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Management of allergic rhinitis

PRACTICAL THERAPEUTICS

 

Dymista contains azelastine and fluticasone and is a new fast-acting treatment for the management of allergic and perennial rhinitis

 

Rod Tucker PhD MRPharmS

Honorary Research Associate,

Faculty of Health and Social Care,

University of Hull, UK

Email: rodtucker.tucker@gmail.com

 

 

Rhinitis is defined as an inflammation in the nasal mucosal membranes and is characterised by rhinorrhoea (both anterior and posterior, that is, runny nose and post-nasal drip), itching, sneezing and nasal blockage (congestion). In addition, symptoms can also occur in the eyes, ears, sinuses and throat (for example, cough and sore throat). There are at least three different causes of rhinitis; allergic; non-allergic and infective. Rhinitis is termed ‘allergic’ when the symptoms are associated with the production of a specific immunoglobulin E (IgE). In contrast, non-allergic rhinitis occurs in the absence of a particular IgE and can be triggered by various factors such as drugs, hormones and malignancy. Infective rhinitis as the name suggests, is produced in response to viruses such as rhinovirus, the common cold or various bacterial and fungal organisms.

 

The prevalence of allergic rhinitis (AR) has increased over the last 30 years and is currently thought to affect over 20% of the UK population.1 The true prevalence of AR however, is likely to be higher as many patients self-treat with products available from pharmacies. Although AR is not life-threatening (unless associated with anaphylaxis), the condition does have a significant impact on quality of life and affects performance at work and school. For example, one US study showed that AR resulted in over 800,000 missed work and school days.2

 

Allergic rhinitis can be either seasonal, for example hay fever or perennial, whereby the condition persists throughout the year. Seasonal AR is usually initiated by outdoor allergens such as pollen from grasses or trees and moulds. In contrast, perennial AR is often (but not exclusively) due to indoor allergens including house dust mite, animal dander, moulds and from occupational exposure to allergens present in flour, wood dust, latex, smoke, glues and solvents etc. However, identification of the specific allergen responsible for symptoms is often difficult because many patients are allergic to several agents. 

 

Risk factors for the development of AR include genetic susceptibility, especially among those with associated atopic co-morbidities that is, asthma and eczema and a family history of AR. The mean age of the onset of symptoms is 8–11 years with the majority of sufferers affected by 20 years of age. Younger individuals are more likely to suffer with seasonal allergic rhinitis whereas adults tend to be affected by perennial rhinitis. Studies on the prognosis of AR suggest that in many individuals the condition either resolves or improves over time.3

 

Pathophysiology

Allergic rhinitis develops when an individual is exposed and then ‘sensitised’ to a particular allergen for instance a foreign protein found in pollen. This sensitisation generates an immunoglobulin E (IgE) specific to the allergen. Upon re-exposure to the allergen, the specific IgE is produced and coats mast cells present in the nasal mucosa. The allergen then binds to the IgE–mast cell complex and this interaction leads to mast cell rupture (degranulation) with the release of several inflammatory agents such as histamine, prostaglandins and leukotrienes.

 

The allergic response is characterised by two distinct phases; an acute and chronic phase. During the acute phase, which happens within minutes of exposure to the allergen, the mediators released from mast cells induce changes in the nasal mucosa producing the classic symptoms of nasal itch, sneezing and watery discharge. The chronic phase occurs over the next six to eight hours during which time the mediators released from mast cells, recruit inflammatory cells such as neutrophils and eosinophils into the nasal mucosa. Symptoms in this late phase include greater nasal congestion and mucus production as well as nasal hyper-reactivity. 

 

Ocular symptoms are particularly common in patients with AR. In one study of over 4000 patients, 31% reported having AR and of these, 52% (663) experienced ocular symptoms including itchy or watering eyes, red eyes and swollen eye lids.4 In addition, systemic effects such as fatigue, malaise and sleepiness can be present leading to a negative impact on quality of life. 

 

Management of AR

According to guidance produced in 2010, patients with AR should, wherever possible, seek to avoid known specific allergens. This applies to those who experience both seasonal and perennial AR. While there is little evidence to support the effectiveness of this approach, the recommendation is pragmatic and based on the biological basis for AR.5 A summary of the management options for AR are shown in Table 1.

 

Intranasal antihistamines

In 2001, a review of the management of AR concluded that intranasal corticosteroids were superior to oral antihistamines. Moreover, despite the recommendation combining oral antihistamines and intranasal corticosteroids, the review found that this strategy offered no advantage over inhaled corticosteroids alone.7 This conclusion was recently re-enforced in a review of how well currently available treatments in the US treat nasal symptoms.8 However, much less attention has been given to intranasal antihistamines. One particular agent, azelastine, has been available in the UK since 1991 and is licenced for the treatment of both AR and perennial rhinitis. Studies suggest that azelastine is effective at relieving the nasal symptoms of AR and can enhance symptom control when added to oral antihistamines.9 The efficacy of azelastine is related to its triple mode of action. The drug blocks histamine release from mast cells, it stabilises mast cells and has an anti-inflammatory action. This latter effect includes inhibition of substance P and bradykinin release which are responsible for nasal itching and sneezing, as well as inhibition of the release of various cytokines that perpetuate the inflammatory response. Finally, studies suggest that azelastine is able to lower neutrophil and eosinophil counts and reduce free radical generation from these inflammatory cells.10

 

Dymista®

Although there was clear evidence that combining oral antihistamines with intranasal corticosteroids did not improve symptom control in AR, the benefits of combining intranasal antihistamines and inhaled corticosteroids were less certain. This uncertainty was resolved in 2008 with the publication of a randomised, double blind study, which compared the efficacy of azelastine, fluticasone and a combination of each agent, in the management of AR. The study randomised 151 patients with moderate to severe nasal symptoms, to either agent alone or a combination (with separate dosing) of each drug. The primary outcome measure (see Box 1 below) was the change from baseline in reflective total nasal symptom scores (rTNSS). The results showed that after two weeks of treatment, the greatest level of symptom control occurred with azelastine and fluticasone in combination. (37.9 % for the combination versus 27.1% with fluticasone nasal spray and 24.8% with azelastine nasal spray, p<0.05 vs either agent alone).11

Azelastine and fluticasone are combined in a new product, Dymista® which was launched in the UK in 2013. According to the Summary of Product Characteristics, the product is licenced for “the relief of symptoms of moderate to severe seasonal and perennial AR if monotherapy with either intranasal antihistamine glucocorticoid is not considered sufficient.”

 

Clinical efficacy

Clinical data for Dymista® (referred to as MP29-02 in published studies) is available in a meta-analysis of three separate studies, involving a total of 3398. Each of the studies (which were not published individually) had the same protocol that involved a seven day placebo lead-in and a 14 day treatment period. The primary outcome measure was the difference between the combined 12 hour reflective total nasal symptom score (morning and evening) over the 14-day treatment period compared to baseline scores during the initial placebo period. Secondary measures assessed the instantaneous total nasal symptom score and a reflective total ocular symptom score.

 

The results for the reflective total nasal symptom scores are summarised in Table 2. The reduction is total scores for Dymista® were significantly different to either agent alone or placebo (p<0.001).

In addition total ocular scores were significantly reduced by Dymista® compared to fluticasone and placebo but not azelastine. Analysis of secondary end points showed that after 14 days of treatment, > 50% reduction in rTNSS was achieved by 49%, 37% and 38% and 28% of patients given Dymista®, azelastine, fluticasone and placebo, respectively. Furthermore, this response was achieved six days earlier with Dymista® than either azelastine or fluticasone. Finally, complete or near complete resolution of symptoms was achieved by 12.4%, 9.3%, 7.1% and 4.2% of patients given Dymista®, fluticasone, azelastine and placebo.

 

In a separate study in 779 patients with moderate to severe AR, Dymista® also produced a significant reduction in rTNSS compared to the individual components but it was also shown that the onset of action was within 30 minutes of the first dose.14 In a recent ‘real world’ study, the efficacy of Dymista® was assessed in 1781 patients with either AR or perennial rhinitis for whom monotherapy with either oral antihistamines or intranasal corticosteroids were considered insufficient. Patients used a validated visual analogue scale (VAS) to score how bothersome their symptoms had been in the last 24 hours. Using the VAS, a score of 0 was defined as not bothersome and a score of 100mm as very bothersome. The scale was used on days 0, 1, 3, 7 and 14 at the end of the study before administration of Dymista®. On day three, patients were asked to state whether they felt that their symptoms were well controlled, partly controlled or uncontrolled. The mean baseline score for patients was 75mm and after 14 days of treatment, Dymista® reduced scores to a mean value of 21mm. In addition, 55% of patients reported that their symptoms were well controlled by three days of treatment.14

 

Adverse effects

The most frequently reported adverse effect was headache (six patients, n=195), followed by dysgeusia or distortion of taste (four patients, n=195). Three patients reported mucosal erosion when using Dymista® though this was reported as mild and did not result in discontinuation of therapy. In a 12-month randomised, open-label, active-controlled, parallel-group study in subjects with chronic allergic or non-allergic rhinitis, 612 subjects were randomized in a 2:1 ratio to Dymista®, one spray per nostril twice daily or fluticasone, two sprays per nostril once daily. Safety and tolerability assessments were made at months 1, 3, 6, 9, and 12. The study found that treatment-related adverse effects occurred in 9.4% of patients assigned to Dymista® and 11.1% of patients on fluticasone. The authors concluded that there were no safety issues that would preclude long-term use of Dymista®.15

 

Place in therapy

Allergic rhinitis places a heavy burden upon patients as evidenced from several studies. In a UK study with 106 patients, it was found that nearly 84% of patients rated their AR as moderate or severe16 and a survey of 1001 Canadian patients found that 61% felt that their symptoms were only somewhat controlled or poorly controlled.17 Similar conclusions were made in a US survey, in which 73.6% (n=329) of patients rated their condition as moderate to severe.18

 

Current advice for patients with moderate to severe disease who remain symptomatic on an intranasal steroid is the addition of an oral antihistamine though there is little evidence to support this approach. Yet in a recent Italian survey of 2760 people with rhinitis, patients’ level of satisfaction with treatment (which included intranasal corticosteroids and oral antihistamines) was rated excellent by only 12.2%, good in 43.1%, fair in 31.2% and poor in 14.5%.19 These data clearly suggest that for many patients, currently used therapies are unable to provide satisfactory relief of symptoms. 

 

A criticism levelled at Dymista® is the lack of comparative studies with oral antihistamines and an intranasal corticosteroid, and this has limited its wider acceptance within the NHS. Although a potential stumbling block, the evidence of greater efficacy and a faster onset of action, which is likely to improve adherence, would suggest that the product is a worthwhile option for patients with moderate to severe symptoms that remain uncontrolled with conventional therapy.

 

Key points

  • Allergic rhinitis (AR) affects up to 20% of the UK population.
  • The majority of patients with AR rate their condition as moderate to severe. 
  • The condition has a negative impact on quality of life and leads to over 800,000 lost work and school days.
  • The current treatment recommendation for moderate to severe disease is an intranasal corticosteroid with add-on oral antihistamine if required.
  • Dymista® combines an intranasal corticosteroid and antihistamine and provides greater level of symptom control and faster onset of action than either agent alone.

 

References

  1. Angier E et al. Management of allergic and non-allergic rhinitis: a primary care summary of the BSACI guideline. Prim Care Respir J 2010;19(3):217–22.
  2. Malone DC et al. A cost of illness study of allergic rhinitis in the United States. J Allergy Clin Immunol 1997;99(1 Pt 1):22–7.
  3. Klossek JM et al. The burden associated with ocular symptoms in allergic rhinitis Int Arch Allergy Immunol 2012;158(4):411–7.
  4. Greisner WA 3rd, Settipane RJ, Settipane GA. Natural history of hay fever: a 23-year follow-up of college students. Allergy Asthma Proc 1998;19(5):271–5.
  5. ARIA (2010). Allergic rhinitis and its impact on asthma (ARIA) 2010 revision. www.whiar.org (accessed 20 May 2015).
  6. National Institute for Health and Care Excellence. Allergic rhinitis. Clinical Knowledge Summaries. http://cks.nice.org.uk/allergic-rhinitis (accessed 20 May 2015).
  7. Nielsen LP, Mygind N, Dahl R. Intranasal corticosteroids for allergic rhinitis. Superior relief? Drugs 2001;61:1563–79.
  8. Benninger M et al. Evaluating approved medications to treat allergic rhinitis in the United States: an evidence-based review of efficacy for nasal symptoms by class. Ann Allergy Asthma Immunol 2010;104(1):13–29.
  9. Bernstein JA. Azelastine hydrochloride: as review of pharmacology, pharmacokinetics, clinical efficacy and tolerability. Curr Med Res Opin 2007;23(10):2441–52.
  10. Horak F. Effectiveness of twice daily azelastine nasal spray in patients with seasonal allergic rhinitis. Ther Clin Risk Manag 2008;4(5):1009–22.
  11. Ratner PH et al. Combination therapy with azelastine hydrochloride nasal spray and fluticasone propionate nasal spray in the treatment of patients with seasonal allergic rhinitis. Ann Allergy Asthma Immunol 2008;100(1):74–81.
  12. Carr W et al. A novel intranasal therapy of azelastine with fluticasone for the treatment of allergic rhinitis. J Allergy Clin Immunol 2012;129(5):1282–9.
  13. Meltzer EO et al. MP29-02 a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate) in the treatment of seasonal allergic rhinitis: a randomized, double-blind, placebo-controlled trial of efficacy and safety. Allergy Asthma Proc 2012;33(4):324–32.
  14. Klimek L et al. Effectiveness of MP29-02 for the treatment of allergic rhinitis in real-life: results from a noninterventional study. Allergy Asthma Proc 2015;36(1):40–7.
  15. Berger WE et al. Long-term, randomized safety study of MP29-02 (a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate in an advanced delivery system) in subjects with chronic rhinitis. J Allergy Clin Immunol Pract 2014;2(2):179–85.
  16. Scadding GK, Williams A. The burden of allergic rhinitis as reported by UK patients compared with their doctors. Rhinology 2008; 46(2):99–106.
  17. Keith PK et al. The burden of allergic rhinitis (AR) in Canada: perspectives of physicians and patients. Allergy Asthma Clin Immunol 2012;8(1):7.
  18. Schatz M. A survey of the burden of allergic rhinitis in the USA. Allergy 2007;62 Suppl 85:9–16.
  19. Frati F et al. A survey of clinical features of allergic rhinitis in adults. Med Sci Monit 2014;20:2151–6.

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