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Pharmacologic rationale for treating allergic and nonallergic rhinitis

2006; Elsevier BV; Volume: 118; Issue: 5 Linguagem: Inglês

10.1016/j.jaci.2006.06.029

1097-6825

Alexander N. Greiner, Eli O. Meltzer,

Olfactory and Sensory Function Studies

Allergic rhinitis (AR) and perennial nonallergic rhinitis (PNAR) represent conditions affecting millions of individuals across the world. Although the diagnosis of AR might be presumptively based on the types of symptoms and the history of allergen triggers, confirmation requires documentation of specific IgE reactivity. In contrast, PNAR is a condition with similar symptomatology but in which the patient has no identifiable specific allergic sensitivities. This review presents the diverse options of currently available pharmacologic agents for the treatment of AR and PNAR, including intranasal corticosteroids, H1-antihistamines, decongestants, cromolyn sodium, antileukotrienes, anticholinergics, capsaicin, anti-IgE, and intranasal saline. Furthermore, appropriate stepped-up, stepped-down pharmacotherapeutic algorithms are described for the various forms of rhinitis. Allergic rhinitis (AR) and perennial nonallergic rhinitis (PNAR) represent conditions affecting millions of individuals across the world. Although the diagnosis of AR might be presumptively based on the types of symptoms and the history of allergen triggers, confirmation requires documentation of specific IgE reactivity. In contrast, PNAR is a condition with similar symptomatology but in which the patient has no identifiable specific allergic sensitivities. This review presents the diverse options of currently available pharmacologic agents for the treatment of AR and PNAR, including intranasal corticosteroids, H1-antihistamines, decongestants, cromolyn sodium, antileukotrienes, anticholinergics, capsaicin, anti-IgE, and intranasal saline. Furthermore, appropriate stepped-up, stepped-down pharmacotherapeutic algorithms are described for the various forms of rhinitis. Rhinitis, an extremely common rhinopathy, is characterized by the presence of nasal pruritus, sneezing, rhinorrhea, and nasal congestion. However, these symptoms do not always reflect an underlying pathologic process. For example, up to 95% of healthy adults sneeze and blow their nose up to 4 times in a given day.1Hansen B. Mygind N. How often do normal persons sneeze and blow the nose?.Rhinology. 2002; 40: 10-12PubMed Google Scholar In addition, nasal cycling, which results in temporary unilateral nasal congestion, as well as exposure to cold air, which promotes rhinorrhea, are 2 examples of normal physiologic mechanisms that sometimes could be misinterpreted as being abnormal. Therefore the magnitude and persistence of the symptoms is an important parameter. Rhinopathies can be classified as being structural, infectious, allergic, or nonallergic (Fig 1). The latter category is the most heterogeneous and includes drug- and hormonal-induced rhinitis, irritative-toxic rhinitis, and perennial nonallergic rhinitis (PNAR). This article will focus on allergic rhinitis (AR) and PNAR. The epidemiology of specific forms of rhinitis can be difficult to study because of the differences in classification and diagnostic assessments. AR has been reported to affect approximately 17% of the general population in the United States,2Nathan R.A. Meltzer E.O. Selner J.C. Storms W. The prevalence of allergic rhinitis in the United States.J Allergy Clin Immunol. 1997; 99: S808-S812Abstract Full Text PDF Scopus (208) Google Scholar and in selected pediatric populations might be present in up to 42%.3Wright A.L. Holberg C.J. Martinez F.D. Halonen M. Morgan W. Taussig L.M. Epidemiology of physician-diagnosed allergic rhinitis in childhood.Pediatrics. 1994; 94: 895-901PubMed Google Scholar Less information is available on the demographics of nonallergic rhinitis in the general population. However, in an attempt to define the prevalence of various forms of rhinitis, the National Rhinitis Classification Task Force retrospectively analyzed 975 patients with rhinitis from a variety of allergy practices. They determined that in the surveyed cohort, 43% of patients had "pure" AR, 23% had "pure" nonallergic rhinitis, and 34% had mixed rhinitis.4Settipane R.A. Lieberman P. Update on nonallergic rhinitis.Ann Allergy Asthma Immunol. 2001; 86: 494-507Abstract Full Text PDF PubMed Google Scholar Thus 57% of the patients with rhinitis had nonallergic rhinitis either alone or of mixed form. AR, an inflammatory condition of the nasal mucosa mediated by an IgE-associated response to indoor and outdoor environmental allergens, has traditionally been classified as being seasonal or perennial, depending on whether an individual is sensitized to cyclic pollens or year-round allergens, such as dust mites, pets, cockroaches, and molds. This classification scheme has proved to be artificial and often inconsistent because, depending on the locale, allergic sensitization to multiple seasonal allergens can result in year-round disease, and conversely, allergic sensitization to perennial allergens, such as animal dander, can result in symptoms during only a limited period of time. Although clinical research and regulatory agencies continue to use this nomenclature, recent global guidelines for classification and treatment of AR, as set forth by the Allergic Rhinitis and Its Impact on Asthma workshop, have proposed that allergic nasal disease be defined as being intermittent or persistent and mild or moderate-severe.5Bousquet J. van Cauwenberge P.B. Khaltaev N. Aria Workshop Group World Health Organization Allergic rhinitis and its impact on asthma. ARIA workshop report.J Allergy Clin Immunol. 2001; 108: S147-S334Abstract Full Text Full Text PDF PubMed Google Scholar Intermittent rhinitis is defined on the basis of symptoms that are present for less than 4 days per week or less than 4 weeks in duration. If symptoms are present for more than 4 days per week and are present for more than 4 weeks, AR is defined as being persistent. Mild symptoms do not affect sleep, interfere with work or school, or impair daily activities, sports, and leisure and, although present, are not considered troublesome. Conversely, moderate-severe symptoms can result in impairment or disturbances of any or all of these activities or aspects of life. Although the duration categories of intermittent and persistent appear to be a practical system, further refinement of the severity categories would be valuable. In addition, development of a validated method for assessing rhinitis control would be useful to monitor the often variable course of a patient's disease. The diagnosis of AR can be made presumptively based on the types of symptoms and the history of allergen triggers. Confirmation requires documentation of specific IgE reactivity through determination of allergen sensitivity by using skin prick testing or in vitro specific IgE determination. These procedures can help detect specific allergic sensitivities and provide information for directing environmental control interventions. PNAR is a condition in which the patient has no identifiable specific allergic sensitivities. Although it is controversial how to best subdivide PNAR, one previous approach has been to do so based on the presence or absence of nasal eosinophilia. Individuals with nasal eosinophilia and with no IgE sensitivity have traditionally been classified as having nonallergic rhinitis with eosinophilia syndrome (NARES). Although the reported number of eosinophils required to make a diagnosis of NARES varies, it is generally accepted that nasal scrapings from the nasal turbinate demonstrating 5 to 25 eosinophils per high-power field are compatible with such a diagnosis.6Scadding G.K. Non-allergic rhinitis: diagnosis and management.Curr Opin Allergy Clin Immunol. 2001; 1: 15-20PubMed Google Scholar Individuals with PNAR who lack nasal eosinophilia can be classified as having vasomotor rhinitis (VMR), which some clinicians have termed idiopathic rhinitis. VMR is characterized by the presence of chronic symptoms for 9 or more months each year.7Ciprandi G. Treatment of nonallergic perennial rhinitis.Allergy. 2004; 59: 16-22Crossref PubMed Google Scholar It can be differentiated from AR by the relative later age of onset, frequent lack of atopic comorbidities, nature of triggering factors, and type of symptoms. Precipitants include climate changes and nonspecific olfactory irritants, such as perfumes and tobacco smoke. Nasal obstruction and rhinorrhea are hallmark features of VMR and are more commonly seen than sneezing or itching.8Lindberg S. Malam L. Comparison of allergic rhinitis and vasomotor rhinitis patients on the basis of a computer questionnaire.Allergy. 1993; 48: 602-607Crossref PubMed Google Scholar A study by Togias9Togias A. Age relationships and clinical features of nonallergic rhinitis.J Allergy Clin Immunol. 1990; 85: 182Google Scholar found that patients with VMR were more likely than patients with AR to report headaches, nasal pressure, and posterior rhinorrhea and less likely to be affected by sneezing, nasal pruritus, and conjunctival symptoms. The exact pathophysiology of PNAR remains elusive. Some groups have found that affected individuals have infiltrating mast cells10Powe D.G. Huskisson R.S. Carney A.S. Jenkins D. McEuen A.R. Walls A.F. et al.Mucosal T-cell phenotypes in persistent atopic and nonatopic rhinitis show an association with mast cells.Allergy. 2004; 59: 204-212Crossref PubMed Scopus (32) Google Scholar and IgE-positive cells in the nasal mucosa11Powe D.G. Huskisson R.S. Carney A.S. Jenkins D. Jones N.S. Evidence for an inflammatory pathophysiology in idiopathic rhinitis.Clin Exp Allergy. 2001; 31: 864-872Crossref PubMed Scopus (72) Google Scholar similar in quantity to their counterparts with AR. In fact, approximately two thirds of individuals with PNAR might respond to nasal allergen challenges with cat, dog, grass, and dust mite allergens.12Carney A.S. Powe D.G. Huskisson R.S. Jones N.S. Atypical nasal challenges in patients with idiopathic rhinitis: more evidence for the existence of allergy in the absence of atopy?.Clin Exp Allergy. 2002; 32: 1436-1440Crossref PubMed Scopus (54) Google Scholar Thus it has been hypothesized that the underlying pathophysiology of PNAR might involve a local allergic process.13Coker H.A. Durham S.R. Gould H.J. Local somatic hypermutation and class switch recombination in the nasal mucosa of allergic rhinitis patients.J Immunol. 2003; 171: 5602-5610PubMed Google Scholar, 14Smurthwaite L. Durham S.R. Local IgE synthesis in allergic rhinitis and asthma.Curr Allergy Asthma Rep. 2002; 2: 231-238Crossref PubMed Google Scholar Consistent with this possibility has been the finding that B cells residing in the nasal mucosa are able to undergo switching to IgE in the context of a local immune response to allergen, a process that was only thought to occur in lymphoid tissue.15Cameron L. Gounni A.S. Frenkiel S. Lavigne F. Vercelli D. Hamid Q. S epsilon S mu and S epsilon S gamma switch circles in human nasal mucosa following ex vivo allergen challenge: evidence for direct as well as sequential class switch recombination.J Immunol. 2003; 171: 3816-3822PubMed Google Scholar In contrast, other groups have noted a lack of cellular inflammation in the nasal mucosa, as evidenced by the absence of infiltrating eosinophils, mast cells, and T cells in biopsy specimens.16van Rijswijk J.B. Blom H.M. KleinJan A. Mulder P.G. Rijntjes E. Fokkens W.J. Inflammatory cells seem not to be involved in idiopathic rhinitis.Rhinology. 2003; 41: 25-30PubMed Google Scholar, 17Numata T. Konno A. Hasegawa S. Hanazawa T. Nagata H. Motosugi H. et al.Pathophysiological features of the nasal mucosa in patients with idiopathic rhinitis compared to allergic rhinitis.Int Arch Allergy Immunol. 1999; 119: 304-313Crossref PubMed Scopus (17) Google Scholar Some of the discrepancies between these various findings might be explained by the fact that individuals with inflammatory changes did not have nasal smears done to rule out NARES, which could possibly account for the observed inflammation. Eosinophils, through production and release of their toxic and proinflammatory products, such as superoxide radicals, major basic protein, and eosinophilic cationic protein, could presumably interfere with normal nasal functioning and lead to pathologic rhinitis.18Ayars G.H. Altman L.C. McManus M.M. Agosti J.M. Baker C. Luchtel D.L. et al.Injurious effect of the eosinophil peroxide-hydrogen peroxide-halide system and major basic protein on human nasal epithelium in vitro.Am Rev Respir Dis. 1989; 140: 125-131Crossref PubMed Google Scholar Increasing evidence points toward the importance of nasal neurovascular mechanisms in the pathogenesis of noneosinophilic PNAR. Neurovascular homeostasis is maintained by a balance of sympathetic and parasympathetic tone in the upper airways.19Garay R. Mechanisms of vasomotor rhinitis.Allergy. 2004; 59: 4-9Crossref PubMed Google Scholar The former pathway controls the release of norepinephrine and neuropeptide Y, which favor a state of nasal patency.20Cervin A. Onnerfalt J. Edvinsson L. Grundemar L. Functional effects of neuropeptide Y receptors on blood flow and nitric oxide levels in the human nose.Am J Respir Crit Care Med. 1999; 160: 1724-1728Crossref PubMed Google Scholar In contrast, parasympathetic fibers release acetylcholine and, among other neuropeptides, vasoactive intestinal peptide. These are thought to induce nasal congestion and mucus secretion. In VMR there might be a state of relative hyperreactivity of the parasympathetic nervous system and hyporesponsiveness of the sympathetic nervous system, perhaps as a result of being exposed to irritants or noxious stimuli, such as cold dry air21Togias A. Proud D. Kagey-Sobotka A. Lichtenstein L.M. Naclerio R.M. Cold dry air (CDA) and histamine (Hist) induce more potent responses in perennial rhinitis compared to normal individuals.J Allergy Clin Immunol. 1991; 87: 148Abstract Full Text PDF Google Scholar or, alternatively, histamine and methacholine.22Borum P. Nasal methacholine challenge.J Allergy Clin Immunol. 1979; 63: 253-257Abstract Full Text PDF PubMed Google Scholar Others groups have hypothesized that the neurogenic imbalance responsible for inducing VMR might be due to overactivity of C-fibers contained in the nasal mucosa. C-fibers define the nonadrenergic noncholinergic system, an abnormally heightened tone of which can promote release of substance P, calcitonin gene-related protein, and neurokinins A and K, which can lead to nasal congestion and overproduction of nasal secretions.19Garay R. Mechanisms of vasomotor rhinitis.Allergy. 2004; 59: 4-9Crossref PubMed Google Scholar With mild intermittent AR, suggested initial pharmacologic therapy consists of an oral H1-blocker, an intranasal H1-blocker, and/or an oral or intranasal decongestant, the last on a strictly short-term or intermittent basis. A leukotriene modifier is also a consideration. If intermittent disease is moderate or severe, initial treatment with an intranasal corticosteroid (INS) is usually preferred to the aforementioned agents. Persistent mild AR is treated in the same manner as moderate or severe intermittent AR. If symptoms are persistent and moderate or severe, INSs should be the first class of medication used. With all grades of severity, appropriate follow-up should take place in a reasonable amount of time, and therapy should be stepped up or stepped down, as indicated. A pharmacologic treatment algorithm for AR is presented in Fig 2. Treatment of PNAR has historically depended on the presence of nasal eosinophilia that, if present, predicted a likely beneficial response to INSs. In contrast, treatment of noneosinophilic nonallergic rhinitis has usually targeted those specific nasal symptoms proving most bothersome. Thus empiric treatment with decongestants, oral antihistamines, INSs, intranasal saline irrigation, intranasal ipratropium bromide, and other agents with anticholinergic properties was often undertaken with varying degrees of success. A stepped-up, stepped-down approach based on progress monitoring is also appropriate for PNAR treatment management. A proposed pharmacologic treatment algorithm for PNAR is presented in Fig 3. INSs improve all nasal symptoms of AR, including nasal congestion, rhinorrhea, itching, and sneezing. They generally do so to a greater extent than any other currently available pharmacologic agent.5Bousquet J. van Cauwenberge P.B. Khaltaev N. Aria Workshop Group World Health Organization Allergic rhinitis and its impact on asthma. ARIA workshop report.J Allergy Clin Immunol. 2001; 108: S147-S334Abstract Full Text Full Text PDF PubMed Google Scholar The comprehensive clinical effects of INSs are based on a broad mechanism of action. As glucocorticoids diffuse across the cell membrane, they bind to specific intracellular receptors, forming a complex that is then transported into the nucleus, where it binds to glucocorticoid response elements.23Luisi B.F. Xu W.X. Otwinoeski Z. Freedman L.P. Yamamoto K.R. Sigler P.B. Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA.Nature. 1991; 352: 497-505Crossref PubMed Scopus (660) Google Scholar As a result, transcription of glucocorticoid response element associated genes is either downregulated or, less frequently, upregulated.24Diamond M.I. Miner J.N. Yoshinaga S.K. Yamamoto K.R. Transcription factors interactions: selectors of positive or negative regulation form a single DNA element.Science. 1990; 249: 1266-1272Crossref PubMed Google Scholar This leads to a reduction of the nasal mucosa inflammatory cells and their associated cytokines.25Meltzer E.O. The pharmacological basis for the treatment of perennial allergic rhinitis and non-allergic rhinitis with topical corticosteroids.Allergy. 1997; 52: 33-40Crossref PubMed Google Scholar Currently available INSs include beclomethasone, budesonide, flunisolide propionate, fluticasone propionate, mometasone furoate, and triamcinolone acetonide. All these are delivered in aqueous preparations and have shown efficacy in both seasonal and perennial AR in a large number of well-controlled studies. Although INSs might vary with regard to their sensory attributes (eg, perceived discomfort, taste, or smell) and thus patient acceptance and adherence, there do not appear to be any clear, clinically relevant differences in efficacy between them.26Corren J. Intranasal corticosteroids for allergic rhinitis: how do different agents compare?.J Allergy Clin Immunol. 1999; 104: S144-S149Abstract Full Text Full Text PDF PubMed Google Scholar Among the reported side effects are nasal burning and stinging, dryness, and epistaxis. These can occur in 5% to 10% of patients,26Corren J. Intranasal corticosteroids for allergic rhinitis: how do different agents compare?.J Allergy Clin Immunol. 1999; 104: S144-S149Abstract Full Text Full Text PDF PubMed Google Scholar with the only exception being flunisolide, which, because of its excipients, appears to cause a higher incidence of nasal discomfort.27Welsh P.W. Stricker W.E. Chu C.P. Naessens J.M. Reese M.E. Reed C.E. et al.Efficacy of beclomethasone nasal solution, flunisolide, and cromolyn in relieving symptoms of ragweed allergy.Mayo Clin Proc. 1987; 62: 125-134Abstract Full Text Full Text PDF PubMed Google Scholar Nasal mucosal atrophy does not occur with chronic INS use, in contrast to local skin atrophy, which occurs with dermatologic high-potency corticosteroids. This is evidenced by the findings of 2 separate year-long studies with fluticasone28Holm A.F. Fokkens W.J. Godthelp T. Mulder P.G. Vroom T.M. Rijntjes E. A 1-yr placebo-controlled study of intranasal fluticasone propionate aqueous nasal spray in patients with perennial allergic rhinitis: a safety and biopsy study.Clin Otolaryngol. 1998; 23: 69-73Crossref PubMed Scopus (73) Google Scholar and mometasone.29Minshall E. Ghaffar O. Cameron L. O'Brien F. Quinn H. Rowe-Jones J. et al.Assessment by nasal biopsy of long-term use of monetasone furoate nasal spray (Nasonex) in the treatment of perennial rhinitis.Otolaryngol Head Neck Surg. 1998; 118: 648-654PubMed Google Scholar Local candidiasis, sometimes seen with inhaled corticosteroids, is extremely rare with INSs. In terms of systemic side effects, laboratory evaluations of the hypothalamic-pituitary-adrenal axis by multiple means have shown minimal to no hypothalamic-pituitary-adrenal axis suppression with recommended doses of INS.30Wilson A.M. McFarlane L.C. Lipworth B.J. Effect of repeated once daily dosing of three intranasal corticosteroids on basal and dynamic measurements of hypothalamic-pituitary-adrenal axis activity.J Allergy Clin Immunol. 1998; 101: 470-474Abstract Full Text Full Text PDF PubMed Google Scholar Osteocalcin, a marker of bone turnover, and eosinophilia were both unaffected by intranasal budesonide, mometasone, and triamcinolone, suggesting that the systemic glucocorticoid burden was clinically insignificant.31Wilson A.M. Sims E.J. McFarlane L.C. Lipworth B.J. Effects of intranasal corticosteroids on adrenal, bone, and blood markers of systemic activity in allergic rhinitis.J Allergy Clin Immunol. 1998; 102: 598-604Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar These results appear to be confirmed by a recent case-control study showing no increased likelihood of bone fractures among octogenarians using INSs, regardless of the dose used.32Suissa S. Baltzan M. Kremer R. Ernst P. Inhaled and nasal corticosteroid use and the risk of fracture.Am J Respir Crit Care Med. 2004; 169: 83-88Crossref PubMed Google Scholar Nevertheless, some concerns have been raised about the effects of INSs on linear growth in children. Intranasal beclomethasone caused a small but significant reduction in linear growth in at least one study with twice-daily dosing.33Skoner D.P. Rachelefsky G.S. Meltzer E.O. Chervinsky P. Morris R.M. Seltzer J.M. et al.Detection of growth suppression in children during treatment with intranasal beclomethasone dipropionate.Pediatrics. 2000; 105: E23Crossref PubMed Google Scholar In contrast, no growth delay was observed in children treated over the course of 1 year with mometasone,34Schenkel E.J. Skoner D.P. Bronsky E.A. Miller S.D. Pearlman D.S. Rooklin A. et al.Absence of growth retardation in children with perennial allergic rhinitis after one year of treatment with mometasone furoate aqueous nasal spray.Pediatrics. 2000; 105: E22Crossref PubMed Google Scholar fluticasone,35Allen D.B. Meltzer E.O. Lemanske Jr., R.F. Philpot E.E. Faris M.A. Kral K.M. et al.No growth suppression in children treated with the maximum recommended dose of fluticasone propionate aqueous nasal spray for one year.Allergy Asthma Proc. 2002; 23: 407-413PubMed Google Scholar or budesonide.36Murphy K.R. Uryniak T. Simpson B. O'Dowd L. Recommended once-daily dose of budesonide aqueous nasal spray does not suppress growth velocity in pediatric patients with perennial allergic rhinitis.J Allergy Clin Immunol. 2004; 113: S175Abstract Full Text PDF PubMed Google Scholar However, a continuing clinical concern is that no studies have examined linear growth in children receiving a combination of an intranasal and an inhaled corticosteroid, a common clinical scenario. INSs are the single most effective class of medications for AR and are thus recommended as first-line therapy by both national and international taskforces for those with moderate-severe or persistent rhinitis.37American Academy of Allergy, Asthma and Immunology The allergy report. American Academy of Allergy, Asthma and Immunology, Milwaukee (WI)2000Google Scholar They are superior to antihistamines38Weiner J.M. Abramson M.J. Puy R.M. Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: sytematicreview of randomized controlled trials.BMJ. 1998; 317: 1624-1629Crossref PubMed Google Scholar, 39Rinne J. Simola M. Malmberg H. Haahtela T. Early treatment of perennial rhinitis with budesonide or cetirizine and it effects on long-term outcome.J Allergy Clin Immunol. 2002; 109: 426-432Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar and leukotriene antagonists40Nathan R.A. Yancey S.W. Waitkus-Edwards K. Prillaman B.A. Stauffer J.L. Philpot E. et al.Fluticasone propionate nasal spray is superior to montelukast for allergic rhinitis while neither affects overall asthma control.Chest. 2005; 128: 1910-1920Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 41Ratner P.H. Howland 3rd, W.C. Arastu R. Philpot E.E. Klein K.C. Baidoo C.A. et al.Fluticasone propionate aqueous nasal spray provided significantly greater improvement in daytime and nighttime nasal symptoms of seasonal allergic rhinitis compared with montelukast.Ann Allergy Asthma Immunol. 2003; 90: 536-542Abstract Full Text PDF PubMed Google Scholar and, with limited information, probably equivalent42Wilson A.M. Orr L.C. Sims E.J. Lipworth B.J. Effects of monotherapy with intra-nasal corticosteroids or combined oral histamine and leukotriene receptor antagonists in seasonal allergic rhinitis.Clin Exp Allergy. 2001; 31: 61-68PubMed Google Scholar or even superior43Di Lorenzo G. Pacor M.L. Pellitteri M.E. Morici G. Di Gregoli A. Lo Bianco C. et al.Randomized placebo-controlled trial comparing fluticasone aqueous nasal spray in mono-therapy, fluticasone plus cetirizine, fluticasone plus montelukast and cetirizine plus montelukast for seasonal allergic rhinitis.Clin Exp Allergy. 2004; 34: 259-267Crossref PubMed Scopus (95) Google Scholar, 44Pullerits T. Praks L. Ristioja V. Lötvall J. Comparison of a nasal glucocorticoid, antileukotriene, and a combination of antileukotriene and antihistamine in the treatment of seasonal allergic rhinitis.J Allergy Clin Immunol. 2002; 109: 949-955Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar to combinations of antihistamines and leukotrienes. For the most part, the addition of an antihistamine to an INS does not appear to confer additional clinical benefits over the use of an INS alone.45Barnes M.L. Ward J.H. Fardon T.C. Lipworth B.J. Effects of levocetirizine as add-on therapy to fluticasone in seasonal allergic rhinitis.Clin Exp Allergy. 2006; 36: 676-684Crossref PubMed Scopus (40) Google Scholar, 46Ratner P.H. van Bavel J.H. Martin B.G. Hampel Jr., F.C. Howland 3rd, W.C. Rogenes P.R. et al.A comparison of the efficacy of fluticasone propionate aqueous nasal spray and loratadine, alone and in combination, for the treatment of seasonal allergic rhinitis.J Fam Pract. 1998; 47: 118-125PubMed Google Scholar In a European seasonal AR study, nasal fluticasone was compared with placebo and various pharmacologic combinations: fluticasone plus cetirizine, fluticasone plus montelukast, and cetirizine plus montelukast. Fluticasone monotherapy was not inferior to the other 3 active treatment groups in reducing individual nasal symptoms except for nasal pruritus, where addition of cetirizine conferred an additional benefit. In terms of nasal congestion, only those treatment arms containing the nasal steroid were superior to placebo in relieving nasal congestion.43Di Lorenzo G. Pacor M.L. Pellitteri M.E. Morici G. Di Gregoli A. Lo Bianco C. et al.Randomized placebo-controlled trial comparing fluticasone aqueous nasal spray in mono-therapy, fluticasone plus cetirizine, fluticasone plus montelukast and cetirizine plus montelukast for seasonal allergic rhinitis.Clin Exp Allergy. 2004; 34: 259-267Crossref PubMed Scopus (95) Google Scholar Of the currently available INS preparations in the United States, only fluticasone has the US Food and Drug Administration indication for the treatment of nonallergic rhinitis regardless of the presence of nasal eosinophilia.47Flonase [prescribing information]. Available at: http://www.flonase.com. Accessed May 17, 2006.Google Scholar In a large study of patients with PNAR, administration of fluticasone at the lower dose, 200 μg once daily, was as effective as at the higher dose, 400 μg once daily, in achieving symptom reduction.48Webb D.R. Meltzer E.O. Finn Jr., A.F. Rickard K.A. Pepsin P.J. Westlund R. et al.Intranasal fluticasone propionate is effective for perennial nonallergic rhinitis with or without eosinophilia.Ann Allergy Asthma Immunol. 2002; 88: 385-390Abstract Full Text PDF PubMed Google Scholar In a separate study in patients with VMR, fluticasone, 200 μg once daily, was significantly superior to placebo in reducing symptoms of nasal obstruction and decreasing inferior turbinate hypertrophy, as assessed by means of computed tomographic (CT) scanning.49Arikan O.K. Koc C. Kendi T. Muluk N.B. Ekici A. CT assessment of the effect of fluticasone propionate aqueous nasal spray treatment on lower turbinate hypertrophy due to vasomotor rhinitis.Acta Otolaryngol. 2006; 126: 37-42Crossref PubMed Scopus (8) Google Scholar However, the evidence for benefit of INSs in PNAR is inconsistent. In a different study mometasone, 200 μg once daily, was not significantly more effective than placebo in reducing overall rhinitis symptoms in a cohort of individuals with PNAR during a 6-week treatment period.50Lundblad L. Sipila P. Farstad T. Drozdziewicz D. Mometasone furoate nasal spray in the treatment of perennial non-allergic rhinitis: a nordic, multicenter, randomized, double-blind, placebo-controlled study.Acta Otolaryngol. 2001; 121: 505-509Crossref PubMed Google Scholar Although many chemical mediators can induce one or more symptoms of AR, histamine remains the quintessential mediator of allergic nasal disease, especially during the early-phase response. Acting at the H1-receptors, histamine can induce most of the allergic symptoms (eg, sneezing; itching of the nose, throat, and palate; and rhinorrhea) through stimulation of the sensory nerves, increase in vascular permeability, and mucus production. H1-antihistamines antagonize the H1-receptor on smooth muscle cells, nerve endings, and glandular cells, leading to a reduction in all of the above symptoms. However, they o