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Current Medical Research & Opinion Vol. 29, No. 9, 2013, 1147–1160
0300-7995 Article FT-0164.R1/818531
doi:10.1185/03007995.2013.818531 All rights reserved: reproduction in whole or part not permitted
Review
What do we know about the safety of
corticosteroids in rheumatoid arthritis?
Olivier Ethgen
Department of Public Health Sciences, Epidemiology
and Health Economics, University of Lie
`ge, Lie
`ge,
Belgium
Fre
´de
´ric de Lemos Esteves
Life Sciences Library, University of Lie
`ge, Lie
`ge,
Belgium
Olivier Bruyere
Jean-Yves Reginster
Department of Public Health Sciences, Epidemiology
and Health Economics, University of Lie
`ge, Lie
`ge,
Belgium
Address for correspondence:
Olivier Ethgen, Department of Public Health Sciences,
Epidemiology and Health Economics, University of
Lie
`ge, CHU Sart Tilman B23, 4000 Lie
`ge, Belgium.
Tel.: +32 471 58 30 10; Fax: +32 4 366 28 12;
o.ethgen@ulg.ac.be
Keywords:
Corticosteroids – Observational research – Review –
Rheumatoid arthritis – Safety
Accepted: 19 June 2013; published online: 3 July 2013
Citation: Curr Med Res Opin 2013; 29:1147–60
Abstract
Background:
Clear information is still lacking on the safety of corticosteroids (GCs) therapy in RA despite six decades of
clinical experience.
Scope:
We performed a literature search in Ovid MEDLINE from January 2000 to December 2012. Our Population
Intervention Comparator Outcomes (PICO) strategy search was: rheumatoid arthritis [Population],
corticosteroids or glucocorticoids [Intervention], any comparison [Comparator], adverse effects
[Outcome]. Studies were selected if they reported any measure of association between GCs intake and
potential adverse effects in RA patients.
Findings:
We identified 1030 papers and selected for analysis 26 observational studies and six systematic reviews.
The major side effects of GCs in RA are bone loss, risk of cardiovascular events and risk of infections as
evidenced by large observational studies and not necessarily RCTs. Others associations were reported with
herpes zoster, tuberculosis, hyperglycemia, cutaneous abnormalities, gastrointestinal perforation,
respiratory infection and self-reported health problems such as cushingoid phenotype, ecchymosis,
parchment-like skin, epistaxis, weight gain and sleep disturbance. Other potential adverse effects of GCs
were studied but no association was found. These included psychological disorders, dermatophytosis, brain
diseases, interstitial lung disease, memory deficit, metabolic syndrome, lymphoma, non-Hodgkin’s
lymphoma, renal function and cerebrovascular accidents. Most of the evidence emanates from
observational researches and the inherent limitations of such data should be kept in mind.
Conclusion:
Recent observational data and systematic reviews suggest that GCs can lead to relatively alarming and
burdensome side effects in RA. This is particularly true for patients who have longer term and higher dose
therapies. GCs are largely used in RA and knowing their safety profile is essential to improve patients care.
The design of new therapeutic strategies intended to minimize the daily dosing of GCs while conserving their
beneficial effect should be encouraged.
Introduction
Corticosteroids, or more specifically glucocorticoids (GCs), are commonly pre-
scribed drugs across a large spectrum of diseases. Their effectiveness in reducing
inflammation has been well established for more than 60 years in medicine.
Their use in rheumatology is also widespread. GCs are among the mainstays
of treatment for rheumatoid arthritis (RA) as they exert strong and fast-acting
anti-inflammatory, immunosuppressive and disease-modifying therapeutic
effect.
However, it is also unanimously acknowledged that GCs can cause adverse
effects. Despite this general awareness of the potential toxicity of GCs and
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nearly six decades of clinical experience, clear information
about the safety of corticotherapy is still lacking
1
. The
real risk–benefit ratio of GCs in RA has been largely
debated
2–7
and the routine use of GCs in RA perceived
as controversial
8,9
.
As with many active compounds, the side effects of GCs
depend on their dosing and duration of use. Over the last
few decades, there has been a trend toward dose-lowering
strategies of GCs with the use of concomitant therapies to
lessen the risk of adverse effects associated with the pro-
longed use of even low-dose GCs
8
. Besides, it has been
argued that potential side effects of low doses of GCs can
be anticipated and avoided with appropriate monitoring
and preventative measures
2,8
. Low-dose GCs have also
been described as safer and more acceptable than generally
thought
10,11
.
Low-dose GC regimens continue to be evaluated in
randomized clinical trials (RCTs) in RA, particularly in
early disease. As monotherapy
12–14
or in combination with
disease modifying antirheumatic drugs
15–18
, results are usu-
ally supportive of GCs with the demonstration of favorable
clinical outcomes and risk–benefit ratio
19,20
. In general,
very few adverse events leading to treatment withdrawal
are reported and safety is deemed acceptable by the studies
investigators. Therefore, adjunctive therapy using low
dose GCs along with the appropriate disease modifying
anti-rheumatic drug has been advocated as a reasonable
treatment plan for selected patients
8,21
. However, RCTs
remain relatively small and/or of relatively short duration.
In this report, we intended to document in a non-sys-
tematic way the various adverse effects of GC therapy in
RA as reported in the literature. Bearing in mind the limi-
tation of RCTs to identify adverse events, our search
embraced observational studies and previous systematic
reviews as well.
Methods
We performed a literature search in Ovid MEDLINE (1946
to November Week 3 2012), Ovid MEDLINE Daily
Update (November 14, 2012) and Ovid MEDLINE In-
Process & Other Non-Indexed Citations (December 06,
2012) databases from January 2000 to December 2012.
Our PICO strategy search was as follows: rheumatoid
arthritis [Population], corticosteroids or glucocorticoids
[Intervention], any comparison [Comparator] and adverse
effects [Outcome]. Using NLM Medical Subject Heading
controlled vocabulary and natural language, we attempted
to exhaustively search Medline considering as many terms
as possible in relation with our PICO strategy.
We did not restrict the search to a specific safety con-
cern or to a specific type of studies like RCTs. As we were
studying safety profile, we expected to find more informa-
tion in large observational studies rather than in RCTs.
Studies were selected if they reported any measure of asso-
ciation between GC intake and potential adverse effects in
RA patients.
We excluded case studies, editorials, commentaries,
non-quantitative reviews and opinion papers. We also
excluded studies whose primary purpose was not the assess-
ment of GC therapy but other therapies. For instance, we
excluded studies on anti-TNF as we expected many studies
would investigate the new anti-TNF in the 2000–2010
decade rather than therapies like GCs. Observational stu-
dies involving RA patients but not presenting RA-specific
results were also excluded. Finally, we limited the search to
articles written in English.
Results
Our search identified 1030 papers. We retrieved and
reviewed all corresponding abstracts. We found and
selected for analysis 41 studies: 35 observational studies
and 6 systematic reviews (Figure 1). No clinical trials
were selected. Reason for non-inclusion were the RCT
objectives (which were not directly the assessment of a
GC therapy, but GCs were authorized in addition to the
studied medication) and the fact that safety concerns were
not stated or deemed acceptable in the abstract.
Of the 35 observational studies, 25 reported an
association between GC exposure and adverse effects
1,030 studies identified
158 clinical trials
All excluded
41 sytematic reviews
6 selected, 35 excluded
207 case reports
All excluded
528 miscellaneous papers
All excluded
41 studies selected
35 observational studies
6 systematic reviews
96 observational studies
35 selected, 61 excluded
Figure 1. Flow-chart of study selection.
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(Table 1) while 10 did not. We report the results of our
search by study type: observational studies or systematic
reviews, keeping those that found an association between
GC exposure and adverse effects.
Findings from observational studies
Bone loss
Sinigaglia et al.
22
studied 925 consecutive female RA
patients and reported that steroid use was associated with
significantly increased lower lumbar and femoral bone
mineral density even after adjusting for the main con-
founding covariates (p¼0.0001). Logistic analysis
showed that age (Odds Ratio [OR] ¼1.05, 95% confidence
interval [CI]: 1.03 to 1.07), the Health Assessment
Questionnaire score (OR ¼1.3, 95% CI: 1.07 to 1.7),
menopause (OR ¼1.9, 95% CI: 1.1 to 3.2), use of steroids
(OR ¼1.5, 95% CI: 1.07 to 2.1), and body mass index
(OR ¼0.8, 95% CI: 0.8 to 0.9) were significantly asso-
ciated with the risk for osteoporosis. The only variables
associated with an increased risk for vertebral fracture
were age (OR ¼1.04, 95% CI: 1.01 to 1.08), the Health
Assessment Questionnaire score (OR ¼1.7, 95% CI: 1.08
to 2.09) and the cumulative steroid intake (OR for 1 g of
prednisone ¼1.03, 95% CI: 1.006 to 1.07).
De Nijs et al.
23
compared 205 RA patients receiving
GCs orally on a daily basis with 205 RA patients who
did not receive GCs, matched for sex and age. The use
of GCs tended to increase the risk of developing a vertebral
deformity (adjusted OR ¼1.56, 95% CI: 0.81 to 2.99) and
symptomatic vertebral fracture (adjusted OR ¼1.42, 95%
CI: 0.24 to 8.32). Each 1 mg increase in the current daily
GC dose increased the risk of a vertebral deformity
(adjusted OR ¼1.05, 95% CI: 0.98 to 1.13) and of a symp-
tomatic vertebral fracture (adjusted OR ¼1.05, 95% CI:
0.89 to 1.24).
Kroot et al.
24
documented the change in bone mineral
density in 76 consecutive patients with recent-onset RA
over the first decade of the disease. Only the use of pred-
nisone was significantly associated with increased bone
loss (¼1.05, 95% CI: 1.62 to 0.48). In a separate
analysis that included only postmenopausal women (34
women), the use of prednisone was significantly associated
with increased bone loss as well (¼0.96 95% CI: 1.80
to 0.12). The authors stressed the fact that the use
of prednisone was the only variable consistently
associated with reduction in bone mineral density in
their RA patient sample.
Roldan et al.
25
measured the combined cortical thick-
ness of the second metacarpal bone from digitized hand
radiographs in a cohort of 649 RA patients who had
2990 hand radiographs in total. Patients who received a
cumulative dose of GCs 11.7 g lost combined cortical
thickness at 0.659 mm/year ½ (95% CI: 0.577 to 0.742)
as compared to a loss of 0.361 mm/year ½ (95% CI: 0.323
to 0.401) in patients who did not receive GCs.
Van Staa et al.
26
specifically assessed the long-term
absolute risk of hip fracture of RA patients. Indicators of
a substantially elevated risk of hip fracture included a dis-
ease duration of more than 10 years (Relative Risk
[RR] ¼3.4, 95% CI: 3.0 to 3.9), a low BMI (RR ¼3.9
95% CI: 3.1 to 4.9), and the use of oral GCs (RR ¼3.4,
95% CI: 3.0 to 4.0).
Oelzner et al.
27
found older age, low BMI and high
cumulative GC dose as being risk factors for osteoporosis
in postmenopausal women with RA. In men with RA, low
BMI and high cumulative GC dose were also identified as
the two risk factors for osteoporosis. Low BMI was the only
risk factor in premenopausal women with RA.
Lee et al.
28
confirmed the role of GCs as a risk factor for
generalized bone loss in a 299 female RA patients matched
with 246 healthy subjects on age. In their study, the preva-
lence of osteoporosis was 1.9 times higher in the female
RA patients as compared to healthy controls (22.1% vs.
11.4%, p¼0.014) and cumulative GC dose was independ-
ently associated with lower hip bone mineral density
(p¼0.016).
Cardiovascular risk
RA has also been associated with increased cardiovascular
morbidity and mortality. Del Rincon et al.
29
examined the
potential role of GCs as a cause of atherosclerosis in RA.
Among the 647 RA patients studied, 66% received GCs.
Of those who had never received GCs, 47% had carotid
plaque and 8% had one or more incompressible lower-limb
artery. Among those who received GCs, the frequency of
carotid plaque increased to 62% (p¼0.006) and that of
lower-limb arterial incompressibility increased to 17%
(p¼0.008) for patients in the highest tertile of GC
exposure (corresponding to a lifetime cumulative GC
dose between 16,338 mg and 121,980mg of prednisone).
These differences remained significant after adjustment for
age at onset, disease duration, sex, cardiovascular risk fac-
tors, and RA clinical manifestations such as tender, swol-
len, and deformed joint counts, subcutaneous nodules,
rheumatoid factor (RF) seropositivity, and erythrocyte
sedimentation rate (ESR). GC exposure was thus asso-
ciated with carotid plaque and arterial incompressibility,
independent of cardiovascular risk factors and RA clinical
manifestations.
Davis et al.
30
followed up 603 adult RA patients
for a median of 13 years (totaling 9066 person-years).
Cumulative GC exposure was defined in tertiles: low ter-
tile (1500 mg), mid tertile (between 1500 and 7000mg)
and high tertile (47000 mg). The authors found that RF-
positive patients in the low, mid and high cumulative
exposure tertile had a 1.69 (Hazard Ratio [HR] ¼1.69,
95% CI: 1.00 to 2.88), a 1.52 (HR ¼1.52, 95% CI: 0.84
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Table 1. Main characteristics of the 25 observational studies reporting safety concerns from exposure to glucocorticoids in rheumatoid arthritis.
Study Design and size of the RA population GC exposure Adjusting factors
Bone Loss
Sinigaglia et al.
22
Multicenter cross-sectional study of 925 consecutive
female RA patients.
631 patients (68.2%) were taking GCs at a current dose of
5.5 4.5 mg in prednisone equivalents. Mean GC
therapy duration was 43.1 5.3 months and cumu-
lative prednisone intake was 7.6 g 9.5 g.
Age, BMI, menopause, disease duration, HAQ
score, no. of swollen joints.
de Nijs et al.
23
Multicenter cross-sectional study including 205 RA
patients taking oral GCs on a daily basis and 205 RA
patients who did not received GCs, matched for age
and sex.
Cumulative oral prednisone (or prednisone equivalent
dose).
Concomitant medication prescribed for the
treatment or prevention of osteoporosis
(calcium supplement, vitamin D supple-
ment, bisphosphonate use).
Kroot et al.
24
Longitudinal analysis of 76 RA patients with 2 bone
mineral density measurements, with mean disease
duration of 2.35 years at the first measurement and
8.9 years at the second measurement.
21 patients received GC treatment between the 2 bone
mineral density measurements. The mean cumulative
prednisone dose between the 2 bone mineral density
measurements was 527.5 mg (range 250–900 mg) for
10 prednisone relevant users prior to first measure-
ment and 10,740 mg (range 850–22,050 mg) for 11
prednisone relevant users prior to second
measurement.
Activity load, erythrocyte sedimentation rate,
menopause status and HAQ score.
Roldan et al.
25
Multicenter longitudinal cohort of 649 consecutive RA
patients with a median time interval of 2 years
between first and last follow-up hand radiographs.
320 (49%) patients received prednisone. The average
cumulative GC dose was 12.3 g (16.6 g).
Gender, ethnicity, HLA-DRB1 shared epitope,
rheumatoid nodules, rheumatoid factor,
erythrocyte sedimentation rate and BMI.
van Staa et al.
26
Database study of 30,262 patients with a recorded diag-
nosis of RA.
Use of oral GCs in prior 6 months: No, 1 or 2, more than 2. Age, gender, BMI, smoking, fracture history,
fall history, general risk factors and use in
the prior 6 months of bisphosphonates,
hormone replacement therapy and
thiazides.
Oelzner et al.
27
Cross-sectional study of 551 RA patients. Average cumulative GC dose 15.3 g (20.3 g), 28% of
patients with a cumulative dose lower than 5 g, 37%
with a cumulative dose between 5 and 20 g, and 35%
of patients with a cumulative dose beyond 20 g.
Age, disease duration and BMI.
Lee et al.
28
299 RA patients age-matched with 246 healthy subjects. Average cumulative GC dose 2177.5g (interquartile range
361.3–5415.0 g).
Age, BMI, postmenopausal status, erythrocyte
sedimentation rate, disease duration,
rheumatoid factor and bisphosphonate
use.
Cardiovascular risk
del Rincon et al.
29
Multicenter longitudinal study of 647 RA patients. 4 cumulative GC exposure levels: unexposed, 5 to
6030 mg, 6072 to 16,240 mg and 16,338 to
121,980 mg.
Age, gender, disease duration, diabetes mel-
litus, hypercholesterolemia, systolic blood
pressure, past or current smoking, BMI,
tender, swollen and deformed joint counts,
rheumatoid nodules, rheumatoid factor and
erythrocyte sedimentation rate.
Davis et al.
30
Longitudinal study of 603 RA patients. 44% of rheumatoid factor-negative patients (n¼210) and
68% of rheumatoid factor positive patients (n¼393)
were exposed to GCs. Cumulative GC dose was 2.28 g
(interquartile range 0.7–8.5 g) in rheumatoid factor-
negative patients and 5.40 g (interquartile range 1.1–
15.2 g) in rheumatoid factor-positive patients.
Age, gender, year of RA incidence, history of
ischemic heart disease, smoking status,
hypertension, diabetes mellitus, BMI, dys-
lipidemia, erythrocyte sedimentation rate,
DMARD use, joint swelling, radiographic
erosions, RA lung disease or vasculitis,
joint surgery.
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Panoulas et al.
31
Cross-sectional study of 398 consecutive RA patients. GC exposures were defined in 3 groups: no or limited
exposure (never received GCs or had been exposed for
less than 3 months at the time of assessment), low-
dose but long-term exposure (patients who received
less than 7.5 mg of oral daily prednisolone for more
than 6 months) and medium-dose and long-term
exposure ( patients on more than 7.5 mg of oral daily
prednisolone for more than 6 months).
Age, gender, BMI, total cholesterol, smoking
status, insulin resistance, modification of
diet in renal disease, disease duration,
health assessment questionnaire and joint
surgery.
Wolfe and Michaud
32
Longitudinal study of 17,738 RA patients and 3001
patients with non-inflammatory rheumatic disorders.
39.1% of patients used prednisone. The average daily
dose of prednisone was 7 mg/day.
College education, ethnicity, smoking status,
diabetes, aerobic exercise, hypertension,
comorbidity index, low-dose aspirin, MI,
baseline myocardial infarction status,
patient activity scale score, total joint
replacement status and RA duration.
Myasoedova et al.
33
Population-based incidence cohort of 795 RA patients. 614 (77%) patients received GCs at some time during
follow-up.
Age, gender and calendar year of RA inci-
dence, cardiovascular risk factors and
coronary heart disease.
Infection risk
Franklin et al.
34
Prospective cohort study from a community-based
register of 2108 patients with inflammatory polyar-
thritis (1239 patients with RA), with an average follow-
up of 7.8 years (2 years).
Ever vs. never GC users. Age, gender, RA, rheumatoid factor, baseline
smoking history, use of DMARDs use,
erosive joints, baseline health assessment
questionnaire.
Lacaille et al.
35
Retrospective longitudinal study of a population-based RA
cohort (n¼27,710).
Current exposure to oral GCs determined daily during
follow-up as binary variable (yes/no). 12,302 (44%)
patients used GCs.
Use of DMARDs, prior infection, comorbidity
index, age, gender, RA duration and
socioeconomic status.
Smitten et al.
36
Retrospective cohort study based on claims data including
24,530 RA patients and 500,000 non-RA subjects.
Oral GC use was categorized into 3 categories of pred-
nisone equivalents: 5, 6–10 and410 mg/day. 46.9%
of RA patients used GCs during follow-up (17.9% at
cohort entry).
Age, gender, other RA medications, comor-
bidities, orthopedic procedures, number of
hospitalizations between cohort entry and
the index date, whether or not the patients
saw a rheumatologist during follow-up.
Dixon et al.
37
Case–control study matching 1947 serious infection
cases to 9735 controls selected from 16,207 RA eld-
erly patients found in an administrative database.
74.4% of cases and 58.5% of controls ever used GCs.
Average oral GC dose in past 90 days was 7.1 mg
prednisolone equivalent for cases and 5.4 mg pred-
nisolone equivalent for controls.
Age, surrogate marker of disease severity, use
of other immunosuppressants, use of
DMARDs, use of gastric-acid-suppressive
drugs, comorbidities, number of hospital
admissions, number of general practitioner
and hospital specialist visits.
Dixon et al.
38
Cohort study of 13,634 RA elderly patients and 68,170
controls from an administrative database.
37.9% of RA patients exposed to oral GCs within past 45
days. Oral GC doses converted to daily prednisolone
equivalent and categorized as 55 mg (3.2%), 5–
9.9 mg (17.8%), 10–14.9 mg (9.5%), 15–19.9mg
(2.7%) and 20 mg (4.7%). 2.2% of RA patients
received systemic GC injection within past 45 days.
Age, gender, surrogate marker of disease
severity, gastric-acid-suppressive drugs,
comorbidities.
(Continued)
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Table 1. Continued.
Study Design and size of the RA population GC exposure Adjusting factors
Herpes zoster
Wolfe et al.
39
Longitudinal study of 10,614 RA patients. 41.1% of patients used prednisone. Age, gender, health assessment questionnaire
score, education level, smoking, comor-
bidities and other RA treatments.
Smitten et al.
40
Retrospective cohort study of 2 large databases,
PharMetrics with 122,272 RA patients and GPRD with
38,621 RA patients.
Exposure was approximated based on the number of days
supplied as observed in the databases.
Age, gender, use of COX-2 inhibitors, use of
NSAIDs, comorbidities, orthopedic pro-
cedures, number of visits to a health care
provider between cohort entry and the
index date, whether or not the patients saw
a rheumatologist during follow-up.
Tuberculosis
Brassard et al.
41
Cohort study of 24,282 RA patients from physician billing
and hospitalization database.
18% of patients with tuberculosis were current GC users
compared to 8% for control subjects (p¼0.03).
Age, gender, comorbidities, use of DMARDs,
COX-2 inhibitors and NSAIDs.
Hyperglycemia
Panthakalam et al.
42
Case notes analysis of 250 RA patients. 102 (40.8%) patients were on GCs for a median duration
of 24 months (range 6 to 60 months). 76 (30.4%)
patients were receiving oral prednisolone (28 at 5 mg/
day, 40 at 7.5 mg/day, 6 at 10 mg/day and 2 at 15mg/
day). 25 (10.0%) patients were given parenteral
methylprednisolone. 1 (0.4%) patient was on deflaza-
cort at 6 mg/day.
No multivariate analysis conducted.
Cutaneous abnormalities
Douglas et al.
43
Cross-sectional study of 205 consecutive RA patients and
144 non-inflammatory rheumatic conditions.
85 (41.5%) patients received oral GCs. Age, gender, disease duration, diagnosis of
RA, use of NSAIDs and DMARDs).
Gastrointestinal perforation
Curtis et al.
44
40,841 RA patients from a large US administrative med-
ical and pharmacy database.
70.3% of gastrointestinal perforation cases were exposed
to oral GCs at the time of the event. 50.1% of non-
cases were exposed to oral GCs.
Age, gender, comorbidities, RA medications
including biologic, methotrexate and
NSAIDS, previously recognized diverticu-
litis and baseline proton pump inhibitor
use.
Respiratory infection
Coyne et al.
45
Clinical records of 1522 RA patients from a single center. 37% of patients admitted for lower respiratory tract
infection were oral GCs users compared to 14% of
patients not admitted.
No multivariate analysis conducted.
Self-reported health problems
Huscher et al.
46
779 RA patients from multiple rheumatology units. 307 (39.4%) patients did not receive GCs over the last 12
months. 101 (13.0%) patients received less than 5 mg/
day GCs, 281 (36.1%) patients received between 5 and
7.5 mg/day GCs and 90 (11.5%) patients received
more than 7.5 mg/day GCs for more than 6 months.
Age, gender, disease duration, disease
severity and comorbidities.
RA, Rheumatoid Arthritis; GC, Glucocorticoid; BMI, body mass index; HAQ, Health Assessment Questionnaire; DMARD, Disease Modifying Anti-Rheumatic Drug; MI, Myocardial Infarction; COX-2, Cyclo-oxygenase 2; NSAID,
Non-Steroidal Anti-inflammatory Drug.
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to 2.74) and a 3.06 (HR ¼3.06, 95% CI: 1.81 to 5.18) -fold
increased risk of cardiovascular events, whereas RF-
negative patients with high cumulative exposure were
not at increased risk. These findings suggest that GCs
interact with the RF status of patients to modulate the
occurrence of cardiovascular events.
Hypertension, that is one of the most common risk fac-
tors for cardiovascular disease, is also highly prevalent in
RA. Panoulas et al.
31
categorized 400 consecutive RA
patients into three groups according to GC exposure: no/
limited exposure; low-dose (57.5 mg)/long-term exposure;
medium-dose (7.5 mg)/long-term exposure. The authors
report that hypertension was more prevalent in the
medium-dose/long-term exposure group (84.7%) than
the low-dose/long-term exposure group (70.7%) or the
no/limited exposure group (67.3%) (p¼0.028). Logistic
regression revealed increased odds for hypertension
when comparing the medium-dose/long-term group
with the no/limited exposure group, after adjustment for
hypertension risk factors (OR ¼2.57, 95% CI: 1.01 to
6.56) and RA disease characteristics (OR ¼3.64, 95%
CI: 1.36 to 9.77). Medium-dose/long-term GC exposure
would be thus associated with a very high prevalence of
hypertension.
Wolfe and Michaud
32
found that prednisone was asso-
ciated with subsequent myocardial infraction regardless of
whether all myocardial infractions or first myocardial
infractions were studied. The odds ratios ranged from 1.4
(95% CI: 1.0 to 1.8) to 1.7 (95% CI: 1.3 to 2.3). Use of
GCs was also associated with future development of dia-
betes (HR ¼1.7, 95% CI: 1.3 to 2.2) and hypertension
(HR ¼1.2, 95% CI: 1.1 to 1.4).
Myasoedova et al.
33
found that the risk of heart failure
was associated with RF positivity (HR ¼1.6, 95% CI: 1.0
to 2.5), ESR at RA incidence (HR ¼1.6, 95% CI: 1.2 to
2.0), repeatedly high ESR (HR ¼2.1, 95% CI: 1.2 to 3.5),
severe extra-articular manifestations (HR ¼3.1, 95% CI:
1.9 to 5.1), and current GC use (HR ¼2.0, 95% CI: 1.3 to
3.2), adjusting for cardiovascular risk factors and coronary
heart disease.
Infections
Excess mortality in RA is a reality and can be partly due to
an increased occurrence of infection. Infections occurring
in RA may be related to host factors, RA itself, inflamma-
tion, or medication side effects such as those caused by
GCs. Franklin et al.
34
reported that smoking history
(RR ¼1.6, 95% CI: 1.0 to 2.5), RF-positivity (RR ¼2.0,
95% CI: 1.3 to 3.0) and GC use (RR ¼2.2, 95% CI: 1.5 to
3.4) were significantly independent predictors of infec-
tion-related hospitalization. Patients with inflammatory
polyarthritis with all three factors were more than 7.4
times as likely to be hospitalized compared with the rest
of the cohort (RR ¼7.4, 95% CI: 3.3 to 16.8).
Lacaille et al.
35
studied risk factors for mild infections
(defined as those requiring a physician visit or antibiotics
prescription) and serious infections (defined as those
requiring or complicating hospitalization) in RA.
The use of Disease Modifying Anti-Rheumatic Drugs
(DMARDs) without GCs was associated with a small
decrease in mild infection risk of statistical significance
but unclear clinical significance (adjusted RR ¼0.90,
95% CI: 0.88 to 0.93) relative to no DMARD and no
GC use. Use of DMARDs without GCs was not associated
with increased serious infection risk (adjusted RR ¼0.92,
95% CI: 0.85 to 1.0). However, the use of GCs increased
the risk of mild (adjusted RR ¼1.15, 95% CI: 1.11 to 1.19)
and serious infections (adjusted RR ¼1.90, 95% CI: 1.75
to 2.06). These findings indicate that use of non-biologic
DMARDs, including methotrexate, does not increase the
risk of infection in RA, whereas use of GCs does.
Smitten et al.
36
also found that the rate of first hospita-
lized infection was higher in a cohort of RA patients as
compared to a comparison cohort of non-RA patients
(adjusted HR ¼2.03, 95% CI: 1.93 to 2.13). In the case–
control analysis, oral GC use increased the risk of hospi-
talized infection (RR ¼1.92, 95% CI: 1.67 to 2.21). There
was also a dose-related effect (5 mg/day: RR ¼1.32 [95%
CI: 1.06 to 1.63], 6 to 10 mg/day: RR¼1.94 [95% CI: 1.53
to 2.46], 410 mg/day: RR ¼2.98 [95% CI: 2.41 to 3.69]).
These data confirm that individuals with RA are at
increased risk of hospitalized infection compared to those
without RA.
Dixon et al.
37
conducted a more specific study. They
explored the relationship of the risk of serious infection
with current and prior oral GC therapy in elderly RA
patients. From a case–control analysis, the authors
showed that a current user of 5 mg prednisolone had a
30%, 46% or 100% increased risk of serious infection
when used continuously for the last 3 months, 6 months
or 3 years, respectively, as compared to a non-user. The risk
associated with 5 mg prednisolone taken for the last 3 years
was similar to that associated with 30 mg taken for the last
month. Discontinuing a 2 year course of 10 mg prednisol-
one 6 months ago halved the risk compared to ongoing use.
GC therapy is thus associated with infection risk in older
patients with RA. In this study, current and recent doses
had the greatest impact on the risk of infection, but the
cumulative impact of doses taken in the last 2–3 years still
affected risk.
The above studies principally reported on the risk of
serious infection associated with GC intake. Dixon
et al.
38
investigated the association between GCs and
common non-serious infections. The authors report an
incidence rate for non-serious infection of 47.5/100
person-years in RA. The crude rate of non-serious infec-
tion in GC-exposed and unexposed person time was 52.4
and 38.8/100 person-years, respectively. GC therapy was
associated with an adjusted RR of 1.20 (95% CI: 1.15 to
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1.25). A dose response was observed, with the adjusted RR
increasing from 1.10 (55 mg prednisolone/day) to 1.85 for
doses greater than 20 mg/day. All GC risk estimates
(including 55 mg/day) were higher than that seen for
methotrexate (adjusted RR ¼1.00, 95% CI: 0.95 to
1.04). GC therapy was thus associated with an
increased risk of non-serious infection. The magnitude
of risk increased with dose, and was higher than that
seen with methotrexate, although residual confounding
may exist.
Herpes zoster
Wolfe et al.
39
researched the rate and predictors of herpes
zoster in RA and non-inflammatory musculoskeletal
patients. The annualized herpes zoster incidence rate per
1000 patient-years was 13.2 (95% CI: 11.9 to 14.5) in RA
and 14.6 (95% CI: 11.2 to 18.1) in musculoskeletal
patients, and did not differ significantly after adjustment
for age and sex. In multivariable analyses in RA patients,
the rarely used cyclophosphamide (HR ¼4.2, 95% CI: 1.6
to 11.5), azathioprine (HR ¼2.1, 95% CI: 1.3 to 3.3),
prednisone (HR ¼1.6, 95% CI: 1.3 to 1.9), leflunomide
(HR ¼1.4, 95% CI: 1.1 to 1.8) and COX-2 Non-Steroidal
Anti-Inflammatory Drugs (NSAIDs) (HR ¼1.3, 95% CI:
1.1 to 1.6) were significant predictors of herpes zoster.
Methotrexate (HR ¼1.1, 95% CI: 0.9 to 1.3) and non-
COX-2 NSAIDs (HR ¼0.9, 95% CI: 0.8 to 1.1) were
not associated with increased incidence of herpes zoster
in this study.
A few years later, Smitten et al.
40
confirmed this find-
ing. The adjusted HR of herpes zoster for patients with
RA compared with non-RA patients were 1.91 (95%
CI: 1.80 to 2.03) and 1.65 (95% CI: 1.57 to 1.75) in the
two data sources they used, the PharMetrics database
in the US and the GPRD database in the UK respectively.
In both data sources, use of oral GCs was associated
with herpes zoster regardless of concomitant therapies.
This large analysis suggests that RA patients are thus
at increased risk of herpes zoster. Among those,
DMARDs and/or use of oral GCs appeared to be associated
with herpes zoster.
Tuberculosis
Brassard et al.
41
found a standardized incidence rate (SIR)
of 45.8 cases of tuberculosis per 100,000 person-years in
RA. This rate is to be compared with the 4.2 cases per
100,000 person-years in the general population
(SIR ¼10.9, 95% CI: 7.9 to 15.0). The adjusted rate
ratio of tuberculosis in RA patients was 2.4 (95% CI: 1.1
to 5.4) with GC use and 3.0 (95% CI: 1.6 to 5.8) with non-
biologic DMARD use. At least some of the tuberculosis
risk may thus be related to non-biologic DMARD and GC
therapies.
Hyperglycemia
Panthakalam et al.
42
reviewed the case notes of 102
patients with established RA and on long-term steroids.
Nine patients (8.8%) developed diabetes mellitus during
treatment, but only one patient was detected and mana-
ged. There were six patients with existing diabetes mellitus
in whom glycemic control worsened between 3 to
6 months, but only one patient had treatment adjusted.
The authors warn that physicians need to be aware
that GCs can increase blood glucose, worsen pre-existing
diabetes and predispose to diabetes mellitus.
Cutaneous abnormalities
Douglas et al.
43
studied 205 RA patients and 144 non-
inflammatory rheumatic patients for cutaneous abnormal-
ities. In the whole group, current steroid use and having
RA were the only important predictors of having any cuta-
neous abnormality. More specifically, scars (3.9% vs. 0.0%,
p50.05), vasculitis skin changes (4.4% vs. 0%, p50.05),
athlete’s foot (7.3% vs. 2.1%, p50.05), cushingoid facies
(9.8% vs. 0%,50.001), bruising (16.1% vs. 4.9%,
p50.01) and rheumatoid nodules (19.0% vs. 0%,
p50.001) were more common in RA patients than in
non-inflammatory controls. In multivariable logistic
regression, the only predictors of cutaneous abnormality
were the diagnosis of RA and the use of oral prednisolone
(Wald’s test 10.38, p¼0.01). In specific logistic regres-
sions for each cutaneous abnormality considered separ-
ately, current use of GCs only predicted bruising (Wald’s
test 22.9, p50.001).
Gastrointestinal perforation
Curtis et al.
44
found 37 hospitalizations for gastrointestinal
perforation in a large cohort of 40,840 RA patients taken
from an administrative database of a large US health plan
treated with biologic agents, methotrexate, oral GCs and
NSAIDs. The rate of gastrointestinal perforation among
patients currently being treated with biologic agents who
were also receiving oral GCs was higher (1.12 per 1000
person-years, 95% CI: 0.50 to 2.49) than for patients being
treated with biologic agents who were not also receiving
GCs (0.47 per 1000 person-years, 95% CI: 0.22 to 0.98) or
for patients being treated with methotrexate who were also
receiving GCs (0.87 per 1000 person-years, 95% CI: 0.36
to 2.10). Neither biologic agents nor methotrexate were
significantly associated with gastrointestinal perforation,
in contrast to current treatment with GCs and NSAIDs
together (HR ¼4.7, 95% CI: 1.9 to 12.0) or GCs alone
(HR ¼2.8, 95% CI: 1.3 to 6.1). Diverticulitis also was a
strong risk factor (HR ¼9.1, 95% CI: 3.1 to 26.4). Of note,
70% of patients with gastrointestinal perforation received
GCs, had antecedent diverticulitis, or both. Even if
uncommon, gastrointestinal perforation remains a serious
adverse event among RA patients and in this study, the
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majority of patients with gastrointestinal perforation was
being treated with GCs or had previously experienced
diverticulitis.
Respiratory infection
Coyne et al.
45
identified all episodes of lower respiratory
tract infection in their RA population over a 12 month
period. The overall annual incidence of lower respiratory
tract infection in RA patients was 2.3% with a mortality
rate reaching 22.5%. Oral steroids and not taking
DMARDs were associated with an increased risk of hos-
pital admission with lower respiratory tract infection.
This study showed that respiratory infection is relatively
common in RA patients and carries a high mortality risk.
Oral steroids predispose to respiratory infection, while
DMARDs do not.
Self-reported health problems
Huscher et al.
46
investigated patterns of adverse effects
related to dose and duration of GC therapy in RA patients
from routine practice. The authors compared four groups of
patients: group 1, patients without any GC treatment for at
least 12 months; groups 2, 3 and 4, patients with ongoing
GC therapy for more than 6 months and current doses of
less than 5 mg/day, between 5 and 7.5 mg/day and over
7.5 mg/day prednisone equivalent, respectively.
Although the analysis was based on self-reported health
problems, two distinct dose-related patterns of adverse
events were observed. On the one hand, a ‘linear pattern’
rising with increasing dose was found for cushingoid
phenotype (2.7%, 4.3%, 15.8% and 24.6% for group 1, 2,
3 and 4 respectively), ecchymosis (6.8%, 17.4%, 23.5%
and 24.6%), leg edema (9.5%, 11.6%, 20.2%, and
26.2%), parchment-like skin (3.2%, 10.1%, 15.8%,
and 21.3%) and sleep disturbance (20.7%, 33.3%, 37.2%
and 44.3%). On the other hand, a ‘threshold pattern’
describing a much higher frequency of certain health
problems beyond a certain threshold value was observed.
For instance, dosages over 5 mg/day were associated
with higher frequencies of epistaxis (1.4%, 1.4%, 6.6%
and 4.9%), and weight gain (9.5%, 8.7%, 22.4%
and 21.3%).
Findings from systematic reviews
General findings
Hoes et al.
47
systematically reviewed the literature on
reported adverse events of low- to medium-dose GCs
during more than 1 month for inflammatory diseases. In
14 studies comprising 796 RA patients in total the risk of
adverse events was 43/100 patient-years (95% CI: 30 to
55). In most studies aimed at efficacy of GCs or other
drugs, adverse events were not systematically assessed.
The authors noticed the lack of clear guidelines on the
assessment of adverse events.
Ravindran et al.
48
conducted a meta-analysis to assess
the toxicity related to medium- to long-term (defined as 1
year or longer) GC therapy in RA. They included six
RCTs totaling 689 RA patients. All RCTs lasted for 2
years or more and allowed concomitant use of NSAIDs
and DMARDs. Toxicity of GC therapy based on number
of patients withdrawn was limited (OR ¼1.09, 95% CI:
0.52 to 2.25). Using the number of adverse events per
patient-year (OR ¼1.19, 95% CI: 0.91 to 1.57) and the
number of serious adverse events (OR ¼1.06, 95% CI:
0.67 to 1.67) produced similar results. The efficacy/toxicity
ratio was rather good for GC therapy (number needed to
harm/number needed to treat ¼0.25).
Bone loss
In their meta-analysis, Lee et al.
49
confirmed the deleteri-
ous effect of low-dose GCs on bone mineral density in RA
patients as evidenced by observational studies. Their
review found that low-dose GCs resulted in a moderate
worsening in lumbar bone mineral density compared
with controls (standardized mean difference
[SMD] ¼0.483, 95% CI: 0.815 to 0.151,
p¼0.004), whereas the femoral bone mineral density dif-
ferences were not significant (SMD ¼0.224, 95% CI:
0.663 to 0.215, p¼0.318). Subgroup analysis of bone
mineral density data performed on a change-from-baseline
basis showed that GCs had a clear effect on both lumbar
and femoral bone mineral densities (SMD ¼0.354, 95%
CI: 0.620 to 0.088, p¼0.009; SMD ¼0.488, 95% CI:
0.911 to 0.065, p¼0.024, respectively).
Infections
Two systematic reviews documented the association
between the use of GCs and the risk of infections.
Ruyssen-Witrand et al.
50
studied the association between
the risk of infection and low-dose GCs (defined as a daily
dose 510 mg/day of prednisone) in RA. They found 15
reports assessing infection risk of low-dose GCs in RA
patients. Of the eight reports that studied all types of infec-
tion, six found no association between risk of infection and
low-dose GCs, one showed an association between severe
infections and low-dose GCs (OR ¼8, 95% CI: 1 to 64)
and another showed a dose-dependent association includ-
ing doses of less than 5 mg/day (RR ¼1.32, 95% CI: 1.06 to
1.63) and doses between 6 to 10 mg/day (RR ¼1.95, 1.53
to 2.46). Of the three trials that studied infection risk sec-
ondary to bacteria, one showed an increased risk
(HR ¼1.7, 95% CI: 1.5 to 2.0) while two did not. None
of the three trials studying postoperative infection risk
found any association between infection risk and low-
dose GC treatment. Two reports studied herpes zoster
risk and found no association with low-dose GCs.
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The authors pointed out a paucity of data about low-dose
GCs and the risk of infection in RA. They conclude that
the risk of infection seems nevertheless mildly increased
and call for further studies.
In another review, Dixon et al.
51
found that in RCTs
GC therapy was not associated with a risk of infection
(RR ¼0.97, 95% CI: 0.69 to 1.36). However, the authors
noted that the small numbers of events in the RCTs meant
that a clinically important increased or decreased risk
could not be ruled out. In observational researches, the
RR reached 1.67 (95% CI: 1.49 to 1.87), although signifi-
cant heterogeneity was present. The increased risk and
heterogeneity persisted when analyses were stratified by
varying definitions of exposure, outcome, and adjustment
for confounders. A positive dose–response effect was seen.
According to the results of this review, observational stu-
dies suggested an increased risk of infection with GC ther-
apy whilst RCTs suggested no increased risk. However, the
authors concluded that the inconsistent reporting of safety
outcomes in the RCTs, marked heterogeneity, probable
residual confounding and publication bias in the observa-
tional studies, limits the opportunity for a definitive
conclusion.
Cardiovascular risk
Ruyssen-Witrand et al.
52
assessed the association between
cardiovascular risk and low-dose GCs (defined as a daily
dose510 mg/day of prednisone) in RA patients. An asso-
ciation of low-dose GCs with major cardiovascular events
was found in four out of six studies. This included myocar-
dial infarction (HR ¼1.7, 95% CI: 1.2 to 2.3), stroke
(OR ¼4.36, 95% CI 1.60 to 11.90 for low-dose GCs
between 6 and 10 mg/day), mortality (HR ¼2.03, 95%
CI: 1.25 to 3.32) and a composite index of cardiovascular
events (in the group of RF positive RA, HR ¼2.21, 95%
CI: 1.22 to 4.00). Two studies out of six did not find any
significant association between low-dose GC exposure and
mortality (OR ¼2.25, 95% CI: 0.29 to 102.5) or a com-
posite index of cardiovascular events (OR ¼1.3, 95% CI:
0.8 to 2.0). Although the literature review showed poor
association between low-dose GCs exposure and cardio-
vascular risk factors, the author identified a trend of
increasing major cardiovascular events with low-dose
GC therapy.
Discussion
The major side effects of GCs in RA are bone loss, risk of
cardiovascular events and risk of infections as evidenced
by large observational studies and not necessarily RCTs.
These are mostly adverse effects resulting from relatively
long-term exposure to GCs. GCs are largely used in RA
and knowing their safety profile is essential to improving
patients care. In any event, these observations suggest that
daily doses of GCs are to be minimized for patients who are
likely to receive long-term treatment for a chronic condi-
tion such as RA. A good understanding of the risks and
benefits of possible therapies has also important practical
implications for selecting the optimal therapy and for
counseling patients
53,54
.
Ideally, a good comprehension of how the risk of
adverse effects depends on dosing patterns is necessary.
However, and despite the scattered evidence emanating
from observational researches, such dosing pattern remains
hard to characterize
46
. Knowing the safety profile of GCs is
also important because GCs are being used to improve the
benefit/risk ratio of newer therapy against more advanced
RA. For instance, daily low-dose GCs has been shown
to significantly decrease the risk for treatment-limiting
infusion reactions to infliximab
55
. Small dose of oral pred-
nisone was shown to be an effective and safe pretreatment
for rituximab in RA patients to decrease acute infusion
reactions
56
.
GC induced osteoporosis is the most acknowledged
long-term adverse effect of GC therapy in RA. Multiple
studies have shown the efficacy of preventive action
and medication against osteoporosis and fracture in RA
patients treated with GCs
57–62
. Nonetheless, several
reports point out the fact that RA patients under GC ther-
apy are not routinely screened with bone densitometry
or prescribed with preventive medication for osteopor-
osis
63–69
. However, it should be kept in mind that the eti-
ology of bone loss is multifactorial and may include local
inflammation around joints, release of bone-absorbing
cytokines, physical inactivity and malnutrition in addition
to GC exposure
70
.
Beside these considerations about GC induced bone
loss, other important concerns such as cardiovascular and
infection risks should also be addressed by clinicians while
patients are under GC therapy. For instance, Gazi et al.
discussed the potential role of statins in prevention of car-
diovascular risk in RA patients
71
. Panoulas et al. called for
RA-specific screening strategies and management algo-
rithms for hypertension
72
. Housden et al. suggested that
it is possible to significantly reduce morbidity and mortal-
ity from chest infections in RA by immunizing patients
against influenza and pneumococcus, by halving steroid
intake and by suspending disease modifying treatments
during acute infection
73
. As for bone loss, the etiology of
those potential cardiovascular and infectious complica-
tions under GC therapy is multifactorial
74,75
.
Other potential adverse effects of GCs were studied
but no association was found with GC therapy. These
include psychological disorders
76
, dermatophytosis
77
,
brain diseases
78
, interstitial lung disease
79
, memory
deficit
80
, metabolic syndrome
81
, lymphoma
82
, non-
Hodgkin’s lymphoma
83
, renal function
84
and cerebrovas-
cular accidents
85
. However, we did not identify any spe-
cific studies on the potential association of GC use and the
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incidence of osteonecrosis of the femoral head. This is
surprising as GCs have been shown to be among the
most common and non-traumatic causes of osteonecrosis
of the femoral head
86,87
. Moreover, our review did not find
evidence with regard to the impact of GCs on eye disorders
and on the endocrinium.
Our review has some limitations that should be
acknowledged. First, it is a non-systematic review. The
selection of studies depended on our own criteria only.
We may have missed important safety information ema-
nating from RCTs. However, we were able to identify sys-
tematic reviews that included RCTs and dealt with the
main adverse effects we also identified in observational
researches, such as bone loss, cardiovascular risk and infec-
tions risk. Second, many of the included studies were
observational studies and the inherent limitations of
such studies should be borne in mind. Nonetheless, most
RCTs aim at assessing efficacy. Insofar as safety outcomes
are concerned, RCTs generally do not reach the 5% sig-
nificance level for showing a relevant safety signal. In add-
ition, in RCT publications, adverse events below 1% or
2% are not listed or just summarized without specification,
making the proper evaluation of safety complicated.
A series of important questions is also left uncharted by
our analysis. First, our analysis only dealt with systemic
GCs and not intra-articular GCs. Intra-articular GCs
also can have systemic adverse effects but of different
extent depending on their galenic formulation and resi-
dence time in the joint. Second, we did not identify any
estimates of the impact of GC therapy in specific subsets of
the RA population such as children, pregnant women, the
elderly or those patients with comorbid conditions such as
diabetes. Third, we were unable to address the safety issue
of individually tailored dosing. Finally, to document how
the increased and early use of methotrexate, followed by
the use of biotherapies really impacted on the use of GCs
in RA. All of the above are important questions for which
there is a lack of quantitative data in the literature.
The use of GCs in RA continues to be debated. Even if
absent from international RA treatment recommenda-
tions, relatively low-dose GCs seem to have their place
in the treatment of RA
88
. This is supported by systematic
reviews of controlled trials of short- or medium-term treat-
ments and long-term accumulated clinical experience
89,90
.
If possible, the findings of larger and longer-term observa-
tional studies should also be taken into account to balance
treatment recommendations. Despite their inherent limi-
tations, observational researches can document clinical
pathways, treatments effectiveness and treatments safety
among more representative samples of real-world patients.
In this review, even though we have identified up to 35
observational researches, it has proven difficult to synthe-
size dose- and duration-dependent adverse effects due to
the heterogeneity of studies, notably in the way they
reported exposure to GCs and analyzed the link to adverse
effects. This calls for further observational researches on
large group of RA patients. Ideally, these studies should
describe GC exposure in sufficient detail to draw more
conclusive safety statements and further contribute to
the debate on the use of GCs in RA.
A better understanding of the GC safety profile may
guide the development of new compounds or new GC for-
mulations, ideally dispensing a similar anti-inflammatory
effect but with lower toxicity
91
. We are today getting a
better sense of the GC mechanism of action which may
help in the design of newer and safer formulations
92–94
. For
instance, Spies et al. mention novel compounds like
Selective Glucocorticoid Receptor Agonist (SEGRAs)
or liposomal GCs with the potential to improve the risk–
benefit ratio
95
.
Optimizing the use of conventional GCs is also a wise
approach
96
. One example is a new modified-release pred-
nisone tablet formulation developed to be taken in accord-
ance with biological rhythms (chronotherapy)
97,98
. This
new formulation has been shown to be clinically and sig-
nificantly better than the conventional immediate-release
preparation with respect to reducing morning stiffness
of the joints
95,99,100
. Moreover, there is some evidence
that the administration of GCs in accordance with the
circadian rhythm may actually improve the hypothal-
amic–pituitary–adrenal axis function
101
.
In today’s resource constrained healthcare systems,
economic considerations cannot be ignored in developing
new compounds. A model to assess the cost of GC asso-
ciated adverse events in RA has been proposed
102
. The
authors developed a Markov model with the following
adverse events: fractures (vertebral, hip, pelvic), hyperten-
sion, diabetes, gastrointestinal complications, pneumonia,
urinary tract infection, cataract, myocardial infraction and
stroke. Such a model could be updated with the latest
safety data identified in this report. Then, the improved
risk–benefit profile of potential newer compounds or GC
dose-lowering strategies could be described.
Conclusion
Our review of recent observational data and systematic
reviews suggests that GCs can lead to relatively larming
and burdensome side effects in RA. This is particularly true
for patients who have longer term and higher dose thera-
pies. The design of new therapeutic strategies intended to
minimize the daily dosing of GC therapies while conser-
ving their beneficial effect should be encouraged.
Transparency
Declaration of funding
The authors received no payment in preparation of this
manuscript.
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Declaration of financial/other relationships
O.E. and F.d.L.E. have disclosed that they have no significant
relationships with or financial interests in any commercial com-
panies related to this study or article. O.B. has received grant
research from IBSA, Merck Sharp & Dohme, Novartis,
Nutraveris, Pfizer, Rottapharm, Servier, and Theramex; consult-
ing or lecture fees from Bayer, Genevrier, IBSA, Rottapharm,
Servier, and SMB; and reimbursement for attending meetings
from IBSA, Merck Sharp & Dohme, Novartis, Pfizer,
Rottapharm, Servier, and Theramex. J.-Y.R. has received con-
sulting fees or paid advisory boards from Servier, Novartis,
Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline, Roche,
Merckle, Nycomed, NPS, Theramex, and UCB; lecture fees
from Merck Sharp and Dohme, Lilly, Rottapharm, IBSA,
Genevrier, Novartis, Servier, Roche, GlaxoSmithKline, Teijin,
Teva, Ebewee Pharma, Zodiac, Analis, Theramex, Nycomed,
Novo-Nordisk, and Nolver; and grant support from Bristol
Myers Squibb, Merck Sharp & Dohme, Rottapharm, Teva,
Lilly, Novartis, Roche, GlaxoSmithKline, Amgen, and Servier.
CMRO peer reviewers may have received honoraria for their
review work. The peer reviewers on this manuscript have dis-
closed that they have no relevant financial relationships.
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