Absence of Nasal Mucosal Atrophy with Fluticasone Aqueous Nasal Spray

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 represent 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 microscopy 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

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©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 (Ն50%) 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 provided 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 nasal 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 included 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. The most common reason respiratory epithelium was seen in the areas examined.

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 identity, treatment, and date of biopsy were not apparent magnification with a microscope with a computer- to those evaluating the specimens. Biopsy samples were pre- controlled stage (Axioplan; Zeiss Inc, Thornwood, NY) pared as follows: coupled to an image analysis program (Neurolucida; Mi- 1. Section 1 of the biopsy specimen was fixed in for- crobrightfield Inc, Colchester, Vt). The thickness of the col- malin, embedded in paraffin, sectioned into 5-µm sec- lagen layer was measured in micrometers at 5 points along tions, and stained with hematoxylin-eosin. These samples the specimen and that of the epithelium at 3 points along were evaluated by means of light microscopy. the specimen. The average value of these respective mea- 2. Section 2 of the biopsy specimen was fixed in 2.5% surements was used for analysis. glutaraldehyde in Millonig buffer (1.7% monobasic so- The presence of edema (presence of lucent spaces) and dium phosphate + 0.3% sodium hydroxide in distilled wa- regularity of collagen fibrils were graded on the scoring sys- ter with pH 7.3-7.4) at 4°C for 24 hours, then transferred tem described in Table 1. Micrographs representative of the and stored in Millonig buffer at 4°C until postfixing in 1% low and high ends of these scales are provided in Figure 2 osmium tetroxide, dehydrating, infiltrating, and embed- and Figure 3, respectively. Figure 2 shows the electron- ding in epoxy resin. The epoxy resin–embedded tissue was lucent spaces between the collagen fibrils. Figure 2A then sectioned into 50- to 70-nm sections, placed on cop- (ϫ15500) demonstrates the lack of lucent spaces (0 or none) per grids, and contrast stained with 1.5% uranyl acetate between the collagen fibrils, and Figure 2B (ϫ14500) dem- aqueous solution and Reynold lead citrate solution and ex- onstrates a large number of electron-lucent spaces (3 or amined by transmission electron microscopy (Philips CM- severe). Figures 3A and 3B show low (+1, least regular) and 10; Philips Inc, Mahway, NJ). high (+3, most regular) regularity, respectively, of collagen fibrils observed at ϫ11500 magnification. ASSESSMENT OF ATROPHY STATISTICAL ANALYSES Atrophy was assessed by means of 4 objective and quantitative measures based on light and transmission electron Atrophy of the nasal mucosa was assessed by the evalua- microscopy (Table 1). In addition, qualitative evaluation of epithelial and collagen layer thickness, presence of tions including the presence of squamous and respiratory edema (lucent spaces), and the regularity of collagen epithelium, elastin, basal lamina duplication, and colla- fibrils. Treatment groups were compared in data sets that gen type were performed with electron microscopy. Speci- included all subjects who had both baseline and end-of- mens were visualized at ϫ1000 to examine the epithe- treatment biopsy data available. Small sample size and lium and underlying stroma (Figure 1), ϫ8000 to evaluate distributional properties required that nonparametric sta- the superficial vessels, ϫ10000 for high-power views of the tistical tests be used for within- and between-treatment basal lamina and the epithelium, and ϫ14000 for evalua- comparisons for both light and electron microscopy data. tion of collagen. Prints at each of these magnifications were Two analyses were conducted: a main-effects analysis unidentified as to subject name and treatment received and using a Wilcoxon rank sum test and a rank analysis of were examined by 2 investigators (C.C.C. and E.S.). covariance. Within treatment group, changes from base- The thickness of the collagen and epithelium was mea- line to study end were also analyzed with a Wilcoxon sured in the hematoxylin-eosin–stained sections under ϫ400 signed rank test.

The nasal biopsy specimens taken at the end of the study baseline effects were included as a covariate in the model similarly included squamous epithelium, although 2 speci- (P=.03, rank analysis of covariance). This was a signifi- mens contained both respiratory and squamous epithe- cantly higher epithelial thickness at the end of treat- lial cells. At both baseline and study end, the collagen ment in the fluticasone group (35.17 µm) compared with was type I, basal lamina duplication was rare, and no elas- the terfenadine group (20.91 µm). tin fibers were seen, providing reassurance that severely Mean collagen layer thickness was not signifi- damaged nasal mucosa had not been observed. cantly different before or after 1 year’s treatment with Biopsy results for epithelial layer thickness, colla- either fluticasone (P=.68) or terfenadine (P=.47). At base- gen layer thickness, lucent spaces score, and regularity line, the mean collagen layer thickness was 11.45 µm in of collagen score are summarized in Table 3. At base- the fluticasone group and 11.71 µm in the terfenadine line, the mean epithelial layer thicknesses in the flutica- group. At study end, mean collagen layer thickness val- sone group (27.77 µm) and the terfenadine group (28.55 ues remained essentially unchanged (11.97 µm in the flu- µm) were not significantly different. After 1 year of treat- ticasone group and 12.46 µm in the terfenadine group). ment, the mean epithelial layer thickness had increased A lucent spaces score, graded on a 4-point scale of 0 to 35.17 µm (+7.40 µm) in the fluticasone group whereas (none), 1 (mild), 2 (moderate), and 3 (severe), was cre- it had decreased to 20.91 µm (−7.64 µm) in the terfena- ated to quantify the degree of tissue edema observed. The dine group. These changes did not represent a signifi- mean scores at baseline were similar: 1.19 for the flutica- cant change from baseline for either group as tested by sone group and 1.09 for the terfenadine group, indicating the Wilcoxon signed rank test (for fluticasone, P=.37; mild edema. No significant within– or between– for terfenadine, P=.23). However, when the treatment treatment group differences were observed after 1 year of groups were compared at study end, significant differ- treatment. The mean score at study end was essentially un- ences were observed for both the main-effects analysis changed for both treatment groups (1.05 for the flutica- based on the Wilcoxon rank sum test (P=.05) and when sone group and 1.14 for the terfenadine group).

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Expected Changes From Baseline if Measure of Atrophy Atrophy Occurred* How Measured Interpretation Epithelium layer thickness ↓ Thickness measured in micrometers at 3 points Decrease in thickness suggestive of (light microscopy) along specimen; mean value analyzed tissue atrophy Collagen layer thickness ↓ Thickness measured in micrometers at 5 points Decrease in thickness suggestive of (light microscopy) along specimen; mean value analyzed tissue atrophy Presence of edema ↑ 4-Point scale for lucent spaces: 0 (none), The higher the score, the more edema; (electron microscopy) 1 (mild), 2 (moderate), 3 (severe) suggestive of tissue damage Regularity of collagen fibrils ↑ 3-Point scale: +1 (least regular) to +3 (most Highest degree of regularity (+3) (electron microscopy) regular) indicated tissue damage

*Downward arrow indicates decreased; upward arrow, increased.

ment for 1 year. The presence of atrophy was primarily based on 4 objective evaluations, including epithelial and basement membrane (collagen layer) thicknesses, the degree of edema (lucent spaces), and the regularity of the collagen fibrils, as well as clinical observation of the nasal mucosa during the monthly visits. Our results showed that there was no evidence that treatment with fluticasone propionate aqueous nasal spray, 200 µg once daily, caused nasal mucosal atrophy as compared with oral terfenadine, the active control. None of the expected quantitative changes that could have indicated atrophy were observed, and qualitative assessments confirmed that elastin was not present, type I collagen was not replaced, and basal lamina duplication did not increase. Furthermore, clinical observations during the monthly visits showed no abnormalities on rhinoscopy. When the treatment groups were compared, no significant differences between treatment groups were observed with the exception of epithelial layer thickness, which showed a significant difference between treatments. The fluticasone group experienced a mean increase in the epithelial layer thickness at study end, while the terfenadine group experienced a mean decrease. This result, coupled with the qualitative assessments based on Figure 1. Low-power transmission electron micrograph of the nasal mucosa visualization of nasal mucosal tissue, suggests that the demonstrating, from top to bottom, the epithelium, collagen layer, lamina integrity of the nasal mucosa was not affected adversely propria, and the glandular layer (original magnification ϫ1200). during treatment with fluticasone in subjects with perennial allergic rhinitis. Furthermore, the increase in epi- The regularity of collagen was graded on a 3-point thelial thickness after fluticasone treatment may repre- scale of +1 (least regular) to +3 (most regular). The mean sent repair of epithelial damage associated with the chronic scores at baseline were not significantly different: 1.83 inflammation that is characteristic of perennial allergic for the fluticasone group and 1.75 for the terfenadine disease. group, indicating a midrange level of regularity. After 1 Our findings are consistent with the existing litera- year of treatment, the regularity scores increased slightly ture and confirm what has been the clinical experience in both groups (2.05 in the fluticasone group and 1.85 for decades, ie, that long-term use of intranasal cortico- in the terfenadine group). No significant within– steroid therapy does not lead to atrophy or other severe treatment group changes were observed, and no signifi- adverse sequelae in the nasal mucosa. Moreover, our study cant differences were observed when the treatment groups is the first, to our knowledge, to use objective and quan- were compared. titative assessment of the nasal mucosa by transmission electron microscopy and in which lack of change in these COMMENT objective criteria were used to conclude that fluticasone treatment did not have deleterious effects on the nasal The primary objective of this study was to evaluate the mucosa. Several other intranasal biopsy studies have simi- effect of fluticasone on the nasal mucosa and determine larly failed to find an atrophic effect of other intranasal whether atrophy would be observed after continuous treat- corticosteroids13-20 or fluticasone.21

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Figure 2. Transmission electron micrographs of the collagen layer showing the presence of electron-lucent spaces between the collagen fibrils. A, Lack of lucent spaces between the collagen fibrils, scored 0 (original magnification ϫ15500). B, Large number of electron-lucent spaces between the collagen fibrils, scored 3. The epithelium is seen above the collagen layer (original magnification ϫ14500).

A B

Figure 3. Transmission electron micrographs of the collagen layer (immediately beneath the epithelium) showing regularity of the collagen fibrils (original magnification ϫ11500). A, Low regularity, scored +1. B, High regularity, scored +3.

Among the findings of interest, Sørensen et al13 in changes of the surface epithelium by transmission elec- 1976 performed biopsies of polyps after treatment with tron microscopy. Quantitative data or controls were not beclomethasone dipropionate aerosol for 1 year and ob- presented. In 1977, Poytner14 observed that no mucosal served decreased interstitial fluid within the tissue by light atrophy occurred in patients treated with beclometha- microscopy. Furthermore, there were no consistent sone for 2.5 to 3.5 years. In 1978, Mygind et al15 re-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Minshall and colleagues20 evaluated nasal biopsy speci- Table 2. Subject Demographics and Disposition mens from an open study of 52 subjects with perennial rhinitis before and after 1 year of treatment with Fluticasone Terfenadine, mometasone furoate by light microscopy and compared Propionate, 60 mg 200 µg/d Twice Daily the results with those from 24 healthy subjects who (n = 38) (n = 37) underwent biopsy at baseline and after 1 year without Mean age (range), y 28.8 (20-58) 30.4 (19-61) treatment. They found no change in epithelial thickness, Sex, No. (%) no signs of atrophy, and a decrease in focal metaplasia. M 22 (58) 25 (68) In 1991, Orgel and colleagues19 evaluated 41 paired F 16 (42) 12 (32) nasal biopsy specimens from an open-label study of fluo- Ethnic origin, No. (%) cortin butyl. They reported no evidence of basement mem- White 31 (82) 32 (86) brane thinning and, similar to our findings, observed a Black 4 (11) 1 (3) Other 3 (7) 4 (11) tendency for improvement of the epithelium toward co- Completed study, No. (%) 25 (66) 26 (70) lumnar. The authors concluded that intranasal cortico- Withdrawn from study, No. (%) 13 (34) 11 (30) steroids improve epithelial injury secondary to chronic Adverse event 3 (8) 1 (3) inflammation. Failed to return 6 (16) 5 (14) Holm and colleagues21 performed a double-blind, pla- Lack of efficacy 0 2 (5) cebo-controlled biopsy study with fluticasone with the Other 4 (11) 3 (8) use of light microscopy in patients with perennial allergic rhinitis. Twenty-eight sets of paired biopsy data were able to be evaluated before and after 1 year of treatment. Table 3. Light and Electron Microscopic Evaluations of Atrophy No differences between the groups were observed before or after treatment. The biopsy site in the Holm et al Fluticasone Terfenadine, study (inferior edge of the inferior turbinate) differed from Propionate, 60 mg that in ours (anterior tip of the inferior turbinate) but 200 µg/d Twice Daily demonstrated that a year’s treatment with fluticasone did not alter the mucosa in the ciliated epithelium. No. of No. of Measure Patients Mean (SE) Patients Mean (SE) Skin atrophy from topically applied corticosteroids can be detected within time frames varying from 1 to 4 Epithelium layer 7-11 thickness, µm months of administration. Why the nasal mucosa acts Baseline 25 27.77 (4.97) 21 28.55 (4.27) differently from the skin is not known. There are sev- Study end 25 35.17 (5.14)* 21 20.91 (2.50) eral possible explanations. One explanation is that, while Collagen layer the nose contains only type I collagen, the skin contains thickness, µm elastin and type IV collagen. The latter elements may be Baseline 26 11.45 (0.58) 25 11.71 (0.82) more glucocorticoid sensitive. Another explanation may Study end 26 11.97 (0.84) 25 12.46 (0.87) Lucent spaces score relate to residence time of drug at the application site. Baseline 21 1.19 (0.15) 22 1.09 (0.13) With dermatologic preparations, the creams or oint- Study end 21 1.05 (0.18) 22 1.14 (0.17) ments are applied to a specific site and left in situ, some- Regularity of collagen times under occluded conditions, for up to 24 hours. With fibrils score an intranasal spray, drug is removed within a few hours Baseline 20 1.83 (0.16) 20 1.75 (0.14) from the airways by mucociliary transport. Study end 20 2.05 (0.14) 20 1.85 (0.11) An open-label study, although not generally opti- *Significant difference vs terfenadine ( PՅ.05). mal, was specifically selected as the design for this study. Any attempt to double-blind this study, given the differences in the formulations of the test medications (intra- ported that biopsy specimens of nasal polyps in patients nasal spray vs oral tablets), would have required a double- receiving beclomethasone treatment for 3 years showed dummy design that would have necessitated that all no changes in epithelial metaplasia or ciliary structure. In subjects take both oral medication and intranasal spray. 1982, Holopainen and colleagues16 performed biopsies in Although not expected to have detrimental effects on the 6 patients after 6 years of treatment with beclomethasone nasal mucosa, a placebo spray or the insertion of the de- and observed no evidence of atrophy. No quantitative data vice into the nostrils to deliver the nasal spray could po- were presented. In 1983, Knight and Kolin17 performed bi- tentially have confounded the biopsy data. To obviate this opsies in 9 patients with perennial rhinitis with or with- problem, all biopsy evaluations were performed by cli- out allergy after the patients had received beclometha- nicians who were otherwise uninvolved in the care of sub- sone for 48 weeks in an open, noncomparative study. They jects and who were blinded to the subject’s treatment and reported no evidence of atrophy or scarring as assessed by identity. This eliminated potential bias and ensured the light microscopy, but few details were presented. In 1988, validity of the nasal mucosa assessments, which were the Pipkorn et al18 reported on a multicenter, open longitu- primary safety assessments in this study. dinal study of 24 patients receiving budesonide. Biopsy This study was not designed to compare the effi- specimens obtained at entry and after 1 year (5 patients) cacy of these compounds in the treatment of allergic rhi- and between 2.5 and 5.5 years (5 patients) of use nitis. Fluticasone and terfenadine have been compared showed no significant change. In a more recent study, in well-controlled clinical trials by others.22-24 However,

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 subjects were examined in this study on a monthly basis University of Chicago, 5841 S Maryland Ave, MC1035, to demonstrate that therapeutic doses of both treatment Chicago, IL 60637 (e-mail: [email protected] .uchicago regimens were being taken by the subjects and to re- .edu). inforce medication adherence. During the study, the treatment groups experienced reductions from baseline in their REFERENCES rhinitis symptom scores as assessed by both clinicians

and subjects. Thus, it appeared from these assessments 1. Storms W, Meltzer EO, Nathan RA, Selner JC. The economic impact of allergic that study medication adherence was sufficient to de- rhinitis. J Allergy Clin Immunol. 1997;99(suppl):S820-S824. rive therapeutic benefit. 2. Naclerio RM. Allergic rhinitis. N Engl J Med. 1991;325:860-869. Study treatments were well tolerated during this year- 3. Mygind N. Glucocorticosteroids and rhinitis. Allergy. 1993;48:476-490. long study. The adverse event profile was similar be- 4. Siegel SC. Topical intranasal therapy in rhinitis. J Allergy Clin Immunol. 1988; 81:984-991. tween treatments and to that observed in numerous other 5. LaForce C. Use of nasal steroids in managing allergic rhinitis. J Allergy Clin Im- studies. No serious or unusual events were observed. Only munol. 1999;103(suppl 3, pt 2):S388-S394. 1 subject withdrew from the fluticasone group because 6. Pipkorn U, Proud D, Lichtenstein LM, Kagey-Sobotka A, Norman PS, Naclerio of localized bleeding. Whether this patient would have RM. Inhibition of mediator release in allergic rhinitis by pretreatment with topical glucocorticosteroids. N Engl J Med. 1987;316:1506-1510. shown changes on a nasal biopsy specimen consistent with 7. Jablonska S, Groniowska M, Dabrowski J. Comparative evaluation of skin mucosal damage is unknown. Our findings, however, sup- atrophy in man induced by topical corticoids. Br J Dermatol. 1979;100:193- port the clinical impression that, if patients are tolerat- 206. ing intranasal corticosteroids, they can safely continue 8. Wilson Jones E. Steroid atrophy—a histological appraisal. Dermatologica. 1976; them. It is therefore prudent to reinforce the clinical prac- 152(suppl 1):107-115. 9. Groniowska M, Dabrowski J, Maciejewski W, Walski M. Electron-microscopic tice of examining patients within 2 to 4 weeks of initia- evaluation of collagen fibrils after topical corticosteroid therapy. Dermatologica. tion of intranasal corticosteroid treatment with careful 1976;152(suppl):147-153. attention to the nasal mucosa. If bothersome bleeding is 10. Lehmann P, Zheng P, Lavker RM, Kligman AM. Corticosteroid atrophy in hu- reported by the subject and the nasal mucosa shows evi- man skin: a study by light, scanning and transmission electron microscopy. J Invest Dermatol. 1983;81:169-176. dence of injury, it is prudent to decrease the dose of ad- 11. Stevanovic DV. Corticosteroid-induced atrophy of the skin with telangiectasia. ministered corticosteroids or even discontinue them. Br J Dermatol. 1972;87:548-566. The results of this study show that the use of intra- 12. Lee BJ, Naclerio RM, Bochner BS, Taylor RM, Lim MC, Baroody FM. Nasal chal- nasal fluticasone propionate aqueous nasal spray, 200 µg lenge with allergen upregulates the local expression of vascular endothelial ad- once daily for 1 year, does not lead to atrophy in the na- hesion molecules. J Allergy Clin Immunol. 1994;94:1006-1016. 13. Sørensen H, Mygind N, Pedersen CB, Prytz S. Long-term treatment of nasal pol- sal mucosa. Conversely, this study shows that treat- yps with beclomethasone dipropionate aerosol, III: morphological studies and ment with fluticasone leads to a significant increase in conclusions. Acta Otolaryngol. 1976;82:260-262. epithelial thickness compared with the posttreatment epi- 14. Poynter D. Beclomethasone dipropionate aerosol and nasal mucosa. Br J Clin thelial thickness in the terfenadine-treated group. This Pharmacol. 1977;4(suppl 3):295S-301S. 15. Mygind N, Sorensen H, Pedersen CB. The nasal mucosa during long-term treat- suggests a positive effect of intranasal fluticasone on the ment with beclomethasone dipropionate aerosol: a light- and scanning electron nasal epithelium. Our study has extended the previous microscopic study of nasal polyps. Acta Otolaryngol. 1978;85:437-443. work of others with nasal biopsy by using quantitative 16. Holopainen E, Malmberg H, Binder E. Long-term follow-up of intranasal beclo- objective measures of atrophy from light and electron mi- methasone treatment: a clinical and histologic study. Acta Otolaryngol Suppl. croscopy in a larger number of subjects and comparing 1982;386:270-273. 17. Knight A, Kolin A. Long term efficacy and safety of beclomethasone dipropio- the results with those of biopsy specimens from sub- nate aerosol in perennial rhinitis. Ann Allergy. 1983;50:81-84. jects using a suitable therapeutic alternative. In compi- 18. Pipkorn U, Pukander J, Suonpa¨a¨J,Ma¨kinen J, Lindqvist N. Long-term safety of lation, these studies all speak to the lack of histologic dam- budesonide nasal aerosol: a 5.5-year follow-up study. Clin Allergy. 1988;18:253- age induced by intranasal corticosteroids. 259. 19. Orgel HA, Meltzer EO, Beirman CW, et al. Intranasal fluocortin butyl in patients In summary, our study should make clinicians feel with perennial rhinitis: a 12-month efficacy and safety study including nasal bi- more secure in their use of intranasal corticosteroids to opsy. J Allergy Clin Immunol. 1991;88:257-264. treat allergic rhinitis. Using light and electron micros- 20. Minshall E, Ghaffar O, Cameron L, et al. Assessment by nasal biopsy of long- copy, we performed a detailed and controlled investiga- term use of mometasone furoate aqueous nasal spray (Nasonex) in the tion of the nasal mucosa and found no evidence of struc- treatment of perennial rhinitis. Otolaryngol Head Neck Surg. 1998;118:648- 654. tural damage after 1 year of use. Combining these 21. Holm AF, Fokkens WJ, Godthelp T, Mulder PG, Vroom TM, Rijntjes E. A 1-year observations with the established efficacy of intranasal placebo-controlled study of intranasal fluticasone propionate aqueous nasal spray corticosteroids in treating nasal symptoms argues that they in patients with perennial allergic rhinitis: a safety and biopsy study. Clin Oto- should be a first-line treatment in patients with peren- laryngol. 1998;23:69-73. 22. Bronsky EA, Dockhorn RJ, Meltzer EO, et al. Fluticasone propionate aqueous na- nial allergic rhinitis. sal spray compared with terfenadine tablets in the treatment of seasonal allergic rhinitis. J Allergy Clin Immunol. 1996;97:915-921. Accepted for publication July 31, 2000. 23. van Bavel J, Findlay SR, Hampel FC Jr, Martin BG, Ratner P, Field E. Intranasal This study was supported in part by grants AI45583 fluticasone propionate is more effective than terfenadine tablets for seasonal al- and DC02714 from the National Institutes of Health, lergic rhinitis [published correction appears in Arch Intern Med. 1995;155:276]. Bethesda, Md, and a grant-in-aid from Glaxo Wellcome Arch Intern Med. 1994;154:2699-2704. 24. Darnell R, Pecoud A, Richards DH. A double-blind comparison of fluticasone pro- Inc, Research Triangle Park, NC. pionate aqueous nasal spray, terfenadine tablets and placebo in the treatment of Corresponding author and reprints: Fuad M. Baroody, patients with seasonal allergic rhinitis to grass pollen. Clin Exp Allergy. 1994; MD, Section of Otolaryngology–Head and Neck Surgery, 24:1144-1150.

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