New treatment paradigms emerge for allergic rhinitis

January 2006

Emerging allergic rhinitis treatments focus on rapid onset of action, treatment of comorbidities, safety, convenience and many other quality-of-life issues.

William E. Berger, MD, MBA, clinical professor in the department of pediatrics in the division of allergy and immunology at the University of California, Irvine, discussed the existing methods of treatment as well as four emerging paradigms of treatment: sublingual immunotherapy (SLIT), anti-immunoglobulin E therapy (IgE), new topical antihistamines and new inhaled corticosteroids.

“These are some of the things that are going to be coming up to help us treat patients with seasonal allergic rhinitis (SAR),” Berger said at the 63rd Annual Meeting of the American College of Allergy, Asthma and Immunology in Anaheim, Calif.

Current forms of therapy

Several therapeutic approaches exist to treat allergic rhinitis: environmental control, pharmacotherapy and allergen immunotherapy. A better understanding is also developing about treating comorbid conditions, Berger added.

Environmental control includes avoidance therapy and intranasal saline irrigation. Some of the major IgE triggers for allergic rhinitis include pollen, mold, house dust mites, animal allergens and cockroaches, according to Berger, and the major non–IgE-dependent triggers are smoke, formaldehyde, perfume, strong odors and newspaper ink.

Pharmacotherapy options include antihistamines, decongestants, corticosteroids, intranasal cromolyn, intranasal anticholinergics and leukotriene receptor antagonists.

Decongestants, or -adrenergic agonists, stimulate receptors to induce local vasoconstriction, decrease the blood volume in the nasal mucosa, reduce blood supply to the mucosa, decrease edema and improve nasal potency, he said. Oral decongestants include phenylephrine and pseudoephedrine, and topical decongestants include phenylephrine, xylometazoline and oxymetazoline.

Intranasal corticosteroids affect inflammatory response by reducing the number of eosinophils and mast cells, Berger said. Products include beclomethasone, budesonide, flunisolide, fluticasone (Flonase, GlaxoSmithKline), mometasone (Nasonex, Schering) and triamcinolone.

Intranasal cromolyn sodium, one of the safer medications, prevents the release of prechemical and newly formed mediators to prevent degranulation, according to Berger.

First generation, oral antihistamine preparations that cause sedation are chlorpheniramine and diphenhydramine, both available over the counter. Nonsedating antihistamines are desloratadine (Clarinex, Shering Plough), fexofenadine (Allegra, Aventis) and loratadin. Mild sedation is associated with cetirizine (Zyrtec, Pfizer).

Non- or low-sedating antihistamines are equally efficacious, he said, as sedating ones, and lack central nervous system and anticholinergic effects.

Allergen immunotherapy, or “good old allergy shots,” Berger said, decrease asthma development and may reduce the symptoms and medication reliance that people have on a long-term basis.

Other medications for rhinitis include ipratropium bromide, an anticholinergic agent that inhibits parasympathetic transmission to submucosal glands and has low lipid solubility. More recently, a leukotriene (LT) modifier, such as montelukast (Singular, Merck), is used against allergic rhinitis. LT modifiers inhibit LT production and impact inflammatory cells that are recruited or activated by LTs.

New therapeutic paradigms

Four therapeutic paradigms — SLIT, anti-IgE therapy, new topical antihistamines and new inhaled corticosteroids — will effect the way physicians will treat SAR in the future, he said.

SLIT is allergen-specific and formulated either as a saline glycerin phenolated dissolvable tablet or in a liquid form placed under the tongue, held for about two minutes and swallowed. It has no direct absorption of the allergen through the mucosa, and the native allergen is actually undetected in the blood, Berger said.

“So we’re not clear exactly how this all works,” he said. “The hypothesis is that there’s drainage into the regional lymph nodes and with processing and allergen presenting through the dendritic cells.”

SLIT is given prior to and during the allergy season. It is administered continuously for perennial allergies such as dust mite.

“Believe it or not, it’s the most widely used noninjection route in Europe,” Berger said.

In 1998, WHO officials concluded that SLIT and local nasal immunotherapy are acceptable alternatives to injection because they are cost-effective and convenient. Disadvantages of SLIT include gastrointestinal issues, patient adherence and compliance.

Clavel et al conducted a seven-month double-blind, placebo-controlled study in 136 people with grass-pollen rhinitis with or without mild asthma. Participants received placebo or grass-pollen extract. Results showed a reduction in drug consumption in the SLIT group compared with the placebo group. From an immunological point of view, Berger said, researchers noted an increase in IgG4 levels but without any correlation with symptoms.

Anti-IgE therapy is a recombinant humanized monoclonal antibody to IgE. It inhibits binding of IgE to high-affinity IgE receptor of the surface of mast cells and basophils, Berger said. It has anti-inflammatory activity. It is administered as a subcutaneous injection.

“Unfortunately, when the medication is discontinued, its effects disappear and studies have shown that pre-IgE levels are obtained once the medication is stopped within a year,” Berger said.

Casale et al showed the effects of anti-IgE in people with asthma and/or SAR. They found that the average nasal symptom severity score over a 12-week period in 536 people was reduced with a 300 mg dose of anti-IgE.

In Germany, Kuehr et al studied a combination treatment of specific immunotherapy (SIT) and monoclonal anti-IgE in children and adolescents with SAR because the two treatments have complementary modes of action. The hypothesis was to combine the therapy and increase the efficacy compared with the efficacy of the individual treatments.

The researchers found a statistically significant difference between SIT grass and omalizumab (Xolair; Genentech, Novartis) and SIT birch and omalizumab. The combination therapy reduced symptom load over two pollen seasons by 48% compared with SIT alone, he said.

“The combination might be useful and certainly worth pursuing,” Berger said.

Azelastine (Astelin, MedPointe) demonstrates an H₁-antagonist effect, stabilizes mast cells, reduces levels of IL-4 and CD23, decreases ICAM-1 and eosinophilic cells, down-regulates calcium release and influx and reduces leukotrienes and platelet-activating factors, he said.

In a trial of 307 adolescents and adults aged 12 to 74 with SAR, Corren et al of the Azelastine Cetirizine Trial No. 1 found that azelastine nasal spray compared with oral cetirizine improved total nasal symptom scores (29.3% vs. 23%, respectively) and had faster onset of action to instantaneous total nasal symptom scores at 60 and 240 minutes after the initial dose (both P<.04).

Olopatadine nasal spray (Patanase, Alcon) – a second-generation and newer topical antihistamine – is a nonsedating, nonsteroidal product that may, according to Berger, modulate the monocyte response, decrease secretion of proinflammatory cytokines TNFa and IL-1ß, stimulate peripheral blood monocytes and have clinical applications in treating allergic inflammatory responses.

Patel et al examined olopatadine at different doses in people aged 17 to 65 with SAR. Olopatadine 0.2%, 0.4% and 0.6%, administered once, demonstrated reduced total nasal symptom scores compared with placebo, Berger said. The 0.6% dose, however, gave the best and longest duration of response.

A new topical nasal corticosteroid, ciclesonide, showed effective changes in total nasal symptom scores in a study presented by Ratner et al. Esterases convert the parent compound of ciclesonide locally in airways to produce active metabolite, desisobutyryl-ciclesonide, Berger said of the new product. Desisobutyryl-ciclesonide has a 100-fold greater relative glucocorticoid receptor binding affinity than ciclesonide itself, Berger added, and is 99% protein bound, metabolized by liver oxidase, resulting in very low systemic exposure.

“So the emerging allergic rhinitis treatments are certainly focusing on the rapid onset and convenience,” Berger said. “We certainly want to improve our patient adherence and compliance, and always to recognize and treat comorbidities.”

Dr. Berger is a paid consult for, is on the speaker’s bureau of and has research grants from AstraZeneca, Novartis, Genetech, Alcon, MedPointe, Schering Plough, GlaxoSmithKline and Sanofi-Aventis.

For more information:

• Mast EE, Huang L-Y, Seto DSY, et al. Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy. J Infect Dis. 2005;192:1880-1889.
• European Paediatric Hepatitis C Virus Network. A significant sex — but no elective cesarean section — effect on mother-to-child transmission of hepatitis C virus infection. J Infect Dis. 2005;192:1872-1879.
• Beasley RP. Nature usually favors females. J Infect Dis. 2005;192:1865-1866.
• Galli L, Puliti D, Chiappini E, et al. Italian Register for HIV infection in children. Lower mother-to-child HIV-1 transmission in boys is independent of type of delivery and antiretroviral prophylaxis. J Acquir Immune Defic Syndr. 2005;40:479-485.