REVIEW URRENT C OPINION
Allergic rhinitis: current options and future perspectives Fulvio Braido a, Federica Arcadipane a,, Fiorenza Marugo a,, Mituki Hayashi b, and Ruby Pawankar b
Purpose of review Allergic rhinitis due its high prevalence and burden needs to be properly treated. The disease’s clinical features impose well tolerated drugs usable for long-term treatment. Nowadays, second-generation antihistamines and inhaled steroids represent the milestone of rhinitis therapy. The aim of the present review is to provide an update on allergic rhinitis treatment. A particular attention has been deserved to clinical trials, published in the last year that assess the efficacy and safety of new formulation of available drugs or new molecules. Recent findings Available and new drugs under investigation seem able to control rhinitis symptoms without a significant patient’s burden. The challenge for the next years will be to improve treatment adherence rather than to introduce new drugs. Summary Allergic Rhinitis and its Impact on Asthma guidelines have brought attention to allergic rhinitis and its impact on asthma, but have also proposed a new classification in terms of symptoms severity and persistence useful for tailoring treatment on patients’ phenotypes. Their further dissemination is needed; furthermore, they represent a cornerstone for the scientific community through a continuous update on relevant issues such as rhinitis phenotypes, disease management on the basis of new treatments, clinical trials transferability in real life, and allergic rhinitis management in public health programs. Keywords allergic rhinitis, drugs safety, efficacy, treatment
INTRODUCTION Allergic rhinitis is an under considered chronic disease clinically characterized by pruritus, sneezing, rhinorrhea, and nasal congestion [1]. It is mediated by early and late-phase allergic response to environmental allergens [2] and part of a systemic inflammatory process (Fig. 1). Allergic rhinitis is associated with inflammatory disorders of upper and lower airways membranes including asthma, rhinosinusitis, conjunctivitis, polyposis, and other comorbidities such as sleep disorders, maxillofacial alterations, and otitis [1]. Allergic rhinitis and asthma often coexist in the same individual: up to 80% of asthmatic patients suffer from allergic rhinitis and up to 40% of rhinitis patients complain of asthma [3,4 ]. The link between these diseases is well known; nevertheless, before the publication of the Allergic Rhinitis and its Impact on Asthma (ARIA) [1] report, its relevance has been ignored in daily practice, and &&
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disease-related guidelines have subestimated their interaction upon therapeutic perspective. Several studies [5,6] suggested that asthma prevalence is higher in patients with moderate–severe rhinitis rather than in milder disease; allergic rhinitis often precedes asthma, and it represents a relevant and independent risk factor of asthma development. Several etiopatoghenetic features are shared
a Allergy and Respiratory Diseases Clinic, DIMI – University of Genoa, IRCCS AOU San Martino-IST, Genova, Italy and bDepartment of Pediatrics, Nippon Medical School, Tokyo, Japan
Correspondence to Professor Fulvio Braido, Allergy and Respiratory Diseases Clinic, DIMI – University of Genoa, IRCCS AOU San MartinoIST, Pad. Maragliano, Largo Rosanna Benzi 10, 16132 Genova, Italy. Tel: +390105553524; fax: +390105553524; e-mail: [email protected] Federica Arcadipane and Fiorenza Marugo contributed equally to the writing of this article.
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productivity) [17]. Furthermore, ARIA suggested that therapeutic approach identifies a different contribution of available drugs according to disease severity. The aim of the present review is to provide an update on allergic rhinitis treatment, particularly considering the evidence published in the last year on available and coming drugs for allergic rhinitis management.
KEY POINTS Both available and new drugs can control rhinitis symptoms without an excessive burden on patients’ life. A new classification in terms of severity and persistence of the symptoms has been proposed by ARIA guidelines. ARIA guidelines are aimed at providing a continuous update on currently relevant issues such as rhinitis phenotypes, disease management, patient empowerment, and clinical trials transferability in real life.
THE AVAILABLE TREATMENTS
with asthma, leading to the definition of united airways disease [7]. The final word sustaining their correlation is related to the evidence that allergic rhinitis treatment influences asthma control [8]. Clinical research showed that nasal inhaled steroid can modify asthma symptoms and airways hyperreactivity [9–12], whereas antihistaminic drugs, despite not being able to directly affect asthma features, can reduce the most relevant asthma triggers [13,14]. In addition, inadequately controlled allergic rhinitis in asthma patients can increase asthma exacerbations and poorer symptom control, which may increase medical resource use [15]. ARIA proposed a distinction between mild or moderate–severe and between intermittent or persistent allergic rhinitis [16]. ARIA classification is consistent with the burden of allergic rhinitis cost and differential treatment approach. Allergic rhinitis costs increase with disease severity and comorbidities; in addition to direct costs (drugs and visits), the disease results also in indirect costs (days off from work and school and poor
Allergic rhinitis is an immunoglobulin E (IgE)-mediated disease causing an inflammation of nasal mucosa. Histamine release from mast cells is one of the major triggers of symptoms. A Th2 response follows, with the release of interleukin-4 (IL-4) and IL-5. The subsequent and concomitant eosinophilic influx also plays a relevant role. Therefore, after allergen exposure, symptoms and related mucosal inflammation can persist for several weeks [18,19]. Severity fluctuates according to degree of airways inflammation and allergen exposure [20]. The therapeutic rationale is closely related to the characterization of severity. For this reason, ARIA [16] guidelines suggest a therapeutic stepwise approach according to symptom duration and severity. It is clear that, in allergic rhinitis, the avoidance of the offending allergen is an essential strategy, as clearly shown in occupational allergy [21]. However, this is not always possible, for example, in the case of pollen sensitization. The development of H1 antihistamines (Tables 1 and 2), followed by the discovery of histamine pathway, and their role in the treatment of allergy and anaphylaxis have been well
Late-phase 3–12 hours
Early-phase 5–15 minutes Antigen IgE antibodies
Mast cell Histamine Leukotrienes PG, TNF, Other mediators
Late-phase reaction Cellular infiltration Eosinophils Basophils Monocytes Lymphocytes
Hyperresponsiveness
Priming
Sneezing. rhinorrhea, congestion; tearing, red, itchy eyes
FIGURE 1. Allergic inflammation. 1528-4050 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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documented. Although the first-generation H1antihistamines were developed and widely used in the past, their association with sedative and anticholinergic side-effects has restricted their current Table 1. Anthistamines and glucocorticosteroids for the treatment of allergic rhinitis Name
Generic name
Antihistamines Oral H1 antihistamines
First generation Chlorphenyramine Clemastine Dimethindene maleate Hydroxyzine Ketotifen Oxatomine Second generation Acrivastine Azelastine Cetirizine Desloratadine Ebastine Fexofenadine Levocetirizine Loratadine Mequitazine Mizolastine Rupatadine Cardiotoxic Astemizole Terfenadine
Local H1 antihistamines (intranasal and intraocular)
Azelastine Levocabastine Olopatadine
Glucocorticosteroids Intranasal glucocorticosteroids
Beclomethasone dipropionate Budesonide Ciclesonide Flunisolide Fluticasone propionate Fluticasone furoate Mometasone furoate Triamcinolone acetonide
Oral/IM glucocorticosteroids
Dexamethasone Hydrocortisone Methylpredisolone Prednisolone Prednisone Triamcinolone
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use and led to the development of more effective and safer second-generation H1 antihistamines [22]. The newer antihistamines (levocabastine, azelastine, bilastine, desloratadine, ebastine, cetirizine, fexofenadine, levocetirizine, loratadine, and rupatadine), thanks to a favorable risk/benefit ratio and the additional anti-inflammatory actions shown for some of them, represent the main stain of all degrees of rhinitis severity [23]. Intranasal corticosteroids (ciclesonide, fluticasone furoate, mometasone furoate, triamcinolone acetonide, fluticasone propionate, budesonide, and beclomethasone dipropionate) (Tables 1 and 2) are considered the most effective therapy to improve allergic rhinitis symptoms in particular in persistent allergic rhinitis [24 ], because they are more effective than antihistamines on nasal obstruction. In general, no relevant topical or systemic side-effects were observed with nasal corticosteroids also in long-term treatments, and newer formulations with a favorable systemic bioavailability may be considered safe for the long-term use [25]. In this regard, a 2-year, randomized, double-blind, placebo-controlled (DBPC) study assessed ocular safety in patients with perennial allergic rhinitis treated with fluticasone furoate nasal spray. The work did not reveal significant differences between active treatment and placebo in time to occurrence of ocular events. Nevertheless, the data coming from this trial show that regular ophthalmic monitoring in patients treated with intranasal corticosteroids is suggested [26]. Decongestants (e.g. ephedrine, pseudoephedrine, and xylometazoline) (Table 3) are frequently used as symptomatic relief in acute viral rhinosinusitis but also in other rhinitis patterns [27]. Topic decongestants are effective vasoconstrictive agents acting only on nasal congestion. Because of their rapid onset of action, they provide a fast relieve of nasal symptoms. This phenomenon facilitates their overuse with the consequent induction of ‘rhinitis medicamentosa’. Decongestants are also available in oral formulation and in combination with antihistamines, but the possibility of short and long-term side-effects (hypertension, insomnia, agitation, and tachycardia) must discourage their use [28]. Chromones and anthicolinergics (Table 3) are certainly well tolerated treatments, but their short half-life that requires multiple administrations (especially for cromones), limits their application. In a 2-week, DBPC, parallel-group study, allergic rhinitis patients were randomized to receive either cromolyn sodium 4% nasal solution in a meteredspray bottle containing 200 doses or an identicalappearing placebo. They were instructed to follow the directions for use on the label: that is to &
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Allergic rhinitis Braido et al. Table 2. Allergic rhinitis pharmacotherapy – oral and intranasal agents Oral agents Antihistamine
Pros
Cons
Relieve sneezing, nasal itching, and rhinorrhea
No effect on nasal congestion
Most are OTC
First generation cause pronounced sedation and have anticholinergic effects
Second generation allow QD dosing and present minimal sedative effects Intranasal agents Corticosteroid (INS)
Pros
Cons
Most effective AR agent overall
Nasal irritation, dryness common; epistaxis can occur
Superior relief of all nasal symptoms
Not immediate symptom relief
Reduces ocular symptoms Low risk of systemic exposure AR, allergic rhinitis; OTC, over-the-counter; QD, once-daily.
administer one spray in each nostril every 4–6 h, no more than six times per day, for the prevention or symptoms relief. Patients rated symptom severity, symptom relief, medication efficacy, drug consumption, and helpfulness of the label instructions. Cromolyn sodium provided a statistically significantly greater relief than placebo on all efficacy measures. The instructions for use were rated helpful to extremely helpful by more than 92% of patients, although only approximately 48% of patients used the drug according to the label instructions [29]. Leukotriene receptor antagonists (montelukast, zafirlukast, and pranlukast) (Table 3), administered per oral somministration (os), are effective on nasal obstruction, rhinorrhea, and conjunctival symptoms but also are able to improve bronchial symptoms in asthma patients. Thus, although well tolerated, they are recommended in rhinitis patients with concomitant asthma [30]. Certainly, leukotriene receptor antagonists play a role in nasal inflammation. Pranlukast, extensively used in Japan, induces a suppression of mucosal eosinophilic inflammation, as shown by Gotoh et al. [31] while one pilot study, designed to explore the effects of montelukast in preventing early and late inflammatory cells response to specific allergen challenge in persistent rhinitis. The results of this study [32] did not show a statistical significance in baseline inflammatory cells count before and after treatment, despite at a basal level a decrease of inflammatory cells in active group after treatment was observed. Subcutaneous and sublingual immunotherapy (SCIT and SLIT), consisting of the administration of an allergen extract, which aimed to suppress or decrease the allergic symptoms through the modulation of the immune system [33], have been shown effective in allergic rhinitis, when a clearly identified IgE-mediated disease is established.
Specific immunotherapy (SIT), besides the effectiveness on symptoms [34], also provides an opportunity to specifically restore a normal immune response against allergens in the long-term course of the disease. It represents the only curative and specific approach to the treatment of allergies [34]. The long-term desensitization against allergens is achieved by mechanisms, which involve an altered allergenspecific memory T and B-cell responses leading to the immune tolerance [35,36]. SIT has shown some further advantages over the above-mentioned treatments. The clinical effects may be sustained for years after its suspension, and also a preventive effect on asthma development has been shown [37]. Although SCIT is effective, a small but unavoidable risk of inducing systemic allergic reactions (fatal or near fatal including anaphylaxis) is possible, and it arises in less than 0.1% of those treated [30,38]. SLIT seems to be safer than SCIT because side-effects are usually restricted to the upper airways and gastrointestinal tract; rare anaphylactic episodes, but no deaths, were reported [39].
NEW INSIGHTS IN ALLERGIC RHINITIS TREATMENT As mentioned before, inhaled steroids are presently considered the most effective medication for the treatment of allergic rhinitis by evidence-based management guidelines to control inflammation and nasal obstruction [4 ,40]. They are frequently used in combination with inhaled steroids for concomitant asthma, theoretically enhancing the potential metabolic effects in long-term treatments [41,42]. Ciclesonide is a pro-drug that offers an alternative to prevent the possible systemic side-effects. It is activated by airway mucosal esterases with a rapid first-pass clearance. Ciclesonide is currently available for asthma therapy, but trials showing its
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effectiveness and safety in allergic rhinitis are also recently published [43–46]. Rofleponide palmitate is another pro-drug with a promising preclinical profile designed to deliver topical airway treatment for allergic rhinitis and asthma that has not been developed beyond the first studies [47]. A new pharmacological approach to the allergic rhinitis is the combination therapy. The association of intranasal formulation of azelastine hydrochloride and fluticasone propionate in an advanced delivery system (MP29–02) provided significant clinical benefit compared with either agent alone with a good safety profile, as demonstrated by several studies. These studies [48–51] included only patients with seasonal allergic rhinitis; therefore, further studies are needed to expand the indication to other clinical pattern of rhinitis. One of them compared the first-line therapy of allergic rhinitis to MP29–02, showing the statistical superiority of the new combination therapy to both an intranasal steroid and an intranasal antihistamine [52]. The most important strengths were relief of symptoms, quality of life (QoL) improvement, and rapid onset of action. New or newly formulated second-generation antihistamines have been proposed. Among them, the fast-dissolving tablets of ebastine improve satisfaction and treatment adherence in patients, maintaining the same efficacy and safety profile of the standard tablets [53]. The rupatadine dual action, platelet-activating factor and H1-receptor antagonist, offers a more extensive antiallergic activity that seems to better control nasal obstruction [54,55,56 ], also available in children. A randomized, DBPC study &
[57] confirms the efficacy and safety of rupatadine oral solution in children with persistent allergic rhinitis, with a significant benefit also in the QoL. Bilastine has a high selectivity for the histamine H1 receptor [58,59], which achieves an interesting safety profile regarding central nervous system and cardiovascular effects [60]. The affinity of this antihistamine to the H1 receptor is respectively five and three times greater than that of fexofenadine and cetirizine molecules belonging to the same pharmacological class [61]. Bilastine behaves as a H1-mixed antagonist depending on the different concentrations of histamine, being 5.5 times more powerful than cetirizine as a competitive antagonist and 10 times as noncompetitive antagonist [62]. It has also been shown that this molecule has anti-inflammatory properties as it inhibits the spontaneous or histamine-induced release of inflammatory mediators such as IL-4 and tumor necrosis factor-a. In laboratory animals, it has been shown to reduce the capillary permeability and microvascular extravasation induced by histamine, and to inhibit the bronchospasm induced by histamine 11 times higher compared with cetirizine. Laboratory studies demonstrated its ability to reduce passive cutaneous anaphylaxis induced by homologous serum and monoclonal antibodies, along with IgG/IgE-dependent active cutaneous anaphylaxis. Tests in humans showed its ability to rapidly inhibit the erythematous area in response to histamine [63], and, in the comparison performed in the Vienna Challenge Chamber or with natural exposure to cetirizine and fexofenadine, it has been shown to be more effective than fexofenadine and as effective as cetirizine in individuals with grass allergic rhinitis [64,65].
Table 3. Leukotriene antagonists, local cromones, decongestants, and anthicolinergics used in allergic rhinitis Name
Generic name
Leukotriene antagonists
Montelukast Pranlukast Zafirlukast
Local cromones (intranasal and intraocular)
Cromoglycate Nedocromil Naaga
Oral decongestants
Ephedrine Phenylephrine Phenyl-propanolamine Pseudoephedrine Oral H1-antihistamine-decongestant combinations
Intranasal decongestants
Oxymethazoline Xylomethazoline Others
Intranasal anticholinergics
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Bilastine and desloratadine have been shown as equally effective versus placebo [61]. The safety profile and the effects on the central nervous system have been tested in both phase II and III studies on rhinitis patients, and in clinical pharmacology studies in healthy volunteers. The incidence of side-effects was similar to placebo and lower than cetirizine with regard to fatigue and somnolence. No prolongation of QTc (even at doses higher than the therapeutic dose) [66], nor an additive effect of bilastine on the reactivity of the psychomotor tests when taking alcohol (0.8 g/kg) or lorazepam have been identified [67]. These studies indicate that the therapeutic arsenal against rhinitis is enriched by an antihistamine with a rapid onset of action (within an hour after administration), long acting (more than 26 h), effective in relief of allergic rhinitis symptoms, and able to improve the disease burden. Recent results suggest the potential utility of histamine H3/H4R antagonists/inverse agonists in inflammatory diseases such asthma and allergic rhinitis but without significant differences from H1 antagonism in reducing nasal blockage [68–70]. The beneficial effects of phosphodiesterase 4 (PDE4) inhibitors have been shown in preclinical and clinical studies of allergic asthma. As allergic rhinitis and asthma share pathogenic mechanisms, PDE4 inhibitors might be effective in allergic rhinitis. A single study [71] explored its effect on allergic rhinitis, but no further experimental works on this topic were published after 2001. b-Tryptase is a multifunctional mast cell serine protease released during mast cell degranulation; therefore, tryptase/trypsin inhibitors were considered for its therapeutic potential for treating allergic or inflammatory disorders. Nevertheless, the latest work published in 2006 did not give satisfactory results [72]. There is evidence that adenosine plays a role in asthma and rhinitis pathogenesis, but a single clinical trial testing an adenosine receptor agonist/antagonist in humans exposed to intranasal allergen challenge showed limited clinical benefit [73]. SIT is often used in patients whose allergic rhinitis and mild allergic asthma symptoms are not controlled by medications, and in patients who cannot tolerate their medications, or who do not comply with chronic medication regimens [74]. SLIT is considered as a standard therapeutic option for allergic rhinitis, but new approaches are in progress [75]. In particular, intralymphatic immunotherapy and epicutaneous routes are being studied. The injection of allergens directly into lymph-nodes (intralymphatic immunotherapy) has been demonstrated as effective as the traditional subcutaneous delivery, but with low doses and fewer injections [76].
Similarly, the epicutaneous route (by patches) is receiving encouraging confirmations [77]. As suggested by the hygiene hypothesis, upregulated Th1 responses, as a consequence of infections, can be associated with reduced Th2 activity. Controlled infection-like stimulation of the immune system may in this context be beneficial, and may be achieved by the use of Toll-like receptor (TLR) agonists. Bacterial product lipopolysaccharides, viral single-stranded RNA, and bacterial/viral C phosphate G DNA, acts as TLR4, TLR7, and TLR9 ligands. The possibility that the sequences of bacterial DNA may act as potent inducers of Th1 via TLR-4 has been demonstrated [78,79] and repeated intranasal stimulation of TLR7, by means of a selective TLR7 agonist optimized for topical airway treatment, causes a sustained reduction in the responsiveness to allergen [80]. Beyond allergen extract standardization, the clinical use of recombinant allergens is promising but still under investigation [81,82]. Nasal neuronal hyper-responsiveness has been studied as a cause of residual symptoms in allergic rhinitis in patients treated with current therapy. The ion channel transient receptor potential vanilloid 1 (TRPV1) is a ligand-gate ion channel expressed on sensory nerve terminals involved in parasympathetic secretory reflex responses and sneeze. It is activated by heat, protons, and capsaicin – the pungent compound in chili pepper – and various membrane-derived lipids. It has been demonstrated that TRPV1 blocker SB-705498, delivered by nasal lavage, inhibits the sensory symptoms evoked by a subsequent capsaicin challenge but failed to reduce allergen challenge-induced symptoms in patients with allergic rhinitis, including the sensory symptom, itch, or sneeze [83]. A recent trial using TRPV1 antagonist in an intranasal formulation did not show any clinical efficacy [84]. An immunomodulator compound (suplatast tosilate) that can restore the Th1/Th2 balance in allergic individuals is currently available in Japan. However, its mechanisms of action in the inhibition of allergic disorders remain to be elucidated. It has been hypothesized that it could have a role in the GATA-binding protein 3/ IL-5 signaling pathway, but the mechanism is under investigation [82]. Due to the IgE-mediated effects in the nose mucosa [85], monoclonal antibodies used for asthma have been pioneered in allergic rhinitis. Many studies on the use of omalizumab in allergic rhinitis are available. It has been proven to have multiple beneficial effects in patients with allergic rhinitis such as decreasing nasal allergen challenge responses, symptoms, and rescue medication use. Furthermore, it improves QoL and reduces missed school or working days [86,87]. Additional
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therapeutic approaches could include monoclonal antibodies directed against other stages of the pathogenic mechanism (anti CD4þ, anti-IL-5, and recombinant IL-12). Cross-linking of IgE with allergen on the mast cell surface also leads to the rapid synthesis of prostaglandin D2 (PGD2) that has been detected in high concentrations in tissues from allergic individuals challenged with allergen, including the nasal mucosa PGD2-mediated activation of eosinophils, and Th2 cells produced by the high affinity interaction with CRTH2 (a G-protein-coupled chemoattractant receptor-homologous molecule on Th2 cells). The CRTH2 antagonist OC000459 has previously been demonstrated to reduce airway inflammation and improve lung function in moderate persistent asthma. The clinical efficacy of a CRTH2 antagonist in reducing both allergic rhinitis nasal and ocular symptoms was assessed in a randomized, DBPC, but has yet to be confirmed [88]. The integrity of the nasal mucosa barrier is fundamental to the correct functioning of the nasal cavity: in particular, it plays an important role in the pathomechanism of allergic diseases. It is thought that the use of liposomes, artificially prepared vesicles composed of a lipid bilayer, could restore the integrity of the mucosal barrier destroyed in many allergic diseases. A recent study compared nasal and conjunctival symptom reduction with liposome nasal spray used as monotherapy, or liposome nasal spray and liposome eye spray combination therapy, against standard cromoglycate combination therapy. The results are encouraging because efficacy, onset of action, and tolerability do not differ significantly from cromoglycate combination therapy [89]. The use of compounds, which through various mechanisms are able to modify the immune system response, has been explored in literature. For example, the use of probiotics, defined as ‘live micro-organisms which, when administered in adequate amounts as part of food, confer a beneficial health effect by producing gut microflora on the host’ [90], may exert a primary prevention of atopic diseases [91]. It has been hypothesized that probiotics could enhance the TH1 response via enteric stimulation of the immune system, but these findings have not been fully confirmed [92]. However, whether these have clinical applications in the prevention or treatment of established allergic airway diseases remains controversial and requires more comprehensive clinical trials. A recent systematic review showed that the current evidence was generated from few trials with a high degree of heterogeneity. The clinical efficacy of Lactobacillus johnsonii EM1 (Lj EM1) and levocetirizine was 174
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assessed for treating perennial allergic rhinitis in children in a 24-week, 2-phase, cross-over treatment program. Levocetirizine and Lj EM1 was more effective than levocetirizine alone, and this difference persisted for at least 3 months after discontinuation of Lj EM1 [93]. Bifidobacterium lactis strain has been reported to be able to modify immune parameters (significantly decreased allergic and proinflammatory cytokines and reduced basophil cell activation compared with placebo treatment) and nasal symptom scores in individuals suffering from seasonal allergic rhinitis [94]. To date, the routine use of probiotics as an additive therapy in individuals with allergic airway diseases cannot be recommended [95]. The glycirrhetic acid in the treatment of children suffering from allergic rhinitis has been investigated. The preliminary findings were encouraging, even though further studies need to confirm this early experience [96].
CONCLUSION ARIA guidelines, published in 2001, have not only brought attention to allergic rhinitis and its impact on asthma, but also proposed a new classification of allergic rhinitis in terms of symptom severity and persistence [15]. These guidelines have been updated in 2008 [97] and analyzed through the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system [4 ]. During the past decade, 251 original articles on over 170 000 patients followed in 43 countries using this classification led to achieved relevant scientific information. In the ARIA classification, intermittent and persistent rhinitis are proposed to replace seasonal and perennial allergic rhinitis, proving to be more relevant to patients’ needs. Severity and persistence are two separate components, and may be independent of rhinitis. For instance, the impact of severity on the timely evaluation of patients’ QoL is similar in patients with intermittent and persistent rhinitis. ARIA guidelines represent a cornerstone for the scientific community and will continue their work through a continuous update on the currently relevant issues such as rhinitis phenotypes, an appropriate disease management on the basis of new available treatments, patient empowerment, the transferability of clinical trials in real life, and the awareness of the importance of allergic rhinitis management in the public health programs [4 ]. Although the majority of patients suffering from allergic rhinitis can be controlled by the treatment, a fraction of them remain symptomatic, and are therefore defined as having severe chronic upper &&
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airway diseases [98]; therefore, the search for new treatments with a favorable risk–benefit ratio is desirable. Acknowledgements The authors thank ASPADIRES (Associazione Pazienti Disturbi Respiratori nel Sonno) and acknowledge Dr Marianna Bruzzone for linguistic assistance with the article. Conflicts of interest The study was supported by ARMIA (Associazione Ricerca Malattie Immunologiche e Allergiche). Competing interests: The authors declare that they have no competing interests.
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Allergic rhinitis: current options and future perspectives Fulvio Braido a, Federica Arcadipane a,, Fiorenza Marugo a,, Mituki Hayashi b, and Ruby Pawankar b
Purpose of review Allergic rhinitis due its high prevalence and burden needs to be properly treated. The disease’s clinical features impose well tolerated drugs usable for long-term treatment. Nowadays, second-generation antihistamines and inhaled steroids represent the milestone of rhinitis therapy. The aim of the present review is to provide an update on allergic rhinitis treatment. A particular attention has been deserved to clinical trials, published in the last year that assess the efficacy and safety of new formulation of available drugs or new molecules. Recent findings Available and new drugs under investigation seem able to control rhinitis symptoms without a significant patient’s burden. The challenge for the next years will be to improve treatment adherence rather than to introduce new drugs. Summary Allergic Rhinitis and its Impact on Asthma guidelines have brought attention to allergic rhinitis and its impact on asthma, but have also proposed a new classification in terms of symptoms severity and persistence useful for tailoring treatment on patients’ phenotypes. Their further dissemination is needed; furthermore, they represent a cornerstone for the scientific community through a continuous update on relevant issues such as rhinitis phenotypes, disease management on the basis of new treatments, clinical trials transferability in real life, and allergic rhinitis management in public health programs. Keywords allergic rhinitis, drugs safety, efficacy, treatment
INTRODUCTION Allergic rhinitis is an under considered chronic disease clinically characterized by pruritus, sneezing, rhinorrhea, and nasal congestion [1]. It is mediated by early and late-phase allergic response to environmental allergens [2] and part of a systemic inflammatory process (Fig. 1). Allergic rhinitis is associated with inflammatory disorders of upper and lower airways membranes including asthma, rhinosinusitis, conjunctivitis, polyposis, and other comorbidities such as sleep disorders, maxillofacial alterations, and otitis [1]. Allergic rhinitis and asthma often coexist in the same individual: up to 80% of asthmatic patients suffer from allergic rhinitis and up to 40% of rhinitis patients complain of asthma [3,4 ]. The link between these diseases is well known; nevertheless, before the publication of the Allergic Rhinitis and its Impact on Asthma (ARIA) [1] report, its relevance has been ignored in daily practice, and &&
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disease-related guidelines have subestimated their interaction upon therapeutic perspective. Several studies [5,6] suggested that asthma prevalence is higher in patients with moderate–severe rhinitis rather than in milder disease; allergic rhinitis often precedes asthma, and it represents a relevant and independent risk factor of asthma development. Several etiopatoghenetic features are shared
a Allergy and Respiratory Diseases Clinic, DIMI – University of Genoa, IRCCS AOU San Martino-IST, Genova, Italy and bDepartment of Pediatrics, Nippon Medical School, Tokyo, Japan
Correspondence to Professor Fulvio Braido, Allergy and Respiratory Diseases Clinic, DIMI – University of Genoa, IRCCS AOU San MartinoIST, Pad. Maragliano, Largo Rosanna Benzi 10, 16132 Genova, Italy. Tel: +390105553524; fax: +390105553524; e-mail: [email protected] Federica Arcadipane and Fiorenza Marugo contributed equally to the writing of this article.
Curr Opin Allergy Clin Immunol 2014, 14:168–176 DOI:10.1097/ACI.0000000000000043 Volume 14 Number 2 April 2014
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Allergic rhinitis Braido et al.
productivity) [17]. Furthermore, ARIA suggested that therapeutic approach identifies a different contribution of available drugs according to disease severity. The aim of the present review is to provide an update on allergic rhinitis treatment, particularly considering the evidence published in the last year on available and coming drugs for allergic rhinitis management.
KEY POINTS Both available and new drugs can control rhinitis symptoms without an excessive burden on patients’ life. A new classification in terms of severity and persistence of the symptoms has been proposed by ARIA guidelines. ARIA guidelines are aimed at providing a continuous update on currently relevant issues such as rhinitis phenotypes, disease management, patient empowerment, and clinical trials transferability in real life.
THE AVAILABLE TREATMENTS
with asthma, leading to the definition of united airways disease [7]. The final word sustaining their correlation is related to the evidence that allergic rhinitis treatment influences asthma control [8]. Clinical research showed that nasal inhaled steroid can modify asthma symptoms and airways hyperreactivity [9–12], whereas antihistaminic drugs, despite not being able to directly affect asthma features, can reduce the most relevant asthma triggers [13,14]. In addition, inadequately controlled allergic rhinitis in asthma patients can increase asthma exacerbations and poorer symptom control, which may increase medical resource use [15]. ARIA proposed a distinction between mild or moderate–severe and between intermittent or persistent allergic rhinitis [16]. ARIA classification is consistent with the burden of allergic rhinitis cost and differential treatment approach. Allergic rhinitis costs increase with disease severity and comorbidities; in addition to direct costs (drugs and visits), the disease results also in indirect costs (days off from work and school and poor
Allergic rhinitis is an immunoglobulin E (IgE)-mediated disease causing an inflammation of nasal mucosa. Histamine release from mast cells is one of the major triggers of symptoms. A Th2 response follows, with the release of interleukin-4 (IL-4) and IL-5. The subsequent and concomitant eosinophilic influx also plays a relevant role. Therefore, after allergen exposure, symptoms and related mucosal inflammation can persist for several weeks [18,19]. Severity fluctuates according to degree of airways inflammation and allergen exposure [20]. The therapeutic rationale is closely related to the characterization of severity. For this reason, ARIA [16] guidelines suggest a therapeutic stepwise approach according to symptom duration and severity. It is clear that, in allergic rhinitis, the avoidance of the offending allergen is an essential strategy, as clearly shown in occupational allergy [21]. However, this is not always possible, for example, in the case of pollen sensitization. The development of H1 antihistamines (Tables 1 and 2), followed by the discovery of histamine pathway, and their role in the treatment of allergy and anaphylaxis have been well
Late-phase 3–12 hours
Early-phase 5–15 minutes Antigen IgE antibodies
Mast cell Histamine Leukotrienes PG, TNF, Other mediators
Late-phase reaction Cellular infiltration Eosinophils Basophils Monocytes Lymphocytes
Hyperresponsiveness
Priming
Sneezing. rhinorrhea, congestion; tearing, red, itchy eyes
FIGURE 1. Allergic inflammation. 1528-4050 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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Special commentary
documented. Although the first-generation H1antihistamines were developed and widely used in the past, their association with sedative and anticholinergic side-effects has restricted their current Table 1. Anthistamines and glucocorticosteroids for the treatment of allergic rhinitis Name
Generic name
Antihistamines Oral H1 antihistamines
First generation Chlorphenyramine Clemastine Dimethindene maleate Hydroxyzine Ketotifen Oxatomine Second generation Acrivastine Azelastine Cetirizine Desloratadine Ebastine Fexofenadine Levocetirizine Loratadine Mequitazine Mizolastine Rupatadine Cardiotoxic Astemizole Terfenadine
Local H1 antihistamines (intranasal and intraocular)
Azelastine Levocabastine Olopatadine
Glucocorticosteroids Intranasal glucocorticosteroids
Beclomethasone dipropionate Budesonide Ciclesonide Flunisolide Fluticasone propionate Fluticasone furoate Mometasone furoate Triamcinolone acetonide
Oral/IM glucocorticosteroids
Dexamethasone Hydrocortisone Methylpredisolone Prednisolone Prednisone Triamcinolone
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use and led to the development of more effective and safer second-generation H1 antihistamines [22]. The newer antihistamines (levocabastine, azelastine, bilastine, desloratadine, ebastine, cetirizine, fexofenadine, levocetirizine, loratadine, and rupatadine), thanks to a favorable risk/benefit ratio and the additional anti-inflammatory actions shown for some of them, represent the main stain of all degrees of rhinitis severity [23]. Intranasal corticosteroids (ciclesonide, fluticasone furoate, mometasone furoate, triamcinolone acetonide, fluticasone propionate, budesonide, and beclomethasone dipropionate) (Tables 1 and 2) are considered the most effective therapy to improve allergic rhinitis symptoms in particular in persistent allergic rhinitis [24 ], because they are more effective than antihistamines on nasal obstruction. In general, no relevant topical or systemic side-effects were observed with nasal corticosteroids also in long-term treatments, and newer formulations with a favorable systemic bioavailability may be considered safe for the long-term use [25]. In this regard, a 2-year, randomized, double-blind, placebo-controlled (DBPC) study assessed ocular safety in patients with perennial allergic rhinitis treated with fluticasone furoate nasal spray. The work did not reveal significant differences between active treatment and placebo in time to occurrence of ocular events. Nevertheless, the data coming from this trial show that regular ophthalmic monitoring in patients treated with intranasal corticosteroids is suggested [26]. Decongestants (e.g. ephedrine, pseudoephedrine, and xylometazoline) (Table 3) are frequently used as symptomatic relief in acute viral rhinosinusitis but also in other rhinitis patterns [27]. Topic decongestants are effective vasoconstrictive agents acting only on nasal congestion. Because of their rapid onset of action, they provide a fast relieve of nasal symptoms. This phenomenon facilitates their overuse with the consequent induction of ‘rhinitis medicamentosa’. Decongestants are also available in oral formulation and in combination with antihistamines, but the possibility of short and long-term side-effects (hypertension, insomnia, agitation, and tachycardia) must discourage their use [28]. Chromones and anthicolinergics (Table 3) are certainly well tolerated treatments, but their short half-life that requires multiple administrations (especially for cromones), limits their application. In a 2-week, DBPC, parallel-group study, allergic rhinitis patients were randomized to receive either cromolyn sodium 4% nasal solution in a meteredspray bottle containing 200 doses or an identicalappearing placebo. They were instructed to follow the directions for use on the label: that is to &
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Allergic rhinitis Braido et al. Table 2. Allergic rhinitis pharmacotherapy – oral and intranasal agents Oral agents Antihistamine
Pros
Cons
Relieve sneezing, nasal itching, and rhinorrhea
No effect on nasal congestion
Most are OTC
First generation cause pronounced sedation and have anticholinergic effects
Second generation allow QD dosing and present minimal sedative effects Intranasal agents Corticosteroid (INS)
Pros
Cons
Most effective AR agent overall
Nasal irritation, dryness common; epistaxis can occur
Superior relief of all nasal symptoms
Not immediate symptom relief
Reduces ocular symptoms Low risk of systemic exposure AR, allergic rhinitis; OTC, over-the-counter; QD, once-daily.
administer one spray in each nostril every 4–6 h, no more than six times per day, for the prevention or symptoms relief. Patients rated symptom severity, symptom relief, medication efficacy, drug consumption, and helpfulness of the label instructions. Cromolyn sodium provided a statistically significantly greater relief than placebo on all efficacy measures. The instructions for use were rated helpful to extremely helpful by more than 92% of patients, although only approximately 48% of patients used the drug according to the label instructions [29]. Leukotriene receptor antagonists (montelukast, zafirlukast, and pranlukast) (Table 3), administered per oral somministration (os), are effective on nasal obstruction, rhinorrhea, and conjunctival symptoms but also are able to improve bronchial symptoms in asthma patients. Thus, although well tolerated, they are recommended in rhinitis patients with concomitant asthma [30]. Certainly, leukotriene receptor antagonists play a role in nasal inflammation. Pranlukast, extensively used in Japan, induces a suppression of mucosal eosinophilic inflammation, as shown by Gotoh et al. [31] while one pilot study, designed to explore the effects of montelukast in preventing early and late inflammatory cells response to specific allergen challenge in persistent rhinitis. The results of this study [32] did not show a statistical significance in baseline inflammatory cells count before and after treatment, despite at a basal level a decrease of inflammatory cells in active group after treatment was observed. Subcutaneous and sublingual immunotherapy (SCIT and SLIT), consisting of the administration of an allergen extract, which aimed to suppress or decrease the allergic symptoms through the modulation of the immune system [33], have been shown effective in allergic rhinitis, when a clearly identified IgE-mediated disease is established.
Specific immunotherapy (SIT), besides the effectiveness on symptoms [34], also provides an opportunity to specifically restore a normal immune response against allergens in the long-term course of the disease. It represents the only curative and specific approach to the treatment of allergies [34]. The long-term desensitization against allergens is achieved by mechanisms, which involve an altered allergenspecific memory T and B-cell responses leading to the immune tolerance [35,36]. SIT has shown some further advantages over the above-mentioned treatments. The clinical effects may be sustained for years after its suspension, and also a preventive effect on asthma development has been shown [37]. Although SCIT is effective, a small but unavoidable risk of inducing systemic allergic reactions (fatal or near fatal including anaphylaxis) is possible, and it arises in less than 0.1% of those treated [30,38]. SLIT seems to be safer than SCIT because side-effects are usually restricted to the upper airways and gastrointestinal tract; rare anaphylactic episodes, but no deaths, were reported [39].
NEW INSIGHTS IN ALLERGIC RHINITIS TREATMENT As mentioned before, inhaled steroids are presently considered the most effective medication for the treatment of allergic rhinitis by evidence-based management guidelines to control inflammation and nasal obstruction [4 ,40]. They are frequently used in combination with inhaled steroids for concomitant asthma, theoretically enhancing the potential metabolic effects in long-term treatments [41,42]. Ciclesonide is a pro-drug that offers an alternative to prevent the possible systemic side-effects. It is activated by airway mucosal esterases with a rapid first-pass clearance. Ciclesonide is currently available for asthma therapy, but trials showing its
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effectiveness and safety in allergic rhinitis are also recently published [43–46]. Rofleponide palmitate is another pro-drug with a promising preclinical profile designed to deliver topical airway treatment for allergic rhinitis and asthma that has not been developed beyond the first studies [47]. A new pharmacological approach to the allergic rhinitis is the combination therapy. The association of intranasal formulation of azelastine hydrochloride and fluticasone propionate in an advanced delivery system (MP29–02) provided significant clinical benefit compared with either agent alone with a good safety profile, as demonstrated by several studies. These studies [48–51] included only patients with seasonal allergic rhinitis; therefore, further studies are needed to expand the indication to other clinical pattern of rhinitis. One of them compared the first-line therapy of allergic rhinitis to MP29–02, showing the statistical superiority of the new combination therapy to both an intranasal steroid and an intranasal antihistamine [52]. The most important strengths were relief of symptoms, quality of life (QoL) improvement, and rapid onset of action. New or newly formulated second-generation antihistamines have been proposed. Among them, the fast-dissolving tablets of ebastine improve satisfaction and treatment adherence in patients, maintaining the same efficacy and safety profile of the standard tablets [53]. The rupatadine dual action, platelet-activating factor and H1-receptor antagonist, offers a more extensive antiallergic activity that seems to better control nasal obstruction [54,55,56 ], also available in children. A randomized, DBPC study &
[57] confirms the efficacy and safety of rupatadine oral solution in children with persistent allergic rhinitis, with a significant benefit also in the QoL. Bilastine has a high selectivity for the histamine H1 receptor [58,59], which achieves an interesting safety profile regarding central nervous system and cardiovascular effects [60]. The affinity of this antihistamine to the H1 receptor is respectively five and three times greater than that of fexofenadine and cetirizine molecules belonging to the same pharmacological class [61]. Bilastine behaves as a H1-mixed antagonist depending on the different concentrations of histamine, being 5.5 times more powerful than cetirizine as a competitive antagonist and 10 times as noncompetitive antagonist [62]. It has also been shown that this molecule has anti-inflammatory properties as it inhibits the spontaneous or histamine-induced release of inflammatory mediators such as IL-4 and tumor necrosis factor-a. In laboratory animals, it has been shown to reduce the capillary permeability and microvascular extravasation induced by histamine, and to inhibit the bronchospasm induced by histamine 11 times higher compared with cetirizine. Laboratory studies demonstrated its ability to reduce passive cutaneous anaphylaxis induced by homologous serum and monoclonal antibodies, along with IgG/IgE-dependent active cutaneous anaphylaxis. Tests in humans showed its ability to rapidly inhibit the erythematous area in response to histamine [63], and, in the comparison performed in the Vienna Challenge Chamber or with natural exposure to cetirizine and fexofenadine, it has been shown to be more effective than fexofenadine and as effective as cetirizine in individuals with grass allergic rhinitis [64,65].
Table 3. Leukotriene antagonists, local cromones, decongestants, and anthicolinergics used in allergic rhinitis Name
Generic name
Leukotriene antagonists
Montelukast Pranlukast Zafirlukast
Local cromones (intranasal and intraocular)
Cromoglycate Nedocromil Naaga
Oral decongestants
Ephedrine Phenylephrine Phenyl-propanolamine Pseudoephedrine Oral H1-antihistamine-decongestant combinations
Intranasal decongestants
Oxymethazoline Xylomethazoline Others
Intranasal anticholinergics
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Bilastine and desloratadine have been shown as equally effective versus placebo [61]. The safety profile and the effects on the central nervous system have been tested in both phase II and III studies on rhinitis patients, and in clinical pharmacology studies in healthy volunteers. The incidence of side-effects was similar to placebo and lower than cetirizine with regard to fatigue and somnolence. No prolongation of QTc (even at doses higher than the therapeutic dose) [66], nor an additive effect of bilastine on the reactivity of the psychomotor tests when taking alcohol (0.8 g/kg) or lorazepam have been identified [67]. These studies indicate that the therapeutic arsenal against rhinitis is enriched by an antihistamine with a rapid onset of action (within an hour after administration), long acting (more than 26 h), effective in relief of allergic rhinitis symptoms, and able to improve the disease burden. Recent results suggest the potential utility of histamine H3/H4R antagonists/inverse agonists in inflammatory diseases such asthma and allergic rhinitis but without significant differences from H1 antagonism in reducing nasal blockage [68–70]. The beneficial effects of phosphodiesterase 4 (PDE4) inhibitors have been shown in preclinical and clinical studies of allergic asthma. As allergic rhinitis and asthma share pathogenic mechanisms, PDE4 inhibitors might be effective in allergic rhinitis. A single study [71] explored its effect on allergic rhinitis, but no further experimental works on this topic were published after 2001. b-Tryptase is a multifunctional mast cell serine protease released during mast cell degranulation; therefore, tryptase/trypsin inhibitors were considered for its therapeutic potential for treating allergic or inflammatory disorders. Nevertheless, the latest work published in 2006 did not give satisfactory results [72]. There is evidence that adenosine plays a role in asthma and rhinitis pathogenesis, but a single clinical trial testing an adenosine receptor agonist/antagonist in humans exposed to intranasal allergen challenge showed limited clinical benefit [73]. SIT is often used in patients whose allergic rhinitis and mild allergic asthma symptoms are not controlled by medications, and in patients who cannot tolerate their medications, or who do not comply with chronic medication regimens [74]. SLIT is considered as a standard therapeutic option for allergic rhinitis, but new approaches are in progress [75]. In particular, intralymphatic immunotherapy and epicutaneous routes are being studied. The injection of allergens directly into lymph-nodes (intralymphatic immunotherapy) has been demonstrated as effective as the traditional subcutaneous delivery, but with low doses and fewer injections [76].
Similarly, the epicutaneous route (by patches) is receiving encouraging confirmations [77]. As suggested by the hygiene hypothesis, upregulated Th1 responses, as a consequence of infections, can be associated with reduced Th2 activity. Controlled infection-like stimulation of the immune system may in this context be beneficial, and may be achieved by the use of Toll-like receptor (TLR) agonists. Bacterial product lipopolysaccharides, viral single-stranded RNA, and bacterial/viral C phosphate G DNA, acts as TLR4, TLR7, and TLR9 ligands. The possibility that the sequences of bacterial DNA may act as potent inducers of Th1 via TLR-4 has been demonstrated [78,79] and repeated intranasal stimulation of TLR7, by means of a selective TLR7 agonist optimized for topical airway treatment, causes a sustained reduction in the responsiveness to allergen [80]. Beyond allergen extract standardization, the clinical use of recombinant allergens is promising but still under investigation [81,82]. Nasal neuronal hyper-responsiveness has been studied as a cause of residual symptoms in allergic rhinitis in patients treated with current therapy. The ion channel transient receptor potential vanilloid 1 (TRPV1) is a ligand-gate ion channel expressed on sensory nerve terminals involved in parasympathetic secretory reflex responses and sneeze. It is activated by heat, protons, and capsaicin – the pungent compound in chili pepper – and various membrane-derived lipids. It has been demonstrated that TRPV1 blocker SB-705498, delivered by nasal lavage, inhibits the sensory symptoms evoked by a subsequent capsaicin challenge but failed to reduce allergen challenge-induced symptoms in patients with allergic rhinitis, including the sensory symptom, itch, or sneeze [83]. A recent trial using TRPV1 antagonist in an intranasal formulation did not show any clinical efficacy [84]. An immunomodulator compound (suplatast tosilate) that can restore the Th1/Th2 balance in allergic individuals is currently available in Japan. However, its mechanisms of action in the inhibition of allergic disorders remain to be elucidated. It has been hypothesized that it could have a role in the GATA-binding protein 3/ IL-5 signaling pathway, but the mechanism is under investigation [82]. Due to the IgE-mediated effects in the nose mucosa [85], monoclonal antibodies used for asthma have been pioneered in allergic rhinitis. Many studies on the use of omalizumab in allergic rhinitis are available. It has been proven to have multiple beneficial effects in patients with allergic rhinitis such as decreasing nasal allergen challenge responses, symptoms, and rescue medication use. Furthermore, it improves QoL and reduces missed school or working days [86,87]. Additional
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therapeutic approaches could include monoclonal antibodies directed against other stages of the pathogenic mechanism (anti CD4þ, anti-IL-5, and recombinant IL-12). Cross-linking of IgE with allergen on the mast cell surface also leads to the rapid synthesis of prostaglandin D2 (PGD2) that has been detected in high concentrations in tissues from allergic individuals challenged with allergen, including the nasal mucosa PGD2-mediated activation of eosinophils, and Th2 cells produced by the high affinity interaction with CRTH2 (a G-protein-coupled chemoattractant receptor-homologous molecule on Th2 cells). The CRTH2 antagonist OC000459 has previously been demonstrated to reduce airway inflammation and improve lung function in moderate persistent asthma. The clinical efficacy of a CRTH2 antagonist in reducing both allergic rhinitis nasal and ocular symptoms was assessed in a randomized, DBPC, but has yet to be confirmed [88]. The integrity of the nasal mucosa barrier is fundamental to the correct functioning of the nasal cavity: in particular, it plays an important role in the pathomechanism of allergic diseases. It is thought that the use of liposomes, artificially prepared vesicles composed of a lipid bilayer, could restore the integrity of the mucosal barrier destroyed in many allergic diseases. A recent study compared nasal and conjunctival symptom reduction with liposome nasal spray used as monotherapy, or liposome nasal spray and liposome eye spray combination therapy, against standard cromoglycate combination therapy. The results are encouraging because efficacy, onset of action, and tolerability do not differ significantly from cromoglycate combination therapy [89]. The use of compounds, which through various mechanisms are able to modify the immune system response, has been explored in literature. For example, the use of probiotics, defined as ‘live micro-organisms which, when administered in adequate amounts as part of food, confer a beneficial health effect by producing gut microflora on the host’ [90], may exert a primary prevention of atopic diseases [91]. It has been hypothesized that probiotics could enhance the TH1 response via enteric stimulation of the immune system, but these findings have not been fully confirmed [92]. However, whether these have clinical applications in the prevention or treatment of established allergic airway diseases remains controversial and requires more comprehensive clinical trials. A recent systematic review showed that the current evidence was generated from few trials with a high degree of heterogeneity. The clinical efficacy of Lactobacillus johnsonii EM1 (Lj EM1) and levocetirizine was 174
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assessed for treating perennial allergic rhinitis in children in a 24-week, 2-phase, cross-over treatment program. Levocetirizine and Lj EM1 was more effective than levocetirizine alone, and this difference persisted for at least 3 months after discontinuation of Lj EM1 [93]. Bifidobacterium lactis strain has been reported to be able to modify immune parameters (significantly decreased allergic and proinflammatory cytokines and reduced basophil cell activation compared with placebo treatment) and nasal symptom scores in individuals suffering from seasonal allergic rhinitis [94]. To date, the routine use of probiotics as an additive therapy in individuals with allergic airway diseases cannot be recommended [95]. The glycirrhetic acid in the treatment of children suffering from allergic rhinitis has been investigated. The preliminary findings were encouraging, even though further studies need to confirm this early experience [96].
CONCLUSION ARIA guidelines, published in 2001, have not only brought attention to allergic rhinitis and its impact on asthma, but also proposed a new classification of allergic rhinitis in terms of symptom severity and persistence [15]. These guidelines have been updated in 2008 [97] and analyzed through the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system [4 ]. During the past decade, 251 original articles on over 170 000 patients followed in 43 countries using this classification led to achieved relevant scientific information. In the ARIA classification, intermittent and persistent rhinitis are proposed to replace seasonal and perennial allergic rhinitis, proving to be more relevant to patients’ needs. Severity and persistence are two separate components, and may be independent of rhinitis. For instance, the impact of severity on the timely evaluation of patients’ QoL is similar in patients with intermittent and persistent rhinitis. ARIA guidelines represent a cornerstone for the scientific community and will continue their work through a continuous update on the currently relevant issues such as rhinitis phenotypes, an appropriate disease management on the basis of new available treatments, patient empowerment, the transferability of clinical trials in real life, and the awareness of the importance of allergic rhinitis management in the public health programs [4 ]. Although the majority of patients suffering from allergic rhinitis can be controlled by the treatment, a fraction of them remain symptomatic, and are therefore defined as having severe chronic upper &&
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airway diseases [98]; therefore, the search for new treatments with a favorable risk–benefit ratio is desirable. Acknowledgements The authors thank ASPADIRES (Associazione Pazienti Disturbi Respiratori nel Sonno) and acknowledge Dr Marianna Bruzzone for linguistic assistance with the article. Conflicts of interest The study was supported by ARMIA (Associazione Ricerca Malattie Immunologiche e Allergiche). Competing interests: The authors declare that they have no competing interests.
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Volume 14 Number 2 April 2014
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