Pharmacologic Treatment of Seasonal Allergic Rhinitis: Synopsis of Guidance From the 2017 Joint Task Force on Practice Parameters

Seasonal allergic rhinitis, which affects up to 14% of the U.S. adult population, is managed by clinicians and patients using a combination of prescription and over-the-counter medications. Most patients who consult an allergy and immunology specialist have already tried many over-the-counter monotherapies without success and are seeking more effective treatment. No consensus exists about whether a particular medication should be used for initial treatment or about the benefit of using 2 or more medications concurrently for initial treatment. This synopsis of a 2017 guideline from the Joint Task Force on Practice Parameters addresses specific recommendations regarding initial pharmacotherapy approaches for patients aged 12 years or older with seasonal allergic rhinitis. Three key questions were addressed in this evidence-based guideline, which was developed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method. Allergen avoidance, which can be effective for indoor allergens, is usually inadequate for the outdoor allergens that cause and perpetuate symptoms in patients with seasonal allergic rhinitis. Many patients with moderate-to-severe seasonal allergic rhinitis may benefit from specific allergen immunotherapy (subcutaneous or sublingual), which is the only disease-modifying therapeutic method (1, 2). These management interventions and pharmacotherapy for perennial allergic rhinitis were not addressed in this guideline. Guideline Development and Review Process The Joint Task Force on Practice Parameters formed a workgroup, comprising volunteers from the American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI), to find and critique evidence relevant to pharmacotherapy for seasonal allergic rhinitis. Three patient advocates were invited to participate in the development of the final recommendations. All workgroup members disclosed potential conflicts of interest in accordance with the standards of the National Academy of Sciences (3). The workgroup developed a list of clinical questions about the use of single or combination medications for seasonal allergic rhinitis. From these, 3 key questions were chosen as the focus of a systematic review. Of note, the 3 questions were also part of a large systematic review on allergic rhinitis that was funded by the Agency for Healthcare Research and Quality (AHRQ) and published in 2013 (4). The AHRQ review was limited to randomized controlled trials of persons aged 12 years or older with seasonal allergic rhinitis of at least 2 weeks' duration during an active pollen season. The workgroup updated the searches used in the AHRQ review (MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials) from 18 July 2012 to 29 July 2016 and found no additional randomized trials of medication therapy for seasonal allergic rhinitis. The workgroup and the Joint Task Force reviewed the quality of the published trials; contacted authors, when possible, for any missing information; evaluated the clinical significance of reported patient-important outcomes; and determined the overall quality of evidence across outcomes. The certainty of the body of evidence, using GRADE quality analysis and evaluating for inconsistency, indirectness, and imprecision, was defined as high, moderate, low, or very low (5). Before determining the final recommendation or suggestion for an intervention, the Joint Task Force considered safety, cost, and patient preference. These considerations were based on experience and were informed by an informal review of the literature. The guideline was externally reviewed by the AAAAI and the ACAAI, by both appointed official reviewers and members at large. The document was posted on the Joint Task Force Web site (www.allergyparameters.org) for general public review. All comments that were received were reviewed by the Joint Task Force, revisions were incorporated, and general feedback was provided to reviewers. The final guideline and appendices are published in the Annals of Allergy, Asthma, & Immunology and are posted at www.allergyparameters.org (6). Recommendations 1. For initial treatment of seasonal allergic rhinitis in persons aged 12 years or older, routinely prescribe monotherapy with an intranasal corticosteroid rather than an intranasal corticosteroid in combination with an oral antihistamine. (Strong recommendation) Eight trials addressed whether using a combination of an oral antihistamine and an intranasal corticosteroid has greater clinical benefit than using an intranasal corticosteroid alone (714), but only 5 trials reported data that could be analyzed (711). All 5 evaluated nasal symptoms as the main outcome, 3 reported ocular symptoms (8, 9, 11), and 1 reported quality of life as a primary end point (10). For measurement of nasal symptoms, 3 studies (8, 10, 11) used the Total Nasal Symptom Score (TNSS), which measures nasal congestion, sneezing, rhinorrhea, and nasal itching, each rated on a 4-point Likert scale of 0 to 3 (0 indicates no symptoms, 1 indicates mild symptoms, 2 indicates moderate symptoms, and 3 indicates severe symptoms) and summed for a total score of 0 to 12. A study that reported on the same 4 nasal symptoms (7) used a visual analogue scale of 0 to 100 for each symptom, for a maximum score of 400, and the remaining study (9) used a scale of 0 to 9 for combined nasal symptom severity. Inclusion criteria included a TNSS of 6 or higher and a congestion score of 2 or higher (11), a score of 200 or higher on a visual analogue scale of 0 to 400 (7), and the presence of at least 1 of 4 nasal symptoms plus headache or 1 additional symptom involving the nose or eyes (9). One study did not require a specific nasal symptom severity score, but the mean TNSS reported at baseline was 4.56 (95% CI, 3.61 to 5.50) (10). Two trials included a placebo group receiving no treatment (7, 11), 2 used a parallel-treatment design (8, 9), and 1 used a crossover design (10). Overall, we judged the evidence as not proving a benefit of adding an oral antihistamine to an intranasal corticosteroid and recognized that oral antihistamines, mainly first-generation, may cause sedation and other adverse effects. Five trials (11, 1517) disclosed and met the sample size needed to determine statistically significant findings, whereas the remaining studies either did not report this value or did not obtain the needed study participants; none of the trials used the concept of minimal clinically important difference to power the study. Although participants in these trials were recruited on the basis of meeting criteria for seasonal allergic rhinitis and reaching a threshold of nasal symptoms, they were not randomly assigned on the basis of treatment failure despite regular use of an intranasal corticosteroid. Because there may be a subgroup of patients who experience treatment failure with an intranasal corticosteroid alone and could benefit from the addition of an oral antihistamine, these data do not permit determination of whether adding an oral antihistamine would benefit patients with residual symptoms despite appropriately dosed intranasal corticosteroids. 2. For initial treatment of seasonal allergic rhinitis in persons aged 15 years or older, recommend an intranasal corticosteroid over a leukotriene receptor antagonist. (Strong recommendation) Five trials addressed the relative efficacy of a leukotriene receptor antagonist (such as oral montelukast) compared with an intranasal corticosteroid (15, 16, 1820). Overall, we judged the evidence as clearly showing that an intranasal corticosteroid was more effective than montelukast for nasal symptom reduction, although in 1 study (19), the numerically greater improvement in symptom-free days did not reach statistical significance. The primary end points were the participant-rated TNSS incorporating nasal congestion, rhinorrhea, sneezing, and nasal itching (discussed earlier) (18); a score of 0 to 400 on a visual analogue scale (discussed earlier) (15, 16, 19); or a Composite Symptom Score of 0 to 4 (20). Three of these studies included a placebo group (1820), and 2 used a parallel-treatment design (15, 16). For inclusion, 3 studies required a visual analogue scale score of 200 out of 400 for nasal symptom severity (15, 16, 19), and 2 trials (18, 20) did not require any degree of nasal symptom severity. Although there is no consensus in the literature about thresholds for a minimal clinically important difference between treatments, the workgroup and the Joint Task Force determined that the reductions in nasal symptoms reported in the trials comparing an intranasal corticosteroid versus montelukast were clinically meaningful according to recently published criteria (21). Some patients do not tolerate or accept the use of an intranasal corticosteroid and prefer an oral agent, such as montelukast, despite its lesser efficacy (22, 23). In patients with a concurrent diagnosis of mild persistent asthma, a leukotriene receptor antagonist may be prescribed and may also provide benefit for seasonal allergic rhinitis; however, this would not be the preferred agent for a patient with either condition (24). Finally, there may be subgroups of patients with seasonal allergic rhinitis who are more responsive to a leukotriene receptor antagonist, as in the case of asthma (25). 3. For treatment of moderate to severe seasonal allergic rhinitis in persons aged 12 years or older, the clinician may recommend the combination of an intranasal corticosteroid and an intranasal antihistamine for initial treatment.

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title: Grading quality of evidence and strength of recommendations in clinical practice guidelines
abstract: The GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach provides guidance to grading the quality of underlying evidence and the strength of recommendations in health care. The GRADE system’s conceptual underpinnings allow for a detailed stepwise process that defines what role the quality of the available evidence plays in the development of health care recommendations. The merit of GRADE is not that it eliminates judgments or disagreements about evidence and recommendations, but rather that it makes them transparent. This first article in a three‐part series describes the GRADE framework in relation to grading the quality of evidence about interventions based on examples from the field of allergy and asthma. In the GRADE system, the quality of evidence reflects the extent to which a guideline panel’s confidence in an estimate of the effect is adequate to support a particular recommendation. The system classifies quality of evidence as high, moderate, low, or very low according to factors that include the study methodology, consistency and precision of the results, and directness of the evidence.

title: Randomized placebo‐controlled trial comparing fluticasone aqueous nasal spray in mono‐therapy, fluticasone plus cetirizine, fluticasone plus montelukast and cetirizine plus montelukast for seasonal allergic rhinitis
abstract: Corticosteroids are considered to be particularly effective in reducing nasal congestion and are therefore recommended as first‐line treatment in allergic rhinitis patients with moderate to severe and/or persistent symptoms.

title: Evaluation of Fluticasone Propionate Aqueous Nasal Spray Taken Alone and in Combination with Cetirizine in the Prophylactic Treatment of Seasonal Allergic Rhinitis
abstract: SummaryThis was a multicentre, double-blind study in 454 patients to compare the effectiveness and tolerability of fluticasone propionate nasal spray (FPANS) 200μg used once daily for 8 weeks on its own or in combination with oral cetirizine 10mg once daily in the treatment of seasonal allergic rhinitis. The results showed no significant difference between treatments in any of the symptoms or in the proportion of symptom-free days. Watery eyes were recorded as being the most troublesome symptom in the previous hayfever season, whilst during the study patients were, on average, free of eye symptoms for 56% of the time. Additionally, no difference was detected between the two groups with regard to the use of rescue medication. More than 75% of patients concluded at the end of the study that their symptoms had been adequately controlled and, similarly, investigators rated both treatments as being successful for the majority of patients. Overall, this study suggests that there is no significant difference in efficacy between FPANS 200μg, taken once daily in the morning, and FPANS 200μg once daily in combination with oral cetirizine 10mg, in the prophylactic treatment of seasonal allergic rhinitis.

title: Effects of levocetirizine as add‐on therapy to fluticasone in seasonal allergic rhinitis
abstract: Addition of H1 antagonists to intranasal corticosteroid treatment of allergic rhinitis (AR) is common in clinical practice and recommended by guidelines, despite some evidence that the additive benefits are negligible.

title: Is the usage of intranasal glucocorticosteroids alone in allergic rhinitis sufficient?
abstract: Recently, it is claimed that the usage of the intranasal glucocorticosteroids alone, instead of H1-antihistamines + intranasal glucocorticosteroids, reduces the complaints in moderate-to-severe seasonal allergic rhinitis (SAR). This study aims to evaluate the efficacy of the intranasal glucocorticosteroids alone during the pollen season by using objective and subjective parameters. Twenty-four patients (mean age, 12.17 +/- 2.26 years) with SAR sensitive to pollen are included in this study. The patients were divided into two groups randomly. Twelve patients in group I were given H1-antihistamine (loratadine) + intranasal glucocorticosteroid (mometasone furoate), and 12 patients in group II were given only intranasal glucocorticosteroid (mometasone furoate) for 12 weeks. To evaluate the results, subjective parameters (daytime nasal symptoms score, daytime eye symptoms score, and nighttime symptoms score) and objective parameters (nasal smear, nasal peak inspiratory flow [NPIF], and nasal biopsy) are used. With regard to the baseline data, it was observed that both groups had a significant decrease in total symptom score (p < 0.01), a significant increase in NPIF values (p < 0.01), and a significant decrease in the number of eosinophils in both nasal smear and biopsy (p < 0.01) after treatment. Comparing groups I and II in terms of treatment success, the improvement in daytime nasal symptoms score (p < 0.01 versus p < 0.01), daytime eye symptoms score (p < 0.01 versus p < 0.01), and total symptom score (p < 0.versus p < 0.01) was not different. However, there was a significant improvement in nighttime symptoms score between groups I and II (p < 0.01 versus p > 0.05). Furthermore, NPIF and nasal biopsy findings did not differ between groups (p > 0.05). The usage of H1-antihistamine + intranasal glucocorticosteroid has no superiority over the administration of intranasal glucocorticosteroid alone for treatment of SAR in pollen season. However, this finding needs to be confirmed in larger series studies.

title: Spectrum of Seasonal Allergic Rhinitis Symptom Relief with Topical Corticoid and Oral Antihistamine Given Singly or in Combination
abstract: Sixty ragweed-sensitive volunteers participated in a 2-week study that compared symptom profiles during treatment with antihistamine (loratadine, LOR) alone, topical corticoid (beclomethasone, BEC) alone, or the two drugs combined. For 5 days commencing shortly after the beginning of the ragweed bloom, patients took no treatment while we collected baseline data. They were then randomized to one of the three treatments, receiving that treatment for the balance of the 2-week study term. Twice each day they recorded the severity of congestion, eye symptoms, running and blowing, itching, and sneezing. At the end of the study they provided an estimate of overall symptom relief, which favored combined treatment (vs LOR P = 0.001, vs BEC P = 0.042). To gain an estimate of disease severity and treatment effectiveness over time, and to smooth out day-to-day variation, we divided symptom diary reports into three segments (days 2–4, 5–7, and 8–10) for analysis. Combined treatment controlled symptoms better than antihistamine alone in nearly all study segments. Corticoid alone or combined with antihistamine provided similar control of congestion, running and blowing, and eye complaints. Combination therapy controlled itching and sneezing better, especially through the study segments 1 and 2. Patient preference for combined treatment seems to relate to control of itching and sneezing and rapid onset of effect.

title: Comparison of fluticasone propionate aqueous nasal spray and oral montelukast for the treatment of seasonal allergic rhinitis symptoms.
abstract: Few studies have directly compared the efficacy of intranasal corticosteroids with that of leukotriene receptor antagonists for the treatment of daytime and nighttime symptoms of seasonal allergic rhinitis (SAR).



To compare fluticasone propionate aqueous nasal spray, 200 microg daily, with oral montelukast, 10 mg daily, for the relief of SAR symptoms.



Patients with SAR 15 years or older were randomized to receive either fluticasone propionate (n = 367) or montelukast (n = 369) in this double-blind, double-dummy, parallel-group study. The primary efficacy measure was the mean change from baseline in daytime total nasal symptom scores (TNSSs) (the sum of 4 daytime individual nasal symptom scores [INSSs] assessing nasal congestion, itching, rhinorrhea, and sneezing), averaged across weeks 1 and 2. Secondary efficacy measures included the 4 daytime INSSs, nighttime TNSSs (the sum of 3 nighttime INSSs assessing congestion on awakening, difficulty going to sleep, and nighttime awakenings), and the 3 nighttime INSSs averaged across weeks 1 and 2.



Mean changes from baseline in daytime TNSSs (P < .001), all daytime INSSs (P < .001), nighttime TNSSs (P < .001), and all nighttime INSSs (P < or = .02) showed significant differences favoring fluticasone propionate over montelukast across 2 weeks of treatment.



Compared with montelukast, fluticasone propionate provided significantly greater improvement in daytime and nighttime SAR symptoms.

title: Fluticasone propionate aqueous nasal spray provided significantly greater improvement in daytime and nighttime nasal symptoms of seasonal allergic rhinitis compared with montelukast.
abstract: The safety and efficacy of intranasal corticosteroids for the treatment of allergic rhinitis is well documented in the literature. Additionally, an expert panel has concluded that intranasal corticosteroids are the first line of therapy when obstruction is a major component of rhinitis. Montelukast is a leukotriene receptor antagonist recently approved for the treatment of seasonal allergic rhinitis (SAR).



This randomized, double-blind, double-dummy, parallel-group study was conducted to compare the effectiveness of a 15-day course of intranasal fluticasone propionate 200 microg, once daily (FP200QD), to oral montelukast 10 mg, once daily (MON10QD), in relieving daytime and nighttime nasal symptoms associated with SAR.



The intent-to-treat (ITT) analysis population consisted of 705 eligible males and females (> or = 15 years) with SAR randomized to either FP200QD (N = 353) or MON10QD (N = 352). The primary efficacy endpoint was the mean change from baseline in subject-rated daytime total nasal symptom scores (the sum of four individual scores: nasal congestion, itching, rhinorrhea, and sneezing), evaluated via visual analog scales, and averaged over weeks 1 to 2. Secondary endpoints included the four daytime individual nasal symptom scores, the nighttime total, and individual nasal symptom scores (each evaluated on a four-point scale from 0 to 3).



Statistically significant differences favoring FP200QD over MON10QD were observed for the mean change from baseline in daytime total nasal symptom scores (P < 0.001), daytime individual nasal symptom scores (P < 0.001), nighttime total (P < 0.001), and all individual nasal symptom scores (P < or = 0.002) over the 15-day treatment period. FP200QD and MON10QD were both well tolerated.



The results of this well controlled study demonstrated that FP200QD was consistently superior to MON10QD with regard to every efficacy endpoint evaluated, including daytime and nighttime nasal congestion, in subjects with SAR.

title: A novel intranasal therapy of azelastine with fluticasone for the treatment of allergic rhinitis.
abstract: Moderate-to-severe allergic rhinitis (AR) is a challenge to treat, with many patients using multiple therapies and achieving limited symptom control. More effective therapies must be developed and tested in well-controlled, randomized, prospective studies with a direct comparison to current standards.



The aim of these studies was to investigate the efficacy of MP29-02 (a novel formulation of azelastine and fluticasone propionate [FP]) in patients with moderate-to-severe seasonal allergic rhinitis (SAR) and to compare its efficacy with 2 first-line therapies (ie, intranasal azelastine and intranasal FP) in this population.



Three thousand three hundred ninety-eight patients (≥12 years old) with moderate-to-severe SAR were enrolled into 3 multicenter, randomized, double-blind, placebo- and active-controlled, parallel-group trials (MP4002 [NCT00651118], MP4004 [NCT00740792], and MP4006 [NCT00883168]). Each trial was conducted for 14 days during different allergy seasons. The primary efficacy variable was the sum of the morning and evening change from baseline in reflective total nasal symptom score (range, 0-24) over the treatment period. Outcomes for the meta-analysis included efficacy according to disease severity and time to response in relevant responder criteria.



In the meta-analysis MP29-02 reduced the mean reflective total nasal symptom score from baseline (-5.7 [SD, 5.3]) more than FP (-5.1 [SD, 4.9], P < .001), azelastine (-4.4 [SD, 4.8], P < .001), or placebo (-3.0 [SD, 4.2], P < .001). This benefit was observed from the first day of assessment, with improvement in each individual nasal symptom, even in the patients with the most severe disease. MP29-02 achieved response consistently days earlier and showed greater efficacy in patients with moderate-to-severe rhinitis than FP and azelastine.



MP29-02 represents a novel therapy that demonstrated superiority to 2 first-line therapies for AR. Patients with moderate-to-severe SAR achieved better control, and their symptoms were controlled earlier with MP29-02 than with recommended medications according to guidelines.

title: Fluticasone propionate nasal spray is superior to montelukast for allergic rhinitis while neither affects overall asthma control.
abstract: Asthma and allergic rhinitis are both highly prevalent diseases and often coexist in patients.



To investigate the effect of rhinitis therapy on asthma outcomes in adult and adolescent patients with both seasonal allergic rhinitis (SAR) and persistent asthma.



A total of 863 patients (mean baseline FEV1 81% predicted) were randomized to receive open-label fluticasone propionate/salmeterol (FSC), 100/50 microg bid for 4 weeks, plus either blinded fluticasone propionate aqueous nasal spray (FPANS) 200 microg/d, montelukast 10 mg/d, or placebo. Patients kept daily records of peak expiratory flow (PEF), asthma, and rhinitis symptoms and rescue albuterol use.



FPANS added to FSC resulted in superior outcomes for daytime total nasal symptom scores (D-TNSS) and individual daytime nasal specific symptoms (congestion, rhinorrhea, sneezing, and itching) compared with montelukast plus FSC and placebo plus FSC (p < or = 0.001). Montelukast plus FSC was superior to placebo plus FSC only for D-TNSS and itching and sneezing. Morning PEF, asthma symptoms, and rescue albuterol use improved significantly (p < or = 0.001) in all treatment groups, but improvements were comparable across the treatment groups.



In patients with persistent asthma treated with FSC, the addition of montelukast or FPANS for the treatment of SAR resulted in no additional improvements in overall asthma control compared with FSC alone. However, FPANS provided superior rhinitis control compared with montelukast. These data suggest that asthma and rhinitis should each be optimally treated.

title: Clinical Studies of Combination Montelukast and Loratadine in Patients with Seasonal Allergic Rhinitis
abstract: Concomitant use of montelukast and loratadine may improve symptoms of seasonal allergic rhinitis (SAR) more than treatment with either drug alone.  We compared the efficacy of this combination versus placebo, nasal beclomethasone, montelukast, and loratadine in study 1 and versus placebo, montelukast, and loratadine in study 2.  Patients were randomly allocated to double-blind treatment with intranasal beclomethasone 200 μ g/twice daily (study 1 only), placebo, montelukast 10 mg+loratadine 10 mg, montelukast 10 mg, or loratadine 10 mg once daily. The primary endpoint was the Composite Symptom Score (CSS): average of daily diary scores for Daytime Nasal Symptoms and Nighttime Symptoms.  In study 1, improvements in the change from baseline in CSS were seen for montelukast+loratadine (least-squares means [95% CI] = −0.43 [−0.51, −0.35]), beclomethasone (−0.57 [−0.64, −0.49]), montelukast, and loratadine. All treatments were significantly better than placebo; montelukast+loratadine had a significantly greater effect on CSS than montelukast alone but no difference compared to loratadine was detected. Beclomethasone provided significantly greater improvement versus montelukast+loratadine on the primary and secondary endpoints except for the rhinoconjunctivitis quality-of-life score. In study 2, the combination treatment was similar to montelukast, loratadine, and placebo for the primary and secondary endpoints.  In study 1, montelukast+loratadine had a significantly greater effect on CSS than placebo and montelukast alone; however, in all comparisons, nasal beclomethasone had a greater effect on daily symptoms. In contrast, the combination of montelukast+loratadine in study 2 did not provide greater improvement compared with placebo, montelukast, or loratadine monotherapy, perhaps due to a large placebo effect.

title: Comparison of a nasal glucocorticoid, antileukotriene, and a combination of antileukotriene and antihistamine in the treatment of seasonal allergic rhinitis.
abstract: Allergic rhinitis requires active intervention for symptom relief. A combination of antileukotriene and antihistamine drugs has been suggested to provide additive treatment benefits for patients with allergic rhinitis.



We evaluated how such a combination treatment would affect symptoms and local mucosal eosinophilia in comparison with a nasal glucocorticoid.



In a double-blind, randomized study 62 patients with grass pollen-induced allergic rhinitis received a nasal glucocorticoid (fluticasone propionate aqueous nasal spray [FPANS], 200 microg/d), an antileukotriene (montelukast, 10 mg/d), a combination of montelukast with an antihistamine (loratadine, 10 mg/d), or placebo throughout the season. Cromoglycate eyedrops and a limited amount of loratadine were allowed as rescue medication for severe symptoms. Patients recorded their symptoms for nasal blockage, itching, rhinorrhea, and sneezing. Before and during the season, nasal biopsy specimens were obtained from patients for evaluation of local eosinophilic inflammation.



During the peak season, both FPANS and combined montelukast-loratadine were significantly more effective than placebo and montelukast alone for daytime symptom prevention. For nighttime symptoms, FPANS was significantly more effective compared with all other treatments, whereas combined montelukast-loratadine and montelukast alone did not provide significant symptom prevention compared with placebo. The pollen-induced increase in the numbers of epithelial eosinophils was significantly lower for FPANS-treated patients compared with that seen in all other treatment groups.



In patients with seasonal allergic rhinitis, intranasal glucocorticoids are more effective than an antileukotriene drug or combined antileukotriene-antihistamine for the reduction of pollen-induced nasal eosinophilic inflammation and for control of nasal symptoms.

title: Minimal Clinically Important Difference (MCID) in Allergic Rhinitis: Agency for Healthcare Research and Quality or Anchor-Based Thresholds?
abstract: In 2013, the Agency for Healthcare Research and Quality (AHRQ) recommended that allergic rhinitis (AR) studies calculate a minimal clinically important difference (MCID) based on an estimated threshold equal to 30% of the maximum total nasal symptom score. Applying this threshold, their data showed no differences between well-established treatments, and a subsequent analysis using prescribing information found no differences between active treatments and placebo controls.



The objective of this study was to demonstrate the application of an evidence-based model to determine MCIDs for AR studies, with an absolute value for an anchor-based threshold and validated methods for calculating distribution-based thresholds.



Using the same studies as the AHRQ report, anchor- and distribution-based MCID thresholds were determined for 3 clinical comparisons identified by the AHRQ: (1) oral antihistamine+intranasal corticosteroid (INCS) versus INCS, (2) montelukast versus INCS, and (3) intranasal antihistamine+INCS in a single device versus the monotherapies. The outcomes were compared with those reported using the AHRQ threshold.



No treatment comparison met the AHRQ-defined MCID threshold; all treatments were determined to be equivalent for all 3 queries. In contrast, the evidence-based model revealed some differences between treatments: INCS > montelukast; intranasal antihistamine+INCS > either monotherapy. No clinically relevant benefit was observed for adding an oral antihistamine to INCS, but some studies were not optimal choices for quantitative determination of MCIDs. Updating the literature search revealed no additional studies that met the AHRQ inclusion criteria.



The evidence-based threshold for MCID determination for AR studies should supersede the threshold recommended in the AHRQ report.

title: MP29-02 (a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate) in the treatment of seasonal allergic rhinitis: a randomized, double-blind, placebo-controlled trial of efficacy and safety.
abstract: Many patients with allergic rhinitis (AR) have uncontrolled symptoms despite available treatment options. This study was designed to evaluate the efficacy and safety of MP29-02 (a novel intranasal formulation of fluticasone propionate [FP] and azelastine [AZ] hydrochloride), compared with monotherapy with FP, AZ, and placebo sprays for the treatment of seasonal allergic rhinitis (SAR). This 2-week randomized, double-blind, placebo-controlled trial was conducted in 779 patients with moderate-to-severe SAR. Treatments were administered 1 spray/nostril twice daily in the same vehicle and delivery device. Daily doses of AZ and FP were 548 and 200 micrograms, respectively. The primary efficacy variable was the 12-hour reflective total nasal symptom score (rTNSS), consisting of nasal congestion, sneezing, itchy nose, and runny nose. Secondary efficacy variables were (1) 12-hour reflective individual nasal symptom scores; (2) onset of action; (3) 12-hour reflective total ocular symptom score (rTOSS), including itchy eyes, watery eyes, and red eyes; and (4) the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) overall score. MP29-02 significantly reduced the mean rTNSS from baseline by -5.54 points compared with FP (-4.55; p = 0.038), AZ (-4.54; p = 0.032), and placebo (-3.03; p < 0.001), improving the rTNSS by 39% beyond the contribution of FP. All individual nasal symptoms contributed to the efficacy of MP29-02. Onset of action was within 30 minutes. MP29-02 significantly improved rTOSS compared with placebo, provided a clinically important improvement in the overall RQLQ score, and was well tolerated. In this study, MP29-02 provided more complete symptom relief than two widely used first-line AR treatments and was well tolerated.

title: Double-blind, placebo-controlled study of azelastine and fluticasone in a single nasal spray delivery device.
abstract: A proof-of-concept study suggested that combination therapy with commercial azelastine hydrochloride nasal spray and fluticasone propionate nasal spray significantly improved nasal symptoms of seasonal allergic rhinitis compared with either agent alone.



To compare an azelastine-fluticasone combination nasal spray administered in a single-delivery device with a commercially available azelastine nasal spray and fluticasone nasal spray.



This 14-day, multicenter, randomized, double-blind study was conducted during the Texas mountain cedar season. After a 5-day placebo lead-in, 610 patients with moderate-to-severe nasal symptoms were randomized to treatment with (1) azelastine nasal spray, (2) fluticasone nasal spray, (3) combination azelastine and fluticasone nasal spray, or (4) placebo nasal spray. All treatments were given as 1 spray per nostril twice daily. The primary efficacy variable was the change from baseline in the total nasal symptom score (TNSS), consisting of nasal congestion, runny nose, itchy nose, and sneezing.



All 3 active groups were statistically superior (P <or= .02) to placebo, and the combination was statistically superior (P <or= .003) to either agent alone. The TNSS improved by 28.4% with combination azelastine-fluticasone, 20.4% with fluticasone, 16.4% with azelastine, and 11.2% with placebo. All 3 treatments were well tolerated.



The combination azelastine-fluticasone nasal spray provided statistically significant improvement in the TNSS and additive clinical benefit compared with either agent alone in patients with moderate-to-severe seasonal allergic rhinitis.

title: Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines—2016 revision
abstract: Allergic rhinitis (AR) affects 10% to 40% of the population. It reduces quality of life and school and work performance and is a frequent reason for office visits in general practice. Medical costs are large, but avoidable costs associated with lost work productivity are even larger than those incurred by asthma. New evidence has accumulated since the last revision of the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines in 2010, prompting its update.  We sought to provide a targeted update of the ARIA guidelines.  The ARIA guideline panel identified new clinical questions and selected questions requiring an update. We performed systematic reviews of health effects and the evidence about patients' values and preferences and resource requirements (up to June 2016). We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence‐to‐decision frameworks to develop recommendations.  The 2016 revision of the ARIA guidelines provides both updated and new recommendations about the pharmacologic treatment of AR. Specifically, it addresses the relative merits of using oral H1‐antihistamines, intranasal H1‐antihistamines, intranasal corticosteroids, and leukotriene receptor antagonists either alone or in combination. The ARIA guideline panel provides specific recommendations for the choice of treatment and the rationale for the choice and discusses specific considerations that clinicians and patients might want to review to choose the management most appropriate for an individual patient.  Appropriate treatment of AR might improve patients' quality of life and school and work productivity. ARIA recommendations support patients, their caregivers, and health care providers in choosing the optimal treatment.

title: The minimally important difference in the Rhinoconjunctivitis Total Symptom Score in grass‐pollen‐induced allergic rhinoconjunctivitis
abstract: The minimally important difference (MID) has been defined as the smallest improvement considered worthwhile by a patient. The MID has not been estimated for the Rhinoconjunctivitis Total Symptom Score (RTSS).

title: The minimal clinically important difference in allergic rhinitis
abstract: When presented with results from clinical measurements or research findings, clinicians must first make an interpretation of their importance, not only in statistical terms, but also the ‘clinical importance’ given the size of the change observed. To do this, they require an understanding of the relationship between their outcome measures, and the patient's perception of change. The minimal clinically important difference (MCID) illustrates this relationship by calculating the smallest change in a given outcome that is meaningful to a patient. There are few reports of calculated MCIDs in the Rhinology literature.