Allergic Rhinitis and Asthma : From the Link to Emerging Therapies

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1 REVIEW ARTICLE Allergic Rhinitis and Asthma : From the Link to Emerging Therapies Department of Otolaryngology, Nippon Medical School, Tokyo, Japan ABSTRACT Epidemiological evidences and clinical as well as experimental observations have suggested a link between rhinitis and asthma. This relationship between rhinitis (and sinusitis) and asthma also involve other aspects, such as viral infections and bronchial hyperreactivity. These have been further confirmed by functional and immunological evidences, challenge studies of the nose and the bronchii, and, indirectly, by observing the therapeutic effects of drugs used mainly for rhinitis on the symptoms of asthama. Therefore, the present article is a review of the most relevant experimental results, so far provided, supporting the One Airway One Disease concept, the possible mechanisms involved in this link and emerging therapeutic strategies like leukotriene receptor antagonists. Key words : Allergic rhinitis (AR), Asthma, Leukotriene receptor antagonists. [Indian J Chest Dis Allied Sci 2003; 45 : ] INTRODUCTION The general pathogenic view of respiratory allergy has deeply changed and evolved during the last ten years. The strict link between rhinitis and asthma has been envisaged through clinical observations and epidemiological studies, but subsequently also through immunological observations and therapeutic outcomes. Furthermore, an increasing number of evidences have accumulated about : (a) the frequent coexistence of rhinitis and asthma, (b) the possible role of upper respiratory infections in asthma exacerbations, (c) the presence of rhinitis as a risk factor for developing asthma, and (d) the importance of paranasal sinuses infections (sinusitis). Most importantly is the fact that all these aspects are particularly evident in children. These observations taken together lead to the definition of Allergic Rhinobronchitis 1 or, United Airways Disease (UAD) 2. The updated knowledge of the intricate mechanisms involved in allergic inflammation of the respiratory tract (i.e. antigen presentation, cytokines, chemokines and adhesion molecules) allow us to clarify atleast in part the functional relationships between the nose and bronchi. Thus, airway allergy is not a disease confined to a specific target organ, but rather a disorder of the whole respiratory tract. [Received : March 27, 2003; accepted : May 27, 2003] Correspondence and reprints request : Prof., Department of Otolaryngology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-Ku, Tokyo , Japan; Telefax : ; <Pawankar_Ruby/ ent@nms. ac.jp>.

2 180 Allergic Rhinitis and Asthma EPIDEMIOLOGICAL LINK Most epidemiological studies were performed by specific questionnaires aimed at assessing a clinical diagnosis while some studies diagnosed atopy based on sensitization like skin test, or serum IgE whereas in other studies no distinction was made between allergic or nonallergic type of rhinitis and asthma. Despite these limitations, the data are rather consistent. As early as in the 1960 s assessment on the effectiveness of specific immunotherapy 3, showed that there was an association between allergic rhinitis and asthma : in that about 50% of the control cohort (no immunotherapy) of children with allergic rhinitis developed asthma within a few years. Further studies have confirmed this in more recent years 4-9. Although cross-sectional studies are important to assess the coexistence of rhinitis and asthma it is even more important to have longitudinal studies in order to elucidate the natural history. It has also been shown that allergic rhinitis usually precedes the onset of asthma, when patients are followed-up for a time period long enough. In a 23-year survey 6, about 2/3 of subjects with allergic rhinitis appeared more likely to develop asthma with respect to controls. The same was seen in other large longitudinal studies 10,11. In a recent survey 12, 99 patients were followed up for 10 years after the initial diagnosis of allergic rhinitis, allergic asthma or both and 32% of rhinitic patients developed asthma and 50% of patients with asthma alone also developed rhinitis. Moreover, in another study, the association with allergic rhinitis was present in more than 70% of asthmatics 13. Also, a relevant proportion of patients with rhinitis alone had nonspecific bronchial hyperresponsiveness, a characteristic feature of asthma 14. Moreover, a support to the hypothesis that rhinitis and asthma are two aspects of a unique disease comes from the study from by Kapsali et al 15. When rigorous diagnostic criteria are used, the presence of concomitant rhinitis can be demonstrated in about 90% of allergic asthmatic patients. By contrast, the analysis of a subpopulation of nonatopic subjects from the European Community Respiratory Health Survey (ECRHS), showed that perennial rhinitis is an independent risk factor for asthma even in absence of any marker of atopic status 16. Again, the coexistence of sinusitis and asthma, especially in children, is well known since at least twenty yeras 17, and the frequent involvement of paranasal sinuses (rhinosinusitis) is presently considered very relevant for the development of the disease of lower respiratory airways in allergic patients 18,19. In an endoscopical assessment in children, sinusitis and/or adenoiditis occurred in more than 50% of asthmatic subjects 20. FUNCTIONAL LINK The respiratory tract can be considered as a single morpho-functional. It is entirely covered, until the smaller bronchi, by ciliated epithelium and mucinous glands and an extensive vasculature and innervation (similar innervation in the upper and lower airways) 21. The respiratory mucosa is rich in mast cells which are important effector and immunoregulatory and these cells are thought to significantly contribute to nose-bronchi connection via cytokine release 22,23. Moreover, the lymphoid tissue constitutes the bronchial-(mucosal) associated lymphoid tissue (BALT or MALT), which is largely represented in both the nose and bronchi. Although these similarities exist between the nose and the lung, cardinal differences also exist in that nose and paranasal sinuses are rigid cavities where erectile sinusoid vessels predominate, whereas the lower airways have an elastic parenchyma, rich in peribronchial smooth muscles 24,25. This anatomical diversity account for the differential clinical features or symptoms to the same offending allergen such as sneezing, rhinorrhea/blockage in the nose and bronchoconstriction in the lung. Similarly, a marked degree of epithelial shedding can be seen in asthma whereas in rhinitis epithelial integrity is more or less maintained. The upper respiratory tract acts as a filter, resonator, heat exchanger and humidifier for the

3 2003; Vol. 45 The Indian Journal of Chest Diseases & Allied Sciences 181 inhaled air. The inhaled air is processed and enters into the bronchi with a temperature of about 37 degrees C and almost completely saturated in humidity. Moreover, the foreign particles greater than 5-6 µ are efficiently removed and therefore filtered off from entering the lower airways 26. Thus, failure of any of these functions may result in an alteration of the homeostasis of the lower respiratory airways 27. In fact, oral hyperventilation with cold air in asthmatic decrease the forced expiratory volume, but also increases the nasal resistance 28. COMMON INFLAMMATORY PATHWAYS In an allergic reaction (i.e. allergen-ige-mast cell), the so-called early phase occurs within minutes 29. This early phase reaction involves: the release of histamine, vasodilatation, increased permeability, bronchoconstriction. This is followed by an inflammatory type of reaction called the late phase allergic reaction in which T lymphocytes, eosinophils, cytokines chemokines and adhesion molecules play a part. While the chemokines and cytokines act to induce the recruitment of cells into the target organ, the adhesion molecules are also crucial for the recruitment of these inflammatory cells by inducing the rolling over, extravasation and migration of cells from the blood vessels into the target organ 30. These mechanisms have been seen in both rhinitis and asthma (Figure 1). PATHOPHYSIOLOGICAL ASPECTS Studies have shown that even in the absence of clinical symptoms of asthma patients with seasonal allergic rhinitis have an increase in the inflammatory cells in-season in their bronchial biopsies (Figure 2). Similarly patients with asthma but without symptoms of rhinitis have increased number of eosinophils in their nasal biopsies and secretions. While the former would be explained more easily through the release of inflammatory mediators from the nose to the lung, the latter would suggest a systemic connection via soluble mediators to the bone marrow 35. In fact studies have shown that the bone marrow responds to nasal challenge by increasing the maturation and production of IL- 5R+eosinophilic precursors Chakir J et al, J Allergy Clin Immunol 2000; 106 (5) : Taken from ARIA WHO Initiative, J Allergy Clin Immunol 2000; 108 (5) : Figure 2. Bronchial biopsies in patients with SAR. Figure 1. Inflammatory cascade : Dual response in rhinitis and asthma. Furthermore, it is important to mention the frequent association of the nonspecific bronchial hyperresponsiveness (NBHR) with rhinitis 14,38,39. A possible, mechanism of the nonspecific reactivity is the so-called neurogenic inflammation, in which neuropeptides (substance P, neurokinin A) are involved. In fact, the regulation of capacitance vessels (and therefore the plasma extravasation and oedema) is mainly due to sensory-neural apparatus 40,41.

4 182 Allergic Rhinitis and Asthma While most clinical and epidemiological observations suggest that the natural progression of the disease from the upper respiratory airways towards the lower ones 42, it has recently been demonstrated that segmental bronchial challenge is able to induce nasal symptoms as well as nasal inflammation in patients with allergic rhinitis 43. This latter aspect is difficult to interpret as there is no clinical situation in humans where a primary bronchial disease can result in a nasal disorder, but a systemic connection via the bone marrow may be a possible mechanism. THERAPEUTIC OUTCOMES : CAN TREATMENT OF RHINITIS IMPROVE SYMPTOMS OF ASTHMA? The strict link existing between rhinitis and asthma can also be envisaged on the basis of therapeutic outcomes. It is well known that β2 agonists are highly effective in asthma but have no effect in rhinitis; conversely, antihistamines treat rhinitis but are not the treatment for asthma. Nevertheless, the effect on asthma symptoms by treating rhinitis or sinusitis has been documented 44. Intranasal beclomethasone 326 µg/day 45 and fluticasone propionate 200 µg/day 46 were able to significantly reduce bronchial hyperresponsiveness to methacholine in asthmatic patients. Moreover 47, intranasal beclomethasone (200 µg twice a day) improved asthma symptoms and significantly reduced the methacholine induced bronchial hyperresponsiveness 47. Again, although antihistamines are not a treatment for asthma, they may have indirect beneficial effects on asthma symptoms, in those patients who have both rhinitis and asthma. In a placebo-controlled study of 186 patients with seasonal allergic rhinitis and seasonal asthma, cetirizine 10 mg was able to reduce significantly asthma symptoms during pollen season 48. In another study, the administration of loratadine 5 mg+ pseudoephedrine 120 mg twice a day could significantly improve asthma symtoms, peak expiratory flow and reduce albuterol intake in patients with seasonal allergic rhinitis and mild asthma 49. Such a synergistic effect between different drugs has been also demonstrated, for instance, with antihistamines in association with antileukotrienes 50,51. The link existing between upper respiratory disease and asthma was further demonstrated in children 52,53, where the occurrence of upper respiratory infections and asthma exacerbations could be controlled by a continuous antihistamine treatment. In a large study, the ETAC study, where a continuous antihistamine treatment with cetirizine was given to children, a marked reduction in the development of asthma was demonstrated 54. Finally, when sinusitis coexists with asthma, a proper treatment (either pharmacological or surgical) of diseased paranasal sinuses can significantly improve asthma symptoms, as demonstrated in several studies POTENTIAL MECHANISMS ON THE LINK A number of theories have been offered over the years as to the mechanism for the link between allergic rhinitis and asthma. The presence of the nasobronchial reflex was proposed over 200 years ago 58 and well studied in animals, but its real role in humans still remains controversial. A possible, and recently highlighted, mechanism of the nonspecific reactivity is the so-called neurogenic inflammation, in which neuropeptides (substance P, neurokinin A) are involved. In fact, the regulation of capacitance vessels (and therefore the plasma extravasation and oedema) is mainly due to sensory-neural apparatus 29,30. The role of mouth breathing/nasal obstruction has also been considered as a cause for this link. Aspirations of nasal secretions was once considered another possible mechanisms, but this does not occur in the conscious human. The proposal of shared inflammatory pathways with systemic reactions to allergens provides the most compelling link between the upper lower airways.

5 2003; Vol. 45 The Indian Journal of Chest Diseases & Allied Sciences 183 EMERGING THERAPEUTIC STRATEGIES FOR RHINITIS AND ASTHMA LTRAs as emerging therapy in allergic rhinitis LTRAs can be considered an established treatment option for asthma, with published clinical evidence for their efficacy and tolerability in this indication dating back to the early 1990s. More recently, evidence has also started to accumulate in support of their utility in the treatment of AR. Data are available for a number of the LTRAs (e.g. zafirlukast, pranlukast), but montelukast is the most studied LTRA in this respect. A multicenter, double-blind trial involving 450 men and 852 women with spring seasonal allergic rhinitis randomized to once-daily montelukast (10 mg), loratadine (10 mg) or placebo for 2 weeks 59 showed that the change from baseline in daytime nasal symptoms score was significantly (p<0.001) greater with montelukast and loratadine than with placebo, but that nighttime symptoms were better controlled with montelukast. Peripheral blood eosinophil counts were significantly (p 0.001) decreased with montelukast but not with loratadine or placebo (Table 1) as also seen in adult and pediatric asthma Table 1. LTRAs-montelukast in allergic rhinitis As monotherapyfor allergic rhinitis, montelukast : Reduced daytime symptoms of allergic rhinitis Reduced nighttime symptoms of allergic rhinitis Reduced peripheralblood eosinophils Montelukast in combination with loratadine : Provided an additiveeffect on symptoms of allergic rhinitis Improved quality of life Montelukast in combination with cetirizine reduced total nasal symptoms to a similar extent as intranasal mometasone LTRAS IN COMBINATION WITH ANTIHISTAMINES The combination of an antihistamine and an LTRA in the treatment of allergic rhinitis is based on the importance of both histamine and cyslts as mediators. In a 2-week study of 460 men and women with spring seasonal AR randomized to one of five once-daily treatments: montelukast 10 mg; montelukast 20 mg; loratadine 10 mg; montelukast 10 mg plus loratadine 10 mg; or placebo, concomitant montelukast and loratadine improved the primary endpoint significantly (p<0.001) compared with placebo and each agent alone 51. Topically administered intranasal steroids are widely recognized to be effective for the treatment of AR. A study by Wilson et al 63 compared the effects of 2 weeks of therapy with either 200 µg intranasal mometasone or 10 mg montelukast plus 10 mg certirizine, both oncedaily. Both mometasone and the combination of montelukast plus cetirizine produced significant (p<0.05) improvements versus placebo in nasal peak expiratory flow rate, nasal oral index, nasal symptoms, nasal itch and blockage, eye symptoms and daily activity score. Importantly, there were no significant differences between mometasone and montelukast plus cetirizine, both treatment regimens producing an approximate 50% reduction in nasal symptom scores (Table 2). The investigators concluded that oral montelukast plus cetirizine and intranasal mometasone provided equivalent objective and subjective clinical efficacy. Table 2. LTRAs- montelukast in asthma In patients with mild persistent asthma, montelukast : Increased lung function (FEV 1 ) Reduced beta agonist use and nocturnal aw akenings In patients on inhaled cor ticosteroids, adding montelukast : Reduced the average daily dose of inhaled corticosteroids Maintained clinical stability with a lower dose of inhaled corticosteroids In pre-school aged children (2 to 5 years), montelukast : Improved a range of asthma symptoms Reduced the need for oral steroids Reduced inflammatory markers (peripheralblood eosinophils) In patients with exercise-induced asthma, montelukast maintained consistent reductions in EIB over the treatment period

6 184 Allergic Rhinitis and Asthma LTRAs IN ASTHMA Mild, persistent asthma Barnes et al, evaluated the results of completed clinical trials to determine the degree to which subsets of patients with mild, persistent asthma were responsive to treatment with montelukast 64. The analysis was conducted across seven double-blind, randomized, placebo-controlled studies of adult patients with mild to moderate persistent asthma. The four cohorts were : (A) forced expiratory volume (FEV 1 )>75% predicted, no limit on rescue β agonist use; (B) FEV 1 >75% predicted, rescue β agonist use less than daily; (C) FEV 1 >80% predicted, no limit on rescue β agonist use; and (D) FEV 1 >80% predicted, rescue β agonist use less than daily. Analysis of the pooled data for all patients with mild, persistent asthma demonstrated that the effects of montelukast were consistent across all cohorts of patients for all endpoints. Montelukast produced a greater effect than placebo, demonstrating increases in FEV 1, reductions in rescue β agonist use, decreased nocturnal awakenings, and more rescue-free dys and a significant reduction in blood eosinophil count compared with placebo. Tapering of inhaled corticosteroid therapy International guidelines recommended that doses of inhaled corticosteroids (ICS) are minimized wherever possible (Asthma Guidelines 1997). This concern may be more pronounced in patients with coexisting rhinitis who may also receive nasal steroids, thereby further increasing the steroid load. In a study of Price et al 65, patients with chronic asthma who were being treated with moderate to high doses of ICS were given montelukast (10 mg/day) for 48 weeks. Patients (n=581) who were clinically stable had their ICS dose reduced at 2-week intervls for the first 12 weeks, and every 6 weeks thereafter. After 12 weeks, the mean ICS dose had been reduced by 82%, and that 60% of patients had been able to completely taper off ICS. Similar effects have also been seen with the LTRA pranlukast 66. The tapering of ICS in the presence of LTRAs can be explained in that ICS do not decrease leukotriene levels in vivo 67,68, thus montelukast down-regulates the leukotriene-mediated inflammation to improve asthma control. Pediatric asthma Traditionally, ICS and cromolyn have been the controller treatments of choice for young children with persistent asthma. Knorr et al, reported the first, large multicenter study of an LTRA in children 2-5 years of age 69, in which they demonstrated that montelukast produced significant improvements versus placebo in multiple efficacy parameters (e.g. daytime/ nighttime asthma symptoms, the percentage of asthma-free days, use of β agonists or oral corticosteroids, physician global evaluations, and peripheral blood eosinophils. Exercise-induced asthma Long-and short-acting β agonists are typically used to control the symptoms of exerciseinduced asthma, but can be associated with the development of tolerance thereby decreasing efficacy. LTRAs do not exhibit any tachyphylaxis, and so may provide benefit in this respect. A study of 197 patients with mild asthma and a post-exercise fall in FEV 1 >18% comparing the effects of montelukast (10 mg once-daily) with salmeterol (50 µg twice daily) 70 showed that the protection afforded by montelukast and salmeterol were similar at day 3 but only the effects of montelukast persisted throughout the 8 weeks of treatment without the development of tolerance. FUTURE POTENTIAL THERAPIES FOR RHINITIS AND ASTHMA Due to the co-existence of asthma with rhinitis, treatment strategies targeting both diseases is a major concern when developing new therapies. However, their potential use should be considered in the light of existing treatment like H1-antihistamines/intra-nasal steroids. One such therapeutic approach now under evaluation is the humanised monoclonal antibody against IgE.

7 2003; Vol. 45 The Indian Journal of Chest Diseases & Allied Sciences 185 Humanised monoclonal antibodies against IgE : A monoclonal antibody raised against the Cε3 domain of IgE molecule is MaE11 and its humanized form used in clinical trials is the rhu- MAb-E25 (E25) 71. This region of the IgE molecule binds to the IgE receptor (FcεRI). Complexing free IgE with the MAb (MaE11) prior to its linking with FcεRI prevents its binding to the IgE receptor. Moreover, MaE11 only binds to free IgE and does not bind to receptor bound IgE, and is therefore nonanaphylactic. Since, FcεRI expression on mast cells/basophils is regulated by IgE and upregulated in allergic patients 23, 72, treatment with the anti-ige MAb not only decreases free IgE levels to 1% of pretreatment levels but also down-regulates FcεRI expression 73. A study using E25 MAb in ragweed pollen induced rhinitis showed only a small effect probably because the dose infused was insufficient 74 and only patients with a dose of 300 mg/4 weeks E25 had a reduction of H1-antihistamine use of over 60% greater than placebo whilst symptoms were reduced by over 20%. E25 was administered to over 300 patients for periods up to one year and no serious adverse event was reported. Other future potential therapies include monoclonal antibodies against IL-5, IL-4R antagonists, chemokine receptor inhibitors, like the CCR3 receptor, ligand inhibitors such as VLA-4 antagonists, the CTLA4 fusion protein, recombinant allergens, peptide vaccines, the use of IL-12 as an adjuvant with specific immunotherapy, bacterial or mycobacterial products to stimulate Th1 response and the plasmid DNA encoding of antigen The common comorbidities and shared pathophysiologies of asthma and allergic rhinitis have led to the concept of one airway, one disease 84 and the need for a common therapeutic approach. To achieve optimal treatment for patients, it is the recommendation of the Allergic Rhinitis and its Impact on Asthma (ARIA) workshop group in collaboration with the World Health Organization (WHO) that patients with persistent AR should be evaluated for asthma, and that patients with asthma should be evaluated for rhinitis 85. A strategy combining the treatment of both uppre and lower airway disease in terms of efficacy and safety appears to be optimal (ARIA guidelines 2001). In many ways, LTRAs represent a rational approach to such one airway disease management (Figure 3) 86. LTRAs are an established treatment option for asthma, with evidence to support their use in mild, persistant disease, pediatric asthma, exercise-induced bronchoconstriction, and in the tapering of ICS (Figure 4). Evidence is also Figure 3. LTRAs in one airway one disease concept. NEED FOR INTEGRATED DISEASE MANAGEMENT FOR RHINITIS AND ASTHMA *p<0.01 montelukast vs. placebo Baseline daytime symptoms score values were 2.09 Montelukast, 2.10 Placebo. Adapted from Reiss TF et al. Arch Intern Med 1998; 158 : ; Malmstrom K et al. J Allergy Clin Immunol 2001; 107(2) : S157. Figure 4. Antileukotriene therapy improves endpoints in allergic rhinitis and asthma.

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