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(Chest. 2004;126:1123-1133.)
© 2004 American College of Chest Physicians

Skin Manifestations of Inhaled Corticosteroids in COPD Patients*

Results From Lung Health Study II

Donald P. Tashkin, MD, FCCP; H. Eileen Murray, MD; Melissa Skeans, MS and Robert P. Murray, PhD; for the Lung Health Study Research Group{dagger}

* From the Department of Pulmonary and Critical Care Medicine (Dr. Tashkin), David Geffen School of Medicine at UCLA, Los Angeles, CA; the Departments of Dermatology, Pediatrics and Child Health (Dr. H.E. Murray) and Community Health Sciences (Dr. R.P. Murray), University of Manitoba, Winnipeg, MB, Canada; and the Division of Biostatistics (Ms. Skeans), University of Minnesota, Minneapolis, MN. {dagger} A list of the principal investigators and senior staff of the clinical and coordinating centers of the Lung Health Study Research Group, the National Heart, Lung, and Blood Institute, and members of the Safety and Data Monitoring Board are listed in the Appendix.

Correspondence to: Donald P. Tashkin, MD, FCCP, Department of Medicine, David Geffen School of Medicine at UCLA, 10833 LeConte Ave, Los Angeles, CA 90095-1690; e-mail: dtashkin{at}mednet.ucla.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
 References
 
Objective: To define the relationship between skin bruising (as well as other cutaneous manifestations) and inhaled corticosteroid (ICS) therapy vs placebo in subjects with COPD who were participating in a clinical trial. To explore the relationship between easy skin bruising and other systemic effects of ICS therapy, including adrenal suppression and loss of bone mineral density (BMD).

Design: Double-blind, randomized, placebo-controlled clinical trial of triamcinolone acetonide (1200 µg daily) vs placebo in participants with mild-to-moderate COPD.

Setting: Lung Health Study II, a clinical trial to assess the effect of ICS compared to placebo in 1,116 participants in 10 centers over > 3.5 to 4.5 years.

Participants: A total of 1,116 smokers or recent ex-smokers with mild-to-moderate COPD (age range, 40 to 69 years; mean age, 56.3 years; 37.2% female).

Measurements and results: Every 6 months, a structured questionnaire was administered to elicit reports of any bruising and/or skin rashes, slow healing of cuts or sores, or other skin changes. Compliance with inhaler use was assessed by canister weighing. A significantly higher proportion of ICS than placebo participants who complied with using their inhaler reported easy bruising (11.2% vs 3.5%, respectively) and the slow healing of skin cuts or sores (2.4% vs 0.5%, respectively). Older men in the ICS group with good inhaler compliance appeared to be at the greatest risk of bruising. In those participants undergoing serial measurements of adrenal function and BMD, no association was noted between skin bruising and either the suppression of adrenal function or the loss of BMD as systemic complications of ICS use.

Conclusion: These findings indicate that moderate-to-high doses of ICSs result in an increased incidence of easy bruising and impairment in skin healing in middle-aged to elderly persons with COPD. No association was noted between skin bruising and other markers of systemic toxicity from the use of ICSs.

Key Words: COPD • inhaled corticosteroids • rash • skin bruising • slow healing


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Appendix
 References
 
Inhaled corticosteroids (ICSs) are generally recommended as first-line controller agents for the management of persistent asthma1 and also have been investigated in several large-scale randomized, controlled clinical trials for their possible efficacy in stable COPD patients, with partially favorable results in some studies,23456 but not all.7 Because of their proven efficacy in asthma and their suspected benefits with regard to symptom improvement and reduced frequency of exacerbations in COPD patients, although not with respect to FEV1 decline with age, these agents are increasingly used in the management of COPD. Regular treatment with ICSs has recently been recommended8 as appropriate treatment for symptomatic COPD patients with severe-to-very severe COPD with repeated exacerbations. Enthusiasm for the use of ICSs in treating these diseases is tempered, however, by concern regarding potential systemic toxicity, including such side effects as reduced rate of bone growth in children, reduced bone mass, cataracts, and open-angle glaucoma.9 While the suppression of the hypothalamic-pituitary-adrenal (HPA) axis, as indicated by very sensitive tests, is a commonly recognized effect of ICSs,9 this effect is thought to be rarely of clinical significance, although it can serve as a marker of systemic absorption and thus potential systemic toxicity. Since the systemic effects of ICSs appear to be dose-dependent,9 the availability and increasing use of high doses of potent ICSs add to the concerns regarding systemic toxicity.

Easy skin bruising is a well-recognized systemic side effect of ICS therapy, particularly when administered in high doses101112 and to older individuals.1112 Skin bruising also has been found to be associated with impairment in adrenal function12 and thus, apart from any annoyance it may cause from the cosmetic standpoint, it too could serve as an easily identifiable marker of systemic absorption. Older persons have an increased risk of skin bruising due to age-related dermal thinning.13 The increasingly widespread use of ICS therapy in COPD patients makes it likely that easy bruising will become an even more commonly encountered side effect of ICSs, especially with the high doses often prescribed for persons with COPD.14

A few randomized, placebo-controlled clinical trials in persons with COPD have systematically evaluated the frequency of bruising as a complication of moderate-to-high doses of ICSs.3615 However, these relied mainly on nondirected complaints regarding adverse events or direct observation of large ecchymotic areas (ie, > 5 cm) on the forearm only and may therefore have underestimated the true frequency of bruising in the study population. Moreover, potentially important cofactors that might be associated with bruising, such as age, gender, and compliance with ICS therapy, have not been analyzed in these studies. Furthermore, few studies have examined the impact of ICS therapy on other skin manifestations, such as skin healing, acne,16 and rash, which are known to be affected by systemic steroids.17

Lung Health Study (LHS) II was a 4.5-year (November 1994 to April 1999) placebo-controlled clinical trial of the possible benefit of ICSs in slowing the rate of decline in FEV1 in 1,116 continuing smokers and recent ex-smokers who had participated in or been screened for LHS I, an early intervention study in 5,887 smokers aged 35 to 60 years with mild-to-moderate COPD.18 Findings from LHS II4 failed to show an impact of ICSs (triamcinolone, acetonide [TAA] 600 µg bid) on FEV1 decline but did demonstrate modest benefits in terms of symptom improvement and a reduction in the frequency of acute exacerbations. On the other hand, while no statistically significant effects were noted on basal or stimulated serum cortisol levels,19 at 3 years following drug assignment, bone mineral density (BMD) declined more in participants receiving the ICS than in those assigned to receive placebo.4

This report describes the relationship between bruising (as reported in response to a structured questionnaire) and assignment to ICS therapy vs placebo therapy in both well-compliant and poorly compliant participants, and analyzes this relationship in participants who have been stratified by gender and age. Significant effects were noted on the frequency of bruising at most time points during this 4.5-year study, especially in participants who are compliant with the use of their assigned medication, as determined by canister weighing. The association between ICS therapy and other skin manifestations that have been historically reported with systemic steroid therapy is also examined. In addition, the relationship between the presence or absence of easy bruising and other systemic effects, namely, measures of HPA axis suppression and change in BMD, was explored in the subset of LHS II participants in whom these measures were obtained.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Appendix
 References
 
Study Sample
LHS II recruited 1,116 participants at 10 clinical centers in the United States and Canada.4 These were individuals who participated in LHS I (1,018 persons) or were screened for LHS I (98 persons),18 and were still smoking or had recently quit (< 2 years). Enrollment took place from November 1994 to November 1995. Other inclusion criteria were age between 40 and 69 years, and the presence of airflow obstruction (FEV1/FVC ratio, < 0.70; FEV1, between 30% and 90% of predicted normal values). Participants were excluded from the study if they had used ICSs or oral corticosteroids within 6 months, or if they had a medical condition that might interfere with participation in the trial. No participants reported using prescribed oral anticoagulants at baseline. Baseline characteristics were determined prior to randomization. Participants were randomized with equal probability to receive either TAA (six puffs bid [1,200 µg per day]), or a placebo of identical appearance. Participants and study staff were unaware of the study drug assignments. The methods and detailed entry criteria have been described elsewhere.4

Inhaler Compliance
Participants returned every 3 months to obtain new inhalers and to report respiratory symptoms or potential side effects. Compliance with the inhaled study drug was measured at each 3-month visit by questioning the participants and by weighing returned canisters, as previously described.4 Canisters were weighed before being dispensed and when they were returned using the same digital electronic scale. The weight difference divided by the number of days between canister issue and canister return was used to calculate mean daily usage. At 6-month intervals, inhaler technique was observed and counseling was provided to improve inhaler technique or compliance, as necessary.

Assessment of Skin Changes
Every 6 months, beginning at the 18-month or 24-month visit, participants were administered a structured questionnaire in which they were asked whether, since their last clinic visit, they had experienced any skin rashes (and the percentage of time any skin rashes were present), any bruises on their skin more often than in previous years, and more dry skin than usual (a "dummy" question used to identify non-steroid-related positive responders). If they reported bruises they were queried as to the percentage of time the bruising had been present, the number of bruises that were usually present at one time, the usual location of the bruises, and the occurrence of trauma as a possible cause of the bruising. They were also questioned with regard to exposure to the sun and the wearing of sunscreen. Every 3 months, beginning at the 3-month visit, participants reported changes in their skin since the last clinic visit, including skin rashes, easy bruising, acne, slow healing of cuts or sores, or any other skin changes. Furthermore, they were asked to grade the severity of their skin changes, as follows: 0, not present; 1, mild (present and noticeable or annoying but does not interfere with normal activities); 2, moderate (interferes with normal activities or requires an outpatient visit to a physician, clinic, or emergency department); or 3, severe (prevents normal activities, requires major medical/surgical intervention or hospitalization, or is life-threatening). The participants were followed from randomization to a common ending date (April 30, 1999) 4.5 years after the initiation of the trial.

Statistical Analysis
LHS II randomized 1,116 participants. Data from the structured skin questionnaire were available on 1,086 participants. All analyses, including baseline characteristics, are limited to this slightly smaller cohort.

Differences in baseline characteristics between the ICS and placebo groups were assessed using t tests for continuous variables and {chi}2 tests for categoric variables. Differences in the rates of new or worsening skin conditions were compared using the Wilcoxon rank-sum test.

The probabilities of reporting bruising or slow healing at some time during the study were analyzed according to the intention-to-treat principle. A logistic regression model was fit to assess the effect of treatment assignment on the probability of participants reporting bruising, adjusted for baseline age, gender, and interaction terms. Significant two-way and three-way interactions were present, which prevented reporting odds ratios of the covariates, and thus parameter estimates and p values are presented. Similar analyses were used for slow healing, although fewer covariates were entered into the final analysis. We also examined the effect of treatment on bruising and slow healing by compliance group.

Differences in the proportions of participants reporting any bruising or reporting bruising ≥ 25% of the time between treatment groups and compliance categories were assessed using {chi}2 tests. Good and poor compliance categories were defined by an average use of six puffs or more per day and less than six puffs per day, respectively, based on canister weights. Differences in the proportion of participants reporting bruising among those who experienced large declines in BMD were assessed using Fisher exact test.

A p value of < 0.05 was considered to be statistically significant. The reported p values are two-sided, and the p values for comparisons of treatment groups have not been adjusted for multiple comparisons.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Appendix
 References
 
Table 1 shows the baseline characteristics of the study sample. A more detailed description has been published elsewhere.4 The TAA and placebo groups appear to be well-balanced following randomization, and no statistically significant differences were noted between the two groups in any of the listed baseline characteristics.


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  		Table 1. Selected Baseline Characteristics of the 1,116 Study Participants*

 
The adverse skin conditions that are well-recognized to result from or be associated with systemic corticosteroid use are listed in Table 2 . Among these, rash, easy bruising, and slow healing differ between the groups, suggesting some systemic absorption. The reports of rash, however, are significantly higher in the placebo group. Also in Table 2 are the reports of mild adverse skin conditions from the subsample of participants who were considered good compliers with their prescribed inhaler (at least 6 puffs per day of a recommended 12 puffs per day). In this subsample, only reports of easy bruising and slow healing differed significantly between the treatment groups. In the subsequent analysis, only easy bruising and slow healing were considered.


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  		Table 2. Reports of Adverse Skin Conditions per 100 Person-Years by Randomized Group Assignment*

 
Easy Bruising
Data on participants who described any bruising are shown in Figure 1 by treatment group and compliance with the study drug, as measured by canister weights, at the semi-annual visits between months 24 and 42. Because relatively few questionnaires were administered at both the 18-month and 48-month visits, data from these visits are not shown. The percentages of participants in the ICS and placebo groups who were classified as good compliers were 54.7% and 59.6%, respectively. The percentages of participants in the placebo group reporting any bruising was uniformly around 10% at all visits shown, and no significant differences were noted between the poor compliers and good compliers. In contrast, the percentage of good compliers in the ICS group reporting one or more bruises was close to 20% at all visits, while the percentage of poor compliers assigned to receive ICSs who reported bruising was generally about half that of the good compliers who were assigned to receive the active study drug and was similar to the percentage of placebo-assigned participants with reported bruising, irrespective of compliance. The differences between reports of bruising by the ICS group who complied with their medication and all other subgroups from 24 to 42 months was highly significant (p < 0.002).



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  		Figure 1. Percentage of participants who reported one or more bruises by drug treatment assignment and compliance. Values above the bars represent the number of participants who reported bruising. Differences between ICS, 6+ puffs per day, and all other subgroups were highly significant (p < 0.002). PLA = placebo.

 
The percentages of participants reporting bruises ≥ 25% of the time are shown in Figure 2 . Again, clear and significant (p < 0.05) differences are found between the good compliers in the ICS group and all of the other subgroups, with > 10% of the former and only approximately 5% of the latter reporting bruises ≥ 25% of the time. Findings were roughly comparable across the visits from 24 to 42 months.



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  		Figure 2. Percentage of participants reporting bruises ≥ 25% of the time by drug treatment assignment and compliance. Values above the bars represent the number of participants reporting bruising ≥ 25% of the time. Differences between ICS, 6+ puffs per day, and all other subgroups were statistically significant (p < 0.05). See the legend of Figure 1 for abbreviation not used in the text.

 
Table 3 shows the parameter estimates and corresponding p values for predictor variables from multiple logistic regression of any bruising reported during the study for all participants, as well as for participants stratified by good and poor compliance. The results indicate a strong treatment effect, mainly among the good compliers. Older age and female gender are also significant predictors in all participants and among good compliers, but not among poor compliers. Similar results were obtained when the dependent variable was any new or worsening bruising.


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  		Table 3. Predictors of Any Bruising Reported During the Study Among All Participants and Among Participants With Good or Poor Inhaler Compliance (Logistic Regression)*

 
Table 4 shows the percentage of participants reporting bruising at any visit by age, gender, and drug group for all participants, and for more compliant participants (ie, six or more puffs per day) and less compliant participants (ie, fewer than six puffs per day). The median age of the study population (56 years) was used as the dividing point between older and younger subjects in post hoc stratified analyses. Among all participants and those with either good or poor compliance, a significantly higher proportion of older men (ie, ≥ 56 years of age) in the ICS group reported bruising, compared to those assigned to placebo. No differences were noted between younger men or older women in the ICS group vs the PLA group. Young compliant women showed a trend toward a treatment effect on bruising (p < 0.08 [{chi}2 test]). Comparing the data in Table 4, we note that compliant subjects, particularly older women, reported much higher rates of bruising than noncompliant women, even in the placebo group. We are unable to explain this by-compliance difference in reported bruising among placebo-treated subjects and cannot exclude the possibility that this difference could reflect a differential recall bias in answering the questionnaire that, in turn, might have impacted the incidence of reported bruising.


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  		Table 4. Percentage of Participants Reporting Bruising at Any Visit By Age, Gender, and Drug Group*

 
Slow Healing
Table 5 shows the results from logistic regression of reports of slow healing of any severity. The results indicate a significant treatment effect, mainly among the good compliers. Older age is also a significant predictor in all participants with a trend toward significance among the good compliers, but not among the poor compliers.


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  		Table 5. Predictors of Slow Healing

 
Table 6 shows the percentage of participants reporting slow healing at any visit by age, compliance, and drug group. Among older participants, a significantly higher proportion of compliant individuals in the ICS group than in the placebo group reported slow healing (4.3-fold higher proportion; p < 0.005). A similar but nonsignificant trend toward a treatment effect was noted in the compliant younger participants (2.6-fold higher proportion in the ICS group than in the placebo group; p < 0.09). No differences in the proportion of noncompliant participants reporting slow healing were noted between treatment groups in either age category.


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  		Table 6. Percentage of Participants Reporting Slow Healing at Any Visit By Age, Compliance, and Drug Group*

 
Correlation Between Reported Bruising and Impairment in Adrenal Function and Reduction in BMD
In an ancillary study19 to LHS II involving a subset of 221 participants in 5 of the 10 centers, the HPA axis was evaluated at baseline, year 1, and year 3. The development of significantly impaired adrenal function was rare (1.8%),19 and no consistent or meaningful differences were noted between the presence or absence of bruising vs change in basal or stimulated morning serum cortisol level, irrespective of whether analyses were performed in all participants or were restricted to only the good compliers.

In another LHS II ancillary study,4 BMD of the femoral neck and the lumbar spine was measured by dual-energy radiograph absorptiometry in a subset of 412 participants (ICS group, 201 participants; placebo group, 211 participants) at baseline and after 1 year and 3 years of treatment. In addition, the serum osteocalcin level was measured at baseline, 3 months, 1 year, and 3 years. After 3 years of treatment, BMD was lower in the ICS group than in the placebo group at both the hip and lumbar spine.4 Osteocalcin levels were also reduced to a greater extent in the ICS group than in the placebo group at 3 months (p = 0.001) and 1 year (p < 0.04) [PD Scanlon, MD; personal communication; September 3, 1999). Thirty-one participants in the ICS group (18%) and 13 participants in the placebo group (7%) had a ≥ 6% decrease in femoral neck BMD compared with baseline, while 14 participants in the ICS group (9%) and 9 participants in the placebo group (6%) had a ≥ 6% decrease in lumbar spine BMD between baseline and year 3. Among participants who experienced ≥ 6% declines in BMD of either the femoral neck or the lumbar spine, the proportion reporting bruising was not significantly different in the ICS group vs the placebo group, irrespective of inhaler compliance. Furthermore, no relationship was found between reported bruising and changes in BMD, either among all participants or in good compliers only.

Easy Bruising and Acetylsalicylic Acid/Nonsteroidal Anti-inflammatory Drug Use
Use of acetylsalicylic acid (ASA) or nonsteroidal anti-inflammatory drugs (NSAIDs) was reported by a slightly but significantly higher proportion of participants who also reported bruising (87.7%) than those who did not (78.8%; p = 0.001 [{chi}2 test]). On the other hand, a higher proportion of those assigned to receive placebo than to receive TAA reported using ASA or NSAIDs, making it unlikely that ASA/NSAID use contributed to the association between ICS use and bruising.

Solar Exposure
The cumulative amount of sun exposure is believed to be an important cofactor in the occurrence of skin bruising.20 However, differences in either total or mean sun exposure, at least over the course of LHS II, were not found to be significant predictors of bruising in LHS II participants, irrespective of drug assignment or compliance.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Appendix
 References
 
The main intention-to-treat findings from LHS II regarding cutaneous manifestations of ICS use in COPD patients were an increased incidence of easy bruising and impairment in skin healing ("slow healing") in those participants assigned to inhaled TAA, 1,200 µg daily, compared to those receiving the placebo preparation. The excess occurrence of these adverse skin events among participants assigned to the active ICS preparation was noted in those who used at least half (ie, ≥ 600 µg) the recommended daily dose of 1,200 µg TAA, but not in those who either did not use their assigned inhaler or used lower average doses than 600 µg per day, implying a dose-response relationship. It is also of interest that assignment to receive TAA was associated with a significant reduction in reported "rash" in all participants, an association that was of borderline significance among the participants who were good compliers. Since it is well-recognized that the use of systemic corticosteroids predisposes a person to easy bruising and slow skin healing, while ameliorating the inflammatory component of skin eruptions, these findings, taken together, provide strong support for the occurrence of the systemic absorption of inhaled TAA in middle-aged to older persons with COPD to a degree sufficient to exert a clinically apparent systemic effect.

The relevance of these findings to potential cutaneous effects of other commonly used ICSs might be inferred from published data21 concerning the equisystemic effects (ie, microgram dose producing equal systemic cortisol suppression) of six inhaled corticosteroid preparations. According to the latter report, TAA produces a systemic effect (10% cortisol suppression) that is equivalent to 1.43 times the microgram dose of beclomethasone chlorofluorocarbon (CFC). By comparison, flunisolide CFC, fluticasone dry powder inhaler, budesonide dry powder inhaler, and fluticasone metered-dose inhaler CFC produce systemic effects equivalent to that of 1.71, 0.81, 0.50, and 0.20 times the microgram dose of beclomethasone CFC, respectively.

Previous cross-sectional studies12 in relatively small numbers of patients with respiratory disease (mainly asthma) using ICSs have reported a higher prevalence of easy bruising (range, 47 to 71%) in the ICS users compared to control subjects (range, 12 to 32%),101112 with the prevalence being higher when based on questionnaire responses than on direct examination. In one study, skin thickness was assessed by pulsed ultrasound and was found to be significantly less than that of control subjects in patients treated with high-dose ICSs (ie, ≥ 1,000 µg beclomethasone) but not in those treated with low doses (ie, ≤ 800 µg beclomethasone).10 In these studies, the frequency of easy bruising was particularly increased in those receiving higher daily doses of ICSs (ie, ≥ 1,000 to 1,388 µg beclomethasone dipropionate)1011 and in older individuals,1112 while the influence of gender was inconsistent.1112 Moreover, one of these studies indicated that adrenal function was significantly lower in those reporting bruising,12 and, while abnormally reduced adrenal function occurred less commonly (14%) than reported skin bruising (71%), adrenal impairment was found only in those who reported bruising.12 These findings suggest that skin bruising, a readily visible side effect, may be a more sensitive marker of the systemic toxicity of ICSs than reduced adrenal function.

Weaknesses of the above-cited older studies are that they were cross-sectional, nonrandomized surveys and that they relied on retrospective reporting of previous, as well as current, ICS use. Moreover, some subjects had received oral corticosteroids in variable amounts at least in short courses, potentially contributing to the occurrence of cutaneous as well as other systemic side effects. More recently, the incidence of skin bruising has been examined in three large-scale, prospective, 2.5-year to 3-year, randomized controlled clinical trials of high-dose ICSs in the management of stable patients with COPD3615 (Table 7 ). Bruising was assessed either by subjective self-reports of side effects3 or by the direct observation of ecchymotic areas > 5 cm2 in size on the volar side of the forearm.615 In two of these clinical trials, the proportion of subjects in whom bruising was found was numerically but not significantly higher in the ICS group than the placebo group (7.3% vs 4%, respectively, in one study;3 and 7% vs 6%, respectively, in the other study6). In the third trial,15 the highest prevalence of bruises at any visit was significantly higher in the ICS arm than in the placebo arm (4.9% vs 1.4%, respectively). The reason for the marked disparity between the relatively low incidence of bruising in these randomized prospective trials among COPD patients receiving ICSs and the much higher prevalence of easy bruising noted in the earlier cross-sectional, retrospective studies in mostly asthmatic patients on ICS therapy is not clear. This disparity might be related to differences in the study design and reliance, in the COPD trials, on relatively insensitive indicators of bruising, such as nondirected reports of any side effects (as opposed to questionnaires focused more specifically on purpura) and physical assessment of the presence or absence of large ecchymotic areas in only a limited anatomic location. Although the development of bruising secondary to ICS therapy appears to be related to both dose and age, these factors were roughly comparable across the different studies. Although the underlying diagnosis was generally different in the earlier studies compared to the more recent studies (asthma vs COPD, respectively), it does not appear likely that differences in diagnosis would account for the disparity in the incidence of bruising. Moreover, the ages of the subjects in the different studies were generally comparable (mean age in all studies, sixth decade), although fewer women were included in the COPD trials (25 to 36%) than in the earlier studies in mainly asthmatic subjects (42 to 66%).


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  		Table 7. Incidence of Skin Bruising Reported in Randomized Controlled Clinical Trials of ICS in COPD*

 
In the present report, easy bruising averaged 7.6% in the ICS group and 3.6% in the placebo group among all participants. These findings are roughly similar to those reported from previously published randomized controlled trials of ICS in COPD patients,3615 in which the findings were not adjusted for compliance with the study drug. When results from the present study were stratified based on measured inhaler compliance, we observed that, among those who complied well with the use of their assigned inhaler, a larger proportion of the ICS group reported easy bruising (11.2%) than those of the placebo group (3.5%). Thus, the incidence of reported bruising was 3.2-fold higher in the ICS group than the placebo group when only good compliers are considered, as opposed to a 2.1-fold difference when all participants were included in the analysis. Failure to control for the effect of compliance, therefore, results in a substantial underestimate of the effect of ICS use on bruising.

In addition to drug assignment and compliance, we observed that age and gender also predicted the occurrence of bruising among all participants and among good compliers (Table 3), but not among the poor compliers. Older men who were assigned to receive ICSs, in comparison to those assigned to placebo, were particularly likely to report easy bruising, especially if they were compliant with their assigned drug treatment. However, in general, women tended to report more bruising than men, irrespective of ICS use (Table 4). Previous findings that skin thickness decreases with age and is lower in women than in men1013 are consistent with these observations. Moreover, similar findings with respect to age have been reported previously,1112 although the effect of gender has been inconsistent, with one study12 reporting that being a woman markedly increased the risk of skin bruising (odds ratio, 22; 95% confidence interval [CI], 7 to 75), while another study11 observed that men taking ICSs had a higher relative risk (RR) for bruising than women (men: RR, 5.80; 95% CI, 2.4 to 14.1; women: RR, 1.80; 95% CI, 1.3 to 2.4).

In the subset of 221 LHS II participants in whom HPA axis function was assessed, almost none of the participants in the ICS group who reported skin changes developed HPA axis suppression. Moreover, similar basal and stimulated serum cortisol levels at years 1 and 3 were observed among the good compliers in the ICS group, regardless of whether they did or did not report skin bruising. Consequently, in contrast to the findings of Roy et al,12 in the present study, no association was noted between reduced adrenal function and skin bruising. Similarly, in the present analysis of data concerning bruising among participants in the ancillary study of BMD,4 we could find no evidence of an association between BMD loss and easy bruising as a systemic complication of ICS use.

While impaired wound healing is a well-known complication of systemic corticosteroid use, the slow healing of skin lesions ("cuts and sores") has not been reported previously among the complications associated with high-dose ICSs.92223242526 The observation of a significant association between assignment to receive inhaled TAA and the reported slow healing of skin lesions, especially among participants with good inhaler compliance, is a novel finding of the present study. Unlike easy skin bruising, which is a side effect of mainly cosmetic concern, the impaired healing of cutaneous wounds may have greater clinical significance as a systemic complication of ICS use, for example, possibly predisposing the patient to infection. In addition, the slow healing of skin wounds suggests the possibility of impairment in the repair of lesions involving other tissues in addition to skin.

The one side effect that was reported more frequently in the placebo group than in the TAA group was described as "rash" (Table 2). This apparently reversed direction of difference may be related to the widely known effect of corticosteroids in reducing the acuity of many forms of rash except acne. In the present study, the systemic bioavailability of inhaled TAA may, in effect, be preventing skin rash, thus lowering its incidence. On the other hand, we did not observe an effect of TAA on reported acne (Table 2), possibly due to the older age range of participants (40 to 69 years of age at enrollment).

A limitation of the present study was the reliance on a questionnaire to determine the incidence of skin changes, since the accuracy of self-reported bruising and slow skin healing could be affected by difficulties in recall using a questionnaire that was administered at 6-month intervals. On the other hand, it does not seem likely that the accuracy of recall would be affected differentially by assignment to receive ICS vs placebo. While other methods of assessment, such as objective examination of the skin by the investigator, might be more accurate, it is noteworthy that the prevalence of skin bruising reported by Mak et al11 was actually higher when based on responses to a questionnaire (71%) compared to direct examination of the skin (48%) in a study of asthmatic subjects treated with high doses of an ICS. Another limitation of our study was that we did not seek to determine other historical factors, such as engaging in physical activities with a high risk of trauma, that could have predisposed our subjects to skin bruising. However, such unstudied factors are unlikely to have significantly confounded our results since they would likely be distributed more or less equally between the two randomly allocated groups. Finally, we did not collect complete data on concomitant medications, such as ASA/NSAIDS, that might have predisposed subjects to easy bruising. Therefore, we cannot rule out a potentially confounding effect of such concurrent medications if there was an imbalance between the two groups in the use of these drugs.

In summary, among 1,116 middle-aged and older participants with COPD assigned to either moderately high doses of an ICS (TAA, 1,200 µg per day) or placebo, we found that a significantly higher proportion of those in the ICS group than in the placebo group reported easy skin bruising over the course of the 3.5 to 4.5 years of the study, especially among those who complied well with using their assigned inhaler (11.2% vs 3.5%, respectively). Older age and female gender, in addition to ICS assignment and inhaler compliance, were significant predictors of the occurrence of bruising, while the effect of ICS use on easy bruising appeared to be greatest in older men who demonstrated good inhaler compliance. The slow healing of skin cuts or sores was also significantly associated with ICS use, being reported by 2.3% and 0.5%, respectively, of the participants in the ICS and placebo groups, among those who complied well with use of their study medication. In contrast, rash was reported by slightly fewer of the ICS group participants than the placebo participants (5.0% vs 6.4%, respectively; p = 0.05), consistent with a systemic effect of ICSs on skin inflammation. These cutaneous effects of ICSs represent easily discernible and potentially useful markers of systemic toxicity due to systemic absorption of the drug. The frequency of easy bruising as a complication of ICS use exceeds that of other markers of systemic toxicity, including clinically significant suppression of adrenal function and excessive annual loss of BMD. No association was noted between bruising and either the suppression of adrenal function or the loss of BMD as systemic complications of ICS use. Taken together, these findings lend support to the view that moderate-to-high doses of ICSs may produce significant systemic adverse effects in a minority of users and may reinforce concerns regarding more serious systemic toxicity than that confined to the skin. At least with respect to a cutaneous manifestation of ICS use, older individuals appear to have a greater risk than younger persons in general, and women have greater risk than men in general, whereas older men seem to be at the greatest risk.


   Appendix
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
References
 
Principal Investigators and Senior Staff of the Clinical and Coordinating Centers of the Lung Health Study Research Group, the National Heart, Lung, and Blood Institute, and Members of the Safety and Data Monitoring Board
Case Western Reserve University (Cleveland, OH)
M.D. Altose, MD (Principal Investigator); S. Redline, MD (Co-Principal Investigator); C.D. Deitz, PhD; and K.J. Quinlan.

Henry Ford Hospital (Detroit, MI)
M.S. Eichenhorn, MD (Principal Investigator); W.A. Conway, Jr., MD (Co-Principal Investigator); R.L. Jentons, MA; K. Braden; and M. Ketchum.

Johns Hopkins University School of Medicine (Baltimore, MD)
R.A. Wise, MD (Principal Investigator); S. Permutt, MD (Co-Principal Investigator); C.S. Rand, PhD (Co-Principal Investigator); M. Daniel; V. Santopietro; and K. Schiller, PhD.

Mayo Clinic (Rochester, MN)
P.D. Scanlon, MD (Principal Investigator); A.M. Patel, MD (Co-Principal Investigator); J.P. Utz, MD (Co-Principal Investigator); D.E. Williams, MD (Co-Principal Investigator); G.M. Caron; K.S. Mieras; and L. Walters.

Oregon Health Sciences University (Portland, OR)
A.S. Buist, MD (Principal Investigator); L.R. Johnson, PhD (Lung Health Study Pulmonary Function Coordinator); V.J. Bortz; S.L. Persons; and H.A. Schueler.

University of Alabama at Birmingham (Birmingham, AL)
W.C. Bailey, MD (Principal Investigator); C.M. Brooks, EdD (Co-Principal Investigator); L.B. Gerald, PhD, MSPH; and L. Montiel.

University of California, Los Angeles (Los Angeles, CA)
D.P. Tashkin, MD (Principal Investigator); A.H. Coulson, PhD (Co-Principal Investigator); E.C. Kleerup, MD (Co-Principal Investigator); V.C. Li, PhD, MPH (Co-Principal Investigator); M.A. Nides, PhD; I.P. Zuniga; and Y.E. Lee.

University of Manitoba (Winnipeg, MB, Canada)
N.R. Anthonisen, MD (Principal Investigator, Steering Committee Chair); J. Manfreda, MD (Co-Principal Investigator); R.P. Murray, PhD (Co-Principal Investigator); S.C. Rempel-Rossum; and J.M. Stoyko.

University of Minnesota Coordinating Center (Minneapolis, MN)
J.E. Connett, PhD (Principal Investigator); M.O. Kjelsberg, PhD (Co-Principal Investigator); M.T. Bollenbeck, MS; K.J. Kurnow, MS; T.C. Madhok, PhD; M.A. Skeans, MS; and H.T. Voelker.

University of Pittsburgh (Pittsburgh, PA)
R.M. Rogers, MD (Principal Investigator); G.R. Owens, MD (former Principal Investigator, deceased); F.M. Vitale, MA; and M.E. Pusateri.

University of Utah (Salt Lake City, UT)
R.E. Kanner, MD (Principal Investigator); G.M. Villegas; C. Esplin; and R.S. Stayner.

Safety and Data Monitoring Board
J.R. Landis, PhD; J.R. Maurer, MD; Y. Phillips, MD; S.I. Rennard, MD; J.K. Stoller, MD; I. Tager, MD; and A. Thomas, Jr., MD.

National Heart, Lung, and Blood Institute (Bethesda, MD)
S.S. Hurd, PhD (Former Director, Division of Lung Diseases); G. Weinmann, MD (Project Officer; Director, Airway Biology and Disease Program); and M.C. Wu, PhD (Division of Epidemiology & Clinical Applications).


   Footnotes
 
Abbreviations: ASA = acetylsalicylic acid; BMD = bone mineral density; CFC = chlorofluorocarbon; CI = confidence interval; HPA = hyothalamic-pituitary-adrenal; ICS = inhaled corticosteroid; LHS = Lung Health Study; NSAID = nonsteroidal antiinflammatory drug; RR = relative risk; TAA = triamcinolone acetonide

This study was supported under a cooperative agreement with the National Institutes of Health (NHLBI-5UO1-HR50267-05). The study drug was kindly supplied by Rhone-Poulenc Roher/Aventis Pharmaceuticals, Inc (Bridgewater, NJ).

Received for publication January 6, 2004. Accepted for publication May 21, 2004.


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 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
 References
 

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