Treatment options for the management of perennial allergic rhinitis, with a focus on intranasal corticosteroids.

Abstract: Perennial allergic rhinitis (PAR) can have a significant impact on a patient's quality of life. While allergen avoidance is the first line of management for PAR, complete avoidance is difficult. Therapeutic options available for PAR include intranasal corticosteroids (INS), [H.sub.1]-antihistamines, decongestants and local chromones, as well as immunotherapy. For mild symptoms, INS and antihistamines are the standard of care, whereas for moderate-to-severe PAR, INS are the preferred therapy due to their proven efficacy. Patient quality of life and therapy preference play a role in maintaining adherence to treatment.

Key Words: perennial allergic rhinitis, avoidance, intranasal corticosteroids, antihistamines

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Allergic rhinitis (AR) is the most prevalent chronic allergic disease. It is thought that up to 10% of adults and 40% of children in the US are affected by AR. (1) As such, AR is one of the most common reasons for visits to primary care practitioners, (2) who play a key role in the management of the disease.

The economic burden associated with AR is substantial. In 1996, the estimated total cost of AR in the US was $6 billion. (3) While the symptoms caused by AR are not life threatening, they can significantly impact on patient quality of life (4); the disease reduces productivity at work, (5) impairs concentration (6) and reduces learning ability in children. (7) AR is often associated with a number of comorbidities, including sinusitis, asthma and otitis media. (8-12) Poorly controlled AR can exacerbate these conditions, adding greatly to the morbidity and economic burden of the disease. (2)

Effective management can prevent the adverse events of perennial AR (PAR), restore patient quality of life, avoid exacerbation of comorbid pathologies and reduce economic burden. This article reviews the current recommendations for the diagnosis and management of PAR, providing a practical overview for the primary care practitioner.

Classification and Diagnosis of Perennial Allergic Rhinitis

AR has traditionally been divided into AR that occurs seasonally due to outdoor allergens such as pollen, and AR that occurs perennially due to indoor allergens such as dust mites and pet dander. (13) However, these definitions are a poor reflection of real life, (14) with some pollens occurring perennially (15) and some symptoms of perennial allergies not being present continuously. Therefore, the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines reclassify AR into intermittent and persistent AR, based on symptom timing and frequency (Table). (11) Both intermittent and persistent AR can be subdivided based on the severity of patient symptoms into mild or moderate-to-severe. The traditional nomenclatures of seasonal and perennial AR are retained herein to allow a direct discussion of published data.

AR clinically presents as some or all of the following symptoms: rhinorrhea, sneezing, nasal congestion, itching of the nose and palate, and ocular symptoms (itchy, watery eyes). Seasonal allergic rhinitis can be easy to diagnose due to the rapid onset of symptoms when the patient is exposed to pollen. (16) For example, the ragweed pollen season occurs during the fall in the northern latitudes of the US; AR symptoms occurring during this period may be caused by ragweed pollen. Conversely, diagnosing PAR can be difficult, as diagnostic criteria can overlap with those of some non-AR diseases such as sinusitis and vasomotor rhinitis. (16) Furthermore, occupational rhinitis can result from both allergic and nonallergic causes. (17) For example, animal dander found in laboratory environments may result in AR, whereas irritants such as wood dust, detergents, dyes and other industrial chemicals can cause non-AR. (18) Diagnosis should focus on symptoms, triggers, seasonal variation, allergies, medical history and current treatments. (17) Accurate diagnosis is paramount, as effective therapies for AR may not be so effective at treating nonallergic rhinitis. (19)

The causative allergens of PAR commonly include house-dust mites, indoor molds, cockroaches and animal dander. (11) The prevalence of the trigger allergen dictates the incidence of a patient's symptoms; the identification of the trigger allergen is an important aspect in the diagnosis of PAR. A thorough clinical history will provide clues as to the probable trigger. Patients should be carefully questioned regarding possible allergens present at home, work or school. Typically, the causative allergens of PAR are ubiquitous and present all year round.

Percutaneous or intradermal skin testing and immunoglobulin E (IgE) testing (assessed by radioallergosorbent testing [CAP-RAST]) are commonly used by qualified personnel to confirm sensitivity to a particular allergen. Skin testing introduces the allergen into the skin and results in a wheal and flare reaction after 15 minutes, (20) whereas CAP-RAST testing is an in vitro test that involves the binding of a specific allergen to specific IgE in serum. Antibodies are used to quantify the amount of specific IgE bound to the allergens. (21,22) The significance of a positive result during these tests must be considered in conjunction with a suggestive clinical history. (23)

Mechanisms of Perennial Allergic Rhinitis

The pathology of AR can be divided into early and late-phase reactions. Early-phase symptoms occur within minutes of allergen exposure and are characterized by rhinorrhea, nasal obstruction, sneezing and pruritus. (24) Immunoglobulin E-mediated activation of mast cells and basophils release mediators, such as histamine and leukotriene, which activate their respective receptors and induce the symptoms of AR. Histamine is probably the major mediator of the early-phase reaction. (25) Both mast cells and T cells also release cytokines such as interleukins, that induce IgE synthesis. (26)

Approximately 30 to 40% of patients develop a late-phase reaction occurring 4 to 5 hours after the initial allergen exposure (25) characterized by nasal obstruction. (25) Cytokines and chemokines, such as interleukin (IL)-8, as well as the mediators released by the early-phase reaction, help recruit and activate inflammatory cells, such as eosinophils, (27) which themselves release mediators. Symptoms are therefore perpetuated, with persistent AR sufferers existing in a continual state of eosinophilia and increased mediator release. (28)

Management of Perennial Allergic Rhinitis

A review of MEDLINE was performed to assess pharmacologic treatment options using the terms 'perennial allergic rhinitis', 'allergen avoidance', 'intranasal corticosteroids', 'antihistamines', 'decongestants' and 'chromones', as well as individual drug names.

Allergen Avoidance

Allergen avoidance is the first line of management for PAR. Reducing the allergens in a patient's immediate environment can have a significant impact on symptom frequency and severity. (29) A range of measures can be employed, depending on the allergen involved. Aggressive cleaning of the home, effective filtering of the air, hot washing of bedding, replacement of carpets with hard flooring and regular wet-wiping of surfaces are general measures that eradicate most allergens. Despite rigorous cleaning, many allergens persist for extended periods of time and are easily transferred between environments. The total exclusion of an allergen from the environment is difficult. If the causative allergen is occupational, allergen avoidance may be unrealistic. Therefore, treatment to control the symptoms of PAR is frequently required.

Mites. Several specific mite-avoidance measures have been investigated in clinical studies, with varying outcomes. For example, tightly woven mattress coverings have been shown to effectively exclude both cat and house-dust mite allergens. (30) In addition, randomized, controlled studies have shown that the use of dust-mite impermeable mattress covers and other specific environmental controls can result in children being less likely to develop sensitization to dust mites (31) and in reductions in nasal symptoms. (32) Another study indicated that impermeable bedding covers significantly reduced the level of exposure to mite allergens, although corresponding improvements in the clinical symptoms of AR were not noted. (33)

Animals. For animal allergy, removing the animal from the home is the first option though this may cause distress to the patient and their family. High-efficiency particulate air (HEPA)-filtered vacuum cleaners have been shown to reduce the concentration and particle size of airborne cat allergens. (34) The effect allergen reduction had on symptoms was not assessed in this study. A further study indicated that despite the combination of a HEPA room air cleaner, the use of mattress and pillow covers and cat exclusion from the bedroom, no effect on disease activity was noted. (35) Therefore, while allergen avoidance can be useful, some avoidance measures may not always be enough as a single approach, and multiple avoidance measures may be needed.

Pharmacologic Options

For PAR, a number of treatment options can be considered. For patients with mild symptoms, [H.sub.1]-receptor antagonists in oral and nasal formulations, INS, local chromones and oral and intranasal decongestants are recommended. Intranasal anticholinergic agents are also recommended for cases where rhinorrhea is the main symptom. (11) Antileukotrienes, such as montelukast, have recently been approved for the treatment of nasal congestion due to AR. (36) In moderate-to-severe PAR, INS are first-line therapy. (11,37-39) Agents can be used individually or in combination to provide optimal symptom relief depending on symptoms.

Intranasal Corticosteroids

Six aqueous INS formulations are currently licensed for the treatment of adult and pediatric PAR in the US: beclomethasone dipropionate (BDP), budesonide, flunisolide, fluticasone propionate (FP), mometasone furoate (MF) and triamcinolone acetonide (TAA).

Mechanism of Action

While the precise mechanism of action of corticosteroids has yet to be fully elucidated, they are known to have a profound impact on the inflammatory response, suppressing many elements of the allergic inflammatory cascade. By binding to the glucocorticoid receptor of nasal epithelial cells, corticosteroids modulate the expression of a number of genes that play a pivotal role in the inflammatory response. (40) Among other functions, corticosteroids have been shown to reduce eosinophil infiltration and survival (41,42) and to suppress the expression of the cytokines IL-3, IL-4, IL-5 and IL-13, (43) dramatically reducing the infiltration of inflammatory cells into the nasal mucosa. Corticosteroids also reduce the release of several chemical mediators of inflammation, including histamine, (44) tryptase (45) and leukotrienes, (46) although these effects may be due to a reduction in the overall number of inflammatory cells in the epithelium.

Safety of Intranasal Corticosteroids

The adverse events arising from the long-term use of systemic corticosteroids, such as skin-thinning, osteoporosis and Cushing syndrome, are well known. (11) However, INS and systemic corticosteroids should not be classified together as they exhibit differing adverse-event profiles. Local application of corticosteroids allows the use of lower doses that are associated with lower risks of adverse events. In addition, the improved pharmacokinetic profile and, hence, reduced bioavailability of the newer INS agents, further reduces the risk of systemic effects.

Local adverse events. Local adverse events associated with INS are generally minor and easily managed; the most common adverse events include irritation of the nasal epithelium, minor nosebleeds and headaches. These adverse events can usually be managed, although if they persist, switching to another agent or delivery device often eliminates the problem. (11) Septal perforation is an extremely rare adverse event of INS therapy that may largely be avoided by correct administration. (47) Patients should be advised to direct the spray away from the septum to minimize any risk of septal perforation. (48)

Systemic adverse events. Suppression of the hypothalamic-pituitary-adrenal (HPA) axis is a well-characterized adverse event of systemic corticosteroids. However, a number of clinical studies have shown that TAA, MF and FP have little or no effect on the HPA axis. (49,50) A preliminary study found no evidence of HPA-axis suppression with both FP 200 [micro]g once daily and TAA 220 [micro]g once daily when used in combination with the same agents administered at clinically recommended dosages for inhaled administration (FP 1760 [micro]g daily and TAA 1600 [micro]g daily). (51) It is advisable to use the lowest corticosteroid dose possible to control allergic disease because of a potential additive effect of intranasal and inhaled corticosteroids.

Concerns have also been raised over the effect of long-term INS therapy on linear growth in young children, (52) with one study suggesting that long-term use of BDP reduced growth in children. (53) The weight of evidence from data collected in recent years suggests that INS therapy has no significant long-term effect on normal growth in children. For example, a 1-year trial of MF 100 [micro]g once daily showed no evidence of growth suppression or impaired bone metabolism in children with PAR. (54) Similarly, a study of FP 100 [micro]g administered twice daily for 1 year to children aged 1 to 3 years showed no significant effect on growth. (55) Another 1-year study in children aged 6 to 14 years also demonstrated no significant effect of TAA treatment on growth velocity. (56) Finally, a comparative study of TAA 110 [micro]g and 220 [micro]g once daily and FP 200 [micro]g in children showed no significant statistical difference in mean growth velocity compared with placebo. (57)

Efficacy

Despite marked differences in the pharmacokinetic properties of the currently available INS formulations, all have proven efficacy in controlling the symptoms of PAR. (58) Furthermore, several head-to-head and comparative studies have indicated no clinical differences in efficacy between INS agents. For example, one study compared the efficacy of MF and FP at treating PAR in a 3-month, double-blind, double-dummy, placebo-controlled trial. Both agents were significantly (P < 0.01) superior to placebo at reducing nasal symptoms. There was no statistically significant difference between the two agents. (59) In a similar trial comparing TAA and FP, both agents were found to be equally effective in reducing total nasal symptom score from baseline (3.17 [+ or -] 0.18 and 3.15 [+ or -] 0.19, respectively). (60)

Quality of Life

PAR can have a strong negative impact on patient quality of life. A study of health-related quality of life found that patients with PAR reported more pain, felt less healthy, had poorer mental health and felt less able to function effectively than healthy volunteers. (61) INS agents have been shown to have benefits in patient health-related quality of life. (62) For example, a placebo-controlled, multicenter, randomized, double-blind study in patients with PAR found that TAA 220 [micro]g once daily significantly (P = 0.04) improved health-related quality of life, as assessed using the Rhinoconjunctivitis Quality of Life Questionnaire. Improvement in quality of life directly correlated with reductions in nasal symptoms. (63) A similar trial compared the effects of budesonide and FP on quality of life in patients with AR. (64) Both agents significantly (P < 0.05) improved patient quality of life as measured by the Rhinoconjunctivitis Quality of Life Questionnaire when compared with placebo. Greater improvements in patient quality of life were seen with budesonide than FP. (64) A study concerning nocturnal symptoms only found that TAA 220 [micro]g once daily for 3 weeks significantly improved (P < 0.001) nocturnal symptoms compared with baseline (65) as measured by the Nocturnal Rhinoconjunctivitis Quality of Life Questionnaire and Pittsburgh Sleep Quality Index.

Patient Preference/Adherence

Successful treatment of PAR requires good long-term patient adherence. (66) Patient education and involvement is crucial to maintaining good treatment compliance, and patient preference for certain aspects of INS treatment, including convenience of administration, sensation during and after administration, irritation upon administration, and INS odor and taste, is thought to play a significant role in maintaining adherence to a therapeutic regimen. (67,68) A number of studies have compared patient preference for MF, FP and TAA; however, these have included the old MF formulation, before the current alcohol-free formulation was available. Therefore, the comparisons with the old formulation are no longer relevant.

For example, a multicenter, randomized, double-blind, crossover study comparing patient assessments of the sensory attributes of MF (old formulation), FP and TAA, found that TAA was rated as having little or no odor, a milder, more pleasant taste and a less drying effect on the throat than FP (P [less than or equal to] 0.05). (67) During the same trial, a greater proportion of patients indicated that they would be more compliant with medication if they were prescribed TAA over FP. (67) An earlier study also demonstrated preference for TAA over FP and BDP when rated for odor or taste. (69) Patient preference has also been shown for budesonide over FP (70) and the new MF formulation over FP based on sensory attributes. (71)

[H.sub.1]-Receptor Antagonists

[H.sub.1]-receptor antagonists are a mainstay treatment for patients with mild-to-moderate PAR, and can be classified into first- and second-generation agents. First-generation antihistamines have been effective treatments for symptoms of AR, but are known to cause adverse events due to their lack of selectivity, resulting in anticholinergic effects such as dry mouth, tachycardia, urinary retention and gastrointestinal disturbances. (72) Further adverse events are caused by the ability of the first-generation agents to cross the blood-brain barrier, resulting in sedation and impairment of psychomotor and cognitive function. (73) Nasal antihistamines such as levocabastine, azelastine and antazoline, however, have almost no associated adverse events, targeting only the organs to which they are administered. (74) Nasal antihistamines are of particular benefit to children whose symptoms are limited to the eyes or the nose. (75)

Second-generation antihistamines, such as cetirizine, loratadine, desloratadine and fexofenadine, are also effective at controlling the main symptoms of mild-to-moderate PAR, (76-79) but are more selective for the [H.sub.1]-receptor than their first-generation predecessors and have a lower tendency to cross the blood-brain barrier. (80) Due to their improved safety profile, a recent consensus report recommended that second-generation antihistamines should be used instead of the first-generation agents in all patients with AR. (80)

Second-generation oral antihistamines generally have a fast onset of action (1-3 h) (81,82) and are convenient to use due to their once-daily formulations. However, compared with INS, oral antihistamines are less effective against nasal congestion. Therefore, in persistent or moderate-to-severe PAR, antihistamines are often used concurrently with an INS or a decongestant.

Oral and Intranasal Decongestants

Decongestants may also be used to relieve nasal congestion. For patients with moderate-to-severe nasal congestion, decongestants are used as add-on therapies to INS. (11) While the intranasal agents are faster than the oral formulations, the duration of treatment is limited to less than 10 days to prevent rhinitis medicamentosa (11); intranasal decongestants are not used as long-term therapy except during severe symptoms. The adverse events associated with oral decongestants are dose-dependent and include irritability, dizziness, headaches, tremor and insomnia. Care should be taken when giving oral decongestants to susceptible patients such as pregnant women and the elderly.

Combinations of oral decongestants with second-generation oral antihistamines are also available. There are limited published studies on the use of such combinations in PAR, but they have been shown to be more effective at treating the whole range of symptoms in patients with seasonal AR, compared with the individual monotherapies. (83-86)

Local Chromones

Intranasal chromones are considered to be less effective than other treatment options, with a short-lasting effect. (11) Although typically associated with the treatment of seasonal AR, chromones can be used for the treatment of mild PAR symptoms, especially in children, due to their excellent safety profile. However, compliance is generally poor due to twice-/three times-daily dosing.

Immunotherapy

Allergen immunotherapy can be an effective method of treating PAR. (11) Patients whose AR cannot be controlled by avoidance measures and pharmacologic treatments and who need to avoid potential adverse events associated with pharmacologic treatments are good candidates for receiving immunotherapy. (87) Immunotherapy works by gradually increasing doses of allergen administered subcutaneously by an allergy specialist to induce tolerance to the allergen. Immunotherapy has been shown to be effective and has a high safety profile, although treatment is typically required over a number of years (88) and anaphylaxis following injection can be fatal. (89)

Omalizumab

Although not yet a United States Food and Drug Administration-approved treatment for PAR, omalizumab has been shown to be an effective treatment for patients with PAR and seasonal AR. (90) Omalizumab is an antibody that binds IgE, preventing IgE from binding to basophils, thereby attenuating mediator release and reducing allergic symptoms. (91) Omalizumab has been shown to be well tolerated. (91)

Conclusions

Perennial AR has a significant negative impact on patient quality of life and may further exacerbate a number of common comorbidities. Allergen avoidance can improve symptoms; however, the allergens most frequently associated with PAR are ubiquitous and complete avoidance is difficult. Many patients affected by PAR require medication to control symptoms.

A number of options exist for the treatment of PAR, including INS, antihistamines, decongestants and chromones. While INS and antihistamines are first-line therapies for mild symptoms, ARIA guidelines have recommended INS therapy as the gold-standard treatment for moderate-to-severe PAR symptoms. The safety profiles of INS agents are associated with few systemic adverse events, with the newer INS agents being associated with little or no HPA-axis suppression and no significant long-term growth reduction in children. The efficacies of the currently available aqueous agents are broadly equivalent. To maximize symptom relief and improve patient quality of life, it is important that patients adhere to an INS treatment regimen. Recent studies have suggested that tailoring treatment to patient preference improves treatment adherence, hence improving long-term clinical outcome.

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Stephen A. Brunton, MD, and Leonard M. Fromer, MD

From the Cabarrus Family Medicine Residency Program, Charlotte, NC, and the Department of Family Medicine, UCLA School of Medicine, CA.

Reprint requests to Dr. Stephen Brunton, Cabarrus Family Medicine Residency Program, 7011 Summerhill Ridge Drive, Charlotte, North Carolina 28226. Email: [e-mail]

Stephen A. Brunton, MD, is a consultant to Sanofi-Aventis, Schering Plough and GlaxoSmithKline; Leonard M. Fromer, MD, has been a participant in CME events and advisory boards funded by unrestricted educational grants from Sanofi-Aventis.

Accepted January 4, 2007.

RELATED ARTICLE: Key Points

* Several classes of pharmacologic agents are available for the treatment of perennial allergic rhinitis (PAR), including intranasal corticosteroids (INS), [H.sub.1]- antihistamines, local chromones and decongestants.

* Intranasal corticosteroids are the first-line option in moderate-to-severe PAR and can also be used in mild PAR, due to their proven efficacy.

* Second-generation oral antihistamines are effective at controlling mild-to-moderate PAR, have a fast onset of action and good safety profiles.

* Oral decongestants, usually in combination with oral antihistamines, are recommended for mild nasal congestion and as add-on therapy to INS for moderate-to-severe nasal congestion. Intranasal decongestants can also be used in severe cases of blockage.

* Local chromones are available as intranasal formulations for reducing the nasal symptoms of PAR, particularly in children.

* Successful treatment of PAR requires long-term treatment and patient adherence. Therefore, patient quality of life and patient preference for an agent should be considered when choosing a therapeutic option.

Table. ARIA classification of allergic rhinitis

Intermittent
Symptoms are present:
* Less than 4 days a week
* OR, for less than 4 weeks

Persistent
Symptoms are present:
* More than 4 days a week
* AND, for more than 4 weeks

Mild
None of the following are present:
* Sleep disturbance
* Impairment of daily activities, leisure and/or sport
* Impairment of school or work
* Troublesome symptoms

Moderate-severe
One or more of the following are present:
* Sleep disturbance
* Impairment of daily activities, leisure and/or sport
* Impairment of school or work
* Troublesome symptoms

Reprinted with permission from Bousquet J, et al. Allergic rhinitis and
its impact on asthma. J Allergy Clin Immunol 2001;108(Suppl 5):S147-
S334.