ALLERGIC RHINITIS AND ASTHMA :

ALLERGIC RHINITIS AND ASTHMA : from the Link to Emerging Therapies Allergic rhinitis and asthma are both chronic heterogeneous disorders, with an overlapping epidemiology of prevalence, health care costs and social costs in quality of life (QoL). 1 It has long been recognized that allergic rhinitis and asthma commonly co-exist, due to their similarities in anatomy, physiology and immunopathology. 2 Patients can present with symptoms of allergic rhinitis then later develop asthma or the opposite can be the presenting scenario. According to the latest guidelines on the treatment and control of allergic rhinitis: The allergic rhinitis and its impact on asthma (ARIA) workshop report; bronchial asthma and allergic rhinitis are distinct manifestations of a single airway and of the same disease. 3 Epidemiological Link Epidemiological evidences and clinical as well as experimental observations have suggested a link between allergic rhinitis and asthma. Asthma and rhinitis, are rightly called the 21 st century epidemic and modern age diseases. The World Health Organization (WHO) estimates there are 300 million asthmatics in the world, and 500 million people with the symptoms of rhinitis. 4 To better understand the possible links between asthma and allergic rhinitis; the WHO, through the ARIA program, examined the impact of allergic rhinitis on asthma: major chronic respiratory disease owing to its prevalence, impact on QoL, impact on school and work performance and productivity and economic burden. According to the ARIA study and previous observations, allergic and non-allergic rhinitis should be considered as risk factors for asthma, along with other known risk factors. 5 The connection between allergic rhinitis and asthma has been the subject of many epidemiological investigations that have shown an important overlap between both diseases. 1 The 1st International Study of Asthma and Allergies in Childhood (ISAAC) study revealed the presence of asthma in 25 35% subjects with rhinitis, and rhinitis symptoms in 75 90% of asthmatics. Burgess et al. found that childhood allergic rhinitis was associated with a 7-fold increased risk of asthma in pre-adolescence (HR 7.12, 95 % CI 3.97-12.75) and an over 4-fold increased risk of asthma in adolescence (HR 4.34, 95 % CI 2.23-8.46). 6 In the early studies, 40% of allergic rhinitis patients had asthma, and 30% to 80% of asthmatic patients reported allergic rhinitis. A study of medical newsletter I as a service to the medical profession I 19

Nose (sinu)-bronchial reflex Postnasal drip Physical filter impairment Adhesion molecules Cytokines Epithelial cells Bone marrow Infections Inflammation Simons et al. suggested that these had probably underestimated the relationship, because more recent, sensitive interview protocols found rhinitis in 98.9% of allergic subjects with asthma and in 78.4% of non-allergic subjects with asthma. Leynaert et al. reviewed several studies demonstrating the strong association between rhinitis and asthma, both in allergic and non-allergic subjects. 1 Studies of both adult and pediatric populations provide evidence for increased risk of asthma development in individuals with allergic rhinitis. 7 expressed in both upper and lower airways. 5 Allergic Rhinitis, Airway Hyper responsiveness and Asthma: It is important to mention the frequent association of the nonspecific bronchial hyperresponsiveness with rhinitis. 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 edema) is mainly due to sensory-neural apparatus. While most clinical and epidemiological observations suggest that the natural progression of the disease from the upper respiratory airways towards the lower ones, 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. 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. 4 Allergens Figure 4.1: Physiopathological hypotheses explaining the concept of one airway disease Bronchial hyperreactivity Pathological Link The clearest connection between allergic rhinitis and asthma is based on a shared physiological response; both are part of the body s immune response to an identified foreign substance. The following section describes similarities and dissimilarities between rhinitis and asthma pathologies. 1 Inflammatory Response: The inflammatory response is similar for both allergic rhinitis and asthma; as share a similar respiratory epithelial structure. In allergic rhinitis, the immediate reaction leads to nasal congestion and runny nose from an increase in vascular permeability. In asthma, the immediate reaction results in bronchospasm. But in late-phase reaction mainly triggered by CD4+ T cells, asthma and allergic rhinitis occur following allergic exposure. There is a common cellular inflammation pattern characterized by eosinophil, mast-cell, and CD4+ T-cell infiltration. Mediators (including histamine; cysteinyl leukotrienes; interleukin [IL]-4 etc.) are Need for Integrated Disease Management for The common co-morbidities and shared pathophysiologies of asthma and allergic rhinitis have led to the concept of one airway, one disease and the need for a common therapeutic approach. To achieve optimal treatment for patients, it is the recommendation of the ARIA workshop group in collaboration with the WHO that patients with persistent allergic rhinitis should be evaluated for asthma, and that also patients with asthma should be evaluated for rhinitis. A strategy combining the treatment of both upper and lower airway disease in terms of efficacy and safety appears to be optimal (ARIA guidelines 2008). In many ways, leukotriene receptor antagonists (LTRAs) represent a rational approach to such one airway disease management (Figure 4.3). Leukotriene receptor antagonists 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 inhaled corticosteroids (ICSs). Evidence is also accumulating in 20 I medical newsletter I as a service to the medical profession

% predicted FEV1 Mast cell mediator release 100 80 60 40 20 0 Antigen Neutrophil influx and mediator release Eosinophil influx and mediator release Histamine, prostaglandins, leukotricnes and thromboxanes 0 1 2 3 4 5 6 7 Time (hours) AR Asthma 5 4 3 2 1 Severity of symptoms 0 8 24 Figure 4.2 : Inflammatory cascade : Dual response in allergic rhinitis and asthma seasonal increase in nasal and lung symptoms. Controlled studies by Walsh and by Wilson show that the combination therapy with antihistamines and antileukotrienes is as effective as corticosteroid use in patients with allergic asthma and seasonal allergic rhinitis. The study by Roquet et al. gives evidence in favor of the use of antileukotrienes to treat asthma and rhinitis. However, more data are needed to understand their full capacity. The combination of antileukotriene and antihistamine produces an inhibition of allergen-induced early-and-late phase airway obstruction in asthmatics. 8 allergic rhinitis to suggest that both alone and in combination with an antihistamine, LTRAs like montelukast can alleviate the signs and symptoms of allergic rhinitis. 4 Emerging Therapeutic Strategies for Leukotriene receptor antagonists 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 allergic rhinitis. Data are available for a number of the LTRAs (e.g. zafirlukast, pranlukast) but montelukast is the most studied LTRA in this respect. 4 The study by Nathan et al. evaluated patient with persistent asthma treated with the combination of fluticasone propionate and salmeterol. Adding montelukast or fluticasone propionate aqueous nasal spray for the treatment of seasonal allergic rhinitis resulted in no additional improvements in overall asthma control compared with the combination therapy with fluticasone and salmeterol alone. The combined use of budesonide nasal steroid with a leukotriene modifier, zafirlukast, was more effective for controlling nasal symptoms and especially bronchial symptoms than combined use of a nasal budesonide with loratadine plus pseudoephedrine. Dahl et al. have shown that in patients with pollen-induced allergic rhinitis and asthma the combination of nasal and inhaled glucocorticosteroids is needed to control the 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 cysteinyl leukotrienes as mediators. In a 2-week study of 460 men and women with spring seasonal allergic rhinitis were 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. Topically administered intranasal steroids are widely recognized to be effective for the treatment of allergic rhinitis. A study by Wilson et al. compared the effects of 2 weeks of therapy with either 200 mg intranasal mometasone or 10 mg montelukast plus 10 mg certirizine, both once daily. 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 4.1). The investigators concluded that oral montelukast plus cetirizine and intranasal mometasone provided equivalent objective and subjective clinical efficacy. 4 medical newsletter I as a service to the medical profession I 21

Rhinitis LTRAs HIs NCSs ICSs L.A. 2s specific immunotherapy allergen avoidance-education Figure 4.3: LTRAs in one airway one disease concept Mild, persistent asthma: LTRAS in Asthma Barnes et al. analyzed the use of montelukast in patients with mild, persistent asthma and found that it improved control of asthma parameters (eg, FEV 1 improved 7% to 8% over baseline). In some patients with stable asthma treated with inhaled corticosteroids, montelukast provides additional control of inflammation and improves QoL scores. Overall, this LTRA was demonstrated to be an effective and well-tolerated treatment. With the effectiveness of LTRAs in treating asthma, Meltzer reviewed the studies on the efficacy of zafirlukast and montelukast in asthma, and explored the use of LTRAs in allergic rhynitis. This study found that the montelukast was an effective treatment for allergic rhinitis. Montelukast produced a greater effect than placebo, demonstrating increases in FEV 1, reductions in rescue agonist use, decreased nocturnal awakenings, and more rescue-free days and a significant reduction in blood eosinophil count compared with placebo. 4 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, 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 agonists or oral corticosteroids, physician global evaluations, and peripheral blood eosinophils). 4 Bisgaard et al. investigated the role of montelukast in the prevention of Asthma wheezing attacks induced by viral infection in children aged 2-5 years with intermittent asthma. The patients were randomized to receive montelukast or placebo for a 12-month period. The group with active treatment presented fewer symptoms and wheezing exacerbations. Spahn et al. have recently confirmed the effects of montelukast on peripheral airway obstruction and the concentration of eosinophilic cationic protein in children and adolescents with moderate asthma. Use of montelukast was associated with less air trapping, hyperinflation and resistance and higher values of spirometry and specific airway conductance as compared with placebo. 9 Exercise-induced asthma: Long-and short-acting agonists are typically used to control the symptoms of exercise induced asthma, but can be associated with the development of tolerance thereby decreasing efficacy. Leukotriene receptor antagonists 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 (10mg once-daily) with salmeterol (50mg twice daily) 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. 4 Future Potential Therapies for Allergic Due to the co-existence of asthma and 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 humanized monoclonal antibody against IgE. It is a monoclonal antibody raised against the Ce3 domain of IgE 22 I medical newsletter I as a service to the medical profession

Table 4.1 : Montelukast in Allergic Rhinitis 4 As monotherapy for allergic rhinitis, montelukast : Reduced daytime symptoms of allergic rhinitis Reduced nighttime symptoms of allergic rhinitis Reduced peripheral blood eosinophils Montelukast in combination with loratadine : Provided an additive effect 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 Table 4.2 : Montelukast in Asthma 4 In patients with mild persistent asthma, as an alternative choice, montelukast : Increased lung function (FEV 1 ) Reduced agonist use and nocturnal awakenings In patients on inhaled corticosteroids, as an add-on therapy, 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), as an add-on choice with ICS, montelukast : Improved a range of asthma symptoms Reduced the need for oral steroids Reduced inflammatory markers (peripheral blood eosinophils) In patients with exercise-induced asthma, montelukast maintained consistent reductions in EIB over the treatment period molecule is MaE11 and its humanized form used in clinical trials is the rhu-mab-e25 (E25). 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. 4 Conclusion Allergic rhinitis is an important risk factor for developing asthma and is also an important cause of nonoptimal control of asthma. Links between upper- and lower-airway diseases exist through inflammatory mediators, but other mechanisms, such as mouth breathing and postnasal drip, can contribute. Allergic rhinitis and asthma often respond to the same treatments, which suggests that there is an intimate connection between the two. Many therapeutic options are currently available although antileukotrienes have beneficial effects on allergic rhinitis and asthma because they work through a systemic effect. References 1. H Kim, J Bouchard, PM Renzi. The link between allergic rhinitis and asthma: A role for antileukotrienes? Can Respir J 2008; 15(2):91-98. 2. Groot EP, Nijkamp A, Duiverman EJ, Brand PLP. Allergic rhinitis is associated with poor asthma control in children with asthma. Thorax. 2012; 67: 582-587. 3. Daabis R. Allergic rhinitis and asthma: The united airways disease. Pulm Res Respir Med Open J. 2016; 3(2): e3-e4. 4. Pawankar R. Allergic rhinitis and asthma: from the link to emerging therapies. Indian J Chest Dis Allied Sci. 2003 Jul-Sep; 45(3):179-89. 5. Bergeron C, Hamid Q. Relationship between Asthma and Rhinitis: Epidemiologic, Pathophysiologic, and Therapeutic Aspects. Allergy Asthma Clin Immunol. 2005 Jun 15; 1(2):81-87. 6. Zvezdin B, Hromiš S, Kolarov V, et al. Allergic asthma and rhinitis comorbidity. Vojnosanit Pregl. 2015; 72(11): 1024 1031. 7. Egan M, Bunyavanich S. Allergic rhinitis: the Ghost Diagnosis in patients with asthma. Egan and Bunyavanich Asthma Research and Practice (2015) 1:8. Available from: https://asthmarp.biomedcentral. com/articles/10.1186/s40733-015-0008-0 8. Valovirta E. Managing Co-Morbid Asthma with Allergic Rhinitis: Targeting the One-Airway With Leukotriene Receptor Antagonists. WAO Journal. 2012; 5:S210 S211. 9. Ribeiro JD, Toro AA, Baracat EC. Antileukotrienes in the treatment of asthma and allergic rhinitis. J Pediatr (Rio J). 2006;82(5 Suppl): S213-21. medical newsletter I as a service to the medical profession I 23