Mechanisms and clinical implications of glucocorticosteroids in the treatment of allergic rhinitis

Abstract

Allergic rhinitis is a common airway disease characterized by hypersensitivity, exudation, hypersecretion, inflammatory cell infiltration and remodelling. Intranasal glucocorticosteroids are the most effective drugs for controlling the inflammation caused by allergic rhinitis. Glucocorticosteroids exert anti-inflammatory effects through at least two pathways: the transactivation pathway and the transrepression pathway. Glucocorticosteroids also exert regulatory functions by inducing regulatory cytokines and forkhead box P3 (FoxP3⁺) regulatory T cells. Evidence suggests that intranasal glucocorticosteroids control not only nasal symptoms but also ocular symptoms. In contrast to sedating H1 receptor antagonists, intranasal glucocorticosteroids 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 treatment of pollinosis; this possibility is supported by the molecular mechanism of the anti-inflammatory action of glucocorticosteroids. These findings suggest that intranasal glucocorticosteroids might be positioned as first-line drugs for the treatment of both perennial and seasonal allergic rhinitis.

Introduction

Allergic rhinitis (AR) is a common manifestation of allergic diseases, affecting approximately 500 million people worldwide [1]. AR is increasing in prevalence. For example, the prevalence of AR in Japan increased from 29·8% in 1998 to 39·4% in 2008. The prevalence of pollinosis, the typical seasonal AR, has been increased from 19·6% in 1998 to 29·8% in 2008 [2].

AR is a major chronic inflammatory condition in the upper airway characterized by hypersensitivity, exudation, hypersecretion, inflammatory cell infiltration and remodelling [3]. Although glucocorticosteroids (GC) are highly effective in mitigating inflammation, their potent action often causes severe adverse effects [4,5]. To decrease the potential for adverse effects, intranasal glucocorticosteroid (INS) formulations with low systemic availability have been developed for the treatment of allergic rhinitis [6].

In this review, we discuss the pathophysiology of allergic rhinitis and the mechanism of action of GC, including the induction of regulatory T cells (T_regs), in the pathogenesis of AR. We also discuss the usefulness and pitfalls of INS in the clinical setting and assess the current status of INS for the treatment of AR.

Pathophysiology of AR

Pathogenesis of AR

Most causal antigens for AR are inhalant allergens. House dust mite, animal dander and pollens are the principal allergens. Many allergens, including the major house dust-mite allergen, Der p 1, have protease activity that impairs epithelial barrier function and facilitates the penetration of allergens into nasal mucosa [7]. Following nasal exposure to the inhalant allergens, professional antigen-presenting cells in the nasal mucosa, such as dendritic cells (DC), capture the allergens and provide two distinct signals, the allergen-derived peptide/MHC complex and co-stimulatory molecules such as CD80 and CD86, to naive T cells [8–10]. Allergen-specific T helper type 2 (Th2) cells are generated in patients with AR, whereas allergen-specific Th1 cells are generated in healthy individuals [11,12]. Early interleukin (IL)-4 and thymic stromal lymphopoietin (TSLP) produced by basophils in response to allergens with protease activity may contribute to Th2 differentiation [12]. Th2 cells produce IL-4/IL-13 and express CD40L, which promote the class-switching of B cells to immunoglobulin (Ig)E [13,14]. When sensitized subjects inhale antigens, the antigens pass through the epithelial tight junctions in the nasal mucosa to bind IgE on the surface of mast cells in the epithelial layer of the nasal mucosa, inducing the release of chemical mediators including histamine, prostaglandins and cysLTs by aggregation of FcεRI. Histamine regulates tight junctions via the coupling of H1 receptors and increases paracellular permeability [15]. This increased permeability allows DC to penetrate epithelial tight junctions easily and enhance antigen presentation to T cells [16]. The early-phase response, which consists of sneezing, rhinorrhoea and nasal congestion, is caused by interactions between chemical mediators and the sensory nerve terminals and blood vessels in the nasal mucosa [17].

After the nasal exposure to allergen, infiltration of inflammatory cells, such as activated eosinophils and Th2 cells, into the nasal mucosa is induced by cytokines, chemical mediators, chemokines and growth factors [18,19]. Cytokines such as IL-5, IL-4, IL-13 and granulocyte–macrophage colony-stimulating factor (GM-CSF) are produced mainly in Th2 cells and mast cells; however, eosinophils also have the potential to produce these cytokines [18,20,21]. Chemical mediators such as platelet-activating factor (PAF), leukotriene B4 (LTB₄), cysteinyl leukotrienes (cysLTs) and thromboxane A₂ (TXA₂) are also released mainly from mast cells and eosinophils [17,20]. Chemokines such as eotaxin, regulated upon activation normal T cell expressed and secreted (RANTES) and thymus and activation regulated chemokine (TARC) are produced mainly in fibroblasts, epithelial cells and vascular endothelial cells [22]. Proinflammatory cytokines such as tumour necrosis factor (TNF)-α from mast cells and eosinophil-derived granules such as eosinophil cationic proteins are also produced and participate in allergic inflammation [23,24]. The sensitivity of the nasal mucosa to different stimulants increases along with the progress of allergic inflammation in the nasal mucosa; this increased sensitivity is referred to as the priming effect [25]. The secondary reaction with inflammatory cells and their mediators, especially the cysLTs produced by eosinophils, causes oedema of the nasal mucosa [26]. This inflammation, which develops 6–10 h after the allergen challenge, is referred to as the late-phase response [17]. Management of allergic rhinitis should be determined based on its mechanism (Fig. 1).

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 FcεRI. 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 6–10 h after allergen challenge and causes prolonged nasal congestion.

Onset of three major AR symptoms

Sneezing

Sensory nerves containing substance P (SP) and calcitonin gene-related peptide (CGRP) are distributed throughout the epithelial and subepithelial layers of the nasal mucosa [27]. Sensory nerve terminals are located in the epithelial junctions and subepithelial layers. In the guinea pig model of allergic rhinitis, the sneezing reflex following allergen challenge is inhibited significantly by pretreatment with capsaicin, which depletes SP and CGRP from the nasal mucosa [28]. When various chemical mediators are applied to the nasal mucosa, histamine is the only mediator that induces a significant sneezing reflex [28,29]. Therefore, the sneezing reflex following allergen challenge is a respiratory reflex induced by the interaction between histamine and the H1 receptor at the sensory nerve terminals containing SP and CGRP and might be a sensory stimulation response amplified by hyperreactivity in the nasal mucosa [25].

Rhinorrhoea

Synchronously with the sneezing reflex, sensory stimulation on the nasal mucosa induces excitation reflexively in the parasympathetic centre. After allergen challenge on the hemilateral nasal mucosa of patients with allergic rhinitis, the weight of rhinorrhoea induced in both sides of nasal cavities is correlated with the number of sneezes. In addition, the weight of rhinorrhoea in the nasal cavity with allergen challenge is correlated with that on the opposite side. Therefore, rhinorrhoea can be regarded as the secretion from the mucous glands by parasympathetic stimulation [30]. Furthermore, allergic inflammation induced by nasal allergen exposure augments this ‘naso-nasal’ reflex [31]. Possible mechanisms for sensory nerve hyperresponsiveness include the increased release of nerve growth factor during allergic inflammation [32].

Chemical mediators including histamine, cysLTs, and PAF induce plasma exudation directly from the blood vessels in the nasal mucosa, which constitutes a part of rhinorrhoea. However, only 4–15% of total rhinorrhoea is attributed to plasma exudation, according to calculations based on the albumin concentration in the rhinorrhoea induced by allergen challenge [33].

Nasal congestion

The underlying causes of nasal congestion in the early phase of allergic rhinitis are the relaxation of the smooth muscle layer of capacitance vessels in the nasal mucosa and the interstitial oedema induced by plasma exudation. Swelling of the nasal turbinate is induced by the parasympathetic reflex and the axon reflex through the nerve centre and the direct effects of the chemical mediators on the vascular system. Dilation of the capacitance vessels and plasma exudation after excitation of the parasympathetic centre are caused by the nitric oxide (NO) released from parasympathetic terminals and vascular endothelial cells [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 histamine, cysLTs, PAF and prostaglandin D₂ (PGD₂) and kinin, on the vascular system in the nasal mucosa [35,36]. Nasal congestion in the late phase is induced by the allergic inflammation, as described above.

Mechanisms of glucocorticosteroid

Molecular level

At the molecular level, the effects of GC begin when GC crosses the cell membrane and binds to the intracellular glucocorticosteroid receptor (GR) [37]. Cytoplasmic GR is maintained in an inactive form by heat shock protein (hsp)90 and hsp70 [38,39]. Binding of GC dissociates the hsps, allowing the GR complex to translocate into the nucleus or interact with cytoplasmic transcriptional factors. An alternative splicing variant, GRβ, lacks the ability to bind GC [40]. GRβ forms heterodimers with the wild-type GR (GRα) and may act as an inhibitor of GRα. In atopic nasal tissue, staphylococcal enterotoxin induces GRβ expression and steroid resistance [41].

GC exerts its anti-inflammatory effects through at least two pathways, transactivation and transrepression [42]. Transactivation occurs when the receptor complex binds to the glucocorticosteroid-response elements (GRE) in the promoter regions of glucocorticosteroid-responsive genes, which encode anti-inflammatory genes such as annexin 1, IκB and CD163 [43]. Alternatively, the GR complex represses the transcription of proinflammatory genes by protein–protein interactions such as GR–nuclear factor kappa B (NFκB) and GR–activator protein 1 (AP-1) [44]. Evidence for a co-activator competition model of transrepression involving CBP/p300 was first provided for GR transrepression of AP-1 target genes [45].

Cellular level (Fig. 2)

Fig. 2.

Effect of glucocorticosteroids (GC) on nasal mucosa. The anti-inflammatory effects of GC on allergic rhinitis are mediated not only by inflammatory cells such as eosinophils, T helper type 2 (Th2) cells, mast cells, B cells, dendritic cells and basophils, but also by nasal constitutive cells such as epithelial cells, endothelial cells, fibroblasts and glands/goblet cells. In addition, treatment with GC can induce regulatory T cells.

GC inhibits the functions of infiltrating inflammatory cells and their recruitment into the nasal mucosa. GC inhibits the maturation, cytokine production, FcεRI expression and mediator release of mast cells [46,47]. GC inhibits histamine release from basophils [48,49], induces apoptosis of eosinophils [50] and reduces the recruitment of antigen-presenting cells such as Langerhans cells [51]. GC decreases the numbers of GATA-3⁺ Th2 cells and the production of Th2 cytokines, such as IL-4, IL-5, IL-6 and IL-13, while having little effect on T-bet⁺ Th1 cells and the production of Th1 cytokines such as IL-2, IL-12 and interferon (IFN)-γ[52,53]. Although the inhibitory effect of GC on B cell recruitment is limited, GC inhibits class-switching to IgE in the nasal mucosa [51,54].

GC also has anti-inflammatory effects on nasal constitutive cells, such as epithelial cells, fibroblasts, vascular endothelial cells and glands. GC inhibits intercellular adhesion molecule 1 (ICAM-1) expression [49] and GM-CSF production [55] by nasal epithelial cells. GC down-regulates nasal fibroblast functions, including basic fibroblast growth factor (bFGF)-induced proliferation, TNF-α-induced ICAM-1 expression, TNF-α- or IL-4-stimulated eotaxin release [56], TNF-α-induced matrix metalloproteinase production [57] and TNF-α-induced vascular endothelial growth factor (VEGF) and bFGF production [58]. GC inhibits TNF-α- or IL-1β-stimulated E-selectin expression on nasal vascular endothelial cells [59]. The effect of GC on vascular cel adhesion molecule 1 (VCAM-1) expression on nasal vascular endothelial cells is controversial [60,61]. The effect of GC on vascular permeability reflects the inhibition of cellular inflammatory processes indirectly rather than the direct effect on nasal vascular endothelial cells [62].

Induction of regulatory cytokines and T_regs

Among the cells with regulatory functions such as CD8⁺, CD4^–CD8^– and γδ T cells, CD4⁺CD25⁺forkhead box P3 (FoxP3⁺) T_reg cells play a central role in immune tolerance and immune homeostasis [63]. T_regs are derived from the thymus and the periphery [64]. The suppressive effect of T_regs is associated with expression of the transcription factor FoxP3, which is used as a T_reg marker [65]. In addition, T_regs express high-affinity IL-2 receptor (CD25), and IL-2 is vital for the development and survival of T_regs[64]. T_regs regulate effector cells by cell-to-cell contact, the production of inhibitory cytokines such as IL-10 and transforming growth factor (TGF)-β, cytotoxicity mediated by perforins and granzymes, and competition for T cell growth factors, especially IL-2 [66].

The impaired expression or function of T_regs is involved in the pathogenesis of allergic rhinitis. For example, regulatory CD4⁺CD25⁺ T cells from patients with birch pollinosis but not healthy controls were defective in down-regulating birch pollen-induced IL-13 and IL-5 production by CD4⁺CD25^– T cells during the pollen season, while their capacity to suppress IFN-γ production and proliferation was retained [67]. The ratio of FoxP3⁺/GATA binding protein 3 (GATA-3⁺) cells in nasal mucosa was decreased significantly in patients with pollinosis as compared with healthy controls outside the pollen season, and the ratio was decreased further during the pollen season in allergic patients [53]. In addition, T_regs are induced in both peripheral blood and nasal mucosa following allergen-specific immunotherapy [68,69].

Treatment with GC induces T_regs. FoxP3 mRNA expression in CD4⁺ cells was increased significantly in adult asthmatic patients receiving GC, and systemic GC treatment led to an early increase in FoxP3 mRNA and T_reg expression in patients with asthma [70]. Paediatric asthma patients treated with GC also had an increased frequency of T_regs in CD4⁺ cells from peripheral blood and bronchoalveolar lavage fluid (BALF). In addition, T_regs in the BALF of asthmatic patients failed to suppress proliferation and production of Th2-associated cytokines by responder T cells, which was restored after inhalation of GC [71]. FoxP3 and IL-10 were down-regulated in nasal polyps compared with control mucosa, and their expression was increased after intranasal GC treatment [72]. We have demonstrated that GC induced CD4⁺ CD25⁺ FoxP3⁺ T_regs in dispersed nasal polyp cells in the presence of IL-2. In fact, combined treatment with GC and IL-2 expands T_regsin vivo, and the induced T_regs suppress the proliferation of responder T cells in mice [73]. GC leads to the production of glucocorticosteroid-induced leucine zipper (GILZ) by dendritic cells; GILZ is critical for commitment of DCs to differentiate into regulatory DCs and for the generation of antigen-specific T_regs[74]. The detailed mechanism by which GC induces T_regs has not been elucidated.

Practical Guideline for Management of Allergic Rhinitis in Japan (PG-MARJ)

To address the classification, epidemiology, pathophysiology and management of allergic rhinitis in Japan, a practical guideline for the management of this condition, PG-MARJ, was first released in 1993. Based on the latest basic and clinical evidence, the sixth edition of PG-MARJ was published in 2008 [2]. The following discussion summarizes the PG-MARJ guidelines regarding the positioning of INS and systemic GC for the management of allergic rhinitis.

INS are potent agents indicated for the treatment of allergic rhinitis. In the treatment of type I allergy, INS are used as anti-inflammatory drugs. INS exert anti-inflammatory effects by the following mechanisms: inhibiting the local infiltration of effector cells of allergic inflammation such as mucosal-type mast cells, eosinophils and lymphocytes; inhibiting the production and release of cytokines; inhibiting vascular permeability and mucus gland secretion; and down-regulating the production of leukotrienes and prostaglandins by inhibiting arachidonic acid cascades. INS are not effective in controlling acute-phase allergic reactions but are effective for late-phase allergic reactions. However, INS are effective in controlling acute-phase allergic reactions when administered continuously.

Beclomethasone propionate, fluticasone propionate, mometasone furoate and fluticasone furoate are currently available as nasal sprays in Japan. These INS have potent local effects at small doses; they are not absorbed easily into the systemic circulation and are metabolized rapidly when absorbed [75]. Thus, the incidence of systemic adverse effects is low, even in patients receiving these drugs for ≥ 1 year, and reliable clinical effects can be expected with their use [76,77]. In addition, INS with lower bioavailability are believed to show fewer systemic adverse effects [78]. Because these drugs are administered locally, mild nasal irritation, dry nose and nasal bleeding may develop in winter when the air is dry.

The onset of the effects of INS is rapid, with efficacy observed in as little as 1 day [79]. Efficacy increases as the treatment period is prolonged. These drugs are effective even in patients with severe allergic rhinitis; their effects are clearly observable, and many patients obtain excellent results. INS are effective for the treatment of nasal obstruction that is unresponsive to H₁-receptor antagonists, for aiding withdrawal from vasoconstrictive nose drops (α-sympathetic stimulants) and for the treatment of vasomotor rhinitis [80].

Oral GC may be used in patients who do not respond to INS (such as those with severe, very severe and intractable allergic rhinitis). Celestamine® (a mixture of H₁-receptor antagonist d-chlorpheniramine maleate and betamethasone) is used relatively widely in Japan; however, no placebo-controlled trials have been reported. In addition, evidence regarding a suitable dosage of this drug is lacking. Among oral GC, only methylprednisolone tablets are confirmed as an effective treatment for allergic rhinitis by a placebo-controlled trial; this trial showed that a daily dosage of 24 mg of methylprednisolone was necessary to obtain a significant improvement in all nasal symptoms [81]. Thus, the use of oral GC corresponding to 20–30 mg of prednisolone should be limited to a brief period of time (within 1 week) when treating patients with allergic rhinitis. Caution is needed to avoid adverse effects including adrenal cortical suppression and difficulty in withdrawing GC following prolonged administration (longer than 2 weeks) [82].

Although some physicians use intramuscular injection with depot glucocorticosteroids for the treatment of pollinosis [83], these injections may induce systemic adverse effects. Therefore, a careful examination including the serum cortisol level and blood glucose level should be performed both before and after treatment. Because adverse effects such as moon face, skin/skin appendage disorders, menstrual disorder, application site disorders, including atrophy, and adrenal cortical hypofunction may develop, depot glucocorticosteroids are not recommended for patients with pollinosis [84].

Based on the above observations, glucocorticosteroids are recommended for patients with moderate-to-severe perennial allergic rhinitis (Table 1) and mild-to-severe pollinosis, except for prophylactic treatment (Table 2).

Table 1.

Management for perennial allergic rhinitis in PG–MARJ.

		Moderate		Severe
Grade type	Mild	Sneeze/discharge type	Congestion type	Sneeze/discharge type	Congestion type
Management	H1 RA CMRI Th2 CS Either , or	H1 RA CMRI Th2 CS INS Either , , or Combination of with , or	LT RA PGD2/TXA2 RA INS Either , , or Combination of with or	HIS + H1 RA	INS + LT RA or PGD2/TXA2 RA Topical decongestant for 5–7 days at initial treatment if necessary
				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.

Table 2.

Management for pollinosis in PG–MARJ.

			Moderate		Severe
Grade type	Prophylactic	Mild	Sneeze/ discharge type	Congestion type	Sneeze/ discharge type	Congestion type
Management	CMRI H1 RA LT RA Th2 CS PGD2/TXA2 RA Either , , , or	H1 RA INS Start with with eye drops Add if necessary	H1 RA + INS	LT RA + INS + H1 RA	INS + H1 RA	INS + LT RA + H1 RA Topical decongestant for 7–10 days at initial treatment if necessary Short-term administration (4–7 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.

Effect of INS on ocular symptoms in patients with allergic rhinitis

Regarding statements on the mechanisms and efficacy of intranasal glucocorticosteroids, the Japanese guideline (PG-MARJ) has many similarities with Allergic Rhinitis and its Impact on Asthma (ARIA), the evidence-based international guideline for allergic rhinitis [1]. However, there are differences between these two guidelines, such as different conclusions regarding the efficacy of INS for ocular symptoms. According to the PG-MARJ, INS are effective only against nasal symptoms [2]. However, the updated ARIA documented that INS are effective not only for nasal but also ocular symptoms in patients with pollinosis.

Bernstein et al. performed a double-blind, double-dummy, randomized study comparing fluticasone propionate aqueous nasal spray 200 µg once daily, oral loratadine 10 mg once daily or placebo for the treatment of seasonal allergic rhinitis and found that fluticasone propionate reduced ocular symptoms, especially ocular itching, tearing and redness, compared with not only placebo but also oral loratadine [85]. More recently, Fokkens et al. performed a multi-centre, randomized, double-blind, placebo-controlled, parallel group study of fluticasone furoate 110 µg once daily nasal spray versus placebo for the treatment of seasonal allergic rhinitis caused by grass pollen, and they found that fluticasone furoate is significantly effective for not only nasal symptoms and quality of life but also ocular symptoms including eye itching/burning, eye tearing/watering and eye redness [86]. The efficacy of fluticasone furoate nasal spray against ocular symptoms was also confirmed in patients with ragweed allergy [87].

Although the precise mechanism remains unclear, several explanations regarding the effectiveness of INS drugs for the treatment of ocular symptoms have been proposed. Because of low bioavailability, systemic absorption and circulation is negligible among second-generation INS drugs [75]. The symptoms of itchy and watery eyes and bilateral ocular secretion weights increase after ipsilateral nasal challenge with allergen, suggesting that the ocular symptoms associated with allergic rhinitis arise, in part, from a naso-ocular reflex [88]. The reduced nasal inflammation caused by INS may lead to a normalization or modification of the naso-ocular reflex. In addition, the reduced inflammation in the nose may lessen the release of inflammatory mediators that can cause inflammation in neighbouring tissues including the conjunctiva. Reduction of oedema and inflammation surrounding the opening of the nasolacrimal duct might also reduce the retention of allergen in the conjunctiva.

Effect of INS on impaired performance

Allergic rhinitis itself impairs performance by causing daytime sleepiness and disrupting cognitive functions such as learning ability [89,90]. Nasal congestion due to allergic reaction and inflammation seems to be the major causative factor of daytime sleepiness, as this symptom can cause obstructive sleep apnoea and microarousals during sleep [91]. Symptomatic seasonal allergic rhinitis has been associated with significant detrimental effects on examination performance in young people [90].

Treatment with sedating H₁-receptor antagonists exacerbates impaired performance [90,92]; students taking these medications on examination days exhibited a significant tendency to unexpectedly drop a grade [90].

On the other hand, INS can improve impaired performance in allergic rhinitis patients [93,94]. Craig et al.[93] showed that intranasal budesonide 128 µg/day, flunisolide 200 µg/day and fluticasone 200 µg/day were each effective in improving sleep and daytime fatigue and somnolence, although significant changes in polysomnography did not always occur. Moreover, treatment with intranasal fluticasone propionate 200 µg once daily significantly improved not only nasal symptoms and daytime sleepiness but also cognitive performance, as measured by the test of variables of attention (TOVA) in patients with seasonal allergic rhinitis [94].

Efficacy of INS for prophylactic (initial) treatment of pollinosis

The PG-MARJ recommends that patients who experience severe symptoms of pollinosis every year should receive prophylactic treatment immediately after the start of pollen release or the onset of symptoms [2,95]. Considering the amount of pollen release expected during the season and the type and severity of symptoms usually experienced by patients during the peak pollen season, physicians should determine the drug regimen for each individual patient by selecting from among chemical mediator–release inhibitors, second-generation H₁-receptor antagonists, leukotriene receptor antagonists, Th2 cytokine inhibitor (suplatast) and PGD₂/TXA₂ receptor antagonist (ramatroban) [2]. Patients with sneezing/rhinorrhoea-type rhinitis should receive chemical mediator–release inhibitors or second-generation anti-histamines, whereas patients with congestion-type disease should be treated with leukotriene receptor antagonist, Th2 cytokine inhibitor or PGD₂/TXA₂ receptor antagonist.

Several reports suggest that INS drugs are effective for the prophylactic treatment of pollinosis. One study of prophylactic treatment with mometasone furoate 200 µg once daily aqueous nasal spray, beclomethasone dipropionate 168 µg b.i.d. aqueous nasal spray or placebo was initiated in patients with ragweed pollinosis 4 weeks before the estimated start of pollen season. Both the proportion of minimal symptom days from start of ragweed season and the number of days from start of ragweed season to first non-minimal symptom day were significantly higher in patients treated with either mometasone furoate or beclomethasone dipropionate compared with placebo [96]. Yokoo [97] compared the efficacy of prophylactic treatment with intranasal fluticasone propionate 200 µg twice daily versus the second-generation oral H₁-antagonist olopatadine 10 mg twice daily in patients with Japanese cedar pollinosis and found that fluticasone propionate delayed the onset of nasal symptoms significantly compared with olopatadine. In addition, treatment with fluticasone suppressed symptoms significantly during peak pollen season. Okubo et al.[98] reported that initial treatment with fluticasone propionate 100 µg b.i.d. prevented exacerbation of nasal symptoms in paediatric patients with seasonal allergic rhinitis. Indeed, nasal symptoms disappeared in 44·0% of patients who had mild symptoms at initiation of treatment.

As described above, one of the pathways of the anti-inflammatory effect of GC is the down-regulation of proinflammatory genes by several mechanisms such as protein–protein interactions that sequester protein kinase A and cAMP enhancer binding protein (CREB)-binding protein from NF-κB [44,45]. The interaction between NF-κB, CREB and CREB-binding protein leads to the acetylation of chromatin and the subsequent transcription of proinflammatory genes, such as genes encoding cytokines, inflammatory enzymes, adhesion molecules and inflammatory receptors [99]. Thus, GC may be more effective for prophylactic treatment compared with post-onset treatment because increased levels of NF-κB in the nose after the onset of pollinosis can attenuate protein–protein interaction by glucocorticosteroids.

Conclusions

In addition to the novel information that appeared in the sixth edition of the PG-MARJ in 2008, considerable evidence supports the use of GC against allergic rhinitis. GC can induce regulatory cytokines and FoxP3⁺ T_regs in the nose. The appropriate use of INS may improve nasal symptoms, ocular symptoms and impaired performance. Moreover, INS can be used for the first-line prophylactic treatment of pollinosis. These recent findings may provide additional information for incorporation into future editions of guidelines for allergic rhinitis treatment, including the PG-MARJ. On the other hand, several issues remain unsolved. For example, although inhaled GC have not been incriminated as teratogens in humans and are used commonly by pregnant women who have asthma, there are no placebo-controlled, randomized, double-blind studies of INS during the first trimester of pregnancy.

Disclosure

The author has received research grants and lecture fees from Banyu, Dainippon Sumitomo Pharma, Glaxo Smith Kline, Kyorin Pharmaceutical, Kyowa Hakko Kirin, Mitsubishi Tanebe Pharma, Nippon Boeringer Ingelheim, Nippon Shinyaku, Ono Pharmaceutical, Sanofi Aventis, Schering-Plough, Shionogi and Taiho Pharmaceutical.