- Email: [email protected]
Intranasal fluticasone propionate is effective for perennial nonallergic rhinitis with or without eosinophilia
Intranasal fluticasone propionate is effective for perennial nonallergic rhinitis with or without eosinophilia D. Robert Webb, MD*; Eli O. Meltzer, MD†; Albert F. Finn, Jr., MD‡; Kathleen A. Rickard, MD§; Pamela J. Pepsin, RN, BA§; Ronald Westlund, MS§; and Cindy K. Cook, MS§
Background: Although response to intranasal corticosteroid therapy has been reported in patients with nonallergic rhinitis with eosinophilic syndrome (NARES), efficacy specifically in non-NARES patients has not been fully characterized. Objective: To evaluate the efficacy of intranasal fluticasone propionate (FP) in the treatment of patients with perennial nonallergic rhinitis, with and without nasal eosinophilia. Methods: Data from 983 patients in three randomized, double-blind, placebocontrolled PNAR trials were integrated. Patients received a total daily dose of FP 200 g (n ⫽ 332), FP 400 g (n ⫽ 325), or placebo (n ⫽ 326) for 28 days. Patients were ⱖ12 years of age with perennial rhinitis and negative skin tests to all allergens relevant to the geographic region. Nasal eosinophils were evaluated using a five-point scale. Patients were classified as non-NARES with a point score of 0 (n ⫽ 674; 69%); patients with a point score between 1 and 4 were classified as NARES (n ⫽ 309; 31%). Efficacy of FP was evaluated by the mean change in total nasal symptom score (TNSS), a sum of patient ratings of nasal obstruction, postnasal drip, and rhinorrhea. Results: Patients with either NARES or non-NARES had similar statistically significant improvement with FP 200 g or 400 g compared with placebo; thus, the total group comprising both varieties of rhinitis responded to FP. In the total population, both FP treatment groups showed significantly greater improvement in TNSS compared with placebo during each week of treatment (P ⱕ 0.002), with mean changes in TNSS for day 22 to day 28 ranging from ⫺84 and ⫺85 in the FP 200 g and FP 400 g groups, respectively, to ⫺64 in the placebo group. The three study treatment groups had similar proportions of non-NARES (68 to 69%) and NARES (31 to 32%) patients at baseline. In the non-NARES subgroup, mean changes in TNSS for each treatment group were similar to changes seen in the total population. In the NARES subgroup, mean changes in TNSS for the FP 200 g and placebo groups were similar to changes seen in the total population; mean change in TNSS for the FP 400 g group was somewhat greater than changes seen in the total population. Conclusions: Intranasal FP is an effective treatment for perennial nonallergic rhinitis with or without nasal eosinophilia (NARES or non-NARES). Ann Allergy Asthma Immunol 2002;88:385–390.
INTRODUCTION Perennial nonallergic rhinitis (PNAR) is characterized by sporadic or persis-
tent nasal symptoms for which an immunoglobulin E-mediated mechanism can not be demonstrated.1 Symptoms
* Allergy and Asthma Research Associates, Kirkland, Washington. † Allergy and Asthma Medical Group and Research Center, San Diego, California. ‡ Allergy and Asthma Centers of Charleston PA, Charleston, South Carolina. § GlaxoSmithKline, Research Triangle Park, North Carolina.
This study was supported in part by a grant from SmithKline Beecham Corporation doing business as GlaxoSmithKline, Research Triangle Park, NC. Presented in part at the Annual Meeting of the American College of Allergy, Asthma, and Immunology, Philadelphia, PA, November 6 –11, 1998. Received for publication August 21, 2001. Accepted for publication in revised form January 1, 2002.
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are often difficult to control with traditional rhinitis pharmacotherapy (eg, antihistamines, decongestants), perhaps because of the variety of triggers, many of which are difficult to avoid. Also, symptoms often persist without any identifiable trigger.2– 4 Cytologic examination shows that some of these patients have prominent nasal eosinophilia,5,6 although skin tests to allergens relevant to the geographic region are negative. These patients are sometimes referred to as having nonallergic rhinitis with eosinophilic syndrome (NARES).1,2 A majority of patients with PNAR do not have eosinophilia and can be regarded as non-NARES patients.7–9 The term vasomotor rhinitis is also used to designate nonNARES patients. Although some studies have shown that intranasal corticosteroids are particularly effective in the treatment of nonallergic rhinitis when nasal eosinophilia is present, the options in the treatment of non-NARES patients, those who have little or no eosinophilia in nasal smears, include either nonspecific, broad-based therapy aimed at multiple symptoms or, alternatively, therapy tailored to treat specific symptoms.7,10,11 Examples of broad-based therapy treatment include topical intranasal corticosteroids and topical antihistamines.10 Efficacy of intranasal corticosteroid therapy in non-NARES patients has not been clearly demonstrated. In the few studies that have been published evaluating the efficacy of intranasal corticosteroids in nonNARES patients, the numbers of patients have been small, or there have been confounding factors (eg, antihistamine rescue medication was al-
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lowed) compromising definitive conclusions.11–14 Nonetheless, there is a clinical impression that intranasal corticosteroids are not as effective in non-NARES patients as in NARES patients.3,7 To further evaluate the efficacy of fluticasone propionate (FP) in PNAR and within the subgroups of PNAR patients with and without nasal eosinophilia, three randomized, double-blind, placebo-controlled efficacy studies were reviewed. Results from these three studies were integrated and subgroup analyses were conducted in NARES and nonNARES patients. METHODS Data from two multicenter (FLTA3010, FLN-351) and one single-center (FLN350), randomized, double-blind, doubledummy, placebo-controlled, parallel group clinical trials were integrated. Each study evaluated the efficacy of FP aqueous nasal spray at daily doses of 200 and 400 g compared with placebo in the treatment of PNAR. In each study, after giving informed consent, subjects 12 years of age or older with perennial rhinitis and a negative skin test to all allergens relevant to the geographic region participated in a 7-day screening period, during which time baseline severity of nasal symptoms was established. Patients with symptom severity of 150 (see total nasal symptom scoring below) on at least 4 of 7 days immediately preceding randomization were randomly assigned to 1 of the 3 treatment groups for 28 days of study medication in double-blind fashion. Study medication was administered each morning (8 AM) and evening (8 PM) as a divided dose. The placebo nasal spray was formulated as a vehicle without active ingredient; active and placebo formulations were indistinguishable in appearance, smell, and taste. Patients were not allowed to take other rhinitis medications (eg, antihistamines) during the study. Each study was conducted in the United States, institutional review boards approved all three protocols, and written informed consent was obtained from all patients. Nasal cytology was evaluated at screening and after 28 days of treat-
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ment for determination of nasal eosinophilia. Clinic personnel collected nasal mucosal specimens from each patient using the Rhino-probe (Arlington Scientific, Springville, UT). Nasal scraping specimens were obtained from the medial aspect of the inferior turbinate of each nostril and fixed according to a standard procedure.15 The relative numbers of eosinophils were evaluated using the following 5-point scale: 0 ⫽ none; 1 ⫽ few, scattered; 2 ⫽ moderate number; 3 ⫽ large clumps, not covering the field; and 4 ⫽ clumps cover the entire field. Patients without eosinophils had a point score of 0 ⫽ none and were classified as non-NARES. Patients with eosinophils had a point score between 1 ⫽ few, scattered and 4 ⫽ clumps covering the entire field and were classified as NARES. Symptom Severity Ratings Patients were evaluated in the clinic at the initial screening visit and after 2 weeks and 4 weeks of treatment. Throughout the studies, patients completed a diary card each evening on which they rated the severity of nasal obstruction, postnasal drip, and rhinorrhea throughout the day. The first posttreatment symptom severity rating was made on day 1 (PM rating), approximately 12 hours after the first dose of study medication. Patients evaluated symptom severity by using an unmarked visual analog scale16 to rate each symptom independently. The scale was a 100-mm line that represented a continuum from 0 (absent) to 100 (most severe). Clinicians measured the distance in millimeters between the left end of each bar, marked zero, and the vertical mark made on the scale by the patient; the number was recorded to represent severity of each of the symptoms. A total nasal symptom score (TNSS) was calculated by summing the individual scores for each of the symptoms evaluated at each time point. Only patients with a self-rated TNSS of 150 of 300 possible points for the combined scores for nasal obstruction, postnasal drip, and rhinorrhea (studies FLTA3010
and FLN-350) or 200 of 400 possible points for the combined scores for nasal obstruction, postnasal drip, rhinorrhea, and sneezing (study FLN-351) on at least 4 of 7 days immediately preceding the first day of double-blind treatment assignment were randomly assigned to treatment. For the purposes of the analysis presented in this paper, the TNSS was defined for all patients as the combined scores for nasal obstruction, postnasal drip, and rhinorrhea; the maximum possible TNSS was 300 points. Statistical Analysis The efficacy of each treatment in reducing nasal symptoms was evaluated by pooling the data from all three studies and comparing the mean change from baseline in the TNSS during each week of treatment among the three treatment groups. Baseline was defined as the mean TNSS for day ⫺6 to day 0. Hypothesis tests, as stated in the individual studies, were conducted using data from all patients exposed to study drug in each of the three studies (intent-to-treat population analysis). All tests were two-sided with statistical significance defined as P ⬍ 0.05. An analysis of covariance of the change from baseline was performed for each weekly interval (adjusting for investigator effect), followed by corresponding pairwise comparisons of treatment groups. Least squares means were used to compare all pairs of treatments. Subgroup Analysis Two subgroups of patients were formed (as described in the methods section) based on eosinophilic status (NARES and non-NARES). For each of the two subgroups the data from all three studies were pooled. Within each subgroup the mean change from baseline in the TNSS during each week of treatment among the three treatment groups was calculated. Qualitative comparisons were conducted to evaluate whether efficacy for each subgroup appeared similar to efficacy in the overall pooled analysis. In each of the three studies, the randomization did not stratify by the factor (NARES/nonNARES), and the power to detect dif-
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
ferences was low for each subgroup. Thus, statistical testing within subgroups is not presented.
Table 1. Patient Characteristics
Characteristic
RESULTS Data from three PNAR studies were combined involving 983 patients treated with FP 200 g (n ⫽ 325), FP 400 g (n ⫽ 332), and placebo (n ⫽ 326). In all, 95% of patients completed the protocol-specified 28 days of treatment, with ⬍2% of any treatment group being withdrawn for lack of efficacy. An adverse event caused 2% of each active group and 3% of the placebo group to withdraw. The most common drug-related adverse event leading to study withdrawal was epistaxis (1 patient in the FP 200 g group, 2 patients in the FP 400 g group). Demographic characteristics for the total population, presented in Table 1, were similar among treatment groups. Patients ranged from 12 to 83 years old, 61 to 66% were females, and 93 to 96% were Caucasian. Duration of PNAR was similar in each treatment group with 23 to 26% having symptoms for 1 to 4 years and 32 to 35% having PNAR for ⬎15 years. Approximately 31 to 32% of patients had NARES and approximately 68 to 69% presented with non-NARES. Baseline TNSSs were similar among treatment groups in the total population and each subgroup, ranging from 191 to 204. Total Population All three treatment groups improved over time, demonstrating lower mean TNSS. The FP 200 g and FP 400 g groups showed nearly identical symptom improvement that was greater than placebo for all time periods. By the end of treatment (day 22 to 28), the mean change in TNSS for patients treated with FP 200 and FP 400 was ⫺84 and ⫺85, respectively. For patients treated with placebo, the mean change in TNSS was ⫺64. Both FP treatment groups showed significantly greater improvement in TNSS compared with placebo during each week of treatment (P ⱕ 0.002; Fig 1). There were no statistical differences between
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Patients enrolled Baseline TNSS day ⫺6-0 NonNARES Baseline TNSS day ⫺6-0 NARES Baseline TNSS day ⫺6-0 Age (year) Mean (SEM) Range % Male/% female Ethnic origin (% Caucasian) Duration of rhinitis (number, %) 1–4 years 5–9 years 10–14 years ⬎15 years
Placebo
Fluticasone propionate aqueous nasal spray (daily dosage) FP 200 g
FP 400 g
326 198 (2) 222 (68%) 199 (3) 104 (32%) 194 (5)
332 200 (3) 230 (69%) 204 (3) 102 (31%) 191 (5)
325 198 (2) 222 (68%) 198 (3) 103 (32%) 199 (5)
43 (0.8) 12–79 38/62 313 (96%)
42 (0.8) 12–83 39/61 310 (93%)
41 (0.8) 12–75 34/66 308 (95%)
84 (26%) 65 (20%) 63 (19%) 114 (35%)
77 (23%) 91 (27%) 57 (17%) 107 (32%)
85 (26%) 70 (22%) 63 (19%) 107 (33%)
Percentages may not add up to 100% because of rounding. Non-NARES patients showed no eosinophils in nasal mucosal specimens. TNSS values for Day ⫺6-0 represent rounded mean of daily scores for nasal obstruction, rhinorrhea, and postnasal drip for 7 days before randomization (maximum possible score of 300).
the two FP treatment groups at any time point. Non-NARES Subgroup Mean changes in TNSS for each treatment in the non-NARES subgroup were similar to those of the total population (Fig 2). During the last week of treatment (day 22 to 28) mean changes in TNSS were ⫺83 and ⫺80 in the FP 200 g and FP 400 g groups, respectively, as opposed to ⫺63 in the placebo group. NARES Subgroup Mean changes in TNSS in the NARES subgroup for the FP 200 g and placebo groups were similar to the total population during each week of treatment. Improvements in the FP 400 g group were greater in the NARES subgroup than in the total population. During the last week of treatment mean changes in TNSS (day 22 to 28) were ⫺86 and ⫺97 in the FP 200 g and FP 400 g groups, respectively, as opposed to ⫺66 in the placebo group (Fig 3). Figure 4 graphically presents the mean change from baseline in TNSS over days 22 to 28 for each subgroup
and clearly shows the similarity between each subgroup and the total population at the end of treatment. DISCUSSION This integrated analysis of data from three double-blind, placebo-controlled studies demonstrates the efficacy of FP in a clearly defined group of patients with nonallergic rhinitis without nasal eosinophilia (non-NARES). The purpose of this integrated analysis was to provide data for non-NARES patients, as there is a clinical impression that they are less responsive to intranasal corticosteroid therapy. In an evaluation of 142 patients with rhinitis, Mullarkey7 showed that patients with allergic rhinitis could be clearly separated from those with nonallergic rhinitis. Although studies have differed in the threshold of nasal eosinophilia used to classify patients as NARES, the prevalence of non-NARES patients generally has been higher than the prevalence of NARES. From our population of 983 patients with perennial symptoms but with negative skin test to all allergens relevant to the geographic re-
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gion, 69% of patients were classified as non-NARES. In the Mullarkey study7 of 73 patients with nonallergic rhinitis, 52 (71%) patients were classified as having vasomotor rhinitis (nonNARES). In the Moneret-Vautrin et al study,9 15 of 22 patients (68%) with vasomotor rhinitis were classified as non-NARES. As part of the Mullarkey study,7 the authors also examined efficacy of intranasal corticosteroids in patients with NARES defined as at least 25% eosinophils in nasal smears; 45% of patients with vasomotor rhinitis (non-NARES) and 93% of patients with NARES responded to therapy with an intranasal corticosteroid, with therapeutic response defined as complete symptom relief according to patient report. However, patients were treated initially with antihistamines and only patients with a history of therapeutic failure or intolerance with antihistamines or patients with severe congestion were given corticosteroids. The results of this integrated analysis showed that the PNAR patients treated with FP aqueous nasal spray at daily dosages of 200 and 400 g noted a reduction of nasal symptoms during the first week of treatment, exhibiting statistically significant decreases in TNSS compared with patients treated with placebo during each week of the 28-day treatment period. The broad efficacy of FP for a range of nasal symptoms in PNAR differentiates it from ipratropium bromide, which has been shown to improve rhinorrhea, but not other nasal symptoms, in PNAR.17 In the current study, the approved 200-g dose seemed to confer efficacy in relieving nasal symptoms comparable with that of the 400-g dose of FP. The lack of a strong relationship between intranasal corticosteroid dose and efficacy in PNAR has also been observed in studies with other corticosteroids, including intranasal budesonide18 and intranasal beclomethasone dipropionate.19 In addition to budesonide and beclomethasone dipropionate, the corticosteroid mometasone furoate has been evaluated for the treatment of PNAR. In a randomized, double-
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Figure 1. Patient-rated mean TNSSs in total population. Between-group comparisons were based on mean changes in TNSS from pretreatment. (* P ⱕ 0.002 vs placebo).
Figure 2. Patient-rated mean TNSSs for the non-NARES subgroup.
Figure 3. Patient-rated mean TNSSs for the NARES subgroup.
blind, placebo-controlled study, 20 mometasone 200 g, once daily, was not significantly more effective than placebo with respect to the pri-
mary efficacy endpoint of patients’ overall evaluation of rhinitis symptoms at the end of a 6-week treatment period.
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
degree of efficacy in patients with and without nasal eosinophilia. ACKNOWLEDGMENTS The data reviewed in this manuscript correspond with study protocol numbers FLTA3010, FLN350, and FLN351. We thank Kate Sanjar, Bethany A. Madison, and Cheryl Beale for scientific writing and management of this manuscript. REFERENCES Figure 4. Patient-rated mean TNSSs for the total population, non-NARES, and NARES subgroups during the last week of treatment (day 22 to 28).
Subgroup analyses showed that efficacy in the FP groups was demonstrated regardless of non-NARES or NARES patient classification. This finding corroborates and extends results of other studies that have shown intranasal corticosteroid therapy to be effective in patients with NARES.7,21 With few exceptions, the efficacy of medications in non-NARES patients has not been evaluated. Banov and Lieberman22 reported that the antihistamine nasal spray azelastine hydrochloride (1.1 mg daily for 21 days) significantly improved total vasomotor rhinitis symptom scores compared with placebo among patients who had both negative skin tests to allergens and negative nasal cytology examination for eosinophils at baseline. The degree to which azelastine improves nasal symptoms in NARES, however, has not been studied. In a small (n ⫽ 12), uncontrolled study, topical furosemide was found to reduce nasal resistance among subjects with perennial nonallergic rhinitis who had no evidence of eosinophils in nasal secretions.23 As opposed to our findings in non-NARES patients, Blom et al14 concluded that FP 200 g and FP 400 g daily did not significantly reduce nasal symptoms compared with placebo in a small study of 65 patients with severe PNAR in a tertiary referral population. There was, however, a statistically significant decrease in sneezing for the FP 400 g group. Although
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patients were not classified as NARES or non-NARES, the authors stated that eosinophilia was rarely present in nasal brush cytology performed after run-in. Different patient selection methods and study design may have accounted for the difference in results between the Blom et al study14 and our analysis. One major difference was that in the Blom et al study, patients were allowed to use an antihistamine as rescue medicine, which may have confounded the results through premature discontinuation of the study medication (ie, before patients reached the therapeutic endpoint). CONCLUSION This integrated analysis of data from three double-blind, placebo-controlled studies demonstrates the efficacy of an intranasal corticosteroid in a clearly defined group of patients with nonallergic rhinitis with and without nasal eosinophilia (NARES and non-NARES). Previously, there has been a clinical impression that intranasal corticosteroid therapy may not be as effective for symptom relief in patients with nonallergic rhinitis who do not demonstrate nasal eosinophilia. In fact, the results of this integrated analysis of data in these PNAR studies do not support that impression. Intranasal FP is significantly more effective than placebo in decreasing the severity of nasal symptoms associated with PNAR, and there is a similar
1. Dykewicz MS, Fineman S. Diagnosis and management of rhinitis: complete guidelines of the Joint Task Force on Practice Parameters in Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol 1998;81: 478 –518. 2. Jacobs RL, Freedman PM, Boswell RN. Nonallergic rhinitis with eosinophilia (NARES syndrome): clinical and immunologic presentation. J Allergy Clin Immunol 1981;67:253–262. 3. Mygind N, Dahl R, Pedersen S, Thestrup-Pedersen K. Perennial rhinitis. In: Instant Allergy. Oxford, England: Blackwell Science Ltd, 1997:92–97. 4. Zeiger RS. Allergic and nonallergic rhinitis: classification and pathogenesis: Part II. Nonallergic rhinitis. Am J Rhinol 1989;3:113–139. 5. Phillips DE, Jones AS, Hoffman J, Gilles J. Distribution of eosinophils in the nose in patients with perennial rhinitis. Clin Otolaryngol 1992;17:478 – 481. 6. Settipane GA, Klein DE. Non-allergic rhinitis: demography of eosinophils in nasal smear, blood total eosinophil counts and IgE levels. N Engl Reg Allergy Proc 1985;6:363–366. 7. Mullarkey MF. Eosinophilic nonallergic rhinitis. J Allergy Clin Immunol 1988;82:941–949. 8. Crobach M, Hermans J, Kaptein A, et al. Nasal smear eosinophilia for the diagnosis of allergic rhinitis and eosinophilic non-allergic rhinitis. Scand J Prim Health Care 1996;14:116 –121. 9. Moneret-Vautrin DA, Hsieh V, Wayoff M, et al. Nonallergic rhinitis with eosinophilia syndrome a precursor of the triad: nasal polyposis, intrinsic asthma, and intolerance to aspirin. Ann Allergy 1990;64:513–518. 10. Meltzer EO, Jalowayski AA, Orgel HA, Harris AG. Subjective and objective assessments in patients with seasonal allergic rhinitis: effects of ther-
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11. 12.
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apy with mometasone furoate nasal spray. J Allergy Clin Immunol 1998; 102:39 – 49. Settipane RA, Lieberman P. Update on nonallergic rhinitis. Ann Allergy Asthma Immunol 2001;86:494 –508. Mullarkey MF, Hill JS, Webb DR. Allergic and nonallergic rhinitis: their characterization with attention to the meaning of nasal eosinophilia. J Allergy Clin Immunol 1980;65:122–126. Small P, Black M, Frenkiel S. Effects of treatment with beclomethasone dipropionate in subpopulations of perennial rhinitis patients. J Allergy Clin Immunol 1982;70:178 –182. Blom HM, Godthelp T, Fokkens WJ, et al. The effect of nasal steroid aqueous spray on nasal complaint scores and cellular infiltrates in the nasal mucosa of patients with nonallergic, noninfectious perennial rhinitis. J Allergy Clin Immunol 1997;100:739 –747. Meltzer EO, Jalowayski AA. Nasal cytology in clinical practice. Am J Rhinol 1988;2:47–54.
16. Linder A. Symptom scores as measures of the severity of rhinitis. Clin Allergy 1988;18:29 –37. 17. Bronsky EA, Druce H, Findlay SR, et al. A clinical trial of ipratropium bromide nasal spray in patients with perennial nonallergic rhinitis. J Allergy Clin Immunol 1995;95:1117–1122. 18. Wight RG, Jones AS, Beckingham E, et al. A double blind comparison of intranasal budesonide 400 micrograms and 800 micrograms in perennial rhinitis. Clin Otolaryngol 1992;17: 354 –358. 19. Malm L, Wihl J. Intra-nasal beclomethasone dipropionate in vasomotor rhinitis. Acta Allergol 1976;31: 245–253. 20. Lundblad L, Sipila P, Farstad T, Drozdziewicz D. Mometasone furoate nasal spray in the treatment of perennial non-allergic rhinitis: a Nordic, multicenter, randomized, double-blind, placebo-controlled study. Acta Otolaryngol 2001;121:505–509. 21. Purello-D’Ambrosio F, Isola S, Ric-
ciardi L, et al. A controlled study on the effectiveness of loratadine in combination with flunisolide in the treatment of nonallergic rhinitis with eosinophilia (NARES). Clin Exp Allergy 1999;29:1143–1147. 22. Banov CH, Lieberman P. Efficacy of azelastine nasal spray in the treatment of vasomotor (perennial nonallergic) rhinitis. Ann Allergy Asthma Immunol 2001;86:28 –35. 23. Masiere S, Cavaliere F, Fillaci F. Nasal obstruction improvement induced by topical furosemide in subjects affected by perennial nonallergic rhinitis. Am J Rhinol 1997;11:443– 447.
Requests for reprints should be addressed to: D. Robert Webb, MD Allergy and Asthma Research Associates 12911 120th Avenue Northeast, Suite 260 Kirkland, Washington 98034 E-mail: [email protected]
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Background: Although response to intranasal corticosteroid therapy has been reported in patients with nonallergic rhinitis with eosinophilic syndrome (NARES), efficacy specifically in non-NARES patients has not been fully characterized. Objective: To evaluate the efficacy of intranasal fluticasone propionate (FP) in the treatment of patients with perennial nonallergic rhinitis, with and without nasal eosinophilia. Methods: Data from 983 patients in three randomized, double-blind, placebocontrolled PNAR trials were integrated. Patients received a total daily dose of FP 200 g (n ⫽ 332), FP 400 g (n ⫽ 325), or placebo (n ⫽ 326) for 28 days. Patients were ⱖ12 years of age with perennial rhinitis and negative skin tests to all allergens relevant to the geographic region. Nasal eosinophils were evaluated using a five-point scale. Patients were classified as non-NARES with a point score of 0 (n ⫽ 674; 69%); patients with a point score between 1 and 4 were classified as NARES (n ⫽ 309; 31%). Efficacy of FP was evaluated by the mean change in total nasal symptom score (TNSS), a sum of patient ratings of nasal obstruction, postnasal drip, and rhinorrhea. Results: Patients with either NARES or non-NARES had similar statistically significant improvement with FP 200 g or 400 g compared with placebo; thus, the total group comprising both varieties of rhinitis responded to FP. In the total population, both FP treatment groups showed significantly greater improvement in TNSS compared with placebo during each week of treatment (P ⱕ 0.002), with mean changes in TNSS for day 22 to day 28 ranging from ⫺84 and ⫺85 in the FP 200 g and FP 400 g groups, respectively, to ⫺64 in the placebo group. The three study treatment groups had similar proportions of non-NARES (68 to 69%) and NARES (31 to 32%) patients at baseline. In the non-NARES subgroup, mean changes in TNSS for each treatment group were similar to changes seen in the total population. In the NARES subgroup, mean changes in TNSS for the FP 200 g and placebo groups were similar to changes seen in the total population; mean change in TNSS for the FP 400 g group was somewhat greater than changes seen in the total population. Conclusions: Intranasal FP is an effective treatment for perennial nonallergic rhinitis with or without nasal eosinophilia (NARES or non-NARES). Ann Allergy Asthma Immunol 2002;88:385–390.
INTRODUCTION Perennial nonallergic rhinitis (PNAR) is characterized by sporadic or persis-
tent nasal symptoms for which an immunoglobulin E-mediated mechanism can not be demonstrated.1 Symptoms
* Allergy and Asthma Research Associates, Kirkland, Washington. † Allergy and Asthma Medical Group and Research Center, San Diego, California. ‡ Allergy and Asthma Centers of Charleston PA, Charleston, South Carolina. § GlaxoSmithKline, Research Triangle Park, North Carolina.
This study was supported in part by a grant from SmithKline Beecham Corporation doing business as GlaxoSmithKline, Research Triangle Park, NC. Presented in part at the Annual Meeting of the American College of Allergy, Asthma, and Immunology, Philadelphia, PA, November 6 –11, 1998. Received for publication August 21, 2001. Accepted for publication in revised form January 1, 2002.
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are often difficult to control with traditional rhinitis pharmacotherapy (eg, antihistamines, decongestants), perhaps because of the variety of triggers, many of which are difficult to avoid. Also, symptoms often persist without any identifiable trigger.2– 4 Cytologic examination shows that some of these patients have prominent nasal eosinophilia,5,6 although skin tests to allergens relevant to the geographic region are negative. These patients are sometimes referred to as having nonallergic rhinitis with eosinophilic syndrome (NARES).1,2 A majority of patients with PNAR do not have eosinophilia and can be regarded as non-NARES patients.7–9 The term vasomotor rhinitis is also used to designate nonNARES patients. Although some studies have shown that intranasal corticosteroids are particularly effective in the treatment of nonallergic rhinitis when nasal eosinophilia is present, the options in the treatment of non-NARES patients, those who have little or no eosinophilia in nasal smears, include either nonspecific, broad-based therapy aimed at multiple symptoms or, alternatively, therapy tailored to treat specific symptoms.7,10,11 Examples of broad-based therapy treatment include topical intranasal corticosteroids and topical antihistamines.10 Efficacy of intranasal corticosteroid therapy in non-NARES patients has not been clearly demonstrated. In the few studies that have been published evaluating the efficacy of intranasal corticosteroids in nonNARES patients, the numbers of patients have been small, or there have been confounding factors (eg, antihistamine rescue medication was al-
385
lowed) compromising definitive conclusions.11–14 Nonetheless, there is a clinical impression that intranasal corticosteroids are not as effective in non-NARES patients as in NARES patients.3,7 To further evaluate the efficacy of fluticasone propionate (FP) in PNAR and within the subgroups of PNAR patients with and without nasal eosinophilia, three randomized, double-blind, placebo-controlled efficacy studies were reviewed. Results from these three studies were integrated and subgroup analyses were conducted in NARES and nonNARES patients. METHODS Data from two multicenter (FLTA3010, FLN-351) and one single-center (FLN350), randomized, double-blind, doubledummy, placebo-controlled, parallel group clinical trials were integrated. Each study evaluated the efficacy of FP aqueous nasal spray at daily doses of 200 and 400 g compared with placebo in the treatment of PNAR. In each study, after giving informed consent, subjects 12 years of age or older with perennial rhinitis and a negative skin test to all allergens relevant to the geographic region participated in a 7-day screening period, during which time baseline severity of nasal symptoms was established. Patients with symptom severity of 150 (see total nasal symptom scoring below) on at least 4 of 7 days immediately preceding randomization were randomly assigned to 1 of the 3 treatment groups for 28 days of study medication in double-blind fashion. Study medication was administered each morning (8 AM) and evening (8 PM) as a divided dose. The placebo nasal spray was formulated as a vehicle without active ingredient; active and placebo formulations were indistinguishable in appearance, smell, and taste. Patients were not allowed to take other rhinitis medications (eg, antihistamines) during the study. Each study was conducted in the United States, institutional review boards approved all three protocols, and written informed consent was obtained from all patients. Nasal cytology was evaluated at screening and after 28 days of treat-
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ment for determination of nasal eosinophilia. Clinic personnel collected nasal mucosal specimens from each patient using the Rhino-probe (Arlington Scientific, Springville, UT). Nasal scraping specimens were obtained from the medial aspect of the inferior turbinate of each nostril and fixed according to a standard procedure.15 The relative numbers of eosinophils were evaluated using the following 5-point scale: 0 ⫽ none; 1 ⫽ few, scattered; 2 ⫽ moderate number; 3 ⫽ large clumps, not covering the field; and 4 ⫽ clumps cover the entire field. Patients without eosinophils had a point score of 0 ⫽ none and were classified as non-NARES. Patients with eosinophils had a point score between 1 ⫽ few, scattered and 4 ⫽ clumps covering the entire field and were classified as NARES. Symptom Severity Ratings Patients were evaluated in the clinic at the initial screening visit and after 2 weeks and 4 weeks of treatment. Throughout the studies, patients completed a diary card each evening on which they rated the severity of nasal obstruction, postnasal drip, and rhinorrhea throughout the day. The first posttreatment symptom severity rating was made on day 1 (PM rating), approximately 12 hours after the first dose of study medication. Patients evaluated symptom severity by using an unmarked visual analog scale16 to rate each symptom independently. The scale was a 100-mm line that represented a continuum from 0 (absent) to 100 (most severe). Clinicians measured the distance in millimeters between the left end of each bar, marked zero, and the vertical mark made on the scale by the patient; the number was recorded to represent severity of each of the symptoms. A total nasal symptom score (TNSS) was calculated by summing the individual scores for each of the symptoms evaluated at each time point. Only patients with a self-rated TNSS of 150 of 300 possible points for the combined scores for nasal obstruction, postnasal drip, and rhinorrhea (studies FLTA3010
and FLN-350) or 200 of 400 possible points for the combined scores for nasal obstruction, postnasal drip, rhinorrhea, and sneezing (study FLN-351) on at least 4 of 7 days immediately preceding the first day of double-blind treatment assignment were randomly assigned to treatment. For the purposes of the analysis presented in this paper, the TNSS was defined for all patients as the combined scores for nasal obstruction, postnasal drip, and rhinorrhea; the maximum possible TNSS was 300 points. Statistical Analysis The efficacy of each treatment in reducing nasal symptoms was evaluated by pooling the data from all three studies and comparing the mean change from baseline in the TNSS during each week of treatment among the three treatment groups. Baseline was defined as the mean TNSS for day ⫺6 to day 0. Hypothesis tests, as stated in the individual studies, were conducted using data from all patients exposed to study drug in each of the three studies (intent-to-treat population analysis). All tests were two-sided with statistical significance defined as P ⬍ 0.05. An analysis of covariance of the change from baseline was performed for each weekly interval (adjusting for investigator effect), followed by corresponding pairwise comparisons of treatment groups. Least squares means were used to compare all pairs of treatments. Subgroup Analysis Two subgroups of patients were formed (as described in the methods section) based on eosinophilic status (NARES and non-NARES). For each of the two subgroups the data from all three studies were pooled. Within each subgroup the mean change from baseline in the TNSS during each week of treatment among the three treatment groups was calculated. Qualitative comparisons were conducted to evaluate whether efficacy for each subgroup appeared similar to efficacy in the overall pooled analysis. In each of the three studies, the randomization did not stratify by the factor (NARES/nonNARES), and the power to detect dif-
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ferences was low for each subgroup. Thus, statistical testing within subgroups is not presented.
Table 1. Patient Characteristics
Characteristic
RESULTS Data from three PNAR studies were combined involving 983 patients treated with FP 200 g (n ⫽ 325), FP 400 g (n ⫽ 332), and placebo (n ⫽ 326). In all, 95% of patients completed the protocol-specified 28 days of treatment, with ⬍2% of any treatment group being withdrawn for lack of efficacy. An adverse event caused 2% of each active group and 3% of the placebo group to withdraw. The most common drug-related adverse event leading to study withdrawal was epistaxis (1 patient in the FP 200 g group, 2 patients in the FP 400 g group). Demographic characteristics for the total population, presented in Table 1, were similar among treatment groups. Patients ranged from 12 to 83 years old, 61 to 66% were females, and 93 to 96% were Caucasian. Duration of PNAR was similar in each treatment group with 23 to 26% having symptoms for 1 to 4 years and 32 to 35% having PNAR for ⬎15 years. Approximately 31 to 32% of patients had NARES and approximately 68 to 69% presented with non-NARES. Baseline TNSSs were similar among treatment groups in the total population and each subgroup, ranging from 191 to 204. Total Population All three treatment groups improved over time, demonstrating lower mean TNSS. The FP 200 g and FP 400 g groups showed nearly identical symptom improvement that was greater than placebo for all time periods. By the end of treatment (day 22 to 28), the mean change in TNSS for patients treated with FP 200 and FP 400 was ⫺84 and ⫺85, respectively. For patients treated with placebo, the mean change in TNSS was ⫺64. Both FP treatment groups showed significantly greater improvement in TNSS compared with placebo during each week of treatment (P ⱕ 0.002; Fig 1). There were no statistical differences between
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Patients enrolled Baseline TNSS day ⫺6-0 NonNARES Baseline TNSS day ⫺6-0 NARES Baseline TNSS day ⫺6-0 Age (year) Mean (SEM) Range % Male/% female Ethnic origin (% Caucasian) Duration of rhinitis (number, %) 1–4 years 5–9 years 10–14 years ⬎15 years
Placebo
Fluticasone propionate aqueous nasal spray (daily dosage) FP 200 g
FP 400 g
326 198 (2) 222 (68%) 199 (3) 104 (32%) 194 (5)
332 200 (3) 230 (69%) 204 (3) 102 (31%) 191 (5)
325 198 (2) 222 (68%) 198 (3) 103 (32%) 199 (5)
43 (0.8) 12–79 38/62 313 (96%)
42 (0.8) 12–83 39/61 310 (93%)
41 (0.8) 12–75 34/66 308 (95%)
84 (26%) 65 (20%) 63 (19%) 114 (35%)
77 (23%) 91 (27%) 57 (17%) 107 (32%)
85 (26%) 70 (22%) 63 (19%) 107 (33%)
Percentages may not add up to 100% because of rounding. Non-NARES patients showed no eosinophils in nasal mucosal specimens. TNSS values for Day ⫺6-0 represent rounded mean of daily scores for nasal obstruction, rhinorrhea, and postnasal drip for 7 days before randomization (maximum possible score of 300).
the two FP treatment groups at any time point. Non-NARES Subgroup Mean changes in TNSS for each treatment in the non-NARES subgroup were similar to those of the total population (Fig 2). During the last week of treatment (day 22 to 28) mean changes in TNSS were ⫺83 and ⫺80 in the FP 200 g and FP 400 g groups, respectively, as opposed to ⫺63 in the placebo group. NARES Subgroup Mean changes in TNSS in the NARES subgroup for the FP 200 g and placebo groups were similar to the total population during each week of treatment. Improvements in the FP 400 g group were greater in the NARES subgroup than in the total population. During the last week of treatment mean changes in TNSS (day 22 to 28) were ⫺86 and ⫺97 in the FP 200 g and FP 400 g groups, respectively, as opposed to ⫺66 in the placebo group (Fig 3). Figure 4 graphically presents the mean change from baseline in TNSS over days 22 to 28 for each subgroup
and clearly shows the similarity between each subgroup and the total population at the end of treatment. DISCUSSION This integrated analysis of data from three double-blind, placebo-controlled studies demonstrates the efficacy of FP in a clearly defined group of patients with nonallergic rhinitis without nasal eosinophilia (non-NARES). The purpose of this integrated analysis was to provide data for non-NARES patients, as there is a clinical impression that they are less responsive to intranasal corticosteroid therapy. In an evaluation of 142 patients with rhinitis, Mullarkey7 showed that patients with allergic rhinitis could be clearly separated from those with nonallergic rhinitis. Although studies have differed in the threshold of nasal eosinophilia used to classify patients as NARES, the prevalence of non-NARES patients generally has been higher than the prevalence of NARES. From our population of 983 patients with perennial symptoms but with negative skin test to all allergens relevant to the geographic re-
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gion, 69% of patients were classified as non-NARES. In the Mullarkey study7 of 73 patients with nonallergic rhinitis, 52 (71%) patients were classified as having vasomotor rhinitis (nonNARES). In the Moneret-Vautrin et al study,9 15 of 22 patients (68%) with vasomotor rhinitis were classified as non-NARES. As part of the Mullarkey study,7 the authors also examined efficacy of intranasal corticosteroids in patients with NARES defined as at least 25% eosinophils in nasal smears; 45% of patients with vasomotor rhinitis (non-NARES) and 93% of patients with NARES responded to therapy with an intranasal corticosteroid, with therapeutic response defined as complete symptom relief according to patient report. However, patients were treated initially with antihistamines and only patients with a history of therapeutic failure or intolerance with antihistamines or patients with severe congestion were given corticosteroids. The results of this integrated analysis showed that the PNAR patients treated with FP aqueous nasal spray at daily dosages of 200 and 400 g noted a reduction of nasal symptoms during the first week of treatment, exhibiting statistically significant decreases in TNSS compared with patients treated with placebo during each week of the 28-day treatment period. The broad efficacy of FP for a range of nasal symptoms in PNAR differentiates it from ipratropium bromide, which has been shown to improve rhinorrhea, but not other nasal symptoms, in PNAR.17 In the current study, the approved 200-g dose seemed to confer efficacy in relieving nasal symptoms comparable with that of the 400-g dose of FP. The lack of a strong relationship between intranasal corticosteroid dose and efficacy in PNAR has also been observed in studies with other corticosteroids, including intranasal budesonide18 and intranasal beclomethasone dipropionate.19 In addition to budesonide and beclomethasone dipropionate, the corticosteroid mometasone furoate has been evaluated for the treatment of PNAR. In a randomized, double-
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Figure 1. Patient-rated mean TNSSs in total population. Between-group comparisons were based on mean changes in TNSS from pretreatment. (* P ⱕ 0.002 vs placebo).
Figure 2. Patient-rated mean TNSSs for the non-NARES subgroup.
Figure 3. Patient-rated mean TNSSs for the NARES subgroup.
blind, placebo-controlled study, 20 mometasone 200 g, once daily, was not significantly more effective than placebo with respect to the pri-
mary efficacy endpoint of patients’ overall evaluation of rhinitis symptoms at the end of a 6-week treatment period.
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degree of efficacy in patients with and without nasal eosinophilia. ACKNOWLEDGMENTS The data reviewed in this manuscript correspond with study protocol numbers FLTA3010, FLN350, and FLN351. We thank Kate Sanjar, Bethany A. Madison, and Cheryl Beale for scientific writing and management of this manuscript. REFERENCES Figure 4. Patient-rated mean TNSSs for the total population, non-NARES, and NARES subgroups during the last week of treatment (day 22 to 28).
Subgroup analyses showed that efficacy in the FP groups was demonstrated regardless of non-NARES or NARES patient classification. This finding corroborates and extends results of other studies that have shown intranasal corticosteroid therapy to be effective in patients with NARES.7,21 With few exceptions, the efficacy of medications in non-NARES patients has not been evaluated. Banov and Lieberman22 reported that the antihistamine nasal spray azelastine hydrochloride (1.1 mg daily for 21 days) significantly improved total vasomotor rhinitis symptom scores compared with placebo among patients who had both negative skin tests to allergens and negative nasal cytology examination for eosinophils at baseline. The degree to which azelastine improves nasal symptoms in NARES, however, has not been studied. In a small (n ⫽ 12), uncontrolled study, topical furosemide was found to reduce nasal resistance among subjects with perennial nonallergic rhinitis who had no evidence of eosinophils in nasal secretions.23 As opposed to our findings in non-NARES patients, Blom et al14 concluded that FP 200 g and FP 400 g daily did not significantly reduce nasal symptoms compared with placebo in a small study of 65 patients with severe PNAR in a tertiary referral population. There was, however, a statistically significant decrease in sneezing for the FP 400 g group. Although
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patients were not classified as NARES or non-NARES, the authors stated that eosinophilia was rarely present in nasal brush cytology performed after run-in. Different patient selection methods and study design may have accounted for the difference in results between the Blom et al study14 and our analysis. One major difference was that in the Blom et al study, patients were allowed to use an antihistamine as rescue medicine, which may have confounded the results through premature discontinuation of the study medication (ie, before patients reached the therapeutic endpoint). CONCLUSION This integrated analysis of data from three double-blind, placebo-controlled studies demonstrates the efficacy of an intranasal corticosteroid in a clearly defined group of patients with nonallergic rhinitis with and without nasal eosinophilia (NARES and non-NARES). Previously, there has been a clinical impression that intranasal corticosteroid therapy may not be as effective for symptom relief in patients with nonallergic rhinitis who do not demonstrate nasal eosinophilia. In fact, the results of this integrated analysis of data in these PNAR studies do not support that impression. Intranasal FP is significantly more effective than placebo in decreasing the severity of nasal symptoms associated with PNAR, and there is a similar
1. Dykewicz MS, Fineman S. Diagnosis and management of rhinitis: complete guidelines of the Joint Task Force on Practice Parameters in Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol 1998;81: 478 –518. 2. Jacobs RL, Freedman PM, Boswell RN. Nonallergic rhinitis with eosinophilia (NARES syndrome): clinical and immunologic presentation. J Allergy Clin Immunol 1981;67:253–262. 3. Mygind N, Dahl R, Pedersen S, Thestrup-Pedersen K. Perennial rhinitis. In: Instant Allergy. Oxford, England: Blackwell Science Ltd, 1997:92–97. 4. Zeiger RS. Allergic and nonallergic rhinitis: classification and pathogenesis: Part II. Nonallergic rhinitis. Am J Rhinol 1989;3:113–139. 5. Phillips DE, Jones AS, Hoffman J, Gilles J. Distribution of eosinophils in the nose in patients with perennial rhinitis. Clin Otolaryngol 1992;17:478 – 481. 6. Settipane GA, Klein DE. Non-allergic rhinitis: demography of eosinophils in nasal smear, blood total eosinophil counts and IgE levels. N Engl Reg Allergy Proc 1985;6:363–366. 7. Mullarkey MF. Eosinophilic nonallergic rhinitis. J Allergy Clin Immunol 1988;82:941–949. 8. Crobach M, Hermans J, Kaptein A, et al. Nasal smear eosinophilia for the diagnosis of allergic rhinitis and eosinophilic non-allergic rhinitis. Scand J Prim Health Care 1996;14:116 –121. 9. Moneret-Vautrin DA, Hsieh V, Wayoff M, et al. Nonallergic rhinitis with eosinophilia syndrome a precursor of the triad: nasal polyposis, intrinsic asthma, and intolerance to aspirin. Ann Allergy 1990;64:513–518. 10. Meltzer EO, Jalowayski AA, Orgel HA, Harris AG. Subjective and objective assessments in patients with seasonal allergic rhinitis: effects of ther-
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16. Linder A. Symptom scores as measures of the severity of rhinitis. Clin Allergy 1988;18:29 –37. 17. Bronsky EA, Druce H, Findlay SR, et al. A clinical trial of ipratropium bromide nasal spray in patients with perennial nonallergic rhinitis. J Allergy Clin Immunol 1995;95:1117–1122. 18. Wight RG, Jones AS, Beckingham E, et al. A double blind comparison of intranasal budesonide 400 micrograms and 800 micrograms in perennial rhinitis. Clin Otolaryngol 1992;17: 354 –358. 19. Malm L, Wihl J. Intra-nasal beclomethasone dipropionate in vasomotor rhinitis. Acta Allergol 1976;31: 245–253. 20. Lundblad L, Sipila P, Farstad T, Drozdziewicz D. Mometasone furoate nasal spray in the treatment of perennial non-allergic rhinitis: a Nordic, multicenter, randomized, double-blind, placebo-controlled study. Acta Otolaryngol 2001;121:505–509. 21. Purello-D’Ambrosio F, Isola S, Ric-
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Requests for reprints should be addressed to: D. Robert Webb, MD Allergy and Asthma Research Associates 12911 120th Avenue Northeast, Suite 260 Kirkland, Washington 98034 E-mail: [email protected]
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