Novel Topical Intranasal Therapies In The Management Of Allergic Rhinitis

INTRODUCTION

Allergic rhinitis (AR) is one the most common immunologic conditions affecting adults. Its prevalence has increased over the last few decades and varies between 10-40% depending on geographical location, with up to 25% of Canadians being affected.¹  

It is defined as an IgE-mediated inflammatory process affecting the nasal mucosa in a previously sensitised individual.² When an atopic patient is exposed to an allergen, the patient develops specific IgE antibodies which become bound to mast cells. Re-exposure to this allergen results in two distinct phases of inflammation: an early phase occurring within minutes, due to mast cell degranulation which causes nasal itching, congestion and discharge; and a late phase occurring after several hours, due to eosinophil activation resulting in increased mucous production, nasal blockage and hyposmia. 

The Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines classifies AR based on duration, as well as severity of symptoms.² (Table 1) 

Table 1: The ARIA guidelines definitions of allergic rhinitis based on duration and severity of symptoms.

There is a strong association between AR and asthma, frequently co-existing in up to 38% of patients, with 74%-89% of asthmatic patients reporting some rhinitis symptoms.³ 

Type II inflammatory cytokines are prevalent in both AR and chronic rhinosinusitis (CRS) resulting in a multifactorial aetiologic linkage between these two conditions. Mucosal oedema and inflammation result in damage to nasal cilia and disruption of the mucocilliary clearance and subsequent release of inflammatory cytokines, with propagation of mucosal inflammation resulting in CRS. Specific phenotypic subsets of CRS, most notably central compartment atopic disease (CCAD) and allergic fungal sinusitis appear to have a strong association with allergies and AR. This association underscores the importance of adequate treatment of rhinitis in improving long-term outcomes of endoscopic sinus surgery in treating CRS with concomitant AR.⁴ 

Diagnosing AR requires a comprehensive history and examination. The type, duration and severity of symptoms, the presence of concomitant asthma or atopic disease, as well as family history should be explored. Anterior rhinoscopy and nasal endoscopy further aid in identifying signs of AR such as pale, inflamed nasal mucosa, inferior turbinate hypertrophy and/ or the presence of nasal discharge. 

Diagnostic tests such as skin prick testing (SPT) (80% sensitivity and specificity; 15% with a positive SPT will not develop symptoms on exposure to allergens) and serum IgE levels could be considered when the diagnosis is uncertain or specific allergen identification is indicated.⁵ 

MANAGEMENT 

Clinicians may consider adopting a multi-faceted approach to the management of AR utilising a broad range of topical therapeutics. (Figure 1) Further, the importance of patient education should not be overlooked as it is central to ensuring patient engagement and compliance with their treatment regimen and, ultimately, with optimal clinical outcomes. Using a patient-centric approach that is highlighted by shared decision-making of therapeutic agents allows patients to identify therapies that have provided them with the most sustainable symptomatic improvement. This approach allows patients to incorporate and titrate medications that work for them, according to fluctuations in their symptoms. 

Topical drug delivery to the nasal mucosa remains the most effective method of controlling nasal inflammation and reducing symptoms, by allowing delivery of high dose medications directly to local inflammatory receptors, thereby increasing treatment success, while minimizing systemic side effects. Intranasal corticosteroid steroids (INCS) and intranasal antihistamines (INAH) are the most widely-advocated treatment modalities employed in the management of AR, with novel combination preparations of these two classes of drug demonstrating substantial improvement in symptom control when compared to INCS and INAH alone. 

Fig 1. Proposed working algorithm for
the management of AR.

SISI: Steroid-impregnated saline irrigation
NSS: Nasal steroid spay
INCS: Intranasal Corticosteroids
INAH: Intranasal Anti-histamines
SCIT: Subcutaneous immunotherapy
SLIT: Sublingual immunotherapy

INTRANASAL SALINE: 

Intranasal saline has been widely utilized in the management of AR as both a standalone treatment, as well as an adjunctive option with a growing body of evidence supporting its use and efficacy.^6,7 In a systematic review of more than 50 relevant trials between 1994 and 2010 examining the use of intranasal saline in the treatment of AR, reviewers selected 10 relevant studies that satisfied the inclusion criteria (> 400 participants total) and found that when used in patients with AR, intranasal saline produced a 27% improvement in nasal symptoms, a 62% reduction in medication consumption, a 31% acceleration of mucociliary clearance (MCC) time and a 27% improvement in quality of life.6 

Nasal irrigation has been used in varying concentrations and regimens with isotonic preparations shown to be most effective at improving MCC in AR and acute sinusitis patients.7 Overall, intranasal saline has a significant benefit when used in any patient with AR. It is inexpensive, readily available, and well-tolerated with minimal side effects, making it suitable for long-term use. 

INTRANASAL CORTICOSTEROID THERAPY 

INCSs are the mainstay of treatment for moderate-to-severe AR. Their potent anti-inflammatory properties enable suppression of early and late phase allergic response by inhibiting pro-inflammatory type II cytokine (IL-5 and IL-13) release, reducing inflammatory cell proliferation and reducing their subsequent presence in nasal secretions.^8,9 

INCSs have a significantly greater efficacy of symptom reduction compared to placebo, anti-histamines (oral or topical) and leukotriene receptor antagonists.^10,11 When compared to the INAH azelastine, INCS are significantly superior at alleviating rhinorrhea, with comparable reduction in nasal symptom scores.¹² A recent systematic review and meta-analysis including five randomized controlled trials with a total of 990 patients found INCS to be superior to oral anti-histamines (OAH) in improving nasal symptoms and quality of life, relieving nasal obstruction and rhinorrhea.¹³ INCS reduce nasal symptoms, in particular nasal congestion, within the first 12-hour interval for evaluation of symptoms.¹⁴ A recent double-blind, placebo-controlled, randomized, parallel-group study of the as-needed usage of fluticasone propionate nasal spray in the management of seasonal allergic rhinitis was performed in which twenty-six subjects in each group completed the 4-week study. The results demonstrated that INCS is more effective when used in daily dosing strategies, whilst the as-needed INCS use is found to be as effective as placebo in management of AR, emphasising the importance of prolonged daily use to achieve maximal effect.¹⁵ 

No significant difference in efficacy has been demonstrated between different agents.¹⁶ Therefore, tolerability and compliance with therapy is largely dependent on such factors as taste, smell and pharyngeal irritation, which should be considered when choosing between INCSs. 

Common side effects include anterior septal dryness, local irritation, nasal pain and burning. Epistaxis in particular may be observed in as much as 20% of patients, which can usually be overcome by corrected use of the intranasal delivery device or simple nasal lubrication measures overnight.¹⁷ Systemic absorption is minimal with very low risk of suppression of hypothalamic-pituitary axis.¹⁸ 

COMBINATION THERAPY: STEROID-IMPREGNATED SALINE IRRIGATION (SISI) 

Clinicians may consider the utilisation of twice-daily steroid impregnated saline irrigation (SISI) as a first-line topical therapy for patients with AR and CRS. This allows for the combined and additive therapeutic benefits of saline irrigation with INCS, most notably the improved MCC and nasal congestion symptom improvement. This approach also facilitates topical drug delivery throughout the entire nasal cavity (anteriorly and posteriorly), thereby allowing better control of global mucosal congestion. Finally, it avoids the common side effects of nasal steroid spray use, such as anterior septal dryness and epistaxis. This modality of topical drug delivery has been shown to provide a meaningful improvement in symptoms and endoscopy scores in patients with CRS.¹⁹ 

Clinicians may find that adding spray preparations, of either INCS alone or combination INCS and INAH to this rinsing regime offers the added benefit of targeting mucosal inflammation anteriorly, with INCS and INAH notably targeting the anterior heads of inferior turbinates, while the SISI work better posteriorly within the nasal cavity. This ‘combined’ mucosal inflammatory control regime seems to offer enhanced global oedema reduction and improve overall airflow thereby significantly reducing overall nasal congestion. 

INTRANASAL ANTI-HISTAMINES 

Histamine-mediated cytokine release is an important component of the early and late phase allergic reaction in AR. INAHs are novel therapeutics enabling delivery of high concentrations of H2-receptor antagonists directly onto the nasal mucosa, enhancing local anti-inflammatory effect whilst avoiding systemic side effects.²⁰ 

These agents have a faster onset of action compared to OAHs (< 15 minutes) and are effective at alleviating nasal symptoms when compared with placebo.²¹ INAHs provide not only an effective rescue therapy solution but also demonstrate higher efficacy when used continuously.²² They are more effective for nasal symptom control than OAHs alone and combination treatment with both OAHs and INAHs confer no additive benefit in alleviating nasal symptoms.²³ When compared with INCSs, INAHs used as monotherapy are less effective in controlling nasal congestion but show superiority in relieving ocular symptoms.²⁴ INAHs are safe with very few side effects, the most notable of which is a bitter taste which can impact tolerability and compliance. 

INAH preparations are readily available in Europe and other parts of the world. Currently in Canada, there are no stand alone INAH preparations that are commercially available. At present, INAH can only be prescribed in combination with INCS (as a single spray formulation). 

COMBINATION INCS AND INAH THERAPIES 

The combination fluticasone propionate (FP) and azelastine hydrochloride (AZE) spray is a novel preparation allowing for concomitant delivery of INCS and INAH in a single device. It has been shown to be more effective at reducing nasal symptoms in moderate-to-severe AR, when compared with either placebo, FP or AZE alone.^25,26 In particular, it has a rapid onset of action of 5-10 minutes (5 minutes for TNSS and 10 minutes for other assessments (TOSS, T7SS, and VAS).²⁷ Furthermore, it alleviates nasal symptoms days earlier than other monotherapies (FP, AZE). 

The main advantages of using a combination topical therapy includes: 1) its rapid onset of action, which can aid significantly with patient compliance, 2) the concurrent reduction of ocular symptoms, 3) its ease of use and convenience as a single spray device, and 4) its homogenous distribution of medication with increased retention resulting in reduced run off. 

It is for these reasons that several guidelines have recommended its use for moderate to severe AR and as first-line therapy in seasonal allergic rhinitis.^2,21 

Moreover, there is emerging evidence to support a potential role of the combination fluticasone propionate (FP) and azelastine hydrochloride (AZE) spray in the management of non-allergic rhinitis (NAR), with studies demonstrating sustained symptomatic improvement in this group of patients.²⁸ It is thought that azelastine’s direct inhibitory actions on the activity of transient receptor potential vanilloid 1 (TRPV1) which is over expressed in patients with NAR, accounts for its anti-inflammatory effects.²⁹ 

Incorporating this combination treatment early into the algorithm for patients with moderate-to-severe AR, and often in combination with SISI may yield positive benefit and may provide an effective approach to targeting nasal mucosal inflammation anteriorly and posteriorly within the nasal cavities. 

CONCLUSION 

Advances in novel intranasal topical therapeutics have enabled different methods for delivery of high potency medication directly to the nasal mucosa. This improves control of local mucosal inflammation and reduces systemic side effects from medications. 

INCS remain the first-line treatment modality of choice and are safe and effective. These agents can be delivered either in spray form, which seems to preferentially target the anterior nasal cavity, or used in combination with SISI that additionally improves MCC and has a greater effect on global congestion (anteriorly and posteriorly in the nose). 

Combination INCS and INAH are substantially more effective at controlling nasal inflammation and improving symptoms than monotherapy alone. Delivered as a single-spray formulation enhances patient compliance with INCS treatment and this modality also has the added benefit of a rapid onset of action as well as significantly reducing ocular symptoms. The main disadvantage of this treatment is the cost of the medication. 

Patient education that empowers patient-centric decision making regarding topical nasal therapies will improve compliance with treatment and enable the patient to tailor their treatment according to fluctuations in their symptoms.