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New therapies and future therapeutic directions.

Authors: PB Van Cauwenberge, MD, PhD
JSJ Vermeiren, MD
J-B Watelet, MD

Allergic rhinitis is clinically defined as a symptomatic disorder of the nose induced by an IgE-mediated inflammation after allergen exposure of the membranes lining the nose.

The disease is clinically characterised by nasal itching, sneezing, watery rhinorrhoea and nasal obstruction. Additional symptoms may include headache, impaired smell and conjunctival symptoms. Furthermore, diseases such as asthma, otitis media, sinusitis, nasal polyposis and lower respiratory tract infections are well-known co-morbidities.

Previously, allergic rhinitis was subdivided, based on the time of exposure, into seasonal and perennial allergic rhinitis. Perennial allergic rhinitis is most frequently caused by indoor allergens such as house dust mites, moulds, insects (cockroaches) and animal dander. Seasonal allergic rhinitis is related to a wide variety of outdoor allergens such as pollens or moulds. Recently, however, a new classification was developed in which allergic rhinitis is subdivided into intermittent and persistent disease. The severity of allergic rhinitis can be classified as "mild" or "moderate-severe".

Allergic rhinitis is recognised as a high prevalence disease in many developed countries, affecting about 10-20% of the general population. Moreover, several studies, based on questionnaire and objective testing or medical examinations, indicate an increasing prevalence in European countries over the last decades.

Whereas allergic rhinitis was once considered not to be an important medical condition, it is now recognised to substantially affect quality of life and to impair both physical and cognitive functioning in adults.

In view of the social and medical impact of this disorder, appropriate treatment of nasal allergy is important to both general practitioners and specialists. Treatment of allergic rhinitis can be preventive, medical or surgical. Pharmacological perspectives are changing rapidly and merit attention.

The European Academy of Allergology and Clinical Immunology guidelines on the Treatment of Allergic Rhinitis1 follow a stepwise approach in the treatment of perennial and seasonal allergic rhinitis. They were designed to achieve optimal symptom control with the currently available treatments. Although most allergic patients can be helped successfully, lack of efficacy in some has resulted in the development of new therapies and new therapeutic directions.

Currently, three new ranges of products are available.
1. Antihistamines are the most commonly prescribed therapeutic agents in allergic rhinitis. Acting as antagonists of the H1-receptor, they tend to reduce nasal itching, sneezing and rhinorrhoea. They are however less effective against nasal obstruction.

The use of first-generation antihistamines was considerably reduced by their sedative and anticholinergic characteristics. In addition, their short half-lives discouraged the use of these antihistamines in the treatment of allergic rhinitis. Second generation antihistamines are at least equally as effective as first generation antihistamines. Since they are characterised by a larger and more lypophobic molecule, the blood-brain barrier is not easily crossed. These distinguishing characteristics result in little or no somnolence, no effect on performance, and no anticholinergic effects. On the other hand, select second-generation antihistamines are known to cause torsades de pointes in combination with certain drugs that are metabolised by the cytochrome P-450 system in the liver.

Third-generation antihistamines are metabolites of second-generation antihistamines and appear to have important advantages, including the absence of cardiac conduction disturbances. Some of these products have been approved for use, others are currently in phase III or IV clinical trials. All of these agents are expected to be at least equally effective, with excellent safety profiles compared to their parent compounds.

2. Anti-IgE therapy (XolairÒ) is based on a monoclonal antibody against the Ce3 domain of IgE molecules. It reduces free IgE in serum by 99% and suppresses all IgE mediated allergic reactions, which may manifest at many different organs, regardless of the specificity of the allergen. It has been shown to be effective in the treatment of allergic rhinitis. An improved disease-specific quality of life was reported by patients, with significant reduction in nasal and ocular symptoms during the pollen season. Clinical trials did not reveal any significant side effects, making anti-IgE therapy a safe and effective alternative to both pharmacotherapy and immunotherapy.

3. Antileukotrienes represent a new class of medication that is able to modulate inflammation. Studies with antileukotrienes in patients with allergic rhinitis demonstrate rapid onset of symptom relief which is similar to that of oral antihistamines. In addition, a combination of antileukotrienes and antihistamines provides a superior symptom control to that achieved by either of the drugs alone.

Despite these promising treatment modalities, scientists continue to work actively on more selective inhibition of the allergic inflammatory reaction. Currently, there is a range of novel approaches for the modification of the allergic inflammation, which are at different stages of development.
IL-4 and IL-5 are key regulators of allergic sensitisation and inflammation.
1. The soluble receptor for IL-4 appeared in early phase studies to be safe and effective in patients with allergic asthma.
2. Since IL-5 receptor antagonists and anti-IL-5 monoclonal antibodies are in development for asthma, it is envisaged that if they prove effective in the treatment of asthmatic patients, they also will play a role in allergic rhinitis. The potential use of these therapies would, however, have to be compared with H1-antihistamines and intranasal glucocorticosteroids, the two main pharmacologic therapies for allergic rhinitis.

Reference:

Consensus Statement on the Treatment of Allergic Rhinitis, European Academy of Allergology and Clinical Immunology; Van Cauwenberge et al; Allergy 2000: 55: 116-134.

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