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\begin{document}

\title{Is there a safe and effective way to wean patients off long-term
glucocorticoids}



\author[1]{Emma Baker}%
\affil[1]{St George's University of London}%


\vspace{-1em}



  
  \date{June 16, 2024}


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\selectlanguage{english}
\begin{abstract}
Glucocorticoids are highly effective medicines in the treatment of
inflammatory disorders. However they cause severe dose-related adverse
reactions, particularly where taken systemically for prolonged periods.
Systemic glucocorticoids are therefore given at dosage sufficient to
control the disease, then withdrawn as fast as is possible to minimise
dose-related adverse effects without losing disease control. End-of-use
adverse reactions present a major challenge in the withdrawal of long
term (\textgreater{}3 weeks) glucocorticoids. Suppression of the
hypothalamic-pituitary-adrenal (HPA) axis causes adrenal insufficiency,
which is potentially life threatening and can become symptomatic as
treatment is withdrawn. Adrenal insufficiency can be extremely difficult
to differentiate from `glucocorticoid withdrawal syndrome', where
patients experience symptoms despite adequate adrenal function, and from
psychological dependence. Long term systemic glucocorticoids should
therefore be withdrawn slowly. The rate at which the dose is tapered
should initially be determined by treatment requirements of the
underlying disease. Once physiological doses (prednisolone 7.5mg or
equivalent) are reached, the rate of reduction is determined by rate of
HPA recovery and need for exogenous glucocorticoid cover while
endogenous secretion recovers. If symptoms prevent treatment withdrawal,
HPA testing should be used to look for adrenal insufficiency. Patients
with adrenal insufficiency require physiological doses of
glucocorticoids for adrenal replacement, which may be lifelong if the
HPA axis fails to recover.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Glucocorticoids are commonly used for their anti-inflammatory and
immunomodulatory properties in the treatment of a wide range of
inflammatory, immunological, allergic and malignant diseases. A recent
population study from Denmark found that the annual prevalence of
systemic (oral and injectable) glucocorticoid use was
\textasciitilde{}3\%, increasing to 6.7-7.7\% in people 60-79 years of
age and to 9.7-11\% in those [?]80 years of age {[}1{]}. In 2018 in
England, 8 million prescriptions for systemic glucocorticoids, 21
million prescriptions for inhaled glucocorticoids and 12 million
prescriptions for topical glucocorticoids were dispensed in the
community {[}2{]}. Glucocorticoids bind to glucocorticoid receptors,
which are expressed in almost every cell in the body and have
pleiotropic effects on multiple signalling pathways {[}3{]}. This makes
them highly effective anti-inflammatory drugs, but also causes diverse
serious adverse effects that limit their use.

\textbf{Adverse effects}

Prolonged and/or high dose glucocorticoid therapy promotes
gluconeogenesis, protein catabolism and lipolysis, reduces proliferation
of actively dividing cells, promotes apoptosis, inhibits the synthesis
of extracellular matrix proteins, has vasopressor effects and suppresses
the hypothalamic pituitary axis {[}3{]}. Adverse effects of treatment
therefore include weight gain, metabolic disorders, growth retardation
and/or bone and muscle loss, poor wound healing, increased
susceptibility to infection and adrenal insufficiency, as well as
neuropsychiatric effects. Some toxicity from oral or injected
glucocorticoids is inevitable, even with short courses of treatment.
However, the adverse effects experienced by an individual depend on both
the average and the cumulative dose of treatment, with harms experienced
even at very low doses of glucocorticoids when given over long periods
of time (figure 1). This means that long term inhaled or topical
glucocorticoids also have potential to cause systemic adverse effects.
This is more likely for inhaled or topical glucocorticoids with greater
potency (table 1) and is dependent on systemic bioavailability, which
may be increased by a wide range of factors including drug-drug
interactions and severity of underlying disease (figure 2).

\emph{Adrenal insufficiency} . The endogenous glucocorticoid, cortisol
is secreted by the adrenal cortex at around 5.7
mg/m\textsuperscript{2}/day {[}16{]}, approximately equivalent to a
therapeutic regimen of 15-25 mg hydrocortisone/day {[}17{]} or
prednisolone 7.5 mg/day. Glucocorticoid release from the adrenal glands
is regulated by the hypothalamic-pituitary-adrenal (HPA) axis. In the
hypothalamus, the circadian oscillator in the suprachiasmatic nucleus
controls secretion of corticotrophin-release hormone (CRH) into
hypophyseal portal veins. CRH stimulates the anterior pituitary gland to
release stored adrenocorticotrophic hormone (ACTH) into the circulation
and promotes synthesis of new ACTH. ACTH simulates cortisol secretion by
the adrenal glands with a pronounced diurnal rhythm. Plasma cortisol
concentrations peak at 06.00 to 07.00 am and reach a nadir at around
24.00 hours. Physiological and emotional stress override this daily
rhythm, stimulating a rapid increase in cortisol levels. Cortisol exerts
negative feedback on the hypothalamus and anterior pituitary gland,
regulating secretion of CRH and ACTH. Exogenous glucocorticoids suppress
the HPA axis by reducing secretion and synthesis of CRH and ACTH, which
in turn reduces endogenous cortisol production and secretion by the
adrenal glands. After a short course of exogenous glucocorticoids these
changes can reverse rapidly {[}18{]}. However if treatment is prolonged,
atrophy of corticotrophin cells in the anterior pituitary {[}19{]} and
of the adrenal glands {[}20{]} may occur and reversal may be prolonged
over weeks {[}21{]}, months or years {[}22{]}.

In a systematic review of studies measuring adrenal function following
systemic glucocorticoid exposure, Joseph and colleagues found that a
median of 37\% (interquartile range 13-63\%) patients had adrenal
insufficiency {[}22{]}. Adrenal insufficiency occurred even with low
dose (\textless{}5 mg prednisolone equivalent) and short duration
(\textless{}4 weeks) glucocorticoid treatment and following tapered
withdrawal. It persisted in 15\% patients retested 3 years after
glucocorticoid withdrawal. In a separate review, Broersen and colleagues
found that there was no administration form, dosage, treatment duration
or underlying disease for which adrenal insufficiency could be excluded,
although increased dose and duration of treatment were associated with
increased risk {[}23{]}.

\textbf{Challenges of glucocorticoid therapy}

Glucocorticoid therapy has the potential for considerable benefit
through control of life-threatening and/or disabling disease, but at the
cost of considerable harms through dose-related and continuous use
adverse reactions. The goal of glucocorticoid therapy is therefore to
obtain the maximum possible therapeutic benefit at the lowest possible
dosage, both average and cumulative, to minimise adverse effects. In
practice, this is achieved by starting glucocorticoid treatment at a
moderate to high dose (e.g. 40 mg prednisolone for an asthma
exacerbation, 1000 mg methyl prednisolone for graft rejection reactions
or relapse in multiple sclerosis) to gain disease control, then
withdrawing glucocorticoid treatment to as low dose as can be achieved
while still maintaining disease control. Glucocorticoid withdrawal is
greatly complicated by the emergence of symptoms, which may be a
manifestation of disease reactivation, an end-of-use adverse reaction
caused by drug withdrawal (adrenal insufficiency, glucocorticoid
withdrawal syndrome) or psychological dependence (figure 3).
Distinguishing between these and supporting patients in successful
withdrawal of glucocorticoids can be a considerable challenge.

\textbf{Is there a safe and effective way to wean patients off long-term
glucocorticoids?}

Long term systemic glucocorticoid treatment can be defined as continuous
treatment for more than 3 weeks. Long term glucocorticoids must be
withdrawn slowly to prevent loss of disease control and manage
end-of-use adverse reactions. This is usually done using a tapering
regimen, an example used for patients with inflammatory rheumatic
diseases is shown in table 2 {[}24{]}. This section discusses practical
approaches to weaning patients off long term glucocorticoids that can
help to minimise harms from loss of disease control and end-of-use
adverse effects. These approaches are illustrated through discussion of
3 clinical cases shown in boxes 1-3.

\emph{Loss of disease control (Case study 1, box 1)}

Effective treatment of chronic inflammatory disorders is essential to
prevent long term structural changes and loss of function, such as joint
destruction and loss of mobility in rheumatoid arthritis or airways
remodelling and chronic breathlessness in asthma. Glucocorticoids are
highly effective in the treatment of inflammation but their utility is
limited by their dose-related and continuous use adverse effects.
`Steroid-sparing' strategies can be employed to improve the benefit:
harm ratio of glucocorticoids. General principles include combining
systemic glucocorticoids with topical glucocorticoids (e.g.
intraarticular for arthritis, high dose inhaled for asthma) and/or with
conventional and biological disease-modifying drugs (e.g. methotrexate
or adalizumab for rheumatoid arthritis, omalizumab for asthma). A
holistic approach should also include reviewing the diagnosis and need
for glucocorticoids. For example a patient with `asthma' who seems
poorly-responsive to high dose glucocorticoids may actually have COPD,
where systemic glucocorticoids are not usually indicated.

As glucocorticoid treatment is weaned, reactivation of disease may be
difficult to distinguish from end of treatment adverse effects or
re-emergence of symptoms of unrelated conditions. For example, a patient
with rheumatic disease who complain of aches and pains as
glucocorticoids are withdrawn may be experiencing reactivation of their
inflammatory disease, `pseudorheumatism' of glucocorticoid withdrawal,
or renewed awareness of underlying osteoarthritis. These will affect the
treatment taper in different ways. A disease flare may require an
increase in glucocorticoid dose, although a relatively modest increase
e.g. to the last effective dose in polymyalgia rheumatica {[}25{]}, may
be enough. Symptoms of glucocorticoid withdrawal syndrome or renewed
awareness of underlying conditions can be managed with alternative
therapies, such as non-steroidal anti-inflammatories for rheumatic
symptoms. Slowing the taper may also allow glucocorticoid withdrawal
symptoms to resolve.

Patient perception of glucocorticoids may affect their willingness to
take treatment, with non-adherence leading to loss of disease control
(Box 1). Anecdotally many patients starting glucocorticoid treatment
express fears of weight gain, skin changes and `becoming addicted' with
one patient being particularly concerned because a relative had died
from glucocorticoid-related adverse effects. These anecdotes are born
out by studies of patient perceptions of glucocorticoid therapy, which
found that patients voiced concerns about adverse effects {[}26{]} and,
given a `risk-free choice', preferred withdrawal of glucocorticoids over
other agents {[}27{]}. It is essential that the benefits and risks of
treatments and patient concerns are fully discussed before starting
treatment and that the decision to undertake glucocorticoid treatment is
made jointly by patient and practitioner.

\emph{Adrenal insufficiency (Case study 2, box 2)}

Patients taking long term systemic glucocorticoids are at risk of HPA
suppression. Where this has occurred, abrupt withdrawal of exogenous
glucocorticoids or physiological stress such as intercurrent illness or
surgery can cause life-threatening acute adrenal insufficiency. Although
not all patients taking long term glucocorticoids develop adrenal
insufficiency {[}22{]}, it can be extremely difficult to distinguish
those who do from those who don't. Potency, dose and duration of
glucocorticoid treatment are imperfect predictors, patients may be
asymptomatic even when therapy is withdrawn and blanket HPA testing is
considered impractical. A general clinical approach therefore is to have
a low threshold for suspecting HPA suppression in patients taking
glucocorticoids and to require a gradual withdrawal of treatment for all
those considered to have reached that threshold. Where treatment
withdrawal is hampered by the emergence of symptoms (e.g. Case study 2,
box 2), testing for HPA suppression can be useful to determine whether
these are manifestations of adrenal insufficiency.

\emph{Suspecting HPA suppression}

Small studies in healthy volunteers found that short (5-7 days) courses
of high dose (40-50mg) prednisolone did not produce sustained HPA
suppression {[}18, 28{]}. However, adrenal suppression was observed in
steroid-na\selectlanguage{ngerman}ïve COPD patients after taking prednisolone 40 mg daily for 14
days. This persisted in some patients for at least 21 days {[}29{]}.
Treatment cessation guidelines in the British National Formulary reflect
this, identifying patients who have received more than 40 mg
prednisolone (or equivalent) daily for more than week or who have
received glucocorticoid treatment for more than 3 weeks as requiring
gradual treatment withdrawal {[}30{]}.

Other patients who are likely to have HPA suppression secondary to
glucocorticoid therapy include those who have been given repeat doses in
the evening, have recently received repeat courses (particularly if
longer than 3 weeks) and those who take a new short course of
glucocorticoids within 1 year of stopping therapy {[}30{]}.

The rate of treatment withdrawal in all patients is determined both by
disease control and by suspicion of adrenal suppression. The rate of
reduction from the initial treatment dose down to physiological doses
(equivalent to prednisolone 7.5 mg) is determined by the treatment
requirements of the underlying disease (e.g. table 2). The rate of
reduction from physiological doses to zero is determined by the rate of
HPA recovery and the need for exogenous glucocorticoid cover while
endogenous glucocorticoid secretion recovers. After relatively short
courses of glucocorticoids, HPA suppression can recover in days to
weeks. However, where treatment duration has been long enough for
adrenal atrophy to occur, recovery may take months to years or may not
occur at all, necessitating long term adrenal replacement.

\emph{Testing for HPA suppression}

HPA function testing is generally reserved for patients who become
symptomatic when withdrawing from glucocorticoids. Its purpose is to
distinguish adrenal insufficiency from glucocorticoid withdrawal
syndrome (table 3). HPA function is tested by measurement of cortisol.
Exogenous glucocorticoids interfere with the cortisol assay, so
measurements must be made at least 12 hours after the last dose of
hydrocortisone or 24 hours after the last dose of prednisolone. If this
period without glucocorticoids is not achievable then treatment should
be switched to an equivalent dose of dexamethasone (table 1) before
testing as this does not interfere with the cortisol assay.

Patients should initially undergo measurement of 9am cortisol. Values of
\textless{}100mmol/L indicate cortisol insufficiency and
\textgreater{}450nmol/L indicate cortisol sufficiency. Where values are
equivocal (100-449nmol/L), a stimulation test should be performed to
measure cortisol before and at 30 and 60 minutes after administration of
intramuscular synthetic ACTH (short synacthen test). A peak cortisol
value of \textless{}550nmol/L after stimulation indicates cortisol
insufficiency. Check all these reference values with your local
laboratory as assays may vary.

\emph{Managing HPA suppression}

Patients diagnosed with cortisol insufficiency require physiological
glucocorticoid replacement with hydrocortisone 15-20 mg/day or
prednisolone 4-5 mg/day. For some patients, very slow weaning of
treatment from these doses over many months may allow full recovery of
the HPA axis and eventual cessation of exogenous glucocorticoids. For
other patients, recovery does not occur, and lifelong glucocorticoid
replacement is required.

Patients with cortisol insufficiency are at risk of an adrenal crisis,
particularly in times of intercurrent illness such as infection, trauma
or surgery. They should be warned of the risk and advised to increase
(double or treble) their glucocorticoid dose to a minimum of 40 mg
hydrocortisone or prednisolone 10 mg if this occurs. Patients should be
signposted to `sick day rules guidance', such as that provided by the
Addison's self-help group to help them with this {[}31{]}.

\emph{Glucocorticoid dependence and withdrawal (Case study 3, box 3)}

Glucocorticoid withdrawal syndrome is defined by symptoms that develop
as glucocorticoid therapy is withdrawn, despite normal HPA function.
These symptoms can be similar to those of adrenal insufficiency, which
makes it difficult to tell the two conditions apart (table 3). One
distinguishing feature is that glucocorticoid withdrawal syndrome can be
symptomatic even at supraphysiological glucocorticoid doses, whereas
adrenal insufficiency is controlled by physiological doses.

Inherent in the description of glucocorticoid withdrawal syndrome is the
implication that patients become dependent on or `addicted to'
glucocorticoids, accounting for both physiological and psychological
discomfort when treatment is withdrawn {[}32{]}. Glucocorticoids have
pleiotropic effects, altering many different pathways and mediators,
which could contribute to development of dependence. Candidates include
CRH, vasopressin, pro-opiomelanocortin and the adrenergic system
{[}33{]}. In the brain, exogenous glucocorticoids may alter
neurotransmitters {[}32{]} and impair recovery from neuronal damage
{[}7{]}. It is well recognised that patients taking glucocorticoids can
develop neuropsychiatric effects including psychotic reactions, as well
as changes in mood, cognition, memory and/or behaviour {[}7{]}.
Neuropsychiatric effects including depression, delirium, confusion or
disorientation, non-psychotic mania and panic disorder have also been
reported during dose reduction {[}34{]} and may complicate treatment
withdrawal. Glucocorticoids have been implicated as a driver of
addictive behaviour {[}35{]} and occasionally are used as drugs of abuse
{[}36{]}. Anfinson and colleagues identified 22 cases of glucocorticoid
dependence on a MEDLINE search that met criteria for DSM I-IV substance
dependence {[}36{]}. They commented that glucocorticoids may induce
dependence through their propensity to induce euphoria and by directly
influencing reward circuitry, as well as through physical dependence.

\emph{Managing glucocorticoid dependence}

The physical and psychological effects of glucocorticoid withdrawal can
make it difficult for patients to reduce the dose of their
glucocorticoids. In case studies 2 and 3 this is illustrated by patients
maintaining themselves on higher doses of glucocorticoids than those
prescribed by their physicians. When discussing glucocorticoid tapering,
patients should be counselled about the possibility of withdrawal
symptoms. If these occur at supraphysiological doses of glucocorticoids,
they can be managed by symptomatic treatments (e.g. non-steroidal
anti-inflammatories for aches and pains) and by slowing the rate of
glucocorticoid taper. If the symptoms are poorly tolerated, the dose of
glucocorticoids can be increased to the lowest dose at which they are
controlled and treatment tapered very slowly. If symptoms occur at or
below physiological glucocorticoid doses, adrenal insufficiency must be
excluded as described above. With time and a very slow treatment taper,
glucocorticoid dependence may resolve. Where patients are unable to stop
glucocorticoid therapy they should be maintained on the lowest possible
dose of treatment. Some endocrinologists recommend switching from
prednisolone to hydrocortisone if long term treatment is required
because hydrocortisone appears to be associated with a lower risk of
fractures {[}37{]}.

\textbf{Conclusion}

Although glucocorticoids are effective anti-inflammatory drugs, long
term use at even low doses has potential to cause harmful adverse
reactions. A key principle of therapy is to use glucocorticoids at as
low as dose and for as short a duration as possible to control disease
to limit these adverse effects. However glucocorticoid withdrawal is
also fraught with risk, including loss of disease control and end-of-use
adverse effects, including the potential for life-threatening adrenal
insufficiency. Steroid sparing strategies, glucocorticoid-tapering
regimens and a low index of suspicion for HPA axis suppression are key
to the safe and effective withdrawal of long term glucocorticoids.



\textbf{BOX 1}

\textbf{Case study 1. Disease control}

A 70-year-old woman experiences bilateral shoulder and hip pain and
stiffness. She is diagnosed with polymyalgia rheumatica and commences
treatment with prednisolone 15mg daily. After 3 weeks her symptoms have
disappeared and she is advised to reduce her prednisolone dose to 12.5
mg for 3 weeks, then to 10 mg for 4 weeks, then by 1mg per month
{[}25{]}. Three months later her concerned son tells her GP that she is
fatigued and depressed and can't get out of bed or the bath. On enquiry
she stopped her prednisolone after 6 weeks of treatment because of
concerns about weight gain.

\textbf{Discussion.} Polymyalgia rheumatica (PMR) is an inflammatory
musculoskeletal disorder of unknown aetiology, which classically
responds well to systemic glucocorticoids. The treatment regimen
described here is based on the recommendations of the British Society
for Rheumatology and British Health Professionals in Rheumatology
{[}25{]} and is consistent with the example tapering regimen shown in
table 2.

This patient stopped glucocorticoid treatment abruptly after 6 weeks of
treatment. At this point rapid withdrawal could cause disease relapse or
adrenal insufficiency. The systemic features of PMR e.g. fatigue,
anorexia, fever, weight loss and depression can be difficult to
distinguish from the symptoms of adrenal insufficiency. Raised
inflammatory markers (C-reactive protein, erythrocyte sedimentation
rate) would be supportive of disease reactivation. As she has now not
had glucocorticoids for \textasciitilde{}9 weeks, one approach would be
to recommence treatment for PMR at 15mg/day followed by the taper as
planned. A key issue for this patient would be to discuss the benefits
of the treatment in the context of her concerns about taking
glucocorticoids to encourage her to adhere to treatment. Advice on
avoiding weight gain with glucocorticoids could also be helpful (e.g.
NHS guidance {[}38{]}). If she recommences glucocorticoid treatment, she
should be advised not to stop prednisolone abruptly and provided with a
steroid card.



\textbf{BOX 2}

\textbf{Case study 2. End-of-use adverse reaction}

A 64-year-old woman has taken prednisolone 10 mg daily for 6 months for
rheumatoid arthritis, which is now well controlled by methotrexate. She
is asked to reduce her prednisolone dose by 1mg/month with the aim of
stopping the glucocorticoids. When she is reviewed 6 months later she is
still taking prednisolone 10 mg daily. She managed to reduce the dose to
5mg daily using this regimen, but felt lethargic, nauseated and weak so
returned to her usual dose.

\textbf{Discussion}

NICE guidelines indicate that long-term glucocorticoids should only be
used for rheumatoid arthritis when all other disease-modifying treatment
options have been offered and long-term complications have been fully
discussed {[}39{]}. Short-term treatment may be considered for rapid
control of inflammation in newly diagnosed rheumatoid arthritis or
disease flares. For this patient, her arthritis is now controlled on
methotrexate and withdrawal of treatment should be attempted.

When she tries to withdraw glucocorticoids, she develops symptoms that
could be due to adrenal insufficiency or glucocorticoid withdrawal
syndrome. The long duration of treatment and symptoms at a prednisolone
dose below daily endogenous glucocorticoid secretion
(\textasciitilde{}7.5 mg prednisolone equivalent) increase the
likelihood that she has hypothalamic-pituitary-adrenal (HPA) axis
suppression and adrenal insufficiency. HPA axis testing is therefore
indicated to determine her long-term management.

A reasonable approach for this patient would be to ask her to repeat the
wean to prednisolone 5mg. She should then undergo measurement of 9am
cortisol at least 24 hours after her last dose of prednisolone, which
can otherwise interfere with the cortisol assay. If this test is
equivocal (9am cortisol 100-449nmol/L), further testing with a short
synacthen test will be required. Differentiating between adrenal
insufficiency, which requires adrenal replacement, and glucocorticoid
withdrawal syndrome, which may resolve if treatment is tapered very
slowly, is important to direct therapy.

\textbf{BOX 3}

\textbf{Case study 3. Psychological dependence}

A 69-year-old man with advanced chronic obstructive pulmonary disease
(COPD), anxiety and depression is seen by his GP to review the need for
long term glucocorticoids. He takes prednisolone 20mg daily and feels
unable to reduce the dose because of breathlessness. His weight has
increased by 10kg in the past year, he has osteoporosis with a vertebral
compression fracture and his random blood glucose is 12.3mmol/L.

\textbf{Discussion}

Long term systemic glucocorticoid therapy is not normally recommended
for the treatment of COPD {[}40{]}. Some patients with advanced COPD may
find it difficult to stop systemic glucocorticoids prescribed for
exacerbations, particularly where exacerbations are frequent. If
patients cannot stop glucocorticoids, the dose should be kept as low as
possible and the focus should be on preventing complications.

This patient feels breathless whenever he tries to reduce the dose of
his prednisolone. There is little evidence that long-term systemic
glucocorticoids improve lung physiology in people with stable COPD
{[}41{]}, so this may be due to `psychological dependence' on
glucocorticoids. A holistic approach would include: medical review to
look for other causes of breathlessness; optimising COPD management
(including smoking cessation, pulmonary rehabilitation and inhaler
review); symptom management and psychological support. Glucocorticoids
should be weaned in parallel to the lowest tolerated dose and measures
to ameliorate the dose-related and continuous use adverse effects of
osteoporosis (e.g. bisphosphonate treatment) and diabetes mellitus (e.g.
low sugar diet, oral hypoglycaemic treatment) should be implemented to
reduce the risks of future harm.

\textbf{Acknowledgement}

None

\textbf{Conflict of interest}

None

\textbf{Funding}

None

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  Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by prescription
  is associated with subsequent cardiovascular disease. \emph{Ann Intern
  Med} . 2004;141(10):764-770.
\item
  Esteban NV, Loughlin T, Yergey AL, Zawadzki JK, Booth JD, Winterer JC,
  Loriaux DL. Daily cortisol production rate in man determined by stable
  isotope dilution/mass spectrometry. \emph{J Clin Endocrinol Metab} .
  1991;72(1):39-45.
\item
  Chan S, Debono M. Replication of cortisol circadian rhythm: new
  advances in hydrocortisone replacement therapy. \emph{Ther Adv
  Endocrinol Metab} . 2010;1(3):129-138. doi:10.1177/2042018810380214
\item
  Streck, W.F.; Lockwood, D.H. Pituitary adrenal recovery following
  short-term suppression with corticosteroids. Am. J. Med. 1979, 66,
  910--914
\item
  Nicolaides NC, Pavlaki AN, Maria Alexandra MA, Chrousos GP.
  Glucocorticoid Therapy and Adrenal Suppression. {[}Updated 2018 Oct
  19{]}. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext
  {[}Internet{]}. South Dartmouth (MA): MDText.com, Inc.; 2000-.
  Available from: https://www.ncbi.nlm.nih.gov/books/NBK279156/ Last
  accessed 3/7/20
\item
  Jasani MK, Boyle JA, Greig WR, Dalakos TG, Browning MC, Thompson A,
  Buchanan WW. Corticosteroid-induced suppression of the
  hypothalamo-pituitary-adrenal axis: observations on patients given
  oral corticosteroids for rheumatoid arthritis. Q J Med. 1967
  Jul;36(143):261-76.
\item
  Mendoza-Cruz, A.C.; Wargon, O.; Adams, S.; Tran, H.; Verge, C.F.
  Hypothalamic-pituitary-adrenal axis recovery following prolonged
  prednisolone therapy in infants. J. Clin. Endocrinol. Metab. 2013, 98,
  E1936--E1940.
\item
  Joseph RM, Hunter AL, Ray DW, Dixon WG. Systemic glucocorticoid
  therapy and adrenal insufficiency in adults: A systematic
  review.\emph{Semin Arthritis Rheum} . 2016;46(1):133-141.
\item
  Broersen LH, Pereira AM, Jørgensen JO, Dekkers OM. Adrenal
  Insufficiency in Corticosteroids Use: Systematic Review and
  Meta-Analysis. \emph{J Clin Endocrinol Metab} . 2015;100(6):2171-2180.
\item
  Furst DE, Matteson EL, Ramirez Curtis M. Glucocorticoid withdrawal.
  https://www.uptodate.com/contents/glucocorticoid-withdrawal Last
  accessed 3/7/20
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  NICE clinical knowledge summaries. Scenario: Management of polymyalgia
  rheumatica
  https://cks.nice.org.uk/polymyalgia-rheumatica\#!scenarioRecommendation
  Last accessed 3/7/20
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  Robson JC, Dawson J, Cronholm PF, Ashdown S, Easley E, Kellom KS,
  Gebhart D, Lanier G, Milman N, Peck J, Luqmani RA, Shea JA, Tomasson
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  anti-neutrophil cytoplasmic antibody-associated
  vasculitis.\emph{Rheumatol Int} . 2018;38(4):675-682.
\item
  Prasad GV, Nash MM, McFarlane PA, Zaltzman JS. Renal transplant
  recipient attitudes toward steroid use and steroid
  withdrawal.\emph{Clin Transplant} . 2003;17(2):135-139.
\item
  Carella MJ, Srivastava LS, Gossain VV, Rovner DR.
  Hypothalamic-pituitary-adrenal function one week after a short burst
  of steroid therapy. \emph{J Clin Endocrinol Metab} .
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  Schuetz P, Christ-Crain M, Schild U, Süess E, Facompre M, Baty F,
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  systemic corticosteroids on the hypothalamic-pituitary-adrenal-axis in
  patients with acute exacerbation of chronic obstructive pulmonary
  disease. \emph{BMC Pulm Med} . 2008;8:1
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  https://www.addisonsdisease.org.uk/newly-diagnosed-sick-day-rules Last
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  Giordano R, Guaraldi F, Mazzoli M, Ghigo E. Do glucocorticoids induce
  addiction in humans?. \emph{J Endocrinol Invest} . 2017;40(8):881-883
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  Hochberg Z, Pacak K, Chrousos GP. Endocrine withdrawal syndromes.
  Endocr Rev. 2003;24(4):523-38
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  Fardet L, Nazareth I, Whitaker HJ, Petersen I: Severe neuropsychiatric
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  Substance Use. Trends Neurosci. 2018 Nov;41(11):853-868.
\item
  Anfinson TJ, Channappa C, Vo HT. Drug dependence involving prednisone:
  two cases and a review of the literature. Psychopharmacol Bull.
  2008;41(1):154-63.
\item
  Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with
  different types of oral corticosteroids and effect of termination of
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  2008;82(4):249-257.
\item
  NHS. Coping with side effects of steroid tablets.
  https://www.nhs.uk/conditions/steroid-tablets/\#side-effects Last
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  https://www.nice.org.uk/guidance/ng100/chapter/Recommendations\#initial-pharmacological-management
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  over 16s: diagnosis and management
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  chronic obstructive pulmonary disease. Cochrane Database of Systematic
  Reviews 2005, Issue 3. Art. No.: CD005374.
\end{enumerate}

\textbf{Table 1. Relative potency of synthetic glucocorticoids}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Corticosteroid}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Routes of administration}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Relative glucocorticoid receptor binding affinity}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Systemic dosage equivalence}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Potency classification when used topically at the concentrations
(weight/volume) shown}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Fluticasone furoate\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Inhaled\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2989\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Clobetasol proprionate\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Topical\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Very potent 0.05\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Fluocinolone Acetonide\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Topical\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Potent - 0.025\% Moderate 0.00625\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Mometasone furoate\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Inhaled, topical\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2100\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Potent 0.1\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Fluticasone propionate\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Inhaled, topical\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1775\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Potent 0.05\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Beclomethasone dipropionate\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Inhaled, topical\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1345\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Potent 0.025-0.05\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Betamethasone diproprionate\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Oral, Topical\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Potent 0.05\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Fludroxycortide\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Topical\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Moderate 0.0125\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Betamethasone valerate\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Topical\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Potent 0.1\% Moderate 0.025\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Hydrocortisone butyrate\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Topical\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Potent 0.1\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Diflucortolone valerate\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Topical\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Very potent 0.3\% Potent 0.1\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Clobetasone butyrate\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Topical\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Moderate 0.05\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Ciclesonide (des-CIC)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Inhaled\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1200\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Budesonide\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Inhaled\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
935\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Triamcinolone acetonide\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Inhaled\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
233\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4mg\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Flunisolide\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Inhaled\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
190\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Betamethasone sodium phosphate\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Oral, injection\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.75mg\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Dexamethasone\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Oral, injection\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.75 mg\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Methylprednisolone\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Oral, injection\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4 mg\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Prednisolone\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Oral\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
12\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
5 mg\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Hydrocortisone\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Oral, injection, topical\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textasciitilde{}2.5\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
20 mg\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Mild 0.1-2.5\%\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

The table shows synthetic glucocorticoids administered systemically
(oral or injection), topically and/or by inhalation ranked as far as
possible from highest to lowest in terms of potency using glucocorticoid
receptor binding affinity {[}4{]}, systemic dosage equivalence {[}5{]}
and topical steroid potency classification {[}6{]}.

\textbf{Table 2. An example tapering regimen for reducing glucocorticoid
dose in patients with inflammatory rheumatic diseases {[}24{]}}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\begin{minipage}[b]{0.47\columnwidth}\raggedright\strut
\textbf{Dose (prednisolone or equivalent)}\strut
\end{minipage} & \begin{minipage}[b]{0.47\columnwidth}\raggedright\strut
\textbf{Taper}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textgreater{}40 mg\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
5-10mg/day every 1-2 weeks\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
20-40mg\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
5mg/day every 1-2 weeks\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
10-20mg\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
2.5mg/day every 2-3 weeks\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
5-10mg\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
1mg/day every 2-4 weeks\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\emph{\textless{}}5mg\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
0.5mg/day every 2-4 weeks (can be achieved by alternating daily doses
e.g. 5 mg on day 1, 4 mg on day 2 etc)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3. Comparison of adrenal insufficiency and glucocorticoid
withdrawal syndrome in patients withdrawing from long term
glucocorticoids}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Adrenal insufficiency}\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Glucocorticoid withdrawal syndrome}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Symptoms\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
anorexia, fatigue, nausea, vomiting, dyspnea, fever, arthralgia,
myalgia, and orthostatic hypotension, dizziness, fainting, circulatory
collapse\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
anorexia, nausea, emesis, weight loss, fatigue, myalgias, arthralgias,
weakness, headache, abdominal pain, lethargy, postural hypotension,
fever, skin desquamation, tachycardia, emotional lability, delirium,
psychotic states\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Steroid dosage\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Symptomatic below physiological doses (prednisolone 7.5mg or
equivalent)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Symptoms can occur at supraphysiological doses of glucocorticoids\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
HPA testing\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Cortisol insufficiency 9am cortisol \textless{}100nmol/L and/or Peak
cortisol after synacthen stimulation \emph{\textless{}}550nmol/L\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Normal HPA function 9am cortisol \textgreater{}450nmol/L and/or Peak
cortisol after synacthen stimulation \textgreater{}550nmol/L\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Risk of adrenal crisis\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
No\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Management\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Reduce glucocorticoids to physiological dose Long term replacement with
hydrocortisone 15-20 mg/ day or prednisolone 4-5 mg/day Increase
glucocorticoids during intercurrent illness Very slow wean over the long
term to allow HPA axis recovery\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Reduce glucocorticoids to the lowest possible dose that controls
symptoms Then withdraw very slowly over months No need to increase
glucocorticoids during intercurrent illness Consider retesting HPA axis
if glucocorticoid wean is very prolonged and difficult\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Figure legends}

\textbf{Figure 1. Adverse effects of glucocorticoids by dose and
duration of treatment}

The adverse effects of systemic glucocorticoids are plotted
approximately at the earliest time after treatment initiation (in
months) and the lowest dose (prednisolone equivalent) at which they have
been reported to occur. For example, neuropsychiatric effects occur
early in people taking high dose treatment whereas cardiovascular
disease is not increased in people taking prednisolone unless the dose
has been \textgreater{}7.5mg for \textgreater{}1 year. Even very low
dose glucocorticoid treatment can cause adverse effects if taken over a
long period of time.

\textbf{Figure 2. Factors increasing the systemic bioavailability of
glucocorticoids administered topically or by inhalation}

Absorption of the drug from the site of administration is greater if
drug molecules are lipophilic and soluble or formulated with a vehicle
with solvent or occlusive properties, which increase epithelial
permeability. It is also greater with higher dosage, application over
greater surface area, and in underlying disease e.g. where there is
inflammation increasing epithelial permeability.

In the plasma, glucocorticoids are bound to corticosteroid-binding
globulin (transcortin) and albumin. Factors that reduce these proteins,
such as disease states with increased protein loss or decreased
synthesis, could increase free circulating glucocorticoids.

Interactions with drugs that inhibit the hepatic enzymes that clear
glucocorticoids (e.g. cyclosporin, erythromycin, itraconazole and
ritonavir) or induce hepatic enzymes that activate glucocorticoid
prodrugs can increase systemic exposure to glucocorticoids. Systemic
exposure is also increased if glucocorticoid clearance is reduced e.g.
by hepatic or renal impairment, and by hypothyroidism and older age

\textbf{Figure 3. Relationship of glucocorticoid dose to disease control
and adverse drug reactions}

At treatment doses of glucocorticoids, disease control comes at the cost
of dose-related and continuous use adverse drug reactions. When
glucocorticoids are withdrawn, disease reactivation and end-of-use
(withdrawal) reactions emerge as dose-related adverse reactions
diminish. Adrenal insufficiency can become symptomatic when the dose of
exogenous glucocorticoids falls below physiological glucocorticoid
levels. Psychological dependence on glucocorticoids is not dose
dependent.

\textbf{Hosted file}

\verb`Deprescribing steroids - figures 1.pptx`  available at \url{https://authorea.com/users/343001/articles/469728-is-there-a-safe-and-effective-way-to-wean-patients-off-long-term-glucocorticoids}

\textbf{Hosted file}

\verb`Deprescribing steroids - figures 2.pptx`  available at \url{https://authorea.com/users/343001/articles/469728-is-there-a-safe-and-effective-way-to-wean-patients-off-long-term-glucocorticoids}

\textbf{Hosted file}

\verb`Deprescribing steroids - figure 3.pptx`  available at \url{https://authorea.com/users/343001/articles/469728-is-there-a-safe-and-effective-way-to-wean-patients-off-long-term-glucocorticoids}

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