechanisms independent of IgE.
Immunologically mediated urticaria may also occur via anti-IgE and anti-FcεRI antibodies. IgG anti-IgE antibody crosslinks IgE molecules, which in turn bind to two adjacent Fc receptors on mast cells. IgG anti-FcεRI antibody crosslinks two adjacent Fc receptors directly and triggers the cascade of mast cell degranulation without allergen exposure. These autoantibodies are present in a large number of patients with chronic idiopathic urticaria, termed chronic autoimmune urticaria.
Urticaria or a distinct disease, urticarial vasculitis, may occur in diseases with circulating immune complexes, such as systemic lupus erythematosus and hepatitis B. Immune complexes activate the complement cascade, generating C3a and C5a, potent anaphylotoxins capable of causing mast cell degranulation.
Nonimmunologic mechanisms independent of IgE can also cause release of mast cell mediators. Radiocontrast media, opiates, some neuropeptides (e.g., substance P), and some foods, including eggs, strawberries, and shellfish, are some examples. They bind to specific receptors on mast cells and produce mast cell degranulation. Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, induce the lipoxygenase pathway and increase the synthesis of arachidonic acid metabolites such as leukotrienes, which are potent vasodilators formerly called slow-reacting substances of anaphylaxis.
Classification
There is a wide spectrum of clinical manifestations of urticaria subtypes. Two or more types of urticaria can sometimes coexist in the same patient. Table 10-2 presents the EAACI/GA 2 LEN/EDF/WAO, an international multispecialty panel consensus on classification of chronic urticaria updated in 2013.
| Chronic urticaria subtypes | Chronic spontaneous urticaria | Spontaneous appearance of wheals, angioedema or both ≥6 weeks due to known or unknown causes |
| Inducible urticaria | ||
| Diseases related to urticaria |
| |
| Syndromes that present with wheals and/or angioedema |
| |
∗ Also called urticaria factitia dermatographic urticaria.
† Also called cold contact urticaria.
‡ Also called pressure urticaria.
Physical urticarias are an important subgroup of the chronic urticarias, where wheals and/or angioedema are induced by environmental stimuli such as heat, cold, pressure, exercise, water, vibration, and sunlight ( Table 10-3 ). Symptomatic dermatographism ( Fig. 10-2 ) is the most common of all physical urticarias. It manifests as a prompt wheal-and-flare response to stroking pressure applied to the skin. Cold contact urticaria refers to pruritus and swelling with exposure of the skin to contact with a cold stimulus. The diagnosis can be confirmed by applying an ice cube to the forearm skin and observing the wheal-and-flare reaction during rewarming of the skin. Systemic symptoms, such as flushing, headache, syncope, and abdominal pain, can develop if the patient is widely exposed to cold, e.g., cold baths and swimming. A less common and potentially life-threatening form of cold urticaria occurs with cold air exposure. Delayed pressure urticaria is swelling with onset 3 to 12 hours after a pressure stimulus is applied to the skin. Solar urticaria happens when the skin is exposed to various wavelengths of ultraviolet and visible light. Its diagnosis can be confirmed with phototesting. Heat urticaria is one of the rarest forms of urticaria. Within minutes of contact with heat, itching and whealing occur at the site of contact. Vibratory angioedema refers to pruritus and localized swelling within minutes of skin exposure to a vibratory stimulus, with lesions lasting for approximately 1 hour. Cholinergic urticaria occurs 15 minutes after an increase in the core body temperature. Triggers include physical exertion, sudden emotional stress, drinking alcohol, eating spicy food, etc. It presents as multiple pinpointed (1 to 3 mm) papules surrounded by large flares with a predilection for the upper body. Aquagenic urticaria is rare. It is characterized by 1 to 3 mm papules, which occur after direct contact of the skin with any source of water independent of the temperature. Interestingly, patients have no problem consuming water. IgE-mediated immediate hypersensitivity mechanisms are involved in several physical urticarias, supported by passive and reverse passive transfer experiments.
| Urticaria | Relative Frequency | Precipitant | Time of Onset | Duration | Local Symptoms | Systemic Symptoms | Tests | Mechanism | Treatment |
|---|---|---|---|---|---|---|---|---|---|
| Symptomatic dermatographism | Most frequent | Stroking skin | Minutes | 2–3 hours | Irregular pruritic attacks | None | Scratch skin | Passive transfer, IgE, histamine, possible role of adenosine triphosphate, substance P, possible direct pharmacologic mechanism | Continual antihistamines |
| Delayed dermatographism | Rare | Stroking skin | 30 minutes to 8 hours | <48 hours | Burning, deep swelling | None | Scratch skin, observe early and late | Unknown | Avoidance of precipitants |
| Primary cold contact urticaria | Frequent | Cold contact | 2–5 minutes | 1–2 hours | Pruritic wheals | Wheezing, syncope, drowning | Apply ice-filled copper beaker to arm, immerse | Passive transfer, reverse passive transfer, IgE (IgM), histamine, vasculitis can be induced | Cyproheptadine hydrochloride, other antihistamines; desensitization; avoidance of precipitants |
| Familial cold urticaria | Rare | Change in skin temperature | 30 minutes to 3 hours | <48 hours | Burning wheals | Tremor; headache; arthralgia; fever | Expose skin to cold air | Unknown | Avoidance of precipitants |
| Delayed pressure urticaria | Frequent | Pressure | 3–12 hours | 8–24 hours | Diffuse, tender swelling | Flu-like symptoms | Apply weight | Unknown | Avoidance of precipitants; if severe, low doses of corticosteroids given for systemic effects |
| Solar urticaria | Frequent | Various wavelengths of light | 2–5 minutes | 15 minutes to 3 hours | Pruritic wheals | Wheezing, dizziness, syncope | Phototest | Passive transfer, reverse passive transfer, IgE, possibly histamine | Avoidance of precipitants; antihistamines, sunscreens, antimalarials |
| Heat urticaria | Rare | Heat contact | 2–5 minutes (rarely delayed) | 1 hour | Pruritic wheals | None | Apply hot water-filled cylinder to arm | Possibly histamine; possibly complement | Antihistamines; desensitization; avoidance of precipitants |
| Vibratory angioedema | Very rare | Vibrating against skin | 2–5 minutes | 1 hour | Angioedema | None reported | Apply vibration to forearm | Unknown | Avoidance of precipitants |
| Cholingeric urticaria | Very frequent | General overheating of body | 2–20 minutes | 30 minutes to 1 hour | Papular, pruritic wheals | Syncope; diarrhea; vomiting, salivation; headaches | Bathe in hot water; exercise until perspiring, inject methacholine chloride | Passive transfer; possible immunoglobulin; product of sweat gland stimulation; histamine, reduced protease | Application of cold water or ice to skin; hydroxyzine regimen; refractory period; anticholinergics |
| Aquagenic urticaria | Rare | Water contact | Several minutes | 30–45 minutes | Papular, pruritic wheals | None reported | Apply water compresses to skin | Unknown | Avoidance of precipitants; antihistamines; application of inert oil |
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