Download 60 - Glucocorticoid Therapy

60
Glucocorticoid
Therapy
JOHANNES W.G. JACOBS • JOHANNES W.J. BIJLSMA
KEY POINTS
Mode of action of glucocorticoids is genomic (via
glucocorticoid receptor) and, in high dosages, also
nongenomic.
Glucocorticoids differ considerably in potency and biologic
half-life.
Cortisone and prednisone are biologically inactive and are
converted in the liver into biologically active cortisol and
prednisolone.
Glucocorticoids have disease-modifying properties in early
rheumatoid arthritis.
The risk of adverse effects of a glucocorticoid is patient, dose,
and time dependent.
The risk of adverse effects of low-dose glucocorticoids
generally is overestimated.
After local injection of a glucocorticoid, the risk of local
bacterial infection is very low.
Low and low-to-moderate doses of prednisolone in
pregnancy appear to be safe.
Glucocorticoids are widely used for the treatment of patients
with rheumatic disease. The first to be isolated, in 1935, was
the naturally occurring glucocorticoid hormone, cortisone.
It was synthesized in 1944 and subsequently became available for clinical use. In 1948, cortisone (then called compound E) was administered by the American physician
Philip S. Hench to a 29-year-old woman with active rheumatoid arthritis (RA) of longer than 4 years’ duration. Her
joints were so painful she could “hardly get out of bed.”
After 2 days of treatment with 100 mg of intramuscular
compound E daily, “She rolled over in bed with ease, and
noted much less muscular soreness.” The next day, she was
able to walk with “only a slight limp.” Hench published this
case of dramatic improvement in 19491 and won the 1950
Nobel Prize in Physiology or Medicine for his research,
which he shared with two colleagues at the Mayo Clinic.
Later, by chemical modification of natural steroids, different
synthetic glucocorticoids were produced, some of which
have proved to be very effective anti-inflammatory and
immunosuppressive substances with rapid, sometimes
instant, effects.
Initially, there was considerable enthusiasm about glucocorticoid therapy because of the striking relief of symptoms
seen in patients treated with supraphysiologic dosages.
When the wide array of potentially serious adverse side
894
effects became apparent, however, the use of glucocorticoids
decreased. Nevertheless, because glucocorticoids can be
considered the most effective anti-inflammatory and immunosuppressive substances currently known, they have
become a cornerstone of therapy for many rheumatic disorders, including systemic lupus erythematosus (SLE), vasculitis, polymyalgia rheumatica, and myositis. The use of
glucocorticoids in therapeutic strategies for patients with
RA has become accepted.
During past decades, knowledge about glucocorticoids
has increased, but much remains to be learned about the
modes of actions of these drugs in rheumatic autoimmune
disorders. It is hoped that the unraveling of these mechanisms eventually may lead to new applications of glucocorticoids or novel classes of therapy.
CHARACTERISTICS OF
GLUCOCORTICOIDS
Structure and Classification
The precursor molecule of all steroid hormones is cholesterol, which is also a building block for vitamin D and cell
membranes and organelles (Figure 60-1). Steroid hormones
and cholesterol are characterized by a sterol skeleton,
formed by three six-carbon hexane rings and one fivecarbon pentane ring. The carbon atoms of this sterol nucleus
are numbered in a specific sequence; the term steroid refers
to this basic sterol nucleus (Figure 60-2).
Steroid hormones can be classified on the basis of their
main function into sex hormones (male and female), mineralocorticoids, and glucocorticoids. Sex hormones are synthesized mainly in the gonads, but also in the adrenal cortex.
Mineralocorticoids and glucocorticoids are synthesized only
in the adrenal cortex; the terms corticosteroid and corticoid
for these hormones refer to the adrenal cortex. Some glucocorticoids also have a mineralocorticoid effect and vice
versa. The main natural mineralocorticoid is aldosterone,
and the main natural glucocorticoid is cortisol (hydrocortisone). Although separation of corticoids into the classes
mineralocorticoids and glucocorticoids is not absolute (see
later), it is better (more precise) to use the term glucocorticoid than the term corticosteroid when referring to one of
these compounds.2 The importance of standardized nomenclature is illustrated by the fact that an electronic literature
search can be complicated by multiple synonyms.
In the 1950s, chemical modification of natural steroids
revealed numerous structural features essential for specific
biologic activities. Synthetic steroid hormones more potent
than natural steroid hormones and steroid hormones with
CHAPTER 60 | Glucocorticoid Therapy
895
Cholesterol
OH
Cell membranes,
myelin
Steroid hormones:
• Glucocorticoids
• Mineralocorticoids
• Male sex hormones
• Female sex hormones
Vitamin D
Cellular organelles
Figure 60-1 Cholesterol as building block for steroid hormones, vitamin D, and cell membranes and organelles.
altered biologic activity were developed. This research
showed that the 17-hydroxy, 21-carbon steroid configuration (see Figure 60-2) is required for glucocorticoid activity
through binding to the glucocorticoid receptor. Glucocorticoids with an 11-keto, instead of an 11-hydroxy, group,
such as cortisone and prednisone, are prohormones that
must be reduced in the liver to their 11-hydroxy configurations. Cortisone is converted by hepatic pathways to cortisol, and prednisone is converted to prednisolone, to become
biologically active. Thus in patients with severe liver
disease, it is rational to prescribe prednisolone instead of
prednisone.
The generation of biologically active glucocorticoids
from their inactive forms is promoted by the reductase
action of the intracellular enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1. The same enzyme can by
dehydrogenation promote the reverse reaction, leading to
inactivation of active glucocorticoids. In contrast, 11βHSD type 2 has dehydrogenase activity only, so it catalyzes
only the conversion of active glucocorticoids to their inactive forms. In different tissues, local balance between the
intracellular enzymes 11β-HSD type 1 and type 2 might
modulate intracellular glucocorticoid concentrations and
thus tissue sensitivity for glucocorticoids.3 Synovial tissue
metabolizes glucocorticoids via the two 11β-HSD enzymes,
with the net effect being glucocorticoid activation; this
increases with inflammation. This endogenous glucocorticoid production in the joint is likely to have an impact on
local inflammation and on bone in the joint.4
No qualitative differences have been noted between the
glucocorticoid effect of endogenous cortisol and that of
exogenously applied synthetic glucocorticoids because these
effects are, except for higher doses, predominantly genomic
(i.e., mediated through the glucocorticoid receptor).5
However, quantitative differences have been identified.
The potency and other biologic characteristics of glucocorticoids depend on structural differences in the steroid
configuration. The introduction of a double bond between
the 1 and 2 positions of cortisol yields prednisolone, which
has about four times more glucocorticoid activity than cortisol (Table 60-1).
Addition of a six-methyl group to prednisolone yields
methylprednisolone, which is about five times more potent
than cortisol. All the aforementioned glucocorticoids also
have a mineralocorticoid effect. The synthetic glucocorticoids triamcinolone and dexamethasone have negligible
mineralocorticoid activity, however.
Biologic Characteristics and
Therapeutic Consequences
Apart from the steroid configuration, biologic characteristics of glucocorticoids also depend on whether they are in
free form (as alcohol) or are chemically bound (as ester or
salt). In their free form, glucocorticoids are virtually insoluble in water, so they can be used in tablets but not in
parenteral preparations. For this reason, synthetic glucocorticoids are formulated as organic esters or as salts. Esters,
such as (di)acetate and (hex)acetonide, are lipid soluble but
have limited water solubility and are suitable for oral use
and intramuscular, intralesional, and intra-articular injection. Salts, such as sodium phosphate and sodium succinate,
are generally more water soluble and thus are also suitable
for intravenous use. Dexamethasone sodium phosphate can
be used intravenously, whereas dexamethasone acetate
cannot. When given intramuscularly, dexamethasone
sodium phosphate is absorbed much faster from the injection site than dexamethasone acetate. If an immediate
effect is required, dexamethasone sodium phosphate given
intravenously is more rapidly effective than the same preparation given intramuscularly; the least rapidly active is that
of intramuscular dexamethasone acetate. For local use, less
solubility means longer duration of the local effect, which
generally is beneficial.
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PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS
OH
1
17
12
11
13
16
14
15
9
8
10
2
3
Basic sterol nucleus
Cholesterol
7
6
5
21 CH2OH
4
20 C
11
19
1
C
OH
17
12
CH2OH
O
18
O
OH
13
16
14
15
OH
OH
9
8
10
2
3
Cortisol
(hydrocortisone)
Cortisone
7
5
O
O
6
O
CH2OH
4
C
CH2OH
C
O
OH
O
OH
OH
Prednisolone
Prednisone
O
O
CH2OH
C
O
CH2OH
C
O
OH
OH
O
OH
OH
OH
F
Methylprednisolone
Triamcinolone
O
O
CH3
CH2OH
C
CH2OH
O
C
OH
OH
CH3
F
Dexamethasone
O
OH
OH
CH3
F
O
Betamethasone
O
Figure 60-2 Basic steroid configuration and structure of cholesterol and of natural and some synthetic glucocorticoids. Structural differences of
glucocorticoids compared with cortisol, the natural active glucocorticoid, are shown in red.
Pharmacokinetics and Pharmacology
Water insolubility does not impair absorption from the
digestive tract. Most orally administered glucocorticoids,
whether in free form or as an ester or salt, are absorbed
readily, probably within about 30 minutes. Bioavailability
of prednisone and prednisolone is high. Commercially
available oral and rectal prednisone and prednisolone preparations are considered approximately bioequivalent.
The affinity of the different glucocorticoids for various
plasma proteins varies (see Table 60-1). Of cortisol in
plasma, 90% to 95% is bound to plasma proteins, primarily
CHAPTER 60 | Glucocorticoid Therapy
897
Table 60-1 Pharmacodynamics of Commonly Used Glucocorticoids
Equivalent
Glucocorticoid
Dose (mg)
Relative
Glucocorticoid
Activity
Relative
Mineralocorticoid
Activity*
Protein
Binding
0.8
1
0.8
1
−
++++
0.5
1.5-2
5
4
4
5
0.5
0.6
0.6
0
−
++
+++
++
>3.5
2.1-3.5
3.4-3.8
2->5
18-36
18-36
18-36
18-36
0
0
++
++
3-4.5
3-5
36-54
36-54
Plasma
Half-Life
Biologic
Half-Life
(hr)
Short-Acting
Cortisone
Cortisol
25
20
8-12
8-12
Intermediate-Acting
Methylprednisolone
Prednisolone
Prednisone
Triamcinolone
4
5
5
4
Long-Acting
Dexamethasone
Betamethasone
0.75
0.6
20-30
20-30
*Clinically; sodium and water retention, potassium depletion.
−, None; ++, high; +++, high to very high; ++++, very high.
transcortin (also called corticosteroid-binding globulin) and, to
a lesser degree, albumin. Protein-bound cortisol is not biologically active, but the remaining 5% to 10% of free cortisol is. Prednisolone has—in contrast to methylprednisolone,
dexamethasone, and triamcinolone—a high affinity for
transcortin and competes with cortisol for this binding
protein. The other synthetic glucocorticoids with little
or no affinity for transcortin are two-thirds (weakly)
bound to albumin, and about one-third circulate as free
glucocorticoid.
Because only unbound glucocorticoids are pharmacologically active, patients with low levels of plasma protein, such
as albumin (e.g., because of liver diseases or chronic active
inflammatory diseases), are more susceptible to effects and
side effects of glucocorticoids. Dosage adjustment should be
considered in these patients. In liver disease, an additional
argument for dosage adjustment is reduced clearance of glucocorticoids (see later).
Glucocorticoids have biologic half-lives 2 to 36 times
longer than their plasma half-lives (see Table 60-1). With
a plasma half-life of about 3 hours, prednisolone can be
dosed once daily for most diseases. Maximal effects of glucocorticoids lag behind peak serum concentrations. Transcortin binds these compounds more strongly than does
albumin. The plasma elimination of glucocorticoids bound
to transcortin is slower than that of glucocorticoids that do
not bind. Transcortin binding is not a major determinant of
biologic half-lives of glucocorticoids, however, in contrast
to distribution to different compartments of the body and
binding to the cytosolic glucocorticoid receptor. Synthetic
glucocorticoids have lower affinity for transcortin but higher
affinity for the cytosolic glucocorticoid receptor than does
cortisol (see later). The affinity of prednisolone and triamcinolone for the glucocorticoid receptor is approximately
two times higher, and for dexamethasone it is seven times
higher. Prednisone and cortisone have had negligible glucocorticoid bioactivity before they have been chemically
reduced because of their very low affinity for the glucocorticoid receptor.
Another important factor determining biologic half-lives
of glucocorticoids is the rate of metabolism. Synthetic glucocorticoids are subject to the same reduction, oxidation,
hydroxylation, and conjugation reactions as cortisol.
Pharmacologically active glucocorticoids are metabolized
primarily in the liver into inactive metabolites and are
excreted by the kidneys; only small amounts of unmetabolized drug are also excreted in the urine. An inverse correlation has been noted between prednisolone clearance and
age, which means that a given dose may have a greater effect
in older individuals.6 Prednisolone clearance also is slower
in African-Americans compared with that in whites.7 The
serum half-life of prednisolone is 2.5 to 5 hours, but it is
increased in patients with renal disease and liver cirrhosis,
and in the elderly. Prednisolone can be removed by hemodialysis, but overall, the amount removed does not require
dosage adjustment in patients on hemodialysis. In patients
with cirrhosis of the liver, clearance of unbound steroid is
about two-thirds of normal—a difference that should be
taken into account with dosing.
Drug Interactions
Cytochrome P450 (CYP) is a family of isozymes responsible
for the biotransformation of several drugs. Drug interactions
can be based on induction or on inhibition of these enzymes.
Certain drugs (e.g., barbiturates, phenytoin, rifampin) by
inducing CYP isoenzymes (e.g., CYP3A4) increase the
metabolism (breakdown) of synthetic and natural glucocorticoids, particularly by enhancing hepatic hydroxylase
activity, thus reducing glucocorticoid concentrations (Figure
60-3). Rifampin-induced nonresponsiveness to prednisone
in inflammatory diseases indeed has been described,8,9 as has
rifampin-induced adrenal crisis in patients on glucocorticoid replacement therapy.10 Clinicians should consider
increasing the dosage of glucocorticoids in patients who are
concomitantly treated with these medications.
Conversely, concomitant use of glucocorticoids with
inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole,
diltiazem, mibefradil and grapefruit juice) decreases glucocorticoid clearance and leads to higher concentrations
and prolonged biologic half-lives of glucocorticoid drugs,
thus increasing the risk of adverse effects.11 Antifungal
therapies, especially ketoconazole, on the other hand
are known to interfere with endogenous glucocorticoid
synthesis and therefore are also used, in doses of 400
to 800 mg per day, to treat hypercortisolism.11 Etomidate, a
Serum prednisolone concentraton (ng/nL)
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PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS
800
600
Without rifampin
400
With rifampin
200
0
0
6
12
Time (h)
18
24
Figure 60-3 Serum prednisolone concentration in time in one patient,
after 0.9 mg/kg prednisone orally daily, in the presence and absence of
therapy with rifampin. Curve with rifampin, during a period of continuous
administration of both drugs. Curve without rifampin, after a washout of
rifampin of 4 weeks. Rifampin induces a reduced area under the curve of
prednisolone, indicating reduced bioavailability.8
short-acting intravenous anesthetic agent used for the
induction of general anesthesia and for sedation, can also
lower cortisol levels, which could be clinically relevant in
critically ill patients.11
Concomitant administration of prednisolone and cyclosporine may result in increased plasma concentrations of the
former drug; concomitant administration of methylprednisolone and cyclosporine may result in increased plasma
concentrations of the latter drug. The mechanism of this
probably is competitive inhibition of microsomal liver
enzymes. Antibiotics such as erythromycin may increase
plasma concentrations of glucocorticoids. Synthetic estrogens in oral contraceptives increase the level of transcortin
and thus total (sum of bound and unbound) glucocorticoid
levels. Therefore, in women taking oral contraceptives,
care is required in the interpretation of cortisol measurements, especially because adrenal insufficiency may be
present even when total cortisol levels are within the
normal range.12 Next to glucocorticoids, other steroid drugs
such as megestrol acetate and medroxyprogesterone inhibit
the hypothalamic-pituitary-adrenal axis11; this risk may be
increased when they are used concomitantly with glucocorticoids. Sulfasalazine has been reported to increase the sensitivity of immune cells for glucocorticoids,13 which could
be beneficial.
maternal-to-fetal dexamethasone blood concentration ratio
is about 1 : 1.
If a pregnant woman has to be treated with glucocorticoids, prednisone, prednisolone, and methylprednisolone
would be good choices; if the unborn child has to be treated,
fluorinated glucocorticoids, such as betamethasone or dexamethasone, would be indicated. Fear of physical (e.g.,
reduced growth) and neurocognitive adverse effects in children exposed to antenatal repeat doses of 12 mg betamethasone has not been substantiated,14,15 in contrast to postnatal
glucocorticoid exposure.16 However, because of a small but
increased risk of an oral cleft, it is advised to avoid high
doses (1 to 2 mg/kg prednisone equivalent) in the first trimester of pregnancy,17,18 whereas low to moderate doses of
prednisone seem to be safe.18
Prednisolone and prednisone are excreted in small quantities in breast milk. Breastfeeding is generally considered
safe for an infant whose mother is taking these drugs.
Because curves of milk and serum concentrations for prednisolone are virtually parallel in time, exposure of the infant
is minimized if breastfeeding is avoided during the first 4
hours after the intake of prednisolone.18
BASIC MECHANISMS OF
GLUCOCORTICOIDS
Genomic and Nongenomic Effects
Glucocorticoids at any therapeutically relevant dosage
exhibit pharmacologic effects via classic genomic mechanisms. The lipophilic glucocorticoid passes across the cell
membrane, attaches to the cytosolic glucocorticoid receptor
and heat shock protein, and binds to glucocorticoidresponsive elements on genomic DNA; it interacts with
nuclear transcription factors. This process takes time. When
acting through genomic mechanisms, it takes at least 30
minutes before the clinical effect of a glucocorticoid begins
to show.19 Only when high doses are given, as in pulse
therapy, can glucocorticoids act within minutes by nongenomic mechanisms; this occurs via specific receptormediated activity or via nonspecific membrane-associated
physicochemical activity.5 The response to high-dose pulse
methylprednisolone therapy may be biphasic, consisting of
an early, rapid, nongenomic effect and a delayed and more
sustained classic genomic effect.20 Clinically, genomic and
nongenomic effects cannot be separated, however.
Pregnancy and Lactation
Genomic Mechanisms
In pregnancy, two mechanisms protect the fetus from
exogenous glucocorticoids. First, glucocorticoids bound
to transport proteins cannot pass the placenta, in contrast
to unbound glucocorticoids. Second, the enzyme 11β-HSD
in the placenta, which catalyzes the conversion of
active cortisol, corticosterone, and prednisolone into
the inactive 11-dehydro-prohormones (cortisone, 11dehydrocorticosterone, and prednisone), protects the fetus
from glucocorticoids in the blood of the mother. The
maternal-to-fetal prednisolone blood concentration ratio is
about 10 : 1, owing to these mechanisms. In contrast, dexamethasone has little or no affinity for transport proteins and
is poorly metabolized by 11β-HSD in the placenta; the
Most of the effects of glucocorticoids are exerted via genomic
mechanisms by binding to the glucocorticoid receptor
located in the cytoplasm of the target cells; glucocorticoids
are lipophilic and have a low molecular mass; thus they can
pass through the cell membrane easily. Next to the tissuespecific intracellular density of glucocorticoid receptors, the
balance of intracellular 11β-HSDs (see earlier) probably
determines the sensitivity of specific tissues for glucocorticoids.3 Of the isoforms α and β of the glucocorticoid receptor, only the α isoform, common in all target tissues, binds
to glucocorticoids.19 This is a 94-kD protein to which several
heat shock proteins (chaperones) are bound. Binding of the
glucocorticoid to this complex causes shedding of
CHAPTER 60 the chaperones. The resulting activated glucocorticoid
receptor–glucocorticoid complex is rapidly translocated
into the nucleus, where it binds (as a dimer) to specific
consensus sites in the DNA (glucocorticoid-responsive elements), regulating the transcription of a large variety of
target genes. This process is termed transactivation. Binding
to glucocorticoid-responsive elements results in stimulation
or suppression of transcription of these target genes. Suppression of genes also may be mediated by mechanisms
involving interaction of the glucocorticoid receptor–glucocorticoid complex (as a momomer) with transcriptional
factors, such as activator protein-1 and nuclear factor κB.21
This process is termed transrepression (Figure 60-4).
The nature and availability of these transcription factors
may be pivotal in determining the differential sensitivity of
different tissues to glucocorticoids because they play a
crucial role in regulating the expression of a wide variety of
proinflammatory genes induced by cytokines. The binding
of transcriptional factors to DNA is inhibited by glucocorticoids, resulting in depressed expression of these genes and
inhibition of their amplifying role in inflammation. Activated glucocorticoid receptors also may inhibit protein synthesis by decreasing the stability of mRNA through the
induction of ribonucleases. This mechanism has been proposed to mediate glucocorticoid-induced inhibition of the
synthesis of interleukin (IL)-1, IL-6, granulocytemacrophage colony-stimulating factor, and inducible cyclooxygenase (COX)-2.22
There is increasing acceptance of the hypothesis that
side effects of glucocorticoids, such as diabetes mellitus,
osteoporosis, skin atrophy, growth retardation, and
cushingoid appearance, may be based predominantly on
transactivation of genes after binding of glucocorticoid
receptor–glucocorticoid to DNA, whereas the antiinflammatory effects may be due mostly to the binding of a
single glucocorticoid receptor-glucocorticoid complex to
Glucocorticoid Therapy
899
transcription factors or co-activators, resulting in gene
repression (transrepression). Understanding of these molecular mechanisms may lead to development of novel glucocorticoids, such as selective glucocorticoid receptor agonists,
with a more favorable balance of transactivation and transrepression and, clinically, to a more favorable balance of
metabolic and endocrine side effects and therapeutic
effects21 (see later).
Expression of multiple target genes at the posttranscriptional level, also those influenced by glucocorticoids, is modulated by microRNAs (miRNAs), short
noncoding RNA molecules that are implicated in a wide
array of cellular and immune processes. Abnormal expression of miRNAs has been found in patients with rheumatoid arthritis. This identifies miRNAs as targets for
immunomodulatory drug development.23
Glucocorticoid Effects on the Immune System
Glucocorticoids reduce activation, proliferation, differentiation, and survival of a variety of inflammatory cells,
including macrophages and T lymphocytes, and promote
apoptosis, especially in immature and activated T cells
(Figure 60-5). This activity is mediated mainly by changes
in cytokine production and secretion. In contrast, B lymphocytes and neutrophils are less sensitive to glucocorticoids, and their survival may be increased by glucocorticoid
treatment. The main effect of glucocorticoids on neutrophils seems to be inhibition of adhesion to endothelial cells.
Glucocorticoids inhibit not only the expression of adhesion
molecules, but also the secretion of complement pathway
proteins and prostaglandins. At supraphysiologic concentrations, glucocorticoids suppress fibroblast proliferation
and IL-1 and tumor necrosis factor (TNF)-induced metalloproteinase synthesis. By these effects, glucocorticoids may
retard bone and cartilage destruction in the inflamed joint.24
Glucocorticoid
responsive
Cell membrane Cytoplasm element
Glucocorticoid
| Nucleus
Nuclear membrane
mRNA
Glucocorticoid
receptor
Up-regulated
synthesis of
proteins
Transactivation
Transrepression
No binding
Transcription
factor NFκB
No
mRNA
DNA
Down-regulated
synthesis of
proteins
NFκB responsive element
Figure 60-4 Genomic action of glucocorticoids. Glucocorticoid binds to the glucocorticoid receptor in the cytoplasm. This complex migrates into
the nucleus. Activation of transcription (transactivation) by binding of glucocorticoid receptor–glucocorticoid dimers to glucocorticoid-responsive
elements of DNA up-regulates synthesis of regulatory proteins, thought to be responsible for metabolic effects and also some anti-inflammatory/
immunosuppressive effects. Interference of glucocorticoid receptor–glucocorticoid monomers with proinflammatory transcription factors, such as
nuclear factor κB (NFκB), inhibits their binding to NFκB-responsive elements of DNA and transcription. This is called transrepression and down-regulates
synthesis of predominantly inflammatory/immunosuppressive proteins.
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PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS
↑ Apoptosis
↑ Apoptosis
Tc cell
Th cell
↓ IL-1β
↓ IL-12
↓ TNF
Macrophage
↑ Apoptosis
↑ Apoptosis
↑ IL-10
(↓ Antibodies at
very high GC doses)
Dendritic
cell
↑ IL-4
B cell line
↓ Cytotoxicity
Glucocorticoids
NK cell
Fibroblast
Tc cell
Th cell
↓ IFN-γ
↓ IL-2
Neutrophil
↓ Proliferation
↓ Fibronectin
↓ Prostaglandins
↓ Migration
↑ Apoptosis
↑ Apoptosis
Figure 60-5 Effects shown in red type. Downregulation of adhesion molecules decreases migration of neutrophils and increases the number of circulating neutrophils. GC, glucocorticoid; IFN-γ, interferon-γ; IL, interleukin; NK, natural killer; Tc, cytotoxic T lymphocyte; Th, helper T lymphocyte; TNF,
tumor necrosis factor. (Modified from Sternberg E: Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens, Nat Rev
Immunol 6:318–328, 2006.)
Leukocytes and Fibroblasts
Administration of glucocorticoids leads to an increase in
the total leukocyte count caused by an increase in circulating neutrophil granulocytes in the blood, although the
numbers of other leukocyte subsets in blood such as eosinophil and basophil granulocytes, monocytes/macrophages
(decreased myelopoiesis and bone marrow release), and T
cells (redistribution effect) are decreased. Table 60-2 summarizes the effects of glucocorticoids on leukocyte subsets.
The redistribution of lymphocytes, which is maximal 4 to 6
hours after administration of a single high dose of prednisone and returns to normal within 24 hours, has no clinical
consequences. B cell function and immunoglobulin production are hardly affected. The effects of glucocorticoids
on monocytes and macrophages, including decreased
expression of major histocompatibility complex (MHC)
class II molecules and Fc receptors, may increase susceptibility to infection, however.25 Effects of glucocorticoids on
fibroblasts include decreased proliferation and decreased
production of fibronectin and prostaglandins.
glucocorticoid action in chronic inflammatory diseases such
as RA. Glucocorticoids exert potent inhibitory effects on
the transcription and action of a large variety of cytokines
with pivotal importance in the pathogenesis of RA. Most
T helper type 1 (Th1) proinflammatory cytokines are inhibited by glucocorticoids, including IL-1β, IL-2, IL-3, IL-6,
Table 60-2 Anti-inflammatory Effects of
Glucocorticoids on Immune Cells
Cell Type
Effects
Neutrophils
Increased blood count, decreased
trafficking, relatively unaltered
functioning
Decreased blood count, decreased
trafficking, decreased phagocytosis and
bactericidal effects, inhibited antigen
presentation, decreased cytokine and
eicosanoid release
Decreased blood count, decreased
trafficking, decreased cytokine
production, decreased proliferation and
impaired activation, little effect on
immunoglobulin synthesis
Decreased blood count, increased
apoptosis
Decreased blood count, decreased release
of mediators of inflammation
Macrophages and
monocytes
Lymphocytes
Cytokines
Eosinophils
The influence of glucocorticoids on cytokine production
and action represents one of the major mechanisms of
Basophils
CHAPTER 60 TNF, interferon-γ (indicative of Th1 helper cells), IL-17
(indicative of Th17 helper cells), and granulocytemacrophage colony-stimulating factor (see Figure 60-5). In
RA, these cytokines are considered responsible for synovitis, cartilage degradation, and bone erosion. Conversely, the
production of Th2 cytokines, such as IL-4, IL-10, and IL-13,
may be stimulated or not affected by glucocorticoids (see
Figure 60-5).26 These cytokines have been related to the
extra-articular features of erosive RA associated with B cell
overactivity, such as immune complex formation and vasculitis. Activation of Th2 cells can suppress rheumatoid
synovitis and joint destruction through release of the antiinflammatory cytokines IL-4 and IL-10, which inhibit Th1
activity and downregulate monocyte and macrophage
functions.27
Inflammatory Enzymes
An important part of the inflammatory cascade is arachidonic acid metabolism, which leads to the production of
prostaglandins and leukotrienes, most of which are strongly
proinflammatory. Through the induction of lipocortin (an
inhibitor of phospholipase A2), glucocorticoids inhibit the
formation of arachidonic acid metabolites. Glucocorticoids
also have been shown to inhibit the production of COX-2
and phospholipase A2 induced by cytokines in monocytes/
macrophages, fibroblasts, and endothelial cells. In addition,
glucocorticoids are potent inhibitors of the production of
metalloproteinases in vitro and in vivo, especially collagenase and stromelysin, which are the main effectors of cartilage degradation induced by IL-1 and TNF.28
Adhesion Molecules and Permeability Factors
Pharmacologic doses of glucocorticoids dramatically inhibit
exudation of plasma and migration of leukocytes into
inflammatory sites. Adhesion molecules play a central role
in chronic inflammatory diseases by controlling the trafficking of inflammatory cells into sites of inflammation. Glucocorticoids reduce the expression of adhesion molecules
through inhibition of proinflammatory cytokines and by
direct inhibitory effects on the expression of adhesion molecules, such as intercellular adhesion molecule-1 and
E-selectin.29 Chemotactic cytokines attracting immune
cells to the inflammatory site, such as IL-8 and macrophage
chemoattractant proteins, also are inhibited by glucocorticoids. Nitric oxide production in inflammatory sites is
increased by proinflammatory cytokines, resulting in
increased blood flow, exudation, and probably amplification
of the inflammatory response. The inducible form of nitric
oxide synthase by cytokines is potently inhibited by
glucocorticoids.30
Hypothalamic-Pituitary-Adrenal Axis
Pathophysiology
Proinflammatory cytokines, such as IL-1 and IL-6, and eicosanoids, such as prostaglandin E2, and endotoxins all activate corticotropin-releasing hormone (CRH) at the
hypothalamic level (Figure 60-6). This activation stimulates the secretion of adrenocorticotropic hormone (ACTH)
| Glucocorticoid Therapy
901
by the pituitary gland and of glucocorticoids by the adrenal
glands. In otherwise healthy individuals with severe infection or other major physical stress, cortisol production may
increase to six times the normal amount.12 In patients with
active RA (or other chronic inflammatory diseases), the
increase in cortisol driven by elevated cytokines might be
inappropriately low,31 meaning that cortisol levels—
although normal or elevated in the absolute sense—are
insufficient to control the inflammatory response. This is
the concept of relative adrenal insufficiency.31-33 En­­
dogenous and exogenous glucocorticoids exert negative
feedback control on the hypothalamic-pituitary-adrenal
axis directly by suppressing secretion of ACTH and CRH,
and indirectly by suppressing release from inflammatory
tissues of proinflammatory cytokines, which stimulate secretion of ACTH and CRH (see Figure 60-6). Sensitivity of
the hypothalamic-pituitary-adrenal axis for proinflammatory cytokines is probably decreased in RA.34
ACTH is secreted in brief, episodic bursts, resulting in
sharp increases in plasma concentrations of ACTH and
cortisol, followed by slower declines in cortisol levels—the
normal diurnal rhythm in cortisol secretion. Secretory
ACTH episodic bursts increase in amplitude but not in
frequency after 3 to 5 hours of sleep, reach a maximum
during the hours before and the hour after awakening,
decline throughout the morning, and are minimal in the
evening. Cortisol levels are highest at about the time of
awakening in the morning, are low in the late afternoon
and evening, and reach their lowest level some hours after
falling asleep (see Figure 60-6). Glucocorticoids are not
stored in the adrenal glands in significant quantities.
Continuing synthesis and release are required to maintain
basal secretion or to increase blood levels during stress. The
total daily basal or physiologic secretion of cortisol in
humans has been estimated to range from 5.7 to 10 mg/m2/
day.35,36 This would be covered in primary adrenal insufficiency by oral administration of 15 to 25 mg cortisol,35
equivalent to about 4 to 6 mg prednisone. This low daily
cortisol production rate may explain the cushingoid
symptoms and other adverse effects that are sometimes
observed in patients with adrenal insufficiency who are
using glucocorticoids at doses previously regarded to be
replacement doses (based on estimates of physiologic secretion of cortisol of 12 to 15 mg/m2/day), which are in fact
supraphysiologic doses.
Effects of Glucocorticoids on the HypothalamicPituitary-Adrenal Axis
Chronic suppression of the hypothalamic-pituitary-adrenal
axis by administration of exogenous glucocorticoids leads by
negative feedback loops on CRH and ACTH (see Figure
60-6) to failure in pituitary ACTH release, and thus to
partial functional adrenal atrophy with loss of cortisol secretory capability in the fasciculata-reticularis zone. This inner
cortical zone is the site of cortisol and adrenal androgen
synthesis and is dependent on ACTH for structure and
function. The outer cortical (glomerulosa) zone is involved
in mineralocorticoid (aldosterone) biosynthesis and is functionally independent of ACTH. It stays functionally intact.
Patients have failure of pituitary ACTH release and adrenal
902
PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS
Psychological and
Cerebral
physical stress
circadian clock
Hypothalamus
CRH
- Cytokines, e.g., IL-1, IL-6
- Endotoxines
- Other mediators of
inflammation
ACTH
Pituitary
anterior lobe
Arthritis and other inflammatory
processes
Cortisol
Exogenous
glucocorticoids
Cortisol levels
in RA
IL-6 levels
in RA
Cortisol levels
in controls
Early morning stiffness in RA
22.00
24.00
02.00
04.00
06.00
08.00
10.00
Figure 60-6 Upper part, Stimulation (plus signs) and inhibition (minus signs) of the hypothalamic-hypopituitary-adrenal axis. Lower part, On the x-axis
hours, plasma cortisol levels (blue line) in rheumatoid arthritis (RA) show an earlier and higher circadian rise compared with those in healthy controls,
possibly caused by the rise in the proinflammatory cytokine interleukin-6 (IL-6); this rise is absent in healthy controls. IL-6 stimulates the hypothalamus
and thus the release of cortisol, but probably also contributes to early morning stiffness and other inflammatory symptoms in (rheumatoid) arthritis.
ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone.
CHAPTER 60 responsiveness to ACTH. Serum cortisol, ACTH levels,
and adrenal responsiveness to ACTH are low, but other
pituitary axes function normally, in contrast to the situation
in most primary pituitary disorders. The time required to
achieve suppression depends on the dosage and the serum
half-life of the glucocorticoid used, but it also varies
among patients, probably because of individual differences
in glucocorticoid sensitivity and rates of glucocorticoid
metabolism. Prediction with certainty of chronic suppression of the hypothalamic-pituitary-adrenal axis and adrenal
insufficiency is impossible. This risk may be increased
when glucocorticoids are used concomitantly with other
steroid drugs such as megestrol acetate and medroxy­
progesterone, inhibiting the hypothalamic-pituitaryadrenal axis.11
The duration of the anti-inflammatory effect of one
dose of a glucocorticoid approximates the duration of
hypothalamic-pituitary-adrenal suppression. After a single
oral dose of 250 mg of hydrocortisone or cortisone, 50 mg
of prednisone or prednisolone, or 40 mg of methylprednisolone, suppression for 1.25 to 1.5 days has been described.
Duration of suppression after 40 mg of triamcinolone and
5 mg of dexamethasone was 2.25 and 2.75 days.37 After
intramuscular administration of a single dose of 40 to 80 mg
of triamcinolone acetonide, the duration of hypothalamicpituitary-adrenal suppression is 2 to 4 weeks, and after 40
to 80 mg of methylprednisolone, suppression lasts 4 to 8
days.37
In the case of long-term therapy, for patients who have
had less than 10 mg of prednisone or its equivalent per day
in one dose in the morning, the risk of clinical (symptomatic) adrenal insufficiency is not high, but neither is it
negligible. A review of adrenal insufficiency stated that if
the daily dose is 7.5 mg of prednisolone or equivalent or
more for at least 3 weeks, adrenal hypofunction should be
anticipated, and acute cessation of glucocorticoid in this
situation could lead to problems.12 Patients who have
received glucocorticoids for less than 3 weeks or have been
treated with alternate-day prednisolone therapy do not
have zero risk of suppression of the hypothalamic-pituitaryadrenal axis, depending on the dose,38,39 but the risk is low.
After 5 to 30 days of at least 25 mg of prednisone or equivalent daily, suppression of adrenal response (measured by a
low-dose corticotropin test) was present in 34 of 75 patients
studied (45%).40 In these patients, a basal plasma cortisol
concentration less than 100 nmol/L was highly suggestive
of adrenal suppression, whereas levels of basal cortisol
greater than 220 nmol/L predicted a normal adrenal
response in most, but not all, patients. When in doubt, it
seems prudent to treat patients as having secondary adrenal
insufficiency. Secondary adrenal insufficiency generally has
a less dramatic presentation than primary adrenal insufficiency because aldosterone levels, which are controlled
predominantly by the renin-angiotensin system, are preserved; mineralocorticoid therapy is not necessary.
TREATMENT WITH GLUCOCORTICOIDS
Glucocorticoids are widely used in various dosages for
several rheumatic diseases. Often it is unclear what is meant
by the semi-quantitative terms used for dosages, such as low
| Glucocorticoid Therapy
903
Table 60-3 Terminology of Dosages of
Glucocorticoids for Use in Rheumatology
Low dose
Medium dose
High dose
Very high dose
Pulse therapy
≤7.5 mg prednisone or equivalent per day
>7.5 mg, but ≤30 mg prednisone or
equivalent per day
>30 mg, but ≤100 mg prednisone or
equivalent per day
>100 mg prednisone or equivalent per
day
≥250 mg prednisone or equivalent per
day for 1 day or a few days
or high. Based on pathophysiologic and pharmacokinetic
data, standardization has been proposed to minimize problems in interpretation of these generally used terms
(Table 60-3).2
Indications
For each disease, indications for glucocorticoid therapy are
discussed in the specific chapters. An overview is given here
(Table 60-4), which summarizes only the general uses and
dosages of glucocorticoids. Without detailed description,
some of the indications could be considered questionable at
first glance. In systemic sclerosis, glucocorticoids, especially
in high doses, are contraindicated because of the risk of
scleroderma renal crisis, but they may be useful for myositis
or interstitial lung disease. Glucocorticoids are a basic part
of the therapeutic strategy in myositis, polymyalgia rheumatica, and systemic vasculitis. For other diseases, glucocorticoids serve as adjunctive therapy or are not used at all. For
instance in RA, glucocorticoids are almost exclusively used
as adjunctive therapy in combination with other diseasemodifying antirheumatic drugs (DMARDs) (see later). In
osteoarthritis, glucocorticoids are not given except for intraarticular injection if signs of synovitis of the osteoarthritic
joint are present.41 For generalized soft tissue disorders, glucocorticoids are not indicated, and for localized soft tissue
disorders, they should be used only for intralesional
injection.42
Glucocorticoid Therapy in Rheumatoid Arthritis
Glucocorticoids are a frequently applied medication in RA.
In the past, more patients with RA seemed to be given
concomitant glucocorticoids in the United States than in
Europe—54% versus 27%43,44—whereas more recent data
suggest that 38% of RA patients in the United States use
glucocorticoids45 versus up to 55% of German RA patients.46
Aims of this therapy include reduction of signs and symptoms and inhibition of joint damage.
Signs and Symptoms
As can be seen in Table 60-4, RA is the only disease in
which glucocorticoid therapy is often started and
maintained at a low dose as additional therapy. The rationale for this therapy is a probable, relative insufficiency of
the adrenal gland in patients with active RA.31 Glucocorticoids are highly effective for relieving symptoms in patients
with active RA in doses of less than 10 mg/day. Many
904
PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS
Table 60-4 General Use of Glucocorticoids in Rheumatology
Initial Oral Dose*
Low†
Medium†
High†
Intravenous,
Very High
Dose† or Pulse
1
−
−
−
−
−
−
2
2
1
−
−
1
−
1
2
2
1
−
−
−
−
1
1
−
−
−
−
−
−
−
1
2
1
1
2
2
1
−
2
Dermatomyositis, polymyositis
Mixed connective tissue disease
Polymyalgia rheumatica
Sjögren’s syndrome, primary
Systemic lupus erythematosus
Systemic sclerosis
−
−
−
−
−
−
−
1
3
−
2
1
3
−
−
1
1
−
1
1
1
−
1
−
−
1
−
−
−
−
Systemic Vasculitis in General
−
−
3
1
−
Intra-articular
Injection
Arthritides
Gout
Juvenile idiopathic arthritis
Osteoarthritis
Pseudogout
Psoriatic arthritis
Reactive arthritis
Rheumatic fever
Rheumatoid arthritis
Collagen Disorders
*Initial dose is the dose at the start of therapy and often is decreased in time depending on disease activity.
†Dose in prednisone equivalents per day: low, ≤7.5 mg; medium, >7.5 but ≤30 mg; high, >30 but ≤100 mg; very high, >100 mg.
−, Rare use.
1, Infrequent use or use for therapy-resistant disease, complications, severe flare, and major exacerbation.
2, Frequently added to the basic therapeutic strategy.
3, Basic part of therapeutic strategy.
patients become functionally dependent on this therapy,
however, and continue it over the long term.47 A review of
seven studies (253 patients) concluded that glucocorticoids,
when administered for approximately 6 months, are effective for the treatment of RA.48 After 6 months of therapy,
the beneficial effects of glucocorticoids seem to diminish. If
this therapy then is tapered off and stopped, however,
patients often—over some months—experience aggravation of symptoms.
Radiologic Joint Damage: Glucocorticoids
as DMARDs
In 1995, joint-preserving effects of 7.5 mg of prednisolone
daily for 2 years were described in patients with RA of short
and intermediate duration who also were treated with
DMARDs. The group of RA patients participating in this
randomized, placebo-controlled trial was heterogeneous,
not only with respect to disease duration, but also with
respect to stages of the disease and types and dosages of
DMARDs.49 In another trial published in 1997, patients
with early RA were randomly assigned to step-down therapy
with two DMARDs (sulfasalazine and methotrexate) and
prednisolone (start 60 mg/day, tapered in six weekly steps
to 7.5 mg/day and stopped at 34 weeks) or to sulfasalazine
alone. In the combined drug strategy group, a statistically
significant and clinically relevant effect in retarding joint
damage was shown compared with the effect of sulfasalazine
alone.50 In an extension of this study, long-term (4 to 5
years) beneficial benefits were shown regarding radiologic
damage after the combination strategy.51 It has been hypothesized that the superior effect of the combination therapy
in this trial can be ascribed to prednisolone because in
three double-blind, randomized trials, the effect of the
combination of methotrexate and sulfasalazine was not
superior to that of either drug alone.52-54
In a German study, 200 patients with early RA were
treated with methotrexate or intramuscular gold and were
randomly assigned to additional treatment with 5 mg of
prednisolone or placebo. After 2 years, progression of radiologic damage proved to be less in the prednisolone-treated
patients than in those treated with placebo.55 In 2002,
results of the Utrecht study on the effects of prednisolone
in DMARD-naïve patients with early RA were published.
This is the only placebo-controlled trial in which prednisolone was applied as monotherapy as the first step. The progression of radiologic joint damage was inhibited by 10 mg
of prednisolone daily in these patients (who received
DMARD therapy only as rescue).56
The Utrecht study reported a 40% decreased need for
intra-articular glucocorticoid injections, a 49% decreased
need for acetaminophen use, and a 55% decreased need for
nonsteroidal anti-inflammatory drugs (NSAIDs) in the
prednisolone group compared with the placebo group. This
indicates that in clinical trials evaluating the clinical
effects of DMARDs or glucocorticoids, additional therapies
should be taken into account. In an extension of this
study, at 3 years after the end of the study and 2 years after
tapering off and stopping the prednisolone therapy, beneficial radiologic benefits of prednisolone were still present
(Figure 60-7).57
In another 2-year study in 250 patients with early RA,
7.5 mg/day of prednisolone added to DMARD therapy
retarded joint damage and increased the remission rate compared with placebo added to DMARDs.58 Even in an intensive treat-to-target methotrexate-based strategy in early
RA, prednisone enhanced clinical efficiency and reduced
erosive joint damage.58a
CHAPTER 60 40
30
20
10
0
0
25
50
75
100
Figure 60-7 Cumulative probability plot of mean yearly radiographic
progression over 3 years since the end of the original 2-year study in
patients originally randomized to receive prednisone therapy (triangles)
or placebo (circles).56,57 At the end of the 2-year trial, the prednisone
therapy was tapered down and stopped, if possible. Y-axis, Yearly progression of radiographic joint damage according to the van der Heijde
modification of the Sharp method.
Negative studies on the effects of glucocorticoids on
radiologic damage have also been published,59-61 but in early
RA, evidence of glucocorticoid joint-sparing effects, which
persist after therapy is stopped, seems convincing, thus
classifying glucocorticoids as DMARDs. A meta-analysis
on radiographic outcome analyzed 15 studies (two with
negative results) that included a total of 1414 patients.
Because different methods had been used in the individual
trials, radiographic scores were expressed as a percentage of
the maximum possible score for the specific radiographic
method used. The standardized mean difference in progression was 0.40 in favor of strategies using glucocorticoids
(95% confidence interval, 0.27 to 0.54). This was con­
sidered a conservative estimate because the most con­
servative estimate of the difference in each study had
been chosen.62
It is still unknown, however, whether glucocorticoids can
also inhibit progression of erosion in RA of longer duration
than 2 years. A so-called window of opportunity may exist
in the treatment of RA.63 If this window is present, effective
treatment of early RA with glucocorticoids and DMARDs
may result in an effect that lasts for a long time and in
disease that is easier to control, whereas if effective treatment starts later, this opportunity may be lost, resulting in
more difficult control of the disease with inflammation
fueled by joint damage. Most studies on glucocorticoids and
radiologic damage employed a dose of 5 to 10 mg/day of
prednisone equivalent during 2 years, but a scheme starting
with 60 mg/day tapered off and stopped within 34 weeks
also was effective. In addition, because glucocorticoidinduced osteoporosis and peptic ulcer complications (if glucocorticoids
are
combined
with
nonsteroidal
anti-inflammatory drugs [NSAIDs]) can be prevented much
more effectively now than some decades ago, the jointprotective effect of prednisolone in RA during the first 2
| Glucocorticoid Therapy
905
years of the disease in a dose of 5 to 10 mg daily is a relevant
finding.
The joint-sparing effect of glucocorticoids probably is
based on inhibition of proinflammatory cytokines such as
IL-1 and TNF,64 which stimulate osteoblasts and T cells to
produce receptor activator of nuclear factor κB (RANK)
ligand. This binds to RANK on osteoclast precursor cells
and on mature osteoblasts, leading to activation of osteoclasts, which are responsible for bone resorption, periarticular osteopenia, and formation of bone erosions in RA.
A toxicity index score for DMARDs was published
(based on symptoms, laboratory abnormalities, and hospitalization data) after evaluation of 3000 patients with more
than 7300 patient-years from the Arthritis, Rheumatism,
and Aging Medical Information System (ARAMIS) database.65 Although this score has not been validated and is
influenced by confounding-by-indication, it gives an impression of the relative toxicity of glucocorticoids. It is comparable with that of other immunosuppressive medications
used in RA, such as methotrexate and azathioprine. A
review also showed that the incidence, severity, and impact
of adverse effects of low-dose glucocorticoid therapy in RA
trials were modest and suggested that probably many of the
well-known adverse effects of glucocorticoids are predominantly associated with high-dose treatment.66
Because many questions remain to be answered, such as
how the effects of glucocorticoids compare with those of
high dosages of methotrexate or of TNF blockers, and for
how long glucocorticoids should be prescribed and in what
dosages, the final place of glucocorticoid therapy in RA has
to be clearly determined. Nevertheless in early RA the use
of glucocorticoids generally has been accepted.66a Guidelines on how to use (low-dose) glucocorticoids and how to
monitor this therapy have been developed.67,68
Prevention of Early (Rheumatoid) Arthritis
Development with Glucocorticoids
Recently, trials have been done to try to prevent arthralgia
or early arthritis from progressing to chronic arthritis. In
patients with (very) early arthritis or individuals with
arthralgia and antibodies to citrullinated proteins or rheumatoid factor, intramuscular glucocorticoid injections did
not prevent arthritis development in two placebo-controlled
trials,69,70 but in another placebo-controlled double-blind
trial these injections postponed the need for DMARDs and
prevented 1 in 10 patients from progressing into RA at
assessment at 12 months.71 These results are preliminary and
nonconclusive, and it is clear that further resarch is needed.
Chronobiology
The rheumatoid inflammatory process and symptoms have
a diurnal rhythm. Early in the morning, patients experience
the most extensive joint stiffness and other symptoms and
signs; this is due to the long rest period during the night
that facilitates edema formation around inflamed joints
and the circadian rhythm of cortisol (see Figure 60-6). In
patients with RA with low or medium disease activity,
serum cortisol maximum and minimum shift to earlier
times of the day and night, whereas in patients with high
906
PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS
disease activity, the circadian rhythm is markedly reduced
or even lost.
The timing of glucocorticoid administration may be
important for efficacy and side effects. Older data in the
literature on this topic are ambiguous.72,73 Recently, a trial
was performed with a newly developed modified-release
prednisone tablet that releases prednisone about 4 hours
after ingestion. When it was taken in the evening, thus
adapting its release to circadian increases in proinflammatory cytokine concentrations, symptoms of RA early in the
morning were lessened compared with those reported when
the same dose of prednisone was taken early in the morning.
This 3-month double-blind trial included RA patients with
a duration of morning stiffness of 45 minutes or longer, a
pain score of 30 mm or less on a 100-mm visual analog scale,
three or more painful joints, one or more swollen joints, and
an erythrocyte sedimentation rate (ESR) of 28 mm or
greater or a C-reactive protein concentration 1.5 times or
more the upper limit of normal, who were on glucocorticoids at least 3 months with a stable daily dose of 2 to 10 mg
prednisone equivalent for at least 1 month. Patients were
randomized to continue their prednisone or to switch to
modified-release prednisone in a double-dummy way. At the
end of the trial, the difference in duration of morning stiffness was about 30 minutes, in favor of the modified-release
prednisone group. However, no differences were noted in
all other variables of disease activity between the two
groups. The safety profile did not differ between treatments.74 Longer-term benefits and risks of this preparation
and application in other inflammatory rheumatic diseases
have yet to be investigated.75
Other Developments to Improve the
Therapeutic Ratio of Glucocorticoids
In addition to guidelines put forth to improve the clinical
use of existing glucocorticoids,67,68 other formulations have
been and are being developed. Deflazacort,76 an oxazoline
derivative of prednisolone introduced in 1969, was initially
thought to be as effective as prednisone while inducing
fewer adverse events, but there was the issue of the real
equivalence ratio compared with prednisone77; this drug has
not represented a major breakthrough. Knowledge about
the mechanisms of glucocorticoids (transrepression and
transactivation leading, respectively, to predominantly beneficial effects and adverse effects; see earlier) led to the
development of selective glucocorticoid receptor agonists or
dissociating glucocorticoids,78 but as yet they have not
entered the market. Glucocorticoid preparations releasing
nitric oxide, the so-called nitrosteroids, could induce stronger anti-inflammatory effects because nitric oxide has antiinflammatory effects too.79 These drugs have to be tested in
patients yet. The drug combination prednisolone and dipyridamole has been reported to boost and extend the net
glucocorticoid effect in laboratory models.80 The next
required step will be to demonstrate the improved therapeutic ratio in patients in adequate comparative clinical trials
by assessing predefined beneficial effects and adverse effects
in a standardized way.81 Liposomes containing glucocorticoids and targeted to integrins expressed on endothelial
cells at sites of inflammation have been studied; these
deliver their glucocorticoids specifically at sites of
inflammation.82 Their selective biodistribution might allow
for less frequent and lower dosing, which could result in an
improved therapeutic ratio. The safety of liposomal prednisolone has been evaluated in a small group of RA patients,
and the results (up until now published only as an abstract)
seem promising.83All of these new applications have to be
tested further before they can be used in daily clinical
practice.
Alternate-Day Regimens
For oral, long-term use of glucocorticoid therapy, alternateday regimens have been devised in an attempt to alleviate
the undesirable side effects, such as hypothalamic-pituitaryadrenal axis suppression. Alternate-day therapy uses a single
dose administered every other morning, which is usually
equivalent to, or higher than, twice the usual or preestablished daily dose. The rationale for this regimen is that
the body, including the hypothalamic-pituitary-adrenal
axis, is exposed to exogenous glucocorticoid only on alternate days. This rationale makes sense only for usage of a
class and dosage of a glucocorticoid that suppresses the
hypothalamic-pituitary-adrenal axis activity for less than 36
hours after a single dose. Another prerequisite is that the
patient should have a responsive hypothalamic-pituitaryadrenal axis that is not chronically suppressed by previous
glucocorticoid regimens. The alternate-day schedule does
not work in patients on long-term medium- or high-dose
glucocorticoids suppressing hypothalamic-pituitary-adrenal
axis activity for longer than 36 hours.
Alternate-day therapy is unsuccessful in most patients
who require glucocorticoids. Patients with RA often experience exacerbation of symptoms on the second day. This
experience is in line with the clinical impression that a
single dose of glucocorticoids daily is less effective in RA
than half that dose, given twice daily. In giant cell arteritis,
alternate-day glucocorticoid therapy also is less effective
than daily administration.84,85 Generally, alternate-day regimens are used rarely in rheumatology today, except in
patients with juvenile idiopathic arthritis, in whom
alternate-day glucocorticoid usage results in less inhibition
of body growth than is associated with daily usage.86 If treatment has been initiated with daily administration, the
change to alternate-day therapy preferably should be made
after the disease has stabilized.
Glucocorticoid Sensitivity and Resistance
A small proportion of patients does not react favorably to
glucocorticoids or even fails to respond to high doses. Also,
susceptibility to adverse effects of glucocorticoids varies
widely. Several different factors are involved in the variability of glucocorticoid sensitivity in patients with rheumatic diseases, and an understanding of the mechanisms
involved might eventually allow their modulation. Potential mechanisms of glucocorticoid resistance in inflammatory diseases have been reviewed extensively.87
Hereditary glucocorticoid resistance (rare) and increased
susceptibility to glucocorticoids have been related to specific polymorphisms of the glucocorticoid receptor gene.
The glucocorticoid receptor exists as α and β isoforms, but
only the α isoform binds glucocorticoids. The β isoform
CHAPTER 60 | Glucocorticoid Therapy
907
Table 60-5 Glucocorticoid Tapering Scheme to Hand Out to Patients*
Period 1
Period 2
Period 3
Period 4
Period 5
Period 6
Period 7
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
Sunday
High
High
High
Low
Low
Low
Low
High
Low
Low
High
High
Low
Low
High
High
High
Low
Low
Low
Low
High
High
Low
High
Low
High
Low
Low
High
High
Low
Low
Low
Low
High
Low
Low
High
High
Low
Low
High
High
High
Low
Low
Low
Low
*At each consecutive period (e.g., 1 week or some weeks), the number of days during which a low dose should be taken increases by 1. After completion
of period 7, the next step in tapering can be taken; the dose called “low” during the previous 7 periods now is “high,” and so on. In case of aggravation of
symptoms, the patient should not diminish the dose and should contact the specialist.
functions as an endogenous inhibitor of glucocorticoids and
is expressed in several tissues. Glucocorticoid resistance has
been associated with enhanced expression of this β receptor,
but this is unlikely to be an important mechanism for glucocorticoid resistance because in most cells, apart from neutrophilic granulocytes, expression of the β receptor is much
less than that of the α receptor.87 The protein lipocortin-1
(or annexin-1) inhibits eicosanoid synthesis. Glucocorticoids are thought to stimulate lipocortin-1. In patients with
RA, autoantibodies to lipocortin-1 have been described.
The titers in these patients correlate with the height of
maintenance doses of glucocorticoids, suggesting that these
antibodies may lead to glucocorticoid resistance.
Although glucocorticoids exert most of their immunosuppressive actions through inhibition of cytokine production, high concentrations of cytokines, especially IL-2,
antagonize the suppressive effects of glucocorticoids in a
dose-dependent manner.77 The balance is usually in favor of
glucocorticoids, but high local concentrations of cytokines
may result in localized glucocorticoid resistance that cannot
be overridden by exogenous glucocorticoids. Also, the macrophage migration inhibitory factor may play a role in
steroid resistance in RA. This proinflammatory cytokine is
involved in TNF synthesis and T cell activation, suggesting
a role in the pathogenesis of RA. Macrophage migration
inhibitory factor is suppressed by higher concentrations of
glucocorticoids, but it is induced by low concentrations,
leading to stimulation of inflammation.78 Other possible
mechanisms of glucocorticoid resistance include activation
of mitogen-activated protein kinase pathways by certain
cytokines, excessive activation of the transcription factor
activator protein-1, reduced histone deacetylase-2 expression, and increased P-glycoprotein–mediated drug efflux.87
Also, drugs may play a role in glucocorticoid sensitivity and
resistance (see also the section on drug interactions). Sulfasalazine increases the sensitivity of immune cells for glucocorticoids and thus might be a future option for preventing
or treating glucocorticoid resistance.13 Mifepristone is an
antiprogesterone drug and glucocorticoid receptor antagonist; chlorpromazine inhibits glucocorticoid receptor–
mediated gene transcription.88
Glucocorticoid Withdrawal Regimens
Because of potential side effects, glucocorticoids usually are
tapered off as soon as the disease being treated is under
control. Tapering must be done carefully to avoid recurrent
activity of the disease and, infrequently, cortisol deficiency
resulting from chronic hypothalamic-pituitary-adrenal axis
suppression. Gradual tapering permits recovery of adrenal
function. There is no best scheme based on controlled,
comparative studies for tapering glucocorticoids. Tapering
depends on the individual disease, the disease activity, doses
and duration of therapy, and clinical response, which also
depends on each individual’s glucocorticoid sensitivity.
Only generic guidelines can be offered. To taper the dose of
prednisone, decrements of 5 to 10 mg every 1 to 2 weeks
can be used when the prednisone dose is more than 40 mg/
day, followed by 5-mg decrements every 1 to 2 weeks at a
dose between 40 and 20 mg/day, and finally 1 to 2.5 mg/day
decrements every 2 to 3 weeks at a prednisone dose of less
than 20 mg/day. Another scheme is to taper 5 to 10 mg
every 1 to 2 weeks down to 30 mg/day of prednisone, and
when the dose is less than 20 mg/day, to taper 2.5 to 5 mg
every 2 to 4 weeks down to 10 mg/day; thereafter, the dose
is tapered 1 mg each month or 2.5 mg (half a 5-mg tablet
of prednisolone) each 7 weeks. For tapering every 7 weeks
or over longer periods, a printed schedule can be given to
the patient, such as the one shown in Table 60-5.
Adaptations of Glucocorticoid Doses, Stress
Regimens, and Perioperative Care
Patients on long-term low-dose glucocorticoid medication
have suppressed adrenal activity and should be advised to
double their daily glucocorticoid dose or to increase the
dose to 15 mg prednisolone or equivalent if they develop
fever attributed to infection, and to seek medical help. In
case of major surgery, given the unreliable prediction of
adrenal suppression on the basis of duration and dose of
glucocorticoid therapy (see the section on effects of glucocorticoids on the hypothalamic-pituitary-adrenal axis),
many physicians recommend “stress doses” of glucocorticoids for patients with low risk of adrenal suppression. The
scheme of 100 mg of hydrocortisone intravenously just
before surgery, followed by an additional 100 mg every 6
hours for 3 days, is based on anecdotal information and is
not always necessary.89,90 A scheme with a lower dose, possibly reducing the risk of postoperative bacterial infectious
complications, is to infuse continuously 100 mg of hydrocortisone intravenously on the day of surgery, followed by
25 to 50 mg of hydrocortisone every 8 hours for 2 or 3 days.
Another option is to administer the usual dose of oral glucocorticoid orally or (the equivalent) parenterally on the
day of surgery, followed by 25 to 50 mg of hydrocortisone
every 8 hours for 2 or 3 days.
In cases of minor surgery, it is probably sufficient to
double the oral dose or to increase the dose to 15 mg of
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PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS
prednisolone or equivalent for 1 to 3 days. No comparative
randomized studies on different perioperative glucocorticoid
stress schemes have been published, however. Because in
glucocorticoid-induced secondary adrenal insufficiency,
aldosterone secretion is preserved, mineralocorticoid
therapy is unnecessary, in contrast to in primary adrenal
insufficiency.
Glucocorticoid-Sparing Agents
For most inflammatory rheumatic diseases, including SLE,
vasculitis, RA, and myositis, other immunomodulatory
drugs are often added to therapy with glucocorticoids, such
as azathioprine and methotrexate, and especially in case of
systemic vasculitis, cyclophosphamide. For these indications, biologic agents are increasingly used.91 An exception
is polymyalgia rheumatica, which is managed primarily with
glucocorticoids alone. Combination therapy is applied early
in the disease when the disease is one for which it is known
that the effect of the combination is better than that of
glucocorticoids alone (e.g., in the case of systemic vasculitis), or if the disease (e.g., inflammatory myositis) seems
resistant to high initial doses of glucocorticoids.
If at a later stage of the disease, immunomodulatory drugs
are added to therapy with glucocorticoids to enable further
reduction of the dose to decrease the risk of side effects,
these immunomodulatory drugs are termed glucocorticoidsparing agents. For this purpose, azathioprine and methotrexate are often used, although any drug that has an additive
or synergistic effect in suppressing the disease, enabling
reduction of the glucocorticoid dose, could be used as a
glucocorticoid-sparing agent.
Glucocorticoid Pulse Therapy
Glucocorticoid pulse therapy is used in rheumatology, especially for remission induction or treatment of flares of
inflammatory rheumatic disorders and vasculitides (see
Table 60-4). In RA, pulse therapy is applied to treat serious
complications of the disease and to induce remission in
active disease, often during the initiation phase of a (new)
DMARD strategy. In the latter patients, pulse therapy with
schemes of 1000 mg of methylprednisolone given intravenously has been proven effective in many studies. The beneficial effect generally lasts about 6 weeks, with large
variation in the duration of the effect.92 It does not seem
sensible to apply pulse therapy in active RA, unless a change
in the therapeutic strategy (i.e., in second-line antirheumatic treatment) aims to stabilize over the long term any
remission induced by the pulse therapy. Short-term effects
of pulse therapy in patients with established, active RA at
various dimensions of health status closely resemble the
long-term effects of effective conventional DMARD
therapy, such as methotrexate, in patients with early RA.93
In 144 patients with biopsy-confirmed giant cell arteritis, of
whom 91 were seen initially with visual loss and 53 without
visual loss, no evidence was found that intravenous glucocorticoid pulse therapy (usually 150 mg dexamethasone
sodium phosphate every 8 hours for 1 to 3 days) was more
effective than high daily doses (80 to 120 mg) of oral prednisone in preventing visual deterioration.94
The risk of adverse effects of pulse therapy is not the
same for all rheumatic disorders. In patients with SLE,
osteonecrosis and psychosis seem to be more frequent side
effects of pulse therapy compared with those seen in patients
with RA.93 Osteonecrosis and psychosis also can be complications of SLE itself, however. Contraindications for pulse
therapy include pregnancy and lactation, infection, current
peptic ulcer disease, glaucoma, badly controlled hypertension, and diabetes mellitus. In cases with a family history of
glaucoma or well-controlled hypertension or diabetes mellitus, pulse therapy can be applied with checks, respectively,
of eye and blood pressure and of blood glucose values.
Intralesional and Intra-articular
Glucocorticoid Injections
Injections with glucocorticoids are widely used for arthritis
(see Table 60-4), tenosynovitis, bursitis, enthesitis, and
compression neuropathies such as carpal tunnel syndrome.42
Generally, the effect occurs within days; it can be longlasting, but if the underlying disease is active, the effect is
of short duration. Administration of a local anesthetic concurrently with intra-articular or soft tissue injection of a
glucocorticoid may provide immediate pain relief.
Soluble glucocorticoids (e.g., phosphate salts) have a
more rapid onset of action with probably less risk of subcutaneous tissue atrophy and depigmentation of the skin when
given intralesionally. Insoluble glucocorticoids are longer
acting and might further decrease the soft tissue fibrous
matrix, so they should be used with caution in places with
thin skin, especially in elderly patients and in those with
peripheral vascular disease. Insoluble glucocorticoids are
more safely given into deep sites. Short-acting soluble glucocorticoids can be mixed with long-acting insoluble
glucocorticoids to combine rapid onset with longacting effect.
The effect of intra-articular glucocorticoid injection
probably depends on several factors: the underlying disease
(e.g., RA, osteoarthritis), the treated joint (size, weight
bearing, or non–weight bearing), the activity of arthritis,
the volume of synovial fluid in the joint to be treated,46 the
application of arthrocentesis (synovial fluid aspiration)
before injection, the choice and dose of the glucocorticoid
preparation, application of rest to the injected joint, and
the injection technique used. The effects of injections seem
to be less favorable in osteoarthritis than in RA.95 Arthrocentesis before injection of the glucocorticoid preparation
reduces the risk for relapse of arthritis. Triamcinolone hexacetonide, which, among the injectable glucocorticoids, is
the least soluble preparation, shows the longest effect.
Theoretically, rest of the injected joint minimizes leakage
of the injected glucocorticoid preparation into the systemic
circulation (via the hyperemic, inflamed synovium by
enhanced pressure in the joint during activity), minimizes
the risk of cartilage damage, and enhances repair of inflammatory tissue damage. Advice and procedures for the postinjection period in terms of activity vary from no restrictions,
to minimal activity of the injected joint for a couple of days,
to bed rest for 24 hours after injection of a knee joint or
splinting of injected joints. Based on the literature, no definite evidence-based recommendations can be made, but it
CHAPTER 60 seems prudent to rest and to not overuse the injected joint
for several days, even if pain is relieved.
It is recommended that intra-articular glucocorticoid
injections be repeated no more often than once every 3
weeks, and that they be given no more frequently than three
times a year in a weight-bearing joint (e.g., the knee) to
minimize glucocorticoid-induced joint damage. This recommendation seems sensible, but no definitive clinical evidence is available to support it. As one would expect,
accuracy of steroid placement influences the clinical
outcome of glucocorticoid injections into the shoulder and
probably into other joints as well.96 This is important
because it is estimated that a few more than half of shoulder
injections are inaccurately placed.96,97 The reported infection rate of joints after local injection with glucocorticoids
is low, ranging from 1 case in 13,900 to 1 in 77,300 injections.98,99 Introduction of disposable needles and syringes
has helped reduce the risk. In a 3-year prospective study in
an urban area of 1 million people in the Netherlands, bacterial infections were detected in 214 joints (including 58
joints with a prosthesis or osteosynthetic material) of 186
patients; only 3 of these joint infections were attributed to
an intra-articular injection.100
Other adverse effects of local glucocorticoid injections
include systemic adverse effects of the glucocorticoid, such
as disturbance in the menstrual pattern, hot flush–like
symptoms the day of or the day after injection, and hyperglycemia in diabetes mellitus.42 Local complications include
subcutaneous fat tissue atrophy (especially after improper
local injection), local depigmentation of the skin, tendon
slip and rupture, and lesions to local nerves.42
Therapeutic effects
Glucocorticoid Therapy
System
Adverse Effect
Skeletal
Gastrointestinal
Osteoporosis, osteonecrosis, myopathy
Peptic ulcer disease (in combination with
nonsteroidal anti-inflammatory drugs),
fatty liver
Predisposition to infection, suppressed
delayed hypersensitivity (Mantoux test)
Fluid retention, hypertension, accelerated
arteriosclerosis, arrhythmias
Glaucoma, cataract
Skin atrophy, striae, ecchymoses, impaired
wound healing, acne, buffalo hump,
hirsutism
Cushingoid appearance, diabetes mellitus,
changes in lipid metabolism, enhanced
appetite and weight gain, electrolyte
abnormalities, hypothalamic-pituitaryadrenal axis suppression, suppression of
gonadal hormones
Insomnia, psychosis, emotional instability,
cognitive effects
Immunologic
Cardiovascular
Ocular
Cutaneous
Endocrine
Behavioral
ADVERSE EFFECTS AND MONITORING
Given the diversity of their mechanisms and sites of action,
it is not surprising that glucocorticoids can cause a wide
array of adverse effects (Table 60-6 and Figure 60-8). Most
of these adverse effects cannot be avoided. However, the
risk of most complications is dosage and time dependent;
minimizing the quantity of glucocorticoid minimizes the
risk of complications.68 Dose-related patterns of adverse
DMARD effect in RA
Pain ↓
Swelling ↓
Stiffness ↓
Physical disability ↓
Vasculitis, serositis ↓
Endothelial
dysfunction ↓
Effect on cells, tissue, and organs:
clinical effects
Vessel
GC treatment
Infections
Bone
Osteonecrosis
Osteoporosis
Eyes
CNS
HPA-axis
Skin
Metabolism
Permeability ↓
Cardiovascular
Muscle
Myopathy
909
Table 60-6 Adverse Effects of Glucocorticoids
Anti-inflammatory
Immunosuppressant
Anti-allergic
| Increased
CV risk
Cataract
Glaucoma
Stomach
Hirsutism
Skin thinning
Weight gain/obesity
Fluid retention/edema
Gastric ulcer
Cushing syndrome
(if concomitant
Impaired glucose metabolism:
NSAIDs)
• insulin resistance
• beta cell dysfunction
Neuropsychiatric
symptoms
HPA insufficiency
Adverse effects
Figure 60-8 The spectrum of glucocorticoid (GC) therapy: beneficial effects in the upper green part of the figure, adverse effects in the lower red part.
CNS, central nervous system; CV, cardiovascular; DMARD, disease-modifying antirheumatic drug; HPA, hypothalamic-pituitary-adrenal; NSAIDs, nonsteroidal anti-inflammatory drugs; RA, rheumatoid arthritis. (Adapted from Buttgereit F, Burmester GR, Lipworth BJ: Optimised glucocorticoids therapy: the
sharpening of an old spear, Lancet 365:801–803, 2005.)
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PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS
Inflammatory disease activity: proinflammatory mediators
D supplementation and prescribing a bisphosphonate on
indication.
Osteonecrosis
Glucocorticoid
therapy
Negative effects
• Bone mass
• Lipids, endothelium
• Glucose metabolism
• Infection risk
Figure 60-9 The interplay of glucocorticoid therapy, the inflammatory
disease, and adverse effects, which, in combination with bias by indication, makes it hard in not randomized trials or cohorts to discriminate the
negative effects of glucocorticoids from negative effects of the disease
itself.
effects of glucocorticoids have been described.101 Low-dose
glucocorticoid therapy is safer than is commonly thought,66
and medium- to long-term glucocorticoid therapy in RA is
associated with limited toxicity compared with use of
placebo,102 but sensitivity for adverse effects differs among
individuals. It is a clinical observation that some patients
develop adverse effects after small doses of glucocorticoids,
whereas other patients receive high doses without serious
adverse effects. Apparent individual susceptibility to adverse
effects does not seem to always parallel individual susceptibility to beneficial effects. Osteoporosis, diabetes, and cardiovascular disease are ranked by both patients and
rheumatologists among the most worrisome adverse effects
of glucocorticoids.103 However, the frequency and the severity of glucocorticoid-related adverse effects have seldom
been studied systematically. A problem for nonrandomized
studies looking at glucocorticoid-related adverse effects is
bias by indication: patients with severe disease tend to take
glucocorticoids more frequently than those with less severe
disease, and the disease as well as the glucocorticoids can
cause unfavorable signs and symptoms104; on the other hand,
glucocorticoids decrease disease activity and therewith
influence the frequency and severity of disease-associated
signs and symptoms (Figure 60-9).
Skeletal Adverse Effects
Osteoporosis
Osteoporosis is a well-known adverse effect of glucocorticoids that can be prevented to a large degree. International
and national guidelines to minimize the occurrence of
glucocorticoid-induced osteoporosis have been developed
and are updated periodically.105,106 Preventive and therapeutic management of glucocorticoid-induced osteoporosis is
discussed in detail in Chapter 99. In short, following the
actual guideline consists of providing calcium and vitamin
High-dose glucocorticoids given over longer periods are
implicated as a cause of osteonecrosis, especially in children
and patients with SLE. Vascular mechanisms seem to be
involved. Ischemia possibly may be caused by microscopic
fat emboli or impingement of the sinusoidal vascular bed by
increased intraosseous pressure caused by fat accumulation.
An early symptom is diffuse pain, which becomes persistent
and increases with activity. Most frequently, hip or knee
joints are involved; ankle and shoulder joints are involved
less frequently. For early assessment, magnetic resonance
imaging is the most sensitive investigative tool. Radionuclide bone scans provide less specific information. Plain
radiographs are adequate only for follow-up. Treatment in
the early stage includes immobilization and decreased
weight bearing. Surgical decompression, joint replacement,
or both follow this if needed. No preventive measures are
known; awareness is the most important factor in early
detection.
Myopathy
Weakness in proximal muscles, especially of the lower
extremities, occurring within weeks to months after initiation of treatment with glucocorticoids, or after an increase
in the dosage, may indicate steroid myopathy. It is often
suspected but is infrequently found; it occurs almost exclusively in patients treated with high dosages (>30 mg/day
prednisone or equivalent). Diagnosis is clinical and can be
confirmed by a muscle biopsy specimen that reveals atrophy
of type II fibers and lack of inflammation; no elevation of
serum muscle enzymes is noted. Treatment consists of withdrawal of the glucocorticoid; if this is possible, a prompt
decrease in symptoms may ensue. A rare syndrome of rapidonset, acute myopathy, occurring within days after the start
of high-dose glucocorticoids or pulse therapy, has been
described; muscle biopsy specimens show atrophy and
necrosis of muscle fibers.
Gastrointestinal Adverse Effects
Peptic Ulcer Disease
Data from the literature on upper gastrointestinal safety
of oral glucocorticoids are inconclusive. The fact that
glucocorticoids inhibit the production of COX-2 without
hampering the production of COX-1 supports studies that
found no increased risk. In other studies, a relative risk of
serious upper gastrointestinal peptic complications of about
2 was found.107 When glucocorticoids are used in combination with NSAIDs, the relative risk of peptic ulcer disease
and associated complications is about 4.108 Therefore in
cases of co-medication with NSAIDs, consider co-treatment
with a proton pump inhibitor, or prescribe a COX-1sparing NSAID.66 In patients treated with glucocorticoids
without concomitant use of NSAIDs, no indication for
gastrointestinal protective agents exists, unless other risk
factors for peptic complications are present.
CHAPTER 60 Other Gastrointestinal Adverse Effects
Although glucocorticoids usually are listed as one of
the many potential causes of pancreatitis, evidence for
such an association is weak and is difficult to separate from
the underlying disease, such as vasculitis or SLE.109 Asymptomatic and symptomatic colonization of the upper gastrointestinal tract with Candida albicans is increased in patients
treated with glucocorticoids, especially when other risk
factors are present, such as advanced age, diabetes mellitus,
and concomitant use of other immunosuppressive agents.
Glucocorticoids may mask symptoms and signs usually associated with the occurrence of intra-abdominal complications, such as perforation of the intestine and peritonitis
(e.g., as a complication of diverticulitis), and can lead to a
delay in diagnosis with increased morbidity and mortality.
Immunologic Adverse Effects
At high doses, glucocorticoids diminish neutrophil phagocytosis and bacterial killing in vitro, whereas in vivo, normal
bactericidal and phagocytic activities are found. Monocytes
are more susceptible; during treatment with medium to high
doses of glucocorticoids, bactericidal and fungicidal activity
in vivo and in vitro is reduced. These factors may influence
the risk of infection. From epidemiologic studies, treatment
with a daily dose of less than 10 mg of prednisone or equivalent seems to lead to no or an only slightly increased risk of
infection; however, if doses of 20 to 40 mg daily are used,
the risk of infection is increased (relative risk of 1.3 to
3.6).110 This risk increases with increased dose and duration
of treatment.45
In a meta-analysis of 71 trials involving more than 2000
patients with different diseases and different doses of glucocorticoids, an increased relative risk of infection of 2 was
found. The risk varied according to the type of disease being
treated. Five of these trials involved patients with rheumatic diseases and showed no increased risk (relative risk of
1).110 The same was found in a double-blind, placebocontrolled, 2-year trial in patients with early RA, in which
the effect of 10 mg of prednisone daily was compared with
that of placebo.56 In one study, after adjustments were made
for covariates, prednisone use dose dependently increased
the risk of hospitalization for pneumonia.45 In patients
treated with glucocorticoids, especially at high doses, clinicians should anticipate infections with usual and unusual
organisms, realizing that glucocorticoids may blunt classic
clinical features, thus delaying diagnosis.
Cardiovascular Adverse Effects
Mineralocorticoid Effects
Some glucocorticoids have mineralocorticoid actions (see
Table 60-1), including reduced renal excretion of sodium
and chloride and increased excretion of potassium, calcium,
and phosphate. This activity may lead to edema, weight
gain, increased blood pressure, and heart failure (caused by
reduced excretion of sodium and chloride); cardiac arrhythmia (resulting from increased excretion of potassium); or
tetany and electrocardiographic changes (related to
hypocalcemia).
| Glucocorticoid Therapy
911
Low doses of glucocorticoid are not a cause of hypertension, in contrast to higher doses.111 No formal studies
addressing the effects of glucocorticoids in previously hypertensive patients have been reported. Two randomized,
controlled studies in patients with myocarditis and idiopathic cardiomyopathy showed no differences between
placebo-treated or glucocorticoid-treated groups after 1 year
or in survival at 2 and 4 years.112,113
Atherosclerosis
Accelerated atherosclerosis and elevated cardiovascular risk
have been reported in patients with SLE and in patients
with RA.114 Glucocorticoids may enhance cardiovascular
risk via their potentially deleterious effects on lipids,115
glucose tolerance, insulin production and resistance, blood
pressure, and obesity.114 However, these conditions seem not
to be adverse effects of low-dose glucocorticoids. Furthermore, atherosclerosis itself has been recognized as an inflammatory disease of arterial walls, for which glucocorticoids
may be beneficial; glucocorticoids have been found to
inhibit macrophage accumulation in injured arterial walls
in vitro, possibly resulting in attenuation of the local inflammatory response.116 Low-dose glucocorticoids might also
improve dyslipidemia associated with inflammatory
disease.114,117-119 However, the effects on lipids and other
cardiovascular risk factors of low-dose glucocorticoids in
inflammatory diseases probably are different from those of
medium and high doses of glucocorticoids,115 or those of
glucocorticoid therapy in noninflammatory diseases. This,
along with the interplay of disease activity, glucocorticoids,
and adverse effects (see Figure 60-9), makes it difficult to
judge the net adverse effects of glucocorticoids on cardiovascular risk and lipids.120 The finding that a common haplotype of the glucocorticoid receptor gene is associated with
heart failure, and that this association is mediated in part
by low-grade inflammation, complicates this issue even
further.121
Ocular Adverse Effects
Cataract
Glucocorticoids tend to stimulate the formation of posterior
subcapsular cataract especially,122 but the risk of cortical
cataract also seems increased, with an odds ratio of 2.6.123
To some extent, the likelihood or severity of this adverse
effect depends on dose and duration of treatment. In patients
treated long term with glucocorticoids at a dosage of 15 mg
or more of prednisone daily for 1 year, cataract is observed
frequently; in patients receiving long-term therapy with less
than 10 mg of prednisone daily, the percentage of cataract
is less, but cataract may develop at dosages greater than
5 mg/day of prednisone equivalent.46 These cataracts are
usually bilateral but progress slowly. They may cause glare
disturbance but usually cause little visual impairment,
except at end stages.
Glaucoma
By increasing intraocular pressure, glucocorticoids may
cause or aggravate glaucoma. Patients with a family history
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PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS
of open-angle glaucoma and patients with high myopia are
probably prone to develop this adverse effect, especially
when receiving high doses of glucocorticoids; checks of
intraocular pressure are then warranted. If increased,
patients need to be treated with medications that reduce
intraocular pressure, often for a prolonged period after stopping the glucocorticoid.124 Topical application of a glucocorticoid in the eye has a more pronounced effect on
intraocular pressure compared with systemic glucocorticoid
therapy.125
Dermal Adverse Effects
Clinically relevant adverse effects of glucocorticoids on skin
include cushingoid appearance, easy bruising, ecchymoses,
skin atrophy, striae, disturbed wound healing, acne, perioral
dermatitis, hyperpigmentation, facial redness, mild hirsutism, and thinning of scalp hair. The physician often considers these changes to be of minor clinical importance, but
they may be disturbing to the patient.103 No reliable data
on the exact frequency of these adverse effects are available,
but these adverse effects are dependent on duration of
therapy and dose.46 Many physicians recognize immediately
the skin of a patient who has been taking glucocorticoids
on a long-term basis.
Endocrine Adverse Effects
Glucose Intolerance and Diabetes Mellitus
Glucocorticoids increase hepatic glucose production and
induce insulin resistance by inhibiting insulin-stimulated
glucose uptake and metabolism by peripheral tissues. Glucocorticoids probably also have a direct effect on beta cells
of the pancreas, resulting in enhanced insulin secretion
during glucocorticoid therapy. It may take only a few weeks
before glucocorticoid-induced hyperglycemia occurs with
low and medium glucocorticoid doses. One case-control,
population-based study in previously nondiabetic subjects
suggested an odds ratio of 1.8 for the need to initiate antihyperglycemic drugs during glucocorticoid therapy with
doses of 10 mg or less of prednisone or equivalent per day.
This risk increased with higher daily doses of glucocorticoids. The odds ratio was 3 for 10 to 20 mg, 5.8 for 20 to
30 mg, and 10.3 for 30 mg or more of prednisone or equivalent per day.126
It is likely that risk is increased further in patients with
other risk factors for diabetes mellitus, such as a family
history of the disease, advanced age, obesity, and previous
gestational diabetes. Postprandial hyperglycemia and only
mildly elevated fasting glucose concentrations are characteristic of glucocorticoid-induced diabetes mellitus. Worsening of glycemic control can be expected in patients with
established glucose intolerance or diabetes mellitus. Usually,
glucocorticoid-induced diabetes is reversible when the drug
is discontinued, unless clear glucose intolerance was
pre-existent.
Fat Redistribution and Body Weight
One of the most notable effects of long-term endogenous or
exogenous glucocorticoid excess is the redistribution of
body fat. Centripetal fat accumulation with thin extremities
is a characteristic feature of patients exposed to long-term
high-dose glucocorticoids. Potential mechanisms include
increased conversion of cortisone to cortisol in visceral adipocytes, hyperinsulinemia, and changes in expression and
activity of adipocyte-derived hormones and cytokines, such
as leptin and TNF.127 Protein loss resulting in muscle atrophy
also contributes to the change in body appearance. Increased
appetite influences body weight during glucocorticoid
therapy, but patients with active inflammatory disease tend
to lose weight, which can be prevented with disease control
by drugs, including glucocorticoids. Trials in patients with
RA given low-dose glucocorticoids for a prolonged period
showed only minor effects on fat redistribution and body
weight.55,56
Dyslipidemia
See the earlier section, “Atheroslerosis.”
Suppression of the Hypothalamic-Pituitary-Adrenal
Axis
In the section on effects of glucocorticoids on the
hypothalamic-pituitary-adrenal axis, mechanisms of
chronic suppression of the hypothalamic-pituitary-adrenal
axis by administration of exogenous glucocorticoids are
described. In such a situation, acute discontinuation of
glucocorticoid therapy may lead to acute adrenal insufficiency with possible circulatory collapse and death.11,128
About 10 years after glucocorticoid therapy became available, the first well-documented case of adrenal insufficiency
after withdrawal of exogenous glucocorticoid was reported.129
Acute cessation of glucocorticoid therapy without tapering
is indicated for corneal ulceration by herpes virus, which
can lead rapidly to perforation of the cornea, and
glucocorticoid-induced acute psychosis. In these patients,
assessment of adrenal responsiveness on a corticotropin test
seems prudent. Not all patients with a blunted cortisol
response have signs or symptoms of adrenal insufficiency,
however.
Clinical signs and symptoms of chronic adrenal hypofunctioning are nonspecific and include fatigue and weakness, lethargy, orthostatic hypotension, nausea, loss of
appetite, vomiting, diarrhea, arthralgia, and myalgia. These
symptoms partially overlap glucocorticoid withdrawal symptoms, such as fatigue, arthralgia, and myalgia. When in
doubt, measurements of serum cortisol levels and the corticotropin stimulation test are indicated. Glucocorticoid
withdrawal symptoms are sometimes difficult to discriminate from symptoms of the primary disease, such as polymyalgia rheumatica. Because mineralocorticoid secretion
remains intact via the renin-angiotensin-aldosterone axis,
serious electrolyte disturbances are uncommon.
Adverse Behavioral Effects
Glucocorticoid treatment is associated with a variety of
behavioral symptoms. Although most attention has been
directed toward specific dramatic disturbances collectively
described under the term glucocorticoid psychosis, less florid
effects also occur that may cause distress to a patient and
CHAPTER 60 warrant medical attention.103 Minor behavioral manifestations may also occur on withdrawal of glucocorticoids.
Steroid Psychosis
Overt psychosis is rare and usually is associated with highdose glucocorticoids or glucocorticoid pulse therapy, but
psychosis may also be a complication of the disease itself,
especially SLE. This makes it difficult to distinguish in
an individual SLE patient with psychosis whether the condition is a complication of the disease, of the therapy, or
of both.
Isolated psychosis is seen in about 10% of glucocorticoidrelated cases, and in most patients, affective disorders are
present as well. Around 40% of cases of glucocorticoidinduced psychosis manifest as depression, whereas mania,
often dominated by irritability, is predominant in 30% of
cases.130 Psychotic symptoms usually start just after initiation of treatment (60% within the first 2 weeks, 90% within
the first 6 weeks), and remission after drug dose reduction
or withdrawal follows the same pattern. Although the data
are largely anecdotal, individuals developing steroid psychosis frequently have had prior evidence of some dissociative
symptoms. Occasionally, remission occurs without dose
reduction.
Minor Mood Disturbances
Glucocorticoids have been associated with a wide variety of
low-grade disturbances, such as depressed or elated mood
(euphoria), insomnia, irritability, emotional instability,
anxiety, memory failure, and other cognition impairments.
Although the symptoms may not become severe enough for
a specific diagnosis, they warrant attention—not only
because they cause distress to the patient, but also because
they may interfere with evaluation and treatment of the
underlying disease. Most physicians recognize the occurrence of such symptoms in many glucocorticoid-treated
patients; these symptoms may occur in varying degrees in
up to 50% of treated patients within the first week. The
exact incidence in rheumatic patients exposed to the usual
doses of glucocorticoids is unknown; most series dedicated
to mood disturbances studied high doses.131 It is important
to inform patients about these minor mood disturbances
before starting glucocorticoid therapy.103
Monitoring
Glucocorticoid-related adverse effects have seldom been
studied systematically. Mostly based on expert and patient
opinion, recommendations have been formulated for monitoring low-dose glucocorticoid therapy. The conclusion is
that in daily practice, standard care monitoring for serious
diseases warranting glucocorticoid therapy need not be
extended for patients on low-dose glucocorticoid therapy,
except for monitoring for osteoporosis (follow national
guidelines) and baseline assessments of fasting blood glucose
and of risk factors for glaucoma, as well as a baseline check
for ankle edema.67 Of course, for medium and high dosages,
monitoring should be extended, not only to monitor for
adverse effects of glucocorticoid therapy, but also to check
for adverse effects of the concomitant medication and
| Glucocorticoid Therapy
913
complications of the severe disease; for these glucocorticoid
dosages, monitoring guidelines are being developed. In
these situations, next to good clinical practice monitoring,
including for instance blood pressure measurements, checks
of ocular pressure and urine glucose specifically seem indicated. For clinical trials on glucocorticoids, it is advised to
monitor and report more comprehensively and to sample
more data on the spectrum, incidence, and severity of
adverse events of glucocorticoids.67 If applied prudently, glucocorticoids are still one of the most relevant therapeutic
tools in clinical medicine of the 21st century.
Future Directions
Although glucocorticoids have been used in clinical
practice for many years, they still are the anchor drugs
in autoimmune and inflammatory diseases and vasculitides. In contrast with their established use, there is a
paucity of data on the spectrum, incidence, and severity
of adverse effects of glucocorticoids at different dosages
and in different diseases. To develop evidence-based
guidelines and to evaluate the adverse effects of new
compounds with glucocorticoid actions that are being
developed, additional research into molecular mechanisms and continued collection of data are needed.67
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The references for this chapter can also be found on www.expertconsult.com.
CHAPTER 60 References
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hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone:
compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis: preliminary report, Proceedings Staff Meetings Mayo
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