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Urticaria

Urticaria, or hives, is truly not one disease, but a reaction pattern of the skin - "a vascular reaction, usually transient, involving the upper dermis, representing localized edema caused by dilatation and increased permeability of the capillaries, and marked by the development of wheals." It manifests as a pruritic, erythematous, raised rash. Urticaria has many etiologies and different pathophysiologies, having acute and chronic forms. The chronic form is by far the more difficult clinical problem, and is the subject of most of the following.

The treatment of patients with chronic urticaria is a significant challenge to even the most experienced physicians. Hives are quite common, with approximately 20% of the population having them at some point in their lives. The clinical presentation varies, as far as appearance and location of lesions, the presence of accompanying angioedema, and the duration of lesions. The etiology also varies and, in most cases of chronic urticaria, the urticaria is idiopathic. Idiopathic urticaria and angioedema can even be accompanied by symptoms and signs of anaphylaxis in a syndrome called idiopathic anaphylaxis. Urticaria may, in fact, be part of a spectrum of disease ranging from simple pruritis to life-threatening anaphylaxis. Whether most of these idiopathic cases are truly due to internal factors or whether they are due to occult external causes is a matter of continual debate.

The definition of chronic urticaria involves daily or intermittent hives for greater than 6 weeks. Acute urticaria, with lesions lasting less than 6 weeks, is likely a distinct disorder. Compared to chronic urticaria, acute urticaria is usually easier to control with medication and is less often idiopathic.

Typical urticarial lesions are very pruritic, erythematous raised papules and plaques with no change in surface markings (i.e., no scaling, blistering, or any permanent change in pigmentation). Individual hives can range in size from a few millimeters to several centimeters, and can be "blotchy" or "streaky" in pattern. The lesions will usually resolve in 24 hours or less, with no residual remaining changes. Distinctions between chronic urticaria and urticarial vasculitis, are that the individual urticarial lesions usually last more than 24 hours, they tend to preferentially involve the lower extremeties, and that there may be residual surface changes (e.g., pupura).

PATHOGENESIS

Urticaria can be mediated by both immunologic and non-immunologic factors. Many substances can trigger urticaria through antigen-driven immediate or Type I (IgE-mediated) hypersensitivity reactions (foods, insect stings, antibiotics, e.g.). Immunological reactions which do not involve IgE include hereditary angioedema and acquired angioedema (which can be associated with collagen vascular diseases), which are complement-mediated, and type III hypersensitivity reactions, caused by circulating immune complexes (e.g., serum sickness). Reasonably good screening tests for these are a CH50 and a C4 complement factor level. Substances such as IV contrast dye may also cause urticaria via non-specific activation of complement pathways.

An autoimmune phenomena, that of autoantibodies to the high affinity IgE receptor on basophils and mast cells, has been implicated as an important cause of chronic, idiopathic urticaria (Hide M, et al. NEJM 1993;328:1599-604). This same group reported that plasmapheresis - a modality that presumably removes autoantibodies - does have some beneficial effects in chronic urticaria patients that have these autoantibodies.

Autoimmunity to thyroid tissue has also been associated with urticaria. In fact, treatment with thyroid supplements in euthyroid individuals (who have elevated anti-thyroid peroxidase and/or anti-thyroglobulin antibodies) has been shown to be beneficial (Rumbyrt J, et al. J Allergy Clin Immunol 1995;96:901-5).

Urticaria results not only from sensitivity to antigens, but also from physical factors such as cold, heat, sunlight, water, pressure, and vibration. The underlying mechanisms are not well understood, but the final common pathway is believed to involve release of mediators by activated mast cells and basophilic leukocytes. These mediators increase vascular permeability, and plasma leaks into the dermis, resulting in urticarial wheals.

DIAGNOSTIC EVALUATION

In many cases of acute urticaria, the source is obvious or the physician and patient stop looking for it upon remission. As mentioned above, chronic hives, are almost always idiopathic. However, identifying a triggering factor, may help in the long-term control of the disorder. The patient should be asked whether the onset of urticaria seems to be associated with specific substances or events. Some of the most common causes of urticaria are listed below. Urticaria also can result from a combination of factors, e.g., eating a particular food and then exercising (a condition known as exercise induced urticaria); so the process of diagnostic evaluation can be complex.

The use diagnostic studies for the work up of chronic urticaria is a controversial topic. It is essential to rule out the presence of serious illnesses of which recurring hives can be a symptom. Examples are hepatitis, hyperthyroidism, lymphomas, collagen vascular diseases, and cancers of the rectum, kidneys and gastrointestinal tract. Chronic infections such as chronic sinustis can be associated with urticaria. Some experts recommend only a history and physical exam to rule out these entities - and they seem to have reasonable justification if one looks a the literature. However, most practicing allergists lean toward history-guided application of a few laboratory tests. For example, for a 45 year old woman with cold intolerance and history of anemia, a CBC with diff, ESR, ANA, SPEP, and Anti-thyroid antibodies might be reasonable. In children, for instance, hidden food allergies and inhalation of dust mite be important factors - thus appropriate skin or RAST tests would be justified.

TREATMENT

Eliminating the etiologic agent is the best way to treat chronic urticaria. When the cause of chronic urticaria cannot be found, drug therapy enables most patients to live normal lives. It is important to emphasize that patients should take the prescribed dose and not use the medication on an "as-needed" basis.

In the great majority of cases, the lesions of chronic urticaria can be controlled with oral antihistamines. A "non-sedating" antihistamines (loratidine, fexofenadine, e.g.) should be the first choice since they have minimal side effects. Although sedating in a slightly higher percentage of patients than the previous drugs, cetirizine (a metabolite of hydroxyzine) is also very effective in chronic urticaria. Although some clinicians feel that cetirizine is the most effective of the "non-sedating" antihistamines for urticaria, there are no good clinical trials directly comparing these drugs.

When these drugs fail, a trial of "classical" antihistamines is warranted. Hydroxyzine, although often sedating, can be used in a single nighttime dose. This drug can be quite effective if high enough doses are given. For those with resistant hives, a morning dose of a less sedating antihistamine can be added to the regimen. The most potent antihistamine, however, is probably the anti-depressant doxepin. Although adverse effects (including sedation, increased appetite, and possible cardiac effects) often limit its use, doxepin is perhaps the most effective of all the antihistamines for urticaria and angioedema (often 10 to 25 mg at bedtime can be quite effective).

Tolerance to the sedative effects of these antihistamines usually occurs within several days of therapy, with no significant drop off in the beneficial effects. However, decreased hand-eye coordination, for example, can occur in the absence of drowsiness.c In theory, adding an H2-blocker (e.g., cimetidine, ranitidine) to the regimen should be helpful since these drugs block histamine receptors - again, there is little data to support this practice. Our results with adding H2-blockers have been quite variable. There have also been reports of benefit with beta-adrenergic drugs (terbutaline, e.g.) and calcium-channel blockers, but again, they are limited numbers of trials to support the use of these drugs. Whatever the case, a discussion of risks and benefits should take place.

Unfortunately, however, a few patients respond only to systemic steroids. In this case the best mode of action is to give a short burst with a moderate dosage (e.g., prednisolone 1 mg/kg/day), and then try to taper the dose of steroid as antihistamines are introduced.

CAUSES OF URTICARIA

(Most important factors, but not necessarily the most common, are indicated by bold letters.)

Drugs And Chemicals

Salicylates, Indomethacin and other nonsteroidal anti-inflammatory drugs, Opiates, Radiocontrast media, Penicillins, Sulfonamides, Sodium benzoate Insulin, Micenthol (cigarettes, toothpaste, iced tea, hand cream, lozenges, candy), Tartrazine - a dye (vitamins, birth control pills, antibiotics, TDC yellow #5)

CONTACTANTS

Latex, perfumes, wool

FOODS

Tree nuts (walnuts, e.g.), peanuts, fish, crustaceans, bananas, soybeans, tomatoes, eggs, milk, berries, wheat

PHYSICAL STIMULI

Simple friction or scratching (dermatographism), sunlight, pressure, heat, cold temperature, water, vibration

INHALANTS

Latex, dust mite, animal danders, pollen

INFECTIONS

Viral upper respiratory infections, bacterial (sinusitis, dental abscess, otitis),viral hepatitis, vaginitis, fungal (tinea pedis - athelete's foot), helminth, protozoa

SYSTEMIC DISEASES

Collagen vascular diseases, leukemia, lymphoma, endocrinopathies (Hyper- and hypothroidism, Hashimoto's thyroiditis), menstruation

REFERENCES

Tharp M. Chronic Urticaria: Pathophysiology and treatment approaches. J Allergy Clin Immunol 1996;98:S325-30.

Volonakis M. et al. Etiologic factors in childhood chronic urticaria. Ann Allergy 1992;69:61-5.

Greaves, M. Current Concepts: Chronic Urticaria. NEJM 1995;332:1767-71.

Neil Gershman, MD Chronic Urticaria Summary 4

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