Overview of the Treatment of Allergic Rhinitis and ... - ATS Journals

Overview of the Treatment of Allergic Rhinitis and Nonallergic Rhinopathy Alexander N. Greiner1,2 and Eli O. Meltzer1,2 1

Allergy and Asthma Medical Group and Research Center, San Diego, California; and 2University of California San Diego School of Medicine, San Diego, California

Allergic rhinitis (AR) and nonallergic rhinopathy (NAR) represent common nasal conditions affecting millions of individuals across the world. Although patients present with similar symptomatology, those with NAR are frequently affected only after childhood and present with a lack of other comorbid atopic disorders such as asthma, atopic dermatitis, and food allergies. Patients with pure NAR usually have no identifiable specific allergen sensitivity, whereas those with mixed (allergic and nonallergic) rhinitis are sensitized to aeroallergens in a manner that does not fully explain the duration or extent of their symptoms. This review presents the diverse options of currently available pharmacologic agents for the treatment of AR and NAR, including intranasal corticosteroids, H1antihistamines, decongestants, cromolyn sodium, antileukotrienes, anticholinergics, capsaicin, anti-IgE, and intranasal saline, in addition to subcutaneous immunotherapy. Furthermore, treatment algorithms for AR and NAR are presented with a stepped-up, stepped-down scheme to aid the clinician in choosing appropriate therapy. Keywords: allergic rhinitis; nonallergic rhinopathy; nonallergic rhinitis; pharmacotherapy

OVERVIEW Rhinitis, a common rhinopathy, is characterized by the presence of one or more of the following symptoms: nasal pruritus, sneezing, rhinorrhea, and nasal congestion. Other symptoms sometimes experienced include pressure, pain (allodynia), exaggerated pain responses (hyperalgesia), and hyposmia (1). Rhinitis can be idiopathic or caused by multiple precipitants, including atopic, drug-induced, hormonal/metabolic, infectious, inflammatory, and structural precipitants (Figure 1). The reader is referred elsewhere for a more detailed review of the various forms of rhinitis (2, 3). This review focuses on allergic rhinitis (AR) and idiopathic nonallergic rhinitis, henceforth referred to as nonallergic rhinopathy (NAR).

EPIDEMIOLOGY The epidemiology of specific forms of rhinitis can be challenging to study due to differences in classification and diagnostic assessments. AR has been reported to affect approximately 14% of the adult population in the United States (4) but in selected pediatric populations may be present in up to 42% (5). The prevalence of NAR has been even more difficult to ascertain in an accurate manner but may account for 23 to

(Received in original form April 29, 2010; accepted in final form July 14, 2010) Correspondence and requests for reprints should be addressed to Alexander N. Greiner, M.D., Allergy and Asthma Medical Group and Research Center, 5776 Ruffin Road, San Diego 92123 Suite B, San Diego, CA 92123. E-mail: greinerallergist@ yahoo.com Proc Am Thorac Soc Vol 8. pp 121–131, 2011 DOI: 10.1513/pats.201004-033RN Internet address: www.atsjournals.org

29% of patients evaluated for AR. A recent review of nine rhinitis prevalence studies concluded that of 52,850 individuals studied, 71% had AR and 29% had NAR (6). Although NAR appears less prevalent than AR, it is nevertheless important to note that these categories are not mutually exclusive. The national rhinitis task force survey categorized 43% of 975 patients with rhinitis as AR, 23% as NAR, and 34% as mixed AR and nonallergic rhinitis, when analyzed retrospectively (7). Thus, 57% of the rhinitis sufferers had nonallergic rhinitis either alone or in mixed form.

CLASSIFICATION AND DIAGNOSIS OF AR AR, an inflammatory condition of the nasal mucosa mediated by an IgE-associated response to indoor or 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, cockroaches, animal dander, and, in certain geographical locales, molds. This classification scheme has proved to be artificial and often inconsistent because, depending on the milieu, allergic sensitization to multiple seasonal allergens can result in year-round disease and, conversely, allergic sensitization to ‘‘perennial’’ allergens such as animal dander can, because of episodic exposure, result in symptoms during only a limited period of time. Although clinical research and regulatory agencies continue to use this nomenclature, global documents for classification and treatment of AR, such as the World Health Organization’s ARIA (Allergic Rhinitis and its Impact on Asthma) guidelines, have proposed that allergic nasal disease be categorized as being intermittent or persistent, and mild or moderate-severe (3). Intermittent rhinitis is characterized by symptoms that are present for fewer 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 classified as being persistent. Mild symptoms do not affect sleep, impair daily activities, impair sports and leisure, or interfere with work or school, and, although present, are not considered troublesome. Conversely, moderatesevere 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, a recently published validated method for assessing rhinitis control may be helpful in better defining the burden of AR in the often variable course of a patient’s disease (8). The diagnosis of AR may be made presumptively based on the types of symptoms and the history of allergen triggers. Confirmation requires documentation of specific IgE reactivity via determination of allergen sensitivity using skin-prick testing or in vitro IgE determination. These procedures can help detect specific allergic sensitivities and provide information for directing environmental control interventions.

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Figure 1. Rhinopathies: classification overview. AERD 5 aspirin-exacerbated respiratory disease; NSAID 5 nonsteroidal antiinflammatory drug.

CLASSIFICATION AND DIAGNOSIS OF NONALLERGIC RHINITIS Nonallergic rhinitis is defined by the absence of systemic allergic sensitivities as measured by allergen-specific IgE determination, as well as the absence of infectious or anatomical/ mechanical causes. This heterogeneous category includes drugand hormone-induced rhinitis, irritative-toxic rhinitis, and NAR, the latter of which also has been termed as vasomotor rhinitis (VMR), idiopathic rhinitis (IR), or perennial nonallergic rhinitis (PNAR). NAR may be the preferred term because the suffix in the word rhinitis implies that inflammation is present, which may not be the case. However, because published clinical studies have included a heterogeneous population defined in a variety of ways, the terms used throughout this review will continue to reflect the ones used in the original studies. The exact pathophysiology of NAR remains uncertain as multiple, perhaps overlapping, mechanisms have been proposed (1). These include the possibilities of localized nasal allergy reactions without systemic evidence for allergy (entopy), nociceptive nerve dysfunction, autonomic dysregulation whether rooted in the nonadrenergic, noncholinergic system or the sympathetic/parasympathetic system, or via other yet-to-bedetermined mechanisms. NAR is characterized by persistent or intermittent nasal symptoms that can be initiated by a variety of stimuli that are usually not trigger factors for healthy individuals. These triggers include irritants such as smoke from tobacco and odors stemming from perfumes and other fragrances, climate changes, humidity, and changing barometric pressure and/or temperature. However, some patients with NAR have persistent nasal

symptoms in the absence of the aforementioned or other clear triggers. NAR may usually be differentiated from AR by characteristics including a relatively later age of onset, female sex, and a frequent lack of atopic comorbidities, such as atopic dermatitis, asthma, and food allergies. Although the nature of triggering factors may be suggestive of NAR, it is important to note that individuals with AR have a high frequency of reacting to nonspecific triggers as well. It is unclear whether this is representative of an underlying nonspecific hyperreactivity of the upper airways, similar to the bronchial hyperreactivity seen in asthma, or whether these individuals have mixed rhinitis. Although nonspecific, the type of nasal symptoms can also be suggestive of NAR: nasal obstruction and rhinorrhea tend to be the hallmark features of NAR and more commonly seen than sneezing, nasal and palatal itch, and concurrent ocular symptoms, which are more suggestive of allergic upper airway disease (9, 10).

OVERVIEW OF PHARMACOLOGICAL TREATMENT Optimal management of rhinitis involves a multifaceted approach including patient education, environmental control(s) and trigger avoidance, pharmacotherapy, and, in appropriately selected patients, subcutaneous immunotherapy (IT). With mild intermittent AR, suggested initial pharmacological therapy consists of an oral H1-blocker, an intranasal H1blocker, and/or an oral or intranasal decongestant, the last on a strictly short-term or intermittent basis. An oral leukotriene modifier is also a consideration. If intermittent disease is moderate, or severe or persistent AR is present, initial treatment with an intranasal corticosteroid (INS) is usually preferred

Greiner and Meltzer: Treatment of Allergic Rhinitis and Nonallergic Rhinopathy

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Figure 2. Algorithmic considerations for pharmacological treatment of allergic rhinitis. dx 5 diagnosis.

to the previously mentioned agents. With all grades of severity, follow-up monitoring should take place after a reasonable amount of time and therapy stepped up or stepped down, as deemed appropriate. Failure of AR to respond to a proper 2- to 4-week trial of an INS should prompt further evaluation. This may include allergy testing if not already done, rhinopharyngoscopy for mechanical obstructions, radiological evaluation of the adenoids and/or sinuses, and other diagnostics depending on the consideration of other possible causes. A proposed pharmacological treatment algorithm for AR is presented in Figure 2. Treatment of NAR frequently entails a therapeutic trial approach with agents targeted at controlling the most bothersome symptom(s). Thus, empiric treatment with decongestants, oral or intranasal antihistamines (AHs), INS, intranasal saline irrigation, intranasal ipratropium bromide, and other agents with anticholinergic properties is often undertaken with varying degrees of success. A regimen that is adjusted by stepping up or down based on improvement and symptom control is also appropriate for NAR treatment management. A proposed pharmacological treatment algorithm for nonallergic rhinitis and NAR is presented in Figure 3.

INS Role of INS in the Treatment of AR

INS 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 pharmacological agent (3). The comprehensive clinical effects of INS 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 (GRE) in promotor regions of responsive genes. As a result, transcription of GRE-associated genes is either downregulated or, less frequently, up-regulated. This leads to a reduction of inflammatory cells and their associated proinflammatory mediators in the nasal mucosa (11). Currently available INS include beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone furoate, 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 INS may vary with regard to the volume emitted per actuated spray and sensory attributes (such as 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 (12). Among the reported side effects are nasal burning, stinging, and irritation; local dryness; and epistaxis. These can occur in 5 to 10% of patients, with the only exception being flunisolide, which, due to its excipients, appears to cause a higher incidence of nasal discomfort (13). As evidenced by the findings of two separate year-long studies with fluticasone propionate and mometasone,

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Figure 3. Algorithmic considerations for pharmacological treatment of nonallergic rhinitis. AERD 5 aspirin-exacerbated respiratory disease; ASA 5 acetylsalicylic acid; dx 5 diagnosis; IR 5 idiopathic rhinitis; NARES 5 nonallergic rhinitis with eosinophilia syndrome; PNAR 5 perennial nonallergic rhinitis; VMR 5 vasomotor rhinitis.

nasal mucosal atrophy does not occur with chronic INS use (14, 15). Clinically apparent local candidiasis, sometimes seen with orally inhaled corticosteroids, is rare with INS. An increased understanding of corticosteroids and glucocorticoid receptor pharmacology has enabled the development of locally active, potent molecules with minimal systemic burden. Laboratory evaluations of the hypothalamic-pituitary-adrenal (HPA) axis by multiple means have shown negligible or no HPA suppression with recommended doses of currently available INS (16). 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 (17). These results appear to be corroborated by the finding that no increased likelihood of bone fractures was present among octogenarians using INS, regardless of the dose used (18). Nevertheless, some concerns have been raised about the effects of INS on linear growth in children, especially with firstgeneration corticosteroids such as intranasal beclomethasone, which caused a small but significant reduction in linear growth with twice-daily dosing (19). In contrast, no growth delay was observed in children treated over the course of 1 year with budesonide (20), fluticasone propionate (21), mometasone (22), or triamcinolone (23). 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. INS are the single most effective class of medications for AR and are thus recommended as first-line therapy by both national and international task forces for those with moderate-severe or persistent rhinitis(2, 3). They are superior to oral AHs (24, 25) and leukotriene antagonists (26, 27) and, with limited information, equivalent (28) or even superior (29, 30) to combinations of AHs and leukotrienes. There is not enough information to conclude that intranasal AHs are therapeutically equivalent to INS, especially after a 14-day treatment period (31). For the

most part, the addition of an oral AH to an INS does not appear to confer additional clinical benefits over the use of an INS alone (32, 33). However, the addition of an intranasal AH to an intranasal corticosteroid does appear to provide greater efficacy than the monotherapies (34). Role of INS in the Treatment of NAR

Of the currently available intranasal corticosteroid preparations in the United States, only fluticasone propionate has a Food and Drug Administration (FDA) indication for the treatment of nonallergic rhinitis, regardless of the presence of nasal eosinophilia (35). In a large study of patients with PNAR, administration of fluticasone propionate at 200 mg (two sprays per side once daily) was as effective as 400 mg once daily in achieving symptom reduction (36). In a separate study in patients with VMR, fluticasone propionate, 200 mg once daily, was significantly superior to placebo in reducing symptoms of nasal obstruction and decreasing inferior turbinate hypertrophy as assessed via CT scan (37). In a small study of nonallergic patients aged 20 to 68 years, budesonide aerosol (no longer available) was found to be significantly more effective than placebo with regard to the symptoms of nasal obstruction, nasal drainage, and sneezing at twice daily dosing of 50, 200, and 800 mg (38). However, the evidence for benefit of INS in NAR is inconsistent, probably reflecting the heterogeneous nature of NAR. In a study of individuals with PNAR, treatment with mometasone 200 mg (two sprays per side once daily) for 6 weeks did not lead to any significant improvement in rhinitis symptoms when compared with placebo (39). Fluticasone furoate, administered as 110 mg (two sprays per side once daily) to 699 subjects with vasomotor rhinitis triggered by weather/temperature, was not superior to placebo in reducing congestion, rhinorrhea, and/ or postnasal drip during the 4-week study period (40). Although not always similarly designed, studies to date suggest that INS treatment for NAR may be of some thera-


peutic value and should, for now, be considered as first-line therapy (41).

H1-ANTIHISTAMINES Role of Oral AHs in the Treatment of AR

Although many chemical mediators can induce one or more symptoms of AR, histamine remains the prototypical mediator of allergic upper airway disease, especially during the early phase response. Acting at the H1 receptors, histamine can induce most of the allergic symptoms (sneezing; itching of the nose, throat, and palate; and rhinorrhea) via 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 in an inverse agonist fashion, leading to a reduction in all of the above symptoms. However, they only have a mild effect on nasal congestion (42). Tolerance to the beneficial effects of H1antihistamines has not been shown to occur (43). Several older or first-generation oral H1-antihistamines are available as over-the-counter formulations (diphenhydramine, clemastine, tripelennamine, pyrilamine, brompheniramine, chlorpheniramine, triprolidine) or as prescription drugs (hydroxyzine, promethazine, and cyproheptadine). These preparations have poor selectivity for the H1 receptor and as such inhibit muscarinic receptors, which may result in various degrees of mucous membrane drying, vision blurring, constipation, urinary retention, and tachycardia. Sedation is a major adverse effect of the older H1-antihistamines. It occurs due to crossing of the blood–brain barrier and binding to H1 receptors in the central nervous system. The term sedation has been used to include both drowsiness and a global reduction in intellectual and motor performance (44). Sedating H1-antihistamines have been linked to air (45) and industrial accidents (46) as well as magnifying the loss of productivity at school and work already experienced due to rhinitis symptoms (47). A single 50-mg dose of diphenhydramine led to a degree of diminished driving performance, as assessed in a driving simulator, greater than that seen from the ingestion of ethanol leading to an estimated blood alcohol level of 0.1% (48). Similar to the effects of ethanol intake, a discrepancy often exists between self-perception of sedation and objective measures of drowsiness and performance (49). Even though dosing for first-generation H1-antihistamines is often undertaken several times a day, the terminal elimination of first-generation AH half-life varies from 9.2 to 27.9 hours (50), leading to potential daytime deficits even when administered only at bedtime. One study suggested that tolerance can develop to the sedating properties of diphenhydramine (51). It also appears that many individuals with chronic urticaria are able to function reasonably normally on high doses of various sedating AHs when taken on a daily basis (A. Kaplan, personal communication, 2006). Unresolved and requiring further study is the extent to which tolerance to sedation really occurs and whether this may be a class effect. Second-generation oral H1-antihistamines currently available in the United States include the over-the-counter preparations loratadine and cetirizine and the prescription drugs desloratadine, fexofenadine, and levocetirizine. In contrast to the older first-generation AHs, for which studies showing clinical efficacy are limited (52), effectiveness for cetirizine and its enantiomer levocetirizine, desloratadine, fexofenadine, and loratadine have been established in a variety of welldesigned, double-blind, placebo-controlled studies. These studies have also helped to establish onset of action, peak effect, and

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duration of action. Such information is lacking with firstgeneration AHs so that current dosing suggestions for agents belonging to this category are based, at best, on the individual AH’s ability to suppress the cutaneous wheal and flare response after allergen or histamine introduction into the skin (53). Second-generation oral H1-antihistamines have better H1 receptor selectivity and thus less anticholinergic and antiserotonergic side effects. All these agents, with the exception of fexofenadine, have the potential to cross the blood–brain barrier and bind to central H1 receptors, resulting in sedation. This process has been observed in individuals using loratadine and desloratadine at higher than recommended doses (54, 55). For the second-generation oral agents available in the United States, only cetirizine and levocetirizine may lead to increased sedation at its recommended dose in those aged 12 years or older (14% on cetirizine vs. 6% receiving placebo and 6% on levocetirizine vs. 2% receiving placebo) (56, 57). A few industry-sponsored studies have directly compared the clinical effect of different second-generation AHs. Despite the frequent finding of therapeutic equivalency between various second-generation AHs in clinical trials, individual patients sometimes perceive differences in efficacy among agents of this class. Second-generation AH should be a first-line consideration in patients with AR who do not have significant nasal congestion/ obstruction and have intermittent symptoms or mild persistent symptoms. Role of Oral AHs in the Treatment of NAR

Although there is no clear established role for AHs in the treatment of NAR, patients who have sneezing as a predominant symptom may respond favorably to oral AHs (3). Also, a single placebo-controlled study comparing flunisolide to a combination of flunisolide and loratadine found that the INS-AH combination was superior to INS in reducing both sneezing and rhinorrhea in a group of patients with nonallergic rhinitis with eosinophilia syndrome (58). Although there are no clinical data showing effectiveness in NAR, the use of firstgeneration AHs may be potentially helpful in reducing rhinorrhea by virtue of their anticholinergic activity. However, this needs to be balanced against the undesirable effects attributable to systemic anticholinergic actions. Role of Intranasal AH in the Treatment of AR and NAR

In addition to their H1 antagonism, several AHs may exhibit antiinflammatory effects in vitro. These include prevention of mast cell and basophil degranulation, down-regulation of adhesion molecules and chemokines, reduction of inflammatory cytokine expression, suppression of neurogenic enhancement of inflammation, and augmentation of inflammatory cell apoptosis (59). However, at customary therapeutic doses, oral AHs rarely reach high enough concentrations in vivo to produce clinically relevant antiinflammatory effects. In contrast, after administration of an intranasal AH, tissue concentrations may be high enough for considerable local antiinflammatory effects. Currently, intranasal azelastine 0.1% is the only AH in the United States with an indication for both AR and VMR. Azelastine 0.15% and olopatadine are indicated for the treatment of AR only. Dose-ranging trials with olopatadine and azelastine 0.15% have shown a therapeutic onset of action within 30 minutes of initial dosing with persistence of efficacy over a 12-hour interval (60, 61). Azelastine (62, 63) and olopatadine (64, 65) have demonstrated efficacy in seasonal rhinitis. Recent findings from industry-sponsored clinical studies suggest that an intranasal AH may be superior to cetirizine

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(azelastine) (66), desloratadine (azelastine) (67), and fexofenadine (azelastine and olopatadine) (68, 69) in its ability to reduce total nasal symptoms scores, including nasal congestion. An older study, however, did not find that azelastine was superior to cetirizine in seasonal AR (70). The most common side effects of azelastine at the recommended dose of two sprays per nostril twice a day are bitter taste and sedation (11.5 vs. 5.4% placebo in the azelastine 0.1% study and , 1% in the azelastine 0.15% study). Olopatadine is usually better tolerated than the current formulation of azelastine 0.1% (71). Comparisons between INS and intranasal AHs are still scarce. Although one study found that intranasal budesonide at 256 mg (four sprays per side once daily) was superior to azelastine 280 mg (one spray per nostril twice daily) for reducing symptoms of AR (72), a recent noninferiority trial concluded that olopatadine has similar efficacy when compared with fluticasone propionate at 200 mg/d (two sprays per side once daily) over a 2-week period (31). As previously noted, the addition of an intranasal AH to an INS may also be a consideration, as there may be an additional benefit over the use of an INS alone. Whether this benefit persists beyond the 2-week period studied is uncertain, however (34). In the two pivotal studies that established a role for intranasal azelastine in the treatment of nonallergic, noneosinophilic chronic rhinitis, all nasal symptoms, including nasal congestion, were reduced compared with placebo (73). A recent study suggests that there may also be role for olopatadine in the treatment of NAR. In addition to reducing symptoms from baseline in patients with moderate/severe symptoms, olopatadine reduced the development of increased nasal obstruction when given 30 minutes before an intranasal mannitol challenge, putatively via capsaicin channel blocking (74). Taken together, studies to date suggest that intranasal AH may be of some therapeutic value for the treatment of NAR and should, for now, be considered as a firstline therapy for NAR as well as AR. Role of Decongestants in the Treatment of AR and NAR

Vasoconstrictors exist in both intranasal and oral form. Topically applied vasoconstrictor sympathomimetic agents belong to the catecholamines (e.g., phenylephrine) or imidazoline family (e.g., oxymetazoline), whereas oral vasoconstricting agents are primarily catecholamines (pseudoephedrine and phenylephrine). These agents exert their effect via the a1- and a2adrenoreceptors present on nasal capacitance vessels responsible for mucosal swelling and associated nasal congestion. The reduction in blood flow to the nasal vasculature after administration leads to increased nasal patency in 5 to 10 minutes when applied topically or in 30 minutes when administered orally. Nasal decongestion may last up to 8 to 12 hours with intranasal preparations and 24 hours with extended-release oral decongestants. Although pseudoephedrine has not been thought to ameliorate rhinitis symptoms other than nasal congestion (75), one study comparing once-daily pseudoephedrine to montelukast showed a reduction in rhinitis symptoms other than nasal congestion in both groups (76). The adverse affects of topical nasal decongestants include nasal burning, stinging, dryness, and, less commonly, mucosal ulceration. Tolerance and rebound congestion can occur when these agents are used for longer than 1 week and can culminate in rhinitis medicamentosa (77). Recently presented data suggest that this negative effect may be prevented by concomitant usage of an INS (78–80). Adverse effects of oral decongestants include central nervous stimulation, such as insomnia (which may occur in a significant portion of individuals), nervousness, anxiety, and tremors, as well as tachycardia, palpitations, and increases in blood pressure.


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Overall, monotherapy with vasoconstrictors has a limited role in the treatment of AR, unless nasal congestion presents as the sole or most bothersome symptom. However, when oral decongestants are combined with an AH, all cardinal symptoms of AR are targeted. Decongestants may be used in the treatment of NAR for symptomatic improvement. When administered topically, intermittent dosing is required for the above-mentioned reasons. Although plausible, no studies have been performed to determine whether topical vasoconstrictor–induced rhinitis medicamentosa can be prevented by addition of an INS in individuals with NAR. Role of Cromolyn Sodium and Nedocromil Sodium in the Treatment of AR and NAR

Cromolyns inhibit the degranulation of sensitized mast cells, thereby blocking the release of inflammatory mediators (81). Cromolyns do not interfere with either the binding of IgE to the high-affinity IgE receptor or binding of the allergen to its specific IgE. In allergen challenge studies of individuals with AR, cromolyn sodium has proved effective in reducing both the early- and late-phase allergic reaction (80). Cromolyn is indicated for both seasonal (83) and perennial AR (84). The onset of relief appears during the first week of treatment and symptoms often continue to improve as the medication is continued over the subsequent weeks. The 4% intranasal solution, recommended for adults and children aged 2 years and older, is to be initially instilled four times daily. However, once symptoms are under control, a less frequent dosing regimen may suffice for adequate symptom control. Topical adverse effects to cromolyn are uncommon. In addition, it exhibits poor systemic absorption, and thus has an excellent safety record. Tolerance to the clinical effects of cromolyn has not been described. The results derived from several older studies about the role of cromolyns in the treatment of NAR are inconclusive. Given the limited role of histamine in the genesis of symptomatology of people with NAR, the role of cromolyns would be expected to be modest at best. One study revealed no symptom improvement in a group of adults with nonallergic rhinitis with eosinophilia syndrome after 2 months of treatment with 4% cromolyn solution (85). In contrast, another group found that 2% disodium cromoglycate was preferred over placebo by a majority of individuals with VMR (86). Role of Antileukotrienes in the Treatment of AR

Cysteinyl-leukotrienes (cys-LTs) are potent lipid mediators derived from the enzymatic action on nuclear membrane phospholipids. Initially studied in the lower airway inflammation of asthma, these inflammatory molecules also appear to play a role in the upper airways, as evidenced by the appearance of high concentrations of LTC4 in nasal secretions of atopic individuals after allergen challenge (87). Furthermore, nasal challenge with LTD4 in normal human subjects can significantly increase nasal mucosal blood flow and nasal airway resistance (88). Leukotrienes do not appear to stimulate the sensory nerves present in the nasal mucosa and thus probably do not contribute significantly to nasal itching or sneezing (89). Although blockage of the LT pathway could be accomplished by either inhibition of synthesis via the 5-lipoxygenase inhibitor zileuton or by receptor blockade of the cys-LT1 receptor with the leukotriene receptor antagonists zafirlukast or montelukast, only montelukast is FDA approved for treatment of AR, wherein it has shown clinical efficacy in seasonal AR (90, 91) and perennial AR (92, 93). Montelukast results in few side effects, has a pregnancy B category, and is approved in children as young as 6 months. Although there is no clear evidence of causation, montelukast has been associ-


ated with adverse neuropsychiatric events, including suicidal thinking and behavior (94). Although a metaanalysis published in 2006 proposed that montelukast should be used as second-line therapy for the treatment of AR (95), the joint task force on practice parameters for allergy and immunology concluded that montelukast may be as effective as oral AHs, with the usual comparator being loratadine. In addition, based on published studies, the task force also suggested a possible additive effect with oral AH and montelukast, although this approach was often still inferior to INS (2, 96). At this time, no published studies have shown a role for leukotriene modifiers in the treatment of NAR. Role of Ipratropium Bromide in the Treatment of AR and NAR

Ipratropium bromide, available as an intranasal preparation, is an antimuscarinic agent that inhibits parasympathetic function within the nasal mucosa, thus controlling the secretory output from serous and seromucous glands. Due to its low systemic absorption, it is relatively free of the side effects usually accompanying the administration of oral compounds with anticholinergic properties, unless administered at higher than recommended doses (97). Ipratropium has an onset of action within 15 to 30 minutes. Due to its pharmacokinetic profile, the recommended 24-hour dose ranges from 120 to 320 mg, administered in three to six daily applications (98). Tolerance to the therapeutic effects of ipratropium has not been described. Side effects are usually limited to local irritation, dryness, and epistaxis, which occur in a dose-dependent manner. Ipratropium has shown efficacy in perennial AR and various forms of nonallergic rhinitis, including infectious, gustatory, and vasomotor rhinitis in both children (99, 100) and adults (101, 102). It is primarily effective at controlling watery anterior nasal discharge, and probably only plays a marginal role in the management of postnasal drip. Ipratropium should primarily be used in the management of isolated anterior rhinorrhea. It may also be prescribed as an adjunct for the treatment of rhinorrhea not fully controlled by other pharmacological agents. Role of Capsaicin in the Treatment of AR and NAR

Local application of capsaicin, a pungent compound present in red hot peppers, can induce nasal burning, rhinorrhea, and nasal congestion via stimulation of the nasal C fibers. With repeated application of capsaicin, neuropeptides from C fibers are presumably depleted, leading to reduced nasal hyperreactivity. Several studies have shown symptomatic improvement in patients with NAR treated with capsaicin (103, 104). A published practical therapeutic approach has suggested induction of local anesthesia followed by five hourly applications of capsaicin. This treatment plan has shown similar efficacy with intermittent treatment over 2 weeks (105). Although some investigators estimate that improvement after a single treatment course may last for more than 1 year (106), more research is required to better define the role and long-term effects of capsaicin therapy in treating NAR. Interestingly, even less is known about the role of capsaicin in treating AR. A Cochrane analysis concluded that there was insufficient evidence to assess the use of capsaicin in the treatment of AR (107). Capsaicin is not commercially available in the United States as a standardized intranasal preparation. Role of Omalizumab (Anti-IgE) in the Treatment of AR

Omalizumab represents the only commercially available monoclonal antibody that modulates allergic inflammation. Although primarily used to treat poorly controlled atopic asthma, it also

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appears to have a role in ameliorating other atopic disorders, including AR. Omalizumab is a ‘‘humanized’’ monoclonal antibody that binds to the constant region of the IgE molecule at its IgE receptor-binding portion, thereby effectively hindering IgE’s interaction with the high-affinity IgE receptor present on mast cells, basophils, and dendritic cells. Anti-IgE binds to circulating but not cell-bound IgE, forming stable, long-lived anti-IgE–IgE complexes. After initial adequate dosing, free IgE concentrations decline in a rapid dosedependent fashion by 97 to 99%. Omalizumab has been shown to be effective for AR in both allergen challenge studies and clinical trials. Multiple randomized, double-blind, placebo-controlled studies have shown efficacy of omalizumab in seasonal (108, 109) and perennial AR (110, 111). It remains to be determined how omalizumab compares to other treatment modalities. Given its high cost, reports of anaphylaxis (112), and lack of oral or inhaled routes of administration, its role in the treatment of AR will likely remain limited. No published studies have shown a role for omalizumab in the treatment of NAR. However, based on current understanding of the mechanism of action of this therapy, it is unlikely to be valuable for this condition. Role of Nasal Saline Irrigation in the Treatment of AR and NAR

For many years, nasal saline irrigation has been used as an adjunct treatment for various forms of rhinitis or sinusitis, even in the absence of published clinical data. In the process of douching, several ounces of isotonic or hypertonic saline are introduced into the nose, nasopharynx, and possibly sinus cavities with the goals of removing mucus, enhancing ciliary clearance and sinus ostial patency, and, perhaps, removing allergenic and irritant material. Devices used include the neti pot, a squeezable plastic bottle with nasal adaptor, or a pulse irrigator combined with a nasal adaptor. Limited data suggest that although hypertonic saline is generally more irritating, it may have a more decongesting effect as well as stimulating ciliary transport to a greater degree than isotonic saline, as evidenced by its ability to improve mucociliary transit times of saccharin (113). In a small study of children with seasonal allergic rhinoconjunctivitis, those rinsing with nasal hypertonic saline three times daily during the 7-week peak pollen season had lower weekly mean rhinoconjunctivitis scores than the control group during all weeks, although only in a statistically significant manner during Weeks 6 and 7. In addition, rinsers had a markedly reduced need for oral AHs during 5 of the 7 weeks (114). Another study looked at the effect of nasal rinsing in pregnant women with seasonal AR during a 6-week period corresponding to the pollen season. In this population, hypertonic irrigation three times daily led to reduced self-reported nasal symptoms, medication use, and objective measurements of nasal patency (115). In a separate prospective study of 211 individuals with ‘‘sinonasal disease,’’ including AR, ‘‘aging rhinitis,’’ atrophic rhinitis, postnasal drip, and chronic rhinosinusitis, 3 to 6 weeks of hypertonic saline irrigation led to statistically significant improvement in 23 of 30 symptoms as measured by a nasal disease–specific symptom questionnaire (116).

IT IN THE TREATMENT OF AR IT is the only treatment currently available with the potential to change the natural history of AR and slow the allergic march seen in many atopic individuals. The ability of subcutaneous immunotherapy to reduce the risk of subsequent asthma was

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demonstrated in a cohort of children aged 6 to 14 years with at least moderate rhinitis and eye symptoms, but no asthma, stemming from grass and/or birch allergies. In this study, all 205 children were randomized to receive specific immunotherapy for 3 years or be in an open control group. The actively treated children had significantly fewer asthma symptoms after 3 years as evaluated by clinical diagnosis (odds ratio [OR], 2.52) (117). After an additional 7 years, 147 of the 205 individuals, now 16 to 25 years old, were reevaluated. Not only did significant improvements in rhinoconjunctivitis and conjunctival sensitivity persist, but significantly fewer subjects who had received immunotherapy developed asthma as evaluated by clinical symptoms (OR, 2.5; 95% confidence interval, 1.1–5.9). When adjusted for bronchial hyperresponsiveness and asthma status at baseline and including all observations over the entire 10-year follow-up (children with or without asthma at baseline, n 5 189; 511 observations), the OR for no asthma was 4.6 (95% confidence interval, 1.5–13.7) in favor of subcutaneous IT (118). The prolonged clinical remission induced by 3 to 5 years of subcutaneous IT is associated with a persistent alteration in immunologic reactivity (119). Until recently, IT has been exclusively administered by subcutaneous injections (SCIT); however, an increasing body of evidence also supports the efficacy of sublingual dosing (SLIT). SLIT has yet to receive FDA approval in the United States, but it is already in widespread use in Europe. SLIT appears to be safer than SCIT, as side effects are usually restricted to the upper airways and gastrointestinal tract; rare anaphylactic episodes have been reported (120). Similar to SCIT, SLIT may have the potential to alter the natural history of atopic disease by decreasing the progression to asthma (121). Unresolved areas include finding the optimal dose for many of the allergens, defining the optimal length of therapy, and deciding on how to approach polysensitized patients. Subcutaneous immunotherapy should be a consideration in carefully selected patients who remain symptomatic despite appropriate pharmacotherapy or those unable or unwilling to take pharmacotherapy for prolonged periods of time (122). A special consideration is the pediatric population who may have a decreased risk of developing asthma with SCIT.

CONCLUSIONS AR and NAR represent common conditions affecting millions of individuals in industrialized nations. Unlike AR, the pathophysiology underlying NAR is not fully understood, probably in part because of the heterogeneity of conditions present in this category. Although a large number of different pharmacological agents have shown clinical efficacy and safety for the treatment of AR, there are fewer effective options available to the clinician for treating NAR. As a better understanding of the pathological processes underlying NAR subtypes emerges, the number of potential therapies able to bring relief to these conditions will likely also increase. Author Disclosure: A.N.G. is Co-director, Allergy & Asthma Medical Group & Research Center. He received lecture fees from the Network for Continuing Medical Education ($5,001–$10,000), MEDA, and the UCB ($1,001–$5,000). He was an expert witness for Smith/Cresto v. Woodrow ($10,001–$50,000) and Caballero vs. Alisol ($1,001–$5,000). He received grant support (institutional) from the UCB (more than $10,000), Alcon, Alexza, Amgen, Antigen Labs, Apotex, Astellas, AstraZeneca, Boehringer Ingelheim, Capnia, Critical Therapeutics, GlaxoSmithKline, MAP, MEDA, Merck, Novartis, Schering-Plough, and Teva (less than $10,000). E.O.M. is Co-director, Allergy & Asthma Medical Group & Research Center. He was a consultant for Alcon ($10,001–$50,000), ISTA ($1,001–$5,000), Capnia ($5,001–$10,000), Johnson & Johnson, and Kalypsys ($1,001–$5,000). He was on the Board or Advisory Board for Amgen ($5,001 – $10,000), Dey ($5,001–$10,000), Merck ($10,001–$50,000), Teva, and Wockhardt ($1,001–$5,000). He received lecture fees from GlaxoSmithKline ($10,001–$50,000), MEDA ($1,001–$5,000), Schering Plough, Sepracor


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($10,001–$50,000), and Sanofi Aventis ($5,001–$10,000). He was an expert witness for Schering vs. Zydus Pharma, Aventis & Sanofi Aventis v. Barr ($5,001– $10,000), Merck & Dohme v. Teva, and Sepracor vs. Barr ($10,001–$50,000). He received grant support from (institutional) the UCB (more than $10,000), Alcon, Alexza, Amgen, Antigen Labs, Apotex, Astellas, AstraZeneca, Boehringer Ingelheim, Capnia, Critical Therapeutics, GlaxoSmithKline, MAP, MEDA, Merck, Novartis, Schering-Plough, and Teva (less than $10,000). He was a consultant for Sandoz ($1,001–$5,000), a speaker for SRxA ($5,001–$10,000), and a consultant/speaker for National Jewish Health ($1,001–$5,000). He was a consultant and was on the Advisory Board for MAP, and MEDA ($1,001–$5,000).

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