5: Allergy and the skin: eczema and chronic urticaria

Oral antihistamines: Oral antihistamines may be useful in reducing pruritus in some patients. Older, sedating antihistamines should not be used, especially in young children, as there have been reports of severe and even life-threatening side effects.4

Emollients: There have been very few randomised controlled trials of the use of emollients in eczema, but those that have been done confirm their usefulness.5 Moisturising the skin improves its barrier function and reduces itch and irritation. There are a huge number of bathing and moisturising products available for treating eczema, and patients will often try many before finding one that suits. Products should not be continued if they cause burning, stinging or increased itching. Soft white paraffin is one of the more suitable moisturisers and is best applied immediately after getting out of the bath, while the patient is still wet and warm. Wet wraps may be effective in patients with moderate to severe eczema and provide a partial barrier to scratching.

Topical steroids: Inflammation needs to be controlled, and topical steroid creams and ointments are effective for this purpose.5 A moderate to potent steroid should be applied at the initial signs of inflammation. As the inflammation subsides, steroid use should be tapered off to prevent rebound. This will generally provide better resolution and require a lower total dose of steroid than if a low potency steroid is used alone for a prolonged period. Parental concern about the effects of steroid use, including thinning of the skin, can lead to problems with compliance. However, if steroids are used appropriately for short periods, there is little evidence to support this concern.6

Topical calcineurin inhibitors: More recently, the topical calcineurin inhibitors pimecrolimus cream and tacrolimus ointment (the latter currently only available in Australia at certain hospital and compounding pharmacies) have become available as alternatives to topical steroids to suppress inflammation.

Tacrolimus ointment has been found to be safe and effective in patients with moderate to severe eczema.7 Transient burning and pruritus can occur when the ointment is initially applied. Pimecrolimus is similar in action to tacrolimus but has only been assessed in mild to moderate disease. It can be used to prevent flaring of eczema,8 and may be useful in body areas where there is concern about applying steroids (eg, on the face, around the eyes and around the groin).

Safety concerns about topical calcineurin inhibitors have been raised with respect to increased risk of skin malignancy (on the basis of animal studies), but a review of the literature suggests that “black box” warnings are not indicated.9 Nevertheless, calcineurin inhibitors should not be used in clinically infected areas. Further, there are few studies assessing the effectiveness of these newer agents compared with appropriate strength topical steroids.7

For patients who fail to respond to topical therapy, systemic therapy may be considered. Long-term treatment with oral steroids cannot be justified, because of side effects. Other treatment options — such as narrow-band ultraviolet B therapy, systemic immunosuppressive drugs or intravenous gammaglobulin therapy — are reserved for very severe disease and should only be given under the guidance of a specialist with experience in their use.

Referral to a specialist is indicated for any young infant with severe eczema and for those in whom food allergy is suspected of playing a role. A specialist should also be consulted if systemic immunosuppressive drugs are being considered.

The role of food allergy in causing or exacerbating eczema is controversial, perhaps because many studies of food avoidance have used an unselected population of children with and without sensitisation to foods. Also, foods used in the control group (eg, soy instead of cows milk) may themselves have elicited reactions. Recently, numerous double-blind, placebo-controlled food studies have demonstrated that about 35%–40% of children with moderate to severe eczema have food allergy, and that eliminating the causative food from their diet can bring about significant improvement in the severity and extent of eczema (Box 3).11-14 However, eczema is often multifactorial, and elimination of allergenic foods does not provide complete resolution in all infants. Food allergy is rare in adult-onset eczema.

Allergy to egg is the most common food allergy associated with eczema. Other commonly associated foods include milk, soy, wheat and peanuts. Thus, food allergy screening tests such as skin prick tests and radioallergosorbent tests should be performed in young infants with severe eczema. False negative tests are uncommon, but false positive tests may occur, particularly in older children.15 Food challenges are more accurate; reactions may be immediate or delayed. Food allergens from the maternal diet may be excreted in breastmilk and cause eczema in a breastfed infant.16 A trial of restriction of maternal diet may be useful if an infant is shown to be allergic to a particular food.

Care should always be taken with any recommendations for dietary restriction in young infants. When special diets are used, it is imperative that adequate nutrition be maintained, particularly in young infants, and consultation with a dietitian is advisable.

Patients with eczema may have sensitisation to environmental allergens such as house dust mite (HDM) or pet dander. There is strong circumstantial evidence that HDM is an important precipitant for atopic eczema. However, there are relatively few randomised controlled trials looking at the role of HDM eradication in treatment of eczema. The limited studies suggest that there is some benefit if a very low level of HDM can be achieved.5

Based on the concept that probiotics, which are normal commensal bacteria of the healthy human gut, play a role in the development of normal immune tolerance and may be immunomodulatory, recent studies have looked at probiotics in the treatment and prevention of allergy.17,18 These studies look promising, but further work is required to clarify whether these agents should be recommended and which is most effective. There is currently no evidence for the use of other dietary supplements such as evening primrose oil, fish oils or omega-3 fatty acids.

Urticaria is characterised by transient weals that last less than 24 hours and then disappear without sequelae. It is associated with intense itch. If these two key features are not present, the diagnosis needs to be reconsidered.

The three main types of chronic urticaria are papular urticaria, urticaria with a physical cause, and urticarial vasculitis. They can be distinguished from chronic idiopathic urticaria by weal appearance and characteristic history.

Papular urticaria: Papular urticaria is a reaction to bites from grass mites, fleas and other arthropods. It most commonly occurs in children and during the warmer months. Lesions, typically seen on the extremities, are intensely itchy, leading to marked excoriation and often secondary infection that results in scarring. Lesions often occur in clusters and may last for days.

Urticaria with a physical cause: A physical cause for chronic urticaria is probably present in about 20% of cases (Box 4, Box 5). Dermatographism and cholinergic urticaria are the most common forms of urticaria with a physical cause and have characteristic appearances. Various types of urticaria may coexist in the same patient. However, once the typical history is elicited, no further investigations are required.

Urticarial vasculitis: An atypical appearance, long-lasting lesions or a lack of responsiveness to antihistamine treatment suggests urticarial vasculitis, a rare condition seen in less than 1% of people with chronic urticaria. Patients suspected of having this condition require further investigation (Box 6).

Angioedema (typically affecting the lips, eyelids, palms, soles or genitalia) coexists with urticaria in about 50% of patients. If it occurs as a recurrent condition in isolation, causes other than urticaria should be considered, such as medication (eg, angiotensin-converting enzyme inhibitors) or rare conditions such as hereditary angioedema or acquired deficiency of C1-esterase inhibitor.

The primary goal of therapy for urticaria is to relieve pruritus, as this is the symptom that impairs the patient’s quality of life and causes sleep disturbance. It is important that the patient understand that, despite taking medication, urticarial lesions may still occur.

Oral antihistamines: Oral antihistamines remain the mainstay of treatment of chronic urticaria. They are best taken prophylactically, as various stimuli can cause mast cell degranulation, resulting in histamine release. While older antihistamines are cheaper and their sedative effect may be useful for sleeping at night, they are undesirable for long-term use because of other side effects.

Addition of a tricyclic antihistamine such as doxepin may be very effective for night-time discomfort and sleep disturbance due to itch. Doxepin is a potent antihistamine, with H1- and H2-histamine blocking activity, as well as having an anti-anxiety effect. However, its sedative side effect is a limitation, especially in older patients.

Some years ago, there were reports that addition of an H2 antagonist could help control chronic urticaria. The benefit is small, but the treatment may be worth trying, as it may help selected patients.21 A number of studies have demonstrated benefit from the use of newer, non-sedating antihistamines over that derived from placebo.22-25

Leukotriene inhibitors: Theoretically, there may be a use for leukotriene antagonists in the treatment of chronic urticaria. However, randomised controlled trials comparing the use of an antihistamine alone with use of a combined treatment (antihistamine plus montelukast) have shown conflicting evidence of efficacy.23,26 Currently, montelukast is not listed for use in chronic urticaria and is an expensive treatment.

Oral corticosteroids: Oral corticosteroids are often used for short-term relief of symptoms of chronic urticaria when antihistamine therapy is ineffective. In this circumstance, patients are grateful for temporary relief. But, unfortunately, corticosteroids cannot be a long-term option, as the risk of side effects will outweigh the benefit. Doctors must be responsible for warning their patients of the long-term consequences of corticosteroid use so that the medication is not taken indiscriminately.

In cases of acute severe urticaria and angioedema with no obvious trigger, or where there is a presumed food or drug trigger, specialist evaluation is required to identify the trigger, if at all possible.

Patients with chronic urticaria and/or angioedema who do not respond to the therapies listed above or who are suspected of having an underlying condition should be referred to a specialist.

In cases of recurrent angioedema, specialist evaluation may be appropriate to exclude hereditary or acquired C1-esterase inhibitor deficiency.

There has been concern, based on anecdotal reports, that chronic urticaria may be an indicator of an underlying malignancy, particularly in older patients. A very large Swedish epidemiological study has shown that there is little evidence to support this fear.27 However, acquired angioedema associated with C1-esterase inhibitor deficiency is associated with malignancy, particularly lymphoma.27

Ingestion of certain foods may produce a generalised acute allergic reaction that includes urticaria. The patient often makes the connection between food ingestion and an acute episode of urticaria, but may fail to consider the possibility of a “hidden ingredient” in the food, such as nuts. In this circumstance, skin prick tests or in-vitro measurement of specific IgE may suggest that a particular food is the likely cause, but food challenges may be the only way to establish a definite relationship. Attributing chronic urticaria to food allergy, rather than some other possible cause, is another common pitfall, with most patients believing a particular food to be the cause of their problem at some stage. Skin prick testing or in-vitro testing for food allergy may relieve the patient from unnecessary avoidance of certain foods.

Idiosyncratic reactions to food additives have been suggested as an important cause of chronic urticaria, but this area suffers from a lack of rigorous placebo-controlled studies and also from the inherent problem of challenging patients with chronic urticaria and then trying to interpret the results. Early studies reporting reactions to tartrazine and benzoates in patients with chronic urticaria were not placebo-controlled.28 Other complicating factors include whether or not an elimination diet was used before challenging, which food additives were included in the challenge battery, the dosages of food additives used, and whether medication was ceased before challenging (and if so, for how long). Based on the few rigorous studies that have been performed, food additives appear to be a distinctly uncommon cause of chronic urticaria.29

The question of whether Helicobacter pylori infection is a cause of chronic urticaria remains controversial. A link between the two, first described in the European literature, has not been confirmed by other studies.30 Reports of improvement in chronic urticaria after eradication of H. pylori infection have added to the debate.31 Although H. pylori seropositivity is not higher in patients with chronic urticaria than in other patients, eradication of the infection where it coexists appears worthwhile. Patients presenting with a history of reflux and urticaria may be considered for investigation for H. pylori and appropriate treatment if found.

A link between chronic urticaria and thyroid autoimmunity has been known of for more than 20 years.32 Kikuchi et al33 reported that patients with chronic urticaria had an increased prevalence of IgG antithyroid antibodies (usually antithyroid peroxidase) compared with controls (10%–13% v 3%–5%). They demonstrated that antithyroid antibodies are definitely associated with the presence of antibodies to the IgE receptor, and concluded that antithyroid antibodies and antibodies to the IgE receptor are associated immune abnormalities, rather than one being the cause of the other.

The use of thyroxine to treat patients with chronic urticaria and thyroid autoimmunity in the absence of thyroid disease remains controversial. Some investigators have reported improvement in chronic urticaria symptoms with thryoxine treatment.34 In a recent study that included both euthyroid and hypothyroid women, 16 of 20 women with chronic urticaria who were given thyroxine to suppress thyroid-stimulating hormone showed improvement in chronic urticarial symptoms after 12 weeks.35

In the past decade, 35%–45% of patients with chronic urticaria have been found to have an autoimmune basis for their condition. An IgG antibody directed to the alpha subunit of the IgE receptor has been demonstrated in 35% of patients, and a functional anti-IgE antibody has been found in a further 5%–10%.36 Measurement of these antibodies is confined to research laboratories. However, an intradermal skin test with autologous sera can induce a delayed weal with a macroscopic and microscopic appearance similar to that seen in chronic urticaria. The stimulus for this autoantibody production is unknown.

The notion that chronic urticaria may be an autoimmune disease opens up the possibility of using immunomodulatory treatment when antihistamines have failed to control the condition. There is one controlled trial demonstrating a positive effect from the use of hydroxychloroquine.37 Cyclosporin A has been shown to be an effective treatment, but its use should be restricted and requires careful monitoring because of its potential to cause renal and other side effects.38 Plasmapheresis or administration of intravenous gammaglobulin or low-dose tacrolimus have also been tried, with some benefit, in small numbers of patients with autoimmune chronic urticaria.