Urticaria or Hives
Urticaria with or without angioedema is frequently encountered in primary care medicine. If the urticaria is of short duration, it is usually not of major clinical concern. Conversely, if urticaria persists, it can become a difficult problem for both patients and physicians.
Although many patients and physicians think that urticaria is evidence of an IgE-mediated allergic reaction, often the etiology of urticaria is unknown. This uncertainty frequently results in patients enduring unnecessary lifestyle changes or extensive testing.
Although this disease typically is associated with a good prognosis, patients with severe urticaria can suffer significant morbidity with a dramatic decline in their quality of life, productivity at work, and emotional well-being.
Urticaria, or hives, are pruritic, edematous, erythematous lesions that are typically round or oval. Pale raised centers called wheals are usually prominent in lesions and vary in size from a few millimeters to a few centimeters.
Approximately 40% of patients with urticaria experience angioedema, which affects deeper subdermal and/or submucosal sites and appears as brawny, nonpitting edema typically without well-defined margins and without erythema.
Unlike other forms of edema, angioedema is usually not distributed in dependent areas of the body and may involve the lips, tongue, eyelids, and genitalia.
Angioedema in the absence of urticaria is rare and should alert the practitioner to alternative diagnoses, such as hereditary or acquired angioedema. Recurrent hives with or without angioedema lasting less than 6 weeks are considered to be acute and episodes lasting longer than 6 weeks are considered chronic.
This somewhat arbitrary distinction of 6 weeks becomes important in regards to potential mechanisms, approaches to evaluation, and options for treatment. Both urticaria and angioedema can peak within minutes to hours and last hours to days.
An episode of urticaria with or without angioedema occurs in 15% to 25% of individuals at some time in life and is most often acute. Only 30% of these cases go on to become chronic. Urticaria affects both genders and all races. Acute urticaria is more common in children and young adults and chronic urticaria is more common in adults, affecting women (w60%) more than men (w40%)
Diagnosis and Evaluation
Acute
Patients are often able to identify a stimulus if the hives occur 5 to 30 minutes after ingestion of a food or drug. If the hives are short-lived or respond rapidly to over-the-counter antihistamines, patients do not typically seek medical care. Patients whose hives occur in the absence of an identifiable trigger and are recurrent in nature often come to the attention of physicians.
The best initial approach to a patient with urticaria is a thorough history and physical. History should include details of the hives in relation to medications (including herbals, supplements), foods, physical triggers, infections, occupational exposures, insect stings, and contact exposures as well as a complete review of systems.
Physical examination should include at least examination of the skin, lymph nodes, eyes, joints, throat, neck, ears, lungs, heart, and abdomen to detect possible associated conditions. Then, food supplements and drugs that are nonessential should be discontinued.
Recently added drugs should be discontinued or replaced with a chemically unrelated agent. Often, no specific agent is found and the hives are treated symptomatically until they resolve spontaneously.
Chronic
As for acute urticaria, evaluation of chronic urticaria begins with a detailed history and physical examination. Because patients often do not have lesions when they are seen in the office, it is also important to determine if the rash is indeed urticaria before embarking on an extensive evaluation.
Not all dermatoses described by patients as hives are really urticaria. The transient nature of the lesions is a good indication that the lesions are indeed urticaria and a photograph taken by the patient can be reassuring. Nonetheless, some skepticism is advised.
Key elements in the history are duration of the episodes, duration of individual lesions, nature of the lesions (eg, pruritic, painful), and presence of angioedema. In addition, a thorough medication history, including herbal remedies and supplements, should be taken.
Some herbal products associated with urticaria include cranberry, echinacea, hypericum, willow, garlic, ginger, glucosamine, horseradish, phytoestrogen, propolis, royal jelly, and valerian. In addition, topical use of herbal soaps may cause urticaria.
In approximately 95% of patients with chronic urticaria, neither the patient nor the physician can identify a specific ingestant or contactant causing hives. This is sometimes difficult for patients and physicians to accept. Therefore, an unnecessarily extensive, invasive, and expensive investigation is pursued without successfully identifying a specific culprit.
Included in a detailed physical examination should be exclusion of possible physical triggers. For instance, for cold-induced urticaria, an ice cube challenge should be done by placing an ice cube on the patient’s skin for 5 minutes. Patients with cold-induced urticaria will develop hives upon rewarming of the skin.
Dermatographism can be tested by stroking the skin and observing for linear hives. Pressure-induced urticaria can be tested by applying pressure perpendicular to the skin (eg, a sandbag across the shoulder) and instructing the patient to observe for swelling 4 to 6 hours later.
Aquagenic urticaria can be tested by applying water regardless of temperature to the skin. In addition, applying heat, vibration, and UV radiation may rule out other physical urticaria. Although foods and drugs are uncommon causes of acute urticaria, many patients are not satisfied until these are ruled out.
As in the evaluation of acute urticaria, patients must discontinue all unnecessary food supplements and drugs. Patients can then keep a food diary to identify suspect foods, which can then be eliminated. If patients are highly motivated, a trial of a very restrictive diet of lamb and rice can be implemented for 2 weeks while off all antihistamines.
If the urticaria resolves, foods can be slowly reintroduced into the diet while monitoring for urticaria with the use of a food diary. This method rarely leads to identification of a specific trigger of chronic urticaria in adults. Chronic infections have also been associated with urticaria.
For example, Helicobacter pylori gastric infection, tinea pedis, cholecystitis, hepatitis, thyroiditis, sinus infections, and dental abscesses have been associated with urticaria.
The association between antithyroid antibodies (antimicrosomal [peroxidase] and antithyroglobulin) that are most commonly seen in Hashimoto’s thyroiditis and chronic urticaria is particularly strong, although urticaria occurs only in a few patients with Hashimoto’s thyroiditis.
There are many reports, but no rigorous proof, that treatment of euthyroid urticaria patients who have antithyroid antibodies with l-thyroxine leads to resolution of the urticaria. In many of these cases, improvement of the urticaria appears to be coincidental. Nonetheless, some specialists do treat these patients with l-thyroxine.
In patients with chronic urticaria, some laboratory evaluation is warranted in addition to the history and physical examination. Physicians should obtain a complete blood count with differential, a basic metabolic panel, liver enzymes, and a urinalysis in all patients with chronic urticaria.
Some experts advocate measurements of erythrocyte sedimentation rate, thyrotropin, and antithyroid antibodies (antimicrosomal and antithyroglobulin thyroid antibodies). Most experts agree that further testing should be determined by specific positive findings from the history and physical examination.
For example, there is no need to obtain an antinuclear antibody titer in a patient with urticaria who has no significant rheumatologic complaints or findings. If patients have atypical lesions or systemic symptoms, a referral to a specialist is appropriate. Additional tests, usually performed in specialty clinics, may be useful in patients with chronic urticaria.
Some allergists order immediate hypersensitivity skin tests or IgE RAST tests for foods if the history is suggestive. Approximately 40% of patients with chronic urticaria have evidence of an autoimmune process that may contribute to their hives.
An in vitro test for antibodies to the a subunit of the FceRI (FceRIa) can be ordered from specialized immunology laboratories. However, this test has not been approved by the Food and Drug Administration. Evidence of autoimmunity can also be demonstrated by the autologous serum skin test.
In this test, a small amount (0.05 mL) of the patient’s serum is injected intradermally into the patient’s own skin (therefore, autologous). If a wheal and flare develops, this is thought to be due to an antibody to either FceRIa or to IgE itself.
A positive test may reassure the patient, prevent further anxiety, and avoid unnecessary testing to find an external cause. In addition, systemic symptoms may necessitate checking antinuclear antibody titer and complement studies. Lastly, a skin biopsy examined by standard staining and immunofluoresecence can be useful to rule out urticarial vasculitis.
Treatment
Acute
Acute urticaria is generally self-limited. Antihistamines work well in patients with acute urticaria, especially if taken prophylactically. First-generation antihistamines, such as diphenhydramine and hydroxyzine, often cause sedation and must be taken three or four times daily to be effective.
Second-generation antihistamines, such as cetirizine, fexofenadine, loratidine, and desloratidine, are taken once daily, are better tolerated, and are often effective. Some patients benefit from a second-generation antihistamine daily with a first-generation drug given at bedtime for breakthrough symptoms. A brief course of corticosteroids may be needed for severe episodes.
Epinephrine (0.3 mL of 1:1000 intramuscularly) rapidly reverses the signs and symptoms of urticaria and angioedema. Patients with life-threatening angioedema or anaphylaxis should always have access to epinephrine and be instructed and prepared to use it if needed. Betablockers can interfere with the action of epinephrine and should be discontinued if it is safe to do so.
Chronic
Management of chronic urticaria also includes H1-type antihistamines. In most cases of chronic urticaria, additional measures are needed to control symptoms. Some specialists empirically use antihistamines at doses twice those approved by the Food and Drug Administration.
However, insurance companies often require prior authorization. Because 15% of the histamine receptors of the skin are of the H2-type, addition of H2-antihistamines (eg, ranitidine or famotidine) may be helpful in treatment of urticaria. Doxepin, a tricyclic antidepressant, has potent H1- and H2-antihistamine activity and can be used as well.
The main drawback of this medication, sedation, can often be managed by starting at 10 mg every night and slowly increasing the dose to a maximal antihistamine dose of 75 to 125 mg every night. Additional issues with doxepin include dry mouth, urinary retention, and increased appetite.
Mast cells release a variety of mediators in addition to histamine. Thus, antileukotriene medications may be added with some success. Severe symptoms may also require oral steroids to achieve control. However, because of the long-term side effects, chronic use of steroids should be limited when possible.
Corticosteroids may be needed in delayed pressure urticaria. Sunscreen and avoidance are the most effective treatments for solar urticaria. A specialized clinic can determine the wavelengths of light affecting the skin and desensitization may be possible.
In some instances, specific H1-type antihistamines may be more efficacious for certain types of urticaria. For example, hydroxyzine is often used for cholinergic urticaria and cyproheptidine for cold-induced urticaria. Specialists who see patients with refractory urticaria often use a variety of anti-inflammatory, immunomodulatory, and antimetabolic medications.
Case reports suggest that hydroxychloroquine, nifedipine, sulfasalazine, dapsone, colchicine, cyclosporine, azathioprine, methotrexate, and intravenous immunoglobulin may be useful in selected patients. Of these, only cyclosporine has been shown to be effective in double-blind, placebocontrolled studies.
Many of these medications are limited by their side effect profiles. In addition to medications, prevention plays an important role in the management of urticaria. For instance, patients with physical urticaria can minimize or avoid triggering factors.
If a systemic disease is present, the urticaria may improve by treating the underlying disease, as in the case of thyroid disease. Other exacerbating factors that may be modifiable for some patients are anxiety, medications (eg, NSAIDs), or cutaneous vasodilatation (eg, from alcohol, hot showers, exercise).
Psychosocial stress plays a large part in many patients by exacerbating urticaria, although the mechanism for this is unclear. Overall urticaria patients should be encouraged to accept their illness and focus on achieving symptomatic control with the most effective treatment while minimizing side effects.