Urticaria; Causes, Symptoms, Diagnosis, Treatment









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Urticaria is a common mast cell-driven disease presenting with wheals or angioedema or both. It is a heterogeneous skin disorder that may be acute or chronic, intermittent or persistent, and may occur alone or in association with other related conditions such as angioedema. During an acute urticaria onset, it is frequently difficult for the clinician to determine whether the urticaria and/or angioedema is self-limiting or part of systemic anaphylaxis.

Another Name

Urticaria (or ‘hives’ or ‘nettle rash’) consists of blancheable, erythematous, oedematous papules or ‘weals [rx].

Types of Urticaria

  • Acute urticaria (short-term) – can develop suddenly and will last less than 6 weeks.[rx] About 1 in 6 people will have acute hives at one point in their life.[rx]
  • Chronic urticaria (long-term) – can develop suddenly and will persist for more than 6 weeks.[rx] This type of urticaria is uncommon[rx] and occurs in only 0.1% of the population.[rx] 20% of people with chronic urticaria report still having problems 10 years after its onset.[rx]

Sub-categories

There are seven sub-categories of physical urticaria

  • Delayed pressure urticaria (DPU)
  • Cholinergic urticaria (ChU)
  • Cold urticaria (CU)
  • Solar urticaria (SU)
  • Acute pressure urticaria (AU)
  • Chronic idiopathic urticaria (CIU)
  • Symptomatic dermatographism urticaria (SDU) (most common) [rx][rx]

Below is a list of some types of physical urticaria and their causes.

  • Dermatographism/dermographism – Firm stroking
  • Delayed pressure urticaria – Pressure
  • Cold urticaria – Cold
  • Aquagenic urticaria – Water exposure
  • Cholinergic urticaria – Heat, exercise, or stress
  • Solar urticaria – Sun exposure
  • Vibratory urticaria – Vibration

Causes of Urticaria

Urticaria occurs when histamine and other chemicals are released from under the skin’s surface, causing the tissues to swell.

Short-term (acute) urticaria

The triggers of acute urticaria are unknown in around half of all cases.

Recognized triggers include

  • a food allergy– to foods such as peanuts, shellfish, eggs and cheese
  • an allergic reaction – to environmental factors such as pollen, dust mites or chemicals
  • an allergic reaction to latex – which can be a common problem in healthcare workers
  • infections– which can range from relatively trivial, such as a cold, to very serious, such as HIV
  • insect bites and stings
  • emotional stress
  • certain medications that can cause urticaria as a side effect – including antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin
  • physical triggers –such as pressure to the skin, changes in temperature, sunlight, exercise or water

Long-term (chronic) urticaria

Chronic urticaria may occur when the body’s immune system attacks its own tissues. This is known as an autoimmune reaction.

About a third to half of all chronic cases of urticaria are thought to be autoimmune related. It’s not known why autoimmune urticaria develops, although it can sometimes occur in combination with other autoimmune conditions, such as:

  • rheumatoid arthritis – when the immune system attacks the joints
  • lupus –when the immune system attacks the joints and skin, and people usually feel tired all the time

Chronic urticaria can also be linked to other chronic illnesses and infections, such as:

  • viral hepatitis (liver infection)
  • intestinal parasites
  • an underactive thyroid gland (hypothyroidism)
  • an overactive thyroid gland (hyperthyroidism)

Chronic urticaria tends to come and go. Many people find that certain things make it reappear or make existing symptoms worse. Triggers sometimes include:

  • stress
  • alcohol
  • caffeine
  • warm temperatures
  • prolonged pressure on the skin – this can happen by wearing tight clothing
  • medications –such as NSAIDs, and the painkiller codeine
  • certain food additives –such as salicylates, which are found in tomatoes, orange juice and tea
  • insect bites and stings
  • exposure to heat, cold, pressure or water

ACE inhibitors that are often used to treat high blood pressure (hypertension) can be linked to deeper swellings of angioedema.

Aetiological classification of urticaria.

Etiology Mechanism
Idiopathic Unknown Investigations: normal
Immunological
Autoimmune IgG autoantibodies to IgE Receptor or IgE on mast cells ASST usually positive
Other autoantibodies may be present, e.g. anti-thyroid antibodies
IgE/contact Contact with allergen cross-links IgE on mast cells Often identified by clinical history
SIgE and/or SPT positive
Immune complex Infection-related Serology according to clinical history
Urticarial vasculitis Usually idiopathic; but also connective tissue disease, infection, drugs
Non-immunological
Physical urticaria Physical factors trigger histamine release from mast cells Often identified by clinical history or, possibly, challenge testing
Drug treatment Sensitivity to COX-inhibitors Urticaria with aspirin, NSAIDs
Direct mast cell histamine release Opiates, radio-contrast media
Dietary pseudo-allergens Sensitivity to natural salicylates, colourings, preservatives
Medical conditions:
Urticaria pigmentosa Increased mast cell load
Cryopyrin-associated Mutation in the CIAS1 gene
Periodic syndrome
(CAPS)

COX: cyclo-oxygenase; NSAID: non-steroidal anti-inflammatory drug.

Idiopathic/others

Most cases of CU are considered idiopathic. It has recently been accepted that autoimmunity plays a critical role in its pathogenesis in some of these patients.[,] A few other offenders are listed as under:

  • Medications – Urticaria may be caused or exacerbated by a number of drugs. More common culprits include aspirin, other nonsteroidal anti-inflammatory drugs, opioids, ACE inhibitors, and alcohol. Aspirin may exacerbate CU in 6.7-67% of patients.[] Other drugs implicated are alcohol, narcotics (codeine, morphine) and oral contraceptives.[]
  • Contacts – Contact urticaria syndrome refers to the onset of urticaria within 30-60 minutes of contact with an inciting agent. The lesions may be localized or generalized. Precipitating factors include latex (especially in health care workers), plants, animals (eg, caterpillars, dander), medications, and food (eg, fish, garlic, onions, tomato).
  • Neurological factors – An Italian study[] reported an association between CU and fibromyalgia. The authors proposed that CU is a consequence of fibromyalgia-neurogenic skin inflammation.
  • Stress – Psychological factors are reported to play a role in a number of patients. The study showed that the decline in dehydroepiandrosterone sulfate observed in CU is associated with psychological distress.[] Depression may also cause or aggravate CU.[]
  • Vasculitic – reported a case of recurrent cutaneous eosinophilic vasculitis presenting as annular urticarial plaques.[] Another confounding condition of interest is urticarial vasculitis, an eruption of erythematous wheals that clinically resemble urticaria but histologically show changes of leukocytoclastic vasculitis.[] Patients with urticarial vasculitis present with an urticarial eruption, often accompanied by a painful or burning sensation. Lesions are generalized wheals or erythematous plaques, occasionally with central clearing, lasting for more than 24 hours in a fixed location (in contrast to urticaria, which resolves in minutes to hours or migrates continually).
  • Pseudoallergic – Some authors suggest that the etiology of disease for a portion of CIU patients is a pseudoallergy to food ingredients. Implicated agents include preservatives, sweeteners, artificial food dyes, aromatic volatile compounds in tomatoes, herbs, wine, salicylic acid, orange oil, alcohol, and high dietary fats. Some patients report the onset of acute urticaria associated with the consumption of certain foods, such as shellfish, eggs, nuts, strawberries or certain baked goods. CU exacerbated by specific foods is fairly common, particularly among infants and children.[]
  • Rubbing or scratching – This is the most frequent cause of physical urticaria. Symptoms appear within a few minutes in the place that was rubbed or scratched and typically last less than an hour.
  • Pressure or constriction – Delayed pressure urticaria can appear as red swelling six to eight hours after pressure (belts or constrictive clothing, for example) has been applied. Symptoms can also occur in parts of the body under constant pressure, such as the soles of the feet.
  • Change in temperature – Cold urticaria is caused by exposure to low temperatures followed by re-warming. This can be severe and life-threatening if there is a general body cooling – for example, after a plunge into a swimming pool.
  • Higher body temperature – Cholinergic urticaria is due to an increase in body temperature because of sweating, exercise, hot showers and/or anxiety.Sun exposure. Solar urticaria may occur within a few minutes after exposure to the sun.
  • Medications including – some antibiotics and non-steroidal anti-inflammatory drugs(NSAIDs), such as aspirin and ACE inhibitors, used for high blood pressure
  • Foods, such as nuts, shellfish, food additives, eggs, strawberries, and wheat products
  • Infections, including influenza, the common cold, glandular fever, and hepatitis B
  • Bacterial infections, including urinary tract infections and strep throat
  • Intestinal parasites
  • Extreme temperatures or changes in temperature
  • High body temperature
  • Pet dander from dogs, cats, horses, and so on
  • Dust mites
  • Cockroaches and cockroach waste
  • Pollen
  • some plants, including nettles, poison ivy, and poison oak
  • Insect bites and stings
  • Some chemicals
  • Chronic illness, such as thyroid disease or lupus
  • Sunlight exposure
  • Water on the skin
  • Scratching
  • Exercise

Symptoms of Urticaria

Symptoms can last anywhere from minutes to months – or even years.

While they resemble bug bites, hives (also known as urticaria) are different in several ways:

  • Hives can appear on any area of the body they may change shape, move around, disappear and reappear over short periods of time.
  • The bumps – red or skin-colored wheels with clear edges – usually appear suddenly and go away just as quickly.
  • Pressing the center of a red hive makes it turn white – a process called “blanching.
  • Batches of red or skin-colored welts (wheals), which can appear anywhere on the body
  • Welts that vary in size, change shape and appear and fade repeatedly as the reaction runs its course
  • Itching, which may be severe
  • Painful swelling (angioedema) of the lips, eyelids and inside the throat
  • A tendency for signs and symptoms to flare with triggers such as heat, exercise, and stress
  • A tendency for signs and symptoms to persist for more than six weeks and to recur frequently and unpredictably, sometimes for months or years

There are two types of hives – short-lived (acute) and long-term (chronic). Neither is typically life-threatening, though any swelling in the throat or any other symptom that restricts breathing requires immediate emergency care.

Diagnosis of Urticaria

Screening test for thyroid function and antithyroid peroxidase and antithyroglobulin antibodies may be carried out in candidate patients. Positive autologous serum skin test (ASST)[] suggests an underlying autoimmune mechanism. Confirmation is needed by in vitro testing of the patient’s serum for the anti-FCeRIa or the anti-IgE autoantibodies. In vitro ‘the basophil histamine release assay[] is currently the gold standard for detecting functional autoantibodies. A diagnosis of C1 esterase inhibitor deficiency should be suspected in the light of C4 hypocomplementemia and angioedema alone.[]

Immunologic associations identified in patients with CSU
  • IgG anti-FcεRIα in 30%-40%
  • IgG antibody to IgE 5%-10%
  • Increased incidence of Hashimoto’s thyroiditis
  • IgG antibody to thyroid antigens (antithyroglobulin and anti peroxidase) 25%
  • IgE antibodies to thyroperoxidase
  • Positive ANA-speckled pattern 30%
  • Expression to Th-2-initiating cytokines in skin biopsies including TSLP, IL-25, and IL-33

CSU, chronic spontaneous urticaria; IgG, immunoglobulin G; IgE, immunoglobulin E; IgG anti-FcεRiα, IgG antibody to the α subunit of the high-affinity IgE receptor; ANA, antinuclear antibody; TSLP, thymic stromal lymphopoietin; IL, interleukin.

Short-term (acute) urticaria

Your GP can usually diagnose acute urticaria by examining the rash.

They’ll also ask you some questions to find out what triggered your symptoms, including:

  • when and where the rash began
  • what you had to eat just before it began and details of your usual diet
  • if you started taking any new medication just before your symptoms began
  • if you live or work in an environment where you come into contact with possible triggers – such as pets, chemicals or latex gloves
  • if you were stung or bitten by an insect just before your symptoms started
  • your current state of health and if you’ve had any recent infections
  • if you’ve recently traveled to a foreign country and if so, where
  • if there’s a history of urticaria in your family

In around half of all cases of acute urticaria, a cause can’t be identified. If your GP thinks your symptoms are caused by an allergic reaction, you may have to go to an allergy clinic. Allergy testing may be needed to find out if you’re allergic to suspected triggers for urticaria.

Long-term (chronic) urticaria

If your urticaria lasts for more than 6 weeks, it’s very unlikely to be caused by an allergy, so allergy tests aren’t usually recommended.

However, your GP should ask about anything that makes your urticaria worse, such as:

  • any medicines you’re taking
  • your alcohol and caffeine consumption
  • your stress levels

You may also be referred for a number of tests to find out if there’s an underlying cause of your chronic urticaria. These tests may include:

  • a full blood count test (FBC) – which can identify anemia
  • tests to determine the levels of antibodies in your blood
  • a stool sample – which can identify intestinal parasites
  • an erythrocyte sedimentation rate (ESR) test – which can help to identify problems with your immune system
  • thyroid function tests – which can be used to check for an underactive thyroid gland (hypothyroidism) or an overactive thyroid gland (hyperthyroidism)
  • liver function tests – which can be used to check if you have any problems with your liver

Medications can interfere with results

Before scheduling a skin test, bring your doctor a list of all of your prescription and over-the-counter medications. Some medications can suppress allergic reactions, preventing skin testing from giving accurate results. Other medications may increase your risk of developing a severe allergic reaction during a test.

Because medications clear out of your system at different rates, your doctor may ask that you stop taking certain medications for up to 10 days. Medications that can interfere with skin tests include:

  • Prescription antihistamines – such as levocetirizine and desloratadine.
  • Over-the-counter antihistamines – such as loratadine, diphenhydramine, chlorpheniramine, cetirizine and fexofenadine.
  • Tricyclic antidepressants – such as nortriptyline and desipramine.
  • Certain heartburn medications – such as cimetidine and ranitidine.
  • The asthma medication omalizumab – This medication can disrupt test results for six months or longer even after you quit using it (most medications affect results for days to weeks).
  • The positive reaction to allergy test – Skin testing is usually done at a doctor’s office. A nurse generally administers the test, and a doctor interprets the results. Typically, this test takes about 20 to 40 minutes. Some tests detect immediate allergic reactions, which develop within minutes of exposure to an allergen. Other tests detect delayed allergic reactions, which develop over a period of several days.
  • Skin prick test – A skin prick test, also called a puncture or scratch test, checks for immediate allergic reactions to as many as 40 different substances at once. This test is usually done to identify allergies to pollen, mold, pet dander, dust mites, and foods. In adults, the test is usually done on the forearm. Children may be tested on the upper back.

To see if your skin is reacting normally, two additional substances are scratched into your skin’s surface

  • Histamine – In most people, this substance causes a skin response. If you don’t react to histamine, your allergy skin test may not reveal an allergy even if you have one.
  • Glycerin or saline – In most people, these substances don’t cause any reaction. If you do react to glycerin or saline, you may have sensitive skin. Test results will need to be interpreted cautiously to avoid a false allergy diagnosis.

About 15 minutes after the skin pricks, the nurse observes your skin for signs of allergic reactions. If you are allergic to one of the substances tested, you’ll develop a raised, red, itchy bump (wheal) that may look like a mosquito bite. A nurse will then measure the bump’s size. After the nurse records the results, he or she will clean your skin with alcohol to remove the marks.

Skin injection test

You may need a test that uses a needle to inject a small amount of allergen extract just into the skin on your arm (intradermal test). The injection site is examined after about 15 minutes for signs of an allergic reaction. Your doctor may recommend this test to check for an allergy to insect venom or penicillin.

Patch test

  • Patch testing is generally done to see whether a particular substance is causing allergic skin irritation (contact dermatitis). Patch tests can detect delayed allergic reactions, which can take several days to develop.
  • Patch tests don’t use needles. Instead, allergens are applied to patches, which are then placed on your skin. During a patch test, your skin may be exposed to 20 to 30 extracts of substances that can cause contact dermatitis. These can include latex, medications, fragrances, preservatives, hair dyes, metals, and resins.

Treatment of Urticaria

Anti-histamines

The initial medical treatment for urticaria is a standard dose of a second-generation H1 anti-histamine. These drugs penetrate the blood-brain barrier to only a slight extent and so cause fewer central nervous system side effects than the older first-generation antihistamines, although symptoms such as sedation and psychomotor impairment may still occur. Cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, and mizolastine, which are all given once a day, and acrivastine which is given three times a day, and may, therefore, be less effective and convenient to use. Cetirizine and levocetirizine [] and loratadine [] may have clinically useful ‘anti-inflammatory’ properties at therapeutic doses.

Certain antihistamines have been proposed as preferred for particular subtypes of chronic urticaria, such as hydroxyzine for cholinergic urticaria and cyproheptadine for cold-induced urticaria.[] Second generation nonsedating (or less sedating) antihistamines like cetirizine, loratadine, fexofenadine, desloratadine, mizolastine, etc. also can be used. It is common to double or triple the dosage of nonsedating antihistamines if patients do not respond to the standard dosage.[,] The EAACI/GA2 LEN recommendation of using nonsedating H 1 antihistamines up to four-fold above the recommended doses appears to be effective with mild sedation. It has been proposed to switch over from the current approach of adding another antihistamine to updating the same antihistamine for desirable results.[] If little response, then the tricyclic antidepressant doxepin,10-25 mg initially up to 75 mg at night[] or H2 antihistamines[] or mast cell stabilizers e.g., ketotifen[] can be added.

Leukotriene receptor antagonists (LTRA)

An alternative second-line treatment to H2 anti-histamines in patients who still have severe urticaria despite high-dose H1 anti-histamine treatment is an LTRA such as montelukast or zafirlukast. LTRA treatment may be particularly effective if the patient is sensitive to aspirin or has a positive ASST []; however, urticaria does not always improve with LTRA and, very occasionally, patients notice worsening of the rash []– in which case they should stop the treatment. LTRA alone is not used for urticaria.

Corticosteroids

In patients with very severe acute urticaria, associated possibly with angioedema or systemic symptoms, a short course of oral steroids is indicated. Dose and duration of the treatment are determined by the patient’s weight and clinical response. Prolonged courses of oral steroids for chronic urticaria should be avoided whenever possible, and if long-term steroid treatment is considered necessary, the patient should be followed-up regularly and prescribed prophylactic treatment against steroid-induced osteoporosis at an early stage [].

Approaches to consider when antihistamines fail
A B C
Omalizumab
Cyclosporine
Dapsone
Hydroxychloroquine
Sulfasalazine
Colchicine
Methotrexate
Intravenous gamma globulin
Plasmapheresis
Corticosteroid
H2 receptor antagonists
Leukotriene antagonists

A: recommended; if “A” fails, consider B; C: not recommended.

Failure of antihistamines, omalizumab, and cyclosporine may leave no option other than those listed as “B” or use of low-dose chronic corticosteroid with the provisos described in the text.

Therapy of CSU
Step I Non-sedating, second or third-generation antihistamines taken 4 times a day. Decrease the dose as tolerated once control of symptoms is attained.
If response inadequate,
Step II Omalizumab 300 mg monthly
If no response after 3-4 injections,
Step III Cyclosporine 200-300 mg/day
Step IV Drugs to consider if steps I-III fail are dapsone, methotrexate, sulfasalazine, hydroxychloroquine, intravenous gamma globulin, and plasmapheresis

The dose of cetirizine, loratadine, desloratadine, or xyzal corresponding to hydroxyzine or diphenhydramine at 50 mg q.i.d. is 6 tablets/day.

Patient response to step I:45%; step II:65% of the remainder(predicted response rate of steps I plus II is 80%); patients response to step III: 65% of the remainder(predicted total response rate for steps I, II, and III is 92%).

  • Antidepressants – The tricyclic antidepressant doxepin (Zonalon), used in cream form, can help relieve itching. This drug may cause dizziness and drowsiness.
  • Asthma drugs with antihistamines – Medications that interfere with the action of leukotriene modifiers may be helpful when used with antihistamines. Examples are montelukast (Singulair) and zafirlukast (Accolate).
  • Man-made (monoclonal) antibodies – The drug omalizumab (Xolair) is very effective against a type of difficult-to-treat chronic hives. It’s an injectable medicine that’s usually given once a month.
  • Immune-suppressing drugs – Options include cyclosporine (Gengraf, Neoral, others) and tacrolimus (Astagraft XL, Prograf, Protopic).
  • Alternative medicine – Few authors have suggested that acupuncture is effective in up to 90% of cases of CIU. In a case-control study, it was shown that the mean attack rate and mean duration of urticaria attack was reduced in the acupuncture treated patients and this effect was mostly seen an in the third week of treatment.[]
  • Psychological therapy – A case has also been made for complementary psychological treatment of patients suffering from CIU, because of the high frequency of psychological symptoms. Particular attention is focused on hypnosis and relaxation techniques because of the improvement of the urticarial wheals reported in studies of cutaneous ability to react in subcutaneous injections of histamine.[]
  • Future prospects – More selective immunotherapies offer promising prospects. The extracellular part of the ‘a’ subunit of FCeRIa or shorter peptide sequences containing the autoantibody epitopes could be used to bind to circulating FCeRIa autoantibodies, thereby inhibiting their attachment to receptors on mast cells or basophils. AST, a modified form of autologous whole blood therapy, has also been found to be fairly effective in CU.[,].
  • Menthol cream – Menthol cream can be used as an alternative or in addition to antihistamines because it helps to relieve itchiness. Your GP can prescribe this.
  • Ciclosporin –  In around two-thirds of cases, a powerful medication called ciclosporin has proved effective in treating urticaria. Ciclosporin works in a similar way to corticosteroids. It suppresses the harmful effects of the immune system and is available in capsule form or as a liquid.
  • Omalizumab – For urticaria that hasn’t responded to antihistamines, there are newer medications becoming available, such as omalizumab. Omalizumab is given by injection and is thought to reduce a type of antibody that can play a part in urticaria.

Diet

There’s some uncertainty over the role of diet in people with long-term urticaria. There are 2 groups of chemicals in foods that may trigger urticaria in some people –vasoactive amines and salicylates.

The Allergy UK website has more information on:

  • vasoactive amines
  • salicylates

Avoiding or cutting down on foods that contain these chemicals may improve your symptoms. You could also keep a food diary to see whether avoiding certain foods helps you. However, you should talk to a dietitian before restricting your diet. They can make sure you’re not avoiding foods unnecessarily and that your diet is healthy.

References

 

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