Absence of Nasal Mucosal Atrophy with Fluticasone Aqueous Nasal Spray
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ORIGINAL ARTICLE Absence of Nasal Mucosal Atrophy With Fluticasone Aqueous Nasal Spray Fuad M. Baroody, MD; Cheng-Chou Cheng, MD; Birgitta Moylan, BSc; Marcy deTineo, RN; Lauran Haney, BS; Kenneth D. Reed, BS; Cindy K. Cook, MS; Ronald E. Westlund, MS; Elizabeth Sengupta, MD; Jacquelynne P. Corey, MD; Alkis Togias, MD; Robert M. Naclerio, MD Objective: To evaluate whether 1 year of continuous larity of collagen fibrils as assessed by electron micros- treatment with intranasal fluticasone propionate would copy. Analyses were performed without knowledge of lead to atrophy in the nasal mucosa compared with an subject identity or treatment assignment. active control, oral terfenadine. Results: Neither fluticasone nor terfenadine treatment Design: Prospective, randomized, multicenter, open- led to atrophy in the nasal mucosa by clinical or histo- label, parallel-group study. logic observation. No significant changes from baseline were observed for any assessment of atrophy. In con- Setting: Two tertiary care academic institutions. trast to what would have been expected if atrophy were to occur, mean epithelial layer thickness in the flutica- Patients: Seventy-five subjects older than 18 years with sone group significantly increased compared with ter- perennial allergic rhinitis. fenadine treatment (P=.03). Interventions: Patients received either fluticasone pro- Conclusions: Treatment with intranasal fluticasone for pionate aqueous nasal spray, 200 µg once daily, or ter- 1 year increases the thickness of the nasal epithelium as fenadine, 60 mg twice daily, for 1 year. Nasal biopsy speci- compared with a year’s treatment with terfenadine and mens were obtained before and after 1 year of treatment does not lead to atrophy in the nasal mucosa. The in- and were evaluated for evidence of atrophy. creased thickness in the fluticasone treatment may rep- resent repair from epithelial damage caused by chronic Main Outcome Measures: Epithelial and collagen layer allergic inflammation. thickness of the nasal mucosa as assessed by light mi- croscopy and the presence and degree of edema, and regu- Arch Otolaryngol Head Neck Surg. 2001;127:193-199 LLERGIC RHINITIS affects been associated with substantial unto- more than 40 million ward adverse events.3 Intranasal cortico- Americans and costs soci- steroids exert a potent topical anti-in- ety more than $3 billion flammatory effect.3,5 They inhibit the each year.1 A major char- recruitment of inflammatory cells and From the Section of acteristic of allergic rhinitis is inflamma- prevent the release of inflammatory me- Otolaryngology–Head and A2 tion. The inflammatory process stimu- diators, resulting in a decrease in symp- Neck Surgery (Drs Baroody, lates the glands, blood vessels, and nerves toms and the blocking of both the early- Cheng, Corey, and Naclerio 3-6 and Mss deTineo and Haney) of the nasal mucosa, creating the symp- and late-phase allergic reactions. and the Department of toms of the disease. Whether this inflam- Appropriate treatment options must Pathology (Dr Sengupta), mation causes changes to matrix struc- be evaluated over the long term for po- Pritzker School of Medicine, tures, such as the epithelium, the basement tential adverse sequelae. This is particu- University of Chicago, Chicago, membrane, and the collagen matrix, is not larly true for patients with perennial Ill; Department of Medicine known. allergic rhinitis who may require long- (Division of Clinical Intranasal corticosteroids are among term treatment over several years to con- Immunology), The Johns the most commonly prescribed and effec- trol their disease. Long-term use of oral Hopkins University School of tive medications used to treat this dis- corticosteroids and topical dermatologic Medicine, Baltimore, Md 3,4 (Ms Moylan and Dr Togias); ease. The safety and efficacy of intrana- corticosteroids (ie, creams and oint- and Glaxo Wellcome Inc, sal corticosteroids have been well established ments) have been observed to lead to atro- 7-11 Research Triangle Park, NC in multiple clinical trials. Furthermore, the phic changes in the skin. Although there (Messrs Reed and Westlund widespread clinical use of these com- is no clinical or histologic evidence that and Ms Cook). pounds during the past 25 years has not intranasal corticosteroid treatment leads (REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 127, FEB 2001 WWW.ARCHOTO.COM 193 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 SUBJECTS AND METHODS tablet twice daily. At the time this study was conducted in the mid-1990s, terfenadine was a commonly prescribed medication for the treatment of allergic rhinitis and was SUBJECTS considered a suitable therapeutic alternative to intranasal corticosteroid therapy. Men and nonpregnant, nonlactating women 18 years of age The study consisted of a 21-day screening phase and or older were recruited from The Johns Hopkins Univer- a 12-month randomized, open-label treatment phase. Dur- sity Hospital, Baltimore, Md, and the University of Chi- ing the screening phase, eligibility for the study was con- cago Hospitals, Chicago, Ill, to participate in this study. All firmed and baseline rhinoscopy and nasal biopsy were per- subjects had to have a diagnosis of perennial allergic rhi- formed. After healing of the nasal biopsy site (approximately nitis and a skin test positive for dust mites. Eligible sub- 1 week later), subjects were randomly assigned to receive jects also had to have nasal symptoms for more than 1 hour 1 of the following study treatments for 1 year: intranasal per day on most days for which they used at least 1 anti- fluticasone propionate once daily (2 sprays of 50 µg per rhinitis medication during the 12 months before the study. spray in each nostril in the morning) or terfenadine, 60-mg Subjects with a marked ($50%) physical obstruction in the tablet orally twice daily. Subjects were allowed to take only nose, previous nasal septal surgery or perforation, or viral pseudoephedrine as needed for the relief of breakthrough or bacterial infection within 30 days of screening were ex- symptoms during the study and were allowed to take other cluded. Medications that could affect rhinitis symptoms or medications that did not interfere with allergic inflamma- allergic inflammation, such as topical and systemic gluco- tion, such as analgesics. Subjects returned to the clinic at corticoid therapy, intranasal cromolyn sodium, and anti- monthly intervals to reinforce medication adherence, re- histamines, were not permitted for at least 1 month before ceive additional medication, and assess their clinical sta- or during the study. None of the subjects was taking im- tus. After 12 months of treatment, another nasal biopsy munotherapy during the study, and those who had re- specimen was obtained from the opposite nostril to avoid ceived previous immunotherapy had to have stopped tak- the confounding effects of scar formation at the site of the ing it at least 2 years before participation. Before initiation first biopsy specimen. of the study, the protocol and informed consent docu- ment were reviewed and approved by the institutional re- NASAL BIOPSY view board governing research at each site. All subjects pro- vided written informed consent before participation. After local anesthesia was induced with 1% lidocaine hy- drochloride with epinephrine 1:100000, biopsy samples DESIGN were obtained with punch forceps from the anterior tip of the inferior turbinate by standard methods.12 This biopsy This was a randomized, open-label, parallel-group study site was selected because it is the expected site of drug im- in 75 subjects with perennial allergic rhinitis that com- pact with aqueous nasal spray medications and a major site pared the effects on the nasal mucosa of 1 year of treat- for allergen deposition. Each biopsy specimen was di- ment with fluticasone propionate aqueous nasal spray, 200 vided into sections to enable light and electron micro- µg once daily, vs an active control, oral terfenadine, 60-mg scopic evaluation of atrophy and labeled such that subject to atrophy of the nasal mucosa, we undertook this com- for attrition during the 12-month study period was that parative nasal biopsy study to investigate the effects of 2 subjects failed to return to the clinic. Four subjects were treatment options for allergic rhinitis. We compared the withdrawn from the study because of nonserious ad- structural characteristics of nasal mucosal biopsy speci- verse events: 3 in the fluticasone group (epistaxis, nasal mens from subjects allergic to dust mites who were treated dryness, and exacerbation of asthma) and 1 in the ter- with either fluticasone propionate aqueous nasal spray fenadine group (exacerbation of uveitis). The adverse or oral terfenadine, the active control. Nasal mucosal at- event profile was similar to that observed in previous stud- rophy was assessed qualitatively and quantitatively by ies. There were no serious or unusual events. means of light and electron microscopy. Thus, this study was designed to examine whether 1 year of treatment with BIOPSY RESULTS a topical corticosteroid (fluticasone) causes atrophic na- sal mucosal changes when compared with an oral anti- All evaluable nasal biopsy specimens from subjects with histamine (terfenadine). both baseline and study end biopsy samples were in- cluded in the analyses of atrophy (n=52). This included RESULTS samples from the 51 subjects who completed the study and 1 subject who was discontinued from the study af- SUBJECT DISPOSITION AND DEMOGRAPHICS ter 8 months of treatment because of relocation. As would be expected because of the location of the Seventy-five subjects (38 in the fluticasone group and 37 biopsy (anterior tip of the inferior turbinate), all speci- in the terfenadine group) were enrolled in the study mens but 1 had nonciliated squamous epithelium pres- (Table 2). The treatment groups were similar with re- ent at baseline. In 2 specimens, both respiratory and squa- spect to age, sex distribution, ethnic origin, and number mous epithelium were seen, and in 1 specimen, only of subjects withdrawn early.