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The role of anti-IgE in managing difficult-to-treat or severe asthma

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Linda Pearce, MSc, RN, SCM, OHNc, N Pract Dip.

Respiratory Nurse Consultant, West Suffolk Hospital, Bury St Edmunds, Suffolk

Despite advances in understanding airway inflammation and the introduction of new treatments, asthma remains a considerable health-care problem in terms of its prevalence and associated morbidity and mortality. In the UK, there are approximately 3.4 million people with the condition, which is responsible for more than 1500 deaths and almost 90 000 hospital admissions each year (National Asthma Campaign, 2000).

Current mortality and hospital admission rates are disappointingly high, but are an improvement on those of the previous decade (Owen, 2001). Practice and respiratory care nurses, who play a major role in diagnosing, monitoring and treating people with asthma, have made a significant contribution to achieving these reductions. It is important to remember that, with the appropriate drug treatment, support and advice, most asthma symptoms are well-controlled and people with the condition are able to lead normal, active lives.

The outstanding need for a new approach to asthma treatment primarily relates to people with difficult-to-treat or severe asthma whose symptoms are not controlled. These are patients who, despite receiving the best available therapy, suffer exacerbations, a poor quality of life and are at increased risk of hospitalisation and death.

Overall, 14% of people with asthma receive treatment at steps 4 or 5 of the British Thoracic Society guidelines (BTS et al, 1997) (Table 1) and some of these patients are difficult to treat with existing therapies. Patients in this group account for more than half of the £700 million spent by the NHS each year on providing asthma care (Hoskins et al, 2000; Barnes, 1999; National Asthma Campaign, 2000).

The potential for side-effects associated with the high doses of steroids used to treat these patients is also of considerable concern. Some asthma experts have also speculated that chronic high-dose steroid use may result in long-term structural damage of the airways (Owen, 2001).

The answer to the problem of managing people with difficult-to-treat or severe asthma may lie with novel anti-immunoglobulin E (IgE) antibody treatments - treatments that are targeted at inhibiting the allergic response. IgE-induced allergy has an important part to play in the pathogenesis of asthma, and anti-IgE therapy may contribute to the management of people with difficult-to-treat or severe asthma in the future.

The role of allergy in asthma
Asthma is a chronic inflammatory lung disease associated with airflow obstruction, increased airway responsiveness to allergens or other stimuli, and, over time, structural changes (Janson-Bjerklie, 1993). Allergy is now recognised as the major factor in the chronic inflammatory process.

Originally, it was thought that there were two forms of asthma. Subjects who showed hypersensitivity to foreign substances were categorised as having allergic (extrinsic) asthma, and all others were said to have non-allergic (intrinsic) asthma (Burrows et al, 1989). After IgE was identified as the antibody responsible for the immediate type of immune response, a number of studies measured IgE levels in patients with what appeared to be atopic and non-atopic asthma. These studies showed that most people with asthma, irrespective of age, have raised IgE levels (Burrows et al, 1989; Holgate and Banik, 2000). Asthma is now regarded primarily as an allergic disorder, that is, a disease that predominantly manifests itself through IgE mechanisms (Global Initiative for Asthma, 1995).

The role of IgE in the allergic inflammatory process can be summarised in several steps (Busse and Lemanske, 2001; Patalano, 1999; Milgrom et al, 1999). In step one, allergen-specific IgE is produced in the body following exposure to an allergen. In step two, this allergen-specific IgE binds to high affinity receptors (Fc_RI) on inflammatory cells (mast cells) in the lining of the airways. In step three, subsequent exposure to the particular allergen causes cross-linking of cell-bound IgE, resulting in mast cells releasing histamine and other inflammatory mediators.

Step four comprises discrete acute and late-phase reactions. The acute-phase reaction, which occurs shortly after exposure to the allergen, includes bronchospasm, oedema and airflow obstruction. The late-phase reaction, airway inflammation, airflow obstruction and airway hyper-responsiveness, occurs between two and eight hours later.

Understanding the IgE-mediated inflammatory response has provided a possible explanation for the development of severe asthma. This occurs when repeated attacks or exacerbations result in structural changes that can have permanent effects on lung function (Holt et al, 1999). It is possible that the acute-phase reaction may provoke responses from the injured tissue, for example ‘repair’, which feedback to intensify the original inflammatory response. This intensified response, the late-phase reaction, can in turn cause further tissue damage.

The significant role played by IgE in the pathogenesis of asthma has led to the search for anti-IgE drugs to treat it. Clinical trials on omalizumab (Xolair) are now in their third phase.

Rationale for the current management
The BTS guidelines, which are summarised in the British National Formulary (BMA/RPSGB, 2001), are the basis for treatment of asthma. It should be noted that these are due to be reviewed and revised this year. The BTS guidelines rely on two distinct categories of drugs, beta2-agonists and corticosteroids, which should be used in a stepwise manner according to the severity of symptoms and the response to treatment (BTS et al, 1997). The rationale for the use of beta2-agonists and corticosteroids is based on their complementary modes of action and effect on different aspects of the disease process.

Beta2-agonists - These are primarily used for symptomatic relief, and provide broncho-dilation and broncho-protection (functional antagonism) (Ahrens et al, 1984). Broncho-dilation is associated with the ability of the beta2-agonist to relax the smooth muscle of the airway, reversing broncho-constriction. Broncho-protection relates to its ability to prevent smooth muscle constriction in response to broncho-constrictor stimuli, such as exercise or allergen. The latter effect of beta2-agonists may be due to a direct action on smooth muscle, or an indirect action arising from inhibition of mast cells (Nathan, 1998). Beta2-agonists do not suppress chronic airway inflammation or reduce airway hyper-responsiveness and should not, therefore, be prescribed as regular therapy for patients with mild-to-moderate asthma (BTS et al, 1997).

Inhaled short-acting beta2-agonists (ISABAs) are recommended for use ‘as required’; inhaled long-acting beta2-agonists (ILABAs) are taken in conjunction with anti-inflammatory agents as a regular treatment for long-term symptom control.

Corticosteroids - Used as a preventive therapy, corticosteroids improve airway calibre by inhibiting or reducing chronic inflammation, by inhibiting or reducing oedema and mucus secretion into the airway (Barnes, 1998). Inhaled corticosteroids (ICSs) are recommended as prophylactic treatment in people who use an ISABA more than once a day (Table 1). According to the National Heart and Lung Institute, regular ICS treatment improves symptom control and reduces the frequency of acute exacerbation (NHLI, 2001a). In addition, early use of ICSs may prevent the irreversible changes in lung function that occur in some people with asthma. Oral corticosteroids are used to supplement ICS therapy, in the event of an acute asthma attack, and for the regular treatment of difficult-to-treat or severe asthma.

Since the BTS guidelines were written, the NHLI has reviewed data on anti-inflammatory anti-leukotrienes and proposed a role for them in the stepwise management of asthma (NHLI, 2001a, 2001b).

Anti-leukotrienes include the leukotriene receptor antagonists zafirlukast (Accolate) and montelukast (Singulair). These agents counteract the effect of leukotrienes, the pro-inflammatory mediators that are released following mast cell degranulation. Leukotriene antagonists have an inhibitory effect on exercise- and allergen-induced bronchoconstriction, and have anti-inflammatory effects on eosinophils. Clinical trials have shown that they have anti-asthma effects, including improvement in lung function, symptoms and a reduction in exacerbations (NHLI, 2001b). However, direct comparisons of the leukotriene antagonists and ‘gold-standard’ inhaled corticosteroids with long-acting bronchodilators, show that they are less effective. The NHLI recommend them as a second-line therapy (NHLI, 2001a).

Developments in anti-IgE therapy
Early clinical trials in allergic asthma showed that anti-IgE treatment significantly reduced serum concentrations of IgE, and significantly attenuated both the early and late phase inflammatory response to allergen challenge (Fahy et al, 1997; Boulet et al, 1997). Results of a clinical trial of symptomatic patients who were experiencing moderate-to-severe allergic asthma, despite inhaled or oral corticosteroid therapy, showed that the addition of omalizumab significantly improved asthma control (Milgrom et al, 1999). Compared with the placebo, omalizumab (Xolair) therapy resulted in significantly greater improvements in symptoms, a greater reduction in the use of a beta2-agonist as additional medication, and significant improvements in quality of life (Table 2). Also, more patients were able to decrease or discontinue corticosteroid treatment. Later studies found that omalizumab reduced the number of exacerbations per patient by approximately 50% (Busse et al, 2001; Soler et al, 2000).

It is increasingly recognised that there is a need for new approaches to asthma. The development of omalizumab (Xolair) offers an additional option in the management of this patient group.



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