Managing Allergic Rhinitis: Why Combination Therapy Works?

Allergic Rhinitis (AR) is an IgE-mediated inflammation of the lining membranes of the nose caused by exposure to allergens. Mucosal inflammation is caused by Type 2 Helper T cells. (1,2) It is a symptomatic disorder characterized by anterior or posterior rhinorrhea, sneezing, nasal itching, and congestion. Often other symptoms like conjunctivitis, postnasal drip, dysfunction of the eustachian tube, sinusitis, and otitis media can also be seen in AR. (1)

What causes AR?

Genetic predisposition plays an important role in the development of AR. (3) AR is an Atopic disease caused by allergens like molds, seasonal pollens, dust mites, pets, pests (2), occupational triggers like latex; tobacco smoke; automobile exhaust including ozone, oxides of nitrogen, and sulfur dioxide. Sometimes aspirin and other non-steroidal anti-inflammatory drugs; hormonal conditions like pregnancy, puberty, hormone replacement therapy, and contraceptives; pepper and spicy foods; cystic fibrosis and other systemic diseases like Sjogren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, antibody deficiency, malignancies, and granulomatous diseases can also trigger AR. (3) Asthma, atopic dermatitis, and nasal polyps are some of the comorbid conditions with which AR can be associated. (1)

On exposure to allergens, inflammatory cells like mast cells, CD4-positive T cells, B cells, macrophages, and eosinophils, infiltrate the nasal lining. The T-helper (Th2) cells release cytokines and promote IgE production by plasma cells which in turn triggers the production of mediators of inflammation like histamine and leukotrienes. These mediators cause early phase reaction in the form of arteriolar dilation, increased vascular permeability, itching, rhinorrhea, mucous secretion, and smooth muscle contraction which in the next 4-8 hrs causes a late-phase inflammatory response. (4)

How to manage AR?

The British Society of Allergy and Clinical Immunology has put forth certain guidelines for the management of AR. Medical management of AR is usually based on the severity of the disease as mild, moderate, or severe. (3) Apart from pharmacotherapy, patient education, avoiding irritants and allergens, irrigation with saline, and carbon dioxide washing, acupuncture, and surgery are some of the recommendations. (5) Medical management currently has oral/nasal corticosteroids, leukotriene receptor antagonists, antihistamines, mast cell stabilizers, intra-nasal anticholinergics, and short-term nasal decongestants. (6)

Antihistamines:

As histamine is the major mediator in the development of AR symptoms, these are the first-line treatment for mild to moderate intermittent and mild persistent disease. They are available in the form of oral, intranasal (INA), and ocular preparations. Even though they improve clinical efficacy first-generation antihistamines can cause sedation and cognitive impairment, while second-generation antihistamines are long-acting, nonsedative, and with no anticholinergic activity. (3)

Corticosteroids:

These are the mainstay of treatment for AR. They are more effective than oral and intranasal antihistamines for persistent or more severe allergic rhinitis. (6) Intranasal steroids (INS) help to improve nasal symptoms like congestion, rhinorrhea, itching and sneezing. They are the recommended first-line therapy for moderate-severe or persistent rhinitis. (7)

Decongestants:

These are available in intranasal and oral formulations. Intranasal decongestants cause relief of nasal congestion by acting on adrenergic receptors which cause vasoconstriction. They are generally considered for short-term use. (6) They act much faster than steroids. Oral decongestants are generally not recommended for AR due to many side effects. (3)

Anti-leukotrienes:

They decrease airway inflammation and relieve nasal congestion by blocking the inflammatory effects of leukotrienes. (8) They are comparable to oral antihistamines but less effective than intranasal corticosteroids. As they reduce bronchospasm and attenuate inflammatory response they can be used in cases of co-existent bronchial asthma. (6)

Anticholinergics:

They are effective for severe rhinorrhoea. They also have no effect on other nasal symptoms and are effective as add-ons when watery rhinorrhoea is present despite topical steroids and antihistamines. (3,6)

Chromones:

Chromones inhibit the release of mediators by inhibiting the degranulation of sensitized mast cells. These are particularly useful in patients who cannot use other drugs like during pregnancy. (3) It is not considered the first-line therapy for AR since it is less effective than steroids and antihistamines. (6)

Immunotherapy:

This is a relatively safe and effective treatment which is the only etiological treatment for allergic rhinitis. These are available as sublingual, subcutaneous therapies and also as intradermal, epicutaneous, intralymphatic, or intranasal routes. (3) This treatment should be preferred for moderate or severe persistent AR unresponsive to usual treatments, and who cannot tolerate long-term medication use. (6)

Combination therapy:

Combination therapy in AR is preferred for those who do not have an adequate response to monotherapy. The major advantage of using combination therapy over monotherapy is the improved effectiveness and symptom control of combined therapy. (9) There are various combinations of drugs that can be used for treating AR. But the most effective therapy is the combination of an intranasal steroid with an intranasal antihistamine.

• A randomized, multicentre, double-blind, Phase III trial was done for 4 weeks on 228 patients in Korea. They compared the efficacy and safety of a fixed-dose combination (FDC) of montelukast (10mg/day) and Levocetirizine (5mg/day) with monotherapy of montelukast (5mg/day) in patients with perennial allergic rhinitis and mild to moderate asthma. They found that the FDC group showed numerical improvement in all allergic rhinitis efficacy endpoints. There was a statistically significant difference in sneezing score and mean daytime nasal symptom score. (10)
• A systematic review and meta-analysis assessing the efficacy of the combination therapy with intranasal azelastine and fluticasone revealed that the combination therapy reduced the patient-related symptom scores in patients with allergic rhinitis. The systematic review identified 8 articles and a meta-analysis revealed the superiority of the combination therapy. When compared to placebo azelastine and fluticasone were superior and were suggested as second-line therapy in patients with allergic rhinitis not controlled by monotherapy. (11)
• The updated clinical practice guidelines by the American Academy of Otolaryngology-Head and Neck have clearly put forth the various combinations of drugs that can be used to treat AR. The guideline has mentioned that the combination of intranasal steroids and intranasal antihistamines is more effective than monotherapy with the same in patients who can tolerate INS or INA spray. They also mentioned another combination of oral antihistamines and decongestants that is better than monotherapy alone as demonstrated in various trials. The guidelines have also mentioned another combination of INS and intranasal oxymetazoline for controlling AR than monotherapy. (9)
• The British Society of Allergy and Clinical Immunology (BSACI) guideline has mentioned that the use of a combination of intranasal antihistamine along with intranasal steroids in patients with uncontrolled symptoms is more effective than monotherapy alone. (3)

Take home points:

• AR is a common immunological disease affecting the quality of life of patients.
• Physical or chemical allergens, drugs, hormones, and granulomatous diseases are some of the etiological agents of AR.
• Patient education, avoidance of allergens, and saline irrigation are some of the ways to reduce AR.
• Medical management of AR includes intranasal/oral antihistamines, intranasal/oral steroids, decongestants, leukotriene receptor antagonists, anticholinergics, chromones, and immunotherapy.
• Combination therapy is better than monotherapy in patients with unresolved symptoms.

AR is an important airway disease that affects the world population. As many aetiologies have been found with the increasing number of studies, the focus has to be placed on combination therapies to effectively reduce the symptoms of AR. 

References:

1. Varshney J, Varshney H. Allergic Rhinitis: an Overview. Indian J Otolaryngol Head Neck Surg. 2015;67(2):143-149. doi:10.1007/s12070-015-0828-5,

2. Wheatley LM, Togias A. Clinical practice. Allergic rhinitis. N Engl J Med. 2015;372(5):456-463. doi:10.1056/NEJMcp1412282.

3. Scadding GK, Kariyawasam HH, Scadding G, et al. BSACI guideline for the diagnosis and management of allergic and non-allergic rhinitis (Revised Edition 2017; First edition 2007). Clin Exp Allergy. 2017;47(7):856-889. doi:10.1111/cea.12953

4. Small, P., Kim, H. Allergic rhinitis. All Asth Clin Immun 7, S3 (2011). https://doi.org/10.1186/1710-1492-7-S1-S3

5. Meng Y, Wang C, Zhang L. Recent developments and highlights in allergic rhinitis. Allergy. 2019;74(12):2320-2328. doi:10.1111/all.14067

6. Sur DK, Plesa ML. Treatment of Allergic Rhinitis. Am Fam Physician. 2015;92(11):985-992.

7. Greiner AN, Meltzer EO. Overview of the treatment of allergic rhinitis and nonallergic rhinopathy. Proc Am Thorac Soc. 2011;8(1):121-131. doi:10.1513/pats.201004-033RN.

8. May JR, Dolen WK. Management of Allergic Rhinitis: A Review for the Community Pharmacist. Clin Ther. 2017;39(12):2410-2419. doi:10.1016/j.clinthera.2017.10.006

9. Seidman MD, Gurgel RK, Lin SY, et al. Clinical practice guideline: Allergic rhinitis. Otolaryngol Head Neck Surg. 2015;152(1 Suppl):S1-S43. doi:10.1177/0194599814561600

10. Kim MK, Lee SY, Park HS, et al. A Randomized, Multicenter, Double-blind, Phase III Study to Evaluate the Efficacy on Allergic Rhinitis and Safety of a Combination Therapy of Montelukast and Levocetirizine in Patients With Asthma and Allergic Rhinitis. Clin Ther. 2018;40(7):1096-1107.e1. doi:10.1016/j.clinthera.2018.04.021

11. Debbaneh PM, Bareiss AK, Wise SK, McCoul ED. Intranasal Azelastine and Fluticasone as Combination Therapy for Allergic Rhinitis: Systematic Review and Meta-analysis. Otolaryngol Head Neck Surg. 2019;161(3):412-418. doi:10.1177/0194599819841883