Clinical and Experimental Immunology R EV I EW ART I CLE doi:10.1111/j.1365-2249.2009.04010.

Mechanisms and clinical implications of glucocorticosteroids in the

treatment of allergic rhinitis

M. Okano Summary
Department of Otolaryngology Head and Neck
Surgery, Okayama University Graduate School of
Allergic rhinitis is a common airway disease characterized by hypersensitiv-
Medicine, Dentistry and Pharmaceutical Sciences, ity, exudation, hypersecretion, inflammatory cell infiltration and remodel-
Okayama, Japan ling. Intranasal glucocorticosteroids are the most effective drugs for
controlling the inflammation caused by allergic rhinitis. Glucocorticoster-
oids exert anti-inflammatory effects through at least two pathways: the
transactivation pathway and the transrepression pathway. Glucocorticoster-
oids also exert regulatory functions by inducing regulatory cytokines and
forkhead box P3 (FoxP3+) regulatory T cells. Evidence suggests that intra-
nasal glucocorticosteroids control not only nasal symptoms but also ocular
symptoms. In contrast to sedating H1 receptor antagonists, intranasal glu-
cocorticosteroids can improve impaired performance symptoms, such as
daytime sleepiness, associated with allergic rhinitis. Recent studies suggest
that intranasal glucocorticosteroids might also be useful for the prophylactic
Accepted for publication 29 July 2009 treatment of pollinosis; this possibility is supported by the molecular
Correspondence: M. Okano, Department of mechanism of the anti-inflammatory action of glucocorticosteroids. These
Otolaryngology Head and Neck Surgery, findings suggest that intranasal glucocorticosteroids might be positioned as
Okayama University Graduate School of first-line drugs for the treatment of both perennial and seasonal allergic
Medicine, Dentistry and Pharmaceutical rhinitis.
Sciences, 2-5-1 Shikatacho, Okayama 700-8558,
Japan. Keywords: impaired performance, intranasal glucocorticosteroids, ocular
E-mail: mokano@cc.okayama-u.ac.jp symptoms, regulatory T cells

AR. We also discuss the usefulness and pitfalls of INS in the

Introduction
clinical setting and assess the current status of INS for the
Allergic rhinitis (AR) is a common manifestation of allergic treatment of AR.
diseases, affecting approximately 500 million people world-
wide [1]. AR is increasing in prevalence. For example, the
Pathophysiology of AR
prevalence of AR in Japan increased from 298% in 1998 to
394% in 2008. The prevalence of pollinosis, the typical sea-
Pathogenesis of AR
sonal AR, has been increased from 196% in 1998 to 298% in
2008 [2]. Most causal antigens for AR are inhalant allergens. House
AR is a major chronic inflammatory condition in the dust mite, animal dander and pollens are the principal
upper airway characterized by hypersensitivity, exudation, allergens. Many allergens, including the major house dust-
hypersecretion, inflammatory cell infiltration and remodel- mite allergen, Der p 1, have protease activity that impairs
ling [3]. Although glucocorticosteroids (GC) are highly epithelial barrier function and facilitates the penetration of
effective in mitigating inflammation, their potent action allergens into nasal mucosa [7]. Following nasal exposure
often causes severe adverse effects [4,5]. To decrease the to the inhalant allergens, professional antigen-presenting
potential for adverse effects, intranasal glucocorticosteroid cells in the nasal mucosa, such as dendritic cells (DC),
(INS) formulations with low systemic availability have been capture the allergens and provide two distinct signals, the
developed for the treatment of allergic rhinitis [6]. allergen-derived peptide/MHC complex and co-stimulatory
In this review, we discuss the pathophysiology of allergic molecules such as CD80 and CD86, to naive T cells [810].
rhinitis and the mechanism of action of GC, including the Allergen-specific T helper type 2 (Th2) cells are generated
induction of regulatory T cells (Tregs), in the pathogenesis of in patients with AR, whereas allergen-specific Th1 cells are

164 2009 British Society for Immunology, Clinical and Experimental Immunology, 158: 164173
 Intranasal glucocorticosteroids

generated in healthy individuals [11,12]. Early interleukin mucosa [27]. Sensory nerve terminals are located in the epi-
(IL)-4 and thymic stromal lymphopoietin (TSLP) pro- thelial junctions and subepithelial layers. In the guinea pig
duced by basophils in response to allergens with protease model of allergic rhinitis, the sneezing reflex following aller-
activity may contribute to Th2 differentiation [12]. Th2 gen challenge is inhibited significantly by pretreatment with
cells produce IL-4/IL-13 and express CD40L, which capsaicin, which depletes SP and CGRP from the nasal
promote the class-switching of B cells to immunoglobulin mucosa [28]. When various chemical mediators are applied
(Ig)E [13,14]. When sensitized subjects inhale antigens, the to the nasal mucosa, histamine is the only mediator that
antigens pass through the epithelial tight junctions in the induces a significant sneezing reflex [28,29]. Therefore, the
nasal mucosa to bind IgE on the surface of mast cells in the sneezing reflex following allergen challenge is a respiratory
epithelial layer of the nasal mucosa, inducing the release of reflex induced by the interaction between histamine and the
chemical mediators including histamine, prostaglandins H1 receptor at the sensory nerve terminals containing SP
and cysLTs by aggregation of FceRI. Histamine regulates and CGRP and might be a sensory stimulation response
tight junctions via the coupling of H1 receptors and amplified by hyperreactivity in the nasal mucosa [25].
increases paracellular permeability [15]. This increased per-
meability allows DC to penetrate epithelial tight junctions Rhinorrhoea. Synchronously with the sneezing reflex,
easily and enhance antigen presentation to T cells [16]. The sensory stimulation on the nasal mucosa induces excitation
early-phase response, which consists of sneezing, rhinor- reflexively in the parasympathetic centre. After allergen chal-
rhoea and nasal congestion, is caused by interactions lenge on the hemilateral nasal mucosa of patients with aller-
between chemical mediators and the sensory nerve termi- gic rhinitis, the weight of rhinorrhoea induced in both sides
nals and blood vessels in the nasal mucosa [17]. of nasal cavities is correlated with the number of sneezes. In
After the nasal exposure to allergen, infiltration of inflam- addition, the weight of rhinorrhoea in the nasal cavity with
matory cells, such as activated eosinophils and Th2 cells, into allergen challenge is correlated with that on the opposite
the nasal mucosa is induced by cytokines, chemical media- side. Therefore, rhinorrhoea can be regarded as the secretion
tors, chemokines and growth factors [18,19]. Cytokines such from the mucous glands by parasympathetic stimulation
as IL-5, IL-4, IL-13 and granulocytemacrophage colony- [30]. Furthermore, allergic inflammation induced by nasal
stimulating factor (GM-CSF) are produced mainly in Th2 allergen exposure augments this naso-nasal reflex [31]. Pos-
cells and mast cells; however, eosinophils also have the poten- sible mechanisms for sensory nerve hyperresponsiveness
tial to produce these cytokines [18,20,21]. Chemical media- include the increased release of nerve growth factor during
tors such as platelet-activating factor (PAF), leukotriene B4 allergic inflammation [32].
(LTB4), cysteinyl leukotrienes (cysLTs) and thromboxane A2 Chemical mediators including histamine, cysLTs, and PAF
(TXA2) are also released mainly from mast cells and eosino- induce plasma exudation directly from the blood vessels in
phils [17,20]. Chemokines such as eotaxin, regulated upon the nasal mucosa, which constitutes a part of rhinorrhoea.
activation normal T cell expressed and secreted (RANTES) However, only 415% of total rhinorrhoea is attributed to
and thymus and activation regulated chemokine (TARC) are plasma exudation, according to calculations based on the
produced mainly in fibroblasts, epithelial cells and vascular albumin concentration in the rhinorrhoea induced by aller-
endothelial cells [22]. Proinflammatory cytokines such as gen challenge [33].
tumour necrosis factor (TNF)-a from mast cells and
eosinophil-derived granules such as eosinophil cationic pro- Nasal congestion. The underlying causes of nasal congestion
teins are also produced and participate in allergic inflamma- in the early phase of allergic rhinitis are the relaxation of the
tion [23,24]. The sensitivity of the nasal mucosa to different smooth muscle layer of capacitance vessels in the nasal
stimulants increases along with the progress of allergic mucosa and the interstitial oedema induced by plasma exu-
inflammation in the nasal mucosa; this increased sensitivity is dation. Swelling of the nasal turbinate is induced by the
referred to as the priming effect [25]. The secondary reaction parasympathetic reflex and the axon reflex through the nerve
with inflammatory cells and their mediators, especially the centre and the direct effects of the chemical mediators on the
cysLTs produced by eosinophils, causes oedema of the nasal vascular system. Dilation of the capacitance vessels and
mucosa [26]. This inflammation, which develops 610 h after plasma exudation after excitation of the parasympathetic
the allergen challenge, is referred to as the late-phase response centre are caused by the nitric oxide (NO) released from
[17]. Management of allergic rhinitis should be determined parasympathetic terminals and vascular endothelial cells
based on its mechanism (Fig. 1). [34]. However, the participation of the nerve reflex in nasal
turbinate swelling after allergen challenge is minor compared
with the direct effects of chemical mediators, such as hista-
Onset of three major AR symptoms
mine, cysLTs, PAF and prostaglandin D2 (PGD2) and kinin, on
Sneezing. Sensory nerves containing substance P (SP) and the vascular system in the nasal mucosa [35,36]. Nasal con-
calcitonin gene-related peptide (CGRP) are distributed gestion in the late phase is induced by the allergic inflamma-
throughout the epithelial and subepithelial layers of the nasal tion, as described above.

2009 British Society for Immunology, Clinical and Experimental Immunology, 158: 164173 165
M. Okano

Mucosal type mast cell Early phase response

Mast cell
Nerve
Allergen
Medulla Sneeze
Hi
Gland
IgE Parasympathetic centre
production Non-specific
Antigen Rhinorrhoea
presenting Hypersecretion hypersensitivity
Vessels
cell LTs Relaxation of smooth muscle
TXA2 Congestion
PGD2 Plasma exudation
TCR PAF
Repeated
IL4, IL5, IL13, GMCSF, IFN, stimulation
Release of chemo- LTs, LTB4, PAF, TXA2,
B cell attractant factors eotaxin, TARC, RANTES, IL8

Th2 cell
Remodelling
Inflammatory cell infiltration

Eosinophil-Neutrophil Late phase response

Basophil-Lymphocyte
Epithelial cell Release of
Allergic
Vascular endothelial cell proinflammatory Congestion
inflammation
Fibroblast molecules

Fig. 1. Pathophysiology of allergic rhinitis as described in Practical Guideline for Management of Allergic Rhinitis in Japan (PG-MARJ). After
allergens are inhaled into the nasal mucosa of sensitized subjects, they bind to immunoglobulin (Ig)E on the surface of mast cells, inducing the
release of chemical mediators including histamine, prostaglandins and cysteinyl leukotrienes (cysLTs) by aggregation of FceRI. Histamine regulates
tight junctions by coupling the H1 receptor, which increases paracellular permeability. The early-phase response, which is characterized by sneezing,
rhinorrhoea and nasal congestion, is the response of the sensory nerve terminals and blood vessels on the nasal mucosa to these chemical
mediators. After the nasal exposure to allergen, infiltration of inflammatory cells, such as activated eosinophils and T helper type 2 (Th2) cells, into
the nasal mucosa is induced by chemoattractant factors such as cytokines including interleukin (IL)-5, chemical mediators including cysLTs and
chemokines including eotaxin. Oedema of the nasal mucosa develops as a secondary reaction with inflammatory cells. This inflammation, referred
to as the late-phase response, develops 610 h after allergen challenge and causes prolonged nasal congestion.

the transcription of proinflammatory genes by protein

Mechanisms of glucocorticosteroid
protein interactions such as GRnuclear factor kappa B
(NFkB) and GRactivator protein 1 (AP-1) [44]. Evidence
Molecular level
for a co-activator competition model of transrepression
At the molecular level, the effects of GC begin when GC involving CBP/p300 was first provided for GR transrepres-
crosses the cell membrane and binds to the intracellular sion of AP-1 target genes [45].
glucocorticosteroid receptor (GR) [37]. Cytoplasmic GR is
maintained in an inactive form by heat shock protein
Cellular level (Fig. 2)
(hsp)90 and hsp70 [38,39]. Binding of GC dissociates the
hsps, allowing the GR complex to translocate into the GC inhibits the functions of infiltrating inflammatory cells
nucleus or interact with cytoplasmic transcriptional factors. and their recruitment into the nasal mucosa. GC inhibits the
An alternative splicing variant, GRb, lacks the ability to bind maturation, cytokine production, FceRI expression and
GC [40]. GRb forms heterodimers with the wild-type GR mediator release of mast cells [46,47]. GC inhibits histamine
(GRa) and may act as an inhibitor of GRa. In atopic nasal release from basophils [48,49], induces apoptosis of eosino-
tissue, staphylococcal enterotoxin induces GRb expression phils [50] and reduces the recruitment of antigen-presenting
and steroid resistance [41]. cells such as Langerhans cells [51]. GC decreases the
GC exerts its anti-inflammatory effects through at least numbers of GATA-3+ Th2 cells and the production of Th2
two pathways, transactivation and transrepression [42]. cytokines, such as IL-4, IL-5, IL-6 and IL-13, while having
Transactivation occurs when the receptor complex binds to little effect on T-bet+ Th1 cells and the production of Th1
the glucocorticosteroid-response elements (GRE) in the cytokines such as IL-2, IL-12 and interferon (IFN)-g [52,53].
promoter regions of glucocorticosteroid-responsive genes, Although the inhibitory effect of GC on B cell recruitment is
which encode anti-inflammatory genes such as annexin 1, limited, GC inhibits class-switching to IgE in the nasal
IkB and CD163 [43]. Alternatively, the GR complex represses mucosa [51,54].

166 2009 British Society for Immunology, Clinical and Experimental Immunology, 158: 164173
 Intranasal glucocorticosteroids

Inflammatory cells Constitutive cells

Number
(apoptosis)
Cytokine
Eosinophils Adhesion molecule

Cytokine Epithelial cells

Th2 cells Adhesion molecule
Number Glucocorticosteroid Permiability
Mediator Endothelial cells
Fig. 2. Effect of glucocorticosteroids (GC) on Cytokine
FcRI
nasal mucosa. The anti-inflammatory effects of Mast cells
Proliferation
GC on allergic rhinitis are mediated not only by IgE Adhesion molecule
inflammatory cells such as eosinophils, T helper Chemokine
Fibroblasts
B cells
type 2 (Th2) cells, mast cells, B cells, dendritic
cells and basophils, but also by nasal Number
Regulatory T cells
constitutive cells such as epithelial cells, Dendritic cells (Treg) Mucin secretion
endothelial cells, fibroblasts and glands/goblet Number Glands
Mediator
cells. In addition, treatment with GC can Regulatory cytokines Goblet cells
induce regulatory T cells. Basophils (IL-10, TGF-)

GC also has anti-inflammatory effects on nasal constitu- latory CD4+CD25+ T cells from patients with birch polli-
tive cells, such as epithelial cells, fibroblasts, vascular endo- nosis but not healthy controls were defective in down-
thelial cells and glands. GC inhibits intercellular adhesion regulating birch pollen-induced IL-13 and IL-5 production
molecule 1 (ICAM-1) expression [49] and GM-CSF produc- by CD4+CD25 T cells during the pollen season, while their
tion [55] by nasal epithelial cells. GC down-regulates nasal capacity to suppress IFN-g production and proliferation
fibroblast functions, including basic fibroblast growth factor was retained [67]. The ratio of FoxP3+/GATA binding
(bFGF)-induced proliferation, TNF-a-induced ICAM-1 protein 3 (GATA-3+) cells in nasal mucosa was decreased
expression, TNF-a- or IL-4-stimulated eotaxin release [56], significantly in patients with pollinosis as compared with
TNF-a-induced matrix metalloproteinase production [57] healthy controls outside the pollen season, and the ratio
and TNF-a-induced vascular endothelial growth factor was decreased further during the pollen season in allergic
(VEGF) and bFGF production [58]. GC inhibits TNF-a- or patients [53]. In addition, Tregs are induced in both periph-
IL-1b-stimulated E-selectin expression on nasal vascular eral blood and nasal mucosa following allergen-specific
endothelial cells [59]. The effect of GC on vascular cel adhe- immunotherapy [68,69].
sion molecule 1 (VCAM-1) expression on nasal vascular Treatment with GC induces Tregs. FoxP3 mRNA expres-
endothelial cells is controversial [60,61]. The effect of GC on sion in CD4+ cells was increased significantly in adult asth-
vascular permeability reflects the inhibition of cellular matic patients receiving GC, and systemic GC treatment led
inflammatory processes indirectly rather than the direct to an early increase in FoxP3 mRNA and Treg expression
effect on nasal vascular endothelial cells [62]. in patients with asthma [70]. Paediatric asthma patients
treated with GC also had an increased frequency of Tregs in
CD4+ cells from peripheral blood and bronchoalveolar
Induction of regulatory cytokines and Tregs
lavage fluid (BALF). In addition, Tregs in the BALF of asth-
Among the cells with regulatory functions such as CD8+, matic patients failed to suppress proliferation and produc-
CD4CD8 and gd T cells, CD4+CD25+forkhead box P3 tion of Th2-associated cytokines by responder T cells,
(FoxP3+) Treg cells play a central role in immune tolerance which was restored after inhalation of GC [71]. FoxP3 and
and immune homeostasis [63]. Tregs are derived from the IL-10 were down-regulated in nasal polyps compared with
thymus and the periphery [64]. The suppressive effect of control mucosa, and their expression was increased after
Tregs is associated with expression of the transcription factor intranasal GC treatment [72]. We have demonstrated that
FoxP3, which is used as a Treg marker [65]. In addition, Tregs GC induced CD4+ CD25+ FoxP3+ Tregs in dispersed nasal
express high-affinity IL-2 receptor (CD25), and IL-2 is vital polyp cells in the presence of IL-2. In fact, combined treat-
for the development and survival of Tregs [64]. Tregs regulate ment with GC and IL-2 expands Tregs in vivo, and the
effector cells by cell-to-cell contact, the production of induced Tregs suppress the proliferation of responder
inhibitory cytokines such as IL-10 and transforming T cells in mice [73]. GC leads to the production of
growth factor (TGF)-b, cytotoxicity mediated by perforins glucocorticosteroid-induced leucine zipper (GILZ) by
and granzymes, and competition for T cell growth factors, dendritic cells; GILZ is critical for commitment of DCs to
especially IL-2 [66]. differentiate into regulatory DCs and for the generation
The impaired expression or function of Tregs is involved of antigen-specific Tregs [74]. The detailed mechanism by
in the pathogenesis of allergic rhinitis. For example, regu- which GC induces Tregs has not been elucidated.

2009 British Society for Immunology, Clinical and Experimental Immunology, 158: 164173 167
M. Okano

oral GC, only methylprednisolone tablets are confirmed as

Practical Guideline for Management of Allergic
an effective treatment for allergic rhinitis by a placebo-
Rhinitis in Japan (PG-MARJ)
controlled trial; this trial showed that a daily dosage of 24 mg
To address the classification, epidemiology, pathophysiology of methylprednisolone was necessary to obtain a significant
and management of allergic rhinitis in Japan, a practical improvement in all nasal symptoms [81]. Thus, the use of
guideline for the management of this condition, PG-MARJ, oral GC corresponding to 2030 mg of prednisolone should
was first released in 1993. Based on the latest basic and clini- be limited to a brief period of time (within 1 week) when
cal evidence, the sixth edition of PG-MARJ was published treating patients with allergic rhinitis. Caution is needed to
in 2008 [2]. The following discussion summarizes the avoid adverse effects including adrenal cortical suppression
PG-MARJ guidelines regarding the positioning of INS and and difficulty in withdrawing GC following prolonged
systemic GC for the management of allergic rhinitis. administration (longer than 2 weeks) [82].
INS are potent agents indicated for the treatment of aller- Although some physicians use intramuscular injection
gic rhinitis. In the treatment of type I allergy, INS are used as with depot glucocorticosteroids for the treatment of polli-
anti-inflammatory drugs. INS exert anti-inflammatory nosis [83], these injections may induce systemic adverse
effects by the following mechanisms: inhibiting the local effects. Therefore, a careful examination including the serum
infiltration of effector cells of allergic inflammation such as cortisol level and blood glucose level should be performed
mucosal-type mast cells, eosinophils and lymphocytes; both before and after treatment. Because adverse effects such
inhibiting the production and release of cytokines; inhibit- as moon face, skin/skin appendage disorders, menstrual dis-
ing vascular permeability and mucus gland secretion; and order, application site disorders, including atrophy, and
down-regulating the production of leukotrienes and pros- adrenal cortical hypofunction may develop, depot gluco-
taglandins by inhibiting arachidonic acid cascades. INS are corticosteroids are not recommended for patients with
not effective in controlling acute-phase allergic reactions but pollinosis [84].
are effective for late-phase allergic reactions. However, INS Based on the above observations, glucocorticosteroids are
are effective in controlling acute-phase allergic reactions recommended for patients with moderate-to-severe peren-
when administered continuously. nial allergic rhinitis (Table 1) and mild-to-severe pollinosis,
Beclomethasone propionate, fluticasone propionate, except for prophylactic treatment (Table 2).
mometasone furoate and fluticasone furoate are currently
available as nasal sprays in Japan. These INS have potent
Effect of INS on ocular symptoms in patients with
local effects at small doses; they are not absorbed easily into
allergic rhinitis
the systemic circulation and are metabolized rapidly when
absorbed [75]. Thus, the incidence of systemic adverse Regarding statements on the mechanisms and efficacy of
effects is low, even in patients receiving these drugs for 1 intranasal glucocorticosteroids, the Japanese guideline (PG-
year, and reliable clinical effects can be expected with their MARJ) has many similarities with Allergic Rhinitis and its
use [76,77]. In addition, INS with lower bioavailability are Impact on Asthma (ARIA), the evidence-based international
believed to show fewer systemic adverse effects [78]. Because guideline for allergic rhinitis [1]. However, there are differ-
these drugs are administered locally, mild nasal irritation, ences between these two guidelines, such as different conclu-
dry nose and nasal bleeding may develop in winter when the sions regarding the efficacy of INS for ocular symptoms.
air is dry. According to the PG-MARJ, INS are effective only against
The onset of the effects of INS is rapid, with efficacy nasal symptoms [2]. However, the updated ARIA docu-
observed in as little as 1 day [79]. Efficacy increases as the mented that INS are effective not only for nasal but also
treatment period is prolonged. These drugs are effective even ocular symptoms in patients with pollinosis.
in patients with severe allergic rhinitis; their effects are Bernstein et al. performed a double-blind, double-
clearly observable, and many patients obtain excellent dummy, randomized study comparing fluticasone propi-
results. INS are effective for the treatment of nasal obstruc- onate aqueous nasal spray 200 mg once daily, oral loratadine
tion that is unresponsive to H1-receptor antagonists, 10 mg once daily or placebo for the treatment of seasonal
for aiding withdrawal from vasoconstrictive nose drops allergic rhinitis and found that fluticasone propionate
(a-sympathetic stimulants) and for the treatment of vaso- reduced ocular symptoms, especially ocular itching, tearing
motor rhinitis [80]. and redness, compared with not only placebo but also
Oral GC may be used in patients who do not respond to oral loratadine [85]. More recently, Fokkens et al. per-
INS (such as those with severe, very severe and intractable formed a multi-centre, randomized, double-blind, placebo-
allergic rhinitis). Celestamine (a mixture of H1-receptor controlled, parallel group study of fluticasone furoate 110 mg
antagonist d-chlorpheniramine maleate and betametha- once daily nasal spray versus placebo for the treatment of
sone) is used relatively widely in Japan; however, no placebo- seasonal allergic rhinitis caused by grass pollen, and they
controlled trials have been reported. In addition, evidence found that fluticasone furoate is significantly effective for
regarding a suitable dosage of this drug is lacking. Among not only nasal symptoms and quality of life but also

168 2009 British Society for Immunology, Clinical and Experimental Immunology, 158: 164173
 Intranasal glucocorticosteroids

Table 1. Management for perennial allergic rhinitis in PGMARJ.

Moderate Severe
Grade type Mild Sneeze/discharge type Congestion type Sneeze/discharge type Congestion type
Management 1 H1 RA 1 H1 RA 1 LT RA HIS + H1 RA INS + LT RA or
2 CMRI 2 CMRI 2 PGD2/TXA2 RA PGD2/TXA2 RA
3 Th2 CS 3 Th2 CS 3 INS Topical decongestant for
Either 1 , 2 or 3 4 INS Either 1 , 2 , or 3 57 days at initial
Either 1 , 2 , 3 or 4 Combination of treatment if necessary
Combination of 4 3 with 1 or 2
with 1 , 2 or 3
Corrective surgery of nasal cavity
Allergen-specific immunotherapy
Allergen avoidance/elimination
H1 RA, second generation H1 receptor antagonists; CMRI, chemical mediator release inhibitors; LT RA, leukotriene receptor antagonists;
PGD2/TXA2 RA, PGD2/TXA2 receptor antagonist (ramatroban); T helper type 2 (Th2) C, Th2 cytokine suppressor (suplatast); INS, intranasal
glucocorticosteroids.

ocular symptoms including eye itching/burning, eye tearing/ may lead to a normalization or modification of the naso-
watering and eye redness [86]. The efficacy of fluticasone ocular reflex. In addition, the reduced inflammation in the
furoate nasal spray against ocular symptoms was also con- nose may lessen the release of inflammatory mediators that
firmed in patients with ragweed allergy [87]. can cause inflammation in neighbouring tissues including
Although the precise mechanism remains unclear, several the conjunctiva. Reduction of oedema and inflammation
explanations regarding the effectiveness of INS drugs for the surrounding the opening of the nasolacrimal duct might also
treatment of ocular symptoms have been proposed. Because reduce the retention of allergen in the conjunctiva.
of low bioavailability, systemic absorption and circulation is
negligible among second-generation INS drugs [75]. The
Effect of INS on impaired performance
symptoms of itchy and watery eyes and bilateral ocular
secretion weights increase after ipsilateral nasal challenge Allergic rhinitis itself impairs performance by causing
with allergen, suggesting that the ocular symptoms associ- daytime sleepiness and disrupting cognitive functions such
ated with allergic rhinitis arise, in part, from a naso-ocular as learning ability [89,90]. Nasal congestion due to allergic
reflex [88]. The reduced nasal inflammation caused by INS reaction and inflammation seems to be the major causative

Table 2. Management for pollinosis in PGMARJ.

Moderate Severe
Sneeze/ Sneeze/
Grade type Prophylactic Mild discharge type Congestion type discharge type Congestion type
Management 1 CMRI 1 H1 RA H1 RA + INS LT RA + INS + INS + H1 RA INS + LT RA + H1 RA
2 H1 RA 2 INS H1 RA Topical decongestant for
3 LT RA Start with 1 with 710 days at initial
4 Th2 CS eye drops treatment if necessary
5 PGD2/TXA2 RA Add 2 if Short-term
Either 1 , 2 , 3 , necessary administration (47
4 or 5 days) of oral
glucocorticoids may
be chosen for patients
with extremely severe
congestion
Eye drops of either H1 RA or CMRI Eye drops of either H1 RA, CMRI or glucocorticoids
Corrective surgery of nasal cavity
Allergen-specific immunotherapy
Allergen avoidance/elimination
H1 RA, second generation H1 receptor antagonists; CMRI, chemical mediator release inhibitors; LT RA, leukotriene receptor antagonists;
PGD2/TXA2 RA, PGD2/TXA2 receptor antagonist (ramatroban); T helper type 2 (Th2) CS, Th2 cytokine suppressor (suplatast); INS, intranasal
glucocorticosteroids.

2009 British Society for Immunology, Clinical and Experimental Immunology, 158: 164173 169
M. Okano

factor of daytime sleepiness, as this symptom can cause onate 200 mg twice daily versus the second-generation oral
obstructive sleep apnoea and microarousals during sleep H1-antagonist olopatadine 10 mg twice daily in patients with
[91]. Symptomatic seasonal allergic rhinitis has been associ- Japanese cedar pollinosis and found that fluticasone pro-
ated with significant detrimental effects on examination per- pionate delayed the onset of nasal symptoms significantly
formance in young people [90]. compared with olopatadine. In addition, treatment with
Treatment with sedating H1-receptor antagonists exacer- fluticasone suppressed symptoms significantly during peak
bates impaired performance [90,92]; students taking these pollen season. Okubo et al. [98] reported that initial treat-
medications on examination days exhibited a significant ten- ment with fluticasone propionate 100 mg b.i.d. prevented
dency to unexpectedly drop a grade [90]. exacerbation of nasal symptoms in paediatric patients with
On the other hand, INS can improve impaired perfor- seasonal allergic rhinitis. Indeed, nasal symptoms disap-
mance in allergic rhinitis patients [93,94]. Craig et al. [93] peared in 440% of patients who had mild symptoms at
showed that intranasal budesonide 128 mg/day, flunisolide initiation of treatment.
200 mg/day and fluticasone 200 mg/day were each effective As described above, one of the pathways of the anti-
in improving sleep and daytime fatigue and somnolence, inflammatory effect of GC is the down-regulation of
although significant changes in polysomnography did not proinflammatory genes by several mechanisms such as
always occur. Moreover, treatment with intranasal fluticasone proteinprotein interactions that sequester protein kinase A
propionate 200 mg once daily significantly improved not only and cAMP enhancer binding protein (CREB)-binding
nasal symptoms and daytime sleepiness but also cognitive protein from NF-kB [44,45]. The interaction between
performance, as measured by the test of variables of attention NF-kB, CREB and CREB-binding protein leads to the acety-
(TOVA) in patients with seasonal allergic rhinitis [94]. lation of chromatin and the subsequent transcription of
proinflammatory genes, such as genes encoding cytokines,
inflammatory enzymes, adhesion molecules and inflamma-
Efcacy of INS for prophylactic (initial) treatment
tory receptors [99]. Thus, GC may be more effective for
of pollinosis
prophylactic treatment compared with post-onset treatment
The PG-MARJ recommends that patients who experience because increased levels of NF-kB in the nose after the onset
severe symptoms of pollinosis every year should receive of pollinosis can attenuate proteinprotein interaction by
prophylactic treatment immediately after the start of pollen glucocorticosteroids.
release or the onset of symptoms [2,95]. Considering the
amount of pollen release expected during the season and
Conclusions
the type and severity of symptoms usually experienced by
patients during the peak pollen season, physicians should In addition to the novel information that appeared in the
determine the drug regimen for each individual patient sixth edition of the PG-MARJ in 2008, considerable evidence
by selecting from among chemical mediatorrelease supports the use of GC against allergic rhinitis. GC can
inhibitors, second-generation H1-receptor antagonists, induce regulatory cytokines and FoxP3+ Tregs in the nose. The
leukotriene receptor antagonists, Th2 cytokine inhibitor appropriate use of INS may improve nasal symptoms, ocular
(suplatast) and PGD2/TXA2 receptor antagonist (rama- symptoms and impaired performance. Moreover, INS can be
troban) [2]. Patients with sneezing/rhinorrhoea-type rhini- used for the first-line prophylactic treatment of pollinosis.
tis should receive chemical mediatorrelease inhibitors or These recent findings may provide additional information
second-generation anti-histamines, whereas patients with for incorporation into future editions of guidelines for aller-
congestion-type disease should be treated with leukotriene gic rhinitis treatment, including the PG-MARJ. On the other
receptor antagonist, Th2 cytokine inhibitor or PGD2/TXA2 hand, several issues remain unsolved. For example, although
receptor antagonist. inhaled GC have not been incriminated as teratogens in
Several reports suggest that INS drugs are effective for the humans and are used commonly by pregnant women who
prophylactic treatment of pollinosis. One study of prophy- have asthma, there are no placebo-controlled, randomized,
lactic treatment with mometasone furoate 200 mg once daily double-blind studies of INS during the first trimester of
aqueous nasal spray, beclomethasone dipropionate 168 mg pregnancy.
b.i.d. aqueous nasal spray or placebo was initiated in patients
with ragweed pollinosis 4 weeks before the estimated start of
Disclosure
pollen season. Both the proportion of minimal symptom
days from start of ragweed season and the number of days The author has received research grants and lecture fees from
from start of ragweed season to first non-minimal symptom Banyu, Dainippon Sumitomo Pharma, Glaxo Smith Kline,
day were significantly higher in patients treated with either Kyorin Pharmaceutical, Kyowa Hakko Kirin, Mitsubishi
mometasone furoate or beclomethasone dipropionate com- Tanebe Pharma, Nippon Boeringer Ingelheim, Nippon
pared with placebo [96]. Yokoo [97] compared the efficacy of Shinyaku, Ono Pharmaceutical, Sanofi Aventis, Schering-
prophylactic treatment with intranasal fluticasone propi- Plough, Shionogi and Taiho Pharmaceutical.

170 2009 British Society for Immunology, Clinical and Experimental Immunology, 158: 164173
 Intranasal glucocorticosteroids

20 Durham SR, Ying S, Varney VA et al. Cytokine messenger RNA

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