Treatment of urticaria and angioedema
In the primary care setting, the common encounter is with that patient who develops acute urticaria following the ingestion of a food or medicine to which he or she is allergic. The patient with an acute allergic reaction often develops urticaria with or without an-gioedema. If the allergic response extends beyond the skin, bronchospasm, laryngeal edema, or hypotension from cardiovascular collapse might occur. However, in the case of urticaria and angioedema, the patient is treated first by avoidance of that agent. If the patient is hemodynamically stable, the acute urticaria will resolve over the next 12-24 h if there is no further allergen exposure.
Treatment of Acute Urticaria and Angioedema
• Avoidance of food, drug, or other allergen
• Symptomatic relief (IT antihistamines, oatmeal baths)
• Short course (no more than several days) of corticosteroid for severe or protracted episodes and to prevent late-phase response
• Epinephrine to be considered only for acute intervention of severe attacks. Use carefully in the older patient.
Some degree of relief can be immediately provided with the use of oatmeal baths. Alcohol-containing beverages should be avoided, as they will cause vasodilation, which can worsen the pruritus. An extensive battery of antihistamines is available for symptomatic relief. First-generation H1 histamine blockers do have the significant side effects of sedation and mucosal drying. Recently developed second-generation antihistamines (e.g., cetirizine [Zyrtec™]; fexofenadine [Allegra™]; loratadine [Claritin™]; desloratadine [Clarinex™]) are less soporific and have been demonstrated to be safe and effective in the treatment of urticaria. If the acute urticarial eruption is persistent or especially pronounced, a short course of systemic corticosteroids could lessen the intensity or duration of the episode.
Systemic corticosteroids must be used judiciously, as they are associated with significant side effects. However, a course of systemic steroids for acute urticaria need not be longer than several days. Exceedingly high doses of systemic steroids or protracted courses are not justified, as this is a short-lived allergic reaction, and the steroids are primarily aimed at preventing any late-phase response. Subcutaneous epinephrine may be employed when acute urticaria and angioedema progress toward frank anaphylaxis. Adrenergic agents should be employed carefully in older patients who might have cardiovascular or cerebrovascular disease predisposing them to myocardial or cerebral ischemia.
Physical urticaria can be similarly treated with antihistamines. However, physical urticaria can be of protracted duration. The first approach to physical urticaria should be avoidance or lessening of the stimulus causing the urticaria or angioedema. In the individual in whom a thermal stimulus is causing the urticaria or angioedema, exposure to extremes of temperatures should be avoided. In those patients with cold-induced urticaria, appropriate clothing should be used to minimize exposure to cold climates. Individuals should avoid holding cold objects, such as soft-drink cans, and should wear cotton inserts under vinyl gloves when preparing cold food. They must avoid swimming or bathing in cold water, as profound hypotension can develop, which could be potentially life threatening. Individuals with urticaria and angioedema secondary to pressure should wear loosely fitting clothing. They should avoid the use of tight shoes or sitting for long periods, which can result in angioedema of the buttocks. Women with pressure-induced urticaria and angioedema should not carry pocketbooks or luggage with a strap that might apply pressure to the shoulder. The use of tools that require the application of pressure, such as drills or sanders, should be avoided. Mechanical tools that induce vibration, such as orbital sanders or jackhammers, should be avoided in individuals with vibratory urticaria and angioedema. Those patients with cholinergic urticaria that is induced by warm environments or exercise causing sweating must limit activities leading to this cholinergic response. Finally, individuals with dermatographism should try to minimize any scratching of their skin, for it will result in linear urticaria. Antihistamines are very helpful, and nonsedating ones should be tried first. If insufficient relief is obtained, the older sedating ones can be utilized. The drugs of choice are: for cold urticaria, cyprohep-tadine (Periactin™) 16-32 mg/d in divided doses (four times a day); for cholinergic urticaria, hydroxyzine (Atarax™) 100-200 mg/d in divided doses (four times a day); and for dermatographism, any of these or diphenhydramine (Benadryl™) 100-200 mg/d in divided doses (four times a day). These are adult doses for severe disease and should be adjusted downward for milder disease and for children.
Long-term care for chronic urticaria and angioedema can be challenging. Antihistamines are the initial mainstay of treatment. H1 antihistamines will result in symptomatic relief, although they are often less than optimal. Because chronic urticaria/angioedema is a chronic disorder, the long-term use of sedating antihistamines can be problematic. Often, H1 antihistamines can be combined with H2 antihistamines in the more severe cases. Approximately 15% of histamine receptors found on endothelial cells are of the H2 subtype, and studies have suggested that the combination of H1 and H2 antihistamines in treating chronic urticaria is beneficial. The antidepressive agent doxepin has been found to be effective in the attenuation of symptoms found in chronic idiopathic urticaria. It does have significant antimuscarinic and antiserotoninergic properties in combination with its antihistaminic activity. However, it is very sedating, and its use generally is limited to nighttime hours. The use of sedating antihistamines must be accompanied by warnings to the patient that these agents do cause sedation, and appropriate precautions must be taken. Nevertheless, high doses spread out four times a day (e.g., 25-50 mg hydroxyzine) lead to tolerance of the soporific effects if taken regularly in the vast majority of patients.
Because up to 25% of patients with chronic idiopathic urticaria have coincident thyroid abnormalities, an interest has developed regarding thyroid replacement. In patients with chemical or clinical hypothyroidism, replacement therapy is the standard of care. However, in individuals in whom there is no evidence of clinical or chemical hypothyroidism, thyroid replacement has not been demonstrated uniformly to be beneficial to the chronic urticarial disease. The use of thyroid supplementation does have significant side effects, including development of clinical hyperthyroidism, osteopenia, and cardiac arrhythmias. In this light, present recommendations are that individuals with the presence of elevated autoimmune thyroid antibodies should be monitored for the development of chemical or clinical hypothyroidism. This monitoring should include measurement of T4 and thyroid-stimulating hormone approx every 6-12 mo. A small percentage of individuals who do have autoimmune thyroiditis will become hypothyroid over time. If this percentage is higher in individuals with chronic idiopathic urticaria and autoimmune thyroiditis has not been determined.
Corticosteroids by the systemic route will attenuate the symptoms of chronic urticaria and angioedema. These effects are generally short lived, and the patient’s symptoms generally recur following discontinuation of the steroid. Because this is a chronic disorder, there is little rationale to the ongoing use of systemic steroids if they will result in significant side effects. Systemic steroids will result in a cushingoid appearance, weight gain, glucose intolerance, hypertension, hyperlipidemia, osteopenia, and easy bruising. With this in mind, the regular or protracted use of systemic corticosteroids is routinely avoided. However, the histopathology of lesions seen in chronic urticaria does reflect an inflammatory aspect with a significant cellular component.
Chronic Urticaria/Angioedema
• HI antihistamines (e.g., nonsedating — cetirizine, fexofenadine, loratadine, desloratidine, or sedating diphenhydramine, hydroxyzine)
• H2 antihistamines (e.g., cimetidine, ranitidine, famotidine)
• Short course of systemic corticosteroid (no longer than 1-2 wk)
• Consideration of alternate-day, low-dose steroid and other immunomodulators in severe, refractory disease
Short bursts of systemic steroids will attenuate the cellular influx. However, the degree to which they affect any autoimmune process that is associated with an anti-immunoglobulin E receptor antibody is not clear. Although systemic corticosteroids have not been demonstrated to affect pathogenic titers of auto antibodies in other disease states or inhibit mast cell degranulation, they do have the potential to modulate secretion of cytokines and/or histamine-releasing factors that could contribute to the local inflammatory response seen in the skin, including the migration of lymphocytes, monocytes, eosinophils, and basophils. However, to reiterate, no studies have been performed to establish steroid regimens as preferred in the long-term treatment of chronic urticaria, and as such, the prolonged use of systemic corticosteroids should be avoided. Thus, alternative therapies are being pursued on a case-by-case basis in the most severe forms of chronic urticaria and an-gioedema. For example, corticosteroids are advocated on an alternate-day basis (e.g., 20 mg prednisone every other day with a slow, gradual decrease in dosage). Regimens of this sort are well tolerated for weeks or even months, but with care being taken to avoid inordinate weight gain or other steroid side effects. Conceptually, the use of plasmapheresis could be considered if an IgG autoantibody is believed to be responsible for the mast cell degranulation. However, plasmapheresis has been demonstrated to have variable success in disease states associated with autoimmune processes. In addition, if significant amounts of the inciting IgG autoantibody were removed, the effect would be short lived, as IgG levels in plasma would be reconstituted from other extravascular sites and the plasma cells would continue synthesis. Controlled studies will be helpful to ascertain the utility of systemic steroid regimens, immunomodulators, immunosuppressives (e.g., cyclosporine), and plasmapheresis in the long term for management of chronic urticaria and angioedema that is secondary to an autoimmune abnormality.
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