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KAPARD-KAAACI & West Pacific Allergy Symposium Joint International Congress

Year in Review (KAPARD-KAAACI)

Allergic and Nonallergic Rhinitis:


Recent Advances in Treatment
Department of Otorhinolaryngology, Dankook University

Ji-Hun Mo

Allergic rhinitis (AR) and nonallergic rhinitis (NAR) are most common nasal conditions affecting millions of
individuals across the world. Although patients present with similar symptomatology, those with NAR are frequently
affected only after childhood and present with a lack of other comorbid atopic disorders such as asthma, atopic
dermatitis, and food allergies. Patients with pure NAR usually have no identifiable specific allergen sensitivity, whereas
those with mixed (allergic and nonallergic) rhinitis are sensitized to aeroallergens in a manner that does not fully
explain the duration or extent of their symptoms.
Even though the mechanism of AR and NAR is different, the treatment option for AR and NAR is quite similar except
for specific immunotherapy. Same pharmacotherapeutic medication and surgical treatment option can be applied
to patients with AR or with NAR. In this review, we will discuss recent advances in the diverse treatment options
of AR and NAR , including medical treatment, immunotherapy, and surgical treatment. Most of treatment advances
are described in terms of AR since most researches are focused on AR rather than NAR. However, they can also be
applied to both patients with NAR or with AR.

Pharmacotherapy
1. Newly developed drugs
Second generation of antihistamines are still considered as the first line therapy for allergic rhinitis and their long
term safety has been documented in RCT both in adults and children and infants after the age of 1.1) In addition to
the already-marketed antihistamines, three second-generation antihistamines have been recently introduced. The
first one is ebastine as fast-dissolving tablets and it is able to induce a quick symptom relief that is associated with
2) nd
good compliance and adherence. The 2 one is Rupatadine that exerts also an antiplatelet activating factor (PAF)
activity. There are several studies showing its anti-allergic activity, mainly related to the control of allergic inflammation
3,4)
that is nasal obstruction. Bilastine is a very recent second-generation antihistamine that is able to efficiently control
the symptoms of allergic rhinitis with a satisfactory safety profile.5)
Some of the drugs developed for asthma were tested also in rhinitis. This is the case of the phosphodiesterase-4

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Ji-Hun MoAllergic and Nonallergic Rhinitis: Recent Advances in Treatment

6)
inhibitor roflumilast. This drug proved effective in the treatment of AR in a single study, but no further experimental
work on this topic was published after 2001.
It was also reported that inhibiting the mast cell-derived beta tryptase is effective in reducing symptoms and cell
7)
influx after nasal specific challenge , and this approach may represent a possible development in therapy, although
another study with a single-dose intranasal administration of mast cell inhibitor reported less favorable results.8)
Adenosine receptors may be considered a promising target in the context of allergic inflammation, but there is
9)
so far only a single clinical trial in humans showing only a marginal beneficial effect. As histamine receptors other
than H1 are involved in the development and maintenance of allergic reaction, compounds antagonizing H3 and
H4 receptors have been synthesized, and used in clinical trials, but with no evident additional effect as compared
10,11)
to the available drugs.
Finally, another promising pharmacological approach, already used in asthma, is the combination therapy. In this
regard, two recent trials were conducted in large population of patients (more than 1,500 patients in total) with the
12,13)
association of azelastine and fluticasone in a single nasal spray device. The association of the two drugs always
resulted superior in efficacy on nasal symptoms to the two compounds administered separately.14) All the studies
were conducted in seasonal allergic rhinitis and, in fact FDA approved the drug for this indication only. Nevertheless,
in principle, it could be used also for perennial AR, although specific studies are needed.

2. Targeted therapy
With more knowledge of immunologic mechanism of allergic rhinitis, targeted therapy is being developed and
introduced in allergy field. IgE and Th2 cytokines (IL-4, IL-5, and IL-12) are being targeted and studied actively for
treatment of allergic diseases.
1) Anti IgE humanized monoclonal antibody (omalizumab)
The anti-IgE humanized monoclonal antibody (omalizumab) has been used for many years and is not a new
treatment option. Nonetheless, its use in AR still raises questions due to its high cost, although its efficacy was
15,16)
ascertained. Since its plasmatic half-life is about 15 days, it can be given twice a month or monthly as subcutaneous
injections. The dose per administration ranges between 150 and 450 mg, depending on the body weight and total
baseline IgE. Its clinical efficacy in AR is well established, and this treatment has the advantage of being independent
of the type of allergen involved and of the mono- or poly-sensitization. Of note, it was shown that omalizumab is
particularly effective in patients with associated asthma and rhinitis, according to the hypothesis of the united airways
disease. So far, the cost (approximately $10,000 per year) is justified only in severe refractory asthma with frequent
16)
exacerbations.
2) Others
Other possible drugs include the administration of anti CD4+ monoclonal antibodies (that inhibit the overall
function of T cells), or giving recombinant IL-12 (that stimulates the Th1 subset) or anti IL-5, which inhibits eosinophil
activity and influx. Nonetheless, the few clinical data available only in human asthma suggest that these approaches
17-19)
are not so promising in rhinitis.

3. Immunomodulators
Tyrosine kinase components (SYK) are considered as important signaling factors for the transmission of

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KAPARD-KAAACI & West Pacific Allergy Symposium Joint International Congress

20) 21)
pro-inflammatory activation pathways , and its modulation has been tried in the treatment of AR. A recent study
reported favorable outcomes with the SYK inhibitor R112, which was tested in more than 300 randomized patients
with a significantly positive outcome in a park environment.22)

Allergen specific immunotherapy

Last year was 100th anniversary for allergen-specific immunotherapy (SIT) and it is still considered as the only
curative treatment for allergic respiratory diseases. Several papers emphasized the efficacy and safety of SIT in children
23-25)
from the age of 5 years and confirmed its preventive effect towards asthma development.
The mechanisms of SIT efficacy are more and more clear.26,27) Many papers have confirmed the key role of Treg
and of its two subsets (FOXP3+CD4+CD25+ Treg and TR1 cells) in inducing tolerance against antigens through
secretion of suppressive cytokines (e.g. IL-10) and discussed the role of specific IgG4.

1. Subcutaneous Immunotherapy (SCIT)


It was reported that a three years-long treatment with dust mite SCIT was sufficient to significantly reduce rhinitis
28)
and asthma symptom scores. An interesting study has investigated a new immunotherapy regimen, based on the
combination of sublingual and subcutaneous routes, and showed a reduction of asthma attacks in patients treated
with SCIT alone and SCIT plus SLIT, against SLIT group and pharmacotherapy group.29) On the same line, a comparison
based on meta-analyses has shown that the relative efficacy of SCIT on seasonal allergic rhinitis symptoms is similar
29)
or even better than that of drugs already in the first season after SCIT initiation. The indications of SCIT are becoming
broader: the treatment of polysensitized patients with SCIT is indeed controversial; nevertheless, new evidences
suggested that multiallergen SIT (up to 2 allergens) could be effective in polysensitized patients.30) New administra-
tion schedules are also investigated: on one hand, ultra short course of SCIT with a pollen allergoid reduced the
use of drugs and resulted well tolerated in most patients with rhinitis and/or asthma31) ; on the other hand, SCIT
32)
proved to be very safe in association with anti-IgE treatment.

2. Sublingual Immunotherapy (SLIT)


The efficacy and safety of SLIT in the treatment of allergic rhinitis in children 5 years has been confirmed in recent
position papers and meta-analysis, even if further evaluations and well done RCT are needed.33-35) Many recent RCT
36-39)
on grass pollen SLIT confirmed the efficacy and tolerability in children even at high-dose regimen. The economic
impact of SCIT and SLIT has been long time discussed: especially in childhood its long term effects may reduce direct
and indirect medical costs40,41) The role of administration schedule and setting has been the object of many trials:
first, the safety of ultra-rush SLIT in tree-pollen allergic children with asthma has been clearly demonstrated, then
42,43)
a co-seasonal regimen for grass SLIT showed a better efficacy during the first season than continuous treatment.

3. Intralymphatic immunotherapy (ILIT)


Efforts to develop safer and more effective AIT for inhalant allergies have led to investigations with modified
allergens and alternate routes.The injection of allergens directly into lymph nodes (intralymphatic immunotherapy)
has been demonstrated to be as effective as the traditional subcutaneous delivery, but with low doses and fewer

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44)
injections. Senti et al. showed that ILIT was safe and induced allergen tolerance after 3 injections in a randomized
double-blind trial ILIT with MAT-Fel d 1 (cat antigen) in alum.45) Hylander et al. also showed that ILIT with grass-pollen
or birch-pollen extracts appears to reduce nasal allergic symptoms without causing any safety problems, suggesting
ILIT might constitute a less time consuming and more cost-effective alternative to conventional subcutaneous
46)
allergen-specific immunotherapy.

4. Epicutaenous immunotherapy (ECIT)


Similarly, the epicutaneous route (by patches) is receiving encouraging confirmations.23) Senti et al. reported that
epicutaneous allergen-specific immunotherapy to grass-pollen reduced symptom score more than 24% in next pollen
season with single 6 week treatment and that it is a convenient, safe, and efficacious treatment for IgE-mediated
23)
allergies, leading to symptom relief after a single treatment season.

5. Adjuvant and recombinant allergens


The adjuvant SIT prepared with monophosphoril-lipid A (MPLA), derived from the bacterial wall of Salmonella
Minnesot has become a reality and is now available in a number of countries.47) Also, bacterial DNA sequences have
been shown to act as powerful Th1 inducers via the toll-like receptors 9. In this regard, the first exploratory study
performed in humans with DNA-conjugated ragweed allergen provided positive results in term of clinical and
48)
immunological response. Recombinant/modified allergens are another attractive possibility to achieve
49,50)
immunization toward allergens, Several clinical studies with recombinant preparations have now shown
significant and meaningful clinical benefit for patients with rhinoconjunctivitis attributable to either birch or grass
pollen. The first studies with modified cat and peanut allergens are now in progress, and it is to be expected that
51)
house dust mite preparations will enter clinical development in the near future.

Surgical treament
1. Conventional surgical treatment
Allergic or noallergic rhinitis that is refractory to medical therapy may necessitate surgical intervention. Reduction
of the inferior turbinate is the primary means of augmenting the nasal airway in AR or NAR patients. A variety of
procedures exist for the surgical reduction of inferior turbinate tissue, including outfracture, submucous resection,
laser vaporization, radiofrequency ablation, and coblation. Septoplasty alone has little role in the treatment of nasal
obstruction for allergic rhinitis. Endoscopic sinus surgery is an important treatment method for allergic rhinitis when
it contributes to chronic sinusitis, nasal polyposis, or allergic fungal disease. No single operation has evolved as the
gold standard for treatment of nasal obstruction in allergic rhinitis; instead the surgeon should be familiar and facile
with several approaches.

2. Endoscopic vidian neurectomy and its modification, posterior nasal neurectomy


Recently, vidian neurectomy, one of historical surgery, has regained its attention. Vidian nerve injury to the sensory
nerve fibers reduces hyperreactivity of the nasal reflex, effectively reducing sneezing and nasal hypersecretion.
Tan et al. reported long-term results (until 3 years) of bilateral endoscopic vidian neurectomy and compared the
52)
symptom improvement and QOL score with those in septoturbinoplasty group or in medical treatment group.

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KAPARD-KAAACI & West Pacific Allergy Symposium Joint International Congress

The average posttreatment bilateral endoscopic vidian neurectomy scores of the Rhinoconjunctivitis Quality of Life
Questionnaire and visual analog scale were significantly improved at 6 months, 1 year, and 3 years compared with
pretreatment scores for vidian neurectomy group and for those in septoturbinoplasty group and medical management
group during the same period. The most frequent and long-term side effect of vidian neurectomy is loss of lacrimation,
or keratoconjunctivitis sicca, which mandates the use of artificial tear substitution. Complications reported by Tan
et al. demonstrated that 26 of 85 patients (30.6%) experienced mild dry eye shortly after surgery; however, their
dry eye resolved 2 months after surgery.
To overcome those complications like loss of lacrimation, transnasal resection of posterior nasal nerve (TPRN)
53,54)
was adopted. Posterior nasal nerve is a postsynaptic branch of vidian nerve and branch into the inferior turbinate
and are distributed around the mucosal layer. The development of endoscopic endonasal surgery has made it possible
to perform transnasal resection of the posterior nasal nerve (TRPN). This surgery overcame the complications of
vidian neurectomy and is minimally invasive. Ogawa et al, reported that good surgical outcome with TPRN after
53)
3 year follow-up. Today, TRPN is considered one of the most effective treatment options for severe intractable
AR. However, it needs further evaluation regarding the long-term results, and comparison with conventional
treatment.

Conclusion

Several drugs have been investigated, new immunotherapy routes or regimen have been developed and new
surgical treatment option have been developed recently although there is much to be improved. What is clearer
is that more knowledge should be congregated for effective treatment of allergic and/or nonallergic rhinitis.

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