Urticaria: An Update

Urticaria, often caused "hives", is a very mixed group of diseases. All the types (and subtypes) of this disease share the common distinctive skin reaction pattern of urticarial skin lesions and or angioedema. The EAACI / GALEN / EDF / WAO (1) guideline defines urticaria as characterized by the sudden appearance of wheals and /or angioedema.

A wheal consists of 3 typical features:

  1. a central swelling of variable size, almost invariably surrounded by a reflex erythema
  2. associated itching or, sometimes, burning sensation
  3. a fleeting nature, with the skin returning to its normal appearance, usually within 1 – 24 hours

Angioedema is characterized by:

  1. a sudden pronounced swelling of the lower dermis and subcutis
  2. sometimes pain rather than itching
  3. frequent involvement under mucous membranes
  4. resolution that is slower than for wheals and can take up to 72 hours.

Classification of urticaria on basis of its duration, frequency, and causes

  • Spontaneous urticaria, sometimes called ordinary urticaria is characterized by the fact that the urticaria episodes occur seemingly "out of the blue", with no apparent specific trigger.
    Spontaneous Urticaria is further subdivided by duration into:
    i. Acute: spontaneous wheals and / or angioedema lasting less than 6 weeks and
    ii. Chronic: spontaneous wheals and / or angioedema lasting longer than 6 weeks
  • Physical Urticaria, is always triggered by a physical stimulus, such as:
    i. Cold contact urticaria, where the trigger is cold liquids, objects, wind, air
    ii. Heat contact urticaria is triggered by localized heat
    iii. Solar urticaria is triggered by UV and / or visible light
    iv. Vibratory urticaria is triggered by vibratory force such as a pneumatic drill
    v. Delayed pressure urticaria is triggered by vertical pressure e.g. the strap of a handbag, and there is 3 – 12 hour latency for the wheal to arise after the pressure is applied.
    vi. Demographic urticaria is triggered by mechanical shearing forces e.g. stroking or scratching the skin. The wheals occur within 1 – 5 minutes.
  • Other types of urticaria
    • Exercise-induced urticaria (with or without anaphylaxis) is elicited by physical exercise such as jogging, tennis or even brisk walking.
    • Contact urticaria is triggered by urticariogenic substances such as latex, raw meat, fish and some plants and vegetables.
    • Aquagenic urticaria is triggered by water of any temperature.
    • Cholinergic urticaria is triggered by any increase of the core body temperature, such as physical exercise and spicy foods. The wheals in cholinergic urticaria are typically small (pinpoint) 2-3 mm and surrounded by patches of red skin. They are sometimes called “heat rash”.

Prevalence of urticarias

Urticaria is a very common skin problem. It is one of the 10 most common skin disorders. It is estimated that up to 25% of adults will experience at least one episode of acute urticaria sometimes in their lifetime, while only about 3% will develop chronic spontaneous urticaria.

Angioedema occurs with wheals in one third of all cases. It mainly affects the face. The eyes are affected in about 70% of cases, the lips in 60%, and the whole face in 35%. Non steroidal anti-inflammatory drugs and antibiotics are the most common drugs causing angioedema without urticaria.

Angioedema occurs without urticaria in about 6% of cases of chronic urticaria.

Physical urticaria account for about 35% of all cases of Urticaria.

In one study of urticaria in Japan, more than one-third of the subjects had more than 1 type of urticaria or angioedema.

Acute spontaneous urticaria

Acute spontaneous urticaria is more common in children. It is usually a self-limiting condition commonly related to infections, food or drugs. In more than 90% of cases there is usually complete resolution within 3 weeks.

Infections, particularly upper respiratory viral infections, are the most commonly identified causes of acute urticaria (40% of cases). In some cases it is the combination of the viral infection - which increases mast cell activity - and drug intake (e.g. nonsteroidal anti-inflammatory drugs) that triggers the urticaria.

Chronic spontaneous urticaria (CSU)

Chronic spontaneous urticaria, formerly known as chronic idiopathic urticaria or chronic urticaria has a point prevalence of about 1% of the population at any time. In accordance with the EAACI / GALEN guideline CSU is defined by at least 6 weeks of continuous or recurrent urticaria (wheals) and / or angioedema. This definition excludes non-histamine-mediated angioedema, which is usually drug-induced.

Age

All ages are affected, but the peak is seen between 20 and 40 years of age (the working population), it is rare in children.

Gender

The majority of studies show that women suffer from chronic spontaneous urticaria nearly twice as often as men.

Aetiology

CSU is thought to have an autoimmune basis in about 45% of patients, where an IgG autoantibody can be found in the serum.

10% to 50% of chronic spontaneous urticaria occurs in combination with physical urticarias, especially symptomatic dermographism and delayed pressure urticaria.

The role of stress in CSU

Several neuroendocrinoimmunological studies show the clear bidirectional crosstalk between the nervous system and the skin. Studies have shown that neurotrophin, a nerve growth factor released during stress is a priming agent for mast cells activation in the skin.

Stress might act as a (precipitating) trigger as well as an exacerbation factor in CSU, but CSU itself is a major cause of stress.

Impact of CSU on Quality of Life (QOL)

The majority of patients with CSU suffer from sleep deprivation.

“The detrimental effect of CSU on QOL is greater than that of most other skin diseases, and is similar to that of severe coronary artery disease”.

“Many patients with CSU exhibit psychiatric comorbidities, most commonly anxiety and depression, which should be taken into account in patient management” (2).

Prognosis

The results of studies on the duration of the disease vary greatly, probably due to differences in patient selection. However, in summary the data shows clearly that many patients suffer for 1 – 5 years. One study showed that 50% of the patients with non-acute urticaria were symptom-free after a period of 3 months and 80% were symptom-free after 12 months. However, 11% still suffered after 5 years. Another study in the Netherlands showed that 51% suffered for more than 10 years.

The prognosis is worse for patients who suffered from wheals and angioedema, compared to patients who have wheals only. The prognosis is even worse for patients who developed angioedema only.

Prognosis is also related to severity of the symptoms; one study showed that while all patients with mild disease were symptom free after 2 years, almost 60% of those with moderate to severe disease still had symptoms.

Autoimmune CSU also has a worse prognosis.

The overall disease duration of physical urticarias is usually longer than that of chronic spontaneous urticaria.

Masqueraders of Urticaria / Skin disease that can be confused with Urticaria

  • Urticarial dermatitis:
    • Usually affects elderly patients ( Average age 60 yrs old)
    • Long lasting (>72 hours) patches of with some features of Urticaria (wheal-like) and some features of eczema / dermatitis.
    • Lesions are extremely itchy
    • Usually affects the trunk bilaterally & symmetrically
    • Drugs are often implicated as triggers
    • Oral steroids are effective treatment
  • Contact Dermatitis
    • Presents with an itchy eczematous reaction
    • Triggered by allergens or irritants at the site of contact
    • Diagnosed by careful history and patch testing
  • Contact Urticaria
    • Wheals occur within 45 minutes of contact with allergens like:
  • Natural latex
  • Foods – fruits, meats, seafood
  • Topical medications
  • Insect bite reactions or popular Urticaria
    • Usually appear as fixed, red itchy bumps
    • More often on exposed areas
    • Lesions often appear in summer and lasts days to months
  • Measles-like drug eruptions
    • Red, fixed, flat or raised wheal-like lesions
    • History of prior drug intake 4 – 14 days prior to onset
    • May be accompanied by low grade fever
    • Commonly bilaterally symmetrical distribution on trunk & upper extremities. Commonly starting in axillae or the groin
  • Cutaneous mastocytosis or Urticaria Pigmentosa
    • Brownish lesions which either occurs spontaneously or after rubbing the skin (Darier sign), heat or sunlight exposure
    • Residual brown pigmentation persists after healing
    • Diagnosis is made from a biopsy of the lesion or blood test for Mast Cell Tryptase level
    • In 65% of cases the disease starts in children under the age of 15 years.

Treatment of chronic spontaneous urticaria

It is important even in CSU (which was formerly called chronic idiopathic urticaria) to attempt to identify and eliminate the underlying cause(s) and / or the trigger – or eliciting factor. Therefore a thorough history is the most important diagnostic procedure. In many patients, the causes and triggers of CSU are not found, and the cornerstone of treatment is symptomatic relief using pharmacotherapy.

Asses the disease using the urticaria activity scores:

Score Wheals Pruritus (Itching)
0 None None
1 Mild (<20 wheals="" / 24 hr) Mild (present but not troublesome)
2 (20-50 wheals/24h) Moderate (troublesome but does not
Interfere with daily activities or sleep)
3 Intense (>50 wheals /24h
Or large, confluent wheals)
Intense (severe itching, interferes with
normal daily activity or sleep)

Sum of score: 0 - 6

Treatment of chronic spontaneous urticaria

H1-antihistamines are considered first-line therapy for CSU.

Classification of Antihistamines:

  1st Generation 2nd Generation 3rd Generation
Ethanolamines Diphenhydramine
Doxylamine
   
Alkylamines Chlorpheniramine    
Piperazine Hydroxyzine Cetirizine Levocetirizine
Piperidine Cyproheptadine Loratidine Desloratidine
Fexofenadine

The older 1st generation H1 antihistamines are efficacious in urticaria, but their use is limited by their sedative side-effects. These drugs are associated with impairment of driving ability and handling tasks requiring concentration and alertness. One survey of fatal road traffic accidents spanning a year found the adjustment culpability rate for antihistamines to be 72%.

Most second-generation H1 antihistamines have little or no sedative side effects. They also have a faster onset of action and a longer duration of action than their predecessors.

Some 2nd generation antihistamines also have anti-inflammatory properties independent of their effects on H1- receptors, due to suppression of cytokines.

Dose of antihistamines in chronic spontaneous urticaria

At the standard recommended doses, second generation antihistamines such as fexofenadine and desloratidine prevented positive skin prick test reactions in only 10 – 20% of patients while more than 50% of patients treated with Hydroxyzine (a first generation antihistamine) had negative reactions to histamine in a double-blind randomized trial(4).

Patients with CSU often require a higher dose of second-generation antihistamines, up to four times the standard dose, to control symptoms.

Beyond Antihistamines: Treating Chronic Urticaria (5)

H2 Antihistamines

H2 antihistamines like ranitidine and cimetidine are often used in conjunction with H1 antihistamines in the treatment of CSU. However, there is very little evidence that H2 antihistamines make a clinically relevant impact in CSU.

Leukotriene Inhibitors

Leukotriene are potent inflammatory mediators, which along with histamine bring about allergic reactions, including asthma, urticaria, and anaphylaxis. In one study, Leukotriene D4 was shown to be more potent than histamine in inducing urticarial wheals. In 5 randomized controlled trials the Leukotriene inhibitors montelukast (Singulair) and zafirlukast (Accolate) were effective alone or in combination with antihistamines in treating urticaria. (5)

Systemic (Cortico) Steroids

In the European guideline, oral steroids are not recommended for maintenance therapy but can be used to treat relapses, while in the USA systemic steroids are regularly used on a long-term basis, at a dose of 10mg daily or 20mg on alternate days. My personal preference is to avoid treatment with steroids at all cost, because of the false hope that it gives, and difficulty in weaning patients off it.

Cyclosporine

Cyclosporine is an attractive alternative to corticosteroids for short-term and rapid control of flares in chronic urticaria, because it has comparable efficacy to steroids, but with relatively fewer side effects and the potential for sustained remission lasting several months after discontinuation. In one study (6) 70% of patient treated with cyclosporine demonstrated improvement, with 40% achieving complete remission. Side effects are dose dependent and amenable to dose reduction.

Omalizumab (Xolair)

Omalizumab is a recombinant humanized monoclonal anti-IgE antibody that selectively bind to IgE and may ultimately down regulate the expression of surface IgE receptors on mast cells, basophils and serum IgE. Over the last few years a growing body of evidence suggest a remarkable reduction in urticaria symptoms by omalizumab, with many patients becoming free of symptoms. The following types of urticaria have been shown to respond to Omalizumab:

  • Autoimmune urticaria
  • Physical urticarias
  • Urticarial vasculitis
  • Angioedema

Antimalarials

Antimalarials like hydroxychloroquine have been used successfully for their anti-inflammatory effects in treating CSU. However, their long latency to onset of effect and modest efficacy make them an infrequent treatment option in chronic urticaria.

Diet in Chronic spontaneous urticaria

In a large prospective study (3) of over 800 patients with CSU in Germany, 30% improved on a food additive-free diet, including those with and without a history of food intolerance. Only a small proportion had a positive challenge to food additives.

Conclusion

Urticaria is a very common disorder with many triggers. Unlike acute urticaria (lasting less than 6 weeks), in chronic urticaria (lasting more than 6 weeks) a specific trigger is usually not identified, but one should always be considered. The response to antihistamines is usually much better in acute urticaria. Chronic urticaria is often refractory to the recommended doses of antihistamines, and up to four times the recommended doses are sometimes required. Because of this treatment-refractoriness of chronic urticaria, newer treatment modalities with less side-effect than steroids were desperately needed. Omalizumab (Xolair) might be just the drug that we have been waiting for.

References:

  1. The EAACI / GALEN / EDF / WAO guideline: definition, classification and diagnosis of urticaria. Allergy 64 Issue 10, 1417 – 1426 (Oct 2009).
  2. Maurer M et al. Unmet clinical needs in Chronic Spontaneous Urticaria. A GALEN task force report. Allergy 66 (2011) 317-330
  3. Di Lorenzo G, Pacor ML, Mansueto P et al. Food-additive-induced urticaria: a survey of 838 patients with recurrent chronic idiopathic urticaria. Int Arch Allergy Immunol 2005; 138: 235-42
  4. Dos Santos RV, Magerl M, Mlynek A, Lima HC et al. Suppression of histamine and allergen-induced skin reactions: Comparison of first- and second-generation antihistamines. Ann Allergy Clin Immunol 2009; 123(1): 174-178
  5. Beyond Antihistamines: Treating Chronic Urticaria Journal of Drugs in Derm 2009; 8 (11) 1043 – 1048
  6. Kessel A et al. Low dose cyclosporine is a good option for severe chronic urticaria. J Allergy Clin Immunol. 2009; 123(4):970

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