As-needed use of fluticasone propionate nasal spray reduces symptoms of seasonal allergic rhinitis

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1 As-needed use of fluticasone propionate nasal spray reduces symptoms of seasonal allergic rhinitis Albert Jen, MD, Fuad Baroody, MD, Marcy detineo, BSN, Lauran Haney, BSc, Christopher Blair, BSc, and Robert Naclerio, MD Chicago, Ill Background: The daily use of intranasal corticosteroids is approved for the treatment of seasonal allergic rhinitis. Objective: Our objective was to test the effectiveness of asneeded use of intranasal corticosteroids in the treatment of seasonal allergic rhinitis. Methods: A double-blind, placebo-controlled, randomized, parallel-group study of the as-needed usage of fluticasone propionate nasal spray in the management of seasonal allergic rhinitis was performed. Outcome measures were symptom score, Rhinitis Quality of Life Questionnaire (RQLQ), and the number of eosinophils and the level of eosinophilic cationic protein (ECP) in nasal lavage. Results: Twenty-six subjects in each group completed the 4- week study. The median symptom score over the duration of the study in the placebo group was 8.5 versus 4.5 in the active group. The active group had significant improvement on the interim visit in the sleep, non-nose/eye, activities, nasal, practical, and overall domains (P <.05) of the RQLQ and on the final visit in the nasal symptom domain. The number of eosinophils was significantly lower in the active than in the placebo group at the final visit. Changes in ECP were not significant. Conclusion: As-needed fluticasone propionate nasal spray is efficacious in the treatment of seasonal allergic rhinitis. (J Allergy Clin Immunol 2000;105:732-8.) Key words: Allergic rhinitis, fluticasone propionate nasal spray, eosinophils, eosinophil cationic protein Allergic rhinitis affects about 20% of the US population, and its incidence is increasing. 1 The treatment of this common disease is increasingly being subjected to guidelines. For treatment purposes, allergic rhinitis is arbitrarily divided into categories of severity: mild, moderate, and severe. The distinction between mild and moderate disease probably resides in the need for daily medication (ie, mild disease requires as-needed treatment, From the Section of Otolaryngology Head and Neck Surgery, Department of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, Ill. Supported in part by grants No. DC and AI from the National Institutes of Health, Bethesda, Md, and by a grant from Glaxo Wellcome, Inc. Received for publication Aug 23, 1999; revised Dec 20, 1999; accepted for publication Dec 21, Reprint requests: Robert M. Naclerio, MD, Section of Otolaryngology Head and Neck Surgery, University of Chicago, 5841 S Maryland Ave, MC 1035, Chicago, IL Copyright 2000 by Mosby, Inc /2000 $ /1/ doi: /mai Abbreviations used ECP: Eosinophil cationic protein RQLQ: Rhinoconjunctivitis Quality of Life Questionnaire whereas moderate and severe disease require continuous, daily treatment). The typical guidelines recommend H 1 antihistamines for the first-line treatment of mild disease, whereas moderate to severe disease is usually treated first with intranasal corticosteroids. 2 The rationale for these recommendations is that H 1 antihistamines have a rapid onset of action (within hours) and are suitable for as-needed treatment, when the patient is seeking immediate relief of symptoms. Although intranasal corticosteroids have multiple positive actions in reducing allergic inflammation, they may take longer to work than do H 1 antihistamines, and the efficacy of their as-needed usage has not been well documented. Fluticasone propionate nasal spray, an intranasal corticosteroid, however, has been shown to have an onset of action within 12 hours, although its peak effect occurs after several days. 3 Most of the guidelines for the management of allergic rhinitis are evidence based; however, there is no study demonstrating the superiority of the as-needed use of H 1 antihistamines over the as-needed use of intranasal corticosteroids. We hypothesize that patients with mild allergic rhinitis treat themselves after symptoms develop. The symptoms relate primarily to the immediate response to pollen, with the cellular infiltration that develops after the immediate reaction priming the mucosa so that it becomes increasingly sensitive to the next antigen or nonantigenic exposure. 2 H 1 antihistamines are mainly effective for the early response, with little or no effect on the late inflammatory response. In essence, taking an H 1 antihistamine treats the next immediate response during the period of time that it remains effective. As the allergy season progresses, each exposure to allergen becomes more intense, and thus H 1 antihistamines become less effective. Intranasal corticosteroids, on the other hand, even if given after the immediate reaction, prevent inflammation from developing and thus prevent priming of the symptomatic response. 4 Therefore individuals treating themselves as needed with intranasal corticosteroids would be expected to have reduced symptoms throughout the season compared with placebo treatment, particularly as the season progresses. If our hypothesis is correct, then the guidelines for the management of aller-

2 J ALLERGY CLIN IMMUNOL VOLUME 105, NUMBER 4 Jen et al 733 gic rhinitis may be changed to the use of intranasal corticosteroids regularly for moderate-to-severe disease and as needed for mild disease. As a first step toward testing the above, we performed a parallel, placebo-controlled, randomized study to test whether symptoms of patients with seasonal allergic rhinitis are reduced by treatment with as-needed intranasal corticosteroids. The results of this study are presented. METHODS Study design We performed a double-blind, placebo-controlled, randomized, parallel study. We recruited 56 individuals with seasonal allergic rhinitis who were more than 18 years old and in excellent health. All subjects had a history of rhinitis during at least the last 2 ragweed seasons in Chicago and a positive puncture skin test to ragweed antigen extract. Patients were excluded if they had symptoms or physical signs suggestive of renal, hepatic, or cardiovascular disease. Patients with nasal polyps, displaced septum, or perennial rhinitis or asthma were excluded. Those who had used topical or systemic steroids, antihistamines, decongestants, or cromolyn in the preceding 2 weeks were excluded. Patients receiving immunotherapy in the last 2 years were excluded. Enrollment occurred during the ragweed pollen season. Women who were pregnant or lactating were excluded from the study. Written informed consent was obtained from all participants, and the study was approved by the Institutional Review Board of The University of Chicago. During their first visit to the nasal physiology laboratory, patients completed the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), which is a validated quality-of-life measure for patients with allergic rhinitis. 5 Subjects also had their noses lavaged with 10 ml of lactated Ringer s solution. We used the lavage to obtain a total eosinophil count and the level of eosinophil cationic protein (ECP). Each subject was given treatment and instructed in its usage. The bottles of fluticasone propionate nasal spray and placebo were indistinguishable and contained 25 ml, which is more than the prescription version. Patients enrolled before August 15 were instructed not to begin treatment or complete their diaries until that date. The subjects were randomized in blocks of 4 to receive fluticasone propionate nasal spray (100 µg per nostril daily) or placebo nasal spray daily as needed for 4 weeks during the ragweed season. If the patients had bothersome nasal symptoms, they were instructed to use two 50 µg sprays in each nostril no more often than once a day. If the patients continued to have significant problems, they were asked to see one of the physicians. No rescue medications were allowed. Patients kept a twice-daily symptom and medication diary during the season in which they recorded the severity, over 12 hours, of episodes of sneezing, rhinorrhea, itchy eyes, and nasal congestion as well as medication usage. The subjects returned in 2 weeks and underwent a nasal lavage and completed the RQLQ. Diaries were collected. The patients continued in the study and returned in 2 weeks for a final visit in which the nose was lavaged, an RQLQ was completed, and medications and diary cards were collected. Pollen counts Ragweed pollen counts for the Chicago area during the study were recorded by Grant Hospital Pulmonary Physiology Laboratory by use of the Rotorod method. Nasal lavage Five milliliters of warmed (37 C) lactated Ringer s solution was instilled into each nostril and, after 10 seconds, the subjects expelled the lavage fluid into a plastic collection vessel. All samples were first vigorously shaken for homogenization of the mixture of sol and gel phase and were stored on ice in plastic tubes until cell counts were performed. After the total cell count was obtained, the samples were centrifuged at 5000g for 15 minutes at 4 C. Aliquots for ECP determination were stored at 20 C until they were assayed. Eosinophil counts and cellular quantification in nasal lavage fluids Total counts of eosinophils recovered from lavage fluids were performed by use of a modification of our previously described method. 6 If sufficient cells were present on the slide, 200 cells were counted and a differential was obtained. When 200 cells could not be counted, as many cells as possible were examined for differential determination. If the total number of cells available for differential estimation was less than 50, the slide was considered technically inadequate for interpretation, and no value was available for analysis. If the slide had a sufficient number of cells to be examined but no eosinophils were counted among these cells, then 50 was assigned as the number of eosinophils because this was the lowest number of eosinophils obtained among all the technically adequate specimens. ECP ECP, a marker of eosinophil secretion, was measured by a double-antibody RIA obtained from Pharmacia AB, Uppsala, Sweden. The assay has a sensitivity of 2 µg/ml. Symptom diaries Each subject recorded symptom scores in a diary twice a day. Subjects reported sneezing and 3 symptom/symptom groups for each nostril: rhinorrhea, nasal congestion, and itchy eyes on a scale from 0 to 3 (0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms, and 3 = severe symptoms). Symptom scores were evaluated separately for each symptom category, and the total symptom score (the sum of individual symptoms) was also evaluated. Quality of life assessment Quality of life was assessed with the self-administered RQLQ as described and validated by Juniper and Guyatt. 5 In brief, the RQLQ has 7 domains: sleep, non-nose/eye symptoms, practical problems, nasal symptoms, eye symptoms, emotional, and activities. The average score for each domain was computed and used for data analysis. The overall quality of life is determined as the average of the 7 domains on the RQLQ. Higher scores indicate a worse quality of life. Statistical analysis Because the data were not normally distributed, nonparametric statistics were used for analysis. The primary variable analyzed was the symptom diary scores. The secondary variables were the RQLQ, ECP levels, total eosinophil counts, and individual symptom scores. The median total daily symptom scores were calculated by adding the individual scores together. The difference between the active and placebo groups was analyzed for each day of the study by a Mann-Whitney U test. The median total symptom score for all 28 days of treatment was also calculated and compared between the active and placebo groups by use of the Mann-Whitney U test. Other symptoms were analyzed similarly. When different time points within a group were analyzed and if repeated measures were being considered (eg, total eosinophils on 3 visits for the same treatment group), Friedman ANOVA was first performed, and if significant changes were detected post-hoc analysis was performed by use

3 734 Jen et al J ALLERGY CLIN IMMUNOL APRIL 2000 FIG 1. Ragweed counts and number of subjects enrolled for duration of study. The x axis represents various days during ragweed season, and y axis represents number of subjects enrolled on each specific day (diamonds) and the ragweed counts on those days (open bars). Levels of ragweed <40 grains/mm 3 (dashed line) are considered low. TABLE I. Demographics of study population of the Wilcoxon signed rank test. Data are presented as median and range. Two-tailed P <.05 was considered to indicate significance. RESULTS Active Placebo Age (y) 27.5 (18-48) 30 (19-44) Sex (male %) Race (white %) Skin test (wheal mm) Values are medians (range). The ragweed counts for the 1998 Chicago ragweed season are shown in Fig 1. The number of subjects enrolled in the study on a particular day is superimposed on this figure. The changing number of subjects reflects the varying days of entry of subjects into the study. Fifty-six subjects entered the study, and 2 patients from each treatment group dropped out before completing the protocol. One subject from each group failed to adhere to the study protocol and did not show up for follow-up visits, 1 subject from the placebo group was dropped because of intake of oral antihistamines, and 1 subject from the fluticasone propionate nasal spray group was found to have a positive urine pregnancy test after being randomized and dispensed study medication. She was immediately notified and was asked to withdraw from the study before taking any study medication. There were 26 subjects randomized to each arm of the study, and, because randomization was blocked in groups of 4, the number of subjects enrolled at any time point was divided equally between active and placebo treatment. The groups were matched for age, sex, race, and skin test sensitivity (Table I). Of the 28 days in which subjects were allowed to take their medication, the active group used medicine on 15.5 (1-27) days and the placebo group used the medicine on 14.5 (4-27) days. The primary variable was total symptoms. We analyzed the score on the basis of the day of enrollment instead of the calendar day. This permitted ease of matching. Analysis by calendar day, however, demonstrated similar results. Significant differences between the active and placebo groups in total symptom scores started to be evident after 5 days of treatment and remained significantly different at most time points until the 24th day of treatment, as seen in Fig 2. The median score for the placebo group over the duration of the study (28 days) was 8.5, whereas the score for the active group was 4.5; the difference was highly significant (P =.0001). The results for the individual symptoms were similar, with the active group reporting fewer symptoms than the placebo group (Table II). The RQLQ found that the groups were similar at entry into the study. The active group had significant improvement on the second visit in the sleep, nonnose/eye, activities, nasal, and practical domains and overall score (P <.05) (Fig 3). The active group also had a significant improvement in the nasal symptoms domain at the third visit. The number of eosinophils and the level of ECP were not different between the groups at entry. ANOVA for

4 J ALLERGY CLIN IMMUNOL VOLUME 105, NUMBER 4 Jen et al 735 FIG 2. Total symptom scores for duration of study. Median total symptom scores are shown for placebo (open circles) and fluticasone propionate nasal spray (closed circles) treatment groups. Asterisk, P <.05 versus placebo on days indicated. total eosinophils during the 3 visits for the patients receiving placebo demonstrated no significant overall difference between the 3 visits. When the data from the subjects receiving fluticasone propionate nasal spray were analyzed, ANOVA for total eosinophils during the 3 visits demonstrated a significant difference (P =.008). Post-hoc analysis showed that the subjects had fewer eosinophils during visit 3 compared with visits 1 and 2 (P =.008). When nonpaired analysis was performed for comparison of the number of total eosinophils at each visit between the 2 treatment groups, the group receiving fluticasone propionate nasal spray had significantly fewer eosinophils during their third and final visits compared with the group receiving placebo (P =.007) (Fig 4). Total eosinophils did not differ between the groups on visits 1 and 2. The ECP levels followed the same pattern, but the differences did not reach statistical significance (Fig 5). There was a significant correlation between the levels of ECP and the number of eosinophils (r s = 0.56, P <.0001). DISCUSSION Fluticasone propionate nasal spray and other intranasal corticosteroids have been shown to be effective drugs for the treatment of allergic rhinitis when used regularly. 7 Reported trials have consistently demonstrated efficacy compared with placebo or an active comparative. Fluticasone propionate nasal spray was initially thought to take days to achieve efficacy. In some recent clinical trials, however, fluticasone propionate nasal spray was seen to be more efficacious than placebo within 12 hours, although peak efficacy took several days to obtain. 3 Although instructed to use intranasal corticosteroids daily, most patients are probably not compliant. The asneeded usage of these agents has been studied to a limited extent. Juniper et al 8 compared regular and as-needed TABLE II. Individual nasal symptoms Statistical Active Placebo significance Sneezes 1 (0-2) 2 (1-3.5) P =.0001 Other 1 (0-2) 2 (0-3) P =.0001 Runny 1 (0-2) 2 (0-2.5) P =.0001 Stuffy 1.5 (0.5-2) 2 (1-3) P =.0001 Data are presented as medians (range). The medians of median total symptom scores over the 28 days of treatment with either placebo or fluticasone propionate nasal spray are presented. usage and found regular usage to be superior. In a more recent study in which a quality of life questionnaire was used, the differences between as-needed and regular use were statistically significant, but the authors did not find that the degree of improvement with regular use was clinically significant compared with as-needed use. 9 In neither of those studies was a placebo comparison included; thus we are not certain whether the as-needed use of intranasal corticosteroids is better than placebo treatment. We believe that our study is the first to demonstrate the efficacy of as-needed intranasal corticosteroid usage compared with as-needed placebo. We used multiple subjective and objective outcome parameters to support our conclusion. The difference on the RQLQ between the active and placebo groups would suggest clinical significance as opposed to mere statistical difference. 9 Our rationale for the efficacy of as-needed usage of fluticasone propionate nasal spray is not based on the vasoconstrictive activity of corticosteroids but rather on the reduction of the inflammation that follows antigen exposure. Vasoconstrictor assays in animals have been used for comparison of the potency of different corticosteroids. 10 In the nose studies evaluating the vasoconstrictor effects of corticosteroids on the nasal vasculature demonstrated no effect. 11 We did not evaluate the vasoconstrictive nasal response to the medications given in this study. Although the symptom of stuffy nose was

5 736 Jen et al J ALLERGY CLIN IMMUNOL APRIL 2000 FIG 3. Individual domains for RQLQ. Median responses at each visit (V) are shown for placebo group (open circles) and fluticasone propionate nasal spray group (closed circles). Asterisk, P <.005 versus placebo. affected by fluticasone propionate nasal spray, all other symptoms were also affected. Topical decongestants have been shown not to affect sneezing, rhinorrhea, and mediator release, thus suggesting that the mechanism of action of intranasal corticosteroids was not related solely to vasoconstrictor effects. 12 In nasal provocation studies antigen causes an immediate response, dominated by mast cell degranulation, followed by eosinophil infiltration and priming (increased responsiveness to antigen). The eosinophil infiltration and priming are inhibited by treatment with intranasal corticosteroids, whether given before or shortly after antigen provocation. 4 On the basis of observed patterns of use of antiallergy medications, we reasoned that patients would elect to take their medication after the antigen caused symptoms. In essence, patients chose to medicate after the immediate reaction and before the eosinophil infiltration and the changes in reactivity occurred, thus preventing the adverse effects of eosinophil infiltration on the nasal mucosa and the priming effects of chronic allergic inflammation. Thus, as the season progressed, subjects receiving fluticasone propionate nasal spray did not increase their reactivity to antigen and had fewer symptoms and a better quality of life on re-exposure to antigen than did the placebo group. The data we collected support this hypothesis. The

6 J ALLERGY CLIN IMMUNOL VOLUME 105, NUMBER 4 Jen et al 737 FIG 4. Total eosinophils in nasal lavage fluids during study. Median numbers obtained at each of 3 study visits are shown. Placebo group is depicted by open circles and fluticasone propionate nasal spray group by closed circles. Dagger, P =.008 versus visits 1 and 2 in fluticasone propionate nasal spray group; asterisk, P =.007 versus placebo on visit 3. FIG 5. Levels of ECP in nasal lavage fluids during study. Median levels obtained at each of 3 study visits are shown. Placebo group is depicted by open circles and fluticasone propionate nasal spray group by closed circles. There was no significant difference within or between groups. patients were matched at the start of the study regardless of the day of entry. As the season progressed, the number of eosinophils and the level of ECP in the fluticasone propionate nasal spray treated group tended to decrease. This decrease was accompanied by a decrease in symptoms and an improvement in the quality of life. Because half the patients were treated with placebo, there was concern that not providing rescue medication would significantly increase the dropout rate. However, there was a low dropout rate in both groups and no difference between them. Because the pollen counts vary daily, even patients treated with placebo will have some days of relief despite the absence of active medication. The placebo effect helps as well as consideration that the placebo maybe having some positive effect, although not as positive as the active medication. Similar low dropout rates in placebo groups were seen in a study done during the mountain cedar season. 13 The absence of rescue medication in our study design made the analysis simpler and the results more clear cut. Our data support the efficacy of fluticasone propionate nasal spray in the treatment of seasonal allergic rhinitis, even if it is used on an as-needed basis. The next step would be to compare the as-needed use of an intranasal corticosteroid to that of an H 1 antihistamine. REFERENCES 1. Evans R. Epidemiology and natural history of asthma, allergic rhinitis, and atopic dermatitis. In: Middleton E Jr, Reed C, Ellis E, et al, editors. Allergy: principles and practice. 4th ed. St Louis: Mosby Year Book; p Naclerio RM, Solomon W. Rhinitis and inhalant allergens. JAMA 1997;278:

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