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Overview of the pharmacologic use of glucocorticoids
INTRODUCTION
Natural and synthetic glucocorticoids (also called steroids) can be used for a variety of
disorders. These agents are most commonly given in pharmacologic doses to manage
conditions that require the suppression of inflammation. Less often, they are used to
establish the diagnosis and cause of Cushing syndrome and for hormone replacement in
adrenal insufficiency and congenital adrenal hyperplasia.
This article will review key points in the pharmacology of glucocorticoids and factors involved
in choosing a glucocorticoid regimen. Other aspects of glucocorticoid use are discussed
separately:
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�������: Daniel E Furst, MD, Kenneth G Saag, MD, MSc
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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2024.
This topic last updated: Mar 11, 2024.
Use of topical corticosteroids (see "Topical corticosteroids: Use and adverse effects")●
Effects of glucocorticoids on the immune system (see "Glucocorticoid effects on the
immune system")
●
Glucocorticoid withdrawal (see "Glucocorticoid withdrawal")●
Perioperative management for patients taking glucocorticoids (see "The management
of the surgical patient taking glucocorticoids")
●
Glucocorticoid use in pregnancy and lactation (see "Safety of rheumatic disease
medication use during pregnancy and lactation", section on 'Glucocorticoids')
●
Adverse effects (see "Glucocorticoid effects on the immune system" and "Major adverse
effects of systemic glucocorticoids" and "Major side effects of inhaled glucocorticoids"
and "Joint aspiration or injection in adults: Complications", section on 'Glucocorticoid-
associated toxicity')
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GENERAL PRINCIPLES OF USE AND INDICATIONS
Glucocorticoids are widely available, quick acting, and often well tolerated when used for
short periods at low doses. However, their wide range of adverse effects and cumulative
toxicity highlight the importance of reserving their use for specific scenarios.
General principles of use — In general, we use the following guidelines for pharmacological
glucocorticoid therapy:
Natural patterns of endogenous cortisol — It is important to understand baseline levels
and rhythms of endogenous glucocorticoids like cortisol to anticipate the effects of adding
exogenous glucocorticoids. Cortisone is normally produced in the adrenal glands and must
be converted to the active form, cortisol. The biosynthesis of endogenous glucocorticoids is
described in detail elsewhere. (See "Adrenal steroid biosynthesis".)
Healthy patients produce a daily amount of cortisol that is equal to approximately 7 to 10 mg
per day [1] and can, rarely, increase this up to 400 mg when subjected to significant
physiologic stress [2,3]. This is why patients taking pharmacologic doses of glucocorticoids
that are less than this physiologic amount (eg, less than prednisone 5 mg per day) are at
slightly lower risk for developing adrenal insufficiency. Similarly, it is why patients who have
Only use glucocorticoids for symptoms or diagnoses for which there is published
evidence of an objective therapeutic benefit. (See 'Indications for pharmacologic
glucocorticoids' below.)
●
Only use glucocorticoids when more specific therapies are insufficient, ineffective, or
contraindicated. (See 'Indications for pharmacologic glucocorticoids' below.)
●
Choose a glucocorticoid preparation, route, and dose that will maximize benefit and
minimize risk for the patient. (See 'Choosing a glucocorticoid regimen' below.)
●
Monitor response to glucocorticoids with objective criteria related to a specific
therapeutic goal.
●
Give glucocorticoids for a sufficient duration to achieve the desired response, but no
longer than necessary.
●
Stop glucocorticoids when maximum benefit has been achieved, if complications arise,
or if the objective therapeutic goal is not observed when expected.
●
Monitor for adverse effects related to glucocorticoids. (See 'Adverse effects' below and
"Major adverse effects of systemic glucocorticoids", section on 'Monitoring and
treatment of adverse effects'.)
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adrenal insufficiency may require temporarily higher doses of pharmacologic glucocorticoids
when they experience stress physiology.
Cortisol levels vary during the day, peaking in the early morning around 6:00 to 9:00 AM and
reaching a nadir in the evening between 8:00 PM and 2:00 AM [4]. This is one reason for
administering pharmacologic glucocorticoid doses in the morning to better mimic the
natural circadian rhythm.
Indications for pharmacologic glucocorticoids — There are numerous indications for
different types of glucocorticoid therapy. We reserve glucocorticoid use for symptoms or
diagnoses for which there is published evidence of an objective therapeutic benefit and only
when more specific therapies are insufficient, ineffective, or contraindicated. While the
following list is not comprehensive, some examples include:
PHARMACOLOGY
Inflammatory, allergic, and immunological disorders – Pharmacologic (usually
supraphysiologic) doses of glucocorticoids are used to treat patients with inflammatory,
allergic, and immunological disorders [5]. Often glucocorticoid courses are short, but
occasionally patients will require therapy for years. Examples of conditions where
glucocorticoids may be used include oral preparations in polymyalgia rheumatica,
inhaled preparations in asthma, and topical preparations in atopic dermatitis (eczema).
Glucocorticoids can also be used to achieve intentional immunosuppression in patients
receiving organ transplantation. (See "Treatment of polymyalgia rheumatica", section
on 'Systemic glucocorticoids' and "An overview of asthma management in children and
adults", section on 'Initiating pharmacologic treatment' and "Treatment of atopic
dermatitis (eczema)", section on 'Topical corticosteroids'.)
●
Endocrine disorders – In endocrine practice, glucocorticoids are given to establish the
diagnosis and cause of Cushing syndrome. They are also used for treatment of adrenal
insufficiency using physiologic replacement doses and for treatment of congenital
adrenal hyperplasia. (See "Establishing the diagnosis of Cushing syndrome", section on
'Low-dose dexamethasone suppression tests' and "Treatment of adrenal insufficiency in
adults", section on 'Glucocorticoid replacement for all patients' and "Treatment of
classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults",
section on 'Glucocorticoid therapy for all patients'.)
●
Medical emergencies – High doses of glucocorticoids may be warranted in emergency
situations in which therapeutic benefit has not been clearly demonstrated but might be
anticipated, such as anaphylaxis, septic shock, or macrophage activation syndrome.
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Mechanisms of action — Glucocorticoids primarily exert effects via up- or downregulation
of gene transcription, but other mechanisms have also been proposed [4]. Mechanisms
include:
Polymorphisms in the glucocorticoid receptor gene may increase or decrease sensitivity to
glucocorticoids and, therefore, affect the response to both endogenous cortisol and
exogenous agents [10,11]. Likewise, polymorphisms of the multidrug-resistant transporter 1
gene may influence the therapeutic response to steroids [12].
The downstream effects of glucocorticoids on the immune system are described elsewhere.
(See "Glucocorticoid effects on the immune system".)
Bioequivalence and bioactivity — Different preparations of oral glucocorticoids have the
same rate of absorption and are roughly bioequivalent (ie, the active moieties are equally
absorbed and the same amount of each gets to the site of action). However, some
glucocorticoids (eg, prednisone, prednisolone, dexamethasone) may differ in their potency
and kinetics or have slight variations in their mechanisms of action. As an example, the
systemic bioavailability of prednisone and dexamethasone are equal, but their potencies,
relative antiinflammatory activity, and duration of action are different ( table 1) [13,14].
Bioavailability of synthetic glucocorticoids varies by route of administration and drug
formulation:
Interaction with glucocorticoid receptors – Glucocorticoids passively diffuse through
the cell membrane and bind to cytoplasmic glucocorticoid receptors [4]. The
glucocorticoid receptor-glucocorticoid complex ultimately influences the activation and
repression of gene transcription in a complex process that may involve a variety of
factors including coactivators, corepressors, and receptor phosphorylation.
Glucocorticoid response elements (GREs) are contained in gene promotors and interact
with glucocorticoid receptorhomodimers to promote gene transcription.
●
Interaction with proinflammatory transcription factors – Glucocorticoids and
glucocorticoid receptors directly interact with proinflammatory transcription factors,
specifically nuclear factor kB and activator protein 1, and therefore reduce transcription
of proinflammatory genes [4].
●
Other mechanisms – Data supporting other mechanisms than those described above
are limited. However, it is theorized that alternative mechanisms may be responsible for
the effect of pulse dose glucocorticoids, since glucocorticoid receptors are estimated to
be saturated after a dose equivalent to prednisolone 100 to 200 mg [6]. Potential
mechanisms may include downstream effects of interaction with glucocorticoid or non-
glucocorticoid receptors independent of gene transcription, as well as interaction with
cell and lysosomal membranes [7-9].
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Many synthetic glucocorticoids bind to transcortin (also called corticosteroid-binding
globulin) and/or albumin and are not able to interact with glucocorticoid receptors when
they are bound [4]. Consequently, patients with lower albumin levels may see higher
concentrations of free glucocorticoid and more adverse effects [17]. Synthetic
glucocorticoids do not bind as well to transcortin. When comparing the relative affinity for
binding transcortin between glucocorticoids, prednisolone has approximately 60 percent,
prednisone has 5 percent, and methylprednisolone, dexamethasone, betamethasone, and
triamcinolone have less than 1 percent affinity compared with cortisol.
Metabolism — There are two key enzymes involved in activating or inactivating
glucocorticoids in target cells:
Oral glucocorticoids – The bioavailability of various forms of oral glucocorticoids is
between 60 and 100 percent [4]. Incomplete bioavailability of oral glucocorticoids has
occasionally been noted in certain patients. As an example, in one study, 20 percent of
patients given methylprednisolone showed poor bioavailability (23 to 65 percent)
compared with only 1 of 12 patients given prednisone [15].
●
Inhaled glucocorticoids – The bioavailability of inhaled glucocorticoids varies with the
physical properties of the particular agent. Eighty percent of inhaled glucocorticoids are
swallowed, with the remainder deposited in the lungs. Correct use of a spacer with
inhaler devices may improve drug delivery. (See "The use of inhaler devices in adults"
and "The use of inhaler devices in children".)
●
The absorption of inhaled glucocorticoids also varies with the specific agents. Drugs
that are highly lipophilic (such as fluticasone and beclomethasone) are relatively poorly
absorbed orally (less than 11 percent) and are retained longer in lung tissue when
deposited there. By comparison, agents which are not lipophilic (such as budesonide)
are somewhat better absorbed orally (less than 20 percent). Since all of the drug
deposited in the lung eventually enters the systemic circulation, overall absorption of
inhaled glucocorticoids varies between 20 and 40 percent of the administered dose
[16].
The 11-beta-hydroxysteroid dehydrogenase type 1 isoenzyme converts inactive
cortisone to active cortisol. Many glucocorticoid target tissues express this isoenzyme.
●
The 11 beta-hydroxysteroid dehydrogenase type 2 isoenzyme converts active cortisol to
inactive cortisone. It is found mainly in mineralocorticoid target tissues (kidney, colon,
salivary glands) and in the placenta, where it protects the cell from cortisol activating
the corticosteroid type 1 (mineralocorticoid) receptor. Several glucocorticoid
preparations are protected from oxidation inactivation by the type 2 isoenzyme and
therefore have greater mineralocorticoid effects, including glucocorticoids that are
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Glucocorticoids are ultimately converted to hydrophilic inactive metabolites and renally
excreted. Exogenous glucocorticoids are subjectto the same hepatic reduction, oxidation,
hydroxylation, and conjugation reactions as endogenous steroids. Certain drugs (eg,
phenobarbital, phenytoin, rifampin, mitotane) increase the metabolism of synthetic and
natural glucocorticoids similarly, particularly by increasing hepatic 6-beta-hydroxylase activity
of cytochrome P450 3A4 (CYP3A4) [19-23]. (See 'Drug interactions' below.)
Clearance — The clearance of prednisolone is 210 mL/min per 1.73 m , with an elimination
half-life of approximately three hours. Clearance decreases with age; as an example, children
less than 12 years of age have a 33 percent higher clearance than older children and adults
[15].
Glucocorticoids exhibit dose-dependent kinetics. Total prednisolone clearance increases by
75 percent as the intravenous dose increases from 5 to 40 mg [24,25]. Free prednisolone
clearances also change with administered dose, but to a lesser degree and require larger
doses to demonstrate such kinetics [26]. The clinical consequence of these properties is that
a somewhat greater, nonlinear drug effect is observed at prednisolone doses over 40 mg
compared with doses between 10 to 20 mg.
Clearances also vary with the time of day. Both prednisolone and methylprednisolone
clearance is lower (18 to 28 percent) in the morning than the evening [27,28]. This property,
in combination with the disruption of the usual cortisol diurnal rhythm with exogenous
glucocorticoids, may result in variations in efficacy when glucocorticoids are administered at
different times during the day [29,30]. In one study, for example, the efficacy of prednisolone
was assessed in seven asthmatic patients in whom the drug was given at 8:00 AM and 3:00
PM, and at 3:00 PM and 8:00 PM [31]. The earlier dosing regimen was more effective in
improving nocturnal pulmonary function and symptoms. Less physiological exogenous
glucocorticoids administration (eg, twice daily) results in greater efficacy but also greater
toxicity.
CHOOSING A GLUCOCORTICOID REGIMEN
fluorinated at the 6-alpha or 9-alpha position (dexamethasone, fludrocortisone,
betamethasone), methylated at the 6-alpha position (methylprednisolone), or
methyloxazoline at position 16,17 (deflazacort) [18]. High amounts of cortisol can also
saturate the isoenzyme and lead to increased mineralocorticoid receptor activation. By
contrast, prednisone is more effectively oxidized by 11 beta-hydroxysteroid
dehydrogenase type 2 than is cortisol, which may explain why prednisone has less salt-
retaining activity than cortisol.
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https://www.uptodate.com/contents/methylprednisolone-drug-information?search=corticosteroid&topicRef=7976&source=see_link
https://www.uptodate.com/contents/overview-of-the-pharmacologic-use-of-glucocorticoids/abstract/27,28
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https://www.uptodate.com/contents/methylprednisolone-drug-information?search=corticosteroid&topicRef=7976&source=see_link
https://www.uptodate.com/contents/deflazacort-drug-information?search=corticosteroid&topicRef=7976&source=see_link
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https://www.uptodate.com/contents/prednisone-drug-information?search=corticosteroid&topicRef=7976&source=see_link
When using glucocorticoids, providers should choose a preparation, route, and dose that will
maximize benefit and minimize risk for the patient. They should also be aware of the need
for adjustments in certain diseases and physiologic states, as well as potential drug
interactions.
Common glucocorticoid preparations — There are multiple preparations of systemic
glucocorticoids that vary in their duration of action and potency. These differences and
equivalent doses are summarized in the table ( table 1). All preparations share key
structural features that are essential for biological activity, including the delta-4,3-keto-11-
beta,17-alpha,21-trihydroxyl configuration ( figure 1 and figure 2) that is present in all
natural and synthetic glucocorticoids [32,33]. Some of the more common glucocorticoid
preparations are:
Route of administration — Synthetic glucocorticoids may be given in multiple ways,
including parenteral, oral, and locally administered (eg, topical, inhaled, intraarticular)
routes. Locally targeted administration is preferred when possible to minimize adverse
effects.
Hydrocortisone – Hydrocortisone is the synthetic version of cortisol and is an active
form of glucocorticoid. It is short acting.
●
Prednisolone and prednisone – Prednisolone is the active form of prednisone.
Prednisone metabolizes to prednisolone after oral ingestion. Both are intermediate
acting and have approximately four times more glucocorticoid activity than cortisol
[34,35].
●
Methylprednisolone – Methylprednisolone is an active form of synthetic glucocorticoid.
It is intermediate acting and has five times more glucocorticoid activity than cortisol.
●
Dexamethasone – Dexamethasone is an active form of synthetic glucocorticoid. It is
long acting and has approximately 30 times more glucocorticoid activity than cortisol.
●
Parenteral therapy – Parenteral administration of high doses may be warranted in
emergencies, such as septic shock and severe acute asthma. This route may also be
preferred when it is critical to ensure adequate delivery (eg, concern for malabsorptive
state such as lupus enteritis).
●
Oral administration – Oral preparations are typically used for chronic therapy. They
are absorbed within approximately 30 minutes [36].
●
Local administration – When possible, local glucocorticoid therapy should be used in
an attempt to deliver higher local concentrations while minimizing systemic exposure.
●
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Different formulations of glucocorticoid preparations are being developed to improve
delivery of these drugs (eg, palmitate large porous particles, oral dissolvable film
formulations, nanosuspensions in soft contact lenses, multidose dry powder inhalers), which
may improve the usefulness of glucocorticoids [40-43].
Glucocorticoid dosing — Occasionally, exogenous glucocorticoids are dosed near or below
physiologic levels (typically 10 mg or less of prednisone or its equivalent), such as in patients
with adrenal insufficiency or those with polymyalgia rheumatica. More commonly, they are
given at supraphysiologic doses. In rare circumstances, they may be given as "pulse" doses
(typically 500 to 1000 mg of intravenous methylprednisolone) for severe manifestations of
autoimmune diseases, such as systemic lupus erythematosus. (See "Treatment of adrenal
insufficiency in adults", section on 'Glucocorticoid replacement for all patients' and
"Treatment of polymyalgia rheumatica", section on 'Systemic glucocorticoids' and "Systemic
As examples, providers may use intraarticular injection for joint inflammation,
inhalation therapy for asthma, and topical application for inflammatory skin disorders.
All topical and inhaled glucocorticoids result in some, though variable, systemic
absorption and therefore have the potential for causing hypothalamic-pituitary-adrenal
axis suppression and Cushing syndrome [37-39]. In particular, inhaled fluticasone
propionate appears to have greater systemic absorption and a greater association with
adrenal suppression [37]. (See "Topical corticosteroids: Use and adverse effects",
section on 'Systemic' and "Major side effects of inhaled glucocorticoids", section on
'Systemic adverse effects'.)
Additional considerations for locally administered glucocorticoids include the following:
Injected glucocorticoids – Injected glucocorticoids vary considerably in the rate of
their absorption. Hydrocortisone salts are absorbed from an intramuscular injection
site within minutes, and less soluble esters are absorbed within one hour. Cortisone
acetate is more slowly absorbed, and triamcinolone salts and esters are absorbed
even more slowly. Absorption from intraarticular sites can be highly variable. (See
"Intraarticular and soft tissue injections: What agent(s) to inject and how
frequently?".)
•
Topical glucocorticoids – The degree of absorption of topically administered
glucocorticoids varies depending on multiple factors, including the site of
application on the body, skin integrity, thickness of the stratum corneum, presence
of agents in the glucocorticoid preparations that increase absorption, and using an
occlusive dressing over the glucocorticoid. This is reviewed in more detail elsewhere.
(See "Topical corticosteroids: Use and adverse effects", section on 'Vehicles and
formulations'.)
•
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lupus erythematosus in adults: Overview of the management and prognosis", section on
'Escalationof therapy based on disease activity and severity'.)
Glucocorticoid dosing is also sometimes categorized as low to moderate versus high in an
attempt to define a threshold above which toxicities become more common with prolonged
use. The threshold between low to moderate and high is often defined as up to 1 mg/kg per
day of prednisone in children or 40 mg of prednisone per day in adults. However, adverse
effects can appear at much lower doses. (See "Glucocorticoid effects on the immune system",
section on 'Dose ranges' and "Major adverse effects of systemic glucocorticoids", section on
'Glucocorticoid dose and duration'.)
Patients with primary or iatrogenic adrenal insufficiency may require higher doses of
glucocorticoids when under physiologic stress. While the American College of Rheumatology
(ACR) does not suggest "stress doses" of glucocorticoids at the time of surgery for joint
replacement for patients with rheumatic diseases who are on daily glucocorticoids, other
types of surgeries and patient populations have not been addressed [44]. (See "Treatment of
adrenal insufficiency in adults", section on 'Circumstances requiring glucocorticoid dose
adjustment' and "The management of the surgical patient taking glucocorticoids".)
Glucocorticoid dosing may need to be adjusted to account for potential drug interactions.
(See 'Drug interactions' below.)
Impact of selected diseases and physiologic states — The pharmacokinetics of
glucocorticoids vary with certain diseases and pathophysiologic conditions.
End-stage kidney disease — Patients with end-stage kidney disease (ESKD) typically do not
require dose adjustments for synthetic glucocorticoids, although the pharmacokinetics may
be altered. Among patients treated with hemodialysis, the clearance of total prednisolone is
dose dependent, while the clearance of unbound prednisolone is constant [45]. Hemodialysis
also removes significant amounts of methylprednisolone, thereby resulting in a 32 percent
reduction in plasma half-life relative to those without ESKD [46]. The removal rate of
unbound cortisol in patients treated with peritoneal dialysis is similar to that in patients
without ESKD [46,47].
Nephrotic syndrome — Patients with nephrotic syndrome have low serum concentrations
of albumin and cortisol-binding globulin. However, there are no data suggesting the need for
dosing changes in these patients. Although their bound and therefore total glucocorticoid
concentrations are reduced, the physiologically important unbound (free) serum
concentrations of prednisone and prednisolone are similar to nonnephrotic individuals.
Perhaps because of the differences in protein binding, nonrenal clearance is higher and
renal clearance is lower in patients with the nephrotic syndrome than in those without
nephrotic syndrome [48]. The total prednisolone clearances are higher in nephrotic patients,
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since the increase in nonrenal clearance is of greater magnitude than the reduction in renal
clearance.
Severe liver disease — In the presence of severe liver disease, we commonly use
prednisolone rather than prednisone or methylprednisolone for these patients. This is
because the activation of prednisone via metabolism to 6-beta-hydroxyl compounds may be
impaired, potentially affecting the efficacy of glucocorticoid therapy [49].
Patients who undergo liver transplantation because of hepatic C viral infection should
receive the lowest dose of glucocorticoids following transplantation that is feasible. The
cumulative glucocorticoid dose is correlated closely with post-transplantation hepatitis C
viral load and with mortality rates [50].
Hyperthyroidism — The clearance of prednisolone is increased in hyperthyroidism and
may require slightly higher dosing. In one small study, total prednisolone clearance was
increased by 58 percent and nonrenal clearance (principally hepatic) was increased by 84
percent [51]. There were also small changes in absorption and binding. These differences did
not result in measurable change efficacy, but vigilance is appropriate.
Obesity — Dosing of glucocorticoids in a person with obesity should be based upon the
ideal, rather than total, body weight. Obesity can affect the uptake, storage, and metabolism
of glucocorticoids, although results are somewhat contradictory.
Cystic fibrosis — When using prednisolone in patients with cystic fibrosis, more frequent
dosing may benecessary due to total prednisolone clearance increasing by over 50 percent
[55].
Pregnancy and lactation — Fluorinated glucocorticoids including betamethasone and
dexamethasone are used when an effect on the fetus is desired (eg, to speed fetal lung
maturity in when anticipating premature delivery) because these cross the placenta. By
contrast, the placenta inactivates prednisolone and prednisone and therefore little active
In one study, the volume of distribution and clearance of prednisone in a person with
obesity weighing more than 133 percent of ideal body weight was 20 to 30 percent
higher than in a person without obesity [52].
●
Another report indicated that each 1 percent higher baseline body mass index (BMI)
was associated with a 2.9 percent decline in wake-up and total area under curve (AUC)
cortisol, suggesting that a higher BMI suppresses cortisol [53].
●
One report examining the metabolism of methylprednisolone and dexamethasone
found that clearance among patients with obesity was decreased by approximately 40
percent when compared with those without obesity [54].
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drug reaches the fetus [56]. Glucocorticoids are excreted in small amounts in human milk
and adjustment to breastfeeding may be indicated for certain doses. A more detailed
discussion of the effects of glucocorticoids in pregnancy and lactation is available elsewhere.
(See "Safety of rheumatic disease medication use during pregnancy and lactation", section
on 'Glucocorticoids'.)
Drug interactions — The major drug interactions with systemic glucocorticoids, a summary
of effect(s), and management suggestions are listed in the table ( table 2). For additional
interactions, see the drug interactions program included with UpToDate.
Medications that strongly inhibit or induce cytochrome P450 3A4 (CYP3A4) and/or P-
glycoprotein transporters may significantly alter the glucocorticoid serum concentration
[4,57]. Glucocorticoids undergo metabolism in the liver and other tissues by CYP3A4 and
other transformations. In vitro data suggest that dexamethasone, methylprednisolone, and
prednisolone are also substrates of P-glycoprotein membrane efflux transporters. A list of
medications that inhibit or induce CYP3A4 can be found in this table ( table 3). Common
examples of medications to consider include:
Intranasal and inhaled glucocorticoids can also be affected by coadministration of drugs that
inhibit or induce CYP3A4, which is discussed in detail elsewhere. (See "Major side effects of
inhaled glucocorticoids", section on 'Medication interactions' and "Pharmacotherapy of
allergic rhinitis", section on 'Glucocorticoid nasal sprays'.)
A number of agents often used with glucocorticoids appear to have no substantial
interaction with them. These include azathioprine, methotrexate, histamine antagonists (eg,
famotidine, cimetidine, ranitidine), proton pump inhibitors (eg, omeprazole, pantoprazole,
rabeprazole), and diazepam [69,75-79].
ADVERSE EFFECTS
There are numerous potential adverse effects from glucocorticoids, which are most notable
for patients receiving high doses and/or those with a high cumulative steroid burden over
Medications that increase the systemic glucocorticoid concentration include estrogen
derivatives, such as oral contraceptives [58-61], and strong inhibitors of CYP3A4
( table 3) including some antibiotics (eg, clarithromycin, ritonavir, telaprevir) [62-64]
and antifungals (eg, posaconazole, voriconazole) [4,65,66].
●
Medications that reduce the systemic glucocorticoid concentration include
aluminum/magnesium containing antacids, which decrease prednisone bioavailability
due to decreased oral absorption [67,68], and strong inducers of CYP3A4 (eg,
carbamazepine, phenobarbital, phenytoin and rifampin) ( table 3) [69-74].
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time ( table 4). However, adverse effects can happen even at lower doses, underscoring
the importance of prescribing glucocorticoids judiciously. Adverse effects and recommended
monitoring are described in more detail elsewhere:
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Side effects of anti-
inflammatory and anti-rheumatic drugs".)
SUMMARY AND RECOMMENDATIONS
(See "Glucocorticoid effects on the immune system".)●
(See "Major adverse effects of systemic glucocorticoids".)●
(See "Major side effects of inhaled glucocorticoids".)●
(See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)●
(See "Joint aspiration or injection in adults: Complications", section on 'Glucocorticoid-
associated toxicity'.)
●
General principles of use and indications – Glucocorticoids are widely available, quick
acting, and often well tolerated when used for short periods at low doses. However,
their wide range of adverse effects and cumulative toxicity highlight the importance of
reserving their use for specific scenarios. (See 'General principles of use and indications'
above.)
●
Pharmacology – Glucocorticoids work through various mechanisms, including
interaction with glucocorticoid receptors and proinflammatory transcription factors.
Various formulations of glucocorticoids may differ in their bioactivity, metabolism, and
clearance. (See 'Pharmacology' above.)
●
Choosing a glucocorticoid regimen●
Preparations and route of administration – Glucocorticoids are commonly
available in multiple preparations (eg, prednisone, prednisolone) and routes of
administration (eg, parenteral, oral, and locally administered). Locally targeted
administration is preferred when possible to minimize adverse effects. (See
'Common glucocorticoid preparations' above and 'Route of administration' above.)
•
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GRAPHICS
Comparison of systemic glucocorticoid preparations
  Equivalent doses
(mg)
Antiinflammatory
activity relative to
hydrocortisone
Duration of action
(hours)
Glucocorticoids
Short acting
Hydrocortisone
(cortisol)
20 1 8 to 12
Cortisone acetate 25 0.8 8 to 12
Intermediate acting
Prednisone 5 4 12 to 36
Prednisolone 5 4 12 to 36
Methylprednisolone 4 5 12 to 36
Triamcinolone 4 5 12 to 36
Long acting
Dexamethasone 0.75 30 36 to 72
Betamethasone 0.6 30 36 to 72
Mineralocorticoids
Fludrocortisone Not used for an antiinflammatory effect . The
typical dose of fludrocortisone for
mineralocorticoid replacement is 0.1 to 0.2 mg.
12 to 36
The mineralocorticoid effect of commonly administered glucocorticoids may be estimated as follows:
When given at replacement doses, triamcinolone, dexamethasone, and betamethasone have no
clinically important mineralocorticoid activity.
20 mg hydrocortisone and 25 mg of cortisone acetate each provide a mineralocorticoid effect
that is approximately equivalent to 0.1 mg fludrocortisone.
Prednisone or prednisolone given at antiinflammatory doses ≥50 mg per day provide a
mineralocorticoid effect that is approximately equivalent to 0.1 mg of fludrocortisone.
* Equivalent antiinflammatory dose shown is for oral or intravenous (IV) administration. Relative
potency for intraarticular or intramuscular administration may vary considerably.
¶ The antiinflammatory potency is 10 to 15 times that of hydrocortisone; however, fludrocortisone is
not used clinically as an antiinflammatory agent.
Data from:
*
¶
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1. Schimmer BP, Funder JW. ACTH, adrenal steroids, and pharmacology of the adrenal cortex. In: Goodman & Gilman's:
The Pharmacological Basis of Therapeutics, 12th ed, Brunton LL, Chabner BA, Knollmann BC (Eds), McGraw-Hill
Education 2011.
2. Liu D, Ahmet A, Ward L, et al. A practical guide to the monitoring and management of the complications of systemic
corticosteroid therapy. Allergy Asthma Clin Immunol 2013, 9:30.
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Glucocorticoid structure
Basic glucocorticoid structure and the chemical modifications (circled) that can be introduced to
increase glucocorticoid and/or mineralocorticoid activity. The rings are lettered A through D. A solid
line indicates that the group lies in front of the plane of the ring (beta position); a dashed line
indicates that the group lies behind the plane of the ring (alpha position). A double bond in a ring (eg,
between carbons 4 and 5) is referred to as "delta" (in this case, "delta-4").
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Steroid structures
Structures of naturally occurring cortisol and cortisone, several of the more commonly prescribed
synthetic glucocorticoids, and the synthetic mineralocorticoid fludrocortisone. Triamcinolone, a
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topical glucocorticoid, is identical to dexamethasone except for a 16 alpha hydroxyl group in place of
the 16 alpha methyl group.
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Examples of some drug interactions with systemic glucocorticoids
Interacting
drug classes
Examples Effect Comment
Co-administration of drugs that are inducers of CYP 3A and/or P-gp may DECREASE
glucocorticoid exposure and efficacy
Antiseizure Carbamazepine,
fosphenytoin,
phenobarbital,
phenytoin,
primidone
Reduced glucocorticoid
effects due to increased
clearance. Maximal effect
occurs approximately 2
weeks after initiating a CYP
inducer and can persist for
2 or more weeks following
discontinuation of a CYP
inducer.
Dose alteration of
methylprednisolone may b
needed. Prednisone and
prednisolone are affected
considerably less by this
interaction.
Antimicrobials
and antivirals
(HIV)
Efavirenz, etravirine,
nafcillin, rifampin,
rifabutin,
rifapentine
Rifampin can decrease
methylprednisolone,
prednisone, and
prednisolone exposure.
Efavirenz, etravirine,
nafcillin, rifabutin, and
rifapentine can decrease
methylprednisolone
exposure but are not likely
to interact with prednisone
or prednisolone.
Co-administration of drugs that are inhibitors of CYP 3A and/or P-gp may INCREASE
glucocorticoid exposure and toxicity
Antimicrobials Clarithromycin,
telithromycin
Increased glucocorticoid
effects due to decreased
clearance.
Methylprednisolone and
dexamethasone clearance
may be reduced by
approximately 30 to 50%.
Monitor biomarkers for
exaggerated glucocorticoid
effects. Dose alteration of
methylprednisolone and
dexamethasone may be
needed.
Interaction with prednisone
or prednisolone appears
less likely. However, in
some pharmacokinetic
studies, increased
glucocorticoid exposure
was observed. Monitoring
for increased glucocorticoid
effects is suggested.
Antifungal Itraconazole,
ketoconazole,
posaconazole,
voriconazole
Antivirals (HIV
and HCV)
Atazanavir,darunavir, ritonavir,
others
*[1-3]
¶
¶
Δ
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Estrogens Estrogen-containing
oral contraceptives,
conjugated
estrogens, esterified
estrogens, others
Estrogens can significantly
increase glucocorticoid
exposure and effects. This
may be due to alteration of
steroid metabolism and
protein binding.
Monitor biomarkers for
exaggerated glucocorticoid
effects. Dose alteration of
glucocorticoid may be
needed.
Multiple effects or additive toxicities
Anticoagulant,
oral
Warfarin Glucocorticoids may
increase anticoagulant
effect of warfarin.
Most patients stabilized on
warfarin will require a
significant alteration in
warfarin dose within 3 to 7
days after initiating
glucocorticoid. Monitor INR
closely to determine need
for dose adjustment.
Antidiabetics Dulaglutide,
glipizide, insulins,
liraglutide,
metformin,
pioglitazone,
semaglutide,
sitagliptin, others
Glucose dysregulation. Closely monitor blood
glucose in patients at risk
for glycemic dysregulation.
Adjust therapy as needed.
Diuretics Furosemide,
hydrochlorothiazide,
others
Glucocorticoids may
potentiate potassium
wasting effect.
Evaluate serum potassium
levels to determine
whether alteration of
diuretic therapy and/or
potassium
supplementation is needed
Fluoroquinolone Ciprofloxacin,
levofloxacin,
moxifloxacin,
ofloxacin, others
Increased risk of
tendinopathy.
Monitor for new-onset
tendon and/or joint pain.
Use combination cautiously
in older adults and children
NSAIDs Ibuprofen,
indomethacin,
ketorolac,
ketoprofen,
naproxen, others
Increased risk of peptic
ulcer disease.
Refer to UpToDate topic on
major side effects of
systemic glucocorticoids.
This table does not show all possible interactions. For additional interactions, refer to appropriate
UpToDate clinical topics and the drug interactions program included with UpToDate.
CYP 3A: cytochrome P450 3A; HCV: hepatitis C virus; HIV: human immunodeficiency virus; INR:
international normalized ratio; NSAIDs: nonsteroidal antiinflammatory drugs; P-gp: P-glycoprotein
efflux membrane transporters.
Δ
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https://www.uptodate.com/drug-interactions
* The classification of effects on drug metabolism are based upon US Food and Drug Administration
(FDA) guidance. Other sources may use a different classification system resulting in some agents
being classified differently. Weak inhibitor effects are not listed. Clinically significant interactions can
occasionally occur due to weak inhibitors, particularly if the target drug has a narrow therapeutic
margin. Refer to the drug interactions program for a full review of potential interactions.
¶ For a list of CYP 3A inducers/inhibitors (which include CYP 3A4 metabolism effects), refer to
UpToDate content including a separate table that lists cytochrome P450 3A inhibitors and inducers.
Δ Biomarkers of glucocorticoid toxicity may include neuropsychiatric reactions, fluid and electrolyte
disturbances, hypertension, and/or hyperglycemia.
References:
1. Czock D, Keller F, Rasche FM, Haussler U. Pharmacokinetics and pharmacodynamics of systemically administered
glucocorticoids. Clin Pharmacokinet 2005; 44:61.
2. UpToDate Lexidrug. More information available at https://online.lexi.com/.
3. Clinical Manual of Drug Interaction Principles for Medical Practice, Wynn GH, Oesterhelf JR, Cozza KL, Armstrong SC
(Eds), APA Publishing, Washington DC 2019.
4. US Food and Drug Administration. Clinical drug interaction studies — Cytochrome P450 enzyme- and transporter-
mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-
transporter-mediated-drug-interactions (Accessed on June 5, 2020).
5. US Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and
Inducers. Available at: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-
table-substrates-inhibitors-and-inducers (Accessed on February 11, 2020).
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https://online.lexi.com/
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers
Cytochrome P450 3A (including 3A4) inhibitors and inducers
Strong inhibitors Moderate
inhibitors
Strong inducers Moderate inducers
Adagrasib
Atazanavir
Ceritinib
Clarithromycin
Cobicistat and
cobicistat-
containing
coformulations
Darunavir
Idelalisib
Indinavir
Itraconazole
Ketoconazole
Levoketoconazole
Lonafarnib
Lopinavir
Mifepristone
Nefazodone
Nelfinavir
Nirmatrelvir-
ritonavir
Ombitasvir-
paritaprevir-
ritonavir
Ombitasvir-
paritaprevir-
ritonavir plus
dasabuvir
Posaconazole
Ritonavir and
ritonavir-containing
coformulations
Saquinavir
Tucatinib
Voriconazole
Amiodarone
Aprepitant
Berotralstat
Cimetidine
Conivaptan
Crizotinib
Cyclosporine
Diltiazem
Duvelisib
Dronedarone
Erythromycin
Fedratinib
Fluconazole
Fosamprenavir
Fosaprepitant
Fosnetupitant-
palonosetron
Grapefruit juice
Imatinib
Isavuconazole
(isavuconazonium
sulfate)
Lefamulin
Letermovir
Netupitant
Nilotinib
Nirogecestat
Ribociclib
Schisandra
Verapamil
Apalutamide
Carbamazepine
Encorafenib
Enzalutamide
Fosphenytoin
Lumacaftor
Lumacaftor-
ivacaftor
Mitotane
Phenobarbital
Phenytoin
Primidone
Rifampin
(rifampicin)
Bexarotene
Bosentan
Cenobamate
Dabrafenib
Dexamethasone
Dipyrone
Efavirenz
Elagolix, estradiol,
and norethindrone
therapy pack
Eslicarbazepine
Etravirine
Lorlatinib
Mitapivat
Modafinil
Nafcillin
Pexidartinib
Repotrectinib
Rifabutin
Rifapentine
Sotorasib
St. John's wort
For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can
alter serum concentrations of drugs that are dependent upon the CYP3A subfamily of liver
enzymes, including CYP3A4, for elimination or activation.
*
¶
¶
¶
¶
Δ
◊
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These classifications are based upon US Food and Drug Administration (FDA) guidance. Other
sources may use a different classification system, resulting in some agents being classified
differently.
Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose,
method, and timing of administration.
Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically
significant interactions can occasionally occur due to weak inhibitors and inducers (eg, target drug
is highly dependent on CYP3A4metabolism and has a narrow therapeutic index). Accordingly,
specific interactions should be checked using a drug interaction program such as the drug
interactions program included within UpToDate.
Refer to UpToDate topics on specific agents and indications for further details.
CYP: cytochrome P450.
* Mifepristone is a significant inhibitor of CYP3A4 when used chronically (eg, for hyperglycemia in
patients with Cushing syndrome), not in single-dose use.
¶ Classified as a weak inhibitor of CYP3A4, according to FDA system.
Δ Classified as a weak inducer of CYP3A4, according to FDA system.
◊ The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4
induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone
and estradiol are not CYP3A4 inducers.
Data from: UpToDate Lexidrug. More information available at https://online.lexi.com/.
References:
1. Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance
for Industry ( January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions.
2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers.
Available at: FDA.gov website.
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https://www.uptodate.com/drug-interactions
https://www.uptodate.com/drug-interactions
https://online.lexi.com/
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm
Major adverse effects associated with systemic glucocorticoid therapy and
potential interventions
System
Reported relationship to
prednisone dosing for
adults
Possible interventions
Metabolic and endocrine
Hypothalamic-pituitary-
adrenal axis suppression
Typically with supraphysiologic
doses (>5 mg)
Rarely reported with <5 mg/day
for <4 weeks
Screen for suppression when
tapering if compatible
symptoms
Hyperglycemia Reported with <10 mg/day Intensify screening for type 2
diabetes
Dermatologic and appearance
Cushingoid features Rare with <5 mg/day Ask about self-image and/or
bullying, especially for pediatric
patients
Weight gain Typically with >5 mg/day Monitor weight at visits
Ask about gastrointestinal
symptoms leading to increased
food intake
Increase intake of high-fiber
foods and water to increase
satiety
Skin thinning and
ecchymoses
Reported with <5 mg/day Encourage sun-protective
measures
Acne, hirsutism, facial
erythema
Few data available  
Cardiovascular/renal
Fluid retention Reported with ≥5 mg/day Monitor weight at visits
Hypertension Rare with <10 mg/day Monitor blood pressure at visits
Premature atherosclerotic
disease and major cardiac
events (eg, myocardial
infarction, stroke)
Reported with ≥7.5 mg/day Include glucocorticoid use as an
additional risk factor when
screening for atherosclerotic
cardiovascular disease
Arrhythmias Sudden cardiac death reported
in patients receiving pulse dose
steroids (methylprednisolone
500 to 1000 mg/day)
Use telemetry for patients with
significant cardiac disease who
receive pulse dose steroids
*
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Venous thromboembolism
(VTE)
Reported with <20 mg/day Include glucocorticoid use as an
additional VTE risk factor when
deciding to use perioperative
VTE prophylaxis
Possible hyperlipidemia Typically with >10 mg/day Intensify screening for
hyperlipidemia
Gastrointestinal
Gastritis, peptic ulcer disease,
and upper gastrointestinal
bleeding
Reported with <20 mg/day Administer glucocorticoids with
food
Evaluate other risk factors for
gastroduodenal toxicity,
particularly the coadministration
of nonsteroidal
antiinflammatory drugs
(NSAIDs), and potential need for
primary prevention
Consider pharmacologic
prophylaxis for upper
gastrointestinal complications in
critically ill patients receiving
high-dose steroids
Drug-induced steatotic liver
disease
Rare, few data available  
Visceral perforation Rare, few data available  
Bone and muscle effects
Osteoporosis Reported with as low as 2.5
mg/day
Screen for osteoporosis in
patients with >3 months of
treatment and prescribe
preventive therapies in those at
greater risk
Osteonecrosis/avascular
necrosis
Rare with <15 to 20 mg/day,
associated with peak dose
 
Myopathy Typically with >40 mg/day
Rare with <10 mg/day
Monitor strength examination a
visits for patients on chronic
glucocorticoids
Neuropsychiatric
Insomnia Reported with <5 mg/day Take in the morning or early
afternoon when possible
Mood disorders, including
anxiety and depression
Typically with >7.5 mg/day Intensify screening for anxiety
and depression, especially in
patients over age 65 and/or with
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history of neuropsychiatric
disorders
Psychosis Almost always with >20 mg/day  
Memory impairment Reported with as low as 5
mg/day for 1 year
 
Ophthalmologic
Cataracts Reported with <5 mg
Typically with >10 mg/day
Ophthalmology referral for
screening in select patients
Elevated intraocular
pressure/glaucoma
Typically with >7.5 mg/day Ophthalmology referral for
screening in select patients
Immune system
Increased risk of infections Reported with <5 mg/day Give indicated vaccinations
when anticipating a prolonged
course of glucocorticoids
Avoid live vaccinations in select
patients
Use Pneumocystis jirovecii
pneumonia (PJP) prophylaxis in
select patients on higher
prolonged dosing
Decreased response to
vaccinations
Typically with ≥20 mg/day for
≥14 days
Modify glucocorticoid dosing
when possible or delay
vaccination depending on
glucocorticoid dose
Other
Tooth hypersensitivity Reported with <20 mg/day,
typically with pulse dose
steroids (methylprednisolone
500 to 1000 mg/day)
 
Epistaxis Typically with >5 mg/day  
Growth impairment in
children
Reported with 3 to 5 mg/m /day Monitor growth
Interventions may vary depending on other patient risk factors, the anticipated dose and duration of
glucocorticoids, and the acuity and complexity of the clinical situation. It may be helpful to minimize
other risk factors for the adverse effect, as well as steroid dose and duration. Refer to UpToDate for
additional details.
* High-dose inhaled glucocorticoid therapy can rarely cause systemic adverse effects. Refer to
UpToDate content for information on local adverse effects of inhaled glucocorticoids.
Δ
Δ
Δ
2 ◊
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¶ Signs and symptoms of hypothalamic-pituitary-adrenal axis suppression include fatigue, weakness,
hypotension, confusion, anorexia, nausea, vomiting, and abdominal pain. Refer to UpToDate content
on clinical manifestations of adrenal insufficiency for additional detail.
Δ Refer to UpToDate contenton the effects of glucocorticoids on the immune system and
immunizations in autoimmune inflammatory rheumatic disease in adults for more details.
◊ Refer to UpToDate content on causes of short stature.
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Contributor Disclosures
Daniel E Furst, MD Grant/Research/Clinical Trial Support: Actelion [SSc, PAH]; Amgen [RA, PsA]; BMS
[SSc]; Boehringer Ingleheim [SSc]; Corbus [SSc]; Emerald [SSc]; Galapagos [SSc]; GSK [SSc]; Horizon
[SSc]; Novartis [RA]; Pfizer [SSc]; Prometheus [SSc]; Roche/Genentech [RA, SSc]; Sanofi [RA, SSc].
Consultant/Advisory Boards: Amgen [RA, PsA]; Corbus [SSc]; Galapagos [SSc]; Novartis [SSc]. All of the
relevant financial relationships listed have been mitigated. Kenneth G Saag, MD,
MSc Grant/Research/Clinical Trial Support: Amgen [Osteoporosis]; Arthrosi Therapeutics [Gout];
Horizon Pharma, PLC [Gout]; Inventis Bio [Osteoporosis]; LG Pharma [Gout]; Novonordisc [Gout]; Olatec
[Gout]. Consultant/Advisory Boards: Amgen [Osteoporosis]; Arthrosi Therapeutics [Gout]; Atom
Bioscience [Gout]; Gruenthal [Osteoporosis]; Horizon Pharma, PLC [Gout]; LG Pharma [Gout]. All of the
relevant financial relationships listed have been mitigated. Kenneth J Warrington,
MD Grant/Research/Clinical Trial Support: BMS [Giant cell arteritis]; Eli Lilly [Giant cell arteritis].
Consultant/Advisory Boards: Amgen [ANCA-associated vasculitis]; Sanofi [Polymyalgia Rheumatica,
Giant Cell Arteritis]. Other Financial Interest: Amgen [Honoraria – ANCA-associated vasculitis]. All of the
relevant financial relationships listed have been mitigated. Siobhan M Case, MD, MHS No relevant
financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
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