|Classification and external resources|
Urticaria on the arm
Urticaria (from the Latin urtica, "nettle" from urere, "to burn"), commonly referred to as hives, is a kind of skin rash notable for pale red, raised, itchy bumps. Hives may cause a burning or stinging sensation. They are frequently caused by allergic reactions; however, there are many nonallergic causes. Most cases of hives lasting less than six weeks (acute urticaria) are the result of an allergic trigger. Chronic urticaria (hives lasting longer than six weeks) is rarely due to an allergy.
The majority of chronic hives cases have an unknown (idiopathic) cause. In perhaps as many as 30–40% of patients with chronic idiopathic urticaria, it is caused by an autoimmune reaction. Acute viral infection is another common cause of acute urticaria (viral exanthem). Less common causes of hives include friction, pressure, temperature extremes, exercise, and sunlight.
- 1 Signs and symptoms
- 2 Classification
- 3 Cause
- 4 Related conditions
- 5 Pathophysiology
- 6 Diagnosis
- 7 Management
- 8 Research
- 9 References
- 10 External links
Signs and symptoms
Wheals (raised areas surrounded by a red base) from urticaria can appear anywhere on the surface of the skin. Whether the trigger is allergic or not, a complex release of inflammatory mediators, including histamine from cutaneous mast cells, results in fluid leakage from superficial blood vessels. Wheals may be pinpoint in size, or several inches in diameter.
Angioedema is a related condition (also from allergic and nonallergic causes), though fluid leakage is from much deeper blood vessels in the subcutaneous or submucosal layers. Individual hives that are painful, last more than 24 hours, or leave a bruise as they heal are more likely to be a more serious condition called urticarial vasculitis. Hives caused by stroking the skin (often linear in appearance) are due to a benign condition called dermatographic urticaria.
Acute versus chronic
- Acute urticaria is defined as the presence of evanescent wheals which completely resolve within six weeks. Acute urticaria becomes evident a few minutes after the person has been exposed to an allergen. The outbreak may last several weeks, but usually the hives are gone in six weeks. Typically, the hives are a reaction to food, but in about half the cases, the trigger is unknown. Common foods may be the cause, as well as bee or wasp stings, or skin contact with certain fragrances.
- Chronic urticaria (ordinary urticaria) is defined as the presence of evanescent wheals which persist for greater than six weeks. Some of the more severe chronic cases have lasted more than 20 years. A survey indicated chronic urticaria lasted a year or more in more than 50% of sufferers and 20 years or more in 20% of them.
Acute and chronic urticaria are visually indistinguishable.
Urticaria can also be classified by the purported causative agent. Many different substances in the environment may cause urticaria, including medications, food and physical agents.
Drugs that have caused allergic reactions evidenced as urticaria include dextroamphetamine, aspirin, ibuprofen, penicillin, clotrimazole, trichazole, sulfonamides, anticonvulsants, cefaclor and antidiabetic drugs. The antidiabetic sulphonylurea glimepiride (trade name Amaryl), in particular, has been documented to induce allergic reactions manifesting as urticaria. Drug-induced urticaria has been known to have an effect on severe cardiorespiratory failure.
Infection or environmental agent
The rash that develops from poison ivy, poison oak, and poison sumac contact is commonly mistaken for urticaria. This rash is caused by contact with urushiol and results in a form of contact dermatitis called urushiol-induced contact dermatitis. Urushiol is spread by contact, but can be washed off with a strong grease- or oil-dissolving detergent and cool water and rubbing ointments.
Dermatographic urticaria (also known as dermatographism or "skin writing") is marked by the appearance of weals or welts on the skin as a result of scratching or firm stroking of the skin. Seen in 4–5% of the population, it is one of the most common types of urticaria, in which the skin becomes raised and inflamed when stroked, scratched, rubbed, and sometimes even slapped.
The skin reaction usually becomes evident soon after the scratching, and disappears within 30 minutes. Dermographism is a common form of chronic hives. Dermatographism is the most common form of a subset of chronic hives, acknowledged as "physical hives".
It stands in contrast to the linear reddening that does not itch seen in healthy people who are scratched. In most cases, the cause is unknown, although it may be preceded by a viral infection, antibiotic therapy, or emotional upset. Dermographism is diagnosed by taking a tongue blade and drawing it over the skin of the arm or back. The hives should develop within a few minutes. Unless the skin is highly sensitive and reacts continually, treatment is not needed. Taking antihistamines can reduce the response in cases that are annoying to the patient.
Pressure or delayed pressure
This type of urticaria can occur right away, precisely after a pressure stimulus or as a deferred response to sustained pressure being enforced to the skin. In the deferred form, the hives only appear after about six hours from the initial application of pressure to the skin. Under normal circumstances, these hives are not the same as those witnessed with most urticariae. Instead, the protrusion in the affected areas is typically more spread out. The hives may last from eight hours to three days. The source of the pressure on the skin can happen from tight fitted clothing, belts, clothing with tough straps, walking, leaning against an object, standing, sitting on a hard surface, etc. The areas of the body most commonly affected are the hands, feet, trunk, abdomen, buttocks, legs and face. Although this appears to be very similar to dermatographism, the cardinal difference is that the swelled skin areas do not become visible quickly and tend to last much longer. This form of the skin disease is, however, rare.
Cholinergic or stress
Cholinergic urticaria (CU) is one of the physical urticaria which is provoked during sweating events such as exercise, bathing, staying in a heated environment, or emotional stress. The hives produced are typically smaller than classic hives and are generally shorter-lasting.
The cold type of urticaria is caused by exposure of the skin to extreme cold, damp and windy conditions; it occurs in two forms. The rare form is hereditary and becomes evident as hives all over the body 9 to 18 hours after cold exposure. The common form of cold urticaria demonstrates itself with the rapid onset of hives on the face, neck, or hands after exposure to cold. Cold urticaria is common and lasts for an average of five to six years. The population most affected is young adults, between 18 and 25 years old. Many people with the condition also suffer from dermographism and cholinergic urticaria.
Severe reactions can be seen with exposure to cold water; swimming in cold water is the most common cause of a severe reaction. This can cause a massive discharge of histamine, resulting in low blood pressure, fainting, shock and even loss of life. Cold urticaria is diagnosed by dabbing an ice cube against the skin of the forearm for 1 to 5 minutes. A distinct hive should develop if a patient suffers cold urticaria. This is different from the normal redness that can be seen in people without cold urticaria. Patients with cold urticaria need to learn to protect themselves from a hasty drop in body temperature. Regular antihistamines are not generally efficacious. One particular antihistamine, cyproheptadine (Periactin), has been found to be useful. The tricyclic antidepressant doxepin has also been found to be an effective blocking agent of histamine discharge. Finally, a medication named ketotifen, which keeps mast cells from discharging histamine, has also been employed with widespread success.
This form of the disease occurs on areas of the skin exposed to the sun; the condition becomes evident within minutes of exposure. After the individual is no longer exposed to the sun, though, the condition starts to weaken within a few minutes to a few hours, and hardly ever lasts longer than 24 hours. Solar urticaria is classified into six different types, depending upon the wavelength of light involved. Since glass absorbs light with a wavelength of 320 nm and below, people suffering from solar urticaria in response to wavelengths of less than 320 nm are protected by glass.
This type of urticaria is also termed rare, and occurs upon contact with water. The response is not temperature-dependent and the skin appears similar to cholinergic form of the disease. The appearance of hives is within one to 15 minutes of contact with the water, and can last from 10 minutes to two hours. The hives that last for 10 to 120 minutes do not seem to be stimulated by histamine discharge like the other physical hives. Most researchers believe this condition is actually skin sensitivity to additives in the water, such as chlorine. Water urticaria is diagnosed by dabbing tap water and distilled water to the skin and observing the gradual response. Aquagenic urticaria is treated with capsaicin (Zostrix) administered to the chafed skin. This is the same treatment used for shingles. Antihistamines are of questionable benefit in this instance, since histamine is not the causative factor.
The condition was first distinguished in 1980. People with exercise urticaria (EU) experience hives, itchiness, shortness of breath and low blood pressure five to 30 minutes after beginning exercise. These symptoms can progress to shock and even sudden death. Jogging is the most common exercise to cause EU, but it is not induced by a hot shower, fever, or with fretfulness. This differentiates EU from cholinergic urticaria.
EU sometimes occurs only when someone exercises within 30 minutes of eating particular foods, such as wheat or shellfish. For these individuals, exercising alone or eating the injuring food without exercising produces no symptoms. EU can be diagnosed by having the patient exercise and then observing the symptoms. This method must be used with caution and only with the appropriate resuscitative measures at hand. EU can be differentiated from cholinergic urticaria by the hot water immersion test. In this test, the patient is immersed in water at 43 °C (109.4 °F). Someone with EU will not develop hives, while a person with cholinergic urticaria will develop the characteristic small hives, especially on the neck and chest.
The immediate symptoms of this uncanny type are treated with antihistamines, epinephrine and airway support. Taking antihistamines prior to exercise may be effective. Ketotifen is acknowledged to stabilise mast cells and prevent histamine release, and has been effective in treating this hives disorder. Avoiding exercise or foods that cause the mentioned symptoms is very important. In particular circumstances, tolerance can be brought on by regular exercise, but this must be under medical supervision.
The most common food allergies in adults are shellfish and nuts. The most common food allergies in children are shellfish, nuts, eggs, wheat, and soy. One study showed Balsam of Peru, which is in many processed foods, to be the most common cause of immediate contact urticaria. A less common cause is exposure to certain bacteria, such as Streptococcus species or possibly Helicobacter pylori.
Angioedema is similar to urticaria, but in angioedema, the swelling occurs in a lower layer of the dermis than in urticaria, as well as in the subcutis. This swelling can occur around the mouth, eyes, in the throat, in the abdomen, or in other locations. Urticaria and angioedema sometimes occur together in response to an allergen, and is a concern in severe cases, as angioedema of the throat can be fatal.
This very rare form of angioedema develops in reply to contact with vibration. In vibratory angioedema, symptoms develop within two to five minutes after contact with vibration and dissolve after about an hour. Patients with this disorder do not suffer from dermographism or pressure urticaria. Vibratory angioedema is diagnosed by holding a vibrating device such as a laboratory vortex machine against the forearm for four minutes. Speedy swelling of the whole forearm extending into the upper arm is also noted later. The principal treatment is avoidance of vibratory stimulants. Antihistamines have also been proven helpful.
The skin lesions of urticarial disease are caused by an inflammatory reaction in the skin, causing leakage of capillaries in the dermis, and resulting in an edema which persists until the interstitial fluid is absorbed into the surrounding cells.
Urticaria is caused by the release of histamine and other mediators of inflammation (cytokines) from cells in the skin. This process can be the result of an allergic or nonallergic reaction, differing in the eliciting mechanism of histamine release.
- Allergic urticaria
- Histamine and other proinflammatory substances are released from mast cells in the skin and tissues in response to the binding of allergen-bound IgE antibodies to high-affinity cell surface receptors. Basophils and other inflammatory cells are also seen to release histamine and other mediators, and are thought to play an important role, especially in chronic urticarial diseases.
- Autoimmune urticaria
- In the past decade, many cases of chronic idiopathic urticaria have been noted to be the result of an autoimmune trigger. For example, roughly one-third of patients with chronic urticaria spontaneously develop autoantibodies directed at the receptor FcεRI located on skin mast cells. Chronic stimulation of this receptor leads to chronic hives. Patients often have other autoimmune conditions, such as autoimmune thyroiditis.
- Hive-like rashes commonly accompany viral illnesses, such as the common cold. They usually appear three to five days after the cold has started, and may even appear a few days after the cold has resolved.
- Nonallergic urticaria
- Mechanisms other than allergen-antibody interactions are known to cause histamine release from mast cells. Many drugs, for example morphine, can induce direct histamine release not involving any immunoglobulin molecule. Also, a diverse group of signaling substances, called neuropeptides, have been found to be involved in emotionally induced urticaria. Dominantly inherited cutaneous and neurocutaneous porphyrias (porphyria cutanea tarda, hereditary coproporphyria, variegate porphyria and erythropoietic protoporphyria) have been associated with solar urticaria. The occurrence of drug-induced solar urticaria may be associated with porphyrias. This may be caused by IgG binding, not IgE.
- Dietary histamine poisoning
- This is termed scombroid food poisoning. Ingestion of free histamine released by bacterial decay in fish flesh may result in a rapid-onset, allergic-type symptom complex which includes urticaria. However, the urticaria produced by scombroid is reported not to include wheals.
- Stress and chronic idiopathic urticaria
- Chronic idiopathic urticaria has been anecdotally linked to stress since the 1940s. A large body of evidence demonstrates an association between this condition and both poor emotional well-being and reduced health-related quality of life. A link between stress and this condition has also been shown. A recent study has demonstrated an association between stressful life events (e.g. bereavement, divorce, etc.) and chronic idiopathic urticaria  and also an association between post-traumatic stress and chronic idiopathic urticaria.
The cause of chronic urticaria can rarely be determined. In some cases regular extensive allergy testing over a long period of time is requested in hopes of getting new insight. No evidence shows regular allergy testing results in identification of a problem or relief for people with chronic urticaria. Regular allergy testing for people with chronic urticaria is not recommended.
The mainstay of therapy for both acute and chronic urticaria is patient education, avoiding triggers, and antihistamines.
Chronic urticaria can be difficult to treat and lead to significant disability. Unlike the acute form, 50-80% of people with chronic urticaria have no identifiable triggers. Fortunately, 50% of people with chronic urticaria will experience remission within 1 year. Overall, treatment is geared towards symptomatic management. Individuals with chronic urticaria may need other medications in addition to antihistamines to control symptoms. Patients that experience urticaria with angioedema require emergent treatment as this is a life threatening condition.
Treatment guidelines for the management of chronic urticaria have been published by professional allergy and dermatology groups. According to the 2014 American practice parameters, treatment involves a step wise approach. Step 1 consists of second generation, H1 receptor blocking antihistamines. Systemic glucocorticoids can also be uses for episodes of severe disease but should not be used long term due to their long list of side effects. Step 2 consists of increasing the dose of the current antihistamine, adding other antihistamines, or adding a leukotriene receptor antagonist such as montelukast. Step 3 consists of adding or replacing the current treatment with hydroxyzine or doxepin. If the individual doesn't respond to steps 1-3 then they are considered to have refractory symptoms. At this point, anti-inflammatory medications (dapsone, sulfasalazine), immunosuppressants (cyclosporin, sirolimus) or other medications like omalizumab can be used. These options are explained in more detail below.
Antihistamines that block the histamine H1 receptors are the first line of therapy. First generation antihistamines such as diphenhydramine (Benadryl) or hydroxyzine (Atarax) block both central and peripheral H1 receptors and can be very sedating. Second generation antihistamines such as loratadine (Claritin), cetirizine (Zyrtec), or desloratadine (Clarinex) selectively antagonize only the peripheral H1 receptors and are therefore less sedating, less anticholinergic, and generally preferred over the first generation antihistamines. To obtain the maximal benefit, it is important to take the antihistamines daily instead of only during acute exacerbations.
Patients who don’t respond to the maximum dose of H1 antihistamines may benefit from the addition of H2 antihistamines. However, not all combinations have proven beneficial. Studies have shown improvement with the combination of hydroxyzine and cimetidine but not with the combination of cetirizine and cimetidine.
Oral glucocorticoids are effective in controlling symptoms of chronic urticaria however they have an extensive list of adverse effects such as adrenal suppression, weight gain, osteoporosis, hyperglycemia, etc. Therefore, their use should be limited to a couple of weeks. In addition, one study found that systemic glucocorticoids combined with antihistamines did not hasten the time to symptom control compared with antihistamines alone.
Leukotrienes are released from mast cells along with histamine. The medications, montelukast and zafirlukast block leukotriene receptors and can be used as add on treatment or in isolation for patients with CU. It is important to note that these medications may be more beneficial for patients with NSAID induced CU.
Other options for refractory symptoms of chronic urticaria include anti-inflammatory medications, omalizumab, and immunosuppressants, Potential anti-inflammatory agents include dapsone, sulfasalazine, and hydroxychloroquine. Dapsone is a sulfone antimicrobial agent and is thought to suppress prostaglandin and leukotriene activity. It is contraindicated in patients with G6PD deficiency. Sulfasalazine, a 5-ASA derivative, is thought to alter adenosine release and inhibit IgE mediated mast cell degranulation, Sulfasalazine is a good option for people with anemia who cannot take dapsone. Hydroxychloroquine is an antimalarial agent that suppresses T lymphocytes. It has a low cost however it takes longer than dapsone or sulfasalazine to work.
Omalizumab was approved by the FDA in 2014 for patients 12 years old and above with chronic urticaria. It is a monoclonal antibody directed against IgE. Significant improvement in pruritus and quality of life was observed in a phase III, multicenter, randomized control trial.
Immunosuppressants used for CU include cyclosporine, tacrolimus, sirolimus, and mycophenolate. Calcineurin inhibitors, such as cyclosporine and tacrolimus, inhibit cell responsiveness to mast cell products and inhibit T cell activity. They are preferred by some experts to treat severe symptoms. Sirolimus and mycophenolate have less evidence for their use in the treatment of chronic urticaria but reports have shown them to be efficacious. Immunosuppressants are generally reserved as the last line of therapy for severe cases due to their potential for serious adverse effects.
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