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Population-based assessment of adverse events associated with long-term glucocorticoid use
Arthritis & Rheumatism (Arthritis Care & Research)Vol. 55, No. 3, June 15, 2006, pp 420 – 426DOI 10.1002/art.21984 2006, American College of Rheumatology
Population-Based Assessment of Adverse Events
Associated With Long-Term Glucocorticoid Use
JEFFREY R. CURTIS,1 ANDREW O. WESTFALL,1 JEROAN ALLISON,1 JOHANNES W. BIJLSMA,2
ALLISON FREEMAN,3 VARGHESE GEORGE,1 STACEY H. KOVAC,4 CLAIRE M. SPETTELL,3 AND
KENNETH G. SAAG1
Objective. The frequency of many adverse events (AEs) associated with low-dose glucocorticoid use is unclear. We
sought to determine the prevalence of glucocorticoid-associated AEs in a large US managed care population.
Methods. Using linked administrative and pharmacy claims, adults receiving
>60 days of glucocorticoids were identi-
ﬁed. These individuals were surveyed about glucocorticoid use and symptoms of 8 AEs commonly attributed to
Results. Of the 6,517 eligible glucocorticoid users identiﬁed, 2,446 (38%) returned the mailed survey. Respondents were
29% men with a mean
؎ SD age of 53
؎ 14 years; 79% were white and 13% were African American. Respondents had
؎ SD of 7
؎ 3 comorbid conditions and were prescribed a mean
؎ SD prednisone-equivalent dosage of 16
mg/day. More than 90% of individuals reported at least 1 AE associated with glucocorticoid use; 55% reported that at least
1 AE was very bothersome. Weight gain was the most common self-reported AE (70% of the individuals), cataracts (15%)
and fractures (12%) were among the most serious. After multivariable adjustment, all AEs demonstrated a strong
dose-dependent association with cumulative glucocorticoid use. Among users of low-dose therapy (
<7.5 mg of prednisone
per day), increasing duration of use was signiﬁcantly associated with acne, skin bruising, weight gain, and cataracts.
Conclusion. The prevalence of 8 commonly attributed self-reported glucocorticoid-associated AEs was signiﬁcantly
associated with cumulative and average glucocorticoid dose in a dose-dependent fashion. Physicians should be vigilant
for glucocorticoid-related AEs and should counsel patients about possible risks, even among low-dose long-term users.
Glucocorticoids; Adverse events; Cataracts; Fractures.
emerging evidence supporting a disease-modifying role inrheumatoid arthritis (3– 6), concern for adverse events
Glucocorticoids are estimated to be used long-term by
(AEs) associated with glucocorticoids often limits their
0.5–1% of the general population and up to 2.5% of older
use. For many individuals, potential AEs such as acne,
adults (1,2). Despite the established role of glucocorticoids
weight gain, and sleep/mood disturbance may be mild. For
in controlling short-term inﬂammation, and despite
others, perceived AEs such as cataracts or glucocorticoid-induced osteoporosis with subsequent fracture may be
Supported in part by the Agency for Healthcare Research
severe and result in substantial morbidity and mortality
and Quality grant HS10389, the National Institute for Ar-
(7–15). Estimates regarding the prevalence and severity of
thritis and Musculoskeletal and Skin Diseases grant P60-
many glucocorticoid-associated AEs are largely unknown,
AR-48095, and NIH grant T32-AR-47512-03.
1Jeffrey R. Curtis, MD, MPH, Andrew O. Westfall, MS,
especially those less likely to require hospitalization or
Jeroan Allison, MD, MS, Varghese George, PhD, Kenneth G.
speciﬁc medications for prevention or treatment. Of note,
Saag, MD, MSc: University of Alabama at Birmingham; 2Jo-
the relationship between these common AEs and various
hannes W. Bijlsma, MD: University Medical Center, Utrecht,
The Netherlands; 3Allison Freeman, MS, Claire M. Spettell,
glucocorticoid doses is also unclear, and the safety of
PhD: Aetna Integrated Informatics, Aetna, Inc., Blue Bell,
long-term, low-dose prednisone (e.g., daily dosage Յ7.5
Pennsylvania; 4Stacey H. Kovac, PhD: Durham VA Medical
Center, and Duke University, Durham, North Carolina.
We hypothesized that the prevalence of AEs associated
Address correspondence to Kenneth G. Saag, MD, MSc,
University of Alabama at Birmingham, Division of Clinical
with even low-dose glucocorticoid use would be high and
Immunology and Rheumatology, FOT 820, 510 20th Street
would be dose and duration dependent. We therefore con-
South, Birmingham, AL 35294. E-mail: firstname.lastname@example.org.
ducted a population-based survey of glucocorticoid users
Submitted for publication May 16, 2005; accepted in re-
to obtain prevalence estimates of glucocorticoid-associ-
vised form August 18, 2005.
ated AEs. We speciﬁcally focused on these endpoints
Glucocorticoids and Adverse Events
among individuals who had prolonged use of an average
Glucocorticoid survey administration.
A 4-page, 69-
daily dose of Յ7.5 mg of prednisone.
question survey was mailed to 6,517 members who met theinclusion criteria for long-term glucocorticoid use. A fol-lowup postcard and a second survey were mailed to non-
SUBJECTS AND METHODS
responders within 60 days of the ﬁrst mailing. In thesurvey, we asked individuals to conﬁrm that they had
Long-term glucocorticoid users were
actually taken oral glucocorticoids and whether they had
identiﬁed within a national managed care organization
experienced Ն1 of 8 speciﬁc AEs commonly attributed to
(MCO) population covering 3 million lives in 36 states.
glucocorticoid use (sleep disturbance, acne, skin bruising/
These users and some of their demographic and disease
thinning, weight gain, mood problems, diabetes or high
characteristics were identiﬁed from the linked claims and
blood sugar, cataracts, and fractures) while taking oral
pharmacy databases of the MCO’s health maintenance or-
glucocorticoids. Respondents were asked to classify symp-
ganization, point of service, and preferred provider orga-
toms as not, a little, or very bothersome. Individuals were
nization health plans. Diseases, medications, and proce-
not requested to speculate on a causal relationship be-
dures were identiﬁed using International Classiﬁcation of
tween glucocorticoid use and the symptoms listed, but
Diseases, Ninth Revision codes; National Drug Codes; and
were only asked, “Have you ever had . . . while taking
Common Procedural Terminology codes, respectively. All
steroids?” Subjects were also asked whether their physi-
individuals in the cohort had pharmacy beneﬁts with vari-
cian had discussed possible AEs of glucocorticoid use
with them prior to use. Questions left blank or with mul-tiple responses were treated as missing data and were
Cohort inclusion criteria.
Individuals were character-
ized as long-term glucocorticoid users if they were Ն18years of age and had ﬁlled Ն60 days of outpatient oral
Descriptive statistics characterized
glucocorticoid prescriptions from July 1, 2001 to Decem-
basic demographics of survey responders and nonre-
ber 31, 2002. Each member was enrolled in the health plan
sponders. Categorical variables were compared using the
at least 6 months prior to and following the ﬁrst qualifying
chi-square test of independence, and continuous variables
glucocorticoid prescription (the index date). A total of
were compared using the 2-tailed t
-test. Despite MCO
6,517 health plan members met the inclusion criteria for
pharmacy data documenting ﬁlled prescriptions for at
long-term glucocorticoid use and were selected for further
least 60 days of glucocorticoids for each subject, only those
who conﬁrmed that they had actually taken the glucocor-
Because of potential differences in the prevalence of
ticoids were analyzed. To facilitate comparison of AEs
both short- and long-term AEs associated with incident
related to glucocorticoid dose, cumulative dose (over 24
and prevalent glucocorticoid use, individuals were de-
months) was categorized into quartiles (Ͻ1.7 gm, 1.7–2.8
scribed as new or prevalent users. New users were deﬁned
gm, 2.8 – 4.7 gm, and Ͼ4.7 gm of prednisone) and average
as adults who had not received any glucocorticoid pre-
daily dose was categorized into groups of clinical rele-
scription in the 90 days prior to their index date; all others
vance (0 –7.5 mg, 7.6 –20 mg, and Ͼ20 mg of prednisone
were considered prevalent users. Individuals were ex-
cluded from the study if they had diseases that might
Multivariable stepwise logistic regression was per-
impact outcomes of interest. These diagnoses included
formed to identify signiﬁcant associations between cumu-
human immunodeﬁciency virus infection, alcoholism, de-
lative glucocorticoid dose and AEs. Cumulative glucocor-
mentia, lymphoma, leukemia, history of organ transplan-
ticoid dose was included in all models, and age and sex
tation, Paget’s disease of bone, and local or metastatic solid
were also included in the fracture models. To test hypoth-
eses related to the safety of increasing duration of useamong recipients of Յ7.5 mg/day of prednisone, total du-
ration of use was forced into each model. For all other
coids identiﬁed using pharmacy data included pred-
variables, a univariate P
value Ͻ 0.25 was required for
nisone, prednisolone, dexamethasone, and other oral sys-
entry into the model and a P
value Ͻ 0.05 was required to
temic glucocorticoids commonly used in practice in the
remain in the model. Model building was conducted ac-
United States. Injectable, topical, and intraocular glu-
cording to Hosmer and Lemeshow (16), and model dis-
cocorticoids were not included. Each prescription was
crimination was assessed using the c statistic (17). To
converted to a daily measure of a prednisone-equivalent
assess trends across glucocorticoid dose groups, we mod-
dose (in milligrams). The number of days the individual
eled increasing dose category as a continuous variable and
received oral glucocorticoids within the 18-month medi-
used a Wald statistic to assess signiﬁcance. All analyses
cation eligibility window was examined to calculate the
were performed using SAS software (SAS Institute, Cary,
average and cumulative glucocorticoid exposure. Prescrip-
tions for implausible daily doses (i.e., Ͼ100 mg/day oforal prednisone) were recoded using the patient’s averagedaily dose computed without these outlier prescriptions.
Of the 60,465 total glucocorticoid prescriptions, only 213(0.35%) prescriptions among 134 subjects needed to be
A total of 2,446 (38%) managed care enrollees that met the
deﬁnition for long-term glucocorticoid use returned the
ticoids, 7% said that they had never taken them, and 2%
Table 1. Characteristics of long-term glucocorticoid
did not answer (data not shown). Sixty-ﬁve percent of the
(GC) users responding to survey (n
ever users reported current use at the time they completed
the survey. Among those who reported ever using glu-cocorticoids, a majority (68%) reported discussing poten-
tial glucocorticoid-related AEs with their doctor prior to
Compared with survey responders, the 4,071 survey
nonresponders were younger (mean age 48 versus 53
years) and were more likely to be male (36% versus 30%).
Nonresponders’ duration of enrollment in the health plan,
mean prednisone dose, and average number of comorbid
conditions were similar to survey responders (data not
Relationship between glucocorticoid dose and AEs.
The prevalence and self-reported severity of AEs experi-
enced, stratiﬁed by quartile of cumulative glucocorticoid
use, are shown in Figure 1. The AE with the greatest
self-reported prevalence was weight gain, which was ex-
perienced by almost 80% of subjects in the highest quartile
of glucocorticoid use. Skin bruising/thinning and sleep
disturbance were the next most commonly reported AEs.
Cataracts (15% overall) and fractures (12% overall) were
reported less frequently. Only 10% of subjects reported
that they had not experienced any of the AEs concurrent
with glucocorticoid use. We examined claims data for
fractures separately during the 30-month observation pe-
riod. Ten percent of the cohort had Ն1 medical service
claims for a fracture during the 2.5-year period of obser-
The adjusted relative risks of AEs associated with cu-
mulative glucocorticoid dose are described in Table 2. A
strong dose-response relationship was observed between
increasing quartiles of glucocorticoid use and all of the
AEs examined. To assess the validity of our self-reported
* N ϭ 2,167 subjects after excluding individuals who did not con-ﬁrm that they had actually taken glucocorticoids. Values are thenumber (percentage) unless otherwise indicated.
† Total Ͻ2,167 because of missing survey data.
‡ During study period of 2 years.
survey. Their characteristics are described in Table 1. In-dividuals were middle aged, predominantly women, andreceived prescriptions for an average of 16 mg/day of pred-nisone. A majority were new users rather than prevalentglucocorticoid users. Persons with rheumatoid arthritiswere prescribed a mean Ϯ SD dosage of 12 Ϯ 8 mg/day ofprednisone, in contrast to persons with inﬂammatory
Prevalence of adverse events associated with long-term
bowel disease who received a mean Ϯ SD prednisone
glucocorticoid use stratiﬁed by cumulative glucocorticoid dosage(n ϭ 2,167 subjects after excluding individuals who did not con-
dosage of 31 Ϯ 16 mg/day (data not shown). The mean
ﬁrm that they had actually taken glucocorticoids). Quartiles of
daily prednisone doses for the other diseases, including
cumulative prednisone-equivalent glucocorticoid dosage: Q1 ϭ
systemic lupus erythematosus, chronic obstructive pulmo-
Ͻ1.7 gm (e.g., 10 mg/day of prednisone for 6 months); Q2 ϭ
nary disease, and asthma, fell between these 2 extremes.
1.7–2.8 gm (e.g., 10 mg/day of prednisone for 9 months);Q3 ϭ 2.9 – 4.7 gm (e.g., 10 mg/day of prednisone for 12 months);
Hypertension and rheumatoid arthritis were among the
Q4 ϭ Ͼ4.7 gm (e.g., 10 mg/day of prednisone for 18 months).
most common comorbid diagnoses. More than 91% of
Ͻ 0.0001 (Cochran-Armitage trend test). † P
Ͻ 0.01 (Cochran-
respondents indicated that they had ever taken glucocor-
Armitage trend test). ‡ P
Ͻ 0.001 (Cochran-Armitage trend test).
Glucocorticoids and Adverse Events
fracture models, we separately modeled fractures using
Table 2. Relationship between cumulative prednisone-
medical claims data. Even after multivariable adjustment,
equivalent dose and self-reported adverse events*
a positive and signiﬁcant association with increasing cu-
mulative glucocorticoid dose was observed (data not
Among users of Ͼ7.5 mg/day of prednisone, glucocorti-
coid dose and duration of use were strongly associated
with all AEs (data not shown). The adjusted odds ratios of
increasing duration of glucocorticoid use among individ-
uals prescribed Յ7.5 mg/day of prednisone are presented
in Table 3. Acne, skin bruising, weight gain, and cataracts
were signiﬁcantly associated with longer durations of low-
dose glucocorticoid use. In contrast, increasing daily dose
(within the 0 –7.5 mg/day range) was more strongly asso-
ciated with sleep disturbance and fractures than was in-
creased duration of use. The Spearman correlation coefﬁ-
cient between cumulative glucocorticoid dose and average
We found a high prevalence of self-reported AEs associ-
ated with glucocorticoid use among individuals treated
long-term for a variety of conditions. Almost all respon-
dents reported at least 1 AE that was temporally associated
with concurrent glucocorticoid use, and more than half
reported that at least 1 AE was very bothersome. Serious
AEs potentially attributable to glucocorticoid exposure
were also common, with 15% of the cohort self reporting
cataracts and 12% self reporting Ն1 fractures. Increasing
cumulative glucocorticoid dose had a strong positive as-
sociation with serious AEs typically attributed to gluco-
corticoid use, even after multivariable adjustment for
demographic and disease comorbidities that were also as-
Long-term observational studies of patients receiving
commonly prescribed doses of glucocorticoids have re-
ported high rates of glucocorticoid-associated AEs. A
study of 120 patients with giant cell arteritis (mean age at
diagnosis 75 years) followed for a median of 10 years
found that 86% of patients experienced Ն1 AEs (18); 58%
of the patients experienced Ն2 serious AEs, the most com-
mon of which were cataracts (41%) and fractures (38%). Ina similarly designed study of 232 patients with polymyal-
* Total sample size for each model shown in parentheses less thanentire cohort (n ϭ 2,167) due to missing survey responses. OR ϭ
gia rheumatica (19) (mean age at diagnosis 73 years) fol-
odds ratio; 95% CI ϭ 95% conﬁdence interval.
lowed for an average of 8 years, 65% of individuals treated
† Quartiles of cumulative glucocorticoid dosage (prednisone equiv-
with glucocorticoids experienced at least 1 AE, the most
alents): Q1 ϭ Ͻ1.7 gm (e.g., 10 mg/day of prednisone for 6 months);Q2 ϭ 1.7–2.8 gm (e.g., 10 mg/day of prednisone for 9 months);
common of which were vertebral fracture (18%) and cat-
Q3 ϭ 2.9 – 4.7 gm (e.g., 10 mg/day of prednisone for 12 months);
aracts (36%). Cumulative glucocorticoid dose had a strong
Q4 ϭ Ͼ4.7 gm (e.g., 10 mg/day of prednisone for 18 months).
association with AEs, particularly after the dosage reached
‡ Adjusted for age, sex, and number of comorbid diseases; c statis-tic ϭ 0.66.
1.8 gm, which was the approximate cutpoint between the
§ Adjusted for age, sex, and ethnicity; c statistic ϭ 0.76.
ﬁrst and second quartiles in our analyses. Our results are
¶ Adjusted for age, sex, new user, and number of comorbid dis-eases; c statistic ϭ 0.67.
similar to these studies because 90% of our subjects re-
# Adjusted for age, sex, new user, ethnicity, and number of comor-
ported at least 1 AE while receiving glucocorticoids. Rates
of self-reported fracture (12%) and cataract (15%) in our
** Adjusted for age, sex, ethnicity, and number of comorbid dis-eases; c statistic ϭ 0.69.
study were high, although lower than these 2 reports,
†† Adjusted for ethnicity and number of comorbid diseases; c sta-
likely reﬂecting a younger population, diverse indications
for glucocorticoid treatment, and lower cumulative glu-
‡‡ Adjusted for age, ethnicity, number of comorbid diseases, andincome; c statistic ϭ 0.72.
§§ Adjusted for age, sex, income, and number of comorbid diseases;
More recent interest has focused on the clinical efﬁcacy
and potential disease-modifying properties of long-term
Table 3. Relationship between glucocorticoid dose and duration and adverse events among low-dose (prednisone
<7.5 mg/day) glucocorticoid users (n
Average daily dose
90-day increase in
(per 1-mg/day increase
duration of use
within 0–7.5 mg/day range)
* 95% CI ϭ 95% conﬁdence interval; NS ϭ not signiﬁcant.
† Adjusted for age, sex, and number of comorbid diseases; c statistic ϭ 0.63.
‡ Adjusted for age and sex; c statistic ϭ 0.77.
§ Adjusted for age and sex; c statistic ϭ 0.65.
¶ Adjusted for age and sex; c statistic ϭ 0.68.
# Adjusted for age, ethnicity, and heart failure; c statistic ϭ 0.69.
** Adjusted for ethnicity; c statistic ϭ 0.64.
†† Adjusted for age and number of comorbid diseases; c statistic ϭ 0.71.
‡‡ Adjusted for age, sex, income, and number of comorbid diseases; c statistic ϭ 0.65.
low-dose prednisone (Յ7.5 mg/day), particularly for pa-
mg/day over 24 months. These data suggest that long-term
tients with arthritis. In small clinical trials of patients with
use of low-dose prednisone in a large, diverse managed
rheumatoid arthritis randomized to low glucocorticoid
care population is typically administered only to a minor-
doses (prednisolone 7.5–10 mg daily), vertebral fractures,
ity of individuals with rheumatoid arthritis.
weight gain, and hyperglycemia were observed among the
Our study has several strengths. The large, population-
glucocorticoid-treated patients, although incidence rates
based design coupled with the claims data and pharmacy
of these AEs were low (3,4). These and other trials with
linkage permitted us to analytically account for a variety of
aggressive glucocorticoid tapering regimens (5) have dem-
comorbid illnesses that were ascertained using both self-
onstrated that low-dose or rapidly tapered glucocorticoids
reported and administrative sources. Pharmacy data,
may result in minimal short-term glucocorticoid-associ-
rather than self report, were used to determine glucocorti-
ated toxicity. The strengths of these randomized, prospec-
coid use patterns and thus reduce potential recall bias. We
tive, placebo-controlled trials are their blinded outcomes
were able to capture self-reported AEs that are often not
assessment; lack of confounding by disease severity; and
assessed in observational studies that utilize only admin-
prohibition of even short-term, high-dose glucocorticoid
istrative data or even medical chart review. Our study
exposure. Factors that may limit their generalizability in-
captured the diverse diseases treated with glucocorticoids
clude selection of individuals with few comorbid illnesses
and included use of intermittent glucocorticoid prescrip-
and insufﬁcient duration of followup to detect many of the
tions, allowing better generalizability than other studies
AEs that develop and/or progress over time.
that have focused on populations treated with glucocorti-
In contrast to these clinical trial ﬁndings, an observa-
coids for only 1 condition or with only continuous ther-
tional study with a longer followup period compared pa-
apy. Finally, we were able to examine demographic covari-
tients with rheumatoid arthritis treated with a mean of 7
ates such as ethnicity and education that are rarely
mg/day of near-continuous prednisone therapy for 4.9
available in medical record or claims-based data sources.
years with similar patients with rheumatoid arthritis not
One limitation of our work is that AEs were self re-
treated with glucocorticoids (12). In the glucocorticoid-
ported, and conﬁrmation by a physician was not available.
treated group, 82% experienced at least 1 AE compared
Although self report may be the only reasonable source of
with 24% in the control group. Fractures (19%) and cata-
information for certain subjective AEs such as mood and
racts (15%) were the most common serious AEs. We also
sleep disturbance, acne, and skin changes associated with
found several AEs that were signiﬁcantly associated with
glucocorticoid use, it may not be optimal for other out-
longer durations and small increments in glucocorticoid
comes such as fracture. However, the positive predictive
dose, even among Յ7.5 mg/day prednisone users (Table 3),
value of self-reported fracture has been reported to be
and we demonstrated a dose-dependent increase in frac-
Ͼ80% at any fracture site and often in excess of 95% for
ture risk in this group that is concordant with other studies
osteoporotic fracture sites (21–24). Because of uncertainty
of low-dose glucocorticoid users (10,20). Moreover, al-
as to whether a medical claim for fracture represented a
though the 892 individuals with rheumatoid arthritis in
new (incident) fracture or followup for a prevalent frac-
our study received the lowest mean daily dosage of pred-
ture, we censored fracture data after a single event and
nisone (12 mg/day) compared with those with other dis-
therefore likely underestimated fracture incidence among
eases that we examined, only 40% received a mean of Յ7.5
individuals who experienced Ͼ1 new fracture. Vertebral
Glucocorticoids and Adverse Events
fractures may be asymptomatic and may not be identiﬁed
uals the expected beneﬁts will outweigh the possible risks.
in as many as two-thirds of patients (25,26), which pro-
For example, among patients with early rheumatoid arthri-
vides an additional reason for our fracture estimates to be
tis, combination therapy that includes glucocorticoids
conservative. We were able to compare our results based
may have a sustained, disease-modifying effect (30). How-
on self-reported outcomes with fracture outcomes from
ever, minimizing potentially avoidable AEs such as glu-
administrative data and achieved similar results. Com-
cocorticoid-induced osteoporosis, for which there are efﬁ-
pared with fractures, less research has been conducted to
cacious but underutilized therapies (31–34), must be a
validate self report of cataracts, but the positive predictive
shared responsibility among physicians and patients. De-
value of self-reported cataracts has been estimated to be
spite advances in chronic disease management, it is un-
ϳ83% (95% conﬁdence interval 79–88%) (27).
likely that the long-term use of glucocorticoids will disap-
Another limitation of our work is that the self-reported
pear any time soon. As such, heightened attention to
outcome data are cross-sectional, and determining the
common glucocorticoid-associated AEs that bother pa-
temporal sequence of AEs to implicate a causal relation-
tients, even among users of lower doses, is warranted.
ship with glucocorticoid exposure is problematic. For thisreason, we intentionally excluded persons with medically
recognized diabetes from our high blood sugar analysis(16% of the cohort). This conservative strategy underesti-
1. Van Staa TP, Leufkens HG, Abenhaim L, Begaud B, Zhang B,
mates the proportion of those who developed incident
Cooper C. Use of oral corticosteroids in the United Kingdom.
diabetes as a consequence of glucocorticoid therapy. De-
2. Walsh LJ, Wong CA, Pringle M, Tattersﬁeld AE. Use of oral
spite the similarity of survey respondents and nonrespon-
corticosteroids in the community and the prevention of sec-
dents in the distribution of comorbid conditions and mean
ondary osteoporosis: a cross sectional study. BMJ 1996;313:
daily prednisone dose (ascertained using administrative
3. Kirwan JR, and the Arthritis and Rheumatism Council Low-
data), possible response bias may have inﬂuenced our
Dose Glucocorticoid Study Group. The effect of glucocorti-
ﬁndings if individuals that experienced glucocorticoid-
coids on joint destruction in rheumatoid arthritis. N Engl
associated AEs were more likely to respond to the survey.
Additionally, glucocorticoids have been associated with a
4. Van Everdingen AA, Jacobs JW, Siewertsz van Reesema DR,
variety of other AEs (e.g., infection, hypertension) that we
Bijlsma JW. Low-dose prednisone therapy for patients withearly active rheumatoid arthritis: clinical efﬁcacy, disease-
modifying properties, and side effects: a randomized, double-
Finally, we were not able to compare our prevalence of
blind, placebo-controlled clinical trial. Ann Intern Med 2002;
self-reported AEs with that of a control group with similar
diseases of equal severity that did not receive glucocorti-
5. Boers M, Verhoeven AC, Markusse HM, van de Laar MA,
Westhovens R, van Denderen JC, et al. Randomised compar-
coids. Confounding by disease severity is a concern in
ison of combined step-down prednisolone, methotrexate and
observational studies where “sicker” patients have in-
sulphasalazine with sulphasalazine alone in early rheumatoid
creased exposure to a drug of interest (28). We adjusted for
arthritis [published erratum appears in Lancet 1998;351:220].
general comorbidity using the number of unique diseases
for which the individual received medical care in the prior
6. Hansen M, Podenphant J, Florescu A, Stoltenberg M, Borch A,
Kluger E, et al. A randomised trial of differentiated pred-
30 months. However, because of the diverse nature of the
nisolone treatment in active rheumatoid arthritis: clinical
diseases for which individuals were prescribed glucocor-
beneﬁts and skeletal side effects. Ann Rheum Dis 1999;58:
ticoids, we were not able to adjust for all factors indicative
of more severe disease (e.g., rheumatoid nodules and ero-
7. National Osteoporosis Foundation. Physician’s guide to pre-
vention and treatment of osteoporosis. Belle Mead (NJ): Ex-
sions for patients with rheumatoid arthritis); therefore,
residual confounding by disease indication or severity is
8. Skalka HW, Prchal JT. Effect of corticosteroids on cataract
possible. However, we demonstrated a strong dose-re-
formation. Arch Ophthalmol 1980;98:1773–7.
sponse relationship between rates and severity of AEs and
9. Van Staa TP, Abenhaim L, Cooper C, Zhang B, Leufkens HG.
increasing doses of cumulative and daily oral glucocorti-
Public health impact of adverse bone effects of oral cortico-steroids. Br J Clin Pharmacol 2001;51:601–7.
coids, even after adjusting for a variety of demographic
10. Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C.
Use of oral corticosteroids and risk of fractures. J Bone Miner
The prevalence of overall and very bothersome AEs
associated with long-term glucocorticoid use was high,
11. Van Staa TP, Leufkens HG, Cooper C. The epidemiology of
corticosteroid-induced osteoporosis: a meta-analysis. Osteo-
even among users of lower doses, and this observation may
be underappreciated by clinicians. Because patients may
12. Saag KG, Koehnke R, Caldwell JR, Brasington R, Burmeister
be concerned about the potential AEs of glucocorticoids
LF, Zimmerman B, et al. Low dose long-term corticosteroid
prior to use (29), physicians need to be well apprised of
therapy in rheumatoid arthritis: an analysis of serious adverse
their risks. A majority of individuals in our cohort re-
13. Michel BA, Bloch DA, Fries JF. Predictors of fractures in early
ported discussing potential glucocorticoid-associated AEs
rheumatoid arthritis. J Rheumatol 1991;18:804 – 8.
with their physician prior to initiating therapy. This ob-
14. Merlino LA, Bagchi I, Taylor TN, Utrie P, Chrischilles E,
servation highlights the opportunity for physicians to dis-
Sumner W 2nd, et al. Preference for fractures and other glu-
cuss with patients the possible AEs of glucocorticoids in
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