Allergies

Allergic Rhinitis
a report by

G i o r g i o W C a n o n i c a and E n r i c o C o m p a l a t i
Allergy and Respiratory Diseases Clinic, University of Genoa

Allergic rhinitis (AR) is an inflammatory disorder of the nose induced by allergen exposure of the mucous membranes lining the nose, characterised by rhinorrhoea, itching, sneezing and nasal obstruction. A high percentage (42%) of patients with AR, typically patients with seasonal pollinosis, have symptoms of allergic conjunctivitis. Nasal symptoms are often trivialised, but can lead to a significant reduction in quality of life for both patients and their family, with a negative impact on work productivity, school performance and social activities. Loss of productivity, doctors appointments and pharmacotherapy represent the relevant direct and indirect costs of AR to society.
Epidemiology

deviation theory). According to another theory (reduced immune suppression theory), lower exposition to infections should involve a reduced activity of regulatory T-cells. These models are still the subject of current research.
Classification
Giorgio W Canonica

In the last five decades, the prevalence of AR has increased from 6% to 18% worldwide. A genetic predisposition to atopy is currently a subject of ongoing research and many polymorphisms have been correlated to the disease; however, this matter still involves several controversies. Aeroallergens are the most frequently involved allergens in AR. Indoor allergens are derived from house dust mites, cats and dogs, cockroaches and moulds, while outdoor allergens include pollens from trees, grasses and weeds, moulds and fungal spores. Symptoms can be aggravated by the inhalation of urban pollutants. Diesel exhaust has been demonstrated as an enhancer of immunoglobulin (Ig)E production and of allergic inflammation. Research conducted over the last 20 years has considered changes in lifestyle as the most probable factors for providing an explanation for the vertiginous rise of the prevalence of atopic diseases. The principal hypothesis, the hygiene hypothesis, is based on the effect of a lower microbial exposition during infancy and is linked to a westernised lifestyle as a promoting factor for the development of allergic diseases. However, the immunological changes following this phenomena are not clear. A reduced shift to the T-helper (Th)1 subset is probably related to lower production of natural immunity cytokines stimulated by bacterial products via the Toll-like receptor system (immune

Traditionally, the AR has been classified into three subgroups seasonal, perennial and occupational. Recently, the World Health Organization (WHO) Allergic Rhinitis and its Impact on Asthma (ARIA) working group has revised the classification, considering intermittent to be a disease lasting less than one month or four days a week and persistent as a disease of longer than one month or more than four days a week. The new classification takes into consideration the severity of the disease and its impact on the patients quality of life; therefore, a mild disease classification is characterised by few troublesome symptoms, not interfering with daily activities and/or sleep and a moderate to severe disease classification is characterised by troublesome symptoms that interfere with daily activities and/or sleep.
Co-morbidities

Enrico Compalati

The most common co-morbid conditions of AR are represented by asthma and eczema. Forty per cent to 50% of patients with AR suffer from asthma and more then 90% of asthmatics also have rhinitis. Chronic nasal congestion may result in rhinosinusitis and the obstruction of sinus ostia due to infections predisposed by negative pressure and mucous stagnation. This condition presents with nasal congestion, post-nasal drip, hyposmia, cough and sometimes facial pain or headache. The same mechanism leads to tubaric involvement and the development of otitis media. Nasal polyposis may result from the chronic inflammation of nasal mucosa. Polyps frequently prolapse from sinusal mucosae down to the middle meatus, inducing nasal blockage, hyposmia, facial pain and encouraging the rise of rhinosinusitis.

Giorgio W Canonica is Chairman of the Allergy and Respiratory Diseases Clinic and Director of the Specialty School of Pulmonary Diseases at the University of Genoa. Professor Canonica is President-elect of the World Allergy Organization (WAO), Vice-President of International Association of Asthmology (Interasma) and President of the Italian Society of Respiratory Medicine (SIMeR). He trained at the University of Nancy INSERM, the University of Uppsala and the Medical University of South Carolina. Enrico Compalati is undertaking a research doctorate in allergy and respiratory physiopathology at the University of Genoa. Dr Compalati is co-author of more than 10 full papers in international journals and is a member of the European Academy of Allergy and Clinical Immunology (EAACI) and of the Italian Society of Allergy and Clinical Immunology (SIAIC). Dr Compalati graduated in 2001 from the Genoa University Medical School and achieved a speciality degree in allergy and clinical immunology in 2005.

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Allergies

Immunopathology

The importance of recognising the underlying immunopathology of allergic disease is related to directing treatment more precisely to the complex inflammatory reaction. Allergens penetrating the epithelial layer of the respiratory tract are processed by antigen-presenting cells and are introduced to the histocompatibility complex molecules, resulting in the development of specific T-cell clones (sensitisation). The B-cell immunoglobulin class switch, as well as the promotion of IgE synthesis by plasmacells, is regulated by interleukins 4 and 13 and by the interaction of membrane-based molecules. Any further contact with allergens leads to fast-response IgE-mediation characterised by mast cells and basophil degranulation with the release of preformed and newly synthesised mediators, which are able to provoke the typical symptoms within minutes.

with over-expression of the intercellular adhesion molecule (ICAM)-1, which represents the principal receptor for rhinoviruses.
Diagnosis

The diagnosis of AR is based on detailed personal and family history, clinical history of typical symptoms, physical examination (nasal examination/ anterior rhinoscopy) and skin prick test or the measurement of allergen-specific IgE antibodies. Additional diagnostic tests include: fibreoptic rhinoscopy; cytology of nasal secretions; nasal challenge with allergen rhinomanometry; conventional radiography (RX); and CT scan.

and

The importance of recognising the underlying immunopathology of allergic disease is related to directing treatment more precisely to the complex inflammatory reaction.
Histamines are the major mediator of the earlyphase reaction; they stimulate sensory nerves, causing sneezing and itching and are also responsible for vasodilation, plasma exudation and the stimulation of mucosal cells leading to rhinorrhoea and nasal obstruction. Histamines sustain inflammation through the upregulation of adhesion molecules and the release of proinflammatory cytokines. A late-phase reaction occurs a few hours after allergen exposure and is associated with cellular eosinophilic inflammation of the nasal mucosa and expression of endothelial and epithelial adhesion molecules, chemokines and cytokines. The release of mediators from infiltrating leucocytes, as well as resident tissue cells, such as mast cells, is implicated in the symptoms and development of nasal unspecific hyper-reactivity. Leukotrienes, released by mast cells, eosinophils, basophils, macrophages, neutrophils and epithelial cells play an important role in the late-phase allergic reaction by influencing nasal obstruction, mucus secretion and cellular recruitment. In persistent AR, the continuous low-dose allergen exposure induces a persistent nasal mucosa inflammation (minimal persistent inflammation) These diagnostic tests are the measurement of total IgE, but are poorly predictive. A differential diagnosis must be assumed with: non-AR infectious and drug-induced rhinitis, hormonal rhinitis, rhinitis from other causes (food, irritants, and emotion), gastro-oesophageal reflux and vasomotory and idiopathic rhinitis; polyposis; ciliary defects; cerebrospinal rhinorrhea; benign/malignant tumours; septum deviation; foreign bodies; blocked nostril (choanal atresia); and granulomatous diseases.
Treatment

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The avoidance of causal allergens represents the fundamental approach for preventing the rise of allergy symptoms. However, this target is difficult to achieve although a reduction in environmental allergens can result in a reduction of the severity of

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Allergies

the disease and can also reduce the requirement for pharmacotherapy. Therapeutic interventions consider the use of different tools on the basis of the severity of the disease with a stepwise approach. A summary of the management protocol and pharmacological treatments for AR can be found in ARIA guidelines. Many classes of drugs are currently available. Antihistamines are commonly used as a first-line treatment they are particularly effective at relieving symptoms, such as sneezing, itching and watery rhinorrhoea. First-generation antihistamines are no longer recommended as they show poor selectivity and their use is limited because of their sedative and anticholinergic effects. Second-generation antihistamines have a higher potency and longer duration of action compared with the first-generation drugs, with minimal or no side effects. The rapid onset of action and the duration of activity of up to 24 hours allow once-daily administrations. Several studies have shown that antihistamines have anti-inflammatory

cromoglycate and nedocromil have mast cellstabilising properties, although the precise mechanism of action is still unknown they are a prophylactic treatment less effective than antihistamines and with the disadvantage of frequent administration in order to achieve adequate results. The excellent safety profile allows its use in children and pregnancy. Topical anticholinergics, such as ipratropium bromide, only appear to improve nasal hypersecretion and should therefore be approved in patients in whom rhinorrhoea is the primary symptom or when it is not fully responsive to other therapies. The combination of this with a nasal corticosteroid has been shown to have a greater impact on rhinorrhoea than either the systemic application of ipratropium or the nasal steroid, respectively. Recently, a new class of drugs, initially used for the treatment of bronchial asthma, has been considered in the treatment of AR (antileukotrienes). Leukotrienes are important inflammatory mediators of the nasal allergic reaction and have been shown to induce nasal obstruction. The

Histamines sustain inflammation through the upregulation of adhesion molecules and the release of pro-inflammatory cytokines.

properties, conferring a therapeutic advantage in the management of the disease. Topical intranasal glucocorticosteroids have a strong anti-inflammatory action, reducing the release of inflammatory mediators and decreasing cellular infiltration within the nasal mucosa they are the first-line medication for moderate to severe persistent AR. Mild local side effects, such as nasal crusting, dryness and epistaxis, may occur, but current preparations can be used for long-term periods without atrophy of the mucosa. Short courses of oral corticosteroids are particularly effective in severely symptomatic patients and when nasal blockage compromises the effective penetration of topical corticosteroids the risk of adverse effects for systemic corticosteroids depends on the duration of therapy. Decongestant drugs inducing vasoconstriction by their action on -adrenergic receptors may be administered intranasally or orally for short-term treatment as effective tools in the treatment of nasal obstruction. Prolonged use of these drugs may lead to tachyphylaxis and rhinitis medicamentosa (RM), mucosal rebound swelling and septal perforation. Oral vasoconstrictors have a weaker effect with respect to topical decongestants, but they do not cause rebound vasodilatation. The two chromones disodium

use of anti-leukotrienes in AR is currently strongly recommended when asthma symptoms co-exist. Allergen-specific immunotherapy, performed under controlled conditions, plays a main role in the global preventive approach to allergic disease and may be of assistance for patients who do not wish to be treated with pharmacotherapy and for patients in whom this produces undesirable side effects. Immunotherapy interferes with the basic mechanism of allergy and alters the natural course of allergic diseases, which therefore offers a long-lasting and preventive effect. Subcutaneous specific immunotherapy (SIT) has been shown to be a causal treatment with long-term efficacy for allergic rhinoconjunctivitis and asthma and a preventive measure against the development of asthma and new sensitisations. Sublingual immunotherapy (SLIT) is now officially accepted as a viable alternative to the traditional subcutaneous route, and is particularly widely used in European countries. Recent data confirmed SLIT safety in very young children and its efficacy in preventing asthma onset in paediatric rhinitis patients. Recent data confirm the clinical value of this treatment and show that it is comparable with subcutaneous immunotherapy from several points of view. Specific immunotherapy should

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Allergic Rhinitis
not be considered an ultimate treatment but an additional tool to pharmacotherapy. Future approaches are related to novel therapeutic interventions against events characterising the inflammatory and remodelling responses that may occur in the nose. Further research into the pathogenesis of AR, with particular emphasis on the previously mentioned areas raised, is therefore needed.

Further Reading 1. Consensus Statement on the Treatment of Allergic Rhinitis, European Academy of Allergology and Clinical Immunology (EAACI), Van Cauwenberge P, Bachert C, Bousquet J et al., Allergy (2000);55: pp, 116134. 2. Kaplan A, Van Cauwenberge P and GLORIA advisory board, Global Resources in Allergy (GLORIA): Allergic rhinitis and allergic conjunctivitis (World Allergy Organization), WAO (2001). 3. Bousquet J, Van Cauwenberge P, Khaltaev N, Allergic rhinitis and its impact on asthma (ARIA), J. Allergy Clin. Immunol. (2001);108 (suppl. 5):S147334. 4. Bousquet J, Cauwenberge P V, Requirements for medications commonly used in the treatment of allergic rhinitis, Allergy (March 2003);58(3): pp. 192197. 5. Canonica G W, Compalati E, Fumagalli F, Passalacqua G, Sublingual and oral immunotherapy, Immunol. Allergy Clin. North Am. (November 2004);24(4): pp. 685704. 6. Passalacqua G, Pasquali M, Guerra L, Lombardi C, Canonica G W, Efficacy and safety of sublingual immunotherapy, Ann. Allergy Asthma Immunol. (July 2004);93(1): pp. 312. 7. Custovic A, Wijk R G, The effectiveness of measures to change the indoor environment in the treatment of allergic rhinitis and asthma: ARIA update (in collaboration with GA(2)LEN), Allergy (September 2005);60(9): pp. 1,1121,115. 8. Bousquet J, Annesi-Maesano I, Carat F, Characteristics of intermittent and persistent allergic rhinitis: DREAMS study group, Clin. Exp. Allergy. (June 2005);35(6): pp. 728732. 9. Milanese M, Ricca V, Canonica G W, Ciprandi G, Eosinophils, specific hyper-reactivity and occurrence of late phase reaction in allergic rhinitis, Allerg. Immunol. (Paris) (January 2005);37(1): pp. 710. 10. Ciprandi G, Cirillo I, Vizzaccaro A et al., Seasonal and perennial allergic rhinitis: is this classification adherent to real life?, Allergy (July 2005);60(7): pp. 882887. 11. Bachert C, Bousquet J, Canonica G W et al., XPERT Study Group, Levocetirizine improves quality of life and reduces costs in long-term management of persistent allergic rhinitis, J. Allergy Clin. Immunol. (October 2004);114(4): pp. 838844. 12. Canonica G W, Compalati E, Fumagalli F, Passalacqua G, Sublingual and oral immunotherapy, Immunol. Allergy Clin. North Am. (November 2004);24(4): pp. 685704. 13. Asher I, Baena-Cagnani C, Boner A, World Allergy Organization, World Allergy Organization guidelines for prevention of allergy and allergic asthma, Int. Arch. Allergy Immunol. (September 2004);135(1): pp. 8392. 14. Passalacqua G, Guerra L, Pasquali M, Lombardi C, Canonica G W, Efficacy and safety of sublingual immunotherapy, Ann. Allergy Asthma Immunol. (July 2004);93(1): pp. 312. 15. Bousquet J, Bindslev-Jensen C, Canonica G W, The ARIA/EAACI criteria for antihistamines: an assessment of the efficacy, safety and pharmacology of desloratadine, Allergy (2004);59(suppl. 77): pp. 416. 16. Passalacqua G, Ciprandi G, Pasquali M, Guerra L, Canonica G W, An update on the asthma-rhinitis link, Curr. Opin. Allergy Clin. Immunol. (June 2004);4(3): pp. 177183. 17. Passalacqua G, Guerra L, Compalati E, Sublingual immunotherapy, Rev. Al. Mex. (NovemberDecember 2003);50(6): pp. 220225. 18. Majani G, Baiardini I, Giardini A et al., Health-related quality of life assessment in young adults with seasonal allergic rhinitis, Allergy (April 2001);56(4): pp. 313317. 19. Baiardini I, Pasquali M, Giardini A, Majani G, Canonica G W, Quality of life in respiratory allergy, Allergy Asthma Proc. (MayJune 2001);22(3): pp. 177181. 20. Vissers J L, van Esch B C, Hofman G A, Allergen immunotherapy induces a suppressive memory response mediated by IL-10 in a mouse asthma model, J. Allergy Clin. Immunol. (June 2004);113(6): pp. 1,2041,210. 21. Virchow J C, Asthma, allergic rhinitis, sinusitis. Concept of the unified respiratory tracts, HNO (May 2005);53 suppl. 1:S1620. 22. Blaiss M S, Rhinitis-asthma connection: epidemiologic and pathophysiologic basis, Allergy Asthma Proc. (JanuaryFebruary 2005);26(1): pp. 3540. 23. Passalacqua G, Ciprandi G, Pasquali M, Guerra L, Canonica G W, An update on the asthma-rhinitis link, Curr. Opin. Allergy Clin. Immunol. (June 2004);4(3): pp. 177183. 24. Pawankar R, Allergic rhinitis and asthma: the link, the new ARIA classification and global approaches to treatment, Curr. Opin. Allergy Clin. Immunol. (February 2004);4(1): pp. 14. 25. Fiocchi A, Pajno G, La Grutta S et al., Safety of sublingual-swallow immunotherapy in children aged 3 to 7 years, Ann. Allergy Asthma Immunol. (September 2005);95(3): pp. 254258.
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